ObjectiveTo systematically characterize the in vitro chemical constituents of Entada phaseoloides and its absorbed prototype compounds and metabolites in a neuropathic pain （NP） model， thereby elucidating the potential pharmacological material basis underlying its analgesic activity. MethodsUltra-high-performance liquid chromatography coupled with quadrupole-Orbitrap high-resolution mass spectrometry （UHPLC-Q-Orbitrap HRMS） was used to analyze the constituents of the 80% methanol extract of E. phaseoloides. Thirty-six mice were divided into a blank group， low-， medium-， and high-dose E. phaseoloides extract groups （25， 50， and 100 mg·kg^-1， respectively）， an aspirin group （400 mg·kg^-1）， and a morphine group （10 mg·kg^-1）， with six mice in each group. The tail-flick threshold was measured. Twenty-four mice were randomly divided into a blank group and low-， medium-， and high-dose E. phaseoloides extract groups （25， 50， and 100 mg·kg^-1， respectively）， with six mice in each group， and motor coordination was evaluated. A spinal nerve ligation （SNL） model was established in mice. Twenty-four mice were randomly divided into a sham-operated （Sham） group， an SNL group， an SNL + E. phaseoloides extract group （750 mg·kg^-1）， and an SNL + pregabalin group （20 mg·kg^-1）， with 6 mice in each group. Mechanical allodynia and thermal hyperalgesia were evaluated. Behavioral assessments were combined to determine the optimal onset time of the analgesic effect， and plasma samples were collected at this time point. Absorbed components and metabolites were systematically identified based on accurate mass， MS/MS fragmentation patterns， retention time， and comparisons with literature data and reference standards. Meanwhile， network pharmacology， target similarity analysis， and molecular docking validation were integrated to evaluate the potential effects of absorbed components on disease intervention. ResultsCompared with the blank group， the high-dose E. phaseoloides extract group and morphine group showed significantly increased pain response thresholds （P<0.01）， without affecting motor coordination in normal mice. Compared with the Sham group， the SNL group exhibited significantly decreased thresholds for mechanical allodynia and thermal hyperalgesia （P<0.01）. Compared with the SNL group， the SNL + E. phaseoloides extract group and SNL + pregabalin group showed significantly increased thresholds for mechanical allodynia and thermal hyperalgesia （P<0.01）. The analgesic effect of E. phaseoloides was most significant at 2 h after administration. A total of 70 constituents were identified in vitro， and 22 prototype compounds and 29 metabolites were detected in plasma. The targets of the absorbed components were mainly enriched in biological processes associated with pain signal perception and transmission and showed a high degree of overlap with disease genes related to neuropathic pain. In addition， multiple components exhibited strong binding energies with core pain-related targets. Based on integrated analysis of in vitro content， plasma exposure levels， and target associations， ketanthamide A-β-D-pyranoside and ketengzide were identified as the most representative pharmacologically active substances responsible for the analgesic effect. ConclusionThis study systematically elucidates the material basis of E. phaseoloides intervention in neuropathic pain from three aspects， including chemical constituent characteristics， in vivo behavioral characteristics， and potential targets， providing important theoretical foundations and experimental support for further studies on its pharmacological mechanism and analgesic drug development.

Nanotechnologies seek to overcome inherent deficiencies of conventional diagnosis and treatment, which attracted sustained attention and a limited number of nanomedicines approved by the FDA. However, the critical gaps in clinical translation remain, and nanomedicines that were initially heralded as magic bullets have yet to reach their realistic potential. The major obstacles of fabrication technologies may be overlooked in the nanoparticles' journey. Suboptimal manufacturing strategies partly hampered the inefficient transformation. In this review, we discuss the nanoparticle manufacturing strategies of "Top-Down" and "Bottom-Up" on precise nanoscale fabrication, including artificial intelligence introduced to guided nanomedicine fabrication for accelerating the transformation. Re-engineering existing nanomedicine fabrication, individual manufacturing, and modular technology might highlight the dilemmas of nanomedicines to meet their initial expectations.

Objective To investigate the roles of glucose-regulated protein 75(GRP75)and voltage-dependent anion channel 1(VDAC1)in heroin-induced arrhythmia.Methods Based on transcriptomic data from primary myocardial cells treated with heroin and the GSE31821 dataset from the Gene Expression Omnibus(GEO),differentially expressed genes(DEGs)were identified using R software.Enrichment analysis of DEGs was performed.The protein-protein interaction(PPI)network was constructed using STRING database,and key genes were selected using Cytoscape.Molecular docking of key genes was performed using HDOCK,followed by in vivo valida-tion.A total of 60 SD rats were randomly divided into control,model,model+7 d,model+14 d,and model+21 d groups.A rat model of heroin addiction was established,and the expression levels of DEGs in myocardial tissue were assessed using immunohistochemical staining and quantitative real-time PCR.Results A total of 51 DEGs primarily enriched in muscle cell development,myofibrils,actin binding,arrhythmic right ventricular cardiomyopathy,calcium signaling,and apoptosis pathways were identified.Based on the PPI and Cytoscape analyses,GRP75 and VDAC1 were identified as key genes.Molecular docking indicated a strong interaction between GRP75 and VDAC1,which form a stable complex.The results of immunohistochemical staining and qRT-PCR showed that the expression levels of GRP75 and VDAC1 were significantly increased in the model group compared to those in the control group(P＜0.05),and their expres-sion increased(P＜0.05)with the intervention period of heroin in a time-dependent manner.Conclusion GRP75 and VDAC1 may con-tribute to heroin-induced arrhythmogenesis.

Objective To investigate the roles of glucose-regulated protein 75(GRP75)and voltage-dependent anion channel 1(VDAC1)in heroin-induced arrhythmia.Methods Based on transcriptomic data from primary myocardial cells treated with heroin and the GSE31821 dataset from the Gene Expression Omnibus(GEO),differentially expressed genes(DEGs)were identified using R software.Enrichment analysis of DEGs was performed.The protein-protein interaction(PPI)network was constructed using STRING database,and key genes were selected using Cytoscape.Molecular docking of key genes was performed using HDOCK,followed by in vivo valida-tion.A total of 60 SD rats were randomly divided into control,model,model+7 d,model+14 d,and model+21 d groups.A rat model of heroin addiction was established,and the expression levels of DEGs in myocardial tissue were assessed using immunohistochemical staining and quantitative real-time PCR.Results A total of 51 DEGs primarily enriched in muscle cell development,myofibrils,actin binding,arrhythmic right ventricular cardiomyopathy,calcium signaling,and apoptosis pathways were identified.Based on the PPI and Cytoscape analyses,GRP75 and VDAC1 were identified as key genes.Molecular docking indicated a strong interaction between GRP75 and VDAC1,which form a stable complex.The results of immunohistochemical staining and qRT-PCR showed that the expression levels of GRP75 and VDAC1 were significantly increased in the model group compared to those in the control group(P＜0.05),and their expres-sion increased(P＜0.05)with the intervention period of heroin in a time-dependent manner.Conclusion GRP75 and VDAC1 may con-tribute to heroin-induced arrhythmogenesis.

ObjectiveTo investigate the analgesic effect and mechanism of Osteoking （OK） on nerve compression in lumbar disc herniation. MethodThe rat model of chronic compression of dorsal root ganglion （CCD） was established to simulate clinical lumbar disc herniation. The CCD rats were randomly divided into model group， low， medium， and high dose OK groups （1.31， 2.63， 5.25 mL·kg^-1·d^-1）， and pregabalin group （5 mg·kg^-1）， with eight rats in each group. Another eight SD rats were taken as the blank group， and the same volume of normal saline was given by gavage. Behavioral tests， side effect evaluation， network analysis， Western blot， immunofluorescence， and antagonist application were used to explore the effect. ResultCompared with the blank group， the mechanical hyperalgesia threshold， thermal hyperalgesia threshold， and the expression of inflammatory factors in the spinal dorsal horn of the model group are significantly increased （P<0.01）， and the related indicators of the affected foot footprints are significantly down-regulated （P<0.01）. The expression of signal transducer and activator of transcription 3 （STAT3）， vascular endothelial growth factor A （VEGFA）， and phosphorylated extracellular regulated protein kinase （p-ERK） in microglia in the spinal dorsal horn is significantly increased in the model group （P<0.01）. Compared with the model group， low， medium， and high dose OK groups can increase the mechanical hyperalgesia and thermal hyperalgesia thresholds of CCD rats （P<0.05， P<0.01） in a dose-dependent manner， improve the gait of CCD rats （P<0.05， P<0.01）， and reduce the expression of inflammatory factors in the spinal dorsal horn （P<0.05， P<0.01）. The expression of STAT3， VEGFA， and p-ERK in the spinal dorsal horn microglia of CCD rats is significantly decreased （P<0.05， P<0.01）， and the acetic acid-induced nociceptive response in rats is effectively reduced （P<0.05， P<0.01）. In addition， there is no tolerance. The results of the body mass test， organ index， forced swimming， and rotation show that OK has no obvious toxic or side effects. Further antagonist experiments show that MRS1523 and RS127445 can reverse the transient analgesic effect of OK compared with the high dose OK group （P<0.01）. ConclusionOK has a good analgesic effect on the CCD model without obvious toxic side effects， and its mechanism may be related to the activation of ADORA3 and HTR2B and the inhibition of STAT3， VEGFA， p-ERK， and other elements in microglia.

Objective:To systematically evaluate the prevalence of norovirus causing sporadic acute gastroenteritis in China.Methods:Relevant articles on acute gastroenteritis caused by norovirus in China published between January 2010 and October 2023 were retrieved from Wanfang, CNKI and PubMed database. The articles met inclusion and exclusion criteria were enrolled in this study. Excel software and SPSS20.0 software were used for statistical analysis. The epidemiological features of sporadic cases of acute gastroenteritis caused by norovirus in China were summarized using descriptive statistical analysis.Results:A total of 500 articles were included in this study, involving 784 486 cases of acute gastroenteritis and 670 292 samples in 32 provinces and regions. Norovirus GⅡ was the predominant genogroup causing acute gastroenteritis in China in recent years, but there were significant differences in the distribution of genotypes and epidemic strains at different times. GⅡ.4 was the predominant genotype in each year, and GⅡ.4/2006b and GⅡ.4 /Sydney_2012 were the main epidemic strains. Norovirus-related diarrhea occurred throughout the year, especially between the months of October and December. The incidence of norovirus infection was high in children under five years old and varied in different regions.Conclusions:Norovirus GⅡ was the predominant genogroup causing norovirus-related sporadic acute gastroenteritis in China, but there was an obvious genetic evolutionary trend in the epidemic strains. Factors such as epidemic strains, season and geographical region should be considered when making strategies for the prevention and control of norovirus-related diarrhea and developing vaccines.

OBJECTIVE To evaluate the effectiveness and safety of trastuzumab biosimilars and original drugs in the treatment of human epidermal growth factor receptor -2（HER-2）positive breast cancer systematically ，and to provide evidence -based basis for the selection of clinical treatment . METHODS Retrieved from PubMed ，Embase，Web of Science ，Cochrane Library ，CNKI， CBM，VIP，Wanfang database ，ClinicalTrials and Clinical Trial Center of China ，randomized controlled trials （RCTs）about trastuzumab biosimilars （trial group ）versus original drugs （control group ）in the treatment of HER -2 positive breast cancer were collected. After data extraction and quality evaluation ，RevMan 5.4 statistical software was used for meta -analysis. RESULTS Totally 11 RCTs were enrolled ，involving 5 812 patients. Results of meta -analysis showed that there was no significant difference in objective response rate （based on whether intention -to-treat population nor per -protocol population ），pathologic complete response ， proportion of progression free survival population ，proportion of overall survival population ，anti-drug antibody positive rate ， neutralizing antibody positive rate ，and incidence of adverse drug reactions between 2 groups（P＞0.05）. CONCLUSIONS The effectiveness and safety of trastuzumab biosimilars are equivalent to those of trastuzumab original drugs .

TRPML1 channel is a non-selective group-2 transient receptor potential (TRP) channel with Ca permeability. Located mainly in late endosome and lysosome of all mammalian cell types, TRPML1 is indispensable in the processes of endocytosis, membrane trafficking, and lysosome biogenesis. Mutations of TRPML1 cause a severe lysosomal storage disorder called mucolipidosis type IV (MLIV). In the present study, we determined the cryo-electron microscopy (cryo-EM) structures of Mus musculus TRPML1 (mTRPML1) in lipid nanodiscs and Amphipols. Two distinct states of mTRPML1 in Amphipols are added to the closed state, on which could represent two different confirmations upon activation and regulation. The polycystin-mucolipin domain (PMD) may sense the luminal/extracellular stimuli and undergo a "move upward" motion during endocytosis, thus triggering the overall conformational change in TRPML1. Based on the structural comparisons, we propose TRPML1 is regulated by pH, Ca, and phosphoinositides in a combined manner so as to accommodate the dynamic endocytosis process.
Animals ; Calcium ; metabolism ; Cryoelectron Microscopy ; Endocytosis ; Endosomes ; metabolism ; Gene Expression ; HEK293 Cells ; Humans ; Hydrogen-Ion Concentration ; Lysosomes ; metabolism ; Mice ; Models, Biological ; Mucolipidoses ; genetics ; metabolism ; pathology ; Nanostructures ; chemistry ; ultrastructure ; Phosphatidylinositols ; metabolism ; Transgenes ; Transient Receptor Potential Channels ; chemistry ; genetics ; metabolism

Objective To assess the clinical application value of single-source dual energy CT(SSDE),by measuring the multi-slice CT(MSCT) and single-source dual energy CT(SSDE) lower limb fractures image noise and contrast noise ratio(CNR),comparing the difference in the radiation dosage.Methods 39 cases of lower extremity fractures by clinical diagnosis were included in the study.Preoperation or postoperation the patients underwent MSCT scans,postoperation or postoperative follow-up SSDE CT scans were conducted,two sets of images were achieved.We measured and compared conventional CT group with 130 key energy spectrum group (prior studies showed the elimination of metal artifacts,images,subjective scoring the highest photon energy level) no significant artifacts cancellous bone area,compared the image background noise and contrast noise ratio (CNR),and radiation dosage,using paired sample t-test.Results Two sets of data for the same patient before and after surgery or after review of images,which body mass index (BMI) was negligible.The CTDIvol value of the conventional MSCT was (7.94 ± 1.69) mGy,the dual-energy CT was (7.04 ± 0.97) mGy,with significant difference (t =2.71,P ＜ 0.05) ; The image noise of the conventional MSCT was (44.36 ± 15.66) Hu,the dual-energy CT was (15.04 ± 8.23) Hu,with significant difference (t =15.26,P ＜ 0.05) ; The CNR of the conventional MSCT was (3.96 ± 1.78),the dual-energy CT was (4.62 ± 2.80),with significant difference (t =-2.14,P ＜ 0.05).Conclusion Compared with conventional MSCT,single source dual-energy CT imaging provides improved image CNR,obviously eliminate metal artifacts,to better show the complex structure for lower limb fracture surgery,and reduction in radiation dosage.