Biomedicines

12 pages, 1874 KiB

Open AccessArticle

Comparison of Two Nuclear Magnetic Resonance Spectroscopy Methods for the Measurement of Lipoprotein Particle Concentrations

by Martin Rief, Reinhard Raggam, Peter Rief, Philipp Metnitz, Tatjana Stojakovic, Markus Reinthaler, Marianne Brodmann, Winfried März, Hubert Scharnagl and Günther Silbernagel

Biomedicines 2022, 10(7), 1766; https://doi.org/10.3390/biomedicines10071766 - 21 Jul 2022

Cited by 4 | Viewed by 1960

Abstract

Background: Measuring lipoprotein particle concentrations may help to improve cardiovascular risk stratification. Both the lipofit (Numares) and lipoprofile (LabCorp) NMR methods are widely used for the quantification of lipoprotein particle concentrations. Objective: The aim of the present work was to perform a method [...] Read more.

Background: Measuring lipoprotein particle concentrations may help to improve cardiovascular risk stratification. Both the lipofit (Numares) and lipoprofile (LabCorp) NMR methods are widely used for the quantification of lipoprotein particle concentrations. Objective: The aim of the present work was to perform a method comparison between the lipofit and lipoprofile NMR methods. In addition, there was the objective to compare lipofit and lipoprofile measurements of standard lipids with clinical chemistry-based results. Methods: Total, LDL, and HDL cholesterol and triglycerides were measured with ß-quantification in serum samples from 150 individuals. NMR measurements of standard lipids and lipoprotein particle concentrations were performed by Numares and LabCorp. Results: For both NMR methods, differences of mean concentrations compared to ß-quantification-derived measurements were ≤5.5% for all standard lipids. There was a strong correlation between ß-quantification- and NMR-derived measurements of total and LDL cholesterol and triglycerides (all r > 0.93). For both, the lipofit (r = 0.81) and lipoprofile (r = 0.84) methods, correlation coefficients were lower for HDL cholesterol. There was a reasonable correlation between LDL and HDL lipoprotein particle concentrations measured with both NMR methods (both r > 0.9). However, mean concentrations of major and subclass lipoprotein particle concentrations were not as strong. Conclusions: The present analysis suggests that reliable measurement of standard lipids is possible with these two NMR methods. Harmonization efforts would be needed for better comparability of particle concentration data. Full article

(This article belongs to the Special Issue Lipid and Lipoprotein Metabolism in Human Health and Diseases)

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11 pages, 1185 KiB

Open AccessArticle

Cardiac Amyloidosis with Normal Wall Thickness: Prevalence, Clinical Characteristics and Outcome in a Retrospective Analysis

by Daniella Nagy, Katalin Révész, Gergely Peskó, Gergely Varga, Laura Horváth, Péter Farkas, András Dávid Tóth, Róbert Sepp, Hajnalka Vágó, Anikó Ilona Nagy, Tamás Masszi and Zoltán Pozsonyi

Biomedicines 2022, 10(7), 1765; https://doi.org/10.3390/biomedicines10071765 - 21 Jul 2022

Cited by 10 | Viewed by 2434

Abstract

Background: Cardiac amyloidosis (CA) is a rare, progressive, infiltrative cardiac disease. Light chain (AL) and transthyretin (ATTR) amyloidosis are in the background in almost all cases. New, easily available diagnostic tools and recently introduced novel therapies for both types of CA put this [...] Read more.

Background: Cardiac amyloidosis (CA) is a rare, progressive, infiltrative cardiac disease. Light chain (AL) and transthyretin (ATTR) amyloidosis are in the background in almost all cases. New, easily available diagnostic tools and recently introduced novel therapies for both types of CA put this disease into the field of interest. Increased left ventricular wall thickness (IWT) detected by echocardiography is generally thought to be a necessary part of the diagnosis. We aimed to determine the proportion of CA patients without IWT, and to define the clinical characteristics of this cohort. Methods: In an academic tertiary center for CA, we identified patients diagnosed and treated for CA between January 2009 and February 2022. In a retrospective analysis we defined the proportion of patients with (≥12 mm) and without (<12 mm) IWT, and described their clinical features. Results: We identified 98 patients suitable for the analysis. In total, 70 had AL and 27 ATTR CA; 89 patients had CA with IWT and 9 patients (9%) had CA without IWT. All non-IWT patients had AL type CA. Both group of patients had clinically significant disease, which is supported by the relevant elevation in cardiac biomarker levels. There was no difference between the outcome of the two groups. Conclusion: Patients without IWT form a relevant subgroup among those with CA. Our results suggest that diagnostic algorithms and criteria should take these individuals into consideration, and, therefore, give them access to effective treatments. Full article

(This article belongs to the Special Issue Novel Diagnostic and Therapeutic Approaches in Cardiac Amyloidosis)

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Figure 1
ECG, echocardiography and CMR images of patients without increased wall thickness and CA. (A): ECG: sinus rhythm, first degree AV block, no low voltage, ST-T changes. (B): Echocardiography. End diastolic frame, parasternal long axis view. (C): CMR image. Long axis four chamber view from a steady-state free precession movie sequence. End diastolic image. Normal left ventricular wall thickness and bilateral pleural effusion. (D): Late gadolinium enhancement from a phase sensitive inversion recovery (PSIR) sequence from the same patient in short axis view. Diffuse subendocardial enhancement, typical for CA. Full article ">Figure 1 Cont.
ECG, echocardiography and CMR images of patients without increased wall thickness and CA. (A): ECG: sinus rhythm, first degree AV block, no low voltage, ST-T changes. (B): Echocardiography. End diastolic frame, parasternal long axis view. (C): CMR image. Long axis four chamber view from a steady-state free precession movie sequence. End diastolic image. Normal left ventricular wall thickness and bilateral pleural effusion. (D): Late gadolinium enhancement from a phase sensitive inversion recovery (PSIR) sequence from the same patient in short axis view. Diffuse subendocardial enhancement, typical for CA. Full article ">Figure 2
(A): Kaplan–Meier curves comparing cardiac amyloidosis patients with and without increased left ventricular wall thickness (IWT: n = 89, non IWT: 9; Log–Rank test: p = 0.7269 (A). (B): only AL patients (IWT: n = 61, non-IWT: = 9) are presented. There was also no significant difference in the outcome (Log-Rank test: p = 0.8651). Dash line represents non IWT patients, continuous line represents IWT patients. Full article ">

12 pages, 1823 KiB

Open AccessArticle

The Hypertensive Effect of Amphotericin B-Containing Liposomes (Abelcet) in Mice: Dissecting the Roles of C3a and C5a Anaphylatoxins, Macrophages and Thromboxane

by Erik Őrfi, László Hricisák, László Dézsi, Péter Hamar, Zoltán Benyó, János Szebeni and Gábor Szénási

Biomedicines 2022, 10(7), 1764; https://doi.org/10.3390/biomedicines10071764 - 21 Jul 2022

Cited by 2 | Viewed by 1930

Abstract

Liposomal amphotericin B (Abelcet) can cause infusion (anaphylactoid) reactions in patients whose mechanism is poorly understood. Here, we used mice to investigate the role of complement (C) receptors and the cellular sources of vasoactive mediators in these reactions. Anesthetized male NMRI and thromboxane [...] Read more.

Liposomal amphotericin B (Abelcet) can cause infusion (anaphylactoid) reactions in patients whose mechanism is poorly understood. Here, we used mice to investigate the role of complement (C) receptors and the cellular sources of vasoactive mediators in these reactions. Anesthetized male NMRI and thromboxane prostanoid receptor (TP) or cyclooxygenase-1 (COX-1)-deficient and wild type C57Bl6/N mice were intravenously injected with Abelcet at 30 mg/kg. Mean arterial blood pressure (MABP) and heart rate (HR) were measured. In untreated mice, Abelcet caused a short (15 min) but large (30%) increase in MABP. C depletion with cobra venom factor (CVF) and inhibition of C5a receptors with DF2593A considerably prolonged, while C3aR inhibition with SB290157 significantly decreased the hypertensive effect. Likewise, the hypertensive response was abolished in COX-1- and TP-deficient mice. CVF caused a late hypertension in TP-deficient mice. Both macrophage depletion with liposomal clodronate and blockade of platelet GPIIb/IIIa receptors with eptifibatide prolonged the hypertensive effect. The early phase of the hypertensive effect is COX-1- and TP-receptor-dependent, partly mediated by C3aR. In contrast, the late phase is under the control of vasoactive mediators released from platelets and macrophages subsequent to complement activation and C5a binding to its receptor. Full article

(This article belongs to the Special Issue Molecular Mechanisms in Anaphylaxis)

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19 pages, 1450 KiB

Open AccessReview

Small Molecules and Immunotherapy Agents for Enhancing Radiotherapy in Glioblastoma

by Jennifer K. Matsui, Haley K. Perlow, Alex R. Ritter, Rituraj Upadhyay, Raju R. Raval, Evan M. Thomas, Sasha J. Beyer, Clement Pillainayagam, Justin Goranovich, Shirley Ong, Pierre Giglio and Joshua D. Palmer

Biomedicines 2022, 10(7), 1763; https://doi.org/10.3390/biomedicines10071763 - 21 Jul 2022

Cited by 8 | Viewed by 3541

Abstract

Glioblastoma (GBM) is an aggressive primary brain tumor that is associated with a poor prognosis and quality of life. The standard of care has changed minimally over the past two decades and currently consists of surgery followed by radiotherapy (RT), concomitant and adjuvant [...] Read more.

Glioblastoma (GBM) is an aggressive primary brain tumor that is associated with a poor prognosis and quality of life. The standard of care has changed minimally over the past two decades and currently consists of surgery followed by radiotherapy (RT), concomitant and adjuvant temozolomide, and tumor treating fields (TTF). Factors such as tumor hypoxia and the presence of glioma stem cells contribute to the radioresistant nature of GBM. In this review, we discuss the current treatment modalities, mechanisms of radioresistance, and studies that have evaluated promising radiosensitizers. Specifically, we highlight small molecules and immunotherapy agents that have been studied in conjunction with RT in clinical trials. Recent preclinical studies involving GBM radiosensitizers are also discussed. Full article

(This article belongs to the Special Issue Potent Agent Research for Glioblastoma Treatment)

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15 pages, 1279 KiB

Open AccessArticle

Hyperreactivity of Salivary Alpha-Amylase to Acute Psychosocial Stress and Norepinephrine Infusion in Essential Hypertension

by Lisa-Marie Walther, Roland von Känel, Claudia Zuccarella-Hackl and Petra H. Wirtz

Biomedicines 2022, 10(7), 1762; https://doi.org/10.3390/biomedicines10071762 - 21 Jul 2022

Cited by 3 | Viewed by 2421

Abstract

It is unknown whether the observed general physiological hyperreactivity to acute psychosocial stress in essential hypertension also extends to salivary alpha-amylase (sAA), a surrogate sympathetic nervous system marker. Here, we investigated sAA reactivity to acute psychosocial stress in essential hypertensive males (HT) as [...] Read more.

It is unknown whether the observed general physiological hyperreactivity to acute psychosocial stress in essential hypertension also extends to salivary alpha-amylase (sAA), a surrogate sympathetic nervous system marker. Here, we investigated sAA reactivity to acute psychosocial stress in essential hypertensive males (HT) as compared to normotensive controls (NT). To shed light on underlying mechanisms, we moreover tested for sAA reactivity following a standardized norepinephrine (NE) infusion. We hypothesized that both acute psychosocial stress and an NE infusion of similar duration would lead to greater sAA reactivity in HT than in NT. In the stress study, we examined sAA reactivity to 15 min of acute psychosocial stress induced by the Trier Social Stress Test (TSST) in 19 HT and 23 NT up to 40 min after stress. In the infusion study, 20 HT and 22 NT received a standardized NE infusion (5 μg/mL/min) over 15 min mimicking NE release in reaction to acute psychosocial stress. HT exhibited greater sAA reactivity to the TSST as compared to NT (p = 0.049, η_p² = 0.08, f = 0.29). In reaction to the standardized NE infusion, HT showed higher sAA reactivity as compared to NT (p = 0.033, η_p² = 1.00, f = 0.33). Our findings suggest stress-induced sAA hyperreactivity in essential hypertension that seems to be at least in part mediated by a higher reactivity to a standardized amount of NE in HT. With respect to clinical implications, sAA stress reactivity may serve as a noninvasive marker indicative of early cardiovascular risk. Full article

(This article belongs to the Collection Cardiovascular Disease: From the Pathogenesis to Novel Therapeutic Approaches)

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Stress study. Salivary alpha-amylase (sAA) reactivity to acute psychosocial stress in hypertensive individuals (black dots) and normotensive controls (white dots). Repeated measures ANCOVA revealed that hypertensive individuals showed higher sAA stress reactivity as compared to normotensive controls (p = 0.049). TSST = Trier Social Stress Test. Paragraphs (§) indicate significant differences between hypertensive and normotensive participants. Asterisks (*) indicate significant differences from baseline within the respective group. Full article ">Figure 2
NE infusion study. Salivary alpha-amylase (sAA) reactivity to norepinephrine (NE) infusion with prior saline (Sal) infusion in hypertensive individuals (black dots) and normotensive controls (white dots). Repeated measures ANCOVA revealed that hypertensive individuals had higher sAA reactivity to NE infusion as compared to normotensive controls (p = 0.045). Paragraphs (§) indicate significant differences between hypertensive and normotensive participants. Asterisks (*) indicate significant differences from baseline within the respective group. Full article ">Figure A1
Salivary alpha-amylase (sAA) output reactivity, i.e., sAA reactivity with control for salivary flow rate, to the TSST in hypertensive individuals (black dots) and normotensive controls (white dots). Repeated measures ANCOVA revealed that hypertensive individuals showed higher sAA output reactivity to the TSST as compared to normotensive controls (p = 0.046; with covariates age and BMI: p = 0.096). Paragraphs (§) indicate significant differences between hypertensive and normotensive participants. Asterisks (*) indicate significant differences from baseline within the respective group. Full article ">

14 pages, 3017 KiB

Open AccessArticle

Tumor Budding Is an Independent Prognostic Factor in Pancreatic Adenocarcinoma and It Positively Correlates with PD-L1 Expression on Tumor Cells

by Rafał Pęksa, Michał Kunc, Piotr Czapiewski, Michał Piątek, Stanisław Hać, Barbara Radecka and Wojciech Biernat

Biomedicines 2022, 10(7), 1761; https://doi.org/10.3390/biomedicines10071761 - 21 Jul 2022

Cited by 3 | Viewed by 2518

Abstract

Pancreatic adenocarcinoma is one of the leading causes of cancer-related death in developed countries. Only 15% of patients are candidates for radical surgery, and adequate prognostication may guide proper postsurgical management. We aimed to retrospectively assess the prognostic significance of the immunohistochemical expression [...] Read more.

Pancreatic adenocarcinoma is one of the leading causes of cancer-related death in developed countries. Only 15% of patients are candidates for radical surgery, and adequate prognostication may guide proper postsurgical management. We aimed to retrospectively assess the prognostic significance of the immunohistochemical expression of immune checkpoint receptors (PD-L1 and VISTA), markers of systemic inflammation, thrombosis in the tumor area, and the tumor budding in the group of 107 patients diagnosed with pancreatic adenocarcinoma in a single center. The high expression of PD-L1 on tumor cells (TCs) was associated with worse overall survival (OS, p = 0.041, log-rank). On the contrary, high PD-L1 or VISTA on tumor-associated immune cells (TAICs) was correlated with better OS (p = 0.006 and p = 0.008, respectively, log-rank). The joint status of PD-L1 on TCs and TAICs stratified patients into three prognostic groups. The cases with high-grade budding were characterized by higher PD-L1 expression on TCs (p = 0.008) and elevated systemic inflammatory markers. Moreover, budding was identified as the independent prognostic factor in multivariate Cox regression analysis (HR = 2.87; 95% CI = 1.75–4.68; p < 0.001). To conclude, the pattern of PD-L1 and VISTA expression was associated with survival in univariate analysis. Tumor budding accurately predicts outcomes in pancreatic cancer and should be incorporated into routine histopathological practice. Full article

(This article belongs to the Special Issue Advances on Pancreatic Cancer)

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Representative examples of immunohistochemical stainings. (A) Intense, membranous PD-L1 reaction in pancreatic carcinoma cells with prominent budding; (B) high expression of PD-L1 restricted to TAICs and lack of reaction in TCs; (C) PD-L1 staining visible mainly in TAICs and in some TCs; (D) negative VISTA staining reaction in both TAICs and TCs; and (E,F) high expression of VISTA in the majority of TAICs and lack of reaction in TCs. Full article ">Figure 2
Associations between markers of systemic inflammation and PD-L1 expression on tumor-associated immune cells (TAICs) (A–C) and tumor cells (TCs) (D–F). Blue and red boxes represent high and low expression of PD-L1, respectively. Grey dots represent individual measures. Full article ">Figure 3
Association between PD-L1 and VISTA expression and the number of tumor buds (A–C). Blue and red boxes represent high and low expression of immune checkpoint receptors, respectively. Grey dots represent individual measures. Full article ">Figure 4
The Kaplan–Meier plots for OS stratified by PD-L1 on TAICs (A), PD-L1 on TCs (B), combined PD-L1 on TAICs/TCs (C), and VISTA on TAICs expression (D) in pancreatic adenocarcinoma. p-values were calculated with log-rank. Full article ">Figure 5
The Kaplan–Meier plots were stratified by budding grade (A), PLR values (B), and MLR values (C). p-values were calculated with log-rank. Full article ">

25 pages, 2326 KiB

Open AccessReview

Biomarkers of Neurodegenerative Diseases: Biology, Taxonomy, Clinical Relevance, and Current Research Status

by Dorota Koníčková, Kateřina Menšíková, Lucie Tučková, Eva Hényková, Miroslav Strnad, David Friedecký, David Stejskal, Radoslav Matěj and Petr Kaňovský

Biomedicines 2022, 10(7), 1760; https://doi.org/10.3390/biomedicines10071760 - 21 Jul 2022

Cited by 36 | Viewed by 5449

Abstract

The understanding of neurodegenerative diseases, traditionally considered to be well-defined entities with distinguishable clinical phenotypes, has undergone a major shift over the last 20 years. The diagnosis of neurodegenerative diseases primarily requires functional brain imaging techniques or invasive tests such as lumbar puncture [...] Read more.

The understanding of neurodegenerative diseases, traditionally considered to be well-defined entities with distinguishable clinical phenotypes, has undergone a major shift over the last 20 years. The diagnosis of neurodegenerative diseases primarily requires functional brain imaging techniques or invasive tests such as lumbar puncture to assess cerebrospinal fluid. A new biological approach and research efforts, especially in vivo, have focused on biomarkers indicating underlying proteinopathy in cerebrospinal fluid and blood serum. However, due to the complexity and heterogeneity of neurodegenerative processes within the central nervous system and the large number of overlapping clinical diagnoses, identifying individual proteinopathies is relatively difficult and often not entirely accurate. For this reason, there is an urgent need to develop laboratory methods for identifying specific biomarkers, understand the molecular basis of neurodegenerative disorders and classify the quantifiable and readily available tools that can accelerate efforts to translate the knowledge into disease-modifying therapies that can improve and simplify the areas of differential diagnosis, as well as monitor the disease course with the aim of estimating the prognosis or evaluating the effects of treatment. The aim of this review is to summarize the current knowledge about clinically relevant biomarkers in different neurodegenerative diseases. Full article

(This article belongs to the Special Issue Molecular Basis of Neurodegenerative Diseases)

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Neuropathological finding showing changes in Alzheimer’s disease. (A) Senile plaques in temporal cortex, immunohistochemically stained with β-amyloid antibodies, magnification 400×; (B) Neurofibrillary tangles, pretangles, and numerous threads in hippocampus, stained with monoclonal antibody (AT8) against phosphorylated tau protein, magnification 400×. Full article ">Figure 2
Neuropathological finding showing changes in Parkinson’s disease. (A) Lewy body in a pigmented neuron substantia nigra, H&E staining, original magnification 200×; (B) The spectrum of α-synuclein pathology in pons. Lewy bodies, neuronal granular cytoplasmic positivity and dystrophic neurites, stained with anti- α-syn monoclonal antibody, original magnification 200×. Full article ">Figure 3
Neuropathological finding showing changes in multiple system atrophy. Typical alpha-synucleinopathy with oligodendroglial cytoplasmic inclusions in striatum, stained with anti- α-syn monoclonal antibody, original magnification 200×. Full article ">Figure 4
Tau pathology spectrum in various brain areas in progressive supranuclear palsy. (A) Numerous threads, coiled bodies, and neurofibrillary tangles in subthalamic region, stained with monoclonal antibody (AT8) against hyperphosphorylated tau protein; (B) Tufted astrocytes in the basal ganglia, stained with monoclonal antibody (AT8) against pathologically changed tau protein; (C) Neurofibrillary tangles in the substantia nigra neurons, stained with monoclonal antibody (4RD) against tau protein, original magnification 100×. Full article ">Figure 5
Neuropathological finding showing changes in FTLD-TDP. (A) Temporal cortex, numerous neuronal cytoplasmic inclusions in all layers of neocortex, stained with monoclonal antibody (phospho-TDP-43) against hyperphosphorylated TDP-43 protein, original magnification 40×; (B) cytoplasmic inclusions in residual neurons nuclei nervi hypoglossi, stained with monoclonal antibody (phospho-TDP-43) against pathologically changed TDP-43 protein, magnification 200×. Full article ">Figure 6
Neuropathological finding showing changes corresponding to Creutzfeldt–Jakob disease. (A) Diffuse synaptic positivity, enhanced perivacuolar “patchy” positivity and “plaque-like” positive structures in cerebral cortex, stained with monoclonal antibody (12F10) against prion protein, original magnification 200×; (B,C) diffuse synaptic positivity and enhanced perivacuolar “patchy” positivity and “plaque-like” positive structures in striatum, stained with monoclonal antibody (6H4) against prion protein, original magnification 200× and H&E staining, original magnification 100×. Full article ">

13 pages, 2974 KiB

Open AccessArticle

Impact of R-Carvedilol on β2-Adrenergic Receptor-Mediated Spontaneous Calcium Release in Human Atrial Myocytes

by Sergi Casabella-Ramón, Verónica Jiménez-Sábado, Carmen Tarifa, Sandra Casellas, Tien Tina Lu, Paloma Izquierdo-Castro, Ignasi Gich, Marcel Jiménez, Antonino Ginel, José M. Guerra, S. R. Wayne Chen, Raul Benítez and Leif Hove-Madsen

Biomedicines 2022, 10(7), 1759; https://doi.org/10.3390/biomedicines10071759 - 21 Jul 2022

Cited by 7 | Viewed by 2646

Abstract

A hallmark of atrial fibrillation is an excess of spontaneous calcium release events, which can be mimicked by β1- or β2-adrenergic stimulation. Because β1-adrenergic receptor blockers (β1-blockers) are primarily used in clinical practice, we here examined the impact of β2-adrenergic stimulation on spontaneous [...] Read more.

A hallmark of atrial fibrillation is an excess of spontaneous calcium release events, which can be mimicked by β1- or β2-adrenergic stimulation. Because β1-adrenergic receptor blockers (β1-blockers) are primarily used in clinical practice, we here examined the impact of β2-adrenergic stimulation on spontaneous calcium release and assessed whether the R- and S-enantiomers of the non-selective β- blocker carvedilol could reverse these effects. For this purpose, human atrial myocytes were isolated from patients undergoing cardiovascular surgery and subjected to confocal calcium imaging or immunofluorescent labeling of the ryanodine receptor (RyR2). Interestingly, the β2-adrenergic agonist fenoterol increased the incidence of calcium sparks and waves to levels observed with the non-specific β-adrenergic agonist isoproterenol. Moreover, fenoterol increased both the amplitude and duration of the sparks, facilitating their fusion into calcium waves. Subsequent application of the non β-blocking R-Carvedilol enantiomer reversed these effects of fenoterol in a dose-dependent manner. R-Carvedilol also reversed the fenoterol-induced phosphorylation of the RyR2 at Ser-2808 dose-dependently, and 1 µM of either R- or S-Carvedilol fully reversed the effect of fenoterol. Together, these findings demonstrate that β2-adrenergic stimulation alone stimulates RyR2 phosphorylation at Ser-2808 and spontaneous calcium release maximally, and points to carvedilol as a tool to attenuate the pathological activation of β2-receptors. Full article

(This article belongs to the Special Issue Beta-Adrenergic Receptors in Physiopathology)

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Effect of fenoterol on calcium spark frequency and properties. (A) Calcium spark recordings in a patient before and after exposure to 3 µM Feno. Spark sites are marked with circles and the signal for each site is shown on the right. Impact of Feno on (B) spark density, (C) spark site density, (D) spark frequency per site. p-values in B–D were obtained using Wilcoxon rank sum exact test. (E) Distance to nearest neighbor (DNN). (F) Spark amplitude. (G) Rate of rise (RoR). (H) Decay time constant. (I) Full duration at half maximum (FDHM). (J) Spark mass. p-values in E–J were obtained using Student’s t-test. Statistically significant differences between pairs of bars are indicated with *: p < 0.05, **: p < 0.01; ***: p < 0.001. Circles in (B–J) correspond with the values of individual data points. Number of cells/number of patients is given below bars. Full article ">Figure 2
Effect of fenoterol on calcium wave frequency. (A) Recordings of a spontaneous calcium transient or wave before and after exposure to 3 µM Feno. Impact of Feno on (B) event frequency, (C) rate of rise of the calcium signal, (D) time integral of the calcium signal. p-values were obtained using Wilcoxon’s rank sum test. Statistically significant differences between pairs of bars are indicated with ***: p < 0.001. Circles in (B–D) correspond with the values of individual data points. Number of cells/number of patients is given below bars. Full article ">Figure 3
Effect of R-Carvedilol on calcium spark frequency and properties. Calcium spark frequency and properties were recorded in myocytes after addition of Feno and increasing doses of R-Carv (given below bars). (A) Spark density. (B) Spark site density. (C) Spark frequency per site. p-values in A–C were obtained using Kruskal–Wallis test followed by Bonferroni-adjusted multiple comparisons. (D) Distance to nearest neighbor (DNN). (E) Spark amplitude. (F) Decay time constant. (G) Full duration at half maximum (FDHM). (H) Spark mass. Data are from 45 cells/11 patients. p-values in D–H were obtained using ANOVA test followed by Tukey’s multiple comparisons test. Statistically significant differences between pairs of bars are indicated with *: p < 0.05, **: p < 0.01; ***: p < 0.001. Solid lines represent fitting using a Hill equation. Dashed lines represent mean values recorded in control conditions before exposure to Feno. Circles in (A–H) correspond with the values of individual data points. Full article ">Figure 4
Effect of R-Carvedilol on calcium wave frequency and properties. The frequency and properties of spontaneous calcium transients or waves were recorded in myocytes after addition of Feno and increasing doses of R-Carv (given below bars). (A) Event frequency. (B) Rate of rise of the calcium signal. (C) Time integral of the calcium signal. Data are from 40 cells/10 patients. p-values were obtained using ANOVA test with Welch correction followed by Bonferroni-adjusted multiple comparisons. Statistically significant differences between pairs of bars are indicated with *: p < 0.05, **: p < 0.01. Solid lines represent fitting using a Hill equation. Circles in (A–C) correspond with the values of individual data points. Full article ">Figure 5
Effect of R- or S-Carvedilol on RyR2 phosphorylation at Ser-2808. (A) Overlay of total RyR2 (green) and Ser-2808-phosphorylated RyR2 (red) for different R-Carv concentrations (given below images). (B) Mean RyR2 phosphorylation at Ser-2808 determined as the fluorescence intensity ratio (Ser-2808/RyR2). (C) Overlay of total RyR2 (green) and Ser-2808-phosphorylated RyR2 (red) for 3 µM R- and S-Carv. (D) Mean RyR2 phosphorylation at Ser-2808 determined as the fluorescence intensity ratio (Ser-2808/RyR2). The number of cells/number of patients is given for each bar. Statistical significance was determined using a one-way ANOVA followed by Tukey’s multiple comparison test. Statistically significant differences between pairs of bars are indicated with *: p < 0.05, **: p < 0.01; ***: p < 0.001. Circles in (B,D) correspond with the values of individual data points. Number of patients is given for each bar. Full article ">

14 pages, 2658 KiB

Open AccessArticle

Bladder Tissue Microbiome Composition in Patients of Bladder Cancer or Benign Prostatic Hyperplasia and Related Human Beta Defensin Levels

by Bassel Mansour, Ádám Monyók, Márió Gajdács, Balázs Stercz, Nóra Makra, Kinga Pénzes, István Vadnay, Dóra Szabó and Eszter Ostorházi

Biomedicines 2022, 10(7), 1758; https://doi.org/10.3390/biomedicines10071758 - 21 Jul 2022

Cited by 10 | Viewed by 2455

Abstract

Balance between the microbiome associated with bladder mucosa and human beta defensin (HBD) levels in urine is a dynamic, sensitive and host-specific relationship. HBD1—possessing both antitumor and antibacterial activity—is produced constitutively, while the inducible production of antibacterial HBD2 and HBD3 is affected by [...] Read more.

Balance between the microbiome associated with bladder mucosa and human beta defensin (HBD) levels in urine is a dynamic, sensitive and host-specific relationship. HBD1—possessing both antitumor and antibacterial activity—is produced constitutively, while the inducible production of antibacterial HBD2 and HBD3 is affected by bacteria. Elevated levels of HBD2 were shown to cause treatment failure in anticancer immunotherapy. Our aim was to assess the relationship between microbiome composition characteristic of tumor tissue, defensin expression and HBD levels measured in urine. Tissue samples for analyses were removed during transurethral resection from 55 bladder carcinoma and 12 prostatic hyperplasia patients. Microbiome analyses were carried out with 16S rRNS sequencing. Levels of HBD mRNA expression were measured with qPCR from the same samples, and urinary amounts of HBD1, 2 and 3 were detected with ELISA in these patients, in addition to 34 healthy volunteers. Mann–Whitney U test, Wilcoxon rank sum test (alpha diversity) and PERMANOVA analysis (beta diversity) were performed. Defensin-levels expressed in the tumor did not clearly determine the amount of defensin measurable in the urine. The antibacterial and antitumor defensin (HBD1) showed decreased levels in cancer patients, while others (HBD2 and 3) were considerably increased. Abundance of Staphylococcus, Corynebacterium and Oxyphotobacteria genera was significantly higher, the abundance of Faecalibacterium and Bacteroides genera were significantly lower in tumor samples compared to non-tumor samples. Bacteroides, Parabacteroides and Faecalibacterium abundance gradually decreased with the combined increase in HBD2 and HBD3. Higher Corynebacterium and Staphylococcus abundances were measured together with higher HBD2 and HBD3 urinary levels. Among other factors, defensins and microorganisms also affect the development, progression and treatment options for bladder cancer. To enhance the success of immunotherapies and to develop adjuvant antitumor therapies, it is important to gain insight into the interactions between defensins and the tumor-associated microbiome. Full article

(This article belongs to the Section Microbiology in Human Health and Disease)

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Comparison of tissue microbiome composition of bladder cancer (BC) and prostatic hyperplasia (PH) patients. (A) Chao1 alpha diversity at genus level, (B) Jaccard beta diversity at genus level, (C) taxa abundance in cohorts at phylum level, (D) taxa abundance in cohorts at genus level. Full article ">Figure 2
Heatmap visualization of the most abundant taxa at genus level among the BC and PH patients. The samples of the PH and BC groups are sharply separated; additionally, 9 samples of the BC group were detached in which some specific genera showed a remarkably high presence. Full article ">Figure 3
Relationship between characteristics of BC patients and microbiome beta diversity The Jaccard beta diversity graph for tumor samples shows two well-separated clusters, but the following properties alone do not show any correlation with cluster classification, (A) smoking habit, (B) hypertension, (C) diabetes mellitus, (D) grade of the cancer, (E) stage of the cancer. (F) There is a significant difference in the classification of female and male tissue samples into microbiome clusters. Full article ">Figure 4
Defensin mRNA expression RQ values from tissue samples and the amounts of HBDs measured in the urine samples. (A) HBD1 RQ in tissue samples, (B) HBD1 levels in urine samples, (C) HBD2 RQ in tissue samples, (D) HBD2 levels in urine samples, (E) HBD3 RQ in tissue samples, (F) HBD3 levels in urine samples. BC: bladder cancer patients, PH: prostatic hyperplasia patients, HV: healthy volunteers. Full article ">Figure 5
Correlation between the amount of defensins in urine and the abundance of the characteristic genera in BC tissue microbiome. (A) Oxyphotobacteria is the only genus whose occurrence differs significantly from the quantitative change in HBD1, Oxyphotobacteria is present only at low HBD1 levels. There is no significant difference due to the amount of (B) HBD2 or (C) HBD3 alone in the abundance of the genera in the BC tissue microbiome. (D) The combined increase in HBD2 and HBD3 levels reduces the abundance of non-tumor specific genera (Bacteroides, Parabacteroides, Faecalibacterium) and increases the abundance of more common in-tumor tissue genera (Staphylococcus, Corynebacterium). Full article ">

18 pages, 5272 KiB

Open AccessReview

The Thioredoxin System of Mammalian Cells and Its Modulators

by Aseel Ali Hasan, Elena Kalinina, Victor Tatarskiy and Alexander Shtil

Biomedicines 2022, 10(7), 1757; https://doi.org/10.3390/biomedicines10071757 - 21 Jul 2022

Cited by 41 | Viewed by 5153

Abstract

Oxidative stress involves the increased production and accumulation of free radicals, peroxides, and other metabolites that are collectively termed reactive oxygen species (ROS), which are produced as by-products of aerobic respiration. ROS play a significant role in cell homeostasis through redox signaling and [...] Read more.

Oxidative stress involves the increased production and accumulation of free radicals, peroxides, and other metabolites that are collectively termed reactive oxygen species (ROS), which are produced as by-products of aerobic respiration. ROS play a significant role in cell homeostasis through redox signaling and are capable of eliciting damage to macromolecules. Multiple antioxidant defense systems have evolved to prevent dangerous ROS accumulation in the body, with the glutathione and thioredoxin/thioredoxin reductase (Trx/TrxR) systems being the most important. The Trx/TrxR system has been used as a target to treat cancer through the thiol–disulfide exchange reaction mechanism that results in the reduction of a wide range of target proteins and the generation of oxidized Trx. The TrxR maintains reduced Trx levels using NADPH as a co-substrate; therefore, the system efficiently maintains cell homeostasis. Being a master regulator of oxidation–reduction processes, the Trx-dependent system is associated with cell proliferation and survival. Herein, we review the structure and catalytic properties of the Trx/TrxR system, its role in cellular signaling in connection with other redox systems, and the factors that modulate the Trx system. Full article

(This article belongs to the Special Issue Oxidative Stress– and Redox–Based Therapeutic Strategy in Cancers)

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20 pages, 1927 KiB

Open AccessReview

The Involvement of Polyamines Catabolism in the Crosstalk between Neurons and Astrocytes in Neurodegeneration

by Manuela Cervelli, Monica Averna, Laura Vergani, Marco Pedrazzi, Sarah Amato, Cristian Fiorucci, Marianna Nicoletta Rossi, Guido Maura, Paolo Mariottini, Chiara Cervetto and Manuela Marcoli

Biomedicines 2022, 10(7), 1756; https://doi.org/10.3390/biomedicines10071756 - 21 Jul 2022

Cited by 17 | Viewed by 3751

Abstract

In mammalian cells, the content of polyamines is tightly regulated. Polyamines, including spermine, spermidine and putrescine, are involved in many cellular processes. Spermine oxidase specifically oxidizes spermine, and its deregulated activity has been reported to be linked to brain pathologies involving neuron damage. [...] Read more.

In mammalian cells, the content of polyamines is tightly regulated. Polyamines, including spermine, spermidine and putrescine, are involved in many cellular processes. Spermine oxidase specifically oxidizes spermine, and its deregulated activity has been reported to be linked to brain pathologies involving neuron damage. Spermine is a neuromodulator of a number of ionotropic glutamate receptors and types of ion channels. In this respect, the Dach-SMOX mouse model overexpressing spermine oxidase in the neocortex neurons was revealed to be a model of chronic oxidative stress, excitotoxicity and neuronal damage. Reactive astrocytosis, chronic oxidative and excitotoxic stress, neuron loss and the susceptibility to seizure in the Dach-SMOX are discussed here. This genetic model would help researchers understand the linkage between polyamine dysregulation and neurodegeneration and unveil the roles of polyamines in the crosstalk between astrocytes and neurons in neuroprotection or neurodegeneration. Full article

(This article belongs to the Special Issue State of the Art: Neurodegenerative Diseases in Italy)

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Enzymes involved in PA biosynthesis (encircled) and catabolism (boxed). ODC, ornithine decarboxylase enzyme; PAOX, N1-acetylpolyamine oxidase; SAT1, spermidine/spermine N1-acetyltransferase; SMS, spermine synthase; SRM, spermidine synthase. The enzyme spermine oxidase (SMOX), which is overexpressed in the Dach-SMOX mice model, is highlighted in red. Full article ">Figure 2
Spermine oxidase chemical reaction. Spermine (Spm) is oxidized to produce spermidine (Spd), 3-aminopropanal (3-AP) and hydrogen peroxide (H2O2). Full article ">Figure 3
Schematic representation of the major mechanisms involved in neuronal damage resulting from polyamine dyshomeostasis in the central nervous system. Polyamine dyshomeostasis-dependent mechanisms that have been suggested to play pivotal roles in representative relevant diseases are also highlighted. AD, Alzheimer’s disease; DR, diabetic retinopathy; HIV D, HIV-associated dementia; PD, Parkinson’s disease. Full article ">Figure 4
SMOX overexpression in neurons resulted in chronic oxidative and excitotoxic stress and in neuron loss. Schematic representation of the main mechanisms taking place at cerebrocortical glutamatergic synapses in the SMOX-overexpressing mouse model. NeuN positive cells were reduced [<a href="#B37-biomedicines-10-01756" class="html-bibr">37</a>,<a href="#B121-biomedicines-10-01756" class="html-bibr">121</a>], and a relative increase in the abundance of astrocyte processes and a decrease in nerve terminals (an increase in GFAP, ezrin and vimentin-positive cells vs. a reduction in synaptophysin and NeuN-positive cells) were found. SMOX overexpression in neurons leads to oxidative stress in neurons, increased by an ROS response in astrocytes and leading to the depletion of catalase (a reduction in the antioxidant defence in nerve terminals). A defective control of the AMPA-evoked intracellular Ca2+ response in the nerve terminals can exacerbate the reactive astrocytes-dependent excitotoxic mechanism activation. For further details, see the text. AMPA, alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor; Glu, glutamate; SMOX, spermine oxidase; Spm, spermine. Full article ">

12 pages, 1478 KiB

Open AccessArticle

Conventional and Resin-Modified Glass Ionomer Cement Surface Characteristics after Acidic Challenges

by Irina Nica, Simona Stoleriu, Alexandru Iovan, Ionuț Tărăboanță, Galina Pancu, Nicoleta Tofan, Răzvan Brânzan and Sorin Andrian

Biomedicines 2022, 10(7), 1755; https://doi.org/10.3390/biomedicines10071755 - 21 Jul 2022

Cited by 10 | Viewed by 3014

Abstract

The aim of the present study was to assess by atomic force microscopy (AFM) the surface roughness of a traditional glass ionomer cement- GIC (Fuji IX GP, GC Corporation, Tokyo, Japan) and a resin modified glass ionomer cement- RMGIC (Vitremer, 3M ESPE, St. [...] Read more.

The aim of the present study was to assess by atomic force microscopy (AFM) the surface roughness of a traditional glass ionomer cement- GIC (Fuji IX GP, GC Corporation, Tokyo, Japan) and a resin modified glass ionomer cement- RMGIC (Vitremer, 3M ESPE, St. Paul, MN, USA) after different immersion regimes on some acidic drinks. Sixteen cylindrical samples having the height of 5 mm and the thickness of 2 mm were obtained from each material and they were divided into two groups: Group I (Fuji IX samples) and Group II (Vitremer samples). Specimens of each group were then randomly divided into 4 subgroups: subgroup A (control)—15 samples were kept in artificial saliva and in the other three subgroups, each having 15 samples the samples were immersed in Coca-Cola (subgroup B), Cappy lemonade and mint (subgroup C) and Fuzetea (subgroup D) for 7 days (subgroups A1–D1), 14 days (subgroups A2–D2), and 21 days (subgroups A3–D3). AFM qualitative and quantitative surface evaluation (mean value of surface roughness parameter, Sa) of each sample was performed. The highest surface roughness was determined when both materials were submerged 14 days in acidic drinks. Traditional GIC was more affected by acidic environment when comparing to RMGIC. Full article

(This article belongs to the Special Issue Modern Polymers for Dental Application)

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17 pages, 1047 KiB

Open AccessReview

Endothelial Nitric Oxide Synthase in the Perivascular Adipose Tissue

by Andy W. C. Man, Yawen Zhou, Ning Xia and Huige Li

Biomedicines 2022, 10(7), 1754; https://doi.org/10.3390/biomedicines10071754 - 21 Jul 2022

Cited by 18 | Viewed by 3215

Abstract

Perivascular adipose tissue (PVAT) is a special type of ectopic fat depot that adheres to most vasculatures. PVAT has been shown to exert anticontractile effects on the blood vessels and confers protective effects against metabolic and cardiovascular diseases. PVAT plays a critical role [...] Read more.

Perivascular adipose tissue (PVAT) is a special type of ectopic fat depot that adheres to most vasculatures. PVAT has been shown to exert anticontractile effects on the blood vessels and confers protective effects against metabolic and cardiovascular diseases. PVAT plays a critical role in vascular homeostasis via secreting adipokine, hormones, and growth factors. Endothelial nitric oxide synthase (eNOS; also known as NOS3 or NOSIII) is well-known for its role in the generation of vasoprotective nitric oxide (NO). eNOS is primarily expressed, but not exclusively, in endothelial cells, while recent studies have identified its expression in both adipocytes and endothelial cells of PVAT. PVAT eNOS is an important player in the protective role of PVAT. Different studies have demonstrated that, under obesity-linked metabolic diseases, PVAT eNOS may be even more important than endothelium eNOS in obesity-induced vascular dysfunction, which may be attributed to certain PVAT eNOS-specific functions. In this review, we summarized the current understanding of eNOS expression in PVAT, its function under both physiological and pathological conditions and listed out a few pharmacological interventions of interest that target eNOS in PVAT. Full article

(This article belongs to the Special Issue Role of NO in Disease: Good, Bad or Ugly)

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The crosstalk between PVAT and the vessel wall modulates vascular functions. PVAT releases vasoactive molecules, hormones, adipokines, and microvesicles. PVAT-derived relaxing factors (PVRFs) include leptin and adiponectin, hydrogen sulphide (H2S), hydrogen peroxide (H2O2), prostaglandins, NO, and angiotensin (Ang) 1–7. PVAT-derived contracting factors (PVCFs) include chemerin, calpastatin, 5-hydroxytryptamine (5-HT), norepinephrine (NE), AngII, and ROS. These factors from PVAT may reach the endothelial layer of blood vessels by either direct diffusion or via vasa vasorum or small media conduit networks connecting the medial layer with the underlying adventitia and modulate vasodilation and vasocontraction. PVAT plays a critical role in vascular homeostasis via secreting adipokine, hormones, and growth factors to modulate the proliferation of VSMCs. Adipocytes from PVAT also secrete different types of extracellular vesicles, including exosomes and microvesicles, which have also been shown to trigger early vascular remodeling in vascular inflammation. Under pathological conditions, PVAT becomes dysfunctional, and the secretion of the PVAT-derived factor becomes imbalanced which could exert detrimental effects on vascular homeostasis and lead to vascular remodeling and arterial stiffening. Full article ">Figure 2
PVAT eNOS is an important modulator of vascular functions. Under HFD-induced obesity, the activity and expression of PVAT eNOS is significantly downregulated. PVAT eNOS may be even more important than endothelium eNOS in obesity-induced vascular dysfunction. Under normal condition, PVAT eNOS has multiple roles in regulating PVAT and vascular functions. PVAT eNOS can generate NO and regulate vasodilation via endothelium-dependent and endothelium-independent mechanisms. NO generated from PVAT eNOS can diffuse to the endothelium and activate EC, or directly activate sGC in the VSMC to evoke vasodilation. NO generated from PVAT eNOS can prevent vascular remodeling and stiffening via inhibiting VSMC proliferation and differentiation. PVAT eNOS is also responsible for modulating mitochondria biogenesis and browning of adipocytes in PVAT. In addition, NO generated from PVAT eNOS may regulate protein activities via SNO modification. Moreover, eNOS may, via protein–protein interactions and NO production, modulate miRNA-encapsulated microvesicles trafficking across PVAT. PVAT eNOS have a bidirectional regulation with adiponectin. Adiponectin is an important adipokine that modulates vascular functions via activating eNOS in both PVAT and EC. Current therapeutical strategies targeting PVAT eNOS include enhancing eNOS activity by phosphorylation, promoting deacetylation of eNOS via activation of SIRT1, activation of upstream kinase of eNOS (Akt, AMPK), and exercise training. AMPK, AMP-activated protein kinase; eNOS, endothelial nitric oxide synthase; EC, endothelial cell; HFD, high fat diet; NO, nitric oxide; PVAT, perivascular adipose tissue; sGC, soluble guanylyl cyclase; SNO, S-nitrosylation; VSMC, vascular smooth muscle cell. Full article ">

26 pages, 4873 KiB

Open AccessArticle

A Quantitative Digital Analysis of Tissue Immune Components Reveals an Immunosuppressive and Anergic Immune Response with Relevant Prognostic Significance in Glioblastoma

by Miguel A. Idoate Gastearena, Álvaro López-Janeiro, Arturo Lecumberri Aznarez, Iñigo Arana-Iñiguez and Francisco Guillén-Grima

Biomedicines 2022, 10(7), 1753; https://doi.org/10.3390/biomedicines10071753 - 21 Jul 2022

Cited by 7 | Viewed by 2435

Abstract

Objectives: Immunostimulatory therapies using immune checkpoint blockers show clinical activity in a subset of glioblastoma (GBM) patients. Several inhibitory mechanisms play a relevant role in the immune response to GBM. With the objective of analyzing the tumor immune microenvironment and its clinical [...] Read more.

Objectives: Immunostimulatory therapies using immune checkpoint blockers show clinical activity in a subset of glioblastoma (GBM) patients. Several inhibitory mechanisms play a relevant role in the immune response to GBM. With the objective of analyzing the tumor immune microenvironment and its clinical significance, we quantified several relevant immune biomarkers. Design: We studied 76 primary (non-recurrent) GBMs with sufficient clinical follow-up, including a subgroup of patients treated with a dendritic cell vaccine. The IDH-mutation, EGFR-amplification, and MGMT methylation statuses were determined. Several relevant immune biomarkers, including CD163, CD8, PD1, and PDL1, were quantified in representative selected areas by digital image analysis and semiquantitative evaluation. The percentage of each immune expression was calculated with respect to the total number of tumor cells. Results: All GBMs were wild-type IDH, with a subgroup of classical GBMs according to the EGFR amplification (44%). Morphologically, CD163 immunostained microglia and intratumor clusters of macrophages were observed. A significant direct correlation was found between the expression of CD8 and the mechanisms of lymphocyte immunosuppression, in such a way that higher values of CD8 were directly associated with higher values of CD163 (p < 0.001), PDL1 (0.026), and PD1 (0.007). In a multivariate analysis, high expressions of CD8+ (HR = 2.05, 95%CI (1.02–4.13), p = 0.034) and CD163+ cells (HR 2.50, 95%CI (1.29–4.85), p = 0.007), were associated with shorter survival durations. The expression of immune biomarkers was higher in the non-classical (non-EGFR amplified tumors) GBMs. Other relevant prognostic factors were age, receipt of the dendritic cell vaccine, and MGMT methylation status. Conclusions: In accordance with the inverse correlation between CD8 and survival and the direct correlation between effector cells and CD163 macrophages and immune-checkpoint expression, we postulate that CD8 infiltration could be placed in a state of anergy or lymphocytic inefficient activity. Furthermore, the significant inverse correlation between CD163 tissue concentration and survival explains the relevance of this type of immune cell when creating a strong immunosuppressive environment. This information may potentially be used to support the selection of patients for immunotherapy. Full article

(This article belongs to the Section Immunology and Immunotherapy)

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22 pages, 4311 KiB

Open AccessArticle

Enhancement of Osteoblast Function through Extracellular Vesicles Derived from Adipose-Derived Stem Cells

by Mei-Ling Ho, Chin-Jung Hsu, Che-Wei Wu, Ling-Hua Chang, Jhen-Wei Chen, Chung-Hwan Chen, Kui-Chou Huang, Je-Ken Chang, Shun-Cheng Wu and Pei-Lin Shao

Biomedicines 2022, 10(7), 1752; https://doi.org/10.3390/biomedicines10071752 - 21 Jul 2022

Cited by 9 | Viewed by 3541

Abstract

Adipose-derived stem cells (ADSCs) are a type of mesenchymal stem cell that is investigated in bone tissue engineering (BTE). Osteoblasts are the main cells responsible for bone formation in vivo and directing ADSCs to form osteoblasts through osteogenesis is a research topic in [...] Read more.

Adipose-derived stem cells (ADSCs) are a type of mesenchymal stem cell that is investigated in bone tissue engineering (BTE). Osteoblasts are the main cells responsible for bone formation in vivo and directing ADSCs to form osteoblasts through osteogenesis is a research topic in BTE. In addition to the osteogenesis of ADSCs into osteoblasts, the crosstalk of ADSCs with osteoblasts through the secretion of extracellular vesicles (EVs) may also contribute to bone formation in ADSC-based BTE. We investigated the effect of ADSC-secreted EVs (ADSC-EVs) on osteoblast function. ADSC-EVs (size ≤ 1000 nm) were isolated from the culture supernatant of ADSCs through ultracentrifugation. The ADSC-EVs were observed to be spherical under a transmission electron microscope. The ADSC-EVs were positive for CD9, CD81, and Alix, but β-actin was not detected. ADSC-EV treatment did not change survival but did increase osteoblast proliferation and activity. The 48 most abundant known microRNAs (miRNAs) identified within the ADSC-EVs were selected and then subjected to gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. The GO analysis revealed that these miRNAs are highly relevant to skeletal system morphogenesis and bone development. The KEGG analysis indicated that these miRNAs may regulate osteoblast function through autophagy or the mitogen-activated protein kinase or Ras-related protein 1 signaling pathway. These results suggest that ADSC-EVs enhance osteoblast function and can contribute to bone regeneration in ADSC-based BTE. Full article

(This article belongs to the Special Issue Regenerative Medicine for Bone and Cartilage and Pathophysiology of Degenerative Diseases)

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Characterization of ADSC-EVs. ADSC-EVs were isolated from three separate batches of conditioned media (CMs) and characterized. (A) Particle size distribution of ADSC-EVs measured through a nanoparticle tracking analysis (NTA). (B) Mean particle sizes of ADSC-EVs measured through NTA. Data are presented as the mean ± standard deviation (SD; n = 3). (C) Morphology of the ADSC-EVs as observed through transmission electron microscopy. (D) Western blot analysis of the protein levels of CD9, CD81, Alix, and β-actin in ADSCs and ADSC-EVs. Full article ">Figure 2
ADSC-EV uptake by osteoblasts. The hFOBs (A) and hOBs (B) were treated with CM-DiI-labeled ADSC-EVs at concentrations of 0 (Control: control group) or 1 × 109 particles/mL (EVs: EV group) for 5 days, and images at days 1 and 5 were obtained using a camera under confocal microscopy. Cell nucleus, blue fluorescence stain; cytoplasm, green fluorescence stain; and CM-DiI-labeled ADSC-EVs, red fluorescence stain. Full article ">Figure 3
Effect of ADSC-EVs on the survival of osteoblasts. The hFOBs (A) and hOBs (B) were treated with ADSC-EVs at concentrations of 0 (Control: control group) or 109 particles/mL (EVs: EV group) for 5 days and analyzed for survival. Live/dead cell assays were performed for hFOBs and hOBs to determine the cell survival on days 1 and 5. Green fluorescence indicates live cells (Live), whereas red fluorescence indicates dead cells (Dead). The hFOBs and hOBs remained alive on days 1 and 5 after the ADSC-EV treatment. Full article ">Figure 4
Effect of ADSC-EVs on the proliferation of osteoblasts. The hFOBs (A) and hOBs (B) were treated with ADSC-EVs at concentrations of 0 (Control: control group) or 1 × 107–1 × 109 particles/mL (EVs: EV group) for 5 days and analyzed for cell proliferation. MTS assays were performed for hFOBs and hOBs on day 5 to determine the cell proliferation. Cell proliferation of hFOBs and hOBs was enhanced after the ADSC-EV treatment. Data are presented as the mean ± SD (n = 6). * p < 0.05 and ** p < 0.01 for comparisons with the control group. # p < 0.05 and ## p < 0.01 for comparisons between the two groups. Full article ">Figure 5
ADSC-EVs promoted osteogenic marker gene expression in osteoblasts. The hFOBs (A) and hOBs (B) were treated with ADSC-EVs at concentrations of 0 (Control: control group) or 109 particles/mL (EVs: EV group) for 5 days. The mRNA expression levels of the osteogenic marker genes (runt-related transcription factor 2 (Runx2), osteocalcin (OC), collagen type I (Col-I), and alkaline phosphatase (ALP)) of hFOBs and hOBs were measured. Gene expression levels are expressed relative to the control group, which is defined as 1. Data are presented as the mean ± SD (n = 3). * p < 0.05 and ** p < 0.01 for comparisons with the control group. Full article ">Figure 6
ADSC-EVs promote ALP activity, calcium deposition, and collagen type I (Col-I) synthesis in osteoblasts. The hFOBs (A) and hOBs (B) were treated with ADSC-EVs at concentrations of 0 (Control: control group) or 1 × 109 particles/mL (EVs: EV group) for 12 days and analyzed through von Kossa staining, Alizarin red S staining and quantification, and ELISA for ALP activity and Col-I synthesis. Data are presented as the mean ± SD (n = 3). * p < 0.05 and ** p < 0.01 for comparisons with the control group. Full article ">Figure 7
miRNA bioinformatics analysis of ADSC-EVs. Next-generation sequencing of the 48 most abundant known miRNAs detected in ADSC-EVs; the total read count is shown (n = 3). Full article ">Figure 8
Gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. GO pathway and KEGG pathway analyses were performed for the target genes of miRNAs enriched in ADSC-EVs. (A) GO enrichment analysis results. (B) KEGG enrichment analysis results. Bar and dot plots of GO and KEGG are shown (n = 3). Full article ">

15 pages, 1066 KiB

Open AccessArticle

The Effect of SGLT2 Inhibitor Dapagliflozin on Serum Levels of Apelin in T2DM Patients with Heart Failure

by Alexander A. Berezin, Ivan M. Fushtey and Alexander E. Berezin

Biomedicines 2022, 10(7), 1751; https://doi.org/10.3390/biomedicines10071751 - 20 Jul 2022

Cited by 8 | Viewed by 2796

Abstract

Apelin is a multifunctional peptide that plays a pivotal role in cardiac remodeling and HF manifestation because of counteracting angiotensin-II. We hypothesized that positive influence of sodium-glucose co-transporter-2 (SGLT2) inhibitor on cardiac function in T2DM patients with HF might be mediated by apelin [...] Read more.

Apelin is a multifunctional peptide that plays a pivotal role in cardiac remodeling and HF manifestation because of counteracting angiotensin-II. We hypothesized that positive influence of sodium-glucose co-transporter-2 (SGLT2) inhibitor on cardiac function in T2DM patients with HF might be mediated by apelin and that its levels seem to be a target of management. A total of 153 type 2 diabetes mellitus (T2DM) patients with II/III HF NYHA class and average left ventricular (LV) ejection fraction (EF) of 46% have been enrolled and treated with dapagliflosin. The serum levels of apelin and N-terminal brain natriuretic pro-peptide (NT-proBNP) were measured at baseline and over a 6-month period of dapagliflosin administration. We noticed that administration of dapagliflozin was associated with a significant increase in apelin levels of up to 18.3% and a decrease in NT-proBNP of up to 41.0%. Multivariate logistic regression showed that relative changes of LVEF, LA volume index, and early diastolic blood filling to longitudinal strain ratio were strongly associated with the levels of apelin, whereas NT-proBNP exhibited a borderline significance in this matter. In conclusion, dapagiflosin exerted a positive impact on echocardiographic parameters in close association with an increase in serum apelin levels, which could be a surrogate target for HF management. Full article

(This article belongs to the Special Issue Advances in Cardiovascular Pharmacology: The Era of Targeted Therapies in Cardiology)

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17 pages, 2110 KiB

Open AccessReview

Interleukin-18 Binding Protein in Immune Regulation and Autoimmune Diseases

by Seung Yong Park, Yasmin Hisham, Hyun Mu Shin, Su Cheong Yeom and Soohyun Kim

Biomedicines 2022, 10(7), 1750; https://doi.org/10.3390/biomedicines10071750 - 20 Jul 2022

Cited by 16 | Viewed by 6987

Abstract

Natural soluble antagonist and decoy receptor on the surface of the cell membrane are evolving as crucial immune system regulators as these molecules are capable of recognizing, binding, and neutralizing (so-called inhibitors) their targeted ligands. Eventually, these soluble antagonists and decoy receptors terminate [...] Read more.

Natural soluble antagonist and decoy receptor on the surface of the cell membrane are evolving as crucial immune system regulators as these molecules are capable of recognizing, binding, and neutralizing (so-called inhibitors) their targeted ligands. Eventually, these soluble antagonists and decoy receptors terminate signaling by prohibiting ligands from connecting to their receptors on the surface of cell membrane. Interleukin-18 binding protein (IL-18BP) participates in regulating both Th1 and Th2 cytokines. IL-18BP is a soluble neutralizing protein belonging to the immunoglobulin (Ig) superfamily as it harbors a single Ig domain. The Ig domain is essential for its binding to the IL-18 ligand and holds partial homology to the IL-1 receptor 2 (IL-1R2) known as a decoy receptor of IL-1α and IL-1β. IL-18BP was defined as a unique soluble IL-18BP that is distinct from IL-18Rα and IL-18Rβ chain. IL-18BP is encoded by a separated gene, contains 8 exons, and is located at chr.11 q13.4 within the human genome. In this review, we address the difference in the biological activity of IL-18BP isoforms, in the immunity balancing Th1 and Th2 immune response, its critical role in autoimmune diseases, as well as current clinical trials of recombinant IL-18BP (rIL-18BP) or equivalent. Full article

(This article belongs to the Collection Feature Papers in Immunology and Immunotherapy)

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IL-18BP Biological Role. Left panel, ① danger stimuli, such as pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), activate the Toll-like receptors (TLR) signaling pathway that triggers MyD88, TRAF, inflammasome oligomerization that leads to subsequent activation of caspase-1 (Cas1). Consequently, the translocation of the NF-κB takes place and leads to ② the production of proinflammatory cytokines, including inductions of the transcriptional activation of pro-interleukin IL-18 (pro-IL-18), which is proteolytically cleaved and converted to its mature active form via the active caspase-1 (Cas1), then ③ IL-18 is secreted from the cell. Right panel, ④ when secreted IL-18 binds to the cells expressing IL-18R (mainly monocytes, NK cells, and T cells) and activates the respective signaling pathways, for example, MAPKs and NF-κB activation, which in turn leads to the ⑤ expression of proinflammatory molecules and induce the production of IFNγ. Next, IFNγ activates macrophages and allows them to produce inflammatory cytokines. This IFNγ induction and the activation cascade of IL-18 is inhibited by its natural neutralizing soluble inhibitor, interleukin IL-18 binding protein (IL-18BP). Full article ">Figure 2
IL-18BP expression induced by IFNγ. IFNγ production is induced due to cytokines that are released in response to infection, tissue damage, activation of pattern recognition receptors (PRRs) or reactive antigen stimulation. Left side (up), the upregulated IL-18BP triggers the negative feedback loop, which in turn allows IL-18BP to inhibit the production of IFNγ. Left side (down), the epigenetic regulation of IL-18BP in various cells, methylation at the IL-18BP promoter region controls its expression upon IFNγ stimulation. Epithelial cells have no CpG methylation; therefore, their IL-18BP inducibility is strong and higher than monocytic cells, which have CpG methylation. Right side, IFNγ signaling starts when it binds to its receptor IFNγR, which consists of two subunits, IFNγR1 and IFNγR2. Later, this binding induces the Janus kinase (JAK) signal transducer and activator of transcription (STAT) signaling, particularly STAT1 makes a dimer, and then cooperates with IFNγ-induced interferon regulatory factors (IRFs), resulting in translocation into the nucleus. IL-18BP promoter holds several response elements, among them IFN regulatory factor 1 response element (IRF-E) and STAT1. These transcriptional activations of the promoter induce IL-18BP expression. Full article ">Figure 3
IL-18BP isoforms. Multiple sequence alignment for the isoforms of human IL-18BP. PTM features are indicated as glycosylation sites, which are displayed above the sequence (N-linked; Triangle, O-linked; circle, blue for confirmed, red for predicted O-glycosylation). Disulfide bridges are exposed as dashed lines (red and orange). Residues with homology are indicated with an asterisk (*) below the residue. Residues shearing identity with the virus IL-18BP are highlighted within an orange color shaded box. The domain of Ig-like C2-type is highlighted in green (starts at 65 and ends at 166 with a length of 102aa based on the sequence of IL-18BPa). Uniport accession number; IL-18BPa (O95998 I18BP_HUMAN/NP_766630.2), IL-18BPb (O95998-3 I18BP_HUMAN/NP_001138527.1), IL-18BPd (O95998-4 I18BP_HUMAN/NP_766632.2), and IL-18BPc (G3V1C5 _HUMAN/NP_005690.2). (:) Conservative residue; (.) Semi-conservative residue; ( ) Non-conservative residue. Full article ">Figure 4
IL-18BP inhibiting IL-18 target cells and therapeutic interventions. IL-18 assists several immune cells, it stimulates NK to produce IFNγ, which activates macrophages and allows them to produce inflammatory cytokines. In addition, it participates in the Th1 and Th2 response, depending on cytokine partners, when IL-18 is combined with IL-12 it facilitates the Th1 immune response, which in turn activates DCs and releases inflammatory cytokines, such as IFNγ and TNFα. In response to Th1 activation, M1 macrophages induce IL-18 and supply the loop. Alternatively, in the absence of IL-12, and when IL-18 is combined with IL-2 and/or IL-4, together they facilitate Th2 immune response, which in turn secreted IgE and numerous Th2 cytokines, such as IL-4, IL-5, IL-9, and IL-13. In response to Th2 activation, M2 macrophages and/or mast cells become activated, and then the production of histamine takes place (allergic response), which is also facilitated when IL-18 is combined with IL-3. When IL-18BP sequestered IL-18, the following activated cascade is inhibited. Therefore, IL-18BP can play potential roles in both Th1 and Th2 autoimmune diseases. Boxes indicated the main pathological condition (RED), potential therapeutic options (BLUE; anticancer molecules in the clinical trial, GREEN; IL-18BP or equivalent; Tadekinig-α, GSK1070806, and APB-3R are in clinical and pre-clinical trials, IL-18BPΔN-EH showed higher affinity than full-length IL-18BP and suggested for use in treating autoimmune diseases). Full article ">

23 pages, 1129 KiB

Open AccessSystematic Review

Tendinopathies and Pain Sensitisation: A Meta-Analysis with Meta-Regression

by Davide Previtali, Alberto Mameli, Stefano Zaffagnini, Paolo Marchettini, Christian Candrian and Giuseppe Filardo

Biomedicines 2022, 10(7), 1749; https://doi.org/10.3390/biomedicines10071749 - 20 Jul 2022

Cited by 6 | Viewed by 2605

Abstract

The presence of pain sensitisation has been documented and reported as being a possible cause of treatment failure and pain chronicity in several musculoskeletal conditions, such as tendinopathies. The aim of the present study is to analyse existing evidence on pain sensitisation in [...] Read more.

The presence of pain sensitisation has been documented and reported as being a possible cause of treatment failure and pain chronicity in several musculoskeletal conditions, such as tendinopathies. The aim of the present study is to analyse existing evidence on pain sensitisation in tendinopathies comparing the local and distant pain thresholds of healthy and affected subjects with distinct analysis for different tendinopathies. PubMed, Cochrane Central Register, Scopus, and Web Of Science were systematically searched after registration on PROSPERO (CRD42020164124). Level I to level IV studies evaluating the presence of pain sensitisation in patients with symptomatic tendinopathies, documented through a validated method, were included. A meta-analysis was performed to compare local, contralateral, and distant pain thresholds between patients and healthy controls with sub-analyses for different tendinopathies. Meta-regressions were conducted to evaluate the influence of age, activity level, and duration of symptoms on results. Thirty-four studies out of 2868 were included. The overall meta-analysis of local pressure pain thresholds (PPT) documented an increased sensitivity in affected subjects (p < 0.001). The analyses on contralateral PPTs (p < 0.001) and distant PPTs (p = 0.009) documented increased sensitivity in the affected group. The results of the sub-analyses on different tendinopathies were conflicting, except for those on lateral epicondylalgia. Patients’ activity level (p = 0.02) and age (p = 0.05) significantly influenced local PPT results. Tendinopathies are characterized by pain sensitisation, but, while features of both central and peripheral sensitisation can be constantly detected in lateral epicondylalgia, results on other tendinopathies were more conflicting. Patients’ characteristics are possible confounders that should be taken into account when addressing pain sensitisation. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Chronic Pain and New Therapeutic Strategies)

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10 pages, 982 KiB

Open AccessArticle

Effect of Anti-Hypertensive Medication on Plasma Concentrations of Lysyl Oxidase: Evidence for Aldosterone-IL-6-Dependent Regulation of Lysyl Oxidase Blood Concentration

by Rolf Schreckenberg, Oliver Dörr, Sabine Pankuweit, Bernhard Schieffer, Christian Troidl, Holger Nef, Christian W. Hamm, Susanne Rohrbach, Ling Li and Klaus-Dieter Schlüter

Biomedicines 2022, 10(7), 1748; https://doi.org/10.3390/biomedicines10071748 - 20 Jul 2022

Viewed by 1858

Abstract

Lysyl oxidase (LOX) is a secretory protein that catalyzes elastin and collagen cross-linking. Lowering LOX expression and activity in endothelial cells is associated with a high risk of aneurysms and vascular malformation. Interleukin-6 (IL-6), elevated in hypertension, is known to suppress LOX expression. [...] Read more.

Lysyl oxidase (LOX) is a secretory protein that catalyzes elastin and collagen cross-linking. Lowering LOX expression and activity in endothelial cells is associated with a high risk of aneurysms and vascular malformation. Interleukin-6 (IL-6), elevated in hypertension, is known to suppress LOX expression. The influence of anti-hypertensive medication on the plasma LOX concentration is currently unknown. In a cohort of 34 patients diagnosed with resistant hypertension and treated with up to nine different drugs, blood concentration of LOX was analyzed to identify drugs that have an impact on plasma LOX concentration. Key findings were confirmed in a second independent patient cohort of 37 patients diagnosed with dilated cardiomyopathy. Blood concentrations of aldosterone and IL-6 were analyzed. In vitro, the effect of IL-6 on LOX expression was analyzed in endothelial cells. Patients receiving aldosterone antagonists had the highest plasma LOX concentration in both cohorts. This effect was independent of sex, age, blood pressure, body mass index, and co-medication. Blood aldosterone concentration correlates with plasma IL-6 concentration. In vitro, IL-6 decreased the expression of LOX in endothelial cells but not fibroblasts. Aldosterone was identified as a factor that affects blood concentration of LOX in an IL-6-dependent manner. Full article

(This article belongs to the Special Issue Vascular Endothelial Functions: Insights from Molecular Perspectives)

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Effect of ACE/AT1 antagonism, statins, or ASA on plasma concentrations of LOX in hypertensive patients. LOX plasma concentrations in patients from cohort 1 (hypertension) either without (control) or with specified treatment (ACE/AT1 antagonism, statins, or ASA). Data are shown separately for the whole cohort, men only, and women only. The box and whiskers plots show the total range (whiskers), Q25, Q50, and Q75. Exact p-values are given and n-values are given. Full article ">Figure 2
Effect of aldosterone blockade on serum concentrations of LOX in DCM patients. LOX serum concentrations in patients from cohort 2 (DCM) either without (control; n = 17) or with aldosterone blockade (Aldo; n = 19). The box and whiskers plots show the total range (whiskers), Q25, Q50, and Q75. Exact p-value is given. Full article ">Figure 3
Effect of interleukin-6 (IL-6) on LOX mRNA expression in isolated microvascular rat endothelial cells and cardiac fibroblasts. mRNA expression of LOX was normalized to beta-2-microglobulin as a housekeeping gene. Mean expression of control cultures is set as 1. Cells were incubated for 24 h with IL-6 (10 ng/mL). The box and whiskers plots show the total range (whiskers), Q25, Q50, and Q75. Exact p-values are given (n = 6 cultures each). Full article ">Figure 4
Correlation between blood concentration of IL-6 and aldosterone. IL-6 and aldosterone serum concentrations from patients of cohort 2 not receiving aldosterone blockade are plotted against each other. Linear regression analysis was performed by Pearson correlation (r = 0.608; p = 0.021). Full article ">

3 pages, 170 KiB

Open AccessEditorial

NAFLD: From Mechanisms to Therapeutic Approaches

by Karim Gariani and François R. Jornayvaz

Biomedicines 2022, 10(7), 1747; https://doi.org/10.3390/biomedicines10071747 - 20 Jul 2022

Cited by 2 | Viewed by 1641

Abstract

Nonalcoholic fatty liver disease (NAFLD) now represents the most frequent chronic liver disease worldwide [...] Full article

(This article belongs to the Special Issue NAFLD: From Mechanisms to Therapeutic Approaches)

19 pages, 2490 KiB

Open AccessArticle

In Vivo and Ex Vivo Mitochondrial Function in COVID-19 Patients on the Intensive Care Unit

by Lucia W. J. M. Streng, Calvin J. de Wijs, Nicolaas J. H. Raat, Patricia A. C. Specht, Dimitri Sneiders, Mariëlle van der Kaaij, Henrik Endeman, Egbert G. Mik and Floor A. Harms

Biomedicines 2022, 10(7), 1746; https://doi.org/10.3390/biomedicines10071746 - 20 Jul 2022

Cited by 13 | Viewed by 2417

Abstract

Mitochondrial dysfunction has been linked to disease progression in COVID-19 patients. This observational pilot study aimed to assess mitochondrial function in COVID-19 patients at intensive care unit (ICU) admission (T1), seven days thereafter (T2), and in healthy controls and a general anesthesia group. [...] Read more.

Mitochondrial dysfunction has been linked to disease progression in COVID-19 patients. This observational pilot study aimed to assess mitochondrial function in COVID-19 patients at intensive care unit (ICU) admission (T1), seven days thereafter (T2), and in healthy controls and a general anesthesia group. Measurements consisted of in vivo mitochondrial oxygenation and oxygen consumption, in vitro assessment of mitochondrial respiration in platelet-rich plasma (PRP) and peripheral blood mononuclear cells (PBMCs), and the ex vivo quantity of circulating cell-free mitochondrial DNA (mtDNA). The median mitoVO₂ of COVID-19 patients on T1 and T2 was similar and tended to be lower than the mitoVO₂ in the healthy controls, whilst the mitoVO₂ in the general anesthesia group was significantly lower than that of all other groups. Basal platelet (PLT) respiration did not differ substantially between the measurements. PBMC basal respiration was increased by approximately 80% in the T1 group when contrasted to T2 and the healthy controls. Cell-free mtDNA was eight times higher in the COVID-T1 samples when compared to the healthy controls samples. In the COVID-T2 samples, mtDNA was twofold lower when compared to the COVID-T1 samples. mtDNA levels were increased in COVID-19 patients but were not associated with decreased mitochondrial O₂ consumption in vivo in the skin, and ex vivo in PLT or PBMC. This suggests the presence of increased metabolism and mitochondrial damage. Full article

(This article belongs to the Special Issue Mitochondrial Metabolism in Health and Disease)

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Flowchart of the inclusion process. Full article ">Figure 2
MitoPO2 (mmHg) in HC, COVID-19 patients on T1 and T2, and general anesthesia group. HC = healthy controls, T1 = time point 1, T2 = time point 2, and GA = general anesthesia. Values are displayed as median with interquartile range (box) and minimum and maximum (whiskers). Full article ">Figure 3
MitoVO2 (mmHg/s) in HC, COVID-19 patients on T1 and T2, and the general anesthesia group. HC = healthy controls, T1 = time point 1, T2 = time point 2, and GA = general anesthesia. Values are displayed as median with interquartile range (box) and minimum and maximum (whiskers). Full article ">Figure 4
Whole blood cell counts for platelets (PLT), PBMC, lymphocytes (LY), monocytes (MO), neutrophils (NE), red blood cells (RBC), and Hb levels for the healthy control (HC), COVID-T1, and COVID-T2 groups. Full article ">Figure 5
Oxygen consumption rate (OCR) for ROUTINE, LEAK, maximal respiration (MAX), and respiration after inhibition of complex I by rotenone (ROT) in (A) platelets and (C) PBMC. LEAK/ET coupling control ratio (L/E Ratio) in (B) platelets and (D) PBMC for the healthy control (HC), COVID-T1, and COVID-T2 groups. Values displayed as median ± min/max values. Full article ">Figure 6
Plasma amount of nuclear DNA (β-globin) and mitochondrial DNA (mtDNA) in HC = healthy controls, COVID-T1, and COVID-T2 groups. (A) Unfiltered nuclear DNA amount. (B) Filtered nuclear DNA amount. (C) Unfiltered mtDNA. (D) Filtered mtDNA. Values are displayed as median ± IQR. Full article ">

19 pages, 1888 KiB

Open AccessEditor’s ChoiceReview

Obesity and Endothelial Function

by Masato Kajikawa and Yukihito Higashi

Biomedicines 2022, 10(7), 1745; https://doi.org/10.3390/biomedicines10071745 - 19 Jul 2022

Cited by 30 | Viewed by 5046

Abstract

Obesity is a major public health problem and is related to increasing rates of cardiovascular morbidity and mortality. Over 1.9 billion adults are overweight or obese worldwide and the prevalence of obesity is increasing. Obesity influences endothelial function through obesity-related complications such as [...] Read more.

Obesity is a major public health problem and is related to increasing rates of cardiovascular morbidity and mortality. Over 1.9 billion adults are overweight or obese worldwide and the prevalence of obesity is increasing. Obesity influences endothelial function through obesity-related complications such as hypertension, dyslipidemia, diabetes, metabolic syndrome, and obstructive sleep apnea syndrome. The excess fat accumulation in obesity causes adipocyte dysfunction and induces oxidative stress, insulin resistance, and inflammation leading to endothelial dysfunction. Several anthropometric indices and imaging modalities that are used to evaluate obesity have demonstrated an association between obesity and endothelial function. In the past few decades, there has been great focus on the mechanisms underlying endothelial dysfunction caused by obesity for the prevention and treatment of cardiovascular events. This review focuses on pathophysiological mechanisms of obesity-induced endothelial dysfunction and therapeutic targets of obesity. Full article

(This article belongs to the Special Issue Endothelial Dysfunction: From a Pathophysiological Mechanism to a Potential Therapeutic Target (Volume II))

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13 pages, 602 KiB

Open AccessArticle

Metabolic Syndrome and Obesity-Related Indices Are Associated with Rapid Renal Function Decline in a Large Taiwanese Population Follow-Up Study

by Wei-Yu Su, I-Hua Chen, Yuh-Ching Gau, Pei-Yu Wu, Jiun-Chi Huang, Yi-Chun Tsai, Szu-Chia Chen, Jer-Ming Chang, Shang-Jyh Hwang and Hung-Chun Chen

Biomedicines 2022, 10(7), 1744; https://doi.org/10.3390/biomedicines10071744 - 19 Jul 2022

Cited by 11 | Viewed by 2320

Abstract

A rapid decline in renal function can cause many complications, and therefore it is important to detect associated risk factors. Few studies have evaluated the associations among obesity-related indices and metabolic syndrome (MetS) with renal function decline. This longitudinal study aimed to explore [...] Read more.

A rapid decline in renal function can cause many complications, and therefore it is important to detect associated risk factors. Few studies have evaluated the associations among obesity-related indices and metabolic syndrome (MetS) with renal function decline. This longitudinal study aimed to explore these relationships in a large cohort of Taiwanese participants. The studied obesity-related indices were waist-to-height ratio (WHtR), A body shape index (ABSI), visceral adiposity index (VAI), lipid accumulation product (LAP), waist-to-hip ratio (WHR), body roundness index (BRI), conicity index (CI), body mass index (BMI), body adiposity index (BAI) and abdominal volume index (AVI). We included 122,068 participants in the baseline study, of whom 27,033 were followed for a median of four years. The baseline prevalence of MetS was 17.7%. Multivariable analysis showed that the participants with MetS and high VAI, WHtR, WHR, LAP, CI, BRI, BMI, BAI, AVI, and ABSI values were significantly associated with a high baseline estimated glomerular filtration rate (eGFR) (all p < 0.001). In addition, the participants with MetS (p < 0.001), high WHtR (p = 0.007), low LAP (p < 0.001), high BRI (p = 0.002), high CI (p = 0.002), high AVI (p = 0.001), high VAI (p = 0.017), and high ABSI (p = 0.013) were significantly associated with a low △eGFR, indicating a rapid decline in renal function. These results showed associations between MetS and high values of obesity-related indices except LAP with high baseline eGFR and rapid decline in kidney function. These findings suggest that screening for MetS and obesity may help to slow the decline in renal function in high-risk populations. Full article

(This article belongs to the Special Issue Pathogenesis and Treatment Progress of Chronic Kidney Diseases)

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16 pages, 3875 KiB

Open AccessReview

Synaptic Disruption by Soluble Oligomers in Patients with Alzheimer’s and Parkinson’s Disease

by Berenice A. Gutierrez and Agenor Limon

Biomedicines 2022, 10(7), 1743; https://doi.org/10.3390/biomedicines10071743 - 19 Jul 2022

Cited by 8 | Viewed by 3503

Abstract

Neurodegenerative diseases are the result of progressive dysfunction of the neuronal activity and subsequent neuronal death. Currently, the most prevalent neurodegenerative diseases are by far Alzheimer’s (AD) and Parkinson’s (PD) disease, affecting millions of people worldwide. Although amyloid plaques and neurofibrillary tangles are [...] Read more.

Neurodegenerative diseases are the result of progressive dysfunction of the neuronal activity and subsequent neuronal death. Currently, the most prevalent neurodegenerative diseases are by far Alzheimer’s (AD) and Parkinson’s (PD) disease, affecting millions of people worldwide. Although amyloid plaques and neurofibrillary tangles are the neuropathological hallmarks for AD and Lewy bodies (LB) are the hallmark for PD, current evidence strongly suggests that oligomers seeding the neuropathological hallmarks are more toxic and disease-relevant in both pathologies. The presence of small soluble oligomers is the common bond between AD and PD: amyloid β oligomers (AβOs) and Tau oligomers (TauOs) in AD and α-synuclein oligomers (αSynOs) in PD. Such oligomers appear to be particularly increased during the early pathological stages, targeting synapses at vulnerable brain regions leading to synaptic plasticity disruption, synapse loss, inflammation, excitation to inhibition imbalance and cognitive impairment. Absence of TauOs at synapses in individuals with strong AD disease pathology but preserved cognition suggests that mechanisms of resilience may be dependent on the interactions between soluble oligomers and their synaptic targets. In this review, we will discuss the current knowledge about the interactions between soluble oligomers and synaptic dysfunction in patients diagnosed with AD and PD, how it affects excitatory and inhibitory synaptic transmission, and the potential mechanisms of synaptic resilience in humans. Full article

(This article belongs to the Special Issue News about Structure and Function of Synapses: Health and Diseases)

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20 pages, 4498 KiB

Open AccessArticle

Nanomechanical and Morphological AFM Mapping of Normal Tissues and Tumors on Live Brain Slices Using Specially Designed Embedding Matrix and Laser-Shaped Cantilevers

by Vladislav M. Farniev, Mikhail E. Shmelev, Nikita A. Shved, Valeriia S. Gulaia, Arthur R. Biktimirov, Alexey Y. Zhizhchenko, Aleksandr A. Kuchmizhak and Vadim V. Kumeiko

Biomedicines 2022, 10(7), 1742; https://doi.org/10.3390/biomedicines10071742 - 19 Jul 2022

Cited by 11 | Viewed by 3114

Abstract

Cell and tissue nanomechanics has been intriguingly introduced into biomedical research, not only complementing traditional immunophenotyping and molecular analysis, but also bringing unexpected new insights for clinical diagnostics and bioengineering. However, despite the progress in the study of individual cells in culture by [...] Read more.

Cell and tissue nanomechanics has been intriguingly introduced into biomedical research, not only complementing traditional immunophenotyping and molecular analysis, but also bringing unexpected new insights for clinical diagnostics and bioengineering. However, despite the progress in the study of individual cells in culture by atomic force microscopy (AFM), its application for mapping live tissues has a number of technical limitations. Here, we elaborate a new technique to study live slices of normal brain tissue and tumors by combining morphological and nanomechanical AFM mapping in high throughput scanning mode, in contrast to the typically utilized force spectroscopy mode based on single-point probe application. This became possible due to the combined use of an appropriate embedding matrix for vibratomy and originally modified AFM probes. The embedding matrix composition was carefully developed by regulating the amounts of agar and collagen I to reach optimal viscoelastic properties for obtaining high-quality live slices that meet AFM requirements. AFM tips were rounded by irradiating them with focused nanosecond laser pulses, while the resulting tip morphology was verified by scanning electron microscopy. Live slices preparation and AFM investigation take only 55 min and could be combined with a vital cell tracer analysis or immunostaining, thus making it promising for biomedical research and clinical diagnostics. Full article

(This article belongs to the Special Issue Regulatory Role of ECM Biophysical Signals on Cell and Nuclear Mechanics)

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Comparative characteristics of the mechanics and viability of tissue sections obtained in different types of embedding matrix with tissue not subjected to vibratomy. (a) A tissue fragment not subjected to vibratomy in the matrix. (b) Tissue section obtained in a matrix consisting of 1.5% agar, 1.5 mg/mL collagen. (c) Tissue section obtained in a matrix consisting of 2.0% agar, 0.5 mg/mL collagen. (d) Tissue section obtained in a matrix consisting of 2.0% agar, 1.0 mg/mL collagen. (e) Tissue section obtained in a matrix consisting of 2.0% agar, 1.5 mg/mL collagen. Full article ">Figure 2
Vibrosectioning of the rat brain embedded in the matrix cone (a–e): (a) brain specimen embedded in the matrix cone; (b) schematic representation of the vibratome components adjusted for live brain sectioning: (1—specimen of brain, 2—embedding matrix cone, 3—vibratome blade, 4—vibratome blade translation, 5—gasket/spacer); (c) Vibrosectioning of the rat brain in the embedding matrix with insufficient stiffness (<2.500 µN/m) and elasticity (<27 kPa); (d) Vibrosectioning of the rat brain in the embedding matrix with suitable stiffness (2.6 µN/m) and elasticity (27 kPa); (e) Vibrosectioning of the rat brain in the embedding matrix with excessive stiffness (>3.5 µN/m) and elasticity (>30 kPa); (f,g) slice quality control by AFM with ScanAsyst Fluid High Resolution tip (Height sensor channel): (f) the slice surface of an agar gel (2.5% agar) without collagen (Height sensor channel); (g) the slice surface of collagen–agar gel (2.0% agar; 0.5 mg/mL type I collagen). Full article ">Figure 3
Comparative characteristics of the AFM probes: SEM images showing (a) stock ScanAsyst Fluid High Resolution probe and (c) laser-modified ScanAsyst Fluid High Resolution probes, as well as (e) NP−10 probe with an attached microbead. (b,d,f) AFM morphological maps of the 2% agar gel surface obtained using the above-mentioned cantilevers. Full article ">Figure 4
Surface properties of the rat brain slice studied by LSM (a,h,i) and AFM (laser-reshaped ScanAsyst Fluid High Resolution probe (b,d,e) and microbead-based cantilevers NP−10 (c,f,g). (a) Large−scale LSM map showing the ratio of live (green glow) to dead cells (red glow). (h,i) Two areas show 3D reconstruction of the smaller map sections chosen for subsequent AFM studies with two types of cantilevers. Surface morphology of the chosen slice obtained using laser-reshaped (b) and microbead-based (c) cantilevers. Insets on both images provide 3D reconstructions of these areas. (d,e) Elasticity and stiffness AFM maps by laser−reshaped ScanAsyst Fluid High Resolution probe. (f,g) Elasticity and stiffness AFM maps by microbead−based cantilevers NP−10. Full article ">Figure 5
Surface properties of the human glioma slice studied by LSM (a,h,i) and AFM (laser-reshaped ScanAsyst Fluid High Resolution probe (b,d,e) and microbead−based cantilevers NP−10 (c,f,g). (a) Large-scale LSM map showing the ratio of live (green glow) to dead cells (red glow). (h,i) Two areas show 3D reconstruction of the smaller map sections chosen for subsequent AFM studies with two types of cantilevers. Surface morphology of the chosen slice obtained using laser-reshaped (b) and microbead−based (c) cantilevers. Insets on both images provide 3D reconstructions of these areas. (d,e) Elasticity and stiffness AFM maps of the chosen areas by laser-reshaped ScanAsyst Fluid High Resolution probe. (f,g). Elasticity and stiffness AFM maps by microbead-based cantilevers NP−10. Full article ">Figure 6
Combined immunohistochemical LSM and AFM analysis of rat brain slices. (a) Immunohistochemistry of slice surface captured by LSM (blue signal–DAPI-cell nucleus; green signal–GFAP-glial cell cytoskeletal protein); (b) merged LSM and AFM channels; (c) morphological map of the slice surface obtained by AFM (height sensor). Full article ">

15 pages, 4455 KiB

Open AccessArticle

Exploring Gut Microenvironment in Colorectal Patient with Dual-Omics Platform: A Comparison with Adenomatous Polyp or Occult Blood

by Po-Li Wei, Ming-Shun Wu, Chun-Kai Huang, Yi-Hsien Ho, Ching-Sheng Hung, Ying-Chin Lin, Mei-Fen Tsao and Jung-Chun Lin

Biomedicines 2022, 10(7), 1741; https://doi.org/10.3390/biomedicines10071741 - 19 Jul 2022

Cited by 6 | Viewed by 2507

Abstract

The gut mucosa is actively absorptive and functions as the physical barrier to separate the gut ecosystem from host. Gut microbiota-utilized or food-derived metabolites are closely relevant to the homeostasis of the gut epithelial cells. Recent studies widely suggested the carcinogenic impact of [...] Read more.

The gut mucosa is actively absorptive and functions as the physical barrier to separate the gut ecosystem from host. Gut microbiota-utilized or food-derived metabolites are closely relevant to the homeostasis of the gut epithelial cells. Recent studies widely suggested the carcinogenic impact of gut dysbiosis or altered metabolites on the development of colorectal cancer (CRC). In this study, liquid chromatography coupled-mass spectrometry and long-read sequencing was applied to identify gut metabolites and microbiomes with statistically discriminative abundance in CRC patients (n = 20) as compared to those of a healthy group (n = 60) ofenrolled participants diagnosed with adenomatous polyp (n = 67) or occult blood (n = 40). In total, alteration in the relative abundance of 90 operational taxonomic units (OTUs) and 45 metabolites were identified between recruited CRC patients and healthy participants. Among the candidates, the gradual increases in nine OTUs or eight metabolites were identified in healthy participants, patients diagnosed with occult blood and adenomatous polyp, and CRC patients. The random forest regression model constructed with five OTUs or four metabolites achieved a distinct classification potential to differentially discriminate the presence of CRC (area under the ROC curve (AUC) = 0.998 or 0.975) from the diagnosis of adenomatous polyp (AUC = 0.831 or 0.777), respectively. These results provide the validity of CRC-associated markers, including microbial communities and metabolomic profiles across healthy and related populations toward the early screening or diagnosis of CRC. Full article

(This article belongs to the Special Issue The Role of Gut Microbiota in Gastrointestinal Cancers: From Pathogenesis to Therapeutic Perspectives)

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14 pages, 3299 KiB

Open AccessArticle

Novel Chloro-Substituted Salicylanilide Derivatives and Their β-Cyclodextrin Complexes: Synthesis, Characterization, and Antibacterial Activity

by Ioana Maria Carmen Ienașcu, Adina Căta, Mariana Nela Ştefănuț, Iuliana Popescu, Gerlinde Rusu, Paula Sfîrloagă, Daniel Ursu, Cristina Moşoarcă, Anamaria Dabici, Corina Danciu, Delia Muntean and Raluca Pop

Biomedicines 2022, 10(7), 1740; https://doi.org/10.3390/biomedicines10071740 - 19 Jul 2022

Cited by 4 | Viewed by 2368

Abstract

The goal of this research was to design novel chloro-substituted salicylanilide derivatives and their β-cyclodextrin complexes in order to obtain efficient antibacterial compounds and to demonstrate the beneficial role of complexation on the efficiency of these compounds. Thus, salicylanilide derivatives, esters, and hydrazides [...] Read more.

The goal of this research was to design novel chloro-substituted salicylanilide derivatives and their β-cyclodextrin complexes in order to obtain efficient antibacterial compounds and to demonstrate the beneficial role of complexation on the efficiency of these compounds. Thus, salicylanilide derivatives, esters, and hydrazides were obtained by microwave-assisted synthesis and their structure proven based on FTIR and NMR spectra. In order to improve water solubility, chemical and physical stability, and drug distribution through biological membranes, the inclusion complexes of the ethyl esters in β-cyclodextrin were also obtained using kneading. Inclusion-complex characterization was accomplished by modern analytical methods, X-ray diffraction, SEM, TGA, FTIR, and UV-vis spectroscopy. The newly synthesized compounds were tested against some Gram-positive and Gram-negative bacteria. Antimicrobial tests revealed good activity on Gram-positive bacteria and no inhibition against Gram-negative strains. The MIC and MBC values for compounds derived from N-(2-chlorophenyl)-2-hydroxybenzamide were 0.125–1.0 mg/mL. N-(4-chlorophenyl)-2-hydroxybenzamide derivatives were found to be less active. The inclusion complexes generally behaved similarly to the guest compounds, and antibacterial activity was not been altered by complexation. Full article

(This article belongs to the Special Issue State-of-the-Art Drug Delivery in Europe)

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13 pages, 4322 KiB

Open AccessArticle

Cellular and Molecular Mechanisms and Effects of Berberine on Obesity-Induced Inflammation

by Ji-Won Noh, Min-Soo Jun, Hee-Kwon Yang and Byung-Cheol Lee

Biomedicines 2022, 10(7), 1739; https://doi.org/10.3390/biomedicines10071739 - 19 Jul 2022

Cited by 15 | Viewed by 3183

Abstract

Obesity represents chronic low-grade inflammation that precipitates type 2 diabetes, cardiovascular disease, and cancer. Berberine (BBR) has been reported to exert anti-obesity and anti-inflammatory benefits. We aimed to demonstrate the underlying immune-modulating mechanisms of anti-obesity effects of BBR. First, we performed in silico [...] Read more.

Obesity represents chronic low-grade inflammation that precipitates type 2 diabetes, cardiovascular disease, and cancer. Berberine (BBR) has been reported to exert anti-obesity and anti-inflammatory benefits. We aimed to demonstrate the underlying immune-modulating mechanisms of anti-obesity effects of BBR. First, we performed in silico study to identify therapeutic targets, describe potential pathways, and simulate BBR docking at M1 and M2 adipose tissue macrophages (ATMs), tumor necrosis factor-α (TNF-α), C-C motif chemokine ligand 2 (CCL2), CCL4, CCL5, and C-X-C motif chemokine receptor 4 (CXCR4). Next, in vivo, we divided 20 C58BL/6 mice into four groups: normal chow, control (high fat diet (HFD)), HFD + BBR 100 mg/kg, and HFD + metformin (MET) 200 mg/kg. We evaluated body weight, organ weight, fat area in tissues, oral glucose and fat tolerance tests, HOMA-IR, serum lipids levels, population changes in ATMs, M1 and M2 subsets, and gene expression of TNF-α, CCL2, CCL3, CCL5, and CXCR4. BBR significantly reduced body weight, adipocyte size, fat deposition in the liver, HOMA-IR, triglycerides, free fatty acids, ATM infiltration, all assessed gene expression, and enhanced the CD206+ M2 ATMs population. In conclusion, BBR treats obesity and its associated metabolic dysfunctions, by modulating ATM recruitment and polarization via chemotaxis inhibition. Full article

(This article belongs to the Special Issue Developing New Agents for Inflammation and Obesity, and Its Related Disease)

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Figure 1
Therapeutic targets of BBR to treat obesity and the functional annotation analysis. (a) The 52 overlapping genes between BBR and obesity; (b) PPI network; (c) Top 10 genes with highest connectivity; (d) KEGG pathways analysis; (e) GO enrichment analysis. BBR: berberine, PPI: protein-protein interaction, KEGG: Kyoto Encyclopedia of Genes and Genomes, GO: gene ontology. Full article ">Figure 2
Molecular docking simulation. (a) BBR and M1 macrophage; (b) BBR and M2 macrophage; (c) BBR and TNF; (d) BBR and CCL2; (e) BBR and CXCR4. M1 macrophage (PDB ID: 1GD0), M2 macrophage (PDB ID: 1JIZ), TNF-α (PDB ID: 2AZ5), CCL2 (PDB ID: 1DOK) and CXCR4 (PDB ID: 3ODU). Binding energy values are written on the top of each subfigure. BBR: berberine, TNF: tumor necrosis factor, CCL2: C-C motif chemokine ligand 2, CXCR4, C-X-C motif chemokine receptor 4. Full article ">Figure 3
Changes in body weight, organ weight, and epididymal fat pads weight, and the fat area in the liver. (a) Body weight; (b) Food intake; (c) Epididymal fat pads weight; (d) Liver weight; (e) Histological results of the liver and epididymal fat pads; (f) Fat area in the liver; and (g) The size of adipocyte. In histological images stained by hematoxylin and eosin (H&E), the scale bar indicates 5 μm in the liver and 100 μm in the epididymal fat. Data are presented as mean ± standard error of the mean (SEM). *** p < 0.001 vs. the NC group and # p < 0.05, ## p < 0.01 and ### p < 0.001 vs. the control group. NC: normal chow, HFD: high fat diet, BBR: berberine, MET: metformin. Full article ">Figure 4
The population and polarization of ATMs and the gene expressions of chemokines. (a) Flow cytometry results and gating strategy of CD45+ & F4/80+ ATMs (red box); the populations of (b) CD45+ & F4/80+ ATMs; (c) CD11c+ ATMs; (d) CD206+ ATMs; and the gene expressions of (e) F4/80; (f) TNF-α; (g) CCL2; (h) CCL4; (i) CCL5; and (j) CXCR4. Data are presented as mean ± standard error of the mean (SEM). * p < 0.05, ** p < 0.01 and *** p < 0.001 vs. the NC group and # p < 0.05, ## p < 0.01 and ### p < 0.001 vs. the control group. ATMs: adipose tissue macrophages, NC: normal chow, HFD: high fat diet, BBR: berberine, MET: metformin, TNF-α: tumor necrosis factor α, CCL2: C-C motif chemokine ligand 2, CCL4: C-C motif chemokine ligand 4, CCL5: C-C motif chemokine ligand 5, CXCR4, C-X-C motif chemokine receptor 4. Full article ">Figure 5
Glucose- and lipid metabolism-related outcomes. (a) OGTT results, (b) AUC of OGTT, (c) OFTT results, (d) AUC of OFTT, (e) fasting blood glucose, (f) HOMA-IR (g) triglycerides (h) NEFA, (i) total cholesterol level, (j) LDL cholesterol level, (k) HDL cholesterol level, and (l) phospholipid level. Data are presented as mean ± standard error of the mean (SEM). * p < 0.05, ** p < 0.01 and *** p < 0.001 vs. the NC group and # p < 0.05, ## p < 0.01 and ### p < 0.001 vs. the control group. AUC: area under curve, OGTT: oral glucose tolerance test, OFTT: oral fat tolerance test, HOMA-IR, homeostatic model assessment for insulin resistance, NEFA: non-esterified fatty acid, LDL: low-density lipoprotein, HDL: high-density lipoprotein NC: normal chow, HFD: high fat diet, BBR: berberine, MET: metformin. Full article ">

18 pages, 1467 KiB

Open AccessReview

Site-Specific Considerations on Engineered T Cells for Malignant Gliomas

by Nirmeen Elmadany, Obada T. Alhalabi, Michael Platten and Lukas Bunse

Biomedicines 2022, 10(7), 1738; https://doi.org/10.3390/biomedicines10071738 - 19 Jul 2022

Cited by 11 | Viewed by 4880

Abstract

Immunotherapy has revolutionized cancer treatment. Despite the recent advances in immunotherapeutic approaches for several tumor entities, limited response has been observed in malignant gliomas, including glioblastoma (GBM). Conversely, one of the emerging immunotherapeutic modalities is chimeric antigen receptors (CAR) T cell therapy, which [...] Read more.

Immunotherapy has revolutionized cancer treatment. Despite the recent advances in immunotherapeutic approaches for several tumor entities, limited response has been observed in malignant gliomas, including glioblastoma (GBM). Conversely, one of the emerging immunotherapeutic modalities is chimeric antigen receptors (CAR) T cell therapy, which demonstrated promising clinical responses in other solid tumors. Current pre-clinical and interventional clinical studies suggest improved efficacy when CAR-T cells are delivered locoregionally, rather than intravenously. In this review, we summarize possible CAR-T cell administration routes including locoregional therapy, systemic administration with and without focused ultrasound, direct intra-arterial drug delivery and nanoparticle-enhanced delivery in glioma. Moreover, we discuss published as well as ongoing and planned clinical trials involving CAR-T cell therapy in malignant glioma. With increasing neoadjuvant and/or adjuvant combinatorial immunotherapeutic concepts and modalities with specific modes of action for malignant glioma, selection of administration routes becomes increasingly important. Full article

(This article belongs to the Special Issue Recent Prospectives in CAR T-based Therapy for Solid and Hematological Malignancies)

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15 pages, 620 KiB

Open AccessArticle

Anti-PD-1 Monotherapy in Advanced Melanoma—Real-World Data from a 77-Month-Long Retrospective Observational Study

by Daniella Kuzmanovszki, Norbert Kiss, Béla Tóth, Tünde Kerner, Veronika Tóth, József Szakonyi, Kende Lőrincz, Judit Hársing, Eleonóra Imrédi, Alexa Pfund, Ákos Szabó, Valentin Brodszky, Fanni Rencz and Péter Holló

Biomedicines 2022, 10(7), 1737; https://doi.org/10.3390/biomedicines10071737 - 19 Jul 2022

Cited by 12 | Viewed by 2604

Abstract

Real-world evidence plays an important role in the assessment of efficacy and safety of novel therapies. The increasing use of immune checkpoint inhibitors (ICIs) in patients with advanced melanoma has led to notably improved clinical outcomes, while they are also associated with immune-related [...] Read more.

Real-world evidence plays an important role in the assessment of efficacy and safety of novel therapies. The increasing use of immune checkpoint inhibitors (ICIs) in patients with advanced melanoma has led to notably improved clinical outcomes, while they are also associated with immune-related adverse events (irAEs). The majority of the available data are based on clinical trials, where the investigated subjects often do not adequately represent the general patient population of the everyday practice. Although there is a niche of objective biomarkers for the future treatment response of ICIs, certain studies suggest that irAEs may be predictive. The aim of this study was to carry out a retrospective analysis of treatment data from patients with advanced melanoma, treated with a single anti-PD-1 agent (pembrolizumab or nivolumab) during a 77-month-long period. Treatment efficacy and occurrence of adverse events were analyzed to identify potential predictive markers. Primary and secondary endpoints were the overall survival (OS) and progression-free survival (PFS). In our cohort, we demonstrated that the occurrence of more than one irAE showed a correlation with response to PD-1 ICI therapy and improved the OS and PFS. Our study suggests, that the grade of toxicity of the irAE may affect the survival rate. Full article

(This article belongs to the Special Issue Diagnostics and Therapeutics of Melanoma)

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