SummaryThe citric acid cycle (CAC) metabolite fumarate has been proposed to be cardioprotective; however, its mechanisms of action remain to be determined. To augment cardiac fumarate levels and to assess fumarate's cardioprotective properties, we generated fumarate hydratase (Fh1) cardiac knockout (KO) mice. These fumarate-replete hearts were robustly protected from ischemia-reperfusion injury (I/R). To compensate for the loss of Fh1 activity, KO hearts maintain ATP levels in part by channeling amino acids into the CAC. In addition, by stabilizing the transcriptional regulator Nrf2, Fh1 KO hearts upregulate protective antioxidant response element genes. Supporting the importance of the latter mechanism, clinically relevant doses of dimethylfumarate upregulated Nrf2 and its target genes, hence protecting control hearts, but failed to similarly protect Nrf2-KO hearts in an in vivo model of myocardial infarction. We propose that clinically established fumarate derivatives activate the Nrf2 pathway and are readily testable cytoprotective agents.

The recent COVID-19 pandemic led to uncertainty and severe health and economic concerns. Previous studies indicated that owning a companion animal, such as a dog or a cat, has benefits for good mental health. Interactions with animals may help with depression and anxiety, particularly under stress-prone conditions. Human–animal interactions may even improve peer-to-peer social relationships, as well as enhance feelings of respect, trust, and empathy between people. Interestingly, it has also been shown that stress and poor well-being of dog owners negatively affect the well-being of their companion animals. However, a dramatic increase in dog abandonment could potentially occur due to COVID-19 related health, economic and social stresses, as well as due to the inconclusive reports of companion animals being potential COVID-19 carriers. Such a scenario may lead to high costs and considerable public health risks. Accordingly, we hypothesized that the COVID-19 pandemic, and the related social isolation, might lead to dramatic changes in human–dog bidirectional relationships. Using unique prospective and retrospective datasets, our objectives were to investigate how people perceived and acted during the COVID-19 pandemic social isolation, in regards to dog adoption and abandonment; and to examine the bidirectional relationship between the well-being of dog owners and that of their dogs. Overall, according to our analysis, as the social isolation became more stringent during the pandemic, the interest in dog adoption and the adoption rate increased significantly, while abandonment did not change. Moreover, there was a clear association between an individual’s impaired quality of life and their perceptions of a parallel deterioration in the quality of life of their dogs and reports of new behavioral problems. As humans and dogs are both social animals, these findings suggest potential benefits of the human–dog relationships during the COVID-19 pandemic, in accordance with the One Welfare approach that implies that there is a bidirectional connection between the welfare and health of humans and non-human animals. As our climate continues to change, more disasters including pandemics will likely occur, highlighting the importance of research into crisis-driven changes in human–animal relationships.

BackgroundInhibition of glucose oxidation during initial reperfusion confers protection against ischemia-reperfusion (IR) injury in the heart. Mitochondrial metabolism is altered with progression of type 2 diabetes (T2DM). We hypothesized that the metabolic alterations present at onset of T2DM induce cardioprotection by metabolic shutdown during IR, and that chronic alterations seen in late T2DM cause increased IR injury.MethodsIsolated perfused hearts from 6 (prediabetic), 12 (onset of T2DM) and 24 (late T2DM) weeks old male Zucker diabetic fatty rats (ZDF) and their age-matched heterozygote controls were subjected to 40 min ischemia/120 min reperfusion. IR injury was assessed by TTC-staining. Myocardial glucose metabolism was evaluated by glucose tracer kinetics (glucose uptake-, glycolysis- and glucose oxidation rates), myocardial microdialysis (metabolomics) and tissue glycogen measurements.ResultsT2DM altered the development in sensitivity towards IR injury compared to controls. At late diabetes ZDF hearts suffered increased damage, while injury was decreased at onset of T2DM. Coincident with cardioprotection, oxidation of exogenous glucose was decreased during the initial and normalized after 5 minutes of reperfusion. Metabolomic analysis of citric acid cycle intermediates demonstrated that cardioprotection was associated with a reversible shutdown of mitochondrial glucose metabolism during ischemia and early reperfusion at onset of but not at late type 2 diabetes.ConclusionsThe metabolic alterations of type 2 diabetes are associated with protection against IR injury at onset but detrimental effects in late diabetes mellitus consistent with progressive dysfunction of glucose oxidation. These findings may explain the variable efficacy of cardioprotective interventions in individuals with type 2 diabetes.

The recent COVID-19 pandemic led to uncertainty and severe health and economic concerns, which may have impacted human-dog relationships. Our objectives were to investigate how people perceived and acted during the COVID-19 pandemic social isolation, in regards to dog adoption and abandonment; and to examine the bidirectional relationships between dog owners’ well-being to that of their dogs. Overall, according to our analysis, the stricter the social isolation became during the pandemic, the interest in dog adoption as well as adoption rate increased significantly, while abandonment did not change. Moreover, there was a clear association between individuals’ impaired quality of life and their perceptions of poorer life quality of their dogs as well as the development of new behavioral problems. These findings suggest potential benefits for human-dog relationship during the COVID-19 pandemic, in compliance with the One Welfare approach.

We here report molecular investigations of a missense mutation in the HSPE1 gene encoding the HSP10 subunit of the HSP60/ HSP10 chaperonin complex that assists protein folding in the mitochondrial matrix. The mutation was identified in an infant who came to clinical attention due to infantile spasms at 3 months of age. Clinical exome sequencing revealed heterozygosity for a HSPE1 NM_002157.2:c.217C>T de novo mutation causing replacement of leucine with phenylalanine at position 73 of the HSP10 protein. This variation has never been observed in public exome sequencing databases or the literature. To evaluate whether the mutation may be disease-associated we investigated its effects by in vitro and ex vivo studies. Our in vitro studies indicated that the purified mutant protein was functional, yet its thermal stability, spontaneous refolding propensity, and resistance to proteolytic treatment were profoundly impaired. Mass spectrometric analysis of patient fibroblasts revealed barely detectable levels of HSP10-p.Leu73Phe protein resulting in an almost 2-fold decrease of the ratio of HSP10 to HSP60 subunits. Amounts of the mitochondrial superoxide dismutase SOD2, a protein whose folding is known to strongly depend on the HSP60/HSP10 complex, were decreased to approximately 20% in patient fibroblasts in spite of unchanged SOD2 transcript levels. As a likely consequence, mitochondrial superoxide levels were increased about 2-fold. Although, we cannot exclude other causative or contributing factors, our experimental data support the notion that the HSP10-p.Leu73Phe mutation could be the cause or a strong contributing factor for the disorder in the described patient.

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The clinical findings indicated that some LMNA mutations may be associated with a favourable prognosis and a low risk of sudden death. Protein expression studies suggested that a severe outcome was associated with the expression of high amounts of mutated protein. These findings may prove to be helpful in counselling and risk assessment of LMNA families.