Declining sperm counts are increasingly reported worldwide, yet their biological and clinical significance remains uncertain. Although meta-analyses suggest a long-term downward trend, interpretation is limited by methodological variation and an overreliance on sperm count as a single marker of male reproductive health. This creates a critical gap between population level observations and underlying biology, leaving many cases labelled as idiopathic despite measurable dysfunction. This review addresses this gap by proposing a hypothesis driven framework that integrates oxidative stress, inflammation, and metabolic dysfunction as interacting drivers of male infertility. Rather than acting independently, environmental exposures, lifestyle factors, and developmental influences converge on shared biological pathways that impair spermatogenesis and sperm function. This model explains the variability in clinical presentation while accounting for consistent population level decline. By shifting the focus from isolated semen parameters to interconnected biological processes, the framework provides a basis for mechanism-based classification and targeted management. It also supports a more coherent interpretation of epidemiological trends. Declining sperm counts are therefore better understood not as an isolated finding, but as an indicator of broader systemic dysfunction with implications for reproductive and general health.
The development of advanced cell culture models has overcome the limitations of conventional monolayer cultures, still doubts remain about the reliability of data obtained using traditional systems, as well as the comparability of results from different models. This is highly relevant to preclinical drug analysis, where in vitro studies determine the fate of molecules. We investigated the molecular mechanisms that regulate the activity of cannabidiolic acid (CBDA) in a 3D model of a glioblastoma cell line, comparing the results with those obtained on a conventional monolayer model of the same cells. CBDA targeted the translation initiation factor EIF2A in both tested models. However, the downstream consequences of the CBDA-EIF2A interaction differed between cells cultured in 3D and 2D, since the biological functions and interactome of EIF2A were found to change significantly. Overall, this study sheds new light on the difficulties associated with comparing results obtained using different in vitro models.
A novel series of pyrazolo[3,4-d]pyrimidine derivatives conjugated with uracil, cytosine, and benzene sulfonamide moieties (5a-11b) were designed as dual inhibitors of tumor-associated carbonic anhydrase (CA) isoforms and and 11b emerged as the most potent candidates, exhibiting nanomolar inhibition against CA II, IX, and XII. Notably, 11a inhibited CA IX with a Ki of 2.6 nM, while 11b showed potent inhibition of CA II (Ki= 7.1 nM) and CA IX (Ki = 2.8 nM). Furthermore, both compounds surpassed erlotinib in EGFR inhibition, with IC50 values of 69 nM (11a) and 64 nM (11b). Biological evaluation revealed significant antiproliferative activity against MCF-7, HePG-2, HCT-116, and A549 cancer cell lines under normoxic and hypoxic conditions. Under hypoxia, 11a demonstrated superior potency (IC50 range: 4.04-9.58 & micro;M). Flow cytometry indicated that 11a induced G1 phase arrest, while 11b triggered G2/M arrest and pronounced apoptosis, reducing cell viability to 12.4%. Molecular analysis confirmed the activation of the intrinsic apoptotic pathway through the upregulation of BAX, caspase-9, and p53, alongside Bcl-2 downregulation. Molecular docking and 100 ns molecular dynamics simulations confirmed stable binding within CA-II, CA-IX, and EGFR active sites. These findings identify 11b as a highly promising multi-target lead for further anticancer development.
The deadliest strain of malaria is caused by Plasmodium falciparum (Pf). Efforts to eliminate malaria continue to rely on the development of new antimalarial drugs, as resistance to existing therapies has emerged. In this work, we used a Bocprotected amine as an internal carbonyl source to transform a hydroxyethylamine group into an oxazolidinone moiety. Synthesized aniline-based compounds were screened for their in vitro antiplasmodial activity against the PfPf3D7 and cytotoxicity on HepG2 cells. Compounds 4c, 4e, and 4k exhibited moderate antiplasmodial activity at 100 mu M concentration with the % inhibition of 66.8, 70.1, and 83.6, respectively. The obtained hits, 4c, 4e, and 4k, did not exhibit any indication of toxicity tested on HepG2 cells and displayed 50% toxic concentration (TC50) of 178.1 mM, 196.6 mM, and 176 mM, respectively. Of note, compound 4k exhibited 58% inhibition of the parasite even at 1 mM concentration, displaying limited potency and suboptimal dose-response behavior, which could be a preliminary hit candidate for further studies, lead optimization, and animal studies.
The global burden of cancer is increasingly shaped by socio-economic determinants that extend beyond geographic incidence patterns. While historically considered a disease of affluence, cancer now reflects a divergence between high-income countries (HICs) and low-and middle-income countries (LMICs), driven by distinct environmental, occupational, and structural exposures. This narrative review examines how socio-economic conditions act as primary determinants of cancer etiology by linking epidemiological trends to molecular evidence. A comprehensive literature search was conducted (2006-2026), focusing on cancer etiology, environmental carcinogenesis, mutational signatures, and health disparities. Three domains of socio-economic influence emerged from search. First, harmful exposures, including asbestos, aflatoxin B1, arsenic, heavy metals, and air pollution, are disproportionately concentrated in under-regulated populations. Second, these exposures produce distinct mutational signatures; aflatoxin-related hepatocellular carcinoma is associated with TP53 R249S and COSMIC Signature 24, while cancers in HICs often involve PI3K/AKT/mTOR pathway alterations. Third, disparities in screening infrastructure create "screening deserts," increasing mortality gaps. Socio-economic context fundamentally shapes cancer biology, incidence, and outcomes. Reducing disparities requires expanded genomic capacity in LMICs, targeted prevention strategies, and equitable access to precision oncology.
Fumonisin B1 (FB1), a mycotoxin, induces toxic and carcinogenic effects in humans and animals by influencing the epigenome. The lncRNA, homeobox A11 antisense (HOXA11-AS) modulates DNA methylation and functions as a competing endogenous RNA or molecular scaffold. However, the role of HOXA11-AS in FB1-toxicity is unknown. Therefore, we investigated the effect of FB1 on p53-dependent apoptosis via the HOXA11-AS/miR-124/DNMT axis. HepG2 cells were treated with various concentrations of FB1 (0, 5, 50, 100, and 200 & micro;M; 24 h). Qualitative polymerase chain reaction and/or western blot were used to determine the expression of HOXA11-AS, miR-124, SP1, DNMT3B, and p53. The OneStep qMethyl Kit was used to assess p53 promoter methylation, while luminometry was used to measure caspase activity. FB1 upregulated HOXA11-AS, leading to a subsequent decrease in miR-124 and increases in SP1 and DNMT3B. This promoted hypermethylation of p53 promoters, thereby reducing p53 expression and caspase activity. Taken together, the data suggest that FB1 inhibits p53-dependent apoptosis via the HOXA11-AS/miR-124/DNMT axis in HepG2 cells.
Monoamine oxidases (MAOs) are mitochondrial enzymes that degrade monoamines released by neurons and glial cells, thereby regulating cellular signalling and redox balance. Increasing evidence indicates that the two isoforms, MAOA and MAOB, play complex and context-dependent roles in cancer biology, including colorectal cancer (CRC). This review summarizes and critically evaluates current literature and available data on the expression patterns, prognostic significance, and functional roles of MAOA and MAOB in CRC, and contrasts these findings with observations reported in other cancer types. Available studies consistently indicate that reduced MAOA expression in CRC is associated with poor patient prognosis, suggesting a potential protective role of MAOA through modulation of oxidative stress and regulation of oncogenic pathways such as EGFR transactivation. In contrast, elevated MAOA expression has been linked to poor survival outcomes in several other malignancies, underscoring strong cancer-type specificity. MAOB expression in CRC is generally low; however, higher MAOB levels have been associated with worse survival, potentially reflecting tumour heterogeneity, microenvironmental influences, or stage-dependent expression. Collectively, these contrasting patterns highlight the biological complexity and context-dependent functions of MAOs in cancer. The review emphasizes the need for larger, well-characterized clinical cohorts and mechanistic studies to clarify the translational potential of MAOA and MAOB as prognostic biomarkers or therapeutic targets in CRC.
Tinospora cordifolia (Willd.) Miers (Menispermaceae), an important medicinal plant in Ayurvedic medicine, is traditionally used as a rejuvenating tonic and immune modulator. Its alkaloids (Alk) and terpenoids (Terp) possess antioxidant and anti-inflammatory properties, suggesting that it may be beneficial in preventing sarcopenia-induced muscle degeneration. This study aimed to evaluate the efficacy of T. cordifolia-derived Alk and Terp in the treatment of sarcopenia in aged mice. Male Swiss albino mice, 10 months old, were administered Alk and Terp for the next 8 months. Muscle tissues were analyzed for the makers of sarcopenia, oxidative stress, inflammation, apoptosis, myogenesis, and histological changes. Aged control mice showed similar to 2.0-fold increases in oxidative stress and inflammatory cytokines, elevated MuRF-1 and Atrogin-1, reduced p-AktSer473, and decreased myogenic marker expression. Alk and Terp supplementation significantly reduced oxidative stress and inflammation, downregulated MuRF-1 and Atrogin-1, restored p-AktSer473 (similar to 1.6-fold), and enhanced PGC-1 alpha, HSP70, Myogenin, MyoD, and Pax7 (similar to 2.5-fold). Bax expression was reduced, indicating decreased apoptosis. Histology revealed preserved muscle fiber architecture, larger cross-sectional area, improved mitochondrial density, and reduced fiber type switching. All the findings were correlated with the decrease of sarcopenic markers, i.e., Bmp-7, Atf4, and Gadd45. Metformin showed comparatively modest effects. Alk and Terp from T. cordifolia reduce sarcopenia symptoms in aged mice by modulating Akt activity, inhibiting apoptosis, oxidative stress, and inflammation, and promoting myogenesis. Overall, Terp was more effective at reducing inflammation than alkaloids. Conversely, Alk increased Akt phosphorylation and, consequently, activity levels compared to Terp.
Arginine/tryptophan-rich peptides are amphipathic, enabling membrane interaction, cargo transport, and antimicrobial activity. To enhance these properties, we synthesized and evaluated hybrid peptide [RW]4K-AH135 (1), combining the antimicrobial α-helical peptide AH135 (AMP) with the cell-penetrating peptide (CPP) [RW]4K, and [R5W4]K-AH135 (2), combining AH135 with another AMP [R5W4]K. Peptides were synthesized by Fmoc solid-phase peptide synthesis and cyclization in solution phase, purified by HPLC, and characterized by MALDI-TOF. While AH135 and [R5W4] showed antimicrobial activity (MICs 3.1-6.2 μg/mL), both hybrids were inactive (MIC ≥ 50 μg/mL). In contrast, the hybrids functioned as molecular transporters in cancer cells. [R5W4]-AH135 enhanced the activity of multiple chemotherapeutics in MDA-MB-231 and SK-OV-3 cells, improving growth inhibition by approximately 15-47% at 72 h, and improved doxorubicin efficacy by approximately 37% in resistant MES-SA cells. Both hybrids promoted the intracellular delivery of green fluorescent protein (50 nM), as confirmed by flow cytometry and confocal microscopy (p < 0.001). [RW]4K-AH135 showed higher uptake in both lines in a dose- and time-dependent manner. [R5W4]K-AH135 acted as a chemotherapeutic agent sensitizer, whereas [RW]4K-AH135 was a superior carrier. Thus, these hybrids act as molecular transporters and represent promising platforms for drug conjugation and intracellular delivery.
Alzheimer's disease (AD) represents a looming global health crisis, with projections estimating 152.8 million affected individuals by 2050, disproportionately impacting ageing populations in China, the United States of America , India. This review examines the complex interplay between demographic risk factors like age, gender, , geographic distribution, along with comorbidities accelerating AD pathogenesis, such as type- 2 diabetes, hypertension, cardiovascular disease, obesity, and depression, through converging mechanisms of neuroinflammation, vascular dysfunction, and metabolic impairment. We critically assess current therapeutic strategies spanning multiple mechanistic approaches, including various hypothesis-based therapeutic strategies. Although new therapies have gained regulatory approval, significant challenges persist, including trial failures, modest efficacy, and multifactorial etiology. Due to the limited success of traditional therapies, several unconventional strategies have also been explored recently. While natural products demonstrate mixed evidence with no major breakthroughs yet, probiotics, multivitamins, and multidomain intervention programs incorporating precision medicine, nanoscience, and lifestyle changes show promise towards future course of action. Advancing these integrated paradigms with careful analysis of current limitations represents the best opportunity to mitigate AD's global burden and a step closer to effective disease-modifying cures.
Tuberculosis (TB) has persistently posed a formidable challenge throughout human history as a contagious disease. Despite the gravity of the global TB burden, the advancement of available therapeutic treatment has been minimal over several decades. The emergence of drug-resistant M. tb has diminished the efficacy of existing treatments. Given the escalating global TB crisis, expediting the drug discovery process is paramount, demanding the development of novel drugs capable of eliminating the drug-resistant as well as latent TB infections. Furthermore, the new drugs should shorten the duration of treatment. This article summarises the current landscape of tuberculosis treatment options, shedding light on the latest efforts in the drug discovery process. This review also delves into various molecular pathways of the mycobacterium in order to ascertain unique drug targets along with their latest novel inhibitors, thus providing a comprehensive platform for the readers.
In this study, we report instantaneous production of near-infrared (NIR) light absorbing gold nanostars (AuNSs) in the nanogold seed-mediated synthetic procedure involving polysorbates (e.g. Tween 80). The electron microscopic (HR-TEM and FE-SEM) studies confirmed the star shaped morphology of AuNSs in the size range of 82 +/- 10 nm. The negative zeta potential, hydrodynamic diameter of 133 +/- 01 nm and FT-IR measurements affirmed the polysorbate mediated stabilization of AuNSs. The X-ray diffraction (XRD) results highlighted the crystalline behavior of AuNSs with characteristic peaks at 38.1 degrees, 44.3 degrees, 64.6 degrees and 77.7 degrees. The 638 nm laser irradiation of AuNSs (75 mu g/mL) led to strong heating effects (52.7 +/- 1.2 degrees C at 1 W/cm(2) for 5 min) in photothermal experiments. These AuNSs could also effectively load the anticancer drug, doxorubicin (DOX) and thus led to a chemo-photothermal effect mediated cytotoxic response in MCF-7 (human breast cancer) cell line which was significantly enhanced in comparison to either modality alone as assessed by CCK-8 assay and annexin-V binding studies. Furthermore, toxicological assessment in Drosophila melanogaster did not reveal any adverse effects which present these AuNSs as biocompatible and promising multifunctional nanotherapeutics suitable for effective and enhanced outcome in cancer therapy.
C-reactive protein (CRP) is a widely used biomarker for inflammation, infection, and various disease states. This review explores the role of CRP in the diagnosis and prognosis of several conditions, including autoimmune diseases, cardiovascular diseases (CVD), chronic kidney disease (CKD), cancer, COVID-19, periodontitis, cirrhosis, and hypertension. CRP levels are elevated in many of these conditions, making it a useful tool for monitoring disease progression. In autoimmune diseases like rheumatoid arthritis, CRP is associated with disease activity and severity. For CVD, high-sensitivity CRP (hs-CRP) is a valuable predictor of cardiovascular events and is included in risk calculators. CRP also plays a role in the pathogenesis of acute kidney injury and CKD, with higher levels linked to worse outcomes. In cancer, elevated CRP is associated with increased risk for various types of malignancies. During the COVID-19 pandemic, CRP levels correlated with disease severity and mortality. Periodontitis, cirrhosis, and hypertension have also been linked to increased CRP levels, although the association with hypertension remains controversial. Furthermore, the article highlights recent advances in CRP detection methods, emerging biomarkers studied alongside CRP, and the application of CRP in precision medicine.
Cell and immunotherapy products are known for targeting the root cause of health ailments and potentially curing cancers and other degenerative indications. The rapid growth in cell therapy products, CRISPR-based gene editing, and stem cell applications in India is changing the face of personalized medicine, putting the country at the forefront of innovative product development. The therapy develops through strong regulatory guidelines and collaborative efforts among academia, industry, and government. However, high costs, less infrastructure, regulatory complexity, and ethics are hurdles in implementing the idea. This review emphasizes the progress made in cell therapy research in India and discusses the challenges as well as the possible strategies for overcoming them.
Bronchial asthma is a chronic inflammatory disease with airway blockage, hyper-responsiveness. Key biomarkers like irisin, myeloperoxidase (MPO), and glucose regulate inflammation and metabolic dysfunction. Irisin is a novel parameter for adolescents asthma. In this study assessed prognostic significance of irisin and MPO in predicting asthma outcomes. A case-control study based on prevalence (2.2%) of asthma in adolescents, involving 70 adolescents after excluding 30 samples from 100 participants (due to presence of infections), categorized to 35 patients with bronchial asthma and 35 age and BMI matched of apparently healthy controls. The study categorized patients into 35 with bronchial asthma and 35 healthy controls. The patients were further divided into 20 with allergic bronchial asthma (P.ABA) and 15 with non-allergic bronchial asthma (P.NABA), techniques were used ELISA (irisin, MPO) , AFIAS (IgE), and Auto Analyzer (glucose). Our results of Irisin, myeloperoxidase, and glucose levels were significantly p<0.05 elevated in P.ABA and P.NABA patients compared to controls. The study found significant positive correlations among all parameters, with over 80% of the AUC for irisin and myeloperoxidase based on ROC curve. These findings highlight importance of monitoring irisin, MPO, IgE, and glucose levels in bronchial asthma patients to better understand and predict long-term outcomes.
The development of biocompatible and structurally defined amphiphilic nanocarriers is crucial for enhancing the solubility, stability, and targeted delivery of poorly water-soluble therapeutics. In this study, we report the design, synthesis, and physicochemical evaluation of four new nonionic dendritic amphiphiles derived from glycerol-based dendrons incorporating biodegradable amide linkers as pH-sensitive moieties. These amphiphiles were synthesized through a modular approach, employing a polyglycerol core and hydrophobic alkyl chains of varying lengths introduced via amide bond formation. Structures were confirmed by using FTIR, H-1 NMR, and C-13 NMR spectroscopy data. Owing to their amphiphilic nature, the molecules spontaneously assemble in aqueous media to form well-defined, stable micellar structures, as confirmed by surface tension analysis and dynamic light scattering (DLS). To evaluate their drug delivery potential, pyrene was used as a model hydrophobic guest molecule. Among the synthesised amphiphiles, the C-12-G(1) dendron demonstrated optimal encapsulation efficiency and was used for a release profile study. Drug release studies conducted under neutral (pH 7.0) and acidic (pH 5.3) conditions revealed a sustained release behaviour over 24 hours, with a significantly enhanced release under acidic conditions. Comparative analysis with previously developed ester-linked analogs revealed that amide-linked systems exhibit lower critical micelle concentrations (CMC), enhanced stability, and pH responsiveness. This work highlights the potential of amide linkers as a promising carrier for next-generation nanocarriers for hydrophobic drug delivery in biomedical applications.
Varicella Zoster Virus (VZV), from the Herpesviridae family, is responsible for causing Varicella, commonly known as chickenpox, during primary infection and Herpes Zoster, known as shingles, upon. Its reactivation can lead to various neurological complications. With more than half of the world population harboring latent VZV, the global burden of herpes zoster and its associated complications significantly contributes to healthcare costs, underscoring the need for effective vaccination strategies and therapeutic interventions. This review explores the recent advancements in VZV epidemiology, pathogenesis, the clinical spectrum of VZV reactivation, vaccine development, including and therapeutics targeting the latent virus and the immune system.
Herein, the synthesis of benzimidazole- thiazolidine2,4-dione -1,2,3-triazole conjugates (7a-7n) using copper activity against MCF-7, MDA-MB468 and MDA-MB-231 human breast cancer cells. Among all the compounds, four compounds namely 7d, 7i, 7k, and 7n displayed superior activity than 5-fluorouracil towards three breast cancer cell lines with IC50 values ranging from 1.8 mu M to 9.7 mu M. In vitro tyrosine kinase EGFR inhibition assay revealed that the compound 7d have 2.8 times more potency than that of erlotinib with IC50 value of 0.15 mu M and remaining three compounds (7i, 7k and 7n) also have more activity than erlotinib. Molecular docking studies on EGFR protein indicated that compound 7d exhibit greatest binding energy i.e. -11.04 kcal/mol compared to erlotinib. The molecule 7d was characterized by using density functional theory (DFT) with B3LYP/6-311++ G (d, p) basis set. The structural parameters were obtained from geometry optimization. Finally in silico pharmacokinetic profile also determined where 7d and 7i followed all the rules like Lipinski rule, Ghose rule, Veber rule, Egan rule and Muegge rule without any deviation.
Breast cancer (BCa) is marked by uncontrolled cell division, causing the reactivation of the multi-unit ribonucleoprotein telomerase enzyme by expression of the catalytic telomerase reverse transcriptase (hTERT) subunit. Targeting hTERT can therefore offer an advantage in BCa management. Medicinal plants such as Hydrastis canadensis, used in homeopathy has therefore been explored for BCa treatment. Hydrastis canadensis mother tincture (MT) showed the presence of phytoactive components exhibiting anti-cancerous potential. The components were identified by GC-MS analysis and 34 phytochemicals were then screened using in-silico tools. The protein targets of the active components were predicted by submitting the Simplified Molecular Input Line Entry System (SMILES) of the compounds to SwissTargetPrediction, giving active components targeting the hTERT protein. Molecular docking studies were performed on AutoDock 4.2 and Molecular Dynamics (MD) simulation studies on GROningen MAchine for Chemical Simulations (GROMACS) 2023.2. The MM/PBSA calculations were performed with the gmxMMPBSA package. The data was then validated through wet lab experiments. Linoleic acid and Gadoleic acid, as modulators of human telomerase reverse transcriptase (hTERT) were identified, influencing cancer cell survival. The results highlighted the mechanistic role of Hydrastis canadensis to target the key oncogenic protein hTERT operative in breast cancer with potential therapeutic applications in cancer treatment.
The rise of antibiotic resistance necessitates new treatment strategies. Although curcumin exhibits antibacterial properties, its poor solubility and bioavailability limit its therapeutic use. This study investigates the antibacterial potential of cyclic peptide [W4KR5], curcumin derivatives, and their new conjugates to overcome curcumin's limitations. Minimum inhibitory concentration (MIC) assays revealed that [W4KR5] had moderate activity (7.8-31.3 mu g/mL), while curcumin alone was less effective (200-225 mu g/mL). Curcumin derivatives showed improved activity (MIC similar to 50 mu g/mL), and conjugates of [W4KR5]-curcumin had MICs of 31.3-62.5 mu g/mL. Physical mixtures of [W4KR5] with curcumin derivatives demonstrated enhanced activity (MIC = 7.8-31.3 mu g/mL) with partial synergy or additive effects (FICI = 0.75-1.5) against S. aureus, E. coli, P. aeruginosa, and K. pneumoniae. In melanoma cells (SK-MEL-28), curcumin derivatives reduced viability to similar to 55% at 500 mu g/mL, while [W4KR5] alone maintained >65% viability. Normal skin cells (Hs-895-Sk) showed >97% viability across all treatments. Hemolysis assays revealed that conjugation reduced [W4KR5]'s hemolytic activity from 34.9% to 15-21%. Time-kill studies in drug-resistant bacterial strains showed that physical mixtures achieved >= 3 log(10) reductions within 2-12 hours. These results support the potential of [W4KR5]-curcumin combinations to enhance antibacterial efficacy and reduce cytotoxicity, making them promising candidates for further development.
