Cadmium contributes to cardiac metabolic disruption by activating endothelial HIF1A-GLUT1 axis.

Cadmium (Cd) is an environmental risk factor of cardiovascular diseases. Researchers have found that Cd exposure causes energy metabolic disorders in the heart decades ago. However, the underlying molecular mechanisms are still elusive. In this study, male C57BL/6 J mice were exposed to cadmium chloride (CdCl2) through drinking water for 4 weeks. We found that exposure to CdCl2 increased glucose uptake and utilization, and disrupted normal metabolisms in the heart. In vitro studies showed that CdCl2 specifically increased endothelial glucose uptake without affecting cardiomyocytic glucose uptake and endothelial fatty acid uptake. The glucose transporter 1 (GLUT1) as well as its transcription factor HIF1A was significantly increased after CdCl2 treatment in endothelial cells. Further investigations found that CdCl2 treatment upregulated HIF1A expression by inhibiting its degradation through ubiquitin-proteasome pathway, thereby promoted its transcriptional activation of SLC2A1. Administration of HIF1A small molecule inhibitor echinomycin and A-485 reversed CdCl2-mediated increase of glucose uptake in endothelial cells. In accordance with this, intravenous injection of echinomycin effectively ameliorated CdCl2-mediated metabolic disruptions in the heart. Our study uncovered the molecular mechanisms of Cd in contributing cardiac metabolic disruption by inhibiting HIF1A degradation and increasing GLUT1 transcriptional expression. Inhibition of HIF1A could be a potential strategy to ameliorate Cd-mediated cardiac metabolic disorders and Cd-related cardiovascular diseases.

Yupingfeng polysaccharide promote the growth of chickens via regulating gut microbiota.

Introduction: Yupingfeng polysaccharide (YPF-P) is the main substance of alcohol deposition in Yupingfeng powder, which has many biological functions such as enhancing immunity, repairing intestinal barrier and enhancing antioxidant ability. This study employed in vitro growth-promoting drug feed additives and animal experiments to comprehensively evaluate the use of YPF-P in broiler production. Methods: A total of 1,296 151 days-old Qingyuan Partridge chickens were randomly divided into four groups with six replicates and 54 hens per replicate: the control group was fed basal diet, and the experimental groups were fed diets supplemented with 4 g/kg, 8 g/kg, and 12 g/kg YPF-P for 14 days. Broilers were weighed before and at the end of the experiment to calculate total weight gain (GW), average daily gain (ADG), and feed compensation. At the end of the experiment, six chickens from each group were randomly selected for subwing vein blood sampling, which was used to measure serum biochemical indicators GHRH, GH, and IGF-1 by ELISA method. Randomly select chickens from control group and 8 g/kg group for slaughter, and cecal contents were collected for 16S high-throughput sequencing. Results: Dietary supplementation of 8 g/kg YPF-P can significantly increase the final body weight, total weight gain, average daily gain and decrease the feed to gain ratio of chickens. During 151-165 days, serum IGF-1 concentrations increased significantly (p < 0.05). There were no significant changes in serum GH concentration (p > 0.05). In terms of gut microbiota, there was no significant difference between control group and test group in Shannon index and Simpson index. Compared with the control group,the addition of 8 g/kgYPF-P significantly increased the abundance of Firmicutes and significantly decreased the abundance of Bacteroides at the phylum level.At the genus level, the relative abundance of unclassified_Oscillospiraceae was significantly increased and the unclassified_Muribaculaceae, uncultured_Bacteroidales_bacterium, Lactobacillus, Alloprevotella, Ligilactobacillus, Prevotellaceae_UCG_001, and unclassified_Atopobiaceae was significantly decreased. Conclusion: The above results showed that adding 8 mg/kg of YPF-P could increase the average daily gain of Qingyuan Partridge chickens, reduce the ratio of feed to meat, and affect the distribution proportion of intestinal microflora in chickens to some extent.

Intrathecal injection of methotrexate and dexamethasone for vasculitis granuloma of the fourth ventricle: a case report and literature review.

Granulomatosis with polyangiitis (GPA) is a pauci-immune small vessel vasculitis characterised by neutrophil-mediated vasculitis and granuloma. The presence of intracranial parenchymal space-occupying lesions is rarely seen in GPA patients. In this manuscript, we report a case of GPA with granuloma of the fourth ventricle accompanied by obstructive hydrocephalus. Treatment with glucocorticoids (GCs) and multiple immunosuppressants cyclophosphamide (CYC), mycophenolate mofetil (MMF), and rituximab (RTX) showed poor efficacy in this case. After removal of the granuloma by craniotomy, GPA relapsed within 3 months. Under the premise of GC and MMF treatment combined with intrathecal injection of dexamethasone (DXM) and methotrexate (MTX), the intracranial granuloma gradually shrank, and the patient's general condition was alleviated, showing that this is an effective treatment method. Key Points • To date, there are few reports of granulomatous vasculitis combined with granuloma of the fourth ventricle, and our case is the second. • In this case, multiple immunosuppressants and rituximab were ineffective treatments, and the intracranial granuloma was effectively controlled by intrathecal injection of dexamethasone (DXM) and methotrexate (MTX). • Based on this report, it can be suggested that intrathecal injection is effective in treating patients with GPA and central nervous system involvement, but large-scale sample studies are needed.

Effects of Yupingfeng Polysaccharides as Feed Supplement on Immune Function and Intestinal Microbiome in Chickens.

The health of chicks is closely related to their productivity. Yupingfeng polysaccharide (YPF-P) is a kind of water-soluble polysaccharide extracted from Yupingfeng powder; it has high pharmacological activity and can be used as a potential substitute for antibiotics to improve the health of chicks. This study aimed to investigate the effects of YPF-P on immune performance, the duodenum, and the cecal microflora of chicks. All chickens (4224) were randomly distributed into four groups (eight replicas/group, 132 hens/replica). The control group was fed a basal diet (0 g/kg YPF-P), while the experimental groups were fed basal diets supplemented with 1, 2, or 4 g/kg YPF-P. The results showed that YPF-P significantly increased the thymus index (p < 0.05). The content of total antioxidant capacity (T-AOC), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), immunoglobulin A (IgA), and IgG and immunoglobulin M (IgM) was upregulated in the serum by YPF-P (p < 0.05). YPF-P decreased the content of malondialdehyde (MDA) (p < 0.05). Further, 16S rRNA sequencing showed that 2 g/kg YPF-P modulated the predominant duodenum and cecal microbial community structure, which increased the number of Faecalibacterium, Megamonas, Bacteroides, Alistipes, NK4A214_group, and Enterococcus. In conclusion, YPF-P ameliorated the growth performance of chicks by regulating serum immune and antioxidant balance, as well as the intestinal microbiota.

Thymoquinone attenuates inflammation in C. Albicans keratitis by activating Nrf2/HO-1 signaling pathway and reducing fungal load.

PURPOSE: This study aims to investigate the anti-inflammatory and antifungal properties of thymoquinone (TQ) and elucidate its mechanism of action in the context of C. albicans keratitis. METHODS: Various methods were employed to identify a safe and effective concentration of TQ with antifungal properties, including the determination of the minimum inhibitory concentration (MIC), the cell counting kit-8 (CCK-8) test, and the Draize experiment. The severity of fungal keratitis (FK) was assessed through clinical ratings and slit-lamp imaging. Fungus burden was determined using plate counting and periodic acid Schiff (PAS) staining. Neutrophil infiltration and activity were investigated through immunofluorescence staining (IFS), myeloperoxidase (MPO) analysis, and hematoxylin and eosin (HE) staining. To explore the anti-inflammatory effects of TQ and its mechanism of action, we employed RT-PCR, ELISA, and western blot techniques. RESULTS: TQ effectively controlled fungal growth at a concentration of 50 µg/mL while preserving the integrity of mouse corneas. Human corneal epithelial cells (HCECs) remained unaffected by TQ at concentrations ≤ 3.75 µg/mL. Treatment with TQ led to significant improvements in clinical scores, fungal burden, neutrophil infiltration, and the expression of inflammatory factors compared to the DMSO group. Moreover, TQ demonstrated the ability to reduce the levels of inflammatory factors in HCECs stimulated by C. albicans. Additionally, TQ enhanced the expressions of Nrf2 and HO-1 in mouse corneas. The downregulation of cytokines induced by TQ was reversed upon pretreatment with inhibitors of Nrf2 or HO-1. CONCLUSION: TQ exhibits a protective effect in the context of C. albicans keratitis through multiple mechanisms, including inhibition of C. albicans growth, reduction of neutrophil recruitment, activation of the Nrf2/HO-1 pathway, and limitation of the expression of pro-inflammatory factors.

LINC00922 decoys SIRT3 to facilitate the metastasis of colorectal cancer through up-regulation the H3K27 crotonylation of ETS1 promoter.

BACKGROUND: Lysine crotonylation (Kcr) is up-regulation in colorectal cancer (CRC) tissues, while its specific contribution remains uncertain. This study aimed to elucidate the role and mechanism of crotonylation on Lys27 of histone H3 (H3K27cr) in facilitating CRC metastasis. METHODS: Immunohistochemistry was employed to investigate the correlation between H3K27cr and CRC metastasis. Both in vitro and in vivo assays employing loss function or gain function approaches were conducted to elucidate the role of LINC00922 in promoting CRC metastasis. ScRNA-seq analysis and immunoprecipitation analyses were employed to explore the underlying mechanism by which LINC00922 facilitates CRC metastasis through H3K27cr. RESULTS: Clinically, H3K27cr was upregulated in metastatic CRC tissues and positively correlated with advanced clinical stages. Functionally, knockdown of LINC00922 inhibited migration of CRC cells both in vitro and in vivo. Furthermore, the supplementation of NaCr restored the migration and invasion levels of LINC00922 stable knockdown cells by restoring the H3K27cr level. Mechanistically, LINC00922 promoted invasion and migration through H3K27cr mediated cell adhesion molecules (CAMs) in epithelial cells. Notably, LINC00922 interacted with the protein sirtuin 3 (SIRT3) and obstructed its binding to the promoter region of ETS1, leading to an elevation in the level of H3K27cr in this promoter region and the subsequent activation of ETS1 transcription. CONCLUSIONS: Our findings uncovered a novel regulatory function of H3K27cr, regulated by LINC00922, in facilitating CRC metastasis. This discovery contributed to a deeper comprehension of the involvement of histone crotonylation in the metastatic process of CRC.

Reduction of H3K27cr Modification During DNA Damage in Colon Cancer.

DNA damage plays an essential role in the initiation and development of colon cancer. Histone crotonylation is a newly discovered post-translational modification that is thought to promote gene expression. Whether histone crotonylation plays a role in DNA damage of cancer remains unknown, as does the putative underlying molecular mechanism. This study aimed to investigate the relationship between histone crotonylation and DNA damage of colon cancer using multiple bioinformatics analysis and western blotting. We discovered that genes with promoter occupied by histone crotonylation were associated with the activity of DNA damage in colon cancer patients. Additionally, we uncovered that the level of crotonylation on Lys27 of histone H3 (H3K27cr) decreased during camptothecin and etoposide treatment. Interestingly, sirtuin 6 was found to regulate the cellular level of H3K27cr. Taking these data together, our study provided a new perspective about histone crotonylation and DNA damage in colon cancer.

Lipid-storage myopathy with glycogen storage disease gene mutations mimicking polymyositis: a case report and review of the literature.

A 26-year-old Asian woman with persistent muscle weakness was diagnosed with polymyositis based on biopsy findings at another hospital 11 years ago. However, her symptoms fluctuated repeatedly under treatment with prednisone and immunosuppressive agents, and worsened 2 months prior to the current presentation. A second muscle biopsy suggested metabolic myopathy, and genetic testing revealed a novel c.1074C > T variant in the glycogen synthase 1 gene (GYS1), which is implicated in muscle glycogen storage disease type 0. However, no abnormalities in glycogen deposition were found by biopsy; rather, muscle fibers exhibited large intracellular lipid droplets. Furthermore, muscle strength was greatly restored and circulating levels of creatine kinase indicative of muscle degeneration greatly reduced by vitamin B2 treatment. Therefore, the final diagnosis was lipid storage myopathy.

Overexpression of eIF3D in Lung Adenocarcinoma Is a New Independent Prognostic Marker of Poor Survival.

The eukaryotic initiation factor 3 (eIF3) is the largest and most complex translation initiation factor in mammalian cells. It consists of 13 subunits and among which several were implicated to have significant prognostic effects on multiple human cancer entities. To examine the expression profiles of eIF3 subunits and determine their prognostic value in patients with lung adenocarcinoma (LUAD), the genomic data, survival data, and related clinical information were obtained from The Cancer Genome Atlas (TCGA) project for a secondary analysis. The results showed that among ten aberrantly expressed eIF3 subunits in tumours compared with adjacent normal counterparts (p < 0.05), only upregulated eIF3D could predict poor overall survival (OS) outcome independent of multiple clinicopathological parameters (HR = 2.043, 95% CI: 1.132-3.689, p = 0.018). Chi-square analysis revealed that the highly expressed eIF3D group had larger ratios of patients with advanced pathological stage (68/40 vs. 184/206, p = 0.0046), residual tumour (13/4 vs. 163/176, p = 0.0257), and targeted molecular therapy (85/65 vs. 138/164, p = 0.0357). In silico analysis demonstrated that the altered expression of eIF3D was at least regulated by both copy number alterations (CNAs) and the hypomethylation of cg14297023 site. In conclusion, high eIF3D expression might serve as a valuable independent prognostic indicator of shorter OS in patients with LUAD.