Objective To investigate the effect of dexmedetomidine(Dex)on inflammatory injury in rats with lipopolysaccharide(LPS)-induced myocarditis(Myo)by regulating AMP-activated protein kinase(AMPK)/silent information regulator 1(SIRT1)/nuclear factor κB(NF-κB)signaling pathway.Methods Rats were randomly divide into the NC group,the Myo group,and the L-Dex group(10 μg/kg Dex),the M-Dex group(30 μg/kg Dex),the H-Dex group(50 μg/kg Dex),the AICAR group(100 mg/kg AMPK/SIRT1/NF-κB signal pathway activator),the H-Dex+GSK690693 group(50 μg/kg Dex+0.2 μmol/kg AMPK/SIRT1/NF-κB signal pathway inhibitor GSK690693),with 10 rats in each group.M-mode echocardiography system was used to evaluate the cardiac function of rats;ELISA kit was used to detect the levels of serum interleukin-1β(IL-1β),interleukin-6(IL-6),tumor necrosis factor-α(TNF-α),superoxide dismutase(SOD),and malondialdehyde(MDA)in rats;TUNEL staining was used to observe cell apoptosis;HE staining was used to observe the pathological changes of myocardial tissue;RT-qPCR was used to detect the mRNA expression of C-X-C motif chemokine ligand 1(CXCL1),C-X-C motif chemokine ligand 2(CXCL2),and vascular cell adhesion molecule-1(VCAM-1)in rat myocardial tissue;Western blot was used to detect the expression of AMPK/SIRT1/NF-κB pathway-related proteins in rat myocardial tissue.Results There was no abnormal change in cardiomyocytes in the NC group,and cardiomyocytes in the Myo group showed deformation,necrosis,inflammatory cell infiltra-tion,and mesenchymal congestion;necrosis,inflammatory cell infiltration,and mesenchymal congestion in the L-Dex group,the M-Dex group,the H-Dex group,and the AICAR group were improved compared with that in the Myo group;changes in cardiomyocytes in the H-Dex group and the AICAR group were similar to those in the NC group,and changes in cardiomyocytes in the H-Dex+GSK690693 group were similar to those in the Myo group.Compared with the NC group,the left ventricular ejection fraction(LVEF),left ventricular fractional shortening(LVFS),expression levels of SOD,p-AMPK/AMPK,p-SIRT1/SIRT1 in the Myo group were obviously decreased(P<0.05),left ventricular end-systolic volume(LVESV),left ventricular end-diastolic volume(LVEDV),left ventricular end-systolic diameter(LVESD),left ventricular end-diastolic diameter(LVEDD),expression levels of IL-1β,IL-6,TNF-α,MDA,CXCL1,CXCL2,VCAM-1,p-NF-κB/NF-κB,NF-κB p65 and cardiomyocyte apoptosis rate were obviously increased(P<0.05).Compared with the Myo group,the LVEF,LVFS,expression levels of SOD,p-AMPK/AMPK,p-SIRT1/SIRT1 in the L-Dex group,the M-Dex group,the H-Dex group and the AICAR group were obviously increased(P<0.05),LVESV,LVEDV,LVESD,LVEDD,expression levels of IL-1β,IL-6,TNF-α,MDA,CXCL1,CXCL2,VCAM-1,p-NF-κB/NF-κB,NF-κB p65 and cardiomyocyte apoptosis rate were obviously decreased(P<0.05),and the effects were more obvious with the increase of the dosage of Dex.There was no significant difference in the above results between the AICAR group and the H-Dex group(P>0.05).Compared with the H-Dex group,the LVEF,LVFS,expression levels of SOD,p-AMPK/AMPK,p-SIRT1/SIRT1 in the H-Dex+GSK690693 group were obviously decreased(P<0.05),LVESV,LVEDV,LVESD,LVEDD,levels of IL-1β,IL-6,TNF-α,MDA,cardiomyocyte apoptosis rate,the expression of CXCL1,CXCL2,VCAM-1,p-NF-κB/NF-κB and NF-κB p65 protein were obviously increased(P<0.05).Conclusion Dex may alleviate LPS-induced inflammatory injury in Myo rats by up-regulating AMPK/SIRT1/NF-κB signaling pathway.

The active ingredients in traditional Chinese medicine(TCM)are the foundation for the efficiency of TCM and the key to the formation of Dao-di herbs. It is of great significance to study the biosynthesis and regulation mechanisms of these active ingredients for analyzing the formation mechanism of Daodi herbs and providing components for the production of active ingredients in TCM by synthetic biology. With the advancements in omics technology, molecular biology, synthetic biology, artificial intelligence, etc., the analysis of biosynthetic pathways for active ingredients in TCM is rapidly progressing. New methods and technologies have promoted the analysis of the synthetic pathways of active ingredients in TCM and have also made this area a hot topic in molecular pharmacognosy. Many researchers have made significant progress in analyzing the biosynthetic pathways of active ingredients in TCM such as Panax ginseng, Salvia miltiorrhiza, Glycyrrhiza uralensis, and Tripterygium wilfordii. This paper systematically reviewed current research me-thods for analyzing the biosynthetic functional genes of active ingredients in TCM, elaborated the mining of gene elements based on multiomics technology and the verification of gene functions in plants in vitro and in vivo with candidate genes as objects. Additionally, the paper summarized new technologies and methods that have emerged in recent years, such as high-throughput screening, molecular probes, genome-wide association studies, cell-free systems, and computer simulation screening to provide a comprehensive reference for the analysis of the biosynthetic pathways of active ingredients in TCM.
Medicine, Chinese Traditional ; Drugs, Chinese Herbal ; Artificial Intelligence ; Biosynthetic Pathways ; Computer Simulation ; Genome-Wide Association Study

Danshen, the dried roots and rhizomes of Salvia miltiorrhiza Bunge (S. miltiorrhiza), is widely used in the treatment of cardiovascular and cerebrovascular diseases. Tanshinones, the bioactive compounds from Danshen, exhibit a wide spectrum of pharmacological properties, suggesting their potential for future therapeutic applications. Tanshinone biosynthesis is a complex process involving at least six P450 enzymes that have been identified and characterized, most of which belong to the CYP76 and CYP71 families. In this study, CYP81C16, a member of the CYP71 clan, was identified in S. miltiorrhiza. An in vitro assay revealed that it could catalyze the hydroxylation of four para-quinone-type tanshinones, namely neocryptotanshinone, deoxyneocryptotanshinone, and danshenxinkuns A and B. SmCYP81C16 emerged as a potential broad-spectrum oxidase targeting the C-18 position of para-quinone-type tanshinones with an impressive relative conversion rate exceeding 90%. Kinetic evaluations andin vivo assays underscored its highest affinity towards neocryptotanshinone among the tested substrates. The overexpression of SmCYP81C16 promoted the accumulation of (iso)tanshinone in hairy root lines. The characterization of SmCYP81C16 in this study accentuates its potential as a pivotal tool in the biotechnological production of tanshinones, either through microbial or plant metabolic engineering.
Humans ; Salvia miltiorrhiza/metabolism* ; Biosynthetic Pathways ; Quinones/metabolism* ; Plant Roots/metabolism* ; Gene Expression Regulation, Plant

Objective: To explore the relationship between low density lipoprotein cholesterol (LDL-C)/high density lipoprotein cholesterol (HDL-C) ratio with the severity of coronary artery disease and 2-yeat outcome in patients with premature coronary heart disease. Methods: This prospective, multicenter, observational cohort study is originated from the PROMISE study. Eighteen thousand seven hundred and one patients with coronary heart disease (CHD) were screened from January 2015 to May 2019. Three thousand eight hundred and sixty-one patients with premature CHD were enrolled in the current study. According to the median LDL-C/HDL-C ratio (2.4), the patients were divided into two groups: low LDL-C/HDL-C group (LDL-C/HDL-C≤2.4, n=1 867) and high LDL-C/HDL-C group (LDL-C/HDL-C>2.4, n=1 994). Baseline data and 2-year major adverse cardiovascular and cerebrovascular events (MACCE) were collected and analyzed in order to find the differences between premature CHD patients at different LDL-C/HDL-C levels, and explore the correlation between LDL-C/HDL-C ratio with the severity of coronary artery disease and MACCE. Results: The average age of the low LDL-C/HDL-C ratio group was (48.5±6.5) years, 1 154 patients were males (61.8%); the average age of high LDL-C/HDL-C ratio group was (46.5±6.8) years, 1 523 were males (76.4%). The number of target lesions, the number of coronary artery lesions, the preoperative SNYTAX score and the proportion of three-vessel coronary artery disease in the high LDL-C/HDL-C group were significantly higher than those in the low LDL-C/HDL-C group (1.04±0.74 vs. 0.97±0.80, P=0.002; 2.04±0.84 vs. 1.85±0.84, P<0.001; 13.81±8.87 vs. 11.70±8.05, P<0.001; 36.2% vs. 27.4%, respectively, P<0.001). Correlation analysis showed that there was a significant positive correlation between LDL-C/HDL-C ratio and preoperative SYNTAX score, the number of coronary artery lesions, the number of target lesions and whether it was a three-vessel coronary artery disease (all P<0.05). The 2-year follow-up results showed that the incidence of MACCE was significantly higher in the high LDL-C/HDL-C group than that in the low LDL-C/HDL-C group (6.9% vs. 9.1%, P=0.011). There was no significant difference in the incidence of all-cause death, cardiac death, myocardial infarction, stroke, revascularization and bleeding between the two groups. Cox multivariate regression analysis showed that the LDL-C/HDL-C ratio has no correlation with 2-year MACCE, death, myocardial infarction, revascularization, stroke and bleeding events above BARC2 in patients with premature CHD. Conclusion: High LDL-C/HDL-C ratio is positively correlated with the severity of coronary artery disease in patients with premature CHD. The incidence of MACCE of patients with high LDL-C/HDL-C ratio is significantly higher during 2 years follow-up; LDL-C/HDL-C ratio may be an indicator for evaluating the severity of coronary artery disease and long-term prognosis in patients with premature CHD.
Male ; Humans ; Adult ; Middle Aged ; Female ; Coronary Artery Disease/complications* ; Cholesterol, HDL ; Cholesterol, LDL ; Prospective Studies ; Myocardial Infarction/etiology* ; Stroke ; Risk Factors

OBJECTIVE: To observe the clinical characteristics and impact on mortality of carbapenem-resistant Pseudomonas aeruginosa (CRPA) colonized or infected patients with hematological disorders in order to provide evidence for the prevention and treatment of CRPA. METHODS: The patients who were colonized or infected with CRPA in the Department of Hematology of The First Affiliated Hospital of Zhejiang Chinese Medical University from January 2020 to March 2021 were selected as the research subjects, the clinical data such as hospitalization time, primary disease treatment regimen, granulocyte count, previous infection and antibiotic regimen of these patients were analyzed, meanwhile, antibiotic regimen and efficacy during CRPA infection, 30-day and long-term survival were also analyzed. RESULTS: A total of 59 patients were included in this study, and divided into CRPA infection group (43 cases) and CRPA colonization group (16 cases). Univariate logistic regression analysis showed that ECOG score (P =0.003), agranulocytosis (P <0.001), and exposure to upper than 3^rd generations of cephalosporins and tigecycline within 30 days (P =0.035, P =0.017) were the high-risk factors for CRPA infection. Multivariate logistic regression analysis showed that ECOG score of 3/4 ( OR=10.815, 95%CI: 1.260-92.820, P =0.030) and agranulocytosis ( OR=13.82, 95%CI: 2.243-85.176, P =0.005) were independent risk factors for CRPA infection. There was a statistically significant difference in cumulative survival rate between CRPA colonization group and CRPA infection group ( χ²=14.134, P < 0.001). Kaplan-Meier survival analysis showed that the influencing factors of 30-day survival in patients with CRPA infection were agranulocytosis (P =0.022), soft tissue infection (P =0.03), and time of hospitalization before CRPA infection (P =0.041). Cox regression analysis showed that agranulocytosis was an independent risk factor affecting 30-day survival of patients with CRPA infection (HR=3.229, 95%CI :1.093-3.548, P =0.034). CONCLUSIONS Patients with hematological disorders have high mortality and poor prognosis after CRPA infection. Bloodstream infection and soft tissue infection are the main causes of death. Patients with high suspicion of CRPA infection and high-risk should be treated as soon as possible.
Humans ; Carbapenems/therapeutic use* ; Pseudomonas aeruginosa ; Soft Tissue Infections/drug therapy* ; Anti-Bacterial Agents/therapeutic use* ; Hematologic Diseases ; Survival Analysis

OBJECTIVE: To investigate the serum microRNA (miRNA) expression and examine the impact of miRNA expression profiles on T helper type 17 (Th17)/regulatory T cells (Treg) imbalance among patients with cystic echinococcosis, so as to provide insights into the illustration of the mechanisms underlying chronic Echinococcus granulosus infections, and long-term pathogenesis. METHODS: Total RNA was extracted from the sera of cystic echinococcosis patients and healthy controls, and subjected to high-throughput sequencing with the Illumina sequencing platform. Known miRNAs were annotated and new miRNAs were predicted using the miRBase database and the miRDeep2 tool, and differentially expressed miRNAs were identified. The target genes of differentially expressed miRNAs were predicted using the software miRanda and TargetScan, and the intersection was selected for Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Among the differentially expressed miRNAs with the 20 highest fold changes, miRNAs that targeted genes relating to key transcription factors RORC and FOXP3 that determine the production of Th17 and Treg cells or their important regulatory pathways (PI3K-Akt and mTOR pathways) were matched. RESULTS: A total of 53 differentially expressed miRNAs were screened in sera of cystic echinococcosis patients and healthy controls, including 47 up-regulated miRNAs and 6 down-regulated miRNAs. GO enrichment analysis showed that these differentially expressed miRNA were involved DNA transcription and translation, cell components, cell morphology, neurodevelopment and metabolic decomposition, and KEGG pathway analysis showed that the differentially expressed miRNA were mainly involved in MAPK, PI3K-Akt and mTOR signaling pathways. Among the differentially expressed miRNAs with the 20 highest fold changes, there were 3 miRNAs that had a potential for target regulation of RORC, and 15 miRNAs that had a potential to target the PI3K-Akt and mTOR signaling pathways. CONCLUSIONS Significant changes are found in serum miRNA expression profiles among patients with E. granulosus infections, and differentially expressed miRNAs may lead to Th17/Treg imbalance through targeting the key transcription factors of Th17/Treg or PI3K-Akt and mTOR pathways, which facilitates the long-term parasitism of E. granulosus in hosts and causes a chronic disease.
Echinococcosis/genetics* ; Gene Expression Profiling ; Humans ; MicroRNAs/metabolism* ; Phosphatidylinositol 3-Kinases/genetics* ; Proto-Oncogene Proteins c-akt/genetics* ; T-Lymphocytes, Regulatory ; TOR Serine-Threonine Kinases/genetics* ; Th17 Cells ; Transcription Factors/genetics*

Modernization of Chinese medicine is an important development direction of traditional Chinese medical sciences. It is of great significance to understand the mechanism of Chinese medicine with basic research, which can also accelerate the development and utilization of Chinese medicine. Salviae Miltiorrhizae Radix et Rhizoma is one of the most commonly used Chinese medicines in China for the prevention and treatment of cardiovascular and cerebrovascular diseases. It has received key and extensive attention worldwide in the following aspects: main active ingredients and their pharmacological mechanism, function and regulation of their biosynthetic pathway and application of their synthetic biology as well as the clinical preparations. The new and developing chemical analysis, network pharmacology, molecular pharmacognosy and omics make the modernization research of Salviae Miltiorrhizae Radix et Rhizoma comprehensive and in-depth. This study systematically reviewed the modernization research of Salviae Miltiorrhizae Radix et Rhizoma, which focused on its pharmacological effects, preparation research, biosynthesis and regulation mechanism of the active ingredients, and expected to exert the model role of Salviae Miltiorrhizae Radix et Rhizoma in the research of Chinese medicine.
Medicine, Chinese Traditional ; Salvia miltiorrhiza/chemistry* ; Drugs, Chinese Herbal/chemistry* ; Rhizome/chemistry* ; Plant Roots

BACKGROUND: The neoadjuvant chemotherapy is increasingly used in advanced gastric cancer, but the effects on safety and survival are still controversial. The objective of this meta-analysis was to compare the overall survival and short-term surgical outcomes between neoadjuvant chemotherapy followed by surgery (NACS) and surgery alone (SA) for locally advanced gastric cancer. METHODS: Databases (PubMed, Embase, Web of Science, Cochrane Library, and Google Scholar) were explored for relative studies from January 2000 to January 2021. The quality of randomized controlled trials and cohort studies was evaluated using the modified Jadad scoring system and the Newcastle-Ottawa scale, respectively. The Review Manager software (version 5.3) was used to perform this meta-analysis. The overall survival was evaluated as the primary outcome, while perioperative indicators and post-operative complications were evaluated as the secondary outcomes. RESULTS: Twenty studies, including 1420 NACS cases and 1942 SA cases, were enrolled. The results showed that there were no significant differences in overall survival (P = 0.240), harvested lymph nodes (P = 0.200), total complications (P = 0.080), and 30-day post-operative mortality (P = 0.490) between the NACS and SA groups. However, the NACS group was associated with a longer operation time (P < 0.0001), a higher R0 resection rate (P = 0.003), less reoperation (P = 0.030), and less anastomotic leakage (P = 0.007) compared with SA group. CONCLUSIONS Compared with SA, NACS was considered safe and feasible for improved R0 resection rate as well as decreased reoperation and anastomotic leakage. While unbenefited overall survival indicated a less important effect of NACS on long-term oncological outcomes.
Humans ; Neoadjuvant Therapy ; Stomach Neoplasms/surgery* ; Treatment Outcome

Cardiac hypertrophy is a common pathological process of various cardiovascular diseases and eventually develops into heart failure. This paper was aimed to study the different pathological characteristics exhibited by different mouse strains after hypertrophy stimulation. Two mouse strains, A/J and FVB/nJ, were treated with isoproterenol (ISO) by osmotic pump to induce cardiac hypertrophy. Echocardiography was performed to monitor heart morphology and function. Mitochondria were isolated from hearts in each group, and oxidative phosphorylation function was assayed in vitro. The results showed that both strains showed a compensatory enhancement of heart contractile function after 1-week ISO treatment. The A/J mice, but not the FVB/nJ mice, developed significant cardiac hypertrophy after 3-week ISO treatment as evidenced by increases in left ventricular posterior wall thickness, heart weight/body weight ratio, cross sectional area of cardiomyocytes and cardiac hypertrophic markers. Interestingly, the heart from A/J mice contained higher mitochondrial DNA copy number compared with that from FVB/nJ mice. Functionally, the mitochondria from A/J mice displayed faster O
Animals ; Cardiomegaly/chemically induced* ; Heart Failure ; Isoproterenol/toxicity* ; Mice ; Mitochondria ; Myocytes, Cardiac/metabolism*

The present study analyzed the current Chinese medicinal health products and Chinese patent medicines effective in boosting memory,aiming at providing references for the formulation and development of memory-boosting health products. The information on memory-boosting health products published by the Department of Special Food Safety Supervision and Management,the State Administration for Market Regulation( SAMR) was collected and the Chinese patent medicines on DRUGDATAEXPY were searched. Microsoft Excel and the TCMISS were used to statistically analyze the characteristics of formulations. A total of 212 memory-boosting health products were obtained from SAMR,including 83 ones containing Chinese medicinal materials. Twelve Chinese herbal medicines showed a usage frequency ≥ 8,with 151 times in use. In DRUGDATAEXPY,258 similar Chinese patent medicines were collected.Twelve Chinese herbal medicines showed a usage frequency ≥ 58,with 907 times in use. Through unsupervised hierarchical entropybased clustering of the above-mentioned Chinese medicinal health products and Chinese patent medicines separately,5 and 12 new formulas were obtained. The selection of Chinese herbal medicines for the new formulas was consistent with the principles of traditional Chinese medicine( TCM) theories,i. e.,tonifying kidney and marrow,benefiting Qi,nourishing Yin,resolving phlegm,and eliminating stasis. According to TCM theories,syndrome differentiation of the users was conducted,and the formulas were designed following the correspondence of syndromes with formulas and Chinese herbal medicines. This study is expected to provide new ideas and methods for the development of Chinese medicinal health products and accurately guide practical applications to exert the advantages of TCM in health care based on syndrome differentiation and improve the effect of Chinese medicinal health products.
China ; Drugs, Chinese Herbal ; Humans ; Medicine, Chinese Traditional ; Nonprescription Drugs ; Syndrome