Exercise accelerates recruitment of CD8+ T cell to promotes anti-tumor immunity in lung cancer via epinephrine.

BACKGROUND AND PURPOSE: In recent years, there has been extensive research on the role of exercise as an adjunctive therapy for cancer. However, the potential mechanisms underlying the anti-tumor therapy of exercise in lung cancer remain to be fully elucidated. As such, our study aims to confirm whether exercise-induced elevation of epinephrine can accelerate CD8+ T cell recruitment through modulation of chemokines and thus ultimately inhibit tumor progression. METHOD: C57BL/6 mice were subcutaneously inoculated with Lewis lung cancer cells (LLCs) to establish a subcutaneous tumor model. The tumor mice were randomly divided into different groups to performed a moderate-intensity exercise program on a treadmill for 5 consecutive days a week, 45 min a day. The blood samples and tumor tissues were collected after exercise for IHC, RT-qPCR, ELISA and Western blot. In addition, another group of mice received daily epinephrine treatment for two weeks (0.05 mg/mL, 200 µL i.p.) (EPI, n = 8) to replicate the effects of exercise on tumors in vivo. Lewis lung cancer cells were treated with different concentrations of epinephrine (0, 5, 10, 20 µM) to detect the effect of epinephrine on chemokine levels via ELISA and RT-qPCR. RESULTS: This study reveals that both pre- and post-cancer exercise effectively impede the tumor progression. Exercise led to an increase in EPI levels and the infiltration of CD8+ T cell into the lung tumor. Exercise-induced elevation of EPI is involved in the regulation of Ccl5 and Cxcl10 levels further leading to enhanced CD8+ T cell infiltration and ultimately inhibiting tumor progression. CONCLUSION: Exercise training enhance the anti-tumor immunity of lung cancer individuals. These findings will provide valuable insights for the future application of exercise therapy in clinical practice.

Angiotensin II type-2 receptor signaling facilitates liver injury repair and regeneration via inactivation of Hippo pathway.

The angiotensin II type 2 receptor (AT2R) is a well-established component of the renin-angiotensin system and is known to counteract classical activation of this system and protect against organ damage. Pharmacological activation of the AT2R has significant therapeutic benefits, including vasodilation, natriuresis, anti-inflammatory activity, and improved insulin sensitivity. However, the precise biological functions of the AT2R in maintaining homeostasis in liver tissue remain largely unexplored. In this study, we found that the AT2R facilitates liver repair and regeneration following acute injury by deactivating Hippo signaling and that interleukin-6 transcriptionally upregulates expression of the AT2R in hepatocytes through STAT3 acting as a transcription activator binding to promoter regions of the AT2R. Subsequently, elevated AT2R levels activate downstream signaling via heterotrimeric G protein Gα12/13-coupled signals to induce Yap activity, thereby contributing to repair and regeneration processes in the liver. Conversely, a deficiency in the AT2R attenuates regeneration of the liver while increasing susceptibility to acetaminophen-induced liver injury. Administration of an AT2R agonist significantly enhances the repair and regeneration capacity of injured liver tissue. Our findings suggest that the AT2R acts as an upstream regulator in the Hippo pathway and is a potential target in the treatment of liver damage.

Efficacy and safety of tafolecimab in Chinese patients with heterozygous familial hypercholesterolemia: a randomized, double-blind, placebo-controlled phase 3 trial (CREDIT-2).

BACKGROUND: Heterozygous familial hypercholesterolemia (HeFH) is largely underdiagnosed and undertreated in China where few patients achieved recommended target levels of low density lipoprotein cholesterol (LDL-C). We conducted the first randomized, placebo-controlled clinical trial in Chinese patients with HeFH to assess the efficacy and safety of tafolecimab, a novel fully human proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibody. METHODS: Patients diagnosed with HeFH by Simon Broome criteria and on a stable lipid-lowering therapy for at least 4 weeks were randomized 2:2:1:1 to receive subcutaneous tafolecimab 150 mg every 2 weeks (Q2W), tafolecimab 450 mg every 4 weeks (Q4W), placebo Q2W or placebo Q4W in the 12-week double-blind treatment period. After that, participants received open-label tafolecimab 150 mg Q2W or 450 mg Q4W for 12 weeks. The primary endpoint was the percent change from baseline to week 12 in LDL-C levels. Secondary endpoints included proportion of participants achieving ≥50% LDL-C reductions and proportion of participants with LDL-C <1.8 mmol/L at week 12 and 24, the change from baseline to week 12 in non-high density lipoprotein cholesterol (non-HDL-C), apolipoprotein B and lipoprotein(a) levels, as well as the change from baseline to week 24 in lipid levels. RESULTS: In total, 149 participants were randomized and 148 received at least one dose of the study treatment. At week 12, tafolecimab treatment induced significant reductions in LDL-C levels (treatment difference versus placebo [on-treatment estimand]: -57.4% [97.5% CI, -69.2 to -45.5] for 150 mg Q2W; -61.9% [-73.4 to -50.4] for 450 mg Q4W; both P <0.0001). At both dose regimens, significantly more participants treated with tafolecimab achieved ≥50% LDL-C reductions or LDL-C <1.8 mmol/L at week 12 as compared with corresponding placebo groups (all P <0.0001). Meanwhile, non-HDL-C, apolipoprotein B and lipoprotein(a) levels were significantly reduced in the tafolecimab groups at week 12. The lipid-lowering effects of tafolecimab were maintained till week 24. During the double-blind treatment period, the most commonly-reported adverse events in the tafolecimab groups included upper respiratory tract infection, increased blood creatine phosphokinase, increased alanine aminotransferase, increased aspartate aminotransferase and hypertension. CONCLUSIONS: Tafolecimab administered either 150 mg Q2W or 450 mg Q4W yielded significant and persistent reductions in LDL-C levels and showed a favorable safety profile in Chinese patients with HeFH. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04179669.

Surface Metallization of Porous Polymer Materials for Multifunctional Applications.

Porous materials have attracted great interest in recent years, and a variety of surface modification methods have been developed to endow porous materials with multifunctional applications. Herein, multifunctional porous materials are fabricated based on surface metallization. Metallized sponges with Ag and Cu are highly hydrophobic and are still hydrophobic under oil. The metallized sponges selectively adsorb oils from oil/water mixtures and can completely remove oils from water. We further demonstrate continuous oil-water separation by the metallized sponges with the aid of a peristaltic pump. The Ag-metallized materials show high catalytic performance for both chemical reduction and dye degradation. The catalytic reduction efficiency of 4-nitrophenol reaches 97.7% within 60 min and remains as high as 96% after 15 cycles. Moreover, the metallized materials show 99.99% bactericidal efficiency for both Staphylococcus aureus and Escherichia coli. Particularly, the Cu-metallized materials exhibit stable conductivity under deformation; and metal patterns are realized via the metallization method combined with a patterned mask, which may provide a feasible approach for flexible electronics. This work provides a versatile method to introduce metal coatings to porous materials, broadening the applications of porous materials.

Ticagrelor Versus Clopidogrel in Patients with Two CYP2C19 Loss-of-Function Alleles Undergoing Percutaneous Coronary Intervention.

PURPOSE: To compare the risk of cardiovascular events between patients with two CYP2C19 loss-of-function alleles who were prescribed ticagrelor or clopidogrel after percutaneous coronary intervention (PCI). METHODS: Patients with two loss-of-function alleles based on the CYP2C19 genotype were selected from patients enrolled in a retrospective institutional registry. Propensity score matching using logistic regression was performed to adjust for bias between patients prescribed ticagrelor or clopidogrel. Multivariate Cox regression was used to compare the risk of adverse events in the ticagrelor and clopidogrel groups. The primary outcome was the incidence of major adverse cardiac events plus any repeat target vessel revascularization within 12 months after PCI. The safety outcomes were minor and major bleeding events. RESULTS: From 1518 patients carrying two loss-of-function alleles based on the CYP2C19 genotype who underwent PCI, 638 patients treated with ticagrelor or clopidogrel were successfully propensity-score matched. The primary outcome occurred in 25 patients (7.8%) in the ticagrelor group and 47 (14.7%) in the clopidogrel group. The risk of the primary outcome was significantly lower in the ticagrelor group versus the clopidogrel group (HR 0.466, 95% CI 0.286-0.759, p = 0.002). The incidence of major bleeding events did not significantly differ between the ticagrelor and clopidogrel groups (0.3% and 0.9%, respectively), while the ticagrelor group had a higher risk of minor bleeding events (HR 1.959, 95% CI 1.396-2.750, p < 0.001). CONCLUSIONS: In patients with two CYP2C19 loss-of-function alleles, ticagrelor was more effective than clopidogrel in preventing cardiovascular events, while the two antiplatelet agents were associated with similar incidences of major bleeding.

Measurement of internal stray radiation of a thermal infrared spectrometer based on temperature variation.

The level of internal stray radiation is an important criterion to evaluate the performance of a thermal infrared spectrometer. In this study, a novel method is proposed and evaluated to measure the internal stray radiation of a thermal infrared spectrometer based on temperature variation. The proposed method was used to measure the internal stray radiation values of an existing instrument. First, two output gray value curves were constructed for a single spectral channel in a cryogenic detector at two different spectrometer temperatures based on radiometric calibration measurements. Subsequently, the gray value and radiation flux of the internal stray radiation of the spectrometer were calculated. In addition, the internal stray radiation data measured at different spectral channels and different integration times were used to verify and evaluate the proposed method. Results show that the proposed method is valid, and the standard deviations of the various internal radiation values of the tested spectral channels and the various integration times are 3.47% and 1.46%, respectively. The proposed method is adaptable, flexible, and efficient.

Valsartan Attenuates Atherosclerosis via Upregulating the Th2 Immune Response in Prolonged Angiotensin II-Treated ApoE(-/-) Mice.

Valsartan has a protective effect against hypertension and atherosclerosis in humans and experimental animal models. This study aimed to determine the effect of prolonged treatment with angiotensin II (Ang II) on atherosclerosis and the effect of valsartan on the activity of CD4(+) T lymphocyte subsets. The results showed that prolonged treatment (8 wks) with exogenous Ang II resulted in an increased atherosclerotic plaque size and a switch of stable-to-unstable plaque via modulating on CD4(+) T lymphocyte activity, including an increase in the T helper cell type 1 (Th1) and Th17 cells and a decrease in Th2 and regulatory T (Treg) cells. In contrast, valsartan treatment efficiently reversed the imbalance in CD4(+) T lymphocyte activity, ameliorated atherosclerosis and elicited a stable plaque phenotype in addition to controlling blood pressure. In addition, treatment with anti-interleukin (IL)-5 monoclonal antibodies weakened the antiatherosclerotic effects of valsartan without affecting blood pressure.

MiR-378 Plays an Important Role in the Differentiation of Bovine Preadipocytes.

BACKGROUND: Adipocyte, the main cellular component of white adipose tissue, plays a vital role in energy balance in higher eukaryotes. In recent years, adipocytes have also been identified as a major endocrine organ involved in immunological responses, vascular diseases, and appetite regulation. In farm animals, fat content and categories are closely correlated with meat quality. MicroRNAs (miRNAs), a class of endogenous single-stranded non-coding RNA molecules, participate in the regulation of adipocyte differentiation and adipogenesis through regulating the transcription or translation of target mRNAs. MiR-378 plays an important role in a number of biological processes, including cell growth, cell differentiation, tumor cell survival and angiogenesis. METHODS: In the present study, bioinformatics analysis and dual-luciferase reporter assay were used to identify and validate the target genes of miR-378. In vitro cell transfection, quantitative reverse transcription polymerase chain reaction (RT-qPCR), western blot analysis, Oil Red O staining, and triglyceride content measurement were conducted to analyze the effects of miR-378 on bovine preadipocyte differentiation. RESULTS: MiR-378 was induced during adipocyte differentiation. In the differentiated adipocytes overexpressing miR- 378, the volume of lipid droplets was enlarged, and the triglyceride content was increased. Moreover, the mRNA expression levels of the adipocyte differentiation marker genes, peroxisome proliferator-activated receptor gamma (PPARγ) and sterol regulatory element-binding protein (SREBP), were significantly elevated in the differentiated, mature adipocytes. In contrast, the mRNA expression level of preadipocyte factor 1 (Pref-1) was markedly reduced. E2F transcription factor 2 (E2F2) and Ras-related nuclear (RAN)-binding protein 10 (RANBP10) were the two target genes of miR-378. The mRNA expression levels of E2F2 and RANBP10 did not significantly change in bovine preadipocytes overexpressing miR-378. However, the protein expression levels of E2F2 and RANBP10 were markedly reduced. CONCLUSION: MiR-378 promoted the differentiation of bovine preadipocytes. E2F2 and RANBP10 were the two target genes of miR-378, and might involve in the effects of miR-378 on the bovine preadipocyte differentiation.

Chemerin is a novel biomarker of acute coronary syndrome but not of stable angina pectoris.

BACKGROUND: Recent evidence demonstrated that the circulating adipokines were associated with the onset of acute coronary syndrome (ACS) including unstable angina pectoris (UAP) and acute myocardial infarction (AMI). As a novel adipokine, chemerin has been related to atherosclerosis and the presence of coronary artery disease. However, the plasma levels of chemerin in patients with ACS have yet to be investigated. METHODS: Plasma levels of chemerin and adiponectin were measured by an enzyme-linked immunosorbent assay (ELISA) in 60 patients with stable angina pectoris (SAP), 60 patients with UAP, 60 patients with AMI and 40 control patients. Left ventricular end-diastolic diameter (LVEDD) and left ventricular ejection fraction (LVEF) were measured using a GE ViVid E7 ultrasonography machine, and the severity of coronary stenosis in patients was estimated with a Gensini coronary score following coronary angiography. RESULTS: Plasma chemerin levels were significantly higher in ACS patients than in the control and SAP groups, while plasma adiponectin levels were significantly lower in ACS patients than the control group. A correlation analysis revealed that plasma chemerin levels were positively correlated with the levels of C-reactive protein (CRP) (r = 0.29, P < 0.01) and LVEDD (r = 0.27, P < 0.01) but negatively correlated with LVEF (r = -0.45, P < 0.01) and that plasma adiponectin levels were positively correlated with LVEF (r = 0.53, P < 0.01) but negatively correlated with CRP (r = -0.33, P < 0.01) and LVEDD (r = -0.30, P < 0.01). Although significant correlations between chemerin, adiponectin and BMI or the Gensini coronary score were found in patients with SAP, neither chemerin nor adiponectin was correlated with BMI and the Gensini coronary score in patients with ACS. Furthermore, both chemerin (OR 1.103, 95% CI 1.065 to 1.142; P = 0.001) and adiponectin (OR 0.871, 95% CI 0.776 to 0.970; P = 0.018) were independently associated with the presence of ACS. CONCLUSIONS: Chemerin is a novel biomarker of acute coronary syndrome but not of stable angina pectoris.

Elevated plasma IL-37, IL-18, and IL-18BP concentrations in patients with acute coronary syndrome.

OBJECTIVE: More recently, evidence showed that the novel anti-inflammatory cytokine interleukin- (IL-) 37 was expressed in the foam-like cells of atherosclerotic coronary and carotid artery plaques, suggesting that IL-37 is involved in atherosclerosis-related diseases. However, the plasma levels of IL-37 in patients with acute coronary syndrome (ACS, including unstable angina pectoris and acute myocardial infarction) have yet to be investigated. METHODS: Plasma IL-37, IL-18, and IL-18BP levels were measured in 50 patients with stable angina pectoris (SAP), 75 patients with unstable angina pectoris (UAP), 67 patients with acute myocardial infarction (AMI), and 65 control patients. RESULTS: The plasma IL-37, IL-18, and IL-18BP levels were significantly increased in ACS patients compared to SAP and control patients. A correlation analysis showed that the plasma biomarker levels were positively correlated with each other and with the levels of C-reactive protein (CRP), N-terminal probrain natriuretic peptide (NT-proBNP), and left ventricular end-diastolic dimension (LVEDD) but negatively correlated with left ventricular ejection fraction (LVEF). Furthermore, the plasma IL-37, IL-18, and IL-18BP had no correlation with the severity of the coronary artery stenosis. CONCLUSIONS: The results indicate that the plasma IL-37 levels are associated with the onset of ACS.

The GSK3ß/Mcl-1 axis is regulated by both FLT3-ITD and Axl and determines the apoptosis induction abilities of FLT3-ITD inhibitors.

Acute myeloid leukemia (AML) patients with FLT3-ITD mutations are associated with poor prognosis. FLT3-ITD inhibitors are developed and result in transient disease remission, but generally resistance develops. We propose that resistance occurs due to apoptosis evasion. We compared the abilities of five clinically used FLT3-ITD inhibitors, namely, midostaurin, crenolanib, gilteritinib, quizartinib, and sorafenib, to induce apoptosis. These drugs inhibit FLT3-ITD and induce apoptosis. Apoptosis induction is associated with GSK3ß activation, Mcl-1 downregulation, and Bim upregulation. Sorafenib-resistant MOLM-13/sor cells have the secondary D835Y mutation and increased Axl signaling pathway with cross-resistance to quizartinib. Gilteritinib and crenolanib inhibit both FLT3-ITD and Axl and induce apoptosis in MOLM-13/sor cells, in which they activate GSK3ß and downregulate Mcl-1. Inactivation of GSK3ß through phosphorylation and inhibitors blocks apoptosis and Mcl-1 reduction. The Axl/GSK3ß/Mcl-1 axis works as a feedback mechanism to attenuate apoptosis of FLT3-ITD inhibition. Homoharringtonine decreases the protein levels of Mcl-1, FLT3-ITD, and Axl. Moreover, it synergistically induces apoptosis with gilteritinib in vitro and prolongs survival of MOLM-13/sor xenografts. The GSK3ß/Mcl-1 axis works as the hub of FLT3-ITD inhibitors and plays a critical role in resistance against FLT3-ITD AML-targeted therapy.

Combinatorial Protein Engineering and Metabolic Engineering for Efficient Synthesis of l-Histidine in Corynebacterium glutamicum.

l-Histidine is an essential proteinogenic amino acid in food with extensive applications in the pharmaceutical field. Herein, we constructed a Corynebacterium glutamicum recombinant strain for efficient biosynthesis of l-histidine. First, to alleviate the l-histidine feedback inhibition, the ATP phosphoribosyltransferase mutant HisGT235P-Y56M was constructed based on molecular docking and high-throughput screening, resulting in the accumulation of 0.83 g/L of l-histidine. Next, we overexpressed rate-limiting enzymes including HisGT235P-Y56M and PRPP synthetase and knocked out the pgi gene in the competing pathway, which increased the l-histidine production to 1.21 g/L. Furthermore, the energy status was optimized by decreasing the reactive oxygen species level and enhancing the supply of adenosine triphosphate, reaching a titer of 3.10 g/L in a shake flask. The final recombinant strain produced 5.07 g/L of l-histidine in a 3 L bioreactor, without the addition of antibiotics and chemical inducers. Overall, this study developed an efficient cell factory for l-histidine biosynthesis by combinatorial protein engineering and metabolic engineering.

Design of Rural Human Resource Management Platform Integrating IoT and Cloud Computing.

With the advent of the Internet of Things era, these hot technologies such as distributed, parallel computing, network storage, and load balancing can provide a good application foundation for the Internet of Things, enabling real-time dynamic management and intelligent analysis of hundreds of millions of items in the Internet of Things to be possible. The Internet of Things has changed from a concept to a reality, quickly reaching every corner of society. On the other hand, with the enhancement of the mobility of social talents, the file management of the talent service center is becoming more and more difficult. However, the traditional management methods of human resources files have problems such as poor resource sharing, asymmetric resources, and heterogeneous information sharing, which can no longer meet the needs of both the supply and demand sides of human resources with diversified and multiple organizational structures. Cloud computing technology has powerful data collection functions, self-service functions, and unified resource scheduling functions. Introducing it into the human resources file management system can greatly improve management efficiency. In order to carry out information management of rural human resources, this paper develops a rural human resources management system based on the Internet of Things. This paper introduces the design scheme of rural human resource management platform based on Internet of Things technology and cloud computing technology. The design of this system mainly includes organization setting, post planning, personnel management, salary management, insurance benefits, recruitment and selection, training management, performance appraisal management, labor contract management, comprehensive inquiry, rules and regulations, employee self-help, system setting, and system management function modules. The research results show that the rural human resource management system based on cloud computing can provide a complete human resource management solution for the vast rural areas. It can only purchase services, save a lot of development and maintenance costs, and also customize functions, so as to better meet the needs of use.

Efficacy and Safety of Direct Oral Anticoagulants in the Treatment of Left Ventricular Thrombus After Acute Anterior Myocardial Infarction in Patients Who Underwent Percutaneous Coronary Intervention.

AIMS: To explore treatment with Direct Oral Anticoagulants (DOACs) in left ventricular thrombus (LVT) after ST-segment elevation myocardial infarction (STEMI) in patients who underwent percutaneous coronary intervention (PCI). BACKGROUND: Contemporary data regarding using DOACs for LVT after STEMI patients who underwent PCI is limited. OBJECTIVES: To investigate the efficacy and safety of DOACs on the treatment of LVT post STEMI and PCI. METHODS: This retrospective study enrolled patients with LVT post STEMI and PCI within 1month from onset who received warfarin or DOACs at discharge. The primary endpoint was LVT resolution. Secondary endpoints were major adverse cardiovascular events (MACEs), including death, stroke, systemic embolism (SE), myocardial infarction (MI) and major or minor bleeding. RESULTS: A total of 128 consecutive patients were recruited, of which 72 received warfarin and 56 DOACs [48 on rivaroxaban and 8 on dabigatran]. The rate of LVT resolution was higher within 1 month in the DOACs group than warfarin (26.8% vs. 11.1%; p = 0.022) (Kaplan-Meier estimates, p = 0.002). No significant differences were found at 3 months (p = 0.246), 6 months (p = 0.201), 9 months (p = 0.171) and 12 months (p = 0.442). No patients treated with DOACs had major bleeding, while two patients with warfarin had upper gastrointestinal bleeding (0 vs. 2 (2.8%); p = 0.209). No death or SE occurred. No significant differences on secondary endpoints were found in both the groups, including stroke, MI, minor bleeding and all bleeding events. CONCLUSION: DOACs appear to be a suitable alternative to warfarin for the management of LVT post STEMI, especially in patients who are intolerant to warfarin.

Evaluation of porcine urine-derived cells as nuclei donor for somatic cell nuclear transfer.

BACKGROUND: Somatic cell nuclear transfer (SCNT) is used widely in cloning, stem cell research, and regenerative medicine. The type of donor cells is a key factor affecting the SCNT efficiency. OBJECTIVES: This study examined whether urine-derived somatic cells could be used as donors for SCNT in pigs. METHODS: The viability of cells isolated from urine was assessed using trypan blue and propidium iodide staining. The H3K9me3/H3K27me3 level of the cells was analyzed by immunofluorescence. The in vitro developmental ability of SCNT embryos was evaluated by the blastocyst rate and the expression levels of the core pluripotency factor. Blastocyst cell apoptosis was examined using a terminal deoxynucleotidyl transferase dUTP nick end-labeling assay. The in vivo developmental ability of SCNT embryos was evaluated after embryo transfer. RESULTS: Most sow urine-derived cells were viable and could be cultured and propagated easily. On the other hand, most of the somatic cells isolated from the boar urine exhibited poor cellular activity. The in vitro development efficiency between the embryos produced by SCNT using porcine embryonic fibroblasts (PEFs) and urine-derived cells were similar. Moreover, The H3K9me3 in SCNT embryos produced from sow urine-derived cells and PEFs at the four-cell stage showed similar intensity. The levels of Oct4, Nanog, and Sox2 expression in blastocysts were similar in the two groups. Furthermore, there is a similar apoptotic level of cloned embryos produced by the two types of cells. Finally, the full-term development ability of the cloned embryos was evaluated, and the cloned fetuses from the urine-derived cells showed absorption. CONCLUSIONS: Sow urine-derived cells could be used to produce SCNT embryos.

Perivascular adipose-derived exosomes reduce macrophage foam cell formation through miR-382-5p and the BMP4-PPARγ-ABCA1/ABCG1 pathways.

Background Perivascular adipose tissue (PVAT) releases exosomes (EXOs) to regulate vascular homeostasis. PVAT-derived EXOs reduce macrophage foam cell formation, but the underlying molecular mechanism has yet to be fully elucidated. We hypothesize that PVAT release miRNA through EXOs and regulate the expression of cholesterol transporter of macrophages, thereby reducing foam cell formation. Methods and results Through RT-qPCR, we identified that miR-382-5p, which was expressed at lower levels in PVAT-EXOs from coronary atherosclerotic heart disease patients than healthy individuals, was expressed at higher levels in wild-type C57BL/6 J mouse aortic PVAT-EXOs than in subcutaneous adipose tissue-derived EXOs. We explored macrophage lipid accumulation through oil red O staining, assessed cholesterol uptake and efflux, and verified cholesterol transporter expression. We found that transfection with a miR-382-5p inhibitor offset PVAT-EXO-related reductions in macrophage foam cell formation and increases in cholesterol efflux mediated by ATP-binding cassette transporter A1 (ABCA1) and ATP-binding cassette transporter G1 (ABCG1). In addition, bone morphogenetic protein 4 (BMP4) pretreatment and si-peroxisome proliferator-activated receptor γ (PPARγ) transfection showed that BMP4-PPARγ participated in PVAT-EXO-mediated upregulation of the cholesterol efflux transporters ABCA1 and ABCG1. Conclusions PVAT-EXOs reduce macrophage foam cell formation through miR-382-5p- and BMP4-PPARγ-mediated upregulation of the cholesterol efflux transporters ABCA1 and ABCG1. This finding suggests a promising strategy for the prevention and treatment of atherosclerosis.

Synthetic Biology Toolkits and Metabolic Engineering Applied in Corynebacterium glutamicum for Biomanufacturing.

Corynebacterium glutamicum is an important workhorse in industrial white biotechnology. It has been widely applied in the producing processes of amino acids, fuels, and diverse value-added chemicals. With the continuous disclosure of genetic regulation mechanisms, various strategies and technologies of synthetic biology were used to design and construct C. glutamicum cells for biomanufacturing and bioremediation. This study mainly aimed to summarize the design and construction strategies of C. glutamicum-engineered strains, which were based on genomic modification, synthetic biological device-assisted metabolic flux optimization, and directed evolution-based engineering. Then, taking two important bioproducts (N-acetylglucosamine and hyaluronic acid) as examples, the applications of C. glutamicum cell factories were introduced. Finally, we discussed the current challenges and future development trends of C. glutamicum-engineered strain construction.

Efficacy and Safety of Evolocumab in Reducing Low-Density Lipoprotein Cholesterol Levels in Chinese Patients with Non-ST-segment Elevation Acute Coronary Syndrome.

AIMS: This study aims to explore early intensive lipid-lowering therapy in patients with non- ST-segment elevation acute coronary syndrome (NSTE-ACS). BACKGROUND: Lowering low-density lipoprotein cholesterol (LDL-C) levels can reduce cardiovascular morbidity and mortality in patients with atherosclerotic cardiovascular disease. Due to many reasons, the need for early intensive lipid-lowering therapy is far from being met in Chinese NSTE-ACS patients at high risk of recurrent ischaemic events. OBJECTIVE: This study evaluates the feasibility, safety and efficacy of starting evolocumab in hospitals to lower LDL-C levels in Chinese patients with NSTE-ACS. METHODS: In this prospective cohort study initiated by researchers, 334 consecutive patients with NSTEACS who had sub-standard LDL-C levels (LDL-C ≥2.3 mmol/L after regular oral statin treatment for at least 4 weeks; or LDL-C ≥3.2 mmol/L without regular oral statin treatment) were included. Patients who agreed to treatment with evolocumab (140 mg subcutaneously every 2 weeks, initiated in hospital and used for 12 weeks after discharge) were enrolled in the evolocumab group (n=96) and others in the control group (n=238). All enrolled patients received regular statin treatment (atorvastatin 20 mg/day or rosuvastatin 10 mg/day; doses unchanged throughout the study). The primary endpoint was the change in LDL-C levels from baseline to week 12. RESULTS: Most patients (67.1%) had not received regular statin treatment before. In the evolocumab group, LDL-C levels decreased significantly at week 4 and remained stable at week 8 and 12 (all p<0.001). At week 12, the LDL-C percentage change from baseline in the evolocumab group was - 79.2±12.7% (from an average of 3.7 to 0.7 mmol/L), while in the control group, it was -37.4±15.4% (from an average of 3.3 to 2.0 mmol/L). The mean difference between these 2 groups was -41.8% (95% CI -45.0 to -38.5%; p<0.001). At week 12, the proportion of patients with LDL-C levels <1.8 mmol/L and 1.4 mmol/L in the evolocumab group was significantly higher than in the control group (96.8 vs 36.1%; 90.6 vs 7.1%; both p<0.001). The incidences of adverse events and cardiovascular events were similar in both the groups. CONCLUSION: In this prospective cohort study, we evaluated the early initiation of evolocumab in NSTEACS patients in China. Evolocumab combined with statins significantly lowered LDL-C levels and increased the probability of achieving recommended LDL-C levels, with satisfactory safety and good tolerance.

Perivascular Adipose-Derived Exosomes Reduce Foam Cell Formation by Regulating Expression of Cholesterol Transporters.

Background: Accumulating evidence demonstrates that perivascular adipose tissue (PVAT) plays an important role in maintaining vascular homeostasis. The formation of macrophage foam cells is a central feature of atherosclerosis. This study aimed to evaluate the effect of PVAT-derived exosomes (EXOs) on the lipid accumulation of macrophages and verify the anti-atherogenic characteristics of PVAT. Methods and Results: We extracted EXOs from the PVAT and subcutaneous adipose tissue (SCAT) of wild-type C57BL/6J mice. After coincubation, the EXOs were taken up by RAW264.7 cells. Oil Red O staining revealed that macrophage foam cell formation and intracellular lipid accumulation were ameliorated by PVAT-EXOs. Flow cytometry showed that PVAT-EXOs significantly reduced macrophage uptake of fluorescence-labelled oxidised low-density lipoprotein (ox-LDL). In addition, high-density lipoprotein-induced cholesterol efflux was promoted by PVAT-EXOs. Western blot analysis showed the downregulation of macrophage scavenger receptor A and the upregulation of ATP-binding cassette transporter A1 and ATP-binding cassette transporter G1, which could be mediated by the overexpression of peroxisome proliferator-activated receptor γ and was independent of liver X receptor α. Conclusion: Our findings suggest that PVAT-EXOs reduce macrophage foam cell formation by regulating the expression of cholesterol transport proteins, which provides a novel mechanism by which PVAT protects the vasculature from atherosclerosis.

Real world effectiveness of PCSK-9 inhibitors combined with statins versus statins-based therapy among patients with very high risk of atherosclerotic cardiovascular disease in China (RWE-PCSK study).

BACKGROUND: The efficacy and safety of proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors were confirmed by several clinical trials, but its effectiveness in routine clinical practice in China has not been evaluated. This study aims to describe the real world effectiveness of PCSK-9 inhibitors combined with statins compared with statins-based therapy among patients with very high risk of atherosclerotic cardiovascular disease (ASCVD). METHODS: This is a multi-center observational study, enrolled patients from 32 hospitals who underwent percutaneous coronary intervention (PCI) from January to June in 2019. There are 453 patients treated with PCSK-9 inhibitors combined with statins in PCSK-9 inhibitor group and 2,610 patients treated with statins-based lipid lowering therapies in statins-based group. The lipid control rate and incidence of major adverse cardiovascular events (MACE) over six months were compared between two groups. A propensity score-matched (PSM) analysis was used to balance two groups on confounding factors. Survival analysis using Kaplan-Meier methods was applied for MACE. RESULTS: In a total of 3,063 patients, 89.91% of patients had received moderate or high-intensity statins-based therapy before PCI, but only 9.47% of patients had low-density lipoprotein cholesterol (LDL-C) levels below 1.4 mmol/L at baseline. In the PSM selected patients, LDL-C level was reduced by 42.57% in PCSK-9 inhibitor group and 30.81% (P < 0.001) in statins-based group after six months. The proportion of LDL-C ≤ 1.0 mmol/L increased from 5.29% to 29.26% in PCSK-9 inhibitor group and 0.23% to 6.11% in statins-based group, and the proportion of LDL-C ≤ 1.4 mmol/L increased from 10.36% to 47.69% in PCSK-9 inhibitor group and 2.99% to 18.43% in statins-based group ( P < 0.001 for both). There was no significant difference between PCSK-9 inhibitor and statins-based treatment in reducing the risk of MACE (hazard ratio = 2.52, 95% CI: 0.49-12.97, P = 0.250). CONCLUSIONS: In the real world, PCSK-9 inhibitors combined with statins could significantly reduce LDL-C levels among patients with very high risk of ASCVD in China. The long-term clinical benefits for patients received PCSK-9 inhibitor to reduce the risk of MACE is still unclear and requires further study.