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1.
Chemistry ; 30(36): e202400828, 2024 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-38640462

RESUMO

Pyridoxal hydrochloride, a vitamin B6 vitamer, was synthetically converted to a series of diverse redox-active benzoyl pyridinium salts. Cyclic voltammetry studies demonstrated redox reversibility under basic conditions, and two of the most promising salts were subjected to laboratory-scale flow battery tests involving galvanostatic cycling at 10 mM in 0.1 M NaOH. In these tests, the battery was charged completely, corresponding to the transfer of two electrons to the electrolyte, but no discharge was observed. Both CV analysis and electrochemical simulations confirmed that the redox wave observed in the experimental voltammograms corresponds to a two-electron process. To explain the irreversibility in the battery tests, we conducted bulk electrolysis with the benzoyl pyridinium salts, affording the corresponding benzylic secondary alcohols. Computational studies suggest that the reduction proceeds in three consecutive steps: first electron transfer (ET), then proton-coupled electron transfer (PCET) and finally proton transfer (PT) to give the secondary alcohol. 1H NMR deuterium exchange studies indicated that the last PT step is not reversible in 0.1 M NaOH, rendering the entire redox process irreversible. The apparent reversibility observed in CV at the basic media likely arises from the slow rate of the PT step at the timescale of the measurement.

2.
J Org Chem ; 89(10): 6987-6990, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38670541

RESUMO

Humilisin E is a diterpenoid possessing a rare epoxidized cyclononene trans-fused with a bicyclo[3.2.0]heptane core. We have identified the P atropisomer of the corresponding cyclononadiene as a potential biosynthetic/synthetic precursor to humilisin E and reported two different strategies for the stereocontrolled synthesis of the appropriately functionalized bicyclic cores of humilisin E. The first route involves a Stork epoxynitrile cyclization via a Mg alkoxide, and the second, more stereoselective approach utilizes the Wolff rearrangement as the key step.

3.
Dermatol Ther ; 34(2): e14827, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33527634

RESUMO

Since the onset of the present pandemic, effect of the novel corona virus on other infectious conditions continues to be investigated. Although the immunological responses to SARS-Cov-2 infection have been elaborated extensively, they fail to explain, variations in its clinical manifestations and its interaction with other diseases. Hansen's disease is known to present as a complex immunological response to the lepra bacilli, resulting in its varied spectral manifestations. An interaction between these two infectious agents, hence, may affect Hansen's disease. We came across six cases of Hansen's disease who developed COVID19 co-infection. This series presents their clinical course and outcome, during the period of co-infection. All cases were followed up for a minimum eight-week period thereafter. In all these cases the active phase of coronavirus infection had no effect on Hansen's disease and those on prednisolone for their lepra reaction had a more favorable outcome, with two cases manifesting exacerbation of their lepra reactions in the follow period.


Assuntos
COVID-19 , Coinfecção , Hanseníase , Coinfecção/tratamento farmacológico , Humanos , SARS-CoV-2
4.
Beilstein J Org Chem ; 17: 932-963, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33981366

RESUMO

Functionalized tetrahydropyran (THP) rings are important building blocks and ubiquitous scaffolds in many natural products and active pharmaceutical ingredients (API). Among various established methods, the Prins reaction has emerged as a powerful technique in the stereoselective synthesis of the tetrahydropyran skeleton with various substituents, and the strategy has further been successfully applied in the total synthesis of bioactive macrocycles and related natural products. In this context, hundreds of valuable contributions have already been made in this area, and the present review is intended to provide the systematic assortment of diverse Prins cyclization strategies, covering the literature reports of the last twenty years (from 2000 to 2019), with an aim to give an overview on exciting advancements in this area and designing new strategies for the total synthesis of related natural products.

5.
Int J Health Care Qual Assur ; ahead-of-print(ahead-of-print)2020 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-32678536

RESUMO

PURPOSE: Use of technology for quality healthcare services has developed into a new field known as "e-Healthcare services." Healthcare providers often judge their quality of services with consumer satisfaction. With e-Healthcare services, consumer satisfaction is influenced by the quality of healthcare services provided and the demographic characteristics. The purpose of the present case study is to recognize the important predictors of quality, which are significant for consumer satisfaction with e-Healthcare services by using Zineldin's 5Qs model. It also aims to find the strength of association among the predictors of consumer satisfaction and the demographic characteristics of the respondents. DESIGN/METHODOLOGY/APPROACH: A questionnaire-based study was conducted at a public (PGIMER, Chandigarh) and a private hospital (Fortis Hospital, Mohali) of Punjab, India, from February 2018 to March 2019. The structured, closed-ended questionnaire, to be marked on a 1-5 point Likert scale, was adapted from Zineldin's 5Qs model and was distributed to the respondents sitting in the waiting halls of the selected hospitals. The respondents comprised of both the patients and their attendants who were aware of e-Healthcare services and were using them. FINDINGS: The analysis identified quality of interaction, quality of hospital atmosphere and quality of object to be the key predictors of consumer satisfaction with e-Healthcare services. The results reveal a strong association between different demographic characteristics and overall consumer satisfaction with e-Healthcare services. PRACTICAL IMPLICATIONS: The results suggest that improvements in the quality of interaction, quality of hospital atmosphere and quality of object may result in higher consumer satisfaction with e-Healthcare services. Working on the identified dimensions of quality will help the e-Healthcare providers in identifying functional problems of e-Healthcare services and developing improvement strategies, which will also result in better health and quality outcomes. The results of this study will help the e-Healthcare providers in better segmentation of e-Healthcare consumers based on their demographic characteristics and in developing better marketing strategies. ORIGINALITY/VALUE: This paper focuses on the quality of e-Healthcare services only and attempts to identify the quality dimensions, which leads to the satisfaction of e-Healthcare consumers. The identified quality dimensions will help in designing better e-Healthcare services and framing policies. It also highlights the association of demographic characteristics with important quality dimensions.


Assuntos
Satisfação do Paciente , Qualidade da Assistência à Saúde , Telemedicina , Adulto , Coleta de Dados/instrumentação , Feminino , Hospitais Privados , Hospitais Públicos , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Fatores Socioeconômicos , Inquéritos e Questionários , Adulto Jovem
6.
J Org Chem ; 83(17): 9968-9977, 2018 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-30005155

RESUMO

Functionalized hydroindole (1), a common chiral synthon, for versatile transformations to synthesize a broad range of Amaryllidaceae alkaloids (AAs) including (-)-crinine, (-)-crinane, (-)-amabiline, (+)-mesembrine, (-)-maritidine, (-)-oxomaritidine, and (+)-mesembrane is reported. Scaffold 1 is found as a prime structural motif in a wide variety of the AAs and is a novel synthon toward designing a divergent route for the synthesis of these natural products. This is established in a few steps, starting from a chiral aza-bicyclo-heptene sulfone scaffold (2) via conjugate addition and concomitant stereoselective ring opening with allylmagnesium bromide, a key step that generates a crucial quaternary stereocenter, fixing the stereochemistry of the rest of the molecule at an early stage. One carbon truncation followed by intramolecular reductive amination led to the desired core 1 in a multigram scale.


Assuntos
Alcaloides de Amaryllidaceae/química , Alcaloides de Amaryllidaceae/síntese química , Técnicas de Química Sintética , Indóis/química , Modelos Moleculares , Conformação Molecular , Fenantridinas/química , Estereoisomerismo
7.
ACS Omega ; 9(10): 11755-11768, 2024 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-38496986

RESUMO

For glucose-stimulated insulin secretion (GSIS) by pancreatic ß-cells in animals, it is believed that ATP generated from glucose metabolism is primarily responsible. However, this ignores two well-established aspects in literature: (a) intracellular ATP generation from other sources resulting in an overall pool of ATP, regardless of the original source, and (b) that intracellular glucose transport is 10- to 100-fold higher than intracellular glucose phosphorylation in ß-cells. The latter especially provides an earlier unaddressed, but highly appealing, observation pertaining to (at least transient) the presence of intracellular glucose molecules. Could these intracellular glucose molecules be responsible for the specificity of GSIS to glucose (instead of the widely believed ATP production from its metabolism)? In this work, we provide a comprehensive compilation of literature on glucose and GSIS using various cellular systems - all studies focus only on the extracellular role of glucose in GSIS. Further, we carried out a comprehensive analysis of differential gene expression in Mouse Insulinoma 6 (MIN6) cells, exposed to low and high extracellular glucose concentrations (EGC), from the existing whole transcriptome data. The expression of other genes involved in glycolysis, Krebs cycle, and electron transport chain was found to be unaffected by EGC, except Gapdh, Atp6v0a4, and Cox20. Remarkably, 3 upregulated genes (Atp6v0a4, Cacnb4, Kif11) in high EGC were identified to have an association with cellular secretion. Using glucose as a possible ligand for the 3 proteins, computational investigations were carried out (that will require future 'wet validation', both in vitro and in vivo, e.g., using primary islets and animal models). The glucose-affinity/binding scores (in kcal/mol) obtained were also compared with glucose binding scores for positive controls (GCK and GLUT2), along with negative controls (RPA1, KU70-80, POLA1, ACAA1A, POLR1A). The binding affinity scores of glucose molecules for the 3 proteins were found to be closer to positive controls. Therefore, we report the glucose binding ability of 3 secretion-related proteins and a possible direct role of intracellular glucose molecules in GSIS.

8.
Am J Infect Control ; 51(1): 29-34, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-35577058

RESUMO

BACKGROUND: Healthcare-associated infections (HAIs) are one of the most common adverse events in patient care that account for substantial morbidity and mortality. We evaluate the existing Infection Prevention and Control (IPC) practices in hospitals participating in the nationally representative HAI Surveillance network. METHODS: This cross-sectional survey was conducted in 23 hospitals across 22 states of India from October-2015 to September-2018 in the HAI surveillance network. The World Health Organization (WHO) IPC core components assessment tool for health-care facility level (IPCAT-H) was adapted from IPC assessment tool developed by US Centers for Disease Control and Prevention (US CDC) under the Epidemiology and Laboratory Capacity (ELC) Infection Control Assessment and Response (ICAR) Program. Mann-Whitney U test was used to calculate the significant difference between scores (P < .05). RESULTS: Amongst the participating hospitals, 7 were private sectors and 16 were public health care facilities. Infection IPCAT-H average score per multimodal strategy was less than 50% for programmed IPC activities (45.7); implementation of health care workers (HCWs) immunization programme (43.5%); monitoring and evaluation component (38.30%). CONCLUSIONS: There is potential for improvement in Human Resources, Surveillance of HAIs as well as Monitoring and Evaluation components.


Assuntos
Infecção Hospitalar , Controle de Infecções , Humanos , Controle de Infecções/métodos , Autorrelato , Estudos Transversais , Infecção Hospitalar/epidemiologia , Infecção Hospitalar/prevenção & controle , Hospitais
9.
Eur J Rheumatol ; 9(4): 212-214, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35156623

RESUMO

Tenosynovitis is an infrequent presentation of Hansen's disease. It may occur during the natural course of disease or treatment as part of type 1 reaction or rarely may be the presenting complaint. We report a case of tenosynovitis of bilateral wrist joints who after being ineffectively treated by an orthopedician as well as rheumatologist for several months and was finally diagnosed as a case of Hansen's disease (borderline lepromatous) in type 1 reaction with excellent response to multidrug therapy and tapering doses of systemic steroids.

10.
Lancet Glob Health ; 10(9): e1317-e1325, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35961355

RESUMO

BACKGROUND: Health-care-associated infections (HAIs) cause significant morbidity and mortality globally, including in low-income and middle-income countries (LMICs). Networks of hospitals implementing standardised HAI surveillance can provide valuable data on HAI burden, and identify and monitor HAI prevention gaps. Hospitals in many LMICs use HAI case definitions developed for higher-resourced settings, which require human resources and laboratory and imaging tests that are often not available. METHODS: A network of 26 tertiary-level hospitals in India was created to implement HAI surveillance and prevention activities. Existing HAI case definitions were modified to facilitate standardised, resource-appropriate surveillance across hospitals. Hospitals identified health-care-associated bloodstream infections and urinary tract infections (UTIs) and reported clinical and microbiological data to the network for analysis. FINDINGS: 26 network hospitals reported 2622 health-care-associated bloodstream infections and 737 health-care-associated UTIs from 89 intensive care units (ICUs) between May 1, 2017, and Oct 31, 2018. Central line-associated bloodstream infection rates were highest in neonatal ICUs (>20 per 1000 central line days). Catheter-associated UTI rates were highest in paediatric medical ICUs (4·5 per 1000 urinary catheter days). Klebsiella spp (24·8%) were the most frequent organism in bloodstream infections and Candida spp (29·4%) in UTIs. Carbapenem resistance was common in Gram-negative infections, occurring in 72% of bloodstream infections and 76% of UTIs caused by Klebsiella spp, 77% of bloodstream infections and 76% of UTIs caused by Acinetobacter spp, and 64% of bloodstream infections and 72% of UTIs caused by Pseudomonas spp. INTERPRETATION: The first standardised HAI surveillance network in India has succeeded in implementing locally adapted and context-appropriate protocols consistently across hospitals and has been able to identify a large number of HAIs. Network data show high HAI and antimicrobial resistance rates in tertiary hospitals, showing the importance of implementing multimodal HAI prevention and antimicrobial resistance containment strategies. FUNDING: US Centers for Disease Control and Prevention cooperative agreement with All India Institute of Medical Sciences, New Delhi. TRANSLATION: For the Hindi translation of the abstract see Supplementary Materials section.


Assuntos
Anti-Infecciosos , Infecção Hospitalar , Pneumonia Associada à Ventilação Mecânica , Sepse , Infecções Urinárias , Criança , Infecção Hospitalar/epidemiologia , Infecção Hospitalar/prevenção & controle , Humanos , Recém-Nascido , Klebsiella , Pneumonia Associada à Ventilação Mecânica/complicações , Pneumonia Associada à Ventilação Mecânica/epidemiologia , Pneumonia Associada à Ventilação Mecânica/microbiologia , Estudos Prospectivos , Centros de Atenção Terciária , Infecções Urinárias/epidemiologia
11.
Am J Infect Control ; 50(4): 390-395, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34600081

RESUMO

BACKGROUND: Healthcare associated infections (HAIs) are prevalent and difficult to treat worldwide. Most HAIs can be prevented by effective implementation of Infection Prevention and Control (IPC) measures. A survey was conducted to assess the existing IPC practices across a network of Indian Hospitals using the World Health Organization designed self-assessment IPC Assessment Framework (IPCAF) tool. METHODS: This was a cross sectional observation study. Thirty-two tertiary care public and private facilities, part of the existing Indian HAI surveillance network was included. Data collected was analyzed by a central team at All India Institute of Medical Sciences, New Delhi, a tertiary care hospital of India. The WHO questionnaire tool was used to understand the capacity and efforts to implement IPC practices across the network. RESULTS: The overall median score of IPCAF across the network was 620. Based on the final IPCAF score of the facilities; 13% hospitals had basic IPC practices, 28% hospitals had intermediate and 59% hospitals had advanced IPC practices. The component multimodal strategies had the broadest range of score while the component IPC guidelines had the narrowest one. CONCLUSIONS: Quality improvement training for IPC nurses and healthcare professionals are needed to be provided to health facilities.


Assuntos
Infecção Hospitalar , Controle de Infecções , Infecção Hospitalar/epidemiologia , Infecção Hospitalar/prevenção & controle , Estudos Transversais , Atenção à Saúde , Instalações de Saúde , Humanos , Autorrelato , Inquéritos e Questionários
12.
Fundam Clin Pharmacol ; 35(6): 955-967, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33576046

RESUMO

AIM: Elucidation of the antiproliferative efficacy and mechanism of action of a design-optimized noscapine analog, N-4-CN. METHODS: Cell viability was studied using an MTT assay. The drug-tubulin interactions were investigated using spectrofluorometry. The architectural defects, hyper stabilization, and recovery competence of cellular microtubules were studied using immunofluorescence microscopy. DCF-DH and rhodamine 123 were used as probes to to examine the levels of reactive oxygen species and the loss of mitochondrial membrane potential, respectively. Flow cytometry revealed the cell cycle progression pattern of the drug-treated cells. KEY FINDINGS: Among the cell lines tested, N-4-CN showed the strongest inhibition of the viability of the triple-negative breast cancer (TNBC) cell line MDA-MB-231(IC50 , 2.7 ± 0.1 µmol/L) and weakest inhibition of the noncancerous epithelial cell line, VERO (IC50 , 60.2 ± 3 µmol/L). It perturbed tertiary structure of tubulin and stabilized colchicine binding to the protein. In cells, N-4-CN hyperstabilized the microtubules, and prevented the recovery of cold-depolymerized microtubules. Its multitude of effects on tubulin and microtubules facilitated cell cycle arrest and subsequent cell death that were complemented by elevated levels of reactive oxygen species (ROS). SIGNIFICANCE: Owing to its ability to perturb a well-defined cancer drug target, tubulin, and to promote ROS-facilitated apoptosis, N-4-CN could be investigated further as a potential therapeutic against many neoplasms, including TNBC.


Assuntos
Antineoplásicos , Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Microtúbulos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Tubulina (Proteína)/farmacologia
13.
Cent Asian J Glob Health ; 9(1): e297, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-35866095

RESUMO

Introduction: Cases of female targeted violence often go uncounted in India. To identify the unreported cases of violence, Sukoon was established in 2014 as a hospital-based 'One Stop Crisis Centre' (OSCC). Sukoon provides counselling, police assistance and legal aid to the victims. The aim of the present study was to recognize the role of Sukoon in preventing violence against women (VAW) in the region. Methods: Secondary data was extracted from 430 victims who approached Sukoon from August 2014 through January 2017. Data was collected on different variables: age, marital status, nature of violence, medium through which victims approached Sukoon and type of assistance provided. Significance of association of studied factors with the type of assault was investigated using χ2 test. Results: Age of study-victims ranged from 4 to 75 years with a median age of 26 years and mean age of 27.61 years with standard deviation of 10.56 years. Major types of VAW (96.51%) were domestic violence, sexual assault, physical assault and poisoning. The types of violences were significantly associated with victims' age (χ2 =5.76, d.f.=1, p<0.05) and marital status (χ2 = 98.23, d.f=4, p<0.001). About 78% of victims were identified from Sukoon through screening and counseling. Around 69% of the cases were resolved directly by Sukoon or through police assistance. Conclusions: The above results indicate a significant role of Sukoon in screening victims of violence and providing them required assistance within the hospital environment in one location. Such centers should be further promoted by the government to address the issues of VAW.

14.
J Pharm Pharmacol ; 72(11): 1585-1594, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32959391

RESUMO

OBJECTIVES: To examine the antiproliferative effect of a rationally designed, novel noscapine analogue, 9-((perfluorophenyl)methylene) aminonoscapine, '9-PAN') on MDA-MB-231 breast cancer cell line, and to elucidate the underlying mechanism of action. METHODS: The rationally designed Schiff base-containing compound, 9-PAN, was characterized using IR, NMR and mass spectra analysis. The effect of the compound on cell viability was studied using an MTT assay. Cell cycle and cell death analyses were performed using flow cytometry. Binding interactions of 9-PAN with tubulin were studied using spectrofluorometry. Reactive oxygen species (ROS) generation and mitochondrial membrane potential (MMP) were investigated using the probes, DCFDA and rhodamine-123, respectively. Immunofluorescence imaging was used to visualize cellular microtubules. KEY FINDINGS: 9-PAN inhibited cell proliferation (IC50 of 20 ± 0.3 µm) and colony formation (IC50 , 6.2 ± 0.3 µm) by arresting the cells at G2 /M phase of the cell cycle. It bound to tubulin in a concentration-dependent manner without considerably altering the tertiary conformation of the protein or the polymer mass of the microtubules in vitro. The noscapinoid substantially damaged cellular microtubule network and induced cell death, facilitated by elevated levels of ROS. CONCLUSIONS: 9-PAN exerts its antiproliferative effect by targeting tubulin and elevating ROS level in the cells.


Assuntos
Antineoplásicos/farmacologia , Noscapina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Apoptose/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Noscapina/análogos & derivados , Transdução de Sinais , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
15.
Biochimie ; 144: 122-133, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29097284

RESUMO

Dihydroxy-1-selenolane (DHS) previously reported to exhibit radioprotective activity was investigated to understand its mechanism of action in CHO cells of epithelial origin. DHS pre-treatment at 25 µM for 16 h significantly protected CHO cells from radiation (4-11 Gy)-induced delayed mitotic cell death. Further to examine, how increased cellular uptake can influence this mechanism, studies have been performed with DHS-C6, a lipophilic conjugate of DHS. Accordingly CHO cells pre-treated with DHS-C6, showed increased survival against radiation exposure. Notably treatment with both DHS and DHS-C6 significantly increased glutathione peroxidase (GPx) activity in cells by âˆ¼ 2.5 fold. Additionally, the compound DHS or DHS-C6 led to faster repair of DNA in irradiated cells and subsequently inhibited the G2/M arrest. Anticipating the role of GPx in radioprotection, our investigations revealed that addition of mercaptosuccinic acid, a pharmacological inhibitor of GPx reversed all the above effects of DHS or DHS-C6. Further inhibitors of check point kinase 1 (CHK1) and DNA-protein kinase (DNA-PK) although abrogated the radioprotective effect of DHS or DHS-C6 separately, did not show additive effect in combination with GPx inhibitor, suggesting their cross talk. In contrast to these results, both DHS and DHS-C6 treatment did not protect spleen lymphocytes from the radiation-induced apoptosis. Thus results confirmed that both DHS and DHS-C6 protected cells from radiation-induced mitotic death by augmenting DNA repair in a GPx dependant manner.


Assuntos
Ácidos Graxos/metabolismo , Glutationa Peroxidase/metabolismo , Compostos Heterocíclicos com 1 Anel/metabolismo , Compostos Heterocíclicos com 1 Anel/farmacologia , Compostos Organosselênicos/metabolismo , Compostos Organosselênicos/farmacologia , Protetores contra Radiação/metabolismo , Protetores contra Radiação/farmacologia , Animais , Células CHO , Morte Celular/efeitos dos fármacos , Morte Celular/efeitos da radiação , Cricetinae , Cricetulus , Dano ao DNA , Reparo do DNA/efeitos dos fármacos , Reparo do DNA/efeitos da radiação , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos da radiação , Glutationa Peroxidase/antagonistas & inibidores , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase M do Ciclo Celular/efeitos da radiação , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/efeitos da radiação
16.
Biol Trace Elem Res ; 179(1): 130-139, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28190183

RESUMO

The aim of the present study is to evaluate the radioprotective effect of low-dose selenium supplementation (multiple administrations) on radiation toxicities and mortality induced by lethal dose of whole-body irradiation (WBI). For this, BALB/c mice received sodium selenite (4 µg/kg body wt) intraperitoneally for five consecutive days and subjected to WBI at an absorbed dose of 8 Gy (60Co, 1 Gy/min). Administration of sodium selenite was continued even during the post irradiation days three times a week till the end of the experiment. The radioprotective effect was evaluated in terms of the improvement in 30 days post irradiation survival, protection from DNA damage, and biochemical and histological changes in radiosensitive organs. The results indicated that low-dose sodium selenite administration did not protect the mice from radiation-induced hematopoietic and gastrointestinal injuries and subsequent mortality. However, it significantly prevented the radiation-induced genotoxicity or DNA damage in peripheral leukocytes. Further sodium selenite administration modulated the messenger RNA (mRNA) expression of GPx1, GPx2, and GPx4 in the spleen and intestine differentially and led to a significant increase in GPx activity (∼1.5 to 2-folds) in these organs. In line with this observation, sodium selenite administration reduced the level of lipid peroxidation in the intestine. In conclusion, our study shows that low-dose sodium selenite supplementation can be an effective strategy to prevent WBI-induced genotoxicity but may not have an advantage against mortality sustained during nuclear emergencies.


Assuntos
Dano ao DNA/efeitos dos fármacos , Gastroenteropatias/prevenção & controle , Intestinos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Selenito de Sódio/administração & dosagem , Selenito de Sódio/farmacologia , Irradiação Corporal Total , Animais , Suplementos Nutricionais , Relação Dose-Resposta a Droga , Injeções Intraperitoneais , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Taxa de Sobrevida
17.
Metallomics ; 9(6): 715-725, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28503683

RESUMO

Diselenonicotinamide (DSNA), a synthetic organoselenium compound, was evaluated for its radioprotective effect in cellular models. A clonogenic assay in Chinese Hamster Ovary (CHO) cells and an apoptosis assay in murine splenic lymphocytes indicated that pre-treatment with DSNA at a concentration of 25 µM significantly protected them from radiation-induced cell death. Upon irradiation (1-12 Gy), dose-response studies were carried out under similar treatment conditions, and its dose modification factor (DMF) was estimated to be 1.26. Furthermore, DSNA showed its radioprotective effect, even when administered after exposure to radiation. Mechanistic investigation revealed that DSNA increased the intracellular levels of GPx and GSH in irradiated cells. In line with this observation, the addition of a pharmacological inhibitor of GPx cycle, abrogated the activity of DSNA. The radioprotective effect of DSNA was also complemented by its ability to prevent radiation-induced DNA damage as monitored by micronucleus and γ-H2AX assays. Furthermore, treatment with DSNA did not show much change in the expressions of Nrf2 dependent genes (γ-GCL and HO-1), but the presence of a pharmacological inhibitor of Nrf2 abrogated the radioprotective activity of DSNA against cell death and DNA damage. Additionally, ATRA treatment also inhibited the DSNA-mediated up-regulation of a repair gene RAD51, suggesting possible involvement of basal Nrf2 in the anti-genotoxic effect of DSNA. In conclusion, the present study demonstrates radioprotection by a synthetic organoselenium compound containing nutritionally important moieties like selenium and nicotinamide.


Assuntos
Proliferação de Células/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Raios gama/efeitos adversos , Regulação da Expressão Gênica/efeitos dos fármacos , Linfócitos/citologia , Niacinamida/análogos & derivados , Compostos Organosselênicos/farmacologia , Protetores contra Radiação/farmacologia , Compostos de Selênio/farmacologia , Animais , Proliferação de Células/efeitos da radiação , Células Cultivadas , Radioisótopos de Cobalto/efeitos adversos , Cricetinae , Cricetulus , Dano ao DNA/efeitos da radiação , Regulação da Expressão Gênica/efeitos da radiação , Humanos , Linfócitos/efeitos dos fármacos , Linfócitos/efeitos da radiação , Células MCF-7 , Camundongos , Micronúcleos com Defeito Cromossômico/efeitos dos fármacos , Micronúcleos com Defeito Cromossômico/efeitos da radiação , Niacinamida/farmacologia , Doses de Radiação , Espécies Reativas de Oxigênio/metabolismo , Baço/citologia , Baço/efeitos dos fármacos , Baço/efeitos da radiação
18.
Toxicol Res (Camb) ; 5(2): 434-445, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30090358

RESUMO

A series of amphiphilic conjugates of dihydroxy selenolane (DHS) and monoamine selenolane (MAS), which we had previously reported to inhibit lipid peroxidation and assist the oxidative protein folding reaction respectively in cell free systems, were evaluated for cytotoxicity, associated mechanisms and antioxidant effects in cells. Our results indicated that a fatty acid/alkyl group of variable chain lengths (C6-14) as a lipophilic moiety of the DHS/MAS conjugates not only improved their ability to incorporate within the plasma membrane of cells but also modulated their cytotoxicity. In the concentration range of 1-50 µM, C6 conjugates were non-toxic whereas the long chain (≥C8) conjugates showed significant cytotoxicity. The induction of toxicity investigated by the changes in membrane leakage, fluidity, mitochondrial membrane potential and annexin-V-propidium iodide (PI) staining by using flow cytometry revealed plasma membrane disintegration and subsequent induction of necrosis as the major mechanism. Further, the conjugates of DHS and MAS also showed differential as well as nonlinear tendency in cytotoxicity with respect to chain lengths and this effect was attributed to their self-aggregation properties. Compared with the parent compounds, C6 conjugates not only exhibited better antioxidant activity in terms of the induction of selenoproteins such as glutathione peroxidase 1 (GPx1), GPx4 and thioredoxin reductase 1 (TrxR1) but also protected cells from the AAPH induced oxidative stress. In conclusion, the present study suggests the importance of hydrophilic-lipophilic balance (HLB) in fine tuning the toxicity and activity of bioinspired amphiphilic antioxidants.

19.
Artigo em Inglês | MEDLINE | ID: mdl-27542713

RESUMO

Dihydroxyselenolane (DHS), a simple water-soluble organoselenium compound, was evaluated for radioprotection in BALB/c mice after whole-body irradiation (WBI) (8Gy (60)Co, 1Gy/min), by monitoring 30-d post-irradiation survival and biochemical/histological changes in radiosensitive organs. Intraperitoneal administration of DHS at 2mg/kg for five consecutive days before irradiation and three times per week during the post-irradiation period showed maximum benefit (40% improvement in 30 d post-irradiation survival). DHS treatment, despite inducing expression of glutathione peroxidases (GPx1, GPx2, and GPx4) in spleen and intestine, did not protect against radiation-induced acute (10-day) haematopoietic and gastrointestinal toxicities. DHS treatment significantly reduced radiation-induced DNA damage in peripheral leukocytes and inflammatory responses in intestine, lung, and circulation. The anti-inflammatory effect of DHS was associated with reductions in lipid peroxidation, expression of pro-inflammatory genes such as Icam-1, Ccl-2, and iNos-2, and subsequent infiltration of inflammatory cells. Irradiated mice treated with DHS survived until day 30 post-irradiation and showed restoration of spleen cellularity and intestinal villi, but had moderately increased systemic and tissue-specific inflammatory responses. Another organoselenium compound, selenomethionine, evaluated in parallel with DHS at the same dose and treatment schedule, showed comparable radioprotective effects. The mechanism of radioprotection by DHS is mainly via suppression of inflammatory responses.


Assuntos
Síndrome Aguda da Radiação/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Compostos Organosselênicos/uso terapêutico , Protetores contra Radiação/uso terapêutico , Irradiação Corporal Total/efeitos adversos , Síndrome Aguda da Radiação/prevenção & controle , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Injeções Intraperitoneais , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/metabolismo , Mucosa Intestinal/metabolismo , Intestinos/efeitos dos fármacos , Intestinos/efeitos da radiação , Peroxidação de Lipídeos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/efeitos da radiação , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Especificidade de Órgãos , Compostos Organosselênicos/administração & dosagem , Compostos Organosselênicos/farmacologia , Protetores contra Radiação/administração & dosagem , Protetores contra Radiação/farmacologia
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