General physiology and biophysics最新文献

Obstructive sleep apnoea (OSA) and type 2 diabetes mellitus (T2DM) frequently co-occur, with long noncoding RNAs (lncRNAs) implicated in their shared pathophysiology (T2DM-OSA). LncRNA sex determining region Y-box protein 2 (SOX2) overlapping transcript (SOX2OT) is downregulated in diabetic models. This study investigated SOX2OT's regulatory roles using in vivo and in vitro T2DM-OSA models. Intermittent hypoxia (IH) and high glucose (HG) significantly suppressed SOX2OT expression in murine systems and HepG2 hepatocytes. SOX2OT overexpression enhanced glucose consumption and uptake in HG/IH-treated cells by activating insulin receptor substrate/phosphatidylinositol 3-kinase/protein kinase B (IRS/PI3K/AKT) signaling. Concurrently, SOX2OT attenuated oxidative stress (reactive oxygen species (ROS), malondialdehyde (MDA)) while elevating antioxidant activity (superoxide dismutase (SOD), glutathione peroxidase (GSH-Px)), and suppressed inflammatory cytokines (tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β)). Mechanistically, SOX2OT functioned as a competing endogenous RNA for microRNA-552-5p (miR-552-5p) to depress SOX2 expression. Crucially, SOX2 knockdown abolished SOX2OT-mediated cytoprotection. Thus, SOX2OT ameliorates insulin resistance in T2DM-OSA through IRS/PI3K/AKT activation and miR-552-5p/SOX2-mediated suppression of oxidative stress and inflammation.

Myocardial ischemia and reperfusion (MIR) injury, a major cause of cardiovascular morbidity, involves oxidative stress, inflammation, and cell death. This study examines the protective effects of trans-chalcone, a natural flavonoid, on MIR-induced myocardial damage via the Sirtuin 1 (SIRT1)-High Mobility Group Box 1 (HMGB1)-inflammasome-pyroptosis axis. Young adult male Sprague-Dawley rats were subjected to MIR injury and treated with trans-chalcone (100 mg/kg) or the SIRT1 inhibitor EX-527 intraperitoneally for seven days prior to MIR induction. Cardiac function, infarct size, mitochondrial function, oxidative stress, inflammasome and pyroptosis markers were assessed, alongside protein expression analysis of SIRT1, HMGB1, caspase-1, gasdermin D N-terminal fragment, Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2), and Nuclear Factor Kappa B-subunit 65 (NF-κB-p65). Trans-chalcone treatment significantly improved left ventricular pressures, infarct size, and mitochondrial function compared to untreated MIR rats. Oxidative stress was reduced, as shown by decreased malondialdehyde and increased glutathione levels. Western blot analysis confirmed upregulation of SIRT1 and Nrf2 and downregulation of HMGB1, NOD-like receptor protein 3 (NLRP3), cleaved-caspase-1, gasdermin D, and NF-κB-p65. SIRT1 inhibition by EX-527 diminished these protective effects, emphasizing SIRT1's role in trans-chalcone-mediated cardioprotection. These results indicate that trans-chalcone mitigates myocardial MIR injury by targeting SIRT1 to suppress HMGB1, enhance mitochondrial function, and reduce oxidative stress, inflammasome, and pyroptotic markers, positioning trans-chalcone as a promising therapeutic option for ischemic heart disease.

Esophageal squamous cell carcinoma (ESCC) is the most common subtype of esophageal cancer (ESCA). ESCC is one of the malignancies with high incidence and mortality rates. Studies have found that laminin subunit alpha 3 (LAMA3) functions as an oncogene in a variety of cancers. SPI1 is highly expressed in ESCC, but whether LAMA3 and SPI1 regulate the development of ESCC is still unclear. In this study, bioinformatics analysis tools were used to predict the expression of LAMA3 and SPI1 in ESCA. Subsequently, the levels of mRNA and protein were respectively detected by RT-qPCR and WB. Then, the cell biological behaviors were measured by CCK-8, colony formation, EdU, and tube formation assays. To investigate the in vivo effects of LAMA3 knockdown on ESCC, a xenograft tumor model was established, followed by IHC analysis. Additionally, glucose consumption, lactate production, ROS, and Fe2+ levels were determined by the corresponding kits. Besides, the interaction of LAMA3 and SPI1 was examined by ChIP and dual luciferase reporter assays. LAMA3 was highly expressed in ESCC and silencing it could curb the viability and proliferation of ESCC cells, tumor growth in vivo, tube formation of HUVECs, and induce oxidative stress and ferroptosis of ESCC cells. SPI1 was highly expressed in ESCC and could bind to the promoter of LAMA3 to jointly regulate the progression of ESCC. This study elucidated that SPI1 aggravated ESCC by binding to the promoter of LAMA3, thereby stimulating the growth and proliferation of ESCC cells and suppressing oxidative stress and ferroptosis.

This study aimed to investigate the protective mechanism of paeonol against diabetic retinopathy (DR) via modulation of the Nrf2/NF-κB signaling pathway. Primary mouse retinal Müller cells exposed to high glucose (HG) and streptozotocin-induced diabetic mice were used as in vitro and in vivo models, respectively. Key techniques included RT-qPCR, Western blot, DCFH-DA-based ROS assays, and ELISA. Paeonol (40-80 μg/ml) significantly reduced HG-induced ROS accumulation (p < 0.01) and restored Nrf2 nuclear translocation, upregulating antioxidant genes HO-1 and NQO1 (p < 0.01). It suppressed NF-κB activation (p-IκBα and p-p65 reduction; p < 0.001) and proinflammatory cytokines (TNF-α, IL-1β, IL-6; p < 0.01) in Müller cells and diabetic retinas. Blood-retinal barrier (BRB) integrity was preserved via upregulation of tight junction proteins (claudin-5, occludin, ZO-1; p < 0.01). In conclusion, paeonol attenuates DR progression by activating Nrf2-mediated antioxidant responses and inhibiting NF-κB-driven inflammation, highlighting its potential as a novel therapeutic agent for DR.

Saponin of Rhizoma Polygonati (SRP) is a key bioactive component obtained from Rhizoma Polygonati, has neuroprotection, antioxidant and anticancer effects. This research aimed to explore whether SRP improves cognitive deficits in Alzheimer's disease (AD) mice. Behavioral testing was performed by the Morris water maze test. Histopathological changes and neuronal apoptosis in mouse hippocampus were observed by Hematoxylin-eosin, Nissl staining, and TUNEL staining. The impact of SRP on amyloid β-protein (Aβ) and neurofibrillary tangles (NFTs) production was determined by immunofluorescence and Glycine silver staining. Western blot detected c-Abl/Mammalian sterile 20 (STE20)-like kinase 1 (MST1) pathway, apoptosis-related protein, and Tau phosphorylation level. AD mice exhibit cognitive deficits compared to normal mice, and SRP ameliorates cognitive deficits. The hippocampal tissues of AD mice showed neuronal damage and apoptosis, with Aβ deposition, loss of Nissl bodies and formation of NFTs. SRP attenuated neuronal damage in AD mice, inhibited Aβ deposition and NFTs formation. Additionally, SRP blocked the c-Abl/MST1 pathway in AD mice. c-Abl inhibitor enhanced the neuroprotective effect of SRP in AD mice, while c-Abl agonist weakened this effect. SRP inhibits hippocampal histopathological damage and enhances cognitive ability in AD mice through blocking the c-Abl/MST1 pathway.

Pancreatic cancer is a common malignant tumor of the digestive tract characterized by high mortality, primarily due to its aggressive proliferation and metastasis. DDB1-CUL4-associated factor 1 (DCAF1) has recently been identified as a cancer ‒ promoting gene in hepatocellular carcinoma and melanoma. However, its role and mechanism of action in pancreatic cancer remain largely unexplored. Analysis of the GEPIA database and experimental validation revealed that DCAF1 is significantly overexpressed in pancreatic cancer tissues and cell lines. Functional assays demonstrated that DCAF1 knockdown inhibited the proliferation, invasion, and migration of pancreatic cancer cells. Moreover, DCAF1 suppression impeded EMT, as evidenced by decreased expression of mesenchymal markers N-cadherin and α-SMA and increased expression of the epithelial marker E-cadherin. Knockdown of DCAF1 can inhibit Phosphatase and Tensin Homolog (PTEN) ubiquitination, leading to inactivation of the PI3K/Akt signaling pathway. In addition, the use of IGF-1 in the replenishment experiment can reverse the effect of knockdown of DCAF1, suggesting that DCAF1 may promote pancreatic cancer metastasis by activating this pathway. These findings suggest that DCAF1 functions as an oncogene in pancreatic cancer, promoting cell proliferation, migration, invasion, and EMT through activation of the PTEN/PI3K/Akt signaling pathway.

Endometrial cancer (EC) is one of the most prevalent gynecologic malignancies, and long non-coding RNA (lncRNA) SOX9-AS1 has been identified as being upregulated in various cancers, indicating its potential role in driving carcinogenesis. However, the involvement and mechanism of SOX9-AS1 in EC have not been thoroughly investigated. The expression of SOX9-AS1 was assessed using qRT-PCR. The impact of molecular intervention on EC cells was evaluated through cell viability, migration, and invasion assays. Survival probability was analyzed using the Kaplan-Meier method. Bioinformatics predictions, dual-luciferase reporter assays, and rescue experiments were conducted to elucidate the specific competitive endogenous RNA (ceRNA) mechanism of the SOX9-AS1/miR-497-5p/E2F3 axis. SOX9-AS1 expression was significantly upregulated in EC tissues and cells, correlating with poor prognosis in EC patients. Knockdown of SOX9-AS1 inhibited the proliferation, migration, invasion, and glycolysis of EC cells. Mechanistically, miR-497-5p suppressed the proliferation, migration, invasion, and glycolysis of EC by targeting E2F3. Molecular interaction analysis indicate that SOX9-AS1 functions as a molecular sponge for miR-497-5p, thereby increasing E2F3 expression. Our work unveiled a novel mechanism by which SOX9-AS1 promotes EC development, suggesting that targeting the SOX9-AS1/miR-497-5p/E2F3 axis may represent a potential therapeutic strategy for EC.

Our previous research has confirmed that curcumin ameliorates pathology of ulcerative colitis (UC) in mice. PANoptosis is closely associated with UC; however, whether curcumin-chitosan microspheres (CCM) alleviate UC by modulating intestinal epithelial cell PANoptosis remains unreported. Here, CCM significantly inhibited UC-induced damage to colon tissue, as evidenced by increased colon length and reduced DAI score, as well as lower concentrations of inflammatory factors (IL-18 and IL-1β). CCM also suppressed expression of tight junction marker ZO-1 and PANoptosis marker NLRP12 induced by UC in colon tissue, and we observed the co-localization of ZO-1 and NLRP12. scRNA-seq revealed eight subpopulations of intestinal epithelial cells and crypt top colonocytes had the highest PANoptosis score. Expression of PANoptosis-related markers (ASC, NLRP3, NLRP12, and caspase-8) was downregulated after CCM treatment in scRNA-seq data. Different concentrations of CCM (20, 40, 80 μM) did not alter the cell viability of Caco-2 cells, but significantly reduced LPS-induced death and the elevation of inflammatory factors. LPS provoked protein expression of PANoptosis-related markers in Caco-2 cells, but this effect was reversed by CCM. In conclusion, CCM ameliorate UC by inhibiting epithelial cell PANoptosis, indicating that CCM is a promising therapeutic strategy against UC from the prospective of epithelial cell PANoptosis.

Lung adenocarcinoma (LUAD) is a type of lung cancer with high incidence and mortality rates. Zinc finger protein 801 (MAZ) regulates cellular growth, proliferation, and differentiation, and its abnormal expression is associated with the occurrence of various tumors. In this study, the objective is to investigate the impact and underlying mechanism of MAZ on the malignant progression of LUAD. The expression of solute carrier family 25 member 1 (SLC25A1) was found to be elevated in LUAD, which indicated a relationship with a negative prognosis. Within LUAD cells, SLC25A1 was observed to not only boost proliferation but also hinder apoptosis and further augment fatty acid synthesis. MAZ, which was identified as the upstream regulator of SLC25A1, was also overexpressed in LUAD, thereby positively regulating the expression of SLC25A1. In addition, MAZ was found to accelerate the malignant behaviors of LUAD cells, specifically through its regulation of SLC25A1. Furthermore, in vivo studies confirmed that MAZ stimulated the malignant progression of LUAD via its influence on SLC25A1. In conclusions, MAZ mediates the upregulation of SLC25A1, which modifies the fatty acid synthesis pathway and fuels the malignant progression of LUAD. These findings suggest a new strategy for the targeting therapy in LUAD patients.

Chronic obstructive pulmonary disease (COPD) is characterized by airway remodeling and inflammation. Cigarette smoke extract (CSE) induces apoptosis, inflammation, and oxidative stress in COPD. Tripterygium glycosides (TG) are an active compound found in the root extracts of Tripterygium wilfordii Hook F (TWHF) that possesses anti-inflammatory and immunosuppressive effects. However, its role in COPD remains elusive. Herein, 2.5% CSE was used to treat human bronchial epithelial cells (BEAS-2B) to construct a cell injury model. Cell viability, apoptosis, and proliferation were assessed using MTT, flow cytometry, and EdU. Gene expression was analyzed using ELISA, Western blot, and RT-qPCR. TG treatment abolished 2.5% CSE-induced BEAS-2B cell viability and proliferation inhibition, apoptosis and inflammatory response promotion, and IL-33 level increase. Moreover, the repression of TG treatment on 2.5% CSE-triggered BEAS-2B cell damage was abrogated by IL-33 overexpression. Phosphorylation of JNK, ERK1/2, and p38 in 2.5% CSE-treated BEAS-2B cells was enhanced, manifesting that MAPK signaling pathways were activated. TG administration attenuated 2.5% of CSE-activated MAPK pathways through IL-33 upregulation. TG treatment repressed CSE-induced BEAS-2B cell damage partly by regulating the IL-33-mediated MAPK signaling pathway, providing a better understanding of the role of TG in the anti-inflammatory therapeutics for COPD treatment.