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1.
PLoS One ; 16(2): e0247170, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33606812

RESUMO

Glutathione transferases (GSTs) constitute an ancient, ubiquitous, multi-functional antioxidant enzyme superfamily that has great importance on cellular detoxification against abiotic and biotic stresses as well as plant development and growth. The present study aimed to a comprehensive genome-wide identification and functional characterization of GST family in one of the economically important legume plants-Medicago truncatula. Here, we have identified a total of ninety-two putative MtGST genes that code for 120 proteins. All these members were classified into twelve classes based on their phylogenetic relationship and the presence of structural conserved domain/motif. Among them, 7 MtGST gene pairs were identified to have segmental duplication. Expression profiling of MtGST transcripts revealed their high level of organ/tissue-specific expression in most of the developmental stages and anatomical tissues. The transcripts of MtGSTU5, MtGSTU8, MtGSTU17, MtGSTU46, and MtGSTU47 showed significant up-regulation in response to various abiotic and biotic stresses. Moreover, transcripts of MtGSTU8, MtGSTU14, MtGSTU28, MtGSTU30, MtGSTU34, MtGSTU46 and MtGSTF8 were found to be highly upregulated in response to drought treatment for 24h and 48h. Among the highly stress-responsive MtGST members, MtGSTU17 showed strong affinity towards its conventional substrates reduced glutathione (GSH) and 1-chloro-2,4-dinitrobenzene (CDNB) with the lowest binding energy of-5.7 kcal/mol and -6.5 kcal/mol, respectively. Furthermore, the substrate-binding site residues of MtGSTU17 were found to be highly conserved. These findings will facilitate the further functional and evolutionary characterization of GST genes in Medicago.

2.
J Biomol Struct Dyn ; : 1-18, 2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33413029

RESUMO

Cellulases are the enzymes with diverse range of industrial applications. Cellulases degrade cellulose into monomeric glucose units by hydrolysing ß-1,4-glycosidic bonds. There are three components of cellulases: a) endoglucanase, b) exoglucanase and c) ß-glucosidase which act synergistically in cellulose bioconversion. The cellulases are the third largest industrial enzymes with a great potential in bioethanol production. In this investigation, a ß-glucosidase of a thermophilic fungus Myceliophthora thermophila (MtBgl3c) was analysed for its structural characterization using in silico approaches. The protein structure of MtBgl3c is unknown, therefore an attempt has been made to model 3D structure using Modeller 9.23 software. The MtBgl3c protein model generated was validated from Verify 3D and ERRAT scores of 89.37% and 71.25%, respectively derived from SAVES. Using RAMPAGE the Ramachandran plot was generated, which predicted the accuracy of the 3D model with 91.5% amino acid residues in the favored region. The ion binding and N-glycosylation sites were also predicted. The generated model was docked with cellobiose to predict the most favorable binding sites of MtBgl3c. The key amino acid residues involved in cellobiose bonding are Val88, Asp106, Asp287, Tyr255, Arg170, Glu514. The catalytic conserved amino residues of MtBgl3c were identified. The dock score of cellobiose with MtBgl3c is much lower (-6.46 kcal/mol) than that of glucose (-5.61 kcal/mol), suggesting its high affinity for cellobiose. The docking data of MtBgl3c with glucose illustrate its tolerance to glucose. The present study provides insight into structural characteristics of the MtBgl3c which can be further validated by experimental data. Highlights 3D structure of ß-glucosidase (MtBgl3c) of Myceliophthora thermophila is being proposed based on computational analyses The amino acid residues Asp106, Asp287, Tyr255, Arg170 and Glu514 have been identified to play catalytically important role in substrate binding Docking and interaction of MtBgl3c with cellobiose and glucose has been confirmed Docking analysis of MtBgl3c with glucose suggested its glucose tolerance The data would be useful in engineering enzymes for attaining higher catalytic efficiency Communicated by Ramaswamy H. Sarma.

3.
J Biomol Struct Dyn ; : 1-18, 2021 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-33475021

RESUMO

Coronavirus disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has caused a global pandemic. RNA-dependent RNA polymerase (RdRp) is the key component of the replication or transcription machinery of coronavirus. Therefore SARS-CoV-2-RdRp has been chosen as an important target for the development of antiviral drug(s). During the early pandemic of the COVID-19, chloroquine and hydroxychloroquine were suggested by the researchers for the prevention or treatment of SARS-CoV-2. In our study, the antimalarial compounds have been screened and docked against SARS-CoV-2-RdRp (PDB ID: 7BTF), and it was observed that the antimalarials chloroquine, hydroxychloroquine, and amodiaquine exhibit good affinity. Since the crystal structure of SARS-CoV-2-RdRp with its substrate is not available, poliovirus-RdRp crystal structure co-crystallized with its substrate ATP (PDB ID: 2ILY) was used as a reference structure. The superimposition of SARS-CoV-2-RdRp and poliovirus-RdRp structures showed that the active sites of both of the RdRps superimposed very well. The amino acid residues involved in the binding of ATP in the case of poliovirus-RdRp and residues involved in binding with the antimalarial compounds with SARS-CoV-2-RdRp were compared. In both cases, the conserved residues were found to be involved in establishing the interactions. The MMGBSA and molecular dynamic simulation studies were performed to strengthen our docking results. Further residues involved in binding of antimalarials with SARS-CoV-2-RdRp were compared with the residues involved in the SARS-CoV-2-RdRp complexed with remdesivir [PDB ID: 7BV2]. It was observed that co-crystallized remdesivir and docked antimalarials bind in the same pocket of SARS-CoV-2 -RdRp. Communicated by Ramaswamy H. Sarma.

4.
Int J Biol Macromol ; 170: 523-531, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33387542

RESUMO

Precise monitoring of the enzyme activity by a suitable modulator is one of the very fundamental aspects of drug designing that provides the opportunity to overcome the challenges of several diseases. Herein, inhibition of human Topoisomerase IIα enzyme which serves as a potential target site for several anti-cancer drugs is demonstrated by using ultra-small size gold nanoclusters (Au NCs) with the dimension comparable with size of the active site of the enzyme. Molecular dynamics simulation results demonstrate that the Au NCs strongly interact with the human Topo IIα enzyme at its active site or allosteric site depending on forms of enzyme. Additionally, binding energy and interaction profile provides the molecular basis of understanding of interactions of ultra-small size Au NCs and human Topo IIα enzyme. Enthalpy change (ΔH) and binding constant (K) are measured based on a sequential binding model of the Au NCs with the enzyme as demonstrated by the ITC study. Moreover, the in-vitro inhibition study of the catalytic activity of the enzyme and gel electrophoresis indicates that the ultra-small size Au NCs may be used as a potent inhibitor of human Topo IIα enzyme.

5.
Bioconjug Chem ; 32(2): 259-278, 2021 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-33347265

RESUMO

Metabolic disorders have been increasing at an alarming rate, and one such example of metabolic disorder is type 2 diabetes mellitus (T2DM). Unregulated gluconeogenesis in T2DM results in increased hepatic glucose output that causes fasting and postprandial hyperglycaemia. Extensive proofs have shown that the downregulation of the key rate-limiting enzyme phosphoenolpyruvate carboxykinase-1 (PCK-1) of gluconeogenesis improved glucose homeostasis in vivo. In the present study, we have synthesized and characterized liver-specific stearic acid conjugated octaarginine (StA-R8) functionalized 4arm-2K-PEGamineylated graphene oxide nanosheets (GPR8) for the delivery of siRNA against PCK-1 in T2DM C57BL/6 mice. We found that a single intravenous administration of siRNA (3 mg/kg BW) conjugated to GPR8 (GPR8:PCK-1siRNA(3 mg/kg BW) conjugate) in an optimized N/P ratio exploited as a therapeutic nanoformulation maintained glucose homeostasis for nearly 4 weeks in the T2DM mice. Efficient silencing of PCK-1 in T2DM liver tissue increased the phosphorylation of serine-256 of FOXO-1, thus showing a marked decrease in hepatic gluconeogenesis. Gluconeogenesis control and consequently glucose output from the liver furthermore partially enhanced liver and muscle insulin sensitivity results in the stimulation of the insulin/AKT-2 signaling pathway which indirectly restored glucose homeostasis in the treated T2DM group. Our therapeutic nanoformulation also improved glycogen storage in the liver and membrane translocation of GLUT4 in the muscle of the treated T2DM group. In conclusion, GPR8:PCK-1siRNA (3 mg/Kg BW) restored glucose homeostasis by controlling the hepatic glucose production and improved peripheral insulin sensitivity as a consequence of reduced hyperglycemia. Thus, the current approach offered an alternative strategy for the therapeutics for T2DM.

6.
J Cancer Res Ther ; 16(6): 1408-1411, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33342805

RESUMO

Introduction: Phyllodes tumor is a group of biphasic fibroepithelial tumors of the breast, graded as benign, borderline, and malignant. The grading of breast phyllodes remains a challenging task for the pathologists as the prognosis, and further treatment depends on it. In this study, an effort has been made to grade phyllodes tumor on the basis of immunohistochemistry. Aims and Objectives: Vascular endothelial growth factor, CD10, and factor 8 have been used as immunohistochemical markers for grading. Results and Conclusion: We have found a significant correlation between the expression of these markers and grading of phyllodes tumor. Positive correlation was also found amongst expression of all three markers. To conclude, increased expression of these markers with increasing grade can aid in diagnosis and guide treatment.

7.
Indian J Pathol Microbiol ; 63(4): 559-563, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33154305

RESUMO

Background: The breast tumors with neuroendocrine differentiation show features similar to their counterparts in other organs. Neuroendorine carcinomas account for less than 0.1% of all breast carcinomas. Aims: To study the demographics and clinicopathological prameters ten cases showing neuroendocrine carcinoma breast. Material and Methods: Ten cases showing neuroendocrine carcinoma were studied. The data was analysed for demographics and clinicopathological prameters. The Immunohistochemistry for ER, PR, Her2neu, Synaptophysin, Chromogranin, NSE, Ki67 index and EMA were done in these cases. Results: Nine Trucut biopsies were reported as infiltrating duct carcinoma and one case as IDC with neuroendocrine differentiation with focal mucinous areas.The histopathological slides of breast excision specimens revealed clusters of cells arranged in sheets and small nests separated by thin fibrous septae in eight of the cases. Trabeculae were noted in two case and in another rosettes were noted. DCIS component was noted in two cases. Infiltration into fat in five of the cases. One case showed pools of mucin. The tumour cells were positive for synaptophysin in 5/10 cases, chromogranin in 8/10 cases and NSE in 9/10 cases. Estrogen receptor positivity was noted 6 cases (6/10), progesterone receptor positivity in 8 cases (8/10) and Her2neu positivity in 5 cases (5/10). Conclusion: NECB cases are more likely to ER/PR positive with variability of expression of neuroendocrine markers. These tumors are more aggressive with propensity for distant metastasis. Endocrine therapy may be more beneficial than standard chemotherapy. Anti-angiogenic markers are an exciting new approach for these case, which is yet to be explored.

8.
J Biomol Struct Dyn ; : 1-20, 2020 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-33107812

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been responsible for the current global pandemic that has caused a death toll of >1.12 million worldwide and number continues to climb in several countries. Currently, there are neither specific antiviral drugs nor vaccines for the treatment and prevention of COVID-19. We screened in silico, a group of natural spice and herbal secondary metabolites (SMs) for their inhibition efficacy against multiple target proteins of SARS-CoV-2 as well as the human angiotensin-converting enzyme 2 protein. Docking and simulation results indicated that epicatechin, embelin, hesperidin, cafestol, murrayanine and murrayaquinone-A have higher inhibition efficacy over at least one of the known antiviral drugs such as Hydroxychloroquine, Remdesivir and Ribavirin. Combination of these potentially effective SMs from their respective plant sources was analysed, and its absorption and acute oral toxicity were examined in Wistar rats and classified as category 5 as per the Globally Harmonized System. The identified SMs may be useful in the development of preventive nutraceuticals, food supplements and antiviral drugs. Communicated by Ramaswamy H. Sarma.

9.
Comput Biol Chem ; 89: 107400, 2020 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-33068917

RESUMO

A series of alkylated benzimidazole derivatives was synthesized and screened for their anti-HIV, anti-YFV, and broad-spectrum antiviral properties. The physicochemical parameters and drug-like properties of the compounds were assessed first, and then docking studies and MD simulations on HIV-RT allosteric sites were conducted to find the possible mode of their action. DFT analysis was also performed to confirm the nature of the hydrogen bonding interaction of active compounds. The in silico studies indicated that the molecules behaved like possible NNRTIs. The nature - polar or non-polar and position of the substituent present at fifth, sixth, and N-1 positions of the benzimidazole moiety played an important role in determining the antiviral properties of the compounds. Among the various compounds, 2-(5,6-dibromo-2-chloro-1H-benzimidazol-1-yl)ethan-1-ol (3a) showed anti-HIV activity with an appreciably low IC50 value as 0.386 × 10-5µM. Similarly, compound 2b, 3-(2-chloro-5-nitro-1H-benzimidazol-1-yl) propan-1-ol, showed excellent inhibitory property against the yellow fever virus (YFV) with EC50 value as 0.7824 × 10-2µM.

10.
J Biomol Struct Dyn ; : 1-12, 2020 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-32900274

RESUMO

Computational approaches have been helpful in high throughput screening of drug libraries and designing ligands against receptors. Alzheimer's disease is a complex neurological disorder, which causes dementia. In this disease neurons are damaged due to formation of Amyloid-beta plaques and neurofibrillary tangles, which along with some other factors contributes to disease development and progression. The objective of this study was to predict tertiary structures of five G-protein coulped neurotransmitter receptors; CHRM5, CYSLTR2, DRD5, GALR1 and HTR2C, that are upregulated in Alzheimer's disease, and to screen potential inhibitors for against these receptors. In this study, Comparative modelling, molecular docking, MMGBSA analysis, ADMET screening and molecular dynamics simulation were performed. Tertiary structures of the five GPCRs were predicted and further subjected to molecular docking against natural compounds. Pharmacokinetic studies of natural compounds were also conducted for assessing drug-likeness properties. Molecular dynamics simulations were performed to investigate the structural stability and binding affinities of each complex. Finally, the results suggested that ZINC04098704, ZINC31170017, ZINC05998597, ZINC67911229, and ZINC67910690 had better binding affinity with CHRM5, CYSLTR2, DRD5, GALR1, and HTR2C (5-HT2C) proteins, respectively. Communicated by Ramaswamy H. Sarma.

11.
Arch Pharm (Weinheim) ; : e2000181, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32945576

RESUMO

In our continuing efforts to develop therapeutically active coumarin-based compounds, a series of new C4-C4' biscoumarin-pyrimidine conjugates (1a-l) was synthesized via SN 2 reaction of substituted 4-bromomethyl coumarin with thymine. All compounds were characterized using spectroscopic techniques, that is, attenuated total reflection infrared (ATR-IR), CHN elemental analysis, and 1 H and 13 C NMR (nuclear magnetic resonance). In addition, the structure of compound 1d (1,3-bis[(7-chloro-2-oxo-2H-chromen-4-yl)methyl]-5-methylpyrimidine-2,4(1H,3H)-dione) was established through X-ray crystallography. Compounds 1a-l were screened for in vitro anticancer activity against C6 rat glioma cells. Among the screened compounds, 1,3-bis[(6-chloro-2-oxo-2H-chromen-4-yl)methyl]-5-methylpyrimidine-2,4(1H,3H)-dione (1c) was identified as the best antiproliferative candidate, exhibiting an IC50 value of 4.85 µM. All the compounds (1a-l) were found to be nontoxic toward healthy human embryonic kidney cells (HEK293), indicating their selective nature. In addition, the most active compound (1c) displayed strong binding interactions with the drug carrier protein, human serum albumin, and exhibited good solution stability at biological pH conditions. Fluorescence, UV-visible spectrophotometry and molecular modeling methodologies were employed for studying the interaction mechanism of compound 1c with protein.

12.
Front Nutr ; 7: 96, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32775340

RESUMO

Enteropathogenic Escherichia coli (EPEC) leads to adverse colonic inflammation associated with poor resolution of inflammation and loss of epithelial integrity. Micronutrient trace element selenium (Se) is incorporated into selenoproteins as the 21st amino acid, selenocysteine (Sec). Previous studies have shown that such an incorporation of Sec into the selenoproteome is key for the anti-inflammatory functions of Se in macrophages and other immune cells. An intriguing mechanism underlying the anti-inflammatory and pro-resolving effects of Se stems from the ability of selenoproteins to skew arachidonic acid metabolism from pro-inflammatory mediators, prostaglandin E2 (PGE2) toward anti-inflammatory mediators derived from PGD2, such as 15-deoxy-Δ12, 14- prostaglandin J2 (15d-PGJ2), via eicosanoid class switching of bioactive lipids. The impact of Se and such an eicosanoid-class switching mechanism was tested in an enteric infection model of gut inflammation by C. rodentium, a murine equivalent of EPEC. C57BL/6 mice deficient in Se (Se-D) experienced higher mortality when compared to those on Se adequate (0.08 ppm Se) and Se supplemented (0.4 ppm Se) diets following infection. Decreased survival was associated with decreased group 3 innate lymphoid cells (ILC3s) and T helper 17 (Th17) cells in colonic lamina propria of Se-D mice along with deceased expression of epithelial barrier protein Zo-1. Inhibition of metabolic inactivation of PGE2 by 15-prostaglandin dehydrogenase blocked the Se-dependent increase in ILC3 and Th17 cells in addition to reducing epithelial barrier integrity, as seen by increased systemic levels of FITC-dextran following oral administration; while 15d-PGJ2 administration in Se-D mice alleviated the effects by increasing ILC3 and Th17 cells. Mice lacking selenoproteins in monocyte/macrophages via the conditional deletion of the tRNA[Sec] showed increased mortality post infection. Our studies indicate a crucial role for dietary Se in the protection against inflammation following enteric infection via immune mechanisms involving epithelial barrier integrity.

13.
Physiol Genomics ; 52(8): 314-321, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32628083

RESUMO

Lipocalin 2 (Lcn2) is a multifunctional innate immune protein that limits microbial overgrowth. Our previous study demonstrated that the gut microbiota directly induces intestinal Lcn2 production, and Lcn2-deficient (Lcn2-/-) mice exhibit gut dysbiosis. Coincidentally, gut dysbiosis is associated with metabolic syndrome pathogenesis, and elevated Lcn2 levels has been considered a potential clinical biomarker of metabolic syndrome. Yet whether Lcn2 mitigates or exacerbates metabolic syndrome remains inconclusive. Our objective was to determine whether Lcn2 deficiency-induced compositional changes in gut microbiota contribute to gain in adiposity in aged mice. Utilizing Lcn2-/- mice and their wild-type (WT) littermates, we measured metabolic markers, including fasting blood glucose, serum lipids, fat pad weight, and insulin resistance at ages 3, 6, and 9 mo old. Relative to WT mice, aged Lcn2-/- mice exhibited a gain in adiposity associated with numerous features of metabolic syndrome, including insulin resistance and dyslipidemia. Surprisingly, supplementation with a high-fat diet did not further aggravate metabolic syndrome that spontaneously occurs in Lcn2-/- mice by 6 mo of age. Interestingly, chow-fed Lcn2-/- mice displayed marked differences in the bacterial abundance and metabolomic profile of the gut microbiota compared with WT mice. Overall, our results demonstrate that Lcn2 is essential to maintain metabolic and gut microbiotal homeostasis, where deficiency induces spontaneous delayed onset of metabolic syndrome.

14.
Spectrochim Acta A Mol Biomol Spectrosc ; 241: 118613, 2020 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-32610216

RESUMO

Two major health crisis of today's world are antimicrobial drug resistance and type II diabetes. To tackle them, there is an immediate requirement for the development of new and safer drugs and the present work is one such quest for novel and efficient drug candidates. We have developed three trace metal coordination compounds tethered with a reduced salen ligand {H2(hpdbal)2-an} (L), namely, a manganese-salan complex, [MnII(H2O)2{(hpdbal)2-an}] (1), a nickel-salan complex, [NiII{(hpdbal)2-an}] (2) and a copper-salan complex, [CuII{(hpdbal)2-an}] (3). The compounds were characterized by elemental analysis, vibrational spectroscopy, electronic spectroscopy, thermogravimetric analysis, nuclear magnetic resonance and electron-paramagnetic resonance techniques. The compounds were evaluated for antimicrobial activity against seven pathogens (Escherichia coli, Klebsiella pneumonia, Acinetobacter baumannii, Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans and Cryptococcus neoformans) and antidiabetic activity by mimicking diabetic environment on the immortal human liver cancer cells, HepG2. Complexes 1 and 2 were additionally tested for their reactivity and stability in biological media mimic conditions. The nickel(II) salan complex (2) exhibited noteworthy antifungal activity against Candida albicans and the manganese(II) salan complex (1) induced increased glucose uptake by the insulin resistant cells. Both compounds were found to be stable when solution pH conditions were varied from 3 to 9. They exhibited strong affinity of binding towards a carrier protein, bovine serum albumin which was evaluated with the aid of multi-spectroscopic techniques.

15.
J Family Med Prim Care ; 9(3): 1647-1655, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32509666

RESUMO

The United Nations Population Fund suggests that the number of elderly persons is expected to grow to 173 million by 2026. The aging phase is further made adverse by conditions such as failty, multimorbidity and polypharmacy. Aim: To assess the status and associates of frailty among elderly (>60 years) residing in a peri-urban slum area in Delhi by using the EDMONSTON Frail scale and evaluate the interplay of multimorbidity (MM) and polypharmacy (PP) on the frail pre-frail spectrum of the community-dwelling elderly cohort. Method: A community study from Dec 2018 till July 2019 with a sample size of 300 participants who were willing and consented to the study. Frailty was assessed and the STOP criteria was used for PP assessment. Result: There were 76 frail, 51 pre-frail, and 173 non-frail elderly. A higher prevalence (51%) of multimorbidity among the pre-frails and a higher probability (74%) of polypharmacy among the frails were found. Of the total in the frail-prefrail spectrum (127), 29.1% had multimorbidity (MM) and 39.4% had polypharmacy (PP). MM and PP were significantly higher among the old. Factors such as sex, marriage, loneliness, social circle, and education also had a positive bearing on the frailty-prefrailty spectrum. The working group had an increased (86%) probability of PP with statistical significance. Regression analysis depicted significant increased odds of MM and PP among female, illiterate, very old, lone, and single subjects. Discussion and Conclusion: Thus, we recommend earlier and timely intervention for the frail-prefrail which can revert their adversities.

16.
J Biol Chem ; 295(25): 8602-8612, 2020 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-32385106

RESUMO

Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) is an mRNA-binding protein that has an oncofetal pattern of expression. It is also expressed in intestinal tissue, suggesting that it has a possible role in intestinal homeostasis. To investigate this possibility, here we generated Villin CreERT2:Igf2bp1flox/flox mice, which enabled induction of an IGF2BP1 knockout specifically in intestinal epithelial cells (IECs) of adult mice. Using gut barrier and epithelial permeability assays and several biochemical approaches, we found that IGF2BP1 ablation in the adult intestinal epithelium causes mild active colitis and mild-to-moderate active enteritis. Moreover, the IGF2BP1 deletion aggravated dextran sodium sulfate-induced colitis. We also found that IGF2BP1 removal compromises barrier function of the intestinal epithelium, resulting from altered protein expression at tight junctions. Mechanistically, IGF2BP1 interacted with the mRNA of the tight-junction protein occludin (Ocln), stabilizing Ocln mRNA and inducing expression of occludin in IECs. Furthermore, ectopic occludin expression in IGF2BP1-knockdown cells restored barrier function. We conclude that IGF2BP1-dependent regulation of occludin expression is an important mechanism in intestinal barrier function maintenance and in the prevention of colitis.

17.
Gastroenterol Rep (Oxf) ; 8(2): 85-89, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32280467

RESUMO

Consumption of processed foods-which are generally composed of nutritionally starved refined ingredients-has increased exponentially worldwide. A rise in public health awareness that low fiber intake is strongly linked to new-age disorders has spurred food manufacturers to fortify processed foods with refined dietary fibers (RDFs). Consumption of whole foods rich in natural fibers undoubtedly confers an array of health benefits. However, it is not clear whether RDFs extracted from the whole plant, kernel, and fruit peels exert similar physiological effects to their naturally occurring counterparts. Recent studies caution that RDFs are not universally beneficial and that inappropriate consumption of RDFs may risk both gastrointestinal and liver health. Herein, we briefly summarize the beneficial and detrimental effects of RDFs on digestive health and discuss the contribution of metabolites derived from microbial fermentation of RDFs in driving such positive or negative health outcomes.

18.
Gut Microbes ; 11(4): 1077-1091, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32223398

RESUMO

Owing to their health benefits, dietary fermentable fibers, such as refined inulin, are increasingly fortified in processed foods to enhance their nutritional value. However, we previously demonstrated that when inulin was fed to Toll-like receptor 5 deficient (T5KO) mice susceptible to dysbiosis, a subset of them developed cholestasis and subsequently liver cancer in a gut microbiota-dependent manner. Therefore, we hypothesized that clearance of bacterial taxa, and thereby gut metabolites, involved in the onset and progression to liver cancer could abate the disease in these mice. Such a reshaping of microbiota by vancomycin treatment was sufficient to halt the development of liver cancer in inulin-fed T5KO mice; however, this intervention did not remedy disease penetrance for cholestatic liver injury and its sequelae, including hyperbilirubinemia, hypolipidemia, cholemia and liver fibrosis. Selective depletion of gut bacterial communities was observed in vancomycin-treated mice, including Gram-positive Lachnospiraceae and Ruminococcaceae belonging to the phylum Firmicutes, Bifidobacteria of the phylum Actinobacteria, which ferment fibers, and Clostridium cluster XIVa, which produce secondary bile acids. Lack of liver cancer in vancomycin-treated mice strongly correlated with the substantial loss of secondary bile acids in circulation. Although cholemia was unabated by vancomycin, the composition of serum bile acids shifted toward an abundance of hydrophilic primary bile acids, denoted by the increase in conjugated-to-unconjugated bile acid ratio. Taken together, the present study suggests that microbiotal regulation of bile acid metabolism is one of the critical mediators of fermentable fiber-induced liver cancer in dysbiotic mice.

19.
J Biomol Struct Dyn ; : 1-17, 2020 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-32216610

RESUMO

In view of the low toxicity of NNRTIs in comparison to NRTIs, a new series of diarylpyrimidine derivatives has been designed as NNRTIs against HIV-1. In silico studies using DS 3.0 software have shown that these compounds behaved as NNRTIs while interacting at the allosteric site of HIV-RT. The designed compounds have shown promising docking results, which revealed that all compounds formed hydrogen bonds with Lys101, Lys103, Tyr181, Tyr318 and π- interactions with Tyr181, Tyr188, Phe227 and Trp229 amino acid residues located in the non-nucleoside inhibitor binding pocket (NNIBP) of HIV-RT protein. The intended molecules have shown high binding affinity with HIV-1 RT, analogous to standard drug molecule-etravirine. TOPKAT results confirmed that the designed compounds were found to be less toxic than the reference drug. Further, employing molecular dynamics simulations, the complexes of the best screened compound 6 and etravirine with the HIV-1 RT protein were analyzed by calculating the RMSD, RMSF, Rg, number of hydrogen bonds, principal components of the coordinates, molecular mechanics-Poisson-Boltzmann surface area-based binding free energy and their decomposition for different interactions. The analysis demonstrated the higher stability of compound 6 than the standard drug etravirine with HIV-1 RT. The interactions like hydrogen-bonding, van-der-Waals, electrostatic and the solvent accessible surface energy have favorable contributions to the complex stability. Thus, the shortlisted designed compound has great promise as a potential inhibitor against HIV-1 RT.

20.
Indian J Palliat Care ; 26(1): 13-18, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32132777

RESUMO

Objective: The objective of the present research was to evaluate the prescription pattern of the drugs used in the pharmacological treatment of cancer-related neuropathic pain (CRNP) and to assess the adherence of the physicians to the Neuropathic Pain Special Interest Group (NeuPSIG) Guidelines. Materials and Methods: This was a cross-sectional, observational study where patients who presented to the pain and palliative care outpatient clinic of the tertiary care hospital with CRNP were prospectively recruited. Participants were screened for neuropathic pain using DN4 questionnaire. Demographic details, diagnosis, medication details, and adherence to NeuPSIG guidelines were assessed using a validated questionnaire. Results: Of 300 patients screened, 64% were male and 36% were female, with a mean age of 48.26 ± 13.05 years. The predominant symptoms found were pin-and-needle sensation (99%) followed by tingling sensation (98.66%). The most common diagnosis was head-and-neck cancers (37.3%) followed by bone cancers (17.3%) and lung cancers (15.3%). Among the first-line drugs recommended in NeuPSIG for CRNP, pregabalin (78.7%) was the most common drug prescribed followed by amitriptyline (67%). The most common co-prescribed drugs were acid suppressants drugs (50.7%). Tapentadol, which is not part of the NeuPSIG guidelines, was prescribed on 51 occasions for neuropathic pain. Underdosing was observed in 272 prescriptions. Only 12 prescriptions completely adhered, while 275 had partial, and 13 prescriptions had poor adherence to NeuPSIG guidelines. Conclusion: The most commonly used drugs in the treatment of CRNP were pregabalin and amitriptyline. Most physician partially or did not adhere to the NeuPSIG guideline in the management of CRNP.

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