Nonlinear association between atherogenic index of plasma and type 2 diabetes mellitus in overweight and obesity patients: evidence from Chinese medical examination data.

BACKGROUND: The atherogenic index of plasma (AIP) is closely associated with the onset of diabetes, with obesity being a significant risk factor for type 2 diabetes mellitus (T2DM). However, the association between the AIP and T2DM in overweight and obese populations has been infrequently studied. Therefore, this study aimed to explore this association in overweight and obese individuals with T2DM. METHODS: This cross-sectional analysis utilized data from 40,633 participants with a body mass index (BMI) ≥ 24 kg/m2 who were screened from January 2018 to December 2023 at Henan Provincial People's Hospital. Participants were categorized into groups of overweight and obese individuals with and without diabetes according to the T2DM criteria. The AIP, our dependent variable, was calculated using the formula log10 [(TG mol/L)/HDL-C (mol/L)]. We investigated the association between the AIP and T2DM in overweight and obese individuals using multivariate logistic regression, subgroup analysis, generalized additive models, smoothed curve fitting, and threshold effect analysis. Additionally, mediation analysis evaluated the role of inflammatory cells in AIP-related T2DM. RESULTS: Overweight and obese patients with T2DM exhibited higher AIP levels than those without diabetes. After adjusting for confounders, our results indicated a significant association between the AIP and the risk of T2DM in overweight and obese individuals (odds ratio (OR) = 5.17, 95% confidence interval (CI) 4.69-5.69). Notably, participants with a high baseline AIP (Q4 group) had a significantly greater risk of T2DM than those in the Q1 group, with an OR of 3.18 (95% CI 2.94-3.45). Subgroup analysis revealed that the association between the AIP and T2DM decreased with increasing age (interaction P < 0.001). In overweight and obese populations, the association between AIP and T2DM risk displayed a J-shaped nonlinear pattern, with AIP > - 0.07 indicating a significant increase in T2DM risk. Various inflammatory cells, including neutrophils, leukocytes, and monocytes, mediated 4.66%, 4.16%, and 1.93% of the associations, respectively. CONCLUSION: In overweight and obese individuals, the AIP was independently associated with T2DM, exhibiting a nonlinear association. Additionally, the association between the AIP and T2DM decreased with advancing age. Multiple types of inflammatory cells mediate this association.

Association between high-density lipoprotein cholesterol and lumbar bone mineral density in Chinese: a large cross-sectional study.

BACKGROUND: The association between lipid and bone metabolism, particularly the role of high-density lipoprotein cholesterol (HDL-C) in regulating bone mineral density (BMD), is of significant interest. Despite numerous studies, findings on this relationship remain inconclusive, especially since evidence from large, sexually diverse Chinese populations is sparse. This study, therefore, investigates the correlation between HDL-C and lumbar BMD in people of different genders using extensive population-based data from physical examinations conducted in China. METHODS: Data from a cross-sectional survey involving 20,351 individuals aged > = 20 years drawn from medical records of health check-ups at the Health Management Centre of the Henan Provincial People's Hospital formed the basis of this study. The primary objective was to determine the correlation between HDL-C levels and lumbar BMD across genders. The analysis methodology included demographic data analysis, one-way ANOVA, subgroup analyses, multifactorial regression equations, smoothed curve fitting, and threshold and saturation effect analyses. RESULTS: Multifactorial regression analysis revealed a significant inverse relationship between HDL-C levels and lumbar BMD in both sexes, controlling for potential confounders (Male: ß = -8.77, 95% CI -11.65 to -5.88, P < 0.001; Female: ß = -4.77, 95% CI -8.63 to -0.90, P = 0.015). Subgroup and threshold saturation effect analyses indicated a stronger association in males, showing that increased HDL-C correlates with reduced lumbar BMD irrespective of age and body mass index (BMI). The most significant effect was observed in males with BMI > 28 kg/m2 and HDL-C > 1.45 mmol/L and in females with a BMI between 24 and 28 kg/m2. CONCLUSION: Elevated HDL-C is associated with decreased bone mass, particularly in obese males. These findings indicate that individuals with high HDL-C levels should receive careful clinical monitoring to mitigate osteoporosis risk. TRIAL REGISTRATION: The research protocol received ethics approval from the Ethics Committee at Beijing Jishuitan Hospital, in conformity with the Declaration of Helsinki guidelines (No. 2015-12-02). These data are a contribution of the China Health Quantitative CT Big Data Research team, registered at clinicaltrials.gov (code: NCT03699228).

Quantitative Relaxometry Assessment of Brain Microstructural Abnormality of Preschool Children With Autism Spectrum Disorder With Synthetic Magnetic Resonance Imaging.

OBJECTIVE: This study aimed to perform an assessment of brain microstructure in children with autism aged 2 to 5 years using relaxation times acquired by synthetic magnetic resonance imaging. MATERIALS AND METHODS: Thirty-four children with autism spectrum disorder (ASD) (ASD group) and 17 children with global developmental delay (GDD) (GDD group) were enrolled, and synthetic magnetic resonance imaging was performed to obtain T1 and T2 relaxation times. The differences in brain relaxation times between the 2 groups of children were compared, and the correlation between significantly changed T1/T2 and clinical neuropsychological scores in the ASD group was analyzed. RESULTS: Compared with the GDD group, shortened T1 relaxation times in the ASD group were distributed in the genu of corpus callosum (GCC) ( P = 0.003), splenium of corpus callosum ( P = 0.002), and right thalamus (TH) ( P = 0.014), whereas shortened T2 relaxation times in the ASD group were distributed in GCC ( P = 0.011), left parietal white matter ( P = 0.035), and bilateral TH (right, P = 0.014; left, P = 0.016). In the ASD group, the T2 of the left parietal white matter is positively correlated with gross motor (developmental quotient [DQ] 2) and personal-social behavior (DQ5), respectively ( r = 0.377, P = 0.028; r = 0.392, P = 0.022); the T2 of the GCC was positively correlated with DQ5 ( r = 0.404, P = 0.018); and the T2 of the left TH is positively correlated with DQ2 and DQ5, respectively ( r = 0.433, P = 0.009; r = 0.377, P = 0.028). All significantly changed relaxation values were not significantly correlated with Childhood Autism Rating Scale scores. CONCLUSIONS: The shortened relaxometry times in the brain of children with ASD may be associated with the increased myelin content and decreased water content in the brain of children with ASD in comparison with GDD, contributing the understanding of the pathophysiology of ASD. Therefore, the T1 and T2 relaxometry may be used as promising imaging markers for ASD diagnosis.

Association between total cholesterol and lumbar bone density in Chinese: a study of physical examination data from 2018 to 2023.

BACKGROUND: The impact of total cholesterol (TC) on lumbar bone mineral density (BMD) is a topic of interest. However, empirical evidence on this association from demographic surveys conducted in China is lacking. Therefore, this study aimed to examine the relationship between serum TC and lumbar BMD in a sample of 20,544 Chinese adults between the ages of 20 and 80 years over a period of 5 years, from February 2018 to February 2023. Thus, we investigated the effect of serum TC level on lumbar BMD and its relationship with bone reduction in a Chinese adult population. METHODS: This cross-sectional study used data obtained from the Department of Health Management at Henan Provincial People's Hospital between February 2018 and February 2023. The aim of this study was to examine the correlation between serum TC and lumbar BMD in individuals of different sexes. The research methodology encompassed population description, analysis of stratification, single-factor and multiple-equation regression analyses, smooth curve fitting, and analysis of threshold and saturation effects. The R and EmpowerStats software packages were used for statistical analysis. RESULTS: After adjusting for confounding variables, a multiple linear regression model revealed a significant correlation between TC and lumbar BMD in men. In subgroup analysis, serum TC was found to have a positive association with lumbar BMD in men, specifically those aged 45 years or older, with a body mass index (BMI) ranging from 24 to 28 kg/m2. A U-shaped correlation arose between serum TC and lumbar BMD was detected in women of different ages and BMI, the inflection point was 4.27 mmol/L for women aged ≥ 45 years and 4.35 mmol/L for women with a BMI of ≥ 28 kg/m2. CONCLUSION: In this study, Chinese adults aged 20-80 years displayed different effects of serum TC on lumbar BMD in sex-specific populations. Therefore, monitoring BMI and serum TC levels in women of different ages could prevent osteoporosis and osteopenia. TRIAL REGISTRATION: The research protocol was approved by the Ethics Committee of Beijing Jishuitan Hospital, in accordance with the Declaration of Helsinki guidelines (No. 2015-12-02). These data are part of the China Health Quantitative CT Big Data Research team, which has been registered at clinicaltrials.gov (code: NCT03699228).

The mediating effect of psychological resilience between social support and anxiety/depression in people living with HIV/AIDS-a study from China.

Objective To understand the relationship between psychological resilience in social support and anxiety/depression in people living with HIV/AIDS and to verify whether there is a mediating effect. Methods The questionnaire was administered to 161 people living with HIV/AIDS in a hospital. The questionnaire contained a general questionnaire, the Hospital Anxiety and Depression Scale (HADS), the Psychological Resilience Inventory (CD-RICS), and the Social Collaborative Support Scale (PSSS), and Pearson correlation analyses were used to explore the correlation between the factors and anxiety/depression, stratified linear regression analyses were used to validate the mediation model, and the bootstrap method was used to test for mediating effects. Results Anxiety was negatively correlated with psychological resilience and social support (r=-0.232, P < 0.01; r=-0.293, P < 0.01); depression was negatively correlated with psychological resilience and social support (r=-0.382, P < 0.01; r=-0.482, P < 0.01); there was a mediation effect model of social support between psychological resilience and anxiety/depression; psychological resilience played a fully mediating role in social support and anxiety/depression, with an effect contribution of 68.42%/59.34% and a 95% CI(-0.256~-0.036)/(-0.341 to~-0.106). Conclusion Psychological resilience plays a complete mediating effect between social support and anxiety/depression. It is recommended that more channels of social support be provided to patients with HIV/AIDS, thereby enhancing their psychological resilience and reducing anxiety/depression levels.

The Quantification of Paclitaxel and Its Two Major Metabolites in Biological Samples by HPLC-MS/MS and Its Application in a Pharmacokinetic and Tumor Distribution Study in Xenograft Nude Mouse.

A rapid and sensitive high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed for the quantification of Paclitaxel (PTX), 6α-hydroxypaclitaxel (6α-OHP), and p-3'-hydroxypaclitaxel (3'-OHP) in mouse plasma and tumor tissue. The analytes were separated using a C18 column (50 × 2.1 mm, 1.8 µm), and a triple-quadrupole mass spectrometry device equipped with an electrospray ionization (ESI) source was applied for their detection. PTX, 6α-OHP, and 3'-OHP were extracted from the biological samples with the solid-phase extraction cartridge. The method was fully validated according to the FDA's guidance. The method was linear over the concentration ranges of 0.5~1000.0 ng/mL for PTX and 0.25~500.0 ng/mL for 6α-OHP and 3'-OHP. The precision, accuracy, extraction recovery, and matrix effects were within acceptable limits. The present method was successfully applied to the study of the pharmacokinetics and distribution of PTX, 6α-OHP, and 3'-OHP in the tumors of post xenograft nude mice intravenously injected with PTX solution.

Quantification of 3-bromopyruvate in rat plasma by HPLC-MS/MS employing precolumn derivatization and the application to a pharmacokinetics study.

A simple high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method has been developed for the determination of 3-bromopyruvate (3-BrPA) in rat plasma for the first time. The analytes were separated on a C18 column (100 × 2.1 mm, 1.7 µm) and a triple-quadrupole mass spectrometry equipped with an electrospray ionization source was applied for detection. 3-BrPA was extracted from rat plasma with protein precipitation, and then derivatized with 4-nitro-1,2-phenylenediamine to obtain the mass signal because 3-BrPA could not be detected in mass spectrometry. The method was fully validated according to the US Food and Drug Administration guidance. The method was linear over the concentration range 0.5-1,000.0 ng/ml for 3-BrPA. The precision and accuracy, extraction recovery, and matrix effect were within acceptable limits. The method was then applied to support a pharmacokinetic study after 3-BrPA and 3-BrPA-l-Val-l-Ile (a dipeptide prodrug of 3-BrPA, 3-BrPA-l-Valine-l-isoleucine) had been administered to the Sprague-Dawley rats, respectively.

Val-Val-Tyr-Pro protects against non-alcoholic steatohepatitis in mice by modulating the gut microbiota and gut-liver axis activation.

Val-Val-Tyr-Pro (VVYP) peptide is one of the main active components of Globin digest (GD). Our previous studies indicated that VVYP could protect against acetaminophen and carbon tetrachloride-induced acute liver failure in mice and decrease blood lipid level. However, the effects and underlying mechanisms of VVYP in the treatment of non-alcoholic steatohepatitis (NASH) have not been discovered. Our present study was designed to investigate the preventive effect of VVYP on NASH and its underlying specific mechanisms. We found that VVYP inhibited the cytotoxicity and lipid accumulation in L-02 cells that were exposed to a mixture of free fatty acid (FFA). VVYP effectively alleviated the liver injury induced by methionine-choline-deficient (MCD) diet, demonstrated by reducing the levels of serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST)/triglycerides (TG)/non-esterified fatty acids (NEFA) and improving liver histology. VVYP decreased expression levels of lipid synthesis-related genes and reduced levels of the proinflammation cytokines in the liver of mice fed by MCD diet. Moreover, VVYP inhibited the increased level of LPS and reversed the liver mitochondria dysfunction induced by MCD diet. Meanwhile, VVYP significantly increased the abundance of beneficial bacteria such as Eubacteriaceae, coriobacteriacease, Desulfovibrionaceae, S24-7 and Bacteroidia in high-fat diet (HFD)-fed mice, however, VVYP reduced the abundance of Lactobacillus. Moreover, VVYP conferred the protective effect of intestinal barrier via promoting the expression of the mucins and tight junction (TJ)-associated genes and inhibited subsequent liver inflammatory responses. These results indicated that the protective role of VVYP on NASH is mediated by modulating gut microbiota imbalance and related gut-liver axis activation. VVYP might be a promising drug candidate for NASH.

Nanocrystal-Loaded Micelles for the Enhanced In Vivo Circulation of Docetaxel.

Prolonging in vivo circulation has proved to be an efficient route for enhancing the therapeutic effect of rapidly metabolized drugs. In this study, we aimed to construct a nanocrystal-loaded micelles delivery system to enhance the blood circulation of docetaxel (DOC). We employed high-pressure homogenization to prepare docetaxel nanocrystals (DOC(Nc)), and then produced docetaxel nanocrystal-loaded micelles (DOC(Nc)@mPEG-PLA) by a thin-film hydration method. The particle sizes of optimized DOC(Nc), docetaxel micelles (DOC@mPEG-PLA), and DOC(Nc)@mPEG-PLA were 168.4, 36.3, and 72.5 nm, respectively. The crystallinity of docetaxel was decreased after transforming it into nanocrystals, and the crystalline state of docetaxel in micelles was amorphous. The constructed DOC(Nc)@mPEG-PLA showed good stability as its particle size showed no significant change in 7 days. Despite their rapid dissolution, docetaxel nanocrystals exhibited higher bioavailability. The micelles prolonged the retention time of docetaxel in the circulation system of rats, and DOC(Nc)@mPEG-PLA exhibited the highest retention time and bioavailability. These results reveal that constructing nanocrystal-loaded micelles may be a promising way to enhance the in vivo circulation and bioavailability of rapidly metabolized drugs such as docetaxel.

Improving Oral Bioavailability of Luteolin Nanocrystals by Surface Modification of Sodium Dodecyl Sulfate.

Luteolin suffers from drawbacks like low solubility and bioavailability, thus hindering its application in the clinic. In this study, we employed sodium dodecyl sulfate (SDS), an efficient tight junction opening agent, to modify the surface of luteolin nanocrystals, aiming to enhance the bioavailability of luteolin (LUT) and luteolin nanocrystals (LNC). The particle sizes of SDS-modified luteolin nanocrystals (SLNC) were slightly larger than that of LNC, and the zeta potential of LNC and SLNC was -25.0 ± 0.7 mV and -43.5 ± 0.4 mV, respectively. Both LNC and SLNC exhibited enhanced saturation solubility and high stability in the liquid state. In the cellular study, we found that SDS has cytotoxicity on caco-2 cells and could open the tight junction of the caco-2 monolayer, which could lead to an enhanced transport of luteolin across the intestinal membrane. The bioavailability of luteolin was enhanced for 1.90-fold by luteolin nanocrystals, and after modification with SDS, the bioavailability was enhanced to 3.48-fold. Our experiments demonstrated that SDS could efficiently open the tight junction and enhance the bioavailability of luteolin thereafter, revealing the construction of SDS-modified nanocrystals is a good strategy for enhancing the oral bioavailability of poorly soluble drugs like luteolin.

Toxicity of ZnO nanoparticles (NPs) to THP-1 macrophages: interactions with saturated or unsaturated free fatty acids.

In a biological microenvironment, free fatty acids (FFA) as ubiquitous biological molecules might interact with nanoparticles (NPs) and consequently change the toxicological responses. However, whether the chemical structures of FFA could influence their interactions with NPs remain unknown. This study investigated the interactions between ZnO NPs and saturated or unsaturated FFA (complexed to BSA), namely stearic acid (SA, C18:0), oleic acid (OA, C18:1), and α-linolenic acid (ALA, C18:3). It was shown that BSA, SA, OA, and ALA increased the atomic force microscope (AFM) heights as well the polydispersity index (PDI) of ZnO NPs. BSA modestly protected THP-1 macrophages from ZnO NP exposure, whereas OA and ALA led to relatively less cyto-protective effects of BSA. Moreover, only co-exposure to ZnO NPs and SA significantly promoted the release of interleukin-8. BSA, SA, OA, and ALA equally changed intracellular ROS and Zn ions associated with ZnO exposure, but co-exposure to ZnO NPs and OA/ALA particularly activated the expression of endoplasmic reticulum stress-apoptosis genes. In combination, these results showed that FFA could influence the colloidal aspects and toxicological signaling pathway of ZnO NPs, which is dependent on the number of unsaturated bonds of FFA.

Design and synthesis of novel senkyunolide analogues as neuroprotective agents.

A class of senkyunolide analogues bearing benzofuranone fragment were designed, synthesized and evaluated for their neuroprotective effect in models of oxygen glucose deprivation (OGD) and oxidative stress. All tested compounds showed neuroprotection profile based on the cell viability assay. In particular, derivatives 1f-1i possessing furoxan-based nitric oxide releasing functionality exhibited significant biological activities in OGD models. More importantly, compound 1g containing short linker with furoxan displayed the most potent neuroprotection at the concentration of 100 µM (cell survival up to 145.2%). Besides, 1g also showed the middle level neuroprotective effect in model of oxidative stress.

Coumarin-dithiocarbamate hybrids as novel multitarget AChE and MAO-B inhibitors against Alzheimer's disease: Design, synthesis and biological evaluation.

A series of new coumarin-dithiocarbamate hybrids were designed and synthesized as multitarget agents for the treatment of Alzheimer's disease. Most of them showed potent and clearly selective inhibition towards AChE and MAO-B. Among these compounds, compound 8f demonstrated the most potent inhibition to AChE with IC50 values of 0.0068 µM and 0.0089 µM for eeAChE and hAChE, respectively. Compound 8g was identified as the most potent inhibitor to hMAO-B, and it is also a good and balanced inhibitor to both hAChE and hMAO-B (0.114 µM for hAChE; 0.101 µM for hMAO-B). Kinetic and molecular modeling studies revealed that 8g was a dual binding site inhibitor for AChE and a competitive inhibitor for MAO-B. Further studies indicated that 8g could penetrate the BBB and exhibit no toxicity on SH-SY5Y neuroblastoma cells. More importantly, 8g did not display any acute toxicity in mice at doses up to 2500 mg/kg and could reverse the cognitive dysfunction of scopolamine-induced AD mice. Overall, these results highlighted 8g as a potential multitarget agent for AD treatment and offered a starting point for design of new multitarget AChE/MAO-B inhibitors based on dithiocarbamate scaffold.

HPLC-MS/MS analysis of peramivir in rat plasma: Elimination of matrix effect using the phospholipid-removal solid-phase extraction method.

A simple HPLC-MS/MS method has been developed for the determination of peramivir in rat plasma in the present study. The analytes were separated on a C18 column (50 × 2.1 mm, 1.7 µm) and a triple-quadrupole mass spectrometer equipped with an electrospray ionization source was applied for the detection. A phospholipid-free cartridge solid-phase extraction was used to pretreat the plasma and eliminate the endogenous phospholipid. The in-source collision-induced dissociation approach showed that this pretreatment could result in negligible ion suppression from the extracted sample and could produce cleaner samples when compared with the protein precipitation. The method was linear over the concentration range of 0.12-1200.0 ng/mL for peramivir. The method was validated and successfully applied to a pharmacokinetic study after peramivir was orally and intravenously administered to Sprague-Dawley rats.

Rutin, A Natural Flavonoid Protects PC12 Cells Against Sodium Nitroprusside-Induced Neurotoxicity Through Activating PI3K/Akt/mTOR and ERK1/2 Pathway.

Free radicals induced neural damage is implicated in CNS diseases and rutin isolated form Lonicera japonica are reported to have neuroprotective activity. Previously, we confirmed that rutin exerted neuroprotective effect against sodium nitroprusside (SNP)-induced cell death in PC12 cells. However, the neuroprotective mechanism of rutin is still not fully uncovered. Here, we found that rutin significantly decreased SNP-induced reactive oxygen species in PC12 cells. Rutin reversed the declined GSH/GSSG ratio and mitochondrial membrane potential induced by SNP. Moreover, rutin activated both the protein Akt/mTOR and the extracellular signal-regulated kinase (ERK1/2) signaling pathways and the neuroprotective effects of rutin were blocked by either the specific PI3K inhibitor LY294002 or the MAPK pathway inhibitor PD98059. In summary, these results demonstrated that the neuroprotective effects of rutin might be through activating both the PI3K/Akt/mTOR and ERK1/2 signaling pathways. Our findings support that rutin may have therapeutic potential for the treatment of CNS diseases related to NO neurotoxicity.

[Simultaneous determination of 9 major components of dachengqi tang in rat plasma by UPLC-MS/MS].

The study established a UPLC-MS/MS method that is used for simultaneous determination nine major bioactive compounds of Dachengqi Tang in rat plasma. Using Aglient C18 column (2.1 mm x 50 mm,1.7 microm) was chromatographed, using methanol-5 mmol x L(-1) ammonium formate mobile phase gradient, elution 0.3 mL x min(-1). In the plasma pre-treatment process, not only the method of methanol and acetonitrile protein precipitation was investigated, and different factors extraction solvent, the type of the scroll time, the number and the type of extraction solvent, the extraction volume of the extraction solution of liquid-liquid extraction is investigated. Finally, with ibuprofen as an internal standard, using ethyl acetate liquid-liquid extraction method pretreatment blood, N2 dry reconstituted supernatant after centrifugation UPLC-MS/MS analysis, in electrospray ionization (ESI) negative mode, using multiple reaction monitoring mode for testing. The linear range of emodin, rhein, aloe-emodin, chrysophanol, magnolol, honokiol, hesperidin and hesperitin is 0.33-660, 0.40-792, 0.41-827, 0.34-680, 0.45-907, 0.46-927, 0.43-867, 0.34-683, 0.39-787 microg x L(-1) respectively, good linear relationship; and extraction recovery were greater than 69.39%, days after the day of the RSD is less than 15%. This method can be used to study the rat gastric large bearing gas after Dachengqi Tang, the simultaneous determination of nine components in plasma for its pharmacokinetics and efficacy material base to provide a theoretical basis.

Exploring White Matter Abnormalities in Young Children with Autism Spectrum Disorder: Integrating Multi-shell Diffusion Data and Machine Learning Analysis.

RATIONALE AND OBJECTIVES: This study employed tract-based spatial statistics (TBSS) to investigate abnormalities in the white matter microstructure among children with autism spectrum disorder (ASD). Additionally, an eXtreme Gradient Boosting (XGBoost) model was developed to effectively classify individuals with ASD and typical developing children (TDC). METHODS AND MATERIALS: Multi-shell diffusion weighted images were acquired from 62 children with ASD and 44 TDC. Using the Pydesigner procedure, diffusion tensor (DT), diffusion kurtosis (DK), and white matter tract integrity (WMTI) metrics were computed. Subsequently, TBSS analysis was applied to discern differences in these diffusion parameters between ASD and TDC groups. The XGBoost model was then trained using metrics showing significant differences, and Shapley Additive explanations (SHAP) values were computed to assess the feature importance in the model's predictions. RESULTS: TBSS analysis revealed a significant reduction in axonal diffusivity (AD) in the left posterior corona radiata and the right superior corona radiata. Among the DK indicators, mean kurtosis, axial kurtosis, and kurtosis fractional anisotropy were notably increased in children with ASD, with no significant difference in radial kurtosis. WMTI metrics such as axonal water fraction, axonal diffusivity of the extra-axonal space (EAS_AD), tortuosity of the extra-axonal space (EAS_TORT), and diffusivity of intra-axonal space (IAS_Da) were significantly increased, primarily in the corpus callosum and fornix. Notably, there was no significant difference in radial diffusivity of the extra-axial space (EAS_RD). The XGBoost model demonstrated excellent classification ability, and the SHAP analysis identified EAS_TORT as the feature with the highest importance in the model's predictions. CONCLUSION: This study utilized TBSS analyses with multi-shell diffusion data to examine white matter abnormalities in pediatric autism. Additionally, the developed XGBoost model showed outstanding performance in classifying ASD and TDC. The ranking of SHAP values based on the XGBoost model underscored the significance of features in influencing model predictions.

Design, synthesis and evaluation of carbamate-bridged amino acid prodrugs of cycloicaritin with improved antitumor activity, aqueous solubility and phase II metabolic stability.

Cycloicaritin (CICT), a bioactive flavonoid derived from the genus Epimedium, exhibits a variety of beneficial biological activities, including promising anticancer effects. However, its poor oral bioavailability is attributed to its extremely low aqueous solubility and rapid elimination via phase II conjugative metabolism. To overcome these limitations, we designed and synthesized a series of carbamate-bridged prodrugs, protecting the hydroxyl group at the 3-position of cycloicaritin by binding with the N-terminus of a natural amino acid. The optimal prodrug 4b demonstrated a significant increase in aqueous solubility as compared to CICT, as well as improved stability in phase II metabolism, while allowing for a rapid release of CICT in the blood upon gastrointestinal absorption. The prodrug 4b also facilitated oral absorption through organic anion-transporting polypeptide 2B1-mediated transport and exhibited moderate cytotoxicity. Importantly, the prodrug enhanced the oral bioavailability of CICT and displayed dose-dependent antitumor activity with superior safety. In summary, the prodrug 4b is a novel potential antitumor drug candidate, and the carbamate-bridged amino acid prodrug approach is a promising strategy for the oral delivery of CICT.

Association between liver fat level and risk of hypertension: evidence from a Chinese health examination dataset.

BACKGROUND: Hypertension development is predominantly influenced by inflammation, excessive fat deposition, and metabolic irregularities. Among these factors, liver fat accumulation is a critical metabolic disorder. However, the quantification of liver fat levels and its associated risk for hypertension incidence remain ambiguous. This project is designed to explore the association between liver fat levels and the risk of hypertension in a healthy population. METHODS: This cross-sectional study involved 4955 participants from the Health Management Center at Henan Provincial People's Hospital who were surveyed between February 2020 and February 2023. Participants were categorized into four groups based on liver fat quartiles. Subgroup analyses, restricted cubic spline regression models, and logistic regression were utilized to assess the association between liver fat levels and hypertension risk. The relationships between liver fat levels and inflammatory markers were examined using multiple linear regression models. Additionally, a mediation analysis was conducted to explore the role of inflammatory factors in the relationship between liver fat and hypertension risk. RESULTS: Participants with hypertension exhibited greater liver fat levels than did those without hypertension. An increased risk of hypertension was associated with elevated liver fat levels, even after adjusting for other covariates [Q4 vs. Q1 in model II: odds ratio (OR = 1.28), 95% confidence interval (CI) = 1.04-1.59, P = 0.022; P for trend = 0.039]. A nonlinear relationship was observed between liver fat level and hypertension risk, with a notable increase in hypertension risk occurring at liver fat levels greater than 8.65%. Additionally, a positive correlation was found between inflammatory markers and liver fat levels. A mediation effect of 4.76% was noted, linking hypertension risk and liver fat levels through neutrophils. CONCLUSION: Liver fat levels exceeding 8.65% significantly elevated the risk of hypertension. Inflammatory factors serve as crucial mediators of the relationship between liver fat and hypertension.

A carrier-mediated prodrug approach to improve the oral absorption of antileukemic drug decitabine.

Decitabine (5-aza-2'-deoxycytidine, DAC) is a novel DNA methyltransferase (DNMT) inhibitor for the treatment of myelodysplastic syndrome, acute and chronic myeloid leukemia. However, it exhibits a low oral bioavailability (only 9% in mice), because of low permeability across the intestine membrane and rapid metabolism to inactive metabolite. To utilize the carrier-mediated prodrug approach for improved absorption of decitabine, a series of amino acid-decitabine conjugates were synthesized to target the intestinal membrane transporter, hPepT1. The Caco-2 permeability of the prodrugs was screened, and two l-val (aliphatic, compound 4a) and l-phe (aromatic, compound 4c) prodrugs with higher permeability were selected for further studies. The uptake of Gly-Sar by Caco-2 cells could be competitively inhibited by compounds 4a and 4c, with IC50 being 2.20 ± 0.28 mM and 3.46 ± 0.16 mM, respectively. The uptake of compounds 4a and 4c was markedly increased in the leptin-treated Caco-2 cells compared with the control Caco-2 cells, suggesting that hPepT1-mediated transport contributes to oral absorption of compounds 4a and 4c. The prodrugs were evaluated for their stability in various phosphate buffers, rat plasma, tissue homogenates, and gastrointestinal fluids. Compounds 4a and 4c were stable in gastrointestinal tract at pH 6.0 but could be quickly converted into DAC in plasma and tissue homogenates after absorption. The oral absolute bioavailability of DAC was 46.7%, 50.9%, and 26.9% after compounds 4a, 4c, and DAC were orally administered to rats at a dose of 15 mg/kg, respectively. The bioavailability of compounds 4a and 4c in rats was both reduced to about 32% when orally coadministrated with typical hPepT1 substrate Gly-Sar (150 mg/kg). Overall, compounds 4a and 4c can significantly enhance the intestinal membrane permeability of DAC, followed by rapid and mostly bioactivation to parent drug in intestinal and hepatic tissues before entry into systemic circulation, and eventually improve oral bioavailability of DAC in rats. The hPepT1-targeted prodrug strategy is a promising strategy to improve the oral bioavailability of poorly absorbed decitabine.