Previous studies have demonstrated the protective signaling of hypoxia-inducible factor (HIF)-1 ␣ against ischemia-reperfusion (I/R) injury in the heart. In the present study, we provide further evidence for a cardioprotective mechanism by HIF-1␣ against I/R injury exerted via the mitochondrial protein frataxin, which regulates mitochondrial Fe-S cluster formation. Disruption of frataxin has been found to induce mitochondrial iron overload and subsequent ROS production. We observed that frataxin expression was elevated in mice hearts subjected to I/R injury, and this response was blunted in cardiomyocyte-specific HIF-1␣ knockout (KO) mice. Furthermore, these HIF-1␣ KO mice sustained extensive cardiac damage from I/R injury compared with control mice. Similarly, reduction of HIF-1␣ by RNA inhibition resulted in an attenuation of frataxin expression in response to hypoxia in H9C2 cardiomyocytes. Therefore, we postulated that HIF-1␣ transcriptionally regulates frataxin expression in response to hypoxia and offers a cardioprotective mechanism against ischemic injury. Our promoter activity and chromatin immunoprecipitation assays confirmed the presence of a functional hypoxia response element in the frataxin promoter. Our data also suggest that increased frataxin mitigated mitochondrial iron overload and subsequent ROS production, thus preserving mitochondrial membrane integrity and viability of cardiomyocytes. We postulate that frataxin may exert its beneficial effects by acting as an iron storage protein under hypoxia and subsequently facilitates the maintenance of mitochondrial membrane potential and promotes cell survival. The findings from our study revealed that HIF-1␣-frataxin signaling promotes a protective mechanism against hypoxic/ischemic stress.hypoxia-inducible factor-1␣; frataxin; iron-sulfur; mitochondria; ischemia-reperfusion NEWS & NOTEWORTHYThe present study provides evidence for a cardioprotective transcriptional regulatory mechanism by hypoxia-inducible factor-1␣ of the mitochondrial protein frataxin against ischemia-reperfusion injury. Frataxin regulates mitochondrial Fe-S cluster formation and protects against mitochondrial iron overload, the subsequent ROS production, and myocardial energy dysregulation.

(DOX) is a highly effective anti-neoplastic agent; however, its cumulative dosing schedules are clinically limited by the development of cardiotoxicity. Previous studies have attributed the cause of DOXmediated cardiotoxicity to mitochondrial iron accumulation and the ensuing reactive oxygen species (ROS) formation. The present study investigates the role of frataxin (FXN), a mitochondrial iron-sulfur biogenesis protein, and its role in development of DOX-mediated mitochondrial dysfunction. Athymic mice treated with DOX (5 mg/ kg, 1 dose/wk with treatments, followed by 2-wk recovery) displayed left ventricular hypertrophy, as observed by impaired cardiac hemodynamic performance parameters. Furthermore, we also observed significant reduction in FXN expression in DOX-treated animals and H9C2 cardiomyoblast cell lines, resulting in increased mitochondrial iron accumulation and the ensuing ROS formation. This observation was paralleled in DOX-treated H9C2 cells by a significant reduction in the mitochondrial bioenergetics, as observed by the reduction of myocardial energy regulation. Surprisingly, similar results were observed in our FXN knockdown stable cell lines constructed by lentiviral technology using short hairpin RNA. To better understand the cardioprotective role of FXN against DOX, we constructed FXN overexpressing cardiomyoblasts, which displayed cardioprotection against mitochondrial iron accumulation, ROS formation, and reduction of mitochondrial bioenergetics. Lastly, our FXN overexpressing cardiomyoblasts were protected from DOX-mediated cardiac hypertrophy. Together, our findings reveal novel insights into the development of DOX-mediated cardiomyopathy.anthracyclines; frataxin; cardiomyopathy; iron overload; mitochondrial damage; oxidative stress DOXORUBICIN (DOX) IS ONE OF the most widely used anti-neoplastic agents used for the treatment of a wide range of solid tumors and leukemia in children and adults (10,36,40). Despite its therapeutic usage, the clinical use of DOX is severely limited due to its cumulative dose-dependent cardiotoxicity, which develops over time into congestive heart failure (30). During this process, mitochondrial dysfunction has been observed to be fundamentally involved in the development of heart failure due to the dysregulation of mitochondrial bioenergetics and the generation of intracellular reactive oxygen species (ROS). The mechanism of DOX-induced cardiotoxicity at the cellular and subcellular levels is highly debatable. However, much attention has been attributed to the DOX-mediated formation of mitochondrial ROS. Although the role of iron has not been emphasized in the failing myocardial model, the role of iron in the formation of ROS has gained significance at the clinical setting with the usage of dexrazoxane (DXZ). DXZ, an iron chelator, is known to induce degradation of topo2␤ and prevent the DOX-mediated initiation of the DNA damage signal, H2AX-␥, in H9C2 cardiomyoblasts (28). However, the use of DXZ has been limited due to its interference with antitumor acti...

Buffaloes represent a major source of milk production, especially in developing countries including Egypt. The buffalo foot is frequently involved in a large proportion of lameness cases. The relatively small size and complexity of its structures often render the radiographic evaluation of the foot challenging. Magnetic resonance imaging (MRI) is a noninvasive imaging technique that is regarded as both safe and accurate for assessment of the foot disorders in both man and animals. The purpose of the current investigation was to describe the MRI anatomy of buffalo foot using cadaveric hind feet. The feet were subjected to consecutive MRI scanning using a 0.3 Tesla scanner. Both T1-weighted (T1-W) and T2-weighted (T2-W) spin-echo pulse sequences were applied in dorsal, sagittal and transverse planes. The heterogeneity of signal intensities noted amongst foot components allowed for clear differentiation of bones, tendons, ligaments, adipose tissue and synovial fluid. The T1-W images provided an excellent overview of the foot. They were valuable for visualizing the bones and the alignment of tendons and ligaments. The T2-W images were particularly useful for the evaluation of synovial structures such as tendon sheaths and joint cavities. A communication between the two plantar sacs of the metatarsophalangeal (fetlock) joints was evident in T2-W images. MRI findings were further confirmed using relevant gross anatomical sections. The present study establishes a detailed MRI anatomic reference of buffalo foot that could help veterinary researchers, clinicians and surgeons for increasing the accuracy of interpretation of foot MRI scans of both healthy and diseased animals.

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Promising therapy is needed for treating inflammatory bowel diseases (IBD) to overcome current treatment that inefficient and associated with unnecessary health risks. Recently, the concept of incorporating natural products into nanocarriers has been intended as a promising therapy for treating IBD via modulating their stability and bioavailability. Thus, we aimed to explore the potential alleviating effects of dietary nano-supplement combined with bacillus strains (Bacillus amyloliquefaciens; BANPs) in colitis model. Rats were orally gavaged by 5% DSS and the efficacy and mechanistic actions of BANPs were evaluated by assessing the severity of clinical signs and inflammatory and apoptosis response, histopathological and immunohistochemistry examination in colonic tissues. The severity of clinical signs was successfully alleviated and fecal Lcn-2 levels, an important colitic marker, were decreased in BANPs then free BA treated groups. In contrast, inflammatory markers overexpression IL-6, IL-1β, TNFα, COX-2, and iNOS in the colitic group were reduced more prominently in BANPs treated group, unlike free BA. The amelioration of BANPs to colon injury was also correlated with oxidative stress suppression along with restoring total antioxidant capacity. Interestingly, BANPs treatment modulated apoptotic markers as proved by downregulation of cytochrome c, and caspase-3 and upregulation of Bcl-2 and Bax than free BA. The severity of the histopathological alterations in the colon was greatly reduced in BANPs than free BA groups. Remarkably, over-expression of ki67 and IL-6 in colonic tissues were suppressed in BANPs group. These findings together highlighted the beneficial efficacy of BANPs in IBD treatment which are evidenced by colonic inflammation alleviation. Taken together, these results recommend that BANPs is a promising agent that encourages its possible therapeutic role in colitis treatment.