Glioma is difficult to treat due to the unique tumor microenvironment and blood-brain barrier. (13aS)-3-Hydroxyl-6,7-dimethoxyphenanthro[9,10-b] indolizidine (PF403), a phenanthroindolizidine alkaloid, has been identified as a promising therapeutic agent for the treatment of glioma. However, the anti-glioma mechanism of PF403 in vivo has not been conclusively verified and must be further elucidated. Hence, a strategy without chemical modification was applied to identify the target of PF403. In this study, we identified nicotinamide phosphoribosyl transferase (NAMPT) as the target of PF403 by using thermal proteome profiling (TPP). Moreover, microscale thermophoresis (MST), surface plasmon resonance (SPR), and isothermal titration calorimetry (ITC) experiments confirmed that NAMPT exhibits good affinity for PF403. Direct and indirect enzyme activity assays revealed that PF403 inhibited the catalytic activity of NAMPT, leading to a decrease in the concentration of nicotinamide adenine dinucleotide (NAD⁺) in U87 cells. X-ray diffraction and amino acid spot mutation experiments revealed that PF403 primarily relies on the formation of pi-pi interactions with residue Tyr188 to maintain binding with NAMPT (PDB code 8Y55). After NAMPT was knocked down with lentivirus, PF403 lost or partially lost its antitumor activity at the cellular and animal levels. These findings suggest that PF403 exerts antitumor activity by directly targeting NAMPT.

BACKGROUND:Aerobic exercise can suppress liver fibrosis in diabetic mice.However,the specific mechanism is yet to be elucidated.OBJECTIVE:To investigate the protective effect and mechanism of aerobic exercise on liver fibrosis in db/db mice via the transforming growth factor-β/Smad signaling pathway.METHODS:8-week-old male db/db mice and age-matched m/m mice were randomly divided into m/m control group,m/m+exercise group,db/db control group,and db/db+exercise group,with 10 mice in each group.Mice in the exercise group were subjected to a 12-week aerobic exercise.After the exercise,fasting blood glucose levels were measured in mice,and glucose tolerance and insulin tolerance tests were conducted.Mouse liver was extracted to calculate liver index and mouse eyeballs were taken to collect blood sample and detect biochemical indicators.Masson,oil red O and Hematoxylin-eosin staining were used to detect and analyze the pathological changes in mouse liver tissues.Immunohistochemistry was used to determine the protein expression levels of transforming growth factor-β1 and p-Smad3.Western blot analysis was applied to determine the protein expression levels of transforming growth factor-β1,Smad3,p-Smad3,α-smooth muscle actin,type I collagen and type III collagen.RESULTS AND CONCLUSION:Compared with the m/m group and m/m+exercise group,body mass,liver mass,liver index,fasting blood glucose,triglycerides,total cholesterol,low-density lipoprotein and creatine kinase levels were significantly increased(P<0.01),but the high-density lipoprotein level significantly decreased(P<0.01)in the db/db group;the protein expressions of transforming growth factor-β1,p-Smad3,α-smooth muscle actin,type I collagen and type III collagen significantly increased(P<0.01)in the db/db group;the area under curve of glucose and insulin tolerance tests significantly increased(P<0.01)in the db/db group;and pathological staining of the liver in the db/db group showed extensive infiltration of inflammatory cells,increased lipid droplets,and significant fibrosis.In the db/db+exercise group,aerobic exercise could significantly reduce body mass,liver mass,liver index,fasting blood glucose,triglycerides,total cholesterol,low-density lipoprotein and creatine kinase levels(P<0.05 or P<0.01),and increase high-density lipoprotein level(P<0.05).Similarly,a marked decrease was observed in the protein expression levels of transforming growth factor-β1,p-Smad3,α-smooth muscle actin,type I collagen and type III collagen(P<0.05 or P<0.01)in the db/db+exercise group.In addition,the area under the curve of glucose tolerance and insulin tolerance tests significantly decreased(P<0.01,P<0.05),and pathological changes in liver tissues were significantly improved.In conclusion,aerobic exercise can attenuate liver fibrosis in diabetic mice,which may be related to the regulation of the transforming growth factor-β1/Smad signaling pathway.

Cancer-induced bone pain(CIBP)causes substantial suffering for cancer patients and also diminishes their quality of life and self-esteem.The mechanisms underlying CIBP are complex and evolve progressively with cancer advancement.Current treatment options show limited efficacy and are often accompanied by adverse effects.Traditional Chinese medicine demonstrates potential advantages in managing CIBP;however,the mechanisms of action remain poorly understood and require further investigation.The development of a standardized,stable,and reproducible animal model is crucial to advancing research on disease pathogenesis and verifying the effectiveness of therapeutic interventions.This review considers recent method for modeling CIBP in animals and summarizes the application of these models in studies of traditional Chinese medicine mechanisms,with the aim of guiding future research directions in CIBP.

BACKGROUND:Aerobic exercise can suppress liver fibrosis in diabetic mice.However,the specific mechanism is yet to be elucidated.OBJECTIVE:To investigate the protective effect and mechanism of aerobic exercise on liver fibrosis in db/db mice via the transforming growth factor-β/Smad signaling pathway.METHODS:8-week-old male db/db mice and age-matched m/m mice were randomly divided into m/m control group,m/m+exercise group,db/db control group,and db/db+exercise group,with 10 mice in each group.Mice in the exercise group were subjected to a 12-week aerobic exercise.After the exercise,fasting blood glucose levels were measured in mice,and glucose tolerance and insulin tolerance tests were conducted.Mouse liver was extracted to calculate liver index and mouse eyeballs were taken to collect blood sample and detect biochemical indicators.Masson,oil red O and Hematoxylin-eosin staining were used to detect and analyze the pathological changes in mouse liver tissues.Immunohistochemistry was used to determine the protein expression levels of transforming growth factor-β1 and p-Smad3.Western blot analysis was applied to determine the protein expression levels of transforming growth factor-β1,Smad3,p-Smad3,α-smooth muscle actin,type I collagen and type III collagen.RESULTS AND CONCLUSION:Compared with the m/m group and m/m+exercise group,body mass,liver mass,liver index,fasting blood glucose,triglycerides,total cholesterol,low-density lipoprotein and creatine kinase levels were significantly increased(P<0.01),but the high-density lipoprotein level significantly decreased(P<0.01)in the db/db group;the protein expressions of transforming growth factor-β1,p-Smad3,α-smooth muscle actin,type I collagen and type III collagen significantly increased(P<0.01)in the db/db group;the area under curve of glucose and insulin tolerance tests significantly increased(P<0.01)in the db/db group;and pathological staining of the liver in the db/db group showed extensive infiltration of inflammatory cells,increased lipid droplets,and significant fibrosis.In the db/db+exercise group,aerobic exercise could significantly reduce body mass,liver mass,liver index,fasting blood glucose,triglycerides,total cholesterol,low-density lipoprotein and creatine kinase levels(P<0.05 or P<0.01),and increase high-density lipoprotein level(P<0.05).Similarly,a marked decrease was observed in the protein expression levels of transforming growth factor-β1,p-Smad3,α-smooth muscle actin,type I collagen and type III collagen(P<0.05 or P<0.01)in the db/db+exercise group.In addition,the area under the curve of glucose tolerance and insulin tolerance tests significantly decreased(P<0.01,P<0.05),and pathological changes in liver tissues were significantly improved.In conclusion,aerobic exercise can attenuate liver fibrosis in diabetic mice,which may be related to the regulation of the transforming growth factor-β1/Smad signaling pathway.

Cancer-induced bone pain(CIBP)causes substantial suffering for cancer patients and also diminishes their quality of life and self-esteem.The mechanisms underlying CIBP are complex and evolve progressively with cancer advancement.Current treatment options show limited efficacy and are often accompanied by adverse effects.Traditional Chinese medicine demonstrates potential advantages in managing CIBP;however,the mechanisms of action remain poorly understood and require further investigation.The development of a standardized,stable,and reproducible animal model is crucial to advancing research on disease pathogenesis and verifying the effectiveness of therapeutic interventions.This review considers recent method for modeling CIBP in animals and summarizes the application of these models in studies of traditional Chinese medicine mechanisms,with the aim of guiding future research directions in CIBP.

This study reports the diagnosis and treatment of a 26-year-old pregnant woman with severe malnutrition combined with acute pyelonephritis causing sepsis,refractory septic shock and multiple organ failure.A female patient,26 years old,was admitted to hospital mainly due to"menelipsis for more than 19 weeks,nausea and vomiting for 20 days,fever with fatigue for 3 days".At the end of 19 weeks of in-trauterine pregnancy,the patient presented with fever accompanied by urinary tract irritation.Laboratory tests showed elevated inflammatory indicators,and ultrasonography showed bilateral pelvicalyceal dila-tion.She was diagnosed with acute pyelonephritis,sepsis,acute kidney injury(AKI)and severe malnu-trition.After a whole-hospital consultation,the patient was treated with meropenem and vancomycin as antimicrobial therapy,and bilateral nephrostomy drainage was performed simultaneously.After that,the patient suffered a sudden decrease in blood pressure,blood oxygen saturation,and rapid heart rate.Sep-tic shock with multiple organ dysfunction was considered,and she was transferred to intensive care unit(ICU)immediately.After the patient was transferred to ICU,emergency tracheal intubation and ventila-tor-assisted ventilation were performed.Rapid fluid resuscitation was administered for the patient.While pulse indicator continuous cardiac output(PICCO)monitoring was performed,norepinephrine,terlipres-sin,and methylene blue were administered to maintain peripheral vascular resistance.Since the patient developed septic cardiomyopathy and cardiogenic shock later,levosimendan and epinephrine were admi-nistered to improve cardiac function.While etiological specimens were delivered,meropenem,teicoplanin and caspofungin were given as initial empiric antimicrobial therapy.Unfortunately,the intrauterine fetal death occurred on the night of admission to ICU.On the 3rd day of ICU admission,a still-born child was delivered vaginally with 1/5 defect of the fetal membrane.On the 6th day of ICU admission,the patient had fever again with elevated inflammatory indicators.After excluding infection in other parts,intrau-terine infection caused by incomplete delivery of fetal membrane was considered.Then emergency uterine curettage was performed and the infection gradually improved.Later the laboratory results showed that the nephrostomy drainage was cultured for Escherichia coli and uterine,cervical and vaginal secretions were cultured for Candida albicans.Due to severe infection and intrauterine incomplete abortion,the patient developed disseminated intravascular coagulation(DIC).Active antimicrobial therapy and blood product supplement were given.However,the patient was critically ill with significant decrease in hemoglobin and platelets combined with multiple organ failure.Thrombotic microangiopathy(TMA)was not excluded yet,so plasma exchange was performed for the patient in order not to delay treatment.The patient under-went bedside continuous renal replacement therapy(CRRT)for AKI.The patient was complicated with acute liver injury,and the liver function gradually returned to normal after liver protection,antimicrobial therapy and other treatments.Due to the application of large doses of vasoactive drugs,the extremities of the patient gradually developed cyanosis and ischemic necrosis.Local dry gangrene of the bilateral toes remained at the time of discharge.In general,the patient suffered from septic shock,cardiogenic shock,combined with DIC and multiple organ dysfunction.After infection source control,antimicrobial therapy,uterine curettage,blood purification treatment,nutritional and metabolic support,the patient was dis-charged with a better health condition.

The incidence and mortality of venous thromboembolism (VTE) are high in critically ill patients, and there is still a risk of VTE and bleeding after the use of fixed-dose low molecular weight heparin (LMWH) for prophylaxis. The level of anti-factor Ⅹa is not up to standard after LMWH prophylaxis in patients with surgery or trauma. The condition of critically ill patients is complicated, and the proportion of patients with low antithrombin Ⅲ is high, which can affect the prophylactic efficacy of LMWH and contribute to VTE occurrence. There is currently no consensus on whether adjusting LMWH dose according to anti-factor Ⅹa levels can reduce VTE occurrence in critically ill patients. High-quality multicenter randomized controlled studies are needed in the future to establish new approaches for precise prevention of VTE in critically ill patients.

Venous thromboembolism(VTE)includes deep venous thrombosis(DVT)and pulmonary embolism(PE).Patients in intensive care unit(ICU)are often at a high risk of VTE due to combining many risk factors.Prevention strategies of VTE in critically ill patients are crucial,including identification of risk factors,the risk as-sessment of thrombosis and bleeding,mechanical prophylaxis and drug prophylaxis,effect monitoring,and quality control.Since the risk of VTE in ICU patients is high,the risk of bleeding should not be ignored.It is a challenge for ICU physicians to comprehensively evaluate the risk of thrombosis and bleeding in critically ill patients and im-plement effective preventive and monitoring measures in time.This article reviews the relevant research progress on prevention strategies of VTE in critically ill patients in order to provide clinical evidence for the prophylaxis of VTE in critically ill patients.

Objective:To investigate the safety and therapeutic effect of split liver transplantation (SLT) in clinical application.Methods:This is a retrospective case-series study. The clinical data of 203 consecutive SLT, 79 living donor liver transplantation (LDLT) and 1 298 whole liver transplantation (WLT) performed at the Third Affiliated Hospital of Sun Yat-sen University from July 2014 to July 2023 were retrospectively analyzed. Two hundred and three SLT liver grafts were obtained from 109 donors. One hundred and twenty-seven grafts were generated by in vitro splitting and 76 grafts were generated by in vivo splitting. There were 90 adult recipients and 113 pediatric recipients. According to time, SLT patients were divided into two groups: the early SLT group (40 cases, from July 2014 to December 2017) and the mature SLT technology group (163 cases, from January 2018 to July 2023). The survival of each group was analyzed and the main factors affecting the survival rate of SLT were analyzed. The Kaplan-Meier method and Log-rank test were used for survival analysis.Results:The cumulative survival rates at 1-, 3-, and 5-year were 74.58%, 71.47%, and 71.47% in the early SLT group, and 88.03%, 87.23%, and 87.23% in the mature SLT group, respectively. Survival rates in the mature SLT group were significantly higher than those in the early SLT group ( χ2=5.560, P=0.018). The cumulative survival rates at 1-, 3- and 5-year were 93.41%, 93.41%, 89.95% in the LDLT group and 87.38%, 81.98%, 77.04% in the WLT group, respectively. There was no significant difference among the mature SLT group, the LDLT group and the WLT group ( χ2=4.016, P=0.134). Abdominal hemorrhage, infection, primary liver graft nonfunction,and portal vein thrombosis were the main causes of early postoperative death. Conclusion:SLT can achieve results comparable to those of WLT and LDLT in mature technology liver transplant centers, but it needs to go through a certain time learning curve.

Objective:To investigate the safety and therapeutic effect of split liver transplantation (SLT) in clinical application.Methods:This is a retrospective case-series study. The clinical data of 203 consecutive SLT, 79 living donor liver transplantation (LDLT) and 1 298 whole liver transplantation (WLT) performed at the Third Affiliated Hospital of Sun Yat-sen University from July 2014 to July 2023 were retrospectively analyzed. Two hundred and three SLT liver grafts were obtained from 109 donors. One hundred and twenty-seven grafts were generated by in vitro splitting and 76 grafts were generated by in vivo splitting. There were 90 adult recipients and 113 pediatric recipients. According to time, SLT patients were divided into two groups: the early SLT group (40 cases, from July 2014 to December 2017) and the mature SLT technology group (163 cases, from January 2018 to July 2023). The survival of each group was analyzed and the main factors affecting the survival rate of SLT were analyzed. The Kaplan-Meier method and Log-rank test were used for survival analysis.Results:The cumulative survival rates at 1-, 3-, and 5-year were 74.58%, 71.47%, and 71.47% in the early SLT group, and 88.03%, 87.23%, and 87.23% in the mature SLT group, respectively. Survival rates in the mature SLT group were significantly higher than those in the early SLT group ( χ2=5.560, P=0.018). The cumulative survival rates at 1-, 3- and 5-year were 93.41%, 93.41%, 89.95% in the LDLT group and 87.38%, 81.98%, 77.04% in the WLT group, respectively. There was no significant difference among the mature SLT group, the LDLT group and the WLT group ( χ2=4.016, P=0.134). Abdominal hemorrhage, infection, primary liver graft nonfunction,and portal vein thrombosis were the main causes of early postoperative death. Conclusion:SLT can achieve results comparable to those of WLT and LDLT in mature technology liver transplant centers, but it needs to go through a certain time learning curve.