Zinc finger BED-type containing 3 promotes hepatic steatosis by interacting with polypyrimidine tract-binding protein 1.

AIMS/HYPOTHESIS: The relationship between metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes mellitus, insulin resistance and the metabolic syndrome is well established. While zinc finger BED-type containing 3 (ZBED3) has been linked to type 2 diabetes mellitus and the metabolic syndrome, its role in MASLD remains unclear. In this study, we aimed to investigate the function of ZBED3 in the context of MASLD. METHODS: Expression levels of ZBED3 were assessed in individuals with MASLD, as well as in cellular and animal models of MASLD. In vitro and in vivo analyses were conducted using a cellular model of MASLD induced by NEFA and an animal model of MASLD induced by a high-fat diet (HFD), respectively, to investigate the role of ZBED3 in MASLD. ZBED3 expression was increased by lentiviral infection or tail-vein injection of adeno-associated virus. RNA-seq and bioinformatics analysis were employed to examine the pathways through which ZBED3 modulates lipid accumulation. Findings from these next-generation transcriptome sequencing studies indicated that ZBED3 controls SREBP1c (also known as SREBF1; a gene involved in fatty acid de novo synthesis); thus, co-immunoprecipitation and LC-MS/MS were utilised to investigate the molecular mechanisms by which ZBED3 regulates the sterol regulatory element binding protein 1c (SREBP1c). RESULTS: In this study, we found that ZBED3 was significantly upregulated in the liver of individuals with MASLD and in MASLD animal models. ZBED3 overexpression promoted NEFA-induced triglyceride accumulation in hepatocytes in vitro. Furthermore, the hepatocyte-specific overexpression of Zbed3 promoted hepatic steatosis. Conversely, the hepatocyte-specific knockout of Zbed3 resulted in resistance of HFD-induced hepatic steatosis. Mechanistically, ZBED3 interacts directly with polypyrimidine tract-binding protein 1 (PTBP1) and affects its binding to the SREBP1c mRNA precursor to regulate SREBP1c mRNA stability and alternative splicing. CONCLUSIONS/INTERPRETATION: This study indicates that ZBED3 promotes hepatic steatosis and serves as a critical regulator of the progression of MASLD. DATA AVAILABILITY: RNA-seq data have been deposited in the NCBI Gene Expression Omnibus ( www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE231875 ). MS proteomics data have been deposited to the ProteomeXchange Consortium via the iProX partner repository ( https://proteomecentral.proteomexchange.org/cgi/GetDataset?ID=PXD041743 ).

Activation of the PPARγ/NF-κB pathway by A-MPDA@Fe3O4@PVP via scavenging reactive oxygen species to alleviate hepatic ischemia-reperfusion injury.

Hepatic ischemia-reperfusion injury (IRI) is a common pathological process during hepatectomy and liver transplantation and the two primary reasons for hepatic IRI are reactive oxygen species (ROS)-mediated oxidative stress and excessive inflammatory responses. Herein, a novel antioxidant nanodrug (A-MPDA@Fe3O4@PVP) is prepared by employing L-arginine-doped mesoporous polydopamine (A-MPDA) nanoparticles as the carrier for deposition of ultra-small ferric oxide (Fe3O4) nanoparticles and further surface modification with polyvinylpyrrolidone (PVP). A-MPDA@Fe3O4@PVP not only effectively reduces the aggregation of ultra-small Fe3O4, but also simultaneously replicates the catalytic activity of catalase (CAT) and superoxide dismutase (SOD). A-MPDA@Fe3O4@PVP with good antioxidant activity can rapidly remove various toxic reactive oxygen species (ROS) and effectively regulate macrophage polarization in vitro. In the treatment of hepatic IRI, A-MPDA@Fe3O4@PVP effectively alleviates ROS-induced oxidative stress, reduces the expression of inflammatory factors, and prevents apoptosis of hepatocytes through immune regulation. A-MPDA@Fe3O4@PVP can further protect liver tissue by activating the PPARγ/NF-κB pathway. This multiplex antioxidant enzyme therapy can provide new references for the treatment of IRI in organ transplantation and other ROS-related injuries such as fibrosis, cirrhosis, and bacterial and hepatic viral infection.

Overexpression of cannabinoid receptor 2 is associated with human breast cancer proliferation, apoptosis, chemosensitivity and prognosis via the PI3K/Akt/mTOR signaling pathway.

INTRODUCTION: The cannabinoid receptor 2 (CB2) is mainly involved in the immune system. However, although CB2 has been reported to play an anti-tumor function in breast cancer (BC), its specific mechanism in BC remains unclear. METHODS: We examined the expression and prognostic significance of CB2 in BC tissues by qPCR, second-generation sequencing, western blot, and immunohistochemistry. We assessed the impacts of overexpression and a specific agonist of CB2 on the growth, proliferation, apoptosis, and drug resistance of BC cells in vitro and in vivo using CCK-8, flow cytometry, TUNEL staining, immunofluorescence, tumor xenografts, western blot, and colony formation assays. RESULTS: CB2 expression was significantly lower in BC compared with paracancerous tissues. It was also highly expressed in benign tumors and ductal carcinoma in situ, and its expression was correlated with prognosis in BC patients. CB2 overexpression and treatment of BC cells with a CB2 agonist inhibited proliferation and promoted apoptosis, and these actions were achieved by suppressing the PI3K/Akt/mTOR signaling pathway. Moreover, CB2 expression was increased in MDA-MB-231 cell treated with cisplatin, doxorubicin, and docetaxel, and sensitivity to these anti-tumor drugs was increased in BC cells overexpressing CB2. CONCLUSIONS: These findings reveal that CB2 mediates BC via the PI3K/Akt/mTOR signaling pathway. CB2 could be a novel target for the diagnosis and treatment of BC.

Identification of STAT5B as a biomarker associated with prognosis and immune infiltration in breast cancer.

BACKGROUND: Breast invasive cancer (BRCA) is the most common malignancy and the second leading cause of malignancy death among women. Signal transducers and activators of transcription (STAT) family played a vital role in regulating certain biological processes and could serve as biomarkers for many diseases or cancers. METHODS: The expression, prognostic value, and clinical functions of STAT family in BRCA were evaluated with several bioinformatics web portals. RESULTS: The expression of STAT5A/5B were downregulated in BRCA in subgroup analyses based on race, age, gender, race, subclasses, tumor histology, menopause status, nodal metastasis status, and TP53 mutation. BRCA patients with high STAT5B expression had a better overall survival, relapse free survival, MDFS and post progression survival. STAT5B expression level can impact the prognosis in BRCA patients with positive PR status, negative Her2 status and wild type TP53. Moreover, STAT5B was positively correlated with immune cell infiltration and the level of immune biomarkers. Drug sensitivity revealed that low STAT5B expression was resistant to the many small molecules or drugs. Functional enrichment analysis revealed that STAT5B was involved in adaptive immune response, translational initiation, JAK-STAT signaling pathway, Ribosome, NF-kappa B signaling pathway and Cell adhesion molecules. CONCLUSIONS: STAT5B was a biomarker associated with prognosis and immune infiltration in breast cancer.

Oxidative stress disrupts the cytoskeleton of spinal motor neurons.

BACKGROUND AND AIM: Traumatic spinal cord injury (SCI) is a common and devastating central nervous disease, the treatment of which faces many challenges to the medical community and society as a whole. Treatment measures based on oxidative stress of spinal motor neurons during SCI are expected to help restore biological functions of neurons under injury conditions. However, to date, there are no systematic reports regarding oxidative stress on spinal motor neuron injury. Our aim is to better understand and explain the influences and mechanisms of oxidative stress on spinal motor neurons during SCI. METHODS: We first exposed VSC4.1 motor neurons to hydrogen peroxide (H2 O2 ) and evaluated the effects on cell viability, morphology, cycling, and apoptosis, with an emphasis on the changes to the cytoskeleton and the effect of N-acetyl-l-cysteine (NAC) on these changes. Then, we investigated the effects of NAC on these cytoskeletal changes in vitro and in vivo. RESULTS: We found that H2 O2 caused severe damage to the normal cytoskeleton, leading to a reduction in neurite length and number, rearrangement of the actin cytoskeleton, and disorder of the microtubules and neurofilaments in VSC4.1. Importantly, NAC attenuated the oxidative damage of spinal motor neurons in vitro and in vivo, promoting the recovery of hindlimb motor ability in mice with SCI at the early stage of injury. CONCLUSION: This study shows that oxidative stress plays an important role in the cytoskeleton destruction of spinal motor neurons in SCI, and treatment of SCI on this basis is a promising strategy. These findings will help to elucidate the role of oxidative stress in spinal motor neuron injury in SCI and provide references for further research into the study of the pathology and underlying mechanism of SCI.

Resveratrol alleviates ethanol-induced neuroinflammation in vivo and in vitro: Involvement of TLR2-MyD88-NF-κB pathway.

Excessive ethanol (EtOH) intake affects cognitive function and leads to permanent learning and memory deficits. EtOH-induced neuroinflammation plays an important role in EtOH neurotoxicity. Studies have shown that EtOH activates microglia and induces an inflammatory response. Resveratrol (Rsv) is a natural polyphenol found in a wide variety of plants and fruits, and produces the neuroprotective and anti-inflammatory effects in the central nervous system. However, effect of Rsv on EtOH-induced neuroinflammation is still unknown. We investigated the anti-inflammatory effect of Rsv in the context of EtOH-induced neurotoxicity and the molecular mechanisms potentially involved in the effect. The results showed that treatment of rats with Rsv prevented the deficits of spatial reference memory induced by EtOH and mitigated EtOH-induced neuroinflammation by inhibiting microglial activation and decreasing the levels of inflammatory cytokines including interleukin-1ß, interleukin-6 and tumor necrosis factor α. The further studies indicated that Rsv reduced TLR2 expression in vivo and in vitro, and downregulated expression of myeloid differentiation primary response 88 (MyD88) and phosphorylation of nuclear factor κB (NF-κB). These data demonstrate that Rsv alleviates the ethanol-induced neuroinflammation via inhibition of TLR2-MyD88-NF-κB signal pathway.

Efficacy and safety of COX-2 inhibitors for advanced non-small-cell lung cancer with chemotherapy: a meta-analysis.

BACKGROUND: The study of cyclooxygenase-2 (COX-2) inhibitors is now mired in controversy. We performed a meta-analysis to assess the efficacy and safety profile of COX-2 inhibitors in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: A literature search of PubMed, EMBASE, the Cochrane Central databases, and ClinicalTrials.gov, up until March 26, 2017, identified relevant randomized controlled trials. Data analysis was performed using Stata 12.0. RESULTS: Six eligible trials (1,794 patients) were selected from the 407 studies that were identified initially. A significant difference, favoring COX-2 inhibitors plus chemotherapy over chemotherapy alone, was observed in the overall response rate (relative risk [RR] =1.25, 95% confidence interval [CI]: 1.06-1.48). Further, we conducted two subgroup analyses according to the type of COX-2 inhibitors (celecoxib, rofecoxib, or apricoxib) and treatment line (first or second chemotherapy). The first-line treatment includes: NP (changchun red bean + cisplatin or carboplatin), GP (double fluorine cytidine + cisplatin or carboplatin), or TP (paclitaxel + cisplatin or carboplatin, docetaxel + cisplatin or carboplatin). The second-line treatment includes two internationally recognized compounds, one is docetaxel and the other is the pemetrexed, both of which are individually selected. In subgroup analysis, significantly increased overall response rate (ORR) results were found for rofecoxib plus chemotherapy (RR =1.56, 95% CI: 1.08-2.25) and COX-2 inhibitor given with first-line chemotherapy (RR =1.27, 95% CI: 1.07-1.50). However, there was no difference between COX-2 inhibitors plus chemotherapy and chemotherapy alone in overall survival (hazard ratio [HR] =1.04, 95% CI: 0.91-1.18), progression-free survival (HR =0.97, 95% CI: 0.86-1.10), and 1-year survival rate (RR =1.03, 95% CI: 0.89-1.20). Toxicity did not differ significantly between COX-2 inhibitors plus chemotherapy and chemotherapy alone with the exception of leukopenia (RR =1.21, 95% CI: 1.03-1.42), thrombocytopenia (RR =1.32, 95% CI: 1.04-1.67), and cardiovascular events (RR =2.39, 95% CI: 1.06-5.42). The results of the Egger's test indicated no significant difference in primary outcomes. CONCLUSION: COX-2 inhibitors improved ORR of advanced NSCLC with chemotherapy, but had no effect on survival indices. Moreover, COX-2 inhibitors may lead to higher rates of hematologic toxicities and cardiovascular events.