RESUMEN
Flavonoids are widely used as phytomedicines. Here, we report on flavonoid phytomedicines with potential for development into prophylactics or therapeutics against coronavirus disease 2019 (COVID-19). These flavonoid-based phytomedicines include: caflanone, Equivir, hesperetin, myricetin, and Linebacker. Our in silico studies show that these flavonoid-based molecules can bind with high affinity to the spike protein, helicase, and protease sites on the ACE2 receptor used by the severe acute respiratory syndrome coronavirus 2 to infect cells and cause COVID-19. Meanwhile, in vitro studies show potential of caflanone to inhibit virus entry factors including, ABL-2, cathepsin L, cytokines (IL-1ß, IL-6, IL-8, Mip-1α, TNF-α), and PI4Kiiiß as well as AXL-2, which facilitates mother-to-fetus transmission of coronavirus. The potential for the use of smart drug delivery technologies like nanoparticle drones loaded with these phytomedicines to overcome bioavailability limitations and improve therapeutic efficacy are discussed.
Asunto(s)
Antivirales/farmacología , Betacoronavirus/efectos de los fármacos , Infecciones por Coronavirus/tratamiento farmacológico , Coronavirus Humano OC43/efectos de los fármacos , Flavonoides/farmacología , Peptidil-Dipeptidasa A/química , Neumonía Viral/tratamiento farmacológico , Glicoproteína de la Espiga del Coronavirus/química , Enzima Convertidora de Angiotensina 2 , Animales , Antivirales/química , Betacoronavirus/química , Betacoronavirus/crecimiento & desarrollo , Sitios de Unión , COVID-19 , Cloroquina/química , Cloroquina/farmacología , Infecciones por Coronavirus/genética , Coronavirus Humano OC43/química , Coronavirus Humano OC43/crecimiento & desarrollo , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/química , Flavonoides/química , Humanos , Interleucinas/antagonistas & inhibidores , Interleucinas/química , Interleucinas/genética , Interleucinas/metabolismo , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/virología , Pulmón/efectos de los fármacos , Pulmón/patología , Pulmón/virología , Ratones , Simulación del Acoplamiento Molecular , Nanopartículas/administración & dosificación , Nanopartículas/química , Pandemias , Peptidil-Dipeptidasa A/genética , Peptidil-Dipeptidasa A/metabolismo , Fitoterapia/métodos , Neumonía Viral/genética , Cultivo Primario de Células , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/química , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas/metabolismo , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus/antagonistas & inhibidores , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/metabolismo , Termodinámica , Internalización del Virus/efectos de los fármacosRESUMEN
Interleukin-34 (IL-34), recently identified as a novel inflammatory cytokine and the second ligand for colony-stimulating factor-1 receptor, is known to play regulatory roles in the development, maintenance, and function of mononuclear phagocyte lineage cells - especially osteoclasts. Regarding its primary effect on osteoclasts, IL-34 has been shown to stimulate formation and activation of osteoclasts, which in turn magnifies osteoclasts-resorbing activity. In addition to its role in osteoclastogenesis, IL-34 has been implicated in inflammation of synovium via augmenting production of inflammatory mediators, in which altered IL-34 expression is regulated by pro-inflammatory cytokines responsible for cartilage degradation. Indeed, IL-34 has been documented to be highly expressed in inflamed synovium of rheumatoid arthritis (RA) and knee osteoarthritis (OA) patients, which are recognized as inflammatory arthritis. Furthermore, a number of clinical studies demonstrated that IL-34 levels were significantly increased in the circulation and synovial fluid of patients with RA and knee OA. Its levels were also found to be positively associated with disease severity - especially radiographic severity of both RA and knee OA patients. Interestingly, emerging evidence has accumulated that functional blockage of IL-34 with specific antibody can alleviate the severity of inflammatory arthritis. It is therefore reasonable to speculate that IL-34 may be developed as a potential biomarker and a new therapeutic candidate for inflammatory arthritis. To date, there are numerous studies showing IL-34 involvement and association with many aspects of inflammatory arthritis. Herein, this review aimed to summarize the recent findings regarding regulatory role of IL-34 in synovial inflammation-mediated cartilage destruction and update the current comprehensive knowledge on usefulness of IL-34-based treatment in inflammatory arthritis - particularly RA and knee OA.
Asunto(s)
Artritis/metabolismo , Interleucinas/metabolismo , Animales , Artritis/tratamiento farmacológico , Biomarcadores/metabolismo , Humanos , Interleucinas/químicaRESUMEN
Produced by CD4(+) helper T cells and natural killer T (NKT) cells, interleukin-21 (IL-21) performs broad regulatory functions on B cells, CD4(+) T cells, CD8(+) T cells, NK cells and NKT cells. Targeting IL-21 to enhance the immune system has attracted great interests in the development of vaccination, anti-infection and anti-tumor therapies. Administration of IL-21 in pre-clinical models is however limited by relatively high expense of the recombinant IL-21 protein. Here, we report a rapid and cost-effective method to produce IL-21 using Escherichia coli (E. coli) by introducing a novel two-step dilution strategy for refolding. The method has been validated to produce milligrams of human IL-21, human IL-21/IL-4 chimera and mouse IL-21 with high bioactivities and low endotoxin, mostly suitable for in vitro and in vivo pre-clinical studies.
Asunto(s)
Escherichia coli/metabolismo , Interleucinas/biosíntesis , Animales , Línea Celular , Evaluación Preclínica de Medicamentos , Escherichia coli/genética , Humanos , Subunidad alfa del Receptor de Interleucina-21/metabolismo , Interleucinas/química , Ratones , Pliegue de Proteína , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/químicaRESUMEN
Type III lambda interferons (IFNs) have activity similar to type I IFNs, but a more restricted receptor distribution. A pegylated human IFN lambda-1 (pegIFNλ) is under development for chronic hepatitis C. Induction of receptor signaling (STAT1 phosphorylation) and expression of interferon-stimulated genes (ISGs) by pegIFNλ were assessed in, respectively, cynomolgus monkey leukocyte subsets and hepatocytes stimulated in vitro. ISG induction by pegIFNλ or IFNα was also assessed in peripheral leukocytes and liver biopsies after single and repeat (x3) dosing of pegIFNλ (0.03, 0.3, 3.0 mg/kg) or unpegylated IFNα-2b (10(7) IU/kg). Single-dose pharmacokinetics of pegIFNλ were evaluated. Strong ISG induction occurred in cultured hepatocytes and liver biopsies with both pegIFNλ and IFNα. However, STAT1 phosphorylation, MHC class 1 upregulation, and ISG induction in leukocytes only occurred with IFNα. Serum neopterin was unaffected by pegIFNλ; however, ß-2-microglobulin was elevated at all doses. The terminal half-life of pegIFNλ was 23 h with a 59 mL/kg volume of distribution, consistent with other pegylated IFNs. Serum exposure was dose-proportional across the dosing range. These data demonstrate the suitability of cynomolgus monkeys for the preclinical evaluation of pegIFNλ. Additionally, the absence of pegIFNλ pharmacologic activity in leukocytes is consistent with its low receptor expression in blood.
Asunto(s)
Hepatitis C Crónica/tratamiento farmacológico , Hepatocitos/efectos de los fármacos , Inmunoterapia , Interleucinas/farmacocinética , Leucocitos Mononucleares/efectos de los fármacos , Animales , Células Cultivadas , Evaluación Preclínica de Medicamentos , Regulación de la Expresión Génica , Hepatitis C Crónica/inmunología , Hepatocitos/inmunología , Humanos , Interferones , Interleucinas/administración & dosificación , Interleucinas/química , Leucocitos Mononucleares/inmunología , Macaca fascicularis , Fosforilación/efectos de los fármacos , Polietilenglicoles/química , Factor de Transcripción STAT1/genética , Factor de Transcripción STAT1/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Current treatment of chronic hepatitis C consists of pegylated interferon-alpha (PEG-IFN-alpha) in combination with ribavirin. This regimen is associated with adverse effects that can limit its use. PEG-IFN-lambda 1 (pegIFNlambda) is a novel IFN that shares many of the biological effects of IFN-alpha but may have fewer side effects due to its more selective receptor distribution. Preclinical data show that pegIFNlambda has antiviral activity against hepatitis C virus (HCV) but does not inhibit myeloid colony formation. A phase 1 study in healthy volunteers demonstrated that pegIFNlambda is well tolerated. Elevated liver enzymes resulted in a dose-limiting toxicity after a single dose of 7.5 microg/kg, the highest dose tested. A phase 1b study in genotype 1 HCV patients who either relapsed after IFN-alpha therapy or naive to therapy was initiated. Interim data from the treatment relapse subset showed viral load reductions of 2.3 to 4.0 logs when pegIFNlambda was administered weekly as a single agent with or without ribavirin for up to 4 weeks. Drug-related side effects included elevation of liver enzymes. Decreases in hemoglobin were observed only in patients receiving ribavirin. Constitutional symptoms appeared lower than historical data for PEG-IFN-alpha. These results form the basis of further development of pegIFNlambda as a novel treatment for chronic hepatitis C.