Chronic constipation and gut microbiota: current research insights and therapeutic implications.

Chronic constipation is a prevalent clinical condition. Its etiology and pathogenesis have not yet been fully understood. In recent years, mounting evidence suggests a close association between chronic constipation and intestinal dysbiosis, including alterations in the colony structure and metabolites, as well as the modulation of bowel movements via the brain-gut-microbiota axis. With the deepening of related research, probiotic-related therapies are expected to become a potential first-line treatment for chronic constipation in the future. In this review, we summarize the current research insights into the intricate relationships between chronic constipation and the gut microbiota and briefly discuss several different approaches for treating chronic constipation. The findings from this review may advance our understanding of the pathological mechanisms underlying chronic constipation and, ultimately, translate them into improvements in patient care.

Cathepsin S (CTSS) in IgA nephropathy: an exploratory study on its role as a potential diagnostic biomarker and therapeutic target.

Introduction: IgA nephropathy (IgAN), a prevalent form of glomerulonephritis globally, exhibits complex pathogenesis. Cathepsins, cysteine proteases within lysosomes, are implicated in various physiological and pathological processes, including renal conditions. Prior observational studies have suggested a potential link between cathepsins and IgAN, yet the precise causal relationship remains unclear. Methods: We conducted a comprehensive bidirectional and multivariable Mendelian randomization (MR) study using publicly available genetic data to explore the causal association between cathepsins and IgAN systematically. Additionally, immunohistochemical (IHC) staining and enzyme-linked immunosorbent assay (ELISA) were employed to evaluate cathepsin expression levels in renal tissues and serum of IgAN patients. We investigated the underlying mechanisms via gene set variation analysis (GSVA), gene set enrichment analysis (GSEA), and immune cell infiltration analysis. Molecular docking and virtual screening were also performed to identify potential drug candidates through drug repositioning. Results: Univariate MR analyses demonstrated a significant link between increased cathepsin S (CTSS) levels and a heightened risk of IgAN. This was evidenced by an odds ratio (OR) of 1.041 (95% CI=1.009-1.073, P=0.012) as estimated using the inverse variance weighting (IVW) method. In multivariable MR analysis, even after adjusting for other cathepsins, elevated CTSS levels continued to show a strong correlation with an increased risk of IgAN (IVW P=0.020, OR=1.037, 95% CI=1.006-1.069). However, reverse MR analyses did not establish a causal relationship between IgAN and various cathepsins. IHC and ELISA findings revealed significant overexpression of CTSS in both renal tissues and serum of IgAN patients compared to controls, and this high expression was unique to IgAN compared with several other primary kidney diseases such as membranous nephropathy, minimal change disease and focal segmental glomerulosclerosis. Investigations into immune cell infiltration, GSEA, and GSVA highlighted the role of CTSS expression in the immune dysregulation observed in IgAN. Molecular docking and virtual screening pinpointed Camostat mesylate, c-Kit-IN-1, and Mocetinostat as the top drug candidates for targeting CTSS. Conclusion: Elevated CTSS levels are associated with an increased risk of IgAN, and this enzyme is notably overexpressed in IgAN patients' serum and renal tissues. CTSS could potentially act as a diagnostic biomarker, providing new avenues for diagnosing and treating IgAN.

The Intestinal Microbiota Composition in Early and Late Stages of Diabetic Kidney Disease.

Many studies have suggested that gut microbiota dysbiosis may be one of the pathogenesis factors of diabetes mellitus (DM), while it is not clear whether it is involved in the development of diabetic kidney diseases (DKD). The objective of this study was to determine bacterial taxa biomarkers during the progression of DKD by investigating bacterial compositional changes in early and late DKD. 16S rRNA gene sequencing was performed on fecal samples, including the diabetes mellitus (DM), DNa (early DKD), and DNb (late DKD) groups. Taxonomic annotation of microbial composition was performed. Samples were sequenced on the Illumina NovaSeq platform. At the genus level, we found counts of Fusobacterium, Parabacteroides, and Ruminococcus_gnavus were significantly elevated both in the DNa group (P = 0.0001, 0.0007, and 0.0174, respectively) and the DNb group (P < 0.0001, 0.0012, and 0.0003, respectively) compared with those in the DM group. Only the level of Agathobacter was significantly decreased in the DNa group than the DM group and in the DNb group than the DNa group. Counts of Prevotella_9, Roseburia were significantly decreased in the DNa group compared with those in the DM group (P = 0.001 and 0.006, respectively) and in the DNb group compared with those in the DM group (P < 0.0001 and 0.003, respectively). Levels of Agathobacter, Prevotella_9, Lachnospira, and Roseburia were positively correlated with an estimated glomerular filtration rate (eGFR), but negatively correlated with microalbuminuria (MAU), 24 h urinary protein quantity (24hUP), and serum creatinine (Scr). Moreover, the areas under the curve (AUCs) of Agathobacter and Fusobacteria were 83.33% and 80.77%, respectively, for the DM and DNa cohorts, respectively. Notably, the largest AUC for DNa and DNb cohorts was also that of Agathobacter at 83.60%. Gut microbiota dysbiosis was found in the early and late stages of DKD, especially in the early stage. Agathobacter may be the most promising intestinal bacteria biomarker that can help distinguish different stages of DKD. IMPORTANCE It is not clear as to whether gut microbiota dysbiosis is involved in the progression of DKD. This study may be the first to explore gut microbiota compositional changes in diabetes, early-DKD, and late DKD. We identify different gut microbial characteristics during different stages of DKD. Gut microbiota dysbiosis is found in the early and late stages of DKD. Agathobacter may be the most promising intestinal bacteria biomarker that can help distinguish different stages of DKD, although further studies are warranted to illustrate these mechanisms.

Rhizosphere-associated soil microbiome variability in Verticillium wilt-affected Cotinus coggygria.

Introduction: Verticillium wilt is the most devastating soil-borne disease affecting Cotinus coggygria in the progress of urban landscape construction in China. Methods: To assess the variability of the rhizosphere-associated soil microbiome in response to Verticillium wilt occurrence, we investigated the microbial diversity, taxonomic composition, biomarker species, and co-occurrence network of the rhizosphere-associated soil in Verticillium wilt-affected C. coggygria using Illumina sequencing. Results: The alpha diversity indices of the rhizosphere bacteria in Verticillium wilt-affected plants showed no significant variability compared with those in healthy plants, except for a moderate increase in the Shannon and Invsimpson indices, while the fungal alpha diversity indices were significantly decreased. The abundance of certain dominant or crucial microbial taxa, such as Arthrobacter, Bacillus, Streptomyces, and Trichoderma, displayed significant variations among different soil samples. The bacterial and fungal community structures exhibited distinct variability, as evidenced by the Bray-Curtis dissimilarity matrices. Co-occurrence networks unveiled intricate interactions within the microbial community of Verticillium wilt-affected C. coggygria, with greater edge numbers and higher network density. The phenomenon was more evident in the fungal community, showing increased positive interaction, which may be associated with the aggravation of Verticillium wilt with the aid of Fusarium. The proportions of bacteria involved in membrane transport and second metabolite biosynthesis functions were significantly enriched in the diseased rhizosphere soil samples. Discussion: These findings suggested that healthy C. coggygria harbored an obviously higher abundance of beneficial microbial consortia, such as Bacillus, while Verticillium wilt-affected plants may recruit antagonistic members such as Streptomyces in response to Verticillium dahliae infection. This study provides a theoretical basis for understanding the soil micro-ecological mechanism of Verticillium wilt occurrence, which may be helpful in the prevention and control of the disease in C. coggygria from the microbiome perspective.

Solitary splenic tuberculosis: A case report.

BACKGROUND: Solitary splenic tuberculosis (TB) is unusual and rarely reported. Whether splenic TB is best treated surgically is still controversial. We describe a 73-year-old man with solitary splenic TB and no extrapulmonary TB. CASE SUMMARY: We report the case of a 73-year-old man with solitary splenic TB who complained of emaciation and fatigue. Abdominal computed tomography (CT) images suggested a splenic space-occupying lesion. We then performed a CT-guided splenic biopsy. The postoperative pathological examination revealed splenic TB. The patient took quadruple anti-TB medication. After 1 year, the patient recovered his normal weight and had no feeling of fatigue, and the splenic lesion had shrunk significantly. CONCLUSION: If patients receive combined, appropriate, regular, full-time anti-TB treatment, solitary splenic TB may be cured.

Identification of diagnostic gene biomarkers and immune infiltration in patients with diabetic kidney disease using machine learning strategies and bioinformatic analysis.

Objective: Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease and end-stage renal disease worldwide. Early diagnosis is critical to prevent its progression. The aim of this study was to identify potential diagnostic biomarkers for DKD, illustrate the biological processes related to the biomarkers and investigate the relationship between them and immune cell infiltration. Materials and methods: Gene expression profiles (GSE30528, GSE96804, and GSE99339) for samples obtained from DKD and controls were downloaded from the Gene Expression Omnibus database as a training set, and the gene expression profiles (GSE47185 and GSE30122) were downloaded as a validation set. Differentially expressed genes (DEGs) were identified using the training set, and functional correlation analyses were performed. The least absolute shrinkage and selection operator (LASSO), support vector machine-recursive feature elimination (SVM-RFE), and random forests (RF) were performed to identify potential diagnostic biomarkers. To evaluate the diagnostic efficacy of these potential biomarkers, receiver operating characteristic (ROC) curves were plotted separately for the training and validation sets, and immunohistochemical (IHC) staining for biomarkers was performed in the DKD and control kidney tissues. In addition, the CIBERSORT, XCELL and TIMER algorithms were employed to assess the infiltration of immune cells in DKD, and the relationships between the biomarkers and infiltrating immune cells were also investigated. Results: A total of 95 DEGs were identified. Using three machine learning algorithms, DUSP1 and PRKAR2B were identified as potential biomarker genes for the diagnosis of DKD. The diagnostic efficacy of DUSP1 and PRKAR2B was assessed using the areas under the curves in the ROC analysis of the training set (0.945 and 0.932, respectively) and validation set (0.789 and 0.709, respectively). IHC staining suggested that the expression levels of DUSP1 and PRKAR2B were significantly lower in DKD patients compared to normal. Immune cell infiltration analysis showed that B memory cells, gamma delta T cells, macrophages, and neutrophils may be involved in the development of DKD. Furthermore, both of the candidate genes are associated with these immune cell subtypes to varying extents. Conclusion: DUSP1 and PRKAR2B are potential diagnostic markers of DKD, and they are closely associated with immune cell infiltration.

Efficacy, safety and pharmacokinetics of recombinant human coagulation factor VIII (omfiloctocog alfa) in previously treated Chinese children with severe hemophilia A.

INTRODUCTION: Omfiloctocog alfa, the first China-developed recombinant factor VIII (FVIII), demonstrated efficacy and safety of prophylaxis in previously treated patients (PTPs) aged ≥12 years with severe hemophilia A in China. AIMS: To investigate efficacy, safety and pharmacokinetics (PK) of omfiloctocog alfa in pediatric PTPs with severe hemophilia A in China. METHODS: PTPs (>50 exposure days [ED] for Chinese patients aged <6 years; >150 EDs for patients aged 6-12 years) were treated with omfiloctocog alfa at 25-50 IU/kg every other day or three times per week for 24 weeks. PK was evaluated after single injection of 50 IU/kg. The primary efficacy endpoint was annualized bleeding rate (ABR). RESULTS: A total of 69 patients were enrolled (<6 years, n = 35; 6-12 years, n = 34) and mean exposure to omfiloctocog alfa was 78.9 days. Mean half-life was 6.7 and 10.2 h in children < 6 years and 6-12 years, respectively. Estimated mean ABRs of all patients were 4.05 for overall bleeding episodes and 1.38 for spontaneous bleeding episodes. Of 127 bleeding episodes, the success rate was 92.1%. 39.7% patients did not experience any bleeding episodes and the mean weekly dose of FVIII was 109.1 IU/kg for these patients. 83% bleeding episodes were controlled with ≤2 injections. Adverse reactions occurred in 2.9% of the patients. One 2-year-old patient developed inhibitors after 12 EDs and it resolved with omfiloctocog alfa immune tolerance induction. CONCLUSION: Omfiloctocog alfa was efficacious and well tolerated for the prevention and treatment of bleeding in Chinese pediatric PTPs with severe hemophilia A.

Retraction Notice to: ANXA3 Silencing Ameliorates Intracranial Aneurysm via Inhibition of the JNK Signaling Pathway.

[This retracts the article DOI: 10.1016/j.omtn.2019.06.005.].

Study on Influencing Factors and Countermeasures of Elderly Nursing Services in the Elderly.

Methods: 500 inpatients with chronic diseases in a famous tertiary hospital in a city were studied, and the corresponding countermeasures were put forward through the analysis of their needs and influencing factors. Results. The study found that the vast majority of elderly patients have higher requirements for elderly care services, which is related to factors such as family income. Compared with the huge medical demand, there is a large gap in the level of domestic medical and health talents. According to relevant research, the current number of beds in China is 1 : 0.27, but in fact it is 1 : 0.4. Therefore, relevant units should strengthen the health examination of the elderly, provide high-quality medical services, make full use of health resources, and strengthen nursing management, so as to improve the quality of nursing services. Conclusion: The survey results show that the vast majority of elderly patients have high requirements for their elderly care services, which is related to family income and other related factors. Therefore, relevant departments should formulate corresponding measures to improve the quality of life of the elderly.

Phase transition and remodeling complex assembly are important for SS18-SSX oncogenic activity in synovial sarcomas.

Oncoprotein SS18-SSX is a hallmark of synovial sarcomas. However, as a part of the SS18-SSX fusion protein, SS18's function remains unclear. Here, we depict the structures of both human SS18/BRG1 and yeast SNF11/SNF2 subcomplexes. Both subcomplexes assemble into heterodimers that share a similar conformation, suggesting that SNF11 might be a homologue of SS18 in chromatin remodeling complexes. Importantly, our study shows that the self-association of the intrinsically disordered region, QPGY domain, leads to liquid-liquid phase separation (LLPS) of SS18 or SS18-SSX and the subsequent recruitment of BRG1 into phase-separated condensates. Moreover, our results show that the tyrosine residues in the QPGY domain play a decisive role in the LLPS of SS18 or SS18-SSX. Perturbations of either SS18-SSX LLPS or SS18-SSX's binding to BRG1 impair NIH3T3 cell transformation by SS18-SSX. Our data demonstrate that both LLPS and assembling into chromatin remodelers contribute to the oncogenic activity of SS18-SSX in synovial sarcomas.

Overexpression of FOXD2-AS1 enhances proliferation and impairs differentiation of glioma stem cells by activating the NOTCH pathway via TAF-1.

Emerging data have highlighted the importance of long noncoding RNAs (lncRNAs) in exerting critical biological functions and roles in different forms of brain cancer, including gliomas. In this study, we sought to investigate the role of lncRNA FOXD2 adjacent opposite strand RNA 1 (FOXD2-AS1) in glioma cells. First, we used sphere formation assay and flow cytometry to select U251 glioma stem cells (GSCs). Then, we quantified the expression of lncRNA FOXD2-AS1, TATA-box binding protein associated factor 1 (TAF-1) and NOTCH1 in glioma tissues and GSCs, as well as the expression of GSC stem markers, OCT4, SOX2, Nanog, Nestin and CD133 in GSCs. Colony formation assay, sphere formation assay, and flow cytometry were used to evaluate GSC stemness. Next, the correlations among lncRNA FOXD2-AS1, TAF-1 and NOTCH1 were investigated. LncRNA FOXD2-AS1, TAF-1 and NOTCH1 were found to be elevated in glioma tissues and GSCs, and silencing lncRNA FOXD2-AS1 inhibited stemness and proliferation, while promoting apoptosis and differentiation of GSCs. LncRNA FOXD2-AS1 overexpression also led to increased NOTCH1 by recruiting TAF-1 to the NOTCH1 promoter region, thereby promoting stemness and proliferation, while impairing cell apoptosis and differentiation. Mechanistically, lncRNA FOXD2-AS1 elevation promoted glioma in vivo by activating the NOTCH signalling pathway via TAF-1 upregulation. Taken together, the key findings of our investigation support the proposition that downregulation of lncRNA FOXD2-AS1 presents a viable and novel molecular candidate for improving glioma treatment.

Role and Mechanism of lncRNA-pvt1 in the Pathogenesis of Acute Lymphoblastic Leukemia in Children.

Objective: To investigate the role and mechanism of lncRNA-pvt1 in the pathogenesis of childhood acute lymphoblastic leukemia (ALL). Methods: The expression of lncRNA-pvt1 in bone marrow tissues of ALL patients after initial diagnosis and complete remission was detected by RT-PCR to explore its possible involvement in the pathogenesis of ALL. The proliferation and apoptosis of Jurkat cells transfected with lncRNA-pvt1 were observed by MTT and flow cytometry. Results: lncRNA-pvt1 expression was upregulated in bone marrow of ALL patients. Knockdown of lncRNA-pvt1 inhibited Jurkat cell proliferation and increased its apoptosis rate. Conclusion: Silencing lncRNA-pvt1 expression can inhibit the development of ALL.

Identification, diagnosis, and early intervention of children with developmental language disorder in Ningxia.

Background: It is reported that the incidence of language development disorder in children at the age of 2 is as high as 17.0%. Timely discovery of the high-risk factors of language development disorder in children and early intervention can greatly reduce the incidence of language development disorder and shorten the course and condition of the patients with language development disorder. Therefore, in order to facilitate prompt diagnosis and early interventions for children with language development disorder (DLD) and improve their language ability, this study explored the influence of perinatal factors on the language development of children in Ningxia and identified the unfavorable and favorable factors that influenced language development. Methods: Children diagnosed in the General Hospital of Ningxia Medical University during 2018-2021 who met the screening criteria for DLD and practical pediatric diagnostic criteria for DLD were enrolled in this study. Perinatal factors (gestational age, weight, sex, delivery mode, maternal age, presence of intrauterine infection, asphyxia) were retrospectively analyzed. The perinatal factors affecting language development were assessed using a one-way analysis of variance (ANOVA). Results: Among 1,500 children aged 0-3, 240 cases (16.00%) had language delay. Of these, 122 were male and 118 were female. There were 115 cases of comprehension and expression disorder, 30 cases of articulation disorder, and 90 cases of mixed manifestation. And there were 194 cases with definite intrauterine and perinatal high-risk factors or neonatal diseases, accounting for 80.83% of the total number of children with language delay. Conclusions: In Ningxia, factors in the neonatal period are the main cause of DLD, followed by fetal and maternal factors. Ischemic encephalopathy is the most common factor.

Investigate the genetic mechanisms of diabetic kidney disease complicated with inflammatory bowel disease through data mining and bioinformatic analysis.

Background: Patients with diabetic kidney disease (DKD) often have gastrointestinal dysfunction such as inflammatory bowel disease (IBD). This study aims to investigate the genetic mechanism leading to IBD in DKD patients through data mining and bioinformatics analysis. Methods: The disease-related genes of DKD and IBD were searched from the five databases of OMIM, GeneCards, PharmGkb, TTD, and DrugBank, and the intersection part of the two diseases were taken to obtain the risk genes of DKD complicated with IBD. A protein-protein interaction (PPI) network analysis was performed on risk genes, and three topological parameters of degree, betweenness, and closeness of nodes in the network were used to identify key risk genes. Finally, Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed on the risk genes to explore the related mechanism of DKD merging IBD. Results: This study identified 495 risk genes for DKD complicated with IBD. After constructing a protein-protein interaction network and screening for three times, six key risk genes were obtained, including matrix metalloproteinase 2 (MMP2), hepatocyte growth factor (HGF), fibroblast growth factor 2 (FGF2), interleukin (IL)-18, IL-13, and C-C motif chemokine ligand 5 (CCL5). Based on GO enrichment analysis, we found that DKD genes complicated with IBD were associated with 3,646 biological processes such as inflammatory response regulation, 121 cellular components such as cytoplasmic vesicles, and 276 molecular functions such as G-protein-coupled receptor binding. Based on KEGG enrichment analysis, we found that the risk genes of DKD combined with IBD were associated with 181 pathways, such as the PI3K-Akt signaling pathway, advanced glycation end product-receptor for AGE (AGE-RAGE) signaling pathway and hypoxia-inducible factor (HIF)-1 signaling pathway. Conclusion: There is a genetic mechanism for the complication of IBD in patients with CKD. Oxidative stress, chronic inflammatory response, and immune dysfunction were possible mechanisms for DKD complicated with IBD.

Palmitate induces fat accumulation via repressing FoxO1-mediated ATGL-dependent lipolysis in HepG2 hepatocytes.

Obesity is closely associated with non-alcoholic fatty liver disease (NAFLD), and elevated serum palmitate is the link between obesity and excessive hepatic lipid accumulation. Forkhead box O-1 (FoxO1) is one of the FoxO family members of transcription factors and can stimulate adipose triglyceride lipase (ATGL) and suppress its inhibitor G0/G1 switch gene 2 (G0S2) expression in the liver. However, previous researches have also shown conflicting results regarding the role of FoxO1 in hepatic lipid accumulation. We therefore examined the role of FoxO1 as a downstream suppressor to palmitate-stimulated hepatic steatosis. Palmitate significantly promoted lipid accumulation but inhibited lipid decomposition in human HepG2 hepatoma cells. Palmitate also significantly reduced FoxO1, ATGL and its activator comparative gene identification-58 (CGI-58) expression but increased peroxisome proliferator-activated receptorγ (PPARγ) and its target gene G0S2 expression. FoxO1 overexpression significantly increased palmitate-inhibited ATGL and CGI-58 expression but reduced palmitate-stimulated PPARγ and its target gene G0S2 expression. FoxO1 overexpression also inhibited lipid accumulation and promoted lipolysis in palmitate-treated hepatocytes. Overall, these results indicate that FoxO1-mediated ATGL-dependent lipolysis may be an effective molecular mechanism in protecting hepatocytes from palmitate-induced fat accumulation.

The Role of Circulating RBP4 in the Type 2 Diabetes Patients with Kidney Diseases: A Systematic Review and Meta-Analysis.

BACKGROUND: Diabetic nephropathy is a common and serious complication of diabetes mellitus (DM) and is one of the leading causes of end-stage renal disease worldwide. Although there have been many investigations on biomarkers for DN, there is no consistent conclusion about reliable biomarkers. The purpose of this study was to perform a systematic review and meta-analysis of the role of circulating retinol-binding protein 4 (RBP4) in the type 2 diabetes mellitus (T2DM) patients with kidney diseases. MATERIALS AND METHODS: We searched the PubMed, MEDLINE, EMBASE, and Web of Science databases for publications. For the 12 cross-sectional studies that we included in the review, we calculated standard mean differences (SMD) with 95% confidence intervals (CI) for continuous data when the applied scales were different. Risk of bias of included trials was assessed by using the Newcastle-Ottawa Scale. RESULTS: RBP4 concentrations in the micro-, macro-, or micro+macroalbuminuria groups were significantly higher than those in the normal albuminuria group of T2DM patients [P = 0.001, SMD 1.07, 95% CI (0.41, 1.73)]. The estimated glomerular filtration rate (eGFR) was negatively associated with circulating RBP4 concentrations in patients with T2DM [summary Fisher's Z = -0.48, 95% CI (-0.69, -0.26), P < 0.0001]. The albumin-to-creatinine ratio (ACR) was positively associated with circulating RBP4 concentrations in patients with T2DM [summary Fisher's Z = 0.20, 95% CI (0.08, 0.32), P = 0.001]. CONCLUSION: The levels of circulating RBP4 were significantly higher both in T2DM subjects with micro/macroalbuminuria and in T2DM subjects with declined eGFR. The levels of circulating RBP4 were positively correlated with ACR but negatively correlated with eGFR. Circulating RBP4 could be a reliable biomarker for kidney diseases in T2DM.

Swimming exercise activates aortic autophagy and limits atherosclerosis in ApoE-/- mice.

BACKGROUND: The aim of this study was to investigate the beneficial effect of swimming exercise on autophagy and atherosclerosis in mice aorta, so as to clarify the possible causal relationship between autophagy activation and atherosclerosis. METHODS: The body weight was monitored regularly. Hematoxylin-eosin staining and Oil Red O staining was conducted to observe vascular morphology and plaque burden respectively. The levels of serum total cholesterol (TC), triglyceride (TG), soluble intercellular adhesion molecule-1 (sICAM-1), matrix metalloproteinase-9 (MMP-9) and interleukin-6 (IL-6) was examined via Enzyme-linked immu-nosorbent assays (ELISA). The mRNA expression level of autophagy markers, including LC3 and Beclin-1, was examined by real-time quantitative polymerase chain reaction (RT-PCR). The expressions of LC3-II/LC3-I and Beclin-1 are detected by Western blotting and immunohistochemistry. RESULTS: Compared with the model group, long-term swimming exercise decreased the weight gain of ApoE-/- mice, improved the structural disorder of artery, reduced the load of atherosclerotic lesion, and attenuated the concentrations of serum TC, TG, sICAM-1, MMP-9, and IL-6. In addition, the expression of autophagy markers LC3 and Beclin-1 increased significantly at the mRNA and protein levels. CONCLUSION: Long-term swimming exercise could activate the autophagy and reduce atherosclerotic lesion in the aorta of ApoE-/- mice. Autophagy activation may be one of the mechanisms by which atherosclerosis is improved through exercise.

The Role of Akt2 in the Protective Effect of Fenofibrate against Diabetic Nephropathy.

Fenofibrate (FF) protects against diabetic nephropathy (DN) in type 1 diabetic (T1D) mice by upregulating the expression of fibroblast growth factor 21 (FGF21), leading to the activation of the Akt-mediated Nrf2 antioxidant pathways. Here, we examined which isoforms of Akt contribute to FF activation of FGF21-mediated renal protection by examining the phosphorylation and expression of three isoforms, Akt1, Akt2, and Akt3. T1D induced by a single intraperitoneal dose of streptozotocin (STZ) resulted in reduced phosphorylation of one isoform, Akt2, but FF treatment increased renal Akt2 phosphorylation in these and normal mice, suggesting a potential and specific role for renal Akt2 in FF protection against T1D. This was further confirmed using in vitro cultured HK-2 human kidney tubule cells exposed to high glucose (HG) with siRNA silencing of the Akt2 gene and STZ-induced diabetic Akt2-knockout mice with and without 3-month FF treatment. In normal HK-2 cells exposed to HG for 24 hours, FF completely prevented cell death, reduced total Akt expression and glycogen synthase kinase (GSK)-3ß phosphorylation, increased nuclear accumulation of Fyn, and reduced nuclear Nrf2 levels. These positive effects of FF were partially abolished by silencing Akt2 expression. Similarly, FF abolished T1D-induced renal oxidative stress, inflammation, and renal dysfunction in wild-type mice, but was only partially effective in Akt2-KO mice. Furthermore, FF treatment stimulated phosphorylation of AMPKα, an important lipid metabolism mediator, which in parallel with Akt2 plays an important role in FF protection against HG-induced HK-2 cells oxidative stress and damage. These results suggest that FF protects against DN through FGF21 to activate both Akt2/GSK-3ß/Fyn/Nrf2 antioxidants and the AMPK pathway. Therefore, FF could be repurposed for the prevention of DN in T1D patients.