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1.
Acta Pharmacol Sin ; 45(1): 166-179, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37605050

RESUMO

Dry eye disease (DED) is a prevalent ocular disorder with a multifactorial etiology. The pre-angiogenic and pre-inflammatory milieu of the ocular surface plays a critical role in its pathogenesis. DZ2002 is a reversible type III S-adenosyl-L-homocysteine hydrolase (SAHH) inhibitor, which has shown excellent anti-inflammatory and immunosuppressive activities in vivo and in vitro. In this study, we evaluated the therapeutic potential of DZ2002 in rodent models of DED. SCOP-induced dry eye models were established in female rats and mice, while BAC-induced dry eye model was established in female rats. DZ2002 was administered as eye drops (0.25%, 1%) four times daily (20 µL per eye) for 7 or 14 consecutive days. We showed that topical application of DZ2002 concentration-dependently reduced corneal neovascularization and corneal opacity, as well as alleviated conjunctival irritation in both DED models. Furthermore, we observed that DZ2002 treatment decreased the expression of genes associated with angiogenesis and the levels of inflammation in the cornea and conjunctiva. Moreover, DZ2002 treatment in the BAC-induced DED model abolished the activation of the STAT3-PI3K-Akt-NF-κB pathways in corneal tissues. We also found that DZ2002 significantly inhibited the proliferation, migration, and tube formation of human umbilical endothelial cells (HUVECs) while downregulating the activation of the STAT3-PI3K-Akt-NF-κB pathway. These results suggest that DZ2002 exerts a therapeutic effect on corneal angiogenesis in DED, potentially by preventing the upregulation of the STAT3-PI3K-Akt-NF-κB pathways. Collectively, DZ2002 is a promising candidate for ophthalmic therapy, particularly in treating DED.


Assuntos
Neovascularização da Córnea , Síndromes do Olho Seco , Ratos , Humanos , Camundongos , Animais , Feminino , Neovascularização da Córnea/tratamento farmacológico , Neovascularização da Córnea/metabolismo , Neovascularização da Córnea/patologia , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Roedores/metabolismo , Células Endoteliais/metabolismo , Angiogênese , Inflamação/tratamento farmacológico , Síndromes do Olho Seco/tratamento farmacológico , Síndromes do Olho Seco/induzido quimicamente , Fator de Transcrição STAT3/metabolismo
2.
Acta Pharmacol Sin ; 42(10): 1653-1664, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33441995

RESUMO

Rheumatoid arthritis (RA) is characterized by joint leukocyte infiltration, synovial inflammation and bone damage result from osteoclastogenesis. Bruton's tyrosine kinase (BTK) is a key regulator of B cell receptor (BCR) and Fc gamma receptor (FcγR) signaling involved in the pathobiology of RA and other autoimmune disorders. SOMCL-17-016 is a potent and selective tricyclic BTK inhibitor, structurally distinct from other known BTK inhibitors. In present study we investigated the therapeutic efficacy of SOMCL-17-016 in a mouse collagen-induced arthritis (CIA) model and underlying mechanisms. CIA mice were administered SOMCL-17-016 (6.25, 12.5, 25 mg·kg-1·d-1, ig), or ibrutinib (25 mg·kg-1·d-1, ig) or acalabrutinib (25 mg·kg-1·d-1, ig) for 15 days. We showed that oral administration of SOMCL-17-016 dose-dependently ameliorated arthritis severity and bone damage in CIA mice; it displayed a higher in vivo efficacy than ibrutinib and acalabrutinib at the corresponding dosage. We found that SOMCL-17-016 administration dose-dependently inhibited anti-IgM-induced proliferation and activation of B cells from CIA mice, and significantly decreased anti-IgM/anti-CD40-stimulated RANKL expression in memory B cells from RA patients. In RANKL/M-CSF-stimulated RAW264.7 cells, SOMCL-17-016 prevented osteoclast differentiation and abolished RANK-BTK-PLCγ2-NFATc1 signaling. In summary, this study demonstrates that SOMCL-17-016 presents distinguished therapeutic effects in the CIA model. SOMCL-17-016 exerts a dual inhibition of B cell function and osteoclastogenesis, suggesting that it to be a promising drug candidate for RA treatment.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Células B de Memória/efeitos dos fármacos , Inibidores de Proteínas Quinases/uso terapêutico , Tirosina Quinase da Agamaglobulinemia/metabolismo , Animais , Autoanticorpos/metabolismo , Inflamação/tratamento farmacológico , Ativação Linfocitária/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos DBA , Osteoclastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Pirimidinas/uso terapêutico , Alcaloides de Pirrolizidina/uso terapêutico , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Transdução de Sinais/efeitos dos fármacos
3.
Acta Pharmacol Sin ; 42(4): 593-603, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32747720

RESUMO

Dry eye disease (DED) is a multifactorial disorder of the tears and ocular surface characterized by manifestations of dryness and irritation. Although the pathogenesis is not fully illuminated, it is recognized that inflammation has a prominent role in the development and deterioration of DED. ß-aminoarteether maleate (SM934) is a water-soluble artemisinin derivative with anti-inflammatory and immunosuppressive activities. In this study, we established scopolamine hydrobromide (SCOP)-induced rodent model as well as benzalkonium chloride (BAC)-induced rat model to investigate the therapeutic potential of SM934 for DED. We showed that topical application of SM934 (0.1%, 0.5%) significantly increased tear secretion, maintained the number of conjunctival goblet cells, reduced corneal damage, and decreased the levels of inflammatory mediators (TNF-α, IL-6, IL-10, or IL-1ß) in conjunctiva in SCOP-induced and BAC-induced DED models. Moreover, SM934 treatment reduced the accumulation of TLR4-expressing macrophages in conjunctiva, and suppressed the expression of inflammasome components, i.e., myeloid differentiation factor88 (MyD88), Nod-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein containing CARD (ASC), and cleaved caspase 1. In LPS-treated RAW 264.7 cells, we demonstrated that pretreatment with SM934 (10 µM) impeded the upregulation of TLR4 and downstream NF-κB/NLRP3 signaling proteins. Collectively, artemisinin analog SM934 exerts therapeutic benefits on DED by simultaneously reserving the structural integrity of ocular surface and preventing the corneal and conjunctival inflammation, suggested a further application of SM934 in ophthalmic therapy, especially for DED.


Assuntos
Artemisininas/uso terapêutico , Síndromes do Olho Seco/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Túnica Conjuntiva/patologia , Síndromes do Olho Seco/induzido quimicamente , Síndromes do Olho Seco/patologia , Feminino , Células Caliciformes/efeitos dos fármacos , Inflamação/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator 88 de Diferenciação Mieloide/metabolismo , Subunidade p50 de NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Células RAW 264.7 , Ratos Sprague-Dawley , Escopolamina , Lágrimas/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo
4.
Acta Pharmacol Sin ; 42(8): 1347-1353, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33116249

RESUMO

To discover effective drugs for COVID-19 treatment amongst already clinically approved drugs, we developed a high throughput screening assay for SARS-CoV-2 virus entry inhibitors using SARS2-S pseudotyped virus. An approved drug library of 1800 small molecular drugs was screened for SARS2 entry inhibitors and 15 active drugs were identified as specific SARS2-S pseudovirus entry inhibitors. Antiviral tests using native SARS-CoV-2 virus in Vero E6 cells confirmed that 7 of these drugs (clemastine, amiodarone, trimeprazine, bosutinib, toremifene, flupenthixol, and azelastine) significantly inhibited SARS2 replication, reducing supernatant viral RNA load with a promising level of activity. Three of the drugs were classified as histamine receptor antagonists with clemastine showing the strongest anti-SARS2 activity (EC50 = 0.95 ± 0.83 µM). Our work suggests that these 7 drugs could enter into further in vivo studies and clinical investigations for COVID-19 treatment.


Assuntos
Antivirais/uso terapêutico , Tratamento Farmacológico da COVID-19 , Reposicionamento de Medicamentos , SARS-CoV-2/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos , Linhagem Celular , Aprovação de Drogas , Ensaios de Triagem em Larga Escala , Humanos , Testes de Sensibilidade Microbiana , SARS-CoV-2/fisiologia , Glicoproteína da Espícula de Coronavírus/efeitos dos fármacos
5.
Pharmacol Res ; 129: 443-452, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29155016

RESUMO

DZ2002, a reversible S-adenosyl-l-homocysteine hydrolase (SAHH) inhibitor with immunosuppressive properties and potent therapeutic activity against various autoimmune diseases in mice. The present study was designed to characterize the potential therapeutic effects of DZ2002 on murine model of psoriasis and reveal the correlated mechanisms. In this report, we demonstrated that in vitro, DZ2002 significantly decreased the expression of pro-inflammatory cytokines and adhesion molecule including IL-1α, IL-1ß, IL-6, IL-8, TNF-α and ICAM-1 by inhibiting the phosphorylation of p38 MAPK, ERK and JNK in TNF-α/IFN-γ-stimulated HaCaT human keratinocytes. Topical administration of DZ2002 alleviated the imiquimod (IMQ)-induced psoriasis-like skin lesions and inflammation in mice, the therapeutic effect was comparable with the Calcipotriol. Moreover, the inflammatory skin disorder was restored by DZ2002 treatment characterized by reducing both of the CD3+ T cell accumulation and the psoriasis-specific cytokines expression. Further, we found that DZ2002 improved IMQ-induced splenomegaly and decreased the frequency of splenic IL-17-producing T cells. Our finding offered the convincing evidence that SAHH inhibitor DZ2002 might attenuate psoriasis by simultaneously interfering the abnormal activation and differentiation of keratinocytes and accumulation of IL-17-producing T cells in skin lesions.


Assuntos
Adenina/análogos & derivados , Adenosil-Homocisteinase/antagonistas & inibidores , Anti-Inflamatórios/farmacologia , Butiratos/farmacologia , Queratinócitos/efeitos dos fármacos , Psoríase/imunologia , Linfócitos T/efeitos dos fármacos , Adenina/farmacologia , Adenina/uso terapêutico , Administração Tópica , Animais , Anti-Inflamatórios/uso terapêutico , Butiratos/uso terapêutico , Células Cultivadas , Citocinas/imunologia , Feminino , Humanos , Imiquimode , Queratinócitos/imunologia , Camundongos Endogâmicos BALB C , Psoríase/induzido quimicamente , Psoríase/tratamento farmacológico , Linfócitos T/imunologia
6.
Acta Pharmacol Sin ; 39(10): 1633-1644, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29849131

RESUMO

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.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Artemisininas/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Animais , Colite Ulcerativa/induzido quimicamente , Colo/metabolismo , Citocinas/metabolismo , Sulfato de Dextrana , Feminino , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos
7.
Acta Pharmacol Sin ; 39(1): 107-116, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28880016

RESUMO

(5R)-5-hydroxytriptolide (LLDT-8) is a novel triptolide analog that has been identified as a promising candidate for treating autoimmune diseases and has been shown to be effective in treating murine collagen-induced arthritis and lupus nephritis. In the present study, we investigated the therapeutic effect and possible mechanism of action of LLDT-8 in a murine anti-glomerular basement membrane (GBM) glomerulonephritis model. NZW mice were injected with rabbit anti-GBM serum (500 µL, ip). The mice were orally treated with LLDT-8 (0.125 mg/kg, every other day) or a positive control prednisolone (2 mg/kg every day) for 14 d. Blood and urine samples as well as spleen and kidney tissues were collected for analyses. LLDT-8 treatment did not affect the generation of mouse anti-rabbit antibodies. LLDT-8 significantly reversed established proteinuria, improved renal histopathology and attenuated renal dysfunction in glomerulonephritis mice. Furthermore, LLDT-8 inhibited inflammation in the kidney evidenced by significantly decreasing C3 and IgG deposition, reducing the levels of the pathogenic cytokines TNF-α, IL-6, IL-17, and IFN-γ, and reducing related chemokine expression and leukocyte infiltration in kidneys. Moreover, LLDT-8 treatment significantly increased the expression of FcγRIIB in the kidney and spleen. In addition, the treatment restored the reduced expression of FcγRIIB on the surface of kidney effector cells, CD11b+ cells, and interfered with FcγR-dependent signaling, especially FcγRIIB-mediated downstream kinases, such as BTK. These results demonstrate that LLDT-8 ameliorates anti-GBM glomerulonephritis by regulating the Fcγ receptor signaling.


Assuntos
Doença Antimembrana Basal Glomerular/tratamento farmacológico , Diterpenos/uso terapêutico , Imunossupressores/uso terapêutico , Receptores de IgG/metabolismo , Animais , Complemento C3/metabolismo , Diterpenos/administração & dosagem , Diterpenos/química , Imunoglobulina G/metabolismo , Imunossupressores/administração & dosagem , Imunossupressores/química , Inflamação/tratamento farmacológico , Interferon gama/metabolismo , Interleucina-17/metabolismo , Interleucina-6/metabolismo , Rim/patologia , Leucócitos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos , Receptores de IgG/genética , Transdução de Sinais/efeitos dos fármacos , Estereoisomerismo , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima
8.
Am J Physiol Renal Physiol ; 312(4): F769-F777, 2017 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-28100505

RESUMO

(5R)-5-hydroxytriptolide (LLDT-8), a triptolide derivative with low toxicity, was previously reported to have strong immunosuppressive effects both in vitro and in vivo, but it remains unknown whether LLDT-8 has a therapy effect on systemic lupus erythematosus. In this study, we aimed to investigate the therapeutic effects of LLDT-8 on lupus nephritis in MRL/lpr mice, a model of systemic lupus erythematosus. Compared with the vehicle group, different clinical parameters were improved upon LLDT-8 treatment as follows: prolonged life span of mice, decreased proteinuria, downregulated blood urea nitrogen and serum creatinine, reduced glomerular IgG deposits, and ameliorated histopathology. A decreased expression of the inflammatory cytokines IFN-γ, IL-17, IL-6, and TNF-α was also observed in the kidney of LLDT-8 treated MRL/lpr mice. Moreover, infiltration of T cells in the kidney was mitigated after LLDT-8 treatment, corresponding with decreased expression of related chemokines IP-10, Mig, and RANTES in the kidney. The proportion of macrophage and neutrophil cells and related chemokines expression was also reduced in kidneys of LLDT-8-treated mice. In the human proximal tubule epithelial cell line and mouse mesangial cell line, consistent with our in vivo experimental results, LLDT-8 suppressed the expression of related chemokines and IL-6. In summary, LLDT-8 has a therapeutic benefit for lupus nephritis via suppressing chemokine expression and inhibiting immune cell infiltration in kidneys of MRL/lpr mice.


Assuntos
Anti-Inflamatórios/farmacologia , Diterpenos/farmacologia , Glomérulos Renais/efeitos dos fármacos , Nefrite Lúpica/prevenção & controle , Macrófagos/efeitos dos fármacos , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Animais , Biomarcadores/sangue , Nitrogênio da Ureia Sanguínea , Linhagem Celular , Creatinina/sangue , Citocinas/metabolismo , Modelos Animais de Doenças , Regulação para Baixo , Feminino , Humanos , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Mediadores da Inflamação/metabolismo , Glomérulos Renais/imunologia , Glomérulos Renais/metabolismo , Glomérulos Renais/fisiopatologia , Nefrite Lúpica/imunologia , Nefrite Lúpica/metabolismo , Nefrite Lúpica/fisiopatologia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos Endogâmicos MRL lpr , Neutrófilos/imunologia , Neutrófilos/metabolismo , Proteinúria/imunologia , Proteinúria/prevenção & controle , Linfócitos T/imunologia , Linfócitos T/metabolismo , Fatores de Tempo
9.
Acta Pharmacol Sin ; 36(2): 188-99, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25619396

RESUMO

AIM: SM934 is a novel water-soluble artemisinin derivative with immunoregulatory activities that has been used to treat murine lupus nephritis. In the current study, we investigated the effects of SM934 on rat experimental membranous nephropathy. METHODS: Passive Heymann nephritis (PHN) was induced in SD rats by intraperitoneal injection of anti-Fx1A serum. The rats were orally administered SM934 (12.5 and 25 mg·kg(-1)·d(-1)) or prednisolone (5 mg·kg(-1)·d(-1)) for 28 d. Blood and urine sample, and kidney tissue were collected for analyses. Human complement C3a-induced injury of HK-2 cells was used for in vitro experiments. RESULTS: Treatment of PHN rats with SM934 or prednisolone attenuated the progression of glomerulonephritis and renal fibrosis, as evidenced by the reduced level of proteinuria and circulating antibodies, as well as by the reduced immune complex deposition, reversed podocyte injuries, and attenuated tubulointerstitial fibrosis in the kidneys. Furthermore, the two drugs suppressed TGF-ß1 expression and Smad2/3 phosphorylation, and increased Smad7 expression in the kidneys. The two doses of SM934 produced almost identical therapeutic effects on PHN rats. Pretreatment with SM934 or a C3a receptor antagonist blocked the C3a-induced epithelial-mesenchymal transition in HK-2 cells in vitro. CONCLUSION: SM934 ameliorates kidney injury and attenuates the tubulointerstitial fibrosis in PHN rats by down-regulation of the TGF-ß1/Smad signaling pathway.


Assuntos
Artemisininas/farmacologia , Fibrose/tratamento farmacológico , Glomerulonefrite Membranosa/tratamento farmacológico , Nefropatias/tratamento farmacológico , Proteinúria/tratamento farmacológico , Animais , Rim/efeitos dos fármacos , Masculino , Modelos Animais , Ratos , Ratos Sprague-Dawley
10.
Acta Pharmacol Sin ; 35(2): 219-29, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24374810

RESUMO

AIM: To examine the therapeutic effects and underlying mechanisms of DZ2002, a reversible S-adenosyl-L-homocysteine hydrolase (SAHH) inhibitor, on lupus-prone female NZB×NZW F1 (NZB/W F1) mice. METHODS: Female NZB/W F1 mice were treated orally with DZ2002 (0.5 mg·kg(-1)·d(-1)) for 11 weeks, and the proteinuria level and body weight were monitored. After the mice ware euthanized, serum biochemical parameters and renal damage were determined. Splenocytes of NZB/W F1 mice were isolated for ex vivo study. Toll-like receptor (TLR)-stimulated human peripheral blood mononuclear cells (PBMCs) or murine bone marrow-derived dendritic cells (BMDCs) were used for in vitro study. RESULTS: Treatment of the mice with DZ2002 significantly attenuated the progression of glomerulonephritis and improved the overall health. The improvement was accompanied by decreased levels of nephritogenic anti-dsDNA IgG2a and IgG3 antibodies, serum IL-17, IL-23p19 and TGF-ß. In ex vivo studies, treatment of the mice with DZ2002 suppressed the development of pathogenic Th17 cells, significantly decreased IL-17, TGF-ß, IL-6, and IL-23p19 production and impeded activation of the STAT3 protein and JNK/NF-κB signaling in splenocytes. DZ2002 (500 µmol/L) significantly suppressed TLR agonists-stimulated up-regulation in IL-6, IL-12p40, TNF-α, and IgG and IgM secretion as well as in HLA-DR and CD40 expression of dendritic cells among human PBMCs in vitro. DZ2002 (100 µmol/L) also significantly suppressed TLR agonists-stimulated up-regulation in IL-6 and IL-23p19 production in murine BMDCs, and prevented Th17 differentiation and suppressed IL-17 secretion by the T cells in a BMDC-T cell co-culture system. CONCLUSION: DZ2002 effectively ameliorates lupus syndrome in NZB/W F1 mice by regulating TLR signaling-mediated antigen presenting cell (APC) responses.


Assuntos
Adenina/análogos & derivados , Células Apresentadoras de Antígenos/efeitos dos fármacos , Butiratos/farmacologia , Receptores Toll-Like/metabolismo , Adenina/farmacologia , Animais , Células Apresentadoras de Antígenos/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Feminino , Glomerulonefrite/tratamento farmacológico , Glomerulonefrite/metabolismo , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NZB
11.
Acta Pharmacol Sin ; 35(3): 410-8, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24487969

RESUMO

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.


Assuntos
Antivirais/farmacologia , Infecções por Hepadnaviridae/tratamento farmacológico , Vírus da Hepatite B do Pato/efeitos dos fármacos , Vírus da Hepatite B/efeitos dos fármacos , Hepatite Viral Animal/tratamento farmacológico , RNA Viral/efeitos dos fármacos , Tiazóis/farmacologia , Replicação Viral/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Farmacorresistência Viral Múltipla/genética , Patos , Células Hep G2 , Infecções por Hepadnaviridae/virologia , Vírus da Hepatite B do Pato/genética , Vírus da Hepatite B do Pato/crescimento & desenvolvimento , Vírus da Hepatite B/genética , Vírus da Hepatite B/crescimento & desenvolvimento , Hepatite Viral Animal/virologia , Humanos , Mutação , Nucleocapsídeo/metabolismo , RNA Viral/biossíntese , Fatores de Tempo , Transfecção
12.
Biomed Pharmacother ; 170: 115975, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38070246

RESUMO

Osteoarthritis (OA) is characterized by gradual articular cartilage degradation, accompanied by persistent low-grade joint inflammation, correlating with radiographic and pain-related progression. The latent therapeutic potential of DZ2002, a reversible inhibitor of S-adenosyl-L-homocysteine hydrolase (SAHH), holds promise for OA intervention. This study endeavored to examine the therapeutic efficacy of DZ2002 within the milieu of OA. The cytotoxicity of DZ2002 was evaluated using the MTT assay on bone marrow-derived macrophages. The inhibitory impact of DZ2002 during the process of osteoclastogenesis was assessed using TRAP staining, analysis of bone resorption pits, and F-actin ring formation. Mechanistic insights were derived from qPCR and Western blot analyses. Through the intra-articular injection of monosodium iodoacetate (MIA), an experimental rat model of OA was successfully instituted. This was subsequently accompanied by a series of assessments including Von Frey filament testing, analysis of weight-bearing behaviors, and micro-CT imaging, all aimed at assessing the effectiveness of DZ2002. The findings emphasized the effectiveness of DZ2002 in mitigating osteoclastogenesis induced by M-CSF/RANKL, evident through a reduction in TRAP-positive OCs and bone resorption. Moreover, DZ2002 modulated bone resorption-associated gene and protein expression (CTSK, CTR, Integrin ß3) via the MEK/ERK pathway. Encouragingly, DZ2002 also alleviates MIA-induced pain, cartilage degradation, and bone loss. In conclusion, DZ2002 emerges as a potential therapeutic contender for OA, as evidenced by its capacity to hinder in vitro M-CSF/RANKL-induced osteoclastogenesis and mitigate in vivo osteoarthritis progression. This newfound perspective provides substantial support for considering DZ2002 as a compelling agent for osteoarthritis intervention.


Assuntos
Reabsorção Óssea , Cartilagem Articular , Osteoartrite , Ratos , Animais , Ácido Iodoacético/efeitos adversos , Ácido Iodoacético/metabolismo , Fator Estimulador de Colônias de Macrófagos/metabolismo , Sistema de Sinalização das MAP Quinases , Osteoartrite/induzido quimicamente , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Dor/tratamento farmacológico , Cartilagem Articular/metabolismo , Reabsorção Óssea/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Modelos Animais de Doenças
13.
Acta Pharmacol Sin ; 34(7): 921-9, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23645010

RESUMO

AIM: To investigate the effects and underlying mechanisms of 118, a novel derivative of mycophenolic acid, in a murine allogeneic skin graft model. METHODS: Skin grafts were conducted by grafting BALB/c donor tail skin into C57BL/6 skin beds (allograft) or by grafting female C57BL/6 donor tail skin into female C57BL/6 skin beds (syngraft). The mice were treated with the derivative 118 (40 mg·kg(-1)·d(-1), po) for 13 d (3 d before and 10 d after transplantation). Skin grafts, splenocytes and graft-infiltrated lymphocytes were isolated and examined ex vivo. The effects of the derivative 118 on naive CD4(+) T cell differentiation were examined in vitro. RESULTS: Treatment with the derivative 118 dramatically increased the survival rate of murine allogeneic skin grafts. Flow cytometric analysis and H&E staining showed that the derivative significantly decreased inflammatory cell infiltration into the grafts. The levels of the chemokines CXCL1, CXCL2, CCL7, and CCL2 were reduced in the derivative 118-treated grafts. Additionally, the derivative 118 significantly suppressed the IL-17 levels in the grafts but did not affect the differentiation of systemic helper T cells in the murine allogeneic skin graft model. Furthermore, IL-23p19 expression was suppressed in the grafts from the derivative 118-treated group, which might be due to decreases in TLR4 and MyD88 expression. Finally, the derivative 118 did not exert direct influences on helper T cell differentiation in vitro. CONCLUSION: Treatment with the mycophenolic acid derivative 118 improves murine allogeneic skin grafts by decreasing IL-23 expression and suppressing local IL-17 secretion in the grafts, rather than directly inhibiting Th17 differentiation.


Assuntos
Sobrevivência de Enxerto/efeitos dos fármacos , Interleucina-17/antagonistas & inibidores , Interleucina-17/biossíntese , Ácido Micofenólico/farmacologia , Transplante de Pele/métodos , Animais , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Técnicas de Cocultura , Feminino , Sobrevivência de Enxerto/imunologia , Interleucina-17/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Resultado do Tratamento
14.
Arthritis Rheum ; 63(8): 2445-55, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21484768

RESUMO

OBJECTIVE: SM934, an artemisinin derivative, possesses potent antiproliferative and antiinflammatory properties. The aim of this study was to examine the effects and explore the mechanisms of SM934 to treat autoimmune disease in lupus-prone female MRL/lpr mice. METHODS: In vitro, the effects of SM934 on the activation of polyclonal CD4+ T cells and the differentiation of naive CD4+ T cells were examined. In vivo, the preventative or therapeutic effects of SM934 in MRL/lpr mice were investigated. Ex vivo, the mechanisms of treatment were explored according to the immunologic correlates of disease. RESULTS: In vitro, SM934 inhibited interferon-γ (IFNγ) and interleukin-17 (IL-17) production from polyclonal CD4+ T cells activated by T cell receptor engagement and the differentiation of naive CD4+ T cells into Th1 and Th17 cells, but not Treg cells. In vivo, 12-week-old MRL/lpr mice treated with SM934 for 4 weeks showed significantly ameliorated proteinuria and renal lesion severity; decreased levels of blood urea nitrogen, serum IFNγ, and serum anti-double-stranded DNA antibodies; decreased spleen size; and a lower percentage of CD3+B220+CD4-CD8- T cells; 16-week-old MRL/lpr mice treated with SM934 for 8 weeks avoided severe proteinuria and survived longer. Ex vivo, SM934 treatment elevated the percentage of Treg cells, inhibited the development of Th1 and Th17 cells, and impeded the comprehensive activation of STAT-1, STAT-3, and STAT-5 proteins in splenocytes. CONCLUSION: Taken together, the results of this study demonstrated that the artemisinin analog SM934 had therapeutic effects in lupus-prone female MRL/lpr mice by inhibiting both Th1 cell and Th17 cell responses. Moreover, this study indicated that both IFNγ and IL-17 are required for the elicitation and development of murine lupus.


Assuntos
Artemisininas/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Células Th1/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Animais , Artemisininas/farmacologia , Modelos Animais de Doenças , Feminino , Interferon gama/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Camundongos , Células Th1/imunologia , Células Th17/imunologia , Resultado do Tratamento
15.
J Ethnopharmacol ; 265: 113345, 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32890713

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Periploca sepium Bunge (P. sepium) is used in traditional Chinese medicine (TCM) for the treatment of autoimmune diseases, particularly rheumatoid arthritis. Periploca sepium periplosides (PePs), isolated from the root bark of P. sepium, characterized as the cardiac glycosides-free pregnane glycosides fraction, is expected to possess therapeutic potential on inflammatory arthritis. AIM OF THE STUDY: The current study is designed to evaluate the anti-nociceptive, anti-inflammatory and anti-arthritic activities effects of the PePs. MATERIALS AND METHODS: The anti-nociceptive activity of PePs was examined in the writhing test and hot-plate test in mice. The anti-inflammatory activity of PePs was determined by the 2, 4-dinitro-1-fluorobenzene (DNFB)-induced ear edema model and the carrageenan induced paw edema model in mice. The anti-arthritic activity of PePs was investigated by evaluating the joint inflammation and arthritis pathology in rat adjuvant induced arthritis (AIA) and murine collagen induced arthritis (CIA). Phytohaemagglutinin M (PHA-M) -elicited human peripheral blood mononuclear cells (PBMCs) were further applied to assess the suppressive activity of PePs on IFN-γ and IL-17 production. RESULTS: PePs treatment markedly decreased the acetic acid-induced visceral nociceptive response and increased the hot-plate pain threshold. Further, oral administration of PePs exhibited anti-inflammatory activity by decreasing DNFB-induced ear edema in mice and carrageenan-induced paw edema in rats. Moreover, oral treatment of PePs ameliorated joint swelling and attenuated bone erosion in rodent arthritis, and the therapeutic benefits were partially attributed to the suppression of proinflammatory cytokines such IFN-γ and IL-17. Moreover, PePs suppressed the proliferation as well as IFN-γ and IL-17 secretion in PHA-M-elicited human PBMCs in a concentration dependent manner. CONCLUSIONS: Taken together, our results justified the traditional use of Periploca sepium Bunge for the treatment of diseases associated with inflammation and pain.


Assuntos
Analgésicos/farmacologia , Antirreumáticos/farmacologia , Glicosídeos/farmacologia , Periploca/química , Pregnanos/farmacologia , Analgésicos/isolamento & purificação , Animais , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Antirreumáticos/isolamento & purificação , Artrite Experimental/tratamento farmacológico , Artrite Experimental/patologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/patologia , Modelos Animais de Doenças , Edema/tratamento farmacológico , Feminino , Glicosídeos/isolamento & purificação , Inflamação/tratamento farmacológico , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos DBA , Camundongos Endogâmicos ICR , Dor/tratamento farmacológico , Pregnanos/isolamento & purificação , Ratos , Ratos Sprague-Dawley
16.
Lupus Sci Med ; 6(1): e000331, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31168402

RESUMO

OBJECTIVE: Rheumatoid arthritis is an autoimmune disease characterised by inflammation and bone loss, leading to joint destruction and deformity. The cervus and cucumis polypeptide (CCP) injection, one of the traditional Chinese medicine injections combined extracts from deer horn and sweet melon seeds, is widely used to treat arthritis and bone fracture in China. The present study investigated the therapeutic efficacy and mechanism of CCP on pathological immune cells and bone homoeostasis in rodent experimental arthritis. METHODS: The effects of CCP (4 mg/kg and 2 mg/kg) on clinical arthritis symptoms, bone erosion, proinflammatory cytokines and pathological immune cells induced by complete Freund's adjuvant was evaluated in male Sprague-Dawley rats. The impacts of CCP (2 mg/kg) on joint erythema and swelling, production of pathogenic antibodies and the proportion of inflammatory cells were assessed in collagen-induced arthritis (CIA) in DBA/1J mice. Regulation of osteoclastogenesis by CCP was observed in the murine macrophage-like RAW264.7 cells treated with receptor activator of nuclear factor-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). RESULTS: CCP administration significantly prevented disease progression in both adjuvant-induced arthritis (AIA) rats and CIA mice. The therapeutic benefits were accompanied by reduction of paw oedema, reversed bone destruction, decreased pathological changes and osteoclast numbers in joints in AIA rats, as well as attenuated clinical manifestation and autoantibodies production in CIA mice. Meanwhile, in vitro supplemented of CCP concentration dependently inhibited RANKL/M-CSF-induced osteoclast differentiation, without showing cytotoxicity in RAW264.7 cells. Further, the presence of CCP dampened the augmented downstream signalling transduction as well as activation of osteoclast-specific genes and transcription factors induced by RANKL/M-CSF in RAW264.7 cells. CONCLUSION: Our study suggested that the therapeutic effects of CCP in experimental arthritis could be attributed to its intervention on RANKL-induced osteoclastogenesis signalling pathway in osteoclast precursor cells.

17.
J Med Chem ; 49(15): 4790-4, 2006 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-16854087

RESUMO

A series of novel benzimidazole derivatives was synthesized and evaluated for their anti-hepatitis B virus (HBV) activity and cytotoxicity in vitro. Strong activity against HBV replication and low cytotoxicity were generally observed in these benzimidazoles. The most promising compounds were 12a and 12b, with similar high antiviral potency (IC50 = 0.9 and 0.7 microM, respectively) and remarkable selectivity indices (>1111 and 714, respectively). They were selected for further evaluation as novel HBV inhibitors.


Assuntos
Antivirais/síntese química , Benzimidazóis/síntese química , Vírus da Hepatite B/efeitos dos fármacos , Antivirais/farmacologia , Antivirais/toxicidade , Benzimidazóis/química , Benzimidazóis/farmacologia , Linhagem Celular Tumoral , DNA Viral/antagonistas & inibidores , Vírus da Hepatite B/genética , Humanos , Relação Estrutura-Atividade
18.
Sci Rep ; 6: 38115, 2016 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-27897259

RESUMO

SM934 is an artemisinin analogue with immunosuppressive properties and potent therapeutic activity against lupus-like diseases in autoimmune mice. In this report, the therapeutic efficacy and underlying mechanisms of SM934 on rheumatoid arthritis (RA) was investigated using collagen-induced arthritis (CIA) in DBA/1J mice. We demonstrated that SM934 treatment alleviate the severity of arthritis in CIA mice with established manifestations. The therapeutic benefits were associated with ameliorated joint swelling and reduced extent of bone erosion and destruction. Further, administration of SM934 diminished the development of T follicular helper (Tfh) cells and Th17 cells and suppressed the production of pathogenic antibodies, without altering the proportion of germinal center B cells. Ex vivo, SM934 treatment inhibited the bovine type II collagen (CII) induced proliferation and inflammatory cytokines secretion of CII -reactive T cells. In vitro, SM934 impeded the polarization of naïve CD4+ T cells into Tfh cells and the expression of its transcript factor Bcl-6. Moreover, SM934 decreased the IL-21-producing CD4+ T cells and dampened the IL-21 downstream signaling through STAT3. These finding offered the convincing evidence that artemisinin derivative might attenuate RA by simultaneously interfering with the generation of Tfh cells and Th17 cells as well as the subsequent antibody-mediated immune responses.


Assuntos
Artemisininas/farmacologia , Artrite Experimental/economia , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/tratamento farmacológico , Colágeno Tipo II/farmacologia , Células Th17/efeitos dos fármacos , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/tratamento farmacológico , Artrite Experimental/metabolismo , Artrite Reumatoide/metabolismo , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Bovinos , Modelos Animais de Doenças , Feminino , Interferon gama/metabolismo , Interleucinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Fator de Transcrição STAT3/metabolismo , Células Th17/metabolismo
19.
PLoS One ; 8(8): e74108, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24009768

RESUMO

BACKGROUND: Artemisinin analogue SM934 was previously reported to possess immunosuppressive properties. The aim of this study was to determine the effects and the underlying mechanisms of SM934 in murine experimental autoimmune encephalomyelitis (EAE). METHODS: Female C57BL/6 mice immunized with MOG35-55 were treated with or without SM934, then the clinical scores and other relevant parameters were assessed. Th1, Th17 and regulatory T (Treg) cell profiles were determined through ELISA, qRT-PCR, flow cytometry and BrdU incorporation assay. The effects of SM934 on Th1, Th17 and Treg cells differentiation were explored through intracellular staining and flow cytometry examination. RESULTS: In vivo, administration of SM934 significantly inhibited the development of EAE and suppressed the elevation of serum IL-17. Ex vivo, upon antigen-recall stimulation, IL-2, IFN-γ, IL-17 and IL-6 production were decreased, whereas IL-10 and TGF-ß production were increased from the splenocytes isolated from SM934-treated mice. Consistently, both flow cytometry and qRT-PCR results showed that SM934 treatment significantly increased the Treg, while strongly suppressed the Th17 and Th1, responses in the peripheral. Furthermore, in the spinal lesion, SM934 treatment dramatically decreased the infiltration of CD4(+) T cells, within which the Treg cells percentage was enlarged, whereas the Th17, but not Th1 percentage, was significantly decreased comparing with the vehicle-treated groups. Finally, both BrdU incorporation and in vitro Treg differentiation assays revealed that SM934 treatment could directly promote the expansion of Treg cells in vivo and in vitro. CONCLUSION: Taken together, this study demonstrated that SM934 treatment could ameliorate the murine EAE disease, which might be mediated by inducing Treg differentiation and expansion.


Assuntos
Artemisininas/farmacologia , Encefalomielite Autoimune Experimental/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Animais , Artemisininas/administração & dosagem , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Diferenciação Celular/efeitos dos fármacos , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/patologia , Citocinas/metabolismo , Encefalomielite Autoimune Experimental/tratamento farmacológico , Feminino , Mediadores da Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Glicoproteína Mielina-Oligodendrócito/administração & dosagem , Glicoproteína Mielina-Oligodendrócito/imunologia , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/imunologia , Baço/citologia , Baço/imunologia , Baço/metabolismo , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/metabolismo
20.
PLoS One ; 7(2): e32424, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22389703

RESUMO

BACKGROUND: Artemisinin and its derivatives were reported to possess strong regulatory effects on inflammation and autoimmune diseases. This study was designed to examine the therapeutic effects and underlying mechanisms of SM934, a water-soluble artemisinin analogue, on lupus-prone female NZB × NZW F(1) mice. METHODOLOGY/PRINCIPAL FINDINGS: NZB/W F(1) mice were treated orally with SM934 for 3 or 6 months respectively to investigate the effect on clinical manifestations and immunological correlates. To further explore the mechanisms of SM934, ovalbumin (OVA)-immunized or interferon (IFN)-γ-elicited C57BL/6 mice were used. In vivo, treatment with SM934 for 3 or 6 months significantly delayed the progression of glomerulonephritis and increased the survival rate of NZB/W F(1) mice. Clinical improvement was accompanied with decreased Th1-related anti-double-strand DNA (dsDNA) IgG2a and IgG3 Abs, serum interleukin (IL)-17, and increased Th2-related anti-dsDNA IgG1 Ab, serum IL-10 and IL-4. SM934 treatment also suppressed the accumulation of effector/memory T cells, induced the apoptosis of CD4(+) T cells, while enhancing the development of regulatory T cells in NZB/W F(1) mice. In addition, SM934 treatment promoted the IL-10 production of macrophages from NZB/W F(1) mice, OVA-immunized C57BL/6 mice and IFN-γ-elicited C57BL/6 mice. In vitro, SM934 enhanced IL-10 production from primary macrophages stimulated with IFN-γ. CONCLUSIONS/SIGNIFICANCE: The results of this study demonstrated that artemisinin analogue SM934 had therapeutic effects on lupus-prone female NZB/W F(1) mice by inhibiting the pathogenic helper T cell development and enhancing anti-inflammatory cytokine IL-10 production.


Assuntos
Artemisininas/uso terapêutico , Interleucina-10/metabolismo , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Administração Oral , Animais , Artemisininas/administração & dosagem , Feminino , Glomerulonefrite/tratamento farmacológico , Glomerulonefrite/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Camundongos , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo
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