Constitutively active neutrophil extracellular traps (NETs) and elevated plasma homocysteine are independent risk factors for Type 2 Diabetes (T2D) associated vascular diseases. Here, we show robust NETosis due to elevated plasma homocysteine levels in T2D subjects and increased components of NETs such as neutrophil elastase and cell free DNA. Cooperative NETs formation was observed in neutrophils exposed to homocysteine, IL-6 and high glucose suggesting acute temporal changes tightly regulate constitutive NETosis. Homocysteine induced NETs by NADPH oxidase dependent and independent mechanisms. Constitutively higher levels of calcium and mitochondrial superoxides under hyperglycemic conditions were further elevated in response to homocysteine leading to accelerated NETosis. Homocysteine showed robust interaction between neutrophils and platelets by inducing platelet aggregation and NETosis in an interdependent manner. Our data demonstrates that homocysteine can alter innate immune function by promoting NETs formation and disturbs homeostasis between platelets and neutrophils which may lead to T2D associated vascular diseases.

There have been magnificent advancements in the understanding of molecular mechanisms of chronic diseases over the past several years, but these diseases continue to be a considerable cause of death worldwide. Most of the approved medications available for the prevention and treatment of these diseases target only a single gene/protein/pathway and are known to cause severe side effects and are less effective than they are anticipated. Consequently, the development of finer therapeutics that outshine the existing ones is far-reaching. Natural compounds have enormous applications in curbing several disastrous and fatal diseases. Oroxylin A (OA) is a flavonoid obtained from the plants Oroxylum indicum, Scutellaria baicalensis, and S. lateriflora, which have distinctive pharmacological properties. OA modulates the important signaling pathways, including NF-κB, MAPK, ERK1/2, Wnt/β-catenin, PTEN/PI3K/Akt, and signaling molecules, such as TNF-α, TGF-β, MMPs, VEGF, interleukins, Bcl-2, caspases, HIF-1α, EMT proteins, Nrf-2, etc., which play a pivotal role in the molecular mechanism of chronic diseases. Overwhelming pieces of evidence expound on the anti-inflammatory, anti-bacterial, anti-viral, and anti-cancer potentials of this flavonoid, which makes it an engrossing compound for research. Numerous preclinical and clinical studies also displayed the promising potential of OA against cancer, cardiovascular diseases, inflammation, neurological disorders, rheumatoid arthritis, osteoarthritis, etc. Therefore, the current review focuses on delineating the role of OA in combating different chronic diseases and highlighting the intrinsic molecular mechanisms of its action.

Despite the extensive research in recent years, the current treatment modalities for neurological disorders are suboptimal. Curcumin, a polyphenol found in Curcuma genus, has been shown to mitigate the pathophysiology and clinical sequalae involved in neuroinflammation and neurodegenerative diseases. We searched PubMed database for relevant publications on curcumin and its uses in treating neurological diseases. We also reviewed relevant clinical trials which appeared on searching PubMed database using ‘Curcumin and clinical trials’. This review details the pleiotropic immunomodulatory functions and neuroprotective properties of curcumin, its derivatives and formulations in various preclinical and clinical investigations. The effects of curcumin on neurodegenerative diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), brain tumors, epilepsy, Huntington's disorder (HD), ischemia, Parkinson's disease (PD), multiple sclerosis (MS), and traumatic brain injury (TBI) with a major focus on associated signalling pathways have been thoroughly discussed. This review demonstrates curcumin can suppress spinal neuroinflammation by modulating diverse astroglia mediated cascades, ensuring the treatment of neurological disorders.

Recent advances in oncological research have highlighted the potential of naturally derived compounds in cancer prevention and treatment. Notably, sulforaphane (SFN), an isothiocyanate derived from cruciferous vegetables including broccoli and cabbage, has exhibited potent chemosensitizing capabilities across diverse cancer types of bone, brain, breast, lung, skin, etc. Chemosensitization refers to the enhancement of cancer cell sensitivity to chemotherapy agents, counteracting the chemoresistance often developed by tumor cells. Mechanistically, SFN orchestrates this sensitization by modulating an array of cellular signaling pathways (e.g., Akt/mTOR, NF-κB, Wnt/β-catenin), and regulating the expression and activity of pivotal genes, proteins, and enzymes (e.g., p53, p21, survivin, Bcl-2, caspases). When combined with conventional chemotherapeutic agents, SFN synergistically inhibits cancer cell proliferation, invasion, migration, and metastasis while potentiating drug-induced apoptosis. This positions SFN as a potential adjunct in cancer therapy to augment the efficacy of standard treatments. Ongoing preclinical and clinical investigations aim to further delineate the therapeutic potential of SFN in oncology. This review illuminates the multifaceted role of this phytochemical, emphasizing its potential to enhance the therapeutic efficacy of anti-cancer agents, suggesting its prospective contributions to cancer chemosensitization and management.

Cancer has become a global health hazard accounting for 10 million deaths in the year 2020. Although different treatment approaches have increased patient overall survival, treatment for advanced stages still suffers from poor clinical outcomes. The ever-increasing prevalence of cancer has led to a reanalysis of cellular and molecular events in the hope to identify and develop a cure for this multigenic disease. Autophagy, an evolutionary conserved catabolic process, eliminates protein aggregates and damaged organelles to maintain cellular homeostasis. Accumulating evidence has implicated the deregulation of autophagic pathways to be associated with various hallmarks of cancer. Autophagy exhibits both tumor-promoting and suppressive effects based on the tumor stage and grades. Majorly, it maintains the cancer microenvironment homeostasis by promoting viability and nutrient recycling under hypoxic and nutrient-deprived conditions. Recent investigations have discovered long non-coding RNAs (lncRNAs) as master regulators of autophagic gene expression. lncRNAs, by sequestering autophagy-related microRNAs, have been known to modulate various hallmarks of cancer, such as survival, proliferation, EMT, migration, invasion, angiogenesis, and metastasis. This review delineates the mechanistic role of various lncRNAs involved in modulating autophagy and their related proteins in different cancers.

Disorganized vessels in the tumor vasculature lead to impaired perfusion, resulting in reduced accessibility to immune cells and chemotherapeutic drugs. In the breast tumor–stroma interplay, paracrine factors such as interleukin-6 (IL-6) often facilitate disordered angiogenesis. We show here that epigenetic mechanisms regulate the cross-talk between IL-6 and vascular endothelial growth factor receptor 2 (VEGFR2) signaling pathways in myoepithelial (CD10+) and endothelial (CD31+, CD105+, CD146+, and CD133-) cells isolated from malignant and non-malignant tissues of clinically characterized human breast tumors. Tumor endothelial (Endo-T) cells in 3D cultures exhibited higher VEGFR2 expression levels, accelerated migration, invasion, and disorganized sprout formation in response to elevated IL-6 levels secreted by tumor myoepithelial (Epi-T) cells. Constitutively, compared with normal endothelial (Endo-N) cells, Endo-T cells differentially expressed DNA methyltransferase isoforms and had increased levels of IL-6 signaling intermediates such as IL-6R and signal transducer and activator of transcription 3 (STAT3). Upon IL-6 treatment, Endo-N and Endo-T cells displayed altered expression of the DNA methyltransferase 1 (DNMT1) isoform. Mechanistic studies revealed that IL-6 induced proteasomal degradation of DNMT1, but not of DNMT3A and DNMT3B and subsequently led to promoter hypomethylation and expression/activation of VEGFR2. IL-6 induced VEGFR2 up-regulation was inhibited by overexpression of DNMT1. Transfection of a dominant-negative STAT3 mutant, but not of STAT1, abrogated VEGFR2 expression. Our results indicate that in the breast tumor microenvironment, IL-6 secreted from myoepithelial cells influences DNMT1 stability, induces the expression of VEGFR2 in endothelial cells via a promoter methylation-dependent mechanism, and leads to disordered angiogenesis.