Developing and identifying effective medications and targets for treating hepatic fibrosis is an urgent priority. Our previous research demonstrated the efficacy of artesunate (ART) in alleviating liver fibrosis by eliminating activated hepatic stellate cells (HSCs). However, the underlying mechanism remains unclear despite these findings. Notably, endocytic adaptor protein (NUMB) has significant implications for treating hepatic diseases, but current research primarily focuses on liver regeneration and hepatocellular carcinoma. The precise function of NUMB in liver fibrosis, particularly its ability to regulate HSCs, requires further investigation. This study aims to elucidate the role of NUMB in the anti-hepatic fibrosis action of ART in HSCs. We observed that the expression level of NUMB significantly decreased in activated HSCs compared to quiescent HSCs, exhibiting a negative correlation with the progression of liver fibrosis. Additionally, ART induced senescence in activated HSCs through the NUMB/P53 tumor suppressor (P53) axis. We identified NUMB as a crucial regulator of senescence in activated HSCs and as a mediator of ART in determining cell fate. This research examines the specific target of ART in eliminating activated HSCs, providing both theoretical and experimental evidence for the treatment of liver fibrosis.
Hepatic Stellate Cells/cytology* ; Liver Cirrhosis/genetics* ; Artesunate/pharmacology* ; Cellular Senescence/drug effects* ; Membrane Proteins/genetics* ; Animals ; Humans ; Nerve Tissue Proteins/genetics* ; Tumor Suppressor Protein p53/genetics* ; Male ; Mice

OBJECTIVE To investigate the mechanism of artesunate increasing the sensitivity of hepatocellular carcinoma(HCC)cells to sorafenib in hypoxic microenvironment.METHODS Firstly,hypoxia-resistant HCC cell models were established.NAC(a ROS scavenger),necrostatin-1(a necrosis inhibitor),and ferrostatin-1(a ferroptosis inhibitor)were added to examine the effects of artesunate on the inhibition rate of HCC cells and the primary modes of cell death in hypoxic microenvironment by MTT assays.Intra-cellular levels of GSH,ROS,lipid peroxidation product MDA,and iron ions were measured using corresponding kits.Mitochondrial membrane potential changes were assessed using JC-1 staining.Western blot and qPCR were performed to detect the expression of fer-roptosis-related proteins after the addition of artesunate.RESULTS The sensitivity of HCC cells to sorafenib decreased under hy-poxic microenvironment,but artesunate significantly enhanced this sensitivity.Further analysis revealed that artesunate promoted sor-afenib-induced ferroptosis by increasing ROS levels in HCC cells(P<0.05,P<0.01,P<0.001).Additionally,artesunate was found to inhibit Nrf2 mRNA and protein levels(P<0.05,P<0.01,P<0.001)and downregulate HIF-1α expression(P<0.05,P<0.01,P<0.001).CONCLUSION Artesunate increases intracellular oxidative stress by inhibiting Nrf2 and HIF-1α protein levels,subse-quently induces ferroptosis and enhances the sensitivity of HCC cells to sorafenib in hypoxic microenvironment.

Objective:To observe the effects of transcutaneous electrical point stimulation(TEPS)on awakening,cognition,and immune function in patients undergoing laparoscopic cholecystectomy(LC)under general anesthesia.Methods:Ninety patients undergoing LC under general anesthesia were selected as the study subjects and were divided into a control group and an observation group according to the random number table method,with 45 cases in each group.The control group was operated with conventional general anesthesia.The observation group was treated with the same anesthesia as the control group,and TEPS was performed at Hegu(LI4),Zusanli(ST36),and Neiguan(PC6)before the induction of anesthesia until the completion of the operation.The quality of postoperative awakening,hemodynamic indicators,cognitive function,and immune function of patients in the two groups were compared,and the occurrence of adverse reactions was recorded.Results:The time of recovery of spontaneous breathing and extubation time of the observation group were shorter than those of the control group(P<0.05);there was no statistically significant difference in the heart rate(HR)and mean arterial pressure(MAP)between the two groups at the moment before the induction of anesthesia(T1)(P>0.05);at the moment of extubation(T2)and 5 min after extubation(T3),the HR and MAP of patients in both groups were higher than those at T1(P<0.05),and those of the observation group were lower than those of the control group(P<0.05).Preoperatively,there was no statistically significant difference in the Montreal cognitive assessment scale(MoCA)score between the two groups(P>0.05);3 d postoperatively,the MoCA score of the two groups decreased and was higher in the observation group than in the control group(P<0.05).Preoperatively,there was no statistical difference in the comparison of CD4+,CD8+,and CD4+/CD8+between the two groups(P>0.05);3 d postoperatively,the above indicators decreased in both groups(P<0.05)and were higher in the observation group than in the control group(P<0.05).There was no statistical difference in the total incidence of adverse reactions between the two groups(P>0.05).Conclusion:The application of TEPS at Hegu(LI4),Zusanli(ST36),and Neiguan(PC6)with general anesthesia can improve the quality of postoperative awakening,promote hemodynamic stabilization,and improve cognitive function and immune function in LC patients,with good safety.

Objective:To observe the effects of transcutaneous electrical point stimulation(TEPS)on awakening,cognition,and immune function in patients undergoing laparoscopic cholecystectomy(LC)under general anesthesia.Methods:Ninety patients undergoing LC under general anesthesia were selected as the study subjects and were divided into a control group and an observation group according to the random number table method,with 45 cases in each group.The control group was operated with conventional general anesthesia.The observation group was treated with the same anesthesia as the control group,and TEPS was performed at Hegu(LI4),Zusanli(ST36),and Neiguan(PC6)before the induction of anesthesia until the completion of the operation.The quality of postoperative awakening,hemodynamic indicators,cognitive function,and immune function of patients in the two groups were compared,and the occurrence of adverse reactions was recorded.Results:The time of recovery of spontaneous breathing and extubation time of the observation group were shorter than those of the control group(P<0.05);there was no statistically significant difference in the heart rate(HR)and mean arterial pressure(MAP)between the two groups at the moment before the induction of anesthesia(T1)(P>0.05);at the moment of extubation(T2)and 5 min after extubation(T3),the HR and MAP of patients in both groups were higher than those at T1(P<0.05),and those of the observation group were lower than those of the control group(P<0.05).Preoperatively,there was no statistically significant difference in the Montreal cognitive assessment scale(MoCA)score between the two groups(P>0.05);3 d postoperatively,the MoCA score of the two groups decreased and was higher in the observation group than in the control group(P<0.05).Preoperatively,there was no statistical difference in the comparison of CD4+,CD8+,and CD4+/CD8+between the two groups(P>0.05);3 d postoperatively,the above indicators decreased in both groups(P<0.05)and were higher in the observation group than in the control group(P<0.05).There was no statistical difference in the total incidence of adverse reactions between the two groups(P>0.05).Conclusion:The application of TEPS at Hegu(LI4),Zusanli(ST36),and Neiguan(PC6)with general anesthesia can improve the quality of postoperative awakening,promote hemodynamic stabilization,and improve cognitive function and immune function in LC patients,with good safety.

OBJECTIVE To investigate the mechanism of artesunate increasing the sensitivity of hepatocellular carcinoma(HCC)cells to sorafenib in hypoxic microenvironment.METHODS Firstly,hypoxia-resistant HCC cell models were established.NAC(a ROS scavenger),necrostatin-1(a necrosis inhibitor),and ferrostatin-1(a ferroptosis inhibitor)were added to examine the effects of artesunate on the inhibition rate of HCC cells and the primary modes of cell death in hypoxic microenvironment by MTT assays.Intra-cellular levels of GSH,ROS,lipid peroxidation product MDA,and iron ions were measured using corresponding kits.Mitochondrial membrane potential changes were assessed using JC-1 staining.Western blot and qPCR were performed to detect the expression of fer-roptosis-related proteins after the addition of artesunate.RESULTS The sensitivity of HCC cells to sorafenib decreased under hy-poxic microenvironment,but artesunate significantly enhanced this sensitivity.Further analysis revealed that artesunate promoted sor-afenib-induced ferroptosis by increasing ROS levels in HCC cells(P<0.05,P<0.01,P<0.001).Additionally,artesunate was found to inhibit Nrf2 mRNA and protein levels(P<0.05,P<0.01,P<0.001)and downregulate HIF-1α expression(P<0.05,P<0.01,P<0.001).CONCLUSION Artesunate increases intracellular oxidative stress by inhibiting Nrf2 and HIF-1α protein levels,subse-quently induces ferroptosis and enhances the sensitivity of HCC cells to sorafenib in hypoxic microenvironment.

Objective To construct,implement and evaluate the effectiveness of the virtual simulation technology-based prenatal health education course.Methods The curriculum included 4 parts:"warm delivery room and easy delivery","medicated analgesic delivery","non-medicated analgesic delivery"and"early maternal and infant health care".From May to September 2022,100 primiparas in an obstetrics and gynecology hospital in Zhejiang Province were investigated by convenient sampling method.Random number table method was used to divide the participants into an experimental group and a control group,with 50 participants per group.The control group received conventional health education,while the experimental group received an augmented virtual reality technology-based prenatal health education course during the late stages of pregnancy on this basis.We conducted a post-intervention comparative analysis of antenatal anxiety levels,fear of childbirth,and birth outcomes between the 2 groups.Furthermore,a post-intervention satisfaction survey was administered to the experimental group.Results After intervention,the antenatal anxiety of the experimental group was lower than that of the control group(x2=4.943,P=0.026),and the decrease in fear of childbirth scores was higher than that of the control group(t=3.200,P=0.002).The experimental group was highly satisfied with all of the 4 dimensions of the course,and the overall evaluation was(31.8±3.23)points.However,there were no significant differences in vaginal delivery rate,postpartum bleeding volume,postpartum hemorrhage incidence,perineal injury degree and duration of each labor stage between the 2 groups(P＞0.05).Conclusion The virtual reality technology-based prenatal health education course was effective in improving the antenatal anxiety and fear of childbirth of primipara,and the use satisfaction is high.

Objective To explore the status quo of depression and medical-social support in human immunodeficiency virus(HIV)/acquired immunodeficiency syndrome(AIDS)hemodialysis patients,as well as the effect of medical-social support on depression.Methods A total of 80 HIV/AIDS hemodialysis patients from Xixi Hospital in Hangzhou from March 2022 to March 2024 were collected.Center for epidemiological survey-depression scale(CES-D)and medical social support scale(MOS-SSS)were used to assess patients for depression and medical social support.Structural equation model was used to analyze relationship between medical social support and depression.Results 42 of the 80 subjects(52.5%)had depressive symptoms(CES-D score≥16 points).The results of univariate analysis showed that health status,antiviral treatment status,medical social support had an impact on HIV depression(P<0.05).Simple linear regression showed that health status(95%CI:-9.901--2.635)and antiviral treatment status(95%CI:-12.969--3.394)were the influencing factors for depression(P<0.05).The total score of medical social support,tangible support dimension,information and emotional support dimension,positive social interaction dimension,emotional support dimension were associated with depression(P<0.001).Multiple linear regression analysis showed that medical social support was negatively associated with depression.The higher medical social support was the lower incidence of depression.Conclusion The prevalence of depression in AIDS hemodialysis patients is high,and medical social support has a positive effect on alleviating their condition.

Objective To explore the status quo of depression and medical-social support in human immunodeficiency virus(HIV)/acquired immunodeficiency syndrome(AIDS)hemodialysis patients,as well as the effect of medical-social support on depression.Methods A total of 80 HIV/AIDS hemodialysis patients from Xixi Hospital in Hangzhou from March 2022 to March 2024 were collected.Center for epidemiological survey-depression scale(CES-D)and medical social support scale(MOS-SSS)were used to assess patients for depression and medical social support.Structural equation model was used to analyze relationship between medical social support and depression.Results 42 of the 80 subjects(52.5%)had depressive symptoms(CES-D score≥16 points).The results of univariate analysis showed that health status,antiviral treatment status,medical social support had an impact on HIV depression(P<0.05).Simple linear regression showed that health status(95%CI:-9.901--2.635)and antiviral treatment status(95%CI:-12.969--3.394)were the influencing factors for depression(P<0.05).The total score of medical social support,tangible support dimension,information and emotional support dimension,positive social interaction dimension,emotional support dimension were associated with depression(P<0.001).Multiple linear regression analysis showed that medical social support was negatively associated with depression.The higher medical social support was the lower incidence of depression.Conclusion The prevalence of depression in AIDS hemodialysis patients is high,and medical social support has a positive effect on alleviating their condition.

Senescence of activated hepatic stellate cells (aHSCs) is a stable growth arrest that is implicated in liver fibrosis regression. Senescent cells often accompanied by a multi-faceted senescence-associated secretory phenotype (SASP). But little is known about how alanine-serine-cysteine transporter type-2 (ASCT2), a high affinity glutamine transporter, affects HSC senescence and SASP during liver fibrosis. Here, we identified ASCT2 is mainly elevated in aHSCs and positively correlated with liver fibrosis in human and mouse fibrotic livers. We first discovered ASCT2 inhibition induced HSCs to senescence in vitro and in vivo. The proinflammatory SASP were restricted by ASCT2 inhibition at senescence initiation to prevent paracrine migration. Mechanically, ASCT2 was a direct target of glutaminolysis-dependent proinflammatory SASP, interfering IL-1α/NF-κB feedback loop via interacting with precursor IL-1α at Lys82. From a translational perspective, atractylenolide III is identified as ASCT2 inhibitor through directly bound to Asn230 of ASCT2. The presence of -OH group in atractylenolide III is suggested to be favorable for the inhibition of ASCT2. Importantly, atractylenolide III could be utilized to treat liver fibrosis mice. Taken together, ASCT2 controlled HSC senescence while modifying the proinflammatory SASP. Targeting ASCT2 by atractylenolide III could be a therapeutic candidate for liver fibrosis.

This research implements the "dual-element and three-step" education model based on the modern apprenticeship system for rural medical students, establishes a complete teacher management system through the joint enrollment of schools and teaching hospitals, and strengthens the professional cognition stage, professional learning stage and professional practice stage. It has certain effects on promoting students' good sense of professional identity and responsibility, enhancing learning initiative and professional vocational ability, and cultivating skilled and service-oriented medical talents with "six-in-one" post competences in rural areas.