Population pharmacokinetics of rotigotine extended-release microspheres for intramuscular injection in patients with early-stage Parkinson's disease.

AIMS: Rotigotine extended-release microspheres is a weekly intramuscular injection formulation to treat Parkinson's disease. This study aimed to develop a population pharmacokinetics (PK) model for rotigotine extended-release microspheres to investigate its PK ethnic differences. METHODS: Data for the study were obtained from three studies in China, Japan and the US. The population PK model was developed using the Phoenix NLME 8.3.5 software. Two parallel absorption models were created to include both zero- and first-order absorptions. The elimination phase was evaluated for one- and two-compartment linear models. Moreover, covariates including sex, body weight, body mass index, albumin, creatinine clearance and race were input into the model using a stepwise covariate method. RESULTS: We constructed a one-compartment linear model with the first parallel absorption model identified as the best-fitting model. Simulation results in patients with lighter body weight (45 kg) exhibited a 27% increase in Cmax,ss and a 31% increase in AUCtau,ss compared to those with median body weight (65 kg). Patients with heavier body weight (103 kg) showed a 27% decrease in Cmax,ss and a 29% decrease in AUCtau,ss compared to the median body weight group. Asian patients displayed only a 21% increase in Cmax,ss and a 6% increase in AUCtau,ss compared to non-Asian. While we could not fully conclude that race does not affect rotigotine exposure, dosage adjustments based on race were not deemed necessary. CONCLUSIONS: Exposure differences were mainly attributed to body weight, while dose adjustments were not needed for patients of different racial identities.

Design of a Synthetic Strategy to Achieve Enhanced Fluorescent Carbon Dots with Sulfur and Nitrogen Codoping and Its Multifunctional Applications.

Here, a rational strategy to achieve multifunctional N, S codoped carbon dots (N, S-CDs) is reported, aiming to improve the photoluminescence quantum yields (PLQYs) of the CDs. The synthesized N, S-CDs have excellent stability and emission properties independent of excitation wavelength. Through the introduction of S element doping, the fluorescence emission of CDs is red-shifted from 430 to 545 nm, and the corresponding PLQYs can be greatly enhanced from 11.2% to 65.1%. It is found that the doping of S elements causes an increase in the size of CDs and an elevated graphite N content, which may be the key factors to cause the redshift of fluorescence emission. Furthermore, the introduction of S element also serves to suppress the nonradiative transitions, which may be responsible for the elevated PLQYs. Besides, the synthesized N, S-CDs have certain solvent effect and can be applied to detect water content in organic solvents, and have strong sensitivity to alkaline environment. More importantly, the N, S-CDs can be used to achieve an "on-off-on" dual detection mode between Zr4+ and NO2 - . In addition, N, S-CDs combinedwith polyvinylpyrrolidone (PVP) can also be utilized as fluorescent inks for anti-counterfeiting applications.

Association of serum VLDL level with hyperhomocysteinemia in hypertensive patients: A cross-sectional study.

BACKGROUND: Increasing evidence suggests that hyperhomocysteinemia (HHcy) and hyperlipidemia have been recognized as two independent risks for cardiovascular disease. However, the association between hyperlipidemia and HHcy in hypertensive patients has not been systemically elucidated. The aim of this study was to investigate the relation between very low-density lipoprotein (VLDL) and HHcy in hypertensive patients. METHODS: From July 2013 to March 2014, a large cross-sectional study was performed using 4012 participants from urban and rural communities in Hunan province, China. Participants underwent accurate assessment of lipid profiles, homocysteine (Hcy), anthropometric, blood pressure, and other biochemical indicators. RESULTS: Among 1257 participants with hypertension, 626 (49.80%) were men and 631 (50.20%) were women. In total, 1081 (86.00%) of the participants were found to have HHcy, of which 559 (44.47%) were men and 522 (41.53%) were women. In the univariate analysis, the OR for patients with hypertension associated with hyperhomocysteinemia was significantly enhanced as the quartiles of the Log VLDL were increased. OR for quartile 4 was significantly higher than that for quartile 1 (OR = 3.7, 95% CI: 2.6-5.1; P< .001). Additional adjustment for the confounding variables did not reduce the ORs for the association between the Log VLDL and hypertension associated with hyperhomocysteinemia (OR = 3.8, 95% CI: 2.7-5.5; P< .001; OR = 4.3, 95% CI: 1.6-11.8; P= .004, respectively). We also conducted analyses with Log VLDL as a continuous variable. Each unit increase in the Log VLDL was associated with the 1.3-fold increased risk of hypertension associated with hyperhomocysteinemia (95% CI: 1.9-2.9; P< .001). Adjusting for Cr, TG, TC, and HDL did not affect the relationship. CONCLUSIONS: Our data indicate that the Log VLDL concentrations appear to be an independent contributor to hypertension associated with hyperhomocysteinemia, even after adjusting for age and other covariables. The utility of the Log VLDL as a diagnostic, prognostic, and therapeutic indicator for the disease warrants further investigation. ABBREVIATIONS: HHcy: hyperhomocysteinemia; Hcy: homocysteine; VLDL: very low-density lipoprotein; CVD: cardiovascular disease; SBP: systolic blood pressure; DBP: diastolic blood pressure; BMI: body mass index; ALT: alanine aminotransferase; Cr: creatinine; UA: uric acid; TG: triglycerides; TC: total cholesterol; HDL: high-density lipoprotein; LDL: low-density lipoprotein; FBG: fasting blood glucose; CRP: C-reactive protein; MTHFR: methylene tetrahydrofolate reductase; NO: nitric oxide; HDL-C: high-density lipoprotein cholesterol.

Predicting physical functioning status in older adults: insights from wrist accelerometer sensors and derived digital biomarkers of physical activity.

OBJECTIVE: Conventional physical activity (PA) metrics derived from wearable sensors may not capture the cumulative, transitions from sedentary to active, and multidimensional patterns of PA, limiting the ability to predict physical function impairment (PFI) in older adults. This study aims to identify unique temporal patterns and develop novel digital biomarkers from wrist accelerometer data for predicting PFI and its subtypes using explainable artificial intelligence techniques. MATERIALS AND METHODS: Wrist accelerometer streaming data from 747 participants in the National Health and Aging Trends Study (NHATS) were used to calculate 231 PA features through time-series analysis techniques-Tsfresh. Predictive models for PFI and its subtypes (walking, balance, and extremity strength) were developed using 6 machine learning (ML) algorithms with hyperparameter optimization. The SHapley Additive exPlanations method was employed to interpret the ML models and rank the importance of input features. RESULTS: Temporal analysis revealed peak PA differences between PFI and healthy controls from 9:00 to 11:00 am. The best-performing model (Gradient boosting Tree) achieved an area under the curve score of 85.93%, accuracy of 81.52%, sensitivity of 77.03%, and specificity of 87.50% when combining wrist accelerometer streaming data (WAPAS) features with demographic data. DISCUSSION: The novel digital biomarkers, including change quantiles, Fourier transform (FFT) coefficients, and Aggregated (AGG) Linear Trend, outperformed traditional PA metrics in predicting PFI. These findings highlight the importance of capturing the multidimensional nature of PA patterns for PFI. CONCLUSION: This study investigates the potential of wrist accelerometer digital biomarkers in predicting PFI and its subtypes in older adults. Integrated PFI monitoring systems with digital biomarkers would improve the current state of remote PFI surveillance.

Salvianolic Acid B Reduces Oxidative Stress to Promote Hair-Growth in Mice, Human Hair Follicles and Dermal Papilla Cells.

Background: Existing research links oxidative stress and inflammation to hair loss. Salvianolic acid B (SAB) is known for its anti-oxidative, anti-inflammatory, and other beneficial pharmacological properties. Objective: To assess the efficacy of SAB in modulating hair growth. Methods: In vivo experiments were conducted using C57BL/6 mice to evaluate the effects of SAB on hair and skin parameters. The study involved ex vivo analysis of human hair follicles (HFs) for hair shaft length and hair growth cycle assessment. In vitro, human dermal papilla cells (hDPCs) were cultured with SAB, and their proliferation, protection against H2O2-induced oxidative damage, and gene/protein expression alterations were examined using various analytical techniques, including Real-Time Cell Analysis (RTCA), DCFH-DA Assay, RNA-seq, and KEGG pathway analysis. Results: SAB treatment in mice significantly improved hair growth and vascularization by day 21. In human HFs, SAB extended hair shaft length and delayed the transition to the catagen phase. SAB-treated hDPCs showed a notable decrease in the expression of oxidation-antioxidation-related genes and proteins, including reduced phosphorylation levels of ERK and p38. Conclusion: The study indicates that SAB promotes hDPC proliferation and offers protection against oxidative stress, highlighting its potential as a therapeutic agent for enhancing hair growth and treating hair loss.

Double-blinded, randomized clinical trial of Gegen Qinlian decoction pinpoints Faecalibacterium as key gut bacteria in alleviating hyperglycemia.

Background: Accumulating evidence suggests that metabolic disorders, including type 2 diabetes mellitus (T2DM), can be treated with traditional Chinese medicine formulas, such as the Gegen Qinlian decoction (GQD). This study elucidates the mechanisms by which gut microbes mediate the anti-diabetic effects of GQD. Methods: We conducted a double-blind randomized clinical trial involving 120 untreated participants with T2DM. During the 12-week intervention, anthropometric measurements and diabetic traits were recorded every 4 weeks. Fecal microbiota and serum metabolites were measured before and after the intervention using 16S rDNA sequencing, liquid chromatography-mass spectrometry, and Bio-Plex panels. Results: Anti-diabetic effects were observed in the GQD group in the human trial. Specifically, glycated hemoglobin, fasting plasma glucose, and two-hour postprandial blood glucose levels were significantly lower in the GQD group than in the placebo group. Additionally, Faecalibacterium was significantly enriched in the GQD group, and the short-chain fatty acid levels were higher and the serum inflammation-associated marker levels were lower in the GQD group compared to the placebo group. Moreover, Faecalibacterium abundance negatively correlated with the levels of serum hemoglobin, fasting plasma glucose, and pro-inflammatory cytokines. Finally, the diabetes-alleviating effect of Faecalibacterium was confirmed by oral administration of Faecalibacterium prausnitzii (DSMZ 17677) in T2DM mouse model. Conclusions: GQD improved type 2 diabetes primarily by modulating the abundance of Faecalibacterium in the gut microbiota, alleviating metabolic disorders and the inflammatory state. Trial registration: Registry No. ChiCTR-IOR-15006626.

Transmission of Microcystins in Natural Systems and Resource Processes: A Review of Potential Risks to Humans Health.

The rapid rise of microcystins (MCs) poses a serious threat to global freshwater ecosystems and has become an important issue of global public health. MCs have considerable stability and are the most widely distributed hepatotoxins. It cannot only accumulate in aquatic organisms and transfer to higher nutrients and levels, but also be degraded or transferred during the resource utilization of cyanobacteria. No matter which enrichment method, it will lead to the risk of human exposure. This review summarizes the research status of MCs, and introduces the distribution of MCs in different components of aquatic ecosystems. The distribution of MCs in different aquatic organisms was summarized, and the potential risks of MCs in the environment to human safety were summarized. MCs have polluted all areas of aquatic ecosystems. In order to protect human life from the health threats caused by MCs, this paper also proposes some future research directions to promote MCs control and reduce human exposure to MCs.

Bufalin inhibits the proliferation of lung cancer cells by suppressing Hippo-YAP pathway.

Lung cancer has high morbidity and mortality. This study demonstrated that Bufalin inhibits the proliferation of lung cancer cells in vivo / in vitro by suppressing Hippo-YAP pathway. Here, we found that Bufalin promoted the binding of LATS and YAP to elevate the level of YAP phosphorylation. Phosphorylated YAP could not successfully enter the nucleus to activate the expression of downstream proliferation-related target genes Cyr61 and CTGF, whereas the YAP retained in the cytoplasm further bound to ß-TrCP and underwent ubiquitination and degradation. This study verified the key role of YAP in stimulating the proliferation of lung cancer and revealed the anticancer target of Bufalin. Therefore, this study provides a theoretical basis for the anticancer effect of Bufalin, and suggests that Bufalin can be a potential anticancer drug.

Integrated Clinical and Prognostic Analysis of the m6A RNA Methylation Regulator YTHDF3 in Pan-Cancer and its Correlation with Cancer Cell Proliferation.

Background: N6-methyladenosine (m6A) is the most abundant and extensive chemical modification of mammalian RNA molecules. Although numerous studies have investigated m6A methylation-related genes, to the best of our knowledge, none have examined the expression patterns of YTH N6-methyladenosine RNA binding protein 3 (YTHDF3) across cancers. Methods: Using various publicly available datasets, we searched for a potential carcinogenic role of YTHDF3 in 33 tumor types. Furthermore, the clinicopathological parameters, clinical prognostic value, enrichment analysis, mutations, microsatellite instability (MSI), tumor mutation burden (TMB), levels of infiltrating cells, and related immune checkpoint genes were included. Finally, we performed a validation analysis using existing clinical samples and proliferation-related functional experiments. Results: YTHDF3 is highly expressed in most cancer types and associated with patient prognosis in certain tumors. The ROC analysis suggested that YTHDF3 has high diagnostic value in 13 types of cancer. Furthermore, we found that the genes associated with YTHDF3 were enriched for translation initiation and mRNA metabolic processes. The results of the GSEA enrichment suggest that YTHDF3 may be associated with different pathways in cells in various tumor types. We further analyzed the correlations between YTHDF3 expression and MSI, TMB, and immune checkpoint genes. YTHDF3 also possibly exerts important antitumor immunotherapy effects. Additionally, the results of the immune analysis using TIMER showed that high YTHDF3 expression levels in pan-cancer tissues were related to an immunosuppressive microenvironment. Finally, we experimentally demonstrated that both overexpression and downregulation of YTHDF3 can affect cancer cell proliferation rates. Conclusion: YTHDF3 is a promising biomarker for cancer diagnosis. This study provides the first comprehensive pan-cancer report on YTHDF3 and increases our understanding of its oncogenic role in different tumors.

Exploring the pathogenesis of type 2 diabetes mellitus intestinal damp-heat syndrome and the therapeutic effect of Gegen Qinlian Decoction from the perspective of exosomal miRNA.

ETHNOPHARMACOLOGICAL RELEVANCE: Diabetes is a common, complex, chronic metabolic disease. A randomized, double-blind, placebo-parallel controlled clinical study has shown that Gegen Qinlian Decoction (GQD) can reduce glycosylated hemoglobin in type 2 diabetes mellitus (T2DM) intestinal damp-heat syndrome patients in a dose-dependent manner. AIM: To explore the pathogenesis of T2DM intestinal damp-heat syndrome and the therapeutic effect of GQD from the perspective of exosomal microRNA (miRNA). METHODS: Eligible patients were selected and treated with GQD for 3 months to evaluate their clinical efficacy. Effective cases were matched with healthy volunteers, and saliva samples were collected. Exosomal miRNA was extracted from saliva and analyzed by chip sequencing. Subsequently, the function of the differential gene and the signal transduction pathway were analyzed using bioinformatics technology. Finally, three target miRNAs were randomly selected from the T2DM group/healthy group, and two target miRNAs in the T2DM before treatment/after treatment group were randomly selected for qPCR verification. Finally, we conducted a correlation analysis of the miRNAs and clinical indicators. The registration number for this research is ChiCTR-IOR-15006626. RESULTS: (1) The expression of exosomal miRNA chips showed that there were 14 differentially expressed miRNAs in the T2DM group/healthy group, and 26 differentially expressed miRNAs in the T2DM before treatment/after treatment group. (2) Enrichment results showed that in the T2DM group/healthy group, it was primarily related to cell development, body metabolism, TGF-ß, and ErbB signaling pathways. In the T2DM before treatment/after treatment group, it was mainly related to cellular metabolic regulation processes, and insulin, Wnt, and AMPK signaling pathways. (3) The qPCR verification showed that the expressions of hsa-miR-9-5p, hsa-miR-150-5p, and hsa-miR-216b-5p in the T2DM group was higher (P<0.05). Following GQD treatment, hsa-miR-342-3p and hsa-miR-221-3p were significantly downregulated (P<0.05). (4) hsa-miR-9-5p was positively correlated with BMI (P<0.05), and hsa-miR-150-5p was positively correlated with total cholesterol and triglycerides (P<0.05). The GQD efficacy-related gene hsa-miR-342-3p was positively correlated with the patient's initial blood glucose level (P<0.05), and hsa-miR-221-3p was positively correlated with total cholesterol and triglycerides (P<0.05). CONCLUSION: The exosomal miRNA expression profile and signaling pathways related to T2DM intestinal damp-heat syndrome and the efficacy of GQD were established, which provides an alternative strategy for precision traditional Chinese medicine treatment.

IGF2BP3 is an essential N6-methyladenosine biotarget for suppressing ferroptosis in lung adenocarcinoma cells.

A lack of promising targets leads to poor prognosis in patients with lung adenocarcinoma (LUAD). Therefore, it is urgent to identify novel therapeutic targets. The importance of the N6-methyladenosine (m6A) RNA modification has been demonstrated in various types of tumors; however, knowledge of m6A-related proteins in LUAD is still limited. Here, we found that insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3), an m6A reader protein, is highly expressed in LUAD and associated with poor prognosis. IGF2BP3 desensitizes ferroptosis (a new form of regulated cell death) in a manner dependent on its m6A reading domain and binding capacity to m6A-methylated mRNAs encoding anti-ferroptotic factors, including but not limited to glutathione peroxidase 4 (GPX4), solute carrier family 3 member 2 (SLC3A2), acyl-CoA synthetase long chain family member 3 (ACSL3), and ferritin heavy chain 1 (FTH1). After IGF2BP3 overexpression, expression levels and mRNA stabilities of these anti-ferroptotic factors were successfully sustained. Notably, significant correlations between SLC3A2, ACSL3, and IGF2BP3 were revealed in clinical LUAD specimens, further establishing the essential role of IGF2BP3 in desensitizing ferroptosis. Inducing ferroptosis has been gradually accepted as an alternative strategy to treat tumors. Thus, IGF2BP3 could be a potential target for the future development of new biomaterial-associated therapeutic anti-tumor drugs.

Development and validation of a UPLC-MS/MS method for simultaneous determination of LBPT and its metabolites in human plasma.

Aim: A UPLC-MS/MS method was developed to determine LBPT as well as its four metabolites in human plasma to support the clinical study aiming to evaluate the efficacy of LBPT tablet in patients undergoing hip/knee replacement. Methodology: Plasma samples were prepared by protein precipitation and then separated on a C18 analytical column using (A) acetonitrile (B) 0.1% formic acid and 10 mM ammonium formate in water. The detection was performed on a triple quadrupole tandem mass spectrometer in positive electrospray ionization using multiple reactions monitoring mode. Results & conclusion: The method has been validated in accordance with the US FDA guidelines and was applied to the measurement of five analytes in human plasma samples from a Phase II clinical trial.

Determination of Isosorbide-5-Mononitrate in Human Plasma by High-Performance Liquid Chromatography-Tandem Mass Spectrometry and Its Application to a Bioequivalence Study.

Isosorbide-5-mononitrate (5-ISMN), an organic nitrate vasodilator, has been widely used worldwide to prevent angina pectoris for more than two decades. A simple and sensitive high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed and validated for the determination of 5-ISMN in human plasma. 13C6-5-ISMN is an internal standard, and 5-ISMN was extracted from human plasma (50 µL) with ethyl acetate (200 µL) by a simple liquid-liquid extraction method. The chromatographic separation was carried out on LC-20A (Shimadzu, Japan) using an analytical column ZORBAX XDB-C18 (4.6 × 50 mm, 5 µm), coupled with API 4000 tandem mass spectrometers in a multiple reaction monitoring (MRM) mode. The mobile phase was composed of acetonitrile (organic phase A) and 2 mM ammonium acetate in water (aqueous phase B) with an isocratic elution of A/B = 90 : 10 (v/v). The total run time was 3.5 min with a small injection volume (5 µL). This method was fully validated in every aspect of selectivity, linearity, accuracy, precision, matrix effect, extraction recovery, and different stabilities. It was proved that the calibration standards within the 5.00-1000 ng/mL concentration range were linear. The lower limit of quantification was 5.00 ng/mL for 5-ISMN. The intrabatch and interbatch accuracy (RE) ranged from -8.8% to 7.1% with precision between 2.4% and 6.6%. The mean values of 5-ISMN extraction recovery and matrix effect were 87.0% and 102.0%, respectively. The fully validated method was successfully applied for a bioequivalence clinical trial of oral 20 mg 5-ISMN tablets in healthy Chinese subjects.

Highly efficient chloramphenicol degradation by UV and UV/H2 O2 processes based on LED light source.

In this study, UV-LED was employed as a novel light source to investigate the degradation of a representative antibiotic compound, chloramphenicol (CAP), in the absence or presence of H2 O2 . The UV-LED irradiation showed a higher capability for degradation of CAP than conventional UV-Hg vapor lamps. Effects of the initial CAP concentration, UV wavelength, and light intensity on the degradation of CAP by UV-LED were evaluated. Introduction of H2 O2 evidently enhanced the degradation efficiency of CAP due to the production of reactive hydroxyl radicals. Results showed that the UV-LED/H2 O2 removed CAP by up to 95% within 60 min at pH 5.0, which was twice as that achieved by the UV-LED alone. The degradation products were identified to propose plausible degradation pathways. Moreover, the formation potentials of typical carbonaceous disinfection by-products (C-DBPs) and nitrogenous disinfection by-products (N-DBPs) were assessed for the CAP polluted water treated by the UV-LED alone and UV-LED/H2 O2 processes. Results indicate unintended formation of certain DBPs, thereby highlighting the importance of health risk assessments before practical application. This study opens a new avenue for developing environment-friendly and high-performance UV-LED photocatalytic reactors for abatement of CAP pollution in water. PRACTITIONER POINTS: UV-LED bore higher capability to degrade CAP than low-pressure Hg lamp. The optimal performance to degrade CAP can be achieved at the UV wavelength of 280 nm. The degradation efficiency under UV-LED/H2 O2 process was double of that under UV-LED process. TCM, DCAN, and TCNM formation were higher under the existence of UV-LED radiation. The addition of H2 O2 had greater influence on the formation of DCAcAm than the introduction of UV-LED.

Copper sulfide nanoparticles as high-performance cathode materials for magnesium secondary batteries.

Magnesium secondary batteries are promising candidates for large-scale energy storage systems with high safety, because of the dendrite-free electrodeposition of the magnesium anode. However, the search for available cathode materials remains a significant challenge, hindering their development. In this work, we report copper sulfide nanoparticles as high-performance cathode materials for magnesium secondary batteries, which deliver a high reversible capacity of 175 mA h g-1 at 50 mA g-1. The cathode also shows an excellent rate capability providing 90 mA h g-1 at 1000 mA g-1 and an outstanding long-term cyclability over 350 cycles. The beneficial properties are ascribed to the small-sized copper sulfide particles which facilitate the solid-state diffusion kinetics. Further investigation on the mechanism demonstrates that the reaction is a typical conversion reaction, and the excellent cycling stability is due to the CuS nanoparticles which are not facile to aggregate during cycling. This work introduces an abundant, low-cost and high-performance cathode material for magnesium secondary batteries, and provides feasibility for the practical application of magnesium secondary battery systems in large-scale energy storage devices.

Effect of γ-Aminobutyric Acid-Chitosan Nanoparticles on Glucose Homeostasis in Mice.

Diabetes mellitus is the most common endocrine disease worldwide; hyperglycemia is a hallmark of this disease. To alleviate the pain caused by diabetes, developing and utilizing effective diabetic drugs to maintain or recover the function of the residual ß-cells is an attractive therapeutic approach. γ-aminobutyric acid (GABA) has been shown to have such effects, but it is easy to have reduced GABA activity under physiological conditions. In the present study, GABA-chitosan nanoparticles (GABA-CS NPs) were prepared, and glucose homeostasis, pancreatic ß-cell protection, and anti-inflammatory effects of GABA-CS NPs were investigated in vivo. The results showed that blood glucose levels and IL-1ß levels in the GABA-CS NP-administered group were both significantly lower, whereas the PDX1 expression was significantly higher than that of the impaired group (p < 0.01). This indicates that GABA-CS NPs can efficiently maintain glucose homeostasis, protect ß-cells, and inhibit inflammation. These nanoparticles have the potential to be applied for future diabetes theranostics.