Sigma-1 receptor (σ ₁R) has become a focus point of drug discovery for central nervous system (CNS) diseases. A series of novel 1-phenylethan-1-one O-(2-aminoethyl) oxime derivatives were synthesized. In vitro biological evaluation led to the identification of 1a, 14a, 15d and 16d as the most high-affinity (K _i < 4 nmol/L) and selective σ ₁R agonists. Among these, 15d, the most metabolically stable derivative exhibited high selectivity for σ ₁R in relation to σ ₂R and 52 other human targets. In addition to low CYP450 inhibition and induction, 15d also exhibited high brain permeability and excellent oral bioavailability. Importantly, 15d demonstrated effective antipsychotic potency, particularly for alleviating negative symptoms and improving cognitive impairment in experimental animal models, both of which are major challenges for schizophrenia treatment. Moreover, 15d produced no significant extrapyramidal symptoms, exhibiting superior pharmacological profiles in relation to current antipsychotic drugs. Mechanistically, 15d inhibited GSK3β and enhanced prefrontal BDNF expression and excitatory synaptic transmission in pyramidal neurons. Collectively, these in vivo proof-of-concept findings provide substantial experimental evidence to demonstrate that modulating σ ₁R represents a potential new therapeutic approach for schizophrenia. The novel chemical entity along with its favorable drug-like and pharmacological profile of 15d renders it a promising candidate for treating schizophrenia.

Circadian rhythms are core regulatory mechanisms that evolved to align biological functions with the Earth's rotation. These rhythms are conserved across organisms from unicellular life to multicellular species and play essential roles in metabolism, immune responses, and sleep-wake cycle. Circadian disruptions are strongly associated with various diseases. Over the past decades, genetic studies in Drosophila and mice have identified key conserved clock genes and uncovered transcription-translation feedback loops governing circadian regulation. Additionally, rhythmic neurons in the brain integrate complex neural circuits to precisely regulate physiological and behavioral rhythms. This review highlights recent advances in understanding the neuronal circuit mechanisms of rhythmic neurons in the Drosophila brain and discusses future directions for translating circadian rhythm research into chronomedicine and precision therapies.
Animals ; Circadian Rhythm/genetics* ; Neurons/physiology* ; Drosophila/physiology* ; Brain/physiology* ; Nerve Net/physiology*

This study was aimed at exploring the epidemiological characteristics of Salmonella typhimurium(S.typhi-murium)and Salmonella typhimurium monophasic variants(S.1,4,[5],12:i:-)at the genome-wide level in Ningxia.Estab-lishment of a whole genome genotyping database would provide a theoretical basis for source and prevention and control of fu-ture outbreaks.We conducted serotyping,MLST,cgMLST typing,and virulence gene and drug resistance phenotype prediction of 92 strains of S.typhimurium and its monophasic variants through whole genome sequencing.Among all strains,21 were S.typhomurium,accounting for 22.83％,71 strains were S.1,4,[5],12:i:-,accounting for 77.17％.MLST and cgMLST typing results indicated that all S.typhimurium strains were ST19-type,and were divided into five evolutionary bran-ches.Five clusters were found,and S.1,4,[5],12:i:-were all ST34-type;on the same evolutionary branch,17 clusters were found.VFDB predicted 155 virulence genes in eight classes,of which 33.33％were S.typhimurium carried nine virulence genes on plasmids,and both serotypes carried virulence genes related to SPI virulence island on chromosomes,12:I:-resistant to 4-14 antibiotics,resulting in 22 multi-drug resistance spectrum.S.typhimurium was resistant to 2-13 antibiotics and produced eight multi-drug resistance profiles.S.1,4,[5],12:i:-was the predominant serotype of S.enteritidis in Ningxia.Typhimurium carried fewer virulence genes than S.typhimurium,and showed a high risk of local outbreaks.

Objective To simulate the microflow field environment between the anastomotic nail surface and intestinal wall tissue after implantation and to study the effect of hydrophobic surfaces on the flow rate of extracellular fluid and the fluid shear force on the wall to regulate bacterial adhesion through changes in the flow field.Methods The microstructure of shark skin was observed,and a simplified two-dimensional(2D)movement model of bacteria in a microflow field was established.Using computational fluid dynamics(CFD)numerical simulation,the movement of bacteria on a smooth surface and micro-textured surface in a static and dynamic flow field were simulated.The flow field characteristics around bacteria and the magnitude of fluid shear force under the two surface environments were compared,and the internal mechanism of the fluid shear force affecting bacterial adhesion was analyzed.Results The addition of the biomimetic microtexture enhanced the flow rate of the extracellular fluid in the microflow field,and the fluid had little viscous effect on the bacteria in the static flow field.The fluid in the dynamic flow field had a stronger pushing effect on the bacteria.The fluid shear force on the microtextured wall increased when the pit width was within a specific range.Conclusions The bionic micro-textured surface of the anastomotic nail can accelerate the flow rate of extracellular fluid,increase the fluid shear force of micro-textured walls and bacteria,and influence bacterial adhesion.These result provide a theoretical basis for studying bacteriostatic surfaces of anastomotic nails.

Hepatic dysregulation of lipid metabolism exacerbates inflammation and enhances the progression of metabolic dysfunction-associated steatotic liver disease (MASLD). STAT3 has been linked to lipid metabolism and inflammation. Jolkinolide B (JB), derived from Euphorbia fischeriana, is known for its pharmacological anti-inflammatory and anti-tumor properties. Therefore, this study investigated whether JB affects MASLD prevention by regulating STAT3 signaling. JB attenuated steatosis and inflammatory responses in palmitic acid (PA)-treated hepatocytes. Additionally, JB treatment reduced the mRNA expression of de-novo lipogenic genes, such as acetyl-CoA carboxylase and stearoyl-CoA desaturase 1. Interestingly, JB-mediated reduction in inflammation and lipogenesis was dependent on STAT3 signaling. JB consistently modulated mitochondrial dysfunction and the mRNA expression of inflammatory cytokines by inhibiting PA-induced JAK/STAT3 activation. This study suggests that JB is a potential therapeutic agent to prevent major stages of MASLD through inhibition of JAK/STAT3 signaling in hepatocytes.

Hepatic dysregulation of lipid metabolism exacerbates inflammation and enhances the progression of metabolic dysfunction-associated steatotic liver disease (MASLD). STAT3 has been linked to lipid metabolism and inflammation. Jolkinolide B (JB), derived from Euphorbia fischeriana, is known for its pharmacological anti-inflammatory and anti-tumor properties. Therefore, this study investigated whether JB affects MASLD prevention by regulating STAT3 signaling. JB attenuated steatosis and inflammatory responses in palmitic acid (PA)-treated hepatocytes. Additionally, JB treatment reduced the mRNA expression of de-novo lipogenic genes, such as acetyl-CoA carboxylase and stearoyl-CoA desaturase 1. Interestingly, JB-mediated reduction in inflammation and lipogenesis was dependent on STAT3 signaling. JB consistently modulated mitochondrial dysfunction and the mRNA expression of inflammatory cytokines by inhibiting PA-induced JAK/STAT3 activation. This study suggests that JB is a potential therapeutic agent to prevent major stages of MASLD through inhibition of JAK/STAT3 signaling in hepatocytes.

Hepatic dysregulation of lipid metabolism exacerbates inflammation and enhances the progression of metabolic dysfunction-associated steatotic liver disease (MASLD). STAT3 has been linked to lipid metabolism and inflammation. Jolkinolide B (JB), derived from Euphorbia fischeriana, is known for its pharmacological anti-inflammatory and anti-tumor properties. Therefore, this study investigated whether JB affects MASLD prevention by regulating STAT3 signaling. JB attenuated steatosis and inflammatory responses in palmitic acid (PA)-treated hepatocytes. Additionally, JB treatment reduced the mRNA expression of de-novo lipogenic genes, such as acetyl-CoA carboxylase and stearoyl-CoA desaturase 1. Interestingly, JB-mediated reduction in inflammation and lipogenesis was dependent on STAT3 signaling. JB consistently modulated mitochondrial dysfunction and the mRNA expression of inflammatory cytokines by inhibiting PA-induced JAK/STAT3 activation. This study suggests that JB is a potential therapeutic agent to prevent major stages of MASLD through inhibition of JAK/STAT3 signaling in hepatocytes.

Objective:To explore the potential causal relationship between gut microbiota and teratozoospermia.Methods:We searched the database of Genome-Wide Association Study(GWAS)for gut microbiota-and teratozoospermia-related data.We used gut microbiota as an exposure factor,determined the instrumental variables according to the GWAS data on 18 340 participants released by the MiBioGen Alliance,and derived the outcome variables from the European data on teratozoospermia,with a sample size of 85 716,including 915 cases and 209 006 controls.Using inverse-variance weighting(IVW),MR-Egger regression and the weighted median estimator(WME),we performed two-sample Mendelian randomization(MR)analysis on the retrieved data,and estimated the causal relationship between gut microbiota and teratozoospermia based on the β value.Results:Two-sample MR analysis indicated that the class Erysipelotrichia,family Erysipelotrichaceae,family Streptococcaceae,genus Coprococcusl,genus Ruminococcaceae UCG009,genus Streptococcus,order Clostridialesm and order Erysipelotrichales were causally related with the increased risk,while the family Porphyromonadaceae with the decreased risk of teratozoospermia.Conclusion:The class Erysipelotrichia,family Erysipe-lotrichaceae,family Streptococcaceae,genus Coprococcusl,genus Ruminococcaceae UCG009,genus Streptococcus,order Clostridia-lesm and order Erysipelotrichales are one of the causes of teratozoospermia,related to the increased risk of the condition,while the family Porphyromonadaceae has a protective effect on sperm morphology,reducing the risk of teratozoospermia.

Objective:To evaluate the efficacy and safety of traditional Chinese medicine(TCM)in the treatment of male im-mune infertility(MII)by meta-analysis.Methods:We retrieved randomized controlled trial(RCT)on the treatment of male im-mune infertility with traditional Chinese medicine from the databases of WanFang,Chinese Biomedical Literature,Cochrane Library,Weipu,PubMed and CNKI,and performed methodological quality assessment of the RCTs identified and statistical analysis and evalua-tion of the publication bias using the RevMan5.4 software.Results:Totally,25 RCTs(2 563 cases)were included in this study.Compared with Western medicine alone in the treatment of MII,TCM achieved a significantly higher total effectiveness rate(OR=6.35,95% CI:4.96-8.13,P<0.000 01),negative conversion rate of seminal plasma anti-sperm antibodies(OR=4.52,95% CI:2.72-7.51,P<0.000 01),negative rate of serum anti-sperm antibodies(OR=2.98,95% CI:2.23-3.96,P<0.000 01),sperm concentration(MD=15.56,95% CI:11.32-19.79,P<0.000 01),grade a sperm motility(MD=3.85,95% CI:1.91-5.79,P=0.000 01),grade a+b sperm motility(MD=13.77,95% CI:7.06-20.48,P<0.000 1),sperm viability(MD=10.32,95% CI:6.78-13.86,P<0.000 01)and pregnancy rate(OR=3.53,95% CI:2.68-4.63,P<0.000 01),but a lower rate of adverse reactions(OR=0.06,95% CI:0.01-0.23,P<0.000 01).There was no statistically significant difference in the percentage of morphologically abnormal sperm between TCM and Western medicine alone in the treatment of MII(MD=-7.53,95% CI:-15.50-0.44,P=0.06).Conclusion:TCM has a definite effectiveness and high safe in the treatment of male immune infertility.

This study was aimed at exploring the epidemiological characteristics of Salmonella typhimurium(S.typhi-murium)and Salmonella typhimurium monophasic variants(S.1,4,[5],12:i:-)at the genome-wide level in Ningxia.Estab-lishment of a whole genome genotyping database would provide a theoretical basis for source and prevention and control of fu-ture outbreaks.We conducted serotyping,MLST,cgMLST typing,and virulence gene and drug resistance phenotype prediction of 92 strains of S.typhimurium and its monophasic variants through whole genome sequencing.Among all strains,21 were S.typhomurium,accounting for 22.83％,71 strains were S.1,4,[5],12:i:-,accounting for 77.17％.MLST and cgMLST typing results indicated that all S.typhimurium strains were ST19-type,and were divided into five evolutionary bran-ches.Five clusters were found,and S.1,4,[5],12:i:-were all ST34-type;on the same evolutionary branch,17 clusters were found.VFDB predicted 155 virulence genes in eight classes,of which 33.33％were S.typhimurium carried nine virulence genes on plasmids,and both serotypes carried virulence genes related to SPI virulence island on chromosomes,12:I:-resistant to 4-14 antibiotics,resulting in 22 multi-drug resistance spectrum.S.typhimurium was resistant to 2-13 antibiotics and produced eight multi-drug resistance profiles.S.1,4,[5],12:i:-was the predominant serotype of S.enteritidis in Ningxia.Typhimurium carried fewer virulence genes than S.typhimurium,and showed a high risk of local outbreaks.