摘要:
Improving hepatic glucose and lipid metabolisms is an important strategy to treat type 2 diabetes mellitus complicated with non-alcoholic fatty liver disease (T2DM-NAFLD). Silybin (SLB) has the potential hepatoprotection, while its oral bioavailability is poor. This study aims to investigate the functional role and mechanism of liposomal SLB in modulating glucose/lipid metabolism in T2DM-NAFLD. SLB was prepared by thin film dispersion method and characterized using dynamic light scattering, scanning electron microscope, high performance liquid chromatography and zeta potential analyzer. A rat model of T2DM-NAFLD was used to determine the role of liposomal SLB in regulating glycolipid metabolism and hepatic damage. Rat primary hepatocytes were used to demonstrate the hepatoprotection mechanism of liposomal SLB. The encapsulation efficiency was more than 80%, which showed the average particle size of 119.76 nm. Also, the average Zeta potential was -4.76 mV. These liposomes were spherical. In rats with T2DM-NAFLD, liposomal SLB alleviated insulin resistance and lipid metabolism, thereby improving hepatic lipid accumulation, inflammation and fibrosis. Besides, liposomal SLB elevated AMPK phosphorylation, and decreased collagen I/III, α-smooth muscle actin (α-SMA), transforming growth factor-β1 (TGF-β1) and the phosphorylation of Smad2/3. In hepatocyte model, compound C partially reversed the effects of liposomal SLB on cell viability, glycolipid metabolism and AMPK/TGF-β1/Smad pathway activation. Liposomal SLB ameliorates hepatic glucose and lipid metabolisms in T2DM-NAFLD via activating AMPK/TGF-β1/Smad pathway, providing an efficient strategy for treating T2DM-NAFLD.
摘要:
Circadian rhythms are internal 24-h intrinsic oscillations that are present in essentially all mammalian cells and can influence numerous biological processes. Cardiac function is known to exhibit a circadian rhythm and is strongly affected by the day/night cycle. Many cardiovascular variables, including heart rate, heart rate variability (HRV), electrocardiogram (ECG) waveforms, endothelial cell function, and blood pressure, demonstrate robust circadian rhythms. Many experiential and clinical studies have highlighted that disruptions in circadian rhythms can ultimately lead to maladaptive cardiac function. Factors that disrupt the circadian rhythm, including shift work, global travel, and sleep disorders, may consequently enhance the risk of cardiovascular diseases. Some cardiac diseases appear to occur at particular times of the day or night; therefore, targeting the disease at particular times of day may improve the clinical outcome. The objective of this review is to unravel the relationship between circadian rhythms and cardiovascular health. By understanding this intricate interplay, we aim to reveal the potential risks of circadian disruption and discuss the emerging therapeutic strategies, specifically those targeting circadian rhythms. In this review, we explore the important role of circadian rhythms in cardiovascular physiology and highlight the role they play in cardiac dysfunction such as ventricular hypertrophy, arrhythmia, diabetes, and myocardial infarction. Finally, we review potential translational treatments aimed at circadian rhythms. These treatments offer an innovative approach to enhancing the existing approaches for managing and treating heart-related conditions, while also opening new avenues for therapeutic development.
期刊:
Journal of Antimicrobial Chemotherapy,2023年78(1):141-149 ISSN:0305-7453
通讯作者:
Xin Li
作者机构:
[Tian, Miaomei; Tong, Huan; Guo, Siwei; Xu, Bing; Li, You; Li, Xin; Yan, Bingqian] Third Hosp Changsha, Changsha, Hunan, Peoples R China.;[Tong, Huan; Guo, Siwei; Xu, Bing; Li, Xin] Inst Clin Applicat Antibiot, Changsha, Hunan, Peoples R China.;[Tian, Miaomei; Li, You; Yan, Bingqian] Hunan Univ Chinese Med, Grad Sch, Changsha, Hunan, Peoples R China.;[Wei, Minji] Peking Univ, Hosp 1, Inst Clin Pharmacol, Beijing, Peoples R China.;[Shao, Jing] Nanjing Yoko Pharmaceut Co Ltd, Nanjing, Peoples R China.
通讯机构:
[Xin Li] T;The Third Hospital of Changsha , Changsha, Hunan , China<&wdkj&>Institute of Clinical Application of Antibiotics , Changsha, Hunan , China
摘要:
OBJECTIVES: Sitafloxacin is one of the newer generation fluoroquinolones with highly active against multidrug-resistant (MDR) bacteria. Our objectives were to identify the sitafloxacin pharmacokinetic/pharmacodynamic (PK/PD) index and breakpoints against MDR isolate in the urinary tract infection model. METHODS: Forty-eight MDR isolates underwent sitafloxacin and levofloxacin microdilution susceptibility testing. A 24 h in vitro model was established that simulated the healthy subjects urodynamics of sitafloxacin fumarate injection. Ten MDR isolates (four carbapenem-resistant Escherichia coli, three carbapenem-resistant P. aeruginosa and three vancomycin-resistant E. faecium) were selected. The drug efficacy was quantified by the change in log colony counts within 24 h. A sigmoid Emax model was fitted to the killing effect data. Monte Carlo simulations were performed to assess target attainment for the sitafloxacin fumarate doses of 100 and 200 mg q24h. RESULTS: Analysis indicated that the MICs of sitafloxacin were all significantly lower than that of levofloxacin (P < 0.01). The UAUC0-24h/MIC targets required to achieve stasis, 1-log10 killing and 2-log10 killing were 63.60, 79.49 and 99.45 (carbapenem-resistant E. coli), 60.85, 90.31 and 128.95 (carbapenem-resistant P. aeruginosa), 65.91, 77.81 and 103.11 (vancomycin-resistant E. faecium). Monte Carlo simulation showed the infusion of sitafloxacin fumarate 100 mg q24h was able to achieve 90% probability of target attainment against bacteria with MIC of 8 mg/L for the common complicated urinary tract infections. CONCLUSIONS: Sitafloxacin fumarate injection is an alternative therapeutic agent for the treatment of UTIs caused by MDR isolates.
作者机构:
[Xiao, Yanni] Hunan Univ Chinese Med, Coll Integrated Tradit Chinese & Western Med, Changsha, Hunan, Peoples R China.;[Xiao, Yanni; Tang, Chuwen; Luo, Zhihong; Xiao, Pengfei; Zeng, Xianxiang] Brain Hosp Hunan Prov, Changsha, Hunan, Peoples R China.;[Yu, Yu] Yale Sch Med, Dept Psychiat, Div Prevent & Community Res, New Haven, CT USA.;[Tang, Chuwen; Zhou, Ziqi] Hunan Univ Chinese Med, Grad Sch, Changsha, Hunan, Peoples R China.;[Zhou, Ziqi] Hunan Univ Chinese Med, Hosp 1, Dept Obstet & Gynecol, Changsha, Hunan, Peoples R China.
通讯机构:
[Shen, MX ; Luo, ZH; Zeng, XX] C;Cent South Univ, Xiangya Sch Publ Hlth, Dept Social Med & Hlth Management, Changsha, Hunan, Peoples R China.;Furong Lab, Changsha, Hunan, Peoples R China.
关键词:
Mental disorder;Schizophrenia;Hospitalization;Spending;Length of hospital stay
摘要:
Objectives: To describe hospital spending and length of stay for mental disorders in Hunan, China.Methods: We extracted hospital care data for Hunan province from the Chinese National Health Statistics Network Reporting System. Patients with mental disorders (ICD-10 codes: F00 to F99) as the principal diagnosis and hospitalized between January 1, 2017 and December 31, 2019 were included. We retrieved information on age, sex, number of comorbidities, diagnosis, level of hospital, hospital costs, date of admission and discharge, length of stay (LOS), and method of payment of eligible participants. Spending at the provincial level, and spending and LOS at the individual level were described. Quantile regression and linear regression were conducted to investigate factors for hospital cost and LOS for major mental disorders.Results: The 2019 annual spending on mental disorders in Hunan province was 160 million US dollars, and 71.7% was paid by insurance. The annual spending on schizophrenia was 84 million dollars, contributing to a primary burden of mental disorders. The median spending for mental disorders was $1,085 per patient, and the median hospital stay was 22 days. The study identified several significant factors associated with hospital cost and LOS, including age, sex, comorbidity, and level of the hospital. In particular, a higher level of the hospital was associated with a higher hospital spending but a shorter LOS. Women with schizophrenia had a comparable hospital spending but a significantly shorter LOS than men with schizophrenia.Conclusion: Hospitalization spending for patients with mental disorders is substantial. Schizo- phrenia is the major burden of hospitalization for mental disorders. While patients treated at a higher level of hospital had higher spending, they stayed shorter in these hospitals.
期刊:
British Journal of Clinical Pharmacology,2023年89(10):3067-3078 ISSN:0306-5251
通讯作者:
Xu, Bing;Li, X
作者机构:
[Tian, Miaomei; Li, You; Yan, Bingqian] Hunan Univ Chinese Med, Grad Sch, Changsha, Hunan, Peoples R China.;[Tian, Miaomei; Tong, Huan; Guo, Siwei; Xu, Bing; Li, You; Li, Xin; Li, Yuan; Yan, Bingqian] Third Hosp Changsha, Changsha, Hunan, Peoples R China.;[Tong, Huan; Guo, Siwei; Xu, Bing; Li, Xin; Li, Yuan] Inst Clin Applicat Antibiot, Changsha, Hunan, Peoples R China.;[Yu, Yunsong] Zhejiang Univ, Sir Run Run Shaw Hosp, Dept Infect Dis, Sch Med, Hangzhou, Peoples R China.;[Shao, Jing; Xin, Yuxia] Nanjing YOKO Pharmaceut Co Ltd, Nanjing, Peoples R China.
通讯机构:
[Li, X ; Xu, B] T;Third Hosp Changsha, 176 Western Laodong Rd, Changsha 410015, Hunan, Peoples R China.
关键词:
Monte Carlo simulation;YK-1169;carbapenem-resistant Klebsiella pneumoniae;pharmacokinetic;pharmacokinetic/pharmacodynamic
摘要:
ObjectiveThis study (NCT05588531) aimed to evaluate the safety and pharmacokinetics of cefepime-avibactam (YK-1169) in healthy Chinese subjects and explore the optimal regimen for treating carbapenem-resistant Klebsiella pneumoniae (CRKP) based on the pharmacokinetic/pharmacodynamic evaluation. MethodsYK-1169 single-ascending doses (0.5, 1.25, 2.5 or 3.75 g, 2-h infusion) and multiple doses (2.5 or 3.75 g every 8 h [q8h], 2-h infusion) given for 7 days were evaluated in pharmacokinetic studies. Subjects were randomized to receive cefepime (2 g), avibactam (0.5 g) or YK-1169 (2.5 g) to assess drug-drug interactions. The minimum inhibitory concentrations (MICs) of YK-1169 were determined by the broth microdilution method. Monte Carlo simulation was used to evaluate 10 different dose regimens. ResultsCefepime and avibactam both showed a linear pharmacokinetic profile. No accumulation was found after multiple doses. The cefepime C-max,C-ss and AUC(0-infinity,ss) were 9.20 and 16.0 mu g/mL, 407.2 and 659.45 mu g center dot h/mL in the 2.5 and 3.75 g multiple-dose groups, respectively. The avibactam C-max,C-ss and AUC(0-infinity,ss) were 0.545 and 0.837 mu g/mL, 53.31 and 79.55 mu g center dot h/mL in the 2.5 and 3.75 g multiple-dose groups, respectively. Cefepime and avibactam did not affect each other's pharmacokinetics. No serious adverse events occurred. All regimens achieved 90% probability of target attainment (PTA) goals when the MIC was <= 8 mg/L. The regimens of 2.5 (q8h, 2-h infusion), 3.75 (q8h, 2-, 3- and 4-h infusions) and 7.5 g (24-h continuous infusion) reached a 90% cumulative fraction of response. ConclusionYK-1169 had good antibacterial activity against CRKP and could be an option for CRKP infections. The regimen of 2.5 g q8h intravenously guttae (ivgtt) 2 h should be considered in future clinical trials.
期刊:
Frontiers in Medicine,2023年10:1259182 ISSN:2296-858X
通讯作者:
Hu, ZX
作者机构:
[Hu, Zhixi; Li, Lin; Hu, ZX; Hu, Siyuan] Hunan Univ Chinese Med, Domest class Discipline Construct Project Chinese, Changsha, Hunan, Peoples R China.;[Hu, Zhixi; Li, Lin; Hu, ZX] Hunan Univ Chinese Med, Prov Key Lab TCM Diagnost, Changsha, Hunan, Peoples R China.;[Li, Lin] Hunan Engn Technol Res Ctr Med & Funct Food, Changsha, Hunan, Peoples R China.;[Zhong, Senjie; Ye, Jiahao] Guangzhou Univ Chinese Med, Affiliated Hosp 1, Guangzhou, Guangdong, Peoples R China.;[Ye, Jiahao] Hunan Univ Chinese Med, Postgrad Sch, Changsha, Hunan, Peoples R China.
通讯机构:
[Hu, ZX ] H;Hunan Univ Chinese Med, Domest class Discipline Construct Project Chinese, Changsha, Hunan, Peoples R China.;Hunan Univ Chinese Med, Prov Key Lab TCM Diagnost, Changsha, Hunan, Peoples R China.
关键词:
Heart Failure;Danhong injection;Metabolomics;transverse aortic constriction;Chinese medicine (CM)
摘要:
BackgroundHeart failure (HF) is characterized by reduced ventricular filling or ejection function due to organic or non-organic cardiovascular diseases. Danhong injection (DHI) is a medicinal material used clinically to treat HF for many years in China. Although prior research has shown that Danhong injection can improve cardiac function and structure, the biological mechanism has yet to be determined.MethodsSerum metabolic analysis was conducted via ultra-high-performance liquid chromatography-quadrupole time-of-flight/mass spectrometry (UHPLC-QE/MS) to explore underlying protective mechanisms of DHI in the transverse aortic constriction (TAC)-induced heart failure. Multivariate statistical techniques were used in the research, such as unsupervised principal component analysis (PCA) and orthogonal projection to latent structures discriminant analysis (OPLS-DA). MetaboAnalyst and Kyoto Encyclopedia of Genes and Genomes (KEGG) were employed to pinpoint pertinent metabolic pathways.ResultsAfter DHI treatment, cardiac morphology and function as well as the metabolism in model rats were improved. We identified 17 differential metabolites and six metabolic pathways. Two biomarkers, PC(18:3(6Z,9Z,12Z)/24:0) and L-Phenylalanine, were identified for the first time as strong indicators for the significant effect of DHI.ConclusionThis study revealed that DHI could regulate potential biomarkers and correlated metabolic pathway, which highlighted therapeutic potential of DHI in managing HF.
摘要:
Background: We aimed to explore the molecular mechanisms underlying the effect of Gugutouhuaisiyu Capsule (GGTHSYC) on traumatic osteonecrosis of the femoral head (ONFH) using rabbit models.Methods: New Zealand rabbits (n = 24) were randomly placed into the control, model, and 30 and 60 mg/kg GGTHSYC treatment groups. Animals in the model and GGTHSYC treatment groups were subjected to surgically induced ONFH. Rabbits in the 30 and 60 mg/kg GGTHSYC treatment groups were administered GGTHSYC via the gastrointestinal route. MRI (magnetic resonance imaging) was employed to assess osteonecrosis. The mRNA and protein expression levels of BMP-2 (bone morphogenetic protein 2), RUNX2 (runt related transcription factor 2), VEGF (vascular endothelial growth factor), HIF-1a (hypoxic-induced factor-1a), and OPG (osteoprotegerin) in femoral head tissues were measured using reverse transcription-quantitative polymerase chain reaction and western blotting and immunochemistry, respectively.Results: GGTHSYC significantly enhanced osteocalcin activities in rabbits with traumatic ONFH by increasing ALP (alkaline phosphatase) expression (p = 0.008). Administration of GGTHSYC also significantly increased the mRNA and protein levels of HIF-1, VEGF, RUNX2, BMP-2, OPG, and BSP (bone sialoprotein) (p < 0.05).Conclusions: Administration of GGTHSYC improved bone regeneration following traumatic ONFH, which was accompanied by increased expression of the transcription factors HIF-1a and RUNX2 as well as other related proteins, suggesting that the transcription factors HIF-1a and RUNX2 may be a potential target for the treatment of traumatic ONFH.
摘要:
BACKGROUND: Bicaudal-D (BICD) Family Like Cargo Adaptor 1 (BICDL1) is an essential component of the molecular mechanism during neuronal development. However, BICDL1 has not been reported in cancer. Using bioinformatics analysis, we systematically evaluated the potential role of BICDL1 in CRC. METHODS: Colorectal cancer (CRC) and normal tissue samples were retrieved from the Gene Expression Omnibus (GEO), Genotype-Tissue Expression (GTEx), and Cancer Genome Atlas (TCGA) databases. Kaplan-Meier (K-M) analysis, nomogram, COX analysis, and receiver operating characteristic (ROC) curves were used to evaluate the prognostic power. Correlation analysis was also conducted to explore the correlation between mRNA expression and the methylation level of BICDL1 using cBioPortal, and the correlation between immune infiltration and BICDL1. RT-qPCR and Western blot assays were performed to analyze BICDL1 expression level between human colorectal cancer cell lines and normal colonic epithelial cells. RESULTS: BICDL1 had a higher expression in CRC tissues than in normal tissues (p < 0.001) in TCGA and GES 74602 datasets. Kaplan-Meier survival analysis revealed that patients with high BICDL1 expression had lower overall survival (OS) (1.53, 95% confidence interval: 1.07-2.17, p=0.019). The ROC curves demonstrated that BICDL1 has high specificity and efficiency in diagnosis (AUC=0.919, CI: 0.895-0.943). The expression level of BICDL1 was significantly correlated with the infiltrating levels of Treg (R=0.146, p <0.001), TFH (R=0.080, p=0.043), NK CD56bright cells (R=0.149, p <0.001), aDC (R=0.095, p=0.016), and T helper cell infiltration (R=-0.084, p=0.034). The correlation between BICDL1 expression and methylation levels was negative (R2=0.134, p <0.001), and CRC patients had lower methylation levels than normal people (p=0.036). BICDL1 mRNA and its protein expression levels in CRC cell lines (SW620) was markedly increased compared with that of normal colonic epithelial cells (NCM460) (p < 0.001). CONCLUSION: BICDL1 may be a potential biomarker for evaluating immune infiltration levels and prognosis of CRC.