Rajiv Gandhi Centre for Biotechnology,Ministry of Science and Technology,Government of India

Background: Aging and various pathological conditions lead to pressure-overload in the left ventricle, promoting maladaptive hypertrophic remodeling and subsequent cardiac dysfunction, ultimately increasing the risk of heart failure. Galectin-3 (Gal-3) plays a central role in this process; however, its critical intracellular functions complicate direct therapeutic targeting. Notably, pathological microenvironments trigger the proteolytic cleavage of Gal-3 into distinct N- and C-terminal fragments. The specific contributions of these cleaved epitope forms to adverse cardiomyocyte mechanotransduction, and their potential as precision therapeutic targets in contrast to the full-length protein, remain unresolved. Methods: To address this gap, we combined rodent models of aging and pressure-overload (PO) induced cardiac hypertrophy with PO mechanobiology-driven in vitro assays and validation in human cardiac tissue and serum. Gal-3 epitope abundance, localization, phosphorylation, oligomerization, and downstream signaling were quantified using biochemical, imaging, and functional approaches. Results: We found that extracellular oligomers of the Gal-3 C-terminal epitope accumulated in serum and on cardiomyocyte surfaces in hypertrophic rodents and human subjects, where they correlated with adverse remodeling and cardiomyocyte loss. Treatment with Amalaki Rasayana (AR), a standardized nutraceutical-based cardioprotective Ayurvedic phytomedicine, and its bioactive component gallic acid (GA) significantly reduced circulating and surface-associated Gal-3 C-epitope oligomers and attenuated hypertrophy-associated cytotoxic signaling. Mechanistically, AR/GA enhanced Ser6 phosphorylation of Gal-3, promoting intracellular retention, while limiting pathological secretion and deleterious extracellular oligomerization. Following AR/GA treatment, the binding of preformed Gal-3 C-epitope oligomers to cardiomyocyte surfaces were further inhibited, thereby suppressing maladaptive mechanotransductive signaling. Importantly, circulating Gal-3 C-epitope oligomers, together with atrial natriuretic peptide (ANP), constituted a drug-responsive biomarker panel that accurately tracked hypertrophy regression, serving as an indicator of drug efficacy. Conclusions: In summary, Gal-3 C-epitope oligomers represent pathogenic signaling, drug-responsive therapeutic targets and circulating biomarkers of cardiac hypertrophy, with broader relevance to other Gal-3-driven neoplastic, fibrotic, and inflammatory diseases. ### Competing Interest Statement The authors have declared no competing interest. Indian Council of Medical Research (ICMR), 2020-0169/CMB/ADHOC-BMS

ETHNOPHARMACOLOGICAL RELEVANCE:Yograj Guggulu (YG) is a 29-ingredient Ayurvedic polyherbal formulation used for the management of degenerative joint disease (Sandhivata). It is described in the Bhaishajya Ratnavali and listed in the Ayurvedic Formulary of India. Despite continued use in Ayurvedic practice, its molecular mechanisms remain unexplored. AIM OF THE STUDY:To evaluate the therapeutic effects of YG in experimental osteoarthritis (OA), identify bioavailable YG constituents, and trace their molecular targets within human OA disease networks. MATERIALS AND METHODS:Human OA disease networks were constructed from ten integrated synovial transcriptome datasets. YG was administered orally at three doses (135, 270, and 540 mg/kg) for 21 days to male Sprague-Dawley rats with mono-iodoacetate-induced knee OA (n = 8 per group). Functional recovery was assessed across five behavioral endpoints. Untargeted plasma metabolomics identified bioavailable YG metabolites. Knee-joint proteomics identified treatment-associated protein changes. Shortest-path analysis traced regulatory cascades from metabolite targets to attenuated proteins. RESULTS:Low and medium YG doses restored pain sensitivity, locomotion, and gait toward normal levels. Qualitative gastric histology showed less mucosal injury than diclofenac sodium. Twenty-three bioavailable YG metabolites converged on four network-identified targets (NFKBIA, MMP9, PTGS2, FOS). Proteomics identified 364 disease-associated proteins that returned toward baseline abundance after treatment. Directed-network analysis connected the four targets to 45 of 70 attenuated proteins across NF-κB, IL-17, and extracellular matrix degradation cascades. CONCLUSIONS:YG treatment is associated with attenuation of inflammatory and matrix-remodeling protein signatures in experimental OA. The four convergent targets provide a candidate mechanistic framework for its use in traditional Ayurvedic practice.

Post-translational modifications (PTMs) are a widespread regulatory strategy that fine-tunes protein stability, activity, interactions, and localisation. This mechanism acts as a critical molecular switch that enables plants to precisely decode the quality, quantity, and duration of light. It integrates these environmental light cues with intrinsic signalling networks to coordinate downstream physiological responses. In this review, we examine the emerging evidence that post-translational modifications (PTMs) dynamically regulate key components of light signalling during seedling development. We highlight how dynamic PTM networks enable rapid, reversible, and context-specific control of protein function, ensuring adaptive growth under different light conditions. We further discuss additional regulatory layers, underscoring the need to investigate transient, combinatorial PTMs and their mechanistic interplay. Finally, we also speculate that proteome-wide PTM mapping, advanced proteomic approaches, and leveraging artificial intelligence and machine learning will be instrumental in fully harnessing the potential of PTMs to enhance plant growth and resilience.

Background and objectivesMoyamoya disease is known to be associated with the Ring Finger 213 gene variant (RNF213 p.R4810K) in East Asians; however, it remains less studied in South Asians. This study aims to identify the RNF213 p.R4810K and non- p.R4810K variants and to investigate their phenotypic correlation in an Indian cohort of Moyamoya patients.MethodsThe study prospectively enrolled 100 patients with unilateral or bilateral Moyamoya disease (June 2023 to June 2024). Whole exome sequencing was performed to identify all the RNF213 exonic variants. The patients were grouped based on the single-nucleotide variants detected (RNF213 p.R4810K and non- p.R4810K variants) and their pathogenicity. The RNF213 p.R4810K variants were further categorized as homozygous and heterozygous. The demographic, clinical, and angiographic characteristics were collected. Statistical correlations of RNF213 polymorphisms with phenotypic features were assessed by Kruskall-Wallis tests and Fisher’s Exact tests.ResultsSeventy-four (74%) patients carried no RNF213 variants, while 26 (26%) carried RNF213 variants. The founder variant p.R4810K was detected in 9 (9%) patients, and non- p.R4810K variants in 19 (19%) patients. Five missense variants were reported as novel variants (p.Gln681Glu, p.Pro2875Ser, p.Leu4117Pro, p.Gln4029Arg, p.Asp4003Val). Among these, p.Leu4117Pro and p.Asp4003Val, located within the RING domain, were predicted to destabilize the protein structure. The genotype–phenotype correlation showed that the domicile state (p = 0.006), family history of Moyamoya disease (p = 0.001), and periventricular anastomosis (p = 0.026) were significantly different among patients with p.R4810K and non- p.R4810K variants than those without. There was no significant difference observed in clinical presentation or severity of the disease between homozygous and heterozygous carriers.ConclusionThe study confirmed that both RNF213 p.R4810K and non- p.R4810K variants increase the risk of Moyamoya disease with variable phenotypic expression. Further functional studies in a large cohort would help in delineating the role of these variants in disease pathophysiology as well as in better genotype- phenotype correlations.

Breast cancer is one of the leading causes of cancer related mortality in women. Triple negative breast cancer (TNBC), characterized by the absence of ER, PR and HER2 receptors, is particularly challenging to target owing to its highly aggressive nature. Conventional chemotherapeutic agents cause drug resistance, cancer remission and high toxicity even to normal cells. Tupistra nutans (TN) is a flowering plant of the Asparagaceae family and is widely consumed in the Northeastern Himalayan regions. This is the first study exploring the anti-tumorigenic effect of TN on triple-negative breast cancer (TNBC) subtype. We perform ICP-MS and GC-MS analysis to provide comprehensive insights into the phytochemical composition of TN. Using the PASS online tool, we predict that compounds identified in GC-MS such as diosgenin, rhodopin and 1,2-cyclopentanedione, act as apoptosis agonist, MMP9 inhibitor and myc inhibitor respectively. In vitro studies demonstrated IC₅₀ values of 15.2, 28.2, and 70.1 µg/mL at 48 hours in the TNBC cells MDA-MB-231 and HCC1937 and in the normal epithelial-like HEK-293T cell line, respectively, suggesting selective cytotoxicity toward cancer cells. TN shows an anti-migratory effect in MDA-MB-231 cells and was not found to cause apoptosis. Through immunofluorescence for γ-H2A.X, and neutral comet assay we also demonstrate that TN does not induce genotoxicity, rather it upregulates NBR2, indicating possible metabolic stress signalling, and downregulates BRCA1 transcript. TN likely has a cytostatic effect selectively in TNBC cells, indicating functional suppression of tumorigenic properties. Further studies are required to elucidate the underlying mechanisms, and its potential use in combinatorial therapies.