OBJECTIVE: To investigate the effects of sodium valproate (VPA) in inhibiting Erastin-induced ferroptosis in bone marrow mesenchymal stem cells (BMSCs) and its underlying mechanisms. METHODS: BMSCs were isolated from bone marrow of 8-week-old Spragur Dawley rats and identified [cell surface antigens CD90, CD44, and CD45 were analyzed by flow cytometry, and osteogenic and adipogenic differentiation abilities were assessed by alizarin red S (ARS) and oil red O staining, respectively]. Cells of passage 3 were used for the Erastin-induced ferroptosis model, with different concentrations of VPA for intervention. The optimal drug concentration was determined using the cell counting kit 8 assay. The experiment was divided into 4 groups: group A, cells were cultured in osteogenic induction medium for 24 hours; group B, cells were cultured in osteogenic induction medium containing optimal concentration Erastin for 24 hours; group C, cells were cultured in osteogenic induction medium containing optimal concentration Erastin and VPA for 24 hours; group D, cells were cultured in osteogenic induction medium containing optimal concentration Erastin and VPA, and 8 μmol/L EX527 for 24 hours. The mitochondrial state of the cells was evaluated, including the levels of malondialdehyde (MDA), glutathione (GSH), and reactive oxygen species (ROS). Osteogenic capacity was assessed by alkaline phosphatase (ALP) activity and ARS staining. Western blot analysis was performed to detect the expressions of osteogenic-related proteins [Runt-related transcription factor 2 (RUNX2) and osteopontin (OPN)], ferroptosis-related proteins [glutathione peroxidase 4 (GPX4), ferritin heavy chain 1 (FTH1), and solute carrier family 7 member 11 (SLC7A11)], and pathway-related proteins [adenosine monophosphate-activated protein kinase (AMPK) and Sirtuin 1 (SIRT1)]. RESULTS: The cultured cells were identified as BMSCs. VPA inhibited Erastin-induced ferroptosis and the decline of osteogenic ability in BMSCs, acting through the activation of the AMPK/SIRT1 pathway. VPA significantly reduced the levels of ROS and MDA in Erastin-treated BMSCs and significantly increased GSH levels. Additionally, the expression levels of ferroptosis-related proteins (GPX4, FTH1, and SLC7A11) significantly decreased. VPA also upregulated the expressions of osteogenic-related proteins (RUNX2 and OPN), enhanced mineralization and osteogenic differentiation, and increased the expressions of pathway-related proteins (AMPK and SIRT1). These effects could be reversed by the SIRT1 inhibitor EX527. CONCLUSION VPA inhibits ferroptosis in BMSCs through the AMPK/SIRT1 axis and promotes osteogenesis.
Mesenchymal Stem Cells/metabolism* ; Ferroptosis/drug effects* ; Animals ; Valproic Acid/pharmacology* ; Rats ; Rats, Sprague-Dawley ; Sirtuin 1/metabolism* ; Cell Differentiation/drug effects* ; Cells, Cultured ; AMP-Activated Protein Kinases/metabolism* ; Osteogenesis/drug effects* ; Piperazines/pharmacology* ; Bone Marrow Cells/cytology* ; Reactive Oxygen Species/metabolism* ; Signal Transduction/drug effects*

This study aimed to comprehensively examine the association of gallstones, cholecystectomy, and cancer risk. Multivariable logistic regressions were performed to estimate the observational associations of gallstones and cholecystectomy with cancer risk, using data from a nationwide cohort involving 239 799 participants. General and gender-specific two-sample Mendelian randomization (MR) analysis was further conducted to assess the causalities of the observed associations. Observationally, a history of gallstones without cholecystectomy was associated with a high risk of stomach cancer (adjusted odds ratio (aOR)=2.54, 95% confidence interval (CI) 1.50-4.28), liver and bile duct cancer (aOR=2.46, 95% CI 1.17-5.16), kidney cancer (aOR=2.04, 95% CI 1.05-3.94), and bladder cancer (aOR=2.23, 95% CI 1.01-5.13) in the general population, as well as cervical cancer (aOR=1.69, 95% CI 1.12-2.56) in women. Moreover, cholecystectomy was associated with high odds of stomach cancer (aOR=2.41, 95% CI 1.29-4.49), colorectal cancer (aOR=1.83, 95% CI 1.18-2.85), and cancer of liver and bile duct (aOR=2.58, 95% CI 1.11-6.02). MR analysis only supported the causal effect of gallstones on stomach, liver and bile duct, kidney, and bladder cancer. This study added evidence to the causal effect of gallstones on stomach, liver and bile duct, kidney, and bladder cancer, highlighting the importance of cancer screening in individuals with gallstones.
Humans ; Mendelian Randomization Analysis ; Gallstones/complications* ; Female ; Male ; Cholecystectomy/statistics & numerical data* ; Middle Aged ; Risk Factors ; Aged ; Adult ; Neoplasms/etiology* ; Stomach Neoplasms/epidemiology*

Gap junction proteins have a significant impact on the propagation of neuroinflammation after cerebral ischemia.Connexin 43(Cx43),the principal connexin in the central nervous system,typically assembles hexameric hemichannels in an oligomeric state that dock with hemichannels on adjacent cells to form gap junction channels.Ordinarily,the likelihood of cell surface hemichannels opening is minimal.However,during cerebral ischemia,the excessive activation of Cx43 hemichannels leads to the liberation of a substantial quantity of ions(Na+,Cl-,Ca2+,and K+),glutamate,aspartate,and adenosine triphosphate(ATP),thereby resulting in impairment of adjacent cells and aggravation of neuronal injury.Furthermore,the activation of Cx43 hemichannels triggers the release of inflammatory factors,which exhibits a strong association with the activation of NLRP3 inflammasome after cerebral ischemia.Hence,the modulation of Cx43 hemichannels presents a potential avenue for mitigating neuroinflammation and subsequently diminishing cerebral ischemic injury.This article focuses on the relationship between Cx43 hemichannels and NLRP3 inflammasome activation,as well as its role in cerebral ischemia,all of which provide novel insights and therapeutic approaches for managing cerebral ischemia.

Objective To explore the effects of M1 polarization of microglia on secondary damage in the thalamus after cerebral cortical infarction.Methods A focal cortical infarct model of adult male SD rats was pre-pared using eletrocoagulation and randomized into Sham and model groups at different time points 1～4 weeks after surgery.Based on the assessment of neurofunctional changes in each group of rats,immunohistochemistry was used to observe the number and morphology of NeuN,GFAP and Iba-1 positive cells in(Ventral posterior nucleus of thalamus,VPN)of the ipsilateral thalamus after distal middle cerebral artery occlusion(dMCAO).Immunofures-cence was used to detect the number and morphology of M1 microglia marker(Iba-1+/CD68+cells)and M2 microg-lia marker(Iba-1+/CD206+cells)in VPN of the ipsilateral thalamus after dMCAO.Western blot was used to detect the expression levels of IL-1β,TNF-α,IL-10 and Arg-1 in VPN of the ipsilateral thalamus after dMCAO.Results The results of immunohistochemistry showed a significant decrease in NeuN positive cells and an increase in the density of GFAP and Iba-1 in the ipsilateral VPN of rats after dMCAO when compared with Sham group(P<0.001).Compared with sham group,the protein levels of TNF α and IL-1β were elevated in the ipsilateral VPN elevated(P<0.05).In addition,the model group rats exhibited higher Bederson scores,beam-walking test and adhesive removal test scores after dMCAO compared with Sham group(P<0.05).The numbers of M1 microglia marker(Iba-1+/CD68+cells)were significantly increased when compared with M2 microglia marker(Iba-1+/CD206+cells)in ipsilateral VPN of rats after dMCAO.Conclusion M1 polarization of microglia may play an essential role in secondary damage of thalamus after cerebral cortical infarction.

As the main water channel expressed in the brain,aquaporin 4(AQP4)has been implicated in the pathological process of ischemic stroke.After ischemic stroke,the expression,phosphorylation and polarity distribution of AQP4 are affected by the process of transcription and post-translational modification.The paper summarized the basic structure,physiological function,dynamic expression changes and mechanisms of AQP4 in this review,specifically discussing the role of AQP4 in cerebral edema,blood-brain barrier permeability and neuroinflammation after ischemic stroke,offering an up-to-date perspective on further effective therapeutic strategies for ischemic stroke.

Objective:To investigate the efficacy of mFOLFOX7 regimen systemic chemo-therapy combined with camrelizumab and apatinib for hepatocellular carcinoma (HCC) with Vp4 portal vain tumor thrombus (PVTT).Methods:The single-arm, open, exploratory clinical study was conducted. The clinicopathological data of 15 HCC patients with Vp4 PVTT who were admitted to the Sun Yat-sen Memorial Hospital of Sun Yat-sen University from April 2021 to October 2023 were collected. There were 14 males and 1 female, aged 48(range, 33-67)years. All patients underwent treatment with mFOLFOX7 regimen combined with camrelizumab and apatinib. Observa-tion indicators: (1) clinical efficacy; (2) survival of patients. Measurement data with skewed distribution were represented as M(rang), and count data were described as absolute numbers or percentages. Results:(1) Clinical efficacy. All 15 patients underwent treatment with mFOLFOX7 regimen combined with camrelizumab and apatinib. According to the response evaluation criteria in solid tumors version 1.1, the ratio of objective response, ratio of complete response, ratio of partial response, ratio of disease control, median progression free survival time and median total survival time of the 15 patients were 10/15, 1/15, 9/15, 15/15, not reached and not reached. The median progression free survival time and median total survival time were both >9 months. According to the modified response evaluation criteria in solid tumors, the ratio of objective response, ratio of complete response, ratio of partial response, ratio of disease control, median progression free survival time and median total survival time of the 15 patients were 12/15, 6/15, 6/15, 15/15, not reached and not reached. The median progression free survival time and median total survival time were both >9 months. Of the 15 patients, 7 cases were successfully treated with conversion therapy with the surgical conversion rate as 7/15, and all of them achieved R 0 resection. The other 6 cases were failed in conversion therapy, and there were 2 cases still undergoing conversion therapy. Of the 7 patients with successful conver-sion therapy, 5 cases achieved complete pathological remission, 1 case achieved major pathological remission with 90% of tumor tissue necrosis, and 1 case achieved complete remission through imaging examination, but new liver lesions appeared in multiple locations during further observation which were surgically removed. Results of histopathology examination on the patient confirmed multiple liver metastases. The proportion of treatment-associated adverse reactions in 15 patients was 13/15, with 7/15 having ≥grade 3 adverse reactions, including diarrhea (3/15), neutropenia (2/15), thrombo-cytopenia (2/15), and elevated aspartate aminotransferase (2/15). One patient may experience ≥1 adverse reaction. All patients were improved after symptomatic treatment. (2) Survival of patients. All 15 patients were followed up for 13.0(range, 2.0-31.0)months. During the follow-up period, 3 patients died. One case died of upper gastrointestinal bleeding after achieving partial remission, with a survival time of 7.5 months. One case died of multiple liver metastases of tumor, with tumors accounting for over 70% volume of liver and a survival time of 9.5 months. One case with multiple liver tumors and bilateral lung metastasis died due to disease progression after achieving partial remission, with a survival time of 13.5 months. The postoperative follow-up time for 7 patients undergoing surgical treatment was 14.0(range, 2.0-25.0)months. Of the 7 patients, 1 case experien-ced tumor recurrence 20.0 months after surgery, and 6 cases had no recurrence at last time of the follow-up (3 cases completed treatment and entered follow-up observation). The longest survival time was 31.0 months. Conclusion:The mFOLFOX7 regimen systemic chemotherapy combined with camrelizumab and apatinib for HCC with Vp4 PVTT is safe and feasible.

Objective To observe the effects of repeated intravitreal injections of ranibizumab and aflibercept on cor-neal morphology of patients with neovascular age-related macular degeneration(nAMD),diabetic macular edema(DME)or retinal vein obstruction(RVO).Methods In this prospective study,64 patients(64 eyes)who underwent therapy in the injection center of the Ophthalmology Department of our hospital from June 2021 to June 2022 were enrolled,including 19 nAMD patients,20 DME patients and 25 RVO patients.Among these patients,29 were treated with aflibercept(40 g·L-1)and 35 were treated with ranibizumab(10 g·L-1).Monocular injections were adopted for all patients,and 3+pro re nata(PRN)therapy was used.Confocal microscope was used for corneal nerve examination,and corneal endo-thelial microscope was used to measure corneal thickness(CT)and corneal endothelial cells.The CT,corneal endothelial cell density(ECD),coefficient of variation(CV),average cell size(ACS),proportion of hexagonal cells(Hex％),cor-neal nerve fiber length(CNFL),corneal nerve fiber density(CNFD)of patients with nAMD,DME and RVO after repeated intravitreal injections of anti-vascular endothelial growth factor(VEGF)drugs were compared,and those parameters at 1 month after injection of different anti-VEGF drugs were compared with the baseline.Results Before injection,ECD in the DME group was lower than that in the nAMD and RVO groups,and the ACS in the DME group was higher than that in the nAMD and RVO groups(all P＜0.05).There was no significant difference in the other indexes among the three groups(all P＞0.05).After 3 injections of anti-VEGF drugs,the ECD in the DME group was lower than that in the nAMD and RVO groups,the ACS in the DME group was higher than that in the nAMD and RVO groups,and the CNFL in the DME group was lower than that in the nAMD and RVO groups(all P＜0.05).The ECD decreased compared with that before injection from the 2nd injection of aflibercept in the nAMD group(all P＜0.05).Hex％decreased significantly after each injection compared with the baseline(all P＜0.05).Other indexes have no significant differences from the baseline(all P＞0.05).In the RVO group,ECD decreased from the 2nd ranibizumab injection compared with the baseline(all P＜0.05).Conclu-sion Repeated intravitreal injections of anti-VEGF drugs can reduce the Hex％and ECD to a certain extent.After injec-tions,CNFL in the DME group is significantly lower than that in the nAMD and RVO groups.

Obejective　To investigate and compare the clinical efficacy of aroma massage with traditional massage in the treatment of chronic fatigue syndrome （CFS）. MethodsSeventy-two CFS patients were randomized into the aroma massage group and the traditional massage group， with 36 patients in each group. Both groups were treated with essential oil aromatherapy and massage were performed on the head， face， and abdomen stimultaneously. The aroma massage group used antifatigue oil， while the traditional massage group used placebo essential oil. The two groups were treated for 30 minutes each time， once every other day， three times a week， for a total of 4 weeks. The fatigue scale （FS-14） score， traditional Chinese medicine （TCM） syndrome score and patient satisfaction evaluation scale score before and after the treatment of the two groups were assessed to study the improvement of fatigue and other clinical symptoms of the patients as well as the changes of the TCM symptom scores， and to evaluate the clinical efficacy of the two groups. ResultsWith three drop-outs in the traditional massage group and two drop-outs in the aroma massage group， 33 cases in the traditional massage group and 34 cases in the aroma massage group were included in the outcome analysis. The FS-14 scores and TCM syndrome scores significantly decreased after treatment in both groups （P＜0.01）； compared to those in the traditional massage group （FS-14： 4.42±2.44； TCM syndrome score： 34.12±7.67）， the FS-14 score （3.06±2.37） and TCM syndrome score （28.79±5.62） in the aroma massage group were significantly lower （P＜0.05 or P＜0.01）. There was no significant difference in the satisfaction scores of the patients in the two groups after the treatment （P＞0.05）. The total effective rate of the aroma massage group was 94.12% （32/34）， which was significantly higher than 84.85% （28/33） of the traditional massage group （P＜0.05）. ConclusionBoth aromatherapy and traditional massage can improve the clinical symptoms of fatigue in CFS patients， and aromatherapy is more effective， which is easy to operate with high patient acceptance.

Objective:To explore the influence of pancreatic stents of different lengths on the incidence of post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP).Methods:Data of 299 patients with biliary tract diseases who received endoscopic retrograde cholangiopancreatography (ERCP) and 5 Fr prophylactic pancreatic stents placement at the First Affiliated Hospital of Air Force Medical University from January 2013 to January 2022 were retrospectively analyzed. Patients were divided into the short-stent group (<5 cm, n=163) and the long-stent group (>5 cm, n=136). Baseline data, intraoperative procedures, and postoperative outcomes were compared between the two groups and propensity score matching (PSM) was used for complementary analysis. The primary endpoint was the incidence of PEP. The risk factors for PEP in patients with prophylactic pancreatic stents placement was explored by logistic regression analysis . Results:The overall PEP incidence was 11.0% (33/299). There was no significant difference in the PEP incidence [11.7% (19/163) VS 10.3% (14/136), χ 2=0.140, P=0.708], moderate-to-severe PEP incidence [1.8% (3/163) VS 2.2% (3/136), χ 2=0.000, P=1.000], or spontaneous stent dislodgement rate within two weeks [81.7% (103/126) VS 78.4% (87/111), χ 2=0.421, P=0.516] between the two groups. After PSM, 123 patients were included in each group, and the overall PEP incidence was 8.9% (22/246). There was no significant difference in PEP incidence [8.9% (11/123) VS 8.9% (11/123), χ 2=0.000, P=1.000], moderate-to-severe PEP incidence [0.8% (1/123) VS 1.6% (2/123), χ 2=0.000, P=1.000], or spontaneous stent dislodgement rate within two weeks [80.6% (75/93) VS 78.6% (77/98), χ 2=0.126, P=0.722] between the two groups. Logistic regression analysis showed that normal liver function ( OR=2.36, 95% CI:1.01-5.51, P=0.046) and failed bile duct cannulation ( OR=7.51, 95% CI:2.18-25.96, P=0.001) were independent risk factors for PEP in patients with biliary tract diseases who received prophylactic pancreatic stents placement. Conclusion:Longer 5 Fr pancreatic stents (>5 cm) do not further reduce the overall risk of PEP or moderate-to-severe PEP compared with 5Fr-5 cm stent. Normal liver function and failure of bile duct intubation were independent risk factors for PEP after prophylactic pancreatic stent placement in patients with biliary diseases.

Gastrointestinal tumors(GT)are characterized by both high malignancy and high mortality and have become the major diseases for prevention in the elderly.GT often present detectable changes, including bleeding and abnormal mucosal morphology.However, many technical difficulties remain in accurately monitoring the tumor itself and related abnormal lesions mentioned above, which are the key factors affecting the early detection rate of gastrointestinal tumors.In recent years, with progresses in artificial intelligence(AI)applications for digestive endoscopy image analysis, biosensors, new biomarkers and other areas, AI holds promise for the detection of bleeding, morphological and structural abnormalities of the mucosa, tumors and other major disorders.Here we review the progress of AI applications in geriatric digestive diseases affecting digestive organs and the mucosa in light of morphology and function, to provide a reference for reducing the incidence of both geriatric emergencies and GT.