Vitamin D3 exacerbates steatosis while calcipotriol inhibits inflammation in non-alcoholic fatty liver disease in Sod1 knockout mice: a comparative study of two forms of vitamin D.

The role of vitamin D (VD) in non-alcoholic fatty liver disease (NAFLD) remains controversial, possibly due to the differential effects of various forms of VD. In our study, Sod1 gene knockout (SKO) mice were utilized as lean NAFLD models, which were administered 15 000 IU VD3 per kg diet, or intraperitoneally injected with the active VD analog calcipotriol for 12 weeks. We found that VD3 exacerbated hepatic steatosis in SKO mice, with an increase in the levels of Cd36, Fatp2, Dgat2, and CEBPA. However, calcipotriol exerted no significant effect on hepatic steatosis. Calcipotriol inhibited the expression of Il-1a, Il-1b, Il-6, Adgre1, and TNF, with a reduction of NFκB phosphorylation in SKO mice. No effect was observed by either VD3 or calcipotriol on hepatocyte injury and hepatic fibrosis. Co-immunofluorescence stains of CD68, a liver macrophage marker, and VDR showed that calcipotriol reduced CD68 positive cells, and increased the colocalization of VDR with CD68. However, VD3 elevated hepatocyte VDR expression, with no substantial effect on the colocalization of VDR with CD68. Finally, we found that VD3 increased the levels of serum 25(OH)D3 and 24,25(OH)2D3, whereas calcipotriol decreased both. Both VD3 and calcipotriol did not disturb serum calcium and phosphate levels. In summary, our study found that VD3 accentuated hepatic steatosis, while calcipotriol diminished inflammation levels in SKO mice, and the difference might stem from their distinct cellular selectivity in activating VDR. This study provides a reference for the application of VD in the treatment of lean NAFLD.

Insight into deep learning for glioma IDH medical image analysis: A systematic review.

BACKGROUND: Deep learning techniques explain the enormous potential of medical image analysis, particularly in digital pathology. Concurrently, molecular markers have gained increasing significance over the past decade in the context of glioma patients, providing novel insights into diagnosis and more personalized treatment options. Deep learning combined with imaging and molecular analysis enables more accurate prognostication of patients, more accurate treatment plan proposals, and accurate biomarker (IDH) prediction for gliomas. This systematic study examines the development of deep learning techniques for IDH prediction using histopathology images, spanning the period from 2019 to 2023. METHOD: The study adhered to the PRISMA reporting requirements, and databases including PubMed, Google Scholar, Google Search, and preprint repositories (such as arXiv) were systematically queried for pertinent literature spanning the period from 2019 to the 30th of 2023. Search phrases related to deep learning, digital pathology, glioma, and IDH were collaboratively utilized. RESULTS: Fifteen papers meeting the inclusion criteria were included in the analysis. These criteria specifically encompassed studies utilizing deep learning for the analysis of hematoxylin and eosin images to determine the IDH status in patients with gliomas. CONCLUSIONS: When predicting the status of IDH, the classifier built on digital pathological images demonstrates exceptional performance. The study's predictive effectiveness is enhanced with the utilization of the appropriate deep learning model. However, external verification is necessary to showcase their resilience and universality. Larger sample sizes and multicenter samples are necessary for more comprehensive research to evaluate performance and confirm clinical advantages.

Predictive Panel for Immunotherapy in Low-Grade Glioma.

BACKGROUND: The main treatment of low-grade glioma (LGG) is still surgical resection followed by radiotherapy and/or chemotherapy, which has certain limitations, including side effects and drug resistance. Immunotherapy is a promising treatment for LGG, but it is generally hindered by the tumor microenvironment with the limited expression of tumor antigens. METHODS: We integrated RNA sequencing data sets and clinical information and conducted consistent cluster analysis to explore the most suitable patients for immune checkpoint therapy. Gene set enrichment analysis, UMAP analysis, mutation correlation analysis, TIMER analysis, and TIDE analysis were used to identify the immune characteristics of 3 immune subtypes and the feasibility of 5 antigens as immune checkpoint markers. RESULTS: We analyzed the isolation and mutation of homologous recombination repair genes (HRR) of the 3 immune subtypes, and the HRR genes of the 3 subtypes were obviously segregated. Among them, the IS2 subtype has a large number of HRR gene mutations, which increases the immunogenicity of tumors-this is consistent with the results of tumor mutation load analysis of 3 immune subtypes. Then we evaluated the immune cell infiltration of immune subtypes and found that IS2 and IS3 subtypes were rich in immune cells. It is worth noting that there are many Treg cells and NK cells in the IS1 subtype. In addition, when analyzing the immune checkpoint gene expression of the 3 subtypes, we found that they were upregulated most in IS2 subtypes compared with other subtypes. Then when we further confirmed the role of immune-related genes in LGG; through TIDE analysis and TISIDB analysis, we obtained 5 markers that can predict the efficacy of ICB in patients with LGG. In addition, we confirmed that they were associated with poor prognosis through survival analysis. CONCLUSIONS: We obtained 3 reliable immune subtypes, and patients with the IS2 subtype are suitable for immunotherapy, in which NAMPT, SLC11A1, TNC, VIM, and SPP1 are predictive panel markers for ICB in the LGG group. Our findings provide a rationale for immunotherapy selection and prediction of patient prognosis in LGG patients.

Physicochemical properties and solution conformation of polysaccharides from Toona sinensis (A. Juss) Roem leaves.

In this study, two polysaccharide fractions (TSP-1 and TSP-2) were isolated from Toona sinensis leaves. The physicochemical properties and solution conformations of TSP-1 and TSP-2 were investigated. DSC and TG results showed that TSP-1 and TSP-2 had thermal stability. The intrinsic viscosities of TSP-1 and TSP-2 solutions were 11.42 and 6.13 mL/g, respectively. Rheological results showed that the viscosities of TSP-1 and TSP-2 solutions were affected by polysaccharide concentration, Ca2+ and extreme pH. Furthermore, TSP-1 exhibited a weak gel behavior at the concentrations of 0.5 %-2.0 %, while TSP-2 showed a weak gel behavior at the concentration of 2 %. HPSEC-MALLS analysis revealed that the Rg values of TSP-1 and TSP-2 were 96.8 nm and 56.2 nm, respectively. Conformation analysis indicated that TSP-1 behaved as a sphere, while TSP-2 behaved like a rigid rod. These results suggest that TSP-1 and TSP-2 can be used as additives in food, pharmaceutical and cosmetic industries.

Quercetin Ameliorates Deoxynivalenol-Induced Intestinal Injury and Barrier Dysfunction Associated with Inhibiting Necroptosis Signaling Pathway in Weaned Pigs.

Quercetin (Que) is a flavonol compound found in plants, which has a variety of biological activities. Necroptosis, a special form of programmed cell death, plays a vital role in the development of many gastrointestinal diseases. This study aimed to explore whether Que could attenuate the intestinal injury and barrier dysfunction of piglets after deoxynivalenol (DON) exposure through modulating the necroptosis signaling pathway. Firstly, twenty-four weaned piglets were used in a 2 × 2 factorial design and the main factors, including Que (basal diet or diet supplemented with 100 mg/kg Que) and DON exposure (control feed or feed contaminated with 4 mg/kg DON). After feeding for 21 d, piglets were killed for samples. Next, the intestinal porcine epithelial cell line (IPEC-1) was pretreated with or without Que (10 µmol/mL) in the presence or absence of a DON challenge (0.5 µg/mL). Dietary Que increased the body weight, average daily gain, and average daily feed intake (p < 0.05) through the trial. Que supplementation improved the villus height, and enhanced the intestinal barrier function (p < 0.05) indicated by the higher protein expression of occludin and claudin-1 (p < 0.05) in the jejunum of the weaned piglets after DON exposure. Dietary Que also down-regulated the protein abundance of total receptor interacting protein kinase 1 (t-RIP1), phosphorylated RIP1 (p-RIP1), p-RIP3, total mixed lineage kinase domain-like protein (t-MLKL), and p-MLKL (p < 0.05) in piglets after DON exposure. Moreover, Que pretreatment increased the cell viability and decreased the lactate dehydrogenase (LDH) activity (p < 0.05) in the supernatant of IPEC-1 cells after DON challenge. Que treatment also improved the epithelial barrier function indicated by a higher transepithelial electrical resistance (TEER) (p < 0.001), lower fluorescein isothiocyanate-labeled dextran (FD4) flux (p < 0.001), and better distribution of occludin and claudin-1 (p < 0.05) after DON challenge. Additionally, pretreatment with Que also inhibited the protein abundance of t-RIP1, p-RIP1, t-RIP3, p-RIP3, t-MLKL, and p-MLKL (p < 0.05) in IPEC-1 cells after DON challenge. In general, our data suggest that Que can ameliorate DON-induced intestinal injury and barrier dysfunction associated with suppressing the necroptosis signaling pathway.

Alteration of static and dynamic intrinsic brain activity induced by short-term spinal cord stimulation in postherpetic neuralgia patients.

Introduction: Short-term spinal cord stimulation (stSCS) is an effective treatment for postherpetic neuralgia (PHN). However, how exactly stSCS affects time-dynamic intrinsic brain activity in PHN patients is not clear. The purpose of this study was to examine the static and dynamic variability of neural activity in PHN patients after stSCS. Methods: In this study, 10 patients with PHN underwent resting-state functional magnetic resonance imaging (rs-fMRI) at baseline and after SCS. The amplitude of low-frequency fluctuations (ALFF) and dynamic ALFF (dALFF) were used to investigate the static and dynamic variability of neural activity in PHN patients after stSCS. We additionally examined the associations between clinical parameters and functional changes in the brain. Results: There was a significant increase in dALFF in the left precuneus and right superior parietal gyrus, and a decrease in dALFF in the left inferior temporal gyrus, right gyrus rectus, left superior temporal gyrus, right orbitofrontal cortex, and left orbitofrontal cortex. There was significantly increased ALFF in the right inferior temporal gyrus, and decreased ALFF in the right lingual gyrus, left superior parietal gyrus, right superior parietal gyrus, and left precuneus. Furthermore, Pittsburgh sleep quality index scores were positively associated with dALFF changes in the left superior temporal gyrus and left orbitofrontal cortex. Hospital anxiety and depression scale scores and continuous pain scores exhibited significant negative correlation with dALFF changes in the right superior parietal gyrus. Conclusion: This study indicated that stSCS is able to cause dALFF changes in PHN patients, thus stSCS might alter brain functions to relieve pain, sleep, and mood symptoms. The findings provide new insights into the mechanisms of stSCS efficacy in the treatment of patients with PHN.

Alterations in the Gut Microbiome of Young Children with Airway Allergic Disease Revealed by Next-Generation Sequencing.

Purpose: Recent studies had shown that gut microbiota played a significant role in the development of the immune system and may affect the course of airway allergic disease. We conducted this study to determine unique gut microbial associated with allergic disease in children by shotgun gene sequencing. Methods: We collected fecal samples from children with allergic asthma (n = 23) and allergic rhinitis (n = 18), and healthy control (n = 19). The gut microbiota of specimens was analyzed by high-throughput metagenomic shotgun gene sequencing. Results: The intestinal microbiota of children with allergic asthma and allergic rhinitis was characterized by increased microbial richness and diversity. Simpson and Shannon were significantly elevated in children with allergic asthma. Principal coordinates analysis (PCoA) showed that the gut microbial communities cluster patterns of children with asthma or rhinitis were significantly different from those of healthy controls. However, no significant difference was found between asthma group and rhinitis group At the phylum level, higher relative abundance of Firmicutes was found in the allergic rhinitis group and allergic asthma group, while the level of Bacteroidetes was significantly lower. At the genus level, Corynebacterium, Streptococcus, Dorea, Actinomyces, Bifidobacterium, Blautia, and Rothia were significantly enriched in the allergic asthma group. Finally, a random forest classifier model selected 16 general signatures to discriminate the allergic asthma group from the healthy control group. Conclusion: In conclusion, children in the allergic rhinitis group and allergic asthma group had altered gut microbiomes in comparison with the healthy control group. Compared to healthy children, the gut microbiome in children with allergic diseases has higher pro-inflammatory potential and increased production of pro-inflammatory molecules.

An update on the association between ambient short-term air pollution exposure and daily outpatient visits for conjunctivitis: a time-series study in Hangzhou, China.

Air pollution is a major public health problem that can lead to conjunctivitis. This study aimed to explore the associations between air pollutants and outpatient visits for conjunctivitis in Hangzhou, China. This study collected data on 50,772 patients with conjunctivitis and the concentrations of six air pollutants from February 1, 2014, to August 31, 2018. A time series analysis using a generalized additive model (GAM) was conducted. We found that the risk of conjunctivitis was related to the air pollutants PM2.5, PM10, SO2, NO2, and O3, which had concentration hysteresis effects. The risk of conjunctivitis increased by 1.009 (95% confidence interval (CI): 1.003, 1.014), 1.011 (95% CI: 1.008, 1.015), 1.238 (95% CI: 1.186, 1.292), 1.028 (95% CI: 1.019, 1.038), and 1.013 (95% CI: 1.008, 1.017) for every 10 µg/m3 increase in PM2.5, PM10, SO2, NO2, and O3 concentrations, respectively. The lag effects of SO2 and NO2 were stronger than those of particulate matter. Females exposed to PM10, PM2.5, SO2, and O3 had a higher risk of conjunctivitis than males, while males exposed to NO2 had a nearly identical risk of conjunctivitis as females. People aged 19-59 were more likely to suffer from conjunctivitis. The risk of conjunctivitis caused by PM10, SO2, and O3 was highest in the transitional season, while the risk caused by NO2 was highest in the winter season. In conclusion, females and middle-aged adults were at higher risk of conjunctivitis. People were more susceptible to conjunctivitis during the transitional season. These findings highlight the importance of atmospheric pollution governance and reference for public health measures.

Increased spontaneous activity of the superior frontal gyrus with reduced functional connectivity to visual attention areas and cerebellum in male smokers.

Background: Chronic smokers have abnormal spontaneous regional activity and disrupted functional connectivity as revealed by previous neuroimaging studies. Combining different dimensions of resting-state functional indicators may help us learn more about the neuropathological mechanisms of smoking. Methods: The amplitude of low frequency fluctuations (ALFF) of 86 male smokers and 56 male non-smokers were first calculated. Brain regions that displayed significant differences in ALFF between two groups were selected as seeds for further functional connectivity analysis. Besides, we examined correlations between brain areas with abnormal activity and smoking measurements. Results: Increased ALFF in left superior frontal gyrus (SFG), left medial superior frontal gyrus (mSFG) and middle frontal gyrus (MFG) as well as decreased ALFF in right calcarine sulcus were observed in smokers compared with non-smokers. In the seed-based functional connectivity analysis, smokers showed attenuated functional connectivity with left SFG in left precuneus, left fusiform gyrus, left lingual gyrus, left cerebellum 4 5 and cerebellum 6 as well as lower functional connectivity with left mSGF in left fusiform gyrus, left lingual gyrus, left parahippocampal gyrus (PHG), left calcarine sulcus, left cerebellum 4 5, cerebellum 6 and cerebellum 8 (GRF corrected, Pvoxel < 0.005, Pcluster<0.05). Furthermore, attenuated functional connectivity with left mSGF in left lingual gyrus and PHG displayed a negative correlation with FTND scores (r = -0.308, p = 0.004; r = -0.326, p = 0.002 Bonferroni corrected). Conclusion: Our findings of increased ALFF in SFG with reduced functional connectivity to visual attention areas and cerebellum subregions may shed new light on the pathophysiology of smoking.

Screening for Bisphenol Chemicals: A Strategy Based on Dansyl Chloride Derivatizatio n Coupled with In-Source Fragmentation by High-Resolution Mass Spectrometry.

Bisphenol chemicals (BPs) represent a complexity of halogenated and nonhalogenated substances sharing a common structure of two phenol functionalities, some of which exhibit ubiquitous environmental distributions and endocrine-disrupting activities. However, environmental monitoring of complex BP-like chemicals has faced analytical challenges arising from the lack of commercially available reference standards and efficient screening strategies. In the present study, we developed a strategy based on dansyl chloride (DnsCl) derivatization in combination with in-source fragmentation (D-ISF) during high-resolution mass spectrometry analysis to screen for bisphenol chemicals in complex environmental samples. The strategy contains three steps, including DnsCl derivatization to enhance the detection sensitivity by one to more than four orders of magnitude, in-source fragmentation to produce characteristic loss of 234.0589, 63.9619, and 298.0208 Da for the identification of DnsCl-derivatized compounds, and data processing and annotation. The D-ISF strategy was further validated and then applied to identify BPs in six types of particular matters as representative environmental samples, including settled dust from an electronic waste dismantling site, homes, offices, and vehicles, and airborne particles from indoor and outdoor environments. A total of six halogenated and fourteen nonhalogenated BPs were identified in the particles, including several chemicals that had rarely or never been identified in environmental samples. Our strategy offers a powerful tool for the environmental monitoring of bisphenol chemicals and assessment of human exposure risks.

Predictive Effect of Cervical Sagittal Parameters and Corresponding Segmental Paravertebral Muscle Degeneration on the Occurrence of Cervical Kyphosis Following Cervical Laminoplasty.

BACKGROUND: Cervical sagittal parameters and paravertebral muscle degeneration are important factors for the occurrence of cervical spondylotic myelopathy. However, the relationship between the 2 risk factors and cervical kyphosis following cervical laminoplasty remains unknown. METHODS: A total of 130 patients undergoing cervical laminoplasty were enrolled from July 2018 to July 2020 and were followed up for at least 24 months. Clinical recovery was recorded, including the Japanese Orthopedic Association, neck disability index and visual analog scale scores. Radiographic sagittal parameters were measured on cervical lateral radiographs: T1 slope (T1S), C2-C7 Cobb lordotic angle (CLA), C2-C7 sagittal vertical axis, O-C2 angle, and T1S-CLA. The magnetic resonance imaging (MRI) parameters of the paraspinal muscles were also measured, including cross-sectional area and fat infiltration (FI). The patients were divided into a kyphosis group and a lordosis group based on the last follow-up results of CLA. Multivariate logistic analysis was performed to analyze risk factors for kyphosis following laminoplasty. RESULTS: Thirty-two patients were assigned to the kyphosis group and 98 were assigned to the lordosis group. Patient baseline and surgical information in the 2 groups showed no statistically significant difference. In the comparison of clinical recovery, patients with kyphosis showed a lower Japanese Orthopedic Association recovery rate than the lordosis group. For the radiographic parameters and muscle condition comparison, CLA, T1S-CLA, and FI were the most significant parameters. The logistic regression revealed that T1S-CLA and FI were the most important variables that predicted kyphosis. CONCLUSIONS: We concluded that FI remarkably differed in the paraspinal muscles in the 2 groups. Multivariate logistic regression demonstrated that T1S-CLA and FI significantly influenced the process of kyphosis after cervical laminoplasty.

Aspirin-triggered Resolvin D1 ameliorates activation of the NLRP3 inflammasome via induction of autophagy in a rat model of neuropathic pain.

Background: Several studies performed thus far indicate that neuroinflammation may be one of the mechanisms underlying the pathogenesis of neuropathic pain (NP). Autophagy, as an adaptive response, has been regarded as an active process of removing the inflammatory stimulus and restoring homeostatic balance. Resolution of inflammation is a biochemical process mediated by the so-called aspirin-triggered specialized proresolving lipid mediators (AT-SPMs), which are thought to exert protective effects in NP. Recent studies have proposed mechanisms in models of inflammatory disorders and showed a relationship between resolution of inflammation and autophagy. This study aimed to validate the functional effects of Aspirin-triggered Resolvin D1 (AT-RvD1) on in vitro and in vivo models of inflammation and to determine their roles in the regulation of autophagy and activation of the Nod-like receptor protein 3 (NLRP3) inflammasome signaling pathway. Methods: An NP model was established using L5-6 spinal nerve ligation (SNL) and a model of tumor necrosis factor alpha (TNF-α)-stimulated primary microglia was established to evaluate the effect of SPMs. Western blotting was used to detect the level of NLRP3 inflammasomes complexes proteins (NLRP3, ASC, and Caspase-1) and autophagy-related proteins (LC3B, and Beclin1). Immunofluorescence staining was used to understand the autophagy and NLRP3 inflammasome activation process. The behavioral changes in rats were analyzed using paw withdrawal thresholds (PWT) and paw withdrawal latency (PWL) test. Results: Our results showed that AT-SPMs significantly upregulated the activation of autophagy, which was characterized by an increase in the ratio of LC3B-II/I and accumulation of ATG5 and Beclin1. AT-RvD1 showed a dose-dependent decrease in the upregulated PWT and PWL induced by SNL and suppressed the expression of the NLRP3 inflammasome protein and the production of its corresponding downstream proinflammatory factors. Additionally, AT-RvD1 induced the activation of autophagy of the microglia and decreased the expression of the NLRP3 inflammasome protein and the accumulation of proinflammatory factors in TNF-ɑ-challenged microglia. Conclusion: Thus, these results showed that AT-RvD1 may be a potential alternative therapeutic strategy for the prevention or treatment of NP by inhibition of the NLRP3 inflammasome signaling pathway by targeting the induction of autophagy.

Protocatechuic acid and quercetin attenuate ETEC-caused IPEC-1 cell inflammation and injury associated with inhibition of necroptosis and pyroptosis signaling pathways.

BACKGROUND: Necroptosis and pyroptosis are newly identified forms of programmed cell death, which play a vital role in development of many gastrointestinal disorders. Although plant polyphenols have been reported to protect intestinal health, it is still unclear whether there is a beneficial role of plant polyphenols in modulating necroptosis and pyroptosis in intestinal porcine epithelial cell line (IPEC-1) infected with enterotoxigenic Escherichia coli (ETEC) K88. This research was conducted to explore whether plant polyphenols including protocatechuic acid (PCA) and quercetin (Que), attenuated inflammation and injury of IPEC-1 caused by ETEC K88 through regulating necroptosis and pyroptosis signaling pathways. METHODS: IPEC-1 cells were treated with PCA (40 µmol/L) or Que (10 µmol/L) in the presence or absence of ETEC K88. RESULTS: PCA and Que decreased ETEC K88 adhesion and endotoxin level (P < 0.05) in cell supernatant. PCA and Que increased cell number (P < 0.001) and decreased lactate dehydrogenases (LDH) activity (P < 0.05) in cell supernatant after ETEC infection. PCA and Que improved transepithelial electrical resistance (TEER) (P < 0.001) and reduced fluorescein isothiocyanate-labeled dextran (FD4) flux (P < 0.001), and enhanced membrane protein abundance of occludin, claudin-1 and ZO-1 (P < 0.05), and rescued distribution of these tight junction proteins (P < 0.05) after ETEC infection. PCA and Que also declined cell necrosis ratio (P < 0.05). PCA and Que reduced mRNA abundance and concentration of tumor necrosis factor-α (TNF-α), interleukin (IL)-6 and IL-8 (P < 0.001), and down-regulated gene expression of toll-like receptors 4 (TLR4) and its downstream signals (P < 0.001) after ETEC infection. PCA and Que down-regulated protein abundance of total receptor interacting protein kinase 1 (t-RIP1), phosphorylated-RIP1 (p-RIP1), p-RIP1/t-RIP1, t-RIP3, p-RIP3, mixed lineage kinase domain-like protein (MLKL), p-MLKL, dynamin- related protein 1 (DRP1), phosphoglycerate mutase 5 (PGAM5) and high mobility group box 1 (HMGB1) (P < 0.05) after ETEC infection. Moreover, PCA and Que reduced protein abundance of nod-like receptor protein 3 (NLRP3), nod-like receptors family CARD domain-containing protein 4 (NLRC4), apoptosis-associated speck-like protein containing a CARD (ASC), gasdermin D (GSDMD) and caspase-1 (P < 0.05) after ETEC infection. CONCLUSIONS: In general, our data suggest that PCA and Que are capable of attenuating ETEC-caused intestinal inflammation and damage via inhibiting necroptosis and pyroptosis signaling pathways.

Selenium-enriched Cardamine violifolia protects against sepsis-induced intestinal injury by regulating mitochondrial fusion in weaned pigs.

Sepsis is a life-threatening organ dysfunction caused by the dysregulated response of the host to an infection, and treatments are limited. Recently, a novel selenium source, selenium-enriched Cardamine violifolia (SEC) has attracted much attention due to its anti-inflammatory and antioxidant properties, but little is known about its role in the treatment of sepsis. Here, we found that SEC alleviated LPS-induced intestinal damage, as indicated by improved intestinal morphology, and increased disaccharidase activity and tight junction protein expression. Moreover, SEC ameliorated the LPS-induced release of pro-inflammatory cytokines, as indicated by decreased IL-6 level in the plasma and jejunum. Moreover, SEC improved intestinal antioxidant functions by regulating oxidative stress indicators and selenoproteins. In vitro, TNF-α-challenged IPEC-1 cells were examined and showed that selenium-enriched peptides, which are the main functional components extracted from Cardamine violifolia (CSP), increased cell viability, decreased lactate dehydrogenase activity and improved cell barrier function. Mechanistically, SEC ameliorated LPS/TNF-α-induced perturbations in mitochondrial dynamics in the jejunum and IPEC-1 cells. Moreover, CSP-mediated cell barrier function is primarily dependent on the mitochondrial fusion protein MFN2 but not MFN1. Taken together, these results indicate that SEC mitigates sepsis-induced intestinal injury, which is associated with modulating mitochondrial fusion.

Necroptosis Contributes to LPS-Induced Activation of the Hypothalamic-Pituitary-Adrenal Axis in a Piglet Model.

Stressors cause activation of the hypothalamic-pituitary-adrenal (HPA) axis and a systemic inflammatory response. As a newly proposed cell death manner in recent years, necroptosis occurs in a variety of tissue damage and inflammation. However, the role of necroptosis in HPA axis activation remains to be elucidated. The aim of this study was to investigate the occurrence of necroptosis and its role in HPA activation in a porcine stress model induced by Escherichia coli lipopolysaccharide (LPS). Several typical stress behaviors like fever, anorexia, shivering and vomiting were observed in piglets after LPS injection. HPA axis was activated as shown by increased plasma cortisol concentration and mRNA expression of pituitary corticotropin-releasing hormone receptor 1 (CRHR1) and adrenal steroidogenic acute regulatory protein (StAR). The mRNA expression of tumor necrosis factor α (TNF-α), interleukin-1ß (IL-1ß) and IL-6 in the hypothalamus, pituitary gland and adrenal gland was elevated by LPS, accompanied by the activation of necroptosis indicated by higher mRNA expression of necroptosis signals including receptor-interacting protein kinase (RIP) 1, RIP3, and phosphorylated mixed-lineage kinase domain-like protein (MLKL). Furthermore, necrostatin-1 (Nec-1), an inhibitor of necroptosis, inhibited necroptosis indicated by decreased mRNA levels of RIP1, RIP3, MLKL, and phosphoglycerate mutase family member 5 (PGAM5) in the hypothalamus, pituitary gland and adrenal gland. Nec-1 also decreased the mRNA expression of TNF-α and IL-ß and inhibited the activation of the HPA axis indicated by lower plasma cortisol concentration and mRNA expression of adrenal type 2 melanocortin receptor (MC2R) and StAR. These findings suggest that necroptosis is present and contributes to HPA axis activation induced by LPS. These findings provide a potential possibility for necroptosis as an intervention target for alleviating HPA axis activation and stress responses.

Transcriptome Profiling and Network Analysis Provide Insights Into the Pathogenesis of Vulvar Lichen Sclerosus.

Vulvar lichen sclerosus (VLS) is a chronic inflammatory dermatosis that affects female anogenital skin. Although VLS is considered a T cell-mediated autoimmune disease, the diagnosis criteria, molecular mechanism, and universally accepted therapies for this disease remain largely unresolved. To explore disease pathogenesis and potential biomarkers, we performed an RNA-Seq-based transcriptome analysis to profile the gene expression of VLS lesions. Differentially expressed gene (DEG) analysis revealed profound changes in expressions of coding genes, microRNAs, and long non-coding RNAs. Pathway and network analysis suggested that T cell activation-associated genes, including CD3G, CD3D, CD8B, LAT, LCK, ZAP70, CCR5, CXCR3, CXCL9, CXCL10, and CXCL11, were highly expressed in VLS, while NR4A family genes (NR4A1, NR4A2, NR4A3), whose coding products inhibit T cell activity, were significantly downregulated, suggesting heightened T cell response in VLS. Neutrophil chemoattractant genes CXCL1, CXCL2, CXCL3, CXCL8, and their cognate receptor CXCR2 were downregulated, suggesting dampened neutrophil activity. We also found the downregulation of genes involved in cell cycle progression, including cyclins (CCNB1, CCNB2, CCNL1, CCNE1, and CCNK) and centrosome factors (CENPA, CENPE, CENPF, and CENPN), while microRNA-203a and let-7, microRNAs known to inhibit cell growth, were found to be upregulated. These data collectively indicate that cell proliferation in VLS is compromised. In sum, these findings comprehensively deciphered key regulatory genes and networks in VLS, which could further our understanding of disease mechanisms and point toward therapeutic strategies.

LncRNA PELATON, a Ferroptosis Suppressor and Prognositic Signature for GBM.

PELATON is a long noncoding RNA also known as long intergenic nonprotein coding RNA 1272 (LINC01272). The known reports showed that PELATON functions as an onco-lncRNA or a suppressor lncRNA by suppressing miRNA in colorectal cancer, gastric cancer and lung cancer. In this study, we first found that PELATON, as an onco-lncRNA, alleviates the ferroptosis driven by mutant p53 and promotes mutant p53-mediated GBM proliferation. We also first confirmed that PELATON is a new ferroptosis suppressor lncRNA that functions as a ferroptosis inhibitor mainly by mutant P53 mediating the ROS ferroptosis pathway, which inhibits the production of ROS, reduces the levels of divalent iron ions, promotes the expression of SLC7A11, and inhibits the expression of ACSL4 and COX2.PELATON can inhibit the expression of p53 in p53 wild-type GBM cells and regulate the expression of BACH1 and CD44, but it has no effect on p53, BACH1 and CD44 in p53 mutant GBM cells. PELATON and p53 can form a complex through the RNA binding protein EIF4A3. Knockdown of PELATON resulted in smaller mitochondria, increased mitochondrial membrane density, and enhanced sensitivity to ferroptosis inducers to inhibit GBM cell proliferation and invasion. In addition, we established a favourite prognostic model with NCOA4 and PELATON. PELATON is a promising target for the prognosis and treatment of GBM.

Establishment and resilience of transplanted gut microbiota in aged mice.

The maintenance of healthy and resilient gut microbiota is critical for the life quality and healthspan of the elderly. Fecal microbiota transplantation (FMT) has been increasingly used to restore healthy gut microbiota. We systemically studied the establishment and resilience of transplanted microbiota after autologous versus heterologous FMT in aged recipients. Gut microbiota of aged mice (20 months old) failed to restore their original diversity and composition over 8 weeks via spontaneous recovery after antibiotics treatment; in contrast, FMT using either autologous or heterologous (2 months old from a different vendor) donors facilitated the recovery successfully, established donor-like microbiota states, and affected host gene expression profile. Furthermore, the transplanted microbiota established by heterologous FMT is not resilient during chemical-induced colonic inflammation, in contrast to that of autologous FMT. Our findings highlighted the need to monitor the long-term stability of transplanted gut microbiota and to perform multiple FMT when necessary.