STING deficiency alleviates ferroptosis through FPN1 stabilization in diabetic kidney disease.

Ferroptosis, a form of cell death driven by iron-dependent lipid peroxidation, has known as one of the most significant pathological processes involved in diabetic kidney disease (DKD). Stimulator of interferon genes (STING) has been demonstrated its potential in regulating ferroptosis, but the regulatory role in DKD mice and underlying mechanisms haven't been illustrated. To elucidate whether and how STING regulates ferroptosis in DKD, we detected the influence of STING on diabetic-related ferroptosis in a diabetic model and in erastin-induced renal tubular epithelial cells (RTECs). Our study demonstrated that STING was abnormally activated and promoted ferroptosis in DKD. STING deficiency alleviated renal pathologic damages and disfunction in diabetic mice via alleviating ferroptosis and reducing oxidative stress. Mechanismly, STING inhibition was shown to improve ferroptosis and reduce oxidative stress in erastin-induced RTECs. The disruption of ferroportin1 (FPN1) on the basis of STING inhibition abolished the improvements in ferroptosis and promoted reactive oxygen species (ROS) generation. Further, STING inhibition alleviated ferroptosis via stabilizing FPN1 protein level by decreasing ubiquitinated FPN1 for proteasomal degradation. In conclusion, STING deficiency protected against diabetic renal injury via alleviating ferroptosis through stabilizing FPN1 and reducing oxidative stress, providing a possible potential approach for the treatment of DKD.

Stimulator of interferon genes promotes diabetic sarcopenia by targeting peroxisome proliferator activated receptors γ degradation and inhibiting fatty acid oxidation.

BACKGROUND: Declined skeletal muscle mass and function are inevitable consequences of long-term diabetes and bring about many adverse events. Muscle fibre atrophy and interstitial fibrosis are major pathological manifestations of diabetic sarcopenia. Stimulator of interferon genes (STING) participates in various metabolic diseases. We aimed to explore whether and how STING regulates the above pathological manifestations of diabetic sarcopenia. METHODS: Wild-type and STINGgt/gt C57BL/6J mice and C2C12 myotubes were used to study the role of STING in the regulation of diabetic sarcopenia and the underlying mechanisms. RESULTS: STING was abnormally activated in diabetic muscles and in PA-treated myotubes (P < 0.01 for all parameters). The diabetic mice demonstrated decreased forelimb grip strength, lean mass, muscle weight and hanging impulse, which were improved by STING deficiency due to alleviated muscle fibre atrophy and interstitial fibrosis (P < 0.05 for all parameters). STING deficiency alleviated muscle fibre atrophy through the following mechanisms. Firstly, STING deficiency or inhibition increased the contents of pDRP1Ser616 , PINK1, Parkin and LC3-II, decreased p62 content, and increased the amount of mito-Keima fluorescent dots at 578 nm in diabetic state (P < 0.05 for all parameters), suggesting improved mitofission and mitophagy. Secondly, STING deficiency or inhibition increased the expression of pAKTSer473 and GLUT4 post-insulin change in diabetic state (P < 0.05 for all), indicating alleviated insulin resistance (IR). Mechanically, STING deficiency or inhibition increased peroxisome proliferator activated receptors γ (PPARγ) protein content by reducing the degradation of ubiquitinated PPARγ through the proteasome pathway and thus increased the expression of fatty acid oxidation (FAO)-related proteins in diabetic state (P < 0.05 for all parameters). Decreased expression of FAO-related proteins caused by PPARγ inhibition abolished the improvements in mitofission, mitophagy and IR achieved by STING inhibition in PA-treated myotubes and thus promoted muscle fibre atrophy (P < 0.05 for all parameters). STING deficiency alleviated interstitial fibrosis by decreasing TGFß1 expression in diabetic state and TGFß1 promoted the fibrogenic differentiation of fibro-adipogenic progenitors (P < 0.05 for all parameters). PPARγ inhibition abolished the effect of STING inhibition on reducing TGFß1 content in PA-treated myotubes (P < 0.01). CONCLUSIONS: STING deficiency exerted protective effects in diabetic sarcopenia by inhibiting the degradation of ubiquitinated PPARγ through the proteasome pathway and enhancing PPARγ-mediated FAO, which alleviated muscle fibre atrophy by promoting mitophagy and ameliorating IR, and alleviated interstitial fibrosis by reducing TGFß1 production and suppressing the fibrogenic differentiation of fibro-adipogenic progenitors.

Hepcidin gene silencing ameliorated inflammation and insulin resistance in adipose tissue of db/db mice via inhibiting METs formation.

As a major feature of diabetes, inflammation is closely related to macrophage extracellular traps and the expression of hepcidin upregulated by diabetes is reportedly involved in chronic inflammation. Therefore, we aimed to explore whether hepcidin could be implicated in inflammation and macrophage extracellular traps (METs) formation. The diabetic db/db mouse model was established exhibiting insulin resistance (IR), inflammation, macrophages infiltration and higher expression of hepcidin, where samples were obtained from epididymal adipose tissue. We observed that inflammation and IR improved in adipose tissue of mice treated with hepcidin gene silencing. Furthermore, METs formation could be markedly inhibited via hepcidin gene silencing followed by attenuated inflammatory response due to METs, indicating hepcidin gene silencing played a key role in anti-inflammation by inhibiting METs formation. So, we concluded that hepcidin gene silencing has a potential for treatment of diabetes due to its ability to ameliorate inflammation via inhibiting METs formation.

Serum complement C1q level is associated with acute coronary syndrome.

BACKGROUND AND OBJECTIVES: The complement system plays an important role in the development of acute coronary syndrome (ACS). Complement C1q is an important initial component of the classical complement pathway and closely related to many chronic inflammatory diseases, including atherosclerosis (AS). We aimed to determine whether there was association between serum complement C1q and the severity of coronary stenosis. SUBJECTS AND METHODS: 320 patients who underwent coronary arteriography (CAG) were stratified into non-ACS group (control group, n = 74), unstable angina group (UA group, n = 197) and acute myocardial infarction group (AMI group, n = 49) according to the severity of coronary stenosis and clinical manifestations. The severity of coronary stenosis was represented in Gensini score, and serum complement C1q level was compared using immunity transmission turbidity among three groups. RESULTS: The level of complement C1q in AMI group was lower significantly than control group and UA group (P < 0.05), but there was no correlation between serum complement C1q and Gensini score (ß=-0.086, P = 0.125). In nitrate-taking patients, serum complement C1q had a negative association with Gensini score (r=-0.275, P = 0.001), and in non-smokers, there was also a negative correlation (ß=-0.159, P = 0.036). After calibrating smoking, drinking or statins, the serum complement C1q levels of control group, UA group and AMI group decreased in sequence (P <  0.05). Logistic regression analysis showed that the decreasing of serum complement C1q was an unfavorable factor for acute myocardial infarction (OR=0.984, 95 %CI=0.972∼0.997, P = 0.015) and for ACS (OR=0.984, 95 %CI=0.971∼0.984, P = 0.025) in drinking patients. Regrettably, ROC curve suggested that the accuracy in diagnosing coronary atherosclerotic heart disease by serum complement C1q was low (AUC=0.568, 95 %CI= 0.492-0.644, P = 0.076, sensitivity 73.6 %, specificity 58.1 %). CONCLUSION: Serum complement C1q in ACS patients, in particular AMI patients, showed lower level. This finding suggests further decrease of complement C1q level in ACS patients may be a contributory factor to instability or rupture of atherosclerotic plaques. Combined with other clinical indicators, it can be helpful to predict the risk and severity of coronary stenosis.

Sarcopenia is attenuated by TRB3 knockout in aging mice via the alleviation of atrophy and fibrosis of skeletal muscles.

BACKGROUND: Sarcopenia causes several adverse events in elderly people. Muscle fibre atrophy and interstitial fibrosis are the main histopathological changes in sarcopenia and account for decreased muscle function. Tribbles homologue 3 (TRB3) was previously reported to exhibit age-related expression and play a vital role in cell proliferation, differentiation, and fibrosis. We aimed to investigate how TRB3 affects sarcopenia. METHODS: Wild-type and TRB3 knockout C57/BL6J mice were randomly divided into young and old groups. Exercise capacity was evaluated, and single-muscle function was detected by electrophysiological techniques, after which the mice were sacrificed to collect their gastrocnemius muscles for assessment of atrophy and fibrosis by histopathological and molecular biological methods. TRB3 expression, autophagy level, and MAPK signalling pathway activity were evaluated through western blotting. The interaction of TRB3 with P62 and the association between TRB3 and the MAPK signalling pathway were detected by co-immunoprecipitation. RESULTS: In aged mice, exercise capacity and cross-sectional area of skeletal muscle fibres were decreased significantly, whereas TRB3, atrophy-related markers atrogin 1 and MuRF 1, and interstitial fibrosis, including collagen volume fraction, contents of collagens I and III, and ratio of collagens I to III, were increased significantly (P < 0.05 for all). Following TRB3 knockout, the cross-sectional area of muscle fibres, mainly fast fibres, was elevated (P < 0.05 for both), the atrogin 1 expression was decreased (P = 0.0163), and the corresponding tetanic force of fast muscles was increased (P = 0.0398). Conversely, interstitial fibrosis was substantially decreased and exercise capacity was significantly increased in the knockout mice. In terms of the underlying mechanisms, the autophagy receptor p62 was markedly increased and the MAPK signalling pathway was activated in aged skeletal muscles, which might be attributed to the interaction of TRB3 with p62 and MAPKKs, including MEK1/MEK2, MEK3/MEK6, and MEK4/MKK4. Notably, TRB3 knockout reduced the accumulation of p62 and LC3 (P < 0.05 for both), decreased the phosphorylation of JNK (P = 0.0015), and increased p38 phosphorylation (P = 0.0021). CONCLUSIONS: TRB3 knockout in mice attenuated muscle fibre atrophy and reduced skeletal muscle fibrosis by increasing autophagy and inhibiting the MAPK signalling pathway. Correspondingly, in aged knockout mice, exercise capacity was improved. Interfering with TRB3 expression in aged skeletal muscles may serve as a target for the prevention and treatment of age-related sarcopenia.

Impact of Perioperative Levosimendan Administration on Risk of Bleeding After Cardiac Surgery: A Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Levosimendan, a calcium sensitizer and potassium channel opener, has been demonstrated to improve myocardial function without increasing oxygen consumption and to show protective effects in other organs. Recently, a prospective, randomized controlled trial (RCT) revealed an association between levosimendan use and a possible increased risk of bleeding postoperatively. Levosimendan's anti-platelet effects have been shown in in vitro studies. Current studies do not provide sufficient data to support a relation between perioperative levosimendan administration and increased bleeding risk. PURPOSE: Our goal was to investigate the relation between perioperative levosimendan administration and increased bleeding risk using a meta-analysis study design. METHODS: The PubMed, Ovid, EMBASE and Cochrane Library databases were searched for relevant RCTs before July 1, 2019. The outcome parameters included reoperation secondary to increased bleeding in the postoperative period, the amount of postoperative recorded blood loss, and the need for transfusion of packed red blood cells (RBCs) and other blood products. RESULTS: A total of 1160 patients in nine RCTs (576 in the levosimendan group and 584 in the control group) were included according to our inclusion criteria. Analysis showed that perioperative levosimendan administration neither increased the rate of reoperation secondary to bleeding nor increased the amount of postoperative chest tube drainage when compared with the control group. In terms of blood product transfusion, levosimendan did not influence the requirement for RBC transfusion, platelet transfusion nor fresh frozen plasma (FFP) transfusion. Levosimendan also did not shorten or prolong the aortic cross-clamp time or the cardiopulmonary bypass time. CONCLUSION: The analyzed parameters, including reoperations due to bleeding, postoperative chest drainage and the requirement for blood products, revealed that levosimendan did not increase postoperative bleeding risk. More studies with a larger sample size are needed to address a more reliable conclusion due to study limitations.