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1.
Cureus ; 15(11): e48523, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-38073916

RESUMEN

Carcinoma of the prostate is the second most common cancer in males, while multiple myeloma is the 17th most common cancer. The synchronous diagnosis of multiple myeloma and carcinoma of the prostate is a sporadic phenomenon with scarce published literature and a diagnostic and therapeutic dilemma. Here, we present a case of synchronous diagnosis of IgG and lambda subtypes of multiple myeloma with multiple lytic lesions, the revised international staging system (R-ISS 2), and non-metastatic acinar adenocarcinoma prostate, a very high-risk category. The patient received 25 weekly doses of cyclophosphamide, bortezomib, and dexamethasone (CyBorD)-based chemotherapy for myeloma and androgen deprivation therapy with injection leuprolide for prostate cancer. After reasonable disease control, the patient underwent an autologous stem cell transplant for multiple myeloma with melphalan at 140 mg/m2 and was offered definitive radiation therapy for prostate cancer. The potential association between carcinoma of the prostate and multiple myeloma has been hypothesized because of similarities in the tumor microenvironment. There are possible common biological pathways leading to co-stimulatory mechanisms, like interleukin-2 (IL-2), insulin-like growth factor 1 (IGF-1), stromal cell-derived factor 1 (SDF-1), and vascular endothelial growth factor (VEGF). However, they are not proven and warrant further research. This case highlights key areas of diagnosis and management of this sporadic occurrence, along with literature analysis and the need for further research, and is likely to be beneficial for clinicians in decision-making in future cases.

2.
Cureus ; 15(10): e47085, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-38022018

RESUMEN

Hairy cell leukemia variant (HCLv) is a sporadic, B-cell non-Hodgkin lymphoma classified under chronic lymphoproliferative disorders. HCLv usually presents with easy fatigue, dragging pain abdomen, anemia, splenomegaly, hepatomegaly, initially leukocytosis followed by leucopenia, hairy cells in the smear and bone marrow, and an increased risk of infections. There is hypercellular bone marrow, and cytopenias are secondary to hypersplenism. It is essential to differentiate HCL from disorders like classic hairy cell leukemia (HCLc), splenic marginal zone lymphoma, and splenic diffuse red pulp lymphoma, as these are biologically different, with divergent approaches and outcomes. HCLv is poorly responsive or primary refractory to standard purine analogs cladribine or pentostatin. It has lower response rates to even cladribine and rituximab combination, a standard of care for classic HCL with very good response rates. Here, we present a case of an elderly male who presented with splenomegaly and leukocytosis, diagnosed as HCLv, and was treated with a cladribine and rituximab-based regime but showed residual cells in bone marrow on flow cytometry at six months post-treatment. There were no residual cells in peripheral blood in flow cytometry. Various aspects of the disease are discussed here with a detailed literature analysis. There is a definite unmet need for research on better treatment options in HCLv to improve its overall outcome.

3.
Development ; 149(18)2022 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-36134690

RESUMEN

Heart regeneration requires multiple cell types to enable cardiomyocyte (CM) proliferation. How these cells interact to create growth niches is unclear. Here, we profile proliferation kinetics of cardiac endothelial cells (CECs) and CMs in the neonatal mouse heart and find that they are spatiotemporally coupled. We show that coupled myovascular expansion during cardiac growth or regeneration is dependent upon VEGF-VEGFR2 signaling, as genetic deletion of Vegfr2 from CECs or inhibition of VEGFA abrogates both CEC and CM proliferation. Repair of cryoinjury displays poor spatial coupling of CEC and CM proliferation. Boosting CEC density after cryoinjury with virus encoding Vegfa enhances regeneration. Using Mendelian randomization, we demonstrate that circulating VEGFA levels are positively linked with human myocardial mass, suggesting that Vegfa can stimulate human cardiac growth. Our work demonstrates the importance of coupled CEC and CM expansion and reveals a myovascular niche that may be therapeutically targeted for heart regeneration.


Asunto(s)
Células Endoteliales , Factor A de Crecimiento Endotelial Vascular , Animales , Proliferación Celular , Células Endoteliales/fisiología , Corazón/fisiología , Humanos , Recién Nacido , Ratones , Miocitos Cardíacos/metabolismo , Transducción de Señal , Factor A de Crecimiento Endotelial Vascular/metabolismo
4.
Indian J Pathol Microbiol ; 65(2): 396-400, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35435378

RESUMEN

Carcinoma cervix usually spreads directly to contiguous structures, such as the vagina, urinary bladder, ureter, and rectum. Intestinal metastasis from cervical cancer is very uncommon and accounts for less than 4% of cases and to date, 24 cases have been reported in Medical literature. These may be asymptomatic or present with features of intestinal obstruction, bowel wall perforation, and mimic acute abdomen. Intestinal metastasis is a late occurrence and carries a poor prognosis, hence a high index of suspicion with prompt diagnosis and management is essential. We report a series of five patients with squamous cell carcinoma (SCC) of the cervix with intestinal metastasis diagnosed in our hospital.


Asunto(s)
Carcinoma de Células Escamosas , Obstrucción Intestinal , Neoplasias del Cuello Uterino , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/secundario , Cuello del Útero/patología , Femenino , Humanos , Intestinos/patología , Neoplasias del Cuello Uterino/diagnóstico , Neoplasias del Cuello Uterino/patología
5.
J Family Med Prim Care ; 11(10): 6529-6532, 2022 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-36618238

RESUMEN

COVID-19 disease has been associated with fungal infections such as aspergillosis and mucormycosis, especially in diabetic patients who have suffered from a moderately severe form of COVID-19 infection and are treated with steroids. Though there are multiple case reports describing co-infection with mucormycosis during the second wave of the COVID outbreak, the report of a dual fungal infection along with superadded bacterial infection is rare. Here we report a case where the same patient had a fungal storm with aspergillosis and mucormycosis and superadded Klebsiella. She was treated aggressively with antifungal agents, antibiotics, surgical debridement, and other supportive care. She improved and was discharged from the hospital after a long stay. She is being followed up regularly in the outpatient department and doing well.

6.
Retrovirology ; 18(1): 26, 2021 09 16.
Artículo en Inglés | MEDLINE | ID: mdl-34530855

RESUMEN

BACKGROUND: Extracellular Vesicles (EV) recently have been implicated in the pathogenesis of HIV-1 syndromes, including neuroinflammation and HIV-1 associated neurological disorder (HAND). Cocaine, an illicit stimulant drug used worldwide is known to exacerbate these HIV-1 associated neurological syndromes. However, the effects of cocaine on EV biogenesis and roles of EVs in enhancing HIV-1 pathogenesis are not yet well defined. RESULTS: Here, we investigated the effects of cocaine on EV biogenesis and release in HIV-1 infected immune cells and explored their roles in elicitation of neuroinflammation. We found that cocaine significantly augmented the release of EVs from uninfected and HIV-1 infected T-cells, DCs and macrophages. Further analysis of the molecular components of EVs revealed enhanced expression of adhesion molecules integrin ß1 and LFA-1 in those EVs derived from cocaine treated cells. Intriguingly, in EVs derived from HIV-1 infected cells, cocaine treatment significantly increased the levels of viral genes in EVs released from macrophages and DCs, but not in T-cells. Exploring the molecular mechanism to account for this, we found that DCs and macrophages showed enhanced expression of the cocaine receptor Sigma 1-Receptor compared to T-cells. In addition, we found that cocaine significantly altered the integrity of the RNA-induced silencing complex (RISC) in HIV-1 infected macrophages and DCs compared to untreated HIV-1 infected cells. Characterizing further the molecular mechanisms involved in how cocaine increased EV release, we found that cocaine decreased the expression of the interferon-inducible protein BST-2; this resulted in altered trafficking of intracellular virus containing vesicles and EV biogenesis and release. We also observed EVs released from cocaine treated HIV-1 infected macrophages and DCs enhanced HIV-1 trans-infection to T-cells compared to those from untreated and HIV-1 infected cells. These EVs triggered release of proinflammatory cytokines in human brain microvascular endothelial cells (HBMECs) and altered monolayer integrity. CONCLUSIONS: Taken together, our results provide a novel mechanism which helps to elucidate the enhanced prevalence of neurological disorders in cocaine using HIV-1 infected individuals and offers insights into developing novel therapeutic strategies against HAND in these hosts.


Asunto(s)
Cocaína/efectos adversos , Cocaína/inmunología , Células Dendríticas/efectos de los fármacos , Vesículas Extracelulares/efectos de los fármacos , VIH-1/inmunología , Macrófagos/efectos de los fármacos , Enfermedades Neuroinflamatorias/complicaciones , Encéfalo/citología , Cocaína/farmacología , Citocinas/inmunología , Células Dendríticas/virología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/inmunología , Células Endoteliales/virología , Vesículas Extracelulares/inmunología , Vesículas Extracelulares/virología , VIH-1/efectos de los fármacos , VIH-1/patogenicidad , Humanos , Inflamación , Macrófagos/inmunología , Macrófagos/virología , Biogénesis de Organelos
7.
Cureus ; 13(12): e20475, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-35047294

RESUMEN

Mucormycosis is an emerging infection in the present post-COVID-19 era, associated with high morbidity and mortality. We are reporting an interesting case of invasive rhino-orbital-cerebral mucormycosis in a 65-year-old female who presented with left nasal and orbital swelling after COVID-19 infection associated with uncontrolled diabetes mellitus. Histopathological and microbiology examination favored mucormycosis. Finally, endoscopic debridement of the lesion was done with left orbital exenteration. The patient at present is clinically stable. As these cases have been seen in many suspected and confirmed COVID-19 cases, early diagnosis and treatment will salvage the patient.

8.
Virusdisease ; 31(2): 179-193, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-32656311

RESUMEN

The recent outbreak of COVID-19 caused by SARS-CoV-2 brought a great global public health and economic concern. SARS-CoV-2 is an enveloped RNA virus, from the genus Betacoronavirus. Although few molecules have been tested and shown some efficacy against SARS-CoV-2 in humans but a safe and cost-effective attachment inhibitors are still required for the treatment of COVID-19. Natural products are gaining attention because of the large therapeutic window and potent antiviral, immunomodulatory, anti-inflammatory, and antioxidant properties. Therefore, this study was planned to screen natural products from Ayurveda that have the potential to modulate host immune system as well as block the virus entry in host cells by interfering its interaction with cellular receptor and may be used to develop an effective and broad-spectrum strategy for the management of COVID-19 as well as other coronavirus infections in coming future. To decipher the antiviral activity of the selected natural products, molecular docking was performed. Further, the drug-likeness, pharmacokinetics and toxicity parameters of the selected natural products were determined. Docking results suggest that curcumin and nimbin exhibits highest interaction with spike glycoprotein (MolDock score - 141.36 and - 148.621 kcal/mole) and ACE2 receptor (MolDock score - 142.647 and - 140.108 kcal/mole) as compared with other selected natural products/drugs and controls. Also, the pharmacokinetics data illustrated that all selected natural products have better pharmacological properties (low molecular weight; no violation of Lipinski rule of five, good absorption profiles, oral bioavailability, good blood-brain barrier penetration, and low toxicity risk). Our study exhibited that curcumin, nimbin, withaferin A, piperine, mangiferin, thebaine, berberine, and andrographolide have significant binding affinity towards spike glycoprotein of SARS-CoV-2 and ACE2 receptor and may be useful as a therapeutic and/or prophylactic agent for restricting viral attachment to the host cells. However, few other natural products like resveratrol, quercetin, luteolin, naringenin, zingiberene, and gallic acid has the significant binding affinity towards ACE2 receptor only and therefore may be used for ACE2-mediated attachment inhibition of SARS-CoV-2.

9.
FEBS Lett ; 594(12): 1947-1959, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32279313

RESUMEN

Human immunodeficiency virus type 1 (HIV-1) subverts intracellular trafficking pathways to avoid its degradation and elimination, thereby enhancing its survival and spread. The molecular mechanisms involved in intracellular transport of HIV-1 are not yet fully defined. We demonstrate that the actin-binding protein lymphocyte-specific protein 1 (LSP1) interacts with the interferon-inducible protein bone marrow stromal antigen 2 (BST-2) in dendritic cells (DCs) to facilitate both endocytosis of surface-bound HIV-1 and the formation of early endosomes. Analysis of the molecular interaction between LSP1 and BST-2 reveals that the N terminus of LSP1 interacts with BST-2. Overall, we identify a novel mechanism of intracellular trafficking of HIV-1 in DCs centering on the LSP1/BST-2 complex. We also show that the HIV-1 accessory protein Vpu subverts this pathway by inducing proteasomal degradation of LSP1, augmenting cell-cell transmission of HIV-1.


Asunto(s)
Antígenos CD/metabolismo , Células Dendríticas/virología , Infecciones por VIH/virología , VIH-1/patogenicidad , Proteínas de Microfilamentos/metabolismo , Células Cultivadas , Células Dendríticas/efectos de los fármacos , Células Dendríticas/metabolismo , Endocitosis , Complejos de Clasificación Endosomal Requeridos para el Transporte/metabolismo , Proteínas Ligadas a GPI/metabolismo , Infecciones por VIH/transmisión , Interacciones Huésped-Patógeno/fisiología , Proteínas del Virus de la Inmunodeficiencia Humana/metabolismo , Humanos , Interferón-alfa/farmacología , Proteínas de Microfilamentos/genética , Proteínas Reguladoras y Accesorias Virales/metabolismo
10.
Virusdisease ; 31(1): 13-21, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32206694

RESUMEN

The emergence of 2019 novel coronavirus (2019-nCoV) is of global concern and might have emerged from RNA recombination among existing coronaviruses. CoV spike (S) protein which is crucial for receptor binding, membrane fusion via conformational changes, internalization of the virus, host tissue tropism and comprises crucial targets for vaccine development, remain largely uncharacterized. Therefore, the present study has been planned to determine the sequence variation, structural and antigenic divergence of S glycoprotein which may be helpful for the management of 2019-nCoV infection. The sequences of spike glycoprotein of 2019-nCoV and SARS coronavirus (SARS-CoV) were used for the comparison. The sequence variations were determined using EMBOSS Needle pairwise sequence alignment tools. The variation in glycosylation sites was predicted by NetNGlyc 1.0 and validated by N-GlyDE server. Antigenicity was predicted by NetCTL 1.2 and validated by IEDB Analysis Resource server. The structural divergence was determined by using SuperPose Version 1.0 based on cryo-EM structure of the SARS coronavirus spike glycoprotein. Our data suggests that 2019-nCoV is newly spilled coronavirus into humans in China is closely related to SARS-CoV, which has only 12.8% of difference with SARS-CoV in S protein and has 83.9% similarity in minimal receptor-binding domain with SARS-CoV. Addition of a novel glycosylation sites were observed in 2019-nCoV. In addition, antigenic analysis proposes that great antigenic differences exist between both the viral strains, but some of the epitopes were found to be similar between both the S proteins. In spite of the variation in S protein amino acid composition, we found no significant difference in their structures. Collectively, for the first time our results exhibit the emergence of human 2019-nCoV is closely related to predecessor SARS-CoV and provide the evidence that 2019-nCoV uses various novel glycosylation sites as SARS-CoV and may have a potential to become pandemic owing its antigenic discrepancy. Further, demonstration of novel Cytotoxic T lymphocyte epitopes may impart opportunities for the development of peptide based vaccine for the prevention of 2019-nCoV.

11.
Front Immunol ; 11: 136, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32117283

RESUMEN

Methamphetamine (Meth) abuse is a worldwide public health problem and contributes to HIV-1 pathobiology and poor adherence to anti-retroviral therapies. Specifically, Meth is posited to alter molecular mechanisms to provide a more conducive environment for HIV-1 replication and spread. Enhanced expression of inflammatory cytokines, such as Interleukin-1ß (IL-1ß), has been shown to be important for HIV-1 pathobiology. In addition, microRNAs (miRNAs) play integral roles in fine-tuning the innate immune response. Notably, the effects of Meth abuse on miRNA expression are largely unknown. We studied the effects of Meth on IL-1ß and miR-146a, a well-characterized member of the innate immune signaling network. We found that Meth induces miR-146a and triggers an IL-1ß auto-regulatory loop to modulate innate immune signaling in CD4+ T-cells. We also found that Meth enhances HIV-1 replication via IL-1 signaling. Our results indicate that Meth activates an IL-1ß feedback loop to alter innate immune pathways and favor HIV-1 replication. These observations offer a framework for designing targeted therapies in HIV-infected, Meth using hosts.


Asunto(s)
Linfocitos T CD4-Positivos/virología , Estimulantes del Sistema Nervioso Central/toxicidad , VIH-1/efectos de los fármacos , Interleucina-1beta/metabolismo , Metanfetamina/toxicidad , Replicación Viral/efectos de los fármacos , Linfocitos T CD4-Positivos/efectos de los fármacos , Células Cultivadas , Retroalimentación Fisiológica/efectos de los fármacos , Retroalimentación Fisiológica/fisiología , Regulación de la Expresión Génica/efectos de los fármacos , Infecciones por VIH/inmunología , Infecciones por VIH/metabolismo , VIH-1/inmunología , Humanos , MicroARNs/biosíntesis , MicroARNs/efectos de los fármacos
12.
Nanomaterials (Basel) ; 9(8)2019 Jul 29.
Artículo en Inglés | MEDLINE | ID: mdl-31362355

RESUMEN

Sodium superionic conductor (NASICON)-type lithium aluminum germanium phosphate (LAGP) has attracted increasing attention as a solid electrolyte for all-solid-state lithium-ion batteries (ASSLIBs), due to the good ionic conductivity and highly stable interface with Li metal. However, it still remains challenging to achieve high density and good ionic conductivity in LAGP pellets by using conventional sintering methods, because they required high temperatures (>800 °C) and long sintering time (>6 h), which could cause the loss of lithium, the formation of impurity phases, and thus the reduction of ionic conductivity. Herein, we report the utilization of a spark plasma sintering (SPS) method to synthesize LAGP pellets with a density of 3.477 g cm-3, a relative high density up to 97.6%, and a good ionic conductivity of 3.29 × 10-4 S cm-1. In contrast to the dry-pressing process followed with high-temperature annealing, the optimized SPS process only required a low operating temperature of 650 °C and short sintering time of 10 min. Despite the least energy and short time consumption, the SPS approach could still achieve LAGP pellets with high density, little voids and cracks, intimate grain-grain boundary, and high ionic conductivity. These advantages suggest the great potential of SPS as a fabrication technique for preparing solid electrolytes and composite electrodes used in ASSLIBs.

13.
Sci Rep ; 9(1): 6326, 2019 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-31004105

RESUMEN

Cerium dioxide (CeO2) is a surrogate material for traditional nuclear fuels and an essential material for a wide variety of industrial applications both in its bulk and nanometer length scale. Despite this fact, the underlying physics of thermal conductivity (kL), a crucial design parameter in industrial applications, has not received enough attention. In this article, a systematic investigation of the phonon transport properties was performed using ab initio calculations unified with the Boltzmann transport equation. An extensive examination of the phonon mode contribution, available three-phonon scattering phase space, mode Grüneisen parameter and mean free path (MFP) distributions were also conducted. To further augment theoretical predictions of the kL, measurements were made on specimens prepared by spark plasma sintering using the laser flash technique. Since the sample porosity plays a vital role in the value of measured kL, the effect of porosity on kL by molecular dynamics (MD) simulations were investigated. Finally, we also determined the nanostructuring effect on the thermal properties of CeO2. Since CeO2 films find application in various industries, the dependence of thickness on the in-plane and cross-plane kL for an infinite CeO2 thin film was also reported.

14.
Sci Rep ; 9(1): 958, 2019 01 30.
Artículo en Inglés | MEDLINE | ID: mdl-30700725

RESUMEN

Methamphetamine (Meth) exacerbates HIV-1 pathobiology by increasing virus transmission and replication and accelerating clinical progression to AIDS. Meth has been shown to alter the expression of HIV-1 co-receptors and impair intrinsic resistance mechanisms of immune cells. However, the exact molecular mechanisms involved in augmenting HIV-1 replication in T-cells are still not yet clear. Here, we demonstrate that pretreatment with Meth of CD4+ T-cells enhanced HIV-1 replication. We observed upregulation of CD4+ T-cell activation markers and enhanced expression of miR-34c-5p and miR-155 in these cells. Further, we noted activation of the sigma-1 receptor and enhanced intracellular Ca2+ concentration and cAMP release in CD4+ T-cells upon Meth treatment, which resulted in increased phosphorylation and nuclear translocation of transcription factors NFκB, CREB, and NFAT1. Increased gene expression of IL-4 and IL-10 was also observed in Meth treated CD4+ T-cells. Moreover, proteasomal degradation of Ago1 occurred upon Meth treatment, further substantiating the drug as an activator of T-cells. Taken together, these findings show a previously unreported mechanism whereby Meth functions as a novel T-cell activator via the sigma-1 signaling pathway, enhancing replication of HIV-1 with expression of miR-34c-5p, and transcriptional activation of NFκB, CREB and NFAT1.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1/fisiología , Metanfetamina/farmacología , Receptores sigma/metabolismo , Proteínas Argonautas/metabolismo , Biomarcadores/metabolismo , Linfocitos T CD4-Positivos/efectos de los fármacos , Calcio/metabolismo , Núcleo Celular/metabolismo , AMP Cíclico/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , VIH-1/efectos de los fármacos , Humanos , MicroARNs/genética , MicroARNs/metabolismo , FN-kappa B/metabolismo , Factores de Transcripción NFATC/metabolismo , Fosforilación/efectos de los fármacos , Transporte de Proteínas/efectos de los fármacos , Proteolisis/efectos de los fármacos , Receptores Dopaminérgicos/metabolismo , Replicación Viral/efectos de los fármacos , Receptor Sigma-1
15.
Sci Rep ; 7(1): 14787, 2017 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-29093555

RESUMEN

Exosomes are membrane enclosed nano-sized vesicles actively released into the extracellular milieu that can harbor genomic, proteomic and lipid cargos. Functionally, they are shown to regulate cell-cell communication and transmission of pathogens. Though studies have implicated a role for exosomes in HIV-1 pathogenesis, their mechanisms are not well defined. Here, we characterized exosomes derived from uninfected or HIV-1 infected T-cells and DCs. We demonstrate substantial differences in morphological, molecular and biogenesis machinery between exosomes derived from these two immune cell types. In addition, exosomes derived from HIV-1 infected DCs were 4 fold more infective than either cell free HIV-1 or exosomes derived from T-cells. Molecular analysis of exosomes detected the presence of fibronectin and galectin-3 in those derived from DCs, whereas T-cell exosomes lacked these molecules. Addition of anti-fibronectin antibody and ß-lactose, a galectin-3 antagonist, significantly blocked DC exosome-mediated HIV-1 infection of T-cells. We also observed increased gene expression of the pro-inflammatory cytokines IFN-γ, TNF-α, IL-1ß and RANTES and activation of p38/Stat pathways in T-cells exposed to exosomes derived from HIV-1 infected DCs. Our study provides insight into the role of exosomes in HIV pathogenesis and suggests they can be a target in development of novel therapeutic strategies against viral infection.


Asunto(s)
Células Dendríticas , Exosomas , Fibronectinas/metabolismo , Galectina 3/metabolismo , Infecciones por VIH/metabolismo , VIH-1/metabolismo , Proteínas Sanguíneas , Citocinas/metabolismo , Células Dendríticas/metabolismo , Células Dendríticas/virología , Exosomas/metabolismo , Exosomas/virología , Femenino , Galectinas , Humanos , Sistema de Señalización de MAP Quinasas , Masculino , Linfocitos T/metabolismo , Linfocitos T/virología
16.
Sci Rep ; 7: 40648, 2017 01 17.
Artículo en Inglés | MEDLINE | ID: mdl-28094782

RESUMEN

DC-SIGN is a dendritic cell surface structure which participates in binding and transmission of HIV-1. Here, for the first time we demonstrate that cocaine induces over expression of DC-SIGN and significantly enhances virus transfer from DCs to T-cells by increasing the binding and internalization of HIV-1 in DCs. We found that cocaine activates a DC-SIGN mediated 'signalosome' complex by enhancing its association with LARG and LSP1. Further, LARG was observed to participate in DC-SIGN mediated internalization of HIV-1 in DCs. Intracellular trafficking studies of HIV-1 in cocaine treated DCs revealed increased co-localization of HIV-1 with endosomal or multi vesicular body (MVB) markers such as CD81 and VPS4 and decreased co-localization with the phagolysomal marker LAMP1; this signified altered intracellular trafficking and decreased degradation of HIV-1 in cocaine treated DCs. Furthermore, we found that cocaine induced activation of LARG which in turn activated Rho A and the focal adhesion molecules FAK, Pyk2 and paxillin. This signaling cascade enhanced the formation of an infectious synapse between DCs and T-cells. Our study provides insight into the molecular mechanisms of cocaine's contribution to key components in HIV pathogenesis and highlights novel targets for interrupting the virus life cycle in substance using hosts.


Asunto(s)
Linfocitos T CD4-Positivos/virología , Moléculas de Adhesión Celular/metabolismo , Cocaína/metabolismo , Células Dendríticas/metabolismo , Infecciones por VIH/metabolismo , Infecciones por VIH/transmisión , Lectinas Tipo C/metabolismo , Proteínas de Microfilamentos/metabolismo , Receptores de Superficie Celular/metabolismo , Factores de Intercambio de Guanina Nucleótido Rho/metabolismo , ATPasas Asociadas con Actividades Celulares Diversas/metabolismo , Transporte Biológico , Linfocitos T CD4-Positivos/efectos de los fármacos , Cocaína/farmacología , Células Dendríticas/efectos de los fármacos , Complejos de Clasificación Endosomal Requeridos para el Transporte/metabolismo , Adhesiones Focales/metabolismo , Expresión Génica , Infecciones por VIH/virología , VIH-1/fisiología , Interacciones Huésped-Patógeno , Humanos , Sinapsis Inmunológicas , Proteínas de Membrana de los Lisosomas/metabolismo , Receptores CCR5/genética , Receptores CCR5/metabolismo , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Tetraspanina 28/metabolismo , ATPasas de Translocación de Protón Vacuolares/metabolismo , Internalización del Virus , Proteína de Unión al GTP rhoA/metabolismo
17.
Oncotarget ; 7(48): 79388-79400, 2016 Nov 29.
Artículo en Inglés | MEDLINE | ID: mdl-27764820

RESUMEN

Squamous cell carcinoma of the head and neck (HNSCC) is characterized by high morbidity and mortality. Treatment failure, drug resistance and chemoradiation toxicity have necessitated the development of alternative treatment strategies. Styryl benzyl sulfones, a family of novel small molecule inhibitors, are being evaluated as anti-neoplastic agents in multiple clinical trials. The activity of these compounds has been well characterized in several preclinical tumor studies, but their activity has yet to be fully examined in HNSCC. We tested ON 01910.Na (rigosertib), a styryl benzyl sulfone in late-stage development, in HNSCC preclinical models. Rigosertib induced cytotoxicity in both HPV(+) and HPV(-) HNSCC cells in a dose-dependent manner. Characterization of the underlying molecular mechanism indicated that rigosertib induced inhibition of the PI3K/Akt/mTOR pathway, induced oxidative stress resulting in increased generation of reactive oxygen species (ROS), and activated extracellular signal-regulated kinases (ERK1/2) and c-Jun NH2-terminal kinase (JNK). Increased phosphorylation and cytoplasmic translocation of ATF-2 were also observed following rigosertib treatment. These changes in cell signaling led us to consider combining rigosertib with HNSCC standard-of-care therapies, such as cisplatin and radiation. Our study highlights the promising preclinical activity of rigosertib in HNSCC irrespective of HPV status and provides a molecular basis for rigosertib in combination with standard of care agents for HNSCC.


Asunto(s)
Antineoplásicos/farmacología , Carcinoma de Células Escamosas/metabolismo , Glicina/análogos & derivados , Neoplasias de Cabeza y Cuello/metabolismo , Infecciones por Papillomavirus/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Sulfonas/farmacología , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/virología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Citoplasma/metabolismo , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Glicina/farmacología , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/virología , Humanos , Estrés Oxidativo , Infecciones por Papillomavirus/tratamiento farmacológico , Fosforilación , Transducción de Señal/efectos de los fármacos , Carcinoma de Células Escamosas de Cabeza y Cuello
18.
Virusdisease ; 27(2): 111-5, 2016 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-27366760

RESUMEN

Zika virus (ZIKV) infection is a new emerging threat around the globe which might be responsible for microcephaly and Guillain-Barre syndrome in the infants. Recently, ZIKV outbreak has caused a public health crisis in Brazil after being linked to a sharp increase in birth defects. ZIKV is ssRNA virus belongs to the family Flaviviridae. It is mainly transmitted by mosquito bite specifically Aedes species and disease symptoms include fever, joint pain, muscle pain, rash, conjunctivitis, and headache. The reservoir of ZIKV is still not known. Protection at personal level by avoiding mosquito bite would help to reduce the incidence of the disease. Control of ZIKV infection by vaccination or antiviral drug either from modern, complementary and alternative medicines may be considered to be one of the most effective strategies in the long run. Large scale immunization of susceptible human population is highly required to prevent this deadly disease. Attempts should be made as soon as possible to develop effective vaccines or antiviral to prevent ZIKV infection. This article provides a current overview of the experimental therapeutics and treatment options based on modern, complementary and alternative medicines.

19.
Muscles Ligaments Tendons J ; 6(1): 35-47, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27331030

RESUMEN

BACKGROUND: rotator cuff tear affects many people. Natural history, and evidence for non-operative treatment remains limited. Our objective is to assess evidence available for the efficacy and morbidity of commonly used systemic medications, physiotherapy, and injections alongside evaluating any negative long-term effects. METHODS: a systematic search was performed of PubMed, Cochrane, EMBASE and CINAHL dates (1 January 1960 - 1 December 2014), search terms: 'rotator cuff tear', 'natural history', 'atraumatic', 'injection', 'physiotherapy' or 'physical therapy', 'injection', 'corticosteroid', 'PRP', 'MSC', risk of conservative treatment', and 'surgical indication'. RESULTS: eleven studies were included. The mean Coleman Methodology Score modified for conservative therapy is 69.21 (range 88-44) (SD 12.31). This included 2 RCTs, 7 prospective, and 2 retrospective studies. Evidence suggests it is safe to monitor symptomatic rotator cuff tears, as tear size and symptoms are not correlated with pain, function, and/or ultimate outcome. CONCLUSIONS: complete rotator cuff tears may be effectively treated with injections, exercise in the short and intermediate terms respectively. Negative effect of corticosteroids on rotator cuff tissue has not been demonstrated. Timing to end conservative treatment is unknown, but likely indicated when a patient demonstrates increased weakness and loss of function not recoverable by physiotherapy.

20.
Virusdisease ; 27(3): 211-214, 2016 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28466030

RESUMEN

Infectious diseases remain a leading source of human morbidity and mortality. Recently, emerging infectious diseases are dominated by zoonoses, and eventually rising considerably. Their emergence is dependent on various factors especially, socioeconomic, environmental and ecological factors etc. Recently, the swift spread of Zika virus (ZIKV) through the Americas, simultaneously with the association of infection with microcephaly and Guillain-Barré syndrome, has strained this previously overlooked virus into the global attention. ZIKV is an emerging mosquito-borne Flavivirus, identified in rhesus monkey in 1947 in Uganda, and eventually in human in 1952. Considering the severity and recent spread over Americas, it has been declared as a public health emergency of international concern, and expected number of cases may be around three to four million. Therefore, it's important for all to assess the risk and be prepared in all possible ways before it makes a huge loss and spread globally. This news tries to discuss the possible reasons for its spread, risk assessment, and options to obliterate ZIKV.

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