Population pharmacokinetics and dosage optimization of linezolid in Chinese older patients.

PURPOSE: To assess the pharmacokinetics and pharmacodynamics of linezolid in a retrospective cohort of hospitalized Chinese older patients. METHODS: Patients > 60 years of age, who received intravenous linezolid (600 mg), were included. A population pharmacokinetics (PPK) model was established using nonlinear mixed-effects modeling. The predictive performance of the final model was assessed using goodness-of-fit plots, bootstrap analyses, and visual predictive checks. Monte Carlo simulations were used to evaluate the achievement of a pharmacodynamics target for the area under the serum concentration-time curve/minimum inhibitory concentration (AUC0-24/MIC). RESULTS: A total of 210 samples were collected from 120 patients. A one-compartment PPK model with linear elimination best predicted the linezolid plasma concentrations. Linezolid clearance (CL) was 4.22 L h-1 and volume of distribution (Vd) was 45.80 L; serum uric acid (SUA) was a significant covariate of CL. CONCLUSION: The results of this study indicated that the standard dose was associated with a risk of overexposure in older patients, particularly those with high SUA values; these patients would benefit from a lower dose (300 mg every 12 h).

Yi-Qi-Huo-Xue decoction alleviates intracerebral hemorrhage injury through inhibiting neuronal autophagy of ipsilateral cortex via BDNF/TrkB pathway.

BACKGROUND: Yi-Qi-Huo-Xue Decoction (YQHXD), a traditional Chinese medicine formula, has demonstrated efficacy in the clinical treatment of intracerebral hemorrhage (ICH) for over a decade. Nevertheless, the precise pharmacotherapeutic compounds of YQHXD capable of penetrating into cerebral tissue and the pharmacological underpinnings of YQHXD remain ambiguous. METHODS: The active components of YQHXD in rat brains was analyzed by ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. The potential targets, pathways and biological progresses of YQHXD ameliorating ICH induced injury was predicted by network pharmacology. Moreover, collagenase-induced ICH rat model, primary cortex neurons exposed to hemin and molecular docking were applied to validate the molecular mechanisms of YQHXD. RESULTS: Eleven active components of YQHXD were identified within the brains. Employing the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases, our investigation concentrated on the roles of autophagy and the BDNF/TrkB signaling pathway in the pharmacological context. The pharmacological results revealed that YQHXD alleviated neurological dysfunction, brain water content, brain swelling, and pathological injury caused by ICH. Meanwhile, YQHXD inhibited autophagy influx and autophagosome in vivo, and regulated cortex neuronal autophagy and TrkB/BDNF pathway both in vivo and in vitro. Subsequently, N-acetyl serotonin (NAS), a selective TrkB agonist, was employed to corroborate the significance of the BDNF/TrkB pathway in this process. The combination of NAS and YQHXD did not further enhance the protective efficacy of YQHXD in ICH rats. Additionally, outcomes of molecular docking analysis revealed that nine compounds of YQHXD exhibited potential regulatory effects on TrkB. CONCLUSIONS: Ipsilateral neuronal autophagy and BDNF/TrkB pathway were activated 72 h after ICH. YQHXD effectively resisted injury induced by ICH, which was related with suppression of ipsilateral neuronal autophagy via BDNF/TrkB pathway. This study provides novel insights into the therapeutic mechanisms of traditional Chinese medicine in the context of ICH treatment.

Investigating the therapeutic effects and mechanisms of Roxadustat on peritoneal fibrosis Based on the TGF-ß/Smad pathway.

Peritoneal fibrosis (PF) is particularly common in individuals undergoing peritoneal dialysis (PD). Fibrosis of the parenchymal tissue typically progresses slowly. Therefore, preventing and reducing the advancement of fibrosis is crucial for effective patient treatment. Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), primarily used to treat and improve renal anemia. Recent studies have found that HIF-1α possesses antioxidant activity and exerts a certain protective effect in ischemic heart disease and spinal cord injury, while it can also delay the progression of pulmonary and renal fibrosis. This study establishes the mice model through intraperitoneal injection of 4.25 % peritoneal dialysate fluid (PDF) and explores the therapeutic effects of Roxadustat by inducing TGF-ß1-mediated epithelial-mesenchymal transition (EMT) in Met-5A cells. The aim is to investigate the protective role and mechanisms of Roxadustat against PD-related PF. We observed thicker peritoneal tissue and reduced permeability in animals with PD-related PF samples. This was accompanied by heightened inflammation, which Roxadustat alleviated by lowering the levels of inflammatory cytokines (IL-6, TNF-α). Furthermore, Roxadustat inhibited EMT in PF mice and TGF-ß1-induced Met-5A cells, as evidenced by decreased expression of fibrotic markers, such as fibronectin, collagen I, and α-SMA, alongside an elevation in the expression of the epithelial marker, E-cadherin. Roxadustat also significantly decreased the expression of TGF-ß1 and the phosphorylation of p-Smad2 and p-Smad3. In conclusion, Roxadustat ameliorates peritoneal fibrosis through the TGF-ß/Smad pathway.

Comprehensive metabolomic characterization of atrial fibrillation.

Background: Using human humoral metabolomic profiling, we can discover the diagnostic biomarkers and pathogenesis of disease. The specific characterization of atrial fibrillation (AF) subtypes with metabolomics may facilitate effective and targeted treatment, especially in early stages. Objectives: By investigating disturbed metabolic pathways, we could evaluate the diagnostic value of biomarkers based on metabolomics for different types of AF. Methods: A cohort of 363 patients was enrolled and divided into a discovery and validation set. Patients underwent an electrocardiogram (ECG) for suspected AF. Groups were divided as follows: healthy individuals (Control), suspected AF (Sus-AF), first diagnosed AF (Fir-AF), paroxysmal AF (Par-AF), persistent AF (Per-AF), and AF causing a cardiogenic ischemic stroke (Car-AF). Serum metabolomic profiles were determined by gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-QTOF-MS). Metabolomic variables were analyzed with clinical information to identify relevant diagnostic biomarkers. Results: The metabolic disorders were characterized by 16 cross-comparisons. We focused on comparing all of the types of AF (All-AFs) plus Car-AF vs. Control, All-AFs vs. Car-AF, Par-AF vs. Control, and Par-AF vs. Per-AF. Then, 117 and 94 metabolites were identified by GC/MS and LC-QTOF-MS, respectively. The essential altered metabolic pathways during AF progression included D-glutamine and D-glutamate metabolism, glycerophospholipid metabolism, etc. For differential diagnosis, the area under the curve (AUC) of specific metabolomic biomarkers ranged from 0.8237 to 0.9890 during the discovery phase, and the predictive values in the validation cohort were 78.8-90.2%. Conclusions: Serum metabolomics is a powerful way to identify metabolic disturbances. Differences in small-molecule metabolites may serve as biomarkers for AF onset, progression, and differential diagnosis.

An Automatic HFO Detection Method Combining Visual Inspection Features with Multi-Domain Features.

As an important promising biomarker, high frequency oscillations (HFOs) can be used to track epileptic activity and localize epileptogenic zones. However, visual marking of HFOs from a large amount of intracranial electroencephalogram (iEEG) data requires a great deal of time and effort from researchers, and is also very dependent on visual features and easily influenced by subjective factors. Therefore, we proposed an automatic epileptic HFO detection method based on visual features and non-intuitive multi-domain features. To eliminate the interference of continuous oscillatory activity in detected sporadic short HFO events, the iEEG signals adjacent to the detected events were set as the neighboring environmental range while the number of oscillations and the peak-valley differences were calculated as the environmental reference features. The proposed method was developed as a MatLab-based HFO detector to automatically detect HFOs in multi-channel, long-distance iEEG signals. The performance of our detector was evaluated on iEEG recordings from epileptic mice and patients with intractable epilepsy. More than 90% of the HFO events detected by this method were confirmed by experts, while the average missed-detection rate was < 10%. Compared with recent related research, the proposed method achieved a synchronous improvement of sensitivity and specificity, and a balance between low false-alarm rate and high detection rate. Detection results demonstrated that the proposed method performs well in sensitivity, specificity, and precision. As an auxiliary tool, our detector can greatly improve the efficiency of clinical experts in inspecting HFO events during the diagnosis and treatment of epilepsy.

Individualized medication of digoxin based on the serum drug concentration and blood biochemical indexes.

Aim: The dose of digoxin is often difficult to be determined precisely. The aim of this study was to retrospectively investigate the effect of blood biochemical indexes on the serum concentration of digoxin. Materials & methods: We collected the data of hospitalized patients treated orally with digoxin in Nanjing Drum Tower Hospital (Nanjing, China) from 2016 to 2018. Descriptive statistics was used to analyze the patients' comprehensive condition. Results: A total of 425 patients were included in the study. Through analysis, nine factors were included in the regression model of the serum concentration of digoxin, and this regression model showed good predictive performance (r2 = 0.83138; p < 0.001). Conclusion: The regression model for the prediction of serum concentration of digoxin has clinical significance, and can provide research basis for individualized medication of digoxin.

Plasma interleukin-22 levels are associated with prediabetes and type 2 diabetes in the Han Chinese population.

AIMS/INTRODUCTION: The objective of the present study was to investigate the relationship between plasma interleukin-22 (IL-22) levels and prediabetes or type 2 diabetes, and search the relevance between plasma concentrations of IL-22 and selected diabetes risk factors in Chinese people. MATERIALS AND METHODS: The Han Chinese origin men and women participants were recruited in our study during a conventional medical checkup. Fasting plasma IL-22 levels were detected by enzyme-linked immunosorbent assay, and their relevance with selected diabetes risk factors was explored. Multiple logistic regression analysis was carried out to assess the odds ratio of impaired fasting glucose (IFG) and type 2 diabetes according to plasma IL-22 level. RESULTS: Compared with normal glucose participants (250 pg/mL [interquartile range 154-901]), the plasma IL-22 levels in IFG participants (185 pg/mL [interquartile range 145-414]) and type 2 diabetes participants (162 pg/mL [interquartile range 128-266]) were significantly lower (P < 0.05, P < 0.001, respectively). Correlation analysis showed that plasma concentrations of IL-22 were negatively associated with some diabetes risk factors, including body mass index, glucose, systolic blood pressure, diastolic blood pressure and triglyceride. Furthermore, the plasma concentrations of IL-22 showed a highly significant association with IFG and type 2 diabetes. CONCLUSIONS: In Chinese subjects, the plasma concentration of IL-22 is profoundly associated with susceptibility to IFG and type 2 diabetes, and decreased plasma IL-22 level is a potential trigger of IFG and type 2 diabetes.

Pentamethylquercetin induces adipose browning and exerts beneficial effects in 3T3-L1 adipocytes and high-fat diet-fed mice.

Browning white adipocytes may be a new target in anti-obesity therapy. Pentamethylquercetin (PMQ) has been shown to have anti-obesity effects in monosodium glutamate-induced obese mice. Here, we aimed to study the anti-obesity effects of PMQ in vitro and in vivo and to determine if adipose browning is involved in the mechanism underlying the anti-obesity effects of PMQ. We evaluated the effects of PMQ on cell proliferation, cell differentiation, glucose consumption, cellular lipid metabolism, and related brown gene expression in 3T3-L1 adipocytes. We also investigated the effects of PMQ in a mouse model of high-fat diet (HFD)-induced obesity. Our results demonstrated that PMQ increased the consumption of glucose, inhibited the accumulation of cellular triglycerides (TGs), and induced the expression of brown adipocyte-specific genes, such as uncoupling protein 1 (UCP-1), during the early stage of differentiation in 3T3-L1 adipocytes. In HFD mice, PMQ treatment reduced waist circumference, LEE index, white adipose tissue (WAT) weight and white adipocyte size and increased brown adipose tissue (BAT) weight. Moreover, PMQ treatment induced mitochondrial biogenesis and upregulated UCP-1 expression in WAT. These findings suggest that PMQ may induce browning of adipose tissue, a phenomenon that is at least partly related to its anti-obesity effects.

A novel polymorphism in protein kinase AMP-activated catalytic subunit alpha 2 (PRKAA2) is associated with type 2 diabetes in the Han Chinese population.

BACKGROUND: It has been proposed that the energy-sensing enzyme AMP-activated protein kinase (AMPK) is a key agent in the pathophysiology of type 2 diabetes mellitus (T2DM). The gene encoding protein kinase AMP-activated catalytic subunit alpha 2 (PRKAA2) is located at one of the Asian T2DM loci (1p32). Therefore, the aim of the present study was to test for the association of common variants in PRKAA2 with T2DM in the Han Chinese population. METHODS: We genotyped 221 T2DM patients and 111 controls to assess possible associations of two tagging single nucleotide polymorphisms (tSNPs) in the PRKAA2 gene with T2DM. RESULTS: The clinical characteristics of T2DM cases compared with controls differed significantly. No significant association was observed with the rs2143754 polymorphism whereas the rs2746342 polymorphism exhibited a highly significant association with T2DM. Fasting plasma glucose (FPG) of subjects carrying the G/G genotype of the rs2746342 polymorphism was higher than that of subjects carrying the T allele (P = 0.0049). These associations were magnified in the presence of the G/G genotype of the rs2143754 polymorphism. CONCLUSIONS: The rs2746342 polymorphism is significantly associated with susceptibility to T2DM and seems to interact with the rs2143754 polymorphism in the modulation of FPG in the Han Chinese population.

Polymorphism in the transcription factor 7-like 2 (TCF7L2) gene is associated with impaired proinsulin conversion--A meta-analysis.

AIMS: Available evidence supports the emerging hypothesis that the T-Allele of the transcription factor 7-like 2 (TCF7L2) rs7903146 may be associated with the risk of impaired proinsulin conversion, but no consensus was available up to now. METHODS: A computer-based search of electronic databases (PubMed, EMBASE, Cochrane Library) and reference lists of relevant articles was carried out, and then 19 studies involving 15830 subjects were identified. The combined weighted mean difference (WMD) and their corresponding 95% confidence interval (CI) were calculated by a fixed or random effect. RESULTS: In the overall analysis, the T-Allele was observed to be significantly associated with the risk of impaired proinsulin conversion (up-regulate fasting proinsulin concentration WMD -0.40 pM/L (95% CI -0.57 to -0.23); down-regulate fasting insulin concentration 3.86 pM/L (95% CI 1.91 to 5.81)). Subgroup analyse stratified by subjects population characteristics and ethnicity were performed. The results indicated the TCF7L2 rs7903146 polymorphism was associated with the risk of impaired proinsulin conversion in various population characteristics study. With only a few of subjects in Asians and Africans were available, we failed to detect significant ethnic difference about TCF7L2 rs7903146 polymorphism and the risk of impaired proinsulin conversion. CONCLUSIONS: Our results indicated that the T-Allele of the TCF7L2 rs7903146 is a significantly risk factor for impaired proinsulin conversion. Future research should gather more data about the effect of TCF7L2 rs7903146 polymorphism on Asians and Africans.

Leptin -2548g/a gene polymorphism in association with antipsychotic-induced weight gain: a meta-analysis study.

BACKGROUND: The leptin -2548G/A (rs7799039) gene polymorphism has been implicated in susceptibility to antipsychotic-induced weight gain (AIWG), but study results are still controversial. The present meta-analysis was performed to investigate the relationship between the leptin -2548G/A gene polymorphism and AIWG. METHODS: Electronic databases were searched for eligible articles in English and Chinese and seven separate studies on the association of the leptin -2548G/A gene polymorphism with AIWG were analyzed. RESULTS: The meta-analysis involved 451 AIWG patients and 568 controls. The pooled odds ratio (OR) and their corresponding 95% confidence interval (CI) were calculated by a fixed or random effect. Overall, our meta-analysis suggests that the leptin -2548G/A gene polymorphism was not significantly associated with AIWG risk under various genetic models. But, in the subgroup analysis by ethnicity, significant association was found between leptin -2548A allele and the AIWG risk in Asian populations under additive, dominant, recessive, and homozygote genetic model. On the contrary, in European populations, the -2548A allele seemed to decrease the risk of AIWG when compared with the -2548G allele under various genetic models, even though they were not statistically significant. CONCLUSION: Our meta-analysis suggests that the correlation between leptin -2548G/A gene polymorphism and AIWG risk has significant racial differences.

[Chemical constituents from stems of Clausena excavata].

OBJECTIVE: To study the chemical constituents from the stems of Clausena excavata. METHODS: The constituents were isolated by various chromatographic techniques(silica gel, RP-MPLC and PHPLC) and their structures were determined on the basis of their spectroscopic data, as well as literatures. RESULTS: Eleven compounds were separated and identified as adicardin(1),7-[O-α-L-rh-amnopyranosyl-(1-->6)-O-ß-D-glucopyranosyloxy]coumarin(2), 6-methoxy-7-[O-α-L-rhamnopyranosyl-(1-->6)-O-ß-D-glucopyranosyloxy] coumarin (3), alloisoimperatorin (4), isopentenoyloxypsoralen (5), nordentatin (6), xanthyletin (7), 7-hydroxycoumarin (8), 3-formylcarbazole(9), 3-formyl-6-methoxy carbazole(10), and murrayanine(11). CONCLUSION: compounds 2-4 and 10 are isolated from this plant for the first time, and compounds 1 and 5 are isolated from Clausena genus for the first time.

Effects of the natural flavone trimethylapigenin on cardiac potassium currents.

The natural flavones and polymethylflavone have been reported to have cardiovascular protective effects. In the present study, we determined whether quecertin, apigenin and their methylated compounds (3,7,3',4'-tetramethylquecertin, 3,5,7,3',4'-pentamethylquecertin, 7,4'-dimethylapigenin, and 5,7,4'-trimethylapigenin) would block the atrial specific potassium channel hKv1.5 using a whole-cell patch voltage-clamp technique. We found that only trimethylapigenin showed a strong inhibitory effect on hKv1.5 channel current. This compound suppressed hKv1.5 current in HEK 293 cell line (IC50=6.4 µM), and the ultra-rapid delayed rectify K⁺ current I(Kur) in human atrial myocytes (IC50=8.0 µM) by binding to the open channels and showed a use- and frequency-dependent manner. In addition, trimethylapigenin decreased transient outward potassium current (I(to)) in human atrial myocytes, inhibited acetylcholine-activated K⁺ current (IC50=6.8µM) in rat atrial myocytes. Interestingly, trimethylapigenin had a weak inhibition of hERG channel current. Our results indicate that trimethyapigenin significantly inhibits the atrial potassium currents hKv1.5/I(Kur) and I(KACh), which suggests that trimethylapigenin may be a potential candidate for anti-atrial fibrillation.