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Spontaneous preterm birth (sPTB) is a global health issue. Studies suggest infections are chiefly associated with sPTB and galectins (gals) play a role in regulation of innate and adaptive maternal immune response against pathogens during sPTB. The aim of this study was to describe the gene expression of gal -1, -3, -8, -9, -13 in relation to gene expression of cyclooxygenase-2 (COX-2) and the cytokines IL-8, IL-10, TNF-α, IFN-ϒ in the setting of sPTB and confirmed infection with Chlamydia trachomatis , Mycoplasma hominis , and Ureaplasma urealyticum. Placental samples were collected from 120 term control and 120 sPTB pregnancies. PCR was used to detect specific pathogens. Gene expression of galectins, cytokines, and COX-2 was performed using real time qPCR. Fold-change expression of gal -1, -3, -8, -9, -13 was 5.13, 6.11, 1.14, 5.23 and 7.16 (p<0.001), respectively; while IL-10, IL-8, TNF-α, IFN-ϒ and COX-2 was 6.29, 6.55, 6.35, 6.36 and 2.73-fold upregulated (p<0.05), respectively in infected sPTB. Gal-1 was positively correlated with IL-10 (r=0.49, p=0.003) while gal-3 showed significant correlation with IL-8 (r=0.42, p=0.0113), TNF-α (r=0.65, p=< 0.001) and COX-2 (r=0.72, p=0.001). However, gal-8 was not significantly correlated with any cytokine. Gal-9, -13 were negatively correlated with IFN-ϒ (r=-0.45, p=0.006) and IL-8 (r=-0.39, p=0.018). Gal-1, -9, -13 are anti-inflammatory and might play role in immune-tolerance while gal-3 is pro-inflammatory and possibly responsible for immunogenic response, having potential to anticipate the clinical beginning of preterm labour during infection. • Gals were significantly upregulated with maximum fold-change in gal-13 (7.16). • Significant upregulation of cytokines, i.e. IL-10, IL-8, TNF-α, IFN-ϒ and COX-2. • Gal-1 was positively correlated with IL-10 while gal-3 with IL-8/TNF-α/COX-2. • Gals-9, -13 were negatively correlated with IFN-ϒ and IL-8. • Gal-3 associated with pre-mature labour; gal-1,-9,-13 involved in immunotolerance. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a multivariate and diversified disease and affects the most sensitive areas of the brain, the cerebral cortex, and the hippocampus. AD is a progressive age-related neurodegenerative disease most often associated with memory deficits and cognition that get more worsen over time. The central theory on the pathophysiological hallmark features of AD is characterized by the accumulation of amyloid β (Aβ) peptides, also associated with tau proteins (τ) dysfunctioning which leads to distorted microtubular structure, affects the cholinergic system, and mitochondrial biogenesis. This review emphasizes how simple it is to find novel treatments for AD and focuses on several recently developed medications through repurposing that can speed up traditional drug development. • Alzheimer's Disease is a multivariate and diversified disease • The cerebral cortex and hippocampus are frequently affected regions in AD. • The pathology of Alzheimer's Disease is characterized by the accumulation of β amyloid peptides and the dysfunctioning of tau proteins. • Recently developed medications through repurposing can speed up traditional drug development. [ABSTRACT FROM AUTHOR]

[Display omitted] Traumatic brain injury (TBI) triggers a bevy of changes including mitochondrial dysfunction, apoptosis, oxidative stress, neurobehavioural impairment, and neuroinflammation, among others. Dantrolene (DNT), a muscle relaxant which inhibits intracellular Ca2+ signaling from the ER, has been repurposed as a potential neuroprotective agent in various neurological diseases. However, there have been limited studies on whether it can mitigate TBI-induced deficits and restore impaired mitochondrial dynamics. This study sought to evaluate whether Dantrolene can potentially provide neuroprotection in an in vivo model of TBI. Male wistar rats subjected to TBI were treated with DNT (10 mg/kg) 1 h and 12 h post surgery. Animals were assessed 24 h post-TBI to evaluate neurobehavioural deficits and cerebral edema. We evaluated the protein expressions of apoptotic, autophagic, and neuroinflammatory markers by immunoblotting, as well as Mitochondrial Membrane Potential (MMP) and Reactive Oxygen Species (ROS) via Flow Cytometry to ascertain the effects of DNT on TBI. We further analysed immunofluorescence staining with Glial Fibrillary Acidic Protein (GFAP) and immunohistochemistry with NF-κβ to investigate neuroinflammation. H&E staining was also performed post-TBI. Our findings revealed DNT administration inhibits mitochondria-mediated apoptotis and reduces heightened oxidative stress. DNT treatment was also found to reverse neurobehavioural impairments and offer neuroprotection by preserving neuronal architechture. We also demonstrated that DNT inhibits neuronal autophagy and alleviates neuroinflammation following TBI by modulating the NF-κβ/Akt signaling pathway. Thus, our results suggest a novel application of DNT in ameliorating the multitude of deficits induced by TBI, thereby conferring neuroprotection. [ABSTRACT FROM AUTHOR]

[Display omitted] • Current status of fast, rapid and on spot diagnosis of rape drugs. • Techniques including identification of several majorly known drugs are illuminated. • Biosensing methods with their future development and possibilities are summarised in this review. Drugs are extracted from plants and synthetic chemicals for their medicinal values and healing properties, these various drugs present worldwide can be of uncountable importance with each of it having different medicinal values that may help in the treatment of numerous lethal diseases, but on the other hand Illegitimate drug-associated incidents like sexual assaults and traffic accidents are gaining recurrence proportions worldwide. As for the clinical and forensic use to spot the evidences in case of sexual assaults the detection of drugs in biological fluids can be very important. Furthermore, there is widespread drug usage at some crucial workplaces, which can cause serious safety issues. This article would shed some light on the drugs that are widely involved in sexual assaults, as well as the many conventional techniques for detecting illicit drugs that have been developed. Ultraviolet spectroscopy, mass spectrometry (MS), thin layer chromatography, Microcrystalline test, infrared spectrometry, ion mobility spectrometry (IMS), Raman spectroscopy, Xray diffraction, spot/colour test, and immunoassay are some of the more prevalent procedures. These methods are primarily employed to identify illicit drugs, but they are both costly and time-consuming. For the fast diagnosis of these drugs, various sensors such as colorimetric sensors, fluorescence sensors, and electrochemical sensors were developed for most popular rape medications, including cocaine, cannabis, methamphetamine, fentanyl, morphine, heroin, and benzodiazepine (diazepam, oxazepam, clonazepam etc). [ABSTRACT FROM AUTHOR]

Spontaneous preterm birth (sPTB) is a global health concern and it is the most prevalent cause of infant mortality and morbidity with occurrence rate of 5 – 18% worldwide. Studies suggest infection and infection-driven activation of inflammatory responses are the potential risk factors for sPTB. MicroRNAs (miRNAs) are thought to control the expression of several immune genes, making them crucial components of the intricate immune regulatory network and the dysregulation of miRNAs in placenta has been associated to several pregnancy-related complications. However, studies on possible role of miRNAs in immunomodulation of cytokine signalling in infection-associated sPTB are scarce. Present study aimed to investigate expression/ correlation of a few circulating miRNAs (miR-223, −150-5p, −185-5p, −191-5p), miRNA target genes and associated cytokines in sPTB women found infected with Chlamydia trachomatis / Mycoplasma hominis / Ureaplasma urealyticum. Non-heparinized blood and placental sample were collected from 140 sPTB and 140 term women visiting Safdarjung hospital, New Delhi (India) for conducting PCR and RT-PCR for pathogen detection and miRNA/ target gene/ cytokine expression, respectively. Common target genes of differentially expressed miRNAs were obtained from databases. The correlation between select target genes/ cytokines and serum miRNAs was determined by Spearman's rank correlation. 43 sPTB were infected with either pathogen and a significant upregulation of serum miRNAs was observed. However, miR-223 and 150–5p showed maximum fold-change (4.78 and 5.58, respectively) in PTB versus control group. IL-6ST, TGF-β R3 and MMP-14 were important target genes among 454 common targets, whereas, IL-6 and TGF-β were associated cytokines. miR-223 and 150–5p showed significant negative correlation with IL-6ST/ IL-6/ MMP-14 and positive correlation with TGF-β R3/ TGF-β. A significant positive correlation was found between IL-6ST and IL-6, TGF-β R3 and TGF-β. However, miR-185–5p and 191–5p were not significantly correlated. Although post-transcriptional validation is required, yet on the basis of mRNA findings, the study concludes that miR-223 and 150–5p are apparently of clinical importance in regulation of inflammatory processes during infection-associated sPTB. • Significant upregulation of miRs with highest fold-change in miR-223 and miR-150–5p. • Significant upregulation of miRs target genes and associated cytokines. • miR-223 and miR-150–5p were negatively correlated with IL-6ST, IL-6 and MMP-14. • miR-223 and miR-150–5p were positively correlated with TGF-βR3 and TGF-β. • miR-223 and miR-150–5p play immunomodulatory function during pre-mature labour. [ABSTRACT FROM AUTHOR]

Globally, Ischemic stroke (IS) has become the second leading cause of mortality and chronic disability. The process of IS has triggered by the blockages of blood vessels to form clots in the brain which initiates multiple interactions with the key signaling pathways, counting excitotoxicity, acidosis, ionic imbalance, inflammation, oxidative stress, and neuronal dysfunction of cells, and ultimately cells going under apoptosis. Currently, FDA has approved only tissue plasminogen activator therapy, which is effective against IS with few limitations. However, the mechanism of excitotoxicity and acidosis has spurred the investigation of a potential candidate for IS therapy. Acid-sensing ion channels (ASICs) and Voltage-gated Ca2+ channels (VDCCs) get activated and disturb the brain's normal physiology. Animal toxins are novel inhibitors of ASICs and VDCCs channels and have provided neuroprotective insights into the pathophysiology of IS. This review will discuss the potential directions of translational ASICs and VDCCs inhibitors research for clinical therapies. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI), an acquired brain injury imparted by a mechanical trauma to the head, has significant ramifications in terms of long-term disability and cost of healthcare. TBI is characterized by an initial phase of cell death owing to direct mechanical injury, followed by a secondary phase in which neuroinflammation plays a pivotal role. Activation of inflammasome complexes triggers a cascade that leads to activation of inflammatory mediators such as caspase-1, Interleukin (IL)-18, and IL-1β, eventually causing pyroptosis. NLRP3 inflammasome, a component of the innate immune response, has been implicated in a number of neurodegenerative diseases, including TBI. Recent findings indicate that NLRP3 inhibitors can potentially ameliorate neuroinflammation and improve cognition and motor function in TBI. The NLRP3 inflammasome also holds potential as a predictive biomarker for the long-term sequelae following TBI. Although several therapeutic agents have shown promising results in pre-clinical studies, none of them have been effective in human trials for TBI, to date. Thus, it is imperative that such promising therapeutic candidates are evaluated in clinical trials to assess their efficacy in alleviating neurological impairments in TBI. This review offers an insight into the pathophysiology of TBI, with an emphasis on neuroinflammation in the aftermath of TBI. We highlight the NLRP3 inflammasome and explore its role in the neuroinflammatory cascade in TBI. We also shed light on its potential as a prospective biomarker and therapeutic target for TBI management. [Display omitted] • Traumatic brain injury (TBI) is an acquired brain injury induced by an external trauma to the head. • Despite causing high mortality rates and significant healthcare costs, there exists no effective therapy for TBI. • NLRP3 inflammasome triggers the activation of several inflammatory mediators like caspase-1, IL-18, and IL-1β. • Recent findings indicate that NLRP3 inhibitors can potentially ameliorate neuroinflammation in the wake of TBI. • NLRP3 inflammasome also holds potential as a predictive biomarker for the long-term sequelae following TBI. [ABSTRACT FROM AUTHOR]

Cerebral stroke is a pressing global health concern, ranking as the second leading cause of mortality and resulting in persistent neurobehavioral impairments. Cerebral strokes, triggered by various embolic events, initiate complex signaling pathways involving neuroexcitotoxicity, ionic imbalances, inflammation, oxidative stress, acidosis, and mitochondrial dysfunction, leading to programmed cell death. Currently, the FDA has approved tissue plasminogen activator as a relatively benign intervention for cerebral stroke, leaving a significant treatment gap. However, a promising avenue has emerged from Earth's toxic creatures. Animal venoms harbor bioactive molecules, particularly neuropeptides, with potential in innovative healthcare applications. These venomous components, affecting ion channels, receptors, and transporters, encompass neurochemicals, amino acids, and peptides, making them prime candidates for treating cerebral ischemia and neurological disorders. This review explores the composition, applications, and significance of toxin-derived peptides as viable therapeutic agents. It also investigates diverse toxins from select venomous creatures, with the primary objective of shedding light on current stroke treatments and paving the way for pioneering therapeutic strategies capable of addressing neurobehavioral deficits. [Display omitted] • Cerebral stroke is the second leading global cause of mortality, resulting in persistent neurobehavioral impairments. • Venomous creatures offer potential bioactive molecules, like neuropeptides, for innovative cerebral stroke treatments. • Current stroke treatment options, like tissue plasminogen activator, leave a significant treatment gap. • Venom-derived peptides target ion channels, receptors, and transporters, promising new treatments for neurological disorders. • Future prospects include exploring animal toxins as neurotherapeutics to address neurobehavioral deficits in stroke patients. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most devastating neurodegenerative disorder, accounting over 46 million cases of dementia globally. Evidence supports that Brain Insulin Resistance (BIR) due to serine phosphorylation of Insulin Receptor Substrate-1 (IRS-1) has an association with AD. GLP-1 an incretin hormone, rapidly degraded by Dipeptidyl Peptidase-4 (DPP-4) has also confirmed its efficacious role in AD. Linagliptin, a DPP-4 inhibitor is hypothesized to increase GLP-1 level, which then crosses Blood Brain Barrier (BBB), decreases Amyloid-beta (Aβ) and insulin resistance in hippocampus. Thus, the present study was designed to evaluate Linagliptin in Aβ (1−42) peptides induced rat model of AD. Following 1 week of induction, rats were administered with Linagliptin (0.513 mg/kg, 3 mg/kg, and 5 mg/kg) orally for 8 weeks and donepezil (5 mg/kg) as a reference standard. At the end of scheduled treatment neurobehavioral parameters were assessed. After this, rats were sacrificed, hippocampus was isolated from the whole brain for histopathological analysis and biochemical parameters estimation. Linagliptin dose-dependently and significantly reversed motor and cognitive impairment, assessed through locomotor activity (LA) and Morris water maze (MWM) test respectively. Moreover, Linagliptin augmented GLP-1 level and attenuated soluble Aβ (1−42), IRS-1 (s307), GSK-3β, TNF-α, IL-1β, IL-6, AchE and oxidative/nitrosative stress level in hippocampus. H&E and Congo red staining also exhibited neuroprotective and anti-amylodogenic effect respectively. Our study findings implies the significant effect of Linagliptin in reversing the behavioural and biochemical deficits by altering Aβ (1−42) and BIR via IRS-1 confirming one of the mechanism underlying the pathophysiology of AD. • DPP-4 inhibitors increases GLP-1 level, ameliorates T2DM. • GLP-1 crosses BBB, decreases APP, Aβ peptides and increases insulin secretion. • BIR or T3DM due to serine phosphorylation of IRS-1 at 307 through over activation of JNK. • Microglial activation due to Aβ plaques releases pro-inflammatory cytokines results in BIR. [ABSTRACT FROM AUTHOR]

Insulin, a well-known hormone, has been implicated as a regulator of blood glucose levels for almost a century now. Over the past few decades, the non-glycemic actions of insulin i.e. neuronal growth and proliferation have been extensively studied. In 2005, Dr. Suzanne de La Monte and her team reported that insulin might be involved in the pathogenesis of Alzheimer's Disease (AD) and thus coined a term "Type-3 diabetes" This hypothesis was supported by several subsequent studies. The nuclear factor erythroid 2- related factor 2 (Nrf2) triggers a cascade of events under the regulation of distinct mechanisms including protein stability, phosphorylation and nuclear cytoplasmic shuttling, finally leading to the protection against oxidative damage. The Nrf2 pathway has been investigated extensively in relevance to neurodegenerative disorders, particularly AD. Many studies have indicated a strong correlation between insulin and Nrf2 signalling pathways both in the periphery and the brainbut merely few of them have focused on elucidating their inter-connective role in AD. The present review emphasizes key molecular pathways that correlate the role of insulin with Nrf2 during AD. The review has also identified key unexplored areas that could be investigated in future to further establish the insulin and Nrf2 influence in AD. [Display omitted] • The insulin dysregulation or resistance might be involved in the pathogenesis and progression of Alzheimer's disease, often referred to as Type3-diabetes. • The key molecular pathways like Nrf2/ARE pathway, PI3K/Akt-Nrf2 pathway, Nrf2/HO-1 pathway etc. establishes the correlation between insulin and Nrf2 signaling pathways both in the periphery and the brain. • The Nrf2 triggers a cascade of events under the regulation of distinct mechanisms that lead to the protection against oxidative damage. • The potential drawbacks, especially development of malignancy, should be outweighed before targeting Nrf2 activation for neurodegeneration therapies. [ABSTRACT FROM AUTHOR]

Due to the growing commercialization of titanium dioxide nanoparticles (TNPs), it is necessary to use these particles in a manner that is safe, healthy and environmental friendly. Through reactive oxygen species (ROS) generation, it has been discovered that TNPs have a harmful effect on the brain. The aim of this study is to provide valuable insights into the possible mechanisms of TNPs induced mitochondrial dysfunction in brain and its amelioration by nutraceuticals, quercetin (QR) and melatonin (Mel) in in vitro and in vivo conditions. Whole brain mitochondrial sample was used for in-vitro evaluation. Pre-treatment of QR (30 μM) and Mel (100 μM) at 25 °C for 1 h was given prior to TNPs (50 μg/ml) exposure. For in-vivo study, male Wistar rats were divided into four groups. Group I was control and group II was exposed to TNPs (5 mg/kg b.wt., i.v.). QR (5 mg/kg b.wt.) and Mel (5 mg/kg b.wt.) were given orally as pre-treatment in groups III and IV, respectively. Biochemical parameters, neurobehavioural paradigms, mitochondrial respiration, neuronal architecture assessment were assessed. QR and Mel restored the mitochondrial oxidative stress biomarkers in both the studies. Additionally, these nutraceuticals resuscitated the neurobehavioural alterations and restored the neuronal architecture alterations in TNPs exposed rats. The mitochondrial dysfunction induced by TNPs was also ameliorated by QR and Mel by protecting the mitochondrial complex activity and mitochondrial respiration rate. Results of the study demonstrated that QR and Mel ameliorated mitochondrial mediated neurotoxic effects induced by TNPs exposure. [ABSTRACT FROM AUTHOR]

Treatment of Ischemic Stroke is inordinately challenging due to its complex aetiology and constraints in shuttling therapeutics across blood-brain barrier. Ropinirole hydrochloride (Rp), a propitious neuroprotectant with anti-oxidant, anti-inflammatory, and anti-apoptotic properties (3A) is repurposed for remedying ischemic stroke and reperfusion (I/R) injury. The drug's low bioavailability in brain however, limits its therapeutic efficacy. The current research work has reported sub-100 nm gamma-L-Glutamyl-L-Cysteine coated Human Serum Albumin nanoparticles encapsulating Rp (C-Rp-NPs) for active targeting in ischemic brain to encourage in situ activity and reduce unwanted toxicities. Confocal microscopy and brain distribution studies confirmed the enhanced targeting potentiality of optimized C-Rp-NPs. The pharmacokinetics elucidated that C-Rp-NPs could extend Rp retention in systemic circulation and escalate bioavailability compared with free Rp solution (Rp-S). Additionally, therapeutic assessment in transient middle cerebral occlusion (tMCAO) model suggested that C-Rp-NPs attenuated the progression of I/R injury with boosted therapeutic index at 1000 times less concentration compared to Rp-S via reinstating neurological and behavioral deficits, while reducing ischemic neuronal damage. Moreover, C-Rp-NPs blocked mitochondrial permeability transition pore (mtPTP), disrupted apoptotic mechanisms, curbed oxidative stress and neuroinflammation, and elevated dopamine levels post tMCAO. Thus, our work throws light on fabrication of rationally designed C-Rp-NPs with enormous clinical potential. [Display omitted] [ABSTRACT FROM AUTHOR]

Bicyclic azetidine compounds possess antimalarial activity via targeting of the cytoplasmic Plasmodium falciparum (Pf) protein translation enzyme phenylalanine-tRNA synthetase (cFRS). These drugs kill parasites both in vitro and in vivo , including the blood, liver, and transmission developmental stages. Here we present the co-crystal structure of Pf cFRS with a potent inhibitor, the bicyclic azetidine BRD7929. Our studies reveal high-affinity binding of BRD7929 with Pf cFRS along with exquisite specificity compared with the human enzyme, leading in turn to potent and selective inhibition of the parasite enzyme. Our co-crystal structure shows that BRD7929 binds in the active site in the α subunit of Pf cFRS, where it occupies the amino acid site, an auxiliary site, and partially the ATP site. This structural snapshot of inhibitor-bound Pf cFRS thus provides a platform for the structure-guided optimization of novel antimalarial compounds. [Display omitted] • BRD7929 is a highly potent inhibitor of Pf cFRS • The co-crystal structure reveals the binding mode of BRD7929 to Pf cFRS • A mutant human-like Pf cFRS protein provides insights into drug selectivity Sharma et al. reveal the structural basis for the inhibition of cytoplasmic Plasmodium falciparum phenylalanine tRNA synthase (Pf cFRS) by the potent and highly selective antimalarial compound BRD7929. Overall, this work provides insights for ongoing structure-based drug design efforts based on the bicyclic azetidine series. [ABSTRACT FROM AUTHOR]

Ischemic reperfusion (I/R) injury causes a wide array of functional and structure alternations of mitochondria, associated with oxidative stress and increased the severity of injury. Despite the previous evidence for N -acetyl-L-cysteine (NAC) provide neuroprotection after I/R injury, it is unknown to evaluate the effect of NAC on altered mitochondrial autophagy forms an essential axis to impaired mitochondrial quality control in cerebral I/R injury. Male wistar rats subjected to I/R injury were used as transient Middle Cerebral Artery Occlusion (tMCAO) model. After I/R injury, the degree of cerebral tissue injury was detected by infarct volume, H&E staining and behavioral assessment. We also performed mitochondrial reactive oxygen species and mitochondrial membrane potential by flow cytometry and mitochondrial respiratory complexes to evaluate the mitochondrial dysfunction. Finally, we performed the western blotting analysis to measure the apoptotic and autophagic marker. We found that NAC administration significantly ameliorates brain injury, improves neurobehavioral outcome, decreases neuroinflammation and mitochondrial mediated oxidative stress. We evaluated the neuroprotective effect of NAC against neuronal apoptosis by assessing its ability to sustained mitochondrial integrity and function. Further studies revealed that beneficial effects of NAC is through targeting the mitochondrial autophagy via regulating the GSK-3β/Drp1mediated mitochondrial fission and inhibiting the expression of beclin-1 and conversion of LC3, as well as activating the p-Akt pro-survival pathway. Our results suggest that NAC exerts neuroprotective effects to inhibit the altered mitochondrial changes and cell death in I/R injury via regulation of p-GSK-3β mediated Drp-1 translocation to the mitochondria. [ABSTRACT FROM AUTHOR]

Phthalate esters such as di-butyl phthalate (DBP) and di-ethyl hexyl phthalate (DEHP) used in personal care and consumer products and medical devices have potential to affect human health. We studied the effect of DBP and DEHP on critical enzymes of glucocorticoid biosynthesis pathway in the adrenal gland and pro-inflammatory cytokines in the serum in male Wistar rats. DEHP and DBP treatment altered the mRNA expression of enzymes of glucocorticoid biosynthesis pathway accompanied by a reduction in glucocorticoid production and elevation in the level of glucocorticoid regulated pro-inflammatory cytokines indicating a cascading effect of phthalates. The analysis of PPI (protein – protein interaction) network involving Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) of enzymes through STRING database revealed that all the proteins have the maximum level of interaction with the selected number of proteins. The STRING database analysis together with in vivo data indicates the potential effects of phthalates on various targets of steroidogenesis pathway with a global biological impact. [Display omitted] • Phthalates (DBP and DEHP) caused histopathological injuries in rat adrenals. • Expression of enzymes of glucocorticoid biosynthesis was affected by DBP and DEHP. • Phthalates caused decrease in serum corticosterone but increase in cytokines. • PPI analysis revealed potential of phthalates to disrupt pathways in vital organs. [ABSTRACT FROM AUTHOR]

Ischemic stroke (IS) is a rapidly increasing global burden and is associated with severe neurological decline and mortality. There is urgent requirement of the efforts, aimed to identify therapeutic strategies that are effective in clinic to promote significant recovery from IS. Studies have shown that mitochondria mediated neuroprotection can be a competent target against ischemic damage. Therefore, we examined whether mitochondrial impairment is regulated by Piperine (PIP), an alkaloid of Piper Longum , which has neuroprotective activity against ischemic brain injury. In this study, transient middle cerebral artery occlusion (tMCAO) surgery was performed on male Wistar rats for 90 min followed by 22.5 h of reperfusion for mimicking the IS condition. This study consisted of three groups: sham, tMCAO and tMCAO + PIP (10 mg/kg b.wt., p.o/day for 15 days), and studied for behavioral tests, infarct volume, brain pathological changes, mitochondrial dysfunction, inflammation alongwith cell survival status. PIP pre-treatment showed reduction in neurological alterations and infarct volume. In addition, PIP pre-treatment suppressed the mitochondrial dysfunction and might have anti-apoptotic potential by preventing Cytochrome c (Cyt c) release from mitochondria to cytoplasm and caspase 3 activation. It also regulates pro-apoptotic, Bax and anti-apoptotic, Bcl-2 proteins accompanied by glial fibrillary acidic protein (GFAP) positive cells in cortex region. Quantitative Reverse transcription-polymerase chain reaction (qRT-PCR) results also showed that PIP reduced the expression of pro-inflammatory protein, interleukin-1 β (IL-1β) and enhanced cell survival by restoring the activity of brain derived neurotrophic factor (BDNF) and its transcription protein, cAMP response element binding protein (CREB). Taken together, PIP reduced the mitochondrial dysfunction, neurological impairment, and enhanced neuronal survival. In conclusion, our findings reinforce PIP as an effective neuroprotective agent and provide important evidence about its role as a potential target to serve as a promising therapy for treatment of IS. Schematic representation of mitochondria mediated mechanisms of neuroprotection against ischemic stroke provided by Piperine. Piperine can inhibit mitochondrial dysfunction by suppressing inflammation and mitochondrial ROS mediated alterations in ETC and reduced mitochondrial membrane permeability (Δѱm) thereby preserving mitochondrial Cyt c level through blockage of mitochondrial permeability transition pore (mPTP). Finally, it might increase anti-apoptotic (Bcl-2) protein and decrease pro-apoptotic (Bax) protein, and alleviated neuronal cell death. Piperine also involved in cell survival processes and ultimately rescued neuronal morphological alterations and neurobehavioral abnormalities. IL-1β (Interleukin-1β), GFAP (Glial Fibrillary Acidic Protein), LPO (Lipid Peroxidation), GSH (Glutathione), Cyt c (Cytochrome c), Electron transport chain (ETC), Reactive oxygen species (ROS). [Display omitted] • Ischemic animals pre-treated with piperine showed reduced neurological alterations and infarct volume. • Piperine improved mitochondrial dysfunction. • Piperine showed anti-apoptotic potential by preventing cytochrome c release from mitochondria to cytoplasm. • PIP reduced neurological impairment and enhanced cell survival. [ABSTRACT FROM AUTHOR]