Objective:To investigate the clinical characteristics of urea cycle disorder (UCD), the efficacy and safety of glyceryl phenylbutyrate (GPB) therapy in pediatric patients with UCD.Methods:This study was a retrospective, single-arm, multicenter clinical study. The clinical data of 20 pediatric patients with UCD who received GPB treatment at 9 hospitals nationwide between December 2021 and August 2024 were collected. The clinical manifestations, laboratory results, and molecular genetic characteristics were analyzed, ammonia levels and other laboratory results were evaluated pre-post GPB therapy by paired t-tests or Wilcoxon tests. Results:Among the 20 pediatric patients with UCD, there were 8 males and 12 females, and the onset age was 2.8 (1.4, 5.7) years. The ammonia levels were 174 (125, 342) μmol/L at first onset. The symptoms included vomiting in 6 cases, drowsiness in 5 cases, epilepsy in 5 cases, developmental delay in 5 cases, psychiatric and behavioral abnormalities in 3 cases, and lethargy in 1 case, and 18 cases exhibited abnormal liver function. Twenty cases included 6 UCD subtypes, with 11 cases being ornithine transcarbamylase deficiency. A total of 27 variants were identified, 11 (41%) of which were novel. The age of patients who began GPB therapy was 4.0 (1.5, 6.6) years. Ten cases stopped GPB after 4.2 (3.4, 5.3) months, with 4 patients undergoing liver transplantation and 6 discontinuing for financial reasons. The remaining ten patients continued GPB therapy for 11.6 (8.6, 14.0) months. The duration of GPB treatment was 6.0 (4.2, 12.3) months, at the final visit, the levels of ammonia, platelets and aspartate aminotransferase were lower compared to those of pre-treatment (all P<0.05). The serum albumin level was higher than that of pre-treatment ( P=0.016). Two patients suffered only one episode of acute hyperammonaemia, with ammonia levels of 232 and 141 μmol/L, respectively. Nine cases experienced adverse effects potentially related to GPB, decreased appetite in 6 cases, vomiting in 3 cases, abnormal skin oil odor in 2 cases, somnolence, fatigue and diarrhea each in 1 case, with symptoms improved within 6 (3, 10) days. Conclusions:UCD primarily manifests with neurological and gastrointestinal symptoms, and early diagnosis of UCD could be achieved through the analysis of ammonia. GPB may effectively reduce ammonia levels in UCD pediatric patients, with favorable safety and tolerability.

OBJECTIVE: To explore the therapeutic effects and underlying mechanisms of Dendrobium officinale (Tiepi Shihu) extract (DOE) on insomnia. METHODS: Forty-two male Sprague-Dawley rats were randomly divided into 6 groups (n=7 per group): normal control, model control, melatonin (MT, 40 mg/kg), and 3-dose DOE (0.25, 0.50, and 1.00 g/kg) groups. Rats were raised in a strong-light (10,000 LUX) and -noise (>80 db) environment (12 h/d) for 16 weeks to induce insomnia, and from week 10 to week 16, MT and DOE were correspondingly administered to rats. The behavior tests including sodium pentobarbital-induced sleep experiment, sucrose preference test, and autonomous activity test were used to evaluate changes in sleep and emotions of rats. The metabolic-related indicators such as blood pressure, blood viscosity, blood glucose, and uric acid in rats were measured. The pathological changes in the cornu ammonis 1 (CA1) region of rat brain were evaluated using hematoxylin and eosin staining and Nissl staining. Additionally, the sleep-related factors gamma-aminobutyric acid (GABA), glutamate (GA), 5-hydroxytryptamine (5-HT), and interleukin-6 (IL-6) were measured using enzyme linked immunosorbent assay. Finally, we screened potential sleep-improving receptors of DOE using polymerase chain reaction (PCR) array and validated the results with quantitative PCR and immunohistochemistry. RESULTS: DOE significantly improved rats' sleep and mood, increased the sodium pentobarbital-induced sleep time and sucrose preference index, and reduced autonomic activity times (P<0.05 or P<0.01). DOE also had a good effect on metabolic abnormalities, significantly reducing triglyceride, blood glucose, blood pressure, and blood viscosity indicators (P<0.05 or P<0.01). DOE significantly increased the GABA content in hippocampus and reduced the GA/GABA ratio and IL-6 level (P<0.05 or P<0.01). In addition, DOE improved the pathological changes such as the disorder of cell arrangement in the hippocampus and the decrease of Nissel bodies. Seven differential genes were screened by PCR array, and the GABA_A receptors (Gabra5, Gabra6, Gabrq) were selected for verification. The results showed that DOE could up-regulate their expressions (P<0.05 or P<0.01). CONCLUSION DOE demonstrated remarkable potential for improving insomnia, which may be through regulating GABA_A receptors expressions and GA/GABA ratio.
Animals ; Dendrobium/chemistry* ; Rats, Sprague-Dawley ; Male ; Sleep Initiation and Maintenance Disorders/blood* ; Plant Extracts/therapeutic use* ; Receptors, GABA-A/metabolism* ; Noise/adverse effects* ; Light/adverse effects* ; gamma-Aminobutyric Acid/metabolism* ; Sleep/drug effects* ; Rats ; Receptors, GABA/metabolism*

Ischemic stroke (IS) is a globally life-threatening disease. Presently, few therapeutic medicines are available for treating IS, and rt-PA is the only drug approved by the US Food and Drug Administration (FDA) in the US. In fact, many agents showing excellent neuroprotection but no blood flow-improving activity in animals have not achieved ideal clinical efficacy, while thrombolytic drugs only improving blood flow without neuroprotection have limited their wider application. To address these challenges and meet the huge unmet clinical need, we have designed and identified a novel compound AAPB with dual effects of neuroprotection and cerebral blood flow improvement. AAPB significantly reduced cerebral infarction and neural function deficit in tMCAO rats, pMCAO rats, and IS rhesus monkeys, as well as displayed exceptional safety profiles and excellent pharmacokinetic properties in rats and dogs. AAPB has now entered phase I of clinical trials fighting IS in China.

OBJECTIVE: Observational studies have found associations between inflammatory bowel disease (IBD) and the risk of dementia, including Alzheimer's dementia (AD) and vascular dementia (VD); however, these findings are inconsistent. It remains unclear whether these associations are causal. METHODS: We conducted a meta-analysis by systematically searching for observational studies on the association between IBD and dementia. Mendelian randomization (MR) analysis based on summary genome-wide association studies (GWASs) was performed. Genetic correlation and Bayesian co-localization analyses were used to provide robust genetic evidence. RESULTS: Ten observational studies involving 80,565,688 participants were included in this meta-analysis. IBD was significantly associated with dementia (risk ratio [ RR] =1.36, 95% CI = 1.04-1.78; I ² = 84.8%) and VD ( RR = 2.60, 95% CI = 1.18-5.70; only one study), but not with AD ( RR = 2.00, 95% CI = 0.96-4.13; I ² = 99.8%). MR analyses did not supported significant causal associations of IBD with dementia (dementia: odds ratio [ OR] = 1.01, 95% CI = 0.98-1.03; AD: OR = 0.98, 95% CI = 0.95-1.01; VD: OR = 1.02, 95% CI = 0.97-1.07). In addition, genetic correlation and co-localization analyses did not reveal any genetic associations between IBD and dementia. CONCLUSION Our study did not provide genetic evidence for a causal association between IBD and dementia risk. The increased risk of dementia observed in observational studies may be attributed to unobserved confounding factors or detection bias.
Humans ; Mendelian Randomization Analysis ; Inflammatory Bowel Diseases/complications* ; Dementia/etiology* ; Observational Studies as Topic ; Genome-Wide Association Study

Silver nanoparticles(AgNPs)are employed as disinfectants due to their extensive antimi-crobial properties,but their biosafety in the livestock industry has not been comprehensively as-sessed.In this study,16 Black-skin Red-crowned chickens aged 32 weeks were randomly divided in-to four groups and sprayed with AgNP solution at the concentration of 0,0.064,0.128 or 0.256 g/L,respectively,every 72 h in their coops for 30 d.The effects of AgNPs as the disinfectant on lung tissue in chicken were investigated through calculation of organ coefficients,observation of lung tissue sections,analysis of bronchoalveolar lavage fluid,measurement of inflammatory factors,de-tection of silver residue in lung tissue,and exploration of signaling pathways in pulmonary fibrosis.The results indicated that chickens in the 0.128 and 0.256 g/L AgNPs treatment groups showed the blurred pulmonary lobule boundaries,the destroyed alveolar structure,and the significant in-crease in pulmonary fibrosis.These pathological changes were accompanied by the decrease in lung organ coefficient,the reduced SP-C content,the increased total protein concentration in lavage flu-id,and the elevated LDH and silver content in lung tissue.The levels of IL-6 and TNF-α in the 0.128 and 0.256 g/L AgNPs treatment groups were significantly higher than the control group,which suggested that AgNPs exposure could induce the pulmonary inflammatory responses.High concentrations of AgNPs can trigger pulmonary tissue fibrosis,damaging the structure and func-tions of lungs.The relative mRNA expression levels of NF-κB in all AgNPs treatment groups,TGF-β in the 0.128 g/L AgNPs treatment group,and Smad3 in the 0.128 and 0.256 g/L AgNPs treatment groups were significantly higher than these in the control group,respectively.Spraying chickens with 0.128 or 0.256 g/L AgNPs for disinfection led to pulmonary deposition of AgNPs,causing direct structural and functional damages to the lungs.It could also induce the chronic pul-monary inflammation through the NF-κB pathway and promote the TGF-β/Smad3 pathway to in-crease collagen synthesis,leading to pulmonary fibrosis.Therefore,the application of high concen-trations of AgNPs in livestock farming requires careful consideration of their potential biological safety issues.

This study was aimed at identifying the pathogenic bacteria responsible for the death of a young tiger at the Fujian Meihua Mountain South China Tiger Breeding Research Institute.Tissue samples from the lungs,liver,and intestines of the deceased tiger were collected,and the bacteria were cultured inasterile environment.The bacterial strains were characterized according to their morphological and molecular biological properties,including assessment of virulence genes and antibiotic resistance genes,mouse lethality tests,and antibiotic susceptibility evaluations.A predominant bacterial strain isolated from the liver of the deceased tiger was identified as enterotoxigenic Escherichia coli(ETEC)strain Tiger22513F.Phylogenetic analysis of the 16S rRNA gene revealed that the Tiger22513F strain exhibited close genetic similarity to the reference strain ETEC(MF919609.1),with 99.9%nucleotide similarity,and resided on the same evolutionary branch.The Tiger22513F strain contained 11 antibiotic resistance genes(tetA,sul1,sul3,cmlA,floR,blaTEM,blaSHV,blaCMY-2,qnrA,qnrS,and qnrD)along with five virulence genes(VT1,fyuA,tsh,iucD,and ST).Mouse lethality tests indicated significant pathogenicity toward mice,affecting primarily the lungs,liver,and intestines.Antibiotic susceptibility testing demonstrated that this strain exhibited resistance to various classes of beta-lactam antibiotics,as well as quinolones and aminoglycosides.This investigation successfully isolated a multi-drug resistant enterotoxigenic Escherichia coli strain with pronounced pathogenicity from the liver of a deceased tiger;thus providing valuable scientific insights for clinical diagnosis,as well as prevention and control measures,against ETEC infections in South China tigers.

The effect of Huanglian Jiedu Decoction on the intestinal flora of type 2 diabetes mellitus(T2DM) was investigated using 16S rRNA sequencing technology. Sixty rats were randomly divided into a normal group(10 rats) and a modeling group(50 rats). After one week of adaptive feeding, a high-fat diet + streptozotocin was given for modeling, and fasting blood glucose >16.7 mmol·L~(-1) was considered a sign of successful modeling. The modeling group was randomly divided into the model group, high-, medium-, and low-dose groups of Huanglian Jiedu Decoction, and metformin group. After seven days of intragastric treatment, the feces, colon, and pancreatic tissue of each group of rats were collected, and the pathological changes of the colon and pancreatic tissue of each group were observed by hematoxylin-eosin staining. The changes in the intestinal flora structure of each group were observed by the 16S rRNA sequencing method. The results showed that compared with the model group, the high-, medium-, and low-dose of Huanglian Jiedu Decoction reduced fasting blood glucose levels to different degrees and showed no significant changes in body weight. The number of islet cells increased, and intestinal mucosal damage attenuated. Alpha diversity analysis revealed that Huanglian Jiedu Decoction reduced the abundance and diversity of intestinal flora in rats with T2DM; at the phylum level, low-and mediam-dose of Huanglian Jiedu Decoction reduced the abundance of Bacteroidota, Proteobacteria, and Desulfobacterota and increased the abundance of Firmicute and Bacteroidota/Firmicutes, while the high-dose of Huanglian Jiedu Decoction increased the relative abundance of Proteobacteria and Bacteroidota/Firmicutes ratio, and decreaseal the relative; abundance of Firmicute; at the genus level, Huanglian Jiedu Decoction increased the relative abundance of Allobaculum, Blautia, and Lactobacillus; LEfse analysis revealed that the biomarker of low-and medium-dose groups of Huanglian Jiedu Decoction was Lactobacillus, and the structure of the intestinal flora of the low-dose group of Huanglian Jiedu Decoction was highly similar to that of the metformin group. PICRUSt2 function prediction revealed that Huanglian Jiedu Decoction mainly affected carbohydrate and amino acid metabolic pathways. It suggested that Huanglian Jiedu Decoction could reduce fasting blood glucose and increase the number of islet cells in rats with T2DM, and its mechanism of action may be related to increasing the abundance of short-chain fatty acid-producing strains and Lactobacillus and affecting carbohydrate and amino acid metabolic pathways.
Animals ; Drugs, Chinese Herbal/administration & dosage* ; Diabetes Mellitus, Type 2/metabolism* ; Gastrointestinal Microbiome/drug effects* ; Rats ; Male ; Rats, Sprague-Dawley ; Humans ; Bacteria/drug effects* ; Blood Glucose/metabolism*