Valsartan: An Angiotensin Receptor Blocker Modulates BDNF Expression and Provides Neuroprotection Against Cerebral Ischemic Reperfusion Injury.

AT1 receptor blockers (ARBs) are commonly used drugs to treat cardiovascular disease and hypertension, but research on their impact on brain disorders is unattainable. Valsartan (VAL) is a drug that specifically blocks AT1 receptor. Despite the previous evidence for VAL to provide neuroprotection in case of ischemic reperfusion injury, evaluation of their potential in mitigating mitochondrial dysfunction that causes neuronal cell death and neurobehavioral impairment remains unknown. The aim of this study was to evaluate the therapeutic effect of repurposed drug VAL against ischemic reperfusion injury-induced neuronal alternation. tMCAO surgery was performed to induce focal cerebral ischemic reperfusion injury. Following ischemic reperfusion injury, we analyzed the therapeutic efficacy of VAL by measuring the infarct volume, brain water content, mitochondrial oxidative stress, mitochondrial membrane potential, histopathological architecture, and apoptotic marker protein. Our results showed that VAL administrations (5 and 10 mg/kg b.wt.) mitigated the brain damage, enhanced neurobehavioral outcomes, and alleviated mitochondrial-mediated oxidative damage. In addition to this, our findings demonstrated that VAL administration inhibits neuronal apoptosis by restoring the mitochondrial membrane potential. A follow-up investigation demonstrated that VAL induces BDNF expression and promoted ischemic tolerance via modulating the Akt/p-Creb signaling pathway. In summary, our results suggested that VAL administration provided neuroprotection, ameliorated mitochondrial dysfunction, preserved the integrity of neurons, and lead to functional improvement after ischemic reperfusion injury.

Dantrolene alleviates mitochondrial dysfunction and neuroinflammation in traumatic brain injury by modulating the NF-ĸß/Akt pathway.

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-κß 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-κß/Akt signaling pathway. Thus, our results suggest a novel application of DNT in ameliorating the multitude of deficits induced by TBI, thereby conferring neuroprotection.

HDAC inhibition by Nigella sativa L. sprouts extract in hepatocellular carcinoma: an approach to study anti-cancer potential.

A wide variety of natural products have been widely used in chemoprevention therapy because they have antioxidant, anti-inflammatory, and anticancer activity. In the present study, we shed light on the 5th day germinated sprouts of N. sativa seeds and evaluated them against HDAC inhibition and antioxidant activity. The extract from the seed and sprout was extracted and characterised by LC-MS/MS, FTIR, and NMR to reveal its chemical composition, especially thymol (THY) and thymoquinone (TQ). Hepatocellular carcinoma (HCC) is a global health concern as it is a major lifestyle disease. Hence, incorporating herbal-based therapeutic compounds into everyday routines has become an attractive alternative for preventing hepatic diseases. Histone deacetylase (HDAC) inhibition (HDACi) is emerging as a promising therapeutic strategy for managing various carcinomas including HCC. Therefore, the 5th day of N. sativa can be used as a potential anticancer agent by inhibiting HDAC activity, as it is reported to have an important role in the management of oxidative stress. The bioactive compound of N. sativa, i.e. thymoquinone, also showed a good binding affinity with the HDAC protein (3MAX) with a stable interaction in an in silico study as compared to the standard drug (Trichostatin A) and thymol.Communicated by Ramaswamy H. Sarma.

Nigella sativa and its nano-mediated approach toward management of neurodegenerative disorders: A review.

Nigella sativa L., also known as black seed or black cumin, is a plant that has been used for centuries. In the past, this flowering plant was used as a food preservative and medicinal herb. A vital component of Nigella sativa, thymoquinone (TQ), plays a significant therapeutic role in the management of most diseases, including cancer, diabetes mellitus, hypertension, inflammation, gastrointestinal disorders, and neurodegenerative disorders. Neurodegenerative disorders are primarily caused by neurotransmitter hypoactivity, particularly insufficient serotonin activity. It has been discovered that many medicinal herbs and their active compounds have therapeutic value. Black cumin seeds have been used to heal ailments and its history traces back to ancient times such as ancient Babylonia. They can be used applied to alleviate edema, hair loss, and bruising, and consumd to treat stomach issues. It is one of the most feasible and effective medicinal plants. The use of nanoformulations based on Nigella sativa and TQ to treat neurodegenerative diseases (NDs) has yielded promising outcomes. Customized administration of nanoparticle (NP) systems and nanomedicine are two of the many options for drug delivery to the central nervous system (CNS) that are attracting increasing interest. Delivering a therapeutic and diagnostic substance to a particular location is the core target of NPs. Because of their distinct cell uptake and trafficking mechanisms, NPs can reduce the amount that accumulates in undesirable organs. The focus of the current review is on recent studies on the various neuroprotective properties of Nigella sativa as well as nanoformulations for NDs and the brain's uptake of NPs. The review summarizes the In vivo, In vitro, and In silico studies on the protective effects of black cumin against neurodegenerative disorders.

Pregnenolone Attenuates the Ischemia-Induced Neurological Deficit in the Transient Middle Cerebral Artery Occlusion Model of Rats.

Neurosteroids are apparent to be connected in the cerebral ischemic injury for their potential neuroprotective effects. We previously demonstrated that progesterone induces neuroprotection via the mitochondrial cascade in the cerebral ischemic stroke of rodents. Here, we sought to investigate whether or not pregnenolone, a different neurosteroid, can protect the ischemic injury in the transient middle cerebral artery occlusion (tMCAO) rodent model. Male Wistar rats were chosen for surgery for inducing stroke using the tMCAO method. Pregnenolone (2 mg/kg b.w.) at 1 h postsurgery was administered. The neurobehavioral tests and (TTC staining) 2, 3, 5-triphenyl tetrazolium chloride staining were performed after 24 h of the surgery. The mitochondrial membrane potential and reactive oxygen species (ROS) were measured using flow cytometry. Oxygraph was used to examine mitochondrial bioenergetics. The spectrum of neurobehavioral tests and 2, 3, 5-triphenyltetrazolium chloride staining showed that pregnenolone enhanced neurological recovery. Pregnenolone therapy after a stroke lowered mitochondrial ROS following ischemia. Our data demonstrated that pregnenolone was not able to inhibit mitochondrial permeability transition pores. There was no effect on mitochondrial bioenergetics such as oxygen consumption and respiratory coupling. Overall, the findings demonstrated that pregnenolone reduced the neurological impairments via reducing mitochondria ROS but not through the inhibition of the mitochondria permeability transition pore (mtPTP).

Assessment of hyaluronic acid-modified imatinib mesylate cubosomes through CD44 targeted drug delivery in NDEA-induced hepatic carcinoma.

This study aimed at the development of hyaluronic acid-functionalised imatinib mesylate cubosomes (HA-IM-CBs) that might be useful in CD44 targeting against hepatic cancer. The HA-IM-CBs had a 130.7 ±â€¯2.92 nm particle size, -31.40 ±â€¯2.76 mV zeta potential, and 76.14 ±â€¯2.69% release. The architecture of HA-IM-CBs was confirmed using HR-TEM and AFM. When compared to plain IM and IM-CBs, in vitro experiments revealed that HA-IM-CBs outperformed by significantly reducing cell viability. DAPI staining and ROS corroborated the apoptotic effects. Biodistribution and Pharmacokinetics studies showedthat HA-IM-CBs exhibit a higher drug concentration in tumour tissue and better pharmacokinetic activity. This is the first study to show that HA-IM-CBs had CD44 targeting activity against HCC. CD44 regulates apoptosis via Bcl-2 family proteins and caspases, which interact with HA. Higher levels of e-NOS, BAD, BAX, and Cyt C and lower expressions of Bcl-xl, i-NOS, and Bcl-2 demonstrated the anti-HCC potential of HA-IM-CBs in qrt-PCR investigations. The remarkable therapeutic potential of HA-IM-CBs began with substantial stimulation of CD44 regulated caspase-mediated mitochondrial apoptotic pathway, accountable for their anti-HCC activity. The perturbed metabolites are restored to acceptable levels as indicated by metabolomic studies (1H NMR). Interestingly, the antineoplastic effect of HA-IM-CBs was proven to be potentially valuable against HCC.

Solid Lipid Nanoparticles of Lepidium Sativum L Seed Extract: Formulation, Optimization and In vitro Cytotoxicity Studies.

The current study focused on important bioactive compounds in plants that make them pharmacologically valuable. Therefore, this study was aimed to develop Lepidium sativum (L. sativum) seed extract loaded solid lipid nanoparticles and explore its cytotoxic effect on human liver cancer cells (HepG2 cells). The ethanolic extract of L. sativam used to develop L. sativum seed extract loaded solid lipid nanoparticles (SLNs) was analyzed by gas chromatography-mass spectrometry, thin-layer chromatography (TLC) and high-performance thin-layer chromatography (HPTLC) for phytochemical profiling. The L. sativum seed extract loaded SLNs were efficaciously prepared by the nanoprecipitation method and screened on the basis of physicochemical properties. The L. sativum seed extract loaded SLN-2 was characterized using various parameters like particle size (237.1±0.104), % entrapment efficiency (80±1.15), zeta potential (42.1±0.102) and % drug release (45% at the end 8 hours and release the entire amount in 12 h). The SLN-2 formulation was optimized based on the recipient factor, and SLN-2 was used to further evaluate the in vitro cytotoxicity of HepG2 cells in a dose-dependent manner by 3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) assay. The IC50 value of SLN2 was 52.37 ug/ml and sub IC50 26.1 ug/ml at 24 h and 48 h, respectively. Thus, we concluded that L. sativum extract loaded SLN-2 could act as an alternative therapy, possibly controlling therapeutic action by making a substantial reduction in side effects.

N-acetyl-L-cysteine ameliorates mitochondrial dysfunction in ischemia/reperfusion injury via attenuating Drp-1 mediated mitochondrial autophagy.

BACKGROUND AND PURPOSE: 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. METHODS: 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. RESULTS: 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-3ß/Drp1mediated mitochondrial fission and inhibiting the expression of beclin-1 and conversion of LC3, as well as activating the p-Akt pro-survival pathway. CONCLUSION: 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-3ß mediated Drp-1 translocation to the mitochondria.

Harnessing the mitochondrial integrity for neuroprotection: Therapeutic role of piperine against experimental ischemic stroke.

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 ß (IL-1ß) 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.

Molecular Docking and Dynamics Simulation Analysis of Thymoquinone and Thymol Compounds from Nigella sativa L. that Inhibit Cag A and Vac A Oncoprotein of Helicobacter pylori: Probable Treatment of H. pylori Infections.

BACKGROUND: Helicobacter pylori infection is accountable for most of the peptic ulcer and intestinal cancers. Due to the uprising resistance towards H. pylori infection through the present and common proton pump inhibitors regimens, the investigation of novel candidates is the inevitable issue. Medicinal plants have always been a source of lead compounds for drug discovery. The research of the related effective enzymes linked with this gram-negative bacterium is critical for the discovery of novel drug targets. OBJECTIVE: The aim of the study is to identify the best candidate to evaluate the inhibitory effect of thymoquinone and thymol against H. pylori oncoproteins, Cag A and Vac A in comparison to the standard drug, metronidazole by using a computational approach. MATERIALS AND METHODS: The targeted oncoproteins, Cag A and Vac A were retrieved from RCSB PDB. Lipinski's rule and ADMET toxicity profiling were carried out on the phytoconstituents of the N. sativa. The two compounds of N. sativa were further analyzed by molecular docking and MD simulation studies. The reported phytoconstituents, thymoquinone and thymol present in N. sativa were docked with H. pylori Cag A and Vac A oncoproteins. Structures of ligands were prepared using ChemDraw Ultra 10 software and then changed into their 3D PDB structures using Molinspiration followed by energy minimization by using software Discovery Studio client 2.5. RESULTS: The docking results revealed the promising inhibitory potential of thymoquinone against Cag A and Vac A with docking energy of -5.81 kcal/mole and -3.61kcal/mole, respectively. On the contrary, the inhibitory potential of thymol against Cag A and Vac A in terms of docking energy was -5.37 kcal/mole and -3.94kcal/mole as compared to the standard drug, metronidazole having docking energy of -4.87 kcal/mole and -3.20 kcal/mole, respectively. Further, molecular dynamic simulations were conducted for 5ns for optimization, flexibility prediction, and determination of folded Cag A and Vac A oncoproteins stability. The Cag A and Vac A oncoproteins-TQ complexes were found to be quite stable with the root mean square deviation value of 0.2nm. CONCLUSION: The computational approaches suggested that thymoquinone and thymol may play an effective pharmacological role to treat H. pylori infection. Hence, it could be summarized that the ligands thymoquinone and thymol bound and interacted well with the proteins Cag A and Vac A as compared to the ligand MTZ. Our study showed that all lead compounds had good interaction with Cag A and Vac A proteins and suggested them to be a useful target to inhibit H. pylori infection.

Post-ischemic administration of dopamine D2 receptor agonist reduces cell death by activating mitochondrial pathway following ischemic stroke.

AIMS: Cerebral ischemic stroke leads to mitochondrial alterations which are key factors for initiation of various cascades resulting in neuronal damage. Dopamine D2 receptor (D2R) agonist, Sumanirole (SUM) has been reported to possess anti-inflammatory, anti-oxidant, and anti-apoptotic properties. However, the role of SUM in ischemic stroke (IS) has not been studied yet. The aim of the present study was to investigate the neuroprotective efficiency of SUM against ischemic injury and its possible effect on mitochondrial restorative mechanisms. MATERIALS AND METHODS: Transient middle cerebral artery occlusion (tMCAO) was performed in Wistar rats for 90 min occlusion and 22.5 h reperfusion to mimic ischemic stroke. Post- treatment with Sumanirole (0.1 mg/kg and 1 mg/kg; s.c.) was done at 1 h, 6 h, 12 hand 18 h after surgery. In addition, neurobehavioral analysis, mitochondrial reactive oxygen species and mitochondrial membrane potential by flow cytometric analysis, mitochondrial complexes analysis, infarct size evaluation and histological analysis were performed. KEY FINDINGS: Sumanirole restored behavioural alterations as measured by rotarod performance, grip strength, adhesive tape removal analysis and neurological deficits. In addition, it also refurbished mitochondrial dysfunction by decreasing mitochondrial reactive oxygen species production, elevating mitochondrial membrane potential and by protecting the activity of mitochondrial complexes along with histological alterations. As a result, infarct sizes were markedly reduced in tMCAO surgery animals. SIGNIFICANCE: Findings from the study provide evidence that SUM promotes neuronal survival in in vivo model of IS through mitochondria mediated neuroprotective features.

Clozapine Improves Behavioral and Biochemical Outcomes in a MK-801-Induced Mouse Model of Schizophrenia.

Glutamatergic N-methyl-D-aspartate (NMDA) receptors have critical roles in several neurological and psychiatric diseases. Dizocilpine (MK-801) is a ligand at phencyclidine recognition sites that is associated with NMDA receptor-coupled cation channels, where it acts as a potent noncompetitive antagonist of central glutamate receptors. In this study, we investigate the effect of clozapine on MK-801-induced neurochemical and neurobehavioral alterations in the prefrontal cortex of mice. Acute administration of NMDA noncompetitive antagonist MK-801 impairs motor coordination, grip strength, and locomotor activity. Clozapine is the only medication that is indicated for treating refractory schizophrenia, due to its superior efficacy among all antipsychotic agents; however, its mechanism is not well understood. To understand its mechanism, we investigated the effects of clozapine on motor coordination, locomotor activity, and grip strength in mice against the NMDA receptor antagonist MK-801. MK-801 induced elevations in acetylcholinesterase (AChE) activity, monoamine oxidase (MAO) activity, and c-fos expression. The administration of clozapine inhibited the effects caused by MK-801 (0.2 mg/kg body weight). Motor coordination and grip strength paradigms that had been altered by MK-801 were restored by clozapine. Moreover, clozapine also ameliorated MK-801-induced elevation in AChE and MAO activity. Our immunostaining results demonstrated that clozapine treatment reduced overexpression of the neuronal activity marker c-fos in cortices of the brain. Results of the current study determine that clozapine ameliorated cognition in MK-801-treated mice via cholinergic and neural mechanisms. These findings show that clozapine possesses the potential to augment cognition in diseases such as schizophrenia.

Nrf2/HO-1 mediates the neuroprotective effects of pramipexole by attenuating oxidative damage and mitochondrial perturbation after traumatic brain injury in rats.

Pramipexole (PPX), a D2-like receptor agonist, is generally used in the treatment of Parkinson's disease and restless leg syndrome. Its neuroprotective effects have been shown against various neurological disorders. Recent research work has demonstrated that PPX exerts neuroprotection through mitochondria. However, the neuromodulator-related effects of PPX against traumatic brain injury (TBI) remain unexplored. The present study, therefore, investigated the mechanism of neuroprotection by PPX against oxidative stress, mitochondrial dysfunction and neuronal damage following TBI in rats. We hypothesized that the neuroprotection by PPX in TBI-subjected rats might involve activation of the Nrf2/HO-1 (also known as Nfe2l2/Hmox1) signaling pathway. PPX was injected intraperitoneally (0.25 mg/kg body weight and 1.0 mg/kg body weight) at different time intervals post-TBI. Several neurobehavioral parameters were assessed at 48 h post-TBI, and the brain was isolated for molecular and biochemical analysis. The results demonstrated that PPX treatment significantly improved the behavioral deficits, decreased the lipid peroxidation rate, increased glutathione levels and decreased 4-hydroxynonenal levels in TBI-subjected rats. PPX also increased the activities of glutathione peroxidase and superoxide dismutase enzymes. In addition, PPX treatment inhibited mitochondrial reactive oxygen species production, restored mitochondrial membrane potential and increased ATP levels after a TBI. Further, PPX treatment reduced the Bax/Bcl2 ratio and translocation of Bax to mitochondria and cytochrome-c to the cytosol. Finally, PPX treatment greatly accelerated the translocation of Nrf2 to the nucleus and upregulated HO-1 protein expression. We conclude that the neuroprotective effects of PPX are mediated by activation of the Nrf2/HO-1 signaling pathway following TBI.This article has an associated First Person interview with the first author of the paper.

Tannic Acid Provides Neuroprotective Effects Against Traumatic Brain Injury Through the PGC-1α/Nrf2/HO-1 Pathway.

The present research was conducted to elucidate a possible molecular mechanism related to neuromodulatory effects of tannic acid (TA) supplementation against traumatic brain injury (TBI) in a rodent model. Oxidative damage and neuroinflammation play a critical role in TBI and lead to behavioral alterations and neuronal dysfunction and death. These changes suggest a potential avenue in neurotherapeutic intervention. The aim of the present study was to investigate the neuroprotective effects of TA and potential mechanism of these effects in a controlled cortical impact injury model of TBI in Wistar rats that were treated with TA (50 mg/kg body weight. i.p.) before 30 min and 6 and 18 h after TBI. TBI-induced rats were examined after 24 h for behavioral dysfunction, Nissl stain, lipid peroxidation rate, glutathione level, activities of antioxidant enzymes (catalase, glutathione S-transferase, glutathione peroxidase, and superoxide dismutase), the expression level of 4-hydroxynonenal, pro-inflammatory cytokines such as tumor necrosis factor alpha and interleukin-1 beta, as well as brain edema and immunoreactivity of glial fibrillary acidic protein. Results indicated that TA supplementation significantly modulated above mentioned alterations. Moreover, TA treatment effectively upregulated the protein expression of peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1α) and nuclear factor-E2-related factor-2 (Nrf2) as well as mitochondrial transcription factor A and heme oxygenase-1 (HO-1) following TBI. Overall, our results suggest that TA effectively ameliorates the behavioral alterations, oxidative damage, mitochondrial impairment, and inflammation against TBI that may be attributed to activation of PGC-1α/Nrf-2/HO-1 signaling pathway.

Molecular Docking and Dynamics Simulation Analysis of Thymoquinone and Thymol Compounds from Nigella sativa L. that Inhibits P38 Protein: Probable Remedies for Hepatocellular Carcinoma.

BACKGROUND: Currently, a novel antagonist against p38 is being designed and applied to inhibit hepatocellular carcinoma. Protein-ligand interaction plays a major role in the identification of the possible mechanism for the pharmacological action. The involvement of p38 remains an important target for anticancer drug development as its activation induces apoptosis in hepatoma cells. OBJECTIVE: The aim is to identify the best candidate from the plants of N. sativa which binds with the hepatocellular carcinoma (HCC) targets by computational approach. MATERIALS AND METHODS: The reported phytoconstituents such as thymoquinone and thymol present in the plant, N. sativa were docked with the HCC target such as p38. Structures of phytoconstituents were prepared using ChemDraw Ultra 10 software and converted into its 3D PDB structure and minimized using Discovery Studio client 2.5. The target protein, p38 was retrieved from RCSB PDB. Lipinski's rule and ADMET toxicity profiling were carried out on the phytoconstituents of the N. sativa, and the compounds were further promoted for molecular docking and MD simulation analysis. RESULTS: The docking results revealed promising inhibitory potential of thymoquinone against p38 with binding energy of -7.67 kcal/mole as compared to its known standard doxorubicin having binding energy of -6.68 kcal/mol respectively. Further, molecular dynamic (MD) simulations for 5ns were conducted for optimization, flexibility prediction, and determination of folded p38 stability. The p38-thymoquinone complex was found to be quite stable with RMSD value of 0.2 nm. CONCLUSION: Obtained results propose thymoquinone binding energy on the selected targets. Hence, this compound bears outstanding potential against hepatocellular carcinoma and has to be taken up for experimental work against hepatocellular carcinoma.

Reversal of Schizophrenia-like Symptoms and Cholinergic Alterations by Melatonin.

BACKGROUND: Melatonin is a neurohormone that is linked to the pathogenesis of schizophrenia. The aim of this study was to assess the potential of melatonin in attenuating MK-801 induced schizophrenia-like behavioral and brain neurotoxicity markers. METHODS: Swiss albino mice were assigned into three groups (n = 6). Animals were administered MK-801 (1 mg/kg/mL, i.p.). MK-801 treated animals were supplemented with melatonin (10 mg/kg/1 mL i.p.) 10 min prior to MK-801 injection. The relative degrees of modulation of induced behaviors by melatonin were assessed in the open field, elevated plus maze, grip strength and rota rod. The changes in neurotoxicity enzymes and neuronal activity (c-fos) were demonstrated in this study. RESULTS: MK-801 injection effected normal open-field behaviors, c-fos expression, motor coordination and muscular strength. Melatonin was able to reduce the histological changes in the prefrontal cortex of mice brain. CONCLUSION: Our data demonstrated that the treatment with melatonin attenuates the schizophrenic like symptoms in the mice having a protective effect on prefrontal cortex region of brain by mitigating the alteration of neurotoxicity markers. The protective effect of the treatment was shown to reduced elevation of AChE, c-fos expression and histopathological alterations.

Pramipexole prevents ischemic cell death via mitochondrial pathways in ischemic stroke.

A dopamine D2 receptor agonist, pramipexole, has been found to elicit neuroprotection in patients with Parkinson's disease and restless leg syndrome. Recent evidence has shown that pramipexole mediates its neuroprotection through mitochondria. Considering this, we examined the possible mitochondrial role of pramipexole in promoting neuroprotection following an ischemic stroke of rat. Male Wistar rats underwent transient middle cerebral artery occlusion (tMCAO) and then received pramipexole (0.25 mg and 1 mg/kg body weight) at 1, 6, 12 and 18 h post-occlusion. A panel of neurological tests and 2,3,5-triphenyl tetrazolium chloride (TTC) staining were performed at 24 h after the surgery. Flow cytometry was used to detect the mitochondrial membrane potential, and mitochondrial levels of reactive oxygen species (ROS) and Ca2+, respectively. Mitochondrial oxidative phosphorylation was analyzed by oxygraph (oxygen electrode). Western blotting was used to analyze the expression of various proteins such as Bax, Bcl-2 and cytochrome c Pramipexole promoted the neurological recovery as shown by the panel of neurobehavioral tests and TTC staining. Post-stroke treatment with pramipexole reduced levels of mitochondrial ROS and Ca2+ after ischemia. Pramipexole elevated the mitochondrial membrane potential and mitochondrial oxidative phosphorylation. Western blotting showed that pramipexole inhibited the transfer of cytochrome c from mitochondria to cytosol, and hence inhibited the mitochondrial permeability transition pore. Thus, our results have demonstrated that post-stroke administration of pramipexole induces the neurological recovery through mitochondrial pathways in ischemia/reperfusion injury.

Melatonin Improves Behavioral and Biochemical Outcomes in a Rotenone-Induced Rat Model of Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease followed only by Alzheimer's disease and affects millions of people worldwide. Despite the plethora of preclinical and clinical studies, there is currently a paucity of therapeutic agents for PD that can promote neuroprotection. In addition, the therapeutic agents currently available only help with improvement of PD symptoms. Therefore, it is imperative to find new therapeutic avenues for PD patients to minimize the economic and social burden on the concerned families. Rotenone is a frequently used neurotoxin in developing a PD model to aid in understanding the mechanisms of neuronal death. In addition, several studies have investigated the effects of melatonin, a neurohormone that is neuroprotective in various neurological diseases due to its anti-apoptotic, anti-inflammatory, and anti-oxidative properties. Our study investigated the role of melatonin-induced tyrosine hydroxylase (TH) and sensory motor function in a rotenone rat model to determine whether melatonin had any positive effects. Our results revealed that melatonin improves motor function by upregulation of TH in striatum of the brain. In addition, melatonin inhibits the striatal degeneration as shown by histopathological analysis. Therefore, results from the current study provide evidence for melatonin as a promising candidate for effective future therapeutic strategies for PD.

Nigella sativa L. and Its Bioactive Constituents as Hepatoprotectant: A Review.

BACKGROUND: The pharmacological properties of Nigella sativa L. are well attributed to the presence of bioactive compounds, mainly, thymoquinone (TQ), thymol (THY) and α hederin and their antioxidant effects. TQ, THY and alpha-hederin (α-hederin) provide protection to liver from injury via different mechanisms including inhibition of iron-dependent lipid peroxidation, elevation in total thiol content and (GSH) level, radical scavenging, increasing the activity of quinone reductase, catalase, superoxide dismutase (SOD) and glutathione transferase (GST), inhibition of NF-κB activity and inhibition of both (COX) and (LOX) protects liver from injuries. Review and Conclusion: The main aim of this literature review is to reflect the relevant role of ROS in inducing hepatic diseases and also the preventive role of N. sativa L. in hepatic diseases. The present article is directed towards highlighting the beneficial contribution of researchers to explore the pharmacological actions with therapeutic potential of this precious natural herb and its bioactive compounds pertaining to the hepatoprotective effects. We systematically searched for research literature through well-framed review question and presented the data in the tabular forms for the convenience of the readers. Two hundred and forty-one papers were embodied in this review, oxidative effect and the reactive oxygen species (ROS) are known to be the major causes of many diseases such as hepatic cancer. Many drugs and chemicals have shown to incite oxidative damage by generation of ROS in the body. Therefore, this review intends to focus the role of ROS in liver diseases and the mechanisms through which N. sativa prevents hepatic diseases. The mechanisms by which N. sativa impede progression in chronic liver diseases should be used as a preventive medicine in patients with hepatic disorders.

Role of Mitochondrial Mechanism in Chemotherapy-Induced Peripheral Neuropathy.

BACKGROUND: Even though chemotherapeutic regimens show considerable importance, it may cause progressive, continuing and sometimes irreversible peripheral neuropathy. Chemotherapy induced peripheral neuropathy (CIPN) is comprised of sensory abnormalities that are most distressing issues. The mechanism associated with CIPN pathogenesis is not completely revealed and its treatment is still questionable. The purpose of this review was to investigate the role of mitochondria in CIPN. METHODS: This review is literature based that describes the mitochondrial mechanism underlying CIPN and the neuropathic complications associated with different antineoplastic agents. RESULTS: For severe pain, a modification towards less efficient chemotherapeutic drugs could possibly be needed and/or patients perhaps prefer to withdrawal therapeutic regimen. The epidemiology of CIPN is still debatable. The major recurrent molecules causing CIPN are platinum based drugs including cisplatin and oxaliplatin, thalidomide, bortezomib, vinka alkaloids and taxanes. Neuropathic pain is one of the symptoms of CIPN. Various neuropathic disorders as well as CIPN are due to mitochondrial impairment, relevant impairment of Ca2+ signalling pathways and reactive oxygen species (ROS) that ultimately leads to apoptosis. CONCLUSION: The pathophysiology of CIPN is complicated as chemotherapeutic medications often involve combination of drugs. With these combinatorial therapies cancer survivors develop continuing effects of CIPN which require rehabilitation strategies for the recovery of patient's condition and quality of life.