Unlike chemosynthetic drugs designed for specific molecular and disease targets,active small-molecule natural products typically have a wide range of bioactivities and multiple targets,necessitating extensive screening and development.To address this issue,we propose a strategy for the direct in situ micro-dynamic examination of potential drug candidates to rapidly identify their effects and mechanisms of action.As a proof-of-concept,we investigated the behavior of mussel oligosaccharide(MOS-1)by tracking the subcellular dynamics of fluorescently labeled MOS-1 in cultured cells.We recorded the entire dynamic process of the localization of fluorescein isothiocyanate(FITC)-MOS-1 to the lysosomes and visualized the distribution of the drug within the cell.Remarkably,lysosomes containing FITC-MOS-1 actively recruited lipid droplets,leading to fusion events and increased cellular lipid consumption.These drug behaviors confirmed MOS-1 is a candidate for the treatment of lipid-related diseases.Furthermore,in a high-fat HepG2 cell model and in high-fat diet-fed apolipoprotein E(ApoE)-/-mice,MOS-1 significantly promoted triglyceride degradation,reduced lipid droplet accumulation,lowered serum triglyceride levels,and mitigated liver damage and steatosis.Overall,our work supports the prioritization of in situ visual monitoring of drug location and distribution in subcellular compartments during the drug development phase,as this methodology contributes to the rapid identification of drug indications.Collectively,this methodology is significant for the screening and development of selective small-molecule drugs,and is expected to expedite the identification of candidate molecules with me-dicinal effects.

The RANKL/RANK/OPG signaling pathway is essential for balancing bone resorption and bone formation. Research shows this signaling pathway exists in various tissues, including liver, muscle, adipose tissue, pancreas, and other tissues that might influence glucose metabolism. Blocking the pathway could protect islet β cell function. Furthermore, RANKL also improves insulin resistance by inducing beige adipocytes differentiation and increasing energy expenditure. Currently, the role of RANKL in glucose metabolism remains controversial. This article reviews current research and discusses the potential use of RANKL inhibitors for treating diabetes with osteoporosis.

Objective To conduct a scoping review on studies of tele-health management for stroke patients at home.Methods According to the reporting framework of scoping review,a system-atic literature search was performed in 9 databases or websites from January 1,2013 to May 1,2023.Results A total of 52 literatures from 12 countries were included,most of which were interventional studies.Tele-health management was gradually becoming a trend in the application of stroke patients at home,relying on rehabilitation robots,virtual reality rehabilitation games,social platforms,home health network platforms and other carriers for rehabilitation training,disease monitoring,health edu-cation and guidance,follow-up and reminder.Conclusion The contents of tele-health management for stroke patients at home are abundant,with many evaluation indexes.In the future,rehabilitation training should enhance the gameplay of rehabilitation video games,improve patient's experience,and use artificial intelligence based on medical big data to provide auxiliary support for patients;at the same time,the content of each module of the tele-health management program should be standardized,and caregivers are encouraged to participate in the tele-health management of stroke patients at home,so as to better play the role of tele-health management in the field of post-stroke health management at home.

Objective To conduct a scoping review on studies of tele-health management for stroke patients at home.Methods According to the reporting framework of scoping review,a system-atic literature search was performed in 9 databases or websites from January 1,2013 to May 1,2023.Results A total of 52 literatures from 12 countries were included,most of which were interventional studies.Tele-health management was gradually becoming a trend in the application of stroke patients at home,relying on rehabilitation robots,virtual reality rehabilitation games,social platforms,home health network platforms and other carriers for rehabilitation training,disease monitoring,health edu-cation and guidance,follow-up and reminder.Conclusion The contents of tele-health management for stroke patients at home are abundant,with many evaluation indexes.In the future,rehabilitation training should enhance the gameplay of rehabilitation video games,improve patient's experience,and use artificial intelligence based on medical big data to provide auxiliary support for patients;at the same time,the content of each module of the tele-health management program should be standardized,and caregivers are encouraged to participate in the tele-health management of stroke patients at home,so as to better play the role of tele-health management in the field of post-stroke health management at home.

Infectious keratitis often occurs in single eye and causes changes in the nervous system, immune system and tear function, which may affect contralateral uninfected eye.Changes in the uninfected eye include a decrease in corneal nerve density and tear secretion, an increase in corneal dendritic cells and changes in tear cytokines.All the changes can be observed by in vivo confocal microscopy, Schirmer test I and tear film break-up time tests.Alternations in immune cells, cytokines and immunodulatory neuropeptide levels in contralateral eyes might mediate the incidence of bilateral infectious keratitis, and are also correlated with lacrimal reflex pathway.This article reviewed the pathophysiological changes in the contralateral uninfected eye of monocular infectious keratitis, which may help increase our understanding of the mechanisms involved in the corneal homeostasis and pathophysiology of corneal diseases.

Objective To evaluate the clinical changes of corneal epithelial cells,dendritic cells,endothelial cells and corneal nerves in contralateral eyes of patients with unilateral infectious keratitis.Methods A prospective serial case observation study was conducted in patients with unilateral infectious keratitis from January to August 2018 in the First Affiliated Hospital of Harbin Medical University.The corneal epithelial cells density,dendritic cells density,endothelial cells density,total nerve density,total number of nerves and branch nerve density were analyzed with in vivo confocal microscopy (IVCM),slit lamp microscopy was performed on all subjects to observe the conjunctiva,cornea and anterior chamber.Corneal branch nerve density and total nerve density were compared with the control group by homogeneity test of variance.This study was approved by the Ethics Committee of the First Affiliated Hospital of Harbin Medical University (No.IRB-AF/SC-04/01.0).Results Slit lamp microscopy showed no significant changes in anterior segment of the contralateral uninfected eyes in the 3 groups.The corneal epithelial cells density of uninfected eyes in viral keratitis group,bacterial keratitis group and fungal keratitis group was 1 834 (1 584,2 107),1 905 (1 651,2 332) and 1 859 (1 477,1 995)/mm2,respectively,which were significantly lower than 3 479 (3 080,3 910)/mm2 in the control group,the dendritic cells densities in viral keratitis group and bacterial keratitis group were 175 (139,214)/mm2 and 156 (118,190)/mm2,which were higher than 69(57,76)/mm2 in the control group,the differences were statistically significant (all at P＜0.05).The corneal endothelial cells density of uninfected eyes in viral keratitis group was 1 107(945,1 270)/mm2,which was less than 1 905(1 651,2 332)/mm2 in the bacterial keratitis group and 1 859(1 477,1 995)/mm2 in the fungal keratitis group (both at P＜0.05).The corneal nerve number and total nerve density of uninfected eyes in viral keratitis group were l0(7,11)/mm2 and (1 822.85±622.34) μm/mm2,which were lower than 11 (9,13)/mm2 and (2 340.91±:408.70)μm/mm2 in the bacterial keratitis group,with significant differences between them (P＜ 0.05,P＜ 0.008 3).The morphology of corneal epithelial cells and endothelial cells in each infectious keratitis group was larger than that in the control group,while the morphology and number of dendritic cells in the contralateral eye of patients with viral and bacterial keratitis increased.Conclusions In unilateral uninfected eyes of infectious keratitis,the density of corneal epithelial cells,dendritic cells,endothelial cells and corneal nerves changes correspondingly.There may be a close relationship of corneal immunity and nervous system between the two eyes.

Objective: To evaluate the feasibility, efficacy and safety of epidermal growth factor receptor-tyrosine kinase inhibitors(EGFR-TKIs) for neoadjuvant therapy. Methods: Eighty-six patients with stage ⅢA EGFR-mutant lung adenocarcinoma were assigned to 2 groups (n=43 in each group) according to the random number table method: neoadjuvant targeted therapy group (single oral dose of erlotinib 150 mg per day, for 9 weeks) and neoadjuvant chemotherapy group (2 cycles of pemetrexed combined with cisplatin chemotherapy followed by 3- week discontinuation). Surgical treatment was underwent after imaging efficacy evaluation. Results: In neoadjuvant targeted therapy group, 4 achieved complete response (CR), 25 achieved partial response (PR), giving an objective response rate (ORR) of 67.4%. In pathological response, 8 patients had grade Ⅰ, 20 patients had grade Ⅱ, giving a pathological response rate of 65.1%. The most frequent adverse events (AEs) were rash and diarrhea. In neoadjuvant chemotherapy group, 2 had CR and 17 had PR, giving an ORR of 44.2%. In pathological response, 3 patients had grade Ⅰ, 15 patients had grade Ⅱ, giving a pathological response rate of 41.9%. The main AEs were hematologic toxic effects. The ORR, histological efficacy and hematologic toxicity showed statistical significance between the two groups (P<0.05). The neoadjuvant targeted therapy group had 90.7% resection rate, (299.8±23.4) ml of hemorrhage volume during operation, (5.2±0.4) days of extubation time and 9.3% postoperative complication rate. Corresponding results were 83.7%, (308.9±22.7) ml, (5.4±0.6) days and 11.6% in neoadjuvant chemotherapy group, which showed no statistical significance (P>0.05). Conclusions Neoadjuvant targeted treatment for stage ⅢA lung adenocarcinoma harboring EGFR mutations. The regimen could be considered as a choice of neoadjuvant treatment for patients with stage ⅢA EGFR-mutant lung adenocarcinoma.

Aim To study the inhibitory activities of potential new anti-influenza virus agents,3-O-β-chaco-triosyl pentacyclic triterpenoids against the entry of H5N1influenza viruses.Methods Three target com-pounds were designed and synthesized structurally re-lated to the lead compound 3-O-β-chacotriosyl dioscin derivative (1 )with inhibitory activities against H5N1 influenza viruses.The inhibitory activities of these tar-get compounds were tested at a cellular level pseudo vi-rus system targeting H5N1 influenza viruse entry.Re-sults All the compounds 1 a,1 b and 1 c showed po-tent inhibitory activities against the entry of A/Thai-land/Kan353/2004 pseudo virus into the target cells, of which compound 1 b showed the best inhibitory activ-ity with an IC50 value of (1.25 ±0.22)μmol·L-1. Conclusion The SARs analysis of these compounds indicated that replacement of the aglycone moiety of compound 1 with pentacyclic triterpenoids could in-crease antiviral activity.Different types of pentacyclic triterpen as aglycone residue had the significant influ-ence on the inhibitory activity (1 b >1 c >1 a),sug-gesting ursane type of triterpenes was superior to the two other kinds of triterpenes as aglycone residue.

OBJECTIVETo study the inhibitory activities of 3-O-β-chacotriosyl benzyl ursolate and its derivatives as potential new anti-influenza virus agents against the entry of H5N1 influenza viruses into the target cells.

METHODSFour target compounds were designed and synthesized, which were structurally related to the lead compound 3-O-β-chacotriosyl methyl ursolate (1). The inhibitory activities of these compounds were tested at a cellular level psuedovirus system targeting H5N1 influenza viruse entry.

RESULTS AND CONCLUSIONThe compounds 1b, 1c and 1d showed potent inhibitory activities against the entry of A/Thailand/Kan353/2004 pseudovirus into the target cells, and among them compound 1d showed the strongest inhibitory activity with an IC50 value of 0.96 ± 0.10 µmol/L. The structure-activity relationship analysis of these compounds indicated that when 17-COOH of ursolic acid was esterified, introduction of Me groups rather than aryl groups more strongly enhanced the inhibitory activity. Changing 17-COOH of ursolic acid into amide could increase the antiviral activity and decrease the cytotoxicity of the compounds in MDCK cells.

Animals ; Antiviral Agents ; chemistry ; Dogs ; Influenza A Virus, H5N1 Subtype ; drug effects ; physiology ; Madin Darby Canine Kidney Cells ; Structure-Activity Relationship ; Triterpenes ; chemistry ; Virus Internalization ; drug effects

Objective To find the key miRNA that relative to peritoneal fibrosis associated with peritoneal dialysis (PD) by microarray technology,and verify its expression in vitro and in vivo.Methods The peritoneal fibrosis mouse model associated with PD were established by intraperitoneal injection of lipopolysaccharide (LPS)+ 4.25％ peritoneal dialysate.The expression of miRNA was detected by microarray in peritoneal tissues.The expression of miRNA profiles between fibrotic and normal peritoneal tissues was compared.The differentially expressed miRNA (miR-200a) was validated by real-time PCR in lager sample size cohorts.The expressions of miR-200a were also detected in the epithelial-mesenchymal transition (EMT) process of human peritoneal mesothelium cells.Results In mice model of PD,peritoneal tissue was markedly thickened and with a massive extracellular matrix accumulation.In contrast with control,the expression level of epithelial marker E-cadherin was significantly decreased,α-SMA,Col-Ⅰ and FN were remarkably increased (P ＜ 0.05).By miRNA microarray analysis,miR-200a was significantly down-regulated (3.31 folds change,P ＜ 0.05) in fibrotic peritoneal tissues.The down-regulated expression level of miR-200a was also validated by realtime PCR in larger cohorts (P ＜ 0.05).Then,the expression level of miR-200a was detected in the EMT process of human peritoneal mesothelium cells.During the process of TGF-β1 induced EMT,miR -200a was significantly down-regulated compared with the control (P ＜ 0.05).Conclusions Downregulated expression of miR-200a was observed both during peritoneal fibrosis and TGF-β 1 induced EMT in vivo and in vitro,suggesting that miR-200a may be involved in the peritoneum fibrosis by regulating the target genes of EMT.