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关键词： Extracellular matrix   Growth factor   IFN gamma   TGF-beta   Liver fibrosis  

摘要： Background & Aims: The extracellular matrix protein 1 (ECM1) is essential for liver homeostasis by keeping latent transforming growth factor-beta quiescent. Upon hepatocyte damage, ECM1 is significantly downregulated, facilitating fibrosis and chronic liver disease (CLD) progression. We investigated the mechanism of ECM1 regulation in hepatocytes under pathophysiological conditions. Methods: We used promoter analysis to predict Ecm1 transcriptional regulators and assessed the expression of Ecm1-related genes by single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq. Functional assays were performed with AML12 cells, mouse and human primary hepatocytes, and liver tissue from mice and patients. Results: In healthy hepatocytes, epidermal growth factor (EGF)/EGF receptor (EGFR) signalling sustains ECM1 expression through phosphorylating signal transducer and activator of transcription 1 (STAT1) at serine727 (S727), thus enhancing its binding to the ECM1 promoter and boosting gene transcription. This process is disrupted during liver inflammation by interferon gamma (IFN gamma), which downregulates EGFR and inhibits EGF/EGFR/STAT1-mediated ECM1 promoter binding. Mechanistically, IFN gamma-induced STAT1 phosphorylation at tyrosine701 (Y701) impairs the binding of p-STAT1 S727 to the ECM1 promoter. Additionally, IFN gamma induces nuclear factor erythroid 2-related factor 2 (NRF2) nuclear translocation, which repressively binds to the promoter of ECM1, further reducing its expression. These findings are confirmed in several CLD mouse models (n = 2-6). Moreover, AAV8-ECM1 attenuates liver fibrosis and injury in Western diet-fed mice (n = 8-10), counteracting the effects of EGF signalling inhibition and IFN gamma/NRF2 activation. In CLD patients (n = 22), ECM1 levels correlate positively with EGFR expression (p <0.0001) and negatively with IFN gamma/NRF2 activation (p <0.0001). Conclusions: EGF/STAT1 signalling promotes whereas IFN gamma/NRF2 inhibits ECM1 expression in hepa

关键词： Small HERC family   Crucian carp HERC7   RNA binding activity   Negative regulation   mRNA decay   Protein degradation  

摘要： Crucian carp (Carassius auratus) HERC7 is a recently identified, fish-specific member of small HERC family that plays a pivotal role in negatively regulating the interferon (IFN) antiviral response by targeting three RLR signaling factors, STING, MAVS and IRF7. Mechanistically, crucian carp HERC7 facilitates proteasomedependent protein degradation to downregulate STING- and MAVS-mediated IFN response. Although HERC7's role in degrading IRF7 protein is known, its potential regulation of IRF7 mRNA has not been clarified. In this study, we further characterized crucian carp HERC7 as an unorthodox RNA binding protein (RBP) that was unique to IRF7 coding RNA, exactly to its N-terminal coding region. These features endowed crucian carp HERC7 to facilitate IRF7 mRNA decay, thereby downregulating IRF7-mediated IFN response. Despite lacking canonical RNA-binding domains (RBDs), the N-terminal RLD domain of crucian carp HERC7 protein exhibited a binding potential to IRF7 mRNA in vitro. However, either the full length or the E3 ligase activity was required for crucian carp HERC7 to bind IRF7 mRNA in living cells. Functional comparisons between wild-type crucian carp HERC7 and its E3 ligase mutant (C958A) further revealed that, crucian carp HERC7 inhibited IRF7-mediated IFN response primarily by targeting IRF7 mRNA decay, which required its E3 ligase activity and RNA binding activity, while C958A did so by targeting IRF7 protein degradation independently of both activities. Taken together, our results suggest that crucian carp HERC7 has acquired RNA-binding activity and E3 ligase activity to fine-tune fish IFN response through two distinct mechanisms.

关键词： Zinc   BPA   Zinc transporter   Inflammation   Reproduction  

摘要： Bisphenol A (BPA) is an endocrine-disrupting chemical that is toxic to reproduction. Zinc (Zn) plays an important role in male reproductive health. Zn deficiency (ZD) can co-exist with BPA. In order to investigate the specific mechanism of reproductive damage caused by BPA exposure in ZD male mice, a mouse model of ZD, BPA exposure, and their combined exposure was established in this study. Forty 4-week-old SPF male ICR mice with an average body weight of 31.7 +/- 4.2 g were divided into four groups including normal Zn diet group 30 mg/(kg center dot d), BPA exposure group 150 mg/(kg center dot d), zinc deficiency diet group 7.5 mg/(kg center dot d), and BPA + ZD combined exposure group (BPA 150 mg/(kg center dot d) + ZD 7.5 mg/(kg center dot d)). The mice were kept for 8 weeks. The results showed that the testicular tissue structure was disturbed, and semen quality, serum Zn, testicular tissue Zn, and testicular tissue free Zn ions were decreased in the BPA-exposed and ZD groups. The expression of zinc transporters (ZIP7, ZIP8, ZIP13, and ZIP14) in testicular tissue was changed. The expressions of pro-inflammatory cytokines including TNF-alpha and IL-1 beta as well as inflammatory pathway-related proteins (IKB-alpha, p-IKB-alpha, NF-kappa B, p-NF-kappa B, Caspase8, and Caspase3) were increased, while the expressions of anti-inflammatory cytokines (TGF-beta and IL-10) were decreased. The changes in the above indexes in the BPA + ZD group were more obvious. Both BPA exposure and ZD can induce testicular tissue inflammation through the TNF-alpha/NF-kappa B/Caspase8 signaling pathway, and BPA further aggravates zinc deficiency-induced testicular tissue inflammation and apoptosis damage.

关键词： Optical coherence tomography angiography   SARS-CoV-2   Ophthalmology   Inflammation   Hypoxia   Peripapillary vessel density  

摘要： BackgroundThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been associated with endothelial dysfunction, which may also compromise the microcirculation within ocular tissues. This prospective study evaluated associations between radial peripapillary capillary (RPC) vessel density (VD) and systemic treatment, age, hypoxia, D-dimer, and interleukin-6 (IL-6) levels in patients recovering from coronavirus disease 2019 (COVID-19) related ***-three individuals who were admitted to the hospital due to COVID-19 bilateral pneumonia underwent ophthalmic examination two months post-discharge. RPC VD was measured using optical coherence tomography angiography. Associations with age, arterial hypertension, and systemic treatment (dexamethasone, remdesivir, and oxygen therapy), oxygen saturation, D-dimer, and IL-6 levels were evaluated. The control group comprised 43 control participants with no history of COVID-19 who attended routine ophthalmic *** ophthalmic abnormalities were detected. RPC VD did not differ significantly with hypertension or systemic treatment with dexamethasone and remdesivir. However, patients receiving oxygen therapy had higher RPC VD. A borderline inverse correlation was observed between inferior RPC VD and age. There were no correlations between RPC VD and oxygen saturation. Significant inverse correlations were found between nasal RPC and mean RPC with D-dimer levels and between inferior RPC VD and IL-6 levels. No significant differences in RPC parameters were observed when comparing the COVID-19 group with *** or systemic treatment had no significant effect on RCP VD. However, VD in specific RPC areas correlated inversely with D-dimer and IL-6 levels, highlighting the need for monitoring peripapillary microvasculature for potential long-term ocular effects of COVID-19.

关键词： Hesperidin   ifosfamide   Apoptosis   Renal toxicity   Antioxidant  

摘要： This study explored the protective effects of hesperidin (HES) against ifosfamide (IFA)-induced nephrotoxicity in rats using biochemical, histopathological, and immunohistochemical techniques. The rats were administered IFA at a dose of 500 mg/kg body weight, followed by oral HES treatment at doses of 200 and 300 mg/kg body weight. The results demonstrated that HES significantly reduced IFA-induced increases in urea and creatinine levels, indicating improved kidney function. HES was shown to mitigate IFA-induced lipid peroxidation, likely due to its antioxidant properties, and to enhance the activities of key antioxidant enzymes, including catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx), as well as elevate glutathione (GSH) levels. Biochemical and immunohistochemical analyses further revealed that HES exhibited anti-inflammatory, antiapoptotic and anti-endoplasmic reticulum stress effects, suppressing the elevated levels of nuclear factor kappa-B (NF-kappa B), interleukin-1n (IL-1n), tumor necrosis factor-alpha (TNF-alpha), Caspase-3, 6, 9, Bax, Apaf1, p53, serine/threonine-protein kinase/endoribonuclease inositol-requiring enzyme 1 alpha (IRE1 alpha), glucose-regulated protein 78 (GRP78), activating transcription factor 6 (ATF-6), and protein kinase R-like ER kinase (PERK), CHOP and alleviating level of Bcl-2 in IFA-exposed kidney tissue. Additionally, the immunohistochemical staining results for TIM-1 in rat kidney tissues showed minimal expression in the control and HES groups. However, the IFA-treated group exhibited a significant increase in TIM-1 expression. Co-administration of IFA with HES at 200 or 300 mg/kg resulted in a significant reduction in TIM-1 expression. In conclusion, these results demonstrate that HES efficiently alleviated kidney toxicity induced by IFA.

关键词： atonic pupil   irreversible mydriasis   paretic pupil   urrets-zavalia syndrome   urrets-zavalia-like syndrome  

摘要： Persistent fixed dilated and tonic pupils following an attack of anterior uveitis is an uncommon finding, particularly in patients with a confirmed diagnosis of human leukocyte antigen B27 (HLA-B27)-associated uveitis. The proposed mechanism in this condition is linked to anterior segment ischemia, a phenomenon known as Urrets-Zavalia-like syndrome. We describe a case of a healthy 38-year-old female patient who presented to the neuro-ophthalmology service with persistently dilated pupils in both eyes. She had a past ocular history of recurrent anterior uveitis that was later associated with an HLA-B27 mutation. During the acute attack of anterior uveitis, the patient received topical cyclopentolate 1% drops as part of her management. Later, she presented with worsening photophobia and high ocular pressure, in addition to widely dilated and fixed pupils (atonic pupils) in both eyes. Upon assessment during follow-up visits, the pupils were found to be persistently dilated even after the discontinuation of the mydriatic drops and stabilization of both ocular pressure and inflammation.

关键词： DvL   CAM assay   Immunohistochemistry   Pro-inflammatory  

摘要： Due to their interesting biological activities, a mannose-binding lectin isolated from Dioclea violacea seeds, known as DvL have attracted considerable attention. In this study, we performed macroscopic, histologic, and immunohistochemical analysis on chicken embryo chorioallantoic membranes (CAM) to investigate the effects of DvL on the angiogenic process. Data showed a potential angiogenic effect of DvL at the highest concentrations tested (50 and 100 mu g/mL). This effect was confirmed through increased neovascularization, inflammatory cells, and fibroblasts in histological analysis of the CAM. In addition, the immunohistochemistry of CAM showed that DvL induced secretion of TNF-alpha and VEGF, important cytokines involved in angiogenesis. Therefore, increased neovascularization may result from a pro-inflammatory response through VEGF and TNF-alpha secretion. In contrast, the DvL effects on the angiogenic process and the TNF-alpha and VEGF secretion were significantly reduced by co-incubation with mannose. Thus, protein-carbohydrate interactions between DvL and cell membrane glycans are likely the main events involved in this effect. Therefore, our results demonstrated that DvL is a potent angiogenic agent, suggesting its potential application as a prototype molecule for developing new drugs with healing properties.

关键词： genetics   population diversity   precision medicine   type 1 diabetes   type 2 diabetes  

摘要： Aims: We have reported that a 9SNPs type 1 diabetes (T1D) Genetic Risk Score (GRS) developed from European data had a lower power in Indians to distinguish T1D from type 2 diabetes (T2D). We explore the performance of an improved (67SNPs) T1DGRS and also the potential reasons for lower discriminative ability to classify types of diabetes in Indians. Methods: We studied the discriminative ability of a 67SNPs European T1DGRS in 611 clinically diagnosed T1D and 1153 T2D patients, and 321 non-diabetic controls, using receiver operating characteristic (ROC) area under the curve (AUC). We also compared the frequency and effect sizes of HLA risk haplotypes between Indians and Europeans. Results: The T1DGRS was discriminative of T1D from T2D and controls. However, the ability is lower in Indians than Europeans (AUC, Europeans 0.92, Indians all T1D 0.83, AA-positive 0.86). The T1DGRS was higher in AA-positive than in AA-negative persons [13.01 (12.79-13.23) vs. 12.09 (11.64-12.56)], p < 0.0001. The association of common HLA-DQA1 similar to HLA-DQB1 haplotypes was broadly similar;however, important differences were noted in the frequency, direction and magnitude of effect for some haplotypes between Indians and Europeans. Conclusions: We confirm broad applicability of European 67SNPs T1DGRS to Indian T1D persons. However, differences in HLA allele frequencies, magnitude and directional differences reduced the predictive value. Our results stress the need to generate ancestry-specific GRS, which we plan to do in the near future.