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1.
Front Microbiol ; 15: 1453998, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39228384

RESUMEN

Drug resistance in Plasmodium falciparum presents a formidable challenge to the humanity. And, unavailability of an effective vaccine worsens the situation further. Autophagy is one of the mechanisms employed by parasite to evade drug pressure to survive. Autophagy induced by the P. falciparum in response to the oleuropein pressure may answer many questions related to the parasite survival as well as evolving drug tolerance. The survival/autophagy axis could be an important avenue to explore in order to address certain questions related to the evolution of drug resistance. In addition, humanized mouse model of P. falciparum infection could serve as an important preclinical tool to investigate the oleuropein-induced autophagy, potentially helping to dissect the mechanisms underlying the development of antimalarial drug resistance.

2.
Discov Nano ; 19(1): 145, 2024 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-39256285

RESUMEN

Breast cancer is one of the leading causes of death among women globally, making its diagnosis and treatment challenging. The use of nanotechnology for cancer diagnosis and treatment is an emerging area of research. To address this issue, multiwalled carbon nanotubes (MWCNTs) were ligand exchanged with butyric acid (BA) to gain hydrophilic character. The successful functionalization was confirmed by FTIR spectroscopy. Surface morphology changes were observed using SEM, while TEM confirmed the structural integrity of the MWCNTs after functionalization. Particle size, zeta potential, and UV spectroscopy were also performed to further characterize the nanoparticles. The breast cancer aptamer specific to Mucin-1 (MUC-1) was then conjugated with the functionalized MWCNTs. These MWCNTs successfully targeted breast cancer cells (MDA-MB-231) as examined by cellular uptake studies and exhibited a reduction in cancer-induced inflammation, as evidenced by gene transcription (qPCR) and protein expression (immunoblotting) levels. Immunoblot and confocal-based immunofluorescence assay (IFA) indicated the ability of CNTs to induce photothermal cell death of MDA-MB-231 cells. Upon imaging, cancer cells were effectively visualized due to the MWCNTs' ability to act as magnetic resonance imaging (MRI) contrast agents. Additionally, MWCNTs demonstrated photothermal capabilities to eliminate bound cancer cells. Collectively, our findings pave the way for developing aptamer-labeled MWCNTs as viable "theranostic alternatives" for breast cancer treatment.

4.
Discov Nano ; 19(1): 136, 2024 Aug 31.
Artículo en Inglés | MEDLINE | ID: mdl-39217276

RESUMEN

The suboptimal efficacies of existing anti-malarial drugs attributed to the emergence of drug resistance dampen the clinical outcomes. Hence, there is a need for developing novel drug and drug targets. Recently silver nanoparticles (AgNPs) constructed with the leaf extracts of Euphorbia cotinifolia were shown to possess antimalarial activity. Therefore, the synthesized AgNPs from Euphorbia cotinifolia (EcAgNPs) were tested for their parasite clearance activity. We determined the antimalarial activity in the asexual blood stage infection of 3D7 (laboratory strain) P. falciparum. EcAgNPs demonstrated the significant inhibition of parasite growth (EC50 of 0.75 µg/ml) in the routine in vitro culture of P. falciparum. The synthesized silver nanoparticles were seen to induce apoptosis in P. falciparum through increased reactive oxygen species (ROS) ROS production and activated programmed cell death pathways characterized by the caspase-3 and calpain activity. Also, altered transcriptional regulation of Bax/Bcl-2 ratio indicated the enhanced apoptosis. Moreover, inhibited expression of PfLPL-1 by EcAgNPs is suggestive of the dysregulated host fatty acid flux via parasite lipid storage. Overall, our findings suggest that EcAgNPs are a non-toxic and targeted antimalarial treatment, and could be a promising therapeutic approach for clearing malaria infection.

5.
STAR Protoc ; 5(3): 103141, 2024 Jun 19.
Artículo en Inglés | MEDLINE | ID: mdl-38905105

RESUMEN

The anti-inflammatory activity of a phytocompound (oleuropein [OLP]) in the lipopolysaccharide (LPS)-mimicked macrophage model of inflammation demonstrates the importance of PI3K-Akt1 signaling in establishing "immune homeostasis." Here, we present a protocol for the cultivation of in vitro cultures of P. falciparum for carrying out drug sensitivity assays. We describe steps for parasite synchronization, drug treatment, DNA isolation, and starvation-induced autophagy. This protocol provides insights into autophagy and parasite tolerance to drug pressure. For complete details on the use and execution of this protocol, please refer to Sharma et al.1.

6.
iScience ; 27(4): 109463, 2024 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-38562521

RESUMEN

Antimalarial drug resistance and unavailability of effective vaccine warrant for newer drugs and drug targets. Hence, anti-inflammatory activity of phyto-compound (oleuropein; OLP) was determined in antigen (LPS)-stimulated human THP-1 macrophages (macrophage model of inflammation; MMI). Reduction in the inflammation was controlled by the PI3K-Akt1 signaling to establish the "immune-homeostasis." Also, OLP treatment influenced the cell death/autophagy axis leading to the modulated inflammation for extended cell survival. The findings with MII prompted us to detect the antimalarial activity of OLP in the wild type (3D7), D10-expressing GFP-Atg18 parasite, and chloroquine-resistant (Dd2) parasite. OLP did not show the parasite inhibition in the routine in vitro culture of P. falciparum whereas OLP increased the antimalarial activity of artesunate. The molecular docking of autophagy-related proteins, investigations with MMI, and parasite inhibition assays indicated that the host activated the autophagy to survive OLP pressure. The challenge model of P. berghei infection showed to induce autophagy for circumventing anti-plasmodial defenses.

7.
Heliyon ; 10(5): e26887, 2024 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-38455541

RESUMEN

Poly(I:C) and R848, synthetic ligands that activate Toll-like receptor 3 (TLR3) and TLR7/8 respectively, have been well-established for their ability to stimulate the immune system and induce antigen-specific immune responses. These ligands are capable of inducing the production of cytokines and chemokines, and hence support the activation and differentiation of B and T cells. We saw the long-lasting and perdurable immune responses by these adjuvants essentially required for an efficacious subunit vaccine. In this study, we investigated the potential of poly(I:C) and R848 to elicit B and T cell responses to the OVA antigen. We assessed the stimulatory effects of these ligands on the immune system, their impact on B and T cell activation, and their ability to enhanced generation of B and T cells. Collectively, our findings contribute to the understanding how poly(I:C) and R848 can be utilized as an adjuvant system to enhance immune responses to protein-based subunit vaccines. In the end, this work provides insights for the development of novel vaccination strategies and improving the vaccine efficacy. Present work shall help formulate newer strategies for subunit vaccines to address the infectious diseases.

8.
Int J Nanomedicine ; 19: 2149-2177, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38482519

RESUMEN

Background: Rheumatoid arthritis (RA) is a common acute inflammatory autoimmune connective tissue arthropathy. The genetic studies, tissue analyses, experimental animal models, and clinical investigations have confirmed that stromal tissue damage and pathology driven by RA mounts the chronic inflammation and dysregulated immune events. Methods: We developed methotrexate (MTX)-loaded lipid-polymer hybrid nanoparticles (MTX-LPHNPs) and aceclofenac (ACE)-loaded nanostructured lipid carriers (ACE-NLCs) for the efficient co-delivery of MTX and ACE via intravenous and transdermal routes, respectively. Bio-assays were performed using ex-vivo skin permeation and transport, macrophage model of inflammation (MMI) (LPS-stimulated THP-1 macrophages), Wistar rats with experimental RA (induction of arthritis with Complete Freund's adjuvant; CFA and BCG), and programmed death of RA affected cells. In addition, gene transcription profiling and serum estimation of inflammatory, signaling, and cell death markers were performed on the blood samples collected from patients with RA. Results: Higher permeation of ACE-NLCs/CE across skin layers confirming the greater "therapeutic index" of ACE. The systemic delivery of MTX-loaded LPHNPs via the parenteral (intravenous) route is shown to modulate the RA-induced inflammation and other immune events. The regulated immunological and signaling pathway(s) influence the immunological axis to program the death of inflamed cells in the MMI and the animals with the experimental RA. Our data suggested the CD40-mediated and Akt1 controlled cell death along with the inhibited autophagy in vitro. Moreover, the ex vivo gene transcription profiling in drug-treated PBMCs and serum analysis of immune/signalling markers confirmed the therapeutic role co-delivery of drug nanoparticles to treat RA. The animals with experimental RA receiving drug treatment were shown to regain the structure of paw bones and joints similar to the control and were comparable with the market formulations. Conclusion: Our findings confirmed the use of co-delivery of drug nanoformulations as the "combination drug regimen" to treat RA.


Asunto(s)
Artritis Experimental , Artritis Reumatoide , Diclofenaco/análogos & derivados , Nanopartículas , Humanos , Ratas , Animales , Metotrexato , Ratas Wistar , Artritis Reumatoide/patología , Nanopartículas/química , Inflamación/tratamiento farmacológico , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/patología , Lípidos/química
10.
Drug Discov Today ; 28(8): 103671, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37330038

RESUMEN

Rheumatoid arthritis (RA) is an inflammatory, autoimmune and connective-tissue arthropathy. The methotrexate (MTX) and aceclofenac (ACL) combination drug regimen is known to regulate the immunological pathways. Also, RA-elicited inflammation is decreased by the combination drug treatment. ACL and MTX combination treatment has been shown to regulate the signaling pathway controlled by NF-κB and FOXO1. The present manuscript reviews the importance of the combination drug regimen to treat and/or manage RA. The combination drug regimen could affect the Th1/Th17 axis to switch the balance toward the immunoregulatory (Th1) phenotype for establishing immune homeostasis. In conclusion, we propose the study of the immunological signaling pathways in experimental humanized RA mice.


Asunto(s)
Antirreumáticos , Artritis Experimental , Artritis Reumatoide , Ratones , Animales , Metotrexato/farmacología , Metotrexato/uso terapéutico , Antirreumáticos/farmacología , Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/metabolismo , Quimioterapia Combinada
11.
Crit Rev Toxicol ; 53(1): 34-51, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-37115714

RESUMEN

Immunotoxicity is the critical endpoint used by some regulatory agencies to establish toxicity values for perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS). However, the hypothesis that exposure to certain per- and polyfluoroalkyl substances (PFAS) causes immune dysregulation is subject to much debate. An independent, international expert panel was engaged utilizing methods to reduce bias and "groupthink". The panel concluded there is moderate evidence that PFOS and PFOA are immunotoxic, based primarily on evidence from animal data. However, species concordance and human relevance cannot be well established due to data limitations. The panel recommended additional testing that includes longer-term exposures, evaluates both genders, includes other species of animals, tests lower dose levels, assesses more complete measures of immune responses, and elucidates the mechanism of action. Panel members agreed that the Faroe Islands cohort data should not be used as the primary basis for deriving PFAS risk assessment values. The panel agreed that vaccine antibody titer is not useful as a stand-alone metric for risk assessment. Instead, PFOA and PFOS toxicity values should rely on multiple high-quality studies, which are currently not available for immune suppression. The panel concluded that the available PFAS immune epidemiology studies suffer from weaknesses in study design that preclude their use, whereas available animal toxicity studies provide comprehensive dataset to derive points of departure (PODs) for non-immune endpoints. The panel recommends accounting for potential PFAS immunotoxicity by applying a database uncertainty factor to POD values derived from animal studies for other more robustly supported critical effects.


Asunto(s)
Ácidos Alcanesulfónicos , Fluorocarburos , Animales , Humanos , Masculino , Femenino , Fluorocarburos/toxicidad , Caprilatos/toxicidad , Estudios Epidemiológicos , Ácidos Alcanesulfónicos/toxicidad
12.
Viruses ; 15(4)2023 03 27.
Artículo en Inglés | MEDLINE | ID: mdl-37112836

RESUMEN

Genetic variant(s) of concern (VoC) of SARS-CoV-2 have been emerging worldwide due to mutations in the gene encoding spike glycoprotein. We performed comprehensive analyses of spike protein mutations in the significant variant clade of SARS-CoV-2, using the data available on the Nextstrain server. We selected various mutations, namely, A222V, N439K, N501Y, L452R, Y453F, E484K, K417N, T478K, L981F, L212I, N856K, T547K, G496S, and Y369C for this study. These mutations were chosen based on their global entropic score, emergence, spread, transmission, and their location in the spike receptor binding domain (RBD). The relative abundance of these mutations was mapped with global mutation D614G as a reference. Our analyses suggest the rapid emergence of newer global mutations alongside D614G, as reported during the recent waves of COVID-19 in various parts of the world. These mutations could be instrumentally imperative for the transmission, infectivity, virulence, and host immune system's evasion of SARS-CoV-2. The probable impact of these mutations on vaccine effectiveness, antigenic diversity, antibody interactions, protein stability, RBD flexibility, and accessibility to human cell receptor ACE2 was studied in silico. Overall, the present study can help researchers to design the next generation of vaccines and biotherapeutics to combat COVID-19 infection.


Asunto(s)
COVID-19 , Glicoproteína de la Espiga del Coronavirus , Humanos , Glicoproteína de la Espiga del Coronavirus/genética , SARS-CoV-2/genética , Mutación , Unión Proteica
13.
Int Rev Immunol ; 42(4): 304-322, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36731424

RESUMEN

The innate lymphoid cell (ILC) system comprising of the circulating and tissue-resident cells is known to clear infectious pathogens, establish immune homeostasis as well as confer antitumor immunity. Human natural killer cells (hNKs) and other ILCs carry out mopping of the infectious pathogens and perform cytolytic activity regulated by the non-adaptive immune system. The NK cells generate immunological memory and rapid recall response tightly regulated by the adaptive immunity. The interaction of NK and B cell, and its role to induce the pathogen specific immunity is not fully understood. Hence, present article sheds light on the interaction between NK and B cells and resulting immune responses in the infectious diseases. The immune responses elicited by the NK-B cell interaction is of particular importance for developing therapeutic vaccines against the infectious pathogens. Further, experimental evidences suggest the immune-response driven by NK cell population elicits the host-specific antibodies and memory B cells. Also, recently developed humanized immune system (HIS) mice and their importance in to understanding the NK-B cell interaction and resulting pathogen specific immunity has been discussed.


Asunto(s)
Enfermedades Transmisibles , Inmunidad Innata , Animales , Humanos , Ratones , Inmunidad Adaptativa , Células Asesinas Naturales , Memoria Inmunológica , Comunicación Celular
14.
Front Immunol ; 13: 972435, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36405684

RESUMEN

Interferon-γ (IFN-γ)-producing natural killer (NK) cells and innate lymphoid cells (ILCs) activate the adaptive system's B and T cells in response to pathogenic invasion; however, how these cells are activated during infections is not yet fully understood. In recent years, a new lymphocyte population referred to as "natural killer-like B (NKB) cells", expressing the characteristic markers of innate NK cells and adaptive B cells, has been identified in both the spleen and mesenteric lymph nodes during infectious and inflammatory pathologies. NKB cells produce IL-18 and IL-12 cytokines during the early phases of microbial infection, differentiating them from conventional NK and B cells. Emerging evidence indicates that NKB cells play key roles in clearing microbial infections. In addition, NKB cells contribute to inflammatory responses during infectious and inflammatory diseases. Hence, the role of NKB cells in disease pathogenesis merits further study. An in-depth understanding of the phenotypic, effector, and functional properties of NKB cells may pave the way for the development of improved vaccines and therapeutics for infectious and inflammatory diseases.


Asunto(s)
Inmunidad Innata , Células Asesinas Naturales , Subgrupos Linfocitarios , Citocinas , Interleucina-12
17.
Future Microbiol ; 17: 931-941, 2022 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-35704297

RESUMEN

Aims: Development of resistance by the malaria parasite, a systemic inflammatory and infectious pathogen, has raised the need for novel efficacious antimalarials. Plant-derived natural compounds are known to modulate the immune response and eradicate the infectious pathogens. Therefore we carried out experiments with swertiamarin to dissect its anti-inflammatory and immunomodulatory potential. Materials & methods: We carried out studies in Swiss albino mice that received infectious challenge with Plasmodium berghei and swertiamarin treatment in a prophylactic manner. Results & conclusion: Oral administration of swertiamarin prior to infectious challenge with P. berghei in experimental mice showed delayed parasite development as compared with untreated control. IFN-γ and IL-10 appeared to be adapted/modulated by regular swertiamarin treatment. Further, withdrawal of swertiamarin pressure did not affect parasite replication. However, the short half-life of swertiamarin limited its long-lasting therapeutic effect, requiring higher and frequent dosing schedules.


Asunto(s)
Antimaláricos , Plasmodium berghei , Animales , Antimaláricos/farmacología , Antimaláricos/uso terapéutico , Inmunidad , Glucósidos Iridoides , Ratones , Pironas
18.
Front Pharmacol ; 12: 713616, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34616297

RESUMEN

Aceclofenac (ACE), a cyclooxygenase-2 inhibitor, is the derivative of the diclofenac group that has been in use for the symptomatic treatment of systemic inflammatory autoimmune disease, rheumatoid arthritis (RA). Partial solubility, high lipophilic nature, and stability challenge its use in developing topical formulations. Hence, we developed and characterized nanostructured lipid carrier (NLC)-based ACE (ACE-NLC) hydrogel for an efficient transdermal delivery. NLC microemulsion was prepared using different lipids by various methods and was characterized with respect to particle size, zeta potential, surface morphology, and drug encapsulation efficiency. The optimized NLC formulation was incorporated into Carbopol® 940 gel, and this arrangement was characterized and compared with the existing marketed gel (Mkt-gel) formulation to assess in vitro drug release, rheology, texture profile, in vivo skin retention and permeation, and stability. Furthermore, prepared and characterized ACE-loaded NLC formulation was evaluated for skin integrity and fitted in a dermatokinetic model. The results of this study confirmed the spherical shape; smooth morphology and nanometric size attested by Zetasizer and scanning and transmission electron microcopy; and stability of the ACE-NLC formulation. The ACE-NLC-gel formulation showed good rheological and texture characteristics, and better skin distribution in the epidermis and dermis. Moreover, ACE-NLC permeated deeper in the skin layers and kept the skin integrity intact. Overall, NLC-based gel formulation of ACE might be a promising nanoscale lipid carrier for topical application when compared with the conventional Mkt-gel formulation.

19.
Immunotherapy ; 13(16): 1345-1353, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34424053

RESUMEN

Extensive research conducted on mouse-human chimeras has advanced our understanding on infectious diseases including the human-malaria parasite, Plasmodium falciparum. In vitro culture of asexual-blood stage infection of P. falciparum does not answer all questions related to parasitology, pharmacology and immunology, and complex life cycle, complicated genome, evolution of drug resistance and poor diagnosis makes it difficult to understand the patho-biology of parasite. Unavailability of effective-vaccine and issues of drug resistance advocates the use of human cell/tissues reconstituted immunodeficient-mice to P. falciparum. A number of immunodeficient-strains (TK/NOG, FRG/NOD, NOD/SCID/IL-2 receptor γ chain null, NOD severe combined immunodeficiency gamma [NSG] mouse and NOD.Rag1-/- IL2Rγ-/-  [NRG; DRAG]) are used for humanization purposes. Additionally, human-hematopoietic stem cells (CD34 reconstituted-NSG [human immune system]) mice support the engraftment and repopulation of immune effecters to study systemic inflammatory diseases.


Asunto(s)
Malaria Falciparum/inmunología , Malaria Falciparum/terapia , Plasmodium falciparum/inmunología , Animales , Modelos Animales de Enfermedad , Humanos , Malaria Falciparum/genética , Ratones , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID
20.
Cells ; 10(8)2021 07 21.
Artículo en Inglés | MEDLINE | ID: mdl-34440615

RESUMEN

Crohn's disease and ulcerative colitis, two major forms of inflammatory bowel disease (IBD) in humans, afflicted in genetically predisposed individuals due to dysregulated immune response directed against constituents of gut flora. The defective immune responses mounted against the regulatory mechanisms amplify and maintain the IBD-induced mucosal inflammation. Therefore, restoring the balance between inflammatory and anti-inflammatory immunepathways in the gut may contribute to halting the IBD-associated tissue-damaging immune response. Phenotypic and functional characterization of various immune-suppressive T cells (regulatory T cells; Tregs) over the last decade has been used to optimize the procedures for in vitro expansion of these cells for developing therapeutic interventional strategies. In this paper, we review the mechanisms of action and functional importance of Tregs during the pathogenesis of IBD and modulating the disease induced inflammation as well as role of mouse models including humanized mice repopulated with the human immune system (HIS) to study the IBD. "Humanized" mouse models provide new tools to analyze human Treg ontogeny, immunobiology, and therapy and the role of Tregs in developing interventional strategies against IBD. Overall, humanized mouse models replicate the human conditions and prove a viable tool to study molecular functions of human Tregs to harness their therapeutic potential.


Asunto(s)
Traslado Adoptivo , Colitis Ulcerosa/terapia , Enfermedad de Crohn/terapia , Linfocitos T Reguladores/trasplante , Animales , Colitis Ulcerosa/genética , Colitis Ulcerosa/inmunología , Colitis Ulcerosa/metabolismo , Enfermedad de Crohn/genética , Enfermedad de Crohn/inmunología , Enfermedad de Crohn/metabolismo , Modelos Animales de Enfermedad , Trasplante de Células Madre Hematopoyéticas , Humanos , Ratones Transgénicos , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Trasplante Heterólogo
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