Tourette syndrome （TS） is a highly prevalent neurodevelopmental disorder in children， clinically characterized primarily by motor and/or vocal tics. Its pathogenesis is associated with hyperactivity of the dopaminergic system in the basal ganglia， and current medical treatments are limited by adverse reactions and unsatisfactory efficacy. In traditional Chinese medicine （TCM）， TS is classified under categories such as "liver wind" and "convulsions"， and is considered to be closely related to liver dysregulation. Uncariae Ramulus Cum Uncis （URCU） is a commonly used wind-dispelling herb. URCU has a clearly defined origin and a rich chemical composition， with alkaloids as its major active constituents， including rhynchophylline and isorhynchophylline. Its plasma components include multiple prototype alkaloids， which exhibit metabolic differences and phenomena such as enterohepatic circulation. Its brain-entering components possess blood-brain barrier permeability， and their distribution is associated with pharmacological effects. In recent years， increasing numbers of studies have focused on the pharmacological effects and mechanisms of the active components of URCU in the treatment of TS. This article systematically reviews the mechanisms by which URCU and its main active constituents exert therapeutic effects on TS from the following aspects： regulation of monoamine and amino acid neurotransmitters to improve neurotransmitter system imbalance， neuroprotection and intervention in neuroinflammation-related pathways； antioxidant effects through activation of antioxidant signaling pathways， and immunomodulatory functions influencing immune cells and the gut microbiota. In addition， the clinical application of compound formulas containing URCU in the treatment of TS is summarized， with the aim of providing new perspectives for further research on the pharmacological mechanisms of URCU and the treatment of TS.

Tourette syndrome （TS） is a highly prevalent neurodevelopmental disorder in children， clinically characterized primarily by motor and/or vocal tics. Its pathogenesis is associated with hyperactivity of the dopaminergic system in the basal ganglia， and current medical treatments are limited by adverse reactions and unsatisfactory efficacy. In traditional Chinese medicine （TCM）， TS is classified under categories such as "liver wind" and "convulsions"， and is considered to be closely related to liver dysregulation. Uncariae Ramulus Cum Uncis （URCU） is a commonly used wind-dispelling herb. URCU has a clearly defined origin and a rich chemical composition， with alkaloids as its major active constituents， including rhynchophylline and isorhynchophylline. Its plasma components include multiple prototype alkaloids， which exhibit metabolic differences and phenomena such as enterohepatic circulation. Its brain-entering components possess blood-brain barrier permeability， and their distribution is associated with pharmacological effects. In recent years， increasing numbers of studies have focused on the pharmacological effects and mechanisms of the active components of URCU in the treatment of TS. This article systematically reviews the mechanisms by which URCU and its main active constituents exert therapeutic effects on TS from the following aspects： regulation of monoamine and amino acid neurotransmitters to improve neurotransmitter system imbalance， neuroprotection and intervention in neuroinflammation-related pathways； antioxidant effects through activation of antioxidant signaling pathways， and immunomodulatory functions influencing immune cells and the gut microbiota. In addition， the clinical application of compound formulas containing URCU in the treatment of TS is summarized， with the aim of providing new perspectives for further research on the pharmacological mechanisms of URCU and the treatment of TS.

Objective To monitor the concentrations of six disinfection byproducts including trichloromethane,dibromochloromethane,bromodichloromethane, tribromomethane, dichloroacetic acid and trichloroacetic acid in drinking water in the main urban area of Wuhan, and to assess the potential health risks. Methods A total of 373 samples were collected from the central urban area during 2023 to 2024. The concentrations of the substances were tested according to the national Standard Examination Methods for Drinking Water. The detection rates of the six disinfection byproducts were statistically analyzed, and the concentration differences of the six disinfection byproducts in different time periods and different types of water samples were compared. The health risk assessment model recommended by the United States Environmental Protection Agency was used for risk assessment. Results Trichloromethane was the most common substance found in drinking water, followed by dichlorobromomethane, chlorodibromomethane, trichloroacetic acid, tribromomethane, and finally dichloroacetic acid. The concentration of dichlorobromomethane in treated water was higher than that in tap water, while the concentration of dichloroacetic acid was lower than the tap water, both with significant differences. The concentrations of the six chlorination disinfection by-products in the dry season were all significantly higher than those in the wet season. The carcinogenic risks of the disinfection byproducts were trichloroacetic acid > dichloroacetic acid > dichlorobromomethane > chlorodibromomethane > tribromomethane, and the non-carcinogenic risks were trichloromethane > trichloroacetic acid > dichlorobromomethane > chlorodibromomethane > dichloroacetic acid > tribromomethane. Conclusion Trichloroacetic acid is the substance with the highest carcinogenic risk, while trichloromethane is the non-carcinogenic substance with the highest risk, which requires special attention.

[Objective] To investigate the molecular prevalence and genotype of human parvovirus B19(B19) among blood donors in Lanzhou, and provide data support for monitoring the positive rate of B19 DNA in local blood donors. [Methods] A total of 7 644 blood donor samples collected from January to September 2022 were randomly screened using real-time fluorescent PCR, resulting in 23 samples testing positive for B19 DNA. The characteristics of the B19 DNA reactive donors including gender, age, blood donation recruitment and promotion mode, and donation frequency were analyzed using SPSS 22.0. Additionally, the VP1 gene fragment of B19 DNA reactive samples was sequenced and an evolutionary tree was constructed by the N-J method. [Results] The results showed that the positive rate of B19 DNA in Lanzhou was 0.30%, and the positive population mainly consisted of female individuals aged 18-30 years old who were first-time blood donors; furthermore, genotype 1a was identified as predominant. [Conclusion] The positive rate of B19 DNA is low among blood donors in Lanzhou, with genotype 1a being predominant. It is recommended to periodically monitor the B19 prevalence in blood donors and enhance prevention and control measures, thus improving blood quality and safety.

Evading host immunity killing is a critical step for virus survival. Inhibiting viral immune escape is crucial for the treatment of viral diseases. Serine/threonine kinase 39 (STK39) was reported to play an essential role in ion homeostasis. However, its potential role and mechanism in viral infection remain unknown. In this study, we found that viral infection promoted STK39 expression. Consequently, overexpressed STK39 inhibited the phosphorylation of interferon regulatory factor 3 (IRF3) and the production of type I interferon, which led to viral replication and immune escape. Genetic ablation or pharmacological inhibition of STK39 significantly protected mice from viral infection. Mechanistically, mass spectrometry and immunoprecipitation assays identified that STK39 interacted with PPP2R1A (a scaffold subunit of protein phosphatase 2A (PP2A)) in a kinase activity-dependent manner. This interaction inhibited DDB1 and CUL4 associated factor 1 (DCAF1)-mediated PPP2R1A degradation, maintained the stabilization and phosphatase activity of PP2A, which, in turn, suppressed the phosphorylation of IRF3, decreased the production of type I interferon, and then strengthened viral replication. Thus, our study provides a novel theoretical basis for viral immune escape, and STK39 may be a potential therapeutic target for viral infectious diseases.

In recent decades, the prevalence of hyperuricemia and gout has increased dramatically due to lifestyle changes. The drugs currently recommended for hyperuricemia are associated with adverse reactions that limit their clinical use. In this study, we report that berberine (BBR) is an effective drug candidate for the treatment of hyperuricemia, with its mechanism potentially involving the modulation of gut microbiota and its metabolite, succinic acid. BBR has demonstrated good therapeutic effects in both acute and chronic animal models of hyperuricemia. In a clinical trial, oral administration of BBR for 6 months reduced blood uric acid levels in 22 participants by modulating the gut microbiota, which led to an increase in the abundance of Bacteroides and a decrease in Clostridium sensu stricto_1. Furthermore, Bacteroides fragilis was transplanted into ICR mice, and the results showed that Bacteroides fragilis exerted a therapeutic effect on uric acid similar to that of BBR. Notably, succinic acid, a metabolite of Bacteroides, significantly reduced uric acid levels. Subsequent cell and animal experiments revealed that the intestinal metabolite, succinic acid, regulated the upstream uric acid synthesis pathway in the liver by inhibiting adenosine monophosphate deaminase 2 (AMPD2), an enzyme responsible for converting adenosine monophosphate (AMP) to inosine monophosphate (IMP). This inhibition resulted in a decrease in IMP levels and an increase in phosphate levels. The reduction in IMP led to a decreased downstream production of hypoxanthine, xanthine, and uric acid. BBR also demonstrated excellent renoprotective effects, improving nephropathy associated with hyperuricemia. In summary, BBR has the potential to be an effective treatment for hyperuricemia through the gut-liver axis.

Anxiety disorder is a major symptom of autism spectrum disorder (ASD) with a comorbidity rate of ~40%. However, the neural mechanisms of the emergence of anxiety in ASD remain unclear. In our study, we found that hyperactivity of basolateral amygdala (BLA) pyramidal neurons (PNs) in Shank3 InsG3680 knock-in (InsG3680^+/+) mice is involved in the development of anxiety. Electrophysiological results also showed increased excitatory input and decreased inhibitory input in BLA PNs. Chemogenetic inhibition of the excitability of PNs in the BLA rescued the anxiety phenotype of InsG3680^+/+ mice. Further study found that the diminished control of the BLA by medial prefrontal cortex (mPFC) and optogenetic activation of the mPFC-BLA pathway also had a rescue effect, which increased the feedforward inhibition of the BLA. Taken together, our results suggest that hyperactivity of the BLA and alteration of the mPFC-BLA circuitry are involved in anxiety in InsG3680^+/+ mice.
Animals ; Prefrontal Cortex/metabolism* ; Basolateral Nuclear Complex/metabolism* ; Mice ; Anxiety/metabolism* ; Nerve Tissue Proteins/genetics* ; Male ; Gene Knock-In Techniques ; Pyramidal Cells/physiology* ; Mice, Transgenic ; Neural Pathways/physiopathology* ; Mice, Inbred C57BL ; Microfilament Proteins

G protein-coupled receptors (GPCRs) are the largest family of membrane proteins in eukaryotes, with nearly 800 genes coding for these proteins. They are involved in many physiological processes, such as light perception, taste and smell, neurotransmitter, metabolism, endocrine and exocrine, cell growth and migration. Importantly, GPCRs and their ligands are the targets of approximately one third of all marketed drugs. GPCRs are traditionally known for their role in transmitting signals from the extracellular environment to the cell's interior via the plasma membrane. However, emerging evidence suggests that GPCRs are also localized on mitochondria, where they play critical roles in modulating mitochondrial functions. These mitochondrial GPCRs (mGPCRs) can influence processes such as mitochondrial respiration, apoptosis, and reactive oxygen species (ROS) production. By interacting with mitochondrial signaling pathways, mGPCRs contribute to the regulation of energy metabolism and cell survival. Their presence on mitochondria adds a new layer of complexity to the understanding of cellular signaling, highlighting the organelle's role as not just an energy powerhouse but also a crucial hub for signal transduction. This expanding understanding of mGPCR function on mitochondria opens new avenues for research, particularly in the context of diseases where mitochondrial dysfunction plays a key role. Abnormalities in the phase conductance pathway of GPCRs located on mitochondria are closely associated with the development of systemic diseases such as cardiovascular disease, diabetes, obesity and Alzheimer's disease. In this review, we examined the various types of GPCRs identified on mitochondrial membranes and analyzed the complex relationships between mGPCRs and the pathogenesis of various diseases. We aim to provide a clearer understanding of the emerging significance of mGPCRs in health and disease, and to underscore their potential as therapeutic targets in the treatment of these conditions.

OBJECTIVE: This study aimed to evaluate the association between susceptibility genes and non-alcoholic fatty liver disease (NAFLD) in children with obesity. METHODS: We conducted a two-step case-control study. Ninety-three participants were subjected to whole-exome sequencing (exploratory set). Differential genes identified in the small sample were validated in 1,022 participants using multiplex polymerase chain reaction and high-throughput sequencing (validation set). RESULTS: In the exploratory set, 14 genes from the NAFLD-associated pathways were identified. In the validation set, after adjusting for sex, age, and body mass index, ECI2 rs2326408 (dominant model: OR = 1.33, 95% CI: 1.02-1.72; additive model: OR = 1.22, 95% CI: 1.01-1.47), C6orf201 rs659305 (dominant model: OR = 1.30, 95% CI: 1.01-1.69; additive model: OR = 1.21, 95% CI: 1.00-1.45), CALML5 rs10904516 (pre-ad dominant model: OR = 1.36, 95% CI: 1.01-1.83; adjusted dominant model: OR = 1.40, 95% CI: 1.03-1.91; and pre-ad additive model: OR = 1.26, 95% CI: 1.04-1.66) polymorphisms were significantly associated with NAFLD in children with obesity ( P < 0.05). Interaction analysis revealed that the gene-gene interaction model of CALML5 rs10904516, COX11 rs17209882, and SCD5 rs3733228 was optional ( P < 0.05), demonstrating a negative interaction between the three genes. CONCLUSION In the Chinese population, the CALML5 rs10904516, C6orf201 rs659305, and ECI2 rs2326408 variants could be genetic markers for NAFLD susceptibility.
Humans ; Non-alcoholic Fatty Liver Disease/genetics* ; Child ; Male ; Female ; Genetic Predisposition to Disease ; Case-Control Studies ; Exome Sequencing ; Adolescent ; Polymorphism, Single Nucleotide ; Obesity/complications* ; Pediatric Obesity/complications* ; China

OBJECTIVE: The study aim was to investigate the effects of exposure to multiple environmental organic pollutants on cardiopulmonary health with a focus on the potential mediating role of oxidative stress. METHODS: A repeated-measures randomized crossover study involving healthy college students in Beijing was conducted. Biological samples, including morning urine and venous blood, were collected to measure concentrations of 29 typical organic pollutants, including hydroxy polycyclic aromatic hydrocarbons (OH-PAHs), bisphenol A and its substitutes, phthalates and their metabolites, parabens, and five biomarkers of oxidative stress. Health assessments included blood pressure measurements and lung function indicators. RESULTS: Urinary concentrations of 2-hydroxyphenanthrene (2-OH-PHE) ( β = 4.35% [95% confidence interval ( CI): 0.85%, 7.97%]), 3-hydroxyphenanthrene ( β = 3.44% [95% CI: 0.19%, 6.79%]), and 4-hydroxyphenanthrene (4-OH-PHE) ( β = 5.78% [95% CI: 1.27%, 10.5%]) were significantly and positively associated with systolic blood pressure. Exposures to 1-hydroxypyrene (1-OH-PYR) ( β = 3.05% [95% CI: -4.66%, -1.41%]), 2-OH-PHE ( β = 2.68% [95% CI: -4%, -1.34%]), and 4-OH-PHE ( β = 3% [95% CI: -4.68%, -1.29%]) were negatively associated with the ratio of forced expiratory volume in the first second to forced vital capacity. These findings highlight the adverse effects of exposure to multiple pollutants on cardiopulmonary health. Biomarkers of oxidative stress, including 8-hydroxy-2'-deoxyguanosine and extracellular superoxide dismutase, mediated the effects of multiple OH-PAHs on blood pressure and lung function. CONCLUSION Exposure to multiple organic pollutants can adversely affect cardiopulmonary health. Oxidative stress is a key mediator of the effects of OH-PAHs on blood pressure and lung function.
Humans ; Oxidative Stress/drug effects* ; Male ; Cross-Over Studies ; Female ; Young Adult ; Environmental Pollutants/toxicity* ; Environmental Exposure/adverse effects* ; Biomarkers/blood* ; Adult ; Blood Pressure/drug effects* ; Polycyclic Aromatic Hydrocarbons/urine* ; Beijing