EXCLI Journal最新文献

Studies in obese polycystic ovary syndrome (PCOS) have shown growth factors that activate rat sarcoma (Ras) proteins, which regulate intracellular signaling pathways, differ in PCOS; however, it is difficult to account for obesity, insulin resistance, and systemic inflammation that are linked to many of the features found in PCOS. This study explores Ras signaling proteins and related growth factors in non-obese women with and without PCOS. Somascan proteomic analysis of circulating KRas, Ras GTPase-activating protein-1 (RASA1), and 45 growth factor-related proteins that signal through Ras was undertaken in a non-obese population of women with (n=44) and without (n=78) PCOS, groups matched for age and body mass index (BMI), without insulin resistance (HOMA-IR) or systemic inflammation (normal CRP; C-reactive protein). There was an increase in the free androgen index (FAI, p<0.0001) and anti-Müllerian hormone (AMH, p<0.0001) in PCOS. Cohen's d showed a moderate effect size for 3 proteins, of which Vascular endothelial growth factor-A (VEGFA) and EGFR were increased and EGFR1 was decreased in PCOS (all FDR p<0.05). EGFR and VEGF pathways interact closely and when EGFR signaling decreases, VEGFA may increase to maintain angiogenic balance, suggesting that in non-obese PCOS there may be a signal for compensatory angiogenesis in a dysfunctional endothelial environment. See also the graphical abstract(Fig. 1).

Tetraselmis sp., a marine microalga amenable to mass cultivation, possesses antiviral properties, partly attributed to chlorophyll a. However, the underlying antiviral mechanisms remain poorly characterized. In this study, we investigated the antiviral activity and mode of action of chlorophyll a derived from Tetraselmis sp. by performing transcriptomic analyses on three experimental groups: untreated, uninfected cells; Zika virus (ZIKV)-infected cells; and chlorophyll a-treated, ZIKV-infected cells. Treatment with 5 µM chlorophyll a induced differential expression of genes associated with interferon-inducible antiviral responses. Gene ontology analysis revealed significant enrichment of biological processes such as "response to external stimulus" and "response to biotic stimulus." Notably, Venn diagram analysis of 130 differentially expressed genes (DEGs) demonstrated restoration of key interferon-stimulated genes, including interferon-induced protein with tetratricopeptide repeats (IFIT)1, IFIT2, IFIT3, and IFIT5, which was further validated by quantitative PCR and immunocytochemistry. These findings suggest that chlorophyll a from Tetraselmis sp. exerts antiviral effects primarily through modulation of interferon-mediated pathways. See also the graphical abstract(Fig. 1).

Mancozeb, a polymeric dithiocarbamate complex fungicide with zinc and manganese salts, has the potential to be neurotoxic to humans. Unfortunately, the parent molecule maneb has attracted far too much attention, limiting the available evidence on mancozeb neurotoxicity to preclinical research and non-human cells. We sought to evaluate mancozeb cytotoxicity in neuroblastoma SH-SY5Y cells at lower concentrations than those used for maneb in in vitro investigations in order to quantify its risk for humans. Commercial mancozeb showed concentration- and time-dependent neurotoxicity in the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction test (EC₅₀= 5.9 µM and 1.7 µM at 24 h and 72 h respectively). Using the trypan blue exclusion dye, cell death toll reached around 100% after 24- and 72-hour exposure to mancozeb 1 µM and 0.5 µM respectively. Reactive oxygen species generated by mancozeb, which peaked at 4 µM, could be the cause of cell death. The number and length of neurites were concentration-dependently reduced by mancozeb at sub-µM concentrations, and this was accompanied by changes in cell biomechanical characteristics (stiffness) as determined by atomic force microscopy. The uncertainty factor obtained from our cytotoxic studies, when performing risk assessment of mancozeb, varied from 200 to 2000, which may result in detectable neurotoxicity in humans in accordance with international regulatory agencies recommendations. See also the graphical abstract(Fig. 1).

Respiratory diseases are global health challenges demanding innovative immunotherapy solutions. Toll-like receptors (TLRs) play a crucial role in immune responses, making them attractive therapeutic targets. This review examines nanoparticle-based Toll-like receptor agonists as a promising approach for respiratory immunotherapy. Nanoparticles offer targeted drug delivery and sustained release, ideal for enhancing TLR agonist efficacy. This article explores TLRs' role in immunomodulation, nanoparticle applications, design considerations, preclinical efficacy, safety assessments, challenges, and future prospects. Promising results from animal studies suggest enhanced immunological responses and reduced inflammation compared to conventional treatments. Safety concerns are addressed with insights from toxicity studies. Challenges include regulatory hurdles and biocompatibility, with strategies proposed for optimization. Nanoparticle-based TLR agonists hold great potential to transform respiratory disease treatment, warranting further research and collaboration for successful clinical translation. See also the graphical abstract(Fig. 1).

Extrapulmonary tuberculosis continues to challenge clinicians with its protean manifestations, particularly when involving the gastrointestinal tract. While ileocecal TB is well-characterized, isolated involvement of the liver, stomach, and esophagus, Duodenum remains exceptionally rare and diagnostically elusive. We describe four rare presentations of gastrointestinal tuberculosis from a tertiary care center in India. Case 1 involves hepatic tuberculosis mimicking intrahepatic cholestasis, diagnosed via liver biopsy and special staining. Case 2A details isolated gastric TB presenting with nonspecific dyspepsia, ultimately diagnosed through endoscopic ultrasound-guided FNAC. Case 2B describes esophageal tuberculosis with bronchoesophageal fistula-an exceedingly rare entity-confirmed radiologically and histologically. Case 2C describes a case of duodenal tuberculosis presenting as partial gastric outlet obstruction (GOO). All cases demonstrated clinical and radiological resolution following standard anti-tubercular therapy. These cases posit the diagnostic complexity of gastrointestinal TB when it involves uncommon sites. Heightened clinical suspicion and timely histopathological confirmation remain key to averting morbidity. Early recognition facilitates successful medical management and obviates unnecessary surgical interventions.

A new bioactive compound, methyl linolenate (Methyl-octadeca-9,12,15-trienote), designated as ML, was isolated and purified from Clerodendrum viscosum leaves. Treatment of Ehrlich ascites carcinoma (EAC) cells with ML induced cancer growth inhibition dose-dependently, with a maximum cell growth inhibition of 67 % at a dose of 3.0 mg/kg/day (p<0.001). It also inhibits EAC cell volume and tumor weight and increases the survival time of EAC-bearing mice (25 versus 41 days) (p<0.001). In addition, EAC-bearing control mice exhibited a drastic deterioration of blood parameters, and treatment of EAC-bearing mice with ML prevented the deterioration of hematological parameters compared to untreated EAC-bearing mice. Also, ML abrogates angiogenesis by inhibiting the development of new blood vessels in the peritoneum of EAC-bearing mice. ML-treated cells exhibited apoptotic features such as condensed, fragmented nuclear material and cell membrane damage. Expression of pro-apoptotic genes such as p53, Bax, Caspase 3, and Caspase 9 was upregulated, whereas anti-apoptotic gene Bcl2 was downregulated in ML-treated EAC cells, which indicates the induction of intrinsic mitochondrial apoptosis of EAC cells. However, as it is a novel anticancer compound showing an antineoplastic effect, inhibiting angiogenesis, and inducing apoptosis in mouse models, thus, using other cellular models and more preclinical and clinical research is essential for further development. See also the graphical abstract(Fig. 1).