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1.
Artigo em Inglês | MEDLINE | ID: mdl-38733467

RESUMO

The COVID-19 pandemic has led to significant disruptions in healthcare systems worldwide, with Varanasi, India, experiencing profound challenges in managing mortality rates. In order to inform public health initiatives, it is important to comprehend how the pandemic has affected all-cause unnatural death in comparison to pre-pandemic patterns. This retrospective study intended to investigate patterns of all-cause unnatural mortality employing autopsy records of cases from Varanasi's Institute of Medical Sciences, Banaras Hindu University during the pre-pandemic and pandemic period (First and Second wave) of COVID-19. The analysis included 2694 cases of unnatural mortality, such as road traffic accident (RTA), poisoning, hanging and other causes. Demographic, clinical, and circumstantial data were collected and compared between the two time periods, that revealed significant as well as non-significant shifts in all-cause unnatural mortality rates. Whilst certain types of unnatural deaths, such as RTAs, witnessed a non-significant 2.03% (p = 0.34722) decrease, others like hanging exhibited an unexpected significant 3.17% (p = 0.01732) rise, burning and poisoning witnessed a significant 4.18% (p = 0.00026) and 2.37% (p = 0.0271) decline respectively. RTA was the leading cause of mortality both during and before pandemic. Male deaths (79.18%) outweighed female deaths (20.82%) by a more substantial amount throughout research periods. Additionally, variations in demographic characteristics, circumstances surrounding deaths, and healthcare utilization were observed during the pandemic period. The majority of unnatural fatalities occur in the age group of 21-30 years old in both pre-pandemic (22.62%) and pandemic conditions (26.65%). This study provides important insights into the secondary effects of the pandemic on unnatural mortality and emphasizes the need for individualized public health. Furthermore, research is warranted to explore the long-term implications and address the associated challenges for healthcare systems and public health initiatives.

2.
Biochemistry ; 62(23): 3347-3359, 2023 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-37967383

RESUMO

Prokaryotes synthesize fatty acids using a type II synthesis pathway (FAS). In this process, the central player, i.e., the acyl carrier protein (ACP), sequesters the growing acyl chain in its internal hydrophobic cavity. As the acyl chain length increases, the cavity expands in size, which is reflected in the NMR chemical shift perturbations and crystal structures of the acyl-ACP intermediates. A few eukaryotic organelles, such as plastids and mitochondria, also harbor type II fatty acid synthesis machinery. Plastid FAS from spinach and Plasmodium falciparum has been characterized at the molecular level, but the mitochondrial pathway remains unexplored. Here, we report NMR studies of the mitochondrial acyl-acyl carrier protein intermediates of Leishmania major (acyl-LmACP). Our studies show that LmACP experiences remarkably small conformational changes upon acylation, with perturbations confined to helices II and III only. CastP determined that the cavity size of apo-LmACP (PDB entry 5ZWT) is less than that of Escherichia coli ACP (PDB 1T8K). Thus, the small chemical shift perturbations observed in the LmACP intermediates, coupled with CastP results, suggest an unusually small cavity when fully expanded. The faster rate of C8-LmACP chain hydrolysis compared to E. coli ACP (EcACP) also supports these convictions. Structure comparison of LmACP with other type II ACP disclosed unique differences in the helix I and loop I conformations, as well as several residues present there. Numerous hydrophobic residues in helix I and loop I (conserved in all mitochondrial ACPs) are substituted with hydrophilic residues in the bacterial/plastid type II ACP. For instance, Phe and leucine at positions 14 and 34 in LmACP are substituted with a hydrophilic residue and Ala in bacterial/plastid type II ACP. Mutation of Leu 34 to Ala (corresponding residue in EcACP) resulted in a complete loss of structure, underscoring its importance in maintaining the ACP fold. Thus, our NMR studies, combined with insights from the crystal structure, highlight several unique features of LmACP, distinct from the prokaryote and plastid type II ACP. Given the high sequence identity, the features might be conserved in all mitochondrial ACPs.


Assuntos
Proteína de Transporte de Acila , Leishmania major , Proteína de Transporte de Acila/metabolismo , Leishmania major/metabolismo , Escherichia coli/metabolismo , Modelos Moleculares , Conformação Molecular
3.
Environ Monit Assess ; 193(8): 468, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34226956

RESUMO

Bamboos due to high soil water conservation potential are gaining increased attention in plantation programs across the globe. Large-scale plantation of fast-growing bamboo, however, can have important hydrological consequences. The study aims to quantify the eco-hydrological parameters, viz., throughfall (TF), stemflow (SF), and interception (I) in seven important sympodial bamboo species in north western Himalayan foothills of India. The species selected include Bambusa balcooa, Bambusa bambos, Bambusa vulgaris., Bambusa nutans, Dendrocalamus hamiltonii, Dendrocalamus stocksii, and Dendrocalamus strictus. Throughfall versus gross rainfall (GR) relationship in different species indicated high throughfall production during high rainfall events with r2 > 0.90. Average throughfall was lowest (62.1%) in D. hamiltonii and highest in B. vulgaris (74.6%). SF ranged from 1.32% in B. nutans to 3.39% in D. hamiltonii. The correlation coefficient (r) between leaf area index (LAI), number of culms, and crown area with the interception were 0.746, 0.691, and 0.585, respectively. The funneling ratio (F) was highest (27.0) in D. hamiltonii and least in B. nutans. Canopy storage capacity was highest in D. strictus (3.57 mm) and least in D. hamiltonii (1.09 mm). Interception loss was highest (34.4%) in D. hamiltonii and lowest in B. vulgaris (23.5%) and D. strictus (23.6%). Higher interception in bamboos make them suitable for soil conservation, but careful selection of species is required in low rainfall areas.


Assuntos
Antozoários , Monitoramento Ambiental , Animais , Hidrologia , Índia , Solo
4.
Biochemistry ; 54(36): 5632-45, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-26293213

RESUMO

The genome of Leishmania major encodes a type II fatty acid biosynthesis pathway for which no structural or biochemical information exists. Here, for the first time, we have characterized the central player of the pathway, the acyl carrier protein (LmACP), using nuclear magnetic resonance (NMR). Structurally, the LmACP molecule is similar to other type II ACPs, comprising a four-helix bundle, enclosing a hydrophobic core. Dissimilarities in sequence, however, exist in helix II (recognition helix) of the protein. The enzymatic conversion of apo-LmACP into the holo form using type I (Escherichia coli AcpS) and type II (Sfp type) phosphopantetheinyl transferases (PPTs) is relatively slow. Mutagenesis studies underscore the importance of the residues present at the protein-protein interaction interface of LmACP in modulating the activity of PPTs. Interestingly, the cognate PPT for this ACP, the L. major 4'-phosphopantetheinyl transferase (LmPPT), does not show any enzymatic activity toward it, though it readily converts other type I and type II ACPs into their holo forms. NMR chemical shift perturbation studies suggest a moderately tight complex between LmACP and its cognate PPT, suggesting inhibition. We surmise that the unique surface of LmACP might have evolved to complement its cognate enzyme (LmPPT), possibly for the purpose of regulation.


Assuntos
Proteína de Transporte de Acila/química , Leishmania major/metabolismo , Proteínas de Protozoários/química , Transferases (Outros Grupos de Fosfato Substituídos)/química , Sequência de Aminoácidos , Bacillus subtilis/metabolismo , Proteínas de Bactérias/química , Escherichia coli/metabolismo , Holoenzimas/química , Humanos , Modelos Moleculares , Dados de Sequência Molecular , Mycobacterium tuberculosis/metabolismo , Ressonância Magnética Nuclear Biomolecular , Plasmodium falciparum/metabolismo , Ligação Proteica , Estrutura Secundária de Proteína , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
5.
BMC Cancer ; 14: 256, 2014 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-24725450

RESUMO

BACKGROUND: Tissue-transglutaminase (TG2), a dual function G-protein, plays key roles in cell differentiation and migration. In our previous studies we reported the mechanism of TG2-induced cell differentiation. In present study, we explored the mechanism of how TG2 may be involved in cell migration. METHODS: To study the mechanism of TG2-mediated cell migration, we used neuroblastoma cells (SH-SY5Y) which do not express TG2, neuroblastoma cells expressing exogenous TG2 (SHYTG2), and pancreatic cancer cells which express high levels of endogenous TG2. Resveratrol, a natural compound previously shown to inhibit neuroblastoma and pancreatic cancer in the animal models, was utilized to investigate the role of TG2 in cancer cell migration. Immunofluorescence assays were employed to detect expression and intracellular localization of TG2, and calcium levels in the migrating cells. Native gel electrophoresis was performed to analyze resveratrol-induced cellular distribution and conformational states of TG2 in migrating cells. Data are presented as the mean and standard deviation of at least 3 independent experiments. Comparisons were made among groups using one-way ANOVA followed by Tukey-Kramer ad hoc test. RESULTS: TG2 containing cells (SHYTG2 and pancreatic cancer cells) exhibit increased cell migration and invasion in collagen-coated and matrigel-coated transwell plate assays, respectively. Resveratrol (1 µM-10 µM) prevented migration of TG2-expressing cells. During the course of migration, resveratrol increased the immunoreactivity of TG2 without affecting the total TG2 protein level in migrating cells. In these cells, resveratrol increased calcium levels, and depletion of intracellular calcium by a calcium chelator, BAPTA, attenuated resveratrol-enhanced TG2 immunoreactivity. In native-polyacrylamide gels, we detected an additional TG2 protein band with slower migration in total cell lysates of resveratrol treated cells. This TG2 form is non-phosphorylated, exclusively present in plasma membrane fractions and sensitive to intracellular Ca(2+) concentration suggesting a calcium requirement in TG2-regulated cell migration. CONCLUSIONS: Taken together, we conclude that resveratrol induces conformational changes in TG2, and that Ca(2+)-mediated TG2 association with the plasma membrane is responsible for the inhibitory effects of resveratrol on cell migration.


Assuntos
Membrana Celular/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pancreáticas/genética , Transglutaminases/genética , Sinalização do Cálcio , Linhagem Celular Tumoral , Membrana Celular/química , Movimento Celular/efeitos dos fármacos , Proteínas de Ligação ao GTP , Humanos , Neoplasias Pancreáticas/patologia , Conformação Proteica , Proteína 2 Glutamina gama-Glutamiltransferase , Transporte Proteico/genética , Resveratrol , Estilbenos/administração & dosagem , Transglutaminases/química , Transglutaminases/metabolismo
6.
Int J Biol Macromol ; 277(Pt 1): 134113, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39048004

RESUMO

Trazodone (TZD) is an antidepressant drug used to treat major depressive and sleeping disorders. Elevated doses of trazodone are associated with central nervous system depression, which manifests as nausea, drowsiness, confusion, vertigo, exhaustion, etc. To develop a clinically viable active pharmaceutical compound with minimal adverse effects, it is imperative to possess a comprehensive knowledge of the drug's action mechanism on DNA. Hence, we investigate the mode of interaction between trazodone and DNA utilizing various spectroscopic and computational techniques. Studies using UV-vis titration showed that the DNA and trazodone have an effective interaction. The magnitude of the Stern-Volmer constant (KSV) has been calculated to be 5.84 × 106 M-1 by the Lehrer equation from a steady-state fluorescence study. UV-vis absorption, DNA melting, dye displacement, and circular dichroism studies suggested that trazodone binds with DNA in minor grooves. Molecular docking and molecular dynamic simulation demonstrated that the TZD-DNA system was stable, and the mode of binding was minor groove. Furthermore, ionic strength investigation demonstrates that DNA and trazodone do not have a substantial electrostatic binding interaction.


Assuntos
Antidepressivos , DNA , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Trazodona , Trazodona/química , DNA/química , DNA/metabolismo , Antidepressivos/química , Antidepressivos/farmacologia , Análise Espectral , Dicroísmo Circular
7.
Carbohydr Polym ; 337: 122156, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38710572

RESUMO

Seaweeds represent a rich source of sulfated polysaccharides with similarity to heparan sulfate, a facilitator of myriad virus host cell attachment. For this reason, attention has been drawn to their antiviral activity, including the potential for anti-SARS-CoV-2 activity. We have identified and structurally characterized several fucoidan extracts, including those from different species of brown macroalga, and a rhamnan sulfate from a green macroalga species. A high molecular weight fucoidan extracted from Saccharina japonica (FSjRPI-27), and a rhamnan sulfate extracted from Monostroma nitidum (RSMn), showed potent competitive inhibition of spike glycoprotein receptor binding to a heparin-coated SPR chip. This inhibition was also observed in cell-based assays using hACE2 HEK-293 T cells infected by pseudotyped SARS-CoV-2 virus with IC50 values <1 µg/mL. Effectiveness was demonstrated in vivo using hACE2-transgenic mice. Intranasal administration of FSjRPI-27 showed protection when dosed 6 h prior to and at infection, and then every 2 days post-infection, with 100 % survival and no toxicity at 104 plaque-forming units per mouse vs. buffer control. At 5-fold higher virus dose, FSjRPI-27 reduced mortality and yielded reduced viral titers in bronchioalveolar fluid and lung homogenates vs. buffer control. These findings suggest the potential application of seaweed-based sulfated polysaccharides as promising anti-SARS-CoV-2 prophylactics.


Assuntos
Antivirais , COVID-19 , Mananas , Polissacarídeos , SARS-CoV-2 , Alga Marinha , Polissacarídeos/química , Polissacarídeos/farmacologia , Animais , Humanos , SARS-CoV-2/efeitos dos fármacos , Alga Marinha/química , Antivirais/farmacologia , Antivirais/química , Células HEK293 , Camundongos , COVID-19/prevenção & controle , COVID-19/virologia , Tratamento Farmacológico da COVID-19 , Camundongos Transgênicos , Glicoproteína da Espícula de Coronavírus/metabolismo , Desoxiaçúcares/farmacologia , Desoxiaçúcares/química , Enzima de Conversão de Angiotensina 2/metabolismo
8.
Methods Mol Biol ; 2671: 349-360, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37308655

RESUMO

Contrast agents are employed to enhance the differentiation of diseased cells or lesions from normal tissues in magnetic resonance imaging (MRI). Protein cages have been explored as templates to synthesize superparamagnetic MRI contrast agents for decades. The biological origin imparts natural precision in forming confined nano-sized reaction vessels. With natural capacity to bind divalent metal ions, ferritin protein cages have been used for the synthesis of nanoparticles containing MRI contrast agents inside their core. Furthermore, ferritin is known to bind transferrin receptor 1 (TfR1) which is overexpressed on specific cancer cell types and could be used for targeted cellular imaging. In addition to iron, other metal ions such as manganese and gadolinium have been encapsulated within the core of ferritin cages. To compare the magnetic properties of ferritin loaded with contrast agents, a protocol for calculating the contrast enhancement power of protein nanocage is required. The contrast enhancement power is demonstrated as relaxivity and can be measured using MRI and solution nuclear magnetic resonance (NMR) methods. In this chapter, we present methods for measuring and calculating the relaxivity of ferritin nanocages loaded with paramagnetic ions in solution (in tube) with NMR and MRI.


Assuntos
Meios de Contraste , Imageamento por Ressonância Magnética , Ferritinas , Ferro , Diferenciação Celular
9.
ACS Appl Mater Interfaces ; 15(43): 50360-50377, 2023 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-37847866

RESUMO

Polyimide (PI) aerogels are promising in various fields of application, ranging from thermal insulators to aerospace. However, they are typically in the form of a bulk monolith, which suffers from a lack of conformability and drapability. Moreover, their electrical conductivity is limited, and they mainly display an insulative behavior. These shortcomings can limit the applications of PI aerogels in energy storage systems, which require ultralightweight flexible conductive films, which at the same time offer high thermal stability, ultralow density, and high surface area. To overcome these obstacles, the present study reports the fabrication of PI-carbon nanotube (PI-CNT) aerogel composite films with varying CNT content prepared through a sol-gel preparation method, followed by a supercritical drying procedure. Compared to pristine PI aerogels, which displayed a large shrinkage and density of 18.3% and 0.12 g cm-3, respectively, the incorporation of only 5 wt % CNTs resulted in a significant reduction of both shrinkage and density to only 11.5% and 0.10 g cm-3, respectively. This suggests the importance of CNTs in improving the dimensional stability of aerogels and creating a robust network. Further characterizations showed that incorporation of 5 wt % CNTs also resulted in the highest pore volume (1.25 cm3 g-1), highest surface area (324 m2 g-1), highest real permittivity (80), highest electrical conductivity (3 × 10-1 S m-1), and ultrahigh service temperature (575 °C). It was also shown that the aerogel films can withstand a large degree of bending, can be twisted, and can be fully rolled with no obvious cracks propagated in the structure. The combined outstanding properties of the developed aerogel composite films make them promising potential candidates for supercapacitor electrodes. Therefore, the electrochemical performance of the devices based on aerogel electrodes was further studied. The device demonstrated a high energy density of 2.6 Wh kg-1 at a power density of 303.8 W kg-1. The total capacitance after 5000 cycles was 91.8% of the initial capacitance, which indicated excellent stability and durability of the device. Overall, this work provides a facile yet effective methodology for the development of high-performance aerogel materials for energy storage applications.

10.
Environ Sci Pollut Res Int ; 30(55): 116804-116830, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36513900

RESUMO

The Hindon River is the main tributary of river Yamuna and it is a significant source of surface water, which flows through the major cities of western Uttar Pradesh, India. The indiscriminate development of industries and urbanization along river basin coupled with rapid population growths contribute various amounts of pollutant in the river. Therefore, the present study was conducted to assess the spatial-temporal variability of river water quality (seventeen physicochemical parameters and eight heavy metals) during pre- and post-monsoon seasons for 5 years data at 19 sampling sites along the river stretch. Indices associated with water quality and heavy metals were computed to scale the accurate state of risk associated to its use for drinking and irrigation. During the pre- and post-monsoon seasons, only four sites were found having safe water quality index (WQI) values. The mean heavy metal concentrations are found in order of Zn > Fe > Pb > Cu > Cr > Cd > Ni > Mn. Considering the spatial and temporal distribution, the study benchmarked the water quality of Hindon River for priority attention.


Assuntos
Metais Pesados , Poluentes Químicos da Água , Qualidade da Água , Monitoramento Ambiental , Rios , Benchmarking , Poluentes Químicos da Água/análise , Índia , Metais Pesados/análise , Medição de Risco
11.
ACS Appl Mater Interfaces ; 15(4): 5086-5098, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36669233

RESUMO

High-performance energy storage devices (HPEDs) play a critical role in the realization of clean energy and thus enable the overarching pursuit of nonpolluting, green technologies. Supercapacitors are one class of such lucrative HPEDs; however, a serious limiting factor of supercapacitor technology is its sub-par energy density. This report presents hitherto unchartered pathway of physical deformation, chemical dealloying, and microstructure engineering to produce ultrahigh-capacitance, energy-dense NiMn alloy electrodes. The activated electrode delivered an ultrahigh specific-capacitance of 2700 F/cm3 at 0.5 A/cm3. The symmetric device showcased an excellent energy density of 96.94 Wh/L and a remarkable cycle life of 95% retention after 10,000 cycles. Transmission electron microscopy and atom probe tomography studies revealed the evolution of a unique hierarchical microstructure comprising fine Ni/NiMnO3 nanoligaments within MnO2-rich nanoflakes. Theoretical analysis using density functional theory showed semimetallic nature of the nanoscaled oxygen-vacancy-rich NiMnO3 structure, highlighting enhanced carrier concentration and electronic conductivity of the active region. Furthermore, the geometrical model of NiMnO3 crystals revealed relatively large voids, likely providing channels for the ion intercalation/de-intercalation. The current processing approach is highly adaptable and can be applied to a wide range of material systems for designing highly efficient electrodes for energy-storage devices.

12.
Indian J Chest Dis Allied Sci ; 54(3): 201-3, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23008931

RESUMO

An intracardiac myxoma is the most common tumour of the heart with an estimated incidence of 0.5 per million population per year. Extensive calcification is rare in these tumours. We describe a rare case of a large left atrial myxoma, visible on the chest radiograph, with extensive calcification and osseous metaplasia.


Assuntos
Calcinose/patologia , Neoplasias Cardíacas/patologia , Mixoma/patologia , Feminino , Átrios do Coração , Neoplasias Cardíacas/cirurgia , Humanos , Pessoa de Meia-Idade , Mixoma/cirurgia , Ossificação Heterotópica/patologia
13.
Indian J Otolaryngol Head Neck Surg ; 74(Suppl 1): 153-159, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36032904

RESUMO

Diseases of adenoids are commonly observed in children. It indirectly leads to pathology in the middle ear cleft. It has been demonstrated both by radiological techniques and middle ear pressure studies that adenoids can and do obstruct the Eustachian Tube. The Adenoid-Nasopharyngeal Ratio (ANR), can offer a simple arithmetic measure of nasopharyngeal obstruction. Coupled with tympanometry, it also predicts the degree to which the middle ear is affected. Multicentric study done at two centres in India. 230 patients were studied. Children were in the age group of 5-14 years. The nasopharyngeal and adenoid dimensions were measured separately using the Fujioka method. The adenoid-nasopharyngeal ratio was derived by the arithmetic method. All patients were also subjected to tympanometry. ANR decreased from 0.728 to 0.663 with an increase in age from 5 to 12 years. ANR between 0.701-0.800 had maximum number of Type B (140) and Type C (71) Tympanogram whereas between 0.801 and 0.900, all Tympanogram were found to be of Type B or Type C with none belonging to Type A. Using ANR and Tympanometry, the effects of the adenoids on the middle ear can be quantified indirectly. Both these modalities are easily available, economical, safe and can be performed at the Out Patient Level. This aids in timely and appropriate management thus preventing discomforting symptoms caused by the adenoids locally and also the morbidity caused to the middle ear in the long term.

14.
Front Physiol ; 13: 826122, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35222088

RESUMO

Alpha-calcitonin gene-related peptide (α-CGRP) is a vasodilator neuropeptide of the calcitonin gene family. Pharmacological and gene knock-out studies have established a significant role of α-CGRP in normal and pathophysiological states, particularly in cardiovascular disease and migraines. α-CGRP knock-out mice with transverse aortic constriction (TAC)-induced pressure-overload heart failure have higher mortality rates and exhibit higher levels of cardiac fibrosis, inflammation, oxidative stress, and cell death compared to the wild-type TAC-mice. However, administration of α-CGRP, either in its native- or modified-form, improves cardiac function at the pathophysiological level, and significantly protects the heart from the adverse effects of heart failure and hypertension. Similar cardioprotective effects of the peptide were demonstrated in pressure-overload heart failure mice when α-CGRP was delivered using an alginate microcapsules-based drug delivery system. In contrast to cardiovascular disease, an elevated level of α-CGRP causes migraine-related headaches, thus the use of α-CGRP antagonists that block the interaction of the peptide to its receptor are beneficial in reducing chronic and episodic migraine headaches. Currently, several α-CGRP antagonists are being used as migraine treatments or in clinical trials for migraine pain management. Overall, agonists and antagonists of α-CGRP are clinically relevant to treat and prevent cardiovascular disease and migraine pain, respectively. This review focuses on the pharmacological and therapeutic significance of α-CGRP-agonists and -antagonists in various diseases, particularly in cardiac diseases and migraine pain.

15.
Mol Pharmacol ; 80(3): 446-57, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21697273

RESUMO

In humans, ethanol exposure during pregnancy produces a wide range of abnormalities in infants collectively known as fetal alcohol spectrum disorders (FASD). Neuronal malformations in FASD manifest as postnatal behavioral and functional disturbances. The cerebellum is particularly sensitive to ethanol during development. In a rodent model of FASD, high doses of ethanol (blood ethanol concentration 80 mM) induces neuronal cell death in the cerebellum. However, information on potential agent(s) that may protect the cerebellum against the toxic effects of ethanol is lacking. Growing evidence suggests that a polyphenolic compound, resveratrol, has antioxidant and neuroprotective properties. Here we studied whether resveratrol (3,5,4'-trihydroxy-trans-stilbene), a phytoalexin found in red grapes and blueberries, protects the cerebellar granule neurons against ethanol-induced cell death. In the present study, we showed that administration of resveratrol (100 mg/kg) to postnatal day 7 rat pups prevents ethanol-induced apoptosis by scavenging reactive oxygen species in the external granule layer of the cerebellum and increases the survival of cerebellar granule cells. It restores ethanol-induced changes in the level of transcription factor nuclear factor-erythroid derived 2-like 2 (nfe2l2, also known as Nrf2) in the nucleus. This in turn retains the expression and activity of its downstream gene targets such as NADPH quinine oxidoreductase 1 and superoxide dismutase in cerebellum of ethanol-exposed pups. These studies indicate that resveratrol exhibits neuroprotective effects in cerebellum by acting at redox regulating proteins in a rodent model of FASD.


Assuntos
Cerebelo/efeitos dos fármacos , Modelos Animais de Doenças , Etanol/toxicidade , Transtornos do Espectro Alcoólico Fetal/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estilbenos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Cerebelo/metabolismo , Cerebelo/patologia , Relação Dose-Resposta a Droga , Feminino , Transtornos do Espectro Alcoólico Fetal/etiologia , Transtornos do Espectro Alcoólico Fetal/patologia , Marcação In Situ das Extremidades Cortadas , Gravidez , Ratos , Ratos Long-Evans , Espécies Reativas de Oxigênio/metabolismo , Resveratrol
16.
Mol Microbiol ; 75(4): 942-56, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20487289

RESUMO

The apicoplast of Plasmodium falciparum carries a 35 kb circular genome (plDNA) that replicates at the late trophozoite stage of the parasite intraerythocytic cycle. plDNA replication proceeds predominantly via a d-loop/bi-directional ori mechanism with replication ori localized within inverted repeat region. Although replication of the apicoplast genome is a validated drug target, the proteins involved in the replication process are only partially characterized. We analysed DNA-protein interactions at a plDNA replication ori region and report the identification of a nuclear-encoded DnaJ homologue that binds directly to ori elements of the plDNA molecule. PfDnaJ(A) interacted with the minor groove of the DNA double-helix and recognized a 13 bp sequence within the ori. Inhibition of binding with anti-PfDnaJ(A) antibodies confirmed identity of the protein in DNA-binding experiments with organellar protein fractions. The DNA-binding domain of the approximately 69 kDa PfDnaJ(A) lay within the N-terminal 38 kDa region that carries DnaJ signature motifs. In contrast to PfDnaJ(A) in parasite organellar fractions, the recombinant protein interacted with DNA in a sequence non-specific manner. Our results suggest a role for PfDnaJ(A) in replication/repair of the apicoplast genome.


Assuntos
Proteínas de Choque Térmico HSP40/metabolismo , Plasmodium falciparum/metabolismo , Plastídeos/metabolismo , Proteínas de Protozoários/metabolismo , Origem de Replicação , Trofozoítos/metabolismo , Sequência de Bases , Núcleo Celular/genética , Replicação do DNA , Genoma de Protozoário , Plasmodium falciparum/citologia , Plasmodium falciparum/genética , Plasmodium falciparum/crescimento & desenvolvimento
19.
Cureus ; 13(8): e17625, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34646675

RESUMO

Several tumors arise from different structures within the mediastinum. Although each type of mediastinal tumor has a predilection for a specific compartment, the progression of growth from one compartment to another can occur. The anterior mediastinum is the site of several tumors that pose interesting diagnostic and therapeutic challenges to thoracic surgeons. The anterior mediastinum is the seat of the majority of neoplastic growths within the mediastinum. Thymomas and lymphomas are the most common pathologies of the anterior mediastinum. Tumors of mesenchymal origin (hemangioma, lymphangioma, lipomas) and their malignant counterparts may occur in any of the mediastinal compartments. Less common tumors of the anterior mediastinal compartment are ectopic thyroid and parathyroid tumors, germ cell tumors, mesenchymal origin tumors, hemangiomas, and cervicomediastinal hygromas. Most of the mediastinal growths usually remain clinically silent until they become large and cause compressive symptoms. Here, we present a case series of five anterior mediastinal tumors consisting of solitary benign teratoma, fibrous benign tumor, malignant fibrosarcoma, hamartomatous chondroma, and malignant thymoma.

20.
Int J Biol Macromol ; 179: 144-153, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33667556

RESUMO

L. major acyl carrier protein (ACP) is a mitochondrial protein, involved in fatty acid biosynthesis. The protein is expressed as an apo-protein, and post-translationally modified at Ser 37 by a 4'-Phosphopantetheinyl transferase. Crystal structure of the apo-form of the protein at pH 5.5 suggests a four helix bundle fold, typical of ACP's. However, upon lowering the pH to 5.0, it undergoes a conformational transition from α-helix to ß-sheet, and displays amyloid like properties. When left for a few days at room temperature at this pH, the protein forms fibrils, visible under Transmission electron microscopy (TEM). Using an approach combining NMR, biophysical techniques, and mutagenesis, we have identified a Phe residue present on helix II of ACP, liable for this change. Phosphopantetheinylation of LmACP, or mutation of Phe 45 to the corresponding residue in E. coli ACP (methionine), slows down the conformational change. Conversely, substitution of methionine 44 of E. coli ACP with a phenylalanine, causes enhanced ThT binding. Thus, we demonstrate the unique property of an exposed Phe in inducing, and phophopantetheine in inhibiting amyloidogenesis. Taken together, our study adds L. major acyl carrier protein to the list of ACPs that act as pH sensors.


Assuntos
Proteína de Transporte de Acila/química , Leishmania major/química , Panteteína/análogos & derivados , Fenilalanina/química , Agregados Proteicos , Proteínas de Protozoários/química , Panteteína/química
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