Search

Purpose: To investigate the therapeutic effect and underlying mechanism of a traditional Chinese medicine (TCM) mixture consisting of Astragalus, rhubarb, and saffron in a mouse model of diabetic kidney disease (DKD). Methods: Forty-eight db/db mice received no TCM (DKD model), low-dose TCM, medium-dose TCM, or high-dose TCM, and an additional 12 db/m mice received no TCM (normal control). Intragastric TCM or saline (controls) was administered daily for 24 weeks. Blood glucose, body weight, serum creatinine (SCr), blood urea nitrogen (BUN), blood lipids, and urinary microalbumin were measured every four weeks, and the urinary albumin excretion rate (UAER) was calculated. After 24 weeks, kidney tissues were collected for transcriptome sequencing, and the main functions of these genes were determined via functional enrichment analysis. Results: Compared with the DKD model group, the medium-dose and high-dose TCM groups had significantly decreased levels of SCr, BUN, total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and UAER (all p< 0.05). We identified 42 genes that potentially functioned in this therapeutic response, and the greatest effect on gene expression was in the high-dose TCM group. We also performed functional enrichment analysis to explore the potential mechanisms of action of these different genes. Conclusion: A high-dose of the Astragalus-rhubarb-saffron TCM provided the best prevention of DKD. Analysis of the kidney transcriptome suggested that this TCM mixture may prevent DKD by altering immune responses and oxygen delivery by hemoglobin. [ABSTRACT FROM AUTHOR]

The aim of the present study is to explore the effect of retinoic acid (RA) on cardiac injury induced by gestational diabetes mellitus (GDM). GDM mice were given 3 mg/kg RA once daily until the 19th day of pregnancy or the 7th day of post-partum. Compared to normal control and normal pregnant control mice, GDM mice before and after delivery showed significantly cardiac injury. RA treatment attenuated cardiac injury as evidenced by decreased heart mass and left ventricular mass, mRNA expressions of ANP and BNP, and cardiac fibrosis compared with that in GDM mice. The protective effect of RA on GDM cardiomyopathy was related to the decreased MDA content and ROS generation, the increased GSH-Px and SOD content as well as the reduced TNF-[alpha] and IL-1[beta] content and inhibition of NF-[kappa]B signaling. In addition, RA treatment delayed the continuous rise of blood glucose before delivery and decreased the higher level of glucose after delivery. In conclusion, RA treatment could increase the activity of the antioxidant enzyme and suppress the oxidative stress, inflammation response, and activation of NF-[kappa]B signaling, thereby improving blood glucose level and cardiac injury of GDM mice before and after delivery. Key words: retinoic acid, gestational diabetes mellitus, oxidative stress, inflammation. Cette etude avait pour but d'explorer l'effet de l'acide retinoique (AR) sur les lesions cardiaques engendrees par le diabete sucre gestationnel (DSG). Nous avons administre de l'AR a des souris DSG a raison de 3 mg/kg une fois par jour jusqu'au 19e jour de gestation ou jusqu'au 7e jour apres la mise bas. Les souris DSG presentaient avant et apres la mise bas des lesions cardiaques marquees par rapport aux souris temoins normales et aux souris gravides temoins normales. L'administration d'AR entrainait une attenuation des lesions cardiaques mises en evidence par une diminution du poids du creur et de la masse du ventricule gauche, de l'expression en ARNm de l'ANP et du BNP, ainsi que par de la fibrose cardiaque par rapport aux souris DSG. L'effet protecteur de l'AR sur la cardiomyopathie DSG etait lie a la diminution des taux de malondialdehyde et de la production de derives reactifs de l'oxygene, a une augmentation des taux de GSH-Px et de superoxyde dismutase, ainsi qu'a une diminution des taux de facteur de necrose tumorale a et d'interleukine ip, avec une inhibition de la voie de signalisation du facteur nucleaire kB. De plus, l'administration d'AR entrainait des retards dans la hausse continue de la glycemie avant la mise bas, avec un abaissement des glycemies maximales apres la mise bas. En conclusion, l'administration d'AR pourrait entrainer une augmentation de l'activite de l'enzyme antioxydante, avec une inhibition du stress oxydatif, de la reaction inflammatoire et de l'activation des voies de signalisation du facteur nucleaire kB, ce qui pourrait avoir des effets positifs sur la glycemie et les lesions cardiaques chez les souris DSG avant et apres la mise bas. [Traduit par la Redaction] Mots-cles: acide retinoique, diabete sucre gestationnel, stress oxydatif, inflammation., Introduction Gestational diabetes mellitus (GDM), a common metabolic disorder, occurs during pregnancy and is estimated to affect 2%-5% of pregnant women (Capobianco et al. 2018; CEMACH 2002; Wendland et al. [...]

We previously reported that simvastatin, an inhibitor of HMG-CoA reductase, inhibits atherosclerosis in rats. The present study was designed to investigate the effect of simvastatin on mouse peritoneal macrophage foam cell formation, the early feature of atherosclerosis, and explore its mechanisms. The results showed that simvastatin decreased cholesterol content and DiI-oxLDL (1,1'-didodecyl 3,3,3',3'-indocarbocyanine perchlorate--oxidized low-density lipoprotein) uptake, reduced the levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the medium, down-regulated the mRNA and protein expression of CD36 (a fatty acid receptor), and reduced the mRNA expressions of peroxisome proliferator-activated receptor gamma (PPARγ), TNF-α, and IL-6 in macrophages treated with oxLDL. However, PPARγ agonist troglitazone partly abolished the effects of simvastatin on foam cells. In addition, simvastatin reduced the protein expression of calpain-1, a [Ca.sup.2+]-sensitive cysteine protease, in oxLDL-treated macrophages. Furthermore, PD150606, a specific calpain inhibitor, reduced mRNA expressions of PPAR^ and CD36 in macrophages treated with oxLDL. Combination of simvastatin and PD150606 had no further effect on mRNA expression of PPARγ and CD36 compared with either alone. However, over-expression of calpain-1 in macrophages partly reversed the simvastatin effects, including cell cholesterol content, mRNA expressions of PPARγ, and CD36. The results suggested that simvastatin inhibits foam cell formation of oxLDL-treated macrophages through a calpain-1-PPARγ-CD36 pathway. Key words: simvastatin, foam cells, CD36, calpain inhibitor, PPARγ. Nous avons rapporte precedemment que la simvastatine, un inhibiteur de l'HMG-CoA reductase, inhibe l'atherosclerose chez le rat. Les presents travaux ont ete concus en vue d'etudier chez la souris l'effet de la simvastatine sur la formation de cellules spumeuses de macrophages peritoneaux, caracteristique precoce de l'atherosclerose, et d'en explorer les mecanismes. Les resultats ont montre que la simvastatine permettait de diminuer les taux de cholesterol et l'utilisation de DiI-oxLDL (<>) ainsi que les taux de facteur de necrose tumorale-α (TNF-α) et d'interleukine-6 (IL-6) dans la substance, de reguler a la baisse l'expression de la proteine CD36 et de l'ARNm relatif, de reduire l'expression du recepteur gamma active par les proliferateurs des peroxysomes (PPARγ), de TNF-α et d'IL-6 dans des macrophages exposes a l' oxLDL. Cependant, la troglitazone, un agoniste du PPARγ, contrait partiellement les effets de la simvastatine sur les cellules spumeuses. De plus, la simvastatine a permis de reduire l'expression de la calpaine-1, une protease a cysteine sensible a l'ion [Ca.sup.2+], dans les macrophages exposes aux oxLDL. En outre, le PD150606, un inhibiteur specifique de la calpaine, entrainait une diminution de l'expression de l'ARNm du PPARγ et du CD36 dans des macrophages exposes aux oxLDL. L'association de simvastatine avec le PD150606 n'a eu aucun effet supplementaire sur l'expression de l'ARNm du PPARγ et du CD36 comparativement a l'exposition a l'un ou a l'autre individuellement. Cependant, la surexpression de la calpaine-1 dans les macrophages a partiellement contre les effets de la simvastatine, y compris sur les taux intracellulaires de cholesterol et sur l'expression de l'ARNm du PPARγ et du CD36. Les resultats laissaient entendre que la simvastatine inhiberait la formation de cellules spumeuses a partir de macrophages exposes aux oxLDL par l'intermediaire de la voie de signalisation calpaine-1-PPARγ-CD36. [Traduit par la Redaction] Mots-cles: simvastatine, cellules spumeuses, CD36, inhibiteur de la calpaine, PPARγ., Introduction Atherosclerotic cardiovascular disease is the prime cause of mortality in developed countries, and its incidence in developing countries has been increasing recently (Zelicoff 2015). Oxidative stress has been involved [...]

Endothelial cell injury caused by reactive oxygen species (ROS) plays a critical role in the pathogenesis of cardiovascular disorders. Astragaloside IV (AslV) possesses potent antioxidant properties against oxidative stress through undefined mechanism(s). We sought to investigate whether AsIV protects human umbilical vein endothelial cells (HUVECs) from hydrogen peroxide ([H.sub.2][O.sub.2]) induced oxidative stress focusing on eNOS uncoupling and the NADPH oxidase--ROS--NF-κB pathway. Compared with HUVECs incubated with [H.sub.2][O.sub.2] alone, pretreatment with AsIV significantly increased the viability of HUVECs, which was accompanied with apparent increase in nitric oxide (NO) production and decrease in intracellular superoxide anion production. Furthermore, pretreatment with AsIV increased endothelial nitric oxide synthase (eNOS) dimer/monomer ratio and its critical cofactor tetrahydrobiopterin (B[H.sub.4]) content, decreased Nox4 protein expression (the most abundant Nox isoform in HUVECs), inhibited translocation of NF-κB p65 subunit into nuclear fraction while enhanced the protein expression of IkB-o (the inhibitor of NF-κB p65), reduced the levels of IL-1β, IL-6, and TNF-a in HUVECs medium, and decreased iNOS protein expression. These results suggest that AsIV may protect HUVECs from [H.sub.2][O.sup.2]-induced oxidative stress via inhibiting NADPH oxidase--ROS NF-κB pathway and eNOS uncoupling. Key words: Astragaloside IV, human umbilical vein endothelial cells, hydrogen peroxide, eNOS uncoupling, NF-κB, NADPH oxidase, tetrahydrobiopterin, superoxide anion. Les dommages causes aux cellules endotheliales par les derives reactifs de l'oxygene (ROS) jouent un role essentiel dans la pathogenese des troubles cardiovasculaires. L'astragaloside IV(AsIV) dispose de puissantes proprietes anti-oxydantes contre le stress oxydatif qui sont portees par des mecanismes toujours indetermines. Nous nous sommes employes a etudier si l'AsIV permet de proteger les cellules endotheliales des veines ombilicales humaines (HUVEC) du stress oxydatif provoque par le peroxyde d'hydrogene ([H.sub.2][O.sub.2]) en centrant nos efforts sur le decouplage de l'oxyde nitrique synthase endotheliale (eNOS) et la voie de signalisation NADPH oxydase--ROS--NF-κB. Comparativement a l'incubation avec le [H.sub.2][O.sub.2] seul, le pretraitement des cellules HUVEC avec de l'AsIV a permis d'augmenter nettement leur viabilite, ce qui etait accompagne d'une augmentation apparente de la production d'oxyde nitrique (NO) et d'une diminution de la production d'anions superoxyde dans le milieu intracellulaire. En outre, le pretraitement avec de l'AsIV a permis d'augmenter le ratio dimeres/monomeres de l'eNOS et les taux de tetrahydrobiopterine (B[H.sub.4]) (son cofacteur essentiel), de diminuer l'expression de la proteine Nox4 (l'isoforme des proteines Nox la plus abondante dans les cellules HUVEC) et d'inhiber la translocation de la sous-unite p65 du facteur NF-κB dans la fraction nucleaire. Ces phenomenes etaient accompagnes d'une augmentation de l'expression de la proteine IκB-α (la proteine inhibitrice de la sous-unite p65 du NF-κB) ainsi que d'une diminution des taux d'IL-1β, d'IL-6 et de TNF-α dans le milieu des cellules HUVEC; l'expression de la proteine iNOS etait aussi diminuee. Ces resultats laissent entendre que l'AsIV pourrait proteger les cellules HUVEC du stress oxydatif cause par le [H.sub.2][O.sub.2] par l'intermediaire de l'inhibition de la voie de signalisation NADPH oxydase--ROS NFκB et du decouplage de l'eNOS. [Traduit par la Redaction] Mots-cles : astragaloside IV, cellules endotheliales des veines ombilicales humaines, peroxyde d'hydrogen, decouplage de l'eNOS, NF-κB, NADPH oxydase, tetrahydrobiopterine, anion superoxyde., Introduction It has been demonstrated that oxidative stress plays a pivotal role in the development of the endothelial dysfunction associated with many cardiovascular disease (Hermida and Balligand 2014; Makarenko et [...]

Long noncoding RNAs (lncRNAs) represent promising therapeutic targets associated with hepatocellular carcinoma (HCC). lncRNA VPS9D1 antisense RNA 1 (VPS9D1-AS1) regulates colon and prostate cancer, but its relevance in HCC remains to be clarified. Using microarray data from the NCBI Gene Expression Omnibus (GEO) database (GSE65485) and The Cancer Genome Atlas (TCGA) database, VPS9D1-AS1 expression in HCC and normal liver tissue sample HCC were compared. Relative lncRNA expression was also measured through real-time quantitative PCR (qPCR) in 80 pairs of HCC tumor and paracancerous tissues and in human HCC cell lines. VPS9D1-AS1 knockdown was achieved by transfecting these HCC cells with a specific siRNA construct in vitro, and the proliferation of these cells was quantified through cell proliferation assays and colony formation assays, while flow cytometry was employed to assess their cell cycle progression. The role of the VPS9D1-AS1 lncRNA as a regulator of HCC tumorigenesis was also assessed in vivo by subcutaneously implanting BALB/c nude mice with HepG2 cells stably expressing either sh-VPS9D1-AS1 or a control shRNA construct. Mechanistic analyses were additionally conducted by examining in vitro CDK4 and HuR expression through western blotting and qPCR. VPS9D1-AS1 expression was significantly increased in HCC tissues in the analyzed databases and our independent tissue samples. Elevated VPS9D1-AS1 expression was related to larger tumor size and more advanced tumor, node, metastasis (TNM) stage, and HCC patients expressing higher levels of this lncRNA exhibited poorer survival outcomes. Knocking down VPS9D1-AS1 impaired the proliferative and colony formation activity of HepG2 cells while promoting their apoptotic death. Consistently, VPS9D1-AS1 silencing suppressed HCC tumor growth in vivo. Mechanistically, VPS9D1-AS1 was able to bind to the HuR protein and thereby influence the stability and expression of the CDK4 mRNA, thus impacting HCC cell proliferation. The VPS9D1-AS1/HuR/CDK4 signaling axis regulates HCC tumor cell oncogenic activity, highlighting this pathway as a promising therapeutic target. [ABSTRACT FROM AUTHOR]