Xanthine oxidase (XO) is an important therapeutic target for the treatment of hyperuricemia and gout. Based on the previously identified potent XO inhibitor 1, seventeen oxadiazoles and their ring-opening analogues were designed and synthesized via the bioisostere replacement strategy. Among them, compounds 2l, 2n, and 3b showed obvious XO inhibitory activity at the concentration of 10 μmol·L^-1, and compound 3b exhibited an IC₅₀ value of 1.45 μmol·L^-1.

OBJECTIVE: To observe the effects of electroacupuncture (EA) with different frequencies on spermatogenic function, testicular morphology and oxidative stress in oligoasthenospermia (OAT) rats, and to explore the mechanism and the optimal parameters of EA for OAT. METHODS: Sixty SPF-grade male SD rats were randomly divided into a solvent control group, a model group, a 2 Hz EA group, a 100 Hz EA group and a 2 Hz/100 Hz EA group, with 12 rats in each group. Except for the solvent control group, the other 4 groups were administered ornidazole suspension (800 mg·kg^-1·d^-1) by gavage for 28 d to establish the OAT model. Starting from the 1st of modeling, EA was applied at "Guanyuan" (CV4), "Qihai" (CV6) and bilateral "Sanyinjiao" (SP6) and "Zusanli" (ST36) in the 3 EA groups, continuous wave of 2 Hz, continuous wave of 100 Hz, and disperse-dense wave of 2 Hz/100 Hz were used in the 2 Hz EA group, the 100 Hz EA group, and the 2 Hz/100 Hz EA group, respectively, with current intensity of 1-3 mA, 30 min a time, once every other day, for 28 consecutive days. After intervention, the testicular index was calculated, epididymal sperm quality was assessed, and the fertility ability was observed; morphology of testicular tissue was observed by HE staining, and the Johnson score was calculated; the positive expression of reactive oxygen species (ROS) in testicular tissue was detected by immunofluorescence; the activity of superoxide dismutase (SOD) and catalase (CAT), as well as the level of malondialdehyde (MDA) in testicular tissue were measured by ELISA; the protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) in testicular tissue was detected by Western blot. RESULTS: Compared with the solvent control group, in the model group, the testicular index, sperm concentration, sperm motility and the number of offspring were decreased (P<0.01), the seminiferous tubules atrophied and the Johnson score decreased (P<0.01); the activity of SOD and CAT, as well as the protein expression of Nrf2 and HO-1 in testicular tissue were decreased (P<0.01); the sperm deformity rate, the positive expression of ROS and the MDA level in testicular tissue were increased (P<0.01). Compared with the model group, in the 2 Hz EA group, the 100 Hz EA group and the 2 Hz/100 Hz EA group, the testicular index, sperm concentration, sperm motility and the number of offspring were increased (P<0.05, P<0.01), the pathological morphology of testicular tissue improved and the Johnson scores increased (P<0.01); the activity of SOD and CAT, as well as the protein expression of Nrf2 and HO-1 in testicular tissue were increased (P<0.05, P<0.01); the sperm deformity rate, the positive expression of ROS and the MDA level in testicular tissue were decreased (P<0.05, P<0.01). Compared with the 2 Hz EA group, in the 2 Hz/100 Hz EA group, the testicular index, sperm concentration, sperm motility, as well as the CAT activity and HO-1 protein expression in testicular tissue were increased (P<0.01, P<0.05); the positive expression of ROS was decreased (P<0.01). Compared with the 100 Hz EA group, in the 2 Hz/100 Hz EA group, the testicular index was increased (P<0.01), the positive expression of ROS in testicular tissue was decreased (P<0.01). CONCLUSION EA with 2 Hz continuous wave, 100 Hz continuous wave, and 2 Hz/100 Hz disperse-dense wave can all improve the spermatogenic arrest and reduce the level of oxidative stress in testicular tissue in OAT rats, the mechanism may be related to up-regulating the protein expression of Nrf2 and HO-1 and improving oxidative stress. EA with disperse-dense wave of 2 Hz/100 Hz shows the optimal effect.
Male ; Animals ; Electroacupuncture ; Oxidative Stress ; Rats ; Rats, Sprague-Dawley ; Spermatogenesis ; Oligospermia/genetics* ; Humans ; Testis/metabolism* ; Superoxide Dismutase/metabolism* ; Asthenozoospermia/genetics* ; Acupuncture Points ; Malondialdehyde/metabolism*

A primary hallmark of pathological cardiac hypertrophy is excess protein synthesis due to enhanced translational activity. However, regulatory mechanisms at the translational level under cardiac stress remain poorly understood. Here we examined the translational regulations in a mouse cardiac hypertrophy model induced by transaortic constriction (TAC) and explored the conservative networks versus the translatome pattern in human dilated cardiomyopathy (DCM). The results showed that the heart weight to body weight ratio was significantly elevated, and the ejection fraction and fractional shortening significantly decreased 8 weeks after TAC. Puromycin incorporation assay showed that TAC significantly increased protein synthesis rate in the left ventricle. RNA-seq revealed 1,632 differentially expressed genes showing functional enrichment in pathways including extracellular matrix remodeling, metabolic processes, and signaling cascades associated with pathological cardiomyocyte growth. When combined with ribosome profiling analysis, we revealed that translation efficiency (TE) of 1,495 genes was enhanced, while the TE of 933 genes was inhibited following TAC. In DCM patients, 1,354 genes were upregulated versus 1,213 genes were downregulated at the translation level. Although the majority of the genes were not shared between mouse and human, we identified 93 genes, including Nos3, Kcnj8, Adcy4, Itpr1, Fasn, Scd1, etc., with highly conserved translational regulations. These genes were remarkably associated with myocardial function, signal transduction, and energy metabolism, particularly related to cGMP-PKG signaling and fatty acid metabolism. Motif analysis revealed enriched regulatory elements in the 5' untranslated regions (5'UTRs) of transcripts with differential TE, which exhibited strong cross-species sequence conservation. Our study revealed novel regulatory mechanisms at the translational level in cardiac hypertrophy and identified conserved translation-sensitive targets with potential applications to treat cardiac hypertrophy and heart failure in the clinic.
Animals ; Humans ; Cardiomegaly/physiopathology* ; Ribosomes/physiology* ; Protein Biosynthesis/physiology* ; Mice ; Cardiomyopathy, Dilated/genetics* ; Ribosome Profiling

Various chromatographic methods were comprehensively applied to study the chemical composition of the ethyl acetate extract from Aucklandiae Radix. The structures of all compounds were identified by analyzing their physicochemical properties and using spectroscopic methods. Two new sesquiterpenoids, named auclappsines A and B(1 and 2) were isolated and identified. Through in vitro high content screening and with the use of a guggulsterone-induced L02 cells, the effects of 1 and 2 on farnesoid X receptor(FXR) protein expression were investigated. The results showed that 1 had a significant FXR activation effect, providing a scientific basis for the development of drugs for the treatment of liver and gallbladder diseases.
Receptors, Cytoplasmic and Nuclear/genetics* ; Humans ; Sesquiterpenes/isolation & purification* ; Drugs, Chinese Herbal/isolation & purification* ; Cell Line ; Molecular Structure

OBJECTIVES: To evaluate the effectiveness of single-balloon and double-balloon enteroscopy in diagnosing pediatric small bowel diseases and assess the diagnostic efficacy of computed tomography enterography (CTE) for small bowel diseases using enteroscopy as the reference standard. METHODS: Clinical data from 576 children who underwent enteroscopy at Hunan Children's Hospital between January 2017 and December 2023 were retrospectively collected. The children were categorized based on enteroscopy type into the single-balloon enteroscopy (SBE) group (n=457) and double-balloon enteroscopy (DBE) group (n=119), and the clinical data were compared between the two groups. The sensitivity and specificity of CTE for diagnosing small bowel diseases were evaluated using enteroscopy results as the standard. RESULTS: Among the 576 children, small bowel lesions were detected by enteroscopy in 274 children (47.6%).There was no significant difference in lesion detection rates or complication rates between the SBE and DBE groups (P>0.05), but the DBE group had deeper insertion, longer procedure time, and higher complete small bowel examination rate (P<0.05). The complication rate during enteroscopy was 4.3% (25/576), with 18 cases (3.1%) of mild complications and 7 cases (1.2%) of severe complications, which improved with symptomatic treatment, surgical, or endoscopic intervention. Among the 412 children who underwent CTE, the sensitivity and specificity for diagnosing small bowel diseases were 44.4% and 71.3%, respectively. CONCLUSIONS SBE and DBE have similar diagnostic efficacy for pediatric small bowel diseases, but DBE is preferred for suspected deep small bowel lesions and comprehensive small bowel examination. Enteroscopy in children demonstrates relatively good overall safety. CTE demonstrates relatively low sensitivity but comparatively high specificity for diagnosing small bowel diseases.
Retrospective Studies ; Treatment Outcome ; Double-Balloon Enteroscopy/statistics & numerical data* ; Single-Balloon Enteroscopy/statistics & numerical data* ; Humans ; Male ; Female ; Child ; Operative Time ; Tomography, X-Ray Computed/statistics & numerical data* ; Sensitivity and Specificity ; Intestine, Small/surgery* ; Intestinal Diseases/surgery*

OBJECTIVES: To investigate the clinical features of children with STAT gene mutations, and to explore corresponding immunotherapy strategies. METHODS: A retrospective analysis was performed for the clinical data of 10 children with STAT gene mutations who were admitted to the Department of Pediatrics of the First Affiliated Hospital of Guangzhou Medical University, from October 2015 to October 2024. Exploratory immunotherapy was implemented in some refractory cases, and the changes in symptoms, imaging manifestations, and cytokine levels were assessed after treatment. RESULTS: For the 10 children, the main clinical manifestations were recurrent rash since birth (7/10), cough (8/10), wheezing (5/10), expectoration (4/10), and purulent nasal discharge (4/10). Genotyping results showed that there was one child with heterozygous loss-of-function (LOF) mutation in the STAT1 gene, four children with heterozygous LOF mutation in the STAT3 gene, and five children with heterozygous gain-of-function (GOF) mutation in the STAT3 gene. Two children with LOF mutation in the STAT3 gene showed decreased interleukin-6 levels and improved clinical symptoms and imaging findings after omalizumab treatment. Three children with GOF mutation in the STAT3 gene achieved effective disease control after treatment with methylprednisolone (0.5 mg/kg per day). Two children with GOF mutation in the STAT3 gene received treatment with JAK inhibitor and then showed some improvement in symptoms. CONCLUSIONS STAT gene mutation screening should be considered for children with recurrent rash and purulent respiratory tract infections. Targeted immunotherapy may improve prognosis in patients with no response to conventional treatment.
Humans ; Male ; Immunotherapy ; Female ; Child, Preschool ; Child ; Gain of Function Mutation ; Retrospective Studies ; Infant ; Loss of Function Mutation ; STAT Transcription Factors/genetics*

OBJECTIVE: To study the correlation between miR-122 and early HBV infection and analyze its application value in early infection of voluntary blood donors. METHODS: A total of 150 samples from voluntary blood donors in Fujian Blood Center from May 2021 to July 2022 were collected and divided into group N (normal group), group E (ELISA single positive group), and group D (both ELISA and nucleic acid positive group), and the general information of the three groups of blood donors was collected. Total RNA was extracted from the three groups of samples, and the expression level of miR-122 was detected by qRT-PCR. The expression differences of miR-122 among the three groups of samples were statistically analyzed, and the correlation between the expression level of miR-122 in group D and its HBV DNA copy number was analyzed. The miRNA database was used to predict the potential target genes of miRNA and perform bioinformatics analysis. RESULTS: There was no statistical difference in gender, education level, and occupation distribution among the three groups, but the age distribution and number of blood donations among different groups were statistically significant. Compared with group N, the relative expression levels of miR-122 in the plasma of group E and group D were significantly downregulated (P < 0.05); the relative expression level of miR-122 in group D was more significantly downregulated than that in group E (P < 0.001). Pearson correlation analysis showed that the expression level of miR-122 in group D was negatively correlated with the HBV-DNA copy number (R ²=-0.804,P < 0.01). Two potential target genes were screened using the miRNA database: ALDOA(aldolase A) and PKM (pyruvate kinase). GO analysis results showed that the potential target genes of miRNA mainly involved in biological processes including cell homeostasis and regulation of transcriptional processes. CONCLUSION Downregulation of miR-122 expression is closely related to early HBV infection and replication activity.
Humans ; MicroRNAs ; Blood Donors ; Hepatitis B/diagnosis* ; Hepatitis B virus ; DNA, Viral/blood* ; Male ; Female ; Early Diagnosis ; Adult

OBJECTIVE: To confirm the sequence of a null allele HLA-C*08:127N produced by a base insertion. METHODS: PCR sequence-specific oligonucleotide probe (SSOP) and PCR sequence-based typing (SBT) were used for HLA routine detection, which discovered abnormal sequence maps of HLA-C in one acute myeloid leukemia patient. The sequence of the above loci was confirmed by next generation sequencing (NGS) technology. RESULTS: The SSOP typing result showed that HLA-C locus was C*03:04, C*08:01, while the sequence was suspected to be inserted or deleted in exon 3 by SBT, and finally confirmed by NGS as C*03:04, C*08:127N. CONCLUSION When base insertion produces HLA null alleles, SBT analysis software cannot provide correct results, but NGS technology can more intuitively obtain accurate HLA typing results.
Humans ; Alleles ; High-Throughput Nucleotide Sequencing ; HLA-C Antigens/genetics* ; Histocompatibility Testing ; Polymerase Chain Reaction ; Leukemia, Myeloid, Acute/genetics* ; Sequence Analysis, DNA ; Mutagenesis, Insertional ; Exons

OBJECTIVE: To elucidate the effect of Huanglian-Renshen-Decoction (HRD) on ameliorating type 2 diabetes mellitus by maintaining islet β -cell identity through regulating paracrine and endocrine glucagon-like peptide-1 (GLP-1)/GLP-1 receptor (GLP-1R) in both islet and intestine. METHODS: The db/db mice were divided into the model (distilled water), low-dose HRD (LHRD, 3 g/kg), high-dose HRD (HHRD, 6 g/kg), and liraglutide (400 µ g/kg) groups using a random number table, 8 mice in each group. The db/m mice were used as the control group (n=8, distilled water). The entire treatment of mice lasted for 6 weeks. Blood insulin, glucose, and GLP-1 levels were quantified using enzyme-linked immunosorbent assay kits. The proliferation and apoptosis factors of islet cells were determined by immunohistochemistry (IHC) and immunofluorescence (IF) staining. Then, GLP-1, GLP-1R, prohormone convertase 1/3 (PC1/3), PC2, v-maf musculoaponeurotic fibrosarcoma oncogene homologue A (MafA), and pancreatic and duodenal homeobox 1 (PDX1) were detected by Western blot, IHC, IF, and real-time quantitative polymerase chain reaction, respectively. RESULTS: HRD reduced the weight and blood glucose of the db/db mice, and improved insulin sensitivity at the same time (P<0.05 or P<0.01). HRD also promoted mice to secrete more insulin and less glucagon (P<0.05 or P<0.01). Moreover, it also increased the number of islet β cell and decreased islet α cell mass (P<0.01). After HRD treatment, the levels of GLP-1, GLP-1R, PC1/3, PC2, MafA, and PDX1 in the pancreas and intestine significantly increased (P<0.05 or P<0.01). CONCLUSION HRD can maintain the normal function and identity of islet β cell, and the underlying mechanism is related to promoting the paracrine and endocrine activation of GLP-1 in pancreas and intestine.
Animals ; Glucagon-Like Peptide 1/metabolism* ; Diabetes Mellitus, Type 2/metabolism* ; Glucagon-Like Peptide-1 Receptor/metabolism* ; Insulin-Secreting Cells/pathology* ; Drugs, Chinese Herbal/pharmacology* ; Male ; Blood Glucose/metabolism* ; Insulin/blood* ; Mice ; Intestinal Mucosa/pathology* ; Apoptosis/drug effects* ; Cell Proliferation/drug effects* ; Islets of Langerhans/pathology*