Current Molecular Medicine - Online First

Anaerobic and aerobic exercise are known to increase reactive oxygen species (ROS) and cytokines, which may lead to oxidative stress when ROS accumulate. However, the findings are still inconsistent, with most studies focusing on short exercise durations. This study aimed to compare the effects of anaerobic and aerobic exercise on oxidative stress and cellular fitness in healthy trained young men.

A randomized trial was conducted involving 18 young male subjects, divided into two groups: anaerobic (short-distance running) and aerobic (long-distance running), with each group exercising three times per week for one month. Blood samples were collected before and after the intervention. Malondialdehyde (MDA) reflected oxidative stress, ROS (H2O2), and antioxidant levels (total antioxidant capacity, superoxide dismutase/SOD, glutathione peroxidase/GPX) were detected using spectrophotometry, while Interleukin-6 (IL-6) and ATPase Inhibitory Factor 1 (ATPIF1) reflected cellular fitness, were measured using ELISA.

Both anaerobic and aerobic exercise significantly reduced MDA levels. Aerobic exercise significantly increased SOD and total antioxidant capacity, while anaerobic exercise resulted in decreased GPX levels. No significant changes were observed in H2O2, IL-6, or ATPIF1 levels in either group.

The findings suggest that aerobic exercise enhances the body’s antioxidant defense system more effectively than anaerobic exercise, contributing to reduced oxidative stress. The participants’ trained status may have influenced the SOD response. Limitations include a lack of control over lifestyle variables and limited generalizability due to the homogenous sample.

One month of exercise reduces oxidative stress in trained young men, with aerobic exercise showing greater benefits in boosting endogenous antioxidants.

In the field of interventional cardiology, coronary in-stent restenosis (ISR) continues to present a clinical hurdle, even with the progress made in stent design and pharmacological interventions. While drug-eluting stents (DESs) and drug-eluting balloons (DEBs) have markedly decreased the occurrence of ISR when compared to bare-metal stents, the condition persists as a complication in revascularization, contributing to increased patient morbidity and challenging long-term treatment outcomes. Thus, a deeper understanding of ISR mechanisms and the development of novel therapeutic approaches are crucial for improving patient outcomes.

In this study, we utilized the A10 cell as an in vitro model and induced common carotid artery balloon dilation injury in Sprague-Dawley rats as an animal model to explore the potential clinical applications of SCH79797, particularly in the treatment of ISR.

SCH79797, a protease-activated receptor-1 antagonist, induced apoptosis of smooth muscle cells through various pathways. SCH79797 promoted apoptosis via JNK/c-Jun and p53 upregulation in the cytosol. We also observed an increased Bax/Bcl-2 ratio in mitochondria, p53 translocation to mitochondria, and changes in the mitochondrial membrane potential to mitochondrial membrane permeabilization. Our comparative analysis with vorapaxar revealed the apoptotic effects of SCH79797 to be independent of its PAR-1 antagonist activity. Furthermore, SCH79797 administration significantly reduced common carotid artery restenosis and thrombosis following balloon injury in vivo.

Our study has been the first to demonstrate SCH79797 to directly induce VSMC apoptosis via the p53-mediated mitochondrial pathway, providing a novel mechanistic insight into ISR treatment. Unlike traditional anti-proliferative agents used in DESs, SCH79797 uniquely combines apoptotic induction with antithrombotic effects, making it a dual-action therapeutic candidate. This research study has laid the groundwork for localized drug-eluting strategies that can leverage SCH79797’s properties to prevent ISR more effectively while minimizing systemic side effects.

Our findings have established SCH79797 as a promising candidate for reducing ISR through apoptosis modulation. By leveraging the p53-mediated mitochondrial apoptotic pathway, SCH79797 may provide a groundbreaking approach to reducing restenosis. These findings could offer significant implications for the future development of targeted drug-eluting strategies by locally delivering SCH79797 in a controlled manner using DES or DEB, presenting SCH79797 as a transformative candidate in interventional cardiology.

This study assessed the effects of the synthesized ACE inhibitory peptide LAP (Leu-Arg-Pro-Val-Ala-Ala) on cognitive impairment in hypertensive rats.

Rho-associated coiled-coil containing protein kinase (ROCK) activity in peripheral blood mononuclear cells (PBMCs) was initially measured in elderly patients with hypertension and cognitive impairment using western blot analysis. The effect of LAP on the ROCK pathway was studied in a human cell line with ROCK1. Sixteen-week-old male spontaneously hypertensive rats (SHR) received intragastric LAP (500 μg/week) for eight weeks. Cognitive function was assessed using the Morris water maze test, and thoracic aorta remodeling was evaluated by determining the media/lumen ratio through immunohistochemistry. Amyloid beta (Aβ), phosphorylated tau (p-tau), and apoptotic neurons in the hippocampus were examined by western blot analysis and immunohistochemistry. Protein expression and activation related to the ROCK pathway, including moesin, myosin light chain (MLC), and myosin phosphatase target subunit (MYPT), were analyzed in the aorta and hippocampus using western blot and immunohistochemistry.

Hypertensive patients with cognitive impairment showed increased phosphorylated/total myosin-binding subunit ratios in PBMCs, indicating higher ROCK pathway activity. In vitro, LAP reduced p-moesin levels, confirming ROCK inhibition. In vivo, oral LAP lowered blood pressure and heart rate in SHR models and improved cognitive function. LAP also reduced aortic remodeling, decreased hippocampal Aβ and p-tau deposition, reduced neuronal apoptosis, and increased neuronal survival. Mechanistically, LAP inhibited ROCK pathway activation in the aorta and hippocampus, similar to the ROCK inhibitor fasudil.

Hypertension contributes to neurodegenerative changes through the activation of the ROCK signaling pathway. The study found that the ACE inhibitory peptide LAP not only sustainably lowered blood pressure, but also inhibited the ROCK pathway, reducing hippocampal Aβ and p-tau deposition, thereby offering a dual therapeutic approach for hypertension-related cognitive impairment.

LAP alleviated hypertension-related cognitive impairment in SHR by inhibiting the hippocampal ROCK pathway, showing therapeutic potential.

Parkinson’s disease (PD) is characterized by the progressive destruction of the dopaminergic cells in the substantia nigra region. The incidence of PD continues to rise, with over 8.5 million people affected in 2019 and projections indicating it could reach over 17 million by 2040 compared with levels observed since 1980. This review examines the mechanistic role of Dynamin-Related Protein 1 (Drp1) and Nod-Like Receptor Family Pyrin Domain-Containing 3 (NLRP3) inflammasome in the development and pathogenesis of PD.

The information was collected from databases such as PubMed, Embase, Google Scholar, Web of Science, and Elsevier database.

There is a potential for Drp1 and NLRP3 pathways to serve as therapeutic targets in PD. Drp1 inhibitors, such as Mdivi-1, aid in mediating mitochondrial homeostasis, and NLRP3 inhibitors prevent inflammation. Natural compounds that modulate such pathways include resveratrol and curcumin, and preclinical models demonstrate multi-target neuroprotection via direct antioxidant and anti-inflammatory properties.

The intricate relationship among oxidative stress, mitochondrial dynamics and inflammation indicates that a combination drug therapy approach is more likely to be effective compared to a single-agent strategy. In a subsequent phase, there is a need for improved formulation and enhancement of natural compounds to maximize their bioavailability and efficacy, particularly in terms of selective Drp1 and NLRP3 inhibitors.

The Drp1–NLRP3 axis is one of the essential mechanistic connections between mitochondrial dynamics and neuroinflammation in PD. Focusing on this axis could offer novel therapeutic options, and advancing these approaches could pave the way for therapies that not only alleviate symptoms but also slow or halt the progression of the disease.

Genistein is an isoflavone primarily extracted from soybeans and the Dyer’s broom (Genista tinctora L.). It has been extensively studied using various extraction methods and characterized via NMR for structural elucidation. Its pharmacological potential, mediated through interactions with multiple receptors and signalling pathways, has been validated through numerous preclinical studies globally.

To analyze the pharmaceutical profile of genistein using PASS software, we correlated it with existing literature, and evaluated its efficacy against various diseases. The study aims to explore the broad-spectrum potential of genistein as a lead compound against the various diseases such as cancer, cardiovascular disease (CVD), neurodegenerative and viral diseases.

It is a broad-spectrum drug that is effective against – cancer, heart associated diseases, neurodegenerative diseases and viral diseases. It is a potential anticancer drug that modulates apoptosis, cell cycle, metastasis, and regulates the cancer signalling pathways. Based on the compilation of reports from the literature reviews, it is effective against breast cancer (23%), neuroblastoma (12.77%), prostate and lung cancer (10.64%). Secondly, it has cardio protectant properties and supports cardiovascular health by improving endothelial function and lowering cholesterol. It is reported to be effective against cardiac dysfunction (38.46%), atherosclerosis (26.92%), and cardiotoxicity (15.39%). Thirdly, it offers various neuroprotective benefits in neurodegenerative diseases like Alzheimer's (69.84%) and Parkinson's (19.05%). Lastly, it was also reported to be effective against HSV (23.08%), HIV (23.08%) and HPV (15.39%) viral infections.

Genistein exhibits a wide range of therapeutic properties, including anticancer, cardioprotective, neuroprotective, and antiviral effects. It has shown notable efficacy in treating cancers such as breast, prostate, and lung, as well as neurodegenerative conditions like Alzheimer's and Parkinson's. Additionally, its benefits in improving cardiovascular health and combating viral infections further support its potential as a multifunctional therapeutic agent. Although genistein has a broad pharmacological spectrum, its clinical relevance is hampered by a suboptimal pharmacokinetic profile, such as poor bioavailability, rapid systemic clearance, extensive first-pass metabolism, and low aqueous solubility, which limit its therapeutic efficacy.

This systematic review highlights genistein’s pharmacological profile, demonstrating its efficacy against various diseases and its potential as a lead candidate for drug development in oncology, cardiovascular health, and neurodegenerative therapies. Thus, underscoring its potential, Genistein can be considered a versatile therapeutic agent.

Obesity is a major risk factor for metabolic and cardiovascular disorders. Recently, emerging biomarkers, such as the Visceral Adiposity Index (VAI) and Lipid Accumulation Product (LAP), have garnered attention for their utility in assessing visceral obesity. Bilirubin, a potent endogenous antioxidant, has been associated with protective effects against various diseases. This study aims to investigate the relationship between serum total bilirubin (STB) levels and VAI/LAP in adults.

This cross-sectional study utilized data from the National Health and Nutrition Examination Survey (NHANES) collected between 2003 and 2020. The calculation of VAI and LAP was performed computationally. Weighted multivariate regression models were used to explore the potential correlation between STB levels and VAI or LAP. RCS curves were used to identify the potential non-linear relationship. Moreover, subgroup analyses were conducted to examine heterogeneity across different populations.

The analysis included a cohort of 10,625 individuals aged 20 to 85 years. Both unadjusted and adjusted statistical models revealed a significant negative association between STB levels and VAI or LAP (all P< 0.001). RCS indicates that these relationships are linear. Subgroup analyses identified particularly strong associations in non-smokers aged 20-59 without hypertension/diabetes (P < 0.05).

Our study's strengths include the use of nationally representative data with appropriate weighting, comprehensive adjustment for confounding variables, and pioneering research on the link between serum bilirubin levels and visceral fat indices, which may indicate early metabolic risk markers. This finding highlights the significant role of bilirubin in body fat distribution and lipid metabolism.

This study revealed that STB was associated with VAI or LAP among the specific general American population aged 20-59 without hypertension/diabetes. Further prospective investigations are warranted to clarify the temporal relationship between STB and novel obesity indices.