Liver fibrosis is a major cause of liver failure, but treatment remains ineffective. In the present study, we investigated the mechanisms and anti-hepatofibrotic activities of asiatic acid (AA) in a rat model of liver fibrosis induced by carbon tetrachloride (CCl4) and in vitro in TGF-beta1-stimulated rat hepatic stellate cell line (HSC-T6). Treatment with AA significantly attenuated CCl4-induced liver fibrosis and functional impairment in a dosage-dependent manner, including blockade of the activation of HSC as determined by inhibiting de novo alpha smooth muscle actin (a-SMA) and collagen matrix expression, and an increase in ALT and AST (all p<0.01). The hepatoprotective effects of AA on fibrosis were associated with upregulation of hepatic Smad7, an inhibitor of TGF-beta signaling, thereby blocking upregulation of TGF-beta1 and CTGF and the activation of TGF-beta/Smad signaling. The anti-fibrosis activity and mechanisms of AA were further detected in vitro in HSC-T6. Addition of AA significantly induced Smad7 expression by HSC-T6 cells, thereby inhibiting TGF-beta1-induced Smad2/3 activation, myofibroblast transformation, and collagen matrix expression in a dosage-dependent manner. In contrast, knockdown of Smad7 in HSC-T6 cells prevented AA-induced inhibition of HSC-T6 cell activation and fibrosis in response to TGF-beta1, revealing an essential role for Smad7 in AA-induced anti-fibrotic activities during liver fibrosis in vivo and in vitro. In conclusion, AA may be a novel therapeutic agent for liver fibrosis. Induction of Smad7-dependent inhibition of TGF-beta/Smad-mediated fibrogenesis may be a central mechanism by which AA protects liver from injury.

Hit, Lead & Candidate Discovery This study investigated the effects of a natural phenolic compound quercetin on surgical‐induced osteoarthritis (OA) in rabbits. Forty‐eight New Zealand White rabbits were used to establish OA model by Hulth modified method, and subsequently randomized into untreated OA group (treatment was drinking water), celecoxib treated group (celecoxib 100 mg kg‑1 by gavage), and quercetin treated group (25 mg kg‑1 by gavage). Sixteen nonoperated rabbits served as the normal controls (drinking water was given). The treatment (length: 4 weeks) started on the 5th week postoperation when the OA pathological changes were manifested. Expressions of superoxide dismutase (SOD), matrix metalloproteinase‐13 (MMP‐13) and tissue inhibitor of metalloproteinases‐1 (TIMP‐1) in serum, synovial fluid, and synovial tissue were measured at 8 and 12 weeks postoperation. Pathological analysis was performed with synovial tissue section and Osteoarthritis Research Society International histopathology grading and staging scores were determined. The quercetin treated group showed higher SOD and TIMP‐1 expressions but lower MMP‐13 expression than untreated OA group in the serum, synovial fluid and synovial tissues (p < .05). There was no significant difference in the SOD, MMP‐13 and TIMP‐1 expressions between the quercetin‐treated and celecoxib‐treated groups. The MMP‐13/TIMP‐1 ratio of the quercetin treated group was significantly lower than that of the untreated OA group (p < .05). Quercetin can up‐regulate SOD and TIMP‐1, down‐regulate MMP‐13, and improve the degeneration of OA through weakening the oxidative stress responses and inhibiting the degradation of cartilage extracellular matrix.

The effects of quercetin liposomes (Q-PEGL) on streptozotocin (STZ)-induced diabetic nephropathy (DN) was investigated in rats. Male Sprague Dawley rats were used to establish a STZ induced DN model. DN rats randomly received one of the following treatments for 8 weeks: blank treatment (DN), free quercetin (Que), pegylated liposomes (PEGL) and pegylated quercetin liposomes (Q-PEGL). A group of healthy rats served as the normal control. The fasting blood glucose (FBG), body weights (BWs), renal hypertrophy index (rHI), serum and urine biochemistry, renal histopathology, oxidative stress and immunohistochemical measurements of AGEs were analyzed to compare the effect of different treatments. Que and Q-PEGL significantly improved DN biochemistry and pathological changes, although the treated rats still had some symptoms of DN. The therapeutic effect of Q-PEGL surpassed that of Que. Pegylated quercetin liposomes allow maintaining higher quercetin concentrations in plasma than non-encapsulated quercetin. In conclusion the use of quercetin liposomes allows to reduce disease symptoms in a rat model of DN.Diabetes mellitus (DM) is a metabolic disorder characterized by hyperglycemia due to impaired body's ability to produce or respond to the hormone insulin 1 . Diabetic nephropathy (DN) is a microvascular complication of DM and causes long-term or end-stage renal disease 2 . Multifactorial interaction between lipid disorders, oxidative stress, renal hemodynamic changes, polyol activation, inflammatory pathways, and mitogen-activated protein kinase signaling pathways are involved in the pathophysiology of DN 3,4,7 . Therefore, strong antioxidants could potentially serve as treatments to diabetes related diseases 5 Quercetin (C 15 H 10 O 7 ,3′,4′,5,7-pentahydroxyflavone) is a potent dietary bioflavonoid found in diverse fruits, seeds, and vegetables such as legumes, apples, and chili peppers 4-7 . Pharmacological studies in humans show that quercetin has multiple biological functions including circulation system protection, anti-allergic, anti-inflammatory, anti-cancer, anti-diabetes, and cataract prevention 7 . Another important attribution of quercetin is to reduce aldose reductase, which is an enzyme that converts glucose to sorbitol through polyol pathway 5 .Natural quercetin has poor water solubility, therefore, quercetin liposomes are laboratory-prepared to improve its solubility and in vivo absorbability 7-9 . Liposomes are the most studied particle carrier systems allowing sustained release, and have the potential of enhancing the oral bioavailability of proteins and peptides 10 . Liposomes are small spherical lipid vesicles, composed of phospholipids and cholesterol, characterized on size, number of lamellae, and inner/outer phases 11,12 . Liposomes have good cell compatibility, reduce drug toxicity, improve drug stability and function for a long time 13 , and have been used to deliver drugs including antibiotic, antifungal, and cytotoxic agents 14 . Coating inert biocompatible polymers, such as PEG, on the liposom...

Objective: To investigate the association between eating behaviours (eating speed and energy intake of main meals) and overweight in pre-school children. Design: Cross-sectional study. Data consisted of measurements (height and weight), questionnaire information (eating behaviours of eating speed and overeating) and on-site observation data (meal duration and energy intake of main meals). Setting: Seven kindergartens in Beijing, China. Subjects: Pre-school children (n 1138; age range 3?1-6?7 years old) from seven kindergartens participated in the study. Results: The multivariate-adjusted odds ratio of overweight in participants with parent-reported 'more than needed food intake' was 3?02 (95 % CI 2?06, 4?44) compared with the 'medium food intake' participants, and higher eating speed was associated with childhood overweight. For the two observed eating behaviours, each 418?7 kJ (100 kcal) increase of lunch energy intake significantly increased the likelihood for overweight by a factor of 1?445, and each 5-min increase in meal duration significantly decreased the likelihood for overweight by a factor of 0?861. Increased portions of rice and cooked dishes were significantly associated with overweight status (OR 5 2?274; 95 % CI 1?360, 3?804 and OR 5 1?378; 95 % CI 1?010, 1?881, respectively). Conclusions: Eating speed and excess energy intake of main meals are associated with overweight in pre-school children.

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