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This study was conducted to extend our previous investigations to examine the cytotoxic efficacy of Smp43 scorpion peptide against colorectal cancer cell line (HCT-116) and revealing its molecular mechanisms of action. Using MTT assay, Smp43 significantly induced cytotoxic effects on HCT-116 cancer cells compared to normal colon epithelial cell line (FHC) of IC50 4.11 and 62.17 µg/ml, respectively. Flow cytometric apoptosis assay showed that IC50 (4.11 µg/ml) of Smp43 induced a remarkable increase in the proportion of HCT-116 cancer cells undergoing late apoptotic cell death. Also, Smp43 caused cell cycle arrest at the S phase. RT-PCR analysis showed highly significant downregulation of Bcl-2 anti-apoptotic gene and ki-67 proliferative markers in HCT-116 treated with IC50 of Smp43. In contrast, caspase-3, −8, −9, Bax, and p53 apoptotic genes were upregulated. Protein expression levels of caspase-3, −8, −9, and p53 were similarly elevated in treated cells using a western blot analysis. The apoptotic characteristics were also confirmed through scanning and transmission electron microscopy. The Smp43 treated HCT-116 cancer cells showed cell membrane blebbing, pore formation, heterochromatin condensation toward the nuclear envelope, leakage of cell organelles, and formation of apoptotic bodies. Consequently, Smp43 peptide provides a great starting point for creating effective cytotoxic agents against human colorectal cancer. [ABSTRACT FROM AUTHOR]

Angiogenesis is regulated in a tissue-specific manner in all patients, especially those with diabetes. In this study, we describe a novel molecular pathway of angiogenesis regulation in diabetic rats with myocardial infarction (MI) and examine the cardioprotective effects of different doses of sitagliptin. Male rats were divided into 5 groups: normal vehicle group, diabetic group, diabetic + MI, diabetic + MI + 5 mg/kg sitagliptin, and diabetic + MI + 10 mg/kg sitagliptin. Isoproterenol in diabetic rats resulted in significant (p < 0.05) disturbance to the electrocardiogram, cardiac histopathological manifestations, and an increase in inflammatory markers compared with the vehicle and diabetic groups. Treatment with sitagliptin improved the electrocardiogram and histopathological sections, upregulated vascular endothelial growth factor (VEGF) and transmembrane phosphoglycoprotein protein (CD34) in cardiac tissues, and increased serum insulin-like growth factor 1 (IGF-1) and decreased cardiac tissue homogenate for interleukin 6 (IL-6) and cyclooxygenase 2 (COX-2). A relationship was found between serum IGF-1 and cardiac VEGF and CD34 accompanied by an improvement in cardiac function of diabetic rats with MI. Therefore, the observed effects of sitagliptin occurred at least partly through an improvement in angiogenesis and the mitigation of inflammation. Consequently, these data suggest that sitagliptin may contribute, in a dose-dependent manner, to protection against acute MI in diabetic individuals. Key words: diabetes mellitus, myocardial infarction, sitagliptin, rats, VEGF. L'angiogenese est regulee de maniere specifique aux tissus chez tous les patients, particulierement chez ceux qui sont atteints de diabete. Dans cette etude, nous decrivons une nouvelle voie de signalisation moleculaire de la regulation de l'angiogenese chez le rat diabetique presentant un infarctus du myocarde (IM), et nous etudions les effets cardioprotecteurs de differentes doses de sitagliptine. Nous avons reparti des rats males dans 5 groupes : normaux avec vehicule, diabete, diabete + IM, diabete + IM + sitagliptine a 5 mg/kg et diabete + IM + sitagliptine a 10 mg/kg. Chez les rats diabetiques, l'isoproterenol entrainait des perturbations marquees de l'electrocardiogramme (p < 0,05) avec des manifestations histopathologiques dans le coeur, ainsi qu'une hausse des marqueurs de l'inflammation par rapport aux groupes vehicule et diabete. L'administration de sitagliptine entrainait une amelioration en matiere d'electrocardiogrammes et de coupes histopathologiques, une regulation a la hausse du facteur de croissance de l'endothelium vasculaire (VEGF) et de la proteine CD34 (phosphoglycoproteine transmembranaire) dans les tissus cardiaques, ainsi qu'une hausse des taux de facteur de croissance IGF-1 (analogue a l'insuline) dans le serum avec un abaissement des taux d'interleukine 6 (IL-6) et de cyclooxygenase 2 (COX-2) dans les homogenats de tissu cardiaque. Nous avons observe un lien entre les taux seriques d'IGF-1 et les taux cardiaques de VEGF et de CD34, accompagne d'une amelioration de la fonction cardiaque chez les rats diabetiques presentant un IM. Par consequent, les effets de la sitagliptine observes ici se manifestaient au moins partiellement par des ameliorations sur le plan de l'angiogenese avec une attenuation de l'inflammation. C'est pourquoi ces donnees laissent entendre que les effets de la sitagliptine pourraient contribuer de maniere proportionnelle a la dose a la protection des personnes atteintes de diabete contre l'IM aigu. [Traduit par la Redaction] Mots-cles : diabete sucre, infarctus du myocarde, sitagliptine, rats, VEGF., Introduction Diabetes mellitus is a major public health problem affecting 347 million people worldwide (Danaei et al. 2011; Kassahun et al. 2016). Long term, uncontrolled hyperglycemia is associated with an [...]

Obesity is associated with dyslipidemia and subclinical inflammation that promotes metabolic disturbances including insulin resistance and pancreatic -cell dysfunction. The nuclear protein, transcriptional regulator 1 (NUPR1) responds to cellular stresses and features tissue protective properties. To characterize the role of NUPR1 in endocrine pancreatic islets during inflammatory stress, we generated transgenic mice with -cell-specific Nupr1 overexpression (NUPR1). Under normal conditions, NUPR1 mice did not differ from wild type (WT) littermates and display normal glucose homeostasis and -cell mass. For induction of inflammatory conditions, mice were treated with multiple low-dose streptozotocin (mld- STZ) and/or fed a high-fat diet (HFD). All treatments significantly worsened glycaemia in WT mice, while NUPR1 mice substantially preserved insulin secretion and glucose tolerance. HFD increased -cell mass in all animals, with NUPR1 mice tending to show higher values. The improved outcome of NUPR1 mice was accompanied by decreased NF-κB activation and lymphocyte infiltration in response to mld-STZ. In vitro, isolated NUPR1 islets preserved insulin secretion and content with insignificantly low apoptosis during culture stress and IL-1 exposure. These findings suggest that NUPR1 plays a vital role in the protection of -cells from apoptosis, related degradation of insulin storages and subsequent secretion during inflammatory and obesity-related tissue stress. [ABSTRACT FROM AUTHOR]