Rat Model of Isoproterenol-Induced Myocardial Injury.

Isoproterenol (ISO) administration produces significant biochemical and histological changes including oxidative stress, reactive oxygen species (ROS) overproduction, and inflammation that leads to aggravation of myocardial injury. Subcutaneous or intraperitoneal ISO injection into rats can replicate several features of human heart disease, making it a useful tool for comprehending the underlying mechanisms and evaluating potential therapeutic strategies. In the present chapter, we elaborate on how depending on the precise experimental goals and the intended level of severity, different dosages and regimens are employed to induce myocardial injury.

Role of SIRT1 in Potentially Toxic Trace Elements (Lead, Fluoride, Aluminum and Cadmium) Associated Neurodevelopmental Toxicity.

The formation of the central nervous system is a meticulously planned and intricate process. Any modification to this process has the potential to disrupt the structure and operation of the brain, which could result in deficiencies in neurological growth. When neurotoxic substances are present during the early stages of development, they can be exceptionally dangerous. Prenatally, the immature brain is extremely vulnerable and is therefore at high risk in pregnant women associated with occupational exposures. Lead, fluoride, aluminum, and cadmium are examples of possibly toxic trace elements that have been identified as an environmental concern in the aetiology of a number of neurological and neurodegenerative illnesses. SIRT1, a member of the sirtuin family has received most attention for its potential neuroprotective properties. SIRT1 is an intriguing therapeutic target since it demonstrates important functions to increase neurogenesis and cellular lifespan by modulating multiple pathways. It promotes axonal extension, neurite growth, and dendritic branching during the development of neurons. Additionally, it contributes to neurogenesis, synaptic plasticity, memory development, and neuroprotection. This review summarizes the possible role of SIRT1 signalling pathway in potentially toxic trace elements -induced neurodevelopmental toxicity, highlighting some molecular pathways such as mitochondrial biogenesis, CREB/BDNF and PGC-1α/NRF1/TFAM.

Protease-activated receptors in kidney diseases: A comprehensive review of pathological roles, therapeutic outcomes and challenges.

Studies have demonstrated that protease-activated receptors (PARs) with four subtypes (PAR1-4) are mainly expressed in the renal epithelial, endothelial, and podocyte cells. Some endogenous and urinary proteases, namely thrombin, trypsin, urokinase, and kallikrein released during diseased conditions, are responsible for activating different subtypes of PARs. Each PAR receptor subtype is involved in kidney disease of distinct aetiology. PAR1 and PAR2 have shown differential therapeutic outcomes in rodent models of type-1 and type-2 diabetic kidney diseases due to the distinct etiological basis of each disease type, however such findings need to be confirmed in other diabetic renal injury models. PAR1 and PAR2 blockers have been observed to abolish drug-induced nephrotoxicity in rodents by suppressing tubular inflammation and fibrosis and preventing mitochondrial dysfunction. Notably, PAR2 inhibition improved autophagy and prevented fibrosis, inflammation, and remodeling in the urethral obstruction model. Only the PAR1/4 subtypes have emerged as a therapeutic target for treating experimentally induced nephrotic syndrome, where their respective antibodies attenuated the podocyte apoptosis induced upon thrombin activation. Strikingly PAR2 and PAR4 subtypes involvement has been tested in sepsis-induced acute kidney injury (AKI) and renal ischemia-reperfusion injury models. Thus, more studies are required to delineate the role of other subtypes in the sepsis-AKI model. Evidence suggests that PARs regulate oxidative, inflammatory stress, immune cell activation, fibrosis, autophagic flux, and apoptosis during kidney diseases.

Wnt/ß-catenin inhibitor pyrivinium attenuates cisplatin-induced acute kidney injury by possibly reducing platinum uptake and accumulation mediated by reduced organic cation transporter-2 expressions.

Aberrant activation of Wnt/ß-catenin induces renal dysfunction by initiating pro-apoptotic cascades, fibrosis, oxidative and inflammatory burden. This study tested the therapeutic effects of Wnt/ß-catenin inhibitor pyrvinium against cisplatin-induced acute kidney injury (AKI) in rats. Cisplatin was administered at a single dose of 5 mg/kg (i.p.) and renal cisplatin accumulation and uptake in cortical slices were determined after the fifth day by atomic absorption spectroscopy. Levels of pro-inflammatory cytokines were checked by ELISA, and organic cation transporter-2 (OCT-2) transcription and expression in renal tissue were evaluated by RT-PCR and immunohistochemical technique. Cisplatin administration produced renal dysfunction manifested as increase in serum creatinine, blood urea nitrogen, proteinuria, reduced clearance and electrolyte imbalance. Oxidative stress indices, pro-inflammatory cytokines, fibronectin, and caspase-3 activity were elevated in cisplatin-challenged rats. Moreover, increased renal OCT-2 transcription and immunostaining were detected in cisplatin kidneys which resulted in platinum accumulation. Additional docking studies depicted strong interaction between the ß-catenin and OCT-2 protein. These manifestations induced mitochondrial dysfunction, histological damage and fibrosis. Notably, Wnt/ß-catenin inhibitor pyrvinium (60 µg/kg; p.o.) treatment reduced the renal OCT-2 gene transcription causing a decline in platinum levels. Thus, the present study concludes that Wnt/ß-catenin inhibition attenuates cisplatin-induced AKI in rats, partly by down-regulating OCT-2 expression.

Trimetazidine an emerging paradigm in renal therapeutics: Preclinical and clinical insights.

Trimetazidine (TMZ) is a well-known anti-ischemic agent used for the treatment of angina pectoris. In the past decades, the efficacy of this drug has been tested in a wide range of kidney injuries, including drug-induced nephrotoxicity (DIN), radio-contrast agent-induced nephropathy, and surgically induced renal ischemic injury. TMZhas renoprotective effects by attenuating oxidative stress, inflammatory cytokine release, maintaining oxygen and energy balance. Moreover, TMZ administration prevented kidney graft rejection in the porcine model by suppressing the infiltration of mononuclear cells, preserving mitochondrial functions, and maintaining Ca+ homeostasis. In DIN and diabetic kidney diseases,TMZ treatment prevents renal injury by inactivating immune cells, attenuating renal fibrosis, inflammation, apoptosis, and histological abnormalities. Interestingly, the clinical therapeutic efficacy of TMZ has also been documented in pre-existing kidney disease patients undergoing contrast exposure for diagnostic intervention. However, the mechanistic insights into the TMZ mediated renoprotective effects in other forms of renal injuries, including type-2 diabetes, drug-induced nephrotoxicity, and hypertension-induced chronic kidney diseases, remain uninvestigated and incomplete. Moreover, the clinical utility of TMZ as a renoprotective agent in radio-contrast-induced nephrotoxicity needs to be tested in a large patient population. Nevertheless, the available pieces of evidence suggest that TMZ is a promising and emerging renal therapy for the treatment and management of kidney diseases of variable etiologies. This review discusses the various pre-clinical and clinical findings and provides mechanistic insights into the TMZ mediated beneficial effects in various kidney diseases.

Evolution of ß-catenin-independent Wnt-GSK3-mTOR signalling in regulation of energy metabolism in isoproterenol-induced cardiotoxicity model.

OBJECTIVE: Isoproterenol (ISO) is widely used agent to study the effects of interventions which could prevent or attenuate the development of myocardial infarction. The sequence of pathological event's revealed that increased myocardial tissue oxygen demand and energy dysregulation exist early during Iso-induced cardiac toxicity. Later, tissue hypoxia results in increased oxidative stress, inflammation and fibrosis along with cardiac dysfunction in this model. The canonical Wnt/ß-catenin pathway has been reported to directly implicate in inducing cardiomyocyte hypertrophy and remodelling. However, less is known about the role of non-canonical Wnt signalling in cardiac diseases. METHOD: Certain evidences have suggested that the activation of Wnt could up-regulate key energy sensor and cell growth regulator mTOR (Mechanistic target of rapamycin) by inhibition of GSK-3ß mediator. RESULT: The GSK-3ß could negatively influence the mTOR activity and produce energy dysregulation during stress or hypoxic conditions. This suggests that the inhibition of GSK-3ß by Wnt signalling could up-regulate mTOR levels and thereby restore early myocardial tissue energy balance and prevent cardiac toxicity in rodents. CONCLUSION: We hereby discuss a novel therapeutic role of the ß-catenin independent, Wnt-GSK3-mTOR axis in attenuation of Iso-induced cardiotoxicity in rodents.