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Background/Aim:Depression-related aggression is linked to serotonin (5-HT) and dendritic spine alterations. AlthoughMallotus oppositifoliusextract (MOE) has potential for reducing this effect, its specific role remains uncertain. Herein, we evaluated this potential and associated alterations in the brain.Methods:A standard resident-intruder model ofpara-chlorophenylalanine (pCPA)-induced depression-associated aggression in male ICR mice was used. The resident mice receivedpCPA (300 mg/kg, i. p.) for 3 consecutive days while saline-treated mice served as negative control. ThepCPA aggressive mice were subsequently treated orally with either MOE (30, 100, 300 mg/kg), fluoxetine (20 mg/kg), tryptophan (20 mg/kg) or saline (untreatedpCPA group) for 28 days. Locomotor activity was assessed using open field test. Serotonin (5-HT) levels in mice brain and phytochemical fingerprint of MOE were determined by high performance liquid chromatography (HPLC) while gas chromatography-mass spectrometry (GC-MS) was used to identify constituents of MOE. Dendritic spine density and morphology were evaluated using Golgi-Cox staining technique and analyzed with ImageJ and Reconstruct software.Results:Administration ofpCPA induced aggressive behavior in mice, evidenced by increased attack behaviors (increased number and duration of attacks), which positively correlated with squeaking and tail rattling. MOE treatment significantly reduced these characteristics of aggression in comparison with vehicle (non-aggressive) and untreatedpCPA groups (p< 0.001), and also reduced social exploration behavior. Although the behavioral effects of MOE were comparable to those of fluoxetine and tryptophan, these effects were quicker compared to fluoxetine and tryptophan. Additionally, MOE also markedly increased 5-HT concentration and dendritic spine density in the prefrontal cortex relative to vehicle and untreatedpCPA groups (p< 0.05). Interestingly, these behavioral effects were produced without compromising locomotor activity. GC-MS analysis of the MOE identified 17 known compounds from different chemical classes with anti-inflammatory, antioxidant, neuroprotective and antidepressant activities, which may have contributed to its anti-aggressive effect.Conclusion:MOE decreased depression-associated aggressive behavior in miceviaincreased 5-HT concentration and dendritic spine density in the prefrontal cortex. The MOE-mediated effects were faster than those of fluoxetine and tryptophan. Our finding suggests that MOE may have clinical promise in decreasing aggressive and depressive behaviors.

BackgroundDiabetes-induced liver injury is a complication of diabetes mellitus of which there are no approved drugs for effective treatment or prevention. This study investigates possible hepatoprotective effect of alpha-lipoic acid (ALA), and sulfane sulfur/hydrogen sulfide pathway as a novel protective mechanism in a rat model of type 2 diabetes-induced liver injury.MethodsThirty Sprague–Dawley rats underwent fasting for 12 h after which fasting blood glucose was measured and rats were randomly assigned to diabetic and non-diabetic groups. Type 2 diabetes mellitus (T2DM) was induced in diabetic group by administration of nicotinamide (110 mg/kg) and streptozotocin (55 mg/kg). Diabetic rats were treated daily with ALA (60 mg/kg/day p.o.) or 40 mg/kg/day DL-propargylglycine (PPG, an inhibitor of endogenous hydrogen sulfide production) for 6 weeks and then sacrificed. Liver, pancreas and blood samples were collected for analysis. Untreated T2DM rats received distilled water.ResultsHypoinsulinemia, hyperglycemia, hepatomegaly and reduced hepatic glycogen content were observed in untreated T2DM rats compared to healthy control group (p ConclusionsTo the best of our knowledge, this is the first experimental evidence showing that ALA prevents diabetes-induced liver injury by activating hepatic sulfane sulfur/hydrogen sulfide pathway via upregulation of hepatic cystathionine γ-lyase and 3-mecaptopyruvate sulfurtransferase expressions. Therefore, ALA could serve as a novel pharmacological agent for the treatment and prevention of diabetes-induced liver injury, with hepatic sulfane sulfur/hydrogen sulfide as a novel therapeutic target.

Alpha-lipoic acid (ALA) is a licensed drug for the treatment of diabetic neuropathy. We recently reported that it also improves diabetic cardiomyopathy (DCM) in type 2 diabetes mellitus (T2DM). In this study, we present evidence supporting our hypothesis that the cardioprotective effect of ALA is via upregulation of cardiac hydrogen sulfide (HFollowing 12 h of overnight fasting, T2DM was induced in 23 out of 30 male Sprague-Dawley rats by intraperitoneal administration of nicotinamide (110 mg/kg) followed by streptozotocin (55 mg/kg) while the rest served as healthy control (HC). T2DM rats then received either oral administration of ALA (60 mg/kg/day; n = 7) or 40 mg/kg/day DL-propargylglycine (PAG, an endogenous HT2DM resulted in weight loss, islet destruction, reduced pancreatic β-cell function and hyperglycemia. Histologically, DCM rats showed significant myocardial damage evidenced by myocardial degeneration, cardiomyocyte vacuolation and apoptosis, cardiac fibrosis and inflammation, which positively correlated with elevated levels of cardiac damage markers compared to HC rats (p 0.001). These pathological alterations worsened significantly in PAG-treated rats (p 0.05). However, ALA treatment restored normoinsulemia, normoglycemia, prevented DCM, and improved lipid and antioxidant status. Mechanistically, ALA significantly upregulated the expression of cardiac HALA preserves myocardial integrity in T2DM likely by maintaining the expression of cardiac H

Bladder cancer (BCa) is the sixth most prevalent cancer in men and seventeenth most prevalent cancer in women worldwide. Current treatment paradigms have limited therapeutic impact, suggesting an urgent need for the investigation of novel therapies. To best emulate the progression of human BCa, a pre-clinical intravesical murine model is required in conjunction with existing non-invasive imaging modalities to detect and evaluate cancer progression. Non-invasive imaging modalities reduce the number of required experimental models while allowing for longitudinal studies of novel therapies to investigate long-term efficacy. In this review, we discuss the individual and multi-modal use of non-invasive imaging modalities; bioluminescence imaging (BLI), micro-ultrasound imaging (MUI), magnetic resonance imaging (MRI), and positron emission tomography (PET) in BCa evaluation. We also provide an update on the potential and the future directions of imaging modalities in relation to intravesical murine models of BCa.

We previously reported that alpha-lipoic acid (ALA) supplementation protects against progression of diabetic kidney disease (DKD). In this study, we aim to investigate whether the mechanism of renal protection by ALA involves renal cystathionine γ-lyase/hydrogen sulfide (CSE/HThirty-seven male Sprague-Dawley rats underwent 12 h of overnight fasting. To induce T2DM, 30 of these rats received intraperitoneal administration of nicotinamide (110 mg/kg) and streptozotocin (55 mg/kg). T2DM rats then received either oral administration of ALA (60 mg/kg/day) or intraperitoneal administration of 40 mg/kg/day DL-propargylglycine (PAG, a CSE inhibitor) or both for 6 weeks after which rats were sacrificed and samples collected for analysis. Untreated diabetic and non-diabetic rats served as diabetic and healthy controls respectively.T2DM was characterized by reduced pancreatic β-cell function and hyperglycemia. Histologically, untreated diabetic rats showed significantly damaged pancreatic islets, glomerular and tubular injury, with elevated levels of renal function markers compared to healthy control rats (p 0.001). These pathological changes worsened significantly following PAG administration (p 0.05). While some renal protection was observed in ALA+PAG rats, ALA administration in untreated diabetic rats provided superior protection comparable to healthy control rats, with improved antioxidant status, lipid profile and reduced inflammation. Mechanistically, ALA significantly activated renal CSE/HOur data suggest that ALA protects against DKD development and progression by activating renal CSE/H

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. Current pharmacological interventions only retard DN progression. Alpha-lipoic acid (ALA) is a potent antioxidant with beneficial effect in other diabetic complications. This study investigates whether ALA supplementation prevents early development and progression of DN.Fifty-eight male Sprague-Dawley rats were randomly assigned to healthy control and diabetic groups and subjected to overnight fasting. Type 2 diabetes mellitus (T2DM) was induced in diabetic group by intraperitoneal administration of nicotinamide (110 mg/kg) and streptozotocin (55 mg/kg). On day 3 after T2DM induction, diabetic rats received oral daily administration of ALA (60 mg/kg), gliclazide (15 mg/kg), ramipril (10 mg/kg) or drug combinations for 6 weeks. Untreated diabetic rats served as diabetic control. Blood, kidneys and pancreas were harvested for biochemical and histological analyses.Induction of T2DM resulted in hypoinsulinemia, hyperglycemia and renal pathology. ALA supplementation maintained β-cell function, normoinsulinemia and normoglycemia in diabetic rats, and prevented renal pathology (PAS, KIM-1, plasma creatinine, total protein, blood urea nitrogen, uric acid and urine albumin/creatinine ratio) and triglycerides level compared to diabetic control (p 0.001). Additionally, ALA supplementation significantly prevented elevated serum and tissue malondialdehyde, collagen deposition, α-SMA expression, apoptosis and serum IL-1β and IL-6 levels while it markedly increased renal glutathione content and plasma HDL-C compared to diabetic control group (p 0.001).ALA supplementation prevents early development and progression of DN by exerting anti-hyperglycemic, antioxidant, anti-inflammatory, anti-fibrotic and anti-apoptotic effects. Our findings provide additional option for clinical treatment of DN in T2DM patients.

Ischemia-reperfusion injury (IRI), a pathological condition resulting from prolonged cessation and subsequent restoration of blood flow to a tissue, is an inevitable consequence of solid organ transplantation. Current organ preservation strategies, such as static cold storage (SCS), are aimed at reducing IRI. However, prolonged SCS exacerbates IRI. Recent research has examined pre-treatment approaches to more effectively attenuate IRI. Hydrogen sulfide (H2S), the third established member of a family of gaseous signaling molecules, has been shown to target the pathophysiology of IRI and thus appears to be a viable candidate that can overcome the transplant surgeon’s enemy. This review discusses pre-treatment of renal grafts and other transplantable organs with H2S to mitigate transplantation-induced IRI in animal models of transplantation. In addition, ethical principles of pre-treatment and potential applications of H2S pre-treatment in the prevention of other IRI-associated conditions are discussed.

Renal transplantation is the preferred treatment for patients with end-stage renal disease. The current gold standard of kidney preservation for transplantation is static cold storage (SCS) at 4 °C. However, SCS contributes to renal ischemia-reperfusion injury (IRI), a pathological process that negatively impacts graft survival and function. Recent efforts to mitigate cold renal IRI involve preserving renal grafts at higher or subnormothermic temperatures. These temperatures may be beneficial in reducing the risk of cold renal IRI, while also maintaining active biological processes such as increasing the expression of mitochondrial protective metabolites. In this review, we discuss different preservation temperatures for renal transplantation and pharmacological supplementation of kidney preservation solutions with hydrogen sulfide to determine an optimal preservation temperature to mitigate cold renal IRI and enhance renal graft function and recipient survival.

The novel coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, is a global pandemic which is primarily considered a respiratory illness. However, emerging reports show that the virus exhibits both pulmonary and extra-pulmonary manifestations in humans, with the kidney as a major extra-pulmonary target due to its abundant expression of angiotensin-converting enzyme 2 and transmembrane protease serine 2, which facilitate entry of the virus into cells. Acute kidney injury has become prevalent in COVID-19 patients without prior any history of kidney dysfunction. In addition, the virus also worsens kidney conditions and increases mortality of COVID-19 patients with pre-existing chronic kidney disease, renal cancer, diabetic nephropathy, end-stage kidney disease as well as dialysis and kidney transplant patients. In the search for antiviral agents for the treatment of COVID-19, hydrogen sulfide (H2S), the third established member of gasotransmitter family, is emerging as a potential candidate, possessing important therapeutic properties including antiviral, anti-inflammatory, anti-thrombotic and antioxidant properties. A recent clinical study revealed higher serum H2S levels in survivors of COVID-19 pneumonia with reduced interleukin-6 levels compared to fatal cases. In this review, we summarize the global impact of COVID-19 on kidney conditions and discuss the emerging role of H2S as a potential COVID-19 therapy.

Pancreatic islet transplantation is a minimally invasive procedure to replace β-cells in a subset of patients with autoimmune type 1 diabetic mellitus, who are extremely sensitive to insulin and lack counter-regulatory measures, and thereby increasing their risk of neuroglycopenia and hypoglycemia unawareness. Thus, pancreatic islet transplantation restores normoglycemia and insulin independence, and prevents long-term surgical complications associated with whole-organ pancreas transplantation. Nonetheless, relative inefficiency of islet isolation and storage process as well as progressive loss of islet function after transplantation due to unvoidable islet inflammation and apoptosis, hinder a successful islet transplantation. Carbon monoxide (CO), a gas which was once feared for its toxicity and death at high concentrations, has recently emerged as a medical gas that seems to overcome the challenges in islet transplantation. This minireview discusses recent findings about CO in preclinical pancreatic islet transplantation and the underlying molecular mechanisms that ensure islet protection during isolation, islet culture, transplantation and post-transplant periods in type 1 diabetic transplant recipients. In addition, the review also discusses clinical translation of these promising experimental findings that serve to lay the foundation for CO in islet transplantation to replace the role of insulin therapy, and thus acting as a cure for type 1 diabetes mellitus and preventing long-term diabetic complications.

Carbon monoxide (CO) has long been considered purely as a toxic gas. It binds to hemoglobin at high concentrations and displaces oxygen from its binding site, resulting in carboxyhemoglobin formation, which reduces oxygen-carrying capacity of blood and culminates in tissue hypoxia and its associated complications. Recently, however, CO is quickly moving past its historic notorious tag as a poisonous gas to a physiological signaling molecule with therapeutic potentials in several clinical situations including transplant-induced injury. This review discusses current knowledge of CO gas and CO-releasing molecules (CO-RMs) in preclinical models of lung and liver transplantation, and underlying molecular mechanisms of cyto- and organ protection during organ procurement, preservation, implantation and post-transplant periods. In addition, a discussion of the future of CO in clinical organ transplantation is provided.

Cold ischemia-reperfusion injury (IRI) is an inevitable and unresolved problem that poses a great challenge in solid organ transplantation (SOT). It represents a major factor that increases acute tubular necrosis, decreases graft survival, and delays graft function. This complicates graft quality, post-transplant patient care and organ transplantation outcomes, and therefore undermines the success of SOT. Herein, we review recent advances in research regarding novel pharmacological strategies involving the use of different donor molecules of hydrogen sulfide (H

Carbon monoxide (CO) was historically regarded solely as a poisonous gas that binds to hemoglobin and reduces oxygen-carrying capacity of blood at high concentrations. However, recent findings show that it is endogenously produced in mammalian cells as a by-product of heme degradation by heme oxygenase, and has received a significant attention as a medical gas that influences a myriad of physiological and pathological processes. At low physiological concentrations, CO exhibits several therapeutic properties including antioxidant, anti-inflammatory, anti-apoptotic, anti-fibrotic, anti-thrombotic, anti-proliferative and vasodilatory properties, making it a candidate molecule that could protect organs in various pathological conditions including cold ischemia-reperfusion injury (IRI) in kidney and heart transplantation. Cold IRI is a well-recognized and complicated cascade of interconnected pathological pathways that poses a significant barrier to successful outcomes after kidney and heart transplantation. A substantial body of preclinical evidence demonstrates that CO gas and CO-releasing molecules (CO-RMs) prevent cold IRI in renal and cardiac grafts through several molecular and cellular mechanisms. In this review, we discuss recent advances in research involving the use of CO as a novel pharmacological strategy to attenuate cold IRI in preclinical models of kidney and heart transplantation through its administration to the organ donor prior to organ procurement or delivery into organ preservation solution during cold storage and to the organ recipient during reperfusion and after transplantation. We also discuss the underlying molecular mechanisms of cyto- and organ protection by CO during transplantation, and suggest its clinical use in the near future to improve long-term transplantation outcomes.

Cold ischemia-reperfusion injury (IRI) is an inevitable and unresolved problem that poses a great challenge in solid organ transplantation (SOT). It represents a major factor that increases acute tubular necrosis, decreases graft survival, and delays graft function. This complicates graft quality, post-transplant patient care and organ transplantation outcomes, and therefore undermines the success of SOT. Herein, we review recent advances in research regarding novel pharmacological strategies involving the use of different donor molecules of hydrogen sulfide (H2S), the third established member of the gasotransmitter family, against cold IRI in different experimental models of SOT (kidney, heart, lung, liver, pancreas and intestine). Additionally, we discuss the molecular mechanisms underlying the effects of these H2S donor molecules in SOT, and suggestions for clinical translation. Our reviewed findings showed that storage of donor organs in H2S-supplemented preservation solution or administration of H2S to organ donor prior to organ procurement and to recipient at the start and during reperfusion is a novel, simple and cost-effective pharmacological approach to minimize cold IRI, limit post-transplant complications and improve transplantation outcomes. In conclusion, experimental evidence demonstrate that H2S donors can significantly mitigate cold IRI during SOT through inhibition of a complex cascade of interconnected cellular and molecular events involving microcirculatory disturbance and microvascular dysfunction, mitochondrial injury, inflammatory responses, cell damage and cell death, and other damaging molecular pathways while promoting protective pathways. Translating these promising findings from bench to bedside will lay the foundation for the use of H2S donor molecules in clinical SOT in the future.

This research was supported by Physicians Services Incorporated (PSI) Foundation (Grant #18-17) and the Kidney Foundation of Canada (Grant #180015). The use of blood for normothermic and subnormothermic kidney preservation hinders the translation of these approaches and promising therapeutics. This study evaluates whether adding hydrogen sulfide donor AP39 to Hemopure, a blood substitute, during subnormothermic perfusion improves kidney outcomes. After 30 min of renal pedicle clamping, porcine kidneys were treated to 4 h of static cold storage (SCS-4 degrees C) or subnormothermic perfusion at 21 degrees C with Hemopure (H-21 degrees C), Hemopure + 200 nM AP39 (H200nM-21 degrees C) or Hemopure + 1 mu M AP39 (H1 mu M-21 degrees C). Then, kidneys were reperfused with Hemopure at 37 degrees C for 4 h with metabolic support. Perfusate composition, tissue oxygenation, urinalysis and histopathology were analyzed. During preservation, the H200nM-21 degrees C group exhibited significantly higher urine output than the other groups and significantly higher tissue oxygenation than the H1 mu M-21 degrees C group at 1 h and 2h. During reperfusion, the H200nM-21 degrees C group exhibited significantly higher urine output and lower urine protein than the other groups. Additionally, the H200nM-21 degrees C group exhibited higher perfusate pO(2) levels than the other groups and significantly lower apoptotic injury than the H-21 degrees C and the H1 mu M-21 degrees C groups. Thus, subnormothermic perfusion at 21 degrees C with Hemopure + 200 nM AP39 improves renal outcomes. Additionally, our novel blood-free model of ex vivo kidney preservation and reperfusion could be useful for studying other therapeutics. Physicians Services Incorporated (PSI) Foundation [18-17]; Kidney Foundation of Canada [180015]

The balance between adaptive and innate immunity in kidney damage in salt-dependent hypertension is unclear. We investigated early renal dysfunction and the influence of Axl, a receptor tyrosine kinase, on innate immune response in hypertensive kidney in mice with lymphocyte deficiency (Rag1(−/−)). The data suggest that increased presence of CD11b(+) myeloid cells in the medulla might explain intensified salt and water retention as well as initial hypertensive response in Rag1(−/−) mice. Global deletion of Axl on Rag1(−/−) background reversed kidney dysfunction and accumulation of myeloid cells in the kidney medulla. Chimeric mice that lack Axl in innate immune cells (in the absence of lymphocytes) significantly improved kidney function and abolished early hypertensive response. The bioinformatics analyses of Axl-related gene-gene interaction networks established tissue-specific variation in regulatory pathways. It was confirmed that complement C3 is important for Axl-mediated interactions between myeloid and vascular cells in hypertensive kidney. In summary, innate immunity is crucial for renal dysfunction in early hypertension, and is highly influenced by the presence of Axl.

Chronic kidney disease (CKD) is a common global health challenge characterized by irreversible pathological processes that reduce kidney function and culminates in development of end-stage renal disease. It is associated with increased morbidity and mortality in addition to increased caregiver burden and higher financial cost. A central player in CKD pathogenesis and progression is renal hypoxia. Renal hypoxia stimulates induction of oxidative and endoplasmic reticulum stress, inflammation and tubulointerstitial fibrosis, which in turn, promote cellular susceptibility and further aggravate hypoxia, thus forming a pathological vicious cycle in CKD progression. Although the importance of CKD is widely appreciated, including improvements in the quality of existing therapies such as dialysis and transplantation, new therapeutic options are limited, as there is still increased morbidity, mortality and poor quality of life among CKD patients. Growing evidence indicates that hydrogen sulfide (H2S), a small gaseous signaling molecule with an obnoxious smell, accumulates in the renal medulla under hypoxic conditions, and functions as an oxygen sensor that restores oxygen balance and increases medullary flow. Moreover, plasma H2S level has been recently reported to be markedly reduced in CKD patients and animal models. Also, H2S has been established to possess potent antioxidant, anti-inflammatory, and anti-fibrotic properties in several experimental models of kidney diseases, suggesting that its supplementation could protect against CKD and retard its progression. The purpose of this review is to discuss current clinical and experimental developments regarding CKD, its pathophysiology, and potential cellular and molecular mechanisms of protection by H2S in experimental models of CKD.

Contrast-induced nephropathy (CIN) is an important complication following diagnostic radiographic imaging and interventional therapy. It results from administration of intravascular iodinated contrast media (CM) and is currently the third most common cause of hospital-acquired acute kidney injury. CIN is associated with increased morbidity, prolonged hospitalization, and higher mortality. Although the importance of CIN is widely appreciated, and its occurrence can be mitigated by the use of pre- and posthydration protocols and low osmolar instead of high osmolar iodine-containing CM, specific prophylactic therapy is lacking. Remote ischemic preconditioning (RIPC), induced through short cycles of ischemia-reperfusion applied to the limb, is an intriguing new strategy that has been shown to reduce myocardial infarction size in patients undergoing emergency percutaneous coronary intervention. Furthermore, multiple proof-of-principle clinical studies have suggested benefit in several other ischemia-reperfusion syndromes, including stroke. Perhaps somewhat surprisingly, RIPC also is emerging as a promising strategy for CIN prevention. In this review, we discuss current clinical and experimental developments regarding the biology of CIN, concentrating on the pathophysiology of CIN, and cellular and molecular mechanisms by which limb ischemic preconditioning may confer renal protection in clinical and experimental models of CIN.

SIGNIFICANCE: Therapeutic hypothermia is commonly applied to limit ischemic injury in organ transplantation, during cardiac and brain surgery and after cardiopulmonary resuscitation. In these procedures, the kidneys are particularly at risk for ischemia/reperfusion injury (IRI), likely due to their high rate of metabolism. Although hypothermia mitigates ischemic kidney injury, it is not a panacea. Residual mitochondrial failure is believed to be a key event triggering loss of cellular homeostasis, and potentially cell death. Subsequent rewarming generates large amounts of reactive oxygen species that aggravate organ injury. Recent Advances: Hibernators are able to withstand periods of profoundly reduced metabolism and body temperature ("torpor"), interspersed by brief periods of rewarming ("arousal") without signs of organ injury. Specific adaptations allow maintenance of mitochondrial homeostasis, limit oxidative stress, and protect against cell death. These adaptations consist of active suppression of mitochondrial function and upregulation of anti-oxidant enzymes and anti-apoptotic pathways. CRITICAL ISSUES: Unraveling the precise molecular mechanisms that allow hibernators to cycle through torpor and arousal without precipitating organ injury may translate into novel pharmacological approaches to limit IRI in patients. FUTURE DIRECTIONS: Although the precise signaling routes involved in natural hibernation are not yet fully understood, torpor-like hypothermic states with increased resistance to ischemia/reperfusion can be induced pharmacologically by 5'-adenosine monophosphate (5'-AMP), adenosine, and hydrogen sulfide (H2S) in non-hibernators. In this review, we compare the molecular effects of hypothermia in non-hibernators with natural and pharmacologically induced torpor, to delineate how safe and reversible metabolic suppression may provide resistance to renal IRI. Antioxid. Redox Signal. 00, 000-000.

Hypertension is the most common cause of cardiovascular morbidities and mortalities, and a major risk factor for renal dysfunction. It is considered one of the causes of chronic kidney disease, which progresses into end-stage renal disease and eventually loss of renal function. Yet, the mechanism underlying the pathogenesis of hypertension and its associated kidney injury is still poorly understood. Moreover, despite existing antihypertensive therapies, achievement of blood pressure control and preservation of renal function still remain a worldwide public health challenge in a subset of hypertensive patients. Therefore, novel modes of intervention are in demand. Hydrogen sulfide (H

Cisplatin is currently one of the most widely-used chemotherapeutic agents against various malignancies. Its clinical application is limited, however, by inherent renal and cardiac toxicities and other side effects, of which the underlying mechanisms are only partly understood. Experimental studies show cisplatin generates reactive oxygen species, which impair the cell's antioxidant defense system, causing oxidative stress and potentiating injury, thereby culminating in kidney and heart failure. Understanding the molecular mechanisms of cisplatin-induced renal and cardiac toxicities may allow clinicians to prevent or treat this problem better and may also provide a model for investigating drug-induced organ toxicity in general. This review discusses some of the major molecular mechanisms of cisplatin-induced renal and cardiac toxicities including disruption of ionic homeostasis and energy status of the cell leading to cell injury and cell death. We highlight clinical manifestations of both toxicities as well as (novel)biomarkers such as kidney injury molecule-1 (KIM-1), tissue inhibitor of metalloproteinase-1 (TIMP-1) and N-terminal pro-B-type natriuretic peptide (NT-proBNP). We also present some current treatment challenges and propose potential protective strategies including combination therapy with novel pharmacological compounds that might mitigate or prevent these toxicities, which include the use of hydrogen sulfide.

K. Seidel, M. Meister, G. J. Dugbartey, M. P. Zijlstra, J. Vinet, E. R. P. Brunt, F. W. van Leeuwen, U. Rub, H. H. Kampinga and W. F. A. den Dunnen (2012) Neuropathology and Applied Neurobiology38, 548558 Cellular protein quality control and the evolution of aggregates in spinocerebellar ataxia type 3 (SCA3) Aims: A characteristic of polyglutamine diseases is the increased propensity of disease proteins to aggregate, which is thought to be a major contributing factor to the underlying neurodegeneration. Healthy cells contain mechanisms for handling protein damage, the protein quality control, which must be impaired or inefficient to permit proteotoxicity under pathological conditions. Methods: We used a quantitative analysis of immunohistochemistry of the pons of eight patients with the polyglutamine disorder spinocerebellar ataxia type 3. We employed the anti-polyglutamine antibody 1C2, antibodies against p62 that is involved in delivering ubiquitinated protein aggregates to autophagosomes, antibodies against the chaperones HSPA1A and DNAJB1 and the proteasomal stress marker UBB+1. Results: The 1C2 antibody stained neuronal nuclear inclusions (NNIs), diffuse nuclear staining (DNS), granular cytoplasmic staining (GCS) and combinations, with reproducible distribution. P62 always co-localized with 1C2 in NNI. DNS and GCS co-stained with a lower frequency. UBB+1 was present in a subset of neurones with NNI. A subset of UBB+1-containing neurones displayed increased levels of HSPA1A, while DNAJB1 was sequestered into the NNI. Conclusion: Based on our results, we propose a model for the aggregation-associated pathology of spinocerebellar ataxia type 3: GCS and DNS aggregation likely represents early stages of pathology, which progresses towards formation of p62-positive NNI. A fraction of NNI exhibits UBB+1 staining, implying proteasomal overload at a later stage. Subsequently, the stress-inducible HSPA1A is elevated while DNAJB1 is recruited into NNIs. This indicates that the stress response is only induced late when all endogenous protein quality control systems have failed.

Hydrogen sulfide (H2S) can induce a hypometabolic, hibernation-like state in small mammals when given in sublethal concentrations. Hibernating animals undergo a repetitive cycle of cooling (torpor) and rewarming without reperfusion injury or other ill effects. Recently, we observed in the ductus deferens cells of the Syrian hamster (hibernating animal) that one of the protective mechanisms against hypothermia-rewarming injury consists of endogenous production of H2S through the enzyme cystathionine-beta-synthase (CBS). We also showed that endogenous H2S is highly produced during torpor in hibernating hamsters and less produced when metabolism is normalized. Therefore in this study, we investigated the role of CBS and H2S in the induction of torpor and renal protection by blocking the CBS enzyme during torpor in hamsters. Our results show that hamsters during hibernation are able to preserve their kidney integrity through activation of CBS enzyme leading to endogenous H2S production under the extreme physiological conditions of torpor. The results demonstrate profound protective effects of CBS/H2S pathway on survival, renal function, and inflammation during hibernation. These findings might have therapeutic potential to protect kidneys that suffer from hypoxia during transplantation, ischemia–reperfusion and other related clinical conditions.