Russel J. Reiter’s research while affiliated with The University of Texas at San Antonio and other places

Delaying the development of atherosclerosis (AS) and decreasing cardiac ischemia-reperfusion damage remain serious challenges for the medical community. Chronic arterial disease, i.e., AS, is frequently linked to oxidative stress and inflammation as significant contributing causes. AS risk factors, such as hyperlipidemia, high blood pressure, age, hyperglycemia, smoking, high cholesterol, and irregular sleep patterns, can exacerbate AS in the carotid artery and further shrink its lumen. Finding new approaches that support plaque inhibition or stability is an ongoing problem. The last ten years have shown us that melatonin (MLT) affects the cardiovascular system, although its exact mechanisms of action are yet unknown. MLT’s direct free radical scavenger activity, its indirect antioxidant qualities, and its anti-inflammatory capabilities all contribute to its atheroprotective effects on several pathogenic signaling pathways. Herein, we examine the evidence showing that MLT treatment has significant protective effects against AS and AS-related cardiovascular diseases. The numerous pieces of the puzzle that have been as for epigenetic and biogenetic targets for prevention and therapy against the atherosclerotic pathogenic processes are identified.

Autophagy is a conserved catabolic process that removes protein clumps and defective organelles, thereby promoting cell equilibrium. Growing data suggest that dysregulation of the autophagic pathway is linked to several cancer hallmarks. Long non-coding RNAs (lncRNAs), which are key parts of gene transcription, are increasingly recognized for their significant roles in various biological processes. Recent studies have uncovered a strong connection between the mutational landscape and altered expression of lncRNAs in the tumor formation and development, including leukemia. Research over the past few years has emphasized the role of lncRNAs as important regulators of autophagy-related gene expression. These RNAs can influence key leukemia characteristics, such as apoptosis, proliferation, epithelial-mesenchymal transition (EMT), migration, and angiogenesis, by modulating autophagy-associated signaling pathways. With altered lncRNA expression observed in leukemia cells and tissues, they hold promise as diagnostic biomarkers and therapeutic targets. The current review focuses on the regulatory function of lncRNAs in autophagy and their involvement in leukemia, potentially uncovering valuable therapeutic targets for leukemia treatment.

In the original publication [...]

The SAR-CoV-2 virus has evolved to co-exist with human hosts, albeit at a substantial energetic cost resulting in post-infection neurological manifestations [Neuro-post-acute sequelae of SARS-CoV-2 infection (PASC)] that significantly impact public health and economic productivity on a global scale. One of the main molecular mechanisms responsible for the development of Neuro-PASC, in individuals of all ages, is the formation and inadequate proteolysis/clearance of phase-separated amyloid crystalline aggregates—a hallmark feature of aging-related neurodegenerative disorders. Amyloidogenesis during viral infection and persistence is a natural, inevitable, protective defense response that is exacerbated by SARS-CoV-2. Acting as chemical catalyst, SARS-CoV-2 accelerates hydrophobic collapse and the heterogeneous nucleation of amorphous amyloids into stable β-sheet aggregates. The clearance of amyloid aggregates is most effective during slow wave sleep, when high levels of adenosine triphosphate (ATP)—a biphasic modulator of biomolecular condensates—and melatonin are available to solubilize amyloid aggregates for removal. The dysregulation of mitochondrial dynamics by SARS-CoV-2, in particular fusion and fission homeostasis, impairs the proper formation of distinct mitochondrial subpopulations that can remedy challenges created by the diversion of substrates away from oxidative phosphorylation towards glycolysis to support viral replication and maintenance. The subsequent reduction of ATP and inhibition of melatonin synthesis during slow wave sleep results in incomplete brain clearance of amyloid aggregates, leading to the development of neurological manifestations commonly associated with age-related neurodegenerative disorders. Exogenous melatonin not only prevents mitochondrial dysfunction but also elevates ATP production, effectively augmenting the solubilizing effect of the adenosine moiety to ensure the timely, optimal disaggregation and clearance of pathogenic amyloid aggregates in the prevention and attenuation of Neuro-PASC.

Ovarian cancer (OC) is characterized by high mortality rates due to late diagnosis, recurrence, and metastasis. Here, we show that extracellular signaling molecules secreted by adipose-derived mesenchymal stem cells (ASCs) and OC cells—either in the conditioned medium (CM) or within small extracellular vesicles (sEVs)—modulate cellular responses and drive OC progression. ASC-derived sEVs and CM secretome promoted OC cell colony formation, invasion, and migration while upregulating tumor-associated signaling pathways, including TGFβ/Smad, p38MAPK/ERK1/2, Wnt/β-catenin, and MMP-9. Additionally, OC-derived sEVs and CM induced a pro-tumorigenic phenotype in ASCs, enhancing their invasiveness and expression of tumor-associated factors. Notably, both ASCs and OC cells exhibited increased expression of E-cadherin and Snail/Slug proteins, key markers of epithelial/mesenchymal hybrid phenotype, enhancing cellular plasticity and metastatic potential. We also demonstrated that these cellular features are, at least in part, due to the presence of tumor-supportive molecules such as TNF-α, Tenascin-C, MMP-2, and SDF-1α in the CM secretome of ASCs and OC cells. In silico analyses linked these molecular changes to poor prognostic outcomes in OC patients. These findings highlight the critical role of sEVs and tumor/stem cell-derived secretome in OC progression through bidirectional interactions that impact cellular behavior and phenotypic transitions. We suggest that targeting EV-mediated communication could improve therapeutic strategies and patient outcomes.

Doxorubicin (DOX), a chemotherapeutic agent utilized in the management of cancer, provokes cardiotoxicity although effective remedy is lacking. Given that DOX provokes oxidative stress and cell death in cardiomyocytes, this study evaluated the possible involvement of cuproptosis, a newly identified form of cell death, in DOX-instigated cardiac remodeling and contractile dysfunction, alongside the impact of the heavy metal scavenger metallothionein (MT) on DOX cardiomyopathy. Cardiac-specific MT transgenic and wild-type (WT) mice were treated with DOX (5 mg/kg/wk., i.p., for 4 wks) prior to assessment of cardiac morphology and function. DOX evoked cardiac remodeling (interstitial fibrosis), compromised echocardiographic (thinner septum, elevated LVESD, reduced ejection fraction and fractional shortening), cardiomyocyte mechanical and intracellular Ca2+ properties alongside mitochondrial injury (ultrastructure, respiration and mitochondrial membrane potential), oxidative stress (higher O2− and ROS, lower GSH level), apoptosis and cuproptosis (upregulated CTR1 and DLAT, downregulated copper exporter ATP7B, FDX1, the Fesingle bondS cluster proteins ACO2 and NDUFS8). Bioinformatics analysis confirmed enrichment of copper-related genes among DEGs in DOX-challenged hearts. DOX-induced anomalies (except the copper importer CTR1) were reversed by MT overexpression. Co-immunoprecipitation and interaction interface revealed a prominent interaction between MT and ATP7B. Further study indicated that copper chelator tetrathiomolybdate mitigated DOX-induced cardiac remodeling and cardiomyocyte abnormalities whereas copper ionophore elesclomol nullified MT-mediated benefit against DOX. These findings favor a vital role for cuproptosis in DOX cardiomyopathy while the antioxidant MT rescues DOX cardiomyopathy possibly through alleviating cuproptosis.