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1.
Acta Pharmacol Sin ; 2024 Apr 29.
Artículo en Inglés | MEDLINE | ID: mdl-38684800

RESUMEN

Ulcerative colitis (UC) is associated with changed dietary habits and mainly linked with the gut microbiota dysbiosis, necroptosis of epithelial cells, and mucosal ulcerations. Liver dysfunction and abnormal level of liver metabolism indices were identified in UC patients, suggesting a close interaction between gut and liver disorders. Methionine-choline deficient diet (MCD) has been shown to induce persistent alterations of gut microbiota and metabolome during hepatitis. In this study we further explored the disease phenotypes in UC patients and investigated whether MCD functioned as a trigger for UC susceptibility. After assessing 88 serum specimens from UC patients, we found significant liver dysfunction and dyslipidemia including abnormal ALT, AST, TG, TC, LDL-c and HDL-c. Liver dysfunction and dyslipidemia were confirmed in DSS-induced colitis mice. We fed mice with MCD for 14 days to cause mild liver damage, and then treated with DSS for 7 days. We found that MCD intake significantly exacerbated the pathogenesis of mucosal inflammation in DSS-induced acute, progressive, and chronic colitis, referring to promotion of mucosal ulcers, colon shortening, diarrhea, inflammatory immune cell infiltration, cytokines release, and abnormal activation of inflammatory macrophages in colon and liver specimens. Intraperitoneal injection of clodronate liposomes to globally delete macrophages dramatically compromised the pathogenesis of MCD-triggering colitis. In addition, MCD intake markedly changed the production pattern of short-chain fatty acids (SCFAs) in murine stools, colons, and livers. We demonstrated that MCD-induced colitis pathogenesis largely depended on the gut microbes and the disease phenotypes could be transmissible through fecal microbiota transplantation (FMT). In conclusion, this study supports the concept that intake of MCD predisposes to experimental colitis and enhances its pathogenesis via modulating gut microbes and macrophages in mice.

2.
Prev Med ; 173: 107567, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37286090

RESUMEN

According to the randomization method, 82 patients can be divided into two groups, the control group and the study group, each with 41 patients participating in the investigation. All patients in the control group were cared for, and the study group used a health education model. The treatment mode of each group needs to adopt adherence, and it is necessary to maintain a healthy diet, smoking cessation and alcohol cessation, and regular review during the treatment of regular exercise and emotional regulation. To enable patients to accurately grasp health knowledge during treatment, score self-management ability (ESCA), and maintain a level of satisfaction with care. (1) In the study group, the standard treatment of patients directly reached 97.56%, regular review reached 95.12%, regular exercise reached 90.24%, the degree of smoking cessation reached 92.68%. (2) The mastery of disease and health knowledge in the first group (95.12%) was significantly higher than that of (78.05%) (P < 0.05). (3) After the intervention, the first group scored higher for self-responsibility (27.07 ± 3.15), self-awareness (25.59 ± 3.11), health knowledge (40.38 ± 4.54), and self-care skills (36.45 ± 3.19). (4) The nursing satisfaction level of the first group was (92.68%), which was significantly higher than that of the other group (75.61%). According to the conclusions, it can be shown that health education for tumor patients can improve patients' compliance with treatment and mastery of disease health knowledge, which is conducive to improving patients' self-management ability.


Asunto(s)
Neoplasias Gastrointestinales , Nanopartículas , Humanos , Conductas Relacionadas con la Salud , Educación en Salud , Nanopartículas/uso terapéutico , Cooperación del Paciente , Microambiente Tumoral
3.
Acta Pharmacol Sin ; 44(8): 1687-1700, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-36964308

RESUMEN

Aberrant NLRP3 activation has been implicated in the pathogenesis of numerous inflammation-associated diseases. However, no small molecular inhibitor that directly targets NLRP3 inflammasome has been approved so far. In this study, we show that Atranorin (C19H18O8), the secondary metabolites of lichen family, effectively prevents NLRP3 inflammasome activation in macrophages and dendritic cells. Mechanistically, Atranorin inhibits NLRP3 activation induced cytokine secretion and cell pyroptosis through binding to ASC protein directly and therefore restraining ASC oligomerization. The pharmacological effect of Atranorin is evaluated in NLRP3 inflammasome-driven disease models. Atranorin lowers serum IL-1ß and IL-18 levels in LPS induced mice acute inflammation model. Also, Atranorin protects against MSU crystal induced mice gouty arthritis model and lowers ankle IL-1ß level. Moreover, Atranorin ameliorates intestinal inflammation and epithelial barrier dysfunction in DSS induced mice ulcerative colitis and inhibits NLRP3 inflammasome activation in colon. Altogether, our study identifies Atranorin as a novel NLRP3 inhibitor that targets ASC protein and highlights the potential therapeutic effects of Atranorin in NLRP3 inflammasome-driven diseases including acute inflammation, gouty arthritis and ulcerative colitis.


Asunto(s)
Artritis Gotosa , Colitis Ulcerosa , Ratones , Animales , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Artritis Gotosa/tratamiento farmacológico , Artritis Gotosa/metabolismo , Inflamación/metabolismo , Interleucina-1beta/metabolismo , Ratones Endogámicos C57BL
4.
Acta Pharmacol Sin ; 43(2): 376-386, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33850274

RESUMEN

Systemic sclerosis (SSc) is a life-threatening chronic connective tissue disease with the characteristics of skin fibrosis, vascular injury, and inflammatory infiltrations. Though inhibition of phosphodiesterase 4 (PDE4) has been turned out to be an effective strategy in suppressing inflammation through promoting the accumulation of intracellular cyclic adenosine monophosphate (cAMP), little is known about the functional modes of inhibiting PDE4 by apremilast on the process of SSc. The present research aimed to investigate the therapeutic effects and underlying mechanism of apremilast on SSc. Herein, we found that apremilast could markedly ameliorate the pathological manifestations of SSc, including skin dermal thickness, deposition of collagens, and increased expression of α-SMA. Further study demonstrated that apremilast suppressed the recruitment and activation of macrophages and T cells, along with the secretion of inflammatory cytokines, which accounted for the effects of apremilast on modulating the pro-fibrotic processes. Interestingly, apremilast could dose-dependently inhibit the activation of M1 and T cells in vitro through promoting the phosphorylation of CREB. In summary, our research suggested that inhibiting PDE4 by apremilast might provide a novel therapeutic option for clinical treatment of SSc patients.


Asunto(s)
Macrófagos/efectos de los fármacos , Inhibidores de Fosfodiesterasa 4/farmacología , Piel/efectos de los fármacos , Linfocitos T/efectos de los fármacos , Talidomida/análogos & derivados , Animales , Western Blotting , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Femenino , Fibrosis , Citometría de Flujo , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Reacción en Cadena en Tiempo Real de la Polimerasa , Piel/metabolismo , Piel/patología , Linfocitos T/metabolismo , Talidomida/farmacología
5.
Acta Pharmacol Sin ; 43(8): 2055-2066, 2022 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-34907359

RESUMEN

Acute lung injury (ALI) is a common and devastating clinical disorder featured by excessive inflammatory responses. Stimulator of interferon genes (STING) is an indispensable molecule for regulating inflammation and immune response in multiple diseases, but the role of STING in the ALI pathogenesis is not well elucidated. In this study, we explored the molecular mechanisms of STING in regulating lipopolysaccharide (LPS)-induced lung injury. Mice were pretreated with a STING inhibitor C-176 (15, 30 mg/kg, i.p.) before LPS inhalation to induce ALI. We showed that LPS inhalation significantly increased STING expression in the lung tissues, whereas C-176 pretreatment dose-dependently suppressed the expression of STING, decreased the production of inflammatory cytokines including TNF-α, IL-6, IL-12, and IL-1ß, and restrained the expression of chemokines and adhesion molecule vascular cell adhesion protein-1 (VCAM-1) in the lung tissues. Consistently, in vitro experiments conducted in TNF-α-stimulated HMEC-1cells (common and classic vascular endothelial cells) revealed that human STING inhibitor H-151 or STING siRNA downregulated the expression levels of adhesion molecule and chemokines in HMEC-1cells, accompanied by decreased adhesive ability and chemotaxis of immunocytes upon TNF-α stimulation. We further revealed that STING inhibitor H-151 or STING knockdown significantly decreased the phosphorylation of transcription factor STAT1, which subsequently influenced its binding to chemokine CCL2 and adhesive molecule VCAM-1 gene promoter. Collectively, STING inhibitor can alleviate LPS-induced ALI in mice by preventing vascular endothelial cells-mediated immune cell chemotaxis and adhesion, suggesting that STING may be a promising therapeutic target for the treatment of ALI.


Asunto(s)
Lesión Pulmonar Aguda , Proteínas de la Membrana , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/prevención & control , Animales , Adhesión Celular , Quimiocinas/metabolismo , Quimiotaxis , Citocinas/metabolismo , Células Endoteliales/metabolismo , Humanos , Lipopolisacáridos/farmacología , Pulmón/patología , Proteínas de la Membrana/antagonistas & inhibidores , Ratones , FN-kappa B/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Molécula 1 de Adhesión Celular Vascular/efectos adversos , Molécula 1 de Adhesión Celular Vascular/metabolismo
6.
Cell Immunol ; 365: 104364, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33932876

RESUMEN

Ulcerative colitis (UC) represents a relapsing and inflammatory bowel disease which is commonly linked with the communications between dysfunction of epithelium and mucosal immune responses. Though caffeic acid (CA) has numerous pharmacological capacities, whether CA demonstrates immunoregulation on the mucosal immune responses remains ill-defined. Herein, the present research demonstrated that CA could dramatically attenuate the mucosal inflammation, as evidenced by improving the disease severity, serum biochemical indexes, mucosal ulcerations, loss of epithelium and crypts, and secretion of inflammatory cytokines in the colonic homogenates and explants culture. Consistently, CA could interfere with the infiltration and function of mononuclear macrophages in the mucosa, MLNs, and spleens of UC. Furthermore, CA exerted direct suppressive effects on the activation of BMDMs upon the exposure of TLRs agonists in vitro. Taken together, CA could attenuate DSS-induced murine UC through interfering with the activation of macrophages, which might provide an alternative therapeutic option for UC.


Asunto(s)
Ácidos Cafeicos/metabolismo , Colitis/inmunología , Enfermedades Inflamatorias del Intestino/inmunología , Macrófagos/inmunología , Receptores Toll-Like/metabolismo , Animales , Ácidos Cafeicos/inmunología , Células Cultivadas , Colitis/terapia , Sulfato de Dextran , Modelos Animales de Enfermedad , Humanos , Mediadores de Inflamación/metabolismo , Enfermedades Inflamatorias del Intestino/terapia , Activación de Macrófagos , Masculino , Ratones , Ratones Endogámicos C57BL , Receptores Toll-Like/agonistas
7.
FASEB J ; 34(6): 8028-8043, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32301543

RESUMEN

Hemoglobin-derived heme was reported to play protective roles in hemorrhagic diseases by modulating the macrophages toward recovery. Mucosal bleeding is one of the pathological features of inflammatory bowel diseases (IBD). However, whether heme provides anti-inflammatory profiles in macrophages, thus contributing to the intestinal mucosal barrier protection, is unclear. In the current study, we investigated the beneficial effects of heme on DSS-induced colitis mice and explored the underlying mechanisms. In vivo, systemic heme supplementation by hemin injection relieved intestinal inflammation and remedied intestinal mucosal barrier damage by correcting abnormal intestinal macrophage polarization. In vitro, we confirmed the reciprocally regulating effects of hemin on M1/M2 macrophage polarization in BMDM. Intriguingly, with knockdown of HO-1, the inhibiting effects of hemin on M1 polarization were maintained, while the promoting effects on M2 polarization were reversed. Further research proved that hemin repressed the inflammatory profiles in macrophages through inhibiting the translocation of NF-κB p65 by disrupting IRF5-NF-κB p65 complex formation in Spi-C-dependent way. In conclusion, these results showed that the modification of colon tissue microenvironment with heme supplementation plays a protective role in DSS-induced colitis mice through regulating the macrophage polarization in both HO-1-dependent and HO-1-independent way, indicating a new choice to therapeutically modulate the macrophage function and prevent IBD.


Asunto(s)
Colitis/metabolismo , Hemo-Oxigenasa 1/metabolismo , Hemo/metabolismo , Mediadores de Inflamación/metabolismo , Mucosa Intestinal/metabolismo , Macrófagos/metabolismo , Proteínas de la Membrana/metabolismo , Animales , Antiinflamatorios/metabolismo , Colitis/inducido químicamente , Colon/metabolismo , Citocinas/metabolismo , Sulfato de Dextran/farmacología , Femenino , Inflamación/metabolismo , Enfermedades Inflamatorias del Intestino/metabolismo , Factores Reguladores del Interferón/metabolismo , Mucosa Intestinal/efectos de los fármacos , Activación de Macrófagos/fisiología , Ratones , Ratones Endogámicos C57BL , Factor de Transcripción ReIA/metabolismo
8.
Pharmacol Res ; 169: 105678, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-34015449

RESUMEN

Triptolide has shown a good immunosuppressive effect on autoimmune diseases. However, the toxicity limited its widely clinical practice. In this study, we investigated the effects and underlying mechanisms of (5R)-5-hydroxytriptolide (LLDT-8), a novel triptolide derivative, on a murine psoriasis-like dermatitis model and related cell lines. Here, we showed that LLDT-8 significantly attenuated symptoms of psoriasis-like dermatitis induced by imiquimod (IMQ, a TLR7 agonist) by reducing the psoriasis area and severity index (PASI) score and inflammatory parameters. The action of LLDT-8 was involved in down-regulated interleukin (IL)-36α expression and blocked IL-36α pathway by LC-MS-based label-free quantitative (LFQ) proteomic approach and further experiments. Meanwhile, we observed that LLDT-8 significantly inhibited the expression of IL-36α in R837-treated bone marrow-derived dendritic cells (BMDCs). In conclusion, LLDT-8 notably alleviated IMQ-induced psoriasis-like skin inflammation via suppressing the IL-36α signaling pathway, suggesting LLDT-8 might be a potential drug for the treatment of psoriasis.


Asunto(s)
Dermatitis/tratamiento farmacológico , Fármacos Dermatológicos/uso terapéutico , Diterpenos/uso terapéutico , Interleucina-1/antagonistas & inhibidores , Psoriasis/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Animales , Western Blotting , Línea Celular , Dermatitis/metabolismo , Modelos Animales de Enfermedad , Femenino , Citometría de Flujo , Humanos , Interleucina-1/metabolismo , Ratones , Ratones Endogámicos BALB C , Psoriasis/metabolismo , Piel/efectos de los fármacos , Piel/metabolismo
9.
Acta Pharmacol Sin ; 39(10): 1633-1644, 2018 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-29849131

RESUMEN

Ulcerative colitis (UC) is a chronic, nonspecific inflammatory bowel disease (IBD) characterized by complicated and relapsing inflammation in the gastrointestinal tract. SM934 is a water-soluble artemisinin analogue that shows anti-inflammatory and immuno-regulatory effects. In this study, we investigated the effects of SM934 on UC both in vivo and in vitro. A mouse model of colitis was established in mice by oral administration of 5% dextran sulfate sodium (DSS). SM934 (3, 10 mg/kg per day, ig) was administered to the mice for 10 days. After the mice were sacrificed, colons, spleens and mesenteric lymph nodes (MLNs) were collected for analyses. We showed that SM934 administration restored DSS-induced body weight loss, colon shortening, injury and inflammation scores. Furthermore, SM934 administration significantly decreased the disease activity index (DAI), histopathological scores, and myeloperoxidase (MPO) activities in colonic tissues. Moreover, SM934 administration dose-dependently decreased the mRNA and protein levels of DSS-induced pro-inflammatory cytokines (IL-1ß, IL-6 and TNF-α), and the percentage of macrophages and neutrophils in colon tissues. The effects of SM934 on LPS-stimulated RAW 264.7 cells and THP-1-derived macrophages were examined in vitro. Treatment with SM934 (0.8, 8, 80 µmol/L) dose-dependently decreased the production of pro-inflammatory mediators in LPS-stimulated RAW264.7 cells and THP-1-derived macrophages via inhibiting activation of the NF-κB signaling. Our results reveal the protective effects of SM934 on DSS-induced colitis can be attributed to its suppressing effects on neutrophils and macrophages and its inhibitory role in the NF-κB signaling, suggests that SM934 might be a potential effective drug for ulcerative colitis.


Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Artemisininas/uso terapéutico , Colitis Ulcerosa/tratamiento farmacológico , Macrófagos/efectos de los fármacos , Neutrófilos/efectos de los fármacos , Animales , Colitis Ulcerosa/inducido químicamente , Colon/metabolismo , Citocinas/metabolismo , Sulfato de Dextran , Femenino , Ratones , Ratones Endogámicos BALB C , FN-kappa B/metabolismo , Células RAW 264.7 , Transducción de Señal/efectos de los fármacos
10.
Antimicrob Agents Chemother ; 59(11): 7061-72, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26349829

RESUMEN

Here we first identified a novel pyridazinone derivative, compound 3711, as a nonnucleosidic hepatitis B virus (HBV) inhibitor in a cell model system. 3711 decreased extracellular HBV DNA levels by 50% (50% inhibitory concentration [IC50]) at 1.5 ± 0.2 µM and intracellular DNA levels at 1.9 ± 0.1 µM, which demonstrated antiviral activity at levels far below those associated with toxicity. Both the 3TC/ETV dually resistant L180M/M204I mutant and the adefovir (ADV)-resistant A181T/N236T mutant were as susceptible to 3711 as wild-type HBV. 3711 treatment induced the formation of genome-free capsids, a portion of which migrated faster on 1.8% native agarose gel. The induced genome-free capsids sedimented more slowly in isopycnic CsCl gradient centrifugation without significant morphological changes. 3711 treatment decreased levels of HBV DNA contained in both secreted enveloped virion and naked virus particles in supernatant. 3711 could interfere with capsid formation of the core protein (Cp) assembly domain. A Cp V124W mutant, which strengthens capsid interdimer interactions, recapitulated the effect of 3711 on capsid assembly. Pyridazinone derivative 3711, a novel chemical entity and HBV inhibitor, may provide a new opportunity to combat chronic HBV infection.


Asunto(s)
Antivirales/farmacología , Cápside/metabolismo , Virus de la Hepatitis B/efectos de los fármacos , Replicación Viral/efectos de los fármacos , Proteínas de la Cápside/metabolismo , ADN Viral/genética , Farmacorresistencia Viral
11.
Acta Pharmacol Sin ; 35(3): 410-8, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24487969

RESUMEN

AIM: To investigate the action of isothiafludine (NZ-4), a derivative of bis-heterocycle tandem pairs from the natural product leucamide A, on the replication cycle of hepatitis B virus (HBV) in vitro and in vivo. METHODS: HBV replication cycle was monitored in HepG2.2.15 cells using qPCR, qRT-PCR, and Southern and Northern blotting. HBV protein expression and capsid assembly were detected using Western blotting and native agarose gel electrophoresis analysis. The interaction of pregenomic RNA (pgRNA) and the core protein was investigated by RNA immunoprecipitation. To evaluate the anti-HBV effect of NZ-4 in vivo, DHBV-infected ducks were orally administered NZ-4 (25, 50 or 100 mg·kg⁻¹·d⁻¹) for 15 d. RESULTS: NZ-4 suppressed intracellular HBV replication in HepG2.2.15 cells with an IC50 value of 1.33 µmol/L, whereas the compound inhibited the cell viability with an IC50 value of 50.4 µmol/L. Furthermore, NZ-4 was active against the replication of various drug-resistant HBV mutants, including 3TC/ETV-dual-resistant and ADV-resistant HBV mutants. NZ-4 (5, 10, 20 µmol/L) concentration-dependently reduced the encapsidated HBV pgRNA, resulting in the assembly of replication-deficient capsids in HepG2.2.15 cells. Oral administration of NZ-4 dose-dependently inhibited DHBV DNA replication in the DHBV-infected ducks. CONCLUSION: NZ-4 inhibits HBV replication by interfering with the interaction between pgRNA and HBcAg in the capsid assembly process, thus increasing the replication-deficient HBV capsids. Such mechanism of action might provide a new therapeutic strategy to combat HBV infection.


Asunto(s)
Antivirales/farmacología , Infecciones por Hepadnaviridae/tratamiento farmacológico , Virus de la Hepatitis B del Pato/efectos de los fármacos , Virus de la Hepatitis B/efectos de los fármacos , Hepatitis Viral Animal/tratamiento farmacológico , ARN Viral/efectos de los fármacos , Tiazoles/farmacología , Replicación Viral/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Farmacorresistencia Viral Múltiple/genética , Patos , Células Hep G2 , Infecciones por Hepadnaviridae/virología , Virus de la Hepatitis B del Pato/genética , Virus de la Hepatitis B del Pato/crecimiento & desarrollo , Virus de la Hepatitis B/genética , Virus de la Hepatitis B/crecimiento & desarrollo , Hepatitis Viral Animal/virología , Humanos , Mutación , Nucleocápside/metabolismo , ARN Viral/biosíntesis , Factores de Tiempo , Transfección
12.
J Med Chem ; 67(8): 6268-6291, 2024 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-38619191

RESUMEN

Overactivation of cyclic GMP-AMP synthase (cGAS) is implicated in the occurrence of many inflammatory and autoimmune diseases, and inhibition of cGAS with a specific inhibitor has been proposed as a potential therapeutic strategy. However, only a few low-potency cGAS inhibitors have been reported, and few are suitable for clinical investigation. As a continuation of our structural optimization on the reported cGAS inhibitor 6 (G140), we developed a series of spiro[carbazole-3,3'-pyrrolidine] derivatives bearing a unique 2-azaspiro[4.5]decane structural motif, among which compound 30d-S was identified with high cellular effects against cGAS. This compound showed improved plasma exposure, lower clearance, and an oral bioavailability of 35% in rats. Moreover, in the LPS-induced acute lung injury (ALI) mice model, oral administration of compound 30d-S at 30 mg/kg markedly reduced lung inflammation and alleviated histopathological changes. These results confirm that 30d-S is a new efficacious cGAS inhibitor and is worthy of further investigation.


Asunto(s)
Lesión Pulmonar Aguda , Carbazoles , Diseño de Fármacos , Nucleotidiltransferasas , Pirrolidinas , Lesión Pulmonar Aguda/tratamiento farmacológico , Animales , Ratones , Masculino , Humanos , Ratas , Carbazoles/síntesis química , Carbazoles/farmacología , Carbazoles/química , Carbazoles/uso terapéutico , Carbazoles/farmacocinética , Pirrolidinas/farmacología , Pirrolidinas/síntesis química , Pirrolidinas/química , Pirrolidinas/uso terapéutico , Pirrolidinas/farmacocinética , Nucleotidiltransferasas/antagonistas & inhibidores , Nucleotidiltransferasas/metabolismo , Lipopolisacáridos , Ratas Sprague-Dawley , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacología , Compuestos de Espiro/química , Compuestos de Espiro/uso terapéutico , Compuestos de Espiro/farmacocinética , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/química , Relación Estructura-Actividad , Simulación del Acoplamiento Molecular
13.
Phytomedicine ; 125: 155343, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38290230

RESUMEN

BACKGROUND: Zika virus (ZIKV) is a single-stranded RNA flavivirus transmitted by mosquitoes. Its infection is associated with neurological complications such as neonatal microcephaly and adult Guillain-Barré syndrome, posing a serious threat to the health of people worldwide. Therefore, there is an urgent need to develop effective anti-ZIKV drugs. Atranorin is a lichen secondary metabolite with a wide range of biological activities, including anti-inflammatory, antibacterial and antioxidant, etc. However, the antiviral activity of atranorin and underlying mechanism has not been fully elucidated. PURPOSE: We aimed to determine the anti-ZIKV activity of atranorin in human glioma cell line SNB-19 and investigate the potential mechanism from the perspective of viral life cycle and the host cell functions. METHODS: We first established ZIKV-infected human glioma cells (SNB-19) model and used Western Blot, RT-qPCR, immunofluorescence, fluorescence-activated cell sorting (FACS) and plaque assay to evaluate the anti-ZIKV activity of atranorin. Then we assessed the regulation effect of atranorin on ZIKV induced IFN signal pathway activation by RT-qPCR. Afterward, we introduced time-of-addition assay, viral adsorption assay, viral internalization assay and transferrin uptake assay to define which step of ZIKV lifecycle is influenced by atranorin. Finally, we performed virus infectivity assay, molecular docking and thermal shift assay to uncover the target protein of atranorin on ZIKV. RESULTS: Our study showed that atranorin could protect SNB-19 cells from ZIKV infection, as evidenced by inhibited viral protein expression and progeny virus yield. Meanwhile, atranorin attenuated the activation of IFN signal pathway and downstream inflammatory response that induced by ZIKV infection. The results of time-of-addition assay indicated that atranorin acted primarily by disturbing the viral entry process. After ruling out the effect of atranorin on AXL receptor tyrosine kinase (AXL) dependent virus adsorption and clathrin-mediated endocytosis, we confirmed that atranorin directly targeted the viral envelope protein and lowered ZIKV infectivity by thermal shift assay and virus infectivity assay respectively. CONCLUSION: We found atranorin inhibits ZIKV infection in SNB-19 cells via targeting ZIKV envelope protein. Our study provided an experimental basis for the further development of atranorin and a reference for antiviral drug discovery from natural resources.


Asunto(s)
Glioblastoma , Hidroxibenzoatos , Infección por el Virus Zika , Virus Zika , Animales , Recién Nacido , Humanos , Infección por el Virus Zika/tratamiento farmacológico , Infección por el Virus Zika/metabolismo , Virus Zika/fisiología , Proteínas del Envoltorio Viral , Glioblastoma/tratamiento farmacológico , Simulación del Acoplamiento Molecular , Replicación Viral , Línea Celular
14.
Inflamm Bowel Dis ; 30(4): 617-628, 2024 Apr 03.
Artículo en Inglés | MEDLINE | ID: mdl-38206334

RESUMEN

BACKGROUND: Ulcerative colitis (UC) is characterized by a complicated interaction between mucosal inflammation, epithelial dysfunction, abnormal activation of innate immune responses, and gut microbiota dysbiosis. Though valeric acid (VA), one type of short-chain fatty acids (SCFAs), has been identified in other inflammatory disorders and cancer development, the pathological role of VA and underlying mechanism of VA in UC remain under further investigation. METHODS: Studies of human clinical specimens and experimental colitis models were conducted to confirm the pathological manifestations of the level of SCFAs from human fecal samples and murine colonic homogenates. Valeric acid-intervened murine colitis and a macrophage adoptive transfer were applied to identify the underlying mechanisms. RESULTS: In line with gut microbiota dysfunction in UC, alteration of SCFAs from gut microbes were identified in human UC patients and dextran sodium sulfate -induced murine colitis models. Notably, VA was consistently negatively related to the disease severity of UC, the population of monocytes, and the level of interluekin-6. Moreover, VA treatment showed direct suppressive effects on lipopolysaccharides (LPS)-activated human peripheral blood mononuclear cells and murine macrophages in the dependent manner of upregulation of GPR41 and GPR43. Therapeutically, replenishment of VA or adoptive transfer with VA-modulated macrophages showed resistance to dextran sodium sulfate-driven murine colitis though modulating the production of inflammatory cytokine interleukin-6. CONCLUSIONS: In summary, the research uncovered the pathological role of VA in modulating the activation of macrophages in UC and suggested that VA might be a potential effective agent for UC patients.


The study collectively indicated that valeric acid (VA) was consistently negatively related to the disease severity of UC, and hypofunction of macrophage driven by VA impeded the progression of UC.


Asunto(s)
Colitis Ulcerosa , Colitis , Ácidos Pentanoicos , Sulfatos , Humanos , Ratones , Animales , Colitis Ulcerosa/patología , Dextranos , Leucocitos Mononucleares/patología , Colon/patología , Colitis/inducido químicamente , Colitis/patología , Ácidos Grasos Volátiles/uso terapéutico , Sulfato de Dextran/toxicidad , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL
15.
Cell Death Discov ; 10(1): 152, 2024 Mar 23.
Artículo en Inglés | MEDLINE | ID: mdl-38521771

RESUMEN

Acute lung injury (ALI) is an acute and progressive hypoxic respiratory failure that could progress to acute respiratory distress syndrome (ARDS) with a high mortality rate, thus immediate medical attention and supportive care are necessary. The pathophysiology of ALI is characterized by the disruption of the alveolar-capillary barrier and activation of neutrophils, leading to lung tissue damage. The receptor-interacting protein kinase 1 (RIPK1) has emerged as a promising target for the treatment of multiple inflammatory diseases, but the role of RIPK1 in the ALI remains poorly understood. In this study, we aimed to figure out the pathological role of RIPK1 in ALI, especially in the pulmonary immune microenvironment involving neutrophils and endothelial cells. In vivo experiments showed that RIPK1 inhibitor protected against lipopolysaccharide (LPS)-induced lung injury in mouse models, with reduced neutrophils and monocytes infiltration in the lungs. Further studies demonstrated that, besides the inhibitory action on necroptosis, RIPK1 inhibitor directly suppressed reactive oxygen species (ROS) generation and inflammatory cytokines secretion from neutrophils. Furthermore, RIPK1 inhibition maintains the barrier function in TNF-α-primed vascular endothelial cells and prevents their activation induced by the supernatant from LPS-stimulated neutrophils. Mechanistically, the aforementioned effects of RIPK1 inhibitor are associated with the NF-κB signaling pathway, which is partially independent of necroptosis inhibition. These results provide new evidence that RIPK1 inhibitor directly regulates the function of neutrophils and endothelial cells, as well as interferes with the interactions between these two cell types, therefore contributing to a better understanding of RIPK1 in ALI and providing a potential avenue for future therapeutic interventions.

16.
Autoimmunity ; 56(1): 2259125, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37740656

RESUMEN

Lysosomal associated membrane protein 3 (LAMP3) has been reported to be a tumour promoter in multiple cancer types by modulating tumour cell autophagy. However, the potential mechanism of LAMP3 in radio-resistance of head and neck squamous cell carcinoma (HNSCC) remains unknown. Therefore, our current study aims to detect the impacts of LAMP3 on the resistance of HNSCC cells to radiotherapy and meanwhile explore its functional mechanism. Through RT-Qpcr examination, LAMP3 expression was identified to be expressed at a significantly high level in irradiation-resistant HNSCC cell lines compared with irradiation-sensitive HNSCC cell lines. Functional assays including CCK-8, colony formation and Transwell assays demonstrated that LAMP3 enhanced the radio-resistance through inducing autophagy to promote HNSCC cell growth. Furthermore, irradiation-resistant HNSCC cells could transfer exosomal LAMP3 to elevate LAMP3 expression in irradiation-sensitive HNSCC cells. Mechanistically, microRNA (miRNA) miR-526b-3p could inhibit LAMP3 expression so as to strengthen sensitivity of HNSCC cells to radiotherapy. In a word, exosomal LAMP3 expression promoted radioresistance of HNSCC cells via inducing autophagy, while this effect could be suppressed by miR-526b-3p in a targeted manner.


Asunto(s)
Neoplasias de Cabeza y Cuello , MicroARNs , Humanos , Proteína 3 de la Membrana Asociada a Lisosoma , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/radioterapia , Autofagia/genética , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/radioterapia , MicroARNs/genética , Proteínas de Neoplasias , Proteínas de Membrana de los Lisosomas/genética
17.
J Photochem Photobiol B ; 238: 112604, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-36525776

RESUMEN

Ultraviolet-B (UVB) exposure on the skin triggers apoptosis, oxidative stress and acute inflammatory responses, which eventually increases the risk of various skin disorders. Hemin, an iron-binding porphyrin, has been clinically used for porphyria treatment. However, whether hemin contributes to the skin protection against UVB injury remains to be elucidated. Here, we found that hemin treatment (10 and 20 mg/kg) by intraperitoneal administration could dramatically relieve UVB irradiation-induced skin damage featured by erythema, edema, epidermal hyperplasia and collagen loss in C57BL/6 J mice. Importantly, hemin treatment attenuated UVB irradiation-triggered cell apoptosis in skin epidermis. Consistently, hemin (10, 20 µM) treatment decreased Caspase-3 activation and protected against UVB-induced apoptosis in HaCaT cells. Besides, hemin treatment reduced the infiltration of neutrophils in skin under UVB irradiation, thus restrained neutrophil extracellular traps (NET) formation and myeloperoxidase (MPO) release. We further revealed that hemin inhibited the expression of inflammation associated cytokines and chemokines in UVB-induced HaCaT cells and blocked the chemotaxis of dHL-60 cells to preconditioned media from HaCaT culture upon UVB irradiation. Furthermore, hemin inhibited the excessive maturation and mobilization of bone marrow neutrophils and rectified the proportion of abnormally elevated neutrophils in the blood under UVB irradiation. In conclusion, our study showed that hemin treatment protects against UVB-induced skin damage through inhibiting keratinocytes apoptosis, and suppressing neutrophils infiltration in the skin via externally restraining the keratinocyte attraction and internally regulating bone marrow neutrophil maturation and mobilization, suggesting that hemin is an effective drug candidate for the therapy of UVB damage.


Asunto(s)
Hemina , Enfermedades de la Piel , Ratones , Animales , Hemina/farmacología , Hemina/metabolismo , Infiltración Neutrófila , Ratones Endogámicos C57BL , Piel/metabolismo , Queratinocitos/metabolismo , Apoptosis , Inflamación/metabolismo , Rayos Ultravioleta
18.
Comput Intell Neurosci ; 2022: 2645528, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36072734

RESUMEN

To many hospitals' management as well as to patients, the nursing service is one of the most important aspects. Many diseases like sugar, blood pressure, urine passage, and gas are a little bit dangerous to handle by patients themselves. The earlier stage models are unable to give good services to patients; therefore, an advanced JHE: Effect of 1 + N extended nursing service is necessary to crossover the above limitations. Colostomy and colorectal cancers are very dangerous syndromes thus, disease monitoring is so difficult. In this research work, an extended JHE: Effect of 1 + N extended nursing service modeling is discussed with experimental modeling. Apart from conventional nursing care provided by the observation group, it was given online training as well as service providing. Self-efficacy and self-care competence were assessed in both groups 6 months after the discharge. Quality of life and mental health were also assessed. Besides, their dimensional and total self-care ability scores, and the observation group's self-efficacy ratings were substantially higher than those of the control group (P 0.05) after the intervention. It was observed that the intervention group's 6-month adjustment to the stoma was statistically more favorable than the control group's (P 0.001), and only the intervention group showed a significantly major change (P 0.001) between their two evaluations. This proposed methodology can improve the accuracy rate by 93.23%, and succussive treatment rate of 92.14% had been attained.


Asunto(s)
Colostomía , Servicios de Enfermería , Colostomía/psicología , Humanos , Calidad de Vida , Autoeficacia
19.
J Oncol ; 2022: 9578436, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36213841

RESUMEN

Aim: To investigate the value of neoadjuvant chemotherapy combined with 3D-image-guided afterloading intracavitary radiotherapy in locally advanced cervical cancer (LACC). Methods: Patients with cervical cancer admitted to our hospital from January 1, 2020 to January 1, 2021 were retrieved and analyzed. Cases treated with neoadjuvant chemotherapy and 3D-image-guided afterloading intracavitary radiotherapy were assigned into the observation group (OG), while cases with neoadjuvant chemotherapy alone were assigned into the control group (CG). The short-term effects were determined by RECIST 1.1. Total effective rate (TR) = complete remission (CR) + partial remission (PR). The serum levels of squamous epithelial cell carcinoma antigen (SCC-Ag), glycoantigen 125 (CA125), carcinoembryonic antigen (CEA), and vascular endothelial growth factor (VEGF) were assessed. In view of the difference between tumor markers and diameters before and after treatment, the correlation between them was analyzed by Pearson test. The adverse events were compared, and the amount of operative bleeding and operation time were evaluated. Cox regression analysis was conducted to assess the influencing factors of 1-year disease-free survival time. Results: Sixty-seven patients were retrieved, including 30 cases in the OG and 37 cases in the CG. There were no significant differences in age, pathological type, tumor size, FIGO stage, past medical history, or smoking history between the two groups (P > 0.05). The TR of patients in the OG was higher than that in the CG (P < 0.05). The SCC-Ag, CA125, CEA, and VEGF levels in the OG decreased markedly after treatment (P < 0.001). The difference in SCC-Ag, CA125, CEA, and VEGF was positively correlated with the difference in tumor diameter before and after treatment (P < 0.05). The incidence of adverse events revealed no obvious difference between the OG and CG (P > 0.05). Cox regression analysis showed that FIGO stage and treatment regimens were independent prognostic factors for 1-year disease-free survival (P < 0.05). Conclusion: Neoadjuvant chemotherapy combined with 3D-image-guided afterloading intracavitary radiotherapy can improve the TR rate and 1-year disease-free survival of LACC patients without increasing the incidence of adverse events.

20.
Antiviral Res ; 203: 105347, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35643150

RESUMEN

Zika virus (ZIKV) is a flavivirus that causes severe neuropathology in newborns and adults. There is no ZIKV-specific treatment or preventative. Therefore, it is urgent to develop safe and effective anti-ZIKV agents. Hemin, an iron-binding porphyrin, has been authorized by FDA to treat acute porphyria since the 1970s. Here, we aim to evaluate the anti-ZIKV effect of hemin in SNB-19 cells (a human glioma cell line) and explore the underlying mechanism based on the virus life cycle and functions of the host cell. Our study found that hemin has a strong activity to protect SNB-19 cells from ZIKV infection presented by decreased expression of viral proteins and virus yield. Meanwhile, ZIKV infection caused STAT1/IRF1 signaling activation and induced inflammatory responses in SNB-19 cells, which was relieved by hemin treatment. HO-1 has been reported to be potently induced by hemin and play a broad-spectrum antiviral effect. Intriguingly, hemin could still exert anti-ZIKV activity upon HO-1 siRNA treatment. Then, we conducted a time-of-addition assay, the result indicated hemin works mainly by interfering with the virus entry process. Further experiments excluded the effects of hemin on AXL-dependent viral adsorption and clathrin-mediated endocytosis processes. Subsequently, by fluorescence spectroscopy studies, intracellular fusion assay and syncytia formation assay, we revealed that hemin acts on the process of virus-endosome fusion. This study elaborated that hemin could play anti-ZIKV activity by disrupting the virus-endosome fusion process and shed new light on developing novel agents against ZIKV infection.


Asunto(s)
Infección por el Virus Zika , Virus Zika , Animales , Chlorocebus aethiops , Virus ADN , Endosomas , Hemina/farmacología , Humanos , Recién Nacido , Células Vero , Internalización del Virus , Replicación Viral , Infección por el Virus Zika/metabolismo
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