Inhibitory interaction of flavonoids with organic anion transporter 3 and their structure-activity relationships for predicting nephroprotective effects.

The organic anion transporter 3 (OAT3), an important renal uptake transporter, is associated with drug-induced acute kidney injury (AKI). Screening and identifying potent OAT3 inhibitors with little toxicity in natural products, especially flavonoids, in reducing OAT3-mediated AKI is of great value. The five strongest OAT3 inhibitors from the 97 flavonoids markedly decreased aristolochic acid I-induced cytotoxicity and alleviated methotrexate-induced nephrotoxicity. The pharmacophore model clarified hydrogen bond acceptors and hydrophobic groups are the critical pharmacophores. These findings would provide valuable information in predicting the potential risks of flavonoid-containing food/herb-drug interactions and optimizing flavonoid structure to alleviate OAT3-related AKI.

[Chemical constituents from Paris rugosa rhizomes and their antimicrobial activities].

Paris rugosa(Melanthiaceae) only grows in Yunnan province of China at present, and its chemical constituents have not been systematically studied. In this study, nine compounds, including one new compound pariposide G(1) and eight known compounds of cerin(2), stigmast-4-en-3-one(3), ß-ecdysone(4), ophiopogonin C'(5), methyl protogracillin(6), gracillin(7), parissaponin H(8), and parisyunnanoside G(9), were isolated and identified from the ethanol extract of P. rugosa rhizomes by column chromatography methods and semi-preparative high-performance liquid chromatography(HPLC). Compounds 1-9 were isolated from this plant for the first time. The antibacterial and antifungal activities of all the compounds were evaluated. The results showed that ophiopogonin C' had strong inhibitory effects on Candida albicans [MIC_(90)=(4.68±0.01) µmol·L~(-1)] and the fluconazole-resistant strain of C. albicans [MIC_(90)=(4.66±0.02) µmol·L~(-1)].

Heterodimers with a cucurbitane-type triterpenoid skeleton from the branches of Elaeocarpus dubius.

Four undescribed and two known cucurbitane-type triterpenoids, including two heterodimers, elaeocarpudubins A and B, were isolated from the branches of Elaeocarpus dubius (Elaeocarpaceae). The chemical structures of these undescribed isolates were determined by analyses of 1D and 2D NMR and MS data, electronic circular dichroism (ECD) calculations, and chemical transformation. Biogenetically, elaeocarpudubins A and B might be derived from cucurbitacin F through Michael addition with vitamin C and (-)-catechin, respectively. These six isolates were evaluated for their cytotoxic activities against human leukemia HL-60, human lung adenocarcinoma A549, human hepatoma SMMC-7721, human breast cancer MCF-7, human colon cancer SW480, and paclitaxel-resistant A549 (A549/Taxol) cell lines, for their antioxidant properties using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging assay, and for their differentiation effects on nerve growth factor (NGF)-mediated neurite outgrowth in rat pheochromocytoma PC12 cells. Cucurbitacins F (IC50 of 4.98-38.11 µM) and D (IC50 of 0.03-4.40 µM) showed growth-inhibitory activities against these six cancer cell lines. Elaeocarpudubin B (IC50 of 61.04 µM) and elaeocarpudoside B (IC50 of 6.93 µM) showed antioxidant activities. Elaeocarpudubin B and elaeocarpudoside B also showed neurite outgrowth-promoting activities in PC12 cells at a concentration of 10 µM.

A Prospective Study of Using Chaihu Shugan Powder Combined with Zu San Li Acupoint Stimulation to Improve the Prognosis of Liver Stagnation and Qi Stagnation Syndrome in Acute Pancreatitis.

Background: This study aimed to explore the clinical efficacy of Chaihu Shugan powder combined with Zu San Li acupoint stimulation on the acute pancreatitis of liver and qi stagnation syndromes, the protection of intestinal barrier function, the prevention of severe tendency, and safety evaluation. Method: Data were collected from October 2019-June 2021 at Xinhua Hospital, which is affiliated with Shanghai Jiao Tong University School of Medicine, Emergency Department. Eighty patients with acute pancreatitis were randomly divided into a control treatment group (40 people) and a combined traditional Chinese medicine (TCM) treatment group (40 people). Detailed records of hospitalised patients were obtained, including the general situation of patients' clinical diagnosis and clinical examination before and after treatment. The changes in inflammatory and immune indexes before and after treatment were recorded. Result: Compared with the standard treatment group, the relief time of abdominal pain in the TCM treatment group was significantly shortened with statistically significant differences. Compared with the standard treatment group, the levels of WBC, ALT, CA, hemodiastase, lipase, TG, and other factors in the TCM treatment group decreased, whereas the levels of DB, SCR, cholesterol, K+, and other factors increased. The differences were statistically significant (P < 0.05). Conclusion: Chaihu Shugan powder combined with Zu San Li acupoint stimulation can reduce the clinical manifestations of liver and qi stagnation syndromes of acute pancreatitis, protect the intestinal barrier function, prevent the tendency of severe illness and improve the prognosis.

The influencing factors and prevention progress of motor complications of Parkinson's disease / 预防医学

Abstract@#Long-term use of levodopa in the treatment of Parkinson's disease can cause motor complications, which seriously impair the patients'motor function, reduce the quality of life, and aggravate the functional disability. Since there has been no effective treatment for motor complications, clarifying the influencing factors and prevention methods are conducive to reducing the risk of incidence and improving the quality of life of the patients. This paper summarizes the types and mechanism of motor complications of Parkinson's disease, the influencing factors ( levodopa dose, onset age, Helicobacter pylori infection and high protein diet ) and preventive measures ( psychological intervention, low protein diet, rehabilitation exercise and drugs ), so as to provide reference for the prevention and control of the disease.

Terpenes isolated from Polyalthia simiarum and their cytotoxic activities.

Two new C31 triterpenes, polysimiaric acid A (1) and B (2) as well as one new clerodane diterpenoid, 16,16-dimethoxy-cleroda-3,13Z-dien-15-oic acid (3), together with six known compounds were isolated from Polyalthia simiarum. Their structures were determined by analysis of 1D and 2D NMR data. Three new compounds were tested for their cytotoxicity against five human tumour cell lines. Compound 3 showed cytotoxic activities against SMMC-7721 with the IC50 value of 22.43 µM.

Two new bis-C20-diterpenoid alkaloids with anti-inflammation activity from Aconitum bulleyanum.

Two new bis-C20-diterpenoid alkaloids, bulleyanines A and B (1 and 2), were isolated from Aconitum bulleyanum. Their structures were elucidated by comprehensive spectroscopic analyses including UV, IR, MS, 1D and 2D NMR. Biological activity tests indicated that compound 1 exhibited significant inhibitory activity against nitric oxide (NO) production in lipopolysaccharide (LPS)-activated RAW264.7 macrophages with the inhibition rate of 74.60% (40 µmol/L), while positive control dexamethasone gave 78.70% inhibition at 100 µg/ml.

Fuzheng Huayu Recipe Ameliorates Liver Fibrosis by Restoring Balance between Epithelial-to-Mesenchymal Transition and Mesenchymal-to-Epithelial Transition in Hepatic Stellate Cells.

Activation of hepatic stellate cells (HSCs) depending on epithelial-to-mesenchymal transition (EMT) reflects the key event of liver fibrosis. Contrastively, mesenchymal-to-epithelial transition (MET) of HSCs facilitates the fibrosis resolution. Here we investigated the effect of Fuzheng Huayu (FZHY) recipe, a Chinese herbal decoction made of Radix Salviae Miltiorrhizae, Semen Persicae, Cordyceps sinensis, Pollen Pini, and Gynostemma pentaphyllum, on liver fibrosis concerning the balance of EMT and MET in HSCs. In contrast to the increased TGF-ß 1/BMP-7 ratio in activated HSCs, FZHY administration induced significant upregulation of BMP-7 and downregulation of TGF-ß 1 at both transcription and translation levels. Restoration of TGF-ß 1/BMP-7 ratio inhibited the expression of p38 MAPK and phosphorylated p38 MAPK, resulting in the reversal of epithelial-to-mesenchymal transition (EMT) to mesenchymal-to-epithelial transition (MET) as characterized by the abolishment of EMT markers (α-SMA and desmin) and reoccurrence of MET marker (E-cadherin). In vivo treatment of FZHY recipe also demonstrated the statistical reduction of activated HSCs with EMT phenotype, which attenuated the carbon tetrachloride- (CCl4-) induced liver fibrosis in a dose-dependent manner. These findings may highlight a novel antifibrotic role of FZHY recipe on the basis of rebalancing EMT and MET in HSCs.

High-saturate-fat diet delays initiation of diethylnitrosamine-induced hepatocellular carcinoma.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a risk factor for hepatocellular carcinoma (HCC), but the association between a high-fat diet (HFD) and HCC is not fully understood. In this study, we investigated whether a high-saturate-fat diet affects hepatocarcinogenesis induced by administration of diethylnitrosamine (DEN). METHODS: Adult SD rats were randomized into the following groups: normal chow diet (NCD), HFD, NCD + DEN, and HFD + DEN. The HFD contains 2% cholesterol and 10% lard oil. In mice with DEN treatment, the carcinogen was given via gavage. Mice were sacrificed at the end of 10, 12, and 14 weeks, respectively. The effects of HFD on hepatic carcinogenesis were assessed by HCC incidence, tumor differentiation, and the number and size of tumor nodules. Western blot and immunohistochemistry for proliferating cell nuclear antigen (PCNA), enzyme-linked immunosorbent assay (ELISA) for caspase-3, and real-time PCR for TNF-α and IL-6 further uncovered the proliferative and apoptotic properties of liver. RESULTS: In contrast to the NCD group, DEN treatment (NCD + DEN group) led to hepatitis, cirrhosis, hepatic tumor, and decreased body weight. Interestingly, HFD, which induced hyperlipidemia and hepatic steatosis, attenuated DEN-related malnutrition and fibrosis progression in HFD + DEN group during 10-14 weeks. Moreover, the HFD + DEN group exhibited that the proportion of well differentiated HCC was much higher than that of NCD + DEN group. The number and average volume of HCC node were also significantly lowered in HFD + DEN group (P < 0.01-0.05). When compared to that of NCD + DEN group, there was an inhibited expression of PCNA, TNF-α, and IL-6, and activation of caspase-3 in the liver of HFD + DEN group at week 10 and 12. CONCLUSIONS: HFD restores malnutrition in the DEN-treated rats, which in turn inhibits the initiation of hepatic carcinogenesis and malignancy.

NAFLD leads to liver cancer: do we have sufficient evidence?

Primary liver cancer has several well-recognized risk factors, such as HBV and HCV infection, alcohol abuse and aflatoxin. Recent studies show that nonalcoholic fatty liver disease (NAFLD), especially its aggressive form nonalcoholic steatohepatitis (NASH) is associated with an increased risk of liver cancer, mainly hepatocellular carcinoma (HCC). On the other hand, clinical and epidemiological data have showed that HCC has rarely been found in a "pure" fatty liver in human. Thus, the question we need to ask is do we have sufficient evidence to support a causative role of NAFLD in liver cancer? Furthermore, if NAFLD is indeed a causative factor for liver cancer, what is the mechanism? Perhaps at this stage, fatty liver and NASH can be regarded as a definite risk factor for liver cancer, but to conclude that NAFLD induces HCC requires more robust in vitro and in vivo data.

[Relationship between vitamin D and autism spectrum disorder].

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder, with multiple genetic and environmental risk factors. The interplay between genetic and environmental factors has become the subject of intensified research in the last several years. Vitamin D deficiency has recently been proposed as a possible environmental risk factor for ASD. Vitamin D has a unique role in brain homeostasis, embryogenesis and neurodevelopment, immunological modulation (including the brain's immune system), antioxidation, antiapoptosis, neural differentiation and gene regulation. Children with ASD had significantly lower serum levels of 25-hydroxy vitamin D than healthy children.Therefore vitamin D deficiency during pregnancy and early childhood may be an environmental trigger for ASD.

Fatty liver reduces hepatitis B virus replication in a genotype B hepatitis B virus transgenic mice model.

BACKGROUND AND AIM: Non-alcoholic fatty liver disease (NAFLD) overlapping with chronic hepatitis B virus (HBV) infection is undergoing a rapid increase in China. Therefore, the establishment and character of an animal model with both NAFLD and chronic HBV infection has become an urgent task. METHODS: Mice with chronic HBV genotype B infection were established with a microinjection of oocytes. Transgenic and nontransgenic mice were then randomized into groups of NAFLD + HBV, HBV, NAFLD, and control and were treated with high-fat diets or common forage. At 8, 16, and 24 weeks, characteristics of NAFLD were evaluated by physical indices, liver function tests, glycolipid metabolism, and histopathological scoring. Viral dynamics were also analyzed by HBV-DNA and HBV-related antigens. RESULTS: Hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) were expressed, and HBV-DNA was replicated in HBV transgenic mice at different stages in the serum and liver. Hepatic steatosis was only induced after exposure of the mice to high-fat diets, and no obvious pathological changes occurred in the HBV group from 8 to 24 weeks. Compared to mice with HBV alone, significant reductions in serum levels of HBV-DNA, HBsAg and HBeAg occurred in the NAFLD + HBV group after 24 weeks (all P < 0.05). Nevertheless, the NAFLD and NAFLD + HBV groups shared comparable physical and metabolic disorders and similar steatotic, inflammatory and fibrotic characteristics in the liver. CONCLUSION: High-fat diets and transgenic operations on the HBV genotype B induced a rodent model of NAFLD overlapping with chronic HBV infection, and this model reduces the HBV viral factors but not the metabolic and histologic features.

Clinical features of nonalcoholic fatty liver disease-associated hepatocellular carcinoma.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD), especially nonalcoholic steatohepatitis, is a recognized risk factor for hepatocellular carcinoma (HCC). However, detailed analysis of the clinical features in patients with NAFLD and their association with HCC is lacking. This study aimed to update the clinical features of patients with NAFLD-associated HCC. DATA SOURCES: The clinical data of patients with NAFLD-associated HCC from 25 studies published between 1990 and 2010 in the Pubmed database were comprehensively reviewed. RESULTS: In a total of 169 patients with NAFLD-associated HCC, 72.8% were male. The median age at abnormal liver function tests and diagnosis of NAFLD and HCC was 60, 64 and 67 years, respectively. Most patients were obese (75%) and diabetic (59.8%), 32.3% had dyslipidemia, and 53% had hypertension. Nearly all patients (98.6%, 71/72) were complicated with at least one metabolic disorder. The majority (76%) of the HCC patients had a solitary tumor nodule, with the tumor size ranging from 0.8 to 20 cm in diameter (mean 3.4 cm). Most (61.1%) of the patients had moderately-differentiated HCC. In 40.2% of the patients, HCC occurred in the absence of cirrhosis. Among 130 patients, 57.7% underwent hepatectomy and 14.6% received liver transplantation. The mean follow-up of the treated patients for 25 months showed that 32.4% (24/74) died and 18.8% (9/48) had recurrence. CONCLUSIONS: Patients with NAFLD-associated HCC are usually accompanied with metabolic disorders. Regular surveillance in patients with NAFLD for HCC is necessary, especially for elderly men with metabolic syndrome.

[Establishment and identification of non-alcoholic fatty liver disease in chronic hepatitis B virus infected mice].

OBJECTIVE: To establish and identify an animal model of non-alcoholic fatty liver disease in chronic HBV infected mice. METHODS: Transgenic mice with sustaining HBV production were established by microinjection of ocyte. Then they were randomly assigned into 4 groups (male control, male NAFLD model, female control and female NAFLD model) and treated with high fat diet (2% cholesterol, 10% lard, 88% forage) and common forage, respectively. NAFLD-related physical indexes, liver and kidney function, glucose and lipid metabolism were investigated at the time points of 8 weeks, 16 weeks and 24 weeks. Meanwhile, HBV type, serum levels of HBV DNA and HBeAg, immunohistochemical staining of hepatic HBsAg were detected. The establishment of NAFLD was evaluated by serum levels of total cholesterol (TC), triglycerides, glucose, aspartate aminotransferase (AST), alkaline phosphatase (ALP), alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT), etc. Histological changes were also analyzed by HE, oil red O and Masson's trichrome staining. The status of CHB was assessed on the basis of immunohistochemistry and real-time PCR. RESULTS: The body and liver weights, liver index in HBV transgenic mice were significantly increased in regardless of the gender of HFD feeding, and the levels of serum ALT, AST, ALP, GGT, TBIL, TBA, TC, TG, HDL-C, LDL and FBG were higher in HFD groups as compared with the control mice. Lipid droplets, cytologic ballooning and liver steatosis could be observed in most lobules of HFD groups after 8-week administration, fatty degeneration of hepatocytes, patch necrosis, mild to moderate chronic inflammatory infiltration were also observed in some of HFD feeding, reflecting the emerge of steatohepatitis. At the time point of 24-week perisinusoidal fibrosis and local fibrosis occurred in HFD groups. Immunohistochemical staining and real-time PCR analysis of the liver tissues showed positive signal of HBsAg in all groups of mice, although no significant difference was documented. CONCLUSION: Our study suggests that animal model of NAFLD can be established in HBV transgenic mice and provide a nice animal model for further studies on NAFLD with chronic hepatitis B infection.

Dyslipidemia in Shanghai, China.

OBJECTIVES: To determine the prevalence of and risk factors for dyslipidemia in Shanghai. METHODS: A cross-sectional survey of 14,385 subjects (6150 men) with mean age of 49.5 (14.5) years was conducted between October 2002 and April 2003 using randomized, stratified cluster sampling. Serum triglyceride, total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C) were measured. RESULTS: Dyslipidemia, as defined by NCEP ATP III criteria, occurred in 5255 subjects (36.5%). The prevalences of mixed hyperlipidemia (elevated TC and triglycerides), isolated hypertriglyceridemia, isolated hypercholesterolemia and isolated low HDL-C were 3.8%, 24.9%, 3.2% and 4.7%, respectively. The prevalence of dyslipidemia increased with age, with the peak prevalence (43%) occurring after age 55. Dyslipidemia was more common in males than females (40.2% vs. 33.8%) and in rural than urban populations (44.2% vs. 32.3%). Serum triglyceride and TC increased with body mass index (BMI) and waist circumference. Mean serum triglyceride concentrations in males and rural residents were higher than those in females and urban residents, respectively, whereas the reverse was true for HDL-C values. Multivariate analysis revealed that dyslipidemia was associated with age, gender, area of residence, BMI and waist circumference. CONCLUSIONS: There is a high prevalence of dyslipidemia, mainly hypertriglyceridemia and low HDL-C, in Shanghai.

Dynamic expression of hepatic thioredoxin mRNA in rats with non-alcoholic fatty liver disease.

OBJECTIVE: To investigate the expression and significance of thioredoxin messenger ribonucleic acid (mRNA) in the development of non-alcoholic fatty liver disease (NAFLD) induced by a high fat diet. METHODS: A total of 48 male Wistar rats were divided into a normal control group and a model group, which were both divided into three subgroups (at weeks 9, 13 and 18, respectively). The levels of serum tumor necrosis factor-alpha (TNF-alpha), free fatty acid (FFA), total cholesterol (TC) and triglyeride (TG), changes in the serum and hepatic tissue superoxide dismutase (SOD), reduced glutathione hormone (GSH) and malondialdehyde (MDA) were measured. The expression of thioredoxin mRNA in rat livers were detected with reverse transcriptase polymerase chain reaction (RT-PCR). Meanwhile, the pathological changes of liver tissue were observed by hematoxylin-eosin stain. RESULTS: Simple fatty liver was observed in model group at week 9. From weeks 13 to 18, liver histopathology showed steatohepatitis. Compared with corresponding normal groups, in the model groups the levels of TNF-alpha, FFA, TC, TG in serum, and MDA in serum and liver increased significantly, while the vitality of SOD and GSH content in serum and liver decreased remarkably. Meanwhile, in the model group, the expression of hepatic thioredoxin mRNA was significantly decreased at week 9 compared with the normal group (P < 0.01), then increased gradually, but were lower than the corresponding normal groups at all times (P < 0.01). CONCLUSION: The expression of thioredoxin mRNA is significantly lower in the liver of rats with NAFLD and might reach the lowest point after developing simple fatty liver. Meanwhile the downregulation of thioredoxin mRNA may cause the inflammatory injury initially in NAFLD.

Identification and characterization of a novel gene, Mcpr1, and its possible function in the proliferation of embryonic palatal mesenchymal cells.

We cloned a novel mouse cDNA, Mcpr1 (mouse cleft palate-related gene 1), between retinoic acid (RA)-treated murine embryonic palatal and control shelves by improved subtractive hybridization. Its transcript was identified by Northern blotting. The open reading frame encodes 132 amino acids and shows almost no identity to other genetic products. Mcpr1 expression could be detected extensively in adult mouse tissues and during murine embryonic development. It was identified to be significantly stimulated by RA in murine palatal shelves at embryonic day 12 and in palatal mesenchymal cells in vitro. We demonstrate that MCPR1 protein was localized primarily in the cytoplasm and could be synthesized and secreted by transfected COS-7 cells. Both the secretory and recombinant proteins of Mcpr1 inhibited proliferation of murine embryonic palatal mesenchymal cells and impeded the progression from the G1 to S phase in the cell cycle. The cells were prone to apoptosis after exposure to glutathione S-transferase-MCPR1. Furthermore, knockdown of MCPR1 protein levels by antisense oligodeoxynucleotides promoted progression of cells from the G1 to S phase and completely abolished the RA-induced block of the cell cycle from the G1 to S phase. These findings suggest that Mcpr1 might function as one of the RA-up-regulated genes involved in inhibiting cell proliferation during palatogenesis and RA-induced cleft palate by regulating proliferation and apoptosis of embryonic palatal mesenchymal cells and might even play a role in the development of many other organs.