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Abstract Background Despite centuries of traditional use of silymarin for hepatoprotection, current randomized controlled trial (RCT) studies on the effectiveness of silymarin in managing metabolic dysfunction-associated steatotic liver disease (MASLD) are limited and inconclusive, particularly when it is administered alone. The low bioavailability of silymarin highlights the possible influence of gut microbiota on the effectiveness of silymarin; however, no human studies have investigated this aspect. Objective To determine the potential efficacy of silymarin in improving MASLD indicators and to investigate the underlying mechanisms related to gut microbiota. Method In this 24-week randomized, double-blind, placebo-controlled trial, 83 patients with MASLD were randomized to either placebo (n = 41) or silymarin (103.2 mg/d, n = 42). At 0, 12, and 24 weeks, liver stiffness and hepatic steatosis were assessed using FibroScan, and blood samples were gathered for biochemical detection, while faecal samples were collected at 0 and 24 weeks for 16S rRNA sequencing. Results Silymarin supplementation significantly reduced liver stiffness (LSM, -0.21 ± 0.17 vs. 0.41 ± 0.17, P = 0.015) and serum levels of γ-glutamyl transpeptidase (GGT, -8.21 ± 3.01 vs. 1.23 ± 3.16, P = 0.042) and ApoB (-0.02 ± 0.03 vs. 0.07 ± 0.03, P = 0.023) but had no significant effect on the controlled attenuation parameter (CAP), other biochemical indicators (aminotransferases, total bilirubin, glucose and lipid parameters, hsCRP, SOD, and UA), physical measurements (DBP, SBP, BMI, WHR, BF%, and BMR), or APRI and FIB-4 indices. Gut microbiota analysis revealed increased species diversity and enrichment of Oscillospiraceae in the silymarin group. Conclusion These findings suggest that silymarin supplementation could improve liver stiffness in MASLD patients, possibly by modulating the gut microbiota. Trial registration The trial was registered at the Chinese Clinical Trial Registry (ChiCTR2200059043).

Objective In the central Yunnan region, the geological structure is complex and karst formations are prevalent. Sudden water gushing and attenuation of spring flow are among the most difficult problems in tunnel construction. The Mengkuanggou karst water system exhibits a high degree of karst conduitization, with significant differences between karst fissures and karst conduits. Methods This study employs the MODFLOW-CFPv2 dual medium numerical model to simulate the karst water system of Mengkuanggou, providing a detailed description of karst pipeline and diversion tunnel to understand the influence of tunnel construction on groundwater flow and spring flow. Results The results show that (1) The MODFLOW-CFPv2 model can describe the complex geological structure of karst areas, and simulate the dynamic characteristics of the groundwater level and the response characteristics of karst spring flow in the study area. (2) Under the condition of strong discharge, the water inflow per unit length of the tunnel is 164 m3/d·m, with a stable water inflow of 69 m3/d·m, while the Mengkuanggou karst spring flow shows a significant downwards trend. During the simulation period, the average spring flow decreased from 1 578 L/s under natural conditions to 1 098 L/s, an overall decrease of 30.4%, and the peak flow rate decreased from 2 133 L/s to 1 375 L/s, a decrease of 35.5%. The construction of strong discharge conditions will have a significant impact on tunnel construction and the groundwater environment. Under the condition of limited discharge, the maximum water inflow of the tunnel is 39 m3/d·m, and the stable water inflow is 24 m3/d·m. The water inflow of the tunnel is significantly reduced, and the downwards trend of the karst spring flow in Mengkuanggou is also improved to a certain extent. During the simulation period, the average spring flow is reduced to 1 284 L/s, a reduction of 18.6%, and the peak flow is reduced to 1 617 L/s, a decrease of 22.1%. Conclusion The MODFLOW-CFPv2 dual-medium model used in this study accurately describes highly heterogeneous karst water systems with pipelines, karst caves and fissures in karst areas. It can be used to quantitatively evaluate the karst water of Mengkuanggou during Xianglushan Tunnel construction.

The Forchheimer equation is one of the basic equations widely used in non-Darcy seepage. The determination of coefficients A and B in the equation has always been a hotspot and difficulty in the field of porous media seepage. Different studies have proposed various empirical formulas for the coefficients A and B from seepage experiments. However, there are few studies evaluating the applicability of each empirical formula under homogeneous condition and heterogeneous with mixed particle size. In this study, to provide basic information for selecting the empirical formula of the Forchheimer equation under different porous media conditions, the normalized objective function (NOF) and linear regression method are used to evaluate the applicability of the empirical formula of the Forchheimer equation, on the basis of the seepage resistance experiment. The results show that: for homogeneous porous media, Sidiropoulou’s formula has a good prediction effect on hydraulic gradient. For the porous media mixed two kinds of particle size, the mass ratio and size factors of the mixed particle size should be considered based on the average particle size. The prediction effect of the Macdonald formula is slightly affected by the mass ratio and the mixed particle size; while the predicted hydraulic gradient from the Kadlecan and Knight formula is relatively stable. As to the porous media mixed five kinds of particle size, the predictive effect of using d60 as the characteristic particle size is fine.The Kadlecan and Knight formula is suitable to predict coefficient A, and the Ergun formula is effective to predict coefficient B. This study can provide a basis for selecting the Forchheimer equation for seepage of homogeneous and heterogeneous loose sand and gravel porous media in engineering.

Background: The physical abilities of older adults decline with age, making them more susceptible to micronutrient deficiency, which may affect their sleep quality. Objectives: This study aimed to construct a risk correlative model for sleep disorders in Chinese older adults based on blood micronutrient levels. Methods: In this matched case-control study, we recruited 124 participants with sleep disorders and 124 matched controls from the Tianjin Elderly Nutrition and Cognition cohort in China. Micronutrient levels in whole blood were measured using the dried blood spot technique. We compared the differences in micronutrient levels between the two groups and also constructed a receiver operating characteristic (ROC) model and nomogram for sleep disorders. Results: In comparison to the control group, the sleep disorders group showed lower levels of blood vitamin A, vitamin E (VE), folate, magnesium, copper, iron, and selenium (Se) in the univariate analysis (p < 0.05). The ROC curve analysis indicated that the combination of VE + folate + Se may have an excellent diagnostic effect on sleep disorders, with an area under the curve of 0.964. This VE + folate + Se was integrated into a nomogram model to demonstrate their relationship with sleep disorders. The consistency index of the model was 0.88, suggesting that the model assessed sleep disorders well. Conclusions: The sleep disorders risk correlative model constructed by the levels of VE, folate, and Se in whole blood might show good performance in assessing the risk of sleep disorders in older adults.

Nattokinase (NK) and red yeast rice (RYR) are both indicated for their potential in cardiovascular disease prevention and management, but their combined effects especially in coronary artery disease (CAD) are scarcely examined. This 90-day randomized, double-blind trial aims to investigate the effect of NK and RYR supplementations on cardiometabolic parameters in patients with stable CAD. 178 CAD patients were randomized to four groups: NK + RYR, NK, RYR, and placebo. No adverse effects due to the interventions were reported. In comparisons across groups, NK + RYR showed the maximum effect in reducing triglyceride (−0.39 mmol), total cholesterol (−0.66 mmol/L), diastolic blood pressure (−7.39 mmHg), and increase in high-density lipoprotein cholesterol (0.195 mmol/L) than other groups (all p for multiple groups comparison

Background: Managing refractory epilepsy presents a significant a substantial clinical challenge. Deep brain stimulation (DBS) has emerged as a promising avenue for addressing refractory epilepsy. However, the optimal stimulation targets and effective parameters of DBS to reduce seizures remian unidentified. Objectives: This study endeavors to scrutinize the therapeutic potential of DBS within the zona incerta (ZI) across diverse seizure models and elucidate the associated underlying mechanisms. Methods: We evaluated the therapeutic potential of DBS with different frequencies in the ZI on kainic acid (KA)-induced TLE model or M1-cortical seizures model, pilocarpine-induced M1-cortical seizure models, and KA-induced epilepsy model. Further, employing calcium fiber photometry combined with cell-specific ablation, we sought to clarified the causal role of ZI GABAergic neurons in mediating the therapeutic effects of DBS. Results: Our findings reveal that DBS in the ZI alleviated the severity of seizure activities in the KA-induced TLE model. Meanwhile, DBS attenuated seizure activities in KA- or pilocarpine-induced M1-cortical seizure model. In addition, DBS exerts a mitigating influence on KA induced epilepsy model. DBS in the ZI showed anti-seizure effects at low frequency spectrum, with 5 Hz exhibiting optimal efficacy. The low-frequency DBS significantly increased the calcium activities of ZI GABAergic neurons. Furthermore, selective ablation of ZI GABAergic neurons with taCasp3 blocked the anti-seizure effect of low-frequency DBS, indicating the anti-seizure effect of DBS is mediated by the activation of ZI GABAergic neurons. Conclusion: Our results demonstrate that low-frequency DBS in the ZI attenuates seizure via driving GABAergic neuronal activity. This suggests that the ZI represents a potential DBS target for treating both hippocampal and cortical seizure through the activation of GABAergic neurons, thereby holding therapeutic significance for seizure treatment.

The consumption of probiotics has been extensively employed for the management or prevention of gastrointestinal disorders by modifying the gut microbiota and changing metabolites. Nevertheless, the probiotic-mediated regulation of host metabolism through the metabolism of bile acids (BAs) remains inadequately comprehended. The gut-liver axis has received more attention in recent years due to its association with BA metabolism. The objective of this research was to examine the changes in BAs and gut microbiota using an in vitro fermentation model. The metabolism and regulation of gut microbiota by commercial probiotics complex containing various species such as Lactobacillus, Bifidobacterium, and Streptococcus were investigated. The findings indicated that the probiotic strains had produced diverse metabolic profiles of BAs. The probiotics mixture demonstrated the greatest capacity for Bile salt hydrolase (BSH) deconjugation and 7α-dehydroxylation, leading to a significant elevation in the concentrations of Chenodeoxycholic acid, Deoxycholic acidcholic acid, and hyocholic acid in humans. In addition, the probiotic mixtures have the potential to regulate the microbiome of the human intestines, resulting in a reduction of isobutyric acid, isovaleric acid, hydrogen sulfide, and ammonia. The probiotics complex intervention group showed a significant increase in the quantities of Lactobacillus and Bifidobacterium strains, in comparison to the control group. Hence, the use of probiotics complex to alter gut bacteria and enhance the conversion of BAs could be a promising approach to mitigate metabolic disorders in individuals.

Silymarin, salvianolic acids B, and puerarin were considered healthy food agents with tremendous potential to ameliorate non-alcoholic fatty liver disease (NAFLD). However, the mechanisms by which they interact with gut microbiota to exert benefits are largely unknown. After 8 weeks of NAFLD modeling, C57BL/6J mice were randomly divided into five groups and fed a normal diet, high-fat diet (HFD), or HFD supplemented with a medium or high dose of Silybum marianum extract contained silymarin or polyherbal extract contained silymarin, salvianolic acids B, and puerarin for 16 weeks, respectively. The untargeted metabolomics and 16S rRNA sequencing were used for molecular mechanisms exploration. The intervention of silymarin and polyherbal extract significantly improved liver steatosis and recovered liver function in the mice, accompanied by an increase in probiotics like Akkermansia and Blautia, and suppressed Clostridium, which related to changes in the bile acids profile in feces and serum. Fecal microbiome transplantation confirmed that this alteration of microbiota and its metabolites were responsible for the improvement in NAFLD. The present study substantiated that alterations of the gut microbiota upon silymarin and polyherbal extract intervention have beneficial effects on HFD-induced hepatic steatosis and suggested the pivotal role of gut microbiota and its metabolites in the amelioration of NAFLD.

Objective: Intermittent energy restriction (IER) is an effective weight loss strategy. However, little is known about the dynamic effects of IER on the brain-gut-microbiome axis. Methods: In this study, a total of 25 obese individuals successfully lost weight after a 2-month IER intervention. FMRI was used to determine the activity of brain regions. Metagenomic sequencing was performed to identify differentially abundant gut microbes and pathways in from fecal samples. Results: Our results showed that IER longitudinally reduced the activity of obeserelated brain regions at different timepoints, including the inferior frontal orbital gyrus in the cognitive control circuit, the putamen in the emotion and learning circuit, and the anterior cingulate cortex in the sensory circuit. IER longitudinally reduced E. coli abundance across multiple timepoints while elevating the abundance of obesity-related Faecalibacterium prausnitzii, Parabacteroides distasonis, and Bacterokles uniformis. Correlation analysis revealed longitudinally correlations between gut bacteria abundance alterations and brain activity changes. Conclusions: There was dynamical alteration of BGM axis (the communication of E. coli with specific brain regions) during the weight loss under the IER. [ABSTRACT FROM AUTHOR]

The 10 vol% ZrMgMo3O12/2024Al composites were fabricated using the powder metallurgy process and consolidation via vacuum hot pressing. The effects of the ball milling process and solution treatment time on the composites’ microstructure, Vickers hardness, and compressive properties were studied. Increasing the ball milling speed and extending the ball milling duration reduce the size of ZrMgMo3O12 particles, resulting in a more uniform dispersion within the aluminum matrix. Extending the solution treatment duration facilitates the dissolution of more primary Al2Cu phase into the aluminum matrix reducing the presence of coarse primary Al2Cu phase and increasing the number of fine Al2Cu precipitates formed during the aging process. The results indicated that an appropriate increase in ball milling speed, extension of ball milling duration, and solution treatment time can enhance the Vickers hardness and room temperature compressive strength of the composites. Specifically, the composites processed with a ball milling speed of 350 rpm for 6 h, a solid solution treatment at 495 °C for 24 h, and an aging treatment at 190 °C for 8 h exhibited a Vickers hardness of 277 HV and a compressive yield strength of 687 MPa, along with a compressive strain of 7.8 %.

Negative thermal expansion (NTE) ceramics Sm0.85Zn0.15MnO3 (SZMO) and ZrMgMo3O12 (ZMMO) were selected to prepare Sm0.85Zn0.15MnO3-ZrMgMo3O12/Al-20Si (SZMO-ZMMO/Al-20Si) composites using ball milling and vacuum heating-press sintering processes in this study. The synergistic effect of the SZMO and ZMMO NTE ceramic reinforcements on the microstructure, mechanical properties, and coefficient of thermal expansion (CTE) of the composites was investigated. The results show that the processes of ball milling and sintering did not induce the decomposition of SZMO or ZMMO NTE ceramic reinforcements, nor did they promote a reaction between the Al-20Si matrix and SZMO or ZMMO NTE ceramic reinforcements. However, the excessive addition of SZMO and ZMMO NTE ceramics led to their aggregation within the composite. Adding a small amount of SZMO in combination with ZMMO effectively increased hardness and yield strength while reducing CTE in the Al-20Si alloy. The improvement in strength was primarily provided by SZMO, while the inhibition effect on CTE was primarily provided by ZMMO. An evaluation parameter denoted as α was proposed to evaluate the synergy effects of SZMO and ZMMO NTE ceramic reinforcements on the mechanical properties and CTE of the composites. Based on this parameter, among all composites fabricated, adding 2.5 vol% SZMO NTE ceramic and 10 vol% ZMMO NTE ceramic resulted in an optimal balance between CTE and strength for these composites with a compressive yield strength of 349.72 MPa and a CTE of 12.55 × 10−6/K, representing a significant increase in yield strength by 79.20% compared to that of Al-20Si alloy along with a notable reduction in CTE by 26.44%.