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Immobility is a risk factor for thrombosis due to low blood flow, which may result in activation of the coagulation system, recruitment of platelets and clot formation. Nevertheless, hibernating animals—who endure lengthy periods of immobility—do not show signs of thrombosis throughout or after hibernation. One of the adaptations of hemostasis in hibernators consists of a rapidly reversible reduction of the number of circulating platelets during torpor, i.e., the hibernation phase with reduction of metabolic rate, low blood flow and immobility. It is unknown whether these platelet dynamics in hibernating hamsters originate from storage and release, as suggested for ground squirrel, or from breakdown and de novo synthesis. A reduction in detaching forces due to low blood flow can induce reversible adhesion of platelets to the vessel wall, which is called margination. Here, we hypothesized that storage-and-release by margination to the vessel wall induces reversible thrombocytopenia in torpor. Therefore, we transfused labeled platelets in hibernating Syrian hamster (Mesocricetus auratus) and platelets were analyzed using flow cytometry and electron microscopy. The half-life of labeled platelets was extended from 20 to 30 h in hibernating animals compared to non-hibernating control hamsters. More than 90% of labeled platelets were cleared from the circulation during torpor, followed by emergence during arousal which supports storage-and-release to govern thrombocytopenia in torpor. Furthermore, the low number of immature platelets, plasma level of interleukin-1α and normal numbers of megakaryocytes in bone marrow make platelet synthesis or megakaryocyte rupture via interleukin-1α unlikely to account for the recovery of platelet counts upon arousal. Finally, using large-scale electron microscopy we revealed platelets to accumulate in liver sinusoids, but not in spleen or lung, during torpor. These results thus demonstrate that platelet dynamics in hibernation are caused by storage and release of platelets, most likely by margination to the vessel wall in liver sinusoids. Translating the molecular mechanisms that govern platelet retention in the liver, may be of major relevance for hemostatic management in (accidental) hypothermia and for the development of novel anti-thrombotic strategies. Supplementary Information The online version contains supplementary material available at 10.1007/s00360-021-01351-3.

BACKGROUND: Sepsis not only leads to short-term mortality during hospitalization, but is also associated with increased mortality during long-term follow-up after hospital discharge. Metabolic stress during sepsis may cause oxidative damage to both nuclear and mitochondrial DNA (mtDNA) and RNA, which could affect long-term health and life span. Therefore, the aim of this study was to assess the association of sepsis with oxidized nucleobases and (mt)DNA damage and long-term all-cause mortality in septic patients.METHODS: 91 patients with sepsis who visited the emergency department (ED) of the University Medical Center Groningen between August 2012 and June 2013 were included. Urine and plasma were collected during the ED visit. Septic patients were matched with 91 healthy controls. Death rate was obtained until June 2020.The degree of oxidation of DNA, RNA and free nucleobases were assessed in urine by mass-spectrometry. Lipid peroxidation was assessed in plasma using a TBAR assay. Additionally, plasma levels of mtDNA and damage to mtDNA were determined by qPCR.RESULTS: Sepsis patients denoted higher levels of oxidated DNA, RNA, free nucleobases and lipid peroxidation than controls (all p CONCLUSIONS: Sepsis is accompanied with oxidation of nuclear and mitochondrial DNA and RNA, where RNA oxidation is an independent predictor of long-term all-cause mortality. In addition, sepsis causes mtDNA damage and an increase in cell free mtDNA in plasma.

Acute kidney injury (AKI) is a global healthcare burden attributable to high mortality and staggering costs of dialysis. The underlying causes of AKI include hypothermia and rewarming (H/R), ischemia/reperfusion (I/R), mitochondrial dysfunction and reactive oxygen species production. Inspired by the mechanisms conferring organ protection in hibernating hamster, 6-chromanol derived compounds were developed to address the need of effective prevention and treatment of AKI. Here we report on the pre-clinical screening of 6-chromanol leads that confer protection during I/R to select compounds with favorable profiles for clinical testing in AKI. A library of 6-chromanols (n = 63) was screened in silico for pharmacochemical properties and druggability. Selected compounds (n = 15) were screened for the potency to protect HEK293 cells from H/R cell death and subjected to a panel of in vitro safety assays. Based on these parameters, SUL-138 was selected as the lead compound and was found to safeguard kidney function and decrease renal injury after I/R in rats. The compound was without cardiovascular or respiratory effects in vivo. SUL-138 pharmacokinetics of control animals (mouse, rat) and those undergoing I/R (rat) was identical, showing a two-phase elimination profile with terminal half-life of about 8 h. Collectively, our phenotype-based screening approach led to the identification of 3 candidates for pre-clinical studies (5%, 3/64). SUL-138 emerged from this small-scale library of 6-chromanols as a novel prophylactic for AKI. The presented efficacy and safety data provide a basis for future development and clinical testing. Section assignments:: Drug discovery and translational medicine, renal, metabolism Significance statement:: Based on in silico druggability parameters, a 63 compound 6-chromanol library was narrowed down to 15 compounds. These compounds were subjected to phenotypical screening of cell survival following hypothermia damage and hit compounds were identified. After subsequent assessment of in vivo efficacy, toxicity, pharmacokinetics, and cardiovascular and respiratory safety, SUL-138 emerged as a lead compound that prevented kidney injury after ischemia/reperfusion and demonstrated a favorable pharmacokinetic profile unaffected by renal ischemia.

Background Sepsis is a life-threatening condition accompanied by organ dysfunction subsequent to a dysregulated host response to infection. Up to 60% of patients with sepsis develop acute kidney injury (AKI), which is associated with a poor clinical outcome. The pathophysiology of sepsis-associated AKI (sepsis-AKI) remains incompletely understood, but mitochondria have emerged as key players in the pathogenesis. Therefore, our aim was to identify mitochondrial damage in patients with sepsis-AKI. Methods We conducted a clinical laboratory study using “warm” postmortem biopsies from sepsis-associated AKI patients from a university teaching hospital. Biopsies were taken from adult patients (n = 14) who died of sepsis with AKI at the intensive care unit (ICU) and control patients (n = 12) undergoing tumor nephrectomy. To define the mechanisms of the mitochondrial contribution to the pathogenesis of sepsis-AKI, we explored mRNA and DNA expression of mitochondrial quality mechanism pathways, DNA oxidation and mitochondrial DNA (mtDNA) integrity in renal biopsies from sepsis-AKI patients and control subjects. Next, we induced human umbilical vein endothelial cells (HUVECs) with lipopolysaccharide (LPS) for 48 h to mimic sepsis and validate our results in vitro. Results Compared to control subjects, sepsis-AKI patients had upregulated mRNA expression of oxidative damage markers, excess mitochondrial DNA damage and lower mitochondrial mass. Sepsis-AKI patients had lower mRNA expression of mitochondrial quality markers TFAM, PINK1 and PARKIN, but not of MFN2 and DRP1. Oxidative DNA damage was present in the cytosol of tubular epithelial cells in the kidney of sepsis-AKI patients, whereas it was almost absent in biopsies from control subjects. Oxidative DNA damage co-localized with both the nuclei and mitochondria. Accordingly, HUVECs induced with LPS for 48 h showed an increased mnSOD expression, a decreased TFAM expression and higher mtDNA damage levels. Conclusion Sepsis-AKI induces mitochondrial DNA damage in the human kidney, without upregulation of mitochondrial quality control mechanisms, which likely resulted in a reduction in mitochondrial mass.

Hydrogen sulfide (H2S) has long been recognized as a putrid, toxic gas. However, as a result of intensive biochemical research in the past two decades, H2S is now considered to be the third gasotransmitter alongside nitric oxide (NO) and carbon monoxide (CO) in mammalian systems. H2S-producing enzymes are expressed in all organs, playing an important role in their physiology. In the kidney, H2S is a critical regulator of vascular and cellular function, although the mechanisms that affect (sub)cellular levels of H2S are not precisely understood. H2S modulates systemic and renal blood flow, glomerular filtration rate and the renin-angiotensin axis through direct inhibition of nitric oxide synthesis. Further, H2S affects cellular function by modulating protein activity via post-translational protein modification: a process termed persulfidation. Persulfidation modulates protein activity, protein localization and protein-protein interactions. Additionally, acute kidney injury (AKI) due to mitochondrial dysfunction, which occurs during hypoxia or ischemia-reperfusion (IR), is attenuated by H2S. H2S enhances ATP production, prevents damage due to free radicals and regulates endoplasmic reticulum stress during IR. In this review, we discuss current insights in the (sub)cellular regulation of H2S anabolism, retention and catabolism, with relevance to spatiotemporal regulation of renal H2S levels. Together, H2S is a versatile gasotransmitter with pleiotropic effects on renal function and offers protection against AKI. Unraveling the mechanisms that modulate (sub)cellular signaling of H2S not only expands fundamental insight in the regulation of functional effects mediated by H2S, but can also provide novel therapeutic targets to prevent kidney injury due to hypoxic or ischemic injury.

Hibernation consists of alternating periods of reduced metabolism (torpor) with brief periods of metabolism similar to summer euthermia (arousal). The function of the innate immune system is reduced during hibernation, of which the underlying mechanisms are incompletely understood. Here, we studied neutrophil functionality during hibernation in Syrian hamsters. The inflammatory response to LPS-induced endotoxemia is inhibited in hibernation, partly mediated by reduced IL-6 production in early arousal. Furthermore, neutrophil pathogen binding, phagocytosis and oxidative burst is profoundly reduced in early arousal. Functionality of both summer and early arousal neutrophils was repressed in plasma from early arousal and mixed plasma from early arousal and summer euthermic, but restored by summer euthermic plasma, signifying that a plasma factor in early arousal inhibits TLR-recognition. Identification of the inhibiting factor may offer a target to modulate neutrophil function with relevance to (auto-)inflammatory diseases.

Significance: Sepsis is the main cause of death among patients admitted to the intensive care unit. As current treatment is limited to antimicrobial therapy and supportive care, mortality remains high, which warrants efforts to find novel therapies. Recent Advances: Mitochondrial dysfunction is emerging as a key process in the induction of organ dysfunction during sepsis, and metabolic resuscitation might reveal to be a novel cornerstone in the treatment of sepsis. Critical Issues: Here, we review novel strategies to maintain organ function in sepsis by precluding mitochondrial dysfunction by lowering energetic demand to allow preservation of adenosine triphosphate-levels, while reducing free radical generation. As the most common strategy to suppress metabolism, that is, cooling, does not reveal unequivocal beneficial effects and may even increase mortality, caloric restriction or modulation of energy-sensing pathways (i.e., sirtuins and AMP-activated protein kinase) may offer safe alternatives. Similar effects may be offered when mimicking hibernation by hydrogen sulfide (H2S). In addition H2S may also confer beneficial effects through upregulation of antioxidant mechanisms, similar to the other gasotransmitters nitric oxide and carbon monoxide, which display antioxidant and anti-inflammatory effects in sepsis. In addition, oxidative stress may be averted by systemic or mitochondria-targeted antioxidants, of which a wide range are able to lower inflammation, as well as reduce organ dysfunction and mortality from sepsis. Future Directions: Mitochondrial dysfunction plays a key role in the pathophysiology of sepsis. As a consequence, metabolic resuscitation might reveal to be a novel cornerstone in the treatment of sepsis.

Background. Mitochondrial dysfunction plays an important role in kidney damage in various pathologies, including acute and chronic kidney injury and diabetic nephropathy. In addition to the well-studied ischaemia/reperfusion (I/R) injury, hypothermia/rewarming (H/R) also inflicts acute kidney injury. Substituted 6-hydroxychromanols are a novel class of mitochondrial medicines that ameliorate mitochondrial oxidative stress and protect the mitochondrial network. To identify a novel 6-hydroxychromanol that protects mitochondrial structure and function in the kidney during H/R, we screened multiple compounds in vitro and subsequently assessed the efficacy of the 6-hydroxychromanol derivatives SUL-109 and SUL-121 in vivo to protect against kidney injury after H/R in rats.Methods. Human proximal tubule cell viability was assessed following exposure to H/R for 48/4 h in the presence of various 6-hydroxychromanols. Selected compounds (SUL-109, SUL-121) or vehicle were administered to ketamine-anaesthetized male Wistar rats (IV 135 mu g/kg/h) undergoing H/R at 15 degrees C for 3 h followed by rewarming and normothermia for 1 h. Metabolic parameters and body temperature were measured throughout. In addition, renal function, renal injury, histopathology and mitochondrial fitness were assessed.Results. H/R injury in vitro lowered cell viability by 94 +/- 61%, which was counteracted dose-dependently by multiple 6-hydroxy-chomanols derivatives. In vivo, H/R in rats showed kidney injury molecule 1 expression in the kidney and tubular dilation, accompanied by double-strand DNA breaks and protein nitrosylation. SUL-109 and SUL-121 ameliorated tubular kidney damage, preserved mitochondrial mass and maintained cortical adenosine 50-triphosphate (ATP) levels, although SUL-121 did not reduce protein nitrosylation.Conclusions. The substituted 6-hydroxychromanols SUL-109 and SUL-121 ameliorate kidney injury during in vivo H/R by preserving mitochondrial mass, function and ATP levels. In addition, both 6-hydroxychromanols limit DNA damage, but only SUL-109 also prevented protein nitrosylation in tubular cells. Therefore SUL-109 offers a promising therapeutic strategy to preserve kidney mitochondrial function.

Background. Perioperative acute kidney injury (AKI) is an important predictor of long-term all-cause mortality after coronary artery bypass (CABG). However, the effect of AKI on long-term mortality after cardiac valve operations is hitherto undocumented.Methods. Perioperative renal injury and long-term allcause mortality after valve operations were studied in a prospective cohort of patients undergoing solitary valve operations (n = 2,806) or valve operations combined with CABG (n = 1,260) with up to 18 years of follow-up. Postoperative serum creatinine increase was classified according to AKI staging 0 to 3. Patients undergoing solitary CABG (n = 4,938) with cardiopulmonary bypass served as reference.Results. In both valve and valve+CABG operations, postoperative renal injury of AKI stage 1 or higher was progressively associated with an increase in long-term mortality (hazard ratio [HR], 2.27, p Conclusions. An increase in serum creatinine by more than 10% during the first week after valve operation is associated with an increased risk for long-term mortality after cardiac valve operation. Thus, AKI classification clearly underestimates long-term mortality risk in patients undergoing valve operations. (C) 2018 by The Society of Thoracic Surgeons

Significance: Renal transplantation is the treatment of choice for end-stage renal disease, during which renal grafts from deceased donors are routinely cold stored to suppress metabolic demand and thereby limit ischemic injury. However, prolonged cold storage, followed by reperfusion, induces extensive tissue damage termed cold ischemia/reperfusion injury (IRI) and puts the graft at risk of both early and late rejection. Recent Advances: Deep hibernators constitute a natural model of coping with cold IRI as they regularly alternate between 4 degrees C and 37 degrees C. Recently, endogenous hydrogen sulfide (H2S), a gas with a characteristic rotten egg smell, has been implicated in organ protection in hibernation. Critical Issues: In renal transplantation, H2S also seems to confer cytoprotection by lowering metabolism, thereby creating a hibernation-like environment, and increasing preservation time while allowing cellular processes of preservation of homeostasis and tissue remodeling to take place, thus increasing renal graft survival. Future Directions: Although the underlying cellular and molecular mechanisms of organ protection during hibernation have not been fully explored, mammalian hibernation may offer a great clinical promise to safely cold store and reperfuse donor organs. In this review, we first discuss mammalian hibernation as a natural model of cold organ preservation with reference to the kidney and highlight the involvement of H2S during hibernation. Next, we present recent developments on the protective effects and mechanisms of exogenous and endogenous H2S in preclinical models of transplant IRI and evaluate the potential of H2S therapy in organ preservation as great promise for renal transplant recipients in the future.

Aims: Low levels of reactive oxygen species and resulting oxidative protein modifications may play a beneficial role in cellular function under stress conditions. Here we studied the influence of age-dependent protein carbonylation on expression and activity of the anti-oxidative selenoenzyme glutathione peroxidase(GPx) in insulin-deficient Ins2(Akita) mice and type 2 diabetic obese db/db mice in context of diabetic nephropathy.Methods: Protein carbonylation, GPx expression and activity were examined in kidney tissue and lysates by common histological and protein biochemical methods.Results: In kidneys of Ins2(Akita) mice, carbonylated proteins, GPx-1 and GPx-4 expression were mainly detected in podocytes and mesangial cells. GPx activity was increased in kidney cortex homogenates of these mice. Remarkably, young animals did not show a concomitant increase in GPx expression but enhanced GPx carbonylation. No carbonylation-dependent modification of GPx activity was detected in db/db mice. In cultured podocytes hyperglycemia induced an increase in GPx expression but had no effect on activity or carbonylation. In kidney tissue sections of type 1 or type 2 diabetes patients, GPx-1 and GPx-4 expression but not overall protein carbonylation was significantly decreased.Conclusions: These results indicate the existence of a threshold for beneficial carbonylation-dependent redox signaling during the progression of diabetic nephropathy. (C) 2017 Elsevier Inc. All rights reserved.

Atrial fibrillation (AF), the most common progressive tachyarrhythmia, results in structural remodeling which impairs electrical activation of the atria, rendering them increasingly permissive to the arrhythmia. Previously, we reported on endoplasmic reticulum stress and NAD+ depletion in AF, suggesting a role for mitochondrial dysfunction in AF progression. Here, we examined mitochondrial function in experimental model systems for AF (tachypaced HL-1 atrial cardiomyocytes and Drosophila melanogaster) and validated findings in clinical AF. Tachypacing of HL-1 cardiomyocytes progressively induces mitochondrial dysfunction, evidenced by impairment of mitochondrial Ca2+-handling, upregulation of mitochondrial stress chaperones and a decrease in the mitochondrial membrane potential, respiration and ATP production. Atrial biopsies from AF patients display mitochondrial dysfunction, evidenced by aberrant ATP levels, upregulation of a mitochondrial stress chaperone and fragmentation of the mitochondrial network. The pathophysiological role of mitochondrial dysfunction is substantiated by the attenuation of AF remodeling by preventing an increased mitochondrial Ca2+-influx through partial blocking or downregulation of the mitochondrial calcium uniporter, and by SS31, a compound that improves bioenergetics in mitochondria. Together, these results show that conservation of the mitochondrial function protects against tachypacing-induced cardiomyocyte remodeling and identify this organelle as a potential novel therapeutic target.

Gasotransmitters fulfill important roles in cellular homeostasis having been linked to various pathologies, including inflammation and cardiovascular diseases. In addition to the known pathways mediating the actions of gasotransmitters, their effects in regulating mitochondrial function are emerging. Given that mitochondria are key organelles in energy production, formation of reactive oxygen species and apoptosis, they are important mediators in preserving health and disease. Preserving or restoring mitochondrial function by gasotransmitters may be beneficial, and mitigate pathogenetic processes. In this review we discuss the actions of gasotransmitters with focus on their role in mitochondrial function and their therapeutic potential.

BackgroundSince the start of organ transplantation, hypothermia-forced hypometabolism has been the cornerstone in organ preservation. Cold preservation showed to protect against ischemia, although post-transplant injury still occurs and further improvement in preservation techniques is needed. We hypothesize that hydrogen sulphide can be used as such a new preservation method, by inducing a reversible hypometabolic state in human sized kidneys during normothermic machine perfusion.MethodsPorcine kidneys were connected to an ex-vivo isolated, oxygen supplemented, normothermic blood perfusion set-up. Experimental kidneys (n = 5) received a 85mg NaHS infusion of 100 ppm and were compared to controls (n = 5). As a reflection of the cellular metabolism, oxygen consumption, mitochondrial activity and tissue ATP levels were measured. Kidney function was assessed by creatinine clearance and fractional excretion of sodium. To rule out potential structural and functional deterioration, kidneys were studied for biochemical markers and histology.ResultsHydrogen sulphide strongly decreased oxygen consumption by 61%, which was associated with a marked decrease in mitochondrial activity/function, without directly affecting ATP levels. Renal biological markers, renal function and histology did not change after hydrogen sulphide treatment.ConclusionIn conclusion, we showed that hydrogen sulphide can induce a controllable hypometabolic state in a human sized organ, without damaging the organ itself and could thereby be a promising therapeutic alternative for cold preservation under normothermic conditions in renal transplantation.

BACKGROUND: Dysregulation of protein kinase-mediated signaling is an early event in many diseases, including the most common clinical cardiac arrhythmia, atrial fibrillation (AF). Kinomic profiling represents a promising technique to identify candidate kinases.OBJECTIVE: In this study we used kinomic profiling to identify kinases altered in AF remodeling using atrial tissue from a canine model of AF (atrial tachypacing).METHODS: Left atrial tissue obtained in a previous canine study was used for kinomic array (containing 1024 kinase pseudosubstrates) analysis. Three groups of dogs were included: nonpaced controls and atrial tachypaced dogs, which were contrasted with geranylgeranylacetone-treated dogs with AF, which are protected from AF promotion, to enhance specificity of detection of putative kinases.RESULTS: While tachypacing changed activity of 50 kinases, 40 of these were prevented by geranylgeranylacetone and involved in differentiation and proliferation (SRC), contraction, metabolism, immunity, development, cell cycle (CDK4), and survival (Akt). Inhibitors of Akt (MK2206) and CDK4 (PD0332991) and overexpression of a dominant-negative CDK4 phosphorylation mutant protected against tachypacing-induced contractile dysfunction in HL-1 cardiomyocytes. Moreover, patients with AF show down- and upregulation of SRC and Akt phosphorylation, respectively, similar to findings of the kinome array.CONCLUSION: Contrasting kinomic array analyses of controls and treated subjects offer a versatile tool to identify kinases altered in atrial remodeling owing to tachypacing, which include Akt, CDK4, and SRC. Ultimately, pharmacological targeting of altered kinases may offer novel therapeutic possibilities to treat clinical AF.

Hibernation consists of torpor, with marked suppression of metabolism and physiological functions, alternated with arousal periods featuring their full restoration. The heart is particularly challenged, exemplified by its rate reduction from 400 to 5–10 beats per minute during torpor in Syrian hamsters. In addition, during arousals, the heart needs to accommodate the very rapid return to normal function, which lead to our hypothesis that cardiac function during hibernation is supported by maintenance of protein homeostasis through adaptations in the protein quality control (PQC) system. Hereto, we examined autophagy, the endoplasmic reticulum (ER) unfolded protein (UPRER) response and the heat shock response (HSR) in Syrian hamster hearts during torpor and arousal. Transition from torpor to arousal (1.5 h) was associated with stimulation of the PQC system during early arousal, demonstrated by induction of autophagosomes, as shown by an increase in LC3B-II protein abundance, likely related to the activation of the UPRER during late torpor in response to proteotoxic stress. The HSR was not activated during torpor or arousal. Our results demonstrate activation of the cardiac PQC system – particularly autophagosomal degradation – in early arousal in response to cardiac stress, to clear excess aberrant or damaged proteins, being gradually formed during the torpor bout and/or the rapid increase in heart rate during the transition from torpor to arousal. This mechanism may enable the large gain in cardiac function during the transition from torpor to arousal, which may hold promise to further understand ‘hibernation’ of cardiomyocytes in human heart disease.

It has been firmly established that ageing constitutes a principal risk factor for cardiac disease. Currently, the underlying mechanisms of ageing that contribute to the initiation or acceleration of cardiac disease are essentially unresolved. Prevailing theories of ageing center on the loss of cellular protein homeostasis, by either design (genetically) or "wear and tear" (environmentally). Either or both ways, the normal protein homeostasis in the cell is affected, resulting in aberrant and misfolded proteins. Should such misfolded proteins escape the protein quality control (PQC) system, they become proteotoxic and accelerate the loss of cellular integrity. Impairment of PQC plays a prominent role in the pathophysiology of ageing-related neurodegenerative disorders such as Parkinson's, Huntington׳s, and Alzheimer׳s disease. The concept of an impaired PQC driving ageing-related diseases has recently been expanded to cardiac diseases, including atrial fibrillation, cardiac hypertrophy, and cardiomyopathy. In this review, we provide a brief overview of the PQC system in relation to ageing and discuss the emerging concept of the loss of PQC in cardiomyocytes as a trigger for cardiac disease. Finally, we discuss the potential of boosting the PQC system as an innovative therapeutic target to treat cardiac disease in the elderly.

Background: Post-transplant tuberculosis (PTTB) is a serious opportunistic infection in renal graft recipients with a 30-70 fold higher incidence compared to the general population. PTTB occurs most frequently within the first years after transplantation, manifesting as pulmonary or disseminated TB. Gastrointestinal TB (GITB) is a rare and potentially lethal manifestation of PTTB and may show delayed onset in renal transplant recipients due to the use of lower doses of immunosuppressants. Further, non-specificity of symptoms and the common occurrence of GI disorders in transplant recipients may delay diagnosis of GITB.Case presentation: Here we report a rare survival case of isolated GITB in a renal transplant recipient, occurring seven years after transplantation. The patient's condition was complicated by severe sepsis with positive blood culture Staphylococcus haemolyticus, septic shock, multiple organ failure including acute respiratory distress syndrome (ARDS) and acute renal failure, requiring mechanical ventilation, vasopressor circulatory support and intermittent hemodialysis. Furthermore, nosocomial infections such as invasive aspergillosis and Pseudomonas aeruginosa occurred during hospitalization. Antituberculosis therapy (rifampicin, isoniazid, ethambutol and pyrazinamide) was initiated upon Mycobacterium confirmation. Moreover, treatment with voriconazole due to the Aspergillus flavus and meropenem due to the Pseudomonas aeruginosa was initiated, the former necessitating discontinuation of rifampicin. After 34 days, the patient was weaned from mechanical ventilation and was discharged to the pulmonary ward, followed by complete recovery.Conclusion: This case offers a guideline for the clinical management towards survival of GITB in transplant patients, complicated by septic shock and multiple organ failure, including acute renal injury and ARDS.

The incidence and prevalence of cardiac diseases, which are the main cause of death worldwide, are likely to increase because of population ageing. Prevailing theories about the mechanisms of ageing feature the gradual derailment of cellular protein homeostasis (proteostasis) and loss of protein quality control as central factors. In the heart, loss of protein patency, owing to flaws in genetically-determined design or because of environmentally-induced 'wear and tear', can overwhelm protein quality control, thereby triggering derailment of proteostasis and contributing to cardiac ageing. Failure of protein quality control involves impairment of chaperones, ubiquitin-proteosomal systems, autophagy, and loss of sarcomeric and cytoskeletal proteins, all of which relate to induction of cardiomyocyte senescence. Targeting protein quality control to maintain cardiac proteostasis offers a novel therapeutic strategy to promote cardiac health and combat cardiac disease. Currently marketed drugs are available to explore this concept in the clinical setting.

Diabetic nephropathy is still a common complication of type 2 diabetes mellitus (T2DM) and improvement of endothelial dysfunction (ED) and inhibition of reactive oxygen species (ROS) are considered important targets for new therapies. Recently, we developed a new class of compounds (Sul compounds) which inhibit mitochondrial ROS production. Here, we tested the therapeutic effects of Sul-121 on ED and kidney damage in experimental T2DM. Diabetic db/db and lean mice were implanted with osmotic pumps delivering Sul-121 (2.2 mg/kg/day) or vehicle from age 10 to 18 weeks. Albuminuria, blood pressure, endothelial mediated relaxation, renal histology, plasma creatinine, and H2O2 levels were assessed. Sul-121 prevented progression of albuminuria and attenuated kidney damage in db/db, as evidenced by lower glomerular fibronectin expression (~50%), decreased focal glomerular sclerosis score (~40%) and normalization of glomerular size and kidney weight. Further, Sul-121 restored endothelium mediated vasorelaxation through increased production of Nitric Oxide production and normalized plasma H2O2 levels. Sul-121 treatment in lean mice demonstrated no observable major side-effects, indicating that Sul-121 is well tolerated. Our data show that Sul-121 inhibits progression of diabetic kidney damage via a mechanism that involves restoration of endothelial function and attenuation of oxidative stress.

Research on deep hibernators almost exclusively uses species captured from the wild or from local breeding. An exception is Syrian hamster (Mesocricetus auratus), the only standard laboratory animal showing deep hibernation. In deep hibernators, several factors influence hibernation quality, including body mass, sex and diet. We examined hibernation quality in commercially obtained Syrian hamsters in relation to body mass, sex and a diet enriched in polyunsaturated fatty acids. Animals (M/F:30/30, 12 weeks of age) were obtained from Harlan (IN, USA) and individually housed at 21 °C and L:D 14:10 until 20 weeks of age, followed by L:D 8:16 until 27 weeks. Then conditions were changed to 5 °C and L:D 0:24 for 9 weeks to induce hibernation. Movement was continuously monitored with passive infrared detectors. Hamsters were randomized to control diet or a diet 3× enriched in linoleic acid from 16 weeks of age. Hamsters showed a high rate of premature death (n = 24, 40%), both in animals that did and did not initiate torpor, which was unrelated to body weight, sex and diet. Time to death (31.7 ± 3.1 days, n = 12) or time to first torpor bout (36.6 ± 1.6 days, n = 12) was similar in prematurely deceased hamsters. Timing of induction of hibernation and duration of torpor and arousal was unaffected by body weight, sex or diet. Thus, commercially obtained Syrian hamsters subjected to winter conditions showed poor survival, irrespective of body weight, sex and diet. These factors also did not affect hibernation parameters. Possibly, long-term commercial breeding from a confined genetic background has selected against the hibernation trait. Electronic supplementary material The online version of this article (doi:10.1007/s00360-017-1072-y) contains supplementary material, which is available to authorized users.

Background Derailment of proteostasis, the homeostasis of production, function, and breakdown of proteins, contributes importantly to the self‐perpetuating nature of atrial fibrillation ( AF ), the most common heart rhythm disorder in humans. Autophagy plays an important role in proteostasis by degrading aberrant proteins and organelles. Herein, we investigated the role of autophagy and its activation pathway in experimental and clinical AF . Methods and Results Tachypacing of HL ‐1 atrial cardiomyocytes causes a gradual and significant activation of autophagy, as evidenced by enhanced LC 3B‐ II expression, autophagic flux and autophagosome formation, and degradation of p62, resulting in reduction of Ca 2+ amplitude. Autophagy is activated downstream of endoplasmic reticulum ( ER ) stress: blocking ER stress by the chemical chaperone 4‐phenyl butyrate, overexpression of the ER chaperone‐protein heat shock protein A 5, or overexpression of a phosphorylation‐blocked mutant of eukaryotic initiation factor 2α ( eIF 2α) prevents autophagy activation and Ca 2+ ‐transient loss in tachypaced HL ‐1 cardiomyocytes. Moreover, pharmacological inhibition of ER stress in tachypaced Drosophila confirms its role in derailing cardiomyocyte function. In vivo treatment with sodium salt of phenyl butyrate protected atrial‐tachypaced dog cardiomyocytes from electrical remodeling (action potential duration shortening, L‐type Ca 2+ ‐current reduction), cellular Ca 2+ ‐handling/contractile dysfunction, and ER stress and autophagy; it also attenuated AF progression. Finally, atrial tissue from patients with persistent AF reveals activation of autophagy and induction of ER stress, which correlates with markers of cardiomyocyte damage. Conclusions These results identify ER stress–associated autophagy as an important pathway in AF progression and demonstrate the potential therapeutic action of the ER ‐stress inhibitor 4‐phenyl butyrate.

Cystathionine beta synthase (CBS) is the main contributor to the production of hydrogen sulfide (H2S) in the brain. Exogenously administered H2S has been reported to protect neurons against hypoxic injury, ischemia and LPS-induced neuro-inflammation and in the facilitating of long term potentiation (LTP). Dysregulation of CBS leads to different diseases, which all have mental retardation in common. Although multiple studies have implicated a link between the CBS/H2S pathway and neurodegeneration, no studies have been performed examining the pathway in healthy aging animals. We hypothesize that CBS/H2S pathway plays an important role in the protection of learning and memory functions in the brain at the level of the hippocampus. Thus, we studied a set of 8 young (4 months) and 14 aged (24 months (n = 6) and 28 months (n = 8)) C57Bl6 mice. The 24-month-old mice displayed a significant decrease of CBS immunoreactivity in the MoDG only, compared to 4-month-old mice. In 28-month-old mice, we observed a significant increase of CBS immunoreactivity in the MoDG, compared to 4-month-old mice. When comparing 28-month-old mice to 24-month-old mice, all areas showed a significant increase of CBS immunoreactivity. Thus, throughout aging, CBS expression is maintained in the hippocampus, and many other forebrain regions as well. Mice at the unusual age of 28 months even have a higher hippocampal CBS expression than young mice. Maintenance (and increase) of CBS levels may sustain memory and learning by precluding neuronal loss in areas of the hippocampus.

Background: Diabetes and particularly high blood glucose levels are implicated in neurodegeneration. One of the hallmarks of neurodegeneration is protein aggregation. We investigated the presence of protein aggregation in the frontal brain of Zucker diabetic fatty (ZDF) rats, an animal model for diabetes. Further, the effect of NaHS in suppressing protein aggregation in cultured brain slices from ZDF was assessed.Results: The levels of protein synthesis, protein/gene expression, autophagy and anti-oxidant defense were evaluated in ZDF and control (Lean) brains.Compared to Lean, ZDF brains displayed a significant increase in protein aggregates, p-tau, fibronectin expression and protein glycosylation. Increased phosphorylation of mTOR and S6 ribosomal protein in ZDF indicated higher protein synthesis, while the increase in ubiquitinated proteins and LC3-I in ZDF brains accompanied by lower LC3-II expression and LC3-II/LC3-I levels indicated the blockage of proteolytic pathways. CBS (cystathionine beta synthase) protein and mRNA expression and thiol group levels in ZDF brains were lower compared to Lean. ZDF brains show a higher level of reactive oxygen species. In vitro NaHS treatment normalized proteostasis while counteracting oxidative stress.Conclusion: Our data demonstrate increased protein synthesis and aggregation in the diabetic ZDF rat brain, which was reversible by NaHS treatment. This is the first report on the potential use of NaHS as a novel strategy against protein aggregation in diabetic brain.

Peroxisome proliferator-activated receptor γ (PPARγ) agonists have been shown to ameliorate diabetic nephropathy, but much less are known about their effects in non-diabetic nephropathies. In the present study, metabolic parameters, blood pressure, aortic endothelial function along with molecular and structural markers of glomerular and tubulointerstitial renal damage, were studied in a rat model of normotensive nephropathy induced by adriamycin and treated with PPARγ agonist pioglitazone (12mg/kg, po), angiotensin converting enzyme (ACE) inhibitor ramipril (1mg/kg, po) or their combination. Pioglitazone had no effect on systolic blood pressure, marginally reduced glycemia and improved aortic endothelium-dependent relaxation. In the kidney, pioglitazone prevented the development of proteinuria and focal glomerulosclerosis to the similar extent as blood-pressure lowering ramipril. Renoprotection provided by either treatment was associated with a reduction in the cortical expression of profibrotic plasminogen activator inhibitor-1 and microvascular damage-inducing endothelin-1, and a limitation of interstitial macrophage influx. Treatment with PPARγ agonist, as well as ACE inhibitor comparably affected renal expression of the renin-angiotensin system (RAS) components, normalizing increased renal expression of ACE and enhancing the expression of Mas receptor. Interestingly, combined pioglitazone and ramipril treatment did not provide any additional renoprotection. These results demonstrate that in a nondiabetic renal disease, such as adriamycin-induced nephropathy, PPARγ agonist pioglitazone provides renoprotection to a similar extent as an ACE inhibitor by interfering with the expression of local RAS components and attenuating related profibrotic and inflammatory mechanisms. The combination of the both agents, however, does not lead to any additional renal benefit.

Winter is coming. Some animals successfully cope with the hostility of this season by hibernating. But how do hibernators survive the procoagulant state of months of immobility at very low body temperatures, with strongly decreased blood flow and increased blood viscosity? Changing the coagulation system seems crucial for preventing thromboembolic complications.