BioFactors最新文献

Natural compounds identified via the SELFormer pipeline for cognitive enhancement may exert neuroprotective effects in ischemic stroke (IS) through both direct actions on the central nervous system and potential modulation of the gut microbiota. However, it remains unclear whether such benefits persist under conditions in which gut-brain neural communication is compromised. We aimed to evaluate the neuroprotective potential of β-citronellol (BCT), β-caryophyllene (BCP), and citronellyl acetate (CTA) in an IS model with compromised vagal signaling. Mongolian gerbils received daily oral treatment with dextrin (Control), BCT (100 mg/kg), BCP (20 mg/kg), or CTA (100 mg/kg) for 2 weeks before undergoing subdiaphragmatic vagotomy followed by bilateral common carotid artery occlusion; sham-operated animals treated with dextrin served as Normal-C. During an additional 4 weeks of treatment, we assessed neuronal survival, cognitive function, metabolism, neuroinflammation, and gut microbiota composition and metabolism. BCT demonstrated superior neuroprotection, followed by BCP, with CTA showing modest efficacy compared to the control. BCT and BCP increased hippocampal CA1 neurons and improved memory function. Treatments reduced hippocampal acetylcholinesterase activity, lipid peroxidation, and inflammatory markers (TNF-α and IL-1β) while enhancing cerebral blood flow, glucose metabolism, and lipid profiles. Gut microbiota analysis revealed increased α-diversity and restoration of beneficial bacteria, including Akkermansia and Faecalibacterium, particularly with BCT treatment. BCT and BCP increased butyrate-producing bacteria. These improvements occurred despite vagal nerve disruption, indicating alternative neuroprotective mechanisms through enhanced intestinal barrier integrity and microbiota-derived metabolites. In conclusion, these compounds, especially BCT, protect against neuronal death and cognitive impairment in IS conditions through integrated effects on neuroinflammation, oxidative stress, and non-vagal gut-brain communication pathways. Therefore, BCT and BCP were potential for IS prevention and treatment strategies.

Pulmonary fibrosis is a debilitating condition characterized by excessive collagen deposition and scar formation. Divergent factors often contribute to mitochondrial dysfunction. Oxidative stress is one of the major triggers for the development of pulmonary fibrosis through downregulation of SIRT3. This study aims to enhance the SIRT3 activity at the organelle level by a targeted drug delivery approach. C12 is a known molecule as a SIRT3 activator and is protective in pulmonary fibrosis in our previous studies. We have designed a mitochondrial-targeted delivery approach by introducing a triphenylphosphonium cation (TPP⁺) into the C12 molecule to enhance its mitochondrial specificity and efficacy. The newly designed MitoC12 attenuated the BLM-induced acute lung injury and pulmonary fibrosis more effectively than C12 primarily through activation of SIRT3. The cellular uptake studies revealed that MitoC12 concentrated more in mitochondria than the cytosolic fraction. MitoC12 reduced BLM-induced oxidative stress in BEAS-2B cells and inhibited TGF-β-induced pulmonary fibrosis in MRC-5 cells. MitoC12 inhibited the EMT by decreasing the expression of vimentin and N-cadherin and increasing the expression of E-cadherin. Further, the in vivo studies of MitoC12 exhibited a protective effect in BLM-induced pulmonary fibrosis by improving lung function, decreasing inflammation, and restoring lung architecture. MitoC12 reduced the collagen deposition and expression of fibrotic markers such as TGF-β, collagen 1A and 3A, α-SMA, fibronectin, and vimentin. Mechanistically, MitoC12 showed an anti-fibrotic effect through activation of SIRT3 thereby preventing mitochondrial dyshomeostasis through regulating MnSOD and OGG1 functioning. Overall, this study suggests that MitoC12 could be a potential therapeutic option for pulmonary fibrosis emphasizing TPP⁺-conjugated molecules in treating mitochondrial dysfunction-related diseases.

This study aims to investigate for the first time the functional role and underlying mechanisms of long intergenic non-coding RNA LINC01783 in glioma progression and development. Glioma tumor tissues of different grades, normal brain tissues, and glioma cell lines were used. Differential expression of LINC01783 and other transcripts was validated in glioma tissues and cell lines using RT-qPCR and western blot assays. Furthermore, the biological functions of LINC01783 were assessed both in vitro and in vivo using various functional assays. We found that LINC01783 was highly expressed in glioma tumor tissues, especially the high-grade glioma samples and glioma cell lines, with its elevated expression associated with glioma cell stemness and progression, while its knockdown had the opposite effects. Functionally, LINC01783 targeted PTEN, and PTEN overexpression significantly suppressed glioma cell proliferation and stemness characteristics, while promoting apoptosis. Mechanistic studies confirmed that GATA3 binds to the PTEN promoter and transcriptionally represses PTEN expression, contributing to glioma progression. Additionally, our findings showed that LINC01783 enhances GATA3 expression by facilitating H3K27 acetylation through its interaction with CBP, which mediates the acetylation process at the GATA3 locus, thereby promoting tumorigenesis in glioma. Collectively, our study provides novel evidence that LINC01783 functions as a tumor promoter and contributes to glioma tumorigenesis by enhancing GATA3 expression via CBP-mediated H3K27 acetylation, thereby suppressing PTEN expression.

Recently, sorghum [Sorghum bicolor (L.) Moench] has been given great attention as an excellent source of polyphenols that exhibit protective effects against multiple chronic disease models. Ulcerative colitis (UC) is strongly linked to the incidence of colon cancer and other intestinal chronic diseases. This study aimed to determine the ability of sorghum ethanolic phenolic extracts (SEPEs) to mitigate intestinal colitis and inflammation induced by dextran sulfate sodium (DSS) in a mice model. Forty C57BL/6 male mice were randomly assigned to one of the experimental groups: negative control, positive control (DSS only), and three groups given SEPEs containing (100 μg gallic acid eq/mL) from specialty brown sorghum accession SC84 grains (BSG) and leaves (BSL) from the same brown cultivar, and white sorghum grains (WSG). SEPEs-fed groups showed a significant reduction of the inflammatory cytokines including IL-6, TNF-alpha, and IL-1-beta in the plasma and colon, colonic disease activity index values, and fecal hemoglobin content compared to the DSS group (p ≤ 0.001). Furthermore, SEPEs mitigated neutrophil infiltration by inhibiting myeloperoxidase activity in the colon and enhancing intestinal integrity by upregulation of tight junction proteins' production such as ZO-1 and claudin-7. Histopathological results showed an improvement in mucosal structure and colon morphology under SEPE uptake. BSL extract exhibited a better effect against DSS compared to BSG and WSG. Metabolomic and enrichment analyses of plasma showed that SEPEs effectively recovered the disrupted metabolomic profiling in UC via modulating key pathways associated with colitis-related inflammation and oxidative stress such as bile acids metabolism, amino acids metabolism, and taurine and hypotaurine metabolism. SEPEs ameliorate colonic colitis and inflammation by suppressing proinflammatory cytokines production, neutrophil infiltration, and enhancement of intestinal integrity and functionality. Thus, specialty sorghum phenolics represent a potential alternative to mitigate colonic inflammation and colitis.

Daidzin (DZN) is a natural flavonoid compound derived from soybeans that has recently been recognized for its potential antitumor properties. In traditional Chinese medicine, soybeans and their extracts are extensively used to prevent and treat various diseases. To evaluate the therapeutic efficacy of DZN on human glioblastoma through in vivo and in vitro experiments, and through multi-omics analyses to elucidate potential molecular mechanisms. Cell viability of LN-229 and U-87MG glioblastoma cells was assessed using the CCK-8 assay. Protein and mRNA levels of proliferation and apoptosis-related genes were analyzed via Western blotting and qPCR. Metabolomics and transcriptomics identified key pathways and targets, which were confirmed by in-cell Western blotting and expression correlation analysis. The in vivo antitumor effects of DZN were evaluated in nude mice with LN-229 tumors. DZN treatment reduced cell viability, migration, and survival in a dose-dependent manner, demonstrating strong antitumor effects in both in vitro and in vivo models. Multi-omics analysis identified amino acid metabolism and ubiquitin-mediated proteolysis as key mechanisms. Bioinformatics highlighted LRP5 as a prognostic biomarker in glioblastoma. DZN decreased LRP5 activity, downregulated p-GSK-3β, and promoted c-Myc degradation, thereby inhibiting the Wnt signaling pathway. In vivo, DZN significantly reduced tumor size and Ki67 expression. These findings highlight LRP5 as a promising therapeutic target, with DZN emerging as a potent LRP5 inhibitor and exhibiting significant antitumor effects in glioblastoma.

Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder and a leading cause of infertility primarily due to impaired folliculogenesis and anovulation. Central to ovarian function and follicular development is the extracellular matrix (ECM), which undergoes significant remodeling facilitated by matrix metalloproteinases (MMPs). In PCOS, the ovarian cortex becomes thickened and collagen-rich, creating a rigid environment that disrupts normal follicular growth and oocyte maturation. Altered MMP activity further complicates this scenario by impairing ECM degradation, leading to the accumulation of small, quiescent follicles, and elevated androgen levels. This review aims to explore the intricate roles of ECM and MMP alterations in PCOS pathogenesis, highlighting their impact on folliculogenesis and steroidogenesis. Understanding MMP/TIMP dynamics offers insights into potential therapeutic targets to restore normal ovarian function and improve fertility outcomes for women with PCOS.

The role of Anillin (ANLN) in clear cell renal cell carcinoma (ccRCC) is not well understood. This study aimed to investigate the possible function and mechanism of ANLN in ccRCC. By using data from the Cancer Genome Atlas (TCGA), we assessed ANLN expression in various cancers. Furthermore, the GEPIA database was used to analyze survival rates, pathway enrichment, and immune infiltration. Experiments were employed to study how ANLN expression affects tumor cell apoptosis, migration, invasion, and proliferation. Protein blotting was conducted to evaluate apoptosis, proliferation, epithelial mesenchymal transition (EMT), and the expression of proteins linked to the PI3K/AKT and P53 signaling pathways. mRNA levels of ANLN were notably increased in diverse cancer tissues, as shown in the TCGA database, a finding that was also observed in ccRCC patients. Remarkably, high ANLN levels were associated with lower pathologic grades and a worse survival prognosis in ccRCC patients. In vitro experiments revealed that knockdown of ANLN in ccRCC cells led to reduced proliferation, migration, invasion, and EMT. Additionally, ANLN seemed to impact immune evasion and increase the likelihood of distant metastasis based on immune infiltration analyses. The use of PI3K/AKT pathway inhibitors or P53 signaling pathway agonists was effective in reducing the invasive behavior of ccRCC and correcting immunosuppression. Overall, ANLN could be a valuable prognostic indicator for the survival of ccRCC patients.

Pulmonary fibrosis (PF) is a progressive, life-threatening disease marked by excessive scarring of lung tissue. Recently, extracellular vesicles (EVs) have emerged as a promising antifibrotic therapy due to their regenerative and anti-inflammatory properties. However, the success of EV-based therapies depends on the route of administration, which can significantly influence their biodistribution and therapeutic effects. Furthermore, in PF, aging is a significant risk factor for the disease and, until today, EV treatment efficacy has not been studied in aged tissues. Specifically, we studied EVs derived from human umbilical cord mesenchymal stem cells and compared the biodistribution of these vesicles delivered via three routes: intravenous (IV), intrapleural (IP), and intratracheal (IT). A protocol was developed to set EV staining and concentration, minimizing animal use while maximizing the accuracy of results. To evaluate therapeutic effects, we conducted three experimental setups: (i) to assess their ability to reverse established fibrosis; (ii) to evaluate their effect on fibrosis progression; and (iii) to study early inflammation and macrophage polarization. Lung fibrosis and inflammation were assessed by analyzing fibrotic markers, inflammatory cytokines, collagen deposition, and bronchoalveolar lavage (BAL) fluid cell analysis, providing insights into EVs therapeutic potential in aged, fibrotic lung tissue. In the biodistribution study, IV administration was identified as the most effective route, successfully delivering EVs to both normal and fibrotic lung tissues. In the therapeutic study, antifibrotic effects were observed only when EVs were administered prophylactically, before the establishment of fibrosis. Under this protocol, IV-administered EVs reduced fibrotic mRNA biomarkers, collagen deposition, inflammatory cell infiltration, and macrophage polarization in BAL, as well as altering cytokine. Our findings emphasize the critical importance of selecting the appropriate route of administration for EV-based therapies. Notably, our work with an aging model reveals that EV treatments primarily exhibit prophylactic effects, with a marked reduction in their regenerative potential compared to previous studies conducted in younger models.