Crosstalk between Nrf2 signaling pathway and inflammation in ischemic stroke: Mechanisms of action and therapeutic implications.

One of the major causes of long-term disability and mortality is ischemic stroke that enjoys limited treatment approaches. On the one hand, oxidative stress, induced by excessive generation of reactive oxygen species (ROS), plays a critical role in post-stroke inflammatory response. Increased ROS generation is one of the basic factors in the progression of stroke-induced neuroinflammation. Moreover, intravenous (IV) thrombolysis using recombinant tissue plasminogen activator (rtPA) as the only medication approved for patients with acute ischemic stroke who suffer from some clinical restrictions it could not cover the complicated episodes that happen after stroke. Thus, identifying novel therapeutic targets is crucial for successful preparation of new medicines. Recent evidence indicates that the transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2) contributes significantly to regulating the antioxidant production in cytosol, which causes antiinflammatory effects on neurons. New findings have shown a relationship between activation of the Nrf2 and glial cells, nuclear factor kappa B (NF-κB) pathway, the nucleotide-binding domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome signaling, and expression of inflammatory markers, suggesting induction of Nrf2 activation can represent a promising therapeutic alternative as the modulators of Nrf2 dependent pathways for targeting inflammatory responses in neural tissue. Hence, this review addresses the relationship of Nrf2 signaling with inflammation and Nrf2 activators' potential as therapeutic agents. This review helps to improve required knowledge for focused therapy and the creation of modern and improved treatment choices for patients with ischemic stroke.

Metal nanoparticles as a potential technique for the diagnosis and treatment of gastrointestinal cancer: a comprehensive review.

Gastrointestinal (GI) cancer is a major health problem worldwide, and current diagnostic and therapeutic approaches are often inadequate. Various metallic nanoparticles (MNPs) have been widely studied for several biomedical applications, including cancer. They may potentially overcome the challenges associated with conventional chemotherapy and significantly impact the overall survival of GI cancer patients. Functionalized MNPs with targeted ligands provide more efficient localization of tumor energy deposition, better solubility and stability, and specific targeting properties. In addition to enhanced therapeutic efficacy, MNPs are also a diagnostic tool for molecular imaging of malignant lesions, enabling non-invasive imaging or detection of tumor-specific or tumor-associated antigens. MNP-based therapeutic systems enable simultaneous stability and solubility of encapsulated drugs and regulate the delivery of therapeutic agents directly to tumor cells, which improves therapeutic efficacy and minimizes drug toxicity and leakage into normal cells. However, metal nanoparticles have been shown to have a cytotoxic effect on cells in vitro. This can be a concern when using metal nanoparticles for cancer treatment, as they may also kill healthy cells in addition to cancer cells. In this review, we provide an overview of the current state of the field, including preparation methods of MNPs, clinical applications, and advances in their use in targeted GI cancer therapy, as well as the advantages and limitations of using metal nanoparticles for the diagnosis and treatment of gastrointestinal cancer such as potential toxicity. We also discuss potential future directions and areas for further research, including the development of novel MNP-based approaches and the optimization of existing approaches.

Calcitriol Pretreatment Attenuates Glutamate Neurotoxicity by Regulating NMDAR and CYP46A1 Gene Expression in Rats Subjected to Transient Middle Cerebral Artery Occlusion.

Although the neuroprotective effects of calcitriol have been demonstrated in a variety of neurological diseases, such as stroke, the precise molecular mechanism has yet to be determined. This study aimed to investigate the possible role of calcitriol as a neuroprotective agent via CYP46A1 and glutamate receptors in a middle cerebral artery occlusion (MCAO) animal model. The MCAO technique was performed on adult male Wistar rats to induce focal cerebral ischemia for 1 hour followed by 23 hours of reperfusion. Calcitriol was given for 7 days prior to stroke induction. Sensorimotor functional tests were done 24 hours after ischemia/reperfusion, and infarct volume was estimated by tetrazolium chloride staining of brain sections. Gene expression of NR2A, NR2B, NR3B, and CYP46A1 was evaluated by RT-PCR followed by western blotting for NR3B protein. Our data revealed that calcitriol pretreatment reduced lesion volume and improved ischemic neurobehavioral parameters. Calcitriol therapy altered the expression of glutamate receptor and CYP46A1 genes. A possible molecular mechanism of calcitriol to reduce the severity and complications of ischemia may be through alterations of glutamate receptor and CYP46A1 gene expression.

Calcitriol Ameliorates Brain Injury in the Rat Model of Cerebral Ischemia-Reperfusion Through Nrf2/HO-1 Signalling Axis: An in Silico and in Vivo Study.

OBJECTIVES: Calcitriol has been revealed to exert neuroprotective effects in ischemic stroke; however, its role and the underlying mechanisms in brain injury induced by ischemia are not well known. The purpose of this study was to determine the neuroprotective effects of calcitriol pretreatment and to assess the possible neuroprotective function of nuclear factor erythroid 2-related factor 2 (Nrf2)/ heme oxygenase-1 (HO-1) signalling pathway against brain ischemia/reperfusion (I/R) injury in the rat models which was followed by a bioinformatics approach. METHODS: The experimental I/R model induction was performed in male Wistar rats for 1 h followed by 23 h reperfusion. Calcitriol was administered intraperitoneally for 7 days prior to stroke. Following ischemia induction 24 h later, neurobehavioral deficits and infarction volume were examined. Oxidative stress was assessed by measurement of malondialdehyde (MDA), nitric oxide (NO) and total antioxidant capacity (TAC). The protein and mRNA expression of HO-1 and Nrf2 were determined by western blot and reverse transcription polymerase chain reaction (RT-PCR), respectively. A molecular docking approach was applied to identify the interaction value of Keap1 with calcitriol. RESULTS: Our data demonstrated that calcitriol significantly decreased infarction volume and ameliorated neurological deficits in brain I/R. MDA and NO levels were decreased and TAC level was elevated significantly after calcitriol pretreatment. Furthermore, calcitriol upregulated the expression of HO-1 and Nrf2 protein and mRNA in ischemic brain. Molecular modelling demonstrated that calcitriol could interact with the pocket of Keap1 by an appropriate binding energy. CONCLUSIONS: The results indicate that calcitriol protects the brain against I/R injury. This effect may pass through inhibition of oxidative stress and Nrf2/HO-1 pathway activation and this may arise by interaction of Keap1 and calcitriol.