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This article describes how methylcobalamin (MeCbl) restores nerve myelination in a moderate-grade hepatic encephalopathy (MoHE) model of ammonia neurotoxicity. The comparative profiles of myelin basic protein (MBP), homocysteine (Hcy) and methionine synthase (MS: a MeCbl- dependent enzyme) activity versus nerve myelination status were studied in the hippocampus of the control, the MoHE (developed by administering 100 mg/kg bw thioacetamide i.p. for 10 days) and the MoHE rats treated with MeCbl (500 μµg/kg BW i.p.) for 7 days. Compared to those of control rats, the hippocampal CA1 and CA3 regions of the MoHE rats showed significantly lower myelinated areas and MBP immunostaining. This coincided with the deranged myelin layering in TEM images, decreased MBP protein and its transcript levels in hippocampus of MoHE rats. However, all these parameters recovered to normal levels after MeCbl treatment. MeCbl is a cofactor of MS that catalyzes the conversion of Hcy to methionine as a feeder step of methylation reactions. We observed significantly increased serum and hippocampal Hcy levels in MoHE rats, however, these levels were restored to control values with a concordant activation of MS due to MeCbl treatment. A significant recovery in neurobehavioral impairments in the MoHE rats due to MeCbl treatment was also observed. These findings suggest that MoHE pathogenesis is associated with deranged nerve myelination in the hippocampus and that MeCbl treatment is able to restore it mainly by activating MS, a MeCbl-dependent Hcy-metabolizing enzyme. [ABSTRACT FROM AUTHOR]

The invasive screening methods and the late stage diagnosis of colorectal carcinoma (CRC) are contributing for the devastative prognosis. The gradual shift of the disease pattern among younger generations requires the implementation of phytochemicals and traditional medicines. Arkeshwara rasa (AR) is a herb–mineral combination of Tamra bhasma/incinerated copper ashes and Dwigun Kajjali/mercury sulphide levigated with Calotropis procera leaf juice, Plumbago zeylanica root decoction and the decoction of three myrobalans (Terminalia chebula, Terminalia bellerica, Emblica Officinalis decoction)/Triphala decoction. The SW-480 cell line was checked for the cytotoxicity and the cell viability criteria with MTT(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide) assay. The acridine orange/ethidium bromide (AO/EtBr) assay revealed the depth of apoptosis affected cells in the fluorescent images. The FTIR analysis exhibited the graphical spectrum of functional groups within the compound AR. The IC50 from the 10−7 to 10−3 concentrations against SW-480 cells was 40.4 μg/mL. The staining of AO/EtBr was performed to visualize live and dead cells and it is evident from the result that number of apoptotic cells increases at increasing concentration of AR. The single bond with stretch vibrations of O–H and N–H are more concentrated in the 2,500–3,200 cm−1 and 3,700–4,000 cm−1 of the spectra whereas, the finger print region carries the O–H and S=O type peaks. The AR shows strong cyto-toxicity against the SW-480 cells by inducing apoptosis. It also modulates cellular metabolism with the involvement of functional groups which antagonizes the strong acids. Moreover, these effects need to be analyzed further based in the in vivo and various in vitro models. [ABSTRACT FROM AUTHOR]

Hepatic encephalopathy (HE), characterized by impaired cerebellar functions during chronic liver failure (CLF), involves N-methyl-D-aspartate receptor (NMDAR) overactivation in the brain cells. Bacopa monnieri (BM) extract is a known neuroprotectant. The present paper evaluates whether BM extract is able to modulate the two NMDAR subunits (NR2A and NR2B) and its downstream mediators in cerebellum of rats with chronic liver failure (CLF), induced by administration of 50 mg/kg bw thioacetamide (TAA) i.p. for 14 days, and in the TAA group rats orally treated with 200 mg/kg bw BM extract from days 8 to 14. NR2A is known to impart neuroprotection and that of NR2B induces neuronal death during NMDAR activation. Neuronal nitric oxide synthase- (nNOS-) apoptosis pathway is known to mediate NMDAR led excitotoxicity. The level of NR2A was found to be significantly reduced with a concomitant increase of NR2B in cerebellum of the CLF rats. This was consistent with significantly enhanced nNOS expression, nitric oxide level, and reduced Bcl2/Bax ratio. Moreover, treatment with BM extract reversed the NR2A/NR2B ratio and also normalized the levels of nNOS-apoptotic factors in cerebellum of those rats. The findings suggest modulation of NR2A and NR2B expression by BM extract to prevent neurochemical alterations associated with HE. [ABSTRACT FROM AUTHOR]

TNF-α led neuro inflammation is considered accountable for over activating glutamate-NMDAR neurotransmission and thereby developing a metabolic brain disorder; hepatic encephalopathy (HE) in the liver cirrhotic patients. Increased susceptibility, for developing liver cirrhosis and thereby HE symptoms, is a more likely situation in the aged population. Sirt-1, a metabolic sensor for bio energetic deficits in the cells, could be functionally associated with NMDAR over activation in the brain cells. We have examined the neuroinflammation- NMDAR-apoptosis pathway and profile of Sirt-1 in cerebral cortex and cerebellum of the adult and old HE rats induced by administration of 100 mg/kg b.w of thioacetamide i.p. for 10 days. In comparison to the control rats, correlative increases in TNF-α & NfkB profiles and a transition of a neuroprotective NR1/NR2A NMDAR composition towards a neurodegenerative NR1/NR2B combination could be observed in both the brain regions of the adult and old HE rats. Concordantly, a significant decline in the expression of Sirt-1 in both the brain regions and in both the age group HE rats could also be observed. However, treatment of those HE rats, with 10 mg/Kg b.w. RSV (a Sirt-1 activator) for a week, was found to bring all the factors towards their normal level in both the brain regions. These changes were consistent with a significant recovery in HE associated neurodegeneration, neuro morphology and neuro behavioural parameters. The results suggest that Sirt-1 activation could be a relevant strategy to ameliorate TNF-α led excitotoxic neurodegenerative condition in the brain of the aging rats. [ABSTRACT FROM AUTHOR]

Highlights • Sirtuins deacetylate an array of proteins to execute cell survival strategies. • Mitochondrial derangement is the central event of neuro-excitotoxic brain disorders. • Mitochondrial SIRT3 alterations vs neuro-excitotoxicity is an evolving concept. • Arguably SIRT3 could be a relevant target to correct excitotoxic brain disorders. • Mito-SIRT3 thus needs detailed study as therapeutic target for brain disorders. Abstract Sirtuins are highly conserved NAD+ dependent class III histone deacetylases and catalyze deacetylation and ADP ribosylation of a number of non-histone proteins. Since, they require NAD+ for their activity, the cellular level of Sirtuins represents redox status of the cells and thereby serves as bona fide metabolic stress sensors. Out of seven homologues of Sirtuins identified in mammals, SIRT3, 4 & 5 have been found to be localized and active in mitochondria. During recent past, clusters of protein substrates for SIRT3 have been identified in mitochondria and thereby advocating SIRT3 as the main mitochondrial Sirtuin which could be involved in protecting stress induced mitochondrial integrity and energy metabolism. As mitochondrial dysfunction underlies the pathogenesis of almost all neurodegenerative diseases, a role of SIRT3 becomes an arguable speculation in such brain disorders. Some recent findings demonstrate that SIRT3 over expression could prevent neuronal derangements in certain in vivo and in vitro models of aging and neurodegenerative brain disorders like; Alzheimer's disease, Huntington's disease, stroke etc. Similarly, loss of SIRT3 has been found to accelerate neurodegeneration in the brain challenged with excitotoxicity. Therefore, it is argued that SIRT3 could be a relevant target to understand pathogenesis of neurodegenerative brain disorders. This review is an attempt to summarize recent findings on (1) the implication of SIRT3 in neurodegenerative brain disorders and (2) whether SIRT3 modulation could ameliorate neuropathologies in relevant models. [ABSTRACT FROM AUTHOR]

An efficient and promising method of treating complex neurodegenerative diseases like Alzheimer's disease (AD) is the multitarget-directed approach. Here in this work, a series of quinazoline derivatives ( AV-1 to AV-21 ) were rationally designed, synthesized, and biologically evaluated as multitargeted directed ligands against human cholinesterase (hChE) and human β-secretase (hBACE-1) that exhibit moderate to good inhibitory effects. Compounds AV-1 , AV-2 , and AV-3 from the series demonstrated balanced and significant inhibition against these targets. These compounds also displayed excellent blood-brain barrier permeability via the PAMPA-BBB assay. Compound AV-2 significantly displaced propidium iodide (PI) from the acetylcholinesterase-peripheral anionic site (AChE-PAS) and was found to be non-neurotoxic at the maximum tested concentration (80 μM) against differentiated SH-SY5Y cell lines. Compound AV-2 also prevented AChE- and self-induced Aβ aggregation in the thioflavin T assay. Additionally, compound AV-2 significantly ameliorated scopolamine and Aβ-induced cognitive impairments in the in vivo behavioral Y-maze and Morris water maze studies, respectively. The ex vivo and biochemical analysis further revealed good hippocampal AChE inhibition and the antioxidant potential of the compound AV-2 . Western blot and immunohistochemical (IHC) analysis of hippocampal brain revealed reduced Aβ, BACE-1, APP/Aβ, and Tau molecular protein expressions levels. The pharmacokinetic analysis of compound AV-2 demonstrated significant oral absorption with good bioavailability. The in silico molecular modeling studies of lead compound AV-2 moreover demonstrated a reasonable binding profile with AChE and BACE-1 enzymes and stable ligand-protein complexes throughout the 100 ns run. Compound AV-2 can be regarded as the lead candidate and could be explored more for AD therapy.

Global metabolism of cancers exhibits a peculiar phenotype that is lactate acidosis (high lactate with acidic pH) in tumor microenvironment. Why tumor microenvironment becomes so responsive towards lactate is still not clear. In this review we have discussed lactate generation and recycling either exogenously, directly or indirectly by cancer cells via some transporters. Tumor cells in hypoxia use glucose rapidly and produce lactate while cells which have profuse oxygen supply take up lactate and use it for energy production which is referred as lactate shuttling between tumor cells. Escaping immune evasion which is also an emerging hallmark of cancer cells has also been discussed in this review with respect of lactate acidosis.