Pharmaceuticals

30 pages, 20432 KiB

Open AccessArticle

α-Glucosidase and α-Amylase Inhibitory Potentials of Quinoline–1,3,4-oxadiazole Conjugates Bearing 1,2,3-Triazole with Antioxidant Activity, Kinetic Studies, and Computational Validation

by Nosipho Cele, Paul Awolade, Pule Seboletswe, Kolawole Olofinsan, Md. Shahidul Islam and Parvesh Singh

Pharmaceuticals 2022, 15(8), 1035; https://doi.org/10.3390/ph15081035 - 22 Aug 2022

Cited by 21 | Viewed by 3327

Abstract

Diabetes mellitus (DM) is a multifaceted metabolic disorder that remains a major threat to global health security. Sadly, the clinical relevance of available drugs is burdened with an upsurge in adverse effects; hence, inhibiting the carbohydrate-hydrolyzing enzymes α-glucosidase and α-amylase while preventing oxidative [...] Read more.

Diabetes mellitus (DM) is a multifaceted metabolic disorder that remains a major threat to global health security. Sadly, the clinical relevance of available drugs is burdened with an upsurge in adverse effects; hence, inhibiting the carbohydrate-hydrolyzing enzymes α-glucosidase and α-amylase while preventing oxidative stress is deemed a practicable strategy for regulating postprandial glucose levels in DM patients. We report herein the α-glucosidase and α-amylase inhibition and antioxidant profile of quinoline hybrids 4a–t and 12a–t bearing 1,3,4-oxadiazole and 1,2,3-triazole cores, respectively. Overall, compound 4i with a bromopentyl sidechain exhibited the strongest α-glucosidase inhibition (IC₅₀ = 15.85 µM) relative to reference drug acarbose (IC₅₀ = 17.85 µM) and the best antioxidant profile in FRAP, DPPH, and NO scavenging assays. Compounds 4a and 12g also emerged as the most potent NO scavengers (IC₅₀ = 2.67 and 3.01 µM, respectively) compared to gallic acid (IC₅₀ = 728.68 µM), while notable α-glucosidase inhibition was observed for p-fluorobenzyl compound 4k (IC₅₀ = 23.69 µM) and phenyl-1,2,3-triazolyl compound 12k (IC₅₀ = 22.47 µM). Moreover, kinetic studies established the mode of α-glucosidase inhibition as non-competitive, thus classifying the quinoline hybrids as allosteric inhibitors. Molecular docking and molecular dynamics simulations then provided insights into the protein–ligand interaction profile and the stable complexation of promising hybrids at the allosteric site of α-glucosidase. These results showcase these compounds as worthy scaffolds for developing more potent α-glucosidase inhibitors with antioxidant activity for effective DM management. Full article

(This article belongs to the Special Issue Hybrid Drugs: Design and Applications)

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14 pages, 1400 KiB

Open AccessArticle

Residual Microscopic Peritoneal Metastases after Macroscopic Complete Cytoreductive Surgery for Advanced High-Grade Serous Ovarian Carcinoma: A Target for Folate Receptor Targeted Photodynamic Therapy?

by Morgane Moinard, Jeremy Augustin, Marine Carrier, Elisabeth Da Maïa, Alix Penel, Jérémie Belghiti, Maryam Nikpayam, Clémentine Gonthier, Geoffroy Canlorbe, Samir Acherar, Nadira Delhem, Céline Frochot, Catherine Uzan and Henri Azaïs

Pharmaceuticals 2022, 15(8), 1034; https://doi.org/10.3390/ph15081034 - 22 Aug 2022

Cited by 3 | Viewed by 2619

Abstract

Despite conventional treatment combining complete macroscopic cytoreductive surgery (CRS) and systemic chemotherapy, residual microscopic peritoneal metastases (mPM) may persist as the cause of peritoneal recurrence in 60% of patients. Therefore, there is a real need to specifically target these mPM to definitively eradicate [...] Read more.

Despite conventional treatment combining complete macroscopic cytoreductive surgery (CRS) and systemic chemotherapy, residual microscopic peritoneal metastases (mPM) may persist as the cause of peritoneal recurrence in 60% of patients. Therefore, there is a real need to specifically target these mPM to definitively eradicate any traces of the disease and improve patient survival. Therapeutic targeting method, such as photodynamic therapy, would be a promising method for such a purpose. Folate receptor alpha (FRα), as it is specifically overexpressed by cancer cells from various origins, including ovarian cancer cells, is a good target to address photosensitizing molecules. The aim of this study was to determine FRα expression by residual mPM after complete macroscopic CRS in patients with advanced high-grade serous ovarian cancer (HGSOC). A prospective study conducted between 1 June 2018 and 10 July 2019 in a single referent center accredited by the European Society of Gynecological Oncology for advanced EOC surgical management. Consecutive patients presenting with advanced HGSOC and eligible for complete macroscopic CRS were included. Up to 13 peritoneal biopsies were taken from macroscopically healthy peritoneum at the end of CRS and examined for the presence of mPM. In case of detection of mPM, a systematic search for RFα expression by immunohistochemistry was performed. Twenty-six patients were included and 26.9% presented mPM. In the subgroup of patients with mPM, FRα expression was positive on diagnostic biopsy before neoadjuvant chemotherapy for 67% of patients, on macroscopic peritoneal metastases for 86% of patients, and on mPM for 75% of patients. In the subgroup of patients with no mPM, FRα expression was found on diagnostic biopsy before neoadjuvant chemotherapy in 29% of patients and on macroscopic peritoneal metastases in 78% of patients. FRα is well expressed by patients with or without mPM after complete macroscopic CRS in patients with advanced HGSOC. In addition to conventional cytoreductive surgery, the use of a therapeutic targeting method, such as photodynamic therapy, by addressing photosensitizing molecules that specifically target FRα may be studied. Full article

(This article belongs to the Special Issue Photodynamic Therapy 2022)

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15 pages, 564 KiB

Open AccessReview

Gastroesophageal Reflux Disease in Idiopathic Pulmonary Fibrosis: Viewer or Actor? To Treat or Not to Treat?

by Barbara Ruaro, Riccardo Pozzan, Paola Confalonieri, Stefano Tavano, Michael Hughes, Marco Matucci Cerinic, Elisa Baratella, Elisabetta Zanatta, Selene Lerda, Pietro Geri, Marco Confalonieri and Francesco Salton

Pharmaceuticals 2022, 15(8), 1033; https://doi.org/10.3390/ph15081033 - 22 Aug 2022

Cited by 25 | Viewed by 3955

Abstract

Background: Idiopathic pulmonary fibrosis (IPF) is a rare and severe disease with a median survival of ∼3 years. Several risk factors have been identified, such as age, genetic predisposition, tobacco exposure, and gastro-oesophageal reflux disease (GERD). Prevalence of GERD in IPF is high [...] Read more.

Background: Idiopathic pulmonary fibrosis (IPF) is a rare and severe disease with a median survival of ∼3 years. Several risk factors have been identified, such as age, genetic predisposition, tobacco exposure, and gastro-oesophageal reflux disease (GERD). Prevalence of GERD in IPF is high and may affect 87% of patients, of whom only half (47%) report symptoms. Objective: The aim of this study is to review current evidence regarding the correlation between GERD and IPF and to evaluate the current studies regarding treatments for GERD-IPF. Methods: A review to identify research papers documenting an association between GERD and IPF was performed. Results: We identified several studies that have confirmed the association between GERD and IPF, with an increased acid exposure, risk of gastric aspiration and bile acids levels in these patients. Few studies focused their attention on GERD treatment, showing how antiacid therapy was not able to change IPF evolution. Conclusions: This review investigating the correlation between GERD and IPF has confirmed the hypothesized association. However, further large prospective studies are needed to corroborate and elucidate these findings with a focus on preventative and treatment strategies. Full article

(This article belongs to the Special Issue Rheumatic Diseases: Pathophysiology, Targeted Therapy, Focus on Vascular and Pulmonary Manifestations 2022)

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18 pages, 1039 KiB

Open AccessReview

Roles of Bromodomain Extra Terminal Proteins in Metabolic Signaling and Diseases

by Dayu Wu and Qiong Duan

Pharmaceuticals 2022, 15(8), 1032; https://doi.org/10.3390/ph15081032 - 22 Aug 2022

Cited by 1 | Viewed by 2796

Abstract

BET proteins, which recognize and bind to acetylated histones, play a key role in transcriptional regulation. The development of chemical BET inhibitors in 2010 greatly facilitated the study of these proteins. BETs play crucial roles in cancer, inflammation, heart failure, and fibrosis. In [...] Read more.

BET proteins, which recognize and bind to acetylated histones, play a key role in transcriptional regulation. The development of chemical BET inhibitors in 2010 greatly facilitated the study of these proteins. BETs play crucial roles in cancer, inflammation, heart failure, and fibrosis. In particular, BETs may be involved in regulating metabolic processes, such as adipogenesis and metaflammation, which are under tight transcriptional regulation. In addition, acetyl-CoA links energy metabolism with epigenetic modification through lysine acetylation, which creates docking sites for BET. Given this, it is possible that the ambient energy status may dictate metabolic gene transcription via a BET-dependent mechanism. Indeed, recent studies have reported that various BET proteins are involved in both metabolic signaling regulation and disease. Here, we discuss some of the most recent information on BET proteins and their regulation of the metabolism in both cellular and animal models. Further, we summarize data from some randomized clinical trials evaluating BET inhibitors for the treatment of metabolic diseases. Full article

(This article belongs to the Special Issue Bromodomains: A New Target Class for Drug Development)

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27 pages, 4102 KiB

Open AccessArticle

Design, Synthesis and Biological Investigation of 2-Anilino Triazolopyrimidines as Tubulin Polymerization Inhibitors with Anticancer Activities

by Romeo Romagnoli, Paola Oliva, Filippo Prencipe, Stefano Manfredini, Federica Budassi, Andrea Brancale, Salvatore Ferla, Ernest Hamel, Diana Corallo, Sanja Aveic, Lorenzo Manfreda, Elena Mariotto, Roberta Bortolozzi and Giampietro Viola

Pharmaceuticals 2022, 15(8), 1031; https://doi.org/10.3390/ph15081031 - 21 Aug 2022

Cited by 8 | Viewed by 3697

Abstract

A further investigation aiming to generate new potential antitumor agents led us to synthesize a new series of twenty-two compounds characterized by the presence of the 7-(3′,4′,5′-trimethoxyphenyl)-[1,2,4]triazolo[1,5-a]pyrimidine pharmacophore modified at its 2-position. Among the synthesized compounds, three were significantly more active [...] Read more.

A further investigation aiming to generate new potential antitumor agents led us to synthesize a new series of twenty-two compounds characterized by the presence of the 7-(3′,4′,5′-trimethoxyphenyl)-[1,2,4]triazolo[1,5-a]pyrimidine pharmacophore modified at its 2-position. Among the synthesized compounds, three were significantly more active than the others. These bore the substituents p-toluidino (3d), p-ethylanilino (3h) and 3′,4′-dimethylanilino (3f), and these compounds had IC₅₀ values of 30–43, 160–240 and 67–160 nM, respectively, on HeLa, A549 and HT-29 cancer cells. The p-toluidino derivative 3d was the most potent inhibitor of tubulin polymerization (IC₅₀: 0.45 µM) and strongly inhibited the binding of colchicine to tubulin (72% inhibition), with antiproliferative activity superior to CA-4 against A549 and HeLa cancer cell lines. In vitro investigation showed that compound 3d was able to block treated cells in the G2/M phase of the cell cycle and to induce apoptosis following the intrinsic pathway, further confirmed by mitochondrial depolarization and caspase-9 activation. In vivo experiments conducted on the zebrafish model showed good activity of 3d in reducing the mass of a HeLa cell xenograft. These effects occurred at nontoxic concentrations to the animal, indicating that 3d merits further developmental studies. Full article

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

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Structures of CA-4 (1a), CA-4P (1b), tirbanibulin, general structure (2) of 1-(3′,4′,5′-trimethoxybenzoyl)-5-amino-1,2,4-triazoles and [1,2,4]triazolo[1,5-a]pyrimidines reported in this manuscript (3) and reported in the literature (4 and 5). Full article ">Figure 2
Chemical structures of newly synthesized compounds 3a–v based on the 7-(3′,4′,5′-trimethoxyphenyl)[1,2,4]triazolo[1,5-a]pyrimidine scaffold and general molecular formula 6a–d of triazolopyrimidines published by us (ref. [<a href="#B65-pharmaceuticals-15-01031" class="html-bibr">65</a>]). Full article ">Figure 3
Colchicine binding conformation (A) and proposed binding for compounds 3d (B), 3f (C), 3h (D) and 3l (E) in the colchicine site. All the derivatives presented the trimethoxyphenyl ring in proximity to βCys241, while the substituted phenyl group at position 2 of the central core was sited at the interface between the two tubulin subunits, pointing toward a loop in the α-subunit (αSer178-αThr179). Compound 3d presented two main interactions with βCys241, different anchoring contacts with the surrounding residues and no clashes with the tubulin structure. The rest of the compounds, even if conserving different interactions, including the important interaction with βCys241, presented different clashes with the surrounding residues, suggesting a non-optimal occupation of the colchicine site and indicating a reduced affinity for tubulin. The carbon atoms of the tubulin α unit residues are shown in lilac, while the carbon atoms of the β unit residues are represented in teal. Hydrogen bonds are shown as orange dashed lines, hydrophobic interactions as green dashed lines and distance clashes as red dashed lines. Full article ">Figure 4
(Panel (A)) Quantitative analysis of cell cycle phase distribution in HeLa cells after a 24 h treatment with 3d, at the concentrations of 10, 25 or 50 nM. Cells were stained with PI to analyze the DNA content by flow cytometry. Data are presented as means of three independent experiments ± SEM. (Panel (B)) Effects of compound 3d on cell cycle regulatory proteins and DNA damage checkpoint proteins. HeLa cells were treated for 24 h with the indicated concentration of 3d, and expression of ATR, cdc2 (Y15) and cyclin B was detected by Western blot analysis. Full article ">Figure 5
Apoptotic effects caused by 3d. HeLa cells were treated with the indicated concentrations of 3d for either 24 or 48 h and then were analyzed by flow cytometry after double staining with annexin-V-FITC and PI. A−/PI− Alive cells; A+/PI− Early apoptotic cells; A+/PI+ Late apoptotic cells; A−/PI+ Necrotic cells. In the histograms, data are represented as mean ± SEM of three independent experiments. Full article ">Figure 6
Assessment of mitochondrial depolarization after treatment with 3d. HeLa cells were treated with the indicated concentrations of compound for 24 or 48 h. Data are represented as mean ± SEM of three independent experiments (** p < 0.01, *** p < 0.001). Full article ">Figure 7
Western blot analysis of Caspase-9 (D330) (Cleaved form) and Bcl-2 levels. HeLa cells were treated for 24 h with 3d at the indicated concentrations. Full article ">Figure 8
Effects of 3d treatment on the zebrafish xenotransplantation model (A). Compound 3d did not induce abnormal phenotypes or developmental anomalies in zebrafish embryos after 24, 48 and 72 h of incubation. DMSO-treated embryos were used as control. (B) Representative images of Tg(fli1:EGFP) zebrafish embryos (blood vessels shown in white) transplanted with DiI + HeLa cells (red). The embryos were treated with the indicated concentrations of 3d for 24 h and then the fluorescence intensity was quantified as depicted in panel (C). Data are expressed as mean ± SD (**** p < 0.001). Scale bar, 200 μm. Effects of 3d treatment on zebrafish embryos. No abnormal phenotypes or developmental defects were seen in comparison to DMSO-treated embryos (as a normal control) after 24, 48 and 72 h. (B) Effects of 3d treatment on the zebrafish xenotransplantation model. Representative images of Tg(fli1:EGFP) zebrafish embryos (blood vessels shown in white) transplanted with DiI + HeLa cells (red). Embryos were treated for 24 h with DMSO (control group), 30 nM 3d or 300 nM 3d. (C) Histograms represent the fluorescence intensity of the tumor xenografts, indicating total HeLa cells present in each embryo after a 24 h treatment with 3d at the indicated concentrations. Data are expressed as mean ± SD (**** p < 0.001). Scale bar, 200 μm. Full article ">Scheme 1
Reagents. a: Appropriate ArNH2, i-PrOH, reflux, 18 h for the preparation of compounds 8a–o or appropriate ArCH2NH2/C6H5(CH2)2NH2/C6H5(CH2)3NH2, i-PrOH, room temperature, 18 h for the synthesis of derivatives 8p–v, 75–92%; b: NH2NH2.H2O, MeOH, reflux, 18 h, 68–93%; c: AcOH, 80 °C, 2 h, 47–66%. Full article ">

14 pages, 3064 KiB

Open AccessArticle

Inter-Ligand STD NMR: An Efficient 1D NMR Approach to Probe Relative Orientation of Ligands in a Multi-Subsite Protein Binding Pocket

by Serena Monaco, Jonathan Ramírez-Cárdenas, Ana Teresa Carmona, Inmaculada Robina and Jesus Angulo

Pharmaceuticals 2022, 15(8), 1030; https://doi.org/10.3390/ph15081030 - 21 Aug 2022

Cited by 8 | Viewed by 3534

Abstract

In recent years, Saturation Transfer Difference NMR (STD NMR) has been proven to be a powerful and versatile ligand-based NMR technique to elucidate crucial aspects in the investigation of protein-ligand complexes. Novel STD NMR approaches relying on “multi-frequency” irradiation have enabled us to [...] Read more.

In recent years, Saturation Transfer Difference NMR (STD NMR) has been proven to be a powerful and versatile ligand-based NMR technique to elucidate crucial aspects in the investigation of protein-ligand complexes. Novel STD NMR approaches relying on “multi-frequency” irradiation have enabled us to even elucidate specific ligand-amino acid interactions and explore the binding of fragments in previously unknown binding subsites. Exploring multi-subsite protein binding pockets is especially important in Fragment Based Drug Discovery (FBDD) to design leads of increased specificity and efficacy. We hereby propose a novel multi-frequency STD NMR approach based on direct irradiation of one of the ligands in a multi-ligand binding process, to probe the vicinity and explore the relative orientation of fragments in adjacent binding sub-sites, which we called Inter-Ligand STD NMR (IL-STD NMR). We proved its applicability on (i) a standard protein-ligand system commonly used for ligand-observed NMR benchmarking: Naproxen as bound to Bovine Serum Albumin, and (ii) the biologically relevant system of Cholera Toxin Subunit B and two inhibitors adjacently bound within the GM1 binding site. Relative to Inter-Ligand NOE (ILOE), the current state-of-the-art methodology to probe relative orientations of adjacent ligands, IL-STD NMR requires about one tenth of the experimental time and protein consumption, making it a competitive methodology with the potential to be applied in the pharmaceutical industries. Full article

(This article belongs to the Special Issue High Field NMR and Ultra-High Field NMR in Medicinal Chemistry)

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21 pages, 1824 KiB

Open AccessReview

Pharmacological Small Molecules against Prostate Cancer by Enhancing Function of Death Receptor 5

by Xia Gan, Yonghong Liu and Xueni Wang

Pharmaceuticals 2022, 15(8), 1029; https://doi.org/10.3390/ph15081029 - 21 Aug 2022

Cited by 1 | Viewed by 2717

Abstract

Death receptor 5 (DR5) is a membrane protein that mediates exogenous apoptosis. Based on its function, it is considered to be a target for the treatment of cancers including prostate cancer. It is encouraging to note that a number of drugs targeting DR5 [...] Read more.

Death receptor 5 (DR5) is a membrane protein that mediates exogenous apoptosis. Based on its function, it is considered to be a target for the treatment of cancers including prostate cancer. It is encouraging to note that a number of drugs targeting DR5 are now progressing to different stages of clinical trial studies. We collected 38 active compounds that could produce anti-prostate-cancer effects by modulating DR5, 28 of which were natural compounds and 10 of which were synthetic compounds. In addition, 6 clinically used chemotherapeutic agents have also been shown to promote DR5 expression and thus exert apoptosis-inducing effects in prostate cancer cells. These compounds promote the expression of DR5, thereby enhancing its function in inducing apoptosis. When these compounds were used in combination with the natural ligand of DR5, the number of apoptotic cells was significantly increased. These compounds are all promising for development as anti-prostate-cancer drugs, while most of these compounds are currently being evaluated for their anti-prostate-cancer effects at the cellular level and in animal studies. A great deal of more in-depth research is needed to evaluate whether they can be developed as drugs. We collected literature reports on small molecules against prostate cancer through modulation of DR5 to understand the current dynamics in this field and to evaluate the prospects of small molecules against prostate cancer through modulation of DR5. Full article

(This article belongs to the Topic Advances in Anti-Cancer Drugs)

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19 pages, 1829 KiB

Open AccessSystematic Review

Schinopsis brasiliensis Engler—Phytochemical Properties, Biological Activities, and Ethnomedicinal Use: A Scoping Review

by Ladaha Pequeno Menna Barreto Linhares, Bruna Vanessa Nunes Pereira, Maria Karoline Gomes Dantas, Wislayne Mirelly da Silva Bezerra, Daniela de Araújo Viana-Marques, Luiza Rayanna Amorim de Lima and Pedro Henrique Sette-de-Souza

Pharmaceuticals 2022, 15(8), 1028; https://doi.org/10.3390/ph15081028 - 20 Aug 2022

Cited by 5 | Viewed by 2912

Abstract

Brazil has the most incredible biodiversity globally and has a vast storehouse of molecules to be discovered. However, there are no pharmacological and phytochemical studies on most native plants. Parts of Schinopsis brasiliensis Engler, a tree from the Anacardiaceae family, are used by [...] Read more.

Brazil has the most incredible biodiversity globally and has a vast storehouse of molecules to be discovered. However, there are no pharmacological and phytochemical studies on most native plants. Parts of Schinopsis brasiliensis Engler, a tree from the Anacardiaceae family, are used by several traditional communities to treat injuries and health problems. The objective of this scoping review was to summarize the pharmacological information about S. brasiliensis, from ethnobotanical to phytochemical and biological studies. Data collection concerning the geographical distribution of S. brasiliensis specimens was achieved through the Reflora Virtual Herbarium. The study’s protocol was drafted using the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR). The search strategy used the keyword “Schinopsis brasiliensis” in the databases: PUBMED, EMBASE, SCOPUS, Science Direct, Web of Science, SciFinder, and SciELO. Rayyan was used for the selection of eligible studies. In total, 35 studies were included in the paper. The most recurrent therapeutic indications were for general pain, flu and inflammation. The bark was the most studied part of the plant. The most used preparation method was decoction and infusion, followed by syrup. Phytochemical investigations indicate the presence of tannins, flavonoids, phenols, and polyphenols. Most of the substances were found in the plant’s leaf and bark. Important biological activities were reported, such as antimicrobial, antioxidant, and anti-inflammatory. S. brasiliensis is used mainly by communities in the semi-arid region of northeastern Brazil to treat several diseases. Pharmacological and phytochemical studies together provide scientific support for the popular knowledge of the medicinal use of S. brasiliensis. In vitro and in vivo analyses reported antimicrobial, antioxidant, anti-inflammatory, antinociceptive, cytotoxic, photoprotective, preservative, molluscicidal, larvicidal, and pupicidal effects. It is essential to highlight the need for future studies that elucidate the mechanisms of action of these phytocompounds. Full article

(This article belongs to the Special Issue Ethnopharmacology in Latin America)

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20 pages, 82590 KiB

Open AccessArticle

Asperuloside Prevents Peri-Implantitis via Suppression of NF-κB and ERK1/2 on Rats

by Xinge Wang, Xutao Chen, Zhaoxin Zhang, Ji Chen, Zeyang Ge, Shitou Huang, Hongbo Wei and Dehua Li

Pharmaceuticals 2022, 15(8), 1027; https://doi.org/10.3390/ph15081027 - 20 Aug 2022

Cited by 8 | Viewed by 2545

Abstract

Peri-implantitis is characterized by inflammatory cell infiltration and hyperactivation of the osteoclasts surrounding dental implants which can result in bone resorption and ultimately implant failure. Therefore, coordinating the activity of inflammatory response and bone-resorbing osteoclasts is crucial for the prevention of peri-implantitis. Asperuloside [...] Read more.

Peri-implantitis is characterized by inflammatory cell infiltration and hyperactivation of the osteoclasts surrounding dental implants which can result in bone resorption and ultimately implant failure. Therefore, coordinating the activity of inflammatory response and bone-resorbing osteoclasts is crucial for the prevention of peri-implantitis. Asperuloside (ASP), an iridoid glycoside, has significant anti-inflammatory activities, suggesting the great potential in attenuating peri-implantitis bone resorption. A ligature-induced peri-implantitis model in the maxilla of rats was established, and the effects of ASP on preventing peri-implantitis were evaluated after four weeks of ligation using micro-CT and histological staining. RT-PCR, western blotting, tartrate-resistant acid phosphatase (TRAP), and immunofluorescent staining were conducted on osteoclasts to confirm the mechanisms of ASP on osteoclastogenesis. The results show that ASP could lead to attenuation of alveolar bone resorption in peri-implantitis by inhibiting osteoclast formation and decreasing pro-inflammatory cytokine levels in vivo. Furthermore, ASP could inhibit osteoclastogenesis by downregulating expression levels of transcription factors nuclear factor of activated T-cell (NFATc1) via restraining the activations of nuclear factor kappa beta (NF-κB) and the phosphorylation of extracellular signal-related kinase 1/2 (ERK1/2). In conclusion, ASP could significantly attenuate bone resorption in peri-implantitis via inhibition of osteoclastogenesis by suppressing NF-κB and ERK1/2 signaling pathways activations. Full article

(This article belongs to the Special Issue Terpenes and Terpenoids As Therapeutic Drugs: Molecular Pharmacology and Toxicology)

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20 pages, 2920 KiB

Open AccessArticle

The Effect of 1,2,4-Triazole-3-thiol Derivatives Bearing Hydrazone Moiety on Cancer Cell Migration and Growth of Melanoma, Breast, and Pancreatic Cancer Spheroids

by Aida Šermukšnytė, Kristina Kantminienė, Ilona Jonuškienė, Ingrida Tumosienė and Vilma Petrikaitė

Pharmaceuticals 2022, 15(8), 1026; https://doi.org/10.3390/ph15081026 - 20 Aug 2022

Cited by 24 | Viewed by 2785

Abstract

4-Phenyl-3-[2-(phenylamino)ethyl]-1H-1,2,4-triazole-5(4H)-thione was used as a starting compound for the synthesis of the corresponding 1,2,4-triazol-3-ylthioacetohydrazide, which reacts with isatins and various aldehydes bearing aromatic and heterocyclic moieties provided target hydrazones. Their cytotoxicity was tested by the MTT assay against human [...] Read more.

4-Phenyl-3-[2-(phenylamino)ethyl]-1H-1,2,4-triazole-5(4H)-thione was used as a starting compound for the synthesis of the corresponding 1,2,4-triazol-3-ylthioacetohydrazide, which reacts with isatins and various aldehydes bearing aromatic and heterocyclic moieties provided target hydrazones. Their cytotoxicity was tested by the MTT assay against human melanoma IGR39, human triple-negative breast cancer (MDA-MB-231), and pancreatic carcinoma (Panc-1) cell lines. The selectivity of compounds towards cancer cells was also studied. In general, the synthesized compounds were more cytotoxic against the melanoma cell line. N′-(2-oxoindolin-3-ylidene)-2-((4-phenyl-5-(2-(phenylamino)ethyl)-4H-1,2,4-triazol-3-yl)thio)acetohydrazide, N′-((1H-pyrrol-2-yl)methylene)-2-((4-phenyl-5-(2-(phenylamino)ethyl)-4H-1,2,4-triazol-3-yl)thio)acetohydrazide and N′-(2-hydroxy-5-nitrobenzylidene)-2-((4-phenyl-5-(2-(phenylamino)ethyl)-4H-1,2,4-triazol-3-yl)thio)acetohydrazide were identified as the most active among all synthesized compounds in 3D cell cultures. N′-(4-(dimethylamino)benzylidene)-2-((4-phenyl-5-(2-(phenylamino)ethyl)-4H-1,2,4-triazol-3-yl)thio)acetohydrazide inhibited all cancer cell migration, was characterized as relatively more selective towards cancer cells, and could be further tested as an antimetastatic candidate. Full article

(This article belongs to the Special Issue Hybrid Drugs: Design and Applications)

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Effect of hydrazones 1–19 on cancer cell viability at a concentration of 50 µM against human melanoma IGR39, human triple-negative breast cancer MDA-MB-231, human pancreatic carcinoma Panc-1 cell lines, and human fibroblasts HF; n = 3. Full article ">Figure 2
EC50 values of the most active hydrazones 4, 7, 8, 10, 14, 17 and 18, obtained by the MTT assay, n = 3. Full article ">Figure 3
Effect of hydrazones 4, 7, 8, 10, 14, 17, and 18 on human malignant melanoma IGR39 (A), human triple-negative breast cancer MDA-MB-231 (B), and human pancreatic carcinoma (Panc-1) (C) cell migration; n = 3. Photos of the ‘wound’ area (marked in yellow) in IGR39 (D), MDA-MB-231 (E), and Panc-1 (F) monolayers at the beginning and the end of the experiment. Scale bar indicates 100 µm. The asterisks (*) indicate p < 0.05 and (**) indicate p < 0.01 compared to the control (untreated cells). Full article ">Figure 4
Effect of the most active hydrazones 4, 7, 8, 10, 14, 17, and 18 on 3D cell cultures. (A) Photos of human melanoma IGR39, human triple-negative breast cancer MDA-MB-231, and human pancreatic carcinoma Panc-1 tumour spheroids at the end of the experiment (after 8 days of incubation with 10 µM of compounds). (B) Spheroid size at the end of the experiment. (C) Cell viability in the IGR39, MDA-MB-231, and Panc-1 spheroids. Asterisks (*) indicate p < 0.05 compared to the control (untreated spheroids), crosses (×) indicate means; inner dashes indicate medians; whiskers indicate maximum and minimum values. Scale bars indicate 200 µm. Full article ">Scheme 1
Synthesis of hydrazones 4–8. Full article ">Scheme 2
Synthesis of hydrazones 9–19. Full article ">

19 pages, 2070 KiB

Open AccessReview

Digital Pills with Ingestible Sensors: Patent Landscape Analysis

by Olena Litvinova, Elisabeth Klager, Nikolay T. Tzvetkov, Oliver Kimberger, Maria Kletecka-Pulker, Harald Willschke and Atanas G. Atanasov

Pharmaceuticals 2022, 15(8), 1025; https://doi.org/10.3390/ph15081025 - 19 Aug 2022

Cited by 24 | Viewed by 8445

Abstract

The modern healthcare system is directly related to the development of digital health tools and solutions. Pills with digital sensors represent a highly innovative class of new pharmaceuticals. The aim of this work was to analyze the patent landscape and to systematize the [...] Read more.

The modern healthcare system is directly related to the development of digital health tools and solutions. Pills with digital sensors represent a highly innovative class of new pharmaceuticals. The aim of this work was to analyze the patent landscape and to systematize the main trends in patent protection of digital pills with ingestible sensors worldwide; accordingly, to identify the patenting leaders as well as the main prevailing areas of therapy for patent protection, and the future perspectives in the field. In July 2022, a search was conducted using Internet databases, such as the EPO, USPTO, FDA and the Lens database. The patent landscape analysis shows an increase in the number of patents related to digital pills with ingestible sensors for mobile clinical monitoring, smart drug delivery, and endoscopy diagnostics. The leaders in the number of patents issued are the United States, the European Patent Office, Canada, Australia, and China. The following main areas of patenting digital pills with ingestible sensors were identified: treatment in the field of mental health; HIV/AIDS; pain control; cardiovascular diseases; diabetes; gastroenterology (including hepatitis C); oncology; tuberculosis; and transplantology. The development of scientific and practical approaches towards the implementation of effective and safe digital pills will improve treatment outcomes, increase compliance, reduce hospital stays, provide mobile clinical monitoring, have a positive impact on treatment costs and will contribute to increased patient safety. Full article

(This article belongs to the Special Issue Feature Reviews in Pharmaceutical Technology)

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21 pages, 1475 KiB

Open AccessReview

Heart Failure with Preserved Ejection Fraction and Pulmonary Hypertension: Focus on Phosphodiesterase Inhibitors

by Artem Ovchinnikov, Alexandra Potekhina, Evgeny Belyavskiy and Fail Ageev

Pharmaceuticals 2022, 15(8), 1024; https://doi.org/10.3390/ph15081024 - 19 Aug 2022

Cited by 5 | Viewed by 3458

Abstract

Pulmonary hypertension (PH) is common in patients with heart failure with preserved ejection fraction (HFpEF). A chronic increase in mean left atrial pressure leads to passive remodeling in pulmonary veins and capillaries and modest PH (isolated postcapillary PH, Ipc-PH) and is not associated [...] Read more.

Pulmonary hypertension (PH) is common in patients with heart failure with preserved ejection fraction (HFpEF). A chronic increase in mean left atrial pressure leads to passive remodeling in pulmonary veins and capillaries and modest PH (isolated postcapillary PH, Ipc-PH) and is not associated with significant right ventricular dysfunction. In approximately 20% of patients with HFpEF, “precapillary” alterations of pulmonary vasculature occur with the development of the combined pre- and post-capillary PH (Cpc-PH), pertaining to a poor prognosis. Current data indicate that pulmonary vasculopathy may be at least partially reversible and thus serves as a therapeutic target in HFpEF. Pulmonary vascular targeted therapies, including phosphodiesterase (PDE) inhibitors, may have a valuable role in the management of patients with PH-HFpEF. In studies of Cpc-PH and HFpEF, PDE type 5 inhibitors were effective in long-term follow-up, decreasing pulmonary artery pressure and improving RV contractility, whereas studies of Ipc-PH did not show any benefit. Randomized trials are essential to elucidate the actual value of PDE inhibition in selected patients with PH-HFpEF, especially in those with invasively confirmed Cpc-PH who are most likely to benefit from such treatment. Full article

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

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Figure 1

Figure 1
Stages of pulmonary hypertension in HFpEF. A chronic increase in mean left atrial (LA) pressure causes an increase in pulmonary artery (PA) pressure (pulmonary hypertension, PH), leading to passive remodeling in pulmonary venule and capillaries and isolated postcapillary PH (Ipc-PH). In approximately 20% of patients with HFpEF, the reactive “precapillary” alterations of pulmonary vasculature occur with the development of the combined pre- and post-capillary PH (Cpc-PH). Ipc-PH is associated with a decrease in pulmonary arterial capacitance (PAC) and mild adaptive changes of the right ventricle (RV). On the other hand, Cpc-PH leads to an increase in pulmonary vascular resistance (PVR), PA-RV uncoupling, and is associated with a marked maladaptive RV remodeling with RV systolic dysfunction and dilation, tricuspid regurgitation, and increase in central venous pressure (CVP). Increased CVP results in a reduction of sodium (Na+) excretion and fluid retention, and a further increase in LA pressure. With RV dilatation and CVP increase, shifting of the interventricular septum (IVS) to the left occurs, resulting in an impaired left ventricular filling. DPG indicates diastolic pulmonary gradient; mPAP, mean pulmonary artery pressure; PA, pulmonary artery, PCWP, pulmonary capillary wedge pressure; TPG, transpulmonary pressure gradient. Full article ">Figure 2
Cyclic nucleotide signaling in cardiomyocyte. Nitric oxide and natriuretic peptide receptor (NPR) activate soluble (sGC) and particulate guanylate cyclases (pGC), respectively, resulting in production of cyclic guanosine monophosphate (cGMP) and activation of protein kinase G (PKG). PKG phosphorylates numerous targets within myocyte. PKG-mediated phosphorylation (P) of phospholamban (PLB) activates sarcoplasmic–endoplasmic reticulum calcium ions (Ca2+)-ATPase pump (SERCA) and increases Ca2+ uptake into sarcoplasmic reticulum (SR); phosphorylation of troponin I (Tn I) reduces myofilament Ca2+ sensitivity increasing lusitropy. PKG-mediated phosphorylation of titin reduces cardiomyocyte stiffness, whereas PKG-mediated phosphorylation of L-type channels decreases Ca2+ influx, possessing a negative inotropic effect. Activation of β1-adrenergic receptors by epinephrine activates adenylate cyclase (AC), increasing the level of cyclic adenosine monophosphate (cAMP), which activates protein kinase A (PKA). High PKA activity leads to a positive inotropic effect due to phosphorylation of the L-type Ca2+ channel and the ryanodine receptor (not shown), increasing the systolic Ca2+ influx. PKA activation also possesses lusitropic effects through phosphorylation of the same targets as PKG-Tn I and PLB. PKA signaling mediates cardiac hypertrophy by increasing Ca2+ and calcineurin activation, as well as by increasing transcription. High cGMP and PKG levels promote negative inotropic effects and counteract PKA-mediated cardiac prohypertrophic signaling. cGMP also affects cAMP levels by inversely modulating PDE3. Phosphodiesterase cleaves cGMP, and PDE5 and PDE9 inhibitors increase cGMP levels. PDE5 primarily cleaves cGMP from the nitric oxide-rGC axis, while PDE9 cleaves cGMP from the natriuretic peptide-rGC axis. ATP indicates adenosine triphosphate; GTP, guanosine triphosphate; Tm, tropomyosin. Full article ">

25 pages, 3286 KiB

Open AccessReview

Chitosan-Based Scaffolds for Facilitated Endogenous Bone Re-Generation

by Yao Zhao, Sinuo Zhao, Zhengxin Ma, Chunmei Ding, Jingdi Chen and Jianshu Li

Pharmaceuticals 2022, 15(8), 1023; https://doi.org/10.3390/ph15081023 - 19 Aug 2022

Cited by 18 | Viewed by 3491

Abstract

Facilitated endogenous tissue engineering, as a facile and effective strategy, is emerging for use in bone tissue regeneration. However, the development of bioactive scaffolds with excellent osteo-inductivity to recruit endogenous stem cells homing and differentiation towards lesion areas remains an urgent problem. Chitosan [...] Read more.

Facilitated endogenous tissue engineering, as a facile and effective strategy, is emerging for use in bone tissue regeneration. However, the development of bioactive scaffolds with excellent osteo-inductivity to recruit endogenous stem cells homing and differentiation towards lesion areas remains an urgent problem. Chitosan (CS), with versatile qualities including good biocompatibility, biodegradability, and tunable physicochemical and biological properties is undergoing vigorously development in the field of bone repair. Based on this, the review focus on recent advances in chitosan-based scaffolds for facilitated endogenous bone regeneration. Initially, we introduced and compared the facilitated endogenous tissue engineering with traditional tissue engineering. Subsequently, the various CS-based bone repair scaffolds and their fabrication methods were briefly explored. Furthermore, the functional design of CS-based scaffolds in bone endogenous regeneration including biomolecular loading, inorganic nanomaterials hybridization, and physical stimulation was highlighted and discussed. Finally, the major challenges and further research directions of CS-based scaffolds were also elaborated. We hope that this review will provide valuable reference for further bone repair research in the future. Full article

(This article belongs to the Special Issue Polysaccharide-Based Nanoparticles for Theranostic Nanomedicine)

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Multifunctional design of chitosan-based scaffolds and the application in facilitating endogenous bone regeneration. Full article ">Figure 2
Comparison of two bone repair strategies. Traditional bone tissue engineering (BTE) needs tissue harvest, cell isolation and co-culture with a scaffold ex vivo, while facilitated endogenous bone tissue engineering (FEBTE) avoids these tedious and risky procedures by using a bioactive scaffold. Full article ">Figure 3
CS is extracted from crustacean shells and applied to the design of bone repair scaffolds through various functionalization strategies. Full article ">Figure 4
The preparation process of icariin-loaded HAP/CMCS/PLGA scaffolds and the application for cranial defects repair Reprinted with permission from ref. [<a href="#B123-pharmaceuticals-15-01023" class="html-bibr">123</a>]. Copyright 2020 Chem. Eng. J. Full article ">Figure 5
Biomineralization-inspired methods for the preparation of chitosan-based hybrid scaffolds. Full article ">Figure 6
The GO/CS/HAP scaffold prepared by in situ mineralization strategy is used for endogenous bone regeneration. Reprinted with permission from ref. [<a href="#B16-pharmaceuticals-15-01023" class="html-bibr">16</a>]. Copyright 2020 Chem. Eng. J. Full article ">Figure 7
The photothermally controlled HAP/GO/CS scaffold for clinical treatment of osteosarcoma and tissue regeneration. Reprinted with permission from ref. [<a href="#B191-pharmaceuticals-15-01023" class="html-bibr">191</a>]. Copyright 2020 Mater. Today. Full article ">

15 pages, 1869 KiB

Open AccessReview

Treatment Options for Troublesome Itch

by Sumika Toyama, Mitsutoshi Tominaga and Kenji Takamori

Pharmaceuticals 2022, 15(8), 1022; https://doi.org/10.3390/ph15081022 - 19 Aug 2022

Cited by 6 | Viewed by 3831

Abstract

Itch (or pruritus) is an unpleasant sensation, inducing the desire to scratch. It is also a major and distressing symptom of many skin and systemic diseases. The involvement of histamine, which is a major itch mediator, has been extensively examined. Recent studies suggest [...] Read more.

Itch (or pruritus) is an unpleasant sensation, inducing the desire to scratch. It is also a major and distressing symptom of many skin and systemic diseases. The involvement of histamine, which is a major itch mediator, has been extensively examined. Recent studies suggest that histamine-independent pathways may play roles in chronic itch. Therefore, antihistamines are not always effective in the treatment of patients with chronic itch. The development of biologics and κ-opioid receptor (KOR) agonists has contributed to advances in the treatment of itch; however, since biologics are expensive for patients to purchase, some patients may limit or discontinue their use of these agents. Furthermore, KOR agonists need to be prescribed with caution due to risks of side effects in the central nervous system. Janus kinase (JAK) inhibitors are sometimes associated with side effects, such as infection. In this review, we summarize antidepressants, antineuralgics, cyclosporine A, antibiotics, crotamiton, phosphodiesterase 4 inhibitor, botulinum toxin type A, herbal medicines, phototherapy, and acupuncture therapy as itch treatment options other than antihistamines, biologics, opioids, and JAK inhibitors; we also explain their underlying mechanisms of action. 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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Antipruritic mechanism of NTP for intractable itch in AD. NTP inhibits SP release from nerve endings, which presumably suppresses neurogenic inflammation caused by nerve-SP-mast cells. In addition, NTP inhibits the elongation of IENFs and reduces itch hypersensitivity. Full article ">Figure 2
Antipruritic mechanism of CsA for intractable itch in AD. CsA down-regulates expressions of IL-31RA and NK1R in peripheral nerves. CsA also inhibits the infiltration of immune cells, such as CD4+ T cells, mast cells, and eosinophils. In addition, CsA reduces the perception of itch stimuli by suppressing the proliferation of IENFs. Full article ">Figure 3
Antipruritic mechanism of minocycline in AD. The number of microglia is increased in the dorsal horn of the spinal cord of mice with AD. The administration of minocycline decreases the number of microglia in the spinal dorsal horn and suppresses itch and dermatitis. Full article ">Figure 4
Antipruritic mechanism of phototherapy. In dry skin, the up-regulated expression of NGF and down-regulated expression of Sema3A increase the number of IENFs. When various types of phototherapy are used for dry skin, they inhibit IENF hyperplasia in the order of PUVA therapy < NB-UVB < excimer lamps. The inhibitory effects of PUVA and NB-UVB therapy on IENF proliferation are due to the down-regulated expression of nerve elongation factors and up-regulated expression of nerve repulsion factors in keratinocytes; however, excimer lamps act directly on IENFs and induce neurodegeneration without altering the expression of these axon guidance molecules. Full article ">

24 pages, 2618 KiB

Open AccessArticle

A Versatile Class of 1,4,4-Trisubstituted Piperidines Block Coronavirus Replication In Vitro

by Sonia De Castro, Annelies Stevaert, Miguel Maldonado, Adrien Delpal, Julie Vandeput, Benjamin Van Loy, Cecilia Eydoux, Jean-Claude Guillemot, Etienne Decroly, Federico Gago, Bruno Canard, Maria-Jose Camarasa, Sonsoles Velázquez and Lieve Naesens

Pharmaceuticals 2022, 15(8), 1021; https://doi.org/10.3390/ph15081021 - 18 Aug 2022

Cited by 3 | Viewed by 2666

Abstract

There is a clear need for novel antiviral concepts to control SARS-CoV-2 infection. Based on the promising anti-coronavirus activity observed for a class of 1,4,4-trisubstituted piperidines, we here conducted a detailed analysis of the structure–activity relationship of these structurally unique inhibitors. Despite the [...] Read more.

There is a clear need for novel antiviral concepts to control SARS-CoV-2 infection. Based on the promising anti-coronavirus activity observed for a class of 1,4,4-trisubstituted piperidines, we here conducted a detailed analysis of the structure–activity relationship of these structurally unique inhibitors. Despite the presence of five points of diversity, the synthesis of an extensive series of analogues was readily achieved by Ugi four-component reaction from commercially available reagents. After evaluating 63 analogues against human coronavirus 229E, four of the best molecules were selected and shown to have micromolar activity against SARS-CoV-2. Since the action point was situated post virus entry and lying at the stage of viral polyprotein processing and the start of RNA synthesis, enzymatic assays were performed with CoV proteins involved in these processes. While no inhibition was observed for SARS-CoV-2 nsp12-nsp7-nsp8 polymerase, nsp14 N7-methyltransferase and nsp16/nsp10 2’-O-methyltransferase, nor the nsp3 papain-like protease, the compounds clearly inhibited the nsp5 main protease (M^pro). Although the inhibitory activity was quite modest, the plausibility of binding to the catalytic site of M^pro was established by in silico studies. Therefore, the 1,4,4-trisubstituted piperidines appear to represent a novel class of non-covalent CoV M^pro inhibitors that warrants further optimization and development. Full article

(This article belongs to the Special Issue Antiviral Drugs 2021)

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(A) chemical structure of compounds 1 and 2, the two N-benzyl 4,4-disubstituted piperidines which we previously identified as inhibitors of influenza virus membrane fusion [<a href="#B10-pharmaceuticals-15-01021" class="html-bibr">10</a>]. (B) general structure (I) of the library of 1,4,4-trisubstituted piperidine compounds that we synthesized in the present work to explore the SAR for anti-CoV activity. Full article ">Figure 2
Inhibition of SARS-CoV-2 replication in A549-AT cells. (A) reduction in viral load in the supernatant at day 3 p.i. (B) compound cytotoxicity based on MTS cell viability assay in mock-infected cells. Data points are the mean ± SEM (N = 3). Reference compound: GS-441524, the nucleoside form of remdesivir. Full article ">Figure 3
One-cycle TOA experiment in HCoV-229E-infected HEL cells. Compounds and concentrations: 1,4,4-trisubstituted piperidine analogue 33 at 15 µM; inhibitors of virus entry: E64d (15 µM) and bafilomycin (0.00625 µM); Mpro inhibitor GC376 (25 µM); and inhibitors of viral RNA synthesis: GS-441524 (20 µM) and K22 (15 µM). Data points are the mean ± SEM (N = 3 for 33 and N = 2 for the reference compounds). The cells were exposed to the compounds at the indicated time points, infected at time point zero, and lysed at 16 h p.i. The Y-axis shows the number of intracellular viral RNA copies, determined by RT-qPCR and expressed relative to the value in the virus control (=set at 100%; dashed grey line). Full article ">Figure 4
Ribbon representation of chymotrypsin-like protease Mpro from SARS-CoV-2. (A) Overlay of 30 snapshots taken at regular intervals from the unrestrained molecular dynamics simulation in water lasting 150 ns. Each monomer is displayed in a different color and the 187Asp-Ala193 stretch is highlighted in yellow. (B) Alignment of active site amino acids from HCoV-229E, SARS-CoV and SARS-CoV-2 Mpro enzymes that are proposed to have a direct bearing on ligand binding, as discussed in the text. (C–E) Theoretical models of one monomer of SARS-CoV-2 Mpro (ribbon with C atoms colored in pink) in complex with compound 34 (C), 45 (D) and 52 (E); the region displayed corresponds to the boxed area in (A). Ligands are shown as sticks with carbon atoms colored in green. Each set of five superposed structures represents a conformational ensemble made up of snapshots taken every 5 ns from the post-equilibrated 75–100 ns interval of the simulated trajectories and then cooled down to 273 K and energy minimized. For reference, some of the residues closest to the ligands have been labeled. Water molecules are not displayed for enhanced clarity. Full article ">Figure 5
Current insights related to the SAR based on evaluation of compounds 1–63 against HCoV-229E. Full article ">Scheme 1
Synthesis of the novel piperidine analogues of general structure I, based on Ugi-4CR reaction. Full article ">

9 pages, 3489 KiB

Open AccessCommunication

Therapeutic Effect of Benidipine on Medication-Related Osteonecrosis of the Jaw

by Ken Matsunaka, Mikio Imai, Koma Sanda, Noriyuki Yasunami, Akihiro Furuhashi, Ikiru Atsuta, Hiroko Wada and Yasunori Ayukawa

Pharmaceuticals 2022, 15(8), 1020; https://doi.org/10.3390/ph15081020 - 18 Aug 2022

Cited by 2 | Viewed by 2218

Abstract

Medication-related osteonecrosis of the jaw (MRONJ) is an intractable disease that is typically observed in patients with osteoporosis or tumors that have been treated with either bisphosphonate (BP) or antiangiogenic medicine. The mechanism of MRONJ pathogenesis remains unclear, and no effective definitive treatment [...] Read more.

Medication-related osteonecrosis of the jaw (MRONJ) is an intractable disease that is typically observed in patients with osteoporosis or tumors that have been treated with either bisphosphonate (BP) or antiangiogenic medicine. The mechanism of MRONJ pathogenesis remains unclear, and no effective definitive treatment modalities have been reported to date. Previous reports have indicated that a single injection of benidipine, an antihypertensive calcium channel blocker, in the vicinity of a tooth extraction socket promotes wound healing in healthy rats. The present study was conducted to elucidate the possibility of using benidipine to promote the healing of MRONJ-like lesions. In this study, benidipine was administered near the site of MRONJ symptom onset in a model rat, which was then sacrificed two weeks after benidipine injection, and analyzed using histological sections and CT images. The analysis showed that in the benidipine groups, necrotic bone was reduced, and soft tissue continuity was recovered. Furthermore, the distance between epithelial edges, length of necrotic bone exposed in the oral cavity, necrotic bone area, and necrotic bone ratio were significantly smaller in the benidipine group. These results suggest that a single injection of benidipine in the vicinity of MRONJ-like lesions can promote osteonecrotic extraction socket healing. Full article

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

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Graphical abstract

Graphical abstract
Full article ">Figure 1
Intraoral and histological findings four weeks after extraction of the upper right first molar. (A). In the MRONJ group, epithelial continuity is disrupted, and necrotic bone characterized by vacant osteocytic lacunae (black arrowheads) is exposed at the coronal region (green square). At the periapical legion, both necrotic bone (the area circled by dotted lines) and vital bone with living osteocytes (white arrowheads) are observed (black square). (B). In the BD-L group, epithelial continuity is restored, and new bone formation is observed. Although small amount of necrotic bone (the area circled by dotted lines) characterized by vacant osteocytic lacunae (black arrowheads) is observed in the coronal region, to a great extent extraction socket is occupied by vital bone with living osteocytes (white arrowheads). (C). In the BD-H group, epithelial continuity is restored, and new bone formation is observed. Vital bone with living osteocytes is observed even at the coronal region of the extraction socket. Full article ">Figure 1 Cont.
Intraoral and histological findings four weeks after extraction of the upper right first molar. (A). In the MRONJ group, epithelial continuity is disrupted, and necrotic bone characterized by vacant osteocytic lacunae (black arrowheads) is exposed at the coronal region (green square). At the periapical legion, both necrotic bone (the area circled by dotted lines) and vital bone with living osteocytes (white arrowheads) are observed (black square). (B). In the BD-L group, epithelial continuity is restored, and new bone formation is observed. Although small amount of necrotic bone (the area circled by dotted lines) characterized by vacant osteocytic lacunae (black arrowheads) is observed in the coronal region, to a great extent extraction socket is occupied by vital bone with living osteocytes (white arrowheads). (C). In the BD-H group, epithelial continuity is restored, and new bone formation is observed. Vital bone with living osteocytes is observed even at the coronal region of the extraction socket. Full article ">Figure 2
μCT findings in the center of the extraction sockets. More new bone formation is observed in the BD-administered group than the MRONJ group. Full article ">Figure 3
Five variables for evaluating the therapeutic effect of BD on MRONJ-like lesions. In the MRONJ, low, and high groups, the (A) BV/TV, (B) distance between the epithelial edges, (C) length of necrotic bone exposed toward the oral cavity, (D) necrotic bone area, and (E) necrotic bone ratio are measured, and statistical analyses are performed (Tukey’s test; **: p < 0.01). Full article ">Figure 4
Experiment timeline. Full article ">

23 pages, 1250 KiB

Open AccessReview

Potential Pharmaceutical Applications of Quercetin in Cardiovascular Diseases

by Paraskevi Papakyriakopoulou, Nikolaos Velidakis, Elina Khattab, Georgia Valsami, Ioannis Korakianitis and Nikolaos PE Kadoglou

Pharmaceuticals 2022, 15(8), 1019; https://doi.org/10.3390/ph15081019 - 18 Aug 2022

Cited by 49 | Viewed by 6375

Abstract

Quercetin, as a member of flavonoids, has emerged as a potential therapeutic agent in cardiovascular diseases (CVDs) in recent decades. In this comprehensive literature review, our goal was a critical appraisal of the pathophysiological mechanisms of quercetin in relation to the classical cardiovascular [...] Read more.

Quercetin, as a member of flavonoids, has emerged as a potential therapeutic agent in cardiovascular diseases (CVDs) in recent decades. In this comprehensive literature review, our goal was a critical appraisal of the pathophysiological mechanisms of quercetin in relation to the classical cardiovascular risk factors (e.g., hyperlipidemia), atherosclerosis, etc. We also assessed experimental and clinical data about its potential application in CVDs. Experimental studies including both in vitro methods and in vivo animal models mainly outline the following effects of quercetin: (1) antihypertensive, (2) hypolipidemic, (3) hypoglycemic, (4) anti-atherosclerotic, and (5) cardioprotective (suppressed cardiotoxicity). From the clinical point of view, there are human studies and meta-analyses implicating its beneficial effects on glycemic and lipid parameters. In contrast, other human studies failed to demonstrate consistent favorable effects of quercetin on other cardiometabolic risk factors such as MS, obesity, and hypertension, underlying the need for further investigation. Analyzing the reason of this inconsistency, we identified significant drawbacks in the clinical trials’ design, while the absence of pharmacokinetic/pharmacodynamic tests prior to the studies attenuated the power of clinical results. Therefore, additional well-designed preclinical and clinical studies are required to examine the therapeutic mechanisms and clinical efficacy of quercetin in CVDs. Full article

(This article belongs to the Special Issue Drug Candidates for the Prevention and Treatment of Cardiovascular Diseases)

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12 pages, 1744 KiB

Open AccessArticle

Neuroprotective Effects of an Edible Pigment Brilliant Blue FCF against Behavioral Abnormity in MCAO Rats

by Jingyang Le, Xiao Xiao, Difan Zhang, Yi Feng, Zhuoying Wu, Yuechun Mao, Chenye Mou, Yanfei Xie, Xiaowei Chen, Hao Liu and Wei Cui

Pharmaceuticals 2022, 15(8), 1018; https://doi.org/10.3390/ph15081018 - 18 Aug 2022

Cited by 1 | Viewed by 3002

Abstract

Ischemic stroke leads to hypoxia-induced neuronal death and behavioral abnormity, and is a major cause of death in the modern society. However, the treatments of this disease are limited. Brilliant Blue FCF (BBF) is an edible pigment used in the food industry that [...] Read more.

Ischemic stroke leads to hypoxia-induced neuronal death and behavioral abnormity, and is a major cause of death in the modern society. However, the treatments of this disease are limited. Brilliant Blue FCF (BBF) is an edible pigment used in the food industry that with multiple aromatic rings and sulfonic acid groups in its structure. BBF and its derivatives were proved to cross the blood-brain barrier and have advantages on the therapy of neuropsychiatric diseases. In this study, BBF, but not its derivatives, significantly ameliorated chemical hypoxia-induced cell death in HT22 hippocampal neuronal cell line. Moreover, protective effects of BBF were attributed to the inhibition of the extracellular regulated protein kinase (ERK) and glycogen synthase kinase-3β (GSK3β) pathways as evidenced by Western blotting analysis and specific inhibitors. Furthermore, BBF significantly reduced neurological and behavioral abnormity, and decreased brain infarct volume and cerebral edema induced by middle cerebral artery occlusion/reperfusion (MCAO) in rats. MCAO-induced increase of p-ERK in ischemic penumbra was reduced by BBF in rats. These results suggested that BBF prevented chemical hypoxia-induced otoxicity and MCAO-induced behavioral abnormity via the inhibition of the ERK and GSK3β pathways, indicating the potential use of BBF for treating ischemic stroke Full article

(This article belongs to the Special Issue Natural Products for Potential Use of Neuroprotective and Neurorestorative Effects in Stroke)

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Figure 1
BBF but not its derivatives prevent chemical hypoxia-induced cell death in HT22 hippocampal cell line. (A) HT22 cells were exposed to various concentrations of IAA as indicated. Cell viability was measured by the MTT assay at 24 h after IAA exposure. (B) HT22 cells were pre-treated with BBF, BBR, BBG, or FGF at the indicated concentrations for 0.5 h, and then exposed to 10 μM IAA. Cell viability was measured by the MTT assay at 24 h after IAA exposure. (C–E) HT22 cells were pre-treated with BBF for 0.5 h, then exposed to 10 μM IAA. (C) The LDH release and (D) FDA/PI double staining was performed at 24 h after IAA exposure. (E) The percentage of FDA-positive cells was analyzed from representative photos. (F) HT22 cells was analyzed by flow cytometry at 24 h after IAA exposure, and the percentage of cells with live (Q4), early apoptosis (Q3), late apoptosis (Q2), and necrosis (Q1) conditions were pointed. Data represent the mean ± SEM; * p < 0.05 and ** p < 0.01 vs. the control group in (A); ## p < 0.01 vs. the control group; * p < 0.05 and ** p < 0.01 vs. IAA group in (B,C) and (E), (one-way ANOVA and Tukey’s test). Con: control; BBF: Brilliant Blue FCF; BBR: Brilliant Blue R; BBG: Brilliant Blue G; FGF: Fast Green FCF; IAA: Iodoacetic acid; LDH: Lactate dehydrogenase; FDA, Fluorescein diacetate; PI, Propidium iodide. Full article ">Figure 2
BBF produces anti-chemical hypoxia protective effects via the inhibition of ERK and GSK3β concurrently in HT22 cells. (A–C) HT22 cells were pre-treated with 10 and 20 μM BBF or vehicle control for 0.5 h, and then exposed to 10 μM IAA. Western blotting analysis was performed at 0.5 h after IAA exposure. (A) The representative blots were shown. The relative units of (B) p-ERK and (C) pSer9-GSK3β were demonstrated. (D) HT22 cells were pre-treated with SB415286, an inhibitor of GSK3β, or U0126, an inhibitor of MEK, at the indicated concentrations for 0.5 h, and then exposed to 10 μM IAA. Cell viability was measured by the MTT assay 24 h after IAA challenge. (E) HT22 cells were pre-treated with 10 μM LY294002 for 0.5 h, and then supplemented with 10 μM BBF for 0.5 h before the exposure to 10 μM IAA. Cell viability was then measured by the MTT assay at 24 h after IAA challenge. Data represent the mean ± SEM; ## p < 0.01 vs. the control group, * p < 0.05 and ** p < 0.01 vs. IAA group, $ p < 0.05 vs. BBF + IAA group (one-way ANOVA and Tukey’s test). ERK: extracellular regulated protein kinase; GSK3β: glycogen synthase kinase-3β; Con: control; BBF: Brilliant Blue FCF; IAA: Iodoacetic acid; LY: LY294002; SB: SB415286. Full article ">Figure 3
BBF prevents neurological and behavioral abnormity, brain infarct and ERK activation in MCAO rats. (A–C) Rats were injected with various drugs as indicated 30 min before, during and 30 min after MCAO surgery. The neurological and behavioral tests were measured 24 h after MCAO. (A) Neurological scores, (B) De Ryck’s behavioral scores, and (C) beam working scores were demonstrated. (D–F) Animals were sacrificed at 24 h after MCAO surgery. (D) The representative TTC staining images were demonstrated. Quantitative analysis for (E) infarct volume and (F) edema extent of each group was shown. (G) The representative blots were shown. (H) The relative units of p-ERK were demonstrated. Data represent the mean ± SEM (n = 6 in (A–F) and n = 3 in (H)); ## p < 0.01 vs. the Sham group, * p < 0.05 and ** p < 0.01 vs. MCAO group (one-way ANOVA and Tukey’s test). MCAO: middle cerebral artery occlusion/reperfusion; ERK: extracellular regulated protein kinase; TTC: 2,3,5-triphenyltetrazolium chloride; BBF: Brilliant Blue FCF. Full article ">Figure 4
BBF prevents neuronal death and behavioral abnormity caused by chemical hypoxia and ischemic stroke. Chemical hypoxia and ischemic stroke activate P2X7 receptor, leading to activation of the GSK3β and ERK pathways, causing neuronal death and behavioral abnormity. BBF might produce neuroprotective effects via acting on ERK and GSK3β, possibly through the inhibition of P2X7 receptor. ERK: extracellular regulated protein kinase; GSK3β: glycogen synthase kinase-3β; BBF: Brilliant Blue FCF. Full article ">

15 pages, 1771 KiB

Open AccessArticle

mRNA-Loaded Lipid Nanoparticles Targeting Immune Cells in the Spleen for Use as Cancer Vaccines

by Ryoya Shimosakai, Ikramy A. Khalil, Seigo Kimura and Hideyoshi Harashima

Pharmaceuticals 2022, 15(8), 1017; https://doi.org/10.3390/ph15081017 - 18 Aug 2022

Cited by 27 | Viewed by 5391

Abstract

mRNA delivery has recently gained substantial interest for possible use in vaccines. Recently approved mRNA vaccines are administered intramuscularly where they transfect antigen-presenting cells (APCs) near the site of administration, resulting in an immune response. The spleen contains high numbers of APCs, which [...] Read more.

mRNA delivery has recently gained substantial interest for possible use in vaccines. Recently approved mRNA vaccines are administered intramuscularly where they transfect antigen-presenting cells (APCs) near the site of administration, resulting in an immune response. The spleen contains high numbers of APCs, which are located near B and T lymphocytes. Therefore, transfecting APCs in the spleen would be expected to produce a more efficient immune response, but this is a challenging task due to the different biological barriers. Success requires the development of an efficient system that can transfect different immune cells in the spleen. In this study, we report on the development of mRNA-loaded lipid nanoparticles (LNPs) targeting immune cells in the spleen with the goal of eliciting an efficient immune response against the antigen encoded in the mRNA. The developed system is composed of mRNA loaded in LNPs whose lipid composition was optimized for maximum transfection into spleen cells. Dendritic cells, macrophages and B cells in the spleen were efficiently transfected. The optimized LNPs produced efficient dose-dependent cytotoxic T lymphocyte activities that were significantly higher than that produced after local administration. The optimized LNPs encapsulating tumor-antigen encoding mRNA showed both prophylactic and therapeutic antitumor effects in mice. Full article

(This article belongs to the Special Issue Challenges and Opportunities in Developing Therapeutic Nucleic Acid Cargo and Delivery)

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Luciferase activity in vivo. (A) Luciferase activity of DODAP-LNP prepared with or without DOPE. The LNP that was injected contained 0.1 mRNA mg/kg and luciferase activity was measured 24 h after injection. Luciferase activity is expressed as relative light unit (RLU) per mg of total protein (** p < 0.01, NS: not significant, two-tailed unpaired t test). (B–D) Optimization of the lipid composition in vivo. (B) The ratio of DODAP and cholesterol (DOPE and DMG-PEG were fixed at 50 and 1.5 mol% of total lipid, respectively. (C) The ratio of DOPE and DODAP (Chol and DMG-PEG were fixed at 10 and 1.5 mo% of total lipid, respectively). (D) The ratio of the amount of total lipid to 10 µg mRNA. (E) The luciferase activity measured 24 h after injection of 0.1 and 0.8 mg/kg. (F) The luciferase activity 24 h after injection of DODAP-LNP and RNA-LPX loading Nluc-IRES-RFP mRNA (** p < 0.01, * p < 0.05, NS: not significant, two-tailed unpaired Student’s t-test). Each bar represents the mean +/− SD of at least 3 different experiments). Full article ">Figure 2
The cellular uptake and gene expression in splenocytes. Different LNPs were prepared by the ethanol dilution method and labeled with 1 mol% DiD. Splenocytes were isolated at 24 h after the injection of 400 µL LNPs. (A) DiD positive cells (%) in each cell type, *** p < 0.001, Tukey-Kramer test. (B) Geo-mean fluorescence intensity in each cell type, *** p < 0.001, ** p < 0.01, Tukey-Kramer test. (C) Luciferase activity per 3000 cells, * p < 0.05, ** p < 0.01, NS: not significant, Student t test. Full article ">Figure 3
Prophylactic anti-tumor effect. C57BL/6J mice were treated with PBS, naked OVA-encoding mRNA (naked OVA-mRNA), LNP encapsulating luciferase-encoding pDNA (Luc-pDNA LNP), and LNP encapsulating OVA-encoding mRNA (OVA-mRNA LNP) at 7 days before tumor inoculation. The mice were inoculated with E.G7-OVA cells and tumor volume was monitored. The plots represent the mean +/− SEM (total of 5 mice/group, * p < 0.05, Tukey-Kramer test). Full article ">Figure 4
CTL analysis after administration of different doses of mRNA formulations using different routes of administration. (A) OVA-specific CTL activity measured after treatment with different doses of OVA-mRNA LNP. LNP encapsulating luciferase gene (Fluc-LNP) or naked OVA mRNA were used as controls at a dose of 0.8 mg/kg (*** p < 0.001, ** p < 0.01, vs. PBS, Fluc-mRNA LNP and naked OVA-mRNA, Tukey-Kramer). (B) Comparison of OVA-specific CTL activity between OVA-mRNA LNP and RNA-LPX using different dose. (C) Comparison of OVA-specific CTL activity between IV and IM injection of OVA-mRNA LNP and RNA-LPX. The administered dose was 0.075 mg/kg. Full article ">Figure 5
Therapeutic anti-tumor effect. C57BL/6J mice were inoculated with E.G7-OVA cells. The mice were treated with different solutions at 8, 11, and 14 days after tumor inoculation and tumor volume was monitored. Mice groups were treated with PBS, naked OVA-encoding mRNA (naked OVA-mRNA), LNP encapsulating luciferase-encoding mRNA (Luc-mRNA LNP), LNP encapsulating OVA-encoding mRNA (OVA-mRNA LNP), and RNA-LPX loading OVA-encoding mRNA (RNA-LPX). The plots represent the mean +/− SEM (total of 5 mice/group, NS: not significant, Tukey-Kramer test). Full article ">

22 pages, 2786 KiB

Open AccessArticle

TLC–Densitometry for Determination of Omeprazole in Simple and Combined Pharmaceutical Preparations

by Wioletta Parys and Alina Pyka-Pająk

Pharmaceuticals 2022, 15(8), 1016; https://doi.org/10.3390/ph15081016 - 18 Aug 2022

Cited by 5 | Viewed by 2857

Abstract

TLC combined with densitometry was used and chromatographic conditions developed to separate omeprazole and diclofenac sodium from their potential impurities. The development of the TLC–densitometry method is based on the elaboration of new chromatographic conditions allowing for the simultaneous determination of omeprazole and [...] Read more.

TLC combined with densitometry was used and chromatographic conditions developed to separate omeprazole and diclofenac sodium from their potential impurities. The development of the TLC–densitometry method is based on the elaboration of new chromatographic conditions allowing for the simultaneous determination of omeprazole and diclofenac sodium in a pharmaceutical preparation. Identification and quantification of omeprazole in simple and combined (with diclofenac) pharmaceutical preparations was performed on silica gel 60F₂₅₄ using one mobile phase: chloroform–methanol–ammonia (36:4:0.60, v/v). Diclofenac sodium was determined in the presence of omeprazole after 2D separation on silica gel using two mobile phases of the first phase of chloroform–methanol–ammonia (36:4:0.60, v/v) and the second mobile phase cyclohexane–chloroform–methanol–glacial acetic acid (6:3:0.5:0.5 v/v). The developed method is simple, economical, specific, precise, accurate, sensitive, and robust, with a good range of linearity for the quantification of omeprazole and diclofenac sodium. TLC in combination with densitometry can be used as an effective analytical tool for quality control and quantitative determination of omeprazole in simple and combined pharmaceutical preparations containing diclofenac sodium. TLC in combination with densitometry can be recommended for the analysis of omeprazole and diclofenac sodium in the absence of HPLC or spectrophotometer in the laboratory or to confirm results obtained with other analytical techniques. Full article

(This article belongs to the Section Pharmaceutical Technology)

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Structural formula of omeprazole. Full article ">Figure 2
Structural formula of diclofenac sodium. Full article ">Figure 3
Densitogram of omeprazole (4 µg) in an acidic solution, which after heating was separated on silica gel using a mobile phase chloroform–methanol–ammonia (36:4:0.60, v/v/v); where: O-omeprazole, A-omeprazole related compound A and P-unidentified omeprazole degradation products. Full article ">Figure 4
Densitogram of omeprazole (0.90 µg) from the extract of Biprazol Bio Max, which was analyzed on silica gel using a mobile phase: chloroform–methanol–ammonia (36:4:0.60, v/v/v). Full article ">Figure 5
Densitogram of DicloDuo Combi extract, which was separated on silica gel using a mobile phase: chloroform–methanol–ammonia (36:4:0.60, v/v/v); where: D-diclofenac sodium (3.38 µg), O-omeprazole (0.90 µg). Full article ">Figure 6
Comparison of the spectrodensitograms of omeprazole standard and omeprazole extracted from simple preparations (Omeprazole Genoptim SPH and Biprazol Bio Max). Full article ">Figure 7
Densitogram of diclofenac sodium (14 µg) after two-dimensional (2-D) separation by TLC using two mobile phases, the first: chloroform–methanol–ammonia (36:4:0.60, v/v/v) and the second (after drying the chromatogram): cyclohexane–chloroform–methanol–glacial acid acetic acid (6:3:0.5:0.5, v/v/v/v). Full article ">Figure 8
Chromatographic plate: (A) with DicloDuo Combi extract (S) or a mixture of diclofenac sodium and omeprazole standards (S) applied; (B) plate (A) after development in the mobile phase chloroform–methanol–ammonia (36:4:0.60, v/v/v); D—a spot representing diclofenac sodium, O—omeprazole; (C) the plate (B) was rotated by an angle of 90o to develop in the mobile phase cyclohexane–chloroform–methanol–glacial acetic acid (6:3:0.5:0.5, v/v/v/v). Full article ">Figure 8 Cont.
Chromatographic plate: (A) with DicloDuo Combi extract (S) or a mixture of diclofenac sodium and omeprazole standards (S) applied; (B) plate (A) after development in the mobile phase chloroform–methanol–ammonia (36:4:0.60, v/v/v); D—a spot representing diclofenac sodium, O—omeprazole; (C) the plate (B) was rotated by an angle of 90o to develop in the mobile phase cyclohexane–chloroform–methanol–glacial acetic acid (6:3:0.5:0.5, v/v/v/v). Full article ">

12 pages, 1927 KiB

Open AccessArticle

HMG-CoA Reductase Inhibitor Statins Activate the Transcriptional Activity of p53 by Regulating the Expression of TAZ

by Chiharu Miyajima, Yurika Hayakawa, Yasumichi Inoue, Mai Nagasaka and Hidetoshi Hayashi

Pharmaceuticals 2022, 15(8), 1015; https://doi.org/10.3390/ph15081015 - 17 Aug 2022

Cited by 11 | Viewed by 2556

Abstract

Transcriptional coactivator with PDZ-binding motif (TAZ) is a downstream transcriptional regulator of the Hippo pathway that controls cell growth and differentiation. The aberrant activation of TAZ correlates with a poor prognosis in human cancers, such as breast and colon cancers. We previously demonstrated [...] Read more.

Transcriptional coactivator with PDZ-binding motif (TAZ) is a downstream transcriptional regulator of the Hippo pathway that controls cell growth and differentiation. The aberrant activation of TAZ correlates with a poor prognosis in human cancers, such as breast and colon cancers. We previously demonstrated that TAZ inhibited the tumor suppressor functions of p53 and enhanced cell proliferation. Statins, which are used to treat dyslipidemia, have been reported to suppress the activity of TAZ and exert anti-tumor effects. In the present study, we focused on the regulation of p53 functions by TAZ and investigated whether statins modulate these functions via TAZ. The results obtained suggest that statins, such as simvastatin and fluvastatin, activated the transcriptional function of p53 by suppressing TAZ protein expression. Furthermore, co-treatment with simvastatin and anti-tumor agents that cooperatively activate p53 suppressed cancer cell survival. These results indicate a useful mechanism by which statins enhance the effects of anti-tumor agents through the activation of p53 and may represent a novel approach to cancer therapy. Full article

(This article belongs to the Special Issue Targeting p53 by Small Molecules: Application in Oncology)

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18 pages, 6132 KiB

Open AccessArticle

Galangin Exhibits Neuroprotective Effects in 6-OHDA-Induced Models of Parkinson’s Disease via the Nrf2/Keap1 Pathway

by Qiu-Xu Chen, Ling Zhou, Tao Long, Da-Lian Qin, Yi-Ling Wang, Yun Ye, Xiao-Gang Zhou, Jian-Ming Wu and An-Guo Wu

Pharmaceuticals 2022, 15(8), 1014; https://doi.org/10.3390/ph15081014 - 17 Aug 2022

Cited by 14 | Viewed by 3595

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disease, and there is still no cure for it. PD is characterized by the degeneration of dopaminergic neurons, and oxidative stress has been considered an important pathological mechanism. Therefore, the discovery of antioxidants to [...] Read more.

Parkinson’s disease (PD) is the second most common neurodegenerative disease, and there is still no cure for it. PD is characterized by the degeneration of dopaminergic neurons, and oxidative stress has been considered an important pathological mechanism. Therefore, the discovery of antioxidants to alleviate the oxidative damage of dopaminergic neurons is a promising therapeutic strategy for PD. First, a network pharmacology approach was used, and nine common core targets of galangin and PD were screened, mainly involving cell aging, apoptosis, and cellular responses to hydrogen peroxide and hypoxia. In addition, the Gene Ontology (GO) function and pathway enrichment analysis of the Kyoto Encyclopedia of Genes and Genomes (KEGG) identified apoptosis, PI3K/Akt, and HIF-1 signaling pathways. Furthermore, the molecular docking results revealed a strong affinity between galangin and the NFE2L2/Nrf2 protein. To validate the above predictions, we employed 6-hydroxydopamine (6-OHDA) to induce neuronal death in HT22 cells and Caenorhabditis elegans (C. elegans). MTT, cell morphology observation, and Hoechst 33342-PI staining results showed that galangin significantly increased the viability of 6-OHDA-treated HT22 cells. In addition, galangin inhibited 6-OHDA-induced ROS generation and apoptosis in HT22 cells. Mechanistic studies demonstrated that galangin activates the Nrf2/Keap1 signaling pathway, as evidenced by the decreased protein expression of Keap1 and increased protein expression of Nrf2 and HO-1. In the 6-OHDA-induced PD model of C. elegans, galangin indeed inhibited the degeneration of dopaminergic neurons, improved behavioral ability, and decreased ROS generation. In conclusion, the current study is the first to show that galangin has the capacity to inhibit neuronal degeneration via the Nrf2/Keap1 pathway, suggesting that galangin is a possible PD treatment. Full article

(This article belongs to the Section Pharmacology)

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Network pharmacology analysis of galangin in PD. (A) Venn diagram of the common targets of galangin in PD. (B) The potential therapeutic targets were analyzed using the STRING database. (C) The construction of the galangin-target-PD network by the Cytoscape v3.7.1 software (Cytoscape Consortium, Seattle, WA, USA). (D) Protein–protein interaction (PPI) network based on the core targets of galangin against PD according to the screening conditions of Degree > 8, BC > 0.01815109, and CC > 0.5. Full article ">Figure 2
GO and KEGG enrichment analyses of galangin in the treatment of PD. (A) Visualization of 20 terms of molecular function enrichment analysis. (B) Visualization of 14 terms of cellular component enrichment analysis. (C) Visualization of 21 terms of biological process enrichment analysis. (D) GO analysis of core targets of galangin in the treatment of PD. Four terms of CC, 6 terms of BP, and 10 terms of MF showing the greatest enrichment of galangin-related processes are listed according to p values. (E) The top 20 KEGG pathways enrichment analysis involved in the potential treatment of galangin in PD. Full article ">Figure 3
Molecular docking of galangin with core targets. (A) Galangin binds to NFE2L2/Nrf2 protein (7K29) via the active residues VAL-420 and VAL-514. (B) Galangin binds to HMOX-1/HO-1 protein (6EHA). (C) Galangin binds to Keap1 protein (1ZGK) via the active residues VAL-418, VAL-606, GLY-367, and LEU-365. Full article ">Figure 4
Galangin decreased cell death in 6-OHDA-treated HT22 cells. (A) MTT assay of the viability of HT22 cells treated with 3.13–400 μM 6-OHDA for 24 h. (B) MTT assay of the viability of HT22 cells treated with 1.56–200 μM galangin for 24 h. (C) MTT assay of the viability of HT22 cells treated with 1.56–50 μM galangin in the absence or presence of 6-OHDA for 24 h. (D) Representative images of the cell morphology of HT22 cells treated with 6.25–50 μM galangin in the absence or presence of 6-OHDA for 24 h. Magnification: 10×; Scale bars: 200 µm. (E) Representative Hoechst/PI staining images of HT22 cells treated with 6.25–50 μM galangin in the absence or presence of 6-OHDA. Magnification: 10×; Scale bars: 100 µm. Bars, S.D., * p ≤ 0.05, ** p ≤ 0.01, *** p ≤ 0.001. Full article ">Figure 5
Galangin reduced 6-OHDA-induced intracellular ROS generation and apoptosis in HT22 cells. (A) HT22 cells were treated with galangin in the absence or presence of 6-OHDA at the indicated concentrations for 24 h. After treatment, the cells were incubated with 5 μM H2DCFDA probe for 30 min and subjected to flow cytometry analysis. (B) Bar chart indicates the percentage of HT22 cells with H2DCFDA signals. Bars, S.D., ** p ≤ 0.01, *** p ≤ 0.001. (C) HT22 cells were treated with galangin in the absence or presence of 6-OHDA at the indicated concentrations for 24 h. After treatment, the cells were collected and analyzed by flow cytometry using an Annexin V-FITC apoptosis detection kit according to the manufacturer’s instructions. (D) Bar chart indicates the apoptosis rate of HT22 cells. Bars, S.D., ** p ≤ 0.01, *** p ≤ 0.001. (E) HT22 cells were treated with galangin in the absence or presence of 6-OHDA at the indicated concentrations for 24 h. After treatment, cell lysates were then collected for the protein detection of Bax, Bcl-2, and β-actin by Western blot. (F) Bar chart indicates the ratio of Bax/Bcl-2. Bars, S.D., ** p ≤ 0.01, *** p ≤ 0.001. The full-length Western blotting images are shown in <a href="#app1-pharmaceuticals-15-01014" class="html-app">Supplementary Figure S1</a>. Full article ">Figure 6
Galangin activates the Keap1/Nrf2/HO-1 signaling pathway. (A) HT22 cells were treated with galangin in the absence or presence of 6-OHDA at the indicated concentrations for 24 h. After treatment, cell lysates were collected and harvested for the protein detection of Keap1, Nrf2, HO-1, and β-actin by western blot. (B) The bar chart indicates the relative density of Keap1 to β-actin. (C) The bar chart indicates the relative density of Nrf2 to β-actin. (D) The bar chart indicates the relative density of HO-1 to β-actin. Bars, S.D., * p ≤ 0.05, *** p ≤ 0.001. The full-length Western blotting images are shown in <a href="#app1-pharmaceuticals-15-01014" class="html-app">Supplementary Figure S1</a>. Full article ">Figure 7
Galangin exerts a neuroprotective effect in 6-OHDA-treated BZ555 worms. (A) Representative images of BZ555 worms treated with galangin (100 μM) or L-Dopa (2 mM) in the presence or absence of 6-OHDA (50 mM) for 72 h. The GFP represents the viability of DA neurons. Magnification: Scale bars: 20 µm. (B) The bar chart indicates the quantification of GFP intensity in BZ555 worms. Bars, S.D., *** p ≤ 0.001. (C) The bar chart indicates the relative slowing rate (%) of BZ555 worms treated with galangin (100 μM) or L-Dopa (2 mM) in the presence or absence of 6-OHDA (50 mM) for 72 h. Bars, S.D., *** p ≤ 0.001. (D) BZ555 worms were treated with galangin (100 μM) or NAC (5 mM) for 72 h in the presence or absence of 6-OHDA (50 mM), which was followed by incubation with DHE solution (100 µM) for 1 h. Representative images of worms were captured by a fluorescence microscope. Magnification: Scale bars: 20 µm. (E) The bar chart indicates the relative RFP. Bars, S.D., *** p ≤0.001. Full article ">

21 pages, 4022 KiB

Open AccessArticle

Efficacy of Kan Jang^® in Patients with Mild COVID-19: Interim Analysis of a Randomized, Quadruple-Blind, Placebo-Controlled Trial

by Levan Ratiani, Elene Pachkoria, Nato Mamageishvili, Ramaz Shengelia, Areg Hovhannisyan and Alexander Panossian

Pharmaceuticals 2022, 15(8), 1013; https://doi.org/10.3390/ph15081013 - 17 Aug 2022

Cited by 7 | Viewed by 3726

Abstract

Kan Jang^®, the fixed combination of Andrographis paniculata (Burm. F.) Wall. ex. Nees and Eleutherococcus senticosus (Rupr. & Maxim.) Maxim extracts, is a herbal medicinal product for relieving symptoms of upper respiratory tract infections. This study aimed to assess the efficacy [...] Read more.

Kan Jang^®, the fixed combination of Andrographis paniculata (Burm. F.) Wall. ex. Nees and Eleutherococcus senticosus (Rupr. & Maxim.) Maxim extracts, is a herbal medicinal product for relieving symptoms of upper respiratory tract infections. This study aimed to assess the efficacy of Kan Jang^®/Nergecov® on duration and the relief of inflammatory symptoms in adults with mild COVID-19. 86 patients with laboratory-confirmed COVID-19 and mild symptoms for one to three days received supportive treatment (paracetamol) and six Kan Jang^® (daily dose of andrographolides—90 mg) or placebo capsules a day for 14 consecutive days in this randomized, quadruple-blinded, placebo-controlled, two-parallel-group study. The primary efficacy outcomes were the decrease in the acute-phase duration and the severity of symptoms score (sore throat, runny nose, cough, headache, fatigue, loss of smell, taste, pain in muscles), an increase in cognitive functions, physical performance, quality of life, and decrease in IL-6, c-reactive protein, and D-dimer in blood. Kan Jang^®/Nergecov^® was effective in reducing the risk of progression to severe COVID-19, decreasing the disease progression rate by almost 2.5-fold compared to placebo. Absolute risk reduction by Kan Jang treatment is 14%, the relative risk reduction is 243.9%, and the number Needed to Treat is 7.14. Kan Jang^®/Nergecov^® reduces the duration of disease, virus clearance, and days of hospitalization and accelerates recovery of patients, relief of sore throat, muscle pain, runny nose, and normalization of body temperature. Kan Jang^®/Nergecov^® significantly relieves the severity of inflammatory symptoms such as sore throat, runny nose, and muscle pain, decreases pro-inflammatory cytokine IL-6 level in the blood, and increases patients’ physical performance (workout) compared to placebo. In this study, for the first time we demonstrate that Kan Jang^®/Nergecov^® is effective in treating mild COVID-19. Full article

(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)

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24 pages, 4591 KiB

Open AccessArticle

Neuroprotective Effect of Morin Hydrate against Attention-Deficit/Hyperactivity Disorder (ADHD) Induced by MSG and/or Protein Malnutrition in Rat Pups: Effect on Oxidative/Monoamines/Inflammatory Balance and Apoptosis

by Hoda A. Salem, Nehal Elsherbiny, Sharifa Alzahrani, Hanan M. Alshareef, Zakaria Y. Abd Elmageed, Sadeem M. Ajwah, Ahmed M. E. Hamdan, Yahia S. Abdou, Omneya O. Galal, Marwa K. A. El Azazy and Karema Abu-Elfotuh

Pharmaceuticals 2022, 15(8), 1012; https://doi.org/10.3390/ph15081012 - 17 Aug 2022

Cited by 14 | Viewed by 3324

Abstract

Monosodium glutamate (MSG) is one of the most widely used food additives. However, it has been linked to protein malnutrition (PM) and various forms of toxicities such as metabolic disorders and neurotoxic effects. The current study is the first to explore the association [...] Read more.

Monosodium glutamate (MSG) is one of the most widely used food additives. However, it has been linked to protein malnutrition (PM) and various forms of toxicities such as metabolic disorders and neurotoxic effects. The current study is the first to explore the association between MSG, PM, and induced brain injury similar to attention-deficit/hyperactivity disorder (ADHD). Moreover, we determined the underlying mechanistic protective pathways of morin hydrate (MH)―a natural flavonoid with reported multiple therapeutic properties. PM was induced by feeding animals with a low protein diet and confirmed by low serum albumin measurement. Subsequently, rat pups were randomized into seven groups of 10 rats each. Group I, III, and VI were normally fed (NF) and groups II, IV, V, and VII were PM fed. Group I served as normal control NF while Group II served as PM control animals. Group III received NF + 0.4 g/kg MSG, Group IV: PM + 0.4 g/kg MSG, Group V: PM + 60 mg/kg MH, Group VI: NF + 0.4 kg/g MSG + 60 mg/kg MH and Group VII: PM + 0.4 kg/kg MSG + 60 mg/kg MH. At the end of the experimental period, animals were subjected to behavioral and biochemical tests. Our results showed that treatment of rats with a combination of MSG + PM-fed exhibited inferior outcomes as evidenced by deteriorated effects on behavioral, neurochemical, and histopathological analyses when compared to rats who had received MSG or PM alone. Interestingly, MH improved animals’ behavior, increased brain monoamines, brain-derived neuroprotective factor (BDNF), antioxidant status and protein expression of Nrf2/HO-1. This also was accompanied by a significant decrease in brain MDA, inflammatory markers (NF-kB, TNF-α and IL1β), and suppression of TLR4/NLRP3/caspase-1 axis. Taken together, MSG and/or PM are associated with neuronal dysfunction. Our findings suggest MH as a potential neuroprotective agent against brain insults via targeting Nrf2/HO-1 and hindering TLR4/NLRP3 inflammasome signaling pathways. Full article

(This article belongs to the Section Pharmacology)

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21 pages, 2286 KiB

Open AccessArticle

Co-Occurrence of β-Lactam and Aminoglycoside Resistance Determinants among Clinical and Environmental Isolates of Klebsiella pneumoniae and Escherichia coli: A Genomic Approach

by Hisham N. Altayb, Hana S. Elbadawi, Faisal A. Alzahrani, Othman Baothman, Imran Kazmi, Muhammad Shahid Nadeem, Salman Hosawi and Kamel Chaieb

Pharmaceuticals 2022, 15(8), 1011; https://doi.org/10.3390/ph15081011 - 17 Aug 2022

Cited by 13 | Viewed by 2775

Abstract

The presence of antimicrobial-resistance genes (ARGs) in mobile genetic elements (MGEs) facilitates the rapid development and dissemination of multidrug-resistant bacteria, which represents a serious problem for human health. This is a One Health study which aims to investigate the co-occurrence of antimicrobial resistance [...] Read more.

The presence of antimicrobial-resistance genes (ARGs) in mobile genetic elements (MGEs) facilitates the rapid development and dissemination of multidrug-resistant bacteria, which represents a serious problem for human health. This is a One Health study which aims to investigate the co-occurrence of antimicrobial resistance determinants among clinical and environmental isolates of K. pneumoniae and E. coli. Various bioinformatics tools were used to elucidate the bacterial strains’ ID, resistome, virulome, MGEs, and phylogeny for 42 isolates obtained from hospitalized patients (n = 20) and environmental sites (including fresh vegetables, fruits, and drinking water) (n = 22). The multilocus sequence typing (MLST) showed that K. pneumoniae belonged to ten sequence types (STs) while the E. coli belonged to seventeen STs. Multidrug-resistant isolates harbored β-lactam, aminoglycoside resistance determinants, and MGE were detected circulating in the environment (drinking water, fresh vegetables, and fruits) and in patients hospitalized with postoperative infections, neonatal sepsis, and urinary tract infection. Four K. pneumoniae environmental isolates (7E, 16EE, 1KE, and 19KE) were multidrug-resistant and were positive for different beta-lactam and aminoglycoside resistance determinants. bla_CTX-M-15 in brackets of ISEc 9 and Tn 3 transposases was detected in isolates circulating in the pediatrics unit of Soba hospital and the environment. This study documented the presence of bacterial isolates harboring a similar pattern of antimicrobial resistance determinants circulating in hospitals and environments. A rapid response is needed from stakeholders to initiate a program for infection prevention and control measures to detect such clones disseminated in the communities and hospitals. Full article

(This article belongs to the Special Issue Antibiotic Resistance in Gram-Negative Bacteria: The Threat from the Pink Corner)

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Map of different antibiotic-resistance genes, transposases, and plasmid, clustered in contig 33 of the K. pneumoniae (1KE) environmental strain. Showing an example of the presence of the CTX-M-15 gene which is located between two transposases. The outer black circle indicates the contig length, black arrows indicate coding sequences (CDS), green arrows indicate genes, and the inner blue zigzag circle indicates GC content. Full article ">Figure 2
Map of antibiotic resistance and transposases cassette, identified in contig 188 of clinical K. pneumonia (14KP), showing the aminoglycoside-resistant genes flanked by three transposase genes. The outer black circle indicates the contig length, black arrows indicate coding sequences (CDS), green arrows indicate genes, and the inner blue zigzag circle indicates GC content. Full article ">Figure 3
Map of ARGs and IS6 transposase cassette, identified in contig 66 of E. coli (1EP). The outer black circle indicates the contig length, black arrows indicate coding sequences (CDS), green arrows indicate genes, and the inner blue zigzag circle indicates GC content. Full article ">Figure 4
Map of antibiotic resistance and transposases cassette, identified in contig 303 of environmental K. pneumoniae (12KE), showing the aminoglycoside-resistant genes flanked by three transposases genes. The outer black circle indicates the length of the contig, black arrows indicate coding sequences (CDS), green arrows indicate genes, and the inner blue zigzag circle indicates GC content. Full article ">Figure 5
Phylogenomic tree for the clinical and environmental isolates of E. coli from different sources in Khartoum and reference strains (Escherichia coli J53, K-12, and ATCC_43887), Sudan. Environmental isolates were EE while clinical isolates were EP. The blue blocks indicate gene presence and absence. The Klebsiella pneumoniae ATCC_BAA-2146 was used as an outgroup for rooting the tree. Full article ">Figure 6
Phylogenomic tree for the clinical and environmental isolates of K. pneumoniae from different sources in Khartoum and reference strains (K. pneumoniae NUHL24835, PittNDM01, and ATCC_BAA-2146), Sudan. Environmental isolates were KE, while clinical isolates were KP. The blue blocks indicate gene presence and absence, Escherichia coli strain ATCC_43887 was used as an outgroup for rooting the tree. Full article ">

32 pages, 5052 KiB

Open AccessArticle

A Study on Repositioning Nalidixic Acid via Lanthanide Complexation: Synthesis, Characterization, Cytotoxicity and DNA/Protein Binding Studies

by Ana-Madalina Maciuca, Alexandra-Cristina Munteanu, Mirela Mihaila, Mihaela Badea, Rodica Olar, George Mihai Nitulescu, Cristian V. A. Munteanu and Valentina Uivarosi

Pharmaceuticals 2022, 15(8), 1010; https://doi.org/10.3390/ph15081010 - 17 Aug 2022

Cited by 5 | Viewed by 2688

Abstract

“Drug repositioning” is a modern strategy used to uncover new applications for out-of-date drugs. In this context, nalidixic acid, the first member of the quinolone class with limited use today, has been selected to obtain nine new metal complexes with lanthanide cations (La [...] Read more.

“Drug repositioning” is a modern strategy used to uncover new applications for out-of-date drugs. In this context, nalidixic acid, the first member of the quinolone class with limited use today, has been selected to obtain nine new metal complexes with lanthanide cations (La³⁺, Sm³⁺, Eu³⁺, Gd³⁺, Tb³⁺); the experimental data suggest that the quinolone acts as a bidentate ligand, binding to the metal ion via the keto and carboxylate oxygen atoms, findings that are supported by DFT calculations. The cytotoxic activity of the complexes has been studied using the tumoral cell lines, MDA-MB-231 and LoVo, and a normal cell line, HUVEC. The most active compounds of the series display selective activity against LoVo. Their affinity for DNA and the manner of binding have been tested using UV–Vis spectroscopy and competitive binding studies; our results indicate that major and minor groove binding play a significant role in these interactions. The affinity towards serum proteins has also been evaluated, the complexes displaying higher affinity towards albumin than apotransferrin. Full article

(This article belongs to the Special Issue Metal-Based Agents in Drug Discovery)

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42 pages, 13456 KiB

Open AccessReview

Multicomponent Reactions for the Synthesis of Active Pharmaceutical Ingredients

by Ángel Cores, José Clerigué, Emmanuel Orocio-Rodríguez and J. Carlos Menéndez

Pharmaceuticals 2022, 15(8), 1009; https://doi.org/10.3390/ph15081009 - 17 Aug 2022

Cited by 35 | Viewed by 6149

Abstract

Multicomponent reactions 9i.e., those that engage three or more starting materials to form a product that contains significant fragments of all of them), have been widely employed in the construction of compound libraries, especially in the context of diversity-oriented synthesis. While relatively less [...] Read more.

Multicomponent reactions 9i.e., those that engage three or more starting materials to form a product that contains significant fragments of all of them), have been widely employed in the construction of compound libraries, especially in the context of diversity-oriented synthesis. While relatively less exploited, their use in target-oriented synthesis offers significant advantages in terms of synthetic efficiency. This review provides a critical summary of the use of multicomponent reactions for the preparation of active pharmaceutical principles. Full article

(This article belongs to the Special Issue Multicomponent and Domino Reactions in Drug Discovery)

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23 pages, 3578 KiB

Open AccessArticle

Neuroprotective Effects of Phytochemicals against Aluminum Chloride-Induced Alzheimer’s Disease through ApoE4/LRP1, Wnt3/β-Catenin/GSK3β, and TLR4/NLRP3 Pathways with Physical and Mental Activities in a Rat Model

by Ahmed Mohsen Elsaid Hamdan, Fatimah Hussain J. Alharthi, Ahmed Hadi Alanazi, Soad Z. El-Emam, Sameh S. Zaghlool, Kamel Metwally, Sana Abdulaziz Albalawi, Yahia S. Abdu, Reda El-Sayed Mansour, Hoda A. Salem, Zakaria Y. Abd Elmageed and Karema Abu-Elfotuh

Pharmaceuticals 2022, 15(8), 1008; https://doi.org/10.3390/ph15081008 - 17 Aug 2022

Cited by 30 | Viewed by 5924

Abstract

Background: Alzheimer’s disease (AD) is a neurodegenerative disorder that is associated with abnormal cognition. AD is aided in its initiation and progression by hereditary and environmental factors. Aluminum (Al) is a neurotoxic agent that causes oxidative stress, which is linked to AD progression. [...] Read more.

Background: Alzheimer’s disease (AD) is a neurodegenerative disorder that is associated with abnormal cognition. AD is aided in its initiation and progression by hereditary and environmental factors. Aluminum (Al) is a neurotoxic agent that causes oxidative stress, which is linked to AD progression. Additionally, Nrf2/HO-1, APOE4/LRP1, Wnt3/β-catenin, and TLR4/NLRP3 are the main signaling pathways involved in AD pathogenesis. Several phytochemicals are promising options in delaying AD evolution. Objectives: This study aimed at studying the neuroprotective effects of some phytochemicals as morin (MOR), thymol (TML), and thymoquinone (TMQ) on physical and mental activities (PhM) in Al chloride (AlCl₃)-induced AD rat model. Another objective was to determine the specificity of phytochemicals to AD signaling pathways using molecular docking. Methods: Eighty male Dawley rats were divided into eight groups. Each group received: saline (control group), AlCl₃, (ALAD), PhM, either alone or with a combination of MOR, TML, and/or TMQ for five weeks. Animals were then subjected to behavioral evaluation. Brain tissues were used for histopathological and biochemical analyses to determine the extent of neurodegeneration. The effect of phytochemicals on AlCl₃-induced oxidative stress and the main signaling pathways involved in AD progression were also investigated. Results: AlCl₃ caused a decline in spatial learning and memory, as well as histopathological changes in the brains of rats. Phytochemicals combined with PhM restored antioxidant activities, increased HO-1 and Nrf2 levels, blocked inflammasome activation, apoptosis, TLR4 expression, amyloide-β generation, and tau hyperphophorylation. They also brought ApoE4 and LRP1 levels back to normal and regulated Wnt3/β-catenin/GSK3β signaling pathway. Conclusions: The use of phytochemicals with PhM is a promising strategy for reducing AD by modulating Nrf2/HO-1, TLR4/NLRP3, APOE4/LRP1, and Wnt3/β-catenin/GSK-3β signaling pathways. Full article

(This article belongs to the Topic Neuroprotection by Drugs, Nutraceuticals and Physical Activity)

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21 pages, 555 KiB

Open AccessReview

Pharmaceutical Prevention and Management of Cardiotoxicity in Hematological Malignancies

by Anastasia Stella Perpinia, Nikolaos Kadoglou, Maria Vardaka, Georgios Gkortzolidis, Apostolos Karavidas, Theodoros Marinakis, Chrysostomi Papachrysostomou, Panagiotis Makaronis, Charikleia Vlachou, Marina Mantzourani, Dimitrios Farmakis and Konstantinos Konstantopoulos

Pharmaceuticals 2022, 15(8), 1007; https://doi.org/10.3390/ph15081007 - 16 Aug 2022

Cited by 5 | Viewed by 3406

Abstract

Modern treatment modalities in hematology have improved clinical outcomes of patients with hematological malignancies. Nevertheless, many new or conventional anticancer drugs affect the cardiovascular system, resulting in various cardiac disorders, including left ventricular dysfunction, heart failure, arterial hypertension, myocardial ischemia, cardiac rhythm disturbances, [...] Read more.

Modern treatment modalities in hematology have improved clinical outcomes of patients with hematological malignancies. Nevertheless, many new or conventional anticancer drugs affect the cardiovascular system, resulting in various cardiac disorders, including left ventricular dysfunction, heart failure, arterial hypertension, myocardial ischemia, cardiac rhythm disturbances, and QTc prolongation on electrocardiograms. As these complications may jeopardize the significantly improved outcome of modern anticancer therapies, it is crucial to become familiar with all aspects of cardiotoxicity and provide appropriate care promptly to these patients. In addition, established and new drugs contribute to primary and secondary cardiovascular diseases prevention. This review focuses on the clinical manifestations, preventive strategies, and pharmaceutical management of cardiotoxicity in patients with hematologic malignancies undergoing anticancer drug therapy or hematopoietic stem cell transplantation. Full article

(This article belongs to the Special Issue Drug Candidates for the Prevention and Treatment of Cardiovascular Diseases)

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17 pages, 3943 KiB

Open AccessArticle

Synthesis and Biological Evaluation of Indole-2-Carboxamides with Potent Apoptotic Antiproliferative Activity as EGFR/CDK2 Dual Inhibitors

by Lamya H. Al-Wahaibi, Yaser A. Mostafa, Mostafa H. Abdelrahman, Ali H. El-Bahrawy, Laurent Trembleau and Bahaa G. M. Youssif

Pharmaceuticals 2022, 15(8), 1006; https://doi.org/10.3390/ph15081006 - 16 Aug 2022

Cited by 20 | Viewed by 2527

Abstract

The apoptotic antiproliferative actions of our previously reported CB1 allosteric modulators 5-chlorobenzofuran-2-carboxamide derivatives VIIa–j prompted us to develop and synthesise a novel series of indole-2-carboxamide derivatives 5a–k, 6a–c, and 7. Different spectroscopic methods of [...] Read more.

The apoptotic antiproliferative actions of our previously reported CB1 allosteric modulators 5-chlorobenzofuran-2-carboxamide derivatives VIIa–j prompted us to develop and synthesise a novel series of indole-2-carboxamide derivatives 5a–k, 6a–c, and 7. Different spectroscopic methods of analysis were used to validate the novel compounds. Using the MTT assay method, the novel compounds were examined for antiproliferative activity against four distinct cancer cell lines. Compounds 5a–k, 6a–c, and 7 demonstrated greater antiproliferative activity against the breast cancer cell line (MCF-7) than other tested cancer cell lines, and 5a–k (which contain the phenethyl moiety in their backbone structure) demonstrated greater potency than 6a–c and 7, indicating the importance of the phenethyl moiety for antiproliferative action. Compared to reference doxorubicin (GI₅₀ = 1.10 µM), compounds 5d, 5e, 5h, 5i, 5j, and 5k were the most effective of the synthesised derivatives, with GI₅₀ ranging from 0.95 µM to 1.50 µM. Compounds 5d, 5e, 5h, 5i, 5j, and 5k were tested for their inhibitory impact on EGFR and CDK2, and the results indicated that the compounds tested had strong antiproliferative activity and are effective at suppressing both CDK2 and EGFR. Moreover, the studied compounds induced apoptosis with high potency, as evidenced by their effects on apoptotic markers such as Caspases 3, 8, 9, Cytochrome C, Bax, Bcl2, and p53. Full article

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

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Pharmaceuticals, Volume 15, Issue 8 (August 2022) – 130 articles

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