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1.
Neurology ; 95(20 Supplement 1): S14, 2020 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-33199578

RESUMO

OBJECTIVE: Our quest was to find an answer for "Why are some people able to recover 100% from a concussion/traumatic brain injury while others tend to have prolonged symptoms after their concussion/traumatic brain injury?" BACKGROUND: The prevalence of hyperhomocysteinemia in general is 5%-7% with increasing evidence showing higher prevalence of HHcy as age increases. The prevalence of vitamin D deficiency was 41.6% in the American population. The prevalence of vitamin B-12 deficiency is at least 40% in the patients of the Americas. With recent data, the prevalence of magnesium deficiency is around 10%-30% of the population. Hyperhomocysteinemia due MTHFR gene mutation B-12, B-6, magnesium, and folic acid deficiency is well established. DESIGN/METHODS: A retrospective study involving 45 patients was conducted in order to correlate the persistent symptoms concussion head injury/traumatic brain injury and their bio nutraceutical deficiency. RESULTS: This data provides evidence that a patient's Homocysteine levels are significantly linearly related with their MoCA scores (t = -5.837, df = 34, p-value = 1.403e-06, [95% CI: -0.8406114 to -0.4936554]). In the mTBI group, for every 1 umol/L increase in Homocysteine levels, there is a 0.54217 decrease in MoCA scores. mTBI patients that had Homocysteine levels greater than 14 umol/L were 76% more likely to experience cognitive decline. The mean MoCA score of mTBI patients is significantly lower than the mean MoCA score of patients in the control group (t = -3.2898, df = 67, p-value = 0.0016, [95% CI: -6.710893 to -1.642642]). The mean Homocysteine levels of mTBI patients are significantly greater than the mean Homocysteine levels of patients in the control group (t = 2.2182, df = 85, p-value = 0.0292, [95% CI: 0.3039847 to 5.5603010]). CONCLUSIONS: mTBI patients should be routinely screened for serum homocysteine, vitamin D, B12, B6 and magnesium levels to know their risk for cognitive decline.

2.
J Food Biochem ; : e13571, 2020 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-33249607

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disorder, and multiple factors are involved in disease progression. This is why there is an urgent need to develop novel molecules with multi-target-directed ligands (MTDLs) potential. The current study explores the active phytoconstituents from traditionally used medicinal spices, namely piperine, cinnamaldehyde, eugenol, cuminaldehyde, and alpha-terpinyl acetate for the inhibition of ß-secretase, monoamine oxidase, cholinesterase enzymes, anti-aggregation of amyloid ß (Aß) fibrils, and their protective effect against hydrogen peroxide (H2 O2 ) and Aß-induced toxicity. Eugenol showed inhibitory activity against MAO-B enzyme, free radical scavenging activity, and anti-aggregation activity against Aß peptides than other phytoconstituents. It also demonstrated a significant cytoprotective effect against H2 O2 -induced oxidative stress and Aß-induced cytotoxicity in pheochromocytoma (PC) 12 cells. A molecular docking study of eugenol showed interactions with active site residue of the target enzymes. The study successfully demonstrated that eugenol could have an MTDLs potential better than synthesized drugs used in the treatment of AD. PRACTICAL APPLICATIONS: The present study demonstrated multi-target-directed ligand potential of eugenol and can be developed to treat complex diseases like Alzheimer's. Eugenol can bind to different Alzheimer's targets such as ß-secretase (BACE1), Monoamine oxidase B (MAO-B), Cholinesterase's, and amyloid ß1-42 fibrils and might have a disease-modifying potential. The other natural phytoconstituents such as piperine, cinnamaldehyde, cuminaldehyde, and alpha-terpinyl acetate also demonstrated MTDL potential could also be used for developing novel molecules for disease-modifying effect. It also protects against oxidative stress.

3.
Nat Prod Res ; : 1-5, 2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33207949

RESUMO

Based on ethnobotanical surveys, an Indian traditional plant, i.e., Baccharoides anthelmintica (L.) Moench (Family - Asteraceae) was selected for detailed phytochemical investigations. B. anthelmintica seeds, purchased from local market, were extracted exhaustively in a Soxhlet apparatus using methanol as solvent. A well-established method was adopted to obtain phenolic compounds and flavonoids rich fraction of methanol extract. This fraction yielded two isolates (AK-1 and AK-2) upon purification by column chromatographic process. AK-1 was characterized as mixture of two isomeric compounds - 3',4',5,6,7- and 3',4',5,7,8-pentahydroxy flavanone, and AK-2 as butein (chalcone derivative) by UV, IR and NMR spectral analysis. A TLC densitometric method was developed and validated to estimate the content of butein in B. anthelmintica seeds, and was found to be 1.252 mg/g. Bioactive Marker (butein) based standardized B. anthelmintica seeds will ensure reproducibility in efficacy and safety of the plant or authenticity of its products.

4.
Biochem J ; 2020 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-33175092

RESUMO

Posttranslational modifications such as phosphorylation, nitrosylation, and pupylation modulate multiple cellular processes in Mycobacterium tuberculosis. While protein methylation at lysine and arginine residues is widespread in eukaryotes, to date only two methylated proteins in Mtb have been identified. Here we report the identification of methylation at lysine and/or arginine residues in nine mycobacterial proteins. Among the proteins identified, we chose MtrA, an essential response regulator of a two-component signaling system, which gets methylated on multiple lysine and arginine residues to examine the functional consequences of methylation. While methylation of K207 confers a marginal decrease in the DNA binding ability of MtrA, methylation of R122 or K204 significantly reduces the interaction with the DNA. Overexpression of S-adenosyl homocysteine hydrolase (SahH), an enzyme that modulates the levels of S-adenosyl methionine in mycobacteria decreases the extent of MtrA methylation. Most importantly, we show that decreased MtrA methylation results in transcriptional activation of mtrA and sahH promoters. Collectively, we identify novel methylated proteins, expand the list of modifications in mycobacteria by adding arginine methylation, and show that methylation regulates MtrA activity. We propose that protein methylation could be a more prevalent modification in mycobacterial proteins.

5.
Artigo em Inglês | MEDLINE | ID: mdl-33028646

RESUMO

Mismatch repair-deficient (dMMR) cancers generate a substantial number of immunogenic neoantigens, rendering them sensitive to immunotherapy. Yet, there is considerable variability in responses, and roughly one-half of dMMR cancers are refractory to immunotherapy. Here we study a patient with dMMR lung cancer refractory to immunotherapy. The tumor exhibited typical dMMR molecular features, including exceptionally high frameshift insertions and deletions (indels). Despite the treatment inducing abundant intratumoral T-cell infiltrates, it failed to elicit tumor regression, pointing to the T cells lacking cytotoxic activity. A post-treatment tumor demonstrated compound heterozygous frameshift deletions located upstream of the kinase domain in the gene encoding JAK1 protein, down-regulation of JAK1 and mediators of its signal transduction, and total loss of JAK1 phosphorylation. Importantly, one of the JAK1 mutations, despite not being detected in the pretreatment tumor, was found at low variant allele frequency in the pretreatment circulating tumor DNA, suggesting clonal selection of the mutation. To our knowledge, this report provides the most detailed look yet at defective JAK1 signaling in the context of dMMR and immunotherapy resistance. Together with observations of JAK1 frameshift indels being enriched in dMMR compared with MMR-proficient tumors, our findings demonstrate the critical function of JAK1 in immunological surveillance of dMMR cancer.

6.
Oman Med J ; 35(5): e181, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33083039

RESUMO

Pharyngocele is a rare pathology of the pharynx caused by the laxity of the thyrohyoid membrane. Only about 60 true lateral pharyngocele cases have been reported in the literature over the last 133 years. Laryngocele is a close differential, and the two are difficult to tell apart. Though they have been described well in the literature, they are often misdiagnosed or interchangeably diagnosed. The acquired type of pharyngocele is due to prolonged increased intrapharyngeal pressure and pharyngeal wall weakness, and it is more common than congenital pharyngoceles. Close differential diagnoses include Zenker's diverticulum, laryngocele, and jugular venous phlebectasia. Acquired lateral pharyngoceles are seen in wind instrument musicians and glassblowers. Hence, these diverticula are described as 'overuse syndrome'. We present a case of bilateral neck swelling, which occurred doing the Valsalva maneuver with imaging studies.

7.
Int Ophthalmol ; 2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33051769

RESUMO

PURPOSE: The current grading systems used for bleb morphology assessment in patients post-trabeculectomy are based on standardized slit-lamp photographs and anterior segment imaging devices. The lack of availability of these expensive and non-portable devices in resource-deficient settings is a significant deterrent in their widespread utilization for proper post-operative management. The rapidly evolving utilization of smartphone photography has significantly benefited diagnostics of posterior segment disorders and is now being increasingly utilized for monitoring anterior segment pathologies as well as post-surgical course. In this study, we study a novel use of smartphones for bleb photography for assessing the morphological characteristics as vascularity and microcysts. METHODS: In this pilot, observational study, we compared the trabeculectomy bleb images of five subjects, obtained by iPhone X (dual lens) and iPhone 6S (single lens). We captured two image sets with both smartphones first with a focussed torchlight and then with a built-in flash video light. RESULTS: The images resulting from the newer iPhone X were substantially superior than those from iPhone 6S. For the 12-megapixel dual-camera set-up on the iPhone X, the 1 × lens resulted in better images than the 2 × lens with contrast and overall clarity of the area of interest. While the macro-lens attachment had promising results at 1 × zoom, there is no added advantage of the macro-lens attachment as it resulted in considerable loss of image quality at twice the zoom. Using a 20 D lens helped attain higher magnification and better framing as it reduced the focussing distance needed to get sharp images. The images obtained from both smartphones were of higher quality when illuminated from an external source when compared to the native iPhone flash due to even exposure and fewer autofocus artefacts. CONCLUSION: Analyses of all image sets showed that the current generation in-built camera app on IOS and newer iPhone camera optics resulted in high-quality images of the ocular surface with high magnification without any loss in clarity.

8.
Autophagy ; : 1-2, 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33070669

RESUMO

Macroautophagy/autophagy delivers cytoplasmic cargo to lysosomes for degradation. In yeast, the single Atg8 protein plays a role in the formation of autophagosomes whereas in mammalian cells there are five to seven paralogs, referred to as mammalian Atg8s (mAtg8s: GABARAP, GABARAPL1, GABARAPL2, LC3A, LC3B, LC3B2 and LC3C) with incompletely defined functions. Here we show that a subset of mAtg8s directly control lysosomal biogenesis. This occurs at the level of TFEB, the principal regulator of the lysosomal transcriptional program. mAtg8s promote TFEB's nuclear translocation in response to stimuli such as starvation. GABARAP interacts directly with TFEB, whereas RNA-Seq analyses reveal that knockout of six genes encoding mAtg8s, or a triple knockout of the genes encoding all GABARAPs, diminishes the TFEB transcriptional program. We furthermore show that GABARAPs in cooperation with other proteins, IRGM, a factor implicated in tuberculosis and Crohn disease, and STX17, are required during starvation for optimal inhibition of MTOR, an upstream kinase of TFEB, and activation of the PPP3/calcineurin phosphatase that dephosphorylates TFEB, thus promoting its nuclear translocation. In conclusion, mAtg8s, IRGM and STX17 control lysosomal biogenesis by their combined or individual effects on MTOR, TFEB, and PPP3/calcineurin, independently of their roles in the formation of autophagosomal membranes. Abbreviations: AMPK: AMP-activated protein kinase; IRGM: immunity related GTPase M; mAtg8s: mammalian Atg8 proteins; MTOR: mechanistic target of rapamycin kinase; PPP3CB: protein phosphatase 3 catalytic subunit beta; RRAGA: Ras related GTP binding A.; STX17: syntaxin 17; ULK1: unc-51 like autophagy activating kinase 1.

9.
Curr Drug Targets ; 2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33045958

RESUMO

BACKGROUND: Fibroblast growth factor (FGF) family is comprised of 23 highly regulated monomeric proteins which regulate a plethora of developmental and pathophysiological processes, including tissue repair, wound healing, angi-ogenesis, and embryonic development. Binding of FGF to fibroblast growth factor receptor (FGFR), a tyrosine kinase re-ceptor, is facilitated by a glycosaminoglycan, heparin. Activated FGFRs phosphorylate the tyrosine kinase residues that mediate induction of downstream signaling pathways such as RAS-MAPK, PI3K-AKT, PLCγ, and STAT. Dysregulation of the FGF/FGFR signaling occurs frequently in cancer due to gene amplification, FGF activating mutations, chromosomal rearrangements, integration, and oncogenic fusions. Aberrant FGFR signaling also affects the organogenesis, embryonic development, tissue homeostasis, and has been associated with cell proliferation, angiogenesis, cancer, and other patho-physiological changes. OBJECTIVE: This comprehensive review will discuss the biology, chemistry and functions of FGFs, and its current applica-tions toward wound healing, diabetes, repair and regeneration of tissues, and fatty liver diseases. In addition, specific aber-rations in FGFR signaling, and drugs that target FGFR and aid in mitigating various disorders, such as cancer are also discussed in detail. CONCLUSION: Inhibitors of FGFR signaling are promising drugs in the treatment of several types of cancers. The clinical benefits of FGF/FGFR targeting therapies is impeded due to activation of other RTK signaling mechanisms or due to the mutations that abolish the drug inhibitory activity on FGFR. Thus, development of drugs with different mechanism of action for FGF/FGFR targeting therapies is the recent focus of several preclinical and clinical studies.

10.
Transl Psychiatry ; 10(1): 347, 2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33051447

RESUMO

Maternal alcohol exposure during pregnancy can substantially impact the development of the fetus, causing a range of symptoms, known as fetal alcohol spectrum disorders (FASDs), such as cognitive dysfunction and psychiatric disorders, with the pathophysiology and mechanisms largely unknown. Recently developed human cerebral organoids from induced pluripotent stem cells are similar to fetal brains in the aspects of development and structure. These models allow more relevant in vitro systems to be developed for studying FASDs than animal models. Modeling binge drinking using human cerebral organoids, we sought to quantify the downstream toxic effects of alcohol (ethanol) on neural pathology phenotypes and signaling pathways within the organoids. The results revealed that alcohol exposure resulted in unhealthy organoids at cellular, subcellular, bioenergetic metabolism, and gene expression levels. Alcohol induced apoptosis on organoids. The apoptotic effects of alcohol on the organoids depended on the alcohol concentration and varied between cell types. Specifically, neurons were more vulnerable to alcohol-induced apoptosis than astrocytes. The alcohol-treated organoids exhibit ultrastructural changes such as disruption of mitochondria cristae, decreased intensity of mitochondrial matrix, and disorganized cytoskeleton. Alcohol exposure also resulted in mitochondrial dysfunction and metabolic stress in the organoids as evidenced by (1) decreased mitochondrial oxygen consumption rates being linked to basal respiration, ATP production, proton leak, maximal respiration and spare respiratory capacity, and (2) increase of non-mitochondrial respiration in alcohol-treated organoids compared with control groups. Furthermore, we found that alcohol treatment affected the expression of 199 genes out of 17,195 genes analyzed. Bioinformatic analyses showed the association of these dysregulated genes with 37 pathways related to clinically relevant pathologies such as psychiatric disorders, behavior, nervous system development and function, organismal injury and abnormalities, and cellular development. Notably, 187 of these genes are critically involved in neurodevelopment, and/or implicated in nervous system physiology and neurodegeneration. Furthermore, the identified genes are key regulators of multiple pathways linked in networks. This study extends for the first time animal models of binge drinking-related FASDs to a human model, allowing in-depth analyses of neurotoxicity at tissue, cellular, subcellular, metabolism, and gene levels. Hereby, we provide novel insights into alcohol-induced pathologic phenotypes, cell type-specific vulnerability, and affected signaling pathways and molecular networks, that can contribute to a better understanding of the developmental neurotoxic effects of binge drinking during pregnancy.

11.
Phytomedicine ; : 153317, 2020 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-32943302

RESUMO

BACKGROUND: Coronavirus disease 2019 (COVID-19) playing havoc across the globe caused 585,727 deaths and 13,616,593 confirmed cases so far as per World Health Organization data released till 17th July 2020. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 2) is responsible for causing this pandemic across different continents. It is not only impacting the world economy but also quarantined millions of people in their homes or hospitals. PURPOSE: At present, there is no Food and Drug Administration-approved drug or vaccine available to treat this disease. Still, people are trying various pre-existing medicines that are known to have anti-viral or anti-parasitic effects. In view of this, the present study aimed to study the binding potential of various phytochemicals present in multiple natural plant extract as a secondary metabolite to non-structural protein 15 (Nsp15) protein, a drug target known to play a crucial role in virulence of coronavirus. METHOD: Nsp15 protein was selected because it shows 89% similarity to the other SARS-CoV, which caused the earlier outbreak. The assumption is that inhibition of Nsp15 slowdowns the viral replication. Phytochemicals are selected as these are present in various plant parts (seed, flower, roots, etc.), which are used in different food cuisines in different geographical regions across the globe. The molecular docking approach was performed using two different software, i.e., Autodock, and Swissdock, to study the interaction of various phytochemicals with Nsp15 protein. Hydroxychloroquine is used as a positive control as it is used by medical professionals showing some positive effects in dealing with coronavirus. RESULTS: The present study demonstrated the binding potential of approximately 50 phytochemicals with Nsp15 and capable of inhibiting the viral replication, although in vitro and in vivo tests are required to confirm these findings. CONCLUSIONS: In conclusion, the present study successfully demonstrated the binding of phytochemicals such as sarsasapogenin, ursonic acid, curcumin, ajmalicine, novobiocin, silymarin and aranotin, piperine, gingerol, rosmarinic acid, and alpha terpinyl acetate to Nsp15 viral protein and they might play a key role in inhibiting SARS-CoV-2 replication.

12.
J Contam Hydrol ; 235: 103718, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32987235

RESUMO

Globally, groundwater heavy metal (HM) pollution is a serious concern, threatening drinking water safety as well as human and animal health. Therefore, evaluation of groundwater HM pollution is essential to prevent accompanying hazardous ecological impacts. In this aspect, the effectiveness of various groundwater HM pollution evaluation approaches should be examined for their level of trustworthiness. In this study, 226 groundwater samples from Arang of Chhattisgarh state, India, were collected and analyzed. Measured concentration for various HMs were further used to calculate six groundwater pollution indices, such as the HM pollution index (HPI), HM evaluation index (HEI), contamination index (CI), entropy-weight based HM contamination index (EHCI), Heavy metal index (HMI), and principal component analysis-based metal index (PMI). Groundwater in the study area was mainly contaminated by elevated Cd, Fe, and Pb concentrations due to natural and anthropogenic pollution. Moreover, this study explored the performance of deep learning (DL)-based predictive models via comparative study. Two hidden layers with 26 and 19 neurons in the first and second hidden layers, respectively, were optimised along with rectified linear unit activation function. A mini-batch gradient descent was also applied to ensure smooth convergence of the training dataset into the model. Results demonstrated that the DL-PMI scored lowest errors, 0.022 for mean square error (MSE), 0.140 for mean absolute error (MAE), and 0.148 for root mean square error (RMSE), in the model validation than the other DL-based groundwater HM pollution model. Prediction performances of all pollution indices were also verified using artificial neural network (ANN)-based models, which also highlighted the lowest validation error for ANN-PMI (MSE = 3.93, MAE = 1.38, and RMSE = 1.98). Furthermore, the prediction accuracies of PMI using both ANN and DL models scored the highest R2 value of 0.95 and 0.99, respectively. Therefore it is suggested that groundwater HM pollution using PMI as the best indexing approach in the present study area. Moreover, compared to benchmark, ANN, the DL performed better; hence, it could be concluded that the proposed DL model may be suitable approach in the field of computational chemistry by handling overfitting problems.

13.
J Biomol NMR ; 74(12): 681-693, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32997264

RESUMO

Many proteins interact with their ligand proteins by recognition of short linear motifs that are often intrinsically disordered. These interactions are usually weak and are characterized by fast exchange. NMR spectroscopy is a powerful tool to study weak interactions. The methods that have been commonly used are analysis of chemicals shift perturbations (CSP) upon ligand binding and saturation transfer difference spectroscopy. These two methods identify residues at the binding interface between the protein and its ligand. In the present study, we used a combination of transferred-NOE, specific methyl-labeling and an optimized isotope-edited/isotope-filtered NOESY experiment to study specific interactions between the 42 kDa p38α mitogen-activated protein kinase and the kinase interaction motif (KIM) on the STEP phosphatase. These measurements distinguished between residues that both exhibit CSPs upon ligand binding and interact with the KIM peptide from residues that exhibit CSPs but do not interact with the peptide. In addition, these results provide information about pairwise interactions that is important for a more reliable docking of the KIM peptide into its interacting surface on p38α. This combination of techniques should be applicable for many protein-peptide complexes up to 80 kDa for which methyl resonance assignment can be achieved.

14.
Environ Sci Pollut Res Int ; 27(36): 44757-44770, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32895790

RESUMO

Epidemiological studies have proven that children mental health can be affected by environmental pollutants which are believed to be visible in the form of psychological disorder later in their childhood. Moreover, the effects of children mental health are evidently clear in the case of phthalates which have been observed to increase psychological disorder, specifically attention-deficit hyperactivity disorder (ADHD). Hence, the present study aims to conduct a systematic review and provide an overview of the existing literature on the association between urinary phthalate metabolite concentrations and ADHD symptoms among children by emphasizing the confounding factors and limitations. Additionally, this review addressed the possible phthalate mechanism insights in human body including its impact on ADHD symptoms. In this case, 16 epidemiological studies (five cross-sectional, nine cohort and two case control studies) that met all the inclusion criteria were selected out of the total of 427 papers screened to show varying quantitative associations between phthalate exposure and ADHD symptoms among children with confounding factors and limitations in the existing studies in regard to the exposure and outcomes. This review also attempted to present possible explanation on phthalate mechanism in children body and its connection on neurodevelopment and ADHD symptom development which remains unclear in most of the studies. Finally, it is highly recommended for further research to carefully design cohort studies from prenatal to later childhood development with a complete sample size in order to understand phthalate impacts on children health.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Poluentes Ambientais , Ácidos Ftálicos , Transtorno do Deficit de Atenção com Hiperatividade/induzido quimicamente , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Criança , Estudos Transversais , Feminino , Humanos , Ácidos Ftálicos/efeitos adversos , Gravidez
15.
Prep Biochem Biotechnol ; : 1-10, 2020 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-32907479

RESUMO

The current research was led to assess the influence of solid-state fermentation (SSF) with Aspergillus oryzae (MTCC 3107) on polyphenols, antioxidant activities, and proximate composition from peanut press cake of variety HNG-10. Total phenolic, flavonoid, and tannin contents were calculated for polyphenols quantification whereas DPPH, ABTS, FRAP, and metal chelating assay were performed for antioxidant activity. Quantification of polyphenols was confirmed by High Performance Liquid Chromatography technique. Maximum value of total phenolic, flavonoid, and tannin content was found to be 25.55 µM/g GAE, 101.17 µM/g QE, and 245.33 µg/g TAE, respectively. The highest inhibition of free radicals scavenging was noticed on the 5th day of fermentation after that decreased gradually with the increase of fermentation time. Significant increase in fat, i.e. 7.05-12.80% and protein content i.e. 44.05-49.60% was observed. Significant difference in proximate composition of fermented and non-fermented press cake concluded that the progressive role of fermentation improved or transformed physico-chemical properties of substrates.

16.
Artigo em Inglês | MEDLINE | ID: mdl-32933456

RESUMO

BACKGROUND: Several human diseases like Parkinson's, Alzheimer's disease, and systemic amyloidosis are associated with the misfolding and aggregation of protein molecules. OBJECTIVE: The present study demonstrated the comparison of 4-methyl coumarin and 4methylthiocoumarin derivative for their anti-amyloidogenic and disaggregation activity. The hen egg-white lysozyme is used as a model system to study protein aggregation and disaggregation under in vitro conditions. METHODS: Techniques used in the study were Thioflavin T fluorescence assay, intrinsic fluorescence assay, circular dichroism, transmission electron microscopy, and molecular dynamics. RESULTS: Fifteen compounds were screened for their anti-amyloidogenic and disaggregation potential. Six compounds significantly inhibited the fibril formation, whereas ten compounds showed disaggregation property of pre-formed fibrils. Under in vitro conditions, the compound C3 and C7 showed significant inhibition of fibril formation in a concentration-dependent manner as compared to control. C3 and C7 demonstrated 93% and 76% inhibition of fibril formation, respectively. DISCUSSION: Furthermore, C3 and C7 exhibited 83% and 76% disaggregation activity, respectively, of pre-formed HEWL fibrils at their highest concentration. These anti-amyloidogenic and disaggregation potential of C3 and C7 were validated by intrinsic fluorescence, CD, molecular dynamics, and TEM study. CONCLUSION: C3 and C7 are novel 4-methylthiocoumarin derivatives that can be used as a lead for alleviation and symptoms associated with protein aggregation disorders.

17.
Artigo em Inglês | MEDLINE | ID: mdl-32986615

RESUMO

The methanol extract and its ethyl acetate fraction (EAF) of Actaea acuminata (Wall. ex. Royle) H. Hara roots were reported to exhibit significant antianxiety, anticonvulsant and antidepressant activities, and mild sedative activity. But the constituents responsible for these activities have not been isolated. The present study was undertaken to isolate neuroprotective compounds of A. acuminata following bioactivity-guided-fractionation. The column chromatography of EAF and its sub-fractions led to the isolation of four phenolic compounds (bergenin, gallic acid, acetyl bergenin and racemic mixture of diacetyl bergenin), which were characterized by IR and NMR spectral analysis. All the compounds exhibited significant antianxiety and antidepressant activities with respect to control. The gallic acid and bergenin did not show anticonvulsant activity, whereas acetyl bergenin and racemic mixture of diacetyl bergenin exhibited significant anticonvulsant activity. Neuropharmacological activities of A. acuminata are attributed due to polyphenolic compounds. Scientific validation of traditional claims of A. acuminata has opened up roadmap of research for the development of CNS affecting lead molecules.

18.
Nat Cell Biol ; 22(8): 973-985, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32753672

RESUMO

Autophagy is a homeostatic process with multiple functions in mammalian cells. Here, we show that mammalian Atg8 proteins (mAtg8s) and the autophagy regulator IRGM control TFEB, a transcriptional activator of the lysosomal system. IRGM directly interacted with TFEB and promoted the nuclear translocation of TFEB. An mAtg8 partner of IRGM, GABARAP, interacted with TFEB. Deletion of all mAtg8s or GABARAPs affected the global transcriptional response to starvation and downregulated subsets of TFEB targets. IRGM and GABARAPs countered the action of mTOR as a negative regulator of TFEB. This was suppressed by constitutively active RagB, an activator of mTOR. Infection of macrophages with the membrane-permeabilizing microbe Mycobacterium tuberculosis or infection of target cells by HIV elicited TFEB activation in an IRGM-dependent manner. Thus, IRGM and its interactors mAtg8s close a loop between the autophagosomal pathway and the control of lysosomal biogenesis by TFEB, thus ensuring coordinated activation of the two systems that eventually merge during autophagy.


Assuntos
Família da Proteína 8 Relacionada à Autofagia/fisiologia , Autofagia/fisiologia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Proteínas de Ligação ao GTP/fisiologia , Serina-Treonina Quinases TOR/metabolismo , Calcineurina/metabolismo , Linhagem Celular , Núcleo Celular/metabolismo , Células HEK293 , Células HeLa , Humanos , Lisossomos/fisiologia , Transporte Proteico , Proteínas Qa-SNARE/metabolismo
20.
Transplant Direct ; 6(8): e584, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32766432

RESUMO

Background: Cholestasis is a sign of hepatic ischemia-reperfusion injury (IRI), which is caused by the dysfunction of hepatocyte membrane transporters (HMTs). As transcriptional regulation of HMTs during oxidative stress is mediated by nuclear factor erythroid 2-related factor 2, we hypothesized that bardoxolone methyl (BARD), a nuclear factor erythroid 2-related factor 2 activator, can mitigate cholestasis associated with hepatic IRI. Methods: BARD (2 mg/kg) or the vehicle was intravenously administered into rats immediately before sham surgery, 60 min of ischemia (IR60), or 90 min of ischemia (IR90); tissue and blood samples were collected after 24 h to determine the effect on key surrogate markers of bile metabolism and expression of HMT genes (Mrp (multidrug resistance-associated protein) 2, bile salt export pump, Mrp3, sodium-taurocholate cotransporter, and organic anion-transporting polypeptide 1). Results: Significantly decreased serum bile acids were detected upon BARD administration in the IR60 group but not in the IR90 group. Hepatic tissue analyses revealed that BARD administration increased mRNA levels of Mrp2 and Mrp3 in the IR60 group, and it decreased those of bile salt export pump in the IR90 group. Protein levels of multidrug resistance-associated protein 2, multidrug resistance-associated protein 3, and sodium-taurocholate cotransporter were higher in the IR90 group relative to those in the sham or IR60 groups, wherein the difference was notable only when BARD was administered. Immunohistochemical and morphometric analyses showed that the area of expression for multidrug resistance-associated protein 2 and for sodium-taurocholate cotransporter was larger in the viable tissues than in the necrotic area, and the area for multidrug resistance-associated protein 3 was smaller; these differences were notable upon BARD administration. Conclusions: BARD may have the potential to change HMT regulation to mitigate cholestasis in hepatic IRI.

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