Lipotoxicity induces cardiomyocyte ferroptosis via activating the STING pathway.

Objective Lipotoxicity is a well-established contributor to cardiomyocyte death and heart damage, with ferroptosis being identified as a crucial death mode in cardiomyocyte disease. This study aims to explore the potential role and mechanism of ferroptosis in lipotoxicity-induced myocardial injury. Methods Eight-weeks high-fat diet (HFD) SD rat and H9c2 cardiomyocytes treated with palmitic acid (PA) were established for in vivo and in vitro lipotoxic model. Ferrostatin-1 (Fer-1) and liproxstatin-1 (Lip-1) were used to inhibit ferroptosis. Myocardial-specific STING knockdown rat (Stingmyo-KD) with HFD was further introduced. Rat cardiac structure and function, cell viability, the level of lipid peroxidation, malondialdehyde (MDA), glutathione (GSH), mitochondrial function, ferroptosis related proteins and STING pathway related proteins in H9c2 cells/myocardium were detected. Results HFD rats with ferroptosis inhibitor showed improved cardiac structure and function, reduced lipid peroxidation and restored GSH, which was further confirmed in H9c2 cell. The time-dependent activation of the STING pathway following PA stimulation was observed. Knockdown the expression of STING could reduce PA-induced cell death, lipid peroxidation and MDA levels while restoring the GSH. In addition, both HFD Stingmyo-KD rats and HFD rats with systematic inhibited by STING inhibitor exhibited mitigating lipotoxicity-induced myocardial ferroptosis and reducing myocardial injury. Innovation and conclusion These findings suggest that lipotoxicity can induce ferroptosis in cardiomyocytes through the activation of the STING pathway, providing new targets, and strategies for the treatment of lipotoxicity cardiomyopathy.

Association between radical versus conservative surgery and short-term outcomes of hepatic cystic echinococcosis in Nyingchi, China: a retrospective cohort study.

BACKGROUND: Radical or conservative surgical treatment for hepatic Cystic Echinococcosis (hepatic CE) is controversial. We aimed to measure the association between radical surgery (RS) versus conservative surgery (CS) and short-term outcomes in our cohort. METHODS: Medical records of hepatic CE patients' demographic, clinical, radiological, operative and postoperative details who underwent surgical treatment between January 3, 2017 and January 3, 2018 at the Department of General Surgery, Nyingchi People's Hospital, Nyingchi, China, were retrieved and analyzed. The primary outcome was overall morbidity. The secondary outcomes included: (i) bile leakage; (ii) complications of lung, pleura, heart, liver, pancreas and biliary tract; (iii) incision infection and residual cavity abscess formation; (iv) anaphylactic reaction and shock; (v) tear of surrounding tissues; (vi) hospital and post-operative length of stay (LOS); (vii) length of surgery; (viii) blood loss during surgery. Multivariable logistic/linear regression models with various adjustment strategies for confounders were performed to evaluate the association. RESULTS: A total of 128 hepatic CE patients were included with 82 (64.1%) and 46 (35.9%) receiving CS and RS, respectively. After fully adjusted, RS was associated with 60% lower risk of overall complication (aOR 0.4; 95%CI, 0.2-0.9) and 0.6-h shorter surgical time (aß 0.4; 95%CI,-0.0-0.8) comparing to CS. However, RS was associated with more blood loss during surgery (aß 179.3; 95%CI, 54.2-304.5). CONCLUSION: To conclude, RS was associated with a 60% reduction in developing overall complication in the short term, but may result in more blood loss during surgery than CS.

Adoptive transfer of Pfkfb3-disrupted hematopoietic cells to wild-type mice exacerbates diet-induced hepatic steatosis and inflammation.

BACKGROUND AND OBJECTIVES: Hepatic steatosis and inflammation are key characteristics of non-alcoholic fatty liver disease (NAFLD). However, whether and how hepatic steatosis and liver inflammation are differentially regulated remains to be elucidated. Considering that disruption of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (Pfkfb3/iPfk2) dissociates fat deposition and inflammation, the present study examined a role for Pfkfb3/iPfk2 in hematopoietic cells in regulating hepatic steatosis and inflammation in mice. METHODS: Pfkfb3-disrupted (Pfkfb3 +/-) mice and wild-type (WT) littermates were fed a high-fat diet (HFD) and examined for NAFLD phenotype. Also, bone marrow cells isolated from Pfkfb3 +/- mice and WT mice were differentiated into macrophages for analysis of macrophage activation status and for bone marrow transplantation (BMT) to generate chimeric (WT/BMT- Pfkfb3 +/-) mice in which Pfkfb3 was disrupted only in hematopoietic cells and control chimeric (WT/BMT-WT) mice. The latter were also fed an HFD and examined for NAFLD phenotype. In vitro, hepatocytes were co-cultured with bone marrow-derived macrophages and examined for hepatocyte fat deposition and proinflammatory responses. RESULTS: After the feeding period, HFD-fed Pfkfb3 +/- mice displayed increased severity of liver inflammation in the absence of hepatic steatosis compared with HFD-fed WT mice. When inflammatory activation was analyzed, Pfkfb3 +/- macrophages revealed increased proinflammatory activation and decreased anti-proinflammatory activation. When NAFLD phenotype was analyzed in the chimeric mice, WT/BMT-Pfkfb3 +/- mice displayed increases in the severity of HFD-induced hepatic steatosis and inflammation compared with WT/BMT-WT mice. At the cellular level, hepatocytes co-cultured with Pfkfb3 +/- macrophages revealed increased fat deposition and proinflammatory responses compared with hepatocytes co-cultured with WT macrophages. CONCLUSIONS: Pfkfb3 disruption only in hematopoietic cells exacerbates HFD-induced hepatic steatosis and inflammation whereas the Pfkfb3/iPfk2 in nonhematopoietic cells appeared to be needed for HFD feeding to induce hepatic steatosis. As such, the Pfkfb3/iPfk2 plays a unique role in regulating NAFLD pathophysiology.

Prediction and Analysis of Hub Genes in Renal Cell Carcinoma based on CFS Gene Selection Method Combined with Adaboost Algorithm.

BACKGROUND: Renal cell carcinoma (RCC) is the most common malignant tumor of the adult kidney. OBJECTIVE: The aim of this study was to identify key genes signatures during RCC and uncover their potential mechanisms. METHODS: Firstly, the gene expression profiles of GSE53757 which contained 144 samples, including 72 kidney cancer samples and 72 controls, were downloaded from the GEO database. And then differentially expressed genes (DEGs) between the kidney cancer samples and the controls were identified. After that, GO and KEGG enrichment analyses of DEGs were performed by DAVID. Furthermore, the correlation-based feature subset (CFS) method was applied to the selection of key genes of DEGs. In addition, the classification model between the kidney cancer samples and the controls was built by Adaboost based on the selected key genes. RESULTS: 213 DEGs including 80 up-regulated and 133 down-regulated genes were selected as the feature genes to build the classification model between the kidney cancer samples and the controls by CFS method. The accuracy of the classification model by using 5-folds cross-validation test and independent set test is 84.4% and 83.3%, respectively. Besides, TYROBP, CD4163, CAV1, CXCL9, CXCL11 and CXCL13 also can be found in the top 20 hub genes screened by proteinprotein interaction (PPI) network. CONCLUSION: It indicated that CFS is a useful tool to identify key genes in kidney cancer. Besides, we also predicted genes such as TYROBP, CD4163, CAV1, CXCL9, CXCL11 and CXCL13 that might target genes to diagnose the kidney cancer.

Prevalence of hepatitis B surface antigen in patients with ankylosing spondylitis and its association with HLA-B27: a retrospective study from south China.

To investigate the prevalence of hepatitis B surface antigen (HBsAg), a seromarker for current infection of hepatitis B virus, in patients with ankylosing spondylitis (AS) from south China and to evaluate its association with human leukocyte antigen (HLA)-B27. The prevalence of HBsAg was retrospectively investigated in 439 patients with AS, 606 age- and sex-matched general individuals, 172 patients with other spondyloarthropathy (SpA), 698 patients with rheumatoid arthritis (RA), and 220 patients with osteoarthritis (OA). The positive rate of HBsAg in AS group was compared with those of the general population group and other disease groups, respectively, and the prevalence of HBsAg was compared between HLA-B27-positive and HLA-B27-negative patients with AS. The positive rate of HBsAg in AS patients, general population, other-SpA, RA, and OA patients were 25.39, 12.87, 14.53, 9.60, and 8.18%, respectively. The HBsAg prevalence of AS group was statistically higher than those of any other groups (P < 0.05). The prevalence of HBsAg in HLA-B27-positive and HLA-B27-negative AS patients were 26.68 and 14.49%, respectively, the positive rate of HBsAg in HLA-B27-positive AS patients was statistically higher than that of HLA-B27-negative AS patients (P < 0.05). The prevalence of HBsAg in AS patients was higher than those in general population, patients with other-SpA, RA, and OA. The high HBsAg prevalence in AS patients might be associated with their high frequency of HLA-B27 gene.

Screening disease-associated proteins from sera of patients with rheumatoid arthritis: a comparative proteomic study.

BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation at the synovial membrane. Although great progress has been made recently in exploring the etiology and pathogenesis of RA, its molecular pathological mechanism remains to be further defined and it is still a great challenge in determining the diagnosis and in choosing the appropriate therapy in early patients. This study was performed to screen candidate RA-associated serum proteins by comparative proteomics to provide research clues to early diagnosis and treatment of RA. METHODS: Sera isolated from 6 RA patients and 6 healthy volunteers were pooled respectively and high-abundance proteins were depleted by Plasma 7 Multiple Affinity Removal System. The protein expression profiles between the two groups were then compared by two-dimensional gel electrophoresis (2-DE) and the proteins over/under-expressed by more than 3-fold were identified by mass spectrometry analysis. To validate the differential expression levels of the identified proteins between the two groups, ELISA was performed in two of the identified proteins in individual sera from 32 RA patients and 32 volunteers. RESULTS: Eight proteins which over/under-expressed in sera of RA patients were identified. Among them, chain A of transthyretin (TTR) was under-expressed, while serum amyloid A protein, apolipoprotein A (ApoA)-IV, ApoA-IV precursor, haptoglobin 2, ceruloplasmin (Cp), immunoglobulin superfamily 22 and HT016 were over-expressed. ELISA test confirmed that Cp expressed remarkably higher while TTR obviously lower in RA group compared with volunteer group. CONCLUSION: There were 8 identified proteins differentially expressed between RA group and volunteer group, which might be candidate RA-associated proteins and might be promising diagnostic indicators or therapeutic targets for RA.

[Expressions of CD147 in peripheral monocytes and T lymphocytes of patients with ankylosing spondylitis].

OBJECTIVE: To investigate the roles of CD147 in the pathogenesis and development of ankylosing spondylitis (AS). METHODS: Flow cytometry was used to detect the expression levels of CD147 in peripheral monocytes and T lymphocytes of 30 AS patients, 30 rheumatoid arthritis (RA) patients and 30 healthy controls (HC). reverse transcription-polymerase chain reaction (RT-PCR) was used to evaluate the expression levels of CD147 mRNA in peripheral blood mononuclear cells (PBMC). Then the expression levels of CD147 were compared among the groups. And a correlation analysis was conducted between CD147 levels and disease activity indices of AS patients. RESULTS: The mean fluorescence intensities of CD147 in monocytes of AS, RA and HC group were 213.5 ± 37.8, 228.7 ± 49.7 and 163.6 ± 44.8, and in T lymphocytes 36.8 ± 10.1, 40.2 ± 10.5 and 28.3 ± 10.6 respectively. Both the expression levels of CD147 in monocytes and T lymphocytes of AS patients were slightly lower than those of RA patients. But the differences was not statistically significant (P > 0.05). Both the CD147 levels in monocytes and T lymphocytes of AS and RA group were significantly higher than those of HC group (P < 0.05). The expression levels of CD147 mRNA in PBMC of AS and RA group were significantly higher than those of HC group (P < 0.05) while no significant difference was found between AS and RA group (P > 0.05). Both the expression levels of CD147 in monocytes and T lymphocytes of AS patients were positively correlated with the patients' erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). CONCLUSION: The expressions of CD147 in peripheral monocytes and T lymphocytes of AS patients are up-regulated and their levels are positively correlated with patients' ESR and CRP. It implies that CD147 plays critical roles in the pathogenesis and development of AS.

[Study on expressions of CD25 and CD127 in CD4+ peripheral T lymphocytes of patients with rheumatoid arthritis].

OBJECTIVE: To study the proportion of regulatory T cells (Tregs) in peripheral blood of patients with rheumatoid arthritis (RA) and investigate the significance of Tregs change in the incidence and inflammatory activity of RA. METHODS: Three-color fluorescence flow cytometry was used to detect the CD4, CD25 and CD127 markers in the peripheral blood lymphocytes of 25 RA patients and 31 healthy volunteers (HVs). The proportions of CD4(+)CD25(+), CD4(+)CD25(high), CD4(+)CD25(+)CD127(-) and CD4(+)CD25(high)CD127(-) cells were compared between the two groups and correlation analysis was conducted between Tregs and disease activity indices which including disease activity score (DAS28-4), tender joint count (TJC), swollen joint count (SJC), time of morning stiffness, patient's global assessment of disease activity on a 100 mm VAS by doctor and patients, erythrocyte sedimentation rate and C-reactive protein. RESULTS: The proportions of CD4(+)CD25(+)CD127(-) and CD4(+)CD25(high)CD127(-) cells in CD4(+) peripheral T lymphocytes were (2.53 +/- 0.85)% and (0.91 +/- 0.32)% respectively in RA group, while they were (3.22 +/- 0.97)% and (1.25 +/- 0.41)% in HV group. Both of the proportions of CD4(+)CD25(+)CD127(-) and CD4(+)CD25(high)CD127(-) cells were lower in RA group comparing with HV group, and both were significantly different between the two groups (P < 0.05). Correlation analysis indicated significant negative correlations of the proportions of CD4(+)CD25(+)CD127(-) and CD4(+)CD25(high)CD127(-) cells with DAS28-4 and TJC (P < 0.05), furthermore, CD4(+)CD25(high)CD127(-) T cells still showed significant negative correlation with the SJC and patient's global assessment of disease activity on a 100 mm VAS by patients (P < 0.05). CONCLUSION: The proportion of Tregs decreased in peripheral blood lymphocytes of patients with RA and the abnormality of Tregs may play an important role in the incidence and inflammatory activity of RA.