Asim K. Duttaroy

Telomeres are complex chromosomal components that are crucial for genome integrity but frequently experience replication stress due to their repetitive, G-rich nature and active transcription. TERRA is a mediator of telomere homeostasis but is also a causative factor of RNA-DNA hybrid (R-loop) formation, which can give rise to transcription-replication conflicts (TRCs). Telomeric R-loops that persist in the genome can act as a barrier to replication fork movement, cause reversal or collapse of replication forks, and result in fragile telomeres, break-induced replication, and telomere dysfunction. Although normal cells undergo senescence in response to this stress, cancer cells, especially those with alternative lengthening of telomeres (ALT), exploit telomeric TRCs to facilitate recombination-mediated telomere elongation.

Background: The human gut and skin microbiota play a vital role in maintaining physiological balance and immune function. Factors such as age, diet, geography, and genetic factors influence their composition, and disruptions can contribute to metabolic alterations and chronic diseases. Coastal populations are exposed to environmental pollutants and experience disrupted gut microbial balance, impaired epithelial barrier integrity, and possibly dysbiosis-associated inflammatory responses. In this study, we aim to analyze microbiome diversity in coastal and non-coastal populations of Tamil Nadu, India, using 16S rRNA sequencing. Methods: Fecal and skin swab samples were collected from 75 participants, 57 from coastal regions and 18 from non-coastal regions. DNA was extracted, and using the Illumina MiSeq platform, the 16S rRNA sequencing was performed. The alpha and beta diversity analyses compared the fecal and skin microbiota diversity and composition. Results: The study revealed that Firmicutes dominated the gut microbiota in both coastal and non-coastal groups, with higher abundances of Bacilli and Clostridia in the coastal group. In skin swabs, Firmicutes and Proteobacteria were predominant, with different clustering patterns observed in coastal samples. Beta diversity analyses revealed overlapping but distinct microbial communities between the two groups. Conclusion: This pilot study highlights differences in gut and skin microbiota between coastal and non-coastal populations. However, further study with a larger sample size is required to better understand the impact of environmental exposures on human health.

Dietary exogenous microRNAs (miRNAs) have emerged as potential mediators of interorganismal communication, with growing interest in their ability to influence gastrointestinal physiology and the gut microbiota. These molecules encompass plant-derived miRNAs implicated in cross-kingdom regulation, animal-derived dietary miRNAs involved in cross-species communication, and maternal milk miRNAs that may participate in mother-to-offspring molecular crosstalk. A proportion of dietary miRNAs are associated with extracellular vesicles or other protective complexes, which may enhance their stability during food processing and gastrointestinal transit and facilitate interactions with intestinal epithelial cells, immune cells, and microbial communities. This review critically evaluates recent computational, detection-based, in vitro , in vivo , and human observational evidence concerning the gastrointestinal stability, uptake, target engagement, and biological activity of dietary exogenous miRNAs. Experimental studies have reported effects on inflammatory signaling, epithelial barrier integrity, macrophage polarization, intestinal development, tumor-associated pathways, and gut microbial composition and gene expression. However, the strength of this evidence varies considerably. In particular, detection of dietary miRNAs in food, extracellular vesicles, feces, or recipient tissues does not by itself establish functional target regulation, while studies using purified vesicles, synthetic miRNA mimics, or engineered delivery systems may involve exposures that differ substantially from normal dietary intake. Moreover, biological effects observed following whole-vesicle administration cannot always be attributed specifically to their miRNA cargo. Collectively, current evidence provides stronger support for the biological plausibility of local gastrointestinal effects than for widespread systemic regulation after dietary exposure. Further studies using physiologically relevant doses, rigorous miRNA-specific loss-of-function approaches, direct target validation, standardized analytical methods, and controlled human interventions will be essential to establish the functional significance and translational potential of dietary exogenous miRNAs.

Breast cancer progression and resistance to therapy are strongly influenced by immune evasion within the tumor microenvironment. Immune checkpoint signaling is a major mechanism by which cancer cells evade immune surveillance, thereby promoting tumor progression and reducing the effectiveness of immunotherapy. Recent evidence suggests that extracellular vesicles (EVs) are important mediators of communication between tumor, stromal, and immune cells, enabling the transfer of proteins, nucleic acids, lipids, and other bioactive molecules that regulate immune responses. This review discusses current knowledge on the role of EVs in immune checkpoint regulation in breast cancer, with an emphasis on both programmed death-ligand 1 (PD-L1)-dependent and additional immunosuppressive pathways that collectively contribute to immune escape. A literature review was conducted using PubMed, Google Scholar, and Web of Science, focusing on studies from the past decade related to EV biology, immune checkpoints, and breast cancer. Findings from multiple studies indicate that tumor-derived EVs contribute to immunosuppression by impairing T-cell function, promoting immune tolerance, facilitating metastatic progression, and supporting resistance to immunotherapy. Importantly, EV-mediated effects are different for the breast cancer subtypes, which may play a role in treatment response, disease progression, and clinical outcomes. EVs also show potential as minimally invasive biomarkers for disease monitoring and as therapeutic targets or delivery systems for precision medicine. Overall, this review highlights current evidence on EV-mediated immune checkpoint regulation in breast cancer, highlighting PD-L1 and CTLA-4associated mechanisms as key drivers of immune evasion and promising targets for precision immunotherapy.

Global declines in male fertility, characterized by reduced sperm count, motility, and quality, raised concerns about environmental exposures to estrogen-mimicking endocrine-disrupting chemicals (EDCs), including bisphenol A (BPA), and reproductive dysfunction. BPA exposure in vivo has been shown to alter gut microbial composition, diversity, and metabolites, leading to dysbiosis. Such gut alterations modulate systemic inflammation, estrogen bioavailability, and the endocrine-immune axis, thereby affecting gonadal function. Even though the gut is the largest endocrine organ in the body, directly regulating multiple metabolites that reach the circulation and influence the functions of peripheral organs and systems, little is known about epigenetic perturbations due to exposure to plastic-derived endocrine-disrupting bisphenols and their role in gut dysbiosis and male infertility risks. Recent evidence on the fetal programming of bisphenol exposure suggests such events can also impact epimutation states beyond diet, potentially carrying across generations. BPA can diffuse across the membrane and enter the nucleus, altering transcription of target genes by modifying nuclear receptor activity and gene promoter methylation, similar to estradiol, a steroid hormone. The genomic imprint is modulated by gene-chemical interactions, which predominantly result in epigenetic alterations. In particular, BPA exposure in utero altered the epigenome, highlighting the urgent need for transgenerational assessment. This narrative review conducted a thorough review of the available data to emphasize the transgenerational impacts of BPA exposure on male infertility risk and the roles of the gut-reproductive axis, underscoring the importance of further research in this area.

Fatty acids serve dual roles in cardiac physiology: as energy substrates and as precursors of bioactive lipid mediators (prostaglandins, leukotrienes, oxylipins) from n-3/n-6 PUFAs that regulate inflammation, thrombosis, and remodeling. Saturated, monounsaturated, and trans fatty acids modulate metabolism and membrane function, thereby shaping these pathways. Clinically, n-3 long-chain PUFAs (EPA and DHA) reduce cardiovascular mortality and aid postischemic remodeling; however, high doses increase the risk of atrial fibrillation. By contrast, trans and saturated fatty acids promote dyslipidemia, dysfunction, and higher rates of coronary artery disease and heart failure. Mechanistically, fatty acid uptake via FABPpm, CD36 (FAT), and FATPs, along with β-oxidation and PPAR signaling, regulates metabolism, while COX/LOX/CYP pathways generate eicosanoids and resolvins that influence inflammation and repair. This review synthesizes evidence on the roles of fatty acids and oxylipins in lipotoxicity, heart failure, ischemia–reperfusion, and arrhythmias, and evaluates dietary and supplemental interventions to optimize cardiac lipid metabolism, aligning with fatty acid signaling.

Gut microbiota, the community of microorganisms in the gastrointestinal (GI) tract, plays many critical roles in the maintenance of an individual’s health by regulating bone metabolism. Bone mass has been linked to the GI system because nutrients (minerals) are absorbed to maintain bone homeostasis. Dysbiosis of gut microbiota due to metabolic deregulation associated with obesity, fatty liver, and inflammatory status of an individual promotes altered gut microbial diversity, gut-epithelial integrity, releases of harmful gut metabolites those could mediate malabsorption of nutrients such as calcium, vitamin D, omega-3 fatty acids, phosphorous, magnesium, and other key minerals essential for bone mineralization and remodeling in maintaining bone mass through the controlled processes of bone formation and resorption activities. Postbiotics and related products show promising roles in restoring intestinal barrier integrity by reducing systemic inflammation and stimulating the immune system, thereby preventing bone loss. Manipulating the host gut microbiota by sustained release of microbiota-derived metabolites at target sites can help modulate gut homeostasis by regulating redox balance, macrophage polarization, and controlling systemic inflammation. Although several reviews highlighted the roles of gut microbiota, the specific roles of gut metabolites in bone metabolism and associated disorders as a result of metabolic dysregulation remain limited. This narrative review highlights the emerging roles of gut metabolites, postbiotics and related products in regulating intestinal integrity, immune responses, and inflammation, thereby protecting against bone loss.