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1.
J Chem Inf Model ; 64(4): 1347-1360, 2024 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-38346863

RESUMO

Incomplete structural details of Mycobacterium tuberculosis (Mtb) fatty acid synthase-I (FAS-I) at near-atomic resolution have limited our understanding of the shuttling mechanism of its mobile acyl carrier protein (ACP). Here, we have performed atomistic molecular dynamics simulation of Mtb FAS-I with a homology-modeled structure of ACP stalled at dehydratase (DH) and identified key residues that mediate anchoring of the recognition helix of ACP near DH. The observed distance between catalytic residues of ACP and DH agrees with that reported for fungal FAS-I. Further, the conformation of the peripheral linker is found to be crucial in stabilizing ACP near DH. Correlated interdomain motion is observed between DH, enoyl reductase, and malonyl/palmitoyl transferase, consistent with prior experimental reports of fungal and Mtb FAS-I.


Assuntos
Proteína de Transporte de Acila , Mycobacterium tuberculosis , Proteína de Transporte de Acila/química , Proteína de Transporte de Acila/metabolismo , Ácido Graxo Sintases/química , Ácido Graxo Sintases/metabolismo , Simulação de Dinâmica Molecular , Catálise
2.
Curr Microbiol ; 81(4): 95, 2024 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-38353761

RESUMO

The present work was carried out during the emergence of Delta Variant of Concern (VoC) and aimed to study the change in SARS CoV-2 viral load in Covishield vaccinated asymptomatic/mildly symptomatic health-care workers (HCWs) to find out the optimum isolation period. The SARS CoV-2 viral load was carried out in sequential samples of 55 eligible HCWs which included unvaccinated (UnV; n = 11), single-dose vaccinated (SDV, n = 20) and double-dose vaccinated [DDV, n = 24; short-interval (<6 weeks)] subjects. The mean load of envelope (E) gene on day 5 in SDV [0.42 × 105 copies/reaction] was significantly lower as compared to DDV [6.3 × 105 copies/reaction, P = 0.005] and UnV [6.6 × 105 copies/reaction, P = 0.001] groups. The rate of decline of SARS CoV-2 viral load in the initial 5 days of PCR positivity was significantly higher in SDV as compared to that in DDV (Mean log decline 0.39 vs. 0.19; P < 0.001). This was possibly due to interference of adenoviral immunity of first dose of adenovirus-vectored vaccine in double-dose vaccinated HCWs who had received vaccines within a shorter interval (<6 weeks).


Assuntos
COVID-19 , ChAdOx1 nCoV-19 , Humanos , SARS-CoV-2/genética , Carga Viral , COVID-19/prevenção & controle
3.
Biochem J ; 480(9): 555-571, 2023 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-36916393

RESUMO

Plant growth and development are governed by selective protein synthesis and degradation. Ubiquitination mediated protein degradation is governed by activating enzyme E1 followed by conjugating enzyme E2 and E3 ligase. Plant Armadillo (ARM) repeat/U-box (PUB) protein family is one of the important classes of E3 ligase. We studied the function of AtPUB2 by loss-of-function (knockout and knock down mutants) and gain-of-function (CaMV 35S promoter driven overexpression lines) approach in Arabidopsis. Under normal growth condition, we observed that loss-of-function mutant plants did not show any significant difference in growth when compared with wild-type possibly due to functional redundancy between PUB2 and PUB4. However, AtPUB2-OE lines exhibit early flowering and improved vegetative growth. Also, AtPUB2-OE seedlings showed sensitive phenotype in the presence of exogenous cytokinin. We found that AtPUB2 expression is induced under oxidative stress. Subcellular localization analysis shows that AtPUB2 is predominantly localized in the nucleus. We performed the phenotypic analysis under oxidative stress condition induced by methyl viologen (MV) and observed that overexpression lines display tolerance to oxidative stress in light and dark conditions. Furthermore, we found less amount of ROS accumulation, enhanced proline accumulation and decreased levels of MDA after MV treatment in AtPUB2-OE lines. PUB2-OE lines showed enhanced oxidative stress marker genes expression. By in vitro auto-ubiquitination assay, we also show that it possesses the E3 ligase activity. Overall, our findings suggest the possible role of AtPUB2 in plants ability to tolerate oxidative stress by enhancing the activity of antioxidant enzymes, which in turn improves ROS scavenging activity and homeostasis.


Assuntos
Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Estresse Oxidativo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Plantas Geneticamente Modificadas , Regulação da Expressão Gênica de Plantas , Estresse Fisiológico/genética , Proteínas de Plantas/metabolismo
4.
Endocr Res ; : 1-11, 2024 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-39106207

RESUMO

BACKGROUND: Monogenic diabetes often occurs as a result of single-gene mutations. The illness is minimally affected by environmental and behavioral factors, and it constitutes around one to five percent of all cases of diabetes. METHODS: Newborn diabetes mellitus (NDM) and maturity-onset diabetes of the young (MODY) are the predominant causes of monogenic diabetes, accounting for a larger proportion of cases, while syndromic diabetes represents a smaller percentage. MODY, a group of inherited non-autoimmune diabetes mellitus disorders, is quite common. However, it remains frequently misdiagnosed despite increasing public awareness. The condition is characterized by insulin resistance, the development of diabetes at a young age (before 25 years), mild high blood sugar levels, inheritance in an autosomal dominant pattern, and the preservation of natural insulin production. RESULTS: Currently, there are 14 distinct subtypes of MODY that have been identified. Each subtype possesses distinct characteristics in terms of their frequency, clinical symptoms, severity of diabetes, related complications, and response to medicinal interventions. Due to the clinical similarities, lack of awareness, and high expense of genetic testing, distinguishing between type I (T1D) and type II diabetes mellitus (T2D) can be challenging, resulting in misdiagnosis of this type of diabetes. As a consequence, a significant number of individuals are being deprived of adequate medical attention. Accurate diagnosis enables the utilization of novel therapeutic strategies and enhances the management of therapy in comparison to type II and type I diabetes. CONCLUSION: This article offers a concise overview of the clinical subtypes and characteristics of monogenic diabetes. Furthermore, this article discusses the various subtypes of MODY, as well as the process of diagnosing, managing, and treating the condition. It also addresses the difficulties encountered in detecting and treating MODY.

5.
Arch Pharm (Weinheim) ; : e2400576, 2024 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-39367561

RESUMO

Several pyrazole-thiazole hybrids featuring two potentially bioactive pharmacophores with or without linker have been synthesized using the molecular hybridization approach as target structures by medicinal chemists to modulate multiple drug targets simultaneously. The presented review aims to provide an overview of the diversified and wide array of pharmacological activities of these hybrids bestowing anticancer, antifungal, antibacterial, analgesic, anti-inflammatory, antioxidant, antitubercular, antiviral, antiparasitic, and miscellaneous activities. The structure-activity relationships and potential mechanism of action are also reviewed to shed light on the development of more effective and biotargeted candidates. This review focuses on the latest research advances in the biological profile of pyrazole-thiazole hybrids reported from 2015 to the present, providing medicinal researchers with a comprehensive platform to rationally design and develop more promising pyrazole-thiazole hybrids.

6.
Mol Biol Rep ; 50(4): 3365-3378, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36729207

RESUMO

BACKGROUND: The state of Manipur, North East India has distinct topology of hill and valley regions with vast agroclimatic variability, being considered as one of the centers of rice diversity. The indigenous Manipur black rice cultivars exhibit wide range of diversity in morphology, pericarp color, shape and size of grain, aroma, glutinous or non-glutinous features but remain less characterised. Many of these cultivars, such as those named Chakhao, are endowed with multiple health benefits due to high anthocyanins, and hold special importance for the local people. It is important to analyse the genetic diversity and population structure for this germplasm with unique allelic combinations to utilize in rice breeding programme. METHODS AND RESULTS: We characterized total soluble seed protein fractions to not only fingerprint the 45 indigenous black rice cultivars but assess their genetic relatedness. Cluster analyses generated mainly two groups, complemented by PCoA scatter plot ascertaining geographical distinction. The hill black rice were more diverse. The population structure analysis revealed seven subpopulations indicating high genetic variability. The 24 polymorphic bands were scored in the range of 127.8 to 10.3 kDa comprised of four protein fractions. Three polypeptide bands each were ascribed to known fractions of glutelins and prolamins, while one band each could be described for albumin and globulin fractions, besides other diagnostic bands. CONCLUSION: Some diverse cultivars were Amubi, Chedo Anal, Chipi Buh, Athebu, Poireton, BuPu Mui, Kotha Chahao II. These cultivars can be used in future black rice breeding programmes. This can further prevent genetic erosion and protect intellectual property rights.


Assuntos
Oryza , Humanos , Oryza/genética , Oryza/metabolismo , Antocianinas/metabolismo , Filogenia , Melhoramento Vegetal , Índia , Sementes/genética , Variação Genética/genética
7.
Environ Res ; 231(Pt 2): 116132, 2023 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-37207734

RESUMO

Excessive usage and unrestricted discharge of antibiotics in the environment lead to their accumulation in the ecosystem due to their highly stable and non-biodegradation nature. Photodegradation of four most consumed antibiotics such as amoxicillin, azithromycin, cefixime, and ciprofloxacin were studied using Cu2O-TiO2 nanotubes. Cytotoxicity evaluation of the native and transformed products was conducted on the RAW 264.7 cell lines. Photocatalyst loading (0.1-2.0 g/L), pH (5, 7 and 9), initial antibiotic load (50-1000 µg/mL) and cuprous oxide percentage (5, 10 and 20) were optimized for efficient photodegradation of antibiotics. Quenching experiments to evaluate the mechanism of photodegradation with hydroxyl and superoxide radicals were found the most reactive species of the selected antibiotics. Complete degradation of selected antibiotics was achieved in 90 min with 1.5 g/L of 10% Cu2O-TiO2 nanotubes with initial antibiotic concentration (100 µg/mL) at neutral pH of water matrix. The photocatalyst showed high chemical stability and reusability up to five consecutive cycles. Zeta potential studies confirms the high stability and activity of 10% C-TAC (Cuprous oxide doped Titanium dioxide nanotubes for Applied Catalysis) in the tested pH conditions. Photoluminescence and Electrochemical Impedance Spectroscopy data speculates that 10% C-TAC photocatalyst have efficient photoexcitation in the visible light for photodegradation of antibiotics samples. Inhibitory concentration (IC50) interpretation from the toxicity analysis of native antibiotics concluded that ciprofloxacin was the most toxic antibiotic among the selected antibiotics. Cytotoxicity percentage of transformed products showed r: -0.985, p: 0.01 (negative correlation) with the degradation percentage revealing the efficient degradation of selected antibiotics with no toxic by-products.


Assuntos
Antibacterianos , Águas Residuárias , Antibacterianos/toxicidade , Ecossistema , Luz , Titânio/toxicidade , Titânio/química , Ciprofloxacina/toxicidade , Catálise
8.
Nanotechnology ; 33(27)2022 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-35412470

RESUMO

The low light absorption and rapid recombination of photogenerated charge carriers are primary contributors to the low activity of various photocatalysts. Fabrication of oxygen vacancy defect-rich materials for improved photocatalytic activities has been attracting tremendous attention from researchers all over the world. In this work, we have compared the photocatalytic activities of oxygen vacancy-rich Bi2MoO6(BMO-OV) and Bi2WO6(BWO-OV) for the degradation of a model pharmaceutical pollutant, ciprofloxacin under visible light irradiation. The photocatalytic activity was increased from 47% to 77% and 40% to-67% for BMO-OVand BWO-OV, respectively in comparison to pristine oxides. This enhancement can be ascribed to suppressed charge carrier recombination and increased surface active sites. In addition, scavenger studies have been done to explain the role of photoinduced charge carriers in the degradation mechanism. Moreover, oxygen vacancy-rich photocatalysts have remained stable even after three consecutive cycles, making them promising materials for practical applications. Overall, this work provides deeper insight into the design and development of oxygen vacancy-rich materials.

9.
Environ Res ; 214(Pt 2): 113957, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35932829

RESUMO

In recent years, due to rapid globalization and urbanization, the demand for fuels, energy, water and nutrients has been continuously increasing. To meet the future need of the society, wastewater is a prominent and emerging source for resource recovery. It provides an opportunity to recover valuable resources in the form of energy, fertilizers, electricity, nutrients and other products. The aim of this review is to elaborate the scientific literature on the valorization of wastewater using wide range of treatment technologies and reduce the existing knowledge gap in the field of resource recovery and water reuse. Several versatile, resilient environmental techniques/technologies such as ion exchange, bioelectrochemical, adsorption, electrodialysis, solvent extraction, etc. are employed for the extraction of value-added products from waste matrices. Since the last two decades, valuable resources such as polyhydroxyalkanoate (PHA), matrix or polymers, cellulosic fibers, syngas, biodiesel, electricity, nitrogen, phosphorus, sulfur, enzymes and a wide range of platform chemicals have been recovered from wastewater. In this review, the aspects related to the persisting global water issues, the technologies used for the recovery of different products and/or by-products, economic sustainability of the technologies and the challenges encountered during the valorization of wastewater are discussed comprehensively.


Assuntos
Fósforo , Águas Residuárias , Fertilizantes , Nitrogênio , Águas Residuárias/análise , Água
10.
Bioorg Chem ; 107: 104620, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33454509

RESUMO

Xanthine oxidase (XO) has been primarily targeted for the development of anti-hyperuriciemic /anti-gout agents as it catalyzes the conversion of xanthine and hypoxanthine into uric acid. XO overexpression in various cancer is very well correlated due to reactive oxygen species (ROS) production and metabolic activation of carcinogenic substances during the catalysis. Herein, we report the design and synthesis of a series of 3,5-diaryl-4,5-dihydro-1H-pyrazole carbaldehyde derivatives (2a-2x) as xanthine oxidase inhibitors (XOIs). A docking model was developed for the prediction of XO inhibitory activity of our novel compounds. Furthermore, our compounds anticancer activity results in low XO expression and XO-harboring cancer cells both in 2D and 3D-culture models are presented and discussed. Among the array of synthesized compounds, 2b and 2m emerged as potent XO inhibitors having IC50 values of 9.32 ± 0.45 µM and 10.03 ± 0.43 µM, respectively. Both compounds induced apoptosis, halted the cell cycle progression at the G1 phase, elevated ROS levels, altered mitochondrial membrane potential, and inhibited antioxidant enzymes. The levels of miRNA and expression of redox sensors in cells were also altered due to increase oxidative stress induced by our compounds. Compounds 2b and 2m hold a great promise for further development of XOIs for the treatment of XO-harboring tumors.


Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Pirazóis/química , Xantina Oxidase/metabolismo , Aldeídos/química , Apoptose/efeitos dos fármacos , Sítios de Ligação , Domínio Catalítico , Linhagem Celular Tumoral , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Humanos , Cinética , Potencial da Membrana Mitocondrial , MicroRNAs/metabolismo , Simulação de Acoplamento Molecular , Estresse Oxidativo/efeitos dos fármacos , Oxirredutases/antagonistas & inibidores , Oxirredutases/metabolismo , Pirazóis/metabolismo , Pirazóis/farmacologia , Relação Quantitativa Estrutura-Atividade , Espécies Reativas de Oxigênio/metabolismo , Xantina Oxidase/antagonistas & inibidores
11.
J Biol Chem ; 294(2): 559-575, 2019 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-30429220

RESUMO

Rapid expression of critical stress response factors is a key survival strategy for diseased or stressed cells. During cell stress, translation is inhibited, and a pre-existing pool of cytoplasmic mRNA-protein complexes reversibly assembles into cytoplasmic stress granules (SGs). Gle1 is a conserved modulator of RNA-dependent DEAD-box proteins required for mRNA export, translation, and stress responses. Proper Gle1 function is critical as reflected by some human diseases such as developmental and neurodegenerative disorders and some cancers linked to gle1 mutations. However, the mechanism by which Gle1 controls SG formation is incompletely understood. Here, we show that human Gle1 is regulated by phosphorylation during heat shock stress. In HeLa cells, stress-induced Gle1 hyperphosphorylation was dynamic, primarily in the cytoplasmic pool, and followed changes in translation factors. MS analysis identified 14 phosphorylation sites in the Gle1A isoform, six of which clustered in an intrinsically disordered, low-complexity N-terminal region flanking the coil-coiled self-association domain. Of note, two mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), phosphorylated the Gle1A N-terminal domain, priming it for phosphorylation by glycogen synthase kinase 3 (GSK3). A phosphomimetic gle1A6D variant (in which six putative Ser/Thr phosphorylation sites were substituted with Asp) perturbed self-association and inhibited DEAD-box helicase 3 (X-linked) (DDX3) ATPase activity. Expression of alanine-substituted, phosphodeficient GFP-gle1A6A promoted SG assembly, whereas GFP-gle1A6D enhanced SG disassembly. We propose that MAPKs and GSK3 phosphorylate Gle1A and thereby coordinate SG dynamics by altering DDX3 function.


Assuntos
RNA Helicases DEAD-box/metabolismo , Quinase 3 da Glicogênio Sintase/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteínas de Transporte Nucleocitoplasmático/metabolismo , Adenosina Trifosfatases/metabolismo , Grânulos Citoplasmáticos/metabolismo , Células HeLa , Humanos , Fosforilação , RNA Mensageiro/metabolismo
12.
J Exp Bot ; 71(2): 608-619, 2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31624829

RESUMO

Potassium (K+) is an essential cation in all organisms that influences crop production and ecosystem stability. Although most soils are rich in K minerals, relatively little K+ is present in forms that are available to plants. Moreover, leaching and run-off from the upper soil layers contribute to K+ deficiencies in agricultural soils. Hence, the demand for K fertilizer is increasing worldwide. K+ regulates multiple processes in cells and organs, with K+ deficiency resulting in decreased plant growth and productivity. Here, we discuss the complexity of the reactive oxygen species-calcium-hormone signalling network that is responsible for the sensing of K+ deficiency in plants, together with genetic approaches using K+ transporters that have been used to increase K+ use efficiency (KUE) in plants, particularly under environmental stress conditions such as salinity and heavy metal contamination. Publicly available rice transcriptome data are used to demonstrate the two-way relationship between K+ and nitrogen nutrition, highlighting how each nutrient can regulate the uptake and root to shoot translocation of the other. Future research directions are discussed in terms of this relationship, as well as prospects for molecular approaches for the generation of improved varieties and the implementation of new agronomic practices. An increased knowledge of the systems that sense and take up K+, and their regulation, will not only improve current understanding of plant K+ homeostasis but also facilitate new research and the implementation of measures to improve plant KUE for sustainable food production.


Assuntos
Homeostase , Nitrogênio/fisiologia , Nutrientes/fisiologia , Oryza/fisiologia , Fenômenos Fisiológicos Vegetais , Potássio/fisiologia , Mudança Climática
13.
Appl Microbiol Biotechnol ; 104(11): 4889-4901, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32249395

RESUMO

In this study, the metagenomic resource generated from an aquatic habitat of extreme temperature was screened for the identification of a novel xylanase, XynM1. Gene sequence analysis designated it as a member of glycoside hydrolase (GH) family 10. The metagenomic DNA fragment was cloned, expressed in Escherichia coli, and the purified protein was biochemically characterized. The optimum temperature and pH for the XynM1 xylanase were found to be at 80 °C and 7, respectively. It exhibited worthwhile pH stability by retaining about 70% activity in the range of pH 6 to 9 after the exposure for 12 h at 25 °C. Thermostability analysis established considerable heat tolerance in XynM1 protein at elevated temperatures, displaying about 50% residual activity after the exposure of 40 °C, 50 °C, 60 °C, and 70 °C for 20 h, 12 h, 6 h, and 1.5 h, respectively. The effects of additives such as metals, surfactants, and organic solvents were evaluated on the activity of XynM1. It was able to retain about 50% of its initial activity in the presence of NaCl concentration of 1 to 5 M. The novel xylanase was capable of hydrolyzing the hemicellulosic polymer, derived from diverse biomass sources, e.g., beechwood xylan, wheat arabinoxylan, corncob xylan, and sweet sorghum xylan. The XynM1-treated beechwood xylan manifested catalytic release of xylooligosaccharides (XOS) of 2-6 DP. The novel GH10 xylanase is a promising biocatalyst that could be ascribed for biomass conversion and production of prebiotic XOS biomolecules.


Assuntos
Endo-1,4-beta-Xilanases/genética , Endo-1,4-beta-Xilanases/metabolismo , Glucuronatos/biossíntese , Fontes Termais , Temperatura Alta , Metagenoma , Oligossacarídeos/biossíntese , Biocatálise , Endo-1,4-beta-Xilanases/isolamento & purificação , Estabilidade Enzimática , Escherichia coli/genética , Glicosídeo Hidrolases/genética , Glicosídeo Hidrolases/isolamento & purificação , Glicosídeo Hidrolases/metabolismo , Concentração de Íons de Hidrogênio , Cinética , Microbiota/genética , Microbiota/fisiologia , Xilanos/metabolismo
14.
Can J Microbiol ; 66(2): 87-98, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31682478

RESUMO

Zika virus (ZIKV) is a mosquito-borne virus that was first isolated from Zika forest, Uganda, in 1947. Since its inception, major and minor outbreaks have been documented from several parts of world. Aedes spp. mosquitoes are the primary vectors of ZIKV, but the virus can also be transmitted through sexual practices, materno-fetal transmission, and blood transfusion. The clinical presentations of symptomatic ZIKV infections are similar to dengue and chikungunya, including fever, headache, arthralgia, retro-orbital pain, conjunctivitis, and rash. ZIKV often causes mild illness in the majority of cases, but in some instances, it is linked with congenital microcephaly and autoimmune disorders like Guillain-Barré syndrome. The recent Indian ZIKV outbreak suggests that the virus is circulating in the South East Asian region and may cause new outbreaks in future. At present, no specific vaccines or antivirals are available to treat ZIKV, so management and control of ZIKV infections rely mostly on preventive measures.


Assuntos
Aedes/virologia , Doenças Transmissíveis Emergentes/epidemiologia , Surtos de Doenças , Complicações Infecciosas na Gravidez/virologia , Infecção por Zika virus/epidemiologia , Zika virus/fisiologia , Animais , Sudeste Asiático/epidemiologia , Doenças Transmissíveis Emergentes/prevenção & controle , Doenças Transmissíveis Emergentes/transmissão , Doenças Transmissíveis Emergentes/virologia , Feminino , Saúde Global , Síndrome de Guillain-Barré , Humanos , Microcefalia , Mosquitos Vetores/virologia , Gravidez , Saúde Pública , Infecção por Zika virus/prevenção & controle , Infecção por Zika virus/transmissão , Infecção por Zika virus/virologia
15.
Arch Pharm (Weinheim) ; 353(11): e2000168, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32776618

RESUMO

This review outlines a literature-based approach with illustrative examples of drug repurposing (one molecule, multiple targets), which will be useful in tackling the problem of antimicrobial resistance (AMR). Globally, the demands for new drugs have increased due to multidrug-resistant pathogens and emerging viruses. Keeping these facts in view, drug repurposing started for utilization of a drug in a different way from a preexisting drug, which reduces the time and cost of development of a new drug. Repurposing increases the potency of a drug and reduces its toxicity level, as it is required in lower amounts, supporting the utilization of the drug as a new therapeutic option. This will be further explored to highlight the application in AMR.


Assuntos
Antibacterianos/uso terapêutico , Bactérias/efeitos dos fármacos , Infecções Bacterianas/tratamento farmacológico , Reposicionamento de Medicamentos , Farmacorresistência Bacteriana Múltipla , Animais , Antibacterianos/efeitos adversos , Bactérias/genética , Bactérias/metabolismo , Infecções Bacterianas/microbiologia , Farmacorresistência Bacteriana Múltipla/genética , Quimioterapia Combinada , Humanos
16.
Drug Dev Ind Pharm ; 46(5): 717-731, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32249604

RESUMO

Objectives: l-Glutathione (GSH) is an endogenous tripeptide with super antioxidant properties. In this study, preformulation parameters of GSH and its degradation products were fully investigated.Significance: To date, no experimental preformulation data is available for GSH. Therefore, to the author's knowledge, this is the first study to experimentally determine the preformulation parameters of GSH, which can be considered more reliable for further studies.Methods: An HPLC method for GSH was optimized and validated to accurately quantify the GSH amount in solution, used to investigate GSH's solubility and Log P. Differential Scanning Calorimeter and Thermogravimetric Analyzer were used to evaluate the thermal properties of GSH. Polarized microscope and Fourier-transform Infrared Spectroscopy were used to determine GSH's crystal habits and functional groups, respectively. Forced degradation kinetics and the degradation products were investigated and identified by LC-MS, respectively. GSH's cellular cytotoxicity on fibroblasts was investigated by MTT assay.Results: It was determined that GSH has high aqueous solubility (252.7 mg/mL), low Log P (-3.1), a melting endotherm of 195 °C and decomposition at 210°C, negligible moisture content, and a rectangular/cylindrical-shaped crystalline form. Seven degradation products were identified; one of the major degradation products of GSH under different conditions is first order kinetic oxidation into glutathione disulfide. No cytotoxicity was observed when fibroblasts were treated with GSH (0.005-10.000 mg/mL).Conclusions: Precise preformulation parameters of GSH were obtained, and these are imperative for the development and optimization of advanced GSH formulations.


Assuntos
Química Farmacêutica/métodos , Citotoxinas/química , Citotoxinas/toxicidade , Glutationa/química , Glutationa/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Células Cultivadas , Fenômenos Químicos/efeitos dos fármacos , Citotoxinas/análise , Relação Dose-Resposta a Droga , Composição de Medicamentos/métodos , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Glutationa/análise , Humanos , Cinética , Espectrometria de Massas em Tandem/métodos , Difração de Raios X/métodos
17.
Ann Clin Microbiol Antimicrob ; 18(1): 42, 2019 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-31847837

RESUMO

BACKGROUND: Urinary tract infection (UTI) is one of the frequently diagnosed infectious diseases which is caused mainly by Escherichia coli. E. coli confers resistance against the two major classes of antibiotics due to the production of extended spectrum ß-lactamase enzymes (ESBL), biofilm, etc. Biofilm produced by uropathogenic E. coli (UPEC) protects from host immune system and prevent entry of antimicrobial compounds. The main objective of this cross-sectional study was to determine the correlation of biofilm production and antibiotic resistance as well as to characterize the pgaA and pgaC genes responsible for biofilm formation among uropathogenic ESBL producing E. coli. METHODS: A total of 1977 mid-stream urine samples were examined and cultured for bacterial strain identification. ESBL was detected by combined disc method following CLSI whereas biofilm formation was analyzed by semi-quantitative method. Furthermore, the pgaA and pgaC genes responsible for biofilm formation in UPEC were detected by multiplex PCR. All the statistical analyses were done via IBM SPSS Statistics 21 where Pearson's correlation test were used to determine correlation (-1 ≥ r ≤ 1). RESULTS: E. coli was the predominant causative agent, which accounted 159 (59.3%) of the Gram-negative bacteria, where 81 (50.9%) E. coli strains were found to be ESBL producers. In addition, 86 (54.1%) E. coli strains were found to be biofilm producers. Both the pgaA and pgaC genes were detected in 45 (93.7%) the UPEC isolates, which were both biofilm and ESBL producers. Moreover, there was a positive correlation between biofilm and ESBL production. CONCLUSION: The analyses presented weak positive correlation between biofilm and ESBL production in which biofilm producing UPEC harbors both pgaA and pgaC genes responsible for biofilm formation.


Assuntos
Biofilmes , Farmacorresistência Bacteriana , Infecções por Escherichia coli , Escherichia coli Uropatogênica , beta-Lactamases/genética , Adolescente , Adulto , Antibacterianos/farmacologia , Proteínas da Membrana Bacteriana Externa/genética , Biofilmes/efeitos dos fármacos , Criança , Pré-Escolar , Estudos Transversais , Infecções por Escherichia coli/tratamento farmacológico , Infecções por Escherichia coli/urina , Proteínas de Escherichia coli/genética , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Nepal , Infecções Urinárias/microbiologia , Escherichia coli Uropatogênica/efeitos dos fármacos , Escherichia coli Uropatogênica/genética , Escherichia coli Uropatogênica/isolamento & purificação , Adulto Jovem
19.
Indian J Med Res ; 149(6): 778-782, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31496531

RESUMO

Background & objectives: High-altitude pulmonary oedema (HAPE) continues to challenge the healthcare providers at remote, resource-constrained settings. High-altitude terrain itself precludes convenience of resources. This study was conducted to evaluate the rise in peripheral capillary saturation of oxygen (SpO2) by the use of a partial rebreathing mask (PRM) in comparison to Hudson's mask among patients with HAPE. Methods: This was a single-centre, randomized crossover study to determine the efficiency of PRM in comparison to Hudson's mask. A total of 88 patients with HAPE referred to a secondary healthcare facility at an altitude of 11,500 feet from January to October 2013 were studied. A crossover after adequate wash-out on both modalities was conducted for first two days of hospital admission. All patients with HAPE were managed with bed rest and stand-alone oxygen supplementation with no adjuvant pharmacotherapy. Results: The mean SpO2on ambient air on arrival was 66.92±10.8 per cent for all patients with HAPE. Higher SpO2values were achieved with PRM in comparison to Hudson's mask on day one (86.08±5.15 vs. 77.23±9.09%) and day two (89.94±2.96 vs. 83.39±5.93%). The difference was more pronounced on day one as compared to day two. Interpretation & conclusions: Mean SpO2values were found to be significantly higher among HAPE patients using PRM compared to those on Hudson's mask. Further studies to understand the translation of this incremental response in SpO2to clinical benefits (recovery times, mortality rates and hospital stay) need to be undertaken.


Assuntos
Doença da Altitude/terapia , Hipertensão Pulmonar/terapia , Oxigênio/administração & dosagem , Respiração , Altitude , Doença da Altitude/fisiopatologia , Estudos Cross-Over , Humanos , Hipertensão Pulmonar/fisiopatologia , Oxigênio/metabolismo
20.
Bioprocess Biosyst Eng ; 42(10): 1681-1693, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31286218

RESUMO

The genes for dextransucrase and dextranase were cloned from the genomic regions of Leuconostoc mesenteroides MTCC 10508 and Streptococcus mutans MTCC 497, respectively. Heterologous expression of genes was performed in Escherichia coli. The purified enzyme fractions were entrapped in the alginate-pectin beads. A high immobilization yield of dextransucrase (~ 96%), and dextranase (~ 85%) was achieved. Alginate-pectin immobilization did not affect the optimum temperature and pH of the enzymes; rather, the thermal tolerance and storage stability of the enzymes was improved. The repetitive batch experiments suggested substantially good operational stability of the co-immobilized enzyme system. The synergistic catalytic reactions of alginate-pectin co-entrapped enzyme system were able to produce 7-10 g L-1 oligosaccharides of a high degree of polymerization (DP 3-9) from sucrose (~ 20 g L-1) containing feedstocks, e.g., table sugar and cane molasses. The alginate-pectin-based co-immobilized enzyme system is a useful catalytic tool to bioprocess the agro-industrial bio-resource for the production of prebiotic biomolecules.


Assuntos
Alginatos/química , Proteínas de Bactérias/química , Dextranase/química , Enzimas Imobilizadas/química , Glucosiltransferases/química , Leuconostoc mesenteroides/enzimologia , Oligossacarídeos/química , Pectinas/química , Streptococcus mutans/enzimologia , Proteínas de Bactérias/genética , Dextranase/genética , Estabilidade Enzimática , Enzimas Imobilizadas/genética , Escherichia coli/enzimologia , Escherichia coli/genética , Glucosiltransferases/genética , Concentração de Íons de Hidrogênio , Leuconostoc mesenteroides/genética , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Streptococcus mutans/genética
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