Rangaswamy Roopashree

Objective (s) Despite the established epidemiological synergy between Porphyromonas gingivalis-induced periodontitis and oral squamous cell carcinoma (OSCC), a critical gap remains in developing single-agent therapeutics that simultaneously neutralize bacterial virulence and suppress host oncogenic signaling. This study aimed to comprehensively evaluate Curcumin 4'-O-β-D-gentiobioside (COG) as a novel, dual-pathway phytochemical intervention targeting the keystone virulence factor RgpB while concurrently disrupting OSCC progression networks. Materials and methods A multi-modal computational approach was used, including network pharmacology, molecular docking, molecular dynamics simulations, and ADMET profiling. Anti-aging activity was predicted through pharmacological activity modeling. Results Network pharmacology identified Curcumin 4'-O-β-D-gentiobioside (COG; PubChem CID: 46926100) targeting hub genes (TNF, IL6, EGFR, AKT1), enriching immune regulation, apoptosis, and oxidative stress pathways (FDR < 0.05). Docking revealed strong binding to RgpB (XP GScore: − 9.867 kcal/mol), supported by hydrogen bonds and π-stacking. Molecular dynamics confirmed stability (RMSD: 1.0–1.5 Å; ΔG = − 14 kcal/mol). COG downregulated pro-inflammatory (CXCL10, MAPK8) and oncogenic (MDM2, BCL2L1) mediators, while enhancing ER stress response (KDELC1, ATF4). ADMET analysis predicted high absorption, negligible neurotoxicity, and no hepatotoxicity/genotoxicity. Predicted anti-aging activities included senolytic, antioxidant, and NF-κB inhibition. Conclusion(s) These results position COG as a promising dual-agent that concurrently neutralizes RgpB virulence, disrupts chronic inflammation, and suppresses OSCC progression, addressing a critical unmet need in oral disease therapeutics. These findings warrant in vivo validation for translation into oral disease therapeutics. Graphical Abstract

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder defined by progressive memory loss and synaptic failure. For decades, therapeutic development has focused on clearing amyloid-beta plaques, yet the repeated clinical failures of this approach necessitate a fundamental paradigm shift toward the brain’s immunometabolic landscape. The “Viral Mimicry” hypothesis posits that AD represents a state of sterile autoimmunity where the innate immune system mistakenly identifies self-nucleic acids as viral pathogens. This “ghost war” is ignited by the convergence of metabolic dysfunction and genomic instability: specifically, the leakage of mitochondrial DNA into the cytosol and the epigenetic derepression of ancient retrotransposons (LINE-1, HERVs). These endogenous ligands activate the cGAS-STING cytosolic sensing axis, a pathway that drives a chronic interferon response. Consequently, microglia and astrocytes are transformed into senescent, pro-inflammatory phenotypes that release a toxic Senescence-Associated Secretory Phenotype (SASP), directly fueling synaptic elimination. Crucially, major genetic risk factors, including APOE4 and TREM2 variants, exacerbate this cascade by compromising mitochondrial integrity and lipid metabolism, thereby sensitizing the brain to innate surveillance failure. By reconceptualizing AD as an acquired interferopathy driven by the “enemy within,” this framework highlights novel therapeutic targets. Specifically, repurposing Nucleoside Reverse Transcriptase Inhibitors (NRTIs) to block retrotransposition and deploying senolytics to clear dysfunctional glia offer promising strategies to arrest the progression from healthy aging to cognitive decline. This review synthesizes current research on the molecular mechanisms of viral mimicry, detailing the impact of genetic risk factors and evaluating emerging therapeutic interventions targeting this innate immune axis. Graphical Abstract The alternative text for this image may have been generated using AI. The Shift from Molecular Containment to Viral Mimicry in Alzheimer’s Disease. The figure contrasts the physiological state of healthy aging with the pathological state of Alzheimer’s Disease. (Left) In the healthy brain, "Molecular Containment" is maintained: immunogenic mitochondrial DNA is sequestered within the organelle, and ancient retrotransposons are epigenetically silenced within the nucleus. (Right) In Alzheimer’s Disease, the convergence of genomic instability and metabolic failure leads to a "loss of inhibition". The derepression of retroelements (LINE-1 (long interspersed nuclear element-1) dsDNA, HERV dsRNA) and the leakage of mitochondrial DNA into the cytosol activate the cGAS-STING innate immune axis. This viral mimicry transforms microglia into a senescent, Lipid-Droplet Accumulating phenotype, driving a chronic Type I Interferon response that fuels neurodegeneration

Tamoxifen remains a cornerstone therapy for estrogen receptor-positive (ER⁺) breast cancer; however, the emergence of drug resistance significantly limits its therapeutic success. Growing evidence has revealed that non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), act as pivotal regulators of the molecular networks driving tamoxifen resistance. These “silent regulators” modulate multiple signaling pathways, including PI3K/AKT, MAPK, and estrogen receptor signaling, through mechanisms such as post-transcriptional regulation, epigenetic modification, and competitive endogenous RNA (ceRNA) interactions. Dysregulated ncRNAs can alter drug efflux, apoptosis, cell cycle progression, and epithelial–mesenchymal transition (EMT), contributing to reduced tamoxifen sensitivity and tumor recurrence. Our knowledge of BC resistance to tamoxifen will be aided by the new molecular insights into the mechanistic understanding of resistance to endocrine treatment as a whole that come from the growing functions of ncRNAs as miRNA sponges, transcriptional scaffolds, and ceRNAs, among others. The biosynthesis and molecular properties of ncRNAs, their involvement in tamoxifen resistance, and their potential use as therapeutic targets or diagnostic biomarkers are the main topics of this thorough analysis. In order to perhaps serve as a foundation for upcoming RNA-based therapies aimed at overcoming endocrine resistance in ER⁺ BC, we would also consolidate the current body of knowledge.

Innate immune cells are emerging as powerful allies in the fight against blood cancers. Natural Killer (NK) cells, macrophages, and dendritic cells (DCs)—once viewed mainly as supporting players—are now at the forefront of next-generation immunotherapies, owing to their rapid, antigen-independent tumor recognition and potent effector functions. This review highlights their distinct anti-tumor roles: NK cells’ cytotoxicity and “missing-self” recognition, the dual and adaptable nature of macrophages in the tumor microenvironment (TME), and the antigen-presenting capabilities of DCs that bridge innate and adaptive immunity. We further examine transformative therapeutic strategies, including adoptive NK cell transfer, CAR-engineered NK cells (CAR-NK), CAR-macrophages (CAR-M), and DC vaccines, with a focus on clinical outcomes and safety—particularly the encouraging toxicity profile of CAR-NK cells. Despite these advances, major challenges persist, including limited persistence and homing of infused cells, TME-driven immunosuppression, and potential on-target/off-tumor effects. To overcome these barriers, synergistic approaches that integrate innate immune therapies with checkpoint inhibitors, conventional treatments, innovative engineering, and precise modulation of the TME will be essential. These strategies hold the promise of translating scientific breakthroughs into durable, safe, and widely accessible treatments for patients with hematological malignancies.

Complex systemic immune dysregulation and chronic inflammation in rheumatological diseases lead to long-term inflammation and morbidity, which are primarily controlled by systemic immunosuppressant agents with diverse effects, underscoring the need for more precise and innovative treatments. The unmatched specificity in targeting disease-driving genes and pathways makes small interfering RNA (siRNA) a transformative treatment approach. This review examines how siRNA can precisely transform the therapy of rheumatological diseases by targeting critical molecular pathways associated with inflammation, immunological dysregulation, and tissue damage. While this study elucidates siRNA therapies targeting inflammatory pathways to treat rheumatological diseases, it moves beyond the conventional therapeutic application of siRNAs targeting pro-inflammatory cytokines; it explicitly focuses on upstream signaling hubs within synovial fibroblasts, T cells, and plasma cells, as well as on non-inflammatory mechanisms that lead to bone damage. The review also integrates in vitro and in vivo, as well as preclinical siRNA studies, to identify the most promising targets and determine whether these siRNA modifications, combined with delivery systems, achieve body-wide and joint-specific immune-stromal network reprogramming through targeted delivery without causing total immune system breakdown.

Cancer remains a formidable global health challenge, with therapeutic resistance and disease relapse frequently attributed to the persistence of a resilient subpopulation of cells known as cancer stem cells (CSCs). These cells, characterized by self-renewal capacity, continuous proliferation, and multi-lineage differentiation potential, drive tumorigenesis, metastasis, and evade conventional therapies. Traditional cancer treatments often fail to eradicate CSCs, leading to their enrichment post-therapy and subsequent tumor recurrence. This comprehensive review explores two innovative and interconnected therapeutic paradigms for targeting CSCs: ferroptosis and metabostemness. Ferroptosis, an iron-dependent form of regulated cell death distinct from apoptosis, offers a promising avenue to overcome apoptosis resistance prevalent in many cancers, including CSCs, by inducing lethal lipid peroxidation. Concurrently, “metabostemness” describes the unique metabolic reprogramming of CSCs, encompassing alterations in glucose, lipid, and amino acid metabolism, which are critical for maintaining their stemness, survival, and resistance to treatment. This review synthesizes the current understanding of the molecular mechanisms underlying ferroptosis and metabostemness in CSCs, highlighting emerging small-molecule strategies designed to exploit these vulnerabilities. The discussion includes direct ferroptosis inducers and compounds that sensitize CSCs to ferroptosis by disrupting their aberrant metabolic pathways. Furthermore, the synergistic potential of combining ferroptosis induction with metabolic inhibitors to enhance therapeutic efficacy and circumvent drug resistance is explored. Finally, the significant challenges in clinical translation, including issues of specificity, systemic toxicity, and tumor heterogeneity, are addressed, while proposing advanced drug delivery systems and integrated multi-omics approaches as crucial future directions for realizing the full potential of these novel anti-CSC strategies in precision oncology.

Glioblastoma (GBM) is the most aggressive and treatment-resistant form of primary brain tumor, characterized by rapid proliferation, extensive heterogeneity, and evasion of programmed cell death. Among emerging molecular regulators, microRNA-34 (miR-34) has gained attention as a potent tumor suppressor with the ability to modulate key signaling pathways involved in cell survival and death. This review explores the dual role of miR-34 in orchestrating apoptosis and autophagy, two fundamental processes that determine glioblastoma cell fate. We summarize current findings on how miR-34 directly targets genes involved in apoptotic signaling—such as BCL2, SIRT1, and NOTCH1—thereby promoting cell death and sensitizing GBM cells to therapeutic agents. Additionally, we highlight the context-dependent influence of miR-34 on autophagic flux, where it can either facilitate cytoprotective responses or trigger autophagy-associated cell death. Understanding this regulatory balance provides insight into the cellular plasticity of GBM and opens new avenues for therapeutic intervention. Targeting miR-34 or its downstream pathways offers promising potential to overcome resistance mechanisms and improve outcomes in glioblastoma treatment.