Hypercholesterolemia is a significant risk factor for the development of atherosclerosis. 2',3',5'-Tri-O-acetyl-N ⁶-(3-hydroxyphenyl) adenosine (IMM-H007), a novel AMPK agonist, has shown protective effects in metabolic diseases. However, its impact on cholesterol and triglyceride metabolism in hypercholesterolemia remains unclear. In this study, we aimed to elucidate the effects and specific mechanisms by which IMM-H007 regulates cholesterol and triglyceride metabolism. To achieve this goal, we used Apoe ^-/- and Ldlr ^-/- mice to establish a hypercholesterolemia/atherosclerosis model. Additionally, hepatocyte-specific Ampka1/2 knockout mice were subjected to a 5-week high-cholesterol diet to establish hypercholesterolemia, while atherosclerosis was induced via AAV-PCSK9 injection combined with a 16-week high-cholesterol diet. Our results demonstrated that IMM-H007 improved cholesterol and triglyceride metabolism in mice with hypercholesterolemia. Mechanistically, IMM-H007 modulated the AMPKα1/2-LDLR signaling pathway, increasing cholesterol uptake in the liver. Furthermore, IMM-H007 activated the AMPKα1-FXR pathway, promoting the conversion of hepatic cholesterol to bile acids. Additionally, IMM-H007 prevented hepatic steatosis by activating the AMPKα1/2-ATGL pathway. In conclusion, our study suggests that IMM-H007 is a promising therapeutic agent for improving hypercholesterolemia and atherosclerosis through the activation of AMPKα.

Sesquiterpenes are natural terpenes containing 15 carbon atoms. They are widely used in the perfume, pharmaceutical, and biofuel industries due to their remarkable biological activities. The traditional production of sesquiterpenes relies on chemical synthesis or plant extraction, which has the disadvantages of low yields and waste of resources. The construction of microbial cell factories for the efficient synthesis of sesquiterpenes by means of synthetic biology provides a new option. In recent years, with the development of metabolic engineering and synthetic biology, the heterologous synthesis of a variety of sesquiterpenes has been successfully achieved by metabolic engineering of the oleaginous yeast, Yarrowia lipolytica. In this paper, we review the research progress in the heterologous synthesis of different sesquiterpenes by Y. lipolytica, discuss the synthetic biology strategies commonly used in this field, and make an outlook on the research directions and engineering approaches to further enhance the sesquiterpene yield in this host. This paper provides a reference for strategies such as synergistic optimization of synthetic biology and metabolic engineering, enhanced precursors, and opens up new directions for the application of synthetic biology in green chemistry and sustainable production.
Yarrowia/genetics* ; Sesquiterpenes/metabolism* ; Metabolic Engineering/methods* ; Synthetic Biology/methods*

Humans ; Gastrointestinal Microbiome ; Constipation/therapy* ; Probiotics/therapeutic use* ; Patients

Objective:To investigate the comorbidity status of hypertension, diabetes, and dyslipidemia (the"three diseases") among residents aged≥40 in Liaoning Province, and to explore the correlation between the comorbidity and cardiovascular disease mortality.Methods:This investigation was a prospective cohort study. From February 2017 to March 2019, a multi-stage stratified cluster random sampling method was used to carry out a baseline survey of 18 758 permanent residents aged≥40 years in Liaoning Province. Demographic information and history of hypertension, diabetes, and dyslipidemia were collected and followed up every year. Death was mainly identified by linkage to the Population Death Information Registration Management System. Cox proportional hazard regression model was used to analyze the association between the comorbidity of the "three diseases" and cardiovascular disease mortality risk.Results:A total of 18 758 residents aged≥40 in Liaoning Province were included, with an age of (60.3±9.9) years and 7 325 males (39.1%). The comorbidity rate of hypertension, diabetes, and dyslipidemia was 6.7% (1 256/18 758), and the standardized prevalence rate was 5.4%. The comorbidity rate increased with age (P<0.001), which was higher in women than in men, and more significant in urban areas than in rural areas (all P<0.001). The comorbidity of "three diseases" accounted for 39.3% (1 256/3 198), 18.7% (1 256/6 710), and 11.8% (1 256/10 653) in patients with diabetes, dyslipidemia, and hypertension, respectively. With a follow-up of (4.3±0.6) years, 463 people died of cardiovascular disease. The mortality rate of cardiovascular disease in the comorbidity of hypertension, diabetes, and dyslipidemia was 8.74/1 000 person-years. After adjusting potential confounders, Cox proportional hazard regression model analysis showed that compared with normal individuals, the hazard ratio of cardiovascular disease mortality in patients with the "three diseases" was 2.55 (95% CI: 1.63-3.99). Conclusion:The prevalence of comorbidity of hypertension, diabetes, and dyslipidemia among residents aged≥40 in Liaoning Province was relatively high, and the risk of cardiovascular disease mortality in patients with the "three diseases" was increased.

Objective:To explore effects and mechanisms of medium and low doses X-ray irradiation on polarization type changes of tumor associated macrophages(TAMs).Methods:Mouse RAW264.7 macrophage line was cultured with supernatant of 4T1 tumor cell culture(4T1-TCS)of mouse breast cancer,and induced to M2 TAMs.On this basis,medium and low doses X-ray irra-diation was conducted,and NO was detected by Griess method,CD86 and CD206 were detected by flow cytometry.ELISA was use to detect cytokines IL-10 and IL-12p70,immunofluorescence was use to detect iNOS and Arg-1.Western blot was used to detect polariza-tion related pathway proteins,and whether medium and low doses of radiation could alter polarization type of TAMs was observed.Results:4T1-TCS induced TAM had decreasing NO secretion and increasing CD206 and Arg-1 expressions,iNOS expression was decreased;with low doses irradiation(0.075 Gy,0.5 Gy,1 Gy)of TCS-TAM,compared with non irradiation group,NO secretion,expressions of CD86,CD206,Arg-1 and iNOS showed no significant changes;medium doses(2 Gy,4 Gy,6 Gy)of irradiation on TCS-TAM resulted in increased secretion of NO,and flow cytometry results showed increased expressions of CD86,decreased CD206 expression;immunofluorescence results showed an increase in iNOS expression and a decrease in Arg-1 expression in cells;ELISA results showed an increase in secretion of IL-12p70 by cells and a decrease in secretion of IL-10.Western blot results showed that NOX2,ATMS1981*,IRF5 proteins expressions were increased.Conclusion:4T1-TCS can successfully induce macrophage RAW264.7 polarize into M2 phenotype,while low dose irradiation has no significant effect on polarization phenotype of TCS-TAM.Medium dose irradiation can induce TCS-TAM polarization into M1 phenotype that inhibits tumor growth,and reversal mechanism of polarization may be related to IRF5 pathway.

Objective:To explore the influence of social exclusion on the relapse tendency of female drug re-hab patients,and the mediating role of self-esteem and the moderating role of positive psychological capital.Method:A total of 288 female drug rehabilitation patients were selected,and the Social Exclusion Question-naire(SEQ)was used to assess the degree of social exclusion experienced by the patients.The Relapse Tendency Questionnaire(RPQ)was used to evaluate the current tendency of drug relapse.The Rosenberg Self-Esteem Scale(RSES)was used to evaluate the self-esteem level of the patients,and the Positive Psychological Capital Question-naire(PPCQ)was used to evaluate their level of positive psychological capital.Results:The SEQ scores of female drug rehab patients were positively correlated with the RPQ scores(β=0.41,P＜0.001),The RSES scores had a mediating effect between the scores of SEQ and RPQ,with a mediation effect size of 0.09(95％CI:0.04-0.15,accounting for 20.6％of the total effect).The PPCQ scores had a moderating effect between the scores of RSES and RPQ(β=-0.08,P＜0.05)and between the scores of SEQ and RPQ(β=0.10,P＜0.05).Conclusion:So-cial exclusion could not only directly affect but also indirectly affect the relapse tendency through self-esteem of fe-male drug rehab patients.Positive psychological capital could moderate the relationship between social exclusion,self-esteem,and relapse tendency.

OBJECTIVES: To explore the physicochemical characteristics and biocompatibility of calcium peroxide (CPO)-loaded polycaprolactone (PCL) microparticle. METHODS: The CPO/PCL particles were prepared. The morphology and elemental distribution of CPO, PCL and CPO/PCL particles were observed with scanning electron microscopy and energy dispersive spectroscopy, respectively. Rat adipose mesenchymal stem cells were isolated and treated with different concentrations (0.10%, 0.25%, 0.50%, 1.00%) of CPO or CPO/PCL particles. The mesenchymal stem cells were cultured in normal media or osteogenic differentiation media under the hypoxia/normoxia conditions, and the amount of released O₂ and H₂O₂ after CPO/PCL treatment were detected. The gene expressions of alkaline phosphatase (ALP), Runt-associated transcription factor 2 (RUNX2), osteopontin (OPN) and osteocalcin (OCN) were detected by realtime RT-PCR. SD rats were subcutaneously injected with 1.00% CPO/PCL particles and the pathological changes and infiltration of immune cells were observed with HE staining and immunohistochemistry at day 7 and day 14 after injection. RESULTS: Scanning electron microscope showed that CPO particles had a polygonal structure, PCL particles were in a small spherical plastic particle state, and CPO/PCL particles had a block-like crystal structure. Energy dispersive spectroscopy revealed that PCL particles showed no calcium mapping, while CPO/PCL particles showed obvious and uniform calcium mapping. The concentrations of O₂ and H₂O₂ released by CPO/PCL particles were lower than those of CPO group, and the oxygen release time was longer. The expressions of Alp, Runx2, Ocn and Opn increased with the higher content of CPO/PCL particles under hypoxia in osteogenic differentiation culture and normal culture, and the induction was more obvious under osteogenic differentiation conditions (all P<0.05). HE staining results showed that the muscle tissue fibers around the injection site were scattered and disorderly distributed, with varying sizes and thicknesses at day 7 after particle injection. Significant vascular congestion, widened gaps, mild interstitial congestion, local edema, inflammatory cell infiltration, and large area vacuolization were observed in some tissues of rats. At day 14 after microparticle injection, the muscle tissue around the injection site and the tissue fibers at the microparticle implantation site were arranged neatly, and the gap size was not thickened, the vascular congestion, local inflammatory cell infiltration, and vacuolization were significantly improved compared with those at day 7. The immunohistochemical staining results showed that the expressions of CD3 and CD68 positive cells significantly increased in the surrounding muscle tissue, and were densely distributed in a large area at day 7 after particle injection. At day 14 of microparticle injection, the numbers of CD3 and CD68 positive cells in peripheral muscle tissue and tissue at the site of particle implantation were lower than those at day 7 (all P<0.01). CONCLUSIONS CPO/PCL particles have good oxygen release activity, low damage to tissue, and excellent biocompatibility.
Rats ; Animals ; Osteogenesis ; Core Binding Factor Alpha 1 Subunit ; Rats, Sprague-Dawley ; Hydrogen Peroxide/pharmacology* ; Cell Differentiation ; Oxygen ; Hypoxia ; Cells, Cultured

【Objective】 To explore and verify the mechanism of curcumin’s inhibition of the proliferation of renal clear cell carcinoma （RCCC） based on network pharmacology and bioinformatics. 【Methods】 We screened common target genes of RCCC and curcumin from PharmMapper and GeneCards databases. We used TCGA database data analysis to screen out common target genes which not only differentially expressed between RCCC tissue samples and normal tissue samples but also affected prognosis. We also used STRING platform to construct curcumin-RCCC targets interaction network， used R software to perform GO biological process analysis and KEGG pathway enrichment analysis based on the above-mentioned screening target proteins. After curcumin and/or active oxygen inhibitor N-acetyl-L-cysteine （NAC） were incubated in renal cancer 786-O and ACHN cells， CCK8 was used to detect the effects of different concentrations of curcumin on cell proliferation and cell viability. Reactive oxygen detection kit （DCFH-DA） was used to detect the level of intracellular reactive oxygen species， and malondialdehyde （MDA） determination kit （TBA method） to detect intracellular malondialdehyde changes. 【Results】 PharmMapper website and GeneCards database screened out 109 common targets of curcumin and RCCC. TCGA database data analysis screened out 37 differentially expressed genes （DEGs） that might affect the overall survival of patients. The core target proteins of curcumin screened out by protein-protein interaction （PPI） that inhibited the biological behavior of RCCC mainly involved CASP3， EGFR， CHEK1， HSP90AA1， and AR. GO enrichment analysis identified 213 items， mainly including reactive oxygen species metabolic process， response to steroid hormones， fibrinolysis and other biologically active processes. KEGG enrichment analysis identified 24 items， which were mainly related to pyruvate metabolism， glycolysis/gluconeogenesis， FoxO signaling pathway， colorectal cancer， tyrosine metabolism， IL-17 signaling pathway， apoptosis and other signaling pathways. Curcumin reduced the cell viability of 786-O and ACHN in a time- and dose-dependent manner （P<0.05）. After curcumin was incubated with kidney cancer cells， the level of reactive oxygen species and MDA increased significantly （P<0.05）. The addition of NAC reversed the effect of curcumin on the cell viability of 786-O and ACHN cells （P<0.05）. 【Conclusion】 Curcumin may participate in the oxidative stress pathway to inhibit the proliferation of renal cell carcinoma.

Vacuum sealing drainage (VSD) is frequently used in abdominal surgeries. However, relevant guidelines are rare. Chinese Trauma Surgeon Association organized a committee composed of 28 experts across China in July 2017, aiming to provide an evidence-based recommendation for the application of VSD in abdominal surgeries. Eleven questions regarding the use of VSD in abdominal surgeries were addressed: (1) which type of materials should be respectively chosen for the intraperitoneal cavity, retroperitoneal cavity and superficial incisions? (2) Can VSD be preventively used for a high-risk abdominal incision with primary suture? (3) Can VSD be used in severely contaminated/infected abdominal surgical sites? (4) Can VSD be used for temporary abdominal cavity closure under some special conditions such as severe abdominal trauma, infection, liver transplantation and intra-abdominal volume increment in abdominal compartment syndrome? (5) Can VSD be used in abdominal organ inflammation, injury, or postoperative drainage? (6) Can VSD be used in the treatment of intestinal fistula and pancreatic fistula? (7) Can VSD be used in the treatment of intra-abdominal and extra-peritoneal abscess? (8) Can VSD be used in the treatment of abdominal wall wounds, wound cavity, and defects? (9) Does VSD increase the risk of bleeding? (10) Does VSD increase the risk of intestinal wall injury? (11) Does VSD increase the risk of peritoneal adhesion? Focusing on these questions, evidence-based recommendations were given accordingly. VSD was strongly recommended regarding the questions 2-4. Weak recommendations were made regarding questions 1 and 5-11. Proper use of VSD in abdominal surgeries can lower the risk of infection in abdominal incisions with primary suture, treat severely contaminated/infected surgical sites and facilitate temporary abdominal cavity closure.
Abdomen ; surgery ; China ; Drainage ; methods ; Evidence-Based Medicine ; Humans ; Practice Guidelines as Topic ; Societies, Medical ; organization & administration ; Surgical Wound Infection ; prevention & control ; Traumatology ; organization & administration ; Vacuum

The analysis of big data in medical field cannot be isolated from the high quality clinical database, and the construction of first aid database in our country is still in the early stage of exploration. This paper introduces the idea and key technology of the construction of multi-parameter first aid database. By combining emergency business flow with information flow, an emergency data integration model was designed with reference to the architecture of the Medical Information Mart for Intensive Care III (MIMIC-III), created by Computational Physiology Laboratory of Massachusetts Institute of Technology (MIT), and a high-quality first-aid database was built. The database currently covers 22 941 medical records for 19 814 different patients from May 2015 to October 2017, including relatively complete information on physiology, biochemistry, treatment, examination, nursing, etc. And based on the database, the first First-Aid Big Data Datathon event, which 13 teams from all over the country participated in, was launched. The First-Aid database provides a reference for the construction and application of clinical database in China. And it could provide powerful data support for scientific research, clinical decision making and the improvement of medical quality, which will further promote secondary analysis of clinical data in our country.
Big Data ; Critical Care ; Databases, Factual ; Humans ; Medical Informatics