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1.
Mol Immunol ; 166: 110-118, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38280829

RESUMO

Th17 cell, an important subpopulation of helper T cell, plays an important role in the development of inflammatory bowel disease (IBD) and is thought to be a potential target for the treatment of IBD. In our previous study, we demonstrated that α-mangostin could relieve lupus nephritis via inhibiting Th17 cell function. In our preliminary study, we obtained four derivatives by adding chemical modification of α-mangostin which could also inhibit Th17 cell differentiation in vitro. In this study, we constructed a chronic IBD mouse model and demonstrated the therapeutic effects of α-mangostin and its derivatives as therapeutic agents for IBD. In compounds treating groups, intestinal inflammation showed significant improvement in symptoms which included weight loss, high disease activity index, colon length shorten and the change of intestinal flora. We also found that compounds could effectively either suppress the number of Th17 cell or increase the number of Treg cell detected by flow cytometry, thus reducing the Th17/Treg ratio and suppressing the level of intestinal inflammation. Notably, IL17-F levels, rather than IL17-A, were reduced in the colon of mice of compounds treating groups. Thus, α-mangostin and its derivatives ameliorate DSS-induced chronic colitis in mice by regulating Th17/Treg balance to alleviate intestinal inflammation and can modulate the intestinal microbial community. These results suggest that α-mangostin and its derivatives may be the new therapeutic option for chronic colitis.


Assuntos
Colite , Doenças Inflamatórias Intestinais , Xantonas , Camundongos , Animais , Células Th17 , Linfócitos T Reguladores , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colo , Inflamação , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL
3.
Chem Biodivers ; 20(6): e202300301, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37097072

RESUMO

Two new indole diketopiperazine alkaloids (IDAs), (+)19-epi-sclerotiamide (1) and (-)19-epi-sclerotiamide (2), along with 13 known analogs (3-15), were isolated from a soft coral-associated epiphytic fungus Aspergillus versicolor CGF 9-1-2. The structures of two new compounds were established based on the combination of HR-ESI-MS, 1D and 2D NMR spectroscopy, optical rotation measurements and quantum chemical 13 C-NMR, the absolute configurations were determined by experimental and electronic circular dichroism (ECD) calculations. The results of molecular docking showed that all the compounds had a good binding with TDP1, TDP2, TOP1, TOP2, Ache, NLRP3, EGFR, EGFR L858R, EGFR T790M and EGFR T790/L858. Biological evaluation of compounds 3, 6, 8, 11 showed that 3 exerted a strong inhibitory effect on TDP2 with a rate of 81.72 %.


Assuntos
Agaricales , Antozoários , Neoplasias Pulmonares , Animais , Dicetopiperazinas/farmacologia , Dicetopiperazinas/química , Simulação de Acoplamento Molecular , Receptores ErbB/metabolismo , Mutação , Inibidores de Proteínas Quinases/metabolismo , Aspergillus/química , Alcaloides Indólicos/química , Antozoários/metabolismo , Estrutura Molecular
4.
Eur J Med Chem ; 242: 114631, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-35985255

RESUMO

Inflammatory Bowel Diseases (IBDs) are chronic disorders with iterative intestinal mucosal inflammation which remain unmet medical needs. PDE4 inhibitors were reported to be novel anti-IBD agents, but their clinical use was hampered by side effects such as emesis and nausea. Herein, structure-based discovery of natural mangostanin (1) targeting the M-pocket resulted in the novel and potent PDE4 inhibitor 22d (IC50 = 3.5 nM) and favorable physico-chemical properties. X-Ray study revealed that 22d interacted tightly with the M-pocket and maintained the key interactions between PDE4 and roflumilast. Worthy to note that compounds 22d and our previously reported 4e and 18a, originating from mangostanin, all caused no emesis on beagle dogs at the oral dose of 10 mg/kg, confirming the safety superiority of scaffold in mangostanin derivatives over that in positive roflumilast. Finally, administration of 22d (5.0 mg/kg, twice-daily) exhibited comparable anti-IBD effects to the positive control dipyridamole (25.0 mg/kg, twice-daily) in the dextran sulfate sodium (DSS)-induced IBD mice model, indicating its potential as a novel anti-IBD agent.


Assuntos
Doenças Inflamatórias Intestinais , Inibidores da Fosfodiesterase 4 , Aminopiridinas , Animais , Benzamidas , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/química , Ciclopropanos , Sulfato de Dextrana , Dipiridamol/uso terapêutico , Cães , Doenças Inflamatórias Intestinais/induzido quimicamente , Doenças Inflamatórias Intestinais/tratamento farmacológico , Camundongos , Inibidores da Fosfodiesterase 4/farmacologia , Inibidores da Fosfodiesterase 4/uso terapêutico
5.
Bioorg Med Chem Lett ; 65: 128717, 2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-35390450

RESUMO

Tumor angiogenesis is an important biological process involved in the proliferation and migration of endothelial cells, regulated by Ang/Tie-2 signaling pathways, which is essential for tumor growth and metastasis. Therefore, blocking Ang/Tie-2 signaling pathways is a promising anti-angiogenic strategy for tumor treatment. 2,5-Diketopiperazines (DKPs) are a kind of bioactive compounds derived from marine fungi and they present a wide spectrum of pharmacological properties, particularly in the field of cancer treatment. Herein, a DKP marine natural product, Cryptoechinuline D (Cry D) was applied to structural modification and twelve derivatives were synthesized. Among which, compound 5 showed significant inhibitory activity against HUVECs with an IC50 value of 12.6 µmol/L, which weakened the proliferation, migration and invasion of HUVECs by inhibiting the Ang2/Tie-2 signaling pathway. The results of these evaluations indicated that compound 5 might be a promising anti-angiogeneic agent and worth further optimization and development for cancer therapy.


Assuntos
Produtos Biológicos , Neoplasias , Inibidores da Angiogênese/farmacologia , Produtos Biológicos/metabolismo , Produtos Biológicos/farmacologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Neoplasias/metabolismo , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo
6.
Eur J Med Chem ; 228: 113962, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34776280

RESUMO

The ligand binding domain (LBD) of retinoid-related orphan nuclear receptor γt (RORγt) has been exploited as a promising target for the new small molecule therapeutics to cure autoimmune diseases via modulating the IL-17 and IL-22 production by Th17 cells. Diverse chemical scaffolds of these small molecules have been discovered by multiple groups with methods such as high throughput screening (HTS) and virtual screening. These different scaffolds are further developed by medicinal chemists to afford lead compounds the best of which enter clinical trials. In this review, we summarize these chemical scaffolds and their evolution paths according to the groups in which they have been discovered or studied. We combine the data of the chemistry, biological assays and structural biology of each chemical scaffold, in order to afford insight to develop new RORγt modulators with higher potency, less toxicity and elucidated working mechanism.


Assuntos
Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Química Farmacêutica , Relação Dose-Resposta a Droga , Humanos , Ligantes , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade , Células Th17
7.
Org Lett ; 24(1): 158-163, 2022 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-34898224

RESUMO

Comprehensive analyses of the metabolite spectra of Aspergillus sp. EGF 15-0-3 under different culture conditions revealed the presence of unique environmental-induced metabolites exclusively from the rice medium. Subsequent target isolation afforded four unprecedented indole diketopiperazine-based hybrids with a pyrano[3',2':7,8]isochromeno[4,3-b]pyrazino[2,1-i]indole core (1 and 2) or a spiro[piperazine-2,2'-pyrano[3,4,5-de]chromene] scaffold (3 and 4). Putative biosynthetic pathways for 1-4, with Diels-Alder cycloadditions as key steps, were proposed. 1-4 exhibited selective cytotoxicities among several human cancer cells.

8.
J Med Chem ; 64(18): 13736-13751, 2021 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-34520193

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease, and its incidence rate is rapidly rising. However, effective therapies for the treatment of IPF are still lacking. Phosphodiesterase 4 (PDE4) inhibitors were reported to be potential anti-fibrotic agents, but their clinical use was hampered by side effects like emesis and nausea. Herein, structure-based hit-to-lead optimizations of natural mangostanin resulted in the novel and orally active PDE4 inhibitor 18a with potent inhibitory affinity (IC50 = 4.2 nM), favorable physico-chemical properties, and a different binding pattern from roflumilast. Emetic activity tests on dogs demonstrated that 18a cannot cause emesis even at an oral dose of 10 mg/kg, whereas rolipram had severe emetic effects at an oral dose of 1 mg/kg. Finally, the oral administration of 18a (10 mg/kg) exhibited comparable anti-pulmonary fibrosis effects with pirfenidone (150 mg/kg) in a bleomycin-induced IPF rat model, indicating its potential as a novel anti-IPF agent with improved safety.


Assuntos
Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Inibidores da Fosfodiesterase 4/uso terapêutico , Células A549 , Animais , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Cães , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/metabolismo , Humanos , Fibrose Pulmonar Idiopática/patologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Estrutura Molecular , Inibidores da Fosfodiesterase 4/síntese química , Inibidores da Fosfodiesterase 4/metabolismo , Ligação Proteica , Ratos Sprague-Dawley , Relação Estrutura-Atividade
9.
Immunol Res ; 69(4): 378-390, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34219199

RESUMO

Retinoic­acid­receptor­related orphan nuclear hormone receptor gamma t (RORγt), a critical transcriptional factor of Th17 cells, is a potential therapeutic target for Th17-mediated autoimmune diseases. In addition, RORγt is essential for thymocyte survival and lymph node development, and RORγt inhibition or deficiency causes abnormal thymocyte development, thymus lymphoma, and lymph node defect. Recent study demonstrated that specific regulation of Th17 differentiation related to the hinge region of RORγt. In this research, we investigated the effect of RORγt inhibitor, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine derivative (TTP), in the therapy of lupus nephritis and its safety on thymocyte development. We demonstrated that TTP repressed the development of Th17 cells and ameliorated the autoimmune disease manifestation in the pristane-induced lupus nephritis mice model. The treatment of TTP in the mice did not interfere with thymocyte development, including total thymocyte number and proportion of CD4+CD8+ double-positive populations in the thymus, and had no substantial effects on the pathogenesis of thymoma. The TTP had a stronger affinity with full-length RORγt protein compared with the truncated RORγt LBD region via surface plasmon resonance, which indicated TTP binding to RORγt beyond LBD region. Molecular docking computation showed that the best binding pocket of TTP to RORγt is located in the hinge region of RORγt. In summary, as a RORγt inhibitor, TTP had a potential to develop the clinical medicine for treating Th17-mediated autoimmune diseases with low safety risk for thymocyte development.


Assuntos
Nefrite Lúpica/tratamento farmacológico , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Pirimidinas/uso terapêutico , Animais , Anticorpos/sangue , Apoptose/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Citocinas/genética , DNA/imunologia , Feminino , Imunossupressores , Rim/efeitos dos fármacos , Rim/imunologia , Rim/patologia , Nefrite Lúpica/induzido quimicamente , Nefrite Lúpica/imunologia , Nefrite Lúpica/patologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Pirimidinas/farmacologia , Baço/efeitos dos fármacos , Baço/imunologia , Terpenos , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Timócitos/efeitos dos fármacos
10.
Mol Immunol ; 132: 30-40, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33540227

RESUMO

Psoriasis is a refractory inflammatory skin disease affecting 2 %-3 % of the world population, characterized by the infiltration and hyper-proliferation of inflammatory cells and aberrant differentiation of keratinocytes. Targeting the IL-23/ Th17 axis has been well recognized as a promising therapeutic strategy, as the IL-23/ Th17 signal plays a vital role in the pathology of psoriasis. Three pentacyclic triterpene compounds isolated from loquat leaves have been reported with significant inhibitory effects on RORγt transcription activity and Th17 cell differentiation, and excellent performance in preventing lupus nephritis pathogenesis. However, the potential effects of these pentacyclic triterpene compounds on psoriasis remain unknown. In this study, we demonstrated the potent therapeutic effects of these pentacyclic triterpene compounds on psoriasis. These three pentacyclic triterpene compounds significantly alleviated skin inflammation as well as aberrant keratinocyte proliferation in an imiquimod-induced mouse psoriasis model. These compounds also inhibited the infiltration of immune cells and the level of pro-inflammatory cytokine in the dermis, as well as the cells number and changed the cytokine profiling expression of Th17 cells. These compounds could reduce the amount of CD4+ and CD8+ T cells in local lymph node, but not in spleen, which is different from hydrocortisone, the positive control treatment. These results suggest better performance of these compounds than steroids on treating psoriasis with less side effects on the integrated immune system. In summary, our findings uncover the potent therapeutic effects of pentacyclic triterpene compounds on psoriasis, providing potential candidate compounds for drug development.


Assuntos
Eriobotrya/química , Hiperplasia/tratamento farmacológico , Inflamação/tratamento farmacológico , Triterpenos Pentacíclicos/uso terapêutico , Folhas de Planta/química , Psoríase/tratamento farmacológico , Células Th17/efeitos dos fármacos , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Epiderme/efeitos dos fármacos , Epiderme/patologia , Humanos , Hiperplasia/metabolismo , Hiperplasia/patologia , Imiquimode/toxicidade , Inflamação/patologia , Queratinócitos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Triterpenos Pentacíclicos/química , Triterpenos Pentacíclicos/metabolismo , Triterpenos Pentacíclicos/farmacologia , Psoríase/induzido quimicamente , Psoríase/imunologia , Psoríase/patologia , Células Th17/imunologia , Células Th17/metabolismo
11.
ACS Chem Neurosci ; 11(15): 2348-2360, 2020 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-32644771

RESUMO

Traumatic brain injury (TBI) is a prevalent public healthcare concern frequently instigated by mechanical shock, traffic, or violence incidents, leading to permanent nerve damage, and there is no ideal treatment for it yet. In this study, a series of Rolipram-Tranilast hybrids were designed and synthesized. The neuroprotective activities of the Rolipram-Tranilast hybrids were evaluated both in vitro and in vivo. Compound 5 has been identified as the strongest neuroprotective molecule among the series with robust anti-oxidant and anti-inflammatory potentials. Compound 5 significantly increased the heme oxygenase-1 (HO-1) levels and the phosphorylated cAMP response elements binding protein (p-CREB) while it down-regulated phosphodiesterase-4 B (PDE4B) expression in vitro. Furthermore, compound 5 remarkably attenuated TBI and had a good safety profile in mice. Taken together, our findings suggested that compound 5 could serve as a novel promising lead compound in the treatment of TBI and other central nervous system (CNS) diseases associated with PDE4B and oxidative stress.


Assuntos
Lesões Encefálicas Traumáticas , Animais , Lesões Encefálicas Traumáticas/tratamento farmacológico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Camundongos , Rolipram/farmacologia , ortoaminobenzoatos
12.
J Med Chem ; 63(6): 3370-3380, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32115956

RESUMO

To validate PDE4 inhibitors as novel therapeutic agents against vascular dementia (VaD), 25 derivatives were discovered from the natural inhibitor α-mangostin (IC50 = 1.31 µM). Hit-to-lead optimization identified a novel and selective PDE4 inhibitor 4e (IC50 = 17 nM), which adopted a different binding pattern from PDE4 inhibitors roflumilast and rolipram. Oral administration of 4e at a dose of 10 mg/kg exhibited remarkable therapeutic effects in a VaD model and did not cause emesis to beagle dogs, indicating its potential as a novel anti-VaD agent.


Assuntos
Demência Vascular/tratamento farmacológico , Inibidores da Fosfodiesterase 4/uso terapêutico , Xantonas/uso terapêutico , Aminopiridinas/metabolismo , Animais , Benzamidas/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Ciclopropanos/metabolismo , Cães , Desenho de Fármacos , Humanos , Masculino , Camundongos Endogâmicos C57BL , Estrutura Molecular , Inibidores da Fosfodiesterase 4/síntese química , Inibidores da Fosfodiesterase 4/metabolismo , Inibidores da Fosfodiesterase 4/farmacocinética , Ligação Proteica , Rolipram/metabolismo , Rolipram/uso terapêutico , Relação Estrutura-Atividade , Vômito/prevenção & controle , Xantonas/síntese química , Xantonas/metabolismo , Xantonas/farmacocinética
13.
Int J Rheum Dis ; 23(1): 74-83, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31769201

RESUMO

AIM: α-mangostin, a polyphenolic xanthone derivative of mangosteen, has been reported to possess multiple therapeutic properties, such as anti-cancer, anti-allergy and anti-inflammatory activity. However, its anti-inflammatory effects in autoimmune diseases such as lupus nephritis (LN) remain unclear. In this study, we want to investigate the therapeutic effect of α-mangostin in LN. METHODS: First, we elucidated the retinoic acid receptor related orphan receptor gamma t (RORγt) inhibitory activity of α-mangostin in cell-based assay and T helper 17 (Th17) differentiation in vitro assay. Then, we established a pristane-induced LN mouse model and randomly divided these into a normal control group, model control group, α-mangostin group and prednisone acetate group. Finally, anti-double-stranded DNA (anti-dsDNA) level in serum was detected by enzyme-linked immunosorbent assay, interleukin (IL)-17A and interferon (IFN)-γ expression in spleen cells by flow cytometry; histomorphology examination of kidneys was performed by periodic acid-Schiff staining and immunofluorescence analysis with an anti-immunoglobulin G (anti-IgG) and anti-IgM antibodies. RESULTS: We found that α-mangostin inhibited RORγt transcription activity in a cell-based assay and also polarized Th17 cells in an in vitro induction experiment. Our results also showed that α-mangostin could significantly decrease serum anti-dsDNA antibody levels, IL-17A and IFN-γ expression and alleviate renal pathological damage in the α-mangostin-treated group mice than in the model group mice. CONCLUSION: Thus, α-mangostin demonstrated its potential as a candidate therapeutic drug for LN and other Th17-mediated autoimmune diseases by inhibiting the function of Th17.


Assuntos
Imunidade Celular/efeitos dos fármacos , Nefrite Lúpica/metabolismo , Células Th17/patologia , Xantonas/farmacologia , Animais , Diferenciação Celular/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Nefrite Lúpica/induzido quimicamente , Nefrite Lúpica/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Terpenos/toxicidade , Células Th17/imunologia
14.
Immunol Invest ; 49(6): 632-647, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31795780

RESUMO

BACKGROUND: Loquat leaf is an herb that is commonly used in traditional Chinese medicine (TCM) for its anti-inflammatory properties. Numerous studies have demonstrated that Th17 cells play a fundamental role in mediating SLE pathological deterioration. In our study, we investigated the inhibitory effect of pentacyclic triterpenes from loquat leaf on T helper 17 (Th17) cells and the therapeutic efficacy of OA in Lupus nephritis (LN) development. METHODS: We isolated three pentacyclic triterpene compounds rom loquat leaf by bioassay-directed fractionation and separation method. There were methyl corosolate (MC), uvaol (UL), and oleanolic acid (OA) Firstly, we elucidated Retinoic acid receptor-related orphan receptor gamma t (RORγt) inhibitory activity of these three compounds in the cell-based assay and Th17 differentiation in vitro assay. Then, we used OA-treated pristine-induced LN mice to evaluate the therapeutic effects of OA in LN development. Anti-dsDNA level in serum was detected by enzyme-linked immunosorbent assay (ELISA), interleukin 17A (IL-17A) and interferon-γ (IFN-γ) expression in spleen cells by Flow cytometry (FCM), histomorphologic examination of kidneys were performed by periodic acid schiff (PAS) staining and immunofluorescence analysis. RESULTS: Pentacyclic triterpene compounds (MC, UL, OA) displayed inhibition of RORγt activity in cell-based assay and Th17 differentiation in vitro. Furthermore, our results also showed that OA could significantly decrease serum anti-dsDNA antibody levels, IL-17A and IFN-γ expression and alleviate renal pathological damage in OA-treated group mice than in the model group mice. CONCLUSION: These results demonstrated that OA can improve the clinical manifestation of LN, indicating potential application in SLE therapy.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Eriobotrya/química , Triterpenos Pentacíclicos/farmacologia , Folhas de Planta/química , Células Th17/citologia , Células Th17/efeitos dos fármacos , Animais , Biomarcadores , Diferenciação Celular/genética , Linhagem Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Mediadores da Inflamação/metabolismo , Nefrite Lúpica/tratamento farmacológico , Nefrite Lúpica/etiologia , Nefrite Lúpica/metabolismo , Nefrite Lúpica/patologia , Camundongos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Triterpenos Pentacíclicos/química , Células Th17/imunologia , Células Th17/metabolismo , Transcrição Gênica
15.
J Immunol Res ; 2019: 2431617, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31240232

RESUMO

Th17 activity has been implicated in systemic lupus erythematosus (SLE), which is a systemic autoimmune disease with a typical clinical manifestation of lupus nephritis (LN). Retinoic acid receptor-related orphan receptor gamma t (RORγt) has been shown to be important for Th17 differentiation. In this study, we evaluated the inhibition of RORγt activity by 3ß-acetyloxy-oleanolic acid (AOA), a small molecule isolated from the root of Symplocos laurina, a traditional herb belonging to South China. We demonstrated that AOA can inhibit RORγt activity and prevent SLE pathogenesis in a pristane-induced LN model. The results showed that AOA decreased RORγt transcription activity in a reporter assay and prevented Th17 differentiation in vitro. In vivo studies showed that AOA treatment decreased serum anti-dsDNA antibody and alleviated renal pathologic damage as well as antibody complex accumulation in the pristane-induced LN model. These results demonstrated that AOA can improve the clinical manifestation of LN, indicating potential application in SLE therapy.


Assuntos
Nefrite Lúpica/etiologia , Nefrite Lúpica/metabolismo , Ácido Oleanólico/farmacologia , Terpenos/efeitos adversos , Células Th17/imunologia , Células Th17/metabolismo , Animais , Anticorpos Antinucleares/imunologia , Biópsia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Sobrevivência Celular/efeitos dos fármacos , Ácidos Nucleicos Livres , Citocinas/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Imunofluorescência , Mediadores da Inflamação/metabolismo , Nefrite Lúpica/tratamento farmacológico , Nefrite Lúpica/patologia , Camundongos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Ácido Oleanólico/química , Células Th17/efeitos dos fármacos , Transcrição Gênica
16.
Eur J Med Chem ; 174: 216-225, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31042617

RESUMO

The identification of a valid therapeutic treatment for Alzheimer's disease (AD) represents nowadays an urgent and still unmet medical need, since currently available anti-AD drugs only relieve symptoms and show a modest efficacy. Recent evidence indicates that multi-target-directed ligands (MTDLs) can potentially provide an effective strategy to develop innovative therapies directed towards the onset and progression of this multifactorial neurodegenerative disorder. In this work we designed, synthesized and evaluated a new series of MTDLs bearing the rivastigmine skeleton (ChE-inhibitor) linked to known metal-chelating moieties with linkers of different length. For all the novel derivatives, AChE/BuChE inhibitory activity, ROS scavenging activity and potential cytotoxicity have been assessed. For the best compound (4), copper chelating properties and neuroprotective effects were also evaluated. Our data demonstrated that hybrid derivative 4 is able to effectively inhibit AChE and BuChE and to chelate copper, showing a protective action on neurons. These results, although preliminary, indicate that compound 4 can be considered as a possible hit molecule for the development of new anti-AD MTDLs.


Assuntos
Quelantes/farmacologia , Complexos de Coordenação/farmacologia , Cobre/química , Fármacos Neuroprotetores/farmacologia , Rivastigmina/análogos & derivados , Rivastigmina/farmacologia , Acetilcolinesterase/metabolismo , Animais , Butirilcolinesterase/metabolismo , Linhagem Celular Transformada , Quelantes/síntese química , Quelantes/toxicidade , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/toxicidade , Complexos de Coordenação/síntese química , Complexos de Coordenação/toxicidade , Sequestradores de Radicais Livres/síntese química , Sequestradores de Radicais Livres/farmacologia , Sequestradores de Radicais Livres/toxicidade , Camundongos , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/toxicidade , Rivastigmina/síntese química , Rivastigmina/toxicidade
17.
Bioorg Med Chem ; 26(3): 543-550, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29310862

RESUMO

Alzheimer's disease (AD), a complex chronic progressive central nervous system degenerative disease and a public health problem of the world, often characters cognitive dysfunction accompaning aggression and depression, and may lead to death. More attentions should be paid on it because there is no modified strategy against AD till now. AD is featured with the loss of cholinergic neurons, the amyloid-beta peptide (Aß) plaques and the neurofibrillary tangles and several hypotheses were established to explain the pathogenesis of AD. Hydroxycinnamic acids, including caffeic acid (CA) and ferulic acid (FA) are widely distributed in natural plants and fruits. CA and FA exert various pharmacological activities, including anti-inflammatory, antioxidant, neuroprotection, anti-amyloid aggregation and so on. All these pharmacological activities are associated with the treatment of AD. Here we summarized the pharmacological activities of CA and FA, and their hybrids as multi-target-directed ligands (MTDLs) against AD. The future application of CA and FA was also discussed, hoping to provide beneficial information for the development of CA- and FA-based MTDLs against AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Ácidos Cumáricos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/metabolismo , Ácidos Cumáricos/química , Ácidos Cumáricos/farmacologia , Humanos , Ligantes , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Agregados Proteicos/efeitos dos fármacos
18.
RSC Adv ; 8(71): 40974-40983, 2018 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-35557894

RESUMO

A series of novel artemisinin (ART) derivatives containing an isothiocyanate (ITC) group were synthesized. All the compounds showed more potent anti-tumor effects than those of parent dihydroartemisinin (DHA) towards glioblastoma multiforme U87 in vitro. Among them, 5b had the strongest cytotoxic activity which exerted its effects in a concentration-dependent but not time-dependent manner (IC50 7.41 µM for 24 h, 7.35 µM for 72 h). Pyknosis was observed in 5b-treated U87 cells. Multiple intrinsic apoptotic pathways were induced by 5b including the upregulation of caspase 9, the release of cytochrome c, an increase of the proapoptotic protein Bax, a decrease of the anti-apoptotic protein Bcl 2, and the activation of execution pathways by the upregulation of caspase 3. In addition to apoptosis, an autophagic mechanism was also involved in 5b-induced cytotoxicity to human GBM U87 cells by upregulating the expression of LC3-II and downregulating p62. Furthermore, 5b also significantly attenuated the migration of U87 cells. Therefore, our results suggest that 5b may be a promising molecule for the further development of a novel drug for the treatment of glioblastoma.

19.
Nat Prod Res ; 31(24): 2836-2841, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28281360

RESUMO

The ethanolic extract of the leaves of Eriobotrya japonica exhibited inhibitory activity against phosphodiesterase-4D (PDE4D), which is a therapeutic target of inflammatory disease. Subsequent bioassay-guided fractionation led to the isolation of a new triterpene (1), together with seven known triterpenoids, methyl corosolate (2), ursolic acid (3), oleanolic acid (4), methyl maslinate (5), α-amyin (6), 3ß,19α,23-trihydroxy-urs-12-ene (7) and uvaol (8). The structure of compound 1 was established as 3ß-hydroxyl-21ß-acetoxyl-urs-12-en-28-carboxylate on the basis of interpretation of its 1D and 2D NMR and HR-ESI-MS spectroscopic data. The bioassay results verified compounds 2, 3 and 8 inhibited PDE4D2 effectively with the IC50 values of 3.06, 2.18 and 5.17 µM, respectively, which may provide a novel mechanism for the anti-inflammatory activity of the leaves of E. japonica.


Assuntos
Eriobotrya/química , Inibidores da Fosfodiesterase 4/isolamento & purificação , Animais , Anti-Inflamatórios/isolamento & purificação , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Ácido Oleanólico/análogos & derivados , Ácido Oleanólico/isolamento & purificação , Folhas de Planta/química , Triterpenos/isolamento & purificação , Triterpenos/farmacologia , Ácido Ursólico
20.
Nat Prod Res ; 31(6): 734-737, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27531418

RESUMO

In this study, a series of novel ferulic and caffeic acid dimers was designed and synthesised, and their multifunctional properties against Alzheimer's disease (AD) were evaluated. Results showed that our multifunctional strategy was great supported by enhancing the inhibition of Aß1-42 self-induced aggregation. Moreover, 7b also had potent protective effects against glutamate-induced cell death without significant cell toxicity in mouse hippocampal neuronal HT22 cells and 10c effectively scavenged diphenylpicrylhydrazyl free radicals. Collectively, these data strongly encourage further optimisation of 7b as a new hit to develop multifunctional agents for the treatment of AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Ácidos Cafeicos/síntese química , Ácidos Cafeicos/uso terapêutico , Ácidos Cumáricos/síntese química , Ácidos Cumáricos/uso terapêutico , Peptídeos beta-Amiloides/antagonistas & inibidores , Animais , Antioxidantes/farmacologia , Compostos de Bifenilo/química , Morte Celular/efeitos dos fármacos , Linhagem Celular , Sequestradores de Radicais Livres/química , Sequestradores de Radicais Livres/farmacologia , Ácido Glutâmico/toxicidade , Humanos , Camundongos , Neurônios/efeitos dos fármacos , Fragmentos de Peptídeos/antagonistas & inibidores , Picratos/química
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