Structural basis for double-stranded RNA recognition by SID1.

The nucleic acid transport properties of the systemic RNAi-defective (SID) 1 family make them attractive targets for developing RNA-based therapeutics and drugs. However, the molecular basis for double-stranded (ds) RNA recognition by SID1 family remains elusive. Here, we report the cryo-EM structures of Caenorhabditis elegans (c) SID1 alone and in complex with dsRNA, both at a resolution of 2.2 Å. The dimeric cSID1 interacts with two dsRNA molecules simultaneously. The dsRNA is located at the interface between ß-strand rich domain (BRD)1 and BRD2 and nearly parallel to the membrane plane. In addition to extensive ionic interactions between basic residues and phosphate backbone, several hydrogen bonds are formed between 2'-hydroxyl group of dsRNA and the contact residues. Additionally, the electrostatic potential surface shows three basic regions are fitted perfectly into three major grooves of dsRNA. These structural characteristics enable cSID1 to bind dsRNA in a sequence-independent manner and to distinguish between DNA and RNA. The cSID1 exhibits no conformational changes upon binding dsRNA, with the exception of a few binding surfaces. Structural mapping of dozens of loss-of-function mutations allows potential interpretation of their diverse functional mechanisms. Our study marks an important step toward mechanistic understanding of the SID1 family-mediated dsRNA uptake.

Diagnosis and treatment of 131 adult patients with bronchopulmonary sequestration: A retrospective analysis / 中国胸心血管外科临床杂志

@#Objective    To explore the safety and feasibility of uni-portal video-assisted thoracic surgery (VATS) for the treatment of bronchopulmonary sequestration (BPS). Methods    The clinical data of BPS patients with surgical resection in Shanghai Pulmonary Hospital from February 2010 to June 2021 were reviewed. The patients were divided into a VATS group and a thoracotomy group according to the operation method. The operation time, intraoperative blood loss, hospital stay and postoperative complication rate were compared between the two groups. The VATS group was subdivided into a uni-portal VATS group and a multi-portal VATS group for subgroup analysis. Results    Finally 131 patients were enrolled, including 62 males and 69 females with an average age of 39.3±13.2 years. There were 103 patients in the VATS group and 28 patients in the thoracotomy group. A total of 104 patients were diagnosed with left lower BPS, 26 with right lower BPS and 1 with bilateral lower BPS. The main symptom was cough (88 patients, 67.2%). There were 119 patients diagnosed by thoracic enhanced CT before operation. Compared with the thoracotomy group, the operation time was not statistically different (P=0.717), but the blood loss was less, the rate of postoperative complication was lower and hospital stay was shorter in the VATS group (P<0.05). The rate of conversion to open surgery in the uni-portal VATS group and multi-portal VATS group was 11.8% and 13.5%, respectively. Meanwhile, patients in the uni-portal VATS group had shorter operation time and postoperative hospital stay, less blood loss and lower postoperative complication rate than those in the multi-portal VATS group (P<0.05). Conclusion     In order to improve the rate of diagnosis, the lung enhanced CT scan should be selected as an optimal noninvasive method in adult suspected patients (especially those with solid cystic and solid lesions in the lower lobe). Uni-portal VATS is a safe and feasible method for BPS which can be widely promoted.

Adipsin inhibits Irak2 mitochondrial translocation and improves fatty acid ß-oxidation to alleviate diabetic cardiomyopathy.

BACKGROUND: Diabetic cardiomyopathy (DCM) causes the myocardium to rely on fatty acid ß-oxidation for energy. The accumulation of intracellular lipids and fatty acids in the myocardium usually results in lipotoxicity, which impairs myocardial function. Adipsin may play an important protective role in the pathogenesis of DCM. The aim of this study is to investigate the regulatory effect of Adipsin on DCM lipotoxicity and its molecular mechanism. METHODS: A high-fat diet (HFD)-induced type 2 diabetes mellitus model was constructed in mice with adipose tissue-specific overexpression of Adipsin (Adipsin-Tg). Liquid chromatography-tandem mass spectrometry (LC-MS/MS), glutathione-S-transferase (GST) pull-down technique, Co-immunoprecipitation (Co-IP) and immunofluorescence colocalization analyses were used to investigate the molecules which can directly interact with Adipsin. The immunocolloidal gold method was also used to detect the interaction between Adipsin and its downstream modulator. RESULTS: The expression of Adipsin was significantly downregulated in the HFD-induced DCM model (P < 0.05). Adipose tissue-specific overexpression of Adipsin significantly improved cardiac function and alleviated cardiac remodeling in DCM (P < 0.05). Adipsin overexpression also alleviated mitochondrial oxidative phosphorylation function in diabetic stress (P < 0.05). LC-MS/MS analysis, GST pull-down technique and Co-IP studies revealed that interleukin-1 receptor-associated kinase-like 2 (Irak2) was a downstream regulator of Adipsin. Immunofluorescence analysis also revealed that Adipsin was co-localized with Irak2 in cardiomyocytes. Immunocolloidal gold electron microscopy and Western blotting analysis indicated that Adipsin inhibited the mitochondrial translocation of Irak2 in DCM, thus dampening the interaction between Irak2 and prohibitin (Phb)-optic atrophy protein 1 (Opa1) on mitochondria and improving the structural integrity and function of mitochondria (P < 0.05). Interestingly, in the presence of Irak2 knockdown, Adipsin overexpression did not further alleviate myocardial mitochondrial destruction and cardiac dysfunction, suggesting a downstream role of Irak2 in Adipsin-induced responses (P < 0.05). Consistent with these findings, overexpression of Adipsin after Irak2 knockdown did not further reduce the accumulation of lipids and their metabolites in the cardiac myocardium, nor did it enhance the oxidation capacity of cardiomyocytes expose to palmitate (PA) (P < 0.05). These results indicated that Irak2 may be a downstream regulator of Adipsin. CONCLUSIONS: Adipsin improves fatty acid ß-oxidation and alleviates mitochondrial injury in DCM. The mechanism is related to Irak2 interaction and inhibition of Irak2 mitochondrial translocation.

Dual interfaces and confinements on Fe2N@Fe3O4/VN heterojunction toward high-efficient lithium storage.

Ferroferric oxide (Fe3O4) as an anode material of lithium-ion battery has been widely investigated due to its high theoretical capacity, environmental friendliness, natural abundance, and low cost. However, it suffers from severe aggregation and volume expansion during energy storage. Herein, we rationally construct an advanced Fe2N@Fe3O4/VN heterostructure via a hydrothermal and followed nitridation process, where the wrapping of conductive Fe2N on the surface of Fe3O4 effectively improves the electron conductivity and alleviates the volume expansion, and VN inhibits the agglomeration of Fe2N@Fe3O4. Benefiting from the dual conductive confinements and promoted interfacial charge transfer, the Fe2N@Fe3O4/VN heterojunction exhibits excellent rate capability and cycling stability. It possesses the highest reversible capacity of 420.8 mAh g-1 at 1 A g-1 after 600 cycles, which is three times that of Fe3O4. Furthermore, a full cell based on a Fe2N@Fe3O4/VN anode and a LiFePO4 cathode delivers considerable electrochemical performance. This work demonstrates that Fe2N@Fe3O4/VN is a potential anode material and provides a model in constructing other high-performance electrode materials.

Structural insight into the human SID1 transmembrane family member 2 reveals its lipid hydrolytic activity.

The systemic RNAi-defective (SID) transmembrane family member 2 (SIDT2) is a putative nucleic acid channel or transporter that plays essential roles in nucleic acid transport and lipid metabolism. Here, we report the cryo-electron microscopy (EM) structures of human SIDT2, which forms a tightly packed dimer with extensive interactions mediated by two previously uncharacterized extracellular/luminal ß-strand-rich domains and the unique transmembrane domain (TMD). The TMD of each SIDT2 protomer contains eleven transmembrane helices (TMs), and no discernible nucleic acid conduction pathway has been identified within the TMD, suggesting that it may act as a transporter. Intriguingly, TM3-6 and TM9-11 form a large cavity with a putative catalytic zinc atom coordinated by three conserved histidine residues and one aspartate residue lying approximately 6 Å from the extracellular/luminal surface of the membrane. Notably, SIDT2 can hydrolyze C18 ceramide into sphingosine and fatty acid with a slow rate. The information presented advances the understanding of the structure-function relationships in the SID1 family proteins.

Regulating d-Band Center of Ti2 C MXene Via Nb Alloying for Stable and High-Efficient Supercapacitive Performances.

Ti2 C MXene with the lowest formula weight is expected to gain superior advantages in gravimetric capacitances over other heavier MXenes. Nevertheless, its poor chemical and electrochemical stability is the most fatal drawback and seriously hinders its practical applications. Herein, an alloy engineering strategy at the transition metal-sites of Ti2 C MXene is proposed. Theoretical calculations reveal that the electronic redistribution of the solid-solution TiNbC MXene improves the electronic conductivity, induces the upward d-band center, tailors the surface functional groups, and increases the electron loss impedance, resulting in its excellent capacitive performance and high chemical stability. The as-prepared flexible TiNbC film delivers specific capacitance up to 381 F g-1 at a scan rate of 2 mV s-1 and excellent electrochemical stability without capacitance loss after 10000 charge/discharging cycles. This work provides a universal approach to develop high-performance and chemically stable MXene electrodes.

Elevated branched-chain amino acid promotes atherosclerosis progression by enhancing mitochondrial-to-nuclear H2O2-disulfide HMGB1 in macrophages.

As the essential amino acids, branched-chain amino acid (BCAA) from diets is indispensable for health. BCAA supplementation is often recommended for patients with consumptive diseases or healthy people who exercise regularly. Latest studies and ours reported that elevated BCAA level was positively correlated with metabolic syndrome, diabetes, thrombosis and heart failure. However, the adverse effect of BCAA in atherosclerosis (AS) and its underlying mechanism remain unknown. Here, we found elevated plasma BCAA level was an independent risk factor for CHD patients by a human cohort study. By employing the HCD-fed ApoE-/- mice of AS model, ingestion of BCAA significantly increased plaque volume, instability and inflammation in AS. Elevated BCAA due to high dietary BCAA intake or BCAA catabolic defects promoted AS progression. Furthermore, BCAA catabolic defects were found in the monocytes of patients with CHD and abdominal macrophages in AS mice. Improvement of BCAA catabolism in macrophages alleviated AS burden in mice. The protein screening assay revealed HMGB1 as a potential molecular target of BCAA in activating proinflammatory macrophages. Excessive BCAA induced the formation and secretion of disulfide HMGB1 as well as subsequent inflammatory cascade of macrophages in a mitochondrial-nuclear H2O2 dependent manner. Scavenging nuclear H2O2 by overexpression of nucleus-targeting catalase (nCAT) effectively inhibited BCAA-induced inflammation in macrophages. All of the results above illustrate that elevated BCAA promotes AS progression by inducing redox-regulated HMGB1 translocation and further proinflammatory macrophage activation. Our findings provide novel insights into the role of animo acids as the daily dietary nutrients in AS development, and also suggest that restricting excessive dietary BCAA consuming and promoting BCAA catabolism may serve as promising strategies to alleviate and prevent AS and its subsequent CHD.

Zero-strain strategy incorporating TaC with Ta2O5 to enhance its rate capacity for long-term lithium storage.

Ta2O5 holds great potential for lithium storage due to its high theoretical capacity and long-life cycling. However, it still suffers from an unsatisfactory rate capability because of its low conductivity and significant volume expansion during the charging/discharging process. In this study, a zero-strain strategy was developed to composite Ta2O5 with zero-strain TaC as an anode for lithium-ion batteries (LIBs). The zero-strain TaC, featuring negligible lattice expansion, can alleviate the volume variation of Ta2O5 when cycling, thereby enhancing the rate capacity and long-term cycling stability of the whole electrode. Further, the formation of a heterostructure between Ta2O5 and TaC was confirmed, giving rise to an enhancement in the electrical conductivity and structural stability. As expected, this anode displayed a reversible specific capacity of 395.5 mA h g-1 at 0.5 A g-1 after 500 cycles. Even at an ultrahigh current density of 10 A g-1, the Ta2O5/TaC anode delivered a high capacity of 144 mA h g-1 and superior durability with a low-capacity decay rate of 0.08% per cycle after 1000 cycles. This zero-strain strategy provides a promising avenue for the rational design of anodes, sequentially contributing to the development of high-rate capacity and long cycling LIBs.

Two-Dimensional Ordered Double-Transition Metal Carbides for the Electrochemical Nitrogen Reduction Reaction.

The electrochemical nitrogen reduction reaction (NRR) provides a green and sustainable strategy as an alternative to the Haber-Bosch process. The development of electrocatalysts with low overpotential, high selectivity, and fast reaction kinetics remains a significant challenge. Here, density functional theory computations are carried out to systematically predict the prospect of 18 two-dimensional (2D) ordered double-transition metal carbides (MXenes) as NRR electrocatalysts. Our results revealed that the basal plane of Mo2Nb2C3 MXene exhibited the most outstanding catalytic activity while effectively suppressed the hydrogen evolution reaction with an overpotential of 0.48 V. The exposed Mo3 moiety moderately regulating the electron transfer between reaction intermediates is answerable for the high activity. Finally, our finding broadens the horizon of 2D materials as NRR electrocatalysts.

Physiological and Disease Models of Respiratory System Based on Organ-on-a-Chip Technology.

The pathogenesis of respiratory diseases is complex, and its occurrence and development also involve a series of pathological processes. The present research methods are have difficulty simulating the natural developing state of the disease in the body, and the results cannot reflect the real growth state and function in vivo. The development of microfluidic chip technology provides a technical platform for better research on respiratory diseases. The size of its microchannel can be similar to the space for cell growth in vivo. In addition, organ-on-a-chip can achieve long-term co-cultivation of multiple cells and produce precisely controllable fluid shear force, periodically changing mechanical force, and perfusate with varying solute concentration gradient. To sum up, the chip can be used to analyze the specific pathophysiological changes of organs meticulously, and it is widely used in scientific research on respiratory diseases. The focus of this review is to describe and discuss current studies of artificial respiratory systems based on organ-on-a-chip technology and to summarize their applications in the real world.

The relationship between genotype of familial hypercholesterolemia and the efficacy of PCSK9 inhibitors / 中华心血管病杂志

Objective: This study intends to explore the difference in the efficacy of PCSK9 inhibitors in patients with different FH phenotypes by analyzing the level of blood lipids before and after treatment with PCSK9 inhibitors in patients with familial hypercholesterolemia (FH) with different allele grades. Methods: Patients with FH phenotype, who admitted to Beijing Anzhen Hospital from January 2019 to October 2020, were enrolled. Age, sex and other clinical information were collected from enrolled, and the pathogenic genes were detected by the second generation sequencing technique. The patients were divided into five groups according to the number of alleles involved and the degree of gene damage: single allele-null mutation group, single allele-defect mutation group, multi-allele-null mutation group, multi-allele-defect mutation group and no major pathogenic gene mutation group. The results of blood lipids were collected before medication, 4-6 weeks of intensive statin treatment and one month after combined treatment with PCSK9 inhibitor (PCSK9i). The LDL-C level were compared among groups. ASCVD risk stratification was performed in all patients, and the proportion of LDL-C level reaching the corresponding risk stratification target value of each genotype group after treatment was analyzed. Results: A total of 66 patients with FH phenotype were included, including 47 males (71.2%) and 19 females (28.8%),the mean age was(43.1±13.4 years). There were 7 cases in single allele-null mutation group (10.6%), 25 cases in single allele-defect mutation group (37.9%), 8 cases in multi-allele-null mutation group (12.1%), 18 cases in multi-allele-defect mutation group (27.3%) and 8 cases in no major pathogenic mutation group (12.1%). The degree of LDL-C reduction post combined PCSK9 inhibitor therapy was as follows: single allele mutation group>no major pathogenic mutation group>multi-allele mutation group, general distribution was in the range of 0-90.0%. Two groups of single allele mutation and no major pathogenic mutation group>50.0%>multi-allele mutation group. Under the combined treatment of PCSK9 inhibitors, the further decrease of LDL-C was in the order of single allele mutation group>non-major pathogenic mutant group>multi-allele mutation group. The efficacy of combined therapy on reducing LDL-C at 1 month after treatment decreased with the increase of baseline LDL-C level (r = 0.46, P<0.001) in patients with FH phenotype. In addition, the further decrease of LDL-C level post high-intensity statin therapy combined with PCSK9 inhibitors decreased with the increase of baseline LDL-C levels (r = 0.40, P<0.001). The degree of LDL-C decrease was high and stable by statin combined with PCSK9 inhibitor therapy in single allele mutation group. In the single allele-defect mutant group, the decrease of LDL-C increased with the increase of baseline LDL-C level post intensive statin treatment and combined PCSK9 inhibitor treatment ((r=0.54, P=0.009); r=0.45,P=0.030), and the further decrease of LDL-C level decreased with the increase of baseline LDL-C level in single allele-defect mutant group post combined therapy with PCSK9 inhibitor (r=0.43, P=0.040). The decrease of LDL-C in patients with the multi-allele mutation group varied with different pathogenic gene loci and combinations post combined therapy with PCSK9 inhibitor. There was no significant difference in the level of blood lipids between the group without major pathogenic gene mutation and the group with single allele mutation before and after treatment. The percentage of patients achieving LDL-C goals with different genotypes of phenotypic FH were as follows: single allele mutation group (86.7%), non-major pathogenic mutant group (75.0%) and multi-allele mutation grou (<5.0%). Conclusions: All patients with different FH phenotypes could benefit from the intensive lipid-lowering therapy with statins and PCSK9 inhibitors, however, there are significant differences in the efficacy of lowering LDL-C in Chinese patients with FH phenotype with different molecular etiologies. Therefore, the pathogenic gene analysis may suggest the lipid-lowering effect of PCSK9 inhibitors in patients with FH.

Risk factor distribution features and trends of young adults with first acute coronary syndrome / 中华心血管病杂志

Objective: To observe the characteristics and trends during the last 11 years of risk factors of young adults with first acute coronary syndrome (ACS). Methods: It was a cross-sectional study. We included young adults (18 to 44 years old) hospitalized for acute coronary syndrome in Beijing Anzhen Hospital for a first time from January 2007 to December 2017. Acute coronary syndromes include ST-elevation myocardial infarction (STEMI), non-ST-elevation myocardial infarction (NSTEMI), and unstable angina (UA). The general information, medical history and laboratory test were recorded. Risk factors of ACS were smoking, dyslipidemia, overweight/obesity, hypertension and diabetes. Results: Data from 7 106 patients were analyzed, mean age was (39.8±4.2) years old and 6 593(92.8%)were men, including 2 254 (31.7%) STEMI, 704 (9.9%) NSTEMI and 4 148 (58.4%) UA. Most patients were male (6 593(92.8%)). Dyslipidemia (85.8%(6 094/7 106)), overweight/obesity (82.3%(5 850/7 106)), and smoking (63.9%(4 545/7 106)) were most prevalent. 98.3% (6 885/7 106) patients had at least 1 risk factor. The prevalence of hypertension, diabetes and overweight/obesity increased from 2007 to 2017. Rates of hypertension increased from 37.1%(111/299) to 48.1%(498/1 035) (Ptrend<0.01), diabetes from 12.0%(36/299) to 19.4%(201/1 035) (Ptrend<0.01), overweight/obesity from 74.2%(222/299) to 83.9%(868/1 035) (Ptrend<0.05), respectively. Conclusions: Dyslipidemia, overweight/obesity and smoking are most prevalent risk factors in young adults with a first ACS and most patients have at least 1 risk factor for ACS. Rates of hypertension, diabetes and overweight/obesity progressively increases over time in this patient cohort.

A liver-on-a-chip for hepatoprotective activity assessment.

Hepatoprotectant is critical for the treatment of liver disease. This study first reported the application of a liver chip in the hepatoprotective effect assessment. We first established a biomimetic sinusoid-on-a-chip by laminating four types of hepatic cell lines (HepG2, HUVEC, LX-2, and U937 cells) in a single microchannel with the help of laminar flow in the microchannel and some micro-fences. This chip was straightforward to fabricate and operate and was able to be long-term cultured. It also demonstrated better hepatic activity (cell viability, albumin synthesis, urea secretion, and cytochrome P450 enzyme activities) over the traditional planar cell culture model. Then, we loaded three hepatoprotectants (tiopronin, bifendatatum, and glycyrrhizinate) into the chip followed by the addition of acetaminophen as a toxin. We successfully observed the hepatoprotective effect of these hepatoprotectants in the chip, and we also found that bifendatatum predominantly reduced alanine transaminase secretion, tiopronin predominantly reduced lactate dehydrogenase secretion, and glycyrrhizinate predominantly reduced aspartate transaminase secretion, which revealed the different mechanisms of these hepatoprotectants and provided a clue for following molecular biological study of the protecting mechanism.

Constructing the Bridge from Isotropic to Anisotropic Pitches for Preparing Pitch-Based Carbon Fibers with Tunable Structures and Properties.

Synthetic naphthalene pitches (SNPs) with isotropy and anisotropy were prepared by a simple thermal polycondensation method to fabricate pitch-based carbon fibers. The structural characteristic, thermal stability, phase-separation behavior, and melt-spinnability of the SNPs and the structural properties of the derived carbon fibers were systematically investigated. The results show that spinnable SNPs with controllable mesophase contents ranging from 0 to 100 vol % and softening points (210-290 °C) could be easily obtained by a nitrogen-bubbling treatment to improve their thermal stability and melt-spinnability by avoiding the phase separation of liquid crystal (LC) in the pitch. An experimental phase diagram of spinnability and mesophase content is newly proposed for predicting the spinnability of a mesophase-containing pitch. The LC has a significant influence not only on the constituents, structure, and physical properties of the SNPs but also on the final structure and properties of the corresponding pitch-based carbon fibers. The low ash content (less than 0.15 wt %) in the pitch precursor is found to have no obvious effect on the pitch spinnability and the mechanical properties of derivative large-diameter carbon fibers.

Grain boundary engineering of Co3O4 nanomeshes for efficient electrochemical oxygen evolution.

The development of high-efficiency and stable electrocatalysts is significant for energy conversion and storage. The oxygen evolution reaction (OER), a pivotal half reaction, is seriously limited in its practical applications due to its sluggish kinetics and thus an excellent electrocatalyst for OER is urgently required. In this paper, we design a novel Co3O4 nanomesh (Co3O4 NMs) with high density grain boundaries (GBs), which functions as a highly efficient and steady OER electrocatalyst. The optimal Co3O4 NMs-500 can achieve a low overpotential of 295 mV at a current density of 10 mA cm-2, and a small Tafel slope of 31 mV dec-1, which exceeds the commercial Ir/C, as well as the majority of other catalysts reported in the literature. The Co3O4 NMs-500 also exhibit promising durability, with a negligible decline in activity after 18 h of operation. Detailed studies indicate that the presence of GBs leads to more exposed active sites and the enhanced adsorption of intermediate species on Co3O4 NMs-500, thereby improving the OER's catalytic activity. This work not only relates to the activity-GBs relationship, but also opens up a unique perspective for the design of the next generation of electrocatalysts.

Drug Toxicity Evaluation Based on Organ-on-a-chip Technology: A Review.

Organ-on-a-chip academic research is in its blossom. Drug toxicity evaluation is a promising area in which organ-on-a-chip technology can apply. A unique advantage of organ-on-a-chip is the ability to integrate drug metabolism and drug toxic processes in a single device, which facilitates evaluation of toxicity of drug metabolites. Human organ-on-a-chip has been fabricated and used to assess drug toxicity with data correlation with the clinical trial. In this review, we introduced the microfluidic chip models of liver, kidney, heart, nerve, and other organs and multiple organs, highlighting the application of these models in drug toxicity detection. Some biomarkers of toxic injury that have been used in organ chip platforms or have potential for use on organ chip platforms are summarized. Finally, we discussed the goals and future directions for drug toxicity evaluation based on organ-on-a-chip technology.

CD226 deletion improves post-infarction healing via modulating macrophage polarization in mice.

Macrophages are essential for wound repair after myocardial infarction (MI). CD226, a member of immunoglobulin superfamily, is expressed on inflammatory monocytes, however, the role of CD226 in infarct healing and the effect of CD226 on macrophage remain unknown. Methods: Wild type and CD226 knockout (CD226 KO) mice were subjected to permanent coronary ligation. CD226 expression, cardiac function and ventricular remodeling were evaluated. Profile of macrophages, myofibroblasts, angiogenesis and monocytes mobilization were determined. Results: CD226 expression increased in the infarcted heart, with a peak on day 7 after MI. CD226 KO attenuated infarct expansion and improved infarct healing after MI. CD226 deletion resulted in increased F4/80+ CD206+ M2 macrophages and diminished Mac-3+ iNOS+ M1 macrophages accumulation in the infarcted heart, as well as enrichment of α-smooth muscle actin positive myofibroblasts and Ki67+ CD31+ endothelial cells, leading to increased reparative collagen deposition and angiogenesis. Furthermore, CD226 deletion restrained inflammatory monocytes mobilization, as revealed by enhanced retention of Ly6Chi monocytes in the spleen associated with a decrease of Ly6Chi monocytes in the peripheral blood, whereas local proliferation of macrophage in the ischemic heart was not affected by CD226 deficiency. In vitro studies using bone marrow-derived macrophages showed that CD226 deletion potentiated M2 polarization and suppressed M1 polarization. Conclusion: CD226 expression is dramatically increased in the infarcted heart, and CD226 deletion improves post-infarction healing and cardiac function by favoring macrophage polarization towards reparative phenotype. Thus, inhibition of CD226 may represent a novel therapeutic approach to improve wound healing and cardiac function after MI.

Glucocorticoids and steroid sparing medications monotherapies or in combination for IgG4-RD: a systematic review and network meta-analysis.

OBJECTIVE: To assess the safety and efficacy of glucocorticoids (GCs), immunosuppressive agents (IM) and rituximab (RTX), alone or in combination, for the treatment of IgG4-RD. METHODS: Relevant articles published were searched in the databases with relevant key words. Network meta-analysis was conducted, with various outcomes including relapse rate, remission rate and adverse events. Data were calculated with odds ratio (ORs) and 95% CI. P-score was used to rank the treatments. RESULTS: A total of 15 studies involving 1169 patients were included. Network meta-analysis indicated that RTX maintenance therapy had the lowest relapse rate of all treatments (OR = 0.10, 95% CI [0.01, 1.63]), whereas GCs + IM was associated with a lower relapse rate compared with GCs alone (OR = 0.39, 95% CI [0.20, 0.80]). Further, patients treated with GCs + IM had a higher remission rate than those given GCs (OR= 3.36, 95% CI [1.44, 7.83]), IM (OR= 55.31, 95% CI [13.73, 222.73]) monotherapies or RTX induction therapy only (OR= 7.38, 95% CI [1.56, 34.94]). The rate of adverse events was comparable among the different treatment groups. CONCLUSION: Treatment of IgG4-RD patients with GCs and IM was associated with higher remission rates and lower relapse rates, as well as comparable safety profiles compared with GC, IM and RTX induction therapy. RTX maintenance therapy had a larger reduction in the relapse rate compared with GC and IM. The current evidence should be carefully scrutinized as the included studies were observational in design. Larger randomized controlled trials are needed to confirm.

PP2Cm overexpression alleviates MI/R injury mediated by a BCAA catabolism defect and oxidative stress in diabetic mice.

Diabetic patients are sensitive to myocardial ischemia-reperfusion (MI/R) injury. During diabetes, branched-chain amino acid (BCAA) catabolism is defective and mitochondrial phosphatase 2C (PP2Cm) expression is reduced. This study aims to elucidate the relationship between PP2Cm downregulation and BCAA catabolism defect in diabetic mice against MI/R injury. PP2Cm was significantly downregulated in hearts of diabetic mice. The cardiac function was improved and the myocardial infarct size and apoptosis were decreased in diabetic mice overexpressing PP2Cm after MI/R. In diabetic mice, the cardiac BCAA and its metabolites branched-chain keto-acids (BCKA) levels, and p-BCKDE1α (E1 subunit of BCKA dehydrogenase)/BCKDE1α ratio were increased while the BCKD activity was decreased. Treatment of diabetic mice subjected to MI/R injury with BT2, a BCKD kinase (BDK) inhibitor, alleviated the BCAA catabolism defect, and improved the cardiac function alongside reduced apoptosis. PP2Cm overexpression alleviated the BCAA catabolism defect and MI/R injury. Similarly, MnTBAP ameliorated the oxidative stress and MI/R injury. BCKA treatment of H9C2 cells under simulated ischemia/reperfusion (SI/R) injury significantly decreased cell viability and increased LDH release and apoptosis. These effects were alleviated by BT2 and MnTBAP treatments. These results suggested that PP2Cm directly mediates the BCAA catabolism defect and oxidative stress observed after MI/R in diabetes. Overexpression of PP2Cm alleviates MI/R injury by reducing the catabolism of BCAA and oxidative stress.