Aim To investigate whether protein inhibitor of activated STAT3(PIAS3)deficiency exacerbates the occurrence and development of atherosclerosis(As)in female ApoE knockout mice.Methods PIAS3 gene knockout mice with ApoE-/-background(PIAS3-/-/ApoE-/-)and their littermate PIAS3+/+/ApoE-/-mice were bred and fed with a high-fat/high-cholesterol diet for 12 weeks to induce As.Body weight(every week)and plasma lipid levels including to-tal cholesterol,triglyceride,high density lipoprotein cholesterol and non-high density lipoprotein cholesterol(every 4 weeks)of the mice were measured.Oil red O staining,HE staining,immunohistochemistry staining and immunofluores-cence staining were performed on mouse aortic tree and frozen sections of aortic root to evaluate the area,cellular composi-tion and stability of As plaques.Moreover,the expression of estrogen receptor α(ERα)and its co-localization with vas-cular smooth muscle cells(VSMC)in plaques were determined by immunofluorescence staining.Results Compared with PIAS3+/+/ApoE-/-mice,PIAS3-/-/ApoE-/-mice showed no significant differences in body weight,major organ weight(heart,liver,spleen,kidney and epididymal fat)and plasma lipid levels;however,PIAS3 deficiency promoted the forma-tion of As in female PIAS3-/-/ApoE-/-mice.Compared with PIAS3+/+/ApoE-/-mice,PIAS3-/-/ApoE-/-mice showed an increased lipid accumulation and a decreased VSMC content in As plaques(P＜0.05),leading to a decrease in plaque stability.In addition,the expression of ERα in the As plaques of PIAS3-/-/ApoE-/-mice was significantly downregulated(P＜0.05),and there was a obvious co-localization between ERα and VSMC.The reduction of VSMC content in PIAS3-/-/ApoE-/-mouse plaques might lead to a decrease of ERα expression,thereby weakening the anti-As effect of es-trogen.Conclusion PIAS3 deficiency exacerbates the formation of As plaques in female PIAS3-/-/ApoE-/-mice,which might be due to the regulatory effect of PIAS3 on ERα expression in plaques.

Aim To investigate whether protein inhibitor of activated STAT3(PIAS3)deficiency exacerbates the occurrence and development of atherosclerosis(As)in female ApoE knockout mice.Methods PIAS3 gene knockout mice with ApoE-/-background(PIAS3-/-/ApoE-/-)and their littermate PIAS3+/+/ApoE-/-mice were bred and fed with a high-fat/high-cholesterol diet for 12 weeks to induce As.Body weight(every week)and plasma lipid levels including to-tal cholesterol,triglyceride,high density lipoprotein cholesterol and non-high density lipoprotein cholesterol(every 4 weeks)of the mice were measured.Oil red O staining,HE staining,immunohistochemistry staining and immunofluores-cence staining were performed on mouse aortic tree and frozen sections of aortic root to evaluate the area,cellular composi-tion and stability of As plaques.Moreover,the expression of estrogen receptor α(ERα)and its co-localization with vas-cular smooth muscle cells(VSMC)in plaques were determined by immunofluorescence staining.Results Compared with PIAS3+/+/ApoE-/-mice,PIAS3-/-/ApoE-/-mice showed no significant differences in body weight,major organ weight(heart,liver,spleen,kidney and epididymal fat)and plasma lipid levels;however,PIAS3 deficiency promoted the forma-tion of As in female PIAS3-/-/ApoE-/-mice.Compared with PIAS3+/+/ApoE-/-mice,PIAS3-/-/ApoE-/-mice showed an increased lipid accumulation and a decreased VSMC content in As plaques(P＜0.05),leading to a decrease in plaque stability.In addition,the expression of ERα in the As plaques of PIAS3-/-/ApoE-/-mice was significantly downregulated(P＜0.05),and there was a obvious co-localization between ERα and VSMC.The reduction of VSMC content in PIAS3-/-/ApoE-/-mouse plaques might lead to a decrease of ERα expression,thereby weakening the anti-As effect of es-trogen.Conclusion PIAS3 deficiency exacerbates the formation of As plaques in female PIAS3-/-/ApoE-/-mice,which might be due to the regulatory effect of PIAS3 on ERα expression in plaques.

The global incidence rate of cancer is increasing yearly,and chemotherapy-induced gastrointestinal mucosal injury has become a crucial factor affecting patients'therapeutic prognosis;however,there is currently a lack of effective therapeutic drugs to address this issue.There is thus an urgent need to establish more ideal animal models of chemotherapy-induced gastrointestinal mucosal injury,to support the exploration of its pathogenesis and the development of therapeutic drugs.This review considered relevant literature published during the period from 2019 to 2024,to provide a comprehensive summary and analysis from several perspectives,including the selection of experimental animals,chemotherapeutic drugs and modeling method,evaluation indicators,and practical applications.Furthermore,we highlight several existing issues with current models,including the lack of standardized modeling method,insufficient research on models with a tumor background,and inadequate exploration of novel cell death mechanisms.This collation of the literature also revealed the gradual emergence of traditional Chinese medicine as a research hotspot,with potential for the treatment of gastrointestinal mucosal injury.Further studies of effective medicines are warranted to identify interventional strategies for chemotherapy-induced gastrointestinal mucosal injury.

The global incidence rate of cancer is increasing yearly,and chemotherapy-induced gastrointestinal mucosal injury has become a crucial factor affecting patients'therapeutic prognosis;however,there is currently a lack of effective therapeutic drugs to address this issue.There is thus an urgent need to establish more ideal animal models of chemotherapy-induced gastrointestinal mucosal injury,to support the exploration of its pathogenesis and the development of therapeutic drugs.This review considered relevant literature published during the period from 2019 to 2024,to provide a comprehensive summary and analysis from several perspectives,including the selection of experimental animals,chemotherapeutic drugs and modeling method,evaluation indicators,and practical applications.Furthermore,we highlight several existing issues with current models,including the lack of standardized modeling method,insufficient research on models with a tumor background,and inadequate exploration of novel cell death mechanisms.This collation of the literature also revealed the gradual emergence of traditional Chinese medicine as a research hotspot,with potential for the treatment of gastrointestinal mucosal injury.Further studies of effective medicines are warranted to identify interventional strategies for chemotherapy-induced gastrointestinal mucosal injury.

ObjectiveThe antitumor activity of sesquiterpenoid M36 isolated from Myrrha against human hepatoma HepG2 cells was investigated in this study. MethodHepG2 cells were treated with M36 at different concentrations （0， 2， 4， 6， 8， 10 μmol·L^-1）. Firstly， the effects of M36 on the proliferation of human hepatoma HepG2 cells were detected by methyl thiazolyl tetrazolium （MTT）， colony formation assay， and EdU proliferation assay. Hoechst staining， flow cytometry analysis， and Western blot were used to explore the effect of M36 on the apoptosis of human hepatoma HepG2 cells. Acridine orange staining and western blotting were used to examine the effect of M36 on autophagy in HepG2 cells. Finally， Western blot was used to detect protein expression of cancer-related signaling pathways. ResultCompared with the blank group， M36 treatment significantly inhibited the proliferation of human hepatoma HepG2 cells （P<0.01）， and the half inhibitory concentration （IC₅₀） value of M36 for 48 h was 5.03 μmol·L^-1， in a dose- and time-dependent manner. M36 was also able to induce apoptosis and autophagy in human hepatoma HepG2 cells. After treatment with 8 μmol·L^-1 M36 for 48 hours， the apoptosis rate of HepG2 cells was （42.03±9.65）% （P<0.01）. Compared with the blank group， HepG2 cells treated with 4 and 8 μmol·L^-1 M36 for 48 h had a significant increase in cleaved poly ADP-ribose polymerase （cleaved-PARP） protein levels （P<0.01）. Acridine orange staining showed that autophagy was significantly activated in HepG2 cells treated with 4 and 8 μmol·L^-1 M36 for 48 h compared with the blank group （P<0.01）， which was further verified by the up-regulation of microtubule-associated protein 1 light chain 3 Ⅱ （LC3 Ⅱ）. Western blot results showed that compared with the blank group， the levels of phosphorylated extracellular regulated protein kinase （p-ERK）， phosphorylated p38 mitogen-activated protein kinase （p-p38 MAPK）， phosphorylated c-Jun N-terminal kinase （p-JNK）， and its downstream nuclear transcription factors c-Jun and p-c-Jun protein were significantly increased in M36 group （P<0.05， P<0.01）. The mechanism may be related to the up-regulation of MAPK signaling pathway. ConclusionThe sesquiterpenoid M36 isolated from Myrrha inhibits the proliferation of human hepatoma HepG2 cells and promotes apoptosis and autophagy， which may be related to the activation of the MAPK signaling pathway.

Objective To evaluate the bioequivalence of two formulations of minocycline hydrochloride capsules administered orally after fasting administration and fed administration.Methods An open-label,randomized,two-period,self-crossover design was employed to assess the bioequivalence study.Twenty-eight healthy subjects were enrolled in both fasting and fed groups,with each period involving a single administration of either the reference formulation or the test formulation of 50 mg,separated by a washout period of 7 days.The concentration of minocycline in human plasma was determined by HPLC-MS/MS and was used for calculating pharmacokinetic parameters and evaluating the bioequivalence of the test formulation and reference formulation.Results After oral administration of test and reference formulations of minocycline under fasting condition,the Cmax Values of minocycline were(541±137)ng·mL-1 for the test formulation and(558±140)ng·mL-1for the reference formulation.The AUC0-t values were(8 347±1 986)h·ng·mL-1 for the test and(8 205±1 790)h·ng·mL-1 for the reference.The t1/2 values were(18.2±2.84)h for the test and(18.0±3.05)h for the reference.After oral administration of the test and reference formulations of minocycline under fed condition,the Cmax values of minocycline were(349±72.1)ng·mL-1 for the test and(352±73.2)ng·mL-1for the reference.The AUC0-twere(6 428±1 077)h·ng·mL-1 for the test and(6 588±1 118)h·ng·mL-1 for the reference.The t1/2values were(18.5±3.10)h for the test and(18.4±3.21)h for the reference.Under fasting condition,the 90% confidence intervals for the geometric mean ratios of Cmax,AUC0-t,and AUC0-∞ between the test and reference formulations were(90.84%,101.46% ),(95.2%,102.8% ),and(95.31%,102.71% ),respectively.Under fed conditions,the 90% confidence intervals for the geometric mean ratios of Cmax,AUC0-t,and AUC0-∞ between the test formulation and the reference formulation were(94.71%,103.42% ),(95.40%,99.83% ),and(95.79%,100.02% ),respectively.Conclusions Bioequivalence of the two minocycline formulations was demonstrated after fasting administration and fed administration in a healthy Chinese population.

Objective To investigate the differential metabolites of lymph node metastasis in pancreatic ductal carcinoma (PDAC) and provide new ideas for the pathogenesis, early diagnosis and treatment of metastatic pancreatic cancer. Methods Forty serum specimens of patients with pancreatic ductal carcinoma were collected and divided into lymph node metastasis group (18 cases) and non-metastasis group (22 cases). Thirty-one serum specimens were also collected from the healthy control group. Liquid chromatographytandem mass spectrometry was used to analyze the differential metabolites and metabolic pathways between patients with PDAC and healthy controls as well as between lymph node metastasis and non-metastasis groups. Results Principal component analysis and partial least squares-discriminant analysis revealed statistically significant differences in metabolites and metabolic pathways between patients with PDAC and the healthy controls and between lymph node metastasis and non-metastasis groups. The differences in profiles were also statistically significant. Seventy-six different metabolites and 11 metabolic pathways were screened between patients with PDAC and the healthy controls, among which phenylalanine metabolism and histidine metabolism were the two most influential metabolic pathways. Four different metabolites were screened between lymph node metastasis and non-metastasis groups, and the expression of ethopropazine and phenylalanine were upregulated but the expression of tetrahydrodeoxycorticosterone and oxprenolol were downregulated. Conclusion Metabolites are significantly altered in the lymph node metastasis group of patients with PDAC compared with the non-metastasis group. Ethopropazine, phenylalanine, tetrahydrodeoxy corticosterone, and oxprenolol are potential biomarkers of lymph node metastasis in patients with PDAC.

Drastic surges in intracellular reactive oxygen species (ROS) induce cell apoptosis, while most chemotherapy drugs lead to the accumulation of ROS. Here, we constructed an organic compound, arsenical N-‍(4-(1,3,2-dithiarsinan-2-yl)phenyl)acrylamide (AAZ2), which could prompt the ROS to trigger mitochondrial-dependent apoptosis in gastric cancer (GC). Mechanistically, by targeting pyruvate dehydrogenase kinase 1 (PDK1), AAZ2 caused metabolism alteration and the imbalance of redox homeostasis, followed by the inhibition of phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway and leading to the activation of B-cell lymphoma 2 (Bcl2)/Bcl2-associated X (Bax)/caspase-9 (Cas9)/Cas3 cascades. Importantly, our in vivo data demonstrated that AAZ2 could inhibit the growth of GC xenograft. Overall, our data suggested that AAZ2 could contribute to metabolic abnormalities, leading to mitochondrial-dependent apoptosis by targeting PDK1 in GC.
Humans ; Signal Transduction ; Stomach Neoplasms/drug therapy* ; Reactive Oxygen Species/metabolism* ; Proto-Oncogene Proteins c-akt/metabolism* ; Apoptosis ; Proto-Oncogene Proteins c-bcl-2 ; Cell Line, Tumor

【Objective】 To study the annual financial expenditure in blood stations with different scales, and to establish the regression equation between blood collection units and total expenditure. 【Methods】 The annual total expenditure, the per capita cost of serving population, as well as the collection units of whole blood and apheresis platelet of 24 blood stations were collected. The financial expenditure required for collecting 10 000U blood was calculated.The statistical analysis was carried out with SPSS statistical software. 【Results】 From 2017 to 2020, the total annual financial expenditure of 24 blood stations showed an upward trend. The total expenditure among blood stations was different. The per capita cost of servicing population in the areas where the 24 blood stations were located had been increasing year by year. The 24 blood stations were divided into two grades according to the blood collection volume as 50 000 U, and the relationship equation between the blood collection volume and the annual total expenditure had been established. After testing, each equation was effective(P<0.05); There was no difference in the financial expenditure required for collecting 10 000U blood among blood stations with different scales. 【Conclusion】 From 2017 to 2020, the blood stations with an annual collection volume more than 50 000 U demonstrated a higher financial expenditure and the per capita cost of serving population than those <50 000 U. The blood collection volume of blood stations is significantly correlated with the annual total expenditure and the per capita cost of serving population.

Objective:This study aims to explore the pathogenic roles of protein S-nitrosylation modification in the development of severe acute pancreatitis, and provide new insights into the molecular mechanisms driving acute pancreatitis development.Methods:Thirty two Sprague Dawley (SD) rats were randomly divided into sham operation group, mild acute pancreatitis (MAP) group, severe acute pancreatitis (SAP) group and SAP + N-nitro-L-arginine methyl ester (L-NAME) group (treated with nitric oxide synthase inhibitor), 8 rats in each group. All rats were sacrificed to take blood from heart and pancreatic tissues 24 h after model construction. Total protein S-nitrosylation modification level in pancreatic tissues was quantitated by the biotin-switch method, followed by histological evaluation via hematoxylin and eosin (HE) staining. The serum endotoxin, D-lactic acid, diamine oxidase, interleukin-6 and tumor necrosis factor-ɑ(TNF-ɑ), amylase, alanine aminotransferase, urea nitrogen and calcium ions in rat were detected. Pearson correlation analysis was used to analyze the correlation between each index and protein S-nitrosylation.Results:Compared with the sham operation group, the modification level of protein S-nitrosylation in pancreatic tissue of MAP group increased significantly ( P<0.05); Compared with MAP group, the modification level of protein S-nitrosylation in pancreatic tissue of SAP group increased significantly ( P<0.05); Compared with SAP group, the modification level of protein S-nitrosylation in pancreatic tissue of SAP + L-NAME group decreased significantly ( P<0.05). HE staining showed that the degree of pancreatic necrosis and inflammatory cell infiltration in SAP + L-NAME group were significantly weaker than those in SAP group. The concentrations of serum endotoxin, diamine oxidase, D-lactic acid, IL-6 and TNF-ɑ, amylase, alanine aminotransferase, and urea nitrogen in the MAP group were significantly higher than those in the sham operation group (all P<0.05); The above indexes in SAP group were significantly higher than those in MAP group and sham operation group (all P<0.05); The above indexes in SAP + L-NAME group were significantly lower than those in SAP group (all P<0.05). The serum IL-6 and TNF-ɑ levels in rats with acute pancreatitis were positively correlated with protein S-nitrosylation in pancreatic tissue (all P<0.05). Conclusions:Protein S-nitrosylation modification plays essential roles in the development and progression of severe acute pancreatitis.