The protective effect of rabeprazole on cisplatin-induced apoptosis and necroptosis of renal proximal tubular cells.

Nephrotoxicity is a major adverse reaction of cisplatin-based chemotherapy. Organic cation transporter 2 (OCT2) which is located on the basement membrane of human proximal renal tubules is responsible for the renal accumulation of cisplatin and its nephrotoxicity. This study aimed to investigate the protective effect of PPIs to CP-induced nephrotoxicity. Three kinds of PPIs including lansoprazole, omeprazole and rabeprazole (Rab) were co-administrated with CP to mice. In addition, OCT2-overexpressed HEK293, HK-2 and A549 cells were co-incubated with CP and PPIs. The results showed that PPIs can attenuate CP-induced increase of CRE, BUN and histological damage of kidney. Among the three PPIs, Rab was found with a superior protective effect. It significantly reduced the accumulation of CP in OCT2-overexpressed HEK293 cells and in the renal cortex tissues of mice, but not in HK-2 cells. Moreover, Rab reduced the expression levels of cleaved-caspase-3, RIPK1, RIPK3, MLKL and p-MLKL and the apoptosis rate of renal tubular cells induced by CP in vivo, but not in HK-2 cells. However, Rab increased the viability of CP-treated cells in a concentration-dependent manner and attenuated CP-induced apoptosis and necroptosis in OCT2 over-expressed HEK293 cells. Finally, we demonstrated that Rab have no influence on the antitumor effect of CP. In conclusion, Rab attenuate CP-induced nephrotoxicity mainly through inhibiting OCT2-mediated CP uptake, without interfering with its anti-tumor property of inducing apoptosis and necroptosis.

Targetted inhibition of CD74 attenuates adipose COX-2-MIF-mediated M1 macrophage polarization and retards obesity-related adipose tissue inflammation and insulin resistance.

Adipose tissue (AT) inflammation is crucial to the development of obesity-associated insulin resistance. Our aim was to investigate the contribution of cyclooxygenase-2 (COX-2)/macrophage migration inhibitory factor (MIF)-mediated cross-talk between hypertrophic adipocytes and macrophages to the etiology of AT inflammation and the involvement of CD74 using human SGBS adipocytes, THP-1 macrophages and mice fed a high-fat (HF) diet. The MIF and CD74 mRNA levels in the adipocytes and stromal vascular cells (SVCs) of white fat were highly correlated with body weight (BW), homeostatic model assessment for insulin resistance (HOMA-IR), and adipose macrophage marker expression levels, especially those in SVCs. COX-2 inhibition suppressed the elevation of MIF production in HF white adipocytes as well as palmitate and hypoxic-treated SGBS adipocytes. Treatment of adipocytes transfected with shCOX-2 and siMIF or subjected to MIF depletion in the medium reversed the pro-inflammatory responses in co-incubated THP-1 cells. Inhibition of NF-κB activation reversed the COX2-dependent MIF secretion from treated adipocytes. The targetted inhibition of macrophage CD74 prevented M1 macrophage polarization in the above co-culture model. The COX-2-dependent increases in CD74 gene expression and MIF release in M1-polarized macrophages facilitated the expression of COX-2 and MIF in co-cultured SGBS adipocytes. CD74 shRNA intravenous injection suppressed HF-induced AT M1 macrophage polarization and inflammation as well as insulin resistance in mice. The present study suggested that COX-2-mediated MIF secretion through NF-κB activation from hypertrophic and hypoxic adipocytes as well as M1 macrophages might substantially contribute to the phenotypic switch of AT macrophages through CD74 in obesity. Inhibition of CD74 could attenuate AT inflammation and insulin resistance in the development of HF diet-induced obesity.

Adult-onset deficiency of acyl CoA:monoacylglycerol acyltransferase 2 protects mice from diet-induced obesity and glucose intolerance.

Acyl-CoA:monoacylglycerol acyltransferase (MGAT) 2 catalyzes triacylglycerol (TAG) synthesis, required in intestinal fat absorption. We previously demonstrated that mice without a functional MGAT2-coding gene (Mogat2(-/-)) exhibit increased energy expenditure and resistance to obesity induced by excess calories. One critical question raised is whether lacking MGAT2 during early development is required for the metabolic phenotypes in adult mice. In this study, we found that Mogat2(-/-) pups grew slower than wild-type littermates during the suckling period. To determine whether inactivating MGAT2 in adult mice is sufficient to confer resistance to diet-induced obesity, we generated mice with an inducible Mogat2-inactivating mutation. Mice with adult-onset MGAT2 deficiency (Mogat2(AKO)) exhibited a transient decrease in food intake like Mogat2(-/-) mice when fed a high-fat diet and a moderate increase in energy expenditure after acclimatization. They gained less weight than littermate controls, but the difference was smaller than that between wild-type and Mogat2(-/-) mice. The moderate reduction in weight gain was associated with reduced hepatic TAG and improved glucose tolerance. Similar protective effects were also observed in mice that had gained weight on a high-fat diet before inactivating MGAT2. These findings suggest that adult-onset MGAT2 deficiency mitigates metabolic disorders induced by high-fat feeding and that MGAT2 modulates early postnatal nutrition and may program metabolism later in life.

7,3'-dimethoxy hesperetin inhibits inflammation by inducing synovial apoptosis in rats with adjuvant-induced arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by pronounced inflammation and excessive synovial hyperplasia within affected joint. We previously reported 7, 3'-dimethoxy hesperetin (DMHP) as a highly anti-inflammatory active derivative of hesperidin showed apparent pro-apoptotic effect in vitro on fibroblast-like synoviocytes of rats with adjuvant arthritis (AA), an animal model of RA. Here, we investigated the therapeutic effects of DMHP on inflammation and synovial apoptosis in rats with AA in vivo. Paw swelling, arthritis index, TNF-α and IL-1ß serum levels were measured to evaluate the effect of DMHP on inflammation in AA rats. DNA ladder detection and TUNEL assay were used to investigate the pro-apoptotic effect of DMHP on synovial apoptosis in vivo. Bcl-2, Bax mRNA and protein expressions in synovium were determined by real-time Q-PCR and western blot, respectively. We found DMHP inhibited secondary hind paw swelling and arthritis index, and decreased TNF-α and IL-1ß serum levels in AA rats. Typical DNA ladder formation was found in DNA extraction of synovium from DMHP treated groups. The number of apoptotic synovial cells was elevated with DMHP treatment in TUNEL assay. DMHP markedly decreased Bcl-2 expression whereas increased Bax expression in synovium of AA rats at both transcription and protein levels. Moreover, DMHP treatment on AA rats significantly decreased the protein ratio of Bcl-2/Bax in synovium. In conclusion, DMHP has an apparent therapeutic effect on inflammation in rats with AA. Mechanisms of this effect are partly related to induction of synovial apoptosis through modulation of Bcl-2 and Bax expression.

[Effect of hesperidin on behavior and HPA axis of rat model of chronic stress-induced depression].

OBJECTIVE: To observe the effect of hesperidin on behavior and hypothalamic-pituitary-adrenal (HPA) axis of ratmodel of chronic stress-induced depression. METHOD: Chronic unpredictable mild stress (CUMS) was used to establish the rat depression model. Sixty male SD rats were divided randomly into six groups: the normal group, the model group, the hesperidin (40, 80, 160 mg x kg(-1)) group and the positive fluoxetine (10 mg x kg(-1)) group. They were orally administered with drugs for three weeks. The sucrose preference test and the forced swimming test (FST) were assayed to detect animal behavior. The levels of corticosterone (CORT) in serum, mRNA of corticotropin release factor (CRF) in hypothalamus as well as protein expression of glucocorticoid receptor (GR) in paraventricular nucleus (PVN) were determined to clarify the anti-depression effect and mechanism of hesperidin. RESULT: Compared with the model group, rats in the hesperidin (40, 80, 160 mg x kg(-1)) treatment group showed significant increase in the sucrose consumption and decrease in the immobility time in FST to varying degrees. Meanwhile, the excessively high serum CORT and adrenal index of CUMS rats were reversed by treatment with hesperidin. In addition, hesperidin inhibited CRF mRNA expression in hypothalamus and up-regulated GR protein expression in PVN among CUMS rats. CONCLUSION: Hesperidin could effectively improve the behavior of CUMS rats and show the anti-depression effect. Its mechanisms may be related to the function of regulating HPA axis.

Pinocembrin Reduces Keratinocyte Activation and Ameliorates Imiquimod-Induced Psoriasis-like Dermatitis in BALB/c Mice through the Heme Oxygenase-1/Signal Transducer and Activator of Transcription 3 Pathway.

Psoriasis is an autoimmune disease characterized by chronic skin inflammation and excessive keratinocyte proliferation. The itchy, scaly, and erythematous lesions present on psoriatic skin negatively affect patients' quality of life. Pinocembrin is a flavonoid present in propolis, fruits, and vegetables. It exerts neuroprotective effects and was used for treating ischemic stroke in a human clinical trial. However, the effects of pinocembrin on psoriasis have never been examined. In this study, we evaluated the effects of pinocembrin on human HaCaT keratinocytes and BALB/c mice with imiquimod- (IMQ-) induced psoriatic dermatitis. In interferon-γ- (IFN-γ-) activated HaCaT cells, pinocembrin reduced the expression of inflammatory cytokines, namely, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and keratinocyte proliferation markers, namely, keratin (K)16, K17, and Ki-67. The mechanism underlying these inhibitory effects involved the regulation of the heme oxygenase- (HO-) 1/signal transducer and activator of transcription (STAT) 3 pathway. In the IMQ-induced psoriatic dermatitis mouse model, the topical application of pinocembrin significantly ameliorated the Skin Psoriasis Area and Severity Index score, epidermal thickness, inflammation, hyperplasia, hyperkeratosis, and cluster of differentiation (CD) 4+ T-cell infiltration. Expression of the inflammatory cytokines and keratinocyte proliferation markers in dorsal skin was significantly decreased in the pinocembrin-treated group. Meanwhile, in lesional skin, the expression of HO-1 was upregulated, but that of phospho-STAT3 (pSTAT3) was downregulated. Collectively, our results indicated the therapeutic potential of pinocembrin. Additional studies are warranted to evaluate its clinical benefits in patients with psoriasis.

Mitochondrial Function and Parkinson's Disease: From the Perspective of the Electron Transport Chain.

Parkinson's disease (PD) is known as a mitochondrial disease. Some even regarded it specifically as a disorder of the complex I of the electron transport chain (ETC). The ETC is fundamental for mitochondrial energy production which is essential for neuronal health. In the past two decades, more than 20 PD-associated genes have been identified. Some are directly involved in mitochondrial functions, such as PRKN, PINK1, and DJ-1. While other PD-associate genes, such as LRRK2, SNCA, and GBA1, regulate lysosomal functions, lipid metabolism, or protein aggregation, some have been shown to indirectly affect the electron transport chain. The recent identification of CHCHD2 and UQCRC1 that are critical for functions of complex IV and complex III, respectively, provide direct evidence that PD is more than just a complex I disorder. Like UQCRC1 in preventing cytochrome c from release, functions of ETC proteins beyond oxidative phosphorylation might also contribute to the pathogenesis of PD.

Health-related risky behaviors and their risk factors in adolescents with high-functioning autism.

BACKGROUND: Health-related risky behaviors generally refer to behaviors that have a negative impact on health and quality of life. Health-related risky behaviors in adolescents with high-functioning autism (HFA) have not been well understood so far. Adolescents with HFA may have more health-related risky behaviors than neurotypical adolescents. AIM: To investigate health-related risky behaviors and their risk factors with HFA. METHODS: This is an observational study. Our study enrolled 110 adolescents aged 12-19-years-old meeting Diagnostic and Statistical Manual of Mental Disorders 4th edition criteria for HFA. They were recruited from Peking University Sixth Hospital. There were also 110 age, sex and nationality matched controls enrolled who came from a public school in Beijing, China. Both groups completed the Adolescents Health-related Risky Behavior Inventory. Nonparametric tests were carried out for comparison of the Adolescents Health-related Risky Behavior Inventory scores between the two groups. Expression recognition, the Inventory of Subjective Life Quality for Child and Adolescent, Chinese Wechsler Intelligence Scale for Children, Wechsler Intelligence Scale for Adult-Chinese Revised, Theory of Mind test and Autism Spectrum Screening Questionnaire were assessed in the autism group to explore factors associated with health-related risky behaviors. Multivariate regression analysis was conducted to explore the risk factors of health-related risky behaviors in the HFA group. RESULTS: The results showed that the total score of the Adolescents Health-related Risky Behavior Inventory and scores of "aggression and violence," "suicide and self-injury," "health compromising behavior" and "unprotected sex" subscales in the HFA group were significantly higher than those in the control group (Z range -4.197 to -2.213, P < 0.05). Among the associated factors, poor emotional experience (B = -0.268, P < 0.001), depression (B = -0.321, P < 0.001), low score of intelligence (B = -0.032, P = 0.042), low score of Theory of Mind test (B = -1.321, P = 0.003) and poor adaptation to school life (B = -0.152, P = 0.006) were risk factors. These risky behaviors may promote the occurrence of health-related risky behaviors in adolescents with HFA. CONCLUSION: This study showed that adolescents with HFA were more likely to be involved in health-related risky behaviors. Different health-related risky behaviors have different reasons.

Mangosteen Concentrate Drink Supplementation Promotes Antioxidant Status and Lactate Clearance in Rats after Exercise.

High-strength or long-duration exercise can lead to significant fatigue, oxidative stress, and muscle damage. The purpose of this study was to examine the effect of mangosteen concentrate drink (MCD) supplementation on antioxidant capacity and lactate clearance in rats after running exercise. Forty rats were divided into five groups: N, non-treatment; C, control; or supplemented with MCD, including M1, M5, and M10 (0.9, 4.5, and 9 mL/day) for 6 weeks. The rats were subjected to 30 min running and exhaustive-running tests using a treadmill. The blood lactate; triglyceride; cholesterol and glucose levels; hepatic and muscular malonaldehyde (MDA) levels; and antioxidant enzymes, including superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT), were analyzed. The results of this study demonstrated that MCD supplementation can increase GPx and CAT activities, alleviate oxidative stress in muscle, and increase lactate clearance, and is thereby beneficial to reduced muscle fatigue after exercise.

Design and Usability Evaluation of Mobile Voice-Added Food Reporting for Elderly People: Randomized Controlled Trial.

BACKGROUND: Advances in voice technology have raised new possibilities for apps related to daily health maintenance. However, the usability of such technologies for older users remains unclear and requires further investigation. OBJECTIVE: We designed and evaluated two innovative mobile voice-added apps for food intake reporting, namely voice-only reporting (VOR) and voice-button reporting (VBR). Each app features a unique interactive procedure for reporting food intake. With VOR, users verbally report the main contents of each dish, while VBR provides both voice and existing touch screen inputs for food intake reporting. The relative usability of the two apps was assessed through the metrics of accuracy, efficiency, and user perception. METHODS: The two mobile apps were compared in a head-to-head parallel randomized trial evaluation. A group of 57 adults aged 60-90 years (12 male and 45 female participants) was recruited from a retirement community and randomized into two experimental groups, that is, VOR (n=30) and VBR (n=27) groups. Both groups were tested using the same set of 17 food items including dishes and beverages selected and allocated to present distinct breakfast, lunch, and dinner meals. All participants used a 7-inch tablet computer for the test. The resulting data were analyzed to evaluate reporting accuracy and time efficiency, and the system usability scale (SUS) was used to measure user perception. RESULTS: For eight error types identified in the experiment, the VBR group participants were significantly (P<.001) more error prone owing to the required use of button-tapping actions. The highest error rates in the VOR group were related to incomprehensible reporting speech (28/420, 6.7%), while the highest error rates in the VBR group were related to failure to make required button taps (39/378, 10.3%). The VOR group required significantly (P<.001) less time to complete food reporting. The overall subjective reactions of the two groups based on the SUS surpassed the benchmark and were not significantly different (P=.20). CONCLUSIONS: Experimental results showed that VOR outperformed VBR, suggesting that voice-only food input reporting is preferable for elderly users. Voice-added apps offer a potential mechanism for the self-management of dietary intake by elderly users. Our study contributes an evidence-based evaluation of prototype design and selection under a user-centered design model. The results provide a useful reference for selecting optimal user interaction design. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Registry ISRCTN17335889; http://www.isrctn.com/ISRCTN17335889.

CT and MRI findings of different types of small round cell tumor in the nasal cavity and sinuses / 实用放射学杂志

Objective To investigate the CT and MRI findings of different types of small round cell tumor(SRCT)in the nasal cavity and sinuses.Methods A retrospective analysis was conducted on the imaging data and clinical data of 35 SRCT patients confirmed by pathology.Thirty-one SRCT patients underwent CT examination,and 19 SRCT patients underwent MRI examination.Results There were 20 cases of tumors that invaded the nasal cavity and 19 cases involved the sinuses,including 11 cases of the maxillary sinus,7 cases of the ethmoid sinus,2 cases of the sphenoid sinus,and 1 case of the frontal sinus.CT findings of SRCT were all soft tissue masses.Lymphoma was relatively homogeneous with mild bone destruction,and usually involved nasal vestibular skin.Rhabdomyosarcoma(embryonic type)happened at an early age and easily caused bone destruction and metastasis.Melanoma generally occurred in the nasal septum and nasal cavity,which was prone to bleeding.Small cell neuroendocrine carcinoma was heterogeneous,with moderate to significant enhancement,bone absorption and destruction were often noticed.The MRI manifestations of SRCT were equal or long signal on T1WI,high signal on T2WI,and significant diffusion limitation on diffusion weighted imaging(DWI)and apparent diffusion coefficient(ADC)except for melanoma.On contrast-enhanced images,lymphoma showed mild to moderate enhancement,rhabdomyosarcoma showed typical"grape sign",and small cell neuroendocrine carcinoma showed"sieve"and"map-like"obvious enhancement.Typical melanoma showed a high signal on T1WI and a low signal on T2WI and usually caused bleeding.The MRI findings were related to the presence of melanoma and hemorrhage within the lesion.Conclusion SRCT of the nasal cavity and sinuses have a high degree of malignancy and poor prognosis,CT and MRI have many similar manifestations.Combining clinical data,bone destruction,MRI enhancement,and DWI sequence can effectively distinguish different types of SRCT,as well as squamous cell carcinoma of the nasal cavity and sinuses and adenoid cystic carcinoma.

Effects of Nutritional Intervention on Nutritional Status and Quality of Life of Patients with Colorectal Cancer Treated with Postoperative Adjuvant Chemotherapy / 肿瘤防治研究

Objective To explore the effects of nutritional intervention on the quality of life and nutritional status of patients with colorectal cancer treated with postoperative adjuvant chemotherapy. Methods Fifty-six patients with colorectal cancer subjected to postoperative chemotherapy were selected. They were divided into nutritional intervention group (n=20) and control group (n=36). Blood test indices, PG-SGA scores, and 36-Item Short Form Health Survey scores were compared 4 weeks after the surgery. Results No significant difference in PG-SGA score was found between the nutritional group and the control group at admission (t=-0.347, P=0.730), but statistically significant difference was detected after 4 weeks (t=-2.708, P=0.009). At 4 weeks after the surgery, the serum levels of prealbumin, albumin, and hemoglobin were not significantly different between the two groups (P > 0.05). Other indices of quality of life assessment (P < 0.05), except for the index of emotional function (P=0.083), were significantly different between the two groups, and the scores of the nutritional intervention group were higher than those of the control group. Conclusion Nutritional intervention can effectively improve the nutritional status and quality of life of patients with colorectal cancer treated with postoperative adjuvant chemotherapy.

Molecular Mechanism of Jingfang Mixture Against H1N1 Influenza Based on Network Pharmacology and Experimental Verification / 中国实验方剂学杂志

ObjectiveTo predict the potential targets and mechanism of Jingfang mixture in the treatment of H1N1 influenza and provide references for clinical application of Jingfang mixture. MethodThe active components and targets of Jingfang mixture against H1N1 influenza were screened out by Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform（TCMSP），SwissTargetPrediction， and TargetNet. The targets of H1N1 influenza were obtained from GeneCards，Online Mendelian Inheritance in Man （OMIM）， and DisGeNET and standardized by UniProt KB. The intersection targets were obtained by Venny 2.1.0. The "drug-component-target" network was constructed with Cytoscape 3.2.1 and analyzed for the topological attributes. The intersection targets were uploaded to STRING 11.5 to obtain the protein-protein interaction （PPI） network. Gene Ontology （GO） enrichment analysis and Kyoto Encyclopedia of Genes and Genomes （KEGG） analysis were carried out by Metascape. Finally，the top active components ranked by degree were docked to the core targets by Autodock vina and visually analyzed by PyMOL. Balb/c female rats were used for experimental verification. Hematoxylin-eosin（HE） staining was used to observe the pathological changes in lung tissues. Enzyme-linked immunosorbent assay（ELISA）was used to detect the levels of tumor necrosis factor-α（TNF-α），interleukin-10（IL-10）， and interleukin-17（IL-17）. Real-time fluorescence-based quantitative polymerase chain reaction（Real-time PCR） and Western blot were used to detect the mRNA and protein expression levels in lung tissues. ResultThere were 144 active components in Jingfang mixture. A total of 421 target genes of Jingfang mixture and 2 956 targets of H1N1 influenza were identified，including 199 common targets. Topological analysis showed that the core components of Jingfang mixture against H1N1 influenza included quercetin，luteolin， and kaempferol，and the core targets included prostaglandin-endoperoxide synthase 2（PTGS2），estrogen receptor alpha（ESR1），inducible nitric oxide synthase 2（iNOS2），peroxisome proliferator-activated receptorγ（PPARγ），and cyclooxygenase-1（PTGS1）. GO enrichment yielded 697 items in biological process （BP） （P<0.01）， 59 items in molecular function （MF）（P<0.01）， and 21 items in cellular component （CC） （P<0.01）. A total of 132 signaling pathways （P<0.01） were obtained by KEGG enrichment analysis， including phosphatidylinositol 3-kinases（PI3K）/protein kinase B（Akt） signaling pathway and mitogen-activated protein kinase（MAPK） signaling pathway，most of which were related to the regulation of immune inflammation. Molecular docking showed that the binding energy of the active components of Jingfang mixture to the core targets was less than -5.0 kcal·mol-1，indicating good binding activity. HE staining showed that the lung tissues were significantly improved after drug intervention，and Real-time PCR and Western blot showed that Jingfang mixture could reduce the mRNA and protein expression of PI3K and Akt in lung tissues. ConclusionJingfang mixture can play an anti-viral effect against the influenza A virus through multiple components，multiple targets， and multiple pathways. The active components quercetin，luteolin， and kaempferol may control the inflammation and regulate immunity on the PI3K/Akt，MAPK， and other signaling pathways by acting on targets such as PTGS2，ESR1，iNOS2，PPARγ， and PTGS1.

The relationship study between endothelial dysfunction and myocardial cell apoptosis during myocardial ischemia and reperfusion / 中华老年医学杂志

Objective:To investigate the correlation between endothelial dysfunction and cardiomyocyte apoptosis during myocardial ischemia-reperfusion.Methods:A total of 63 male rats were selected to establish the rat model of myocardial ischemia-reperfusion by the ligation of the left anterior descending(LAD)coronary artery to simulate myocardial ischemia.Rats were divided into the control group and group Ⅰb, group Ⅰa, group Ⅱb, group Ⅱa, group Ⅲb and group Ⅲa.Control rats were treated only with LAD threading without ligation.In observation group, at 30, 90, 120 min after LAD ligation(marked as Ⅰ, Ⅱ, Ⅲ group respectively), loosen the ligation to simulate ischemia-reperfusion.In the observation group, captopril sublingual injection of 0.25 mg/kg before ligation were marked as group b, and as group a with no captopril injection.The circulating endothelial cells(CEC), endothelin(ET), nitric oxide(NO)and the apoptosis rate of cardiomyocytes in each group were measured.Results:The CEC and ET levels showed a continuous upward trend, and a NO level showed a continuous downward trend from group Ⅰa to Ⅱa to Ⅲa as compared with the control group( P<0.05). After using preventive intervention of captopril, the CEC and ET levels were lower and NO levels were higher in group Ⅱb and Ⅲb than in group Ⅱa and Ⅲa, respectively( P<0.05). The apoptotic rate of cardiomyocytes was higher in group Ⅰa than in the control group, and the apoptotic rate from high to low were from group Ⅲa[(235.71±40.25)%]to group Ⅱa[(197.28±43.56)%]to group Ⅰa[(138.55±32.87)%]and to the control group[(5.81±2.02)%]( P<0.05). The apoptotic rate of cardiomyocytes was lower in group Ⅱb[(125.67±26.51)%]and Ⅲb[(124.91±33.28)%]than in group Ⅱa and Ⅲa, respectively( P<0.05). Conclusions:The ischemia-reperfusion can cause endothelial dysfunction and the apoptosis of cardiomyocytes, and there is a close relationship between the degree of this lesions and the duration of ischemia-reperfusion.While, the appropriate application of angiotensin converting enzyme inhibitor can inhibit the damage of cardiomyocytes to a some extent.

The anti-glioma effects of borneol and RGD co-modified docetaxel loaded nanoparticles after intranasal administration / 药学学报

Borneol (Bo) and Arg-Gly-Asp (RGD) co-modified docetaxel (DTX) loaded MPEG-PLGA nanoparticles (DTX-Bo-RGD-NPs) were prepared to improve the therapeutic effect of DTX against glioma after intranasal administration. DTX-Bo-RGD-NPs were prepared by emulsification-solvent evaporation method, and their morphology, particle size, zeta potential, drug loading capacity (DLC), stability, and in vitro release properties were investigated. The fluorescence probe coumarin-6 loaded NPs were prepared for investigating the NPs' uptake property on C6 and 16HBE cell models to evaluate in vitro targeting ability. The DiR loaded NPs were prepared for observing the fluorescence intensity at the brain tumor site after intranasal administration through in vivo imaging system in a C6 rat orthotropic model, evaluating the targeting ability in vivo. The anti-tumor effects of DTX-Bo-RGD-NPs were also investigated in such C6 rat orthotropic model in vivo. Animal welfare and experimental procedures are in compliance with the regulations of the Animal Ethics Committee of Shanghai University of Traditional Chinese Medicine. The results showed that DTX-Bo-RGD-NPs were spherical and uniformly distributed, with a particle size of about 140 nm and a zeta potential of -20 to -30 mV. The drug delivery system showed good stability and sustained release property in vitro, and favorable brain tumor targeting effect in vitro and in vivo. Such novel drug delivery system significantly improved the accumulation of DTX-Bo-RGD-NPs in tumor sites and displayed a higher brain tumor targeting efficiency, providing promising therapeutics of DTX for the treatment of glioma after intranasal administration.

SMYD3-PARP16 axis accelerates unfolded protein response and mediates neointima formation

Neointimal hyperplasia after vascular injury is a representative complication of restenosis. Endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) is involved in the pathogenesis of vascular intimal hyperplasia. PARP16, a member of the poly(ADP-ribose) polymerases family, is correlated with the nuclear envelope and the ER. Here, we found that PERK and IRE1

Opposite Expression of HNRNPA2B1 in Cancer and Senescent Cells and Its Regulatory Role in Senescence of Cancer Cells / 中国生物化学与分子生物学报

Splicing factor Heterogeneous Nuclear Ribonucleoprotein A2/B1 (HNRNPA2B1 ) is associated with mouse lifespan and human longevity.It also plays a causal role in cancer development.However, whether it participates in cellular senescence, a biological process that contributes to individual aging and inhibits cancer, remains unknown.Here, we report that HNRNPA2B1 showed significantly increased expression in various cancer types while consistently decreased expression in multiple cellular senescence models.Knocking down HNRNPA2B1 in cancer cells leads to a series of senescence- associated phenotvpes.In line with its function as a splicing factor, HNRNPA2B1 downregulation causes alternative splicing changes in over one thousand genes, including those known to have a causal role in senescence.Our results also suggests that the E2F transcription factor 1 (E2F1 ) could regulate the expression of HNRNPA2BI, and E2F1-HNRNPA2B1 may be a new regulatory axis functioning in both cancer and cellular senescence, which might also have potential medical implications for cancer therapies.

Expression of hedgehog signal pathway in articular cartilage is associated with the severity of cartilage damage in rats with adjuvant-induced arthritis.

BACKGROUND: Cartilage damage is a crucial step in rheumatoid arthritis (RA) disease progress while its molecular mechanisms are not fully understood. Here we investigated the expression of hedgehog (Hh) signal pathway in articular cartilage of adjuvant-induced arthritis (AIA) rats and its possible pathological role in cartilage damage. METHODS: 30 rats were divided into sham and AIA group (n = 15). Complete Freund's adjuvant was used to induce AIA. Secondary paw swelling was measured on day 10, 14, 18, 22 and 26 after induction. Rats were sacrificed on day 26 and knee joints and cartilage tissues were collected. Paw swelling, cartilage histopathologic changes and OARSI scores were used to evaluate AIA in rats. The protein expression of Hh signal related genes (Shh, Ptch1, Smo and Gli1) in cartilage were assayed by immunohistochemistry. The mRNA levels of Shh, Ptch1, Smo, Gli1, type-II collagen (COII) and aggrecan in cartilage were assayed by real-time PCR. In vitro study, cultured AIA chondrocytes were treated with cyclopamine (a specific inhibitor of Hh signal) and the mRNA levels of Hh signal and ECM components (COII and aggrecan) were measured by real-time PCR. RESULTS: Immunohistochemical results revealed that Shh, Ptch1, Smo and Gli1 proteins showed higher expression in the articular cartilage of AIA rats than those of sham rats. Real-time PCR results confirmed that Shh, Ptch1, Smo and Gli1 mRNA levels in cartilage tissues of AIA rats were significantly increased compared with those of sham rats (1.6, 1.4, 1.6, 2.0 fold, respectively). The mRNA levels of Shh, Ptch1, Smo, and Gli1 were associated with the severity of cartilage damage (indicated by OARSI scores, COII and aggrecan mRNA levels in cartilage). In vitro, cyclopamine effectively decreased the mRNA levels of Shh, Ptch1, Smo and Gli1, and increased the mRNA levels of COII and aggrecan in AIA chondrocytes, suggesting Hh signal inhibition might directly promote ECM production. CONCLUSIONS: Our findings present certain experimental evidence that Hh signal pathway is involved in the pathogenesis of cartilage damage in RA.

Inhibition of hedgehog signal pathway by cyclopamine attenuates inflammation and articular cartilage damage in rats with adjuvant-induced arthritis.

OBJECTIVES: We investigated whether inhibition of hedgehog (Hh) signal by cyclopamine attenuated inflammation and cartilage damage in adjuvant-induced arthritis (AIA) rats. METHODS: Cyclopamine (2.5, 5, 10 mg/kg) was given by intraperitoneal injection once daily from day 12 to 21 after AIA induction. Paw swelling (volume changes), serum pro-inflammatory cytokines levels (ELISA), histological analysis of joint damage (H&E staining), proteoglycans expression (Alcian blue staining), mRNA levels of sonic Hh (Shh), glioma-associated oncogene homologue 1 (Gli1), type II collagen (COII) and aggrecan in cartilage (real-time PCR) and articular chondrocyte apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling) were measured respectively. KEY FINDINGS: Cyclopamine effectively attenuated inflammation and cartilage damage of AIA rats, as evidenced by reduced paw swelling, serum levels of tumor necrosis factors (TNF)-α, IL-1ß, IL-6 and histological scores of joint damage, increased proteoglycans expression and mRNA levels of COII and aggrecan in articular cartilage. Shh or Gli1 mRNA level was correlated negatively with COII and aggrecan mRNA levels, suggesting Hh signal inhibition was associated with promotion of cartilage extracellular matrix production. Furthermore, cyclopamine decreased the number of apoptotic articular chondrocytes of AIA rats, which might be partly related to its mechanisms on relieving cartilage damage. CONCLUSIONS: Our findings present some experimental evidence that Hh signal inhibition might be of potential clinical interest in rheumatoid arthritis treatment.

Antidepressant-like effect of geniposide on chronic unpredictable mild stress-induced depressive rats by regulating the hypothalamus-pituitary-adrenal axis.

Geniposide as the major active component of Gardenia jasminoides Ellis has neuroprotective activity. This study elucidated the potential antidepressant-like effect of geniposide and its related mechanisms using a depression rat model induced by 3 consecutive weeks of chronic unpredictable mild stress (CUMS). Sucrose preference test, open field test (OFT) and forced swimming test (FST) were applied to evaluate the antidepressant effect of geniposide. Adrenocorticotropic hormone (ACTH) and corticosterone (CORT) serum levels, adrenal gland index and hypothalamic corticotrophin-releasing hormone (CRH) mRNA expression were measured to assess the activity of hypothalamus-pituitary-adrenal (HPA) axis. Hypothalamic glucocorticoid receptor α (GRα) mRNA expression and GRα protein expression in hypothalamic paraventricular nucleus (PVN) were also determined by real-time PCR and immunohistochemistry, respectively. We found that geniposide (25, 50, 100mg/kg) treatment reversed the CUMS-induced behavioral abnormalities, as suggested by increased sucrose intake, improved crossing and rearing behavior in OFT, shortened immobility and prolonged swimming time in FST. Additionally, geniposide treatment normalized the CUMS-induced hyperactivity of HPA axis, as evidenced by reduced CORT serum level, adrenal gland index and hypothalamic CRH mRNA expression, with no significant effect on ACTH serum level. Moreover, geniposide treatment upregulated the hypothalamic GRα mRNA level and GRα protein expression in PVN, suggesting geniposide could recover the impaired GRα negative feedback on CRH expression and HPA axis. These aforementioned therapeutic effects of geniposide were essentially similar to fluoxetine. Our results indicated that geniposide possessed potent antidepressant-like properties that may be mediated by its effects on the HPA axis.