Pharmaceuticals

26 pages, 4178 KiB

Open AccessReview

Traditional Uses, Phytochemistry, and Pharmacological Properties of the Genus Blechnum—A Narrative Review

by Emmanuel Nyongesa Waswa, Felix Wambua Muema, Wyclif Ochieng Odago, Elizabeth Syowai Mutinda, Consolata Nanjala, Elijah Mbandi Mkala, Sarah Getachew Amenu, Shi-Xiong Ding, Jing Li and Guang-Wan Hu

Pharmaceuticals 2022, 15(7), 905; https://doi.org/10.3390/ph15070905 - 21 Jul 2022

Cited by 5 | Viewed by 4284

Abstract

Blechnum L. is a genus belonging to the Blechnaceae family with 236 accepted species that grow in intertropical, subtropical, and southern temperate regions. Several species of the genus have long been used in folk medicines to treat a broad spectrum of ailments, including [...] Read more.

Blechnum L. is a genus belonging to the Blechnaceae family with 236 accepted species that grow in intertropical, subtropical, and southern temperate regions. Several species of the genus have long been used in folk medicines to treat a broad spectrum of ailments, including typhoid, urinary infections, influenza, wounds, pulmonary complaints, blisters, boils, and antihelmintic-related complications. So far, about 91 chemical compounds have been isolated from different parts of 20 Blechnum species. Among these metabolites, phenolic compounds, sterols, and fatty acids are the main constituents. Modern pharmacological investigations revealed several isolated compounds and extracts to exhibit exceptional biological properties including the antioxidant, antimicrobial, anti-inflammatory, anticancer, insecticidal, antitrematocidal and wound healing. In various tests, both quercetin-7′,3′,4′-trimethoxy and phytol metabolites showed potential antioxidant and antitrematocidal properties, while ponasterone exhibited insecticidal activity. Despite having a broad range of traditional medicinal benefits and biological properties, understanding the scientific connotations based on the available data is still challenging. This article presents a comprehensive review of the traditional uses, phytochemical compounds, and pharmacological aspects of the Blechnum species. Full article

(This article belongs to the Special Issue Natural Pharmacons: Biologically Active Plant-Based Pharmaceuticals 2022)

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10 pages, 1743 KiB

Open AccessArticle

Bolus Injection of Liraglutide Raises Plasma Glucose in Normal Rats by Activating Glucagon-like Peptide 1 Receptor in the Brain

by Chia-Chen Hsu, Juei-Tang Cheng, Ping Hao Hsu, Yingxiao Li and Kai-Chun Cheng

Pharmaceuticals 2022, 15(7), 904; https://doi.org/10.3390/ph15070904 - 21 Jul 2022

Cited by 1 | Viewed by 2227

Abstract

Diabetes is commonly treated with glucagon-like peptide-1 receptor (GLP-1R) agonists including liraglutide and others. However, liraglutide was found to raise plasma glucose levels in normal rats. The current study aims to determine how liraglutide causes this contentious condition in rats, both normal and [...] Read more.

Diabetes is commonly treated with glucagon-like peptide-1 receptor (GLP-1R) agonists including liraglutide and others. However, liraglutide was found to raise plasma glucose levels in normal rats. The current study aims to determine how liraglutide causes this contentious condition in rats, both normal and diabetic. An adrenalectomy was performed to investigate the relationship between steroid hormone and liraglutide. To investigate the effect of central liraglutide infusion on blood glucose in rats, rats were intracerebroventricularly administrated with liraglutide with or without HPA axis inhibitors such as berberine and dexamethasone. The results showed that a single injection of liraglutide caused a temporary increase in blood glucose in healthy rats. Another GLP-1R agonist, Exendin-4 (Ex-4), increased blood sugar in a manner similar to that of liraglutide. The effects of liraglutide were also blocked by guanethidine pretreatment and vanished in normal rats with adrenalectomy. Additionally, central infusion of liraglutide via intracerebroventricular (icv) injection into normal rats also causes a temporary increase in blood glucose that was blocked by GLP-1R antagonists or the inhibitors such as berberine and dexamethasone. Similarly, central liraglutide treatment causes temporary increases in plasma glucose, adrenocorticotropic hormone (ACTH), and cortisol levels, which were reversed by inhibitors for the hypothalamic-pituitary-adrenal (HPA) axis. In normal rats, the temporary glucose-increasing effect of liraglutide was gradually eliminated during consecutive daily treatments, indicating tolerance formation. Additionally, liraglutide and Ex-4 cross-tolerance was also discovered in normal rats. Liraglutide was more effective in diabetic rats than in normal rats in activating GLP-1R gene expression in the isolated adrenal gland. Interestingly, the effect of liraglutide on glycemic control varied depending on whether the rats were diabetic or not. In normal rats, bolus injection of liraglutide, such as Ex-4, may stimulate the HPA axis, resulting in hyperglycemia. The cross-tolerance of liraglutide and Ex-4 provided a novel perspective on GLP-1R activation. Full article

(This article belongs to the Section Pharmacology)

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Figure 1

Figure 1
Liraglutide-induced acute hyperglycemia in healthy rats; (a) The dose–response curve (open column) of liraglutide that is reduced by guanethidine (closed column). IP injection of guanethidine (30 mg/kg) for 60 min prior to liraglutide treatment. (b) Liraglutide-induced hyperglycemia in rats receiving adrenalectomy or sham-operation (Sham). Hyperglycemia by liraglutide disappeared in adrenalectomized rats but was observed in sham-operated rats. The data are shown as means ± SEM (n = 8). * p < 0.05, ** p < 0.01 vs. normal control group; # p < 0.05 vs. vehicle-treated group. Full article ">Figure 2
Effect of liraglutide on hypothalamic-pituitary-adrenal (HPA) axis in healthy rats. Liraglutide was injected into the brain directly and changes induced by liraglutide were compared with pretreatment of inhibitors including EX-9 (i.c.v.), berberine (BER, 200 mg/kg, i.p.) and dexamethasone (DEX, 5 μg/kg, s.c.). Each inhibitor was pretreated by peripheral administration for 60 min, except EX-9, which was pretreated for 30 min by injection into the brain. (a) Changes in plasma glucose in rats; (b) Changes in plasma ACTH in rats; (c) Changes in plasma cortisol in rats; (d) Changes in feeding behavior in rats. The data are shown as means ± SEM (n = 8). * p < 0.05 vs. normal control group; # p < 0.05 vs. vehicle (Veh)-treated group. Full article ">Figure 2 Cont.
Effect of liraglutide on hypothalamic-pituitary-adrenal (HPA) axis in healthy rats. Liraglutide was injected into the brain directly and changes induced by liraglutide were compared with pretreatment of inhibitors including EX-9 (i.c.v.), berberine (BER, 200 mg/kg, i.p.) and dexamethasone (DEX, 5 μg/kg, s.c.). Each inhibitor was pretreated by peripheral administration for 60 min, except EX-9, which was pretreated for 30 min by injection into the brain. (a) Changes in plasma glucose in rats; (b) Changes in plasma ACTH in rats; (c) Changes in plasma cortisol in rats; (d) Changes in feeding behavior in rats. The data are shown as means ± SEM (n = 8). * p < 0.05 vs. normal control group; # p < 0.05 vs. vehicle (Veh)-treated group. Full article ">Figure 3
Cross-tolerance of hyperglycemia between liraglutide and Exendin-4 (Ex-4) in normal rats. (a) Hyperglycemia by peripheral injection of liraglutide (SC) was blocked by EX-9 in the brain (ICV); (b) Tolerance of hyperglycemia by liraglutide observed in normal rats received a repeated daily injection for one week. Another agonist of GLP-1R Ex-4 also failed to induce hyperglycemia in normal rats with tolerance to liraglutide. The data are shown as means ± SEM (n = 8). * p < 0.05 vs. normal control group; # p < 0.05 vs. first day. Full article ">Figure 4
Influence of liraglutide in type-1 diabetic rats. (a) Dose-dependent effects of liraglutide on plasma glucose in diabetic rats were different with that in normal rats. Glycemic change was calculated by the percentage change in resulted plasma glucose prior; (b) Tolerance to liraglutide-induced hypoglycemia was not observed in diabetic rats and hypoglycemic response to liraglutide produced in diabetic rats receiving daily injection; (c) Effects of liraglutide on adrenal gland isolated from diabetic rats were different with that from normal rats. Beta-endorphin released by liraglutide as the functions of GLP-1R activation was observed in adrenal glands isolated from diabetic rats only; (d) The mRNA level of GLP-1R in adrenal glands between normal and diabetic rats. GLP-1R expression promoted by liraglutide in adrenal glands was higher in diabetic rats than normal rats. Thus, liraglutide promotes the mRNA level of GLP-1R in adrenal glands isolated from diabetic rats only. The data are shown as means ± SEM (n = 8). * p < 0.05 vs. low dose of liraglutide (a), vs. vehicle (Veh)-treated group (b), vs. normal rats (c) vs. normal group (d); # p < 0.05 vs. low dose of liraglutide (a), vs. vehicle (Veh)-treated group (c,d). Full article ">

16 pages, 2065 KiB

Open AccessArticle

Siccanin Is a Dual-Target Inhibitor of Plasmodium falciparum Mitochondrial Complex II and Complex III

by Keisuke Komatsuya, Takaya Sakura, Kazuro Shiomi, Satoshi Ōmura, Kenji Hikosaka, Tomoyoshi Nozaki, Kiyoshi Kita and Daniel Ken Inaoka

Pharmaceuticals 2022, 15(7), 903; https://doi.org/10.3390/ph15070903 - 21 Jul 2022

Cited by 13 | Viewed by 4692

Abstract

Plasmodium falciparum contains several mitochondrial electron transport chain (ETC) dehydrogenases shuttling electrons from the respective substrates to the ubiquinone pool, from which electrons are consecutively transferred to complex III, complex IV, and finally to the molecular oxygen. The antimalarial drug atovaquone inhibits complex [...] Read more.

Plasmodium falciparum contains several mitochondrial electron transport chain (ETC) dehydrogenases shuttling electrons from the respective substrates to the ubiquinone pool, from which electrons are consecutively transferred to complex III, complex IV, and finally to the molecular oxygen. The antimalarial drug atovaquone inhibits complex III and validates this parasite’s ETC as an attractive target for chemotherapy. Among the ETC dehydrogenases from P. falciparum, dihydroorotate dehydrogenase, an essential enzyme used in de novo pyrimidine biosynthesis, and complex III are the two enzymes that have been characterized and validated as drug targets in the blood-stage parasite, while complex II has been shown to be essential for parasite survival in the mosquito stage; therefore, these enzymes and complex II are considered candidate drug targets for blocking parasite transmission. In this study, we identified siccanin as the first (to our knowledge) nanomolar inhibitor of the P. falciparum complex II. Moreover, we demonstrated that siccanin also inhibits complex III in the low-micromolar range. Siccanin did not inhibit the corresponding complexes from mammalian mitochondria even at high concentrations. Siccanin inhibited the growth of P. falciparum with IC₅₀ of 8.4 μM. However, the growth inhibition of the P. falciparum blood stage did not correlate with ETC inhibition, as demonstrated by lack of resistance to siccanin in the yDHODH-3D7 (EC₅₀ = 10.26 μM) and Dd2-ELQ300 strains (EC₅₀ = 18.70 μM), suggesting a third mechanism of action that is unrelated to mitochondrial ETC inhibition. Hence, siccanin has at least a dual mechanism of action, being the first potent and selective inhibitor of P. falciparum complexes II and III over mammalian enzymes and so is a potential candidate for the development of a new class of antimalarial drugs. Full article

(This article belongs to the Special Issue Drug Candidates for the Treatment of Infectious Diseases)

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Graphical abstract

Graphical abstract
Full article ">Figure 1
Schematic representation of the mitochondrial electron transport chain in human (top) and P. falciparum (bottom). Orange and green arrows indicate the flow of electrons and protons, respectively. The anchor subunits of complex II (CybL and CybS) from P. falciparum have yet to be identified. The reactions mediated by complex II are known to be reversible, such that complex II can act as a succinate:quinone reductase (SQR, forward reaction) or a quinol:fumarate reductase (QFR, reverse reaction). Genes encoding the plasmodial homologues of human SQOR, MDH, PRODH, ETF, and complex I are missing from the P. falciparum genome, as are the genes encoding human homologues of P. falciparum NDH2, and MQO from the human genome. NADH, reduced nicotinamide adenine dinucleotide; NAD+, oxidized nicotinamide adenine dinucleotide; DHO, dihydroorotate; DHODH, DHO dehydrogenase; P5C, (S)-1-pyrroline-5-carboxylate; PRODH; proline dehydrogenase; SQOR, sulfide:quinone oxidoreductase; G3P, glycerol-3-phosphate; DHAP, dihydroxyacetone phosphate; G3PDH, G3P dehydrogenase; ETF, electron transfer flavoprotein; ETFDH, ETF dehydrogenase; Q, ubiquinone; QH2, ubiquinol; Cyt c, cytochrome c; MDH, soluble malate dehydrogenase; MQO, malate:quinone oxidoreductase; NDH2, type-II NADH dehydrogenase; ADP, adenosine diphosphate; Pi, inorganic phosphate; and ATP, adenosine triphosphate. Full article ">Figure 2
Siccanin is a potent inhibitor of Plasmodium falciparum complex II. (a) Chemical structure of siccanin. (b) Biphasic inhibition of succinate:ubiquinone reductase (SQR) activity by siccanin. Using a crude mitochondrial fraction isolated from parasite culture, the SQR activity was determined by monitoring 2,6-dichlorophenolindophenol (DCIP) reduction (see <a href="#sec4-pharmaceuticals-15-00903" class="html-sec">Section 4</a> for detailed information). The 50% inhibitory concentrations (IC50s) of 0.016 ± 0.006 μM and 8.93 ± 2.44 μM were calculated using the biphasic dose-response equation in GraphPad Prism® ver.6.01. Data are presented as mean ± SD (n = 3). Full article ">Figure 3
Siccanin is a specific inhibitor of P. falciparum complex II amongst P. falciparum electron transport chain (ETC) dehydrogenases. (a) Specific activities of five ETC dehydrogenases from a P. falciparum mitochondria-rich fraction. Specific activities of dihydroorotate dehydrogenase (DHODH), malate:quinone oxidoreductase (MQO), glycerol-3-phosphate dehydrogenase (G3PDH), and succinate:quinone oxidoreductase (SQR) were determined by monitoring the absorbance change associated with reduction of 2,6-dichlorophenolindophenol (DCIP). The type-II NADH dehydrogenase (NDH2) activity was determined by monitoring the reduction of NADH (see <a href="#sec4-pharmaceuticals-15-00903" class="html-sec">Section 4</a>). DHODH-, MQO-, G3PDH-, SQR-, and NDH2-specific activities are 13.4 ± 1.2, 17.5 ± 1.1, 7.25 ± 0.1, 7.63 ± 1.3, and 32.3 ± 1.6 nmol/min/mg protein, respectively. (b) The inhibitory effect of siccanin at a concentration of 10 μM against the five dehydrogenases. Relative residual activities (%) of DHODH, MQO, G3PDH, SQR, and NDH2 were 101.2 ± 8.1, 109.2 ± 2.0, 72.5 ± 4.0, 2.7 ± 6.5, and 101.8 ± 8.1 nmol/min/mg protein, respectively. Data are presented as mean ± SD (n = 3). Full article ">Figure 4
P. falciparum complex II is not the primary target of siccanin at the blood stage. (a) Synchronized parasites were incubated for 16, 24, 32, and 48 h with vehicle (dimethyl sulfoxide; DMSO) (blue) or 50 µM siccanin (red) and parasitemia was measured by Giemsa staining. (b) P. falciparum 3D7 was incubated for 72 h with different concentrations of siccanin in the absence (black) and presence of either 5 mM succinate (blue) or 5 mM fumarate (red). The IC50s were calculated as 8.40 ± 0.60, 10.8 ± 2.16, and 11.5 ± 1.09 μM, respectively. (c) Effect of siccanin on the growth of Δsdha-3D7 (red) and the parent (wild-type) 3D7 (blue). The IC50s were calculated as 6.13 ± 0.91 μM and 6.10 ± 1.00 μM for Δsdha-3D7 and wild-type parasites, respectively, using the four-parameter logistic equation in GraphPad Prism® ver.6.01. Data are presented as mean ± SD (n = 3). Full article ">Figure 5
Inhibition of complex III by siccanin and its isobologram versus atovaquone. (a) Siccanin does not inhibit dihydroorotate dehydrogenase activity (red) but does exhibit dose-dependent inhibition of dihydroorotate–cytochrome c activity (corresponding to the coupled activity of DHODH and complex III) (blue). (b) The 50% inhibitory concentration (IC50) of siccanin against complex III was determined as 8.39 ± 2.92 μM using the four-parameter logistic method in GraphPad Prism® ver.6.01. Data are presented as mean ± SD (n = 3). (c) Isobologram analysis showing the combinatory effect of atovaquone and siccanin against the P. falciparum 3D7 strain (n = 3). Normalized fractional inhibitory concentration (FIC) index values were calculated as described in <a href="#sec4-pharmaceuticals-15-00903" class="html-sec">Section 4</a>. The line connecting the FIC = 1.0 points on the two axes represents the line of additivity. The plots of FIC calculated for siccanin in the presence of varying concentrations of atovaquone are shown as black circles, which coincide with the line of additivity. This result clearly indicates an additive effect when parasites are treated with a combination of siccanin and atovaquone. Full article ">Figure 6
P. falciparum 3D7 (wild-type parent) and 3D7-yDHODH, as well as Dd2 and Dd2-derived mutant strains, are not resistant to siccanin. Growth inhibition of P. falciparum 3D7 and 3D7-yDHODH strains by (a) siccanin and (b) atovaquone. Data represent the means of three biological replicates, each tested in triplicate. (c) Growth inhibition of P. falciparum Dd2 (parent) and Dd2-derived mutant strains resistant to MMV390048 (048), DDD107498 (DDD), cipargamin (DHIQ), GNF156 (GNF), and ELQ300 (ELQ300). The calculated 50% effective concentration (EC50) values are shown next to the corresponding symbols in each panel. Data represent the means of two biological replicates, each tested in triplicate. Full article ">

17 pages, 2698 KiB

Open AccessArticle

Naturally Occurring 8ß,13ß-kaur-15-en-17-al and Anti-Malarial Activity from Podocarpus polystachyus Leaves

by Mira Syahfriena Amir Rawa, Mohammad G. Al-Thiabat, Toshihiko Nogawa, Yushi Futamura, Akiko Okano and Habibah A. Wahab

Pharmaceuticals 2022, 15(7), 902; https://doi.org/10.3390/ph15070902 - 21 Jul 2022

Cited by 12 | Viewed by 2468

Abstract

Despite much interest and studies toward the genus Podocarpus, the anti-malarial evaluation of Podocarpus polystachyus’s phytoconstituents remains lacking. Herein, the phytoconstituents of P. polystachyus leaves and their anti-malarial effect against Plasmodium falciparum were investigated for the first time. One new natural [...] Read more.

Despite much interest and studies toward the genus Podocarpus, the anti-malarial evaluation of Podocarpus polystachyus’s phytoconstituents remains lacking. Herein, the phytoconstituents of P. polystachyus leaves and their anti-malarial effect against Plasmodium falciparum were investigated for the first time. One new natural product, 8ß,13ß-kaur-15-en-17-al (1), along with three known compounds, 8ß,13ß-kaur-15-en-17-ol (2) and 13ß-kaur-16-ene (3), and α-tocopherol hydroquinone (4) were isolated via HR-ESI-MS and NMR analyses. Compounds 1 and 2 inhibited P. falciparum growth at 12 and 52 µM of IC₅₀, respectively. Their anti-malarial activity was associated with the in silico P. falciparum lactate dehydrogenase (PfLDH) inhibition. Molecular docking of ligands 1 and 2 with the putative target PfLDH revealed ~−2 kcal/mol of binding energies more negative than the control. Molecular dynamic simulations (100 ns) showed equal or smaller deviation values (RMSD, RMSF, Rg) and stronger interactions of PfLDH-1 and PfLDH-2 complexes via at least one consistent H-bond than the control. Additionally, a slightly increased PfLDH H-bond profile in their interactions improved the PfLDH dynamic and structural stabilities. Overall, this study supports the relevance of 1 and 2 as plasmodial growth inhibitors with their putative anti-PfLDH activity, which could be a potential scaffold for developing anti-malarial drugs. Full article

(This article belongs to the Special Issue Botanicals: Bioactive Molecules and Therapeutic Properties for Human Health 2021)

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Graphical abstract
Full article ">Figure 1
Structures of 1–4. Full article ">Figure 2
Two-dimensional interaction analysis of docked models of compounds 1 (a) and 2 (b) with PfLDH binding site. Full article ">Figure 3
The root mean square deviation (RMSD) plots of the enzyme and ligand backbone atoms for the selected systems. Apo-PfLDH (black), PfLDH-control (red and orange), PfLDH-1 (Dark green and lime), and PfLDH-2 (blue and cyan). Full article ">Figure 4
The RMSF graphs of the PfLDH backbone atoms throughout the 100 ns MD simulation time for all systems. The RMSF values indicate the residual atomic fluctuations of each amino acid residue when they interact with the ligands throughout the trajectory. Full article ">Figure 5
Radius of gyration (Rg) plots of the PfLDH backbone atoms of all systems at MD interval time (0–100 ns); Apo-PfLDH (black), PfLDH-control (red), PfLDH-1 (dark green), and PfLDH-2 (blue). Full article ">Figure 6
Two-dimensional interaction models show how H-bonds are formed between PfLDH-1 (a) and PfLDH-2 (b) with the amino acid residues in the PfLDH active binding site at 100 ns (last snapshot) of MD time intervals. Full article ">

13 pages, 2205 KiB

Open AccessArticle

Sensitive Detection of Pharmaceutical Drugs and Metabolites in Serum Using Data-Independent Acquisition Mass Spectrometry and Open-Access Data Acquisition Tools

by Syed Muhammad Zaki Shah, Arslan Ali, Muhammad Noman Khan, Adeeba Khadim, Mufarreh Asmari, Jalal Uddin and Syed Ghulam Musharraf

Pharmaceuticals 2022, 15(7), 901; https://doi.org/10.3390/ph15070901 - 21 Jul 2022

Cited by 3 | Viewed by 2693

Abstract

Data-independent acquisition (DIA) based strategies have been explored in recent years for improving quantitative analysis of metabolites. However, the data analysis is challenging for DIA methods as the resulting spectra are highly multiplexed. Thus, the DIA mode requires advanced software analysis to facilitate [...] Read more.

Data-independent acquisition (DIA) based strategies have been explored in recent years for improving quantitative analysis of metabolites. However, the data analysis is challenging for DIA methods as the resulting spectra are highly multiplexed. Thus, the DIA mode requires advanced software analysis to facilitate the data deconvolution process. We proposed a pipeline for quantitative profiling of pharmaceutical drugs and serum metabolites in DIA mode after comparing the results obtained from full-scan, Data-dependent acquisition (DDA) and DIA modes. using open-access software. Pharmaceutical drugs (10) were pooled in healthy human serum and analysed by LC-ESI-QTOF-MS. MS1 full-scan and Data-dependent (MS2) results were used for identification using MS-DIAL software while deconvolution of MS1/MS2 spectra in DIA mode was achieved by using Skyline software. The results of acquisition methods for quantitative analysis validated the remarkable analytical performance of the constructed workflow, proving it to be a sensitive and reproducible pipeline for biological complex fluids. Full article

(This article belongs to the Section Pharmaceutical Technology)

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Graphical abstract

Graphical abstract
Full article ">Figure 1
Schematic illustration of the workflow used in this study. Full article ">Figure 2
(A) Extracted precursor ion chromatogram [top] and fragment ion chromatogram [bottom] of a drug standard dipyridamole (as an example). (B). Comparison of peak areas of the precursor [top] and fragment [bottom] ions in multiple samples and replicates. (C) The retention time view provides information of each precursor and its fragments present in each serum replicate. (D) The calibration curve in the figure proved the consistency and reproducibility of 10 standard drugs in each replicate over the retention time. Full article ">Figure 3
Extracted ion chromatograms of 10 drug standards (1. Ranitidine; 2. Oxytetracycline; 3. Ranolazine; 4. Atropine; 5. Diphenhydramine; 6. Haloperidol; 7. Dipyridamole; 8. Duloxetine; 9. Finasteride; 10. Phenylbutazone) in the QC sample and improved sensitivity of drug standards in various modes. Full article ">Figure 4
In total, 372 features of the QC sample were annotated using MS1 mode in MS-DIAL, then compared using the DIA mode in Skyline with the transition list (1-naphthylamine, a serum metabolite taken as an example) that resulted in (A) enhanced sensitivity in DIA and (B) resolved co-elution of peaks and quantitative analysis on the MS1 level in DIA mode. Full article ">Figure 5
Clustering heatmap of MS1 data of 10 drugs compared between MS1 full scan, DDA, and DIA. DIA MS2 data of all drugs compared between DIA MS1 in all dilution points with replicates. Full article ">Figure 6
Clustering heatmap of serum metabolites analyzed by MS1 with three replicates in MS1 full-scan, DDA, and DIA modes and DIA MS2 level. Full article ">

16 pages, 5094 KiB

Open AccessArticle

Novel p38 Mitogen-Activated Protein Kinase Inhibitor Reverses Hypoxia-Induced Pulmonary Arterial Hypertension in Rats

by Grazielle Fernandes Silva, Jaqueline Soares da Silva, Allan Kardec Nogueira de Alencar, Marina de Moraes Carvalho da Silva, Tadeu Lima Montagnoli, Bruna de Souza Rocha, Rosana Helena Coimbra Nogueira de Freitas, Roberto Takashi Sudo, Carlos Alberto Manssour Fraga and Gisele Zapata-Sudo

Pharmaceuticals 2022, 15(7), 900; https://doi.org/10.3390/ph15070900 - 21 Jul 2022

Cited by 4 | Viewed by 2941

Abstract

Mitogen-activated protein kinase (MAPK) signaling is strongly implicated in cardiovascular remodeling in pulmonary hypertension (PH) and right ventricle (RV) failure. The effects of a newly designed p38 inhibitor, LASSBio-1824, were investigated in experimentally induced PH. Male Wistar rats were exposed to hypoxia and [...] Read more.

Mitogen-activated protein kinase (MAPK) signaling is strongly implicated in cardiovascular remodeling in pulmonary hypertension (PH) and right ventricle (RV) failure. The effects of a newly designed p38 inhibitor, LASSBio-1824, were investigated in experimentally induced PH. Male Wistar rats were exposed to hypoxia and SU5416 (SuHx), and normoxic rats were used as controls. Oral treatment was performed for 14 days with either vehicle or LASSBio-1824 (50 mg/kg). Pulmonary vascular resistance and RV structure and function were assessed by echocardiography and catheterization. Histological, immunohistochemical and Western blot analysis of lung and RV were performed to investigate cardiovascular remodeling and inflammation. Treatment with LASSBio-1824 normalized vascular resistance by attenuating vessel muscularization and endothelial dysfunction. In the heart, treatment decreased RV systolic pressure, hypertrophy and collagen content, improving cardiac function. Protein content of TNF-α, iNOS, phosphorylated p38 and caspase-3 were reduced both in lung vessels and RV tissues after treatment and a reduced activation of transcription factor c-fos was found in cardiomyocytes of treated SuHx rats. Therefore, LASSBio-1824 represents a potential candidate for remodeling-targeted treatment of PH. Full article

(This article belongs to the Section Pharmacology)

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Figure 1

Figure 1
Molecular structure of LASSBio-1824. Full article ">Figure 2
Effect of LASSBio-1824 on pulmonary vascular resistance and remodeling in SuHx. (A) Time course of pulmonary vascular resistance development after model induction and treatments (n = 5 rats per group). (B) Representative images of RVOT Doppler TTE, α-SMA immunostain and PSR stain of lung vessels. Arrow depicts a mid-systolic notch in pulmonary flux profile. Bars represent 20 μm. (C), Medial wall hypertrophy of lung vessels (n = 5 rats per group). (D) Perivascular fibrosis around lung vessels (n = 5 rats per group). (E) Maximal ACh-induced relaxation of pulmonary arteries (n = 5 rats per group). (F) Correlation analysis between endpoint pulmonary vascular resistance and wall hypertrophy. (G) Correlation analysis between endpoint pulmonary vascular resistance and endothelial function. ACh, acetylcholine; PAT, pulmonary acceleration time; PET, total ejection time; PSR, picro-Sirius red; RVOT, right-ventricle outflow tract; SMA, smooth-muscle actin; TTE, transthoracic echocardiography. * p < 0.05 compared to normoxia. # p < 0.05 compared to SuHx + Vehicle. Full article ">Figure 3
Effect of LASSBio-1824 on right-ventricle remodeling and hemodynamics in SuHx. (A) RV systolic pressures after treatment (n = 5 rats per group). (B) Representative images of cardiac structure by TTE. Traced lines depict ventricular endocardial surfaces. (C) Fulton index of hypertrophy of RV (n = 5 rats per group). (D) Echocardiographic measurement of RV wall hypertrophy (n = 5 rats per group). (E) Echocardiographic measurement of RV end-diastolic area (n = 5 rats per group). Ao, aorta; LV, left ventricle; RV, right ventricle; RVSP, right-ventricle systolic pressure; TTE, transthoracic echocardiography. * p < 0.05 compared to normoxia. # p < 0.05 compared to SuHx + Vehicle. Full article ">Figure 4
Impact of LASSBio-1824 on RV histology in SuHx. (A) Representative micrographs of RV sections with H&E and PSR stains. White arrowheads indicate interstitial cell nuclei. Bars represent 20 μm. (B) Interstitial cell density in RV tissue (n = 5 rats per group). (C) Red-stained collagen area of RV (n = 5 rats per group). H&E, hematoxylin-eosin; PSR, picro-Sirius red; RV, right ventricle. * p < 0.05 compared to normoxia. # p < 0.05 compared to SuHx + Vehicle. Full article ">Figure 5
Effect of LASSBio-1824 on lung vasculature content of tissue-inflammation mediators in SuHx. (A) Representative micrographs of TNF-α, iNOS and total p38 immunohistochemistry. Bars represent 20 μm. (B) Brown-stained wall area of pulmonary vessels corresponding to detected TNF-α (n = 5 rats per group). (C) Brown-stained wall area of pulmonary vessels corresponding to detected iNOS (n = 5 rats per group). (D), Brown-stained wall area of pulmonary vessels corresponding to detected total p38 (n = 5 rats per group). iNOS, inducible nitric oxide synthase; TNF, tumor necrosis factor. * p < 0.05 compared to normoxia. # p < 0.05 compared to SuHx + Vehicle. Full article ">Figure 6
Effect of LASSBio-1824 on RV content of tissue inflammation mediators and cardiac stress and apoptosis in SuHx. (A) Representative images of TNF-α, iNOS, phosphorylated and total p38, cleaved caspase 3 and GAPDH immunodetection after Western blot (n = 5 biological replicates). (B) Relative densities of TNF-α, iNOS, cleaved caspase 3 and phosphorylated p38 in RV samples, respectively (n = 5 rats per group). (C) Representative micrographs of c-fos immunohistochemistry in RV sections. Bars represent 20 μm. (D) Brown-stained cardiomyocyte nuclei abundance in RV samples (n = 5 rats per group). cl., cleaved; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; iNOS, inducible nitric oxide synthase; RV, right ventricle; TNF, tumor necrosis factor. * p < 0.05 compared to normoxia. # p < 0.05 compared to SuHx + Vehicle. Full article ">Figure 7
Model induction, therapeutic protocol and measurement schedules. (A) Control animals (n = 5) were maintained in room air (normoxia, FiO2: 21%) throughout the experimental protocol and received both weekly SU-vehicle (i.p.) and after 3 weeks, daily vehicle (DMSO, 100 μL p.o.). (B) SuHx animals were maintained in hypoxic chamber (FiO2: 10%) and received both weekly SU5416 (20 mg/kg i.p.) for 3 weeks and after return to normoxia, daily vehicle (DMSO, 100 μL p.o., n = 5) or LASSBio-1824 (50 mg/kg p.o., n = 5). TTE, transthoracic echocardiography. Full article ">

12 pages, 1884 KiB

Open AccessReview

Phosphodiesterase-4 Inhibitor Roflumilast-Mediated Protective Effect in Sepsis-Induced Late-Phase Event of Acute Kidney Injury: A Narrative Review

by Imran Kazmi, Fahad A. Al-Abbasi, Muhammad Afzal, Muhammad Shahid Nadeem, Hisham N. Altayb and Gaurav Gupta

Pharmaceuticals 2022, 15(7), 899; https://doi.org/10.3390/ph15070899 - 20 Jul 2022

Cited by 6 | Viewed by 3120

Abstract

Severe infections such as viral, bacterial, or fungal sepsis can cause an inflammatory response in the host, leading to organ failure and septic shock—phosphodiesterase-4 (PDE-4) inhibiting related agents from suppressing cyclic adenosine monophosphate (cAMP) degradation. Regulatory organisations have approved some substances in this [...] Read more.

Severe infections such as viral, bacterial, or fungal sepsis can cause an inflammatory response in the host, leading to organ failure and septic shock—phosphodiesterase-4 (PDE-4) inhibiting related agents from suppressing cyclic adenosine monophosphate (cAMP) degradation. Regulatory organisations have approved some substances in this category to reduce the risk of chronic obstructive pulmonary disease (COPD) exacerbations in patients with chronic bronchitis and a history of COPD exacerbations. Roflumilast has been shown to alleviate inflammatory responses, thus regulating airway inflammation. Additionally, roflumilast therapy dramatically enhanced B-cell lymphoma 2 (Bcl-2) expression, an anti-apoptotic marker lowered in septic animals. Previous research has indicated that roflumilast may help reverse sepsis-induced liver and lung harm, but whether it is also effective in reversing sepsis-induced renal impairment remains unknown. Therefore, this review determines whether roflumilast protects against renal dysfunction, inflammatory response, and apoptosis in sepsis-induced kidney damage. Additionally, we discussed the molecular mechanism through which roflumilast exerts its protective effect to uncover a possible treatment agent for sepsis-induced renal impairment. Full article

(This article belongs to the Special Issue Phosphodiesterases as Drug Targets: Development and Challenges)

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16 pages, 862 KiB

Open AccessReview

Nutraceutical Interventions for Post-Traumatic Stress Disorder in Animal Models: A Focus on the Hypothalamic–Pituitary–Adrenal Axis

by Mudan Cai, Hee Ra Park and Eun Jin Yang

Pharmaceuticals 2022, 15(7), 898; https://doi.org/10.3390/ph15070898 - 20 Jul 2022

Cited by 7 | Viewed by 5824

Abstract

Post-traumatic stress disorder (PTSD) occurs after exposure to traumatic events and is characterized by overwhelming fear and anxiety. Disturbances in the hypothalamic–pituitary–adrenal (HPA) axis are involved in the pathogenesis of mood disorders, including anxiety, PTSD, and major depressive disorders. Studies have demonstrated the [...] Read more.

Post-traumatic stress disorder (PTSD) occurs after exposure to traumatic events and is characterized by overwhelming fear and anxiety. Disturbances in the hypothalamic–pituitary–adrenal (HPA) axis are involved in the pathogenesis of mood disorders, including anxiety, PTSD, and major depressive disorders. Studies have demonstrated the relationship between the HPA axis response and stress vulnerability, indicating that the HPA axis regulates the immune system, fear memory, and neurotransmission. The selective serotonin reuptake inhibitors (SSRIs), sertraline and paroxetine, are the only drugs that have been approved by the United States Food and Drug Administration for the treatment of PTSD. However, SSRIs require long treatment times and are associated with lower response and remission rates; therefore, additional pharmacological interventions are required. Complementary and alternative medicine therapies ameliorate HPA axis disturbances through regulation of gut dysbiosis, insomnia, chronic stress, and depression. We have described the cellular and molecular mechanisms through which the HPA axis is involved in PTSD pathogenesis and have evaluated the potential of herbal medicines for PTSD treatment. Herbal medicines could comprise a good therapeutic strategy for HPA axis regulation and can simultaneously improve PTSD-related symptoms. Finally, herbal medicines may lead to novel biologically driven approaches for the treatment and prevention of PTSD. Full article

(This article belongs to the Special Issue Therapeutic Agents for Neurological Disorders 2022)

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17 pages, 829 KiB

Open AccessReview

The Future of Tissue-Targeted Lipid Nanoparticle-Mediated Nucleic Acid Delivery

by Ruvanthi N. Kularatne, Rachael M. Crist and Stephan T. Stern

Pharmaceuticals 2022, 15(7), 897; https://doi.org/10.3390/ph15070897 - 20 Jul 2022

Cited by 46 | Viewed by 22974

Abstract

The earliest example of in vivo expression of exogenous mRNA is by direct intramuscular injection in mice without the aid of a delivery vehicle. The current state of the art for therapeutic nucleic acid delivery is lipid nanoparticles (LNP), which are composed of [...] Read more.

The earliest example of in vivo expression of exogenous mRNA is by direct intramuscular injection in mice without the aid of a delivery vehicle. The current state of the art for therapeutic nucleic acid delivery is lipid nanoparticles (LNP), which are composed of cholesterol, a helper lipid, a PEGylated lipid and an ionizable amine-containing lipid. The liver is the primary organ of LNP accumulation following intravenous administration and is also observed to varying degrees following intramuscular and subcutaneous routes. Delivery of nucleic acid to hepatocytes by LNP has therapeutic potential, but there are many disease indications that would benefit from non-hepatic LNP tissue and cell population targeting, such as cancer, and neurological, cardiovascular and infectious diseases. This review will concentrate on the current efforts to develop the next generation of tissue-targeted LNP constructs for therapeutic nucleic acids. Full article

(This article belongs to the Special Issue Current Insights on Lipid-Based Nanosystems)

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12 pages, 20875 KiB

Open AccessArticle

Phloridzin Reveals New Treatment Strategies for Liver Fibrosis

by Yahong Shi, Tun Yan, Xi Lu, Kai Li, Yifeng Nie, Chuqiao Jiao, Huizhen Sun, Tingting Li, Xiang Li and Dong Han

Pharmaceuticals 2022, 15(7), 896; https://doi.org/10.3390/ph15070896 - 20 Jul 2022

Cited by 11 | Viewed by 2745

Abstract

Liver fibrosis is an urgent public health problem which is difficult to resolve. However, various drugs for the treatment of liver fibrosis in clinical practice have their own problems during use. In this study, we used phloridzin to treat hepatic fibrosis in the [...] Read more.

Liver fibrosis is an urgent public health problem which is difficult to resolve. However, various drugs for the treatment of liver fibrosis in clinical practice have their own problems during use. In this study, we used phloridzin to treat hepatic fibrosis in the CCl₄-induced C57/BL6N mouse model, which was extracted from lychee core, a traditional Chinese medicine. The therapeutic effect was evaluated by biochemical index detections and ultrasound detection. Furthermore, in order to determine the mechanism of phloridzin in the treatment of liver fibrosis, we performed high-throughput sequencing of mRNA and lncRNA in different groups of liver tissues. The results showed that compared with the model group, the phloridzin-treated groups revealed a significant decrease in collagen deposition and decreased levels of serum alanine aminotransferase, aspartate aminotransferase, laminin, and hyaluronic acid. GO and KEGG pathway enrichment analysis of the differential mRNAs was performed and revealed that phloridzin mainly affects cell ferroptosis. Gene co-expression analysis showed that the target genes of lncRNA were obvious in cell components such as focal adhesions, intercellular adhesion, and cell–substrate junctions and in metabolic pathways such as carbon metabolism. These results showed that phloridizin can effectively treat liver fibrosis, and the mechanism may involve ferroptosis, carbon metabolism, and related changes in biomechanics. Full article

(This article belongs to the Section Natural Products)

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The compound phloridzin derived from lychee seed in the treatment of liver fibrosis. Full article ">Figure 2
Pharmacodynamic results of phloridzin in the treatment of liver fibrosis. (A) Representative photos of liver appearance in each group. (B) Detailed view of liver appearance in each group. (C) Histological images of liver in each group after H&E stain. (D) Histological images of liver in each group after Sirius red stain. (E) Representative in vivo ultrasound imaging of livers from different groups. Fibrosis improvement can be seen by a decreased intensity in hepatic echogenicity. The 3D surface plots of the ultrasound images within the orange-lined squares correspond to the echogenic uniformity in the liver. (F) Statistics of the liver brightness of each group shows that compared with the model group, each treatment group has different degrees of reduction. Among them, the results of the silibinin treatment group and the high-dose phloridzin group are significantly different. (G) Percentage of area occupied by fibers in Sirius red-stained sections of liver in each group. (H,I) AST and ALT levels of each group were detected. (J,K) LN and HA levels of each group were detected by ELISA. Full article ">Figure 3
The statistics of DE mRNAs between control group vs model group, silibinin group vs. model group, and phloridzin vs. model group. DE mRNAs in the samples are shown using a heat map (A), bar chart (B), Venn upset diagram (C), and Venn diagram (D). Full article ">Figure 4
GO and KEGG pathway analysis explain the different mechanism between silibinin and phloridzin. (A–C) Top 10 terms of GO enrichment analysis of DEG mRNAs between silibinin group and model group. (D–F) Top 10 terms of GO enrichment analysis of DEG mRNAs between phloridzin group and model group. (G,H) Top 20 terms of KEGG pathway enrichment analysis of DEG mRNAs between silibinin group and model group. (I,J) Top 20 terms of KEGG pathway enrichment analysis of DEG mRNAs between phloridzin group and model group. Full article ">Figure 5
lncRNA-mRNA interaction and lncRNA target gene prediction. A visual regulatory nework for the lncRNA-mRNA relationship was drawn from target gene prediction results by Ctoscape 3.7.2, shown in (A). Then, we preformed the GO and KEGG pathway analysis based on the predicted mRNAs. (B) shows the top 30 terms of GO analysis and (C) shows the top 30 terms of KEGG pathway analysis. Full article ">

16 pages, 6008 KiB

Open AccessArticle

Investigation of Patient-Centric 3D-Printed Orodispersible Films Containing Amorphous Aripiprazole

by Ju-Hyun Lee, Chulhun Park, In-OK Song, Beom-Jin Lee, Chin-Yang Kang and Jun-Bom Park

Pharmaceuticals 2022, 15(7), 895; https://doi.org/10.3390/ph15070895 - 19 Jul 2022

Cited by 18 | Viewed by 3258

Abstract

The objective of this study was to design and evaluate an orodispersible film (ODF) composed of aripiprazole (ARP), prepared using a conventional solvent casting technique, and to fuse a three-dimensional (3D) printing technique with a hot-melt extrusion (HME) filament. Klucel^® LF (hydroxypropyl [...] Read more.

The objective of this study was to design and evaluate an orodispersible film (ODF) composed of aripiprazole (ARP), prepared using a conventional solvent casting technique, and to fuse a three-dimensional (3D) printing technique with a hot-melt extrusion (HME) filament. Klucel^® LF (hydroxypropyl cellulose, HPC) and PE-05JPS^® (polyvinyl alcohol, PVA) were used as backbone polymers for 3D printing and solvent casting. HPC-, PVA-, and ARP-loaded filaments were applied for 3D printing using HME. The physicochemical and mechanical properties of the 3D printing filaments and films were optimized based on the composition of the polymers and the processing parameters. The crystalline states of drug and drug-loaded formulations were investigated using differential scanning calorimetry (DSC) and powder X-ray diffraction (XRD). The dissolution and disintegration of the 3D-printed films were faster than those of solvent-cast films. HPC-3D printed film was fully disintegrated within 45 ± 3.5 s. The dissolution rate of HPC films reached 80% within 30 min at pH 1.2 and pH 4.0 USP buffer. There was a difference in the dissolution rate of about 5 to 10% compared to PVA films at the same sampling time. The root mean square of the roughness (Rq) values of each sample were evaluated using atomic force microscopy. The higher the Rq value, the rougher the surface, and the larger the surface area, the more salivary fluid penetrated the film, resulting in faster drug release and disintegration. Specifically, The HPC 3D-printed film showed the highest Rq value (102.868 nm) and average surface roughness (85.007 nm). The puncture strength of 3D-printed films had desirable strength with HPC (0.65 ± 0.27 N/mm²) and PVA (0.93 ± 0.15 N/mm²) to prevent deformation compared to those of marketed film products (over 0.34 N/mm²). In conclusion, combining polymer selection and 3D printing technology could innovatively design ODFs composed of ARP to solve the unmet medical needs of psychiatric patients. Full article

(This article belongs to the Special Issue 3D Printing of Drug Formulations)

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11 pages, 575 KiB

Open AccessArticle

Analgesic and Anesthetic Efficacy of Rocuronium/Sugammadex in Otorhinolaryngologic Surgery: A Propensity Score-Matched Analysis

by En-Bo Wu, Chao-Ting Hung, Sheng-Dean Luo, Shao-Chun Wu, Tsung-Yang Lee, Jo-Chi Chin, Peng-Neng Tsai and Johnson Chia-Shen Yang

Pharmaceuticals 2022, 15(7), 894; https://doi.org/10.3390/ph15070894 - 19 Jul 2022

Cited by 2 | Viewed by 2817

Abstract

The use of rocuronium/sugammadex in otorhinolaryngologic surgery improves intubation conditions and surgical rating scales. This study primarily aimed to evaluate the effect of the combination of rocuronium and sugammadex on intraoperative anesthetic consumption. The secondary outcomes were the intraoperative and postoperative morphine milligram [...] Read more.

The use of rocuronium/sugammadex in otorhinolaryngologic surgery improves intubation conditions and surgical rating scales. This study primarily aimed to evaluate the effect of the combination of rocuronium and sugammadex on intraoperative anesthetic consumption. The secondary outcomes were the intraoperative and postoperative morphine milligram equivalent (MME) consumption, duration of intraoperative hypertension, extubation time, incidence of delayed extubation and postoperative nausea and vomiting, pain score, and length of stay. A total of 2848 patients underwent otorhinolaryngologic surgery at a tertiary medical center in southern Taiwan. After applying the exclusion criteria, 2648 of these cases were included, with 167 and 2481 in the rocuronium/sugammadex and cisatracurium/neostigmine groups, respectively. To reduce potential bias, 119 patients in each group were matched by propensity scores for sex, age, body weight, and type of surgery. We found that the rocuronium/sugammadex group was associated with significant preservation of the intraoperative sevoflurane and MME consumption, with reductions of 14.2% (p = 0.009) and 11.8% (p = 0.035), respectively. The use of the combination of rocuronium and sugammadex also significantly increased the dose of intraoperative labetalol (p = 0.002), although there was no significant difference in intraoperative hypertensive events between both groups. In conclusion, our results may encourage the use of the combination of rocuronium and sugammadex as part of volatile-sparing and opioid-sparing anesthesia in otorhinolaryngologic surgery. Full article

(This article belongs to the Special Issue Drug Candidates for Anesthesia and Analgesia)

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13 pages, 1948 KiB

Open AccessArticle

Pennogenin-3-O-α-L-Rhamnopyranosyl-(1→2)-[α-L-Rhamnopyranosyl-(1→3)]-β-D-Glucopyranoside (Spiroconazol A) Isolated from Dioscorea bulbifera L. var. sativa Induces Autophagic Cell Death by p38 MAPK Activation in NSCLC Cells

by Yo Sook Ki, Kyung-Sook Chung, Heon-Woo Lee, Jung-Hye Choi, Léon Azefack Tapondjou, Eungyeong Jang and Kyung-Tae Lee

Pharmaceuticals 2022, 15(7), 893; https://doi.org/10.3390/ph15070893 - 19 Jul 2022

Cited by 2 | Viewed by 2306

Abstract

In our previous study, we reported the isolation of pennogenin-3-O-α-L-rhamnopyranosyl-(1→2)-[α-L-rhamnopyranosyl-(1→3)]-β-D-glucopyranoside (spiroconazol A), a steroidal saponin, from the flowers of Dioscorea bulbifera L. var. sativa. In the present study, we aimed to investigate the effects [...] Read more.

In our previous study, we reported the isolation of pennogenin-3-O-α-L-rhamnopyranosyl-(1→2)-[α-L-rhamnopyranosyl-(1→3)]-β-D-glucopyranoside (spiroconazol A), a steroidal saponin, from the flowers of Dioscorea bulbifera L. var. sativa. In the present study, we aimed to investigate the effects of spiroconazol A on autophagy and its underlying mechanisms in A549 and NCI-H358 human non-small cell lung cancer (NSCLC) cells. Spiroconazol A inhibited the proliferation of NSCLC cells in a concentration- and time-dependent manner. To determine the type of programmed cell death induced by spiroconazol A, we performed a characterization of apoptosis in spiroconazol A-treated A549 cells. Our results showed that spiroconazol A significantly suppressed A549 cell viability but did not influence cell apoptosis because phosphatidylserine and caspase activation were not detected. Furthermore, spiroconazol A treatment upregulated the expression of LC3-II and autophagy-related Beclin-1 protein, suggesting that spiroconazol A induces autophagy in A549 cells. Moreover, spiroconazol A activated the phosphorylation of p38 mitogen-activated protein kinase (MAPK) but did not affect the phosphorylation of Janus kinase or ERK1/2. Notably, SB203580, a p38 MAPK inhibitor, had a significant inhibitory effect on spiroconazol A-induced autophagic cell death in A549 cells. Our results indicated that spiroconazol A-induced autophagy is dependent on p38 MAPK signaling and has potential as a therapeutic target in NSCLC. Full article

(This article belongs to the Section Natural Products)

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Non-apoptotic features were presented by spiroconazol A in A549 cells. (A) Cells were exposed to spiroconazol A (2 μM) and were stained with the PI solution. For detection of sub-G1, indicating cell death, cells were determined by flow cytometry. (B) After treatment with spiroconazol A (2 μM) for the indicated times, cells were stained with FITC-conjugated Annexin V and PI (Cis: cisplatin) and then detected by flow cytometry. (C) After treatment with 50 μM z-VAD-fmk (broad caspase inhibitor) for 1 h, cells were treated with spiroconazol A (2 μM) for 24 h. Cells were stained with the PI solution and then examined by flow cytometry. Experiments were repeated at least three times, and data are expressed as mean ± S.D. * p < 0.05, ** p < 0.01, and *** p < 0.001 vs. control group by the Student’s t-test. Full article ">Figure 2
Autophagy induced by spiroconazol A in NSCLC cells. (A) Representative images showed the morphological changes in spiroconazol A (2 μM)-treated NSCLC cells using an OLYMPUS IX51 inverted microscope (Southend-on-Sea, Essex, UK). (B) Protein expression of cells exposed to 2 μM of spiroconazol A, using Western blot analysis. β-actin was utilized as an internal control. The relative optical density ratio was determined using a densitometric analysis program (Bio-Rad Quantity One® Software, version 4.6.3 (Basic), Bio-Rad Laboratories Inc., CA, USA), normalized to the internal control. * p < 0.05, ** p < 0.01 vs. untreated A549 cells, by the Student’s t-test. Full article ">Figure 3
Cell death by spiroconazol A-induced autophagy. (A) The pEGFP-LC3-II-transfected A549 cells were treated with 2 μM of spiroconazol A for 24 h; immunofluorescence of pEGFP-LC3-II was detected by confocal fluorescence microscopy. After pretreatment with 10 mM of 3-MA for 1 h, cells were treated with 2 μM of spiroconazol A for 24 h and then examined by (B) Western blot analysis and (C) PI staining, respectively. Experiments were repeated at least three times, and data are expressed as mean ± S.D. The relative optical density ratio was determined using a densitometric analysis program (Bio-Rad Quantity One® Software, version 4.6.3 (Basic), Bio-Rad Laboratories Inc., CA, USA), normalized to the internal control. * p < 0.05, *** p < 0.001 vs. untreated A549 cells and # p < 0.05, ### p < 0.001 vs. spiroconazol A-treated A549 cells, by the Student’s t-test. Full article ">Figure 4
The p38 MAPK kinase signaling pathway is required in spiroconazol A-induced autophagic cell death. (A) After treatment with 2 μM of spiroconazol A for the indicated times, cells were examined by Western blot analysis. After pretreatment with 40 μM of SB203580 (p38 MAPK inhibitor), cells were treated with spiroconazol A for 24 h and then examined by (B) Western blot analysis and (C) PI staining, respectively. Experiments were repeated at least three times, and data are expressed as mean ± S.D. The relative optical density ratio was determined using a densitometric analysis program (Bio-Rad Quantity One® Software, version 4.6.3 (Basic), Bio-Rad Laboratories Inc., CA, USA), normalized to the internal control. * p < 0.05, ** p < 0.01, *** p < 0.001 vs. untreated A549 cells and # p < 0.05, ### p < 0.001 vs. spiroconazol A-treated A549 cells, by the Student’s t-test. Full article ">Figure 5
Chemical structures of pennogenin (1), mannioside A (2), and spiroconazol A (3) isolated from D. bulbifera L. var. sativa. Full article ">

21 pages, 882 KiB

Open AccessReview

Druggable Targets and Compounds with Both Antinociceptive and Antipruritic Effects

by Hao-Jui Weng, Quoc Thao Trang Pham, Chia-Wei Chang and Tsen-Fang Tsai

Pharmaceuticals 2022, 15(7), 892; https://doi.org/10.3390/ph15070892 - 19 Jul 2022

Viewed by 3973

Abstract

Pain and itch are both important manifestations of various disorders, such as herpes zoster, atopic dermatitis, and psoriasis. Growing evidence suggests that both sensations have shared mediators, overlapping neural circuitry, and similarities in sensitization processes. In fact, pain and itch coexist in some [...] Read more.

Pain and itch are both important manifestations of various disorders, such as herpes zoster, atopic dermatitis, and psoriasis. Growing evidence suggests that both sensations have shared mediators, overlapping neural circuitry, and similarities in sensitization processes. In fact, pain and itch coexist in some disorders. Determining pharmaceutical agents and targets for treating pain and itch concurrently is of scientific and clinical relevance. Here we review the neurobiology of pain and itch and discuss the pharmaceutical targets as well as novel compounds effective for the concurrent treatment of these sensations. Full article

(This article belongs to the Special Issue Novel Target for the Treatment of Itch (Pruritus) and Pruritus-Related Pain of Different Origin)

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Interaction between pain and itch transmission in physiological conditions. The activation of itch primary afferents in dorsal root ganglia by pruritogens stimulates the release of excitatory neurotransmitters from the terminals of the secondary itch neurons in the spinal cord, leading to the release of GRP and opioids to activate GRPR+ interneurons for itch transmission. Stimulation of nociceptors induces the activation of secondary nociceptive neurons in the spinal cord for nociceptive transduction. Simultaneously, the activation of nociceptors results in the subsequent activation of Bhlhb5+ inhibitory neurons to compress itch transmission in GRPR+ neurons. Furthermore, spinal cord opioids can activate k-opioid receptors to suppress both pain and itch via reducing µ-opioid receptor activity and enhancing the activity of Bhlhb5+ inhibitory neurons. GRPR—gastrin-related peptide receptor; GRP—gastrin-related peptide; Bhlhb5—Class B basic helix-loop-helix protein 5. Full article ">Figure 2
Interaction between pain and itch signaling in pathological (chronic) conditions relating to druggable targets with both antinociceptive and antipruritic effects. Multiple elements can contribute to the development of the mismatch and sensitization of chronic pain and itch in pathological conditions. (1) Afferents involved in pain and itch can be activated by either pruritogens or algogens, leading to the mismatched activation of pruriceptors or nociceptors, and partly account for peripheral sensitization. Moreover, central sensitization of spinal cord neurons is associated with (2) the upregulation of GRP and GRPR, and (3) reduction or loss of inhibitory control from Bhlhb5+ inhibitory neurons. Subsequently, these events disrupt the normal interaction between itch and pain. Arrow—activation; diamond—inhibition. Full article ">

39 pages, 7183 KiB

Open AccessArticle

Synthesis and Evaluation of Some New 4H-Pyran Derivatives as Antioxidant, Antibacterial and Anti-HCT-116 Cells of CRC, with Molecular Docking, Antiproliferative, Apoptotic and ADME Investigations

by Nahed N. E. El-Sayed, Magdi E. A. Zaki, Sami A. Al-Hussain, Abir Ben Bacha, Malika Berredjem, Vijay H. Masand, Zainab M. Almarhoon and Hanaa S. Omar

Pharmaceuticals 2022, 15(7), 891; https://doi.org/10.3390/ph15070891 - 19 Jul 2022

Cited by 16 | Viewed by 3119

Abstract

Colorectal cancer oncogenesis is linked to dysbiosis, oxidative stress and overexpression of CDK2. The 4H-pyran scaffold is considered an antitumoral, antibacterial and antioxidant lead as well as a CDK2 inhibitor. Herein, certain 4H-pyran derivatives were evaluated as antibacterial, antioxidant [...] Read more.

Colorectal cancer oncogenesis is linked to dysbiosis, oxidative stress and overexpression of CDK2. The 4H-pyran scaffold is considered an antitumoral, antibacterial and antioxidant lead as well as a CDK2 inhibitor. Herein, certain 4H-pyran derivatives were evaluated as antibacterial, antioxidant and cytotoxic agents against HCT-116 cells. Derivatives 4g and 4j inhibited all the tested Gram-positive isolates, except for B. cereus (ATCC 14579), with lower IC₅₀ values (µM) than ampicillin. In addition, 4g and 4j demonstrated the strongest DPPH scavenging and reducing potencies, with 4j being more efficient than BHT. In cell viability assays, 4d and 4k suppressed the proliferation of HCT-116 cells, with the lowest IC₅₀ values being 75.1 and 85.88 µM, respectively. The results of molecular docking simulations of 4d and 4k, inhibitory kinase assays against CDK2, along with determination of CDK2 protein concentration and the expression level of CDK2 gene in the lysates of HCT-116 treated cells, suggested that these analogues blocked the proliferation of HCT-116 cells by inhibiting kinase activity and downregulating expression levels of CDK2 protein and gene. Moreover, 4d and 4k were found to induce apoptosis in HCT-116 cells via activation of the caspase-3 gene. Lastly, compounds 4g, 4j, 4d and 4k were predicted to comply with Lipinski’s rule of five, and they are expected to possess excellent physiochemical and pharmacokinetic properties suitable for in vivo bioavailability, as predicted by the SwissADME web tool. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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14 pages, 3648 KiB

Open AccessArticle

C-Myc Expression in Oral Squamous Cell Carcinoma: Molecular Mechanisms in Cell Survival and Cancer Progression

by Guya Diletta Marconi, Ylenia Della Rocca, Luigia Fonticoli, Francesco Melfi, Thangavelu Soundara Rajan, Simone Carradori, Jacopo Pizzicannella, Oriana Trubiani and Francesca Diomede

Pharmaceuticals 2022, 15(7), 890; https://doi.org/10.3390/ph15070890 - 19 Jul 2022

Cited by 13 | Viewed by 2676

Abstract

Oral squamous cell carcinoma (OSCC) represents 90% of malignant epithelial cancer that occurs in the oral cavity. The c-Myc factor is expressed in multiple types of cancer, comprising head and neck squamous cell carcinoma (HNSCC), where it plays a fundamental role in tumor [...] Read more.

Oral squamous cell carcinoma (OSCC) represents 90% of malignant epithelial cancer that occurs in the oral cavity. The c-Myc factor is expressed in multiple types of cancer, comprising head and neck squamous cell carcinoma (HNSCC), where it plays a fundamental role in tumor prognosis and in the self-renewal of tumor stem cells. However, the role of c-Myc in controlling OSCC cells is not well-known. The aim of the present study is the evaluation of the biological roles and regulatory mechanism of c-Myc in the pathogenesis of OSCC. Results indicated that c-Myc, c-Jun, Bcl-2, hypoxia inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), matrix metalloproteinase-9 (MMP-9), ERK 1/2 and pERK1/2 were overexpressed in a cellular model of squamous cell carcinoma, Cal-27. Doxorubicin (Doxo), a common chemotherapeutic agent, inhibited cell invasion, hypoxia, angiogenesis and inflammation in a cellular model of Cal-27 cells as indicated by downregulation of MMP-9, VEGF, ERK 1/2 and pERK 1/2 as well as promoted apoptosis as evidenced by the downregulation of Bcl-2 protein. This work aimed at underlying the functional relevance of c-Myc in OSCC and the HIF-Myc collaboration by integrating the knowledge on this molecular link in an OSCC tumor microenvironment. The results obtained showed for the first time the vital role of c-Myc in Cal-27 in cell survival/proliferation and tumor growth as well as the negative regulatory effect of Doxo against c-Myc signaling pathway. Full article

(This article belongs to the Special Issue Novel Anti-proliferative Agents)

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(A) Cell viability on Cal-27 cells treated with Doxo at 1, 2.5, 5 and 10 μM for 24 h. Cell viability was assessed using MTS assay and normalized to control cells treated with DMSO (0.2% as final concentration). ** p < 0.01; * p < 0.05. (B) the IC50 value graph for Doxo. (C) MTT assay reported the Doxo treatment on Cal-27 cells at 24, 48 and 72 h. * p < 0.05. Full article ">Figure 2
Confocal microscopic analysis on the expression of c-Myc and c-Jun in Cal-27 cell lines. Expression of c-Myc and c-Jun analyzed by confocal microscopy in untreated cells (CTRL) (A1–A4,C1–C4); expression of c-Myc and c-Jun expression in Cal-27 treated with Doxo 2.5 μM (B1–B4,D1–D4). Red fluorescence: cytoskeleton actin. Green fluorescence: c-Myc and c-Jun. Blue fluorescence: cell nuclei. Scale bar: 20 µm. Full article ">Figure 3
Confocal microscopic analysis on the expression of Bcl-2 and HIF-1α in Cal-27 cell lines. Expression of Bcl-2 and HIF-1α analyzed by confocal microscopy in untreated cells (CTRL) (A1–A4,C1–C4); expression of Bcl-2 and HIF-1α expression in Cal-27 treated with Doxo 2.5 μM (B1–B4,D1–D4). Red fluorescence: cytoskeleton actin. Green fluorescence: Bcl-2 and HIF-1α. Blue fluorescence: cell nuclei. Scale bar: 20 µm. Full article ">Figure 4
Confocal microscopic analysis on the expression of VEGF and MMP-9 in Cal-27 cell lines. Expression of VEGF and MMP-9 analyzed by confocal microscopy in untreated cells (CTRL) (A1–A4,C1–C4); expression of VEGF and MMP-9 analyzed by confocal microscopy in Cal-27 treated with Doxo 2.5 μM (B1–B4,D1–D4). Red fluorescence: cytoskeleton actin. Green fluorescence: VEGF, MMP-9, ERK 1/2 and pERK 1/2. Blue fluorescence: cell nuclei. Scale bar: 20 µm. Full article ">Figure 5
Confocal microscopic analysis on the expression of ERK 1/2 and pERK 1/2 in Cal-27cell lines. Expression of ERK 1/2 and pERK 1/2 analyzed by confocal microscopy in untreated cells (CTRL) (A1–A4,C1–C4); expression of ERK 1/2 and pERK 1/2 analyzed by confocal microscopy in Cal-27 treated with Doxo 2.5 μM (B1–B4,D1–D4). Red fluorescence: cytoskeleton actin. Green fluorescence: ERK 1/2 and pERK 1/2. Blue fluorescence: cell nuclei. Scale bar: 20 µm. Full article ">Figure 6
Western blotting analysis. (A) c-Myc, c-Jun, Bcl-2, HIF-1α, VEGF, MMP-9, ERK 1/2 and pERK1/2 proteins expression in Cal-27 cell line untreated and treated with 2.5 μM Doxo. Each membrane was probed with β-actin antibody to verify loading consistency. Western blot data shown are the representative data from three different experiments. (B1–B8) Histograms represent densitometric measurements of protein bands expressed as integrated optical intensity (IOI) mean of three separate experiments. The error bars show standard deviation (±SD). Densitometric values analyzed by t-test (unpaired t-test) return significant differences. *** p < 0.001, ** p < 0.01. Full article ">Figure 7
Western blotting analysis of apoptosis related markers. (A) Caspase-3, caspase-9 and Bax proteins expression in Cal-27 cell line untreated and treated with 2.5 μM Doxo. Each membrane was probed with β-actin antibody to verify loading consistency. Western blot data shown are the representative data from three different experiments. (B1–B3) Histograms represent densitometric measurements of proteins bands expressed as integrated optical intensity (IOI) mean of three separate experiments. The error bars show standard deviation (± SD). Densitometric values analyzed by t-test (unpaired t-test) return significant differences. *** p < 0.001, * p < 0.05. Full article ">

8 pages, 1849 KiB

Open AccessCase Report

Good Response of Advanced Thymic Carcinoma with Low PD-L1 Expression to Chemotherapy plus Pembrolizumab as First-Line Therapy and to Pembrolizumab as Maintenance Therapy: A Case Report

by Yoichi Nishii, Kazuki Furuhashi, Kentaro Ito, Tadashi Sakaguchi, Yuta Suzuki, Kentaro Fujiwara, Taro Yasuma, Tetsu Kobayashi, Corina N. D’Alessandro-Gabazza, Esteban C. Gabazza, Osamu Taguchi and Osamu Hataji

Pharmaceuticals 2022, 15(7), 889; https://doi.org/10.3390/ph15070889 - 19 Jul 2022

Cited by 5 | Viewed by 2718

Abstract

Thymic carcinoma is a rare malignant tumor with a poor prognosis. No standard treatment is currently available. The present case was a 64-year-old male smoker with no symptoms referred to our hospital because of abnormal chest radiological findings. The CT study showed a [...] Read more.

Thymic carcinoma is a rare malignant tumor with a poor prognosis. No standard treatment is currently available. The present case was a 64-year-old male smoker with no symptoms referred to our hospital because of abnormal chest radiological findings. The CT study showed a tumor between the anterior mediastinum and the right lung upper lobe, multiple nodular shadows along the right pleura, and pleural effusion. A CT-guided needle biopsy revealed squamous cell carcinoma. However, the differential diagnosis between thymic carcinoma and primary lung cancer was difficult. Treatment with carboplatin, nanoparticle albumin-bound paclitaxel, and pembrolizumab was initiated. The CT scan showed tumor shrinkage and good clinical response after four treatment cycles. Therapy was switched to maintenance therapy with pembrolizumab alone. Imaging studies showed further tumor shrinkage after twelve cycles of maintenance therapy with pembrolizumab. Sixteen cycles of maintenance therapy were continued without performance status deterioration. An abnormal radiological finding was detected after a twelve-month exacerbation-free period. The diagnosis was thymic carcinoma. Treatment with lenvatinib was initiated, and tumor-size reduction was observed. This is the first report of a case showing a successful maintenance therapy with pembrolizumab after effective first-line therapy with a combination of carboplatin-based chemotherapy plus pembrolizumab in advanced thymic carcinoma. Full article

(This article belongs to the Special Issue Therapeutic Strategies and Targets to Improve the Efficacy of PD-1/PD-L1 Blockade)

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Figure 1
Radiological findings. Plain radiograph (A) and computed tomography (B–E). The computed tomography revealed a tumor between the anterior mediastinum and the right lung upper lobe (B,C), multiple nodular shadows along the right pleura (D), and pleural effusion (E). Arrows indicate the lesion. Full article ">Figure 2
Bronchoscopy and computed tomography-guided biopsy. A thin bronchoscope, endobronchial ultrasonography, and a guide sheath were used during the bronchoscopy (A). Biopsy was performed under computed tomography guidance (B). Full article ">Figure 3
Tumor pathological findings. Hematoxylin/eosin staining of the tissue specimen revealed a solid tumor with interstitial fibrosis (A,B) and positive immunostaining for p40 (C) and CK5/6 (D). Scale bars indicate 200 µm (A) and 80 µm (B). Full article ">Figure 4
Positron emission tomography–computed tomography. Before therapy, the primary tumor’s positron emission tomography–computed tomography showed high 18F-fluorodeoxyglucose accumulation and a maximum standardized uptake value of 10.95 (A–C). After therapy, the primary tumor’s positron emission tomography–computed tomography showed a maximum standardized uptake value of 4.5 (D–F). Full article ">Figure 5
The clinical course of the patient. PET, positron emission tomography; CT, computed tomography; C, chemotherapy, CBDCA, carboplatin; PTX, paclitaxel; nab, nanoparticle albumin-bound. Full article ">

18 pages, 2825 KiB

Open AccessArticle

Application of Plackett–Burman Design for Spectrochemical Determination of the Last-Resort Antibiotic, Tigecycline, in Pure Form and in Pharmaceuticals: Investigation of Thermodynamics and Kinetics

by Ahmed S. El-Shafie, Aseel Yousef and Marwa El-Azazy

Pharmaceuticals 2022, 15(7), 888; https://doi.org/10.3390/ph15070888 - 19 Jul 2022

Cited by 8 | Viewed by 2068

Abstract

Tigecycline (TIGC) reacts with 7,7,8,8-tetracyanoquinodimethane (TCNQ) to form a bright green charge transfer complex (CTC). The spectrum of the CTC showed multiple charge transfer bands with a major peak at 843 nm. The Plackett–Burman design (PBD) was used to investigate the process variables [...] Read more.

Tigecycline (TIGC) reacts with 7,7,8,8-tetracyanoquinodimethane (TCNQ) to form a bright green charge transfer complex (CTC). The spectrum of the CTC showed multiple charge transfer bands with a major peak at 843 nm. The Plackett–Burman design (PBD) was used to investigate the process variables with the objective being set to obtaining the maximum absorbance and thus sensitivity. Four variables, three of which were numerical (temperature—Temp; reagent volume—RV; reaction time—RT) and one non-numerical (diluting solvent—DS), were studied. The maximum absorbance was achieved using a factorial blend of Temp: 25 °C, RV: 0.50 mL, RT: 60 min, and acetonitrile (ACN) as a DS. The molecular composition that was investigated using Job’s method showed a 1:1 CTC. The method’s validation was performed following the International Conference of Harmonization (ICH) guidelines. The linearity was achieved over a range of 0.5–10 µg mL⁻¹ with the limits of detection (LOD) and quantification (LOQ) of 166 and 504 ng mL⁻¹, respectively. The method was applicable to TIGC per se and in formulations without interferences from common additives. The application of the Benesi–Hildebrand equation revealed the formation of a stable complex with a standard Gibbs free energy change (∆G°) value of −26.42 to −27.95 kJ/mol. A study of the reaction kinetics revealed that the CTC formation could be best described using a pseudo-first-order reaction. Full article

(This article belongs to the Special Issue Perspectives and Challenges in the Synthesis and Analysis of Drugs—49th Conference “Synthesis and Analysis of Drugs” (SAD 2021))

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18 pages, 2817 KiB

Open AccessArticle

Assessing the Immunomodulatory Effect of Size on the Uptake and Immunogenicity of Influenza- and Hepatitis B Subunit Vaccines In Vitro

by Rick Heida, Philip A. Born, Gabriela Tapia-Calle, Henderik W. Frijlink, Anna Salvati, Anke L. W. Huckriede and Wouter L. J. Hinrichs

Pharmaceuticals 2022, 15(7), 887; https://doi.org/10.3390/ph15070887 - 18 Jul 2022

Cited by 1 | Viewed by 3055

Abstract

Viral subunit vaccines are a safer and more tolerable alternative to whole inactivated virus vaccines. However, they often come with limited efficacy, necessitating the use of adjuvants. Using free and particle-bound viral antigens, we assessed whether size affects the uptake of those antigens [...] Read more.

Viral subunit vaccines are a safer and more tolerable alternative to whole inactivated virus vaccines. However, they often come with limited efficacy, necessitating the use of adjuvants. Using free and particle-bound viral antigens, we assessed whether size affects the uptake of those antigens by human monocyte-derived dendritic cells (Mo-DCs) and whether differences in uptake affect their capacity to stimulate cytokine production by T cells. To this end, influenza antigens and hepatitis B surface antigen (HBsAg) were covalently conjugated to polystyrene particles of 500 nm and 3 μm. Cellular uptake of the antigens, either unconjugated or conjugated, and their capacity to stimulate T cells within a population of human peripheral blood mononuclear cells (PBMCs) were measured by flow cytometry. Conjugation of both antigens to particles significantly increased their uptake by Mo-DCs. Moreover, both the 500 nm and 3 μm influenza conjugates induced significantly higher numbers of cytokine-producing CD4⁺ T cells and induced increased production of the pro-inflammatory cytokines IFNγ and TNFα. In contrast, conjugation of HBsAg to particles did not notably affect the T cell response. In conclusion, conjugation of antigen to 500 nm and 3 μm particles leads to increased antigen uptake by human Mo-DCs, although the capacity of such conjugates to induce T cell stimulation likely depends on the immunological status of the PBMC donor. Full article

(This article belongs to the Section Biopharmaceuticals)

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Figure 1
Schematic overview of the different conjugate types used in this study. (a) Unlabeled antigen conjugated to fluorescently labeled carboxyl-functionalized polystyrene particles used for fluorescence microscopy. (b) Fluorescently labeled antigen conjugated to unlabeled amino-functionalized polystyrene particles used for uptake quantification with flow cytometry. (c) Unlabeled antigen conjugated to unlabeled amino-functionalized polystyrene particles for assessing the immune response in a population of human PBMCs. All conjugate types were made with both 500 nm and 3 µm polystyrene particles. Full article ">Figure 2
Visual conformation of successful conjugation of antigens to particles. (a) Conjugation of FITC-labeled influenza antigens to 3 µm particles. (b) Conjugation of FITC-labeled HBsAg to 3 µm particles. (c) Conjugation of FITC-labeled influenza antigens to 500 nm particles. (d) Conjugation of FITC-labeled HBsAg to 500 nm particles. (e) Unconjugated 3 µm particles. (f) Unconjugated 500 nm particles. Bar is 3 µm. Full article ">Figure 3
Diameter (a) and zeta potential (b) of polystyrene particles without and with conjugated influenza antigens (Flu) or hepatitis B surface antigen (Hep). The average hydrodynamic diameter and zeta potential of the 500 nm-conjugated particles were determined by a Mobius zeta potential and DLS detector. The average geometrical diameter of the 3 µm particles was determined by a Helos/BF parallel beam laser diffraction set-up (n = 3, mean ± SD). All particles were suspended in PBS, pH 7.4. Full article ">Figure 4
Uptake of nano- and microparticles by monocyte-derived dendritic cells (Mo-DCs). Mo-DCs were incubated for 20–24 h at 37 °C (5% CO2) with unconjugated fluorescently labeled particles (a,c) or influenza antigen-conjugated (b,d) particles with a diameter of 3 µm (a,b) and 500 nm (c,d). Cells were then fixed and stained, for filamentous actin using Phalloidin-iFluor 594 (Abcam, Cambridge, UK), and for nuclei using Hoechst 33342, trihydrochloride, and trihydrate (Invitrogen, Waltham, MA, USA), and subsequently examined using a Deltavision™ Elite high-resolution fluorescence microscope (GE Healthcare, Chicago, IL, USA). Actin filaments are shown in green, the nucleus in blue, and the particles, either conjugated or conjugated, in red. Bar is 10 µm. Full article ">Figure 5
Mean fluorescence intensity (MFI) of dendritic cells over time upon stimulation with FITC-labeled antigen conjugates versus unconjugated antigens. (a) 3 μm FITC-labeled influenza antigen conjugates versus unconjugated FITC-labeled antigens. (b) 3 μm FITC-labeled HBsAg conjugates versus unconjugated FITC-labeled HBsAg. (c) 500 nm influenza antigen conjugates versus unconjugated FITC-labeled antigens. (d) 500 nm HBsAg conjugates versus unconjugated FITC-labeled HBsAg. Filled lines represent the MFI over time of cells stimulated with the FITC-labeled conjugates; dashed lines represent the MFI over time of cells stimulated with unconjugated FITC-labeled antigens. The black lines were used to calculate the slope of MFI over time using linear regression analysis. Data points represent the average MFI of four donors ± SEM. Full article ">Figure 6
T cell responses upon stimulation with influenza antigen conjugates versus unconjugated antigens. Human PBMCs were stimulated with either unconjugated influenza antigens (Flu), influenza antigens conjugated to 500 nm particles (Flu-0.5 μm), or influenza antigens conjugated to 3 µm particles (Flu-3 μm). Cells from the control condition were stimulated with either unconjugated 500 nm or 3 µm particles. After 10 days, cells were harvested and evaluated by multicolor flow cytometry. Depicted are the frequencies of IFNγ-, TNFα-, and IL-10-producing CD4+ (a–c) and CD8+ (g–i) T cells and the respective integrated mean fluorescence intensities (iMFIs) ((d–f,j–l), respectively). Each symbol represents one donor (n = 6). Colors correspond to the different treatments as shown on the x-axis. Statistical analysis was performed using a one-way ANOVA, followed by a Tukey test. Significant differences (p < 0.05) between particle-conjugated antigens and unconjugated particles are represented with #. Full article ">Figure 7
T cell responses upon stimulation with HBsAg conjugates versus unconjugated antigens. Human PBMCs were stimulated with either unconjugated HBsAg (Hep), HBsAg conjugated to 500 nm particles (Hep-0.5 μm), or HBsAg conjugated to 3 µm particles (Hep-3 μm). Cells from the control condition were stimulated with either unconjugated 500 nm or 3 µm particles. After 10 days, cells were harvested and evaluated by multicolor flow cytometry. Depicted are the frequencies of IFNγ-, TNFα-, and IL-10-producing CD4+ (a–c) and CD8+ (g–i) T cells and the respective iMFIs ((d–f,j–l), respectively). Each symbol represents one donor (n = 6). Colors correspond to the different treatments as shown on the x-axis. Statistical analysis was performed using a one-way ANOVA, followed by a Tukey test. Significant differences (p < 0.05) between particle-conjugated antigens and unconjugated particles are represented with #. Full article ">

40 pages, 4791 KiB

Open AccessArticle

Palladium(II) Complexes of Substituted Salicylaldehydes: Synthesis, Characterization and Investigation of Their Biological Profile

by Ariadni Zianna, George Geromichalos, Augusta-Maria Fiotaki, Antonios G. Hatzidimitriou, Stavros Kalogiannis and George Psomas

Pharmaceuticals 2022, 15(7), 886; https://doi.org/10.3390/ph15070886 - 18 Jul 2022

Cited by 14 | Viewed by 2719

Abstract

Five palladium(II) complexes of substituted salicylaldehydes (X-saloH, X = 4-Et₂N (for 1), 3,5-diBr (for 2), 3,5-diCl (for 3), 5-F (for 4) or 4-OMe (for 5)) bearing the general formula [Pd(X-salo)₂] were synthesized and structurally [...] Read more.

Five palladium(II) complexes of substituted salicylaldehydes (X-saloH, X = 4-Et₂N (for 1), 3,5-diBr (for 2), 3,5-diCl (for 3), 5-F (for 4) or 4-OMe (for 5)) bearing the general formula [Pd(X-salo)₂] were synthesized and structurally characterized. The crystal structure of complex [Pd(4-Et₂N-salo)₂] was determined by single-crystal X-ray crystallography. The complexes can scavenge 1,1-diphenyl-picrylhydrazyl and 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) radicals and reduce H₂O₂. They are active against two Gram-positive (Staphylococcus aureus and Bacillus subtilis) and two Gram-negative (Escherichia coli and Xanthomonas campestris) bacterial strains. The complexes interact strongly with calf-thymus DNA via intercalation, as deduced by diverse techniques and via the determination of their binding constants. Complexes interact reversibly with bovine and human serum albumin. Complementary insights into their possible mechanisms of bioactivity at the molecular level were provided by molecular docking calculations, exploring in silico their ability to bind to calf-thymus DNA, Escherichia coli and Staphylococcus aureus DNA-gyrase, 5-lipoxygenase, and membrane transport lipid protein 5-lipoxygenase-activating protein, contributing to the understanding of the role complexes 1–5 can play both as antioxidant and antibacterial agents. Furthermore, in silico predictive tools have been employed to study the chemical reactivity, molecular properties and drug-likeness of the complexes, and also the drug-induced changes of gene expression profile (as protein- and mRNA-based prediction results), the sites of metabolism, the substrate/metabolite specificity, the cytotoxicity for cancer and non-cancer cell lines, the acute rat toxicity, the rodent organ-specific carcinogenicity, the anti-target interaction profiles, the environmental ecotoxicity, and finally the activity spectra profile of the compounds. Full article

(This article belongs to the Special Issue Pd Derivatives in Drug Discovery)

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16 pages, 10247 KiB

Open AccessArticle

Morphological Changes, Antibacterial Activity, and Cytotoxicity Characterization of Hydrothermally Synthesized Metal Ions-Incorporated Nanoapatites for Biomedical Application

by Ssu-Meng Huang, Shih-Ming Liu, Wen-Cheng Chen, Chia-Ling Ko, Chi-Jen Shih and Jian-Chih Chen

Pharmaceuticals 2022, 15(7), 885; https://doi.org/10.3390/ph15070885 - 18 Jul 2022

Cited by 7 | Viewed by 2319

Abstract

The objective of this study was to prepare hydroxyapatite (HA) with potential antibacterial activity against gram-negative and gram-positive bacteria by incorporating different atomic ratios of Cu²⁺ (0.1–1.0%), Mg²⁺ (1.0–7.0%), and Zn²⁺ (1.0–7.0%) to theoretically replace Ca²⁺ ions during the [...] Read more.

The objective of this study was to prepare hydroxyapatite (HA) with potential antibacterial activity against gram-negative and gram-positive bacteria by incorporating different atomic ratios of Cu²⁺ (0.1–1.0%), Mg²⁺ (1.0–7.0%), and Zn²⁺ (1.0–7.0%) to theoretically replace Ca²⁺ ions during the hydrothermal synthesis of grown precipitated HA nanorods. This study highlights the role of comparing different metal ions on synthetic nanoapatite in regulating the antibacterial properties and toxicity. The comparisons between infrared spectra and between diffractograms have confirmed that metal ions do not affect the formation of HA phases. The results show that after doped Cu²⁺, Mg²⁺, and Zn²⁺ ions replace Ca²⁺, the ionic radius is almost the same, but significantly smaller than that of the original Ca²⁺ ions, and the substitution effect causes the lattice distance to change, resulting in crystal structure distortion and reducing crystallinity. The reduction in the length of the nanopatites after the incorporation of Cu²⁺, Mg²⁺, and Zn²⁺ ions confirmed that the metal ions were mainly substituted during the growth of the rod-shape nanoapatite Ca²⁺ distributed along the longitudinal site. The antibacterial results show that nanoapatite containing Cu²⁺ (0.1%), Mg²⁺ (3%), and Zn²⁺ (5–7%) has obvious and higher antibacterial activity against gram-positive bacteria Staphylococcus aureus within 2 days. The antibacterial effect against the gram-negative bacillus Escherichia coli is not as pronounced as against Staphylococcus aureus. The antibacterial effect of Cu²⁺ substituted Ca²⁺ with an atomic ratio of 0.1~1.0% is even better than that of Mg²⁺- and Zn²⁺- doped with 1~7% groups. In terms of cytotoxicity, nanoapatites with Cu²⁺ (~0.2%) exhibit cytotoxicity, whereas Mg²⁺- (1–5%) and Zn²⁺- (~1%) doped nanoapatites are biocompatible at low concentrations but become cytotoxic as ionic concentration increases. The results show that the hydrothermally synthesized nanoapatite combined with Cu²⁺ (0.2%), Mg²⁺ (3%), and Zn²⁺ (3%) exhibits low toxicity and high antibacterial activity, which provides a good prospect for bypassing antibiotics for future biomedical applications. Full article

(This article belongs to the Special Issue Synthesis of Metal Nanoparticles and Their Pharmaceutical Applications)

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Graphical abstract

Graphical abstract
Full article ">Figure 1
Fourier transform infrared spectra of rod-shaped nanoapatites synthesized with and without Cu2+, Mg2+, and Zn2+ at different ion concentrations. Full article ">Figure 2
X-ray diffraction patterns of the rod-shaped nanoapatites synthesized with and without Cu2+, Mg2+, and Zn2+ at different ion concentrations. Full article ">Figure 3
High-resolution transmission electron microscopy images, lattice images of the (002) facet of apatite were identified, and selected area electron diffraction analysis of rod-shape nanoapatites hydrothermal synthesized with different ionic co-precipitation concentrations in the absence (top left) and presence of Cu2+ (top row), Mg2+ (middle row), and Zn2+ (bottom row). Full article ">Figure 4
Relative quantitative antibacterial ability against gram-positive S. aureus in the presence of different ionic concentrations of Cu2+ (a), Mg2+ (b), and Zn2+ (c), the rod-shaped nanoapatites with different ion concentrations (n = 3; * indicates significantly different p < 0.05). Full article ">Figure 5
Relative quantitative antibacterial ability against gram-negative E. coli in the presence of different ionic concentrations of Cu2+ (a), Mg2+ (b), and Zn2+ (c), the rod-shaped nanoapatites with different ion concentrations (n = 3; * p < 0.05). Full article ">Figure 6
(a) Quantitative results of cytotoxicity (n = 6) after culturing L929 cells with nanoapatite doped with different metallic ions for 1 day; (b) qualitative analysis of cytotoxicity. Full article ">

19 pages, 3565 KiB

Open AccessArticle

Hybrid Nanosystems Based on Nicotinate-Functionalized Mesoporous Silica and Silver Chloride Nanoparticles Loaded with Phenytoin for Preventing Pseudomonas aeruginosa Biofilm Development

by Maider Ugalde-Arbizu, John Jairo Aguilera-Correa, Aranzazu Mediero, Jaime Esteban, Paulina L. Páez, Eider San Sebastian and Santiago Gómez-Ruiz

Pharmaceuticals 2022, 15(7), 884; https://doi.org/10.3390/ph15070884 - 18 Jul 2022

Cited by 8 | Viewed by 2504

Abstract

Pseudomonas aeruginosa (PA) is one of the most common bacteria isolated from chronic wounds and burns. Its treatment is a challenge due to antimicrobial drug resistance and biofilm formation. In this context, this study aimed to perform the synthesis and full characterization of [...] Read more.

Pseudomonas aeruginosa (PA) is one of the most common bacteria isolated from chronic wounds and burns. Its treatment is a challenge due to antimicrobial drug resistance and biofilm formation. In this context, this study aimed to perform the synthesis and full characterization of hybrid nanosystems based on mesoporous silica nanoparticles (MSNs) functionalized with a nicotinic ligand and silver chloride nanoparticles, both phenytoin sodium (Ph)-loaded and unloaded, to evaluate the antibacterial properties against three different strains of PA (including two clinical strains) in a planktonic state and as biofilms. Ph is a well-known proliferative agent, which was incorporated into the hybrid nanomaterials to obtain an effective material for tissue healing and prevention of infection caused by PA. The Ph-loaded materials promoted a quasi-complete inhibition of bacterial growth in wound-like medium and biofilm development, with values of 99% and 96%, respectively, with selectivity indices above the requirements for drugs to become promising agents for the topic preventive treatment of chronic wounds and burns. Full article

(This article belongs to the Special Issue Novel Antibacterial Agents 2022)

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9 pages, 547 KiB

Open AccessTechnical Note

Chronic Pruritus in Atopic Patients Treated with Dupilumab: Real Life Response and Related Parameters in 354 Patients

by Luca Mastorino, François Rosset, Federica Gelato, Michela Ortoncelli, Giovanni Cavaliere, Pietro Quaglino and Simone Ribero

Pharmaceuticals 2022, 15(7), 883; https://doi.org/10.3390/ph15070883 - 17 Jul 2022

Cited by 21 | Viewed by 2422

Abstract

Chronic pruritus is a major symptom of atopic dermatitis (AD). Its etiopathogenesis is complex, and an understanding of the driving factors of its pathogenesis allows for the development of new molecule-targeted therapies. Dupilumab, targeting and blocking interleukin-4 (IL-4) and interleukin-13 (IL-13) molecules, has [...] Read more.

Chronic pruritus is a major symptom of atopic dermatitis (AD). Its etiopathogenesis is complex, and an understanding of the driving factors of its pathogenesis allows for the development of new molecule-targeted therapies. Dupilumab, targeting and blocking interleukin-4 (IL-4) and interleukin-13 (IL-13) molecules, has shown great efficacy in treating AD symptoms such chronic itching. We performed a retrospective observational study to evaluate possible chronic-itch-related characteristics and parameters in 356 AD patients who received dupilumab. The objective of the study was to evaluate the factors associated with the level of pruritus reported by patients at each of the 1575 detections in the form of the peak pruritus numerical rating scale (NRSpp) and sleep disturbance numerical rating scale (NRSsd). We focused on: the eczema area and severity index (EASI), dermatology life quality index (DLQI), patient-oriented eczema measure (POEMS), eosinophilia, L-lactate dehydrogenase (LDH), immunoglobulin E (IgE) and the time from the start of dupilumab therapy. NRSpp fell from 8.6 (sd 1.7) at baseline to 1.7 (sd 2.3) at 36 months and NRSsd from 7 (sd 3) to 0. Regarding the parameters that correlate with NRSpp, all the parameters analysed were significantly correlated except for eosinophils (p = 0.136). In the multivariate analysis, both considering and not considering treatment duration, the parameters were correlated (p < 0.001); EASI, DLQI, POEM, and LDH significantly correlated with NRSpp (p < 0.001 for each, except for LDH p = 0.003); while IgE tot lost significance (p = 0.337). Similar results were obtained for the parameters correlating with NRSsd. Our results confirm the efficacy of dupilumab on pruritus. The use of questionnaires such as DLQI and POEM is advisable in clinical practice and is adequate for assessing the impact of itching on AD. The low correlation of IgE and eosinophils, the ambiguity of LDH levels with the level of pruritus, and a poor clinical validity and unclear correlation with disease severity suggest a progressive abandonment of monitoring of these values. Full article

(This article belongs to the Special Issue Novel Target for the Treatment of Itch (Pruritus) and Pruritus-Related Pain of Different Origin)

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17 pages, 2903 KiB

Open AccessArticle

The N-Methyl-D-Aspartate Receptor Blocker REL-1017 (Esmethadone) Reduces Calcium Influx Induced by Glutamate, Quinolinic Acid, and Gentamicin

by Ezio Bettini, Sara De Martin, Andrea Mattarei, Marco Pappagallo, Stephen M. Stahl, Francesco Bifari, Charles E. Inturrisi, Franco Folli, Sergio Traversa and Paolo L. Manfredi

Pharmaceuticals 2022, 15(7), 882; https://doi.org/10.3390/ph15070882 - 17 Jul 2022

Cited by 10 | Viewed by 3497

Abstract

REL-1017 (esmethadone) is a novel N-methyl-D-aspartate receptor (NMDAR) antagonist and promising rapid antidepressant candidate. Using fluorometric imaging plate reader (FLIPR) assays, we studied the effects of quinolinic acid (QA) and gentamicin, with or without L-glutamate and REL-1017, on intracellular calcium ([Ca²⁺] [...] Read more.

REL-1017 (esmethadone) is a novel N-methyl-D-aspartate receptor (NMDAR) antagonist and promising rapid antidepressant candidate. Using fluorometric imaging plate reader (FLIPR) assays, we studied the effects of quinolinic acid (QA) and gentamicin, with or without L-glutamate and REL-1017, on intracellular calcium ([Ca²⁺]_in) in recombinant cell lines expressing human GluN1-GluN2A, GluN1-GluN2B, GluN1-GluN2C, and GluN1-GluN2D NMDAR subtypes. There were no effects of QA on [Ca²⁺]_in in cells expressing GluN1-GluN2C subtypes. QA acted as a low-potency, subtype-selective, NMDAR partial agonist in GluN1-GluN2A, GluN1-GluN2B, and GluN1-GluN2D subtypes. REL-1017 reduced [Ca²⁺]_in induced by QA. In cells expressing the GluN1-GluN2D subtype, QA acted as an agonist in the presence of 0.04 μM L-glutamate and as an antagonist in the presence of 0.2 μM L-glutamate. REL-1017 reduced [Ca²⁺]_in induced by L-glutamate alone and with QA in all cell lines. In the absence of L-glutamate, gentamicin had no effect. Gentamicin was a positive modulator for GluN1-GluN2B subtypes at 10 μM L-glutamate, for GluN1-GluN2A at 0.2 μM L-glutamate, and for GluN1-GluN2A, GluN1-GluN2B, and GluN1-GluN2D at 0.04 μM L-glutamate. No significant changes were observed with GluN1-GluN2C NMDARs. REL-1017 reduced [Ca²⁺]_in induced by the addition of L-glutamate in all NMDAR cell lines in the presence or absence of gentamicin. In conclusion, REL-1017 reduced [Ca²⁺]_in induced by L-glutamate alone and when increased by QA and gentamicin. REL-1017 may protect cells from excessive calcium entry via NMDARs hyperactivated by endogenous and exogenous molecules. Full article

(This article belongs to the Special Issue NMDA Receptor-Based Therapeutics)

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18 pages, 15912 KiB

Open AccessArticle

Co-Delivery of 5-Fluorouracil and Paclitaxel in Mitochondria-Targeted KLA-Modified Liposomes to Improve Triple-Negative Breast Cancer Treatment

by Tianyu Chen, Hui Chen, Yichun Jiang, Qi Yan, Shuling Zheng and Min Wu

Pharmaceuticals 2022, 15(7), 881; https://doi.org/10.3390/ph15070881 - 17 Jul 2022

Cited by 19 | Viewed by 3251

Abstract

In this research, KLA-modified liposomes co-loaded with 5-fluorouracil and paclitaxel (KLA-5-FU/PTX Lps) were developed, and their antitumor activity against triple-negative breast cancer (TNBC) was evaluated. KLA-5-FU/PTX Lps were prepared using the thin-film dispersion method, and their in vitro anticancer efficacy was assessed in [...] Read more.

In this research, KLA-modified liposomes co-loaded with 5-fluorouracil and paclitaxel (KLA-5-FU/PTX Lps) were developed, and their antitumor activity against triple-negative breast cancer (TNBC) was evaluated. KLA-5-FU/PTX Lps were prepared using the thin-film dispersion method, and their in vitro anticancer efficacy was assessed in human breast cancer cells (MDA-MB-231). An MDA-MB-231 tumor-bearing mouse model was also established to evaluate their antitumor efficacy in vivo. KLA-5-FU/PTX Lps showed enhanced cytotoxicity against MDA-MB-231 cells, improved drug delivery to mitochondria, and induced mitochondria-mediated apoptosis. The modified liposomes also showed favorable antitumor activity in vivo due to their strong ability to target tumors and mitochondria. The liposomes showed no obvious systemic toxicity. Our results suggest that KLA-5-FU/PTX Lps are a promising system with which to target the delivery of antitumor drugs to mitochondria as a treatment for TNBC. Full article

(This article belongs to the Special Issue Synergistic Effects of Plant Derivatives with Other Drugs)

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23 pages, 2615 KiB

Open AccessReview

The Pivotal Role of Quantum Dots-Based Biomarkers Integrated with Ultra-Sensitive Probes for Multiplex Detection of Human Viral Infections

by Seyyed Mojtaba Mousavi, Seyyed Alireza Hashemi, Masoomeh Yari Kalashgrani, Navid Omidifar, Chin Wei Lai, Neralla Vijayakameswara Rao, Ahmad Gholami and Wei-Hung Chiang

Pharmaceuticals 2022, 15(7), 880; https://doi.org/10.3390/ph15070880 - 17 Jul 2022

Cited by 26 | Viewed by 4264

Abstract

The spread of viral diseases has caused global concern in recent years. Detecting viral infections has become challenging in medical research due to their high infectivity and mutation. A rapid and accurate detection method in biomedical and healthcare segments is essential for the [...] Read more.

The spread of viral diseases has caused global concern in recent years. Detecting viral infections has become challenging in medical research due to their high infectivity and mutation. A rapid and accurate detection method in biomedical and healthcare segments is essential for the effective treatment of pathogenic viruses and early detection of these viruses. Biosensors are used worldwide to detect viral infections associated with the molecular detection of biomarkers. Thus, detecting viruses based on quantum dots biomarkers is inexpensive and has great potential. To detect the ultrasensitive biomarkers of viral infections, QDs appear to be a promising option as biological probes, while physiological components have been used directly to detect multiple biomarkers simultaneously. The simultaneous measurement of numerous clinical parameters of the same sample volume is possible through multiplex detection of human viral infections, which reduces the time and cost required to record any data point. The purpose of this paper is to review recent studies on the effectiveness of the quantum dot as a detection tool for human pandemic viruses. In this review study, different types of quantum dots and their valuable properties in the structure of biomarkers were investigated. Finally, a vision for recent advances in quantum dot-based biomarkers was presented, whereby they can be integrated into super-sensitive probes for the multiplex detection of human viral infections. Full article

(This article belongs to the Special Issue The Biomedical Applications of Graphene and Graphene-Related Materials)

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24 pages, 886 KiB

Open AccessReview

Bone Tissue Engineering in the Treatment of Bone Defects

by Nannan Xue, Xiaofeng Ding, Rizhong Huang, Ruihan Jiang, Heyan Huang, Xin Pan, Wen Min, Jun Chen, Jin-Ao Duan, Pei Liu and Yiwei Wang

Pharmaceuticals 2022, 15(7), 879; https://doi.org/10.3390/ph15070879 - 17 Jul 2022

Cited by 163 | Viewed by 11760

Abstract

Bones play an important role in maintaining exercise and protecting organs. Bone defect, as a common orthopedic disease in clinics, can cause tremendous damage with long treatment cycles. Therefore, the treatment of bone defect remains as one of the main challenges in clinical [...] Read more.

Bones play an important role in maintaining exercise and protecting organs. Bone defect, as a common orthopedic disease in clinics, can cause tremendous damage with long treatment cycles. Therefore, the treatment of bone defect remains as one of the main challenges in clinical practice. Today, with increased incidence of bone disease in the aging population, demand for bone repair material is high. At present, the method of clinical treatment for bone defects including non-invasive therapy and invasive therapy. Surgical treatment is the most effective way to treat bone defects, such as using bone grafts, Masquelet technique, Ilizarov technique etc. In recent years, the rapid development of tissue engineering technology provides a new treatment strategy for bone repair. This review paper introduces the current situation and challenges of clinical treatment of bone defect repair in detail. The advantages and disadvantages of bone tissue engineering scaffolds are comprehensively discussed from the aspect of material, preparation technology, and function of bone tissue engineering scaffolds. This paper also summarizes the 3D printing technology based on computer technology, aiming at designing personalized artificial scaffolds that can accurately fit bone defects. Full article

(This article belongs to the Special Issue Development of Bone Targeted Drug Delivery Technologies)

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14 pages, 1691 KiB

Open AccessSystematic Review

Dexamethasone Increases the Anesthetic Success in Patients with Symptomatic Irreversible Pulpitis: A Meta-Analysis

by Lorenzo Franco-de la Torre, Eduardo Gómez-Sánchez, Nicolás Addiel Serafín-Higuera, Ángel Josabad Alonso-Castro, Sandra López-Verdín, Nelly Molina-Frechero, Vinicio Granados-Soto and Mario Alberto Isiordia-Espinoza

Pharmaceuticals 2022, 15(7), 878; https://doi.org/10.3390/ph15070878 - 16 Jul 2022

Cited by 2 | Viewed by 3106

Abstract

Inferior alveolar nerve block (IANB) has a high failure rate in subjects with symptomatic irreversible pulpitis (SIP). It has been suggested that drugs with anti-inflammatory activity could improve the efficacy of the anesthetic used for IANB. The aim of this study was to [...] Read more.

Inferior alveolar nerve block (IANB) has a high failure rate in subjects with symptomatic irreversible pulpitis (SIP). It has been suggested that drugs with anti-inflammatory activity could improve the efficacy of the anesthetic used for IANB. The aim of this study was to assess the effect of dexamethasone on the success of dental anesthesia in patients with SIP. An information search was performed using PubMed and Google Scholar. The risk of bias of the included studies was evaluated with the Cochrane Collaboration’s risk-of-bias tool. The anesthetic success rate, pain intensity (VAS), and adverse effects were extracted. Data were analyzed using the Mantel–Haenszel test and odds ratio or the inverse variance and standardized mean difference. Dexamethasone increased the anesthetic success in comparison with placebo (n = 502; p < 0.001; OR = 2.59; 95% CIs: 1.46 to 4.59). Moreover, patients who were given dexamethasone had lower pain scores at 6 h (n = 302; p < 0.001; MD= −1.43; 95% CIs: −2.28 to −0.58), 12 h (n = 302; p < 0.0001; MD = −1.65; 95% CIs: −2.39 to −0.92), and 24 h (n = 302; p < 0.0008; MD = −1.27; 95% CIs: −2.01 to −0.53) when compared with placebo. In conclusion, the systemic administration of dexamethasone increases the anesthetic success rate and improves pain management in patients with SIP. Full article

(This article belongs to the Special Issue Drug Candidates for Anesthesia and Analgesia)

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22 pages, 2116 KiB

Open AccessReview

Novel Pharmaceutical Strategies for Enhancing Skin Penetration of Biomacromolecules

by Luyu Zhang, Zirong Dong, Wenjuan Liu, Xiying Wu, Haisheng He, Yi Lu, Wei Wu and Jianping Qi

Pharmaceuticals 2022, 15(7), 877; https://doi.org/10.3390/ph15070877 - 16 Jul 2022

Cited by 16 | Viewed by 6388

Abstract

Skin delivery of biomacromolecules holds great advantages in the systemic and local treatment of multiple diseases. However, the densely packed stratum corneum and the tight junctions between keratinocytes stand as formidable skin barriers against the penetration of most drug molecules. The large molecular [...] Read more.

Skin delivery of biomacromolecules holds great advantages in the systemic and local treatment of multiple diseases. However, the densely packed stratum corneum and the tight junctions between keratinocytes stand as formidable skin barriers against the penetration of most drug molecules. The large molecular weight, high hydrophilicity, and lability nature of biomacromolecules pose further challenges to their skin penetration. Recently, novel penetration enhancers, nano vesicles, and microneedles have emerged as efficient strategies to deliver biomacromolecules deep into the skin to exert their therapeutic action. This paper reviews the potential application and mechanisms of novel skin delivery strategies with emphasis on the pharmaceutical formulations. Full article

(This article belongs to the Special Issue Delivery Systems of Peptides and Proteins: Challenges, Status Quo and Future Perspectives)

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27 pages, 3393 KiB

Open AccessReview

Tumor-Derived Membrane Vesicles: A Promising Tool for Personalized Immunotherapy

by Jiabin Xu, Wenqiang Cao, Penglai Wang and Hong Liu

Pharmaceuticals 2022, 15(7), 876; https://doi.org/10.3390/ph15070876 - 16 Jul 2022

Cited by 10 | Viewed by 3757

Abstract

Tumor-derived membrane vesicles (TDMVs) are non-invasive, chemotactic, easily obtained characteristics and contain various tumor-borne substances, such as nucleic acid and proteins. The unique properties of tumor cells and membranes make them widely used in drug loading, membrane fusion and vaccines. In particular, personalized [...] Read more.

Tumor-derived membrane vesicles (TDMVs) are non-invasive, chemotactic, easily obtained characteristics and contain various tumor-borne substances, such as nucleic acid and proteins. The unique properties of tumor cells and membranes make them widely used in drug loading, membrane fusion and vaccines. In particular, personalized vectors prepared using the editable properties of cells can help in the design of personalized vaccines. This review focuses on recent research on TDMV technology and its application in personalized immunotherapy. We elucidate the strengths and challenges of TDMVs to promote their application from theory to clinical practice. Full article

(This article belongs to the Special Issue Recent Progress of Nanomedicine and Targeted Drug Delivery for Cancer Treatment)

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Graphical abstract
Full article ">Figure 1
Properties and application prospects of TDMVs. TCMVs, tumor-derived cell membrane vesicles; TEXs, tumor-derived exosomes; TMVs, tumor-derived microvesicles. Full article ">Figure 2
Schematic diagram of TCMVs-based CpG-anti-tumor vaccines. Use of cancer cell membranes carrying tumor-specific antigens to wrap CpG-loaded nanoparticles to generate nanoparticle tumor vaccines. The tumor-specific antigens on the surface of TCMVs promote uptake and presentation by antigen-presenting cells, activating multiple specific T cells that act to monitor and kill tumor cells. Reproduced with permission [<a href="#B81-pharmaceuticals-15-00876" class="html-bibr">81</a>]. Copyright 2017, Wiley-VCH. Full article ">Figure 3
Schematic illustration of fusion vesicles of bacterial outer membrane and TCMVs for personalized immunotherapy. (A) The fabrication of fusion vesicles. (B) Accumulation and retention behavior of inguinal lymph nodes following right posterior intraplantar injection. (C) Fusion vesicles inhibit tumor lung metastasis. (D) Bilateral tumor model to validate the effect of fusion vesicle personalized immunotherapy. Reproduced with permission [<a href="#B191-pharmaceuticals-15-00876" class="html-bibr">191</a>]. Copyright 2021, American Chemical Society. Full article ">Figure 4
Gene-edited fusion vesicles for multi-targeted immune checkpoint therapy. (A) SIRPα variants CV1 and PD-1 were overexpressed on 4T1 and B16F10 cancer cells, respectively, and fusion vesicles were then prepared. (B) Fusion vesicles promote antigen uptake and presentation by antigen-presenting cells and enhance anti-tumor T-cell immunity by blocking CD47/SIRPα and PD-1/PD-L1immunosuppressive axis. Reproduced with permission [<a href="#B73-pharmaceuticals-15-00876" class="html-bibr">73</a>]. Copyright 2021, Wiley-VCH. Full article ">Figure 5
Fusion vesicles encapsulating MOFs for tumor prevention. (A) Preparation of fused vesicles encapsulating MOFs. (B) Fusion vesicle vaccination for tumor prophylaxis. (C) Mechanisms by which fusion vesicles induce immune response. Reprinted/adapted with permission from Ref. [<a href="#B62-pharmaceuticals-15-00876" class="html-bibr">62</a>]. 2019, Springer Nature. Full article ">Figure 6
Schematic diagram of TCMVs-based injectable hydrogels for ICT. (A) Oxidized sodium alginate is adsorbed on the surface of TCMVs to form a gel, and after injection into the tumor, Ca2+ in the microenvironment would chelate with the particles to form a gel, causing an antigen reservoir effect and continuous recruitment to activate antigen-presenting cells and lymphocytes. (B) Adding DMA and ROSCO to the gel blocks Ca2+ entry into tumor cells and inhibits the secretion of circulating PD-L1 and tumor PD-L1 exosomes. Reproduced with permission [<a href="#B74-pharmaceuticals-15-00876" class="html-bibr">74</a>]. Copyright 2021, Wiley-VCH. Full article ">Figure 7
Integrated CS-I/J@CM NPs remodel the tumor immunosuppressive microenvironment to improve glioblastoma immunotherapy [<a href="#B63-pharmaceuticals-15-00876" class="html-bibr">63</a>]. Full article ">

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Pharmaceuticals, Volume 15, Issue 7 (July 2022) – 138 articles

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