Role of Physical Exercise and Nutraceuticals in Modulating Molecular Pathways of Osteoarthritis

Osteoarthritis (OA) is a painful and disabling disease that affects millions of patients. Its etiology is largely unknown, but it is most likely multifactorial. OA pathogenesis involves the catabolism of the cartilage extracellular matrix and is supported by inflammatory and oxidative signaling pathways and marked epigenetic changes. To delay OA progression, a wide range of exercise programs and naturally derived compounds have been suggested. This literature review aims to analyze the main signaling pathways and the evidence about the synergistic effects of these two interventions to counter OA. The converging nutrigenomic and physiogenomic intervention could slow down and reduce the complex pathological features of OA. This review provides a comprehensive picture of a possible signaling approach for targeting OA molecular pathways, initiation, and progression.

Vitamin D supplementation as a rational pharmacological approach in the COVID-19 pandemic

The COVID-19 pandemic has reached most of the countries worldwide causing death, which often results from an inflammatory storm associated with severe acute respiratory syndrome (SARS). This has prompted researchers to seek specific novel and definitive treatments urgently. In this context, it is interesting to evaluate the preventive and therapeutic effects of existing pharmacological agents that could be useful. In this regard, vitamin D supplementation, particularly in individuals likely to be deficient, may be a promising option. Vitamin D is a hormone that modulates many of the same inflammatory and oxidative signaling pathways triggered during COVID-19. For example, vitamin D suppresses the actions of the renin-angiotensin system, which has a determining role in the pathophysiology of the inflammatory response related to COVID-19. This paper analyzes the evidence that vitamin D supplementation might be a valuable preventive/therapeutic measure in groups at risk for or infected with COVID-19. It also discusses how clinical studies could be best designed to evaluate the possible advantages of vitamin D supplementation for the benefit of public health during the pandemic.

GM-CSF differentiation of human monocytes stabilizes macrophage state via oxidative signaling

Macrophages are central mediators of immunity that integrate diverse signals derived from differentiation cues, tissue location, and disease. Controlling macrophage state and function is an appealing therapeutic objective across many diseases including cancer, atherosclerosis, and tuberculosis. Despite the growing appreciation for the in vivo complexity of macrophage state, existing in vitro models of human monocyte-derived macrophages have used a limited number of individual perturbations to explore the complex phenotypic space that macrophages can occupy. Here, we leverage a tiered differentiation, activation, and stimulation strategy to generate libraries of in vitro monocyte-derived macrophages and examine the in vitro state space of macrophage function using high-dimensional technologies. Our tiered experimental approach further revealed a striking relationship between GM-CSF differentiation and IL-10 production. Cells that were differentiated with GM-CSF produced very low or undetectable levels of IL-10 independent of activation or stimulation condition. To nominate candidate regulators of this IL-10 response, we leverage unbiased single-cell mRNA sequencing to identify transcriptional networks associated with GM-CSF-derived cells. Using these data, we identify oxidative signaling pathways as upregulated in GM-CSF derived cells and demonstrate that scavenging of oxidative radicals can enhance IL-10 production in these cells. Collectively, these data underscore the complexity of monocyte-derived macrophage state over time and highlight a dominant role for GM-CSF in tuning macrophage inflammatory phenotype, metabolic state, and plasticity.

The Therapeutic Implications of Tea Polyphenols Against Dopamine (DA) Neuron Degeneration in Parkinson’s Disease (PD)

: Accumulative evidence indicated that the pathologically accumulated metal ions (iron species and Mn3+) and abnormally up-regulated monoamine oxidase B (MAOB) activity induced oxidation of endogenous dopamine (DA) can lead to mitochondria impairment, lysosome dysfunction, proteasome inhibition, and selective DA neuron vulnerability, which is implicated in the pathogenesis of Parkinson’s disease (PD). The DA oxidation can generate deleterious reactive oxygen species (ROS) and highly reactive DA quinones (DAQ) to induce DA-related toxicity, which can be alleviated by DA oxidation suppressors, ROS scavengers, DAQ quenchers, and MAOB inhibitors. On the other hand, the nuclear factor erythroid 2-related factor 2 (Nrf2)-Keap1 and Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) anti-oxidative and proliferative signaling pathways play roles in anti-oxidative cell defense and mitochondria biogenesis, which is implicated in DA neuron protections. Therefore, agents with capabilities to suppress DA-related toxicity including inhibition of DA oxidation, scavenge of ROS, detoxification of DAQ, inhibition of MAOB, and modulations of anti-oxidative signaling pathways can be protective to DA neurons. Accumulative evidence shows that tea or coffee consumptions and smoking are related to deceased PD prevalence with unknown mechanisms. In this study, we investigate the protective capabilities of tea polyphenols and other PD relevant agents to inhibit DA-related toxicity and protect against environmental or genetic factors induced DA neuron degeneration in vitro and in vivo. We find that tea polyphenols can significantly suppress DA-related toxicity to protect DA neurons. The tea polyphenols can protect DA neurons via inhibition of DA oxidation, conjugation with DAQ, scavenge of ROS, inhibition of MAOB, and modulations of Nrf2-Keap1 and PGC-1α anti-oxidative signaling pathways. The tea polyphenols with more phenolic hydroxyl groups and ring structures have stronger protective functions. The protective capabilities of tea polyphenols is further strengthened by evidence that phenolic hydroxyl groups can directly conjugate with DAQ. However, GSH and other sulfhydyl groups containing agents have weaker capabilities to abrogate DA oxidation, detoxify ROS and DAQ and inhibit MAOB; whereas nicotine (NICO) and caffeine (CAF) can only modulate Nrf2-Keap1 and PGC-1α pathways to protect DA neurons weakly. The tea polyphenols are identified to protect against overexpression of mutant A30P α-synuclein (α-syn) induced DA neuron degeneration and PD-like symptoms in transgenic Drosophila. Based on achievements from current studies, the excellent and versatile protective capabilities of tea polyphenols are highlighted, which will contribute and benefit to future anti-PD therapy.