Intrinsic Capacity, Polygenic Risk Score, APOE Genotype, and Risk of Dementia: A Prospective Cohort Study Based on the UK Biobank.

BACKGROUND AND OBJECTIVES: The World Health Organization recently released a novel metric for healthy aging: intrinsic capacity (IC). The relationship between IC and the incidence of dementia, and its subtypes, is unknown. We aimed to analyze the relationship between IC and the incidence of dementia and its subtypes. Moreover, we tested whether genetic susceptibility to dementia could be modified by IC. METHODS: This cohort study involved 366,406 participants from the UK Biobank between 2006 and 2010. We analyzed 7 factors that reflected functional status across 4 IC domains to compute a comprehensive IC deficit score. Cox models were used to elucidate the relationship between the IC deficit score and the incidence of dementia. RESULTS: Among the 366,406 participants, 5,207 cases of dementia were documented, encompassing 2,186 and 1,175 cases of Alzheimer disease (AD) and vascular dementia (VD), respectively. Compared with participants with an IC score of 0, individuals with an IC score of 4+ had a markedly elevated risk of dementia (hazard ratio [HR] 2.17, 95% CI 1.92-2.45). In the joint analysis, for participants with a high polygenic risk score (PRS) and an IC score of 4 or more, the HR of all-cause dementia was 8.11 (95% CI 6.28-10.47) compared with individuals with a low PRS and an IC score of 0. Similar results were seen in the AD and VD groups. DISCUSSION: In summary, IC is associated with a higher risk of dementia, particularly in those combined with genetically predisposed to dementia.

Ethanol responsive lnc171 promotes migration and invasion of HCC cells via mir-873-5p/ZEB1 axis.

BACKGROUNDS: Long nonconding RNAs (lncRNAs) have been found to be a vital regulatory factor in the development process of human cancer, and could regarded as diagnostic or prognostic biomarkers for human cancers. Here, we aim to confirm the expression and molecular mechanism of RP11-171K16.5 (lnc171) in hepatocellular carcinoma (HCC). METHODS: Screening of differentially expressed lncRNAs by RNA sequencing. Expression level of gene was studied by quantitative real-time PCR (qRT-PCR). The effects of lnc171, mir-873-5p, and ethanol on migration and invasion activity of cells were studied used transwell assay, and luciferase reporter assay was used to confirm the binding site. RESULTS: RNA sequencing showed that lnc171 was markedly up-regulated in HCC. siRNA-mediated knockdown of lnc171 repressed the migration and invasion ability of HCC cells. Bioinformatic analysis, dual luciferase reporter assay, and qRT-PCR indicated that lnc171 interacted with mir-873-5p in HCC cells, and Zin-finger E-box binding homeobox (ZEB1) was a downstream target gene of mir-873-5p. In addition, lnc171 could enhance migration and invasion ability of HCC cells by up-regulating ZEB1 via sponging mir-873-5p. More interestingly, ethanol stimulation could up-regulate the increase of lnc171, thereby regulating the expression of competing endogenous RNA (ceRNA) network factors which lnc171 participated in HCC cells. CONCLUSIONS: Our date demonstrates that lnc171 was a responsive factor of ethanol, and plays a vital role in development of HCC via binding of mir-873-5p.

Timing of first abdominal operation in Crohn's disease based on a diagnostic model.

This study aims to develop a clinical diagnostic model for assessing the need for initial abdominal surgery in patients diagnosed with Crohn's disease (CD) and create a nomogram to facilitate clinical decision-making. A total of 164 surgical CD patients and 230 control CD patients were included in this retrospective analysis. Least Absolute Shrinkage and Selection Operator (Lasso) regression and binomial logistic regression were employed to select clinical variables. The 394 CD patients were randomly allocated to a training set and a validation set in a 7:3 ratio. The filtered variables were used to establish a diagnostic model and nomogram in the training set, subsequently validated in the testing set. Decision Curve Analysis (DCA) and clinical impact curve were constructed to validate the clinical applicability of the model. Binomial logistic regression analysis identified seven clinical variables with a p-value less than 0.01, including Biomarker (B), Waist-to-Height Ratio (WHtR), Intestinal obstruction, Albumin (ALB), Crohn's Disease Activity Index (CDAI), Myocardial Flow Index (MFI), and C-reactive protein (CRP). These variables were utilized to establish the diagnostic model. Calibration curves showed good alignment, with a C-index of 0.996 in the training set and 0.990 in the testing set. DCA and clinical impact curve demonstrated that the diagnostic model had good clinical efficiency and could provide clinical benefits. A validated diagnostic model for determining the timing of the first abdominal operation in CD patients was established and evaluated, showing high discriminative ability, calibration, and clinical efficiency. It can be utilized by clinicians to assess the optimal timing for transitioning CD patients from medical treatment to surgical intervention, providing valuable references for individualized treatment decisions for CD patients.

Dementia classification using a graph neural network on imaging of effective brain connectivity.

Alzheimer's disease (AD) and Parkinson's disease (PD) are two of the most common forms of neurodegenerative diseases. The literature suggests that effective brain connectivity (EBC) has the potential to track differences between AD, PD and healthy controls (HC). However, how to effectively use EBC estimations for the research of disease diagnosis remains an open problem. To deal with complex brain networks, graph neural network (GNN) has been increasingly popular in very recent years and the effectiveness of combining EBC and GNN techniques has been unexplored in the field of dementia diagnosis. In this study, a novel directed structure learning GNN (DSL-GNN) was developed and performed on the imaging of EBC estimations and power spectrum density (PSD) features. In comparison to the previous studies on GNN, our proposed approach enhanced the functionality for processing directional information, which builds the basis for more efficiently performing GNN on EBC. Another contribution of this study is the creation of a new framework for applying univariate and multivariate features simultaneously in a classification task. The proposed framework and DSL-GNN are validated in four discrimination tasks and our approach exhibited the best performance, against the existing methods, with the highest accuracy of 94.0% (AD vs. HC), 94.2% (PD vs. HC), 97.4% (AD vs. PD) and 93.0% (AD vs. PD vs. HC). In a word, this research provides a robust analytical framework to deal with complex brain networks containing causal directional information and implies promising potential in the diagnosis of two of the most common neurodegenerative conditions.

Identification of novel N7-methylguanine-related gene signatures associated with ulcerative colitis and the association with biological therapy.

OBJECTIVE: Ulcerative colitis (UC) is an inflammatory disease characterized by recurrent episodes of chronic intestinal inflammation. It is closely associated with immune dysregulation in the intestines. However, the mechanisms underlying the role of immune-related N7-methylguanosine (m7G) internal modification in UC remain unclear. METHODS: We conducted a screening of differentially expressed genes (DEGs) associated with m7G and performed immune infiltration analysis. We then investigated the correlation between m7G-related DEGs and immune cells or pathways. To further explore the functional implications, we conducted functional enrichment analysis to identify gene modules that strongly correlated with hub gene expression. In addition, we constructed a miRNA regulatory network for the hub genes in UC. Furthermore, we examined the association between hub genes and disease remission in UC patients undergoing biologic therapy. RESULTS: We obtained 13 m7G-related DEGs and conducted an in-depth analysis of immune infiltration. Among them, we identified five hub genes (NUDT7, NUDT12, POLR2H, QKI, and PRKCB) that showed diagnostic potential for UC. Through WGCNA and KEGG analysis, we found that gene modules strongly correlated with m7G hub gene expression were enriched in inflammation-related pathways. Furthermore, Kaplan-Meier survival analysis revealed a significant association between changes in hub gene expression levels and disease remission in UC patients undergoing biologic therapy. CONCLUSION: The findings of this study demonstrate that five m7G-related DEGs, including the m7G-modified recognition protein QKI, play a key role in the occurrence and progression of UC intestinal inflammation, which is closely related to intestinal immunity. These results provide valuable insights into the mechanisms of m7G modification in UC development and offer new perspectives for exploring novel therapeutic targets for UC.

The predictive significance of a 5-m6A RNA methylation regulator signature in colorectal cancer.

Colorectal cancer attacks the colon or rectum, with increasing morbidity and mortality globally. The RNA modification 6-methyladenine (m6A) is related to RNA modifications, playing a critical role in colorectal cancer. We aimed to identify prognostic signatures for colorectal cancer using risk prediction algorithms, and to validate these signatures using independent datasets and clinical samples. In this study, 175 cases in GSE17536 were assigned into two clusters using consistent clustering and PCA analysis. A multivariate Cox risk regression model revealed that among 21 m6A RNA methylation regulators, RBM15B, FTO, IGF2BP2, ZCCHC4, and KIAA1429 were remarkably associated with colorectal cancer patients' overall survival (OS); however, Kaplan-Meier (KM) survival assessment showed no significant association between these five regulators and colorectal cancer patients' prognosis. A 5-m6A RNA methylation regulator signature was established using LASSO algorithm. Risk scores of cases in GSE17536, GSE17537 and GSE75500 were calculated, and lower risk scores were associated with better DSS/OS. receiver operating characteristic (ROC) curve and the nomogram revealed the satisfactory predictive efficiency of the risk score model. The risk score could distinguish cases in Cluster1 and Cluster2 and normal and tumor tissues based on GSE37182. The prognostic variables for colorectal cancer patients were assessed using both univariate and multivariate Cox's proportional hazard regression models, which revealed that the stage and risk score were significant risk factors. In this study, a comprehensive set of integrative bioinformatics analyses was conducted to investigate the prognostic and diagnostic potential of a panel of 5 m6A RNA methylated regulators in colorectal cancer patients. The conducted studies included the use of several statistical methods, such as the LASSO regression model, KM survival evaluation, ROC curve, and univariate and multivariate Cox's proportional hazard regression analyses. The findings from these analyses collectively established the prognostic marker, highlighting its significance in predicting patient outcomes and diagnosing colorectal cancer.

Oleoylethanolamide ameliorates motor dysfunction through PPARα-mediates oligodendrocyte differentiation and white matter integrity after ischemic stroke.

BACKGROUND AND AIM: Our previous study has revealed that OEA promotes motor function recovery in the chronic stage of ischemic stroke. However, the neuroprotective mechanism of OEA on motor function recovery after stroke still is unexplored. Therefore, the aim of this study was to explore the effects of OEA treatment on angiogenesis, neurogenesis, and white matter repair in the peri-infarct region after cerebral ischemia. EXPERIMENTAL PROCEDURE: The adult male rats were subjected to 2 h of middle cerebral artery occlusion. The rats were treated with 10 and 30 mg/kg OEA or vehicle daily starting from day 2 after ischemia induction until they were sacrificed. KEY RESULTS AND CONCLUSIONS: The results revealed that OEA increased cortical angiogenesis, neural progenitor cells (NPCs) proliferation, migration, and differentiation. OEA treatment enhanced the survival of newborn neurons and oligodendrogenesis, which eventually repaired the cortical neuronal injury and improved motor function after ischemic stroke. Meanwhile, OEA treatment promoted the differentiation of oligodendrocyte progenitor cells (OPCs) and oligodendrogenesis by activating the PPARα signaling pathway. Our results showed that OEA restores motor function by facilitating cortical angiogenesis, neurogenesis, and white matter repair in rats after ischemic stroke. Therefore, we demonstrate that OEA facilitates functional recovery after ischemic stroke and propose the hypothesis that the long-term application of OEA mitigates the disability after stroke.

URB597 exerts neuroprotective effects against transient brain ischemia injury in mice by regulating autophagic flux and necroptosis.

Ischemic stroke is a leading cause of death and disability, and medical treatments for ischemic stroke are very limited. URB597 is a potent and selective inhibitor of fatty acid amide hydrolase (FAAH). However, the effect of URB597 on ischemic stroke and the underlying molecular mechanisms remain little known. In this study, focal cerebral ischemia was induced by transient middle cerebral artery occlusion in mice. Our results showed that URB597 dose-dependently improved neurological function and reduced brain infarct volume and brain edema 24 h after brain ischemia. The most effective dose was 1 mg/kg and the therapeutic time window was within 3 h after ischemic stroke. To further investigate the underlying mechanism, necroptosis and autophagy flux were detected by Western blot and/or immunofluorescence staining with or without chloroquine, an autophagic flux inhibitor. Our results showed that URB597 promoted autophagic flux and reduced neuronal necroptosis after brain ischemia and these effects could be abolished by chloroquine. In addition, we found that peroxisome proliferator-activated receptor α (PPARα) antagonist GW6471 partly abolished the effect of URB597 against brain ischemia and URB597 upregulated the expressions of PPARα. In conclusion, URB597 exerts a neuroprotective effect in a dose- and time-dependent manner, and this effect may be related to its restoration of autophagic flux and inhibition of neuronal necroptosis. PPARα is involved in the neuroprotective effect of URB597. This study provides novel evidence that URB597 may be a promising agent for the clinical treatment of ischemic stroke.

Vasorin promotes proliferation and migration via STAT3 signaling and acts as a promising therapeutic target of hepatocellular carcinoma.

Abnormal expression of Vasorin (VASN) is related to many types of cancer, but the signaling pathway and mechanism of how VASN contributes to the carcinogenesis of hepatocellular carcinoma (HCC) are poorly understood. Here, we found that VASN was up-regulated in serum/serum exosome and tissues of HCC patients. The expression of VASN in serum improve the detection rate of HCC in alpha-fetoprotein-negative HCC patients. Immunohistochemistry revealed that VASN was highly expressed in HCC tissues and associated with different stages of HCC. Noticeably, when serum VASN combined with α-fetoprotein, the area under the curve (AUC), sensitivity, and specificity of HCC patients compared with healthy patients reached 0.918 (95% CI: 0.869-0.967, P < 0.001), 90.91%, and 90.20%, respectively. VASN knockout HCC cells were obtained by CRISPR/Cas9 and a VASN-specific monoclonal antibody was prepared by hybridoma technology. Knockout of VASN or the addition of VASN-specific monoclonal antibody suppressed the proliferation and migration of HCC. Mechanistically, VASN promote the proliferation and migration of HCC by regulating the phosphorylation of STAT3 and the expression of downstream genes CCND1 and MMP2. In conclusion, our findings suggest that VASN plays a crucial role in the activation of STAT3 signaling pathway in HCC, which is a promising target for the diagnosis and therapy of HCC.

Surgical management of duodenal Crohn's disease.

BACKGROUND: The case of Crohn's disease involving the duodenum is rare, and its surgical management requires a thorough understanding. AIM: To investigate the surgical management of duodenal Crohn's disease. METHODS: We systematically reviewed patients diagnosed with duodenal Crohn's disease who underwent surgery in the Department of Geriatrics Surgery of the Second Xiangya Hospital of Central South University from January 1, 2004, to August 31, 2022. The general information, surgical procedures, prognosis, and other information of these patients were collected and summarized. RESULTS: A total of 16 patients were diagnosed with duodenal Crohn's disease, where 6 cases had primary duodenal Crohn's disease, and 10 had secondary duodenal Crohn's disease. Among patients with primary disease, 5 underwent duodenal bypass and gastrojejunostomy, and 1 received pancreaticoduodenectomy. Among those with a secondary disease, 6 underwent closure of duodenal defect and colectomy, 3 received duodenal lesion exclusion and right hemicolectomy, and 1 underwent duodenal lesion exclusion and double-lumen ileostomy. CONCLUSION: Crohn's disease involving the duodenum is a rare condition. Different surgical management should be applied for patients with Crohn's disease presenting with different clinical manifestations.

The impact of multiple non-pharmaceutical interventions for China-bound travel on domestic COVID-19 outbreaks.

Objectives: Non-pharmaceutical interventions (NPIs) implemented on China-bound travel have successfully mitigated cross-regional transmission of COVID-19 but made the country face ripple effects. Thus, adjusting these interventions to reduce interruptions to individuals' daily life while minimizing transmission risk was urgent. Methods: An improved Susceptible-Infected-Recovered (SIR) model was built to evaluate the Delta variant's epidemiological characteristics and the impact of NPIs. To explore the risk associated with inbound travelers and the occurrence of domestic traceable outbreaks, we developed an association parameter that combined inbound traveler counts with a time-varying initial value. In addition, multiple time-varying functions were used to model changes in the implementation of NPIs. Related parameters of functions were run by the MCSS method with 1,000 iterations to derive the probability distribution. Initial values, estimated parameters, and corresponding 95% CI were obtained. Reported existing symptomatic, suspected, and asymptomatic case counts were used as the training datasets. Reported cumulative recovered individual data were used to verify the reliability of relevant parameters. Lastly, we used the value of the ratio (Bias2/Variance) to verify the stability of the mathematical model, and the effects of the NPIs on the infected cases to analyze the sensitivity of input parameters. Results: The quantitative findings indicated that this improved model was highly compatible with publicly reported data collected from July 21 to August 30, 2021. The number of inbound travelers was associated with the occurrence of domestic outbreaks. A proportional relationship between the Delta variant incubation period and PCR test validity period was found. The model also predicted that restoration of pre-pandemic travel schedules while adhering to NPIs requirements would cause shortages in health resources. The maximum demand for hospital beds would reach 25,000/day, the volume of PCR tests would be 8,000/day, and the number of isolation rooms would reach 800,000/day within 30 days. Conclusion: With the pandemic approaching the end, reexamining it carefully helps better address future outbreaks. This predictive model has provided scientific evidence for NPIs' effectiveness and quantifiable evidence of health resource allocation. It could guide the design of future epidemic prevention and control policies, and provide strategic recommendations on scarce health resource allocation.

Quantitative analysis of adipose tissue for predicting Crohn's disease postoperative endoscopic recurrence and anastomotic ulcer.

OBJECTIVE: Inflammation and ulcers at the anastomotic site are frequently observed after intestinal resection surgery for Crohn's disease (CD), which often signify postoperative recurrence. Crohn's disease causes abnormalities in whole-body fat metabolism, and alterations in subcutaneous and visceral fat are potential indicators of disease development. This study aimed to quantify the areas of subcutaneous (SFA) and visceral fat (VFA) and investigate the relationship between fat tissue and endoscopic recurrence and anastomotic ulceration after Crohn's disease surgery. METHODS: We conducted a retrospective analysis of clinical data from 279 patients diagnosed with Crohn's disease. Using abdominal CT (Computed Tomography) scans at the level of the umbilicus, we measured the area of subcutaneous and visceral fat, and calculated the Mesenteric Fat Index (MFI), which is defined as the ratio of the area of visceral fat to subcutaneous fat. We compared the changes in fat tissue between surgical Crohn's disease patients and non-surgical patients in remission, as well as changes in fat tissue before and after surgery, and between patients with and without endoscopic recurrence after surgery. RESULTS: The MFI value of the surgical group was higher than that of the non-surgical group(0.88(1.27 ± 1.26) VS 0.39(0.44 ± 0.21), P < 0.001), while the SFA value was lower(70.16(92.97 ± 78.23) VS 157.64(175.96 ± 101.58), P < 0.001). Of the 134 surgical patients who underwent abdominal CT examination after surgery, the SFA value was significantly higher after surgery(143.61 ± 81.86 VS 90.87 ± 71.93, P < 0.001), and the MFI value decreased accordingly(0.57 ± 0.36 VS 1.30 ± 1.35, P < 0.001). Multivariate Cox analysis indicated that high VFA and MFI values, smoking history, and preoperative biologic therapy were all risk factors for postoperative endoscopic recurrence(p < 0.05), while high MFI values and preoperative biologic therapy were also risk factors for anastomotic ulcers(p < 0.05). The Kaplan-Meier analysis showed that these factors increased the risk of reaching the endpoint with time(p < 0.05). The ROC curve results showed that MFI value had high diagnostic value for postoperative endoscopic recurrence [AUC:0.831, 95% CI: 0.75-0.91, p < 0.001] and anastomotic ulcers [AUC:0.801, 95% CI: 0.71-0.89, p < 0.001]. CONCLUSIONS: Surgical CD patients have significantly higher MFI values but the values decline after surgery. When the preoperative MFI value is > 0.82, the risk of postoperative endoscopic recurrence increases significantly, and when the MFI value is ≥ 1.10, the risk of anastomotic ulceration after surgery increases significantly. Meanwhile, biologic therapy preoperatively also is a high-risk factor for early postoperative endoscopic recurrence or anastomotic ulcers after intestinal resection surgery.

Oleoylethanolamide Protects against Acute Ischemic Stroke by Promoting PPARα-Mediated Microglia/Macrophage M2 Polarization.

Oleoylethanolamide (OEA) has been demonstrated to be a feasible protectant in ischemic stroke. However, the mechanism for OEA-afforded neuroprotection remains elusive. The present study aimed to investigate the neuroprotective effects of OEA on peroxisome proliferator-activated receptor α (PPARα)-mediated microglia M2 polarization after cerebral ischemia. Transient middle cerebral artery occlusion (tMCAO) was induced for 1 h in wild-type (WT) or PPARα-knock-out (KO) mice. Mouse small glioma cells (BV2) microglia and primary microglia cultures were used to evaluate the direct effect of OEA on microglia. A coculture system was used to further elucidate the effect of OEA on microglial polarization and ischemic neurons' fate. OEA promoted the microglia switch from an inflammatory M1 phenotype to the protective M2 phenotype and enhanced the binding of PPARα with the arginase1 (Arg1) and Ym1 promoter in WT mice but not in KO mice after MCAO. Notably, the increased M2 microglia caused by OEA treatment were strongly linked to neuron survival after ischemic stroke. In vitro studies confirmed that OEA shifted BV2 microglia from (lipopolysaccharide) LPS-induced M1-like to M2-like phenotype through PPARα. Additionally, the activation of PPARα in primary microglia by OEA led to an M2 protective phenotype that enhanced neuronal survival against oxygen-glucose deprivation (OGD) in the coculture systems. Our findings demonstrate the novel effects of OEA in enhancing microglia M2 polarization to protect neighboring neurons by activating the PPARα signal, which is a new mechanism of OEA against cerebral ischemic injury. Therefore, OEA might be a promising therapeutic drug for stroke and targeting PPARα-mediated M2 microglia may represent a new strategy to treat ischemic stroke.

Combination of NIR spectroscopy and algorithms for rapid differentiation between one-year and two-year stored rice.

Storage is necessary for rice to ensure the year-round consumption of rice. With the increase in storage time, the taste quality and commercial value of rice gradually decrease. The accurate determination of the freshness of rice is critical to the rice trade. However, it is difficult to distinguish aging rice from fresh rice, so a quick and simple method is needed to identify the freshness of the rice. In this study, a combination of near-infrared spectroscopy (NIR) and various algorithms, such as partial least squares discriminant analysis (PLS-DA), support vector machines (SVM), and classification and regression trees (CART), were used to differentiate the freshness of rice. PLS-DA and SVM demonstrated excellent classification ability in identifying the freshness of rice, with sensitivity and specificity of 1. The original spectra were used with 100% accuracy in the test set to determine the freshness of the rice. As a result, PLS-DA and SVM can be used to determine the freshness of the rice.

Increased hsa-miR-100-5p Expression Improves Hepatocellular Carcinoma Prognosis in the Asian Population with PLK1 Variant rs27770A>G.

Hepatocellular carcinoma (HCC) has the highest incidence and mortality in the Asian population, and race is an independent risk factor affecting survival time in liver cancer. Micro RNAs (miRNAs) are remarkably dysregulated in HCC and closely associated with HCC prognosis. Recent studies show that genetic variability between ethnic groups may result in differences in the specificity of HCC miRNA biomarkers. Here, we reveal a high expression level of hsa-miR-100-5p, an HCC prognosis-related miRNA, which improves HCC prognosis in the Asian Population with Polo-like kinase 1 (PLK1) variant rs27770A>G. In this study, we discovered that hsa-miR-100-5p was downregulated in various HCC cell lines. While mimics transient transfection and mouse liver cancer model confirmed the interaction between hsa-miR-100-5p and PLK1, a stratified analysis based on the Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) data suggest both low hsa-miR-100-5p expression level and high PLK1 expression level associated with poor HCC prognosis, especially in the Asian population. According to the 1000 Genomes Project database, the SNP rs27770 located in 3'UTR of PLK1 had a significantly higher G allele frequency in the East Asian population. Bioinformatics analysis suggested that rs27770 A>G affects PLK1 mRNA secondary structure and alters the hsa-miR-100-5p/PLK1 interaction by forming an additional seedless binding site. This racial variation caused PLK1 to be more vulnerable to hsa-miR-100-5p inhibition, resulting in hsa-miR-100-5p being more favorable for HCC prognosis in the Asian population.

Vasorin Deletion in C57BL/6J Mice Induces Hepatocyte Autophagy through Glycogen-Mediated mTOR Regulation.

Abnormal vasorin (Vasn) expression occurs in multiple diseases, particularly liver cancers. Vasn knockout (KO) in mice causes malnutrition, a shortened life span, and decreased physiological functions. However, the causes and underlying mechanisms remain unknown. Here, we established Vasn KO C57BL/6J mice by using the CRISPR/Cas9 system. The animals were weighed, and histology, immunohistochemistry, electronic microscopy, and liver function tests were used to examine any change in the livers. Autophagy markers were detected by Western blotting. MicroRNA (miRNA) sequencing was performed on liver samples and analyses to study the signaling pathway altered by Vasn KO. Significant reductions in mice body and liver weight, accompanied by abnormal liver function, liver injury, and reduced glycogen accumulation in hepatocytes, were observed in the Vasn KO mice. The deficiency of Vasn also significantly increased the number of autophagosomes and the expression of LC3A/B-II/I but decreased SQSTM1/p62 levels in hepatocytes, suggesting aberrant activation of autophagy. Vasn deficiency inhibited glycogen-mediated mammalian target of rapamycin (mTOR) phosphorylation and activated Unc-51-like kinase 1 (ULK1) signaling, suggesting that Vasn deletion upregulates hepatocyte autophagy through the mTOR-ULK1 signaling pathway as a possible cause of diminished life span and health. Our results indicate that Vasn is required for the homeostasis of liver glycogen metabolism upstream of hepatocyte autophagy, suggesting research values for regulating Vasn in pathways related to liver physiology and functions. Overall, this study provides new insight into the role of Vasn in liver functionality.

Surgical strategies for intestinal Crohn's disease. / è‚ é“å ‹ç½—æ©ç— çš„å¤–ç§‘æ²»ç–—ç­–ç•¥.

OBJECTIVES: As a type of inflammatory bowel disease, Crohn's disease (CD) is characterized by jumping lesions and transmural inflammation. The treatment goal is to control the development of inflammation with drugs such as 5-Amino Salicylic Acid, azathioprine and hormones, but most patients still need surgical treatment eventually. The surgical treatment of CD requires exquisite surgical design and solid surgical procedures to minimize the progression of intestinal lesions and preserve the normal bowel segment as much as possible. This study aims to summarize and discuss the surgical treatments for intestinal CD, and to provide references for the surgical treatment of intestinal CD. METHODS: Clinical data of 122 patients with CD were analyzed retrospectively. They all received surgical treatments in the Second Xiangya Hospital of Central South University between Jan. 1, 2015 and Jan. 1, 2021. The data included general information, clinical manifestations, preoperative examination, preoperative preparation, surgical methods, pathological examination, complications, and follow-up data. RESULTS: Except 1 case of emergency surgery, all the other patients met the surgical indications of intestinal CD after multi-disciplinary discussion (MDT) and they were transferred to surgery for elective surgery, and received high-quality intestinal preparation before surgery. Among them, 99 cases underwent one-stage abdominal operation and 23 cases underwent the second abdominal operation. All patients underwent successful surgery with good surgical results, with significantly alleviated clinical symptoms and the BMI significantly increased compared with those before surgery. There were 14 cases (11.5%) of postoperative complications. One case of delayed anastomotic fistula and one case of small intestinal cutaneous fistula which were successfully treated by conservative treatment, the other 12 cases were successfully treated by reoperation, and there were no complications with follow-up operation. The postoperative pathological diagnosis for all patients was clear. All patients received regular follow-up with 5-70 (median 36) months and no clinical recurrence was found. CONCLUSIONS: As the surgical treatment of intestinal CD, surgeons should strictly grasp the surgical indications based on the MDT. During the operation of small intestinal CD, it is advisable to preserve bowel segment as much as possible. For patients with short remaining normal bowel segment, the intestinal canal should be preserved as far as possible, even for the mildly diseased bowel, so as to avoid the occurrence of short bowel syndrome and leave room for possible reoperation. In the treatment of secondary duodenal CD, it is necessary to carefully identify the nature of the local lesions. Different surgical treatments should be performed according to whether there is an internal fistula and the size of this fistula. Meanwhile, duodenectomy or pancreaticoduodenectomy should be considered as the final surgical method in the treatment of primary duodenal CD.

Vasorin contributes to lung injury via FABP4-mediated inflammation.

BACKGROUND: Lung injury caused by pulmonary inflammation is one of the main manifestations of respiratory diseases. Vasorin (VASN) is a cell-surface glycoprotein encoded by the VASN gene and is expressed in the lungs of developing mouse foetuses. Previous research has revealed that VASN is associated with many diseases. However, its exact function in the lungs and the underlying mechanism remain poorly understood. METHODS AND RESULTS: To investigate the molecular mechanisms involved in lung disease caused by VASN deficiency, a VASN gene knockout (VASN-/-) model was established. The pathological changes in the lungs of VASN-/- mice were similar to those in a lung injury experimental mouse model. We further analysed the transcriptomes of the lungs of VASN-/- mice and wild-type mice. Genes in twenty-four signalling pathways were enriched in the lungs of VASN-/- mice, among which PPAR signalling pathway genes (3 genes, FABP4, Plin1, AdipoQ, were upregulated, while apoA5 was downregulated) were found to be closely related to lung injury. The most significantly changed lung injury-related gene, FABP4, was selected for further verification. The mRNA and protein levels of FABP4 were significantly increased in the lungs of VASN-/- mice, as were the mRNA and protein levels of the inflammatory factors IL-6, TNF-α and IL-1ß. CONCLUSIONS: We believe that these data provide molecular evidence for the regulatory role of VASN in inflammation in the context of lung injury.

MicroRNA-200c-5p targets NIMA Related Kinase 7 (NEK7) to inhibit NOD-like receptor 3 (NLRP3) inflammasome activation, MODE-K cell pyroptosis, and inflammatory bowel disease in mice.

Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is characterized by chronic inflammation of the lower gastrointestinal tract with unknown etiology. In our previous study, NOD-like receptor 3 (NLRP3) inflammasome activation requiring the interaction of NLRP3 with NIMA Related Kinase 7 (NEK7) had been reported to regulate MODE-K cell pyroptosis and dextran sulfate sodium (DSS)-induced murine colitis. In the present study, miR-200c was closely related to IBD using weighted gene correlation network analysis (WGCNA). MicroRNA-200c (miR-200c) expression was down-regulated in IBD samples and negatively correlated with NLRP3. In MODE-K cells, miR-200c overexpression inhibited cellular inflammation; under adenosine triphosphate (ATP) and lipopolysaccharides (LPS) co-stimulation, miR-200c overexpression attenuated ATP and LPS-induced cell pyroptosis. In the DSS-induced IBD mice model, miR-200c overexpression alleviated DSS-induced IBD symptoms and improved physiological and biochemical indexes. Through direct targeting, miR-200c inhibited NEK7 expression. In MODE-K cells, NEK7 overexpression promoted cellular inflammation and ATP and LPS-induced cell pyroptosis; when co-transduced into MODE-K cells, NEK7 overexpression partially attenuated miR-200c agomir effects on cellular inflammation and ATP and LPS-induced cell pyroptosis. In conclusion, miR-200c, through targeting NEK7, could decrease cellular inflammation levels and NLRP3 inflammasome-related MODE-K cell pyroptosis in vitro and improve DSS-induced murine IBD symptoms in vivo.

Cinnamic Acid Improved Lipopolysaccharide-Induced Depressive-Like Behaviors by Inhibiting Neuroinflammation and Oxidative Stress in Mice.

AIM: Recent evidence indicates that neuroinflammation and oxidative stress play vital roles in the pathological process of major depressive disorder (MDD). Cinnamic acid (CA), a naturally occurring organic acid, has been reported to ameliorate neuroinflammation and oxidative stress for treatment of diabetes-related memory deficits. Here, we explored whether CA pretreatment ameliorated lipopolysaccharide (LPS)-induced depressive-like behaviors in mice by suppressing neuroinflammation and by improving oxidative stress status. METHODS: The mice were treated with CA, vehicle, or fluoxetine as a positive control. After 14 days, LPS (1 mg/kg, i.p.) or saline was administered. The depression-like behaviors were examined by the sucrose preference test (SPT), the forced swimming test (FST), and the tail suspension test (TST). Furthermore, the levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA), and brain-derived neurotrophic factor (BDNF) in the hippocampus and cortex of mice were assayed. RESULTS: Our results demonstrated that CA pretreatment at the doses of 100 and 200 mg/kg significantly attenuated depressive-like behaviors in the TST, FST, and SPT. In addition, not only the upregulation of pro-inflammatory cytokines (IL-6 and TNF-α) but also oxidative stress parameters including SOD, GSH, and MDA in the hippocampus and cortex of mice treated with LPS were dramatically improved by CA pretreatment. Finally, CA pretreatment strikingly ameliorated the downregulation of BDNF induced by LPS in the hippocampus and cortex of mice. CONCLUSION: Our results indicated that CA may have therapeutic potential for MDD treatment through attenuating the LPS-induced inflammation and oxidative stress along with significant improvement of BDNF impairment.