Fisetin treatment alleviates kidney injury in mice with diabetes-exacerbated atherosclerosis through inhibiting CD36/fibrosis pathway.

Diabetes-related vascular complications include diabetic cardiovascular diseases (CVD), diabetic nephropathy (DN) and diabetic retinopathy, etc. DN can promote the process of end-stage renal disease. On the other hand, atherosclerosis accelerates kidney damage. It is really an urge to explore the mechanisms of diabetes-exacerbated atherosclerosis as well as new agents for treatment of diabetes-exacerbated atherosclerosis and the complications. In this study we investigated the therapeutic effects of fisetin, a natural flavonoid from fruits and vegetables, on kidney injury caused by streptozotocin (STZ)-induced diabetic atherosclerosis in low density lipoprotein receptor deficient (LDLR-/-) mice. Diabetes was induced in LDLR-/- mice by injecting STZ, and the mice were fed high-fat diet (HFD) containing fisetin for 12 weeks. We found that fisetin treatment effectively attenuated diabetes-exacerbated atherosclerosis. Furthermore, we showed that fisetin treatment significantly ameliorated atherosclerosis-enhanced diabetic kidney injury, evidenced by regulating uric acid, urea and creatinine levels in urine and serum, and ameliorating morphological damages and fibrosis in the kidney. In addition, we found that the improvement of glomerular function by fisetin was mediated by reducing the production of reactive oxygen species (ROS), advanced glycosylation end products (AGEs) and inflammatory cytokines. Furthermore, fisetin treatment reduced accumulation of extracellular matrix (ECM) in the kidney by inhibiting the expression of vascular endothelial growth factor A (VEGFA), fibronectin and collagens, while enhancing matrix metalloproteinases 2 (MMP2) and MMP9, which was mainly mediated by inactivating transforming growth factor ß (TGFß)/SMAD family member 2/3 (Smad2/3) pathways. In both in vivo and in vitro experiments, we demonstrated that the therapeutic effects of fisetin on kidney fibrosis resulted from inhibiting CD36 expression. In conclusion, our results suggest that fisetin is a promising natural agent for the treatment of renal injury caused by diabetes and atherosclerosis. We reveal that fisetin is an inhibitor of CD36 for reducing the progression of kidney fibrosis, and fisetin-regulated CD36 may be a therapeutic target for the treatment of renal fibrosis.

Apigenin protects mice against 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced cholestasis.

Cholestasis can induce liver fibrosis and cirrhosis. Apigenin has anti-oxidant and anti-inflammatory effects. Herein, we determined whether apigenin can protect mice against cholestasis. In vitro, apigenin protected TFK-1 cells (a human bile duct cancer cell line) against H2O2-induced ROS generation and inhibited transforming growth factor-ß-activated collagen type 1 alpha 1 and α-smooth muscle actin in LX2 cells (a human hepatic stellate cell line). In vivo, cholestatic mice induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) were treated with apigenin. Apigenin potently blocked DDC-induced gallbladder atrophy and associated liver injury, fibrosis and collagen accumulation. Moreover, apigenin relieved the DDC-caused abnormality of bile acid metabolism and restored the balance between bile secretion and excretion by regulating the farnesoid X receptor signaling pathway. Furthermore, apigenin reduced inflammation or oxidative stress in the liver by blocking the DDC-activated Toll-like receptor 4, nuclear factor κB and tumor necrosis factor α, or DDC-suppressed superoxidase dismutase 1/2, catalase and glutathione peroxidase. Taken together, apigenin improves DDC-induced cholestasis by reducing inflammation and oxidative damage and improving bile acid metabolism, indicating its potential application for cholestasis treatment.

NaoXinTong Capsule ameliorates memory deficit in APP/PS1 mice by regulating inflammatory cytokines.

Alzheimer's disease (AD) is the most common neurodegenerative disease in aging population. Neuroinflammation, hyperphosphorylated Tau (p-Tau) and the imbalance between production and clearance of ß-amyloid peptide (Aß) are the major causes for AD development. NaoXinTong Capsule (NXT), a traditional Chinese medicine, is wildly used for treatment of cardiovascular and cerebrovascular diseases. Hence, we used the double transgenic mice expressing chimeric human amyloid precursor protein and mutant human presenilin 1 (APP/PS1) and HT-22 cells to determine the neuroprotective effects of NXT in AD development and the involved mechanisms. The 3-month-old APP/PS1 mice were randomly divided into 3 groups and received following treatment: Control group, mice were fed normal chow; NXT groups, mice were fed normal chow containing NXT at a normal and a high dose, respectively. While the age-matched C57BL/6J mice fed normal chow were used as the normal control. The NXT treatment was lasted for 5 months. We found that NXT treatment improved spatial memory impairment and cognitive decline in APP/PS1 mice by decreasing p-Tau levels and Aß accumulation in the brain. Mechanistically, we observed that NXT inhibited neuron atrophy and apoptosis by downregulating inflammatory cytokines, interleukin 1ß (IL-1ß), IL-6 and tumor necrosis factor α (TNF-α), and inflammation mediators, nuclear factor κB (NF-κB) and toll-like receptor 4 (TLR4) in the brain. Consistently, NXT blocked l-glutamic acid-induced reactive oxygen species production, inflammation and apoptosis in HT-22 cells partially by inhibiting TLR4/NF-κB/IL-1ß signaling pathway. Our study demonstrates that NXT ameliorates AD by reducing p-Tau, Aß accumulation, inflammation and neuron apoptosis via regulation of TLR4-mediated inflammatory system. It also suggests the potential application of NXT for AD treatment.

LongShengZhi Capsule Attenuates Alzheimer-Like Pathology in APP/PS1 Double Transgenic Mice by Reducing Neuronal Oxidative Stress and Inflammation.

Alzheimer's disease (AD) is the most common form of dementia in the elderly. It may be caused by oxidative stress, inflammation, and cerebrovascular dysfunctions in the brain. LongShengZhi Capsule (LSZ), a traditional Chinese medicine, has been approved by the China Food and Drug Administration for treatment of patients with cardiovascular/cerebrovascular disease. LSZ contains several neuroprotective ingredients, including Hirudo, Astmgali Radix, Carthami Flos (Honghua), Persicae Semen (Taoren), Acori Tatarinowii Rhizoma (Shichangpu), and Acanthopanax Senticosus (Ciwujia). In this study, we aimed to determine the effect of LSZ on the AD process. Double transgenic mice expressing the amyloid-ß precursor protein and mutant human presenilin 1 (APP/PS1) to model AD were treated with LSZ for 7 months starting at 2 months of age. LSZ significantly improved the cognition of the mice without adverse effects, indicating its high degree of safety and efficacy after a long-term treatment. LSZ reduced AD biomarker Aß plaque accumulation by inhibiting ß-secretase and γ-secretase gene expression. LSZ also reduced p-Tau expression, cell death, and inflammation in the brain. Consistently, in vitro, LSZ ethanol extract enhanced neuronal viability by reducing L-glutamic acid-induced oxidative stress and inflammation in HT-22 cells. LSZ exerted antioxidative effects by enhancing superoxide dismutase and glutathione peroxidase expression, reduced Aß accumulation by inhibiting ß-secretase and γ-secretase mRNA expression, and decreased p-Tau level by inhibiting NF-κB-mediated inflammation. It also demonstrated neuroprotective effects by regulating the Fas cell surface death receptor/B-cell lymphoma 2/p53 pathway. Taken together, our study demonstrates the antioxidative stress, anti-inflammatory, and neuroprotective effects of LSZ in the AD-like pathological process and suggests it could be a potential medicine for AD treatment.

Structure-based design and SAR development of novel selective polo-like kinase 1 inhibitors having the tetrahydropteridin scaffold.

Polo-like kinase 1 (Plk1) is a validated target for the treatment of cancer. In this report, by analyzing amino acid residue differences among the ATP-binding pockets of Plk1, Plk2 and Plk3, novel selective Plk1 inhibitors were designed based on BI 2536 and BI 6727, two Plk1 inhibitors in clinical studies for cancer treatments. The Plk1 inhibitors reported herein have more potent inhibition against Plk1 and better isoform selectivity in the Plk family than these two lead compounds. In addition, by introducing a hydroxyl group, our compounds have significantly improved solubility and may target specific polar residues Arg57, Glu69 and Arg134 of Plk1. Moreover, most of our compounds exhibited antitumor activities in the nanomolar range against several cancer cell lines in the MTT assay. Through this structure-based design strategy and SAR study, a few promising selective Plk1 inhibitors having the tetrahydropteridin scaffold, for example, L34, were identified and could be for further anticancer research.

Treatment of aortic root aneurysm and mitral valve pathology through a single aortotomy.

BACKGROUND: Aortic root aneurysms combined with lesions of the mitral valve requires synchronous operations. The conventional approach is to treat the two lesions through separate aortic and atrial incisions. METHODS: From May 2009 to August 2012, 28 transaortic mitral valve operations were performed. There were 23 males and five females, the age ranged from 18 to 75 years, mean 41 ± 16 years. The operative procedures included Bentall+MVR in 20 patients, Bentall+MVP in three patients, Bentall+total arch replacement+stent elephant trunk+MVP in one patient, Bentall+total arch replacement+stent elephant trunk+MVR in two patients, Bentall+MVP+CABG in two patients. Follow-up was completed for all patients, with a mean follow-up period of 22 ± 10 months and a maximum of 42 months. RESULTS: Transaortic mitral valve surgery was successful for all patients. There was a reoperation in two patients for bleeding. In the MVP group, there was mild regurgitation in two cases before discharge, without further development during the follow-up. In the MVR group, there was paravalvular leakage in one patient three months later, which required repair. There were no deaths in the hospital and the follow-up period, and no valve-associated complication during the follow-up period. The heart function of all patients during the follow-up period was Level I-II (NYHA). CONCLUSION: Transaortic mitral valve operation is a feasible surgical approach to treat patients with aortic root aneurysms combined with mitral valve lesions.