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1.
Mini Rev Med Chem ; 2024 Aug 26.
Artículo en Inglés | MEDLINE | ID: mdl-39192639

RESUMEN

While the use of plants in traditional medicine dates back to 1500 B.C., modern advancements led to the development of innovative therapeutic techniques. On the other hand, in the field of anti-infective agents, lack of efficacy and the onset of resistance stimulate the search for novel agents. Genus Artemisia is one of the most diverse among perennial plants with a variety of species, properties, and chemical components. The genus is known for its therapeutic values and, in particular, for its role in the origin of antimalarial agents derived from artemisinin. In this review, we aim to provide an updated overview of the evolution of natural and natureinspired compounds related to the genus Artemisia that have been proven, in vitro and in vivo, to possess antimalarial properties. An overview of the chemical composition and a description of the ethnopharmacological aspects will be presented, as well as an updated report on in vitro and in vivo evidence that allowed the translation of artemisinin and its derivatives from traditional chemistry into modern medicinal chemistry. The biological and structural properties will be discussed, also dedicating attention to the challenging tasks that still are open, such as the identification of optimal combination strategies, the routes of administration, and the full assessment of the mechanism of action.

2.
Cytokine ; 182: 156699, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39033730

RESUMEN

Psoriasis, a prevalent inflammatory skin condition impacting millions globally, continues to pose treatment challenges, despite the availability of multiple therapies. This underscores the demand for innovative treatments. Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic option due to their capacity to modulate the immune system and facilitate tissue healing. Recent research indicates that MSCs don't just work through direct cell-to-cell interactions but also release extracellular vesicles (EVs), containing various bioactive substances like proteins, lipids, and nucleic acids. This article explores our current knowledge of psoriasis's origins and the potential utilization of MSCs and their EVs, particularly exosomes, in managing the condition. Additionally, we delve into how MSCs and EVs function in therapy, including their roles in regulating immune responses and promoting tissue repair. Lastly, we discuss the obstacles and opportunities associated with translating MSC-based treatments for psoriasis into clinical practice.


Asunto(s)
Exosomas , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Psoriasis , Psoriasis/terapia , Humanos , Células Madre Mesenquimatosas/inmunología , Células Madre Mesenquimatosas/metabolismo , Trasplante de Células Madre Mesenquimatosas/métodos , Exosomas/metabolismo , Animales , Vesículas Extracelulares/metabolismo
3.
Med Oncol ; 41(7): 182, 2024 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-38900329

RESUMEN

Interleukin-6 (IL-6), a pro-inflammatory cytokine, plays a crucial role in host immune defense and acute stress responses. Moreover, it modulates various cellular processes, including proliferation, apoptosis, angiogenesis, and differentiation. These effects are facilitated by various signaling pathways, particularly the signal transducer and activator of transcription 3 (STAT3) and Janus kinase 2 (JAK2). However, excessive IL-6 production and dysregulated signaling are associated with various cancers, promoting tumorigenesis by influencing all cancer hallmarks, such as apoptosis, survival, proliferation, angiogenesis, invasiveness, metastasis, and notably, metabolism. Emerging evidence indicates that selective inhibition of the IL-6 signaling pathway yields therapeutic benefits across diverse malignancies, such as multiple myeloma, prostate, colorectal, renal, ovarian, and lung cancers. Targeting key components of IL-6 signaling, such as IL-6Rs, gp130, STAT3, and JAK via monoclonal antibodies (mAbs) or small molecules, is a heavily researched approach in preclinical cancer studies. The purpose of this study is to offer an overview of the role of IL-6 and its signaling pathway in various cancer types. Furthermore, we discussed current preclinical and clinical studies focusing on targeting IL-6 signaling as a therapeutic strategy for various types of cancer.


Asunto(s)
Interleucina-6 , Neoplasias , Transducción de Señal , Humanos , Interleucina-6/metabolismo , Interleucina-6/antagonistas & inhibidores , Neoplasias/metabolismo , Neoplasias/inmunología , Neoplasias/patología , Neoplasias/tratamiento farmacológico , Animales , Progresión de la Enfermedad , Factor de Transcripción STAT3/metabolismo , Antineoplásicos/uso terapéutico
4.
Front Aging Neurosci ; 16: 1379431, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38867846

RESUMEN

Background: Taurine, an amino acid abundantly found in the brain and other tissues, has potential neuroprotective properties. Alzheimer's disease (AD) is a commonly occurring type of dementia, which becomes more prevalent as people age. This experiment aimed to assess the neuroprotective effects of taurine on SH-SY5Y cells by examining its impact on Dihydrotestosterone (DHT), Dihydroprogesterone (DHP), as well as the expression of miRNA-21 and miRNA-181. Methods: The effects of various taurine concentrations (0.25, and 0.75 mg/mL), and LPS (0.1, and 12 mg/mL) on the SH-SY5Y cell line were assessed using the MTT assay. The levels of DHT and DHP were quantified using an ELISA kit. Additionally, the expression levels of miRNA-181 and miRNA-21 genes were examined through Real-Time PCR analysis. Results: The results of the MTT assay showed that treatment with taurine at concentrations of 0.25, and 0.75 mg/mL reduces the toxicity of LPS in SH-SY5Y cells. ELISA results indicated that taurine at a concentration of 0.25, and 0.75 mg/mL significantly elevated DHT and DHP hormones in the SH-SY5Y cell line compared to the untreated group (p < 0.01). The expression levels of IL-1ß and IL-6 were decreased under the influence of LPS in SH-SY5Y cells after taurine treatment (p < 0.01). Gene expression analysis revealed that increasing taurine concentration resulted in heightened expression of miRNA-181 and miRNA-21, with the most significant increase observed at a concentration of 0.75 mg/mL (p < 0.001). Conclusion: Our study findings revealed that the expression of miRNA-181 and miRNA-21 can be enhanced by taurine. Consequently, exploring the targeting of taurine, miRNA-181, and miRNA-21 or considering hormone therapy may offer potential therapeutic approaches for treating AD or alleviating severe symptoms. Nonetheless, in order to fully comprehend the precise mechanisms involved, additional research is required.

5.
Med Oncol ; 41(6): 134, 2024 May 04.
Artículo en Inglés | MEDLINE | ID: mdl-38703282

RESUMEN

Primary liver cancer is a type of cancer that develops in the liver. Hepatocellular carcinoma is a primary liver cancer that usually affects adults. Liver cancer is a fatal global condition that affects millions of people worldwide. Despite advances in technology, the mortality rate remains alarming. There is growing interest in researching alternative medicines to prevent or reduce the effects of liver cancer. Recent studies have shown growing interest in herbal products, nutraceuticals, and Chinese medicines as potential treatments for liver cancer. These substances contain unique bioactive compounds with anticancer properties. The causes of liver cancer and potential treatments are discussed in this review. This study reviews natural compounds, such as curcumin, resveratrol, green tea catechins, grape seed extracts, vitamin D, and selenium. Preclinical and clinical studies have shown that these medications reduce the risk of liver cancer through their antiviral, anti-inflammatory, antioxidant, anti-angiogenic, and antimetastatic properties. This article discusses the therapeutic properties of natural products, nutraceuticals, and Chinese compounds for the prevention and treatment of liver cancer.


Asunto(s)
Neoplasias Hepáticas , Transducción de Señal , Animales , Humanos , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/uso terapéutico , Carcinoma Hepatocelular/prevención & control , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/metabolismo , Suplementos Dietéticos , Neoplasias Hepáticas/prevención & control , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Fitoquímicos/farmacología , Fitoquímicos/uso terapéutico , Transducción de Señal/efectos de los fármacos
6.
Int J Biol Macromol ; 270(Pt 2): 132245, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38729477

RESUMEN

This study investigates the use of nanodiamonds (ND) as a promising carrier for enzyme immobilization and compares the effectiveness of immobilized and native enzymes. Three different enzyme types were tested, of which Rhizopus niveus lipase (RNL) exhibited the highest relative activity, up to 350 %. Under optimized conditions (1 h, pH 7.0, 40 °C), the immobilized ND-RNL showed a maximum specific activity of 0.765 U mg-1, significantly higher than native RNL (0.505 U mg-1). This study highlights a notable enhancement in immobilized lipase; furthermore, the enzyme can be recycled in the presence of a natural deep eutectic solvent (NADES), retaining 76 % of its initial activity. This aids in preserving the native conformation of the protein throughout the reusability process. A test on brine shrimp revealed that even at low concentrations, ND-RNL had minimal toxicity, indicating its low cytotoxicity. The in silico molecular dynamics simulations performed in this study offer valuable insights into the mechanism of interactions between RNL and ND, demonstrating that RNL immobilization onto NDs enhances its efficiency and stability. All told, these findings highlight the immense potential of ND-immobilized RNL as an excellent candidate for biological applications and showcase the promise of further research in this field.


Asunto(s)
Disolventes Eutécticos Profundos , Enzimas Inmovilizadas , Lipasa , Nanodiamantes , Lipasa/química , Lipasa/metabolismo , Enzimas Inmovilizadas/química , Enzimas Inmovilizadas/metabolismo , Nanodiamantes/química , Disolventes Eutécticos Profundos/química , Simulación de Dinámica Molecular , Estabilidad de Enzimas , Animales , Concentración de Iones de Hidrógeno , Rhizopus/enzimología , Temperatura , Artemia/efectos de los fármacos , Solventes/química
7.
Med Oncol ; 41(5): 122, 2024 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-38652344

RESUMEN

Drug repositioning or repurposing has gained worldwide attention as a plausible way to search for novel molecules for the treatment of particular diseases or disorders. Drug repurposing essentially refers to uncovering approved or failed compounds for use in various diseases. Cancer is a deadly disease and leading cause of mortality. The search for approved non-oncologic drugs for cancer treatment involved in silico modeling, databases, and literature searches. In this review, we provide a concise account of the existing non-oncologic drug molecules and their therapeutic potential in chemotherapy. The mechanisms and modes of action of the repurposed drugs using computational techniques are also highlighted. Furthermore, we discuss potential targets, critical pathways, and highlight in detail the different challenges pertaining to drug repositioning for cancer immunotherapy.


Asunto(s)
Reposicionamiento de Medicamentos , Inmunoterapia , Neoplasias , Humanos , Reposicionamiento de Medicamentos/métodos , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Neoplasias/terapia , Inmunoterapia/métodos , Antineoplásicos/uso terapéutico
8.
Cureus ; 16(4): e58360, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38628378

RESUMEN

Background Herpes zoster (HZ) or shingles, arises from the reactivation of the varicella zoster virus (VZV), mainly affecting older and immunocompromised individuals. Despite the efficacy of vaccines, vaccination rates in Saudi Arabia are low. Thus, this study aimed to assess the knowledge, attitude, and practice of the Saudi Arabian population toward HZ and its vaccination. Methods An observational cross-sectional study was carried out to evaluate the public perception in Saudi Arabia toward HZ and its vaccination, during the period from January to March 2024. Participants were selected using a non-probability, convenience sampling method, with recruitment facilitated through WhatsApp, a messaging app. Data has been analyzed using the statistical software Statistical Package for Social Sciences (SPSS), version 26.0 (IBM Corp., Armonk, NY). A p-value of <0.05 has been used to report the statistical significance. Results The study's demographic profile included 1237 participants, predominantly younger than 30 years (65.5%), with a female majority (65.7%). Public knowledge about HZ was limited, only 29.6% of participants recognized the risk of HZ post-chickenpox. More than half of the participants were not aware that the vaccine is provided by the Saudi Ministry of Health (MOH) for certain groups. However, over 75% are willing to receive the HZ vaccine upon physician recommendation. Conclusion This study shows a general lack of awareness about HZ and its vaccination in Saudi Arabia, including misconceptions about vaccination availability, recommendations, and the disease's complications. Gender differences in attitude and interest highlight the potential for tailored educational campaigns. Addressing these issues is essential for improving vaccination rates and mitigating HZ's impact.

12.
Artículo en Inglés | MEDLINE | ID: mdl-38319988

RESUMEN

Hereditary spherocytosis (HS) is the most common hereditary hemolytic disorder induced by red blood cell (RBC) membrane defect. This study was undertaken to determine mutations in genes associated with RBC membrane defect in patients with HS such as α-spectrin gene (SPTA1), ß-spectrin gene (SPTB), ankyrin gene (ANK1), band 3 anion transport gene (SLC4A1) and erythrocyte membrane protein band 4.1 gene (EPB41). Blood samples were collected from 23 unrelated patients with HS. Patients were diagnosed according to the guidelines from the British Society for Hematology. All hematological examinations for the determination of RBC abnormalities and osmotic fragility tests were conducted. Genomic DNA were extracted from peripheral blood cells and coding exons of known genes for hereditary spherocytosis were enriched using Roche/KAPA sequence capture technology and sequenced on an Illumina system via next-generation sequencing (NGS). The data showed that most of the HS patients confirmed splenomegaly and showed elevated reticulocytes and abnormal bilirubin values. NGS analysis identified the heterozygous variant c.5501G > A in the exon 39 of SPTA1 gene, resulted in a Trp1834*, which leads to a premature stop codon and subsequent mRNA degradation (nonsense- mediated decay) or truncation in α spectrin. Moreover, our data also revealed conventional mutations in genes SPTB, ANK, SLC4A1 and EBP41 in severe patients of HS. In short, this is the first report that determined a novel mutation c.5501G > A in SPTA1 gene in the Saudi population. To the best of our knowledge, this variant c.5501G > A has not been described in global literature so far. This novel mutation in SPTA1 gene is unique in the Saudi population.

13.
BMC Vet Res ; 20(1): 26, 2024 Jan 18.
Artículo en Inglés | MEDLINE | ID: mdl-38233918

RESUMEN

BACKGROUND: Compared with corn, wheat contains higher crude protein, amino acids concentration. However, wheat contains a mass of anti-nutritional factors, resulting in increased of the digesta viscosity and impaired the intestinal function in ruminant. OBJECTIVE: This study aimed to investigate the effects of substitution of different amounts of wheat for corn on hepatic metabolism in the Tibetan lamb. METHODS: Ninety Tibetan lambs (Body weight = 12.37 ± 0.92 kg) were randomly assigned to three groups: 0% wheat diet (Control), 10% wheat diet (Low group), and 15% wheat diet (High group). The feeding trial lasted for 130 d, including a 10 d adaption period. Hepatic gene expression profiling was performed via RNA sequencing after the conclusion of the feeding trials. RESULTS: Results showed that greater level of glutathione peroxidase levels in L group compared with those of the C and H groups (P < 0.05). The immune indexes, including interleukin-1ß (IL-1ß), immunoglobulin A (IgA), and IgM were also elevated in L group compared with the other groups (P < 0.05). Compared with H group, the hepatocytes were arranged radially, and hepatic plates anastomosed with each other to form a labyrinth-like structure in L group. Transcriptomic analysis showed 872 differentially expressed genes (DEG) between H and L group, of which 755 were down-regulated and 117 were up-regulated. Through Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, 32 pathways were significantly enriched (Q-value < 0.05), such as the cAMP signaling pathway, Th1 and Th2 cell differentiation, leukocyte transendothelial migration, platelet activation and adipocytokine signaling pathway. Additionally, the expression of comment DEGs were verified via quantitative reverse-transcription polymerase chain reaction. CONCLUSION: In summary, our findings suggest that wheat can be supplemented up to 10% in Tibetan sheep, contributing to improve the hepatic oxidative stress, immune response and lipid metabolism through regulating the expression of related genes.


Asunto(s)
Oveja Doméstica , Triticum , Ovinos , Animales , Metabolismo de los Lípidos , Tibet , Estrés Oxidativo , Dieta/veterinaria , Inmunidad
14.
Reprod Sci ; 31(7): 1958-1972, 2024 07.
Artículo en Inglés | MEDLINE | ID: mdl-38267808

RESUMEN

The effective combination of semen cryopreservation and artificial insemination has a positive effect on the conservation of germplasm resources, production and breeding, etc. However, during the process of semen cryopreservation, the sperm cells are very susceptible to different degrees of physical, chemical, and oxidative stress damage. Oxidative damage is the most important factor that reduces semen quality, which is affected by factors such as dilution equilibrium, change of osmotic pressure, cold shock, and enzyme action during the freezing-thawing process, which results in the aggregation of a large amount of reactive oxygen species (ROS) in sperm cells and affects the quality of semen after thawing. Therefore, the method of adding antioxidants to semen cryoprotective diluent is usually used to improve the effect of semen cryopreservation. The aim of this experiment was to investigate the effects of adding five antioxidants (GLP, Mito Q, NAC, SLS, and SDS) to semen cryoprotection diluent on the cryopreservation effect of semen from Saanen dairy goats. The optimal preservation concentrations were screened by detecting sperm viability, plasma membrane integrity, antioxidant capacity, and acrosomal enzyme activities after thawing, and the experimental results were as follows: the optimal concentrations of GLP, Mito Q, NAC, SLS, and SDS added to semen cryopreservation diluent at different concentrations were 0.8 mg/mL, 150 nmol/L, 0.6 mg/mL, 0.15 mg/ mL, 0.6 mg/mL, and 0.15 mg/mL. The optimal concentrations of the five antioxidants were added to the diluent and analyzed after 1 week of cryopreservation, and it was found that sperm viability, plasma membrane integrity, and mitochondrial activity were significantly enhanced after thawing compared with the control group (P < 0.05), and their antioxidant capacity was significantly enhanced (P < 0.05). Therefore, the addition of the above five antioxidants to goat sperm cryodilution solution had a better enhancement of sperm cryopreservation. This study provides a useful reference for exploring the improvement of goat semen cryoprotection effect.


Asunto(s)
Antioxidantes , Criopreservación , Crioprotectores , Cabras , Preservación de Semen , Animales , Masculino , Criopreservación/métodos , Criopreservación/veterinaria , Antioxidantes/farmacología , Preservación de Semen/métodos , Preservación de Semen/veterinaria , Crioprotectores/farmacología , Espermatozoides/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Semen/efectos de los fármacos , Motilidad Espermática/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Análisis de Semen , Membrana Celular/efectos de los fármacos
15.
J Appl Genet ; 65(2): 341-354, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38030871

RESUMEN

The coronavirus disease 2019 (COVID-19) was first found in Wuhan, China, in December 2019. Because the virus spreads quickly, it quickly became a global worry. Coronaviridae is the family that contains both SARS-CoV-2 and the viruses that came before (i.e., MERS-CoV and SARS-CoV). Recent sources portray that the COVID-19 virus has affected 344,710,576 people worldwide and killed about 5,598,511 people in the last 2 years. The B.1.1.529 strain, later called "Omicron," was named a Variant of Concern on November 24, 2021. The SARS-CoV-2 virus has gone through a never-ending chain of changes that have never happened before. As a result, it has many different traits. Most of these changes have occurred in the spike protein, where antibodies bind. Because of these changes, the Omicron type is very contagious and easy to pass on. There have been a lot of studies done to try to figure out this new challenge in the COVID-19 strains race, but there is still a lot that needs to be explained. This study focuses on virtual screening, docking, and molecular dynamic analysis; we aimed to identify therapeutic candidates for the SARS-CoV-2 variant Omicron based on their ability to inhibit non-structural proteins. We investigate the prediction of the properties of a substantial database of drug molecules obtained from the OliveNet™ database. Compounds that did not exhibit adequate gastrointestinal absorption and failed the Lipinski test are not considered for further research. The filtered compounds were coupled with our primary target, SARS-CoV-2 Omicron spike protein. We focused on SARS-CoV-2 Omicron spike protein and filtering potent olive compounds. Pinoresinol, the most likely candidate, is bound best (- 8.5 kcal/mol). Pinoresinol's strong interaction with the active site made the complex's dynamic structure more resilient. MD simulations explain the protein-ligand complex's stability and function. Pinoresinol may be a promising SARS-CoV-2 Omicron spike protein receptor lead drug, and additional research may assist the scientific community.


Asunto(s)
COVID-19 , Furanos , Lignanos , Olea , SARS-CoV-2 , Humanos , Simulación de Dinámica Molecular , Glicoproteína de la Espiga del Coronavirus
16.
Metab Brain Dis ; 39(1): 77-88, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38129732

RESUMEN

Neuro-oncological and neurodegenerative disorders, represented paradigmatically by glioblastoma and Alzheimer's disease, respectively, persist as formidable challenges in the biomedical realm. The interconnected molecular underpinnings of these conditions necessitate rigorous and novel therapeutic examinations. This comprehensive research was anchored on the premise of unveiling the therapeutic potential and specificity of Lupenone, a potent phytoconstituent, in targeting the molecular pathways underpinning both glioblastoma and Alzheimer's amyloid beta pathology. This was gauged through its interactions with key protein structures, 5H08 and 2ZHV. An integrative approach was adopted, marrying advanced proteomics and modern computer-aided drug design techniques. Molecular docking of Lupenone with 5H08 and 2ZHV was meticulously executed, with subsequent molecular dynamics simulations providing insights into the stability, viability, and intricacies of these interactions. Lupenone demonstrated profound binding affinities, evidenced by robust docking scores of -9.54 kcal/mol for 5H08 and -10.59 kcal/mol for 2ZHV. These interactions underscored Lupenone's eminent therapeutic potential in mitigating glioblastoma and modulating the amyloid beta pathology inherent to Alzheimer's. The introduction of Proteolysis Targeting Chimeras (PROTACs) further magnified the therapeutic prospects, accentuating Lupenone's efficacy. The findings of this study not only underscore the therapeutic acumen of Lupenone in addressing the challenges posed by glioblastoma and Alzheimer's but also lay a strong foundation for its consideration as a leading candidate in future neuro-oncological and neurodegenerative research endeavors. Given the compelling in-silico data, a clarion call is made for its empirical validation in holistic in-vivo settings, potentially pioneering a new therapeutic epoch in both glioblastoma and Alzheimer's interventions.


Asunto(s)
Enfermedad de Alzheimer , Glioblastoma , Lupanos , Humanos , Péptidos beta-Amiloides/metabolismo , Simulación de Dinámica Molecular , Enfermedad de Alzheimer/metabolismo , Glioblastoma/tratamiento farmacológico , Simulación del Acoplamiento Molecular
17.
Sci Rep ; 13(1): 17684, 2023 10 17.
Artículo en Inglés | MEDLINE | ID: mdl-37848584

RESUMEN

Bruton's tyrosine kinase (BTK) is a non-receptor protein kinase that plays a crucial role in various biological processes, including immune system function and cancer development. Therefore, inhibition of BTK has been proposed as a therapeutic strategy for various complex diseases. In this study, we aimed to identify potential inhibitors of BTK by using a drug repurposing approach. To identify potential inhibitors, we performed a molecular docking-based virtual screening using a library of repurposed drugs from DrugBank. We then used various filtrations followed by molecular dynamics (MD) simulations, principal component analysis (PCA), and Molecular Mechanics Poisson Boltzmann Surface Area (MM-PBSA) analysis to further evaluate the binding interactions and stability of the top-ranking compounds. Molecular docking-based virtual screening approach identified several repurposed drugs as potential BTK inhibitors, including Eltrombopag and Alectinib, which have already been approved for human use. All-atom MD simulations provided insights into the binding interactions and stability of the identified compounds, which will be helpful for further experimental validation and optimization. Overall, our study demonstrates that drug repurposing is a promising approach to identify potential inhibitors of BTK and highlights the importance of computational methods in drug discovery.


Asunto(s)
Agammaglobulinemia Tirosina Quinasa , Reposicionamiento de Medicamentos , Simulación de Dinámica Molecular , Inhibidores de Proteínas Quinasas , Humanos , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Descubrimiento de Drogas , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/uso terapéutico
18.
J Alzheimers Dis ; 96(2): 827-844, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37899058

RESUMEN

BACKGROUND: Tyrosine-protein kinase Fyn (Fyn) is a critical signaling molecule involved in various cellular processes, including neuronal development, synaptic plasticity, and disease pathogenesis. Dysregulation of Fyn kinase has been implicated in various complex diseases, including neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, as well as different cancer types. Therefore, identifying small molecule inhibitors that can inhibit Fyn activity holds substantial significance in drug discovery. OBJECTIVE: The aim of this study was to identify potential small-molecule inhibitors among bioactive phytoconstituents against tyrosine-protein kinase Fyn. METHODS: Through a comprehensive approach involving molecular docking, drug likeliness filters, and molecular dynamics (MD) simulations, we performed a virtual screening of a natural compounds library. This methodology aimed to pinpoint compounds potentially interacting with Fyn kinase and inhibiting its activity. RESULTS: This study finds two potential natural compounds: Dehydromillettone and Tanshinone B. These compoundsdemonstrated substantial affinity and specific interactions towards the Fyn binding pocket. Their conformations exhibitedcompatibility and stability, indicating the formation of robust protein-ligand complexes. A significant array of non-covalentinteractions supported the structural integrity of these complexes. CONCLUSION: Dehydromillettone and Tanshinone B emerge as promising candidates, poised for further optimization as Fynkinase inhibitors with therapeutic applications. In a broader context, this study demonstrates the potential of computationaldrug discovery, underscoring its utility in identifying compounds with clinical significance. The identified inhibitors holdpromise in addressing a spectrum of cancer and neurodegenerative disorders. However, their efficacy and safety necessitatevalidation through subsequent experimental studies.


Asunto(s)
Fitoquímicos , Proteínas Proto-Oncogénicas c-fyn , Humanos , Enfermedad de Alzheimer , Simulación del Acoplamiento Molecular , Neoplasias , Tirosina , Proteínas Proto-Oncogénicas c-fyn/antagonistas & inhibidores , Fitoquímicos/farmacología
19.
Int J Nanomedicine ; 18: 5531-5559, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37795042

RESUMEN

The recent developments in the study of clustered regularly interspaced short palindromic repeats/associated protein 9 (CRISPR/Cas9) system have revolutionized the art of genome-editing and its applications for cellular differentiation and immune response behavior. This technology has further helped in understanding the mysteries of cancer progression and possible designing of novel antitumor immunotherapies. CRISPR/Cas9-based genome-editing is now often used to engineer universal T-cells, equipped with recombinant T-cell receptor (TCR) or chimeric antigen receptor (CAR). In addition, this technology is used in cytokine stimulation, antibody designing, natural killer (NK) cell transfer, and to overcome immune checkpoints. The innovative potential of CRISPR/Cas9 in preparing the building blocks of adoptive cell transfer (ACT) immunotherapy has opened a new window of antitumor immunotherapy and some of them have gained FDA approval. The manipulation of immunogenetic regulators has opened a new interface for designing, implementation and interpretation of CRISPR/Cas9-based screening in immuno-oncology. Several cancers like lymphoma, melanoma, lung, and liver malignancies have been treated with this strategy, once thought to be impossible. The safe and efficient delivery of CRISPR/Cas9 system within the immune cells for the genome-editing strategy is a challenging task which needs to be sorted out for efficient immunotherapy. Several targeting approaches like virus-mediated, electroporation, microinjection and nanoformulation-based methods have been used, but each procedure offers some limitations. Here, we elaborate the recent updates of cancer management through immunotherapy in partnership with CRISPR/Cas9 technology. Further, some innovative methods of targeting this genome-editing system within the immune system cells for reprogramming them, as a novel strategy of anticancer immunotherapy is elaborated. In addition, future prospects and clinical trials are also discussed.


Asunto(s)
Sistemas CRISPR-Cas , Neoplasias , Humanos , Sistemas CRISPR-Cas/genética , Edición Génica/métodos , Inmunoterapia Adoptiva , Linfocitos T , Neoplasias/genética , Neoplasias/terapia
20.
Curr Pharm Des ; 29(26): 2078-2090, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37670700

RESUMEN

BACKGROUND: The IL-17 (interleukin 17) family consists of six structurally related pro-inflammatory cytokines, namely IL-17A to IL-17F. These cytokines have garnered significant scientific interest due to their pivotal role in the pathogenesis of various diseases. Notably, a specific subset of T-cells expresses IL-17 family members, highlighting their importance in immune responses against microbial infections. INTRODUCTION: IL-17 cytokines play a critical role in host defense mechanisms by inducing cytokines and chemokines, recruiting neutrophils, modifying T-cell differentiation, and stimulating the production of antimicrobial proteins. Maintaining an appropriate balance of IL-17 is vital for overall health. However, dysregulated production of IL-17A and other members can lead to the pathogenesis of numerous inflammatory and autoimmune diseases. METHOD: This review provides a comprehensive overview of the IL-17 family and its involvement in several inflammatory and autoimmune diseases. Relevant literature and research studies were analyzed to compile the data presented in this review. RESULTS: IL-17 cytokines, particularly IL-17A, have been implicated in the development of various inflammatory and autoimmune disorders, including multiple sclerosis, Hashimoto's thyroiditis, systemic lupus erythematosus, pyoderma gangrenosum, autoimmune hepatic disorders, rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, osteoarthritis, and graft-versus-host disease. Understanding the role of IL-17 in these diseases is crucial for developing targeted therapeutic strategies. CONCLUSION: The significant involvement of IL-17 cytokines in inflammatory and autoimmune diseases underscores their potential as therapeutic targets. Current treatments utilizing antibodies against IL-17 cytokines and IL-17RA receptors have shown promise in managing these conditions. This review consolidates the understanding of IL-17 family members and their roles, providing valuable insights for the development of novel immunomodulators to effectively treat inflammatory and autoimmune diseases.


Asunto(s)
Artritis Reumatoide , Enfermedades Autoinmunes , Humanos , Interleucina-17/metabolismo , Citocinas/metabolismo , Enfermedades Autoinmunes/tratamiento farmacológico , Células Th17/metabolismo
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