MST1 selective inhibitor Xmu-mp-1 ameliorates neuropathological changes in a rat model of sporadic Alzheimer's Disease by modulating Hippo-Wnt signaling crosstalk.

Alzheimer's disease (AD), the most prevalent form of dementia, is characterized by progressive cognitive impairment accompanied by aberrant neuronal apoptosis. Reports suggest that the pro-apoptotic mammalian set20-like kinase 1/2 (MST1/2) instigates neuronal apoptosis via activating the Hippo signaling pathway under various stress conditions, including AD. However, whether inhibiting MST1/2 has any therapeutic benefits in AD remains unknown. Thus, we tested the therapeutic effects of intervening MST1/2 activation via the pharmacological inhibitor Xmu-mp-1 in a sporadic AD rat model. Sporadic AD was established in adult rats by intracerebroventricular streptozotocin (ICV-STZ) injection (3 mg/kg body weight). Xmu-mp-1 (0.5 mg/kg/body weight) was administered once every 48 h for two weeks, and Donepezil (5 mg/kg body weight) was used as a reference standard drug. The therapeutic effects of Xmu-mp-1 on ICV-STZ rats were determined through various behavioral, biochemical, histopathological, and molecular tests. At the behavioral level, Xmu-mp-1 improved cognitive deficits in sporadic AD rats. Further, Xmu-mp-1 treatment reduced STZ-associated tau phosphorylation, amyloid-beta deposition, oxidative stress, neurotoxicity, neuroinflammation, synaptic dysfunction, neuronal apoptosis, and neurodegeneration. Mechanistically, Xmu-mp-1 exerted these neuroprotective actions by inactivating the Hippo signaling while potentiating the Wnt/ß-Catenin signaling in the AD rats. Together, the results of the present study provide compelling support that Xmu-mp-1 negated the neuronal dysregulation in the rat model of sporadic AD. Therefore, inhibiting MST/Hippo signaling and modulating its crosstalk with the Wnt/ß-Catenin pathway can be a promising alternative treatment strategy against AD pathology. This is the first study providing novel mechanistic insights into the therapeutic use of Xmu-mp-1 in sporadic AD.

The interplay between hippo signaling and mitochondrial metabolism: Implications for cellular homeostasis and disease.

Mitochondria are the membrane-bound organelles producing energy for cellular metabolic processes. They orchestrate diverse cell signaling cascades regulating cellular homeostasis. This functional versatility may be attributed to their ability to regulate mitochondrial dynamics, biogenesis, and apoptosis. The Hippo pathway, a conserved signaling pathway, regulates various cellular processes, including mitochondrial functions. Through its effectors YAP and TAZ, the Hippo pathway regulates transcription factors and creates a seriatim process that mediates cellular metabolism, mitochondrial dynamics, and survival. Mitochondrial dynamics also potentially regulates Hippo signaling activation, indicating a bidirectional relationship between the two. This review outlines the interplay between the Hippo signaling components and the multifaceted role of mitochondria in cellular homeostasis under physiological and pathological conditions.

Evaluation of Potential Neuroprotective Effects of Vanillin Against MPP+/MPTP-Induced Dysregulation of Dopaminergic Regulatory Mechanisms in SH-SY5Y Cells and a Mouse Model of Parkinson's Disease.

Parkinson's disease (PD) is a progressive neurodegenerative condition. The pathogenesis of PD is still unknown, and drugs available for PD treatment either have side effects or have suboptimal efficacy. Flavonoids are potent antioxidants having little toxicity with extended use, suggesting they might hold promising therapeutic potential against PD. Vanillin (Van) is a phenolic compound that has exhibited neuroprotective properties in various neurological disorders, including PD. However, the neuroprotective role of Van in PD and its underlying mechanisms are scarce and therefore need more exploration. Here, we evaluated the neuroprotective potential of Van and its associated mechanisms against MPP+/MPTP-induced neuronal loss in differentiated human neuroblastoma (SH-SY5Y) cells and the mouse model of PD. In the present study, Van treatment significantly enhanced the cell viability and alleviated oxidative stress, mitochondrial membrane potential, and apoptosis in MPP+-intoxicated SH-SY5Y cells. Moreover, Van significantly ameliorated the MPP+-induced dysregulations in protein expression of tyrosine hydroxylase (TH) and mRNA expressions of GSK-3ß, PARP1, p53, Bcl-2, Bax, and Caspase-3 genes in SH-SY5Y cells. Similar to our in vitro results, Van significantly alleviated MPTP-induced neurobehavioral dysregulations, oxidative stress, aberrant TH protein expressions, and immunoreactivity in SNpc of mice brains. Treatment of Van also prevented MPTP-mediated loss of TH-positive intrinsic dopaminergic neurons to SNpc and TH-fibers projecting to the striatum of mice. Thus, Van exhibited promising neuroprotective properties in the current study against MPP+/MPTP-intoxicated SH-SY5Y cells and mice, indicating its potential therapeutic properties against PD pathology.

Neurobiology of depression in Parkinson's disease: Insights into epidemiology, molecular mechanisms and treatment strategies.

Parkinson's disease (PD) is characterized mainly by motor dysfunctions due to the progressive loss of dopaminergic neurons. However, PD patients experience a multitude of debilitating non-motor symptoms, including depression, which may have deleteriously detrimental effects on life. Depression is multifactorial and exhibits a bimodal progression in PD, but its underlying molecular mechanisms are poorly understood. Studies demonstrating the pathophysiology of depression in PD and the specific treatment strategies for depression-like symptoms in PD patients are largely lacking, often underrated, under-recognized and, consequently, inadequately/under-treated. Nevertheless, reports suggest that the incidence of depression is approximately 20-30% of PD patients and may precede the onset of motor symptoms. Diagnosing depression in PD becomes difficult due to the clinical overlap in symptomatology between the two diseases, and the nigrostriatal dysfunction alone is insufficient to explain depressive symptoms in PD. Therefore, the current study provides an overview of the molecular mechanisms underlying the development of depression in PD and new insights into developing current antidepressant strategies to treat depression in PD. This review will identify and understand the molecular pathological mechanisms of depression in PD that will fundamentally help tailoring therapeutic interventions for depressive symptoms in PD.

Detrimental Effects of Alcohol-Induced Inflammation on Brain Health: From Neurogenesis to Neurodegeneration.

Alcohol consumption is known to cause several brain anomalies. The pathophysiological changes associated with alcohol intoxication are mediated by various factors, most notable being inflammation. Alcohol intoxication may cause inflammation through several molecular mechanisms in multiple organs, including the brain, liver and gut. Alcohol-induced inflammation in the brain and gut are intricately connected. In the gut, alcohol consumption leads to the weakening of the intestinal barrier, resulting in bacteria and bacterial endotoxins permeating into the bloodstream. These bacterial endotoxins can infiltrate other organs, including the brain, where they cause cognitive dysfunction and neuroinflammation. Alcohol can also directly affect the brain by activating immune cells such as microglia, triggering the release of pro-inflammatory cytokines and neuroinflammation. Since alcohol causes the death of neural cells, it has been correlated to an increased risk of neurodegenerative diseases. Besides, alcohol intoxication has also negatively affected neural stem cells, affecting adult neurogenesis and causing hippocampal dysfunctions. This review provides an overview of alcohol-induced brain anomalies and how inflammation plays a crucial mechanistic role in alcohol-associated pathophysiology.

Neural crest cells development and neuroblastoma progression: Role of Wnt signaling.

Neuroblastoma (NB) is one of the most common heterogeneous extracranial cancers in infancy that arises from neural crest (NC) cells of the sympathetic nervous system. The Wnt signaling pathway, both canonical and noncanonical pathway, is a highly conserved signaling pathway that regulates the development and differentiation of the NC cells during embryogenesis. Reports suggest that aberrant activation of Wnt ligands/receptors in Wnt signaling pathways promote progression and relapse of NB. Wnt signaling pathways regulate NC induction and migration in a similar manner; it regulates proliferation and metastasis of NB. Inhibiting the Wnt signaling pathway or its ligands/receptors induces apoptosis and abrogates proliferation and tumorigenicity in all major types of NB cells. Here, we comprehensively discuss the Wnt signaling pathway and its mechanisms in regulating the development of NC and NB pathogenesis. This review highlights the implications of aberrant Wnt signaling in the context of etiology, progression, and relapse of NB. We have also described emerging strategies for Wnt-based therapies against the progression of NB that will provide new insights into the development of Wnt-based therapeutic strategies for NB.

Convergent Molecular Pathways in Type 2 Diabetes Mellitus and Parkinson's Disease: Insights into Mechanisms and Pathological Consequences.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by hyperglycemic conditions. A higher risk of developing Parkinson's disease (PD) in patients with T2DM has become evident in recent years. However, the molecular mechanisms underlying the interplay between T2DM and PD pathogenesis remain unknown. Nevertheless, emerging epidemiological studies have demonstrated many common molecular pathways that play an essential role in regulating normal cellular functioning are independently implicated in the progression and etiopathogenesis of T2DM and PD. This review summarizes some common shared pathophysiological mechanisms, including insulin resistance, inflammation, mitochondrial dysfunction, endoplasmic reticulum stress (ER stress), autophagy, and the ubiquitin-proteasome system (UPS) that independently mediate the onset and etiopathogenesis of T2DM and PD. In this review, we summarize the studies that have reported the relationship between T2DM and PD. This review will provide insights into the common involvement of molecular pathways that may provide alternative treatment strategies for both T2DM and PD.

Targeting NRF2 in Type 2 diabetes mellitus and depression: Efficacy of natural and synthetic compounds.

Evidence supports a strong bidirectional association between depression and Type 2 diabetes mellitus (T2DM). The harmful impact of oxidative stress and chronic inflammation on the development of both disorders is widely accepted. Nuclear factor erythroid 2-related factor 2 (NRF2) is a pertinent target in disease management owing to its reputation as the master regulator of antioxidant responses. NRF2 influences the expression of various cytoprotective phase 2 antioxidant genes, which is hampered in both depression and T2DM. Through interaction and crosstalk with several signaling pathways, NRF2 endeavors to contain the widespread oxidative damage and persistent inflammation involved in the pathophysiology of depression and T2DM. NRF2 promotes the neuroprotective and insulin-sensitizing properties of its upstream and downstream targets, thereby interrupting and preventing disease advancement. Standard antidepressant and antidiabetic drugs may be powerful against these disorders, but unfortunately, they come bearing distressing side effects. Therefore, exploiting the therapeutic potential of NRF2 activators presents an exciting opportunity to manage such bidirectional and comorbid conditions.

Naringenin alleviates paraquat-induced dopaminergic neuronal loss in SH-SY5Y cells and a rat model of Parkinson's disease.

Parkinson's disease (PD), a common neurodegenerative disease is characterized by the progressive loss of dopaminergic neurons in the substantia nigra. The cause of dopaminergic loss in PD remains unknown for a long time, however, recent reports suggest oxidative stress plays a key role in the pathogenesis of PD. Paraquat (PQ), a widely used herbicide is an oxidative stress inducer that has been implicated as a potential risk factor for the development of PD. Flavonoids are naturally occurring polyphenolic compounds that display a variety of therapeutic properties against oxidative stress. Naringenin (NAR), a natural flavonoid, exhibits neuroprotection against PD-related pathology. However, studies on its neuroprotective role and the underlying mechanisms are scarce, therefore the present study explored the potential neuroprotective role of NAR in PQ-induced parkinsonism in SH-SY5Y cells and rat model. The effect of NAR on PQ-induced cellular toxicity was determined by measuring cell viability, oxidative stress, ATP levels and the same effect was determined by assessing behavioral, biochemical, immunohistochemical, qRT-PCR and Western blot in rat model. NAR treatment in SH-SY5Y cells resulted in increased cell viability, reduced oxidative stress, elevated mitochondrial membrane potential, and higher cellular ATP levels. In rats, NAR treatment resulted in significant neuroprotection against PQ-induced behavioral deficits, oxidative stress, mitochondrial dysfunction, and astrocytosis. NAR treatment significantly modulated PQ-induced mRNA expressions of DRD2, DAT, LRRK2, SNCA, ß-catenin, caspase-3, BDNF genes. NAR treatment increased TH protein expression and modulated its immunoreactivity in rat striatum. Also, GFAP decreased in response to NAR treatment. So, in the present study, NAR exhibits neuroprotection against PQ-induced neurotoxicity and neurodegeneration indicating its novel therapeutic potential against PD.

Pathophysiological implications of neuroinflammation mediated HPA axis dysregulation in the prognosis of cancer and depression.

Cancer patients are more likely to develop depressive symptoms and show a poor prognosis compared to the normal healthy individuals. Cancer occurrence and the anticancer treatments result in the pro-inflammatory cytokines-mediated inflammation, which dysregulates the HPA-axis activity that may result in depression-like behaviour. Conversely, depression causes the activation of the HPA-axis that results in the downstream release of endogenous glucocorticoids which may result in depressive signs and symptoms in some cancer patients. Depression may also result in non-adherence to treatment and increased mortality in cancer patients. In this review, we have focused on the role of neuroimmune axis and hyperactive HPA-axis in case of both cancer and depression. Therefore, therapeutics targeting the HPA-axis dysregulation could be effective in ameliorating symptoms of depression in cancer patients.

A selective D2 dopamine receptor agonist alleviates depression through up-regulation of tyrosine hydroxylase and increased neurogenesis in hippocampus of the prenatally stressed rats.

Prenatal stress (PNS) has its negative impact on both the infant hippocampal neurogenesis and pregnancy outcomes in the neonates that serves as a risk factor for postnatal depression in adult offsprings. Therefore, main objectives of the present study were to evaluate the effect of maternal chronic unpredictable mild stress (CUMS) on behavioural changes, levels of oxidative stress, changes in selective developmental signaling genes and neurogenesis in the adult brain of Wistar rats and its reversal through a selective non-ergoline D2 type dopamine receptor (D2R) agonist Ropinirole (ROPI). Effects of ROPI treatment on CUMS induced adult rats offspring were measured by assessment of behavioural tests (sucrose preference test and forced swim test), biomarkers of oxidative stress, protein expression of tyrosine hydroxylase (TH), mRNA expression of SHH, GSK-3ß, ß-catenin, Notch, brain-derived neurotrophic factor (BDNF), Dopamine receptor 2 (Drd2) and bromodeoxyuridine (BrdU) cell proliferation assay. The oxidative stress, protein and mRNA expression were determined in the hippocampus and prefrontal cortex while the BrdU cell proliferation was observed in the hippocampus of rat brain. PNS induced changes resulted in depression validated by the depression-like behaviours, increased oxidative stress, decreased TH expression, altered expression of selective developmental genes, along with the reduced hippocampal neurogenesis and BDNF expression in the brain of adult offsprings. Chronic ROPI treatment reversed those effects and was equally effective like Imipramine (IMI) treatment. So, the present study suggested that ROPI can be used as an antidepressant drug for the treatment of depressive disorders.

Effects of chronic unpredictable mild stress induced prenatal stress on neurodevelopment of neonates: Role of GSK-3ß.

Prenatal stress (PNS) has gained attention with regard to its impact on hippocampal neurogenesis in neonates which serves as a risk factor for postnatal neurodevelopmental deficits. Evidences from animal models have suggested that depression responsive hypothalamic-pituitary-adrenal (HPA) axis and its hormonal response via cortisol, is responsible for critical neurodevelopmental deficits in the offspring which is transduced due to gestational stress. But knowledge in the area of assessing the effects of maternal chronic unpredictable mild stress (CUMS) on neurogenesis and expression of some key signaling molecules in the offsprings are limited. We have used Wistar rats to induce PNS in offsprings by maternal CUMS during pregnancy. Prefrontal cortex (PFC) and hippocampus were assessed for biomarkers of oxidative stress, neurogenesis, neurodevelopmental signaling molecules and DNA damage in the male Wister offsprings. Our investigations resulted in sufficient evidences which prove how maternal psychological stress has widespread effect on the fetal outcomes via major physiological alteration in the antioxidant levels, neurogenesis, signaling molecules and DNA damage. PNS leads to the upregulation of GSK-3ß which in turn inhibited mRNA and protein expressions of sonic hedgehog (SHH), ß-catenin, Notch and brain derived neurotrophic factor (BDNF). The study explored multifaceted signaling molecules especially, GSK-3ß responsible for crosstalks between different neurodevelopmental molecules like SHH, Notch, BDNF and ß-catenin affecting neurodevelopment of the offsprings due to PNS.

Role of Hypothalamic-Pituitary-Adrenal Axis, Hypothalamic-Pituitary-Gonadal Axis and Insulin Signaling in the Pathophysiology of Alzheimer's Disease.

Alzheimer's disease (AD), the commonest progressive neurodegenerative disorder of the brain, is clinically characterized by the formation of extracellular amyloid plaques and intracellular neurofibrillary tangles. Recent studies suggest a relationship between the endocrinal dysregulation and the neuronal loss during the AD pathology. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and hypothalamic-pituitary-gonadal (HPG) axis regulating circulating levels of glucocorticoid hormones has been implicated in the pathophysiology of AD. Likewise, dysregulated insulin signaling, impaired glucose uptake and insulin resistance are some of the prime factors in the onset/progression of AD. In this review, we have discussed the changes in HPA and HPG axes, implicated insulin resistance/signaling and glucose regulation during the onset/progression of AD. Therefore, simultaneous detection of these endocrinal markers in the early or presymptomatic stages may help in the early diagnosis of AD. This evidence for implicated endocrinal functions supports the fact that modulation of endocrinal pathways can be used as therapeutic targets for AD. Future studies need to determine how the induction or inhibition of endocrinal targets could be used for predictable neuroprotection in AD therapies.

Influence of microglia and astrocyte activation in the neuroinflammatory pathogenesis of Alzheimer's disease: Rational insights for the therapeutic approaches.

Alzheimer's disease (AD), the most common progressive neurodegenerative disorder is characterized by the formation of extracellular amyloid plaques and intracellular neurofibrillary tangles (NFTs). Increasing evidences suggest a link between neuroinflammation and neuronal dysfunction in AD, orchestrated by the progressive activation of microglial cells and astrocytes with the consequent overproduction of proinflammatory molecules. The concomitant release of anti-inflammatory mediators antagonizes the inflammatory processes and leading to the severity of the AD pathology. The simultaneous detection of these inflammatory molecules in the pre-symptomatic stage may help in the early diagnosis of the AD. We have discussed the impact of microglia and astrocytic cells, the principal agents in the neuroinflammation process, in relation to the progression of the AD. Modulation of the risk factors and targeting of these immune mechanisms could lead to better therapeutic or preventive strategies for the AD. Further studies need to determine, how the inhibition of inflammatory factors could be used for the AD alternative therapies.

Evaluation of naproxen-induced oxidative stress, hepatotoxicity and in-vivo genotoxicity in male Wistar rats.

Naproxen (NP), a nonsteroidal anti-inflammatory drug (NSAID), is used for the treatment of common pain, inflammation and tissue damage. Genotoxicity testing of NP is of prime importance as it represents the largest group of drugs to which humans are exposed. Not many genotoxic studies are reported on NP; therefore, the present study investigated the detailed genotoxic and oxidative stress properties of NP. Male Wistar rats were administered NP orally at the doses of 38.91 and 65.78 mg/kg body weight for 14 days. Reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and lipid peroxidation (LPO) activities/levels were measured in the liver, kidney and brain tissues. The aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) activities, and total bilirubin (TBIL) levels were measured in the liver tissues. Micronucleus frequency (micronucleus test MNT) and DNA damage (comet assay) were performed in the bone marrow cells and leukocytes, respectively. The results showed that NP treatment decreased the GSH levels and increased the SOD, CAT, LPO, ALT, AST, ALP and TBIL activities/levels compared to the control (p < 0.05). Results of MNT showed an increased micronucleus induction and comet assay showed a significant increase in DNA damage in the NP treated animals (p < 0.05). Treatment of NP resulted in the biochemical imbalance and induced oxidative stress that deteriorated the integrity of the cells, which caused significant damage to the genetic material and affected liver function in male Wistar rats. Therefore, NP is a potential genotoxic agent that induces genotoxicity and oxidative stress.

In vivo induction of antioxidant response and oxidative stress associated with genotoxicity and histopathological alteration in two commercial fish species due to heavy metals exposure in northern India (Kali) river.

Heavy metals can significantly bioaccumulate in fish tissues. The step wise mechanism of heavy metal toxicities on fish health is still limited. The present study assessed the tissue-specific antioxidant response and oxidative stress biomarkers of commercially important fish species namely, Channa striatus and Heteropneustes fossilis inhabiting Kali River of northern India where heavy-metal load is beyond the World Health Organisation - maximum permissible limits. Heavy metals chromium (Cr), nickel (Ni), lead (Pb) and cadmium (Cd) were elevated in both fish species compared to recommended values of the Federal Environmental Protection Agency (FEPA), 1999 for edible fishes. Reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CATA) activities in all tissues (brachial, neural, renal and hepatic) were altered. Cellular lipid and protein compromisation in both fishes induced by heavy metals was determined by lipid peroxidation (LPO) and protein carbonylation (PC) assays. Micronucleus (MN) test of erythrocytes and comet assay of liver cells confirmed genotoxicity. Histopathology of the liver, kidney and brain of affected fishes was distorted significantly with its reference fishes thereby affecting the quality and quantity of these fish stocks. This raises a serious concern as these fishes are consumed by the local population which would ultimately affect human health.