Animal models have historically played a critical role in the exploration and characterization of disease pathophysiology and target identification and in the evaluation of novel therapeutic agents and treatments in vivo. Diabetes mellitus disease, commonly known as diabetes, is a group of metabolic disorders characterized by high blood glucose levels for a prolonged time. To avoid late complications of diabetes and related costs, primary prevention and early treatment are therefore necessary. Due to its chronic symptoms, new treatment strategies need to be developed, because of the limited effectiveness of the current therapies. We overviewed the pathophysiological features of diabetes in relation to its complications in type 1 and type 2 mice along with rat models, including Zucker Diabetic Fatty (ZDF) rats, BB rats, LEW 1AR1/-iddm rats, Goto-Kakizaki rats, chemically induced diabetic models, and Nonobese Diabetic mouse, and Akita mice model. The advantages and disadvantages that these models comprise were also addressed in this review. This paper briefly reviews the wide pathophysiological and molecular mechanisms associated with type 1 and type 2 diabetes, particularly focusing on the challenges associated with the evaluation and predictive validation of these models as ideal animal models for preclinical assessments and discovering new drugs and therapeutic agents for translational application in humans.

Dipeptidyl peptidase-4 (DPP-4) inhibitors are a class of oral anti-diabetic drugs, implicated in pleiotropic secondary cardioprotective effects. The aim of the study was to unveil the unknown and possible cardioprotective targets that can be exerted by sitagliptin (Sitg) against ischemia-reperfusion (I/R) injury. Male wistar rats received 2 weeks’ Sitg oral treatment of different doses (25, 50, 100, and 150 mg/kg/day), or saline as a Control. Hearts were then isolated and subjected to two different I/R injury protocols: 10 min perfusion, 45 min regional ischemia, and 120 min reperfusion for infarct size (IS) measurement, or: 10 min perfusion, 45 min regional ischemia and 10 min reperfusion for biochemical analysis: nitric oxide synthases (NOSs) and DPP-4 activity, glucagon-like peptide-1 (GLP-1), Calcium, transient receptor potential vanilloid (TRPV)-1 and calcitonin gene-related peptide (CGRP) levels, transient receptor potential canonical (TRPC)-1 and e-NOS protein expression. NOS inhibitor (l-NAME) and TRPV-1 inhibitor (Capsazepine) were utilized to confirm the implication of both signaling mechanisms in DPP-4 inhibition-induced at the level of IS. Findings show that Sitg (50 mg) resulted in significant decrease in IS and DPP-4 activity, and significant increase in GLP-1, NOS activity, e-NOS expression, TRPV-1 level and TRPC-1 expression, compared to controls. Results of CGRP are in line with TRPV-1, as a downstream regulatory effect. NOS system and transient receptor potential (TRP) channels can contribute to DPP-4 inhibition-mediated cardioprotection against I/R injury using Sitagliptin.

Myocardial extracellular matrix (ECM) is essential for proper cardiac function and structural integrity; thus, the disruption of ECM homeostasis is associated with several pathological processes. Female Wistar rats underwent surgical ovariectomy (OVX) or sham operation (SO) and were then divided into eight subgroups based on the type of diet (standard chow or high-triglyceride diet/HT) and exercise (with or without running). After 12 weeks, cardiac MMP-2 activity, tissue inhibitor of metalloproteinase-2, content of collagen type I, the level of nitrotyrosine (3-NT) and glutathione (GSH), and the ratio of infarct size were determined. Our results show that OVX and HT diet caused an excessive accumulation of collagen; however, this increase was not observed in the trained animals. Twelve weeks of exercise promoted elevation in the levels of 3-NT and GSH and similarly an increase in MMP-2 activity of both SO and OVX animals. The high infarct-size ratio caused by OVX and HT diet was mitigated by physical exercise. Our findings demonstrate that ovarian estrogen loss and HT diet caused collagen accumulation and increased ratio of the infarct size. However, exercise-induced cardiac remodeling serves as a compensatory mechanism by enhancing MMP-2 activity and reducing fibrosis, thus minimizing the ischemia/reperfusion injury.

Hydrogen sulfide (HS) is an endogenous mediator that contributes to many important physiological processes including vasodilation and vascular smooth muscle relaxation; in turn, preventing tissue damage and reducing inflammation. Heme oxygenase (HO) enzymes, of which HO-1 is inducible by harmful stimuli, were found to regulate intestinal inflammation in experimental animal models of colitis. We aimed to investigate the protective effects of HS against 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis in rats, and whether HO enzyme system is involved in the HS-induced colonic cytoprotection. Male Wistar rats were treated with TNBS to induce colitis, and HS donor (Lawesson's reagent) was prepared two times/day at different concentrations, and delivered per os (from day 1 to day 3). Our results suggest that daily treatment (2 times/day) with HS donor, could significantly decrease the extent of colonic inflammation compared to vehicle treatment, and the most effective daily dose of HS donor against inflammation was 18.75 µM/kg/day. Per os administration of HS donor increased the colonic HO enzyme activity; on the contrary, the protective effect of HS was abolished by the co-treatment with HO inhibitor. Our findings suggest that HS confers colonoprotection, probably by modulation of anti-inflammatory parameters and HO enzyme activity.

Aging is a multifactorial process, which is considered as a decline over time. It is increasingly clear that there is a gender difference in aging and in the prevalence of age-related diseases as well. We aimed to examine the effects of the aging process in the colonic tissue of female Wistar rats aged 10 weeks (young) and 13 months (middle-aged) at an early stage, according to three main symptoms associated with aging: a decrease in the efficacy of the proteasome and muscle function and an increase in oxidative stress. The aging process was found to cause a significant decrease in ubiquitin C-terminal hydrolase ligase (UCHL-1) and a significant increase in 3-nitrotyrosine (3-NT), total glutathione (GSH), calcium (Ca2+), calcitonin gene-related peptide (CGRP) and superoxide dismutase (SOD) activity in middle-aged animals. In summary, it is suggested that the reduced activity of the proteasomal degradation system may be the result of the diminished expression of the UCHL-1 enzyme and the decreased levels of ubiquitin; furthermore, we found some key targets which may help to better understand the fundamental aging process.

No abstract

Background Cardiac troponin T (cTnT) and troponin I (cTnI) are expressed as an obligate 1:1 complex in the myocardium. However, blood levels of cTnI often rise much higher than cTnT in myocardial infarction (MI), whereas cTnT is often higher in patients with stable conditions such as atrial fibrillation. Here we examine hs-cTnI and hs-cTnT after different durations of experimental cardiac ischemia. Methods hs-cTnI, hs-cTnT, and the hs-cTnT/hs-cTnI ratio were measured in plasma samples from rats before and at 30 and 120 minutes after 5, 10, 15, and 30 minutes of myocardial ischemia. The animals were killed after 120 minutes of reperfusion, and the infarct volume and volume at risk were measured. hs-cTnI, hs-cTnT, and the hs-cTnT/hs-cTnI ratio were also measured in plasma samples collected from patients with ST-elevation myocardial infarction. Results hs-cTnT and hs-cTnI increased over ten-fold in all rats subjected to ischemia. The increase of hs-cTnI and hs-cTnT after 30 minutes was similar, resulting in a hs-cTnI/hs-cTnT ratio around 1. The hs-cTnI/hs-cTnT ratio was also around 1 in blood samples collected at 120 minutes in rats subjected to 5 or 10 minutes of ischemia where no localized necrosis was observed. In contrast, the hs-cTnI/hs-cTnT ratio at 2 hours was 3.6-5.5 after longer ischemia that induced cardiac necrosis. The large hs-cTnI/hs-cTnT ratio was confirmed in patients with anterior STEMI. Conclusion Both hs-cTnI and hs-cTnT increased similarly after brief periods of ischemia that did not cause overt necrosis, whereas the hs-cTnI/hs-cTnT ratio tended to increase following longer ischemia that induced substantial necrosis. A low hs-cTnI/hs-cTnT ratio around 1 may signify non-necrotic cTn release.

No abstract