We studied the influence of experimentally induced DM1, in combination with different dietary n6:n3 polyunsaturated fatty acid (PUFA) ratios on different types of nerve fibers in rat myocardium, in order to reveal whether protective/unfavorable effects of different PUFAs on myocardial function in diabetic patients could be a (partial) repercussion of their effect on the changes in cardiac innervation. The control group (c) and diabetic group (stz) were fed with an n6/n3 ratio of ≈7; the diet of the stz+n6 group had an n6/n3 ratio ≈60, while the diet for the stz+DHA group contained 2.5% of fish oil (containing 16% eicosapentaenoic acid—EPA and 19% docosahexaenoic acid—DHA), n6/n3 ratio of ≈1. DM1 was induced by i.p. injection of streptozotocin (55 mg/kg) and rats were euthanized 30 days after induction. Immunohistochemistry was used for the detection and quantification of different types of neuronal fibers in the cardiac septum. We found changes in cardiac innervations characteristics for the initial phase of experimental DM1, which manifested as an increase in total number and area density of all neuronal fibers, measured by Pgp9.5 immunoreactivity. By detailed analysis, we found that this increase consisted mostly of heavy myelinated NF200 immunoreactive fibers and TH immunoreactive sympathetic fibers, while the density of ChAT immunoreactive parasympathetic fibers decreased. In the deep (middle) part of the myocardium, where rare fibers (of all studied types) were found, significant differences were not found. Surprisingly, we found a more consistent protective effect of n6 PUFAs, in comparison to n3 PUFAs supplementation. These results may provide a better understanding of the potential impacts of different PUFA ratios in the diet of diabetic patients on cardiac innervation and genesis and outcome of diabetic autonomic cardiomyopathy.

Background/Objectives: The mitochondrial unfolded protein response (UPRmt) is one of the mitochondrial quality control mechanisms that is responsible for reparation and removal of damaged proteins in mitochondria. Methods: Here we investigated the role of the UPRmt in the myocardium of humans with and without heart failure and in the cell culture model. Results: The analysis of myocardial samples by ELISA from patients with ischemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM), as well as healthy donors, revealed a significantly reduced expression of the UPRmt proteins HSP10, CLPP, LONP1, OMA1, and SPG7 in patients with DCM and ICM. Furthermore, patients with DCM and ICM exhibited elevated levels of myocardial reactive oxygen species (ROS, tested by 4-hydroxynonenal) compared to controls, and a positive correlation between ROS production and mt-HSP70, OMA1, and SPG7 protein expression. The correlation analysis indicated a negative correlation between cardiomyocyte hypertrophy and the expression of several UPRmt genes. The inhibition of four tested UPRmt effector proteins exacerbated the injury of cultured cells under oxidative stress. The patients with ICM, DCM, or both, who showed lower myocardial expression of HSP10, HSP60, HTRA2, OMA1, SPG7, and YME1L, underwent heart transplantation or implantation of a left ventricular assist device earlier in life compared to those with the higher protein expression. Conclusions: In conclusion, our findings indicate that the reduced expression of several UPRmt effector proteins is associated with accelerated heart failure in patients, which, together with other results, indicates that impaired UPRmt may contribute to the pathogenesis of heart failure in humans.

Precision medicine is a developing trend in oncology, and it includes the prognosis and treatment of advanced-stage ccRCC. New predictive factors and therapeutic targets for this disease are steadily needed. The aim of this study was to explore the tumor expression of inversin as a potential prognostic factor and/or therapeutic target in ccRCC. We compared the expression of inversin between primary ccRCC and normal renal tissues by using immunohistochemistry and rtPCR in our cohort, and we also analyzed publicly available data from the TCGA-KIRC cohort. We found that the expression of inversin was significantly lower in primary tumor tissue, in comparison to solid normal tissue. Data from the KIRC study confirmed that a lower INVS expression level in ccRCC was significantly related with the overall and disease-specific survival, as well as with a shorter progression-free interval (p < 0.05). Four out of ten inversin interactome partners were significantly related with the overall and disease-specific survival in ccRCC. A lower expression of ANKS6 was a negative survival predictor, while a higher expression of NPHP3, DVL1, or DVL3 was related with a lower survival. The expression of INVS and its interactome partners in ccRCC was correlated with the differentiation of the tumor and metastasis. The expression of INVS and its partners was also correlated with tumor leukocyte infiltration and the expression of immune checkpoint genes. The results of this study point to inversin and a distinguished group of its interactome partners as potential prognostic factors in ccRCC, with their predominant involvement in the modulation of the inflammatory infiltration of the tumor microenvironment and a strong relationship with the metastatic potential of the tumor.

A 44-year-old female patient with chemotherapy-induced cardiomyopathy presented with acute cardiogenic shock requiring ECMO support. Multiple failed weaning trials from temporary mechanical circulatory assistance prompted a transition to staged durable biventricular support. Her course was complicated with recurrent RVAD stoppages. The initial event was treated with pump exchange, while for the subsequent RVAD standstill, we employed a device wash-out and reimplantation strategy. A brief period of circulatory arrest was employed to explore the right-sided cardiac chambers using a single-use bronchoscope.