BACKGROUND:Although vitamin C has an anti-oxidation role and can promote cell proliferation, there is a lack of research about the promoting effect of vitamin C on the proliferation of adipose-derived stem cells under high glucose conditions and the related molecular mechanisms.OBJECTIVE:To explore the promoting effect of vitamin C on the proliferation adipose-derived stem cells treated by the high glucose and the related molecular mechanisms.METHODS:Passage 3 human adipose-derived stem cells were cultured under high glucose conditions and then treated with different concentrations of vitamin C (0, 100, 150, 200, 250, 300 μmol/L). Cells cultured under low glucose conditions acted as controls. The expression levels of p-ERK and p-AKT proteins were detected by western blot. MTT method was used to choose the optimal concentration and time of vitamin C for all the subsequent tests. Human adipose-derived stem cells cultured under high glucose conditions were divided into four groups, and cells in blank control group had no treatment. Cells in the other three groups were treated with the optimal concentration of vitamin C (vitamin C group), LY294002+the optimal concentration of vitamin C (LY294002 group), or U0126+the optimal concentration of vitamin C (U0126 group) for 48 hours.EdU staining assay was used to detect the cell proliferation of human adipose-derived stem cells.RESULTS AND CONCLUSION:(1) Cell counting kit detection:We found that high glucose reduced the proliferation of human adipose-derived stem cells, and vitamin C promoted the proliferation of these cells. The best concentration of vitamin C was 200 μmol/L and the optimal effect time was 48 hours. (2) Western blot detection:Compared with the 0 μmol/L vitamin C group, the level of p-ERK in the 200 μmol/L vitamin C group was upregulated significantly (P < 0.01),while no significant expression change in p-AKT protein was found in control, 0 and 200 μmol/L vitamin C groups.(3) EdU test:the number of EdU positive cells was significantly higher in the vitamin C, LY294002, and control groups compared with the blank control group (P < 0.01). Moreover, compared with the vitamin C group, the EdU positive cells in the U0126 group were decreased significantly in number (P < 0.01). In conclusion, the ERK/MAPK signaling pathway is involved in the promotion effect of vitamin C on the proliferation of human adipose-derived stem cells under high glucose conditions.

Objective To explore the effect of NE/α1-AT on the pathogenesis of NASH and the adjustment function of berberine to the imbalance of NE/α1-A and the therapeutic action of berberine to NAFLD.Methods 8-week-old male C57BL/6JApoE/ mice (26),according to the weight assigned to the high-fat-high-cholesterol group (18) and standard chow group (8).HFHC group fed with high fat high cholesterol diet and normal water;the SC group fed with normal diet and drank normal water.After 8 weeks,the HFHC group divided into HFHC group and BBR group according to the weight,Berberine group with 200mg/kg/d berberine,the other two groups fed with the same volume of distilled water.12 weeks all mice were sacrificed.We detected body weight,live weight,live function and lipid metabolism.HE and oil red O staining were used to evaluate pathological changes.ELISA method was used to detect NE and α1-AT expression in mice live tissue;RT-PCR method was used to detect protein α1-AT mRNA expression in live tissue; Immunohistochemistry and Western Blotting were applied to determine expression of NE.Results Compared with the SC group at the end of 12 weeks,ALT,AST were significantly increased in HFHC group,TG was significantly higher than the SC group.Body weight and live weight of ApoE-/-mice fed with HFHC diet significantly higher than the SC group.HE staining showed obvious steatosis and inflammatory foci in HFHC group.The NAS score at the end of model establishment was 5-8 points,which reached the diagnostic criterion for NASH.The concentration and activity of NE in the SC group were significantly increased,and the level of α1-AT was decreased,which lead to ratio NE/α1-AT was significantly higher than the SC group.BBR in mice treated with HE staining showed inflammation ballooning lower than HFHC group.At week 12,ALT,AST of BBR group increased compared with the SC group,and significantly lower compared with the HFHC group.NE/α1-AT was significantly higher than the HFHC group.Conclusions 12 weeks of high fat and high cholesterol feeding,ApoE-/-mice can successfully establish the NASH mouse model;a marked change and contact exist between NE and α1-AT in the process of development of NASH; Berberine can reduce liver lipid deposition and the degree of inflammation in NASH mice,and can improve the NE/ alpha 1-AT imbalance.

Gefitinib is the well-tolerated first-line treatment of non-small cell lung cancer. As it needs analgesics during oncology treatment, particularly in the context of the coronavirus disease, where patients are more susceptible to contract high fever and sore throat.This has increased the likelihood of taking both gefitinib and antipyretic analgesic acetaminophen (APAP). Given that gefitinib and APAP overdose can predispose patients to liver injury or even acute liver failure, there is a risk of severe hepatotoxicity when these two drugs are used concomitantly. However, little is known regarding their safety at therapeutic doses. This study simulated the administration of gefitinib and APAP at clinically relevant doses in an animal model and confirmed that gefitinib in combination with APAP exhibited additional hepatotoxicity. We found that gefitinib plus APAP significantly exacerbated cell death, whereas each drug by itself had little or minor effect on hepatocyte survival. Mechanistically, combination of gefitinib and APAP induces hepatocyte death via the apoptotic pathway obviously. Reactive oxygen species (ROS) generation and DNA damage accumulation are involved in hepatocyte apoptosis. Gefitinib plus APAP also promotes the expression of Kelch-like ECH-associated protein 1 (Keap1) and downregulated the antioxidant factor, Nuclear factor erythroid 2-related factor 2 (Nrf2), by inhibiting p62 expression.Taken together, this study revealed the potential ROS-mediated apoptosis-dependent hepatotoxicity effect of the combination of gefitinib and APAP, in which the p62/Keap1/Nrf2 signaling pathway participates and plays an important regulatory role.

Gefitinib is the well-tolerated first-line treatment of non-small cell lung cancer. As it needs analgesics during oncology treatment, particularly in the context of the coronavirus disease, where patients are more susceptible to contract high fever and sore throat.This has increased the likelihood of taking both gefitinib and antipyretic analgesic acetaminophen (APAP). Given that gefitinib and APAP overdose can predispose patients to liver injury or even acute liver failure, there is a risk of severe hepatotoxicity when these two drugs are used concomitantly. However, little is known regarding their safety at therapeutic doses. This study simulated the administration of gefitinib and APAP at clinically relevant doses in an animal model and confirmed that gefitinib in combination with APAP exhibited additional hepatotoxicity. We found that gefitinib plus APAP significantly exacerbated cell death, whereas each drug by itself had little or minor effect on hepatocyte survival. Mechanistically, combination of gefitinib and APAP induces hepatocyte death via the apoptotic pathway obviously. Reactive oxygen species (ROS) generation and DNA damage accumulation are involved in hepatocyte apoptosis. Gefitinib plus APAP also promotes the expression of Kelch-like ECH-associated protein 1 (Keap1) and downregulated the antioxidant factor, Nuclear factor erythroid 2-related factor 2 (Nrf2), by inhibiting p62 expression.Taken together, this study revealed the potential ROS-mediated apoptosis-dependent hepatotoxicity effect of the combination of gefitinib and APAP, in which the p62/Keap1/Nrf2 signaling pathway participates and plays an important regulatory role.

Gefitinib is the well-tolerated first-line treatment of non-small cell lung cancer. As it needs analgesics during oncology treatment, particularly in the context of the coronavirus disease, where patients are more susceptible to contract high fever and sore throat.This has increased the likelihood of taking both gefitinib and antipyretic analgesic acetaminophen (APAP). Given that gefitinib and APAP overdose can predispose patients to liver injury or even acute liver failure, there is a risk of severe hepatotoxicity when these two drugs are used concomitantly. However, little is known regarding their safety at therapeutic doses. This study simulated the administration of gefitinib and APAP at clinically relevant doses in an animal model and confirmed that gefitinib in combination with APAP exhibited additional hepatotoxicity. We found that gefitinib plus APAP significantly exacerbated cell death, whereas each drug by itself had little or minor effect on hepatocyte survival. Mechanistically, combination of gefitinib and APAP induces hepatocyte death via the apoptotic pathway obviously. Reactive oxygen species (ROS) generation and DNA damage accumulation are involved in hepatocyte apoptosis. Gefitinib plus APAP also promotes the expression of Kelch-like ECH-associated protein 1 (Keap1) and downregulated the antioxidant factor, Nuclear factor erythroid 2-related factor 2 (Nrf2), by inhibiting p62 expression.Taken together, this study revealed the potential ROS-mediated apoptosis-dependent hepatotoxicity effect of the combination of gefitinib and APAP, in which the p62/Keap1/Nrf2 signaling pathway participates and plays an important regulatory role.

Gefitinib is the well-tolerated first-line treatment of non-small cell lung cancer. As it needs analgesics during oncology treatment, particularly in the context of the coronavirus disease, where patients are more susceptible to contract high fever and sore throat.This has increased the likelihood of taking both gefitinib and antipyretic analgesic acetaminophen (APAP). Given that gefitinib and APAP overdose can predispose patients to liver injury or even acute liver failure, there is a risk of severe hepatotoxicity when these two drugs are used concomitantly. However, little is known regarding their safety at therapeutic doses. This study simulated the administration of gefitinib and APAP at clinically relevant doses in an animal model and confirmed that gefitinib in combination with APAP exhibited additional hepatotoxicity. We found that gefitinib plus APAP significantly exacerbated cell death, whereas each drug by itself had little or minor effect on hepatocyte survival. Mechanistically, combination of gefitinib and APAP induces hepatocyte death via the apoptotic pathway obviously. Reactive oxygen species (ROS) generation and DNA damage accumulation are involved in hepatocyte apoptosis. Gefitinib plus APAP also promotes the expression of Kelch-like ECH-associated protein 1 (Keap1) and downregulated the antioxidant factor, Nuclear factor erythroid 2-related factor 2 (Nrf2), by inhibiting p62 expression.Taken together, this study revealed the potential ROS-mediated apoptosis-dependent hepatotoxicity effect of the combination of gefitinib and APAP, in which the p62/Keap1/Nrf2 signaling pathway participates and plays an important regulatory role.

Objective: We aimed, in our prospective study, to assess the predictive value of serum non-invasive and biochemical markers for clinical diagnosis of significant fibrosis (including early stages). Methods: We measured sH2a levels in serum, comparing with routine liver function markers. We compared blindly pretreatment serum samples from a cohort of hepatitis B patients without non-alcoholic fatty liver disease(NAFLD), which had histological grades of liver fibrosis, with NAFLD individuals and CHB with NAFLD patients. Statistical analysis was by Student′s t test, and receiver-operating characteristic (ROC) curves were drawn. Results: ROC curves showed that serum sH2a had greater diagnostic performance than routine liver function markers compared with histological grades of liver fibrosis(S0, S1-2, S3-4). ROC curves showed that using a sH2a cut-off point of 0.79 was with highest sensitivity as 63% and highest specificity as 80%. And sensitivity as 96.7% and specificity as 75.5% when using a sH2a cut-off point of 0.77. Conclusions sH2a has the potential to be a uniquely sensitive and specific novel marker for liver fibrosis and function.

Objective To investigate the correlation between the concentration of air pollutants (PM₁₀, SO₂, NO₂) and the number of outpatient and emergency visits for pediatric respiratory diseases in a general hospital in Shanghai. Methods Data including pediatric respiratory disease outpatient and emergency visits in a hospital in Pudong New Area of Shanghai from May 1, 2013 to March 20, 2022 were collected. Daily concentration of air pollutants including PM₁₀, SO₂ and NO₂ and meteorological data in Pudong New Area during the same period were collected. A case-crossover study with distributed lag non-linear model was conducted to explore the correlation between air pollutants (PM₁₀, SO₂, NO₂) and the number of outpatient and emergency visits for pediatric respiratory diseases. Results The concentrations of PM₁₀, SO₂ and NO₂ were positively with the number of outpatient and emergency visits for pediatric respiratory diseases. The strongest cumulative effect was observed on six days lag (Lag0-5) for PM₁₀. For a 10 μg/m³ increase of the concentrations of PM₁₀, the corresponding increase of cumulative pediatric respiratory disease outpatients was 1.10% (95%CI:0.97%, 1.23%) in Lag0-5. The strongest cumulative effect was observed on eight days lag (Lag0-7) for SO₂ and NO₂. For a 10 μg /m³ increase of the concentrations of SO₂ and NO₂, the corresponding increase of cumulative pediatric respiratory disease outpatients was 5.64% (95%CI:5.16%, 6.13%) and 5.41% (95%CI:5.15%, 5.66%) in Lag 0-7, respectively. The association of PM₁₀ and SO₂ with the number of pediatric respiratory disease visits in males was significantly stronger than that in females. The impact of PM₁₀ on the number of pediatric respiratory disease visits in children aged 0-6 was higher than that in children aged 7-14, while the impact of SO₂ and NO₂ on the number of pediatric respiratory disease visits in children aged 7-14 was higher than that in children aged 0-6. Conclusion The concentration of ambient PM₁₀, SO₂, and NO₂ is positively correlated with outpatient and emergency visits for pediatric respiratory diseases, with obvious lag and cumulative effect. Boys and children aged 0-6 are more susceptible to the hazard of air pollution.

Objective: To investigate the value of 1H-magnetic resonance spectroscopy (¹H-MRS) in determining the content of liver triglyceride in patients with fatty liver disease (FLD), as well as its influencing factors. Methods: A total of 124 patients with nonalcoholic fatty liver disease (NAFLD), chronic hepatitis B (CHB), or hepatitis B complicated by FLD who underwent liver biopsy in the Affiliated Hospital of Hangzhou Normal University were enrolled, and the clinical data, serological markers, FibroScan results, and ¹H-MRS results were collected. A correlation analysis was performed with the results of liver biopsy as the gold standard, and the influence of factors including hepatitic B virus (HBV) infection and obesity on accuracy was analyzed. A one-way analysis of variance was used for comparison of means between the three groups, and the LSD or SNK test (for homogeneity of variance) or the Tamhane’s or Dunnett’s test (heterogeneity of variance) was used for comparison between any two groups. The t-test was used for comparison of continuous data between groups, and the chi-square test was used for comparison of categorical data. The MRS-PDFF receiver operating characteristic (ROC) curve was plotted, the area under the ROC curve (AUC) was calculated, the optimal cut-off points for the diagnosis of NAFLD were estimated, and sensitivity and specificity were calculated. Results: The NAFLD group (42 patients) and the CHB + NAFLD group (40 patients) had a significantly higher proton density fat fraction (PDFF, the content of triglyceride in the liver) than the CHB group (42 patients) (16.84±9.76/9.39 ± 5.50 vs 3.45 ± 1.63, P < 0.001). The results were significantly correlated with the degree of steatosis confirmed by liver biopsy (P < 0.001), but it was not significantly correlated with inflammation or fibrosis grade. The correlation analysis showed that the MRS-PDFF value measured by 1H-MRS was significantly correlated with body mass index (BMI), blood lipids, alkaline phosphatase, and blood glucose, while it was not significantly correlated with age, sex, or the presence or absence of hepatitis B. The ROC curve analysis showed that the AUCs of PDFF measured by 1H-MRS were 0.93, 0.974, and 0.976, respectively, for the diagnosis of steatosis S1(≥5%), S2(≥34%), and S3(≥66%), and the corresponding optimal thresholds were 5.14%, 11.16%, and 16.7%, respectively. Conclusion 1H-MRS has a high diagnostic value in quantitative evaluation of the degree of liver steatosis in patients with FLD and is not affected by the factors such as HBV infection, age, and sex, while it is correlated with BMI and lipid metabolism.