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1.
Int J Pharm ; 660: 124172, 2024 Jul 20.
Artículo en Inglés | MEDLINE | ID: mdl-38679243

RESUMEN

The goal of this study was to formulate tacrolimus nanogel based on nanostructured lipid carrier (NLC) in order to improve the efficacy, aesthetic, and patient compliance for the treatment of psoriasis. The microemulsion method was used to create phase diagrams and NLCs were prepared using points obtained from the microemulsion region and characterized. The gelling agent carbopol was used to develop an NLC-based nanogel. The pH, drug assay, viscosity, spreadability, and in vitro release of the nanogel, were evaluated. Ex vivo cytotoxicity of the formulation was assessed in murine fibroblast cells. Oxazolone and imiquimod models of psoriasis were used to assess the effectiveness of the nanogel. The NLCs exhibited a submicron particle size of 320 ± 10 nm, a low polydispersity index (<0.3), and a zeta potential of -19.4 mV. Morphological analysis revealed spherical nanoparticles with an encapsulation efficiency of 60 ± 3 %. The nanogel maintained a pH of 6.0 ± 0.5 and possessed a remarkable drug content of 99.73 ± 1.4 %. It exhibited pseudoplastic flow behaviour, ensuring easy spreadability, and demonstrated sustained drug release exceeding 90 % over a 24-hr period. Ex vivo cytotoxicity assessments revealed that the nanogel was safe because no cell death was induced. Nanogel resolved psoriatic blisters, was non-irritating and improved skin elasticity. The favorable properties, safety profile, and remarkable efficacy show the potential of the nanogel as a patient-friendly and effective therapeutic option for psoriasis treatment.


Asunto(s)
Portadores de Fármacos , Liberación de Fármacos , Lípidos , Nanogeles , Psoriasis , Tacrolimus , Psoriasis/tratamiento farmacológico , Animales , Portadores de Fármacos/química , Ratones , Lípidos/química , Lípidos/administración & dosificación , Tacrolimus/administración & dosificación , Tacrolimus/química , Tacrolimus/farmacocinética , Nanogeles/química , Preparaciones de Acción Retardada , Tamaño de la Partícula , Nanoestructuras/química , Nanoestructuras/administración & dosificación , Nanopartículas/química , Inmunosupresores/administración & dosificación , Inmunosupresores/química , Masculino , Imiquimod/administración & dosificación , Fibroblastos/efectos de los fármacos , Química Farmacéutica/métodos , Geles , Polietilenglicoles/química , Polietilenglicoles/administración & dosificación , Polietileneimina
2.
Viruses ; 15(8)2023 07 29.
Artículo en Inglés | MEDLINE | ID: mdl-37631994

RESUMEN

Marek's disease virus (MDV) causes a deadly lymphoproliferative disease in chickens, resulting in huge economic losses in the poultry industry. It has been suggested that MDV suppresses the induction of type I interferons and thus escapes immune control. Cholesterol 25-hydroxylase (CH25H), a gene that encodes an enzyme that catalyses cholesterol to 25-hydroxycholesterol (25-HC), is an interferon-stimulating gene (ISG) known to exert antiviral activities. Other oxysterols, such as 27-hydroxycholesterols (27-HC), have also been shown to exert antiviral activities, and 27-HC is synthesised by the catalysis of cholesterol via the cytochrome P450 enzyme oxidase sterol 27-hydroxylase A1 (CYP27A1). At 24 h post infection (hpi), MDV stimulated a type I interferon (IFN-α) response, which was significantly reduced at 48 and 72 hpi, as detected using the luciferase assay for chicken type I IFNs. Then, using RT-PCR, we demonstrated that chicken type I IFN (IFN-α) upregulates chicken CH25H and CYP27A1 genes in chicken embryo fibroblast (CEF) cells. In parallel, our results demonstrate a moderate and transient upregulation of CH25H at 48 hpi and CYP27A1 at 72hpi in MDV-infected CEF cells. A significant reduction in MDV titer and plaque sizes was observed in CEFs treated with 25-HC or 27-HC in vitro, as demonstrated using a standard plaque assay for MDV. Taken together, our results suggest that 25-HC and 27-HC may be useful antiviral agents to control MDV replication and spread.


Asunto(s)
Interferón Tipo I , Enfermedad de Marek , Animales , Embrión de Pollo , Hidroxicolesteroles/farmacología , Pollos , Interferón-alfa/farmacología , Antivirales/farmacología , Replicación Viral
3.
Vaccines (Basel) ; 11(7)2023 Jul 14.
Artículo en Inglés | MEDLINE | ID: mdl-37515055

RESUMEN

Antibody Dependent Enhancement (ADE) of an infection has been of interest in the investigation of many viruses. It is associated with the severity of the infection. ADE is mediated by non-neutralizing antibodies, antibodies at sub-neutralizing concentrations, or cross-reactive non-neutralizing antibodies. Treatments like plasma therapy, B cell immunizations, and antibody therapies may trigger ADE. It is seen as an impediment to vaccine development as well. In viruses including the Dengue virus (DENV), severe acute respiratory syndrome (SARS) virus, Middle East respiratory syndrome (MERS) virus, human immunodeficiency virus (HIV), Ebola virus, Zika virus, and influenza virus, the likely mechanisms of ADE are postulated and described. ADE improves the likelihood of productively infecting cells that are expressing the complement receptor or the Fc receptor (FcR) rather than the viral receptors. ADE occurs when the FcR, particularly the Fc gamma receptor, and/or complement system, particularly Complement 1q (C1q), allow the entry of the virus-antibody complex into the cell. Moreover, ADE alters the innate immune pathways to escape from lysis, promoting viral replication inside the cell that produces viral particles. This review discusses the involvement of FcR and the downstream immunomodulatory pathways in ADE, the complement system, and innate antiviral signaling pathways modification in ADE and its impact on facilitating viral replication. Additionally, we have outlined the modes of ADE in the cases of different viruses reported until now.

4.
J Control Release ; 349: 812-830, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35914614

RESUMEN

Breast cancer (BC) is a highly diagnosed and topmost cause of death in females worldwide. Drug repurposing (DR) has shown great potential against BC by overcoming major shortcomings of approved anticancer therapeutics. However, poor physicochemical properties, pharmacokinetic performance, stability, non-selectivity to tumors, and side effects are severe hurdles in repurposed drug delivery against BC. The variety of nanocarriers (NCs) has shown great promise in delivering repurposed therapeutics for effective treatment of BC via improving solubility, stability, tumor selectivity and reducing toxicity. Besides, delivering repurposed cargos via theranostic NCs can be helpful in the quick diagnosis and treatment of BC. Localized delivery of repurposed candidates through apt NCs can diminish the systemic side effects and improve anti-tumor effectiveness. However, breast tumor variability and tumor microenvironment have created several challenges to nanoparticulate delivery of repurposed cargos. This review focuses on DR as an ingenious strategy to treat BC and circumvent the drawbacks of approved anticancer therapeutics. Various nanoparticulate avenues delivering repurposed therapeutics, including non-oncology cargos and vaccines to target BC effectively, are discussed along with case studies. Moreover, clinical trial information on repurposed medications and vaccines for the treatment of BC is covered along with various obstacles in nanoparticulate drug delivery against cancer that have been so far identified. In a nutshell, DR and drug delivery of repurposed drugs via NCs appears to be a propitious approach in devastating BC.


Asunto(s)
Neoplasias de la Mama , Vacunas , Neoplasias de la Mama/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Reposicionamiento de Medicamentos , Femenino , Humanos , Preparaciones Farmacéuticas , Microambiente Tumoral , Vacunas/uso terapéutico
5.
Front Microbiol ; 13: 848250, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35663884

RESUMEN

Certain rural and semiurban settings in the Unnao district, Uttar Pradesh, India observed an unprecedented increase in the detection of HIV cases during July 2017. Subsequent investigations through health camps and a follow-up case-control study attributed the outbreak to the unsafe injection exposures during treatment. In this study, we have undertaken a secondary analysis to understand the phylogenetic aspects of the outbreak-associated HIV-1 sequences along with the origin and phylodynamics of these sequences. The initial phylogenetic analysis indicated separate monophyletic grouping and there was no mixing of outbreak-associated sequences with sequences from other parts of India. Transmission network analysis using distance-based and non-distance-based methods revealed the existence of transmission clusters within the monophyletic Unnao clade. The median time to the most recent common ancestor (tMRCA) for sequences from Unnao using the pol gene region was observed to be 2011.87 [95% highest posterior density (HPD): 2010.09-2013.53], while the estimates using envelope (env) gene region sequences traced the tMRCA to 2010.33 (95% HPD: 2007.76-2012.99). Phylodynamics estimates demonstrated that the pace of this local epidemic has slowed down in recent times before the time of sampling, but was certainly on an upward track since its inception till 2014.

6.
AIDS Res Hum Retroviruses ; 37(12): 990-993, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34652967

RESUMEN

Transgenders (TGs) are highly affected by HIV with high prevalence of 3.14% in India. Since 2017, targeted preventive efforts have been initiated by the government and HIV-infected TGs are being provided the antiretroviral (ART) treatment. Information on the primary HIV drug resistance is crucial for appropriate treatment selection to curb further spread of HIV in this population. In this study, we analyzed HIV-1 pol gene sequences from 36 TGs for presence of drug resistance mutations. To our knowledge, this first study from India reports high-level primary drug resistance (13.8%) among the TG population. Mutations M184V, A98G, K103N, G190A, and Y318F associated with resistance to nucleoside reverse transcriptase inhibitor and non-nucleoside reverse transcriptase inhibitors were observed. All pol gene sequences revealed HIV-1 subtype C in all study TG. High-level HIV-1 drug resistance warrant nationwide larger studies on TGs to understand the level of primary ART drug resistance among this population.


Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Personas Transgénero , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Farmacorresistencia Viral/genética , Genotipo , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Transcriptasa Inversa del VIH/genética , VIH-1/genética , Humanos , India , Mutación
7.
J Neuroinflammation ; 18(1): 136, 2021 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-34130738

RESUMEN

BACKGROUND: The crucial role of type I interferon (IFN-I, IFN-α/ß) is well known to control central nervous system (CNS) neuroinflammation caused by neurotrophic flaviviruses such as Japanese encephalitis virus (JEV) and West Nile virus. However, an in-depth analysis of IFN-I signal-dependent cellular factors that govern CNS-restricted tropism in JEV infection in vivo remains to be elucidated. METHODS: Viral dissemination, tissue tropism, and cytokine production were examined in IFN-I signal-competent and -incompetent mice after JEV inoculation in tissues distal from the CNS such as the footpad. Bone marrow (BM) chimeric models were used for defining hematopoietic and tissue-resident cells in viral dissemination and tissue tropism. RESULTS: The paradoxical and interesting finding was that IFN-I signaling was essentially required for CNS neuroinflammation following JEV inoculation in distal footpad tissue. IFN-I signal-competent mice died after a prolonged neurological illness, but IFN-I signal-incompetent mice all succumbed without neurological signs. Rather, IFN-I signal-incompetent mice developed hemorrhage-like disease as evidenced by thrombocytopenia, functional injury of the liver and kidney, increased vascular leakage, and excessive cytokine production. This hemorrhage-like disease was closely associated with quick viral dissemination and impaired IFN-I innate responses before invasion of JEV into the CNS. Using bone marrow (BM) chimeric models, we found that intrinsic IFN-I signaling in tissue-resident cells in peripheral organs played a major role in inducing the hemorrhage-like disease because IFN-I signal-incompetent recipients of BM cells from IFN-I signal-competent mice showed enhanced viral dissemination, uncontrolled cytokine production, and increased vascular leakage. IFN-I signal-deficient hepatocytes and enterocytes were permissive to JEV replication with impaired induction of antiviral IFN-stimulated genes, and neuron cells derived from both IFN-I signal-competent and -incompetent mice were vulnerable to JEV replication. Finally, circulating CD11b+Ly-6C+ monocytes infiltrated into the distal tissues inoculated by JEV participated in quick viral dissemination to peripheral organs of IFN-I signal-incompetent mice at an early stage. CONCLUSION: An IFN-I signal-dependent model is proposed to demonstrate how CD11b+Ly-6C+ monocytes are involved in restricting the tissue tropism of JEV to the CNS.


Asunto(s)
Antígeno CD11b/inmunología , Virus de la Encefalitis Japonesa (Especie)/inmunología , Interferón Tipo I/inmunología , Interferón Tipo I/metabolismo , Monocitos/inmunología , Monocitos/microbiología , Receptor de Interferón alfa y beta , Animales , Sistema Nervioso Central/microbiología , Sistema Nervioso Central/patología , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/microbiología , Modelos Animales de Enfermedad , Virus de la Encefalitis Japonesa (Especie)/patogenicidad , Encefalitis Japonesa/inmunología , Encefalitis Japonesa/microbiología , Hemorragia/inmunología , Hemorragia/microbiología , Interacciones Huésped-Patógeno , Mediadores de Inflamación/inmunología , Tejido Linfoide/inmunología , Tejido Linfoide/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptor de Interferón alfa y beta/genética , Receptor de Interferón alfa y beta/inmunología , Receptor de Interferón alfa y beta/metabolismo , Transducción de Señal/inmunología , Tropismo Viral
8.
Retrovirology ; 18(1): 12, 2021 05 14.
Artículo en Inglés | MEDLINE | ID: mdl-33990195

RESUMEN

BACKGROUND: The potential use of the broadly neutralizing monoclonal antibodies (bnAbs) towards prophylaxis and treatment to HIV-1 is currently being explored. While a number of promising bnAbs have been discovered and a few of them have progressed towards clinical development, their extent of neutralization coverage with respect to global HIV-1 variants given the existence of genetically distinct subtypes and recombinants circulating globally is not clearly known. In the present study, we examined the variation in the neutralization susceptibility of pseudoviruses expressing 71 full length primary HIV-1 subtype C envs obtained from limited cross-sectional individuals over different time points against four bnAbs that target gp120 with distinct specificities: VRC01, CAP256-VRC26.25, PGDM1400 and PGT121. RESULTS: We found significant variations in the susceptibility of Indian clade C to these four bnAbs. These variations were found to be distinct to that observed in African subtype C based on the existing datasets and concordant with their sequence diversity. Trend analysis indicated an increasing neutralization resistance observed over time with CAP25-VRC26.25, PGDM1400 and PGT121 when tested on pseudoviruses expressing envs obtained from 1999 to 2016. However, inconsistent trend in neutralization susceptibility was observed, when pseudoviruses expressing envs obtained from three followed up individuals were examined. Finally, through predictive analysis of the 98 Indian subtype C including those assessed in the present study by employing additive model implemented in CombiNAber ( http://www.hiv.lanl.gov ), we observed two possibilities where combinations of three bnAbs (VRC01/CAP56-VRC26.25/PGT121 and PGDM1400/CAP256-VRC26.25/PGT121) could achieve near 100% neutralization coverage. CONCLUSIONS: Our findings not only indicate disparate intra-clade C genetic vis-à-vis neutralization diversities but also warrant the need for more comprehensive study using additional isolates towards comparing inter and intra-clade neutralization diversities which will be necessary for selecting the bnAb combinations suitable for optimal coverage of the region-specific HIV-1 circulating subtypes. Expanding these efforts is imperative for designing efficacious bnAb based intervention strategies for India as well as subtype C in general.


Asunto(s)
Anticuerpos Monoclonales/inmunología , Anticuerpos ampliamente neutralizantes/sangre , Anticuerpos Anti-VIH/sangre , Proteína gp120 de Envoltorio del VIH/inmunología , VIH-1/genética , VIH-1/inmunología , Anticuerpos ampliamente neutralizantes/inmunología , Estudios Transversales , Estudios de Seguimiento , Anticuerpos Anti-VIH/clasificación , Infecciones por VIH/virología , VIH-1/clasificación , Humanos , India , Pruebas de Neutralización , Filogenia
9.
PLoS One ; 15(6): e0234133, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32525892

RESUMEN

BACKGROUND: The first case of HIV infection in Sri Lanka was reported in 1987 and at the end of 2018 there were 3500 people living with HIV. There have been commendable efforts made towards the detection, treatment, and prevention of HIV in the country. Even though the genetic diversity of HIV has been shown to affect the parameters ranging from detection to vaccine development, there is no data available with respect to the molecular epidemiology of HIV-1 in Sri Lanka. METHODS: In this report we have performed the ancillary analysis of pol gene region sequences (n = 85) obtained primarily for the purpose of HIV-1 drug resistance genotyping. Briefly, dried blood spot specimens (DBS) collected from HIV-1 infected individuals between December 2015 and August 2018 were subjected to pol gene amplification and sequencing. These pol gene sequences were used to interpret the drug resistance mutation profiles. Further, sequences were subjected to HIV-1 subtyping using REGA 3.0, COMET, jPHMM and, RIP online subtyping tools. Moreover, Bayesian phylogenetic analysis was employed to estimate the evolutionary history of HIV-1 subtype C in Sri Lanka. RESULTS: Our analysis revealed that the majority (51.8%) of pol gene sequences were subtype C. Other than subtype C, there were sequences categorized as subtypes A1, B, D and G. In addition to pure subtypes there were sequences which were observed to be circulating recombinant forms (CRFs) and a few of the recombinants were identified as potential unique recombinants (URFs). We also observed the presence of drug resistance mutations in 56 (65.9%) out of 85 sequences. Estimates of the Bayesian evolutionary analysis suggested that the HIV-1 subtype C was introduced to Sri Lanka during the early 1970s (1972.8). CONCLUSION: The findings presented here indicate the presence of multiple HIV-1 subtypes and the prevalence of drug resistance mutations in Sri Lanka. The majority of the sequences were subtype C, having their most recent common ancestor traced back to the early 1970s. Continuous molecular surveillance of HIV-1 molecular epidemiology will be crucial to keep track of drug resistance, genetic diversity, and evolutionary history of HIV-1 in Sri Lanka.


Asunto(s)
Variación Genética , VIH-1/metabolismo , Productos del Gen pol del Virus de la Inmunodeficiencia Humana/genética , Adolescente , Adulto , Anciano , Antirretrovirales/uso terapéutico , Teorema de Bayes , Niño , Preescolar , Farmacorresistencia Viral/genética , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Infecciones por VIH/patología , Humanos , Masculino , Persona de Mediana Edad , Mutación , Filogenia , Sri Lanka/epidemiología , Adulto Joven , Productos del Gen pol del Virus de la Inmunodeficiencia Humana/química , Productos del Gen pol del Virus de la Inmunodeficiencia Humana/clasificación
10.
Microb Pathog ; 143: 104117, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-32135221

RESUMEN

Lack of viral monitoring in HIV infected patients on anti-retroviral therapy in low income countries may result in missing virologic non-responders (VNR) who show immunologic recovery in spite of unsuppressed viral replication. Biomarkers and drug resistance patterns in these discordant patients in comparison to the concordant treatment failure group need to be studied to understand possible risk factors associated with this condition. HIV infected patients on anti-retroviral therapy for one year were enrolled under three categories namely VNRs (n = 25), treatment failures (n = 18) and treatment responders (n = 40). They were assessed for HIV drug resistance by sequencing, plasma cytokines by luminex assay, T cell activation status by flow cytometry and total IgE levels by ELISA. VNR and failure patients had significantly lower median baseline CD4 counts than the responders. VNRs had significantly higher CD4 counts but lower viral load than treatment failures at one year of ART. VNRs had the highest eosinophil counts and the highest IL-5 levels among all the groups. IL-5 levels in them correlated with their viral load values. Frequency of Treg cells was also highest among the VNR group participants. More than 60% of the viremic patients irrespective of their groups harboured multiple HIV drug resistance mutations and mutation pattern did not differ between the groups. Low baseline CD4 counts and presence of multiple drug resistance mutations in the viremic groups highlighted the importance of early ART initiation and viral load monitoring irrespective of presence of immunologic failure. High IL-5 levels in VNR group indicated a need for investigating causal relationship between IL-5 and viral replication to devise therapeutic strategies to control viremia.


Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Interleucina-5/sangre , Viremia/tratamiento farmacológico , Adolescente , Adulto , Relación CD4-CD8 , Farmacorresistencia Viral/genética , Femenino , Infecciones por VIH/virología , Humanos , Masculino , Persona de Mediana Edad , Insuficiencia del Tratamiento , Viremia/sangre , Adulto Joven
11.
Fertil Steril ; 112(4): 758-763, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31351702

RESUMEN

OBJECTIVE: To study the effects of increasingly prosperous diet content on clinical features of polycystic ovary syndrome (PCOS). DESIGN: A cross-sectional cohort study of 711 women with PCOS from a heterogeneous population spanning a wide spectrum of socioeconomic strata. SETTING: Independent hospital. PATIENT(S): A total of 711 women with PCOS in whom the diagnosis was based on Rotterdam criteria. Results were compared with a locally recruited reference group. INTERVENTION(S): Clinical assessment of women with PCOS. MAIN OUTCOME MEASURE(S): Clinical characteristics were assessed with particular reference to diet composition. Four diet groups were identified: simple rice with vegetables, vegetarian with mixed carbohydrates, nonvegetarian with mixed carbohydrates, and an urban diet of processed foods. RESULT(S): Women with PCOS showed the characteristic features of raised LH and androstenedione concentrations and increased ovarian volume and antral follicle count. There was a notable association between an increasingly affluent diet, the presence of hirsutism, raised body mass index, insulin resistance, and higher serum antimüllerian hormone concentrations. The positive association between antimüllerian hormone and body mass index is an unusual feature possibly explained by the wide spectrum of lifestyles in this cohort. CONCLUSION(S): Urbanization of women in India is associated with increasingly severe phenotype of PCOS, which is likely to have implications on fertility outcomes.


Asunto(s)
Dieta , Síndrome del Ovario Poliquístico/etiología , Urbanización , Adulto , Hormona Antimülleriana/sangre , Índice de Masa Corporal , Estudios de Cohortes , Estudios Transversales , Femenino , Humanos , India , Resistencia a la Insulina , Fenotipo , Clase Social
12.
Artículo en Inglés | MEDLINE | ID: mdl-30806205

RESUMEN

Mixed micelles self-assembled from two or more dissimilar block copolymers provide a direct and convenient approach to improved drug delivery. The present review is focused on mixed micelles (prepared from block copolymers only) for various drug delivery applications along with their merits over single-copolymer micelles. Presented are the physicochemical properties of mixed and single-copolymer micelles, various stimuli-responsive mixed micelles for the treatment of cancer, interesting combinations of multifunctional mixed micelles along with their in vitro and in vivo performance, and the potential of mixed micelles as a gene delivery system. Finally, the performance of mixed micelles in preclinical and clinical testing is explained. In addition, the interaction of mixed micelles with cancer cells and the biosafety of mixed micelles are summarized. The in vitro and in vivo performance presented here clearly reveals that the mixed-micelle approach has a wider scope than that of the single-copolymer micelle approach and directs researchers to focus on this approach to delivery of drugs/gene/biologics for various applications.

13.
Carbohydr Polym ; 210: 289-301, 2019 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-30732765

RESUMEN

Oligo-chitosan (82.20 kDa) was prepared from chitosan (337.73 kDa) by application of 100 kGy γ-irradiation. UV-vis spectroscopy, FTIR, XRD, DSC and TGA analyses showed typical properties of chitosan with slight variations after γ-irradiation. Degree of deacetylation of chitosan and oligo-chitosan was 82%, while 1,1-diphenyl-2-picrylhydrzyl and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) radical scavenging activity were 10.01 ± 0.18 and 43.30 ± 3.75 µMTE/mL and 13.64 ± 0.16 and 79.93 ± 4.44 µMTE/mL, respectively. Chitosan and oligo-chitosan was applied as foliar spray on potato plants to analyze growth promoting and stress tolerance inducing effects. Improvement in shoot height and number of nodes was observed after foliar spray of chitosan and oligo-chitosan at 50-75 mg/L. Furthermore, membrane stability index and malondialdehyde reduced while chlorophyll, carotenoids, proline, reducing and total sugars, enhanced considerably. The antioxidant and defense enzymes CAT, POD, SOD, chitinase and chitosanase showed prominent increment. Overall results indicated that chitosan (75 mg/L) and oligo-chitosan (50 mg/L) can augment plant growth and induce defense mechanism for drought stress tolerance in potato.


Asunto(s)
Quitosano/química , Quitosano/farmacología , Rayos gamma , Solanum tuberosum/efectos de los fármacos , Solanum tuberosum/crecimiento & desarrollo , Estrés Fisiológico , Antioxidantes/metabolismo , Carotenoides/metabolismo , Clorofila/metabolismo , Hidrólisis , Peroxidación de Lípido/efectos de los fármacos , Peso Molecular , Prolina/metabolismo , Solanum tuberosum/metabolismo , Solanum tuberosum/fisiología , Solubilidad , Estrés Fisiológico/efectos de los fármacos , Azúcares/metabolismo , Temperatura , Viscosidad
14.
AIDS Res Hum Retroviruses ; 35(5): 505-508, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30681008

RESUMEN

HIV-2 is important due to its unique challenges in diagnosis, treatment, and drug resistance. The data on Indian HIV-2 pol gene as well as resistance to antiretroviral drugs are limited. Here we report sequence data of protease (PR) and reverse transcriptase (RT) genes from HIV-2 infected treatment naive individuals (N = 32) from Maharashtra, India. These sequences were found to be closely related to HIV-2 subtype A sequences from Guinea Bissau. We observed two unique residues at positions 14 and 70 in the PR region specific to Indian HIV-2. Mutations associated with resistance to RT and protease inhibitors were observed in 3 of 32 (9.37%) samples. To our knowledge, this is the first study from India to report drug resistance among treatment naive HIV-2 infected individuals. The results emphasize need for larger nationwide surveillance for HIV-2 drug resistance to better understand the primary drug resistance among HIV-2 infected individuals.


Asunto(s)
Farmacorresistencia Viral/genética , Infecciones por VIH/virología , VIH-2/genética , Mutación , Productos del Gen pol del Virus de la Inmunodeficiencia Humana/genética , Adolescente , Adulto , Anciano , Femenino , Proteasa del VIH/genética , Transcriptasa Inversa del VIH/genética , VIH-2/aislamiento & purificación , Humanos , India , Masculino , Persona de Mediana Edad , Adulto Joven
15.
Sci Rep ; 8(1): 8917, 2018 06 11.
Artículo en Inglés | MEDLINE | ID: mdl-29891975

RESUMEN

ALG-2 interacting protein X (ALIX) links HIV-1 Gag to the components of ESCRT-III. HIV-1 engages the ALIX via its nucleocapsid and LYPXnL motif in p6. Overexpression of ALIX corrects the release defect of PTAP deleted HIV-1 via LYPXnL/ALIX pathway. However, HIV-1 subtype C lacks the LYPXnL motif and hence cannot employ LYPXnL/ALIX mechanism. Though the preferential occurrences of PYXE insertion in HIV-1 C p6 is predicted to restore the ALIX binding site there is no functional proof to support these observations. In this study we show that HIV-1 construct with subtype C p6 having PTAP deletion and PYRE insertion (pNL-INp6ΔPTAP/PYRE) could respond to ALIX overexpression. Notably, conserved Phenyl alanine residue (F676) in ALIX was critical for ALIX mediated release of pNL-INp6ΔPTAP/PYRE implying the critical role of this hydrophobic patch in ALIX recruitment. In addition, we show that Nedd4-1 could also correct the release defect of pNL-INp6ΔPTAP/PYRE. Moreover, Nedd4-1 was more robust compared to ALIX in its ability to stimulate the release of pNL-INp6ΔPTAP/PYRE. Replication kinetic data highlights the positive effect of PYRE insertion on virus replication. In summary, our data reveals the functional role of PYRE insertion towards the cooperative mechanism of ALIX/Nedd4-1 in virus release in the absence of PTAP/Tsg101 pathway.


Asunto(s)
Proteínas de Unión al Calcio/metabolismo , Proteínas de Ciclo Celular/metabolismo , Complejos de Clasificación Endosomal Requeridos para el Transporte/metabolismo , VIH-1/fisiología , Mutagénesis Insercional , Liberación del Virus , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/metabolismo , Genotipo , Células HEK293 , VIH-1/clasificación , VIH-1/genética , Humanos , Eliminación de Secuencia , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/genética
16.
Front Immunol ; 9: 905, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29760708

RESUMEN

The importance of TLR2 and TLR9 in the recognition of infection with herpes simplex virus (HSV) and HSV-caused diseases has been described, but some discrepancies remain concerning the benefits of these responses. Moreover, the impact of TLR2/9 on innate and adaptive immune responses within relevant mucosal tissues has not been elucidated using natural mucosal infection model of HSV. Here, we demonstrate that dual TLR2/9 recognition is essential to provide resistance against mucosal infection with HSV via an intravaginal route. Dual TLR2/9 ablation resulted in the highly enhanced mortality with exacerbated symptoms of encephalitis compared with TLR2 or TLR9 deficiency alone, coinciding with highly increased viral load in central nervous system tissues. TLR2 appeared to play a minor role in providing resistance against mucosal infection with HSV, since TLR2-ablated mice showed higher survival rate compared with TLR9-ablated mice. Also, the high mortality in dual TLR2/9-ablated mice was closely associated with the reduction in early monocyte and NK cell infiltration in the vaginal tract (VT), which was likely to correlate with low expression of cytokines and CCR2 ligands (CCL2 and CCL7). More interestingly, our data revealed that dual TLR2/9 recognition of HSV infection plays an important role in the functional maturation of TNF-α and iNOS-producing dendritic cells (Tip-DCs) from monocytes as well as NK cell activation in VT. TLR2/9-dependent maturation of Tip-DCs from monocytes appeared to specifically present cognate Ag, which effectively provided functional effector CD4+ and CD8+ T cells specific for HSV Ag in VT and its draining lymph nodes. TLR2/9 expressed in monocytes was likely to directly facilitate Tip-DC-like features after HSV infection. Also, dual TLR2/9 recognition of HSV infection directly activated NK cells without the aid of dendritic cells through activation of p38 MAPK pathway. Taken together, these results indicate that dual TLR2/9 recognition plays a critical role in providing resistance against mucosal infection with HSV, which may involve a direct regulation of Tip-DCs and NK cells in VT. Therefore, our data provide a more detailed understanding of TLR2/9 role in conferring antiviral immunity within relevant mucosal tissues after mucosal infection with HSV.


Asunto(s)
Sistema Nervioso Central/virología , Herpes Simple/inmunología , Células Asesinas Naturales/inmunología , Activación de Linfocitos , Monocitos/inmunología , Receptor Toll-Like 2/inmunología , Receptor Toll-Like 9/inmunología , Animales , Sistema Nervioso Central/inmunología , Citocinas/genética , Células Dendríticas/inmunología , Encefalitis Viral/mortalidad , Femenino , Inmunidad Innata , Inmunidad Mucosa , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Receptor Toll-Like 2/genética , Receptor Toll-Like 9/genética , Vagina/inmunología , Vagina/virología , Carga Viral
17.
Curr Drug Deliv ; 15(4): 564-575, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-28637416

RESUMEN

BACKGROUND: Docetaxel (DTX) has been used to treat several types of cancers, but it has provided pharmaceutical challenges due to its poor water solubility and toxicities associated with the co-solvents (tween-80 and ethanol). Nanopolymer therapeutics can be engineered to deliver anticancer agent specifically to cancer cells, thereby leaving normal healthy cells unaffected by toxic drugs such as DTX. The objective of the present study was to synthesize the polyacrylic acid (PAA)-DTX conjugate (PAADC) and preparation of nanopolymer therapeutics such as PAADC/DSPE-mPEG2000 mixed micelles (PAADC-DP MMs). METHODS: The prepared PAADC-DP MMs were characterized for mean particle size and zeta potential, in vitro release profile using dialysis technique, hemolytic behavior against human blood, and cytotoxicity against human cancer cell line (A549) using MTT assay. In vivo acute toxicity of PAADC-DP MMs was determined in albino mice at intravenous single dose of 40 mg/kg. RESULTS: PAADC-DP MMs showed mean particle size of 443±9nm. PAADC-DP MMs showed maximum DTX loading (DTX equivalent; 90.5±2.7%) with minimum DSPE-mPEG2000 molecules (1:1 ratio), while to load 77.9±2.2% of plain DTX, more DSPE-mPEG2000 is required(1:10 ratio). The developed PAADC-DP MMs system showed significantly lower CMC (5 ng/mL), sustained release profile (28.6±1.9% after 48 h of study), lower hemolytic behavior (13.7±1.3% of hemolysis ratio at 40 µg/mL concentration and after 1 h incubation), higher in vitro cytotoxicity (IC50 of 0.0064±0.001 nM after 48 h study) and remarkably reduced in vivo toxicity (9.9±2.1% body weight loss) in mice when compared to marketed Taxotere®. CONCLUSION: The obtained results clearly demonstrated that the developed PAADC-DP MMs system is a promising approach for cancer chemotherapy with reduced toxicity.


Asunto(s)
Supervivencia Celular/efectos de los fármacos , Sistemas de Liberación de Medicamentos/métodos , Micelas , Polímeros/química , Taxoides/administración & dosificación , Taxoides/química , Resinas Acrílicas/química , Animales , Línea Celular Tumoral , Docetaxel , Liberación de Fármacos , Femenino , Hemólisis/efectos de los fármacos , Humanos , Ratones , Nanotecnología/métodos , Tamaño de la Partícula , Solubilidad , Propiedades de Superficie , Taxoides/farmacología , Taxoides/toxicidad
18.
Oncotarget ; 8(62): 106050-106070, 2017 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-29285314

RESUMEN

Possible risk mediators in primary dengue virus (DenV) infection that favor secondary DenV infection to life-threatening dengue hemorrhagic fever (DHF) and shock syndrome (DSS) via antibody-dependent enhancement (ADE) have not yet been described. Here, DenV infection enhanced the expression of inflammatory mediators and activation molecules in dendritic cells (DCs) through TLR2/MyD88 pathway. TLR2 appeared to facilitate DenV infection in DCs that were less permissive than macrophages for viral replication. In experiments using separate evaluations of DenV-infected and uninfected bystander DCs, infected DCs showed impaired maturation accompanied with TLR2-dependent production of inflammatory cytokines, by which uninfected bystander DCs showed increased expression of co-stimulatory molecules. Differential phosphorylation of MAPK and STAT3 was also detected between DenV-infected and uninfected DCs. Furthermore, DenV infection stimulated Th2-polarized humoral and cellular immunity against foreign and DenV Ag via TLR2/MyD88 pathway, and DenV-infected DCs were revealed to facilitate Th2-biased immune responses in TLR2-dependent manner. TLR2/MyD88-mediated Th2-biased Ab responses to primary DenV infection increased the infectivity of secondary homotypic or heterotypic DenV via ADE. Collectively, these results indicate that TLR2/MyD88 pathway in DC-priming receptors can drive Th2-biased immune responses during primary DenV infection, which could favor secondary DenV infection to DHF/DSS via ADE.

19.
PLoS One ; 12(8): e0181889, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28763465

RESUMEN

BACKGROUND: The free antiretroviral therapy (ART) program in India still relies on the clinico-immunological monitoring for diagnosis of treatment failure. As the nucleoside reverse transcriptase inhibitor (NRTI) backbone is shared in first- and second-line regimens, accumulation of drug resistant mutations (DRMs) can compromise the efficacy of NRTI. This study was undertaken to describe the pattern of HIV DRMs following immunological monitoring and investigate its impact on the cycling of NRTI between first- and second-line ART. METHODS AND FINDINGS: This cross-sectional study was performed at a state-sponsored ART clinic of Pune city in western India between January and June 2016. Consecutive adults receiving first-line ART with immunological failure (IF) were recruited for plasma viral load (PVL) estimation. Randomly selected 80 participants with PVL >1000 copies/mL underwent HIV drug resistance genotyping. Of these, 75 plasma sample were successfully genotyped. The median CD4 count and duration of ART at the time of failure were 98 (IQR: 61.60-153.50) cells/µL and 4.62 (IQR: 3.17-6.15) years, respectively. The prevalence of NRTI, non-NRTI, and major protease inhibitor resistance mutations were 89.30%, 96%, and 1.33%, respectively. Following first-line failure, sequences from 56.67% of individuals indicated low- to high-level resistance to all available NRTI. The proportion of sequences with ≥2 thymidine analogue mutations (TAMs) and ≥3 TAMs were 62.12% and 39.39%, respectively. An average of 1.98 TAMs per sequence were observed following IF as compared to 0.37 TAMs per sequence following targeted PVL monitoring at 12 months of ART from a prior study; this difference was significant (p<0.001). CONCLUSION: The option of cycling of NRTI analogues between first- and second-line regimens would no longer be effective if individuals are followed-up by immunological monitoring due to accumulation of mutations. Introduction of routine PVL monitoring is a priority for the long-term sustainability of free ART program in India.


Asunto(s)
Fármacos Anti-VIH/farmacología , Farmacorresistencia Viral , Infecciones por VIH/tratamiento farmacológico , Monitorización Inmunológica , Adolescente , Adulto , Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa , Recuento de Linfocito CD4 , Estudios Transversales , Farmacorresistencia Viral/genética , Femenino , Genotipo , VIH-1/efectos de los fármacos , VIH-1/genética , Humanos , Sistema Inmunológico , India , Masculino , Mutación , Filogenia , Inhibidores de la Transcriptasa Inversa/farmacología , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Timidina/genética , Resultado del Tratamiento , Carga Viral , Adulto Joven
20.
AIDS Res Hum Retroviruses ; 33(11): 1171-1174, 2017 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-28737979

RESUMEN

HECT domain and RCC1-like domain-containing protein 5 (HERC-5) is one of the novel host restriction factors that is known to inhibit HIV release in vitro. Polymorphisms in other host restriction factors have been associated with HIV infection and disease progression. However, no report is available on the HERC-5 polymorphism in HIV-infected individuals. We studied the HERC-5 gene polymorphism in HIV-infected individuals and explored whether it is associated with different disease outcomes. Genomic DNA was isolated from 41 HIV-1 progressors, 39 long-term nonprogressors, and 74 HIV seronegative healthy donors for amplification of HERC5 Exon-18 and other regulatory regions followed by sequencing. We found no genetic variation in the known single-nucleotide polymorphism (SNP)-rs34457268 (Exon-18) of HERC-5 in HIV-infected individuals. Instead, a synonymous mutation at rs6857425 (T-C) was present in the same region among all study groups (p > .05), irrespective of their HIV status. We further noted two novel SNPs in Intron-18 region. To the best of our knowledge, this is first study to report the HERC5 gene polymorphism among HIV-infected groups.


Asunto(s)
Predisposición Genética a la Enfermedad , Infecciones por VIH/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Polimorfismo Genético , Adolescente , Adulto , Femenino , Humanos , India , Masculino , Persona de Mediana Edad , Análisis de Secuencia de ADN , Adulto Joven
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