Artemisinin relieves osteoarthritis by activating mitochondrial autophagy through reducing TNFSF11 expression and inhibiting PI3K/AKT/mTOR signaling in cartilage.

Osteoarthritis (OA) is a widespread chronic degenerative joint disease characterized by the degeneration of articular cartilage or inflamed joints. Our findings indicated that treatment with artemisinin (AT) downregulates the protein levels of MMP3, MMP13, and ADAMTS5, which are cartilage degradation-related proteins in OA, and inhibits the expression of inflammatory factors in interleukin-1ß (IL-1ß)-stimulated chondrocytes. However, the mechanism of the role of AT in OA remains unclear. Here, we performed gene sequencing and bioinformatics analysis in control, OA, and OA + AT groups to demonstrate that several mRNA candidates were enriched in the PI3K/AKT/mTOR signaling pathway, and TNFSF11 was significantly downregulated after AT treatment. TNFSF11 was downregulated in the OA + AT group, whereas it was upregulated in rat OA tissues and OA chondrocytes. Therefore, we confirmed that TNFSF11 was the target gene of AT. In addition, our study revealed that AT relieved cartilage degradation and defection by activating mitochondrial autophagy via inhibiting the PI3K/AKT/mTOR signaling pathway in IL-1ß-induced chondrocytes. Furthermore, an OA model was established in rats with medial meniscus destabilization. Injecting AT into the knee joints of OA rat alleviated surgical resection-induced cartilage destruction. Thus, these findings revealed that AT relieves OA by activating mitochondrial autophagy by reducing TNFSF11 expression and inhibiting PI3K/AKT/mTOR signaling.

KLF4, negatively regulated by miR-7, suppresses osteoarthritis development via activating TGF-ß1 signaling.

Osteoarthritis (OA) is a chronic degenerative disease which seriously affects the patients' daily activities and quality of life. In our previous findings, we demonstrated that overexpression of miR-7 was found in OA and promoted OA development. Its exact mechanism remains unclear. Herein, we confirmed that KLF4 was the target gene of miR-7 and KLF4 was down-regulated in human OA tissues and OA chondrocyte. KLF4 was negatively modulated by miR-7 via dual luciferase reporter assay. Cartilage-specific genes (SOX9, COL2A1, RUNX2, MMP13) are crucial regulators in cartilage degeneration. Through qRT-PCR and western blot, we observed that KLF4 overexpression could increase the expression of SOX9 and COL2A1, decrease RUNX2 and MMP13. In the meanwhile, miR-7 was proven to regulate the expression of the above cartilage-specific genes by targeting KLF4, which demonstrated KLF4 could prevent OA development. Subsequently, KLF4 also activated TGF-ß1 signaling pathway, thereby affecting OA progression. Excessive KLF4 could up-regulate TGF-ß1 and p-Smad2/3 level, and Smad4 level was prevented in OA chondrocytes, while adding TGF-ß1 inhibitor SB525334 could rescue this impact, along with reduced TGF-ß1 and p-Smad2/3 level, enriched Smad4 level. KLF4 could also reverse the effect of miR-7 on TGF-ß1 signaling. Besides, it was confirmed that KLF4 could improve OA in rat OA models by HE and Safranin O-Fast green staining, and immunohistochemistry. Collectively, our findings will give more detailed evidence about miR-7 and KLF4 in OA diagnosis and treatment.

Development and validation of a novel risk score to predict 5-year mortality in patients with acute myocardial infarction in China: a retrospective study.

BACKGROUND: The disease burden from ischaemic heart disease remains heavy in the Chinese population. Traditional risk scores for estimating long-term mortality in patients with acute myocardial infarction (AMI) have been developed without sufficiently considering advances in interventional procedures and medication. The goal of this study was to develop a risk score comprising clinical parameters and intervention advances at hospital admission to assess 5-year mortality in AMI patients in a Chinese population. METHODS: We performed a retrospective observational study on 2,722 AMI patients between January 2013 and December 2017. Of these patients, 1,471 patients from Changsha city, Hunan Province, China were assigned to the development cohort, and 1,251 patients from Xiangtan city, Hunan Province, China, were assigned to the validation cohort. Forty-five candidate variables assessed at admission were screened using least absolute shrinkage and selection operator, stepwise backward regression, and Cox regression methods to construct the C2ABS2-GLPK score, which was graded and stratified using a nomogram and X-tile. The score was internally and externally validated. The C-statistic and Hosmer-Lemeshow test were used to assess discrimination and calibration, respectively. RESULTS: From the 45 candidate variables obtained at admission, 10 potential predictors, namely, including Creatinine, experience of Cardiac arrest, Age, N-terminal Pro-Brain Natriuretic Peptide, a history of Stroke, Statins therapy, fasting blood Glucose, Left ventricular end-diastolic diameter, Percutaneous coronary intervention and Killip classification were identified as having a close association with 5-year mortality in patients with AMI and collectively termed the C2ABS2-GLPK score. The score had good discrimination (C-statistic = 0.811, 95% confidence intervals (CI) [0.786-0.836]) and calibration (calibration slope = 0.988) in the development cohort. In the external validation cohort, the score performed well in both discrimination (C-statistic = 0.787, 95% CI [0.756-0.818]) and calibration (calibration slope = 0.976). The patients were stratified into low- (≤148), medium- (149 to 218) and high-risk (≥219) categories according to the C2ABS2-GLPK score. The predictive performance of the score was also validated in all subpopulations of both cohorts. CONCLUSION: The C2ABS2-GLPK score is a Chinese population-based risk assessment tool to predict 5-year mortality in AMI patients based on 10 variables that are routinely assessed at admission. This score can assist physicians in stratifying high-risk patients and optimizing emergency medical interventions to improve long-term survival in patients with AMI.

A new antibacterial nano-system based on hematoporphyrin-carboxymethyl chitosan conjugate for enhanced photostability and photodynamic activity.

To promote bactericidal activity, improve photostability and safety, novel antibacterial nanoparticle system based on photodynamic action (PDA) was prepared here through conjugation of photosensitizer hematoporphyrin (HP) onto carboxymethyl chitosan (CMCS) via amide linkage and followed by ultrasonic treatment. The system was stable in PBS (pH 7.4) and could effectively inhibit the photodegradation of conjugated HP because of aggregation-caused quenching effect. ROS produced by the conjugated HP under light exposure could change the structure of nanoparticles by oxidizing the CMCS skeleton and thereby significantly promote the photodynamic activity of HP and its photodynamic activity after 6 h was higher than that of HP·2HCl under the same conditions. Antibacterial experiments showed that CMCS-HP nanoparticles had excellent photodynamic antibacterial activity, and the bacterial inhibition rates after 60 min of light exposure were greater than 97%. Safety evaluation exhibited that the nanoparticles were safe to mammalian cells, showing great potential for antibacterial therapy.

Effects of mechanical circulatory support devices in patients with acute myocardial infarction undergoing stent implantation: a systematic review and meta-analysis of randomised controlled trials.

OBJECTIVE: The survival benefit of using mechanical circulatory support (MCS) in patients with acute myocardial infarction (AMI) is still controversial. It is necessary to explore the impact on clinical outcomes of MCS in patients with AMI undergoing stenting. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Embase, Cochrane Library, Medline, PubMed, Web of Science, ClinicalTrials.gov and Clinicaltrialsregister.eu databases were searched from database inception to February 2021. ELIGIBILITY CRITERIA: Randomised clinical trials (RCTs) on MCS use in patients with AMI undergoing stent implantation were included. DATA EXTRACTION AND SYNTHESIS: Data were extracted and summarised independently by two reviewers. Risk ratios (RRs) and 95% CIs were calculated for clinical outcomes according to random-effects model. RESULTS: Twelve studies of 1497 patients with AMI were included, nine studies including 1382 patients compared MCS with non-MCS, and three studies including 115 patients compared percutaneous ventricular assist devices (pVADs) versus intra-aortic balloon pump (IABP). Compared with non-MCS, MCS was not associated with short-term (within 30 days) (RR=0.90; 95% CI 0.57 to 1.41; I2=46.8%) and long-term (at least 6 months) (RR=0.82; 95% CI 0.57 to 1.17; I2=37.6%) mortality reductions. In the subset of patients without cardiogenic shock (CS) compared with non-MCS, the patients with IABP treatment significantly had decreased long-term mortality (RR=0.49; 95% CI 0.27 to 0.90; I2=0), but without the short-term mortality reductions (RR=0.51; 95% CI 0.22 to 1.19; I2=17.9%). While in the patients with CS, the patients with MCS did not benefit from the short-term (RR=1.09; 95% CI 0.67 to 1.79; I2=46.6%) or long-term (RR=1.00; 95% CI 0.75 to 1.33; I2=22.1%) survival. Moreover, the application of pVADs increased risk of bleeding (RR=1.86; 95% CI 1.15 to 3.00; I2=15.3%) compared with IABP treatment (RR=1.86; 95% CI 1.15 to 3.00; I2=15.3%). CONCLUSIONS: In all patients with AMI undergoing stent implantation, the MCS use does not reduce all-cause mortality. Patients without CS can benefit from MCS regarding long-term survival, while patients with CS seem not.

Caspase-11-Gasdermin D-Mediated Pyroptosis Is Involved in the Pathogenesis of Atherosclerosis.

Background: Pyroptosis is a form of cell death triggered by proinflammatory signals. Recent studies have reported that oxidized phospholipids function as caspase-11 agonists to induce noncanonical inflammasome activation in immune cells. As the levels of oxidized phospholipids derived from ox-LDL are largely elevated in atherosclerotic lesions, this study sought to determine whether oxidized lipids trigger pyroptosis and subsequent inflammation in the pathogenesis of atherosclerosis. Methods and Results: In our current study, after integrating transcriptomic data available from the Gene Expression Omnibus with data from hyperlipidemic mice and ox-LDL-treated peritoneal macrophages, we discovered that caspase-4/11-gasdermin D-associated inflammatory signaling was significantly activated. Consistently, the mRNA expression of caspase-4 and gasdermin D was upregulated in peripheral blood mononuclear cells from patients with coronary heart disease. In particular, the expression of caspase-4 was closely associated with the severity of lesions in the coronary arteries. An in vivo study showed that caspase-11-gasdermin D activation occurred in response to a high-fat/high-cholesterol (HFHC) diet in ApoE-/- mice, while caspase-11 deletion largely attenuated the volume and macrophage infiltration of atherosclerotic lesions. An in vitro mechanistic study showed that caspase-11-mediated inflammation occurred partly via gasdermin D-mediated pyroptosis in macrophages. Suppressing gasdermin D in HFHC-fed ApoE-/- mice via delivery of an adeno-associated virus markedly decreased lesion volume and infiltrating macrophage numbers. Conclusion: Caspase-11-gasdermin D-mediated pyroptosis and the subsequent proinflammatory response in macrophages are involved in the pathogenesis of atherosclerosis. Therefore, targeting the caspase 11-gasdermin D may serve as an alternative strategy for the treatment of atherosclerosis.

A sodium alginate-based nano-pesticide delivery system for enhanced in vitro photostability and insecticidal efficacy of phloxine B.

To improve in vitro photostability and enhance insecticidal activity, a novel esterase/glutathione (GSH) responsive photoactivated nano-pesticide delivery system was synthesized by conjugation of photoactivated pesticide phloxine B(PB) to sodium alginate (SA) via esterase/GSH sensitive phenolic ester bond followed by ultrasonic dispersion. The system was stable in PBS (pH 7.4) and could protect effectively the conjugated PB from in vitro photodegradation because of aggregation-caused quenching effect, whose maximum photodegradation rate did not exceed 10 % after 270 min illumination. However, upon exposure to esterase-6 or GSH stimulus, high photoactivity was observed due to the destruction of the system and accompanied by PB release. The combined stimulation could trigger more PB release than any single stimulus and thus resulting in a higher photoactivity. Compared with free PB, The system showed a higher phototoxicity on Sf9 insect cells and the in vitro light exposure had little influence on the phototoxicity.

Regulator of G Protein Signaling 6 Facilities Cardiac Hypertrophy by Activating Apoptosis Signal-Regulating Kinase 1-P38/c-JUN N-Terminal Kinase 1/2 Signaling.

Background Regulator of G protein signaling 6 ( RGS 6) is an important member of the RGS family and produces pleiotropic regulatory effects on cardiac pathophysiology. However, the role of RGS 6 protein in cardiomyocytes during angiotensin II - and pressure overload-induced cardiac hypertrophy remain unknown. Methods and Results Here, we used a genetic approach to study the regulatory role of RGS 6 in cardiomyocytes during pathological cardiac hypertrophy. RGS 6 expression was significantly increased in failing human hearts and in hypertrophic murine hearts. The extent of aortic banding-induced cardiac hypertrophy, dysfunction, and fibrosis in cardiac-specific RGS 6 knockout mice was alleviated, whereas the hearts of transgenic mice with cardiac-specific RGS 6 overexpression exhibited exacerbated responses to pressure overload. Consistent with these findings, RGS 6 also facilitated an angiotensin II -induced hypertrophic response in isolated cardiomyocytes. According to the mechanistic studies, RGS 6 mediated cardiac hypertrophy by directly interacting with apoptosis signal-regulating kinase 1, which further activates the P38-c- JUN N-terminal kinase 1/2 signaling pathway. Conclusions Based on our findings, RGS 6 aggravates cardiac hypertrophy, and the RGS 6-apoptosis signal-regulating kinase 1 pathway represents a potential therapeutic target to attenuate pressure overload-driven cardiac remodeling.