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2.
Nat Immunol ; 20(7): 824-834, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31209403

RESUMO

Multiple genome-wide studies have identified associations between outcome of human immunodeficiency virus (HIV) infection and polymorphisms in and around the gene encoding the HIV co-receptor CCR5, but the functional basis for the strongest of these associations, rs1015164A/G, is unknown. We found that rs1015164 marks variation in an activating transcription factor 1 binding site that controls expression of the antisense long noncoding RNA (lncRNA) CCR5AS. Knockdown or enhancement of CCR5AS expression resulted in a corresponding change in CCR5 expression on CD4+ T cells. CCR5AS interfered with interactions between the RNA-binding protein Raly and the CCR5 3' untranslated region, protecting CCR5 messenger RNA from Raly-mediated degradation. Reduction in CCR5 expression through inhibition of CCR5AS diminished infection of CD4+ T cells with CCR5-tropic HIV in vitro. These data represent a rare determination of the functional importance of a genome-wide disease association where expression of a lncRNA affects HIV infection and disease progression.


Assuntos
Regulação da Expressão Gênica , Variação Genética , Infecções por HIV/genética , Infecções por HIV/virologia , HIV-1 , RNA Antissenso/genética , RNA Longo não Codificante/genética , Receptores CCR5/genética , Regiões 3' não Traduzidas , Alelos , Biomarcadores , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/virologia , Membrana Celular/metabolismo , Genes Reporter , Genótipo , Infecções por HIV/metabolismo , Humanos , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único , Grupos Populacionais/genética , Prognóstico , Estabilidade de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores CCR5/metabolismo , Carga Viral
3.
Prostaglandins Other Lipid Mediat ; 171: 106806, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38185280

RESUMO

Bacterial endophthalmitis is a blinding infectious disease typically acquired during ocular surgery. We previously reported significant alterations in retinal metabolism during Staphylococcus (S) aureus endophthalmitis. However, the changes in retinal lipid composition during endophthalmitis are unknown. Here, using a mouse model of S. aureus endophthalmitis and an untargeted lipidomic approach, we comprehensively analyzed temporal alterations in total lipids and oxylipin in retina. Our data showed a time-dependent increase in the levels of lipid classes, sphingolipids, glycerolipids, sterols, and non-esterified fatty acids, whereas levels of phospholipids decreased. Among lipid subclasses, phosphatidylcholine decreased over time. The oxylipin analysis revealed increased prostaglandin-E2, hydroxyeicosatetraenoic acids, docosahexaenoic acid, eicosapentaenoic acid, and α-linolenic acid. In-vitro studies using mouse bone marrow-derived macrophages showed increased lipid droplets and lipid-peroxide formation in response to S. aureus infection. Collectively, these findings suggest that S. aureus-infection alters the retinal lipid profile, which may contribute to the pathogenesis of bacterial endophthalmitis.


Assuntos
Endoftalmite , Staphylococcus aureus , Humanos , Staphylococcus aureus/fisiologia , Lipidômica , Oxilipinas , Endoftalmite/microbiologia , Endoftalmite/patologia , Retina/patologia
4.
Cell Mol Life Sci ; 80(10): 309, 2023 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-37770649

RESUMO

Bacterial endophthalmitis is a severe complication of eye surgeries that can lead to vision loss. Current treatment involves intravitreal antibiotic injections that control bacterial growth but not inflammation. To identify newer therapeutic targets to promote inflammation resolution in endophthalmitis, we recently employed an untargeted metabolomics approach. This led to the discovery that the levels of S-nitroso-L-glutathione (GSNO) were significantly reduced in an experimental murine Staphylococcus aureus (SA) endophthalmitis model. In this study, we tested the hypothesis whether GSNO supplementation via different routes (oral, intravitreal) provides protection during bacterial endophthalmitis. Our results show that prophylactic administration of GSNO via intravitreal injections ameliorated SA endophthalmitis. Therapeutically, oral administration of GSNO was found to be most effective in reducing intraocular inflammation and bacterial burden. Moreover, oral GSNO treatment synergized with intravitreal antibiotic injections in reducing the severity of endophthalmitis. Furthermore, in vitro experiments using cultured human retinal Muller glia and retinal pigment epithelial (RPE) cells showed that GSNO treatment reduced SA-induced inflammatory mediators and cell death. Notably, both in-vivo and ex-vivo data showed that GSNO strengthened the outer blood-retinal barrier during endophthalmitis. Collectively, our study demonstrates GSNO as a potential therapeutic agent for the treatment of intraocular infections due to its dual anti-inflammatory and cytoprotective properties.


Assuntos
Endoftalmite , Infecções Oculares Bacterianas , Infecções Estafilocócicas , Camundongos , Humanos , Animais , Modelos Animais de Doenças , Endoftalmite/tratamento farmacológico , Endoftalmite/microbiologia , Infecções Estafilocócicas/tratamento farmacológico , Inflamação/tratamento farmacológico , Staphylococcus aureus , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Glutationa , Infecções Oculares Bacterianas/tratamento farmacológico , Infecções Oculares Bacterianas/microbiologia , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Administração Oral
5.
Infect Immun ; 91(1): e0025222, 2023 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-36515524

RESUMO

Despite an important link between the gut and ocular health, the role of the gut-eye axis remains elusive in ocular infections. In this study, we investigated the role of butyrate, a gut microbial metabolite, in the pathobiology of intraocular bacterial (Staphylococcus aureus) infection, endophthalmitis. We found that intravitreal administration of butyrate derivatives, sodium butyrate (NaB), or phenylbutyrate (PBA) reduced intraocular bacterial growth and retinal inflammatory response. The ocular tissue architecture and retinal function were preserved in butyrate-treated eyes. In cultured mouse bone marrow-derived macrophages (BMDMs) and human retinal Müller glia, NaB or PBA treatment reduced S. aureus-induced inflammatory response by inhibiting NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome. However, in vivo data showed NLRP3-independent effects of butyrate. The butyrate-treated mouse retina and cells exhibited induced expression of antimicrobial molecules CRAMP (LL37) and S100A7/A8, resulting in increased bacterial phagocytosis and killing. Moreover, butyrate treatment enhanced AMP-activated protein kinase (AMPK)-dependent autophagy and promoted the co-localization of CRAMP in autophagosomes, indicating autophagy-mediated bacterial killing. Furthermore, pharmacological inhibition of autophagy in mice revealed its role in butyrate-mediated protection. Finally, butyrate exhibited synergy with antibiotic in promoting endophthalmitis resolution. Collectively, our study demonstrated the protective mechanisms of butyrate in ameliorating bacterial endophthalmitis. Therefore, butyrate derivatives could be explored as immunomodulatory and anti-bacterial therapeutics to improve visual outcomes in ocular bacterial infections.


Assuntos
Endoftalmite , Infecções Oculares Bacterianas , Infecções Estafilocócicas , Humanos , Animais , Camundongos , Butiratos/farmacologia , Staphylococcus aureus/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Autofagia , Inflamassomos , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Endoftalmite/tratamento farmacológico , Endoftalmite/microbiologia , Camundongos Endogâmicos C57BL
6.
Infect Immun ; 90(5): e0010322, 2022 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-35404106

RESUMO

Staphylococcal endophthalmitis is one of the leading causes of blindness following ocular surgery and trauma. Dysregulated inflammation during bacterial endophthalmitis causes host-induced inflammatory damage and vision loss if it remains unchecked. Emerging evidence indicates that inflammasome plays a critical role in regulating innate immunity in various infectious and inflammatory diseases. However, the role of the inflammasome in endophthalmitis remains elusive. Here, using a mouse model of Staphylococcus (S) aureus endophthalmitis, we show that NLRP3/ASC/Caspase-1 signaling regulates IL-1ß production in endophthalmitis. We also show that S. aureus and its cell wall components and toxins induce the activation of the NLRP3 inflammasome complex in mouse eyes. Moreover, we found that both infiltrating neutrophils and retinal microglia contribute toward NLRP3 activation and IL-1ß production in S. aureus-infected eyes. Furthermore, our data using NLRP3-/- and IL-1ß-/- mice revealed that NLRP3 and IL-1ß deficiency leads to increased intraocular bacterial burden and retinal tissue damage. Altogether, our study demonstrated an essential role of NLRP3 inflammasome activation in regulating innate immune responses in bacterial endophthalmitis.


Assuntos
Endoftalmite , Infecções Estafilocócicas , Caspase 1 , Humanos , Inflamassomos , Interleucina-1beta/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus
7.
Cytokine ; 133: 155177, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32593952

RESUMO

OBJECTIVES: To study the natural course of patients with acute pancreatitis (AP) with acute kidney injury (AKI) and their cytokine profile. METHODS: Natural course of patients with AP and AKI was studied in 97 individuals. Levels of TNFα, IL-6, IL-10, IL-8 and IL-1ß were measured at presentation and at 72 h in patients who developed AKI. RESULTS: Amongst the entire cohort, 16.4% patients developed AKI (persistent AKI - 11 patients, transient AKI - 5 patients). Mortality rate was 25% amongst patients with AKI. Levels of IL-6 (p = 0.035) and IL-8 (p = 0.002) were found to be significantly higher in the AKI group. On multivariate analysis, IL-8 levels at baseline were found to be an independent predictor of AKI. AKI group had significant rise of TNF-α (P < 0.001), IL-6 (P < 0.001) and IL- 1ß (P < 0.001) on day 3 whereas persistent-AKI group had significant rise of TNF-α (p = 0.031), IL-6 (p = 0.001) and IL-1ß on day 3 and significant decline of IL-10 (p = 0.015). Using a cut-off of 105 pg/ml, IL-8 levels at baseline could predict AKI with a sensitivity of 87.5% and specificity of 59.2%, with area under the curve being 0.744 (p = 0.002). CONCLUSION: AP patients developing AKI have poor prognosis. IL-8 levels can predict AKI in patients with AP.


Assuntos
Injúria Renal Aguda/metabolismo , Citocinas/metabolismo , Pancreatite/metabolismo , Adulto , Feminino , Humanos , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Masculino , Estudos Prospectivos , Fator de Necrose Tumoral alfa/metabolismo
8.
Exp Eye Res ; 197: 108079, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32454039

RESUMO

Previously, we have shown that Staphylococcus (S) aureus induces a glycolytic response in retinal residential (microglia) and infiltrated cells (neutrophils and macrophages) during endophthalmitis. In this study, we sought to investigate the physiological role of glycolysis in bacterial endophthalmitis using a glycolytic inhibitor, 2-deoxyglucose (2DG). Our data showed that 2DG treatment attenuated the inflammatory responses of mouse bone marrow-derived macrophages (BMDM) and neutrophils (BMDN) when challenged with either live or heat-killed S. aureus (HKSA). Among the inflammatory mediators, 2DG caused a significant reduction in levels of cytokines (TNF-α, IL-1ß, IL-6) and chemokines (CXCL1 and CXCL2). Western blot analysis of 2DG treated cells showed downregulation of bacterial-induced MEK/ERK pathways. In vivo, intravitreal administration of 2DG both pre- and post-bacterial infection resulted in a significant reduction in intraocular inflammation in C57BL/6 mouse eyes and downregulation of ERK phosphorylation in retinal tissue. Collectively, our study demonstrates that 2DG attenuates inflammatory response in bacterial endophthalmitis and cultured innate immune cells via inhibition of ERK signaling. Thus glycolytic inhibitors in combination with antibiotics could mitigate inflammation-mediated tissue damage in ocular infections.


Assuntos
Desoxiglucose/farmacologia , Endoftalmite/tratamento farmacológico , Infecções Oculares Bacterianas/tratamento farmacológico , Imunidade Inata/efeitos dos fármacos , Infecções Estafilocócicas/tratamento farmacológico , Animais , Antimetabólitos/farmacologia , Western Blotting , Modelos Animais de Doenças , Endoftalmite/imunologia , Endoftalmite/patologia , Ensaio de Imunoadsorção Enzimática , Infecções Oculares Bacterianas/imunologia , Infecções Oculares Bacterianas/patologia , Feminino , Glicólise/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/patologia
9.
J Immunol ; 199(11): 3892-3899, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29055006

RESUMO

Genomic variation in the untranslated region (UTR) has been shown to influence HLA class I expression level and associate with disease outcomes. Sequencing of the 3'UTR of common HLA-A alleles indicated the presence of two polyadenylation signals (PAS). The proximal PAS is conserved, whereas the distal PAS is disrupted within certain alleles by sequence variants. Using 3'RACE, we confirmed expression of two distinct forms of the HLA-A 3'UTR based on use of either the proximal or the distal PAS, which differ in length by 100 bp. Specific HLA-A alleles varied in the usage of the proximal versus distal PAS, with some alleles using only the proximal PAS, and others using both the proximal and distal PAS to differing degrees. We show that the short and the long 3'UTR produced similar mRNA expression levels. However, the long 3'UTR conferred lower luciferase activity as compared with the short form, indicating translation inhibition of the long 3'UTR. RNA affinity pull-down followed by mass spectrometry analysis as well as RNA coimmunoprecipitation indicated differential binding of Syncrip to the long versus short 3'UTR. Depletion of Syncrip by small interfering RNA increased surface expression of an HLA-A allotype that uses primarily the long 3'UTR, whereas an allotype expressing only the short form was unaffected. Furthermore, specific blocking of the proximal 3'UTR reduced surface expression without decreasing mRNA expression. These data demonstrate HLA-A allele-specific variation in PAS usage, which modulates their cell surface expression posttranscriptionally.


Assuntos
Regiões 3' não Traduzidas/genética , Antígenos HLA-A/genética , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Isoformas de Proteínas/genética , Sítios de Splice de RNA/genética , Motivos de Ligação ao RNA/genética , Regulação da Expressão Gênica , Genótipo , Ribonucleoproteínas Nucleares Heterogêneas/genética , Humanos , Células Jurkat , Poliadenilação , Polimorfismo Genético , Ligação Proteica , Processamento Pós-Transcricional do RNA , RNA Interferente Pequeno/genética
10.
J Sci Food Agric ; 99(11): 5073-5082, 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-30980532

RESUMO

BACKGROUND: Pomegranate fruit is an excellent source of bioactive polyphenolics, known to contribute significantly to human health. India is the largest producer of pomegranate in the world and produces the finest quality fruit with highly desirable consumer traits such as soft seeds, low acidity, and attractive fruit and aril color. Knowledge of the extent of variation in key metabolites (sugars, organic acids, phenolics, and anthocyanins) is key to selecting superior genotypes for germplasm improvement. Relevant information with respect to Indian genotypes is scarce. The present study therefore aims to evaluate quantitatively important metabolites in some cultivars and elite germplasm of pomegranate in India. RESULTS: Identification and quantification of primary and secondary metabolites such as sugars, organic acids, vitamin C, polyphenolics, and anthocyanins were conducted using a liquid chromatography - mass spectrometry (LC-MS) platform. Fructose and citric acid were the predominant sugar and organic acid, respectively. Wild genotypes had significantly higher concentrations of organic acids, antioxidant activity, and phenolics, namely punicalagin, ellagic acid, sinapic, and ferulic acid. CONCLUSION: Cyanidin and delphinidin derivatives of anthocyanins were more abundant in red aril commercial genotypes. Results suggest that wild-sour accessions represent a rich source of polyphenolics that can be utilized in future breeding programs to breed healthier varieties, food supplements, and pharmaceutical products. © 2019 Society of Chemical Industry.


Assuntos
Células Germinativas Vegetais/classificação , Lythraceae/química , Lythraceae/metabolismo , Antocianinas/análise , Antocianinas/metabolismo , Ácido Ascórbico/análise , Ácido Ascórbico/metabolismo , Cromatografia Líquida de Alta Pressão , Cor , Frutas/química , Frutas/classificação , Frutas/genética , Frutas/metabolismo , Genótipo , Células Germinativas Vegetais/metabolismo , Índia , Lythraceae/classificação , Lythraceae/genética , Espectrometria de Massas , Polifenóis/análise , Polifenóis/metabolismo , Metabolismo Secundário , Sementes/química , Sementes/genética , Sementes/crescimento & desenvolvimento , Sementes/metabolismo , Açúcares/análise , Açúcares/metabolismo
11.
Cytokine ; 77: 135-44, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26579633

RESUMO

Rate of HIV disease progression varies considerably among individuals, host genetic makeup be one of the possible reasons. We aimed to determine association of functional single nucleotide polymorphism (SNPs), (-179G/T and +874T/A) in IFN-γ and (-1082A/G, -819C/T and -592C/A) in IL-10 genes, with the rate of disease progression or susceptibility to HIV infection. Therapy naïve HIV infected individuals from North India, categorized as slow progressors or fast progressors and HIV exposed seronegative individuals were recruited for this study. Genotyping results revealed significantly higher frequencies of low producer AA genotype at +874T/A in IFN-γ gene and -592C/A position in IL-10 gene in FPs (p<0.002). Multifactor dimensional reduction (MDR) analysis revealed this to be a high risk combination for faster disease progression in HIV-1 infected individuals. Low producer AA genotype carriers at +874T/A in IFN-γ gene produced significantly low amounts of cellular IFN-γ. Low producing haplotype 'ATA' at -1082, -819 and -592 loci in IL-10 gene was significantly over-represented in FPs as compared to SPs (p<0.01) and these individuals showed poor response to therapy in terms of CD4 count gains after one year of ART, compared to high producing haplotype (GCC) carriers. Thus, a combination of genetic variations in IFN-γ and IL-10 cytokine genes in a single host associate with HIV disease progression and may help clinicians to better manage the HIV disease if known earlier.


Assuntos
Predisposição Genética para Doença/genética , Infecções por HIV/genética , Interferon gama/genética , Interleucina-10/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Alelos , Antirretrovirais/uso terapêutico , Contagem de Linfócito CD4 , DNA Viral/genética , Progressão da Doença , Feminino , Frequência do Gene , Genótipo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/genética , HIV-1/fisiologia , Haplótipos , Humanos , Interferon gama/sangue , Interferon gama/metabolismo , Interleucina-10/sangue , Interleucina-10/metabolismo , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Fatores de Risco , Resultado do Tratamento , Adulto Jovem
12.
Artigo em Inglês | MEDLINE | ID: mdl-38351693

RESUMO

In recent years, the growing demand for herbal-based formulations, including functional foods, has acquired significant attention. This study highlights historical, botanical, ecological, and phytochemical descriptions and different extraction mechanisms of Ocimum sanctum utilized in its processing. Besides this, it explores the utilization of Ocimum sanctum as a functional food ingredient in various food products such as bakery products (biscuits, bread), dairy products (herbal milk, cheese), and beverages (tea, juice, wine) while focusing on their evaluation parameters, preparation techniques, and pharmacological activities. In terms of other pharmacological properties, Ocimum sanctum-infused functional foods exhibited cognitiveenhancing properties, adaptogenic qualities, anti-obesity effects, gastroprotective, antiinflammatory, hypoglycemic, and immuno-modulatory effects. Thus, the diverse properties of Ocimum sanctum offer exciting opportunities for the development of functional foods that can promote specific health issues, so future research should focus on developing and analyzing novel Ocimum sanctum-based functional foods to meet the growing demand of the functional food industry.

13.
Ann Noninvasive Electrocardiol ; 18(3): 299-303, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23714091

RESUMO

A 78-year-old male was referred for exercise stress testing. He developed incomplete right bundle branch block during first stage of exercise and later on developed incomplete and complete right bundle branch block on alternate beats (2:1). During first minute of recovery he developed complete right bundle branch block on all beats (1:1). At 3 minutes of recovery, baseline electrocardiographic pattern was resumed. Variable degree of right bundle branch block on alternate beats is a rare phenomenon. The plausible mechanisms responsible for this phenomenon are being discussed.


Assuntos
Bloqueio de Ramo/fisiopatologia , Eletrocardiografia , Idoso , Teste de Esforço , Humanos , Masculino
14.
Food Res Int ; 173(Pt 2): 113484, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37803804

RESUMO

Black garlic is rich in brown pigments and Maillard reaction products are known for antioxidant activity and health promoting effects. In the present investigation, we report a facile strategy for fabricating low-fat innovative mayonnaise (IM) using black garlic particles (BGP) as a natural pigment, and a functional ingredient. Whey protein concentrate and high methoxyl pectin at optimized concentrations were utilized for fabricating an IM which served as a control. IM5 and IM10 were ternary composites constituting whey protein, high methoxyl pectin along with BGP (@5 and 10% respectively). The formulation IM10 (BGP @10%) showed high firmness and low spreadability quotient, hence IM5 was taken forward for fabrication for two more variants namely IM-J (using low methoxyl pectin (LMP) from jackfruit peels) and IM-C (LMP from citrus). The effect of BGP and LMP on the functional quality of IM was confirmed through zeta potential, antioxidant activity, textural, rheological, and microscopic evaluation. Fluorescence microscopy confirmed the presence of solid particles over the fat phase of IM, while interaction of pectin and whey proteins was demonstrated through fluorescence emission spectroscopy which clearly displayed stabilization of IM through the formation of Pickering emulsion. Pronounced difference in color and flavor score with BGP established high sensory scores in IM5, IM-J, and IM-C. Rheology supported the stabilizing effects of LMP in IM-J and IM-C in terms of speedy recovery of thixotropy, with recovering storage modulus (G'). Enhanced viscosity of IM-C and IM-J further corroborated the dual effect of LMP and BGP in improving emulsifying and functional quality of IM. Enhanced oxidative stability of IM was established by reduced peroxide and Totox values. Overall our results suggest the promising applications of black garlic as functional ingredient in protein and pectin based Pickering emulsions.


Assuntos
Alho , Emulsões/química , Proteínas do Soro do Leite/química , Antioxidantes , Emulsificantes , Pectinas/química , Reologia
15.
Pharm Biol ; 50(7): 823-7, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22468852

RESUMO

CONTEXT: Eucalyptus has been a source of a number of biologically active compounds. The anti-leishmanial activity of terpenoids from Eucalyptus loxophleba (Benth.) ssp. lissophloia (Myrtaceae) has not yet been investigated. OBJECTIVE: Isolation of the terpenoidal constituents for evaluation of in vitro anti-leishmanial activity against the Leishmania donovani (Dd8 strain) promastigotes. MATERIALS AND METHODS: The chloroform-methanol (8:2) extract of dried leaves of Eucalyptus loxophleba was used to isolate terpenoidal constituents employing solvent partitioning, column chromatography and preparative high performance liquid chromatography and characterized from spectral data. The anti-leishmanial activity of the isolated compounds was tested in vitro using an Alamar blue assay against a culture of L. donovani (Dd8 strain) promastigotes. RESULTS: Two new naturally occurring triterpenes, named loxanic acid and 3-acetyl loxanic acid together with four known ursane triterpenoids and one bis-monoterpene glycoside, cuniloside B isolated from the leaves showed anti-leishmanial activity (IC(50) 133 to 235 µM) against the promastigotes of the tested strain. CONCLUSION: The terpenes isolated from the leaves of E. loxophleba showed moderate anti-leishmanial activity.


Assuntos
Eucalyptus , Leishmania donovani/efeitos dos fármacos , Extratos Vegetais/farmacologia , Triterpenos/farmacologia , Leishmania donovani/fisiologia , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Folhas de Planta , Triterpenos/química , Triterpenos/isolamento & purificação
16.
J Neurosci Rural Pract ; 13(2): 301-306, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35694050

RESUMO

Background Children with epilepsy (CWE) are at high risk of psychopathological problems because of neurobiological, social, and treatment factors. Objectives This study was conducted to estimate the prevalence of psychopathological problems in CWE and their contributing factors. Methods This cross-sectional study was done in pediatric neurology clinic and outpatient department of a government medical college in Northern India. Children between the ages of 4 and 14 years with intelligence quotient > 70 were enrolled; for CWE, the criteria were antiepileptic drugs therapy for more than 6 months and for controls it was being free from any chronic illness. Childhood Psychopathology Measurement Schedule (CPMS) was used for assessing psychopathological problems. Results A total of 135 CWE and 70 controls were enrolled, groups were similar in respect of age, gender, socioeconomic status, and family history. CWE group had significantly high mean ± standard deviation CPMS scores (13.68 ± 10.57) as compared with controls (9.75 ± 7.97) ( p < 0.0001). These scores were particularly high in sectors of low intelligence, conduct disorder, psychotic symptoms, and depression. Academic performance was significantly poor in CWE (39%) versus controls (6%) ( p 0.042). Age of onset, duration, type, and etiology of epilepsy had no significant relation with CPMS scores. Polytherapy and treatment with valproate were associated with high CPMS scores ( p 0.005 and 0.045). Conclusion Psychopathological problems are frequently associated with epilepsy in children and antiepileptic drug therapy might contribute to it.

17.
Microbiol Spectr ; 10(4): e0165822, 2022 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-35913202

RESUMO

Candida albicans is the leading cause of endogenous fungal endophthalmitis; however, its pathobiology studies are limited. Moreover, the contribution of host factors in the pathogenesis of Candida endophthalmitis remains unclear. In the present study, we developed a murine model of C. albicans endogenous endophthalmitis and investigated the molecular pathobiology of ocular candidiasis and blood-retinal barrier permeability. Our data show that intravenous injection of C. albicans in immunocompetent C57BL/6 mice led to endogenous endophthalmitis without causing mortality, and C. albicans was detected in the eyes at 3 days postinfection and persisted for up to 10 days. The intraocular presence of C. albicans coincided with a decrease in retinal function and increased expression of inflammatory mediators (tumor necrosis factor alpha [TNF-α], interleukin 1ß [IL-1ß], MIP2, and KC) and antimicrobial peptides (human ß-defensins [hBDs] and LL37) in mouse retinal tissue. C. albicans infection disrupted the blood-retinal barrier (BRB) by decreasing the expression of tight junction (ZO-1) and adherens junction (E-cadherin, N/R-cadherin) proteins. In vitro studies using human retinal pigment epithelial (ARPE-19) cells showed time-dependent activation of eIF2α, extracellular signal-related kinase (ERK), and NF-κB signaling and decreased activity of AMP-activated protein kinase (AMPK) leading to the induction of an inflammatory response upon C. albicans infection. Moreover, C. albicans-infected cells exhibited increased cellular permeability coinciding with a reduction in cellular junction proteins. Overall, our study provides new insight into the molecular pathogenesis of C. albicans endogenous endophthalmitis. Furthermore, the experimental models developed in the study can be used to identify newer therapeutic targets or test the efficacy of drugs to treat and prevent fungal endophthalmitis. IMPORTANCE Patients with candidemia often experience endophthalmitis, a blinding infectious eye disease. However, the pathogenesis of Candida endophthalmitis is not well understood. Here, using in vivo and in vitro experimental models, we describe events leading to the invasion of Candida into the eye. We show that Candida from the systemic circulation disrupts the protective blood-retinal barrier and causes endogenous endophthalmitis. Our study highlights an important role of retinal pigment epithelial cells in evoking innate inflammatory and antimicrobial responses toward C. albicans infection. This study allows a better understanding of the pathobiology of fungal endophthalmitis, which can lead to the discovery of novel therapeutic targets to treat ocular fungal infections.


Assuntos
Candidíase , Endoftalmite , Infecções Oculares Fúngicas , Animais , Barreira Hematorretiniana/microbiologia , Barreira Hematorretiniana/patologia , Candida , Candida albicans , Endoftalmite/tratamento farmacológico , Endoftalmite/microbiologia , Endoftalmite/patologia , Infecções Oculares Fúngicas/tratamento farmacológico , Infecções Oculares Fúngicas/microbiologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Pigmentos da Retina/uso terapêutico
18.
iScience ; 25(9): 104862, 2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-36034221

RESUMO

Increasing antibiotic resistance among ocular pathogens often results in treatment failure for blinding infections such as endophthalmitis. Hence, newer therapeutics is needed to combat multidrug-resistant infections. Here, we show a drug repurposing approach using a connectivity map based on temporal transcriptomics of Staphylococcus aureus (SA) infected mouse retina. The analysis predicted three non-antibiotic drugs, Dequalinium chloride (DC), Clofilium tosylate (CT), and Glybenclamide (Glb) which reversed the SA infection signatures. Predicted drugs exhibited anti-inflammatory properties in human retinal cells against sensitive and resistant strains of SA. Intravitreal administration of all drugs reduced intraocular inflammation in SA-infected mouse eyes while DC and CT also reduced bacterial burden. Drug treatment improved visual function coinciding with reduced Caspase-3 mediated retinal cell death. Importantly, all drugs exhibited synergy with vancomycin in improving disease outcomes. Overall, our study identified three non-antibiotic drugs and demonstrated their therapeutic and prophylactic efficacies in ameliorating intraocular bacterial infection.

19.
Foods ; 11(10)2022 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-35626980

RESUMO

In this study, we investigated the impact of harvest maturity stages and contrasting growing climates on secondary metabolites in Kinnow mandarin. Fruit samples were harvested at six harvest maturity stages (M1−M6) from two distinct growing locations falling under subtropical−arid (STA) and subtropical−humid (STH) climates. A high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) technique was employed to identify and quantify secondary metabolites in the fruit juice. A total of 31 polyphenolics and 4 limonoids, with significant differences (p < 0.05) in their concentration, were determined. With advancing maturity, phenolic acids and antioxidant activity were found to increase, whereas flavonoids and limonoids decreased in concentration. There was a transient increase in the concentration of some polyphenolics such as hesperidin, naringin, narirutin, naringenin, neoeriocitrin, rutin, nobiletin and tangeretin, and limonoid aglycones such as limonin and nomilin at mid-maturity stage (M3) which coincided with prevailing low temperature and frost events at growing locations. A higher concentration of limonin and polyphenolics was observed for fruit grown under STH climates in comparison to those grown under STA climates. The data indicate that fruit metabolism during advanced stages of maturation under distinct climatic conditions is fundamental to the flavor, nutrition and processing quality of Kinnow mandarin. This information can help in understanding the optimum maturity stage and preferable climate to source fruits with maximum functional compounds, less bitterness and high consumer acceptability.

20.
Indian Heart J ; 63(5): 481-2, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-23550434

RESUMO

Patient presenting with acute lateral wall myocardial infarction was taken up for primary angioplasty. Angiogram revealed a totally occluded left main coronary artery. Thrombosuction revealed a trifurcation with disease at proximal part of all 3 branches. Y-stenting with kissing balloon technique was performed to open anterior descending and ramus branches. Patient was free of angina till 6 months of follow-up. Kissing balloon technique in primary angioplasty of left main artery is reported uncommonly.


Assuntos
Oclusão Coronária/cirurgia , Stents , Angioplastia Coronária com Balão , Oclusão Coronária/complicações , Oclusão Coronária/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/etiologia , Radiografia
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