Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 493
Filtrar
1.
Molecules ; 26(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34361701

RESUMO

Arthritis is a chronic inflammatory disease accompanied by pathological reactions such as swelling, redness, fever, and pain in various joint areas. The drugs currently available to treat arthritis are associated with diverse side-effects. Therefore, there is a need for safer and more effective treatments to alleviate the inflammation of arthritis with fewer side-effects. In this study, a new sterol, Δ8(14)-ergostenol, was discovered, and its glycosides were synthesized and found to be more efficient in terms of synthesis or anti-inflammatory activity than either spinasterol or 5,6-dihydroergosterol is. Among these synthetic glycosides, galactosyl ergostenol inhibited the expression of inflammatory mediators in TNF-α-stimulated FLS and TNF-α-induced MMPs and collagen type II A1 degradation in human chondrocytes. These results suggest the new galactosyl ergostenol as a treatment candidate for arthritis.


Assuntos
Anti-Inflamatórios/farmacologia , Condrócitos/efeitos dos fármacos , Ergosterol/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Glicosídeos/farmacologia , Sinoviócitos/efeitos dos fármacos , Anti-Inflamatórios/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Condrócitos/citologia , Condrócitos/metabolismo , Colágeno Tipo II/genética , Colágeno Tipo II/metabolismo , Ergosterol/química , Glicosídeos/síntese química , Humanos , Inflamação/prevenção & controle , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Interleucina-8/genética , Interleucina-8/metabolismo , Metaloproteinases da Matriz/genética , Metaloproteinases da Matriz/metabolismo , Modelos Biológicos , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Transdução de Sinais , Sinoviócitos/citologia , Sinoviócitos/metabolismo , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/farmacologia
2.
Molecules ; 26(11)2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34200464

RESUMO

Due to lifespan extension and changes in global climate, the increase in mycoses caused by primary and opportunistic fungal pathogens is now a global concern. Despite increasing attention, limited options are available for the treatment of systematic and invasive mycoses, owing to the evolutionary similarity between humans and fungi. Although plants produce a diversity of chemicals to protect themselves from pathogens, the molecular targets and modes of action of these plant-derived chemicals have not been well characterized. Using a reverse genetics approach, the present study revealed that thymol, a monoterpene alcohol from Thymus vulgaris L., (Lamiaceae), exhibits antifungal activity against Cryptococcus neoformans by regulating multiple signaling pathways including calcineurin, unfolded protein response, and HOG (high-osmolarity glycerol) MAPK (mitogen-activated protein kinase) pathways. Thymol treatment reduced the intracellular concentration of Ca2+ by controlling the expression levels of calcium transporter genes in a calcineurin-dependent manner. We demonstrated that thymol decreased N-glycosylation by regulating the expression levels of genes involved in glycan-mediated post-translational modifications. Furthermore, thymol treatment reduced endogenous ergosterol content by decreasing the expression of ergosterol biosynthesis genes in a HOG MAPK pathway-dependent manner. Collectively, this study sheds light on the antifungal mechanisms of thymol against C. neoformans.


Assuntos
Antifúngicos/farmacologia , Criptococose/tratamento farmacológico , Cryptococcus neoformans/efeitos dos fármacos , Timol/farmacologia , Calcineurina/metabolismo , Criptococose/metabolismo , Cryptococcus neoformans/metabolismo , Ergosterol/farmacologia , Proteínas Fúngicas/metabolismo , Humanos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Monoterpenos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Thymus (Planta)/química
3.
Molecules ; 26(14)2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34299538

RESUMO

Trichophyton rubrum causes ringworm worldwide. Citral (CIT), extracted from Pectis plants, is a monoterpene and naturally composed of geometric isomers neral (cis-citral) and geranial (trans-citral). CIT has promising antifungal activities and ergosterol biosynthesis inhibition effects against several pathogenic fungi. However, no study has focused on neral and geranial against T. rubrum, which hinders the clinical application of CIT. This study aimed to compare antifungal activities of neral and geranial and preliminarily elucidate their ergosterol biosynthesis inhibition mechanism against T. rubrum. Herein, the disc diffusion assays, cellular leakage measurement, flow cytometry, SEM/TEM observation, sterol quantification, and sterol pattern change analyses were employed. The results showed geranial exhibited larger inhibition zones (p < 0.01 or 0.05), higher cellular leakage rates (p < 0.01), increased conidia with damaged membranes (p < 0.01) within 24 h, more distinct shriveled mycelium in SEM, prominent cellular material leakage, membrane damage, and morphological changes in TEM. Furthermore, geranial possessed more promising ergosterol biosynthesis inhibition effects than neral, and both induced the synthesis of 7-Dehydrodesmosterol and Cholesta-5,7,22,24-tetraen-3ß-ol, which represented marker sterols when ERG6 was affected. These results suggest geranial is more potent than neral against T. rubrum, and both inhibit ergosterol biosynthesis by affecting ERG6.


Assuntos
Monoterpenos Acíclicos/farmacologia , Antifúngicos/farmacologia , Arthrodermataceae/efeitos dos fármacos , Dermatomicoses/tratamento farmacológico , Ergosterol/farmacologia , Testes de Sensibilidade Microbiana/métodos , Monoterpenos/farmacologia , Micélio/efeitos dos fármacos , Extratos Vegetais/farmacologia , Esporos Fúngicos/efeitos dos fármacos
4.
Vet Res ; 52(1): 86, 2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34127062

RESUMO

Porcine deltacoronavirus (PDCoV) is a newly discovered swine enteropathogenic coronavirus with worldwide distribution. However, efficient strategies to prevent or treat the infection remain elusive. Our in vitro study revealed that ergosterol peroxide (EP) from the mushroom Cryptoporus volvatus has efficient anti-PDCoV properties. The aim of this study is to evaluate the potential of EP as a treatment for PDCoV in vivo and elucidate the possible mechanisms. Seven-day-old piglets were infected with PDCoV by oral administration in the presence or absence of EP. Piglets infected with PDCoV were most affected, whereas administration of EP reduced diarrhea incidence, alleviated intestinal lesion, and decreased viral load in feces and tissues. EP reduced PDCoV-induced apoptosis and enhanced tight junction protein expressions in the small intestine, maintaining the integrity of the intestinal barrier. EP showed immunomodulatory effect by suppressing PDCoV-induced pro-inflammatory cytokines and the activation of IκBα and NF-κB p65, and upregulating IFN-I expression. Knockdown of p38 inhibited PDCoV replication and alleviated PDCoV-induced apoptosis, implying that EP inhibited PDCoV replication and alleviated PDCoV-induced apoptosis via p38/MAPK signaling pathway. Collectively, ergosterol peroxide can protect piglets from PDCoV, revealing the potential of EP for development as a promising strategy for treating and controlling the infection of PDCoV.


Assuntos
Apoptose/efeitos dos fármacos , Infecções por Coronavirus/veterinária , Deltacoronavirus , Ergosterol/análogos & derivados , Doenças dos Suínos/virologia , Junções Íntimas/efeitos dos fármacos , Animais , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Deltacoronavirus/efeitos dos fármacos , Ergosterol/farmacologia , Ergosterol/uso terapêutico , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/virologia , Células LLC-PK1 , Masculino , Suínos , Doenças dos Suínos/tratamento farmacológico
5.
Molecules ; 26(10)2021 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-34067678

RESUMO

Intracerebral hemorrhage (ICH) is a devastating neurological disorder characterized by an exacerbation of neuroinflammation and neuronal injury, for which few effective therapies are available at present. Inhibition of excessive neuroglial activation has been reported to alleviate ICH-related brain injuries. In the present study, the anti-ICH activity and microglial mechanism of ergosta-7,9(11),22-trien-3ß-ol (EK100), a bioactive ingredient from Asian medicinal herb Antrodia camphorate, were evaluated. Post-treatment of EK100 significantly attenuated neurobehavioral deficit and MRI-related brain lesion in the mice model of collagenase-induced ICH. Additionally, EK100 alleviated the inducible expression of cyclooxygenase (COX)-2 and the activity of matrix metalloproteinase (MMP)-9 in the ipsilateral brain regions. Consistently, it was shown that EK100 concentration-dependently inhibited the expression of COX-2 protein in Toll-like receptor (TLR)-4 activator lipopolysaccharide (LPS)-activated microglial BV-2 and primary microglial cells. Furthermore, the production of microglial prostaglandin E2 and reactive oxygen species were attenuated by EK100. EK100 also attenuated the induction of astrocytic MMP-9 activation. Among several signaling pathways, EK100 significantly and concentration-dependently inhibited activation of c-Jun N-terminal kinase (JNK) MAPK in LPS-activated microglial BV-2 cells. Consistently, ipsilateral JNK activation was markedly inhibited by post-ICH-treated EK100 in vivo. In conclusion, EK100 exerted the inhibitory actions on microglial JNK activation, and attenuated brain COX-2 expression, MMP-9 activation, and brain injuries in the mice ICH model. Thus, EK100 may be proposed and employed as a potential therapeutic agent for ICH.


Assuntos
Lesões Encefálicas/tratamento farmacológico , Ergosterol/análogos & derivados , Ergosterol/farmacologia , Animais , Encéfalo/metabolismo , Lesões Encefálicas/metabolismo , Hemorragia Cerebral/tratamento farmacológico , Hemorragia Cerebral/metabolismo , Ciclo-Oxigenase 2/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/fisiologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Polyporales/metabolismo , Transdução de Sinais/efeitos dos fármacos
6.
Am J Physiol Endocrinol Metab ; 321(2): E246-E251, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34181461

RESUMO

Vitamin D deficiency significantly correlates with the severity of SARS-CoV-2 infection. Molecular docking-based virtual screening studies predict that novel vitamin D and related lumisterol hydroxymetabolites are able to bind to the active sites of two SARS-CoV-2 transcription machinery enzymes with high affinity. These enzymes are the main protease (Mpro) and RNA-dependent RNA polymerase (RdRP), which play important roles in viral replication and establishing infection. Based on predicted binding affinities and specific interactions, we identified 10 vitamin D3 (D3) and lumisterol (L3) analogs as likely binding partners of SARS-CoV-2 Mpro and RdRP and, therefore, tested their ability to inhibit these enzymes. Activity measurements demonstrated that 25(OH)L3, 24(OH)L3, and 20(OH)7DHC are the most effective of the hydroxymetabolites tested at inhibiting the activity of SARS-CoV-2 Mpro causing 10%-19% inhibition. These same derivatives as well as other hydroxylumisterols and hydroxyvitamin D3 metabolites inhibited RdRP by 50%-60%. Thus, inhibition of these enzymes by vitamin D and lumisterol metabolites may provide a novel approach to hindering the SARS-CoV-2 infection.NEW & NOTEWORTHY Active forms of vitamin D and lumisterol can inhibit SARS-CoV-2 replication machinery enzymes, which indicates that novel vitamin D and lumisterol metabolites are candidates for antiviral drug research.


Assuntos
Antivirais/farmacologia , Ergosterol/metabolismo , RNA Polimerase Dependente de RNA/antagonistas & inibidores , SARS-CoV-2/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Vitamina D/farmacologia , Antivirais/química , Ergosterol/análogos & derivados , Ergosterol/química , Ergosterol/farmacologia , Simulação de Acoplamento Molecular , RNA Polimerase Dependente de RNA/química , SARS-CoV-2/fisiologia , Vitamina D/química
7.
Biochem Pharmacol ; 190: 114645, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34090877

RESUMO

Increasing evidence have reported that NLRP3 inflammasome has a crucial role in various kinds of immunological diseases including colitis. However, there have only a few drug candidates directly targeting inflammasomes for the therapy of colitis. Here, we first reported that Tubocapsanolide A (TA), a natural small molecule, as a novel inhibitor of NLRP3 inflammasome for the treatment of colitis. TA inhibited the activation of NLRP3 inflammasome and suppressed the secretion of IL-1ß and IL-18 in macrophages. Moreover, the ASC oligomerization was inhibited by TA. The assembly of the NLRP3 inflammasome was also restrained by TA, while had little effects on potassium and chloride efflux. Biolayer interferometry analysis showed that TA could directly bind to NLRP3. Importantly, LC-MS/MS analysis further demonstrated that TA covalently bound to the cysteine 514 residue (Cys514) of NLRP3. In vivo experiments showed that TA remarkably ameliorated DSS-induced experimental colitis in mice. However, the protection of TA against DSS-induced experimental colitis was abrogated in NLRP3-deficient (Nlrp3-/-) mice. Taken together, this study indicates TA as a novel inhibitor of NLRP3, which identifies Cys514 as a novel regulatory site of NLRP3 and suggests TA as a promising candidate compound for the treatment of colitis.


Assuntos
Colite/induzido quimicamente , Colite/tratamento farmacológico , Ergosterol/análogos & derivados , Regulação da Expressão Gênica/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Animais , Linhagem Celular , Ergosterol/farmacologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Camundongos
8.
Int J Biol Macromol ; 182: 1628-1637, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34022311

RESUMO

Cancer dominates among many causes of mortality worldwide. Traditional chemotherapeutic agents are powerful anti-cancer agents employed for treatment of this deadly disease. However, they are always associated with toxic side effects and immunosuppression making person more vulnerable to tumor relapse and fatalities. A promising alternative could be identification, isolation and transfer of naturally occurring bioactive macromolecules to the tumorigenic population. Oyster mushroom, a major source of nutraceuticals, belonging to class basidiomycetes of kingdom Mycota is known to have immense therapeutic properties. It is a reservoir of macromolecules like ß-glucan, α-glucan, resveratrol, concanavalin A, cibacron blue affinity protein, p-hydroxybenzoic acid, ergosterol, linoleic acid etc. that are responsible for mediating anti-tumor, immunomodulatory, antioxidant, and anti-diabetic roles. Various studies have shown that extracts derived from oyster mushroom is rich in polysaccharides like ß-glucan and other macro molecules which have an anti-proliferative effect against cancer cell lines, without harming the normal cells. This review presents a brief highlight of the work covering the overall significance of oyster mushroom in different types of cancer treatment. It also explores the immunomodulatory effects of polysaccharides, proteoglycans and polypeptides derived from oyster mushroom that boosts the immune system to overcome the limitation of traditional cancer therapies.


Assuntos
Polissacarídeos Fúngicos/farmacologia , Pleurotus/química , Polissacarídeos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ergosterol/química , Ergosterol/farmacologia , Polissacarídeos Fúngicos/química , Humanos , Parabenos/química , Parabenos/farmacologia , Polissacarídeos/química , Resveratrol/química , Resveratrol/farmacologia , beta-Glucanas/química , beta-Glucanas/farmacologia
9.
Vet Microbiol ; 257: 109068, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33894664

RESUMO

Porcine deltacoronavirus (PDCoV) is a swine enteropathogenic coronavirus (CoV) that continues to spread globally, placing strain on economic and public health. Currently, the pathogenic mechanism of PDCoV remains largely unclear, and effective strategies to prevent or treat PDCoV infection are still limited. In this study, the interaction between autophagy and PDCoV replication in LLC-PK1 cells was investigated. We demonstrated that PDCoV infection induced a complete autophagy process. Pharmacologically induced autophagy with rapamycin increased the expression of PDCoV N, while pharmacologically inhibited autophagy with wortmannin decreased the expression of PDCoV N, suggesting that PDCoV-induced autophagy facilitates virus replication. Further experiments showed that PDCoV infection activated p38 signaling pathway to trigger autophagy. Besides, ergosterol peroxide (EP) alleviated PDCoV-induced activation of p38 to suppress autophagy, thus exerting its antiviral effects. Finally, we employed a piglet model of PDCoV infection to demonstrate that EP prevented PDCoV infection by suppressing PDCoV-induced autophagy via p38 signaling pathway in vivo. Collectively, these findings accelerate the understanding of the pathogenesis of PDCoV infection and provide new insights for the development of EP as an effective therapeutic strategy for PDCoV.


Assuntos
Antivirais/farmacologia , Autofagia , Infecções por Coronavirus/veterinária , Deltacoronavirus/efeitos dos fármacos , Ergosterol/análogos & derivados , Sistema de Sinalização das MAP Quinases , Replicação Viral/efeitos dos fármacos , Animais , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/virologia , Deltacoronavirus/fisiologia , Ergosterol/farmacologia , Células LLC-PK1 , Suínos , Doenças dos Suínos/virologia
10.
Bioorg Med Chem Lett ; 43: 128066, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33915258

RESUMO

In order to discover potential antitumor agents from natural products, chemical modifications of ergostane-type triterpenoids from Antrodia camphorata yielded ten new compounds. They include nine C-26 amide derivatives of antcin G (1) and a methyl antcin B (4) derivative with hydroxyamino groups at C-3 and C-7. Chemical structures of the new compounds were elucidated by NMR and MS analyses. Furthermore, cytotoxicities of the triterpenoid derivatives were evaluated using four human cancer cell lines (HL60, U251, SW480, and MCF-7). As a result, 1a, 1g, and 4a exhibited potent cytotoxic activities against HL60, U251, and SW480 with IC50 values of 0.7 ± 0.9, 2.9 ± 1.3, and 2.2 ± 0.6 µM, respectively. Molecular docking indicates that 1a, 1g, and 4a have strong binding affinity with DNA topoisomerase IIα (-9.3, -7.9, and -7.4 kcal/mol, respectively), and that they could be potent topoisomerase IIα inhibitors.


Assuntos
Antineoplásicos/farmacologia , DNA Topoisomerases Tipo II/metabolismo , Ergosterol/análogos & derivados , Polyporales/química , Inibidores da Topoisomerase II/farmacologia , Triterpenos/farmacologia , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Ergosterol/química , Ergosterol/isolamento & purificação , Ergosterol/farmacologia , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase II/isolamento & purificação , Triterpenos/química , Triterpenos/isolamento & purificação
11.
Drug Des Devel Ther ; 15: 1357-1368, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33824580

RESUMO

Introduction: In this study, Callyspongia aerizusa (CA), one of the most popular marine sponges for cancer therapy research, was investigated for its phytochemical compounds and evaluated for its anticancer activity in various cell lines. Since lung cancer is the most frequently diagnosed cancer, a solution from this marine source is a good choice to address the resistance to anticancer agents. Elucidation of the underlying mechanism of cell death elicited by a CA extract in human lung carcinoma cells A549 was undertaken. Methods: The presence of secondary metabolites in CA methanol extract was revealed by gas chromatography-mass spectrometry (GC-MS) and evaluated on four cancerous cell lines and a non-cancerous cell line using Cell Counting Kit-8. Since the activity of CA extract in A549 cells was then evaluated through clonogenic assay, morphological detection of apoptosis, polymerase chain reaction (PCR) and Western blot assay, were also presented in this study. Results: GC-MS analysis revealed the presence of two ergosteroids, ergost-22-en-3-one, (5ß,22E), and ergost-7-en-3-ol, (35ß) in the sponge extract that was suggested to suppress A549 cells (IC50 9.38 µg/mL), and another cancerous cell's viability (IC50 3.12-10.72 µg/mL) in 24 h, but not in the non-cancerous cells. Moreover, CA extract was also able to reduce the colony-forming ability of A549 cells, and through A549 cells morphology seems that apoptosis is the underlying mechanism of cell death. Further, the treatment with CA extract induced the up-regulation of caspase-9, caspase-3, and PARP-1, and the down-regulation of BCL-2, in both mRNA and proteins expression level, promoting apoptotic cell death via caspase cascade. Conclusion: These findings suggest that the compounds in CA extract possess the ability to induce apoptotic cell death in A549 cells and could become a promising candidate for future anticancer therapy.


Assuntos
Antineoplásicos/farmacologia , Callyspongia/química , Caspases/metabolismo , Ergosterol/farmacologia , Células A549 , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Ensaios de Seleção de Medicamentos Antitumorais , Ergosterol/química , Ergosterol/isolamento & purificação , Humanos
12.
Sci Rep ; 11(1): 8002, 2021 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-33850196

RESUMO

The interactions of derivatives of lumisterol (L3) and vitamin D3 (D3) with liver X receptors (LXRs) were investigated. Molecular docking using crystal structures of the ligand binding domains (LBDs) of LXRα and ß revealed high docking scores for L3 and D3 hydroxymetabolites, similar to those of the natural ligands, predicting good binding to the receptor. RNA sequencing of murine dermal fibroblasts stimulated with D3-hydroxyderivatives revealed LXR as the second nuclear receptor pathway for several D3-hydroxyderivatives, including 1,25(OH)2D3. This was validated by their induction of genes downstream of LXR. L3 and D3-derivatives activated an LXR-response element (LXRE)-driven reporter in CHO cells and human keratinocytes, and by enhanced expression of LXR target genes. L3 and D3 derivatives showed high affinity binding to the LBD of the LXRα and ß in LanthaScreen TR-FRET LXRα and ß coactivator assays. The majority of metabolites functioned as LXRα/ß agonists; however, 1,20,25(OH)3D3, 1,25(OH)2D3, 1,20(OH)2D3 and 25(OH)D3 acted as inverse agonists of LXRα, but as agonists of LXRß. Molecular dynamics simulations for the selected compounds, including 1,25(OH)2D3, 1,20(OH)2D3, 25(OH)D3, 20(OH)D3, 20(OH)L3 and 20,22(OH)2L3, showed different but overlapping interactions with LXRs. Identification of D3 and L3 derivatives as ligands for LXRs suggests a new mechanism of action for these compounds.


Assuntos
Ergosterol/farmacologia , Receptores X do Fígado/metabolismo , Vitamina D/farmacologia , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Animais , Animais Recém-Nascidos , Células CHO , Calcitriol , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Enzima de Clivagem da Cadeia Lateral do Colesterol/metabolismo , Biologia Computacional , Cricetulus , Derme/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Ligação de Hidrogênio , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Ligantes , Receptores X do Fígado/química , Receptores X do Fígado/genética , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Secundária de Proteína , Transporte Proteico/efeitos dos fármacos , RNA-Seq , Eletricidade Estática , Termodinâmica
13.
Int Immunopharmacol ; 93: 107317, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33493866

RESUMO

Porcine deltacoronavirus (PDCoV) is an emerging swine enteropathogenic coronavirus (CoV) that poses economic and public health burdens. Currently, there are no effective antiviral agents against PDCoV. Cryptoporus volvatus often serves as an antimicrobial agent in Traditional Chinese Medicines. This study aimed to evaluate the antiviral activities of ergosterol peroxide (EP) from C. volvatus against PDCoV infection. The inhibitory activity of EP against PDCoV was assessed by using virus titration and performing Quantitative Reverse transcription PCR (RT-qPCR), Western blotting and immunofluorescence assays in LLC-PK1 cells. The mechanism of EP against PDCoV was analyzed by flow cytometry, RT-qPCR and Western blotting. We found that EP treatment inhibited PDCoV infection in LLC-PK1 cells in a dose-dependent manner. Subsequently, we demonstrated that EP blocked virus attachment and entry using RT-qPCR. Time-of-addition assays indicated that EP mainly exerted its inhibitory effect at the early and middle stages in the PDCoV replication cycle. EP also inactivated PDCoV infectivity directly as well as suppressed PDCoV-induced apoptosis. Furthermore, EP treatment decreased the phosphorylation of IκBα and p38 MAPK induced by PDCoV infection as well as the mRNA levels of cytokines (IL-1ß, IL-6, IL-12, TNF-α, IFN-α, IFN-ß, Mx1 and PKR). These results imply that EP can inhibit PDCoV infection and regulate host immune responses by downregulating the activation of the NF-κB and p38/MAPK signaling pathways in vitro. EP can be used as a potential candidate for the development of a new anti-PDCoV therapy.


Assuntos
Antivirais/farmacologia , Deltacoronavirus/efeitos dos fármacos , Deltacoronavirus/imunologia , Ergosterol/análogos & derivados , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , NF-kappa B/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Citocinas/metabolismo , Ergosterol/química , Ergosterol/farmacologia , Proteínas I-kappa B/metabolismo , Fatores Imunológicos/química , Fatores Imunológicos/farmacologia , Células LLC-PK1 , Polyporaceae , Suínos , Doenças dos Suínos , Fator de Transcrição RelA/metabolismo , Vírion/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
14.
Int J Biol Macromol ; 173: 56-65, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33465364

RESUMO

Here, we have studied the ameliorative effects of Withania somnifera derivatives (Withanolide A, Withanolide B, Withanoside IV, and Withanoside V) on the fibril formation of amyloid-ß 42 for Alzheimer's disease. We analyzed reduction in the aggregation of ß amyloid protein with these Ashwagandha derivatives by Thioflavin T assay in the oligomeric and fibrillar state. We have tested the cytotoxic activity of these compounds against human SK-N-SH cell line for 48 h, and the IC 50 value found to be 28.61 ± 2.91, 14.84 ± 1.45, 18.76 ± 0.76 and 30.14 ± 2.59 µM, respectively. After the treatment of the cells with half the concentration of IC 50 value, there was a remarkable decrease in the number of apoptotic cells stained by TUNEL assay indicating the DNA damage and also observed significant decrease of reactive oxygen species. Also, the binding and molecular stability of these derivatives with amyloid ß was also studied using bioinformatics tools where these molecules were interacted at LVFFA region which is inhibition site of amyloid-ß1 42. These studies revealed that the Withanolides and Withanosides interact with the hydrophobic core of amyloid-ß 1-42 in the oligomeric stage, preventing further interaction with the monomers and diminishing aggregation.


Assuntos
Peptídeos beta-Amiloides/antagonistas & inibidores , Ergosterol/análogos & derivados , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/antagonistas & inibidores , Withania/química , Vitanolídeos/farmacologia , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ergosterol/química , Ergosterol/metabolismo , Ergosterol/farmacologia , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/metabolismo , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/metabolismo , Extratos Vegetais/química , Agregados Proteicos/efeitos dos fármacos , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Vitanolídeos/química , Vitanolídeos/metabolismo
15.
Nat Prod Res ; 35(1): 41-48, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31215239

RESUMO

To investigate the influence of reactive oxygen species (ROS) on the secondary metabolites of the marine-derived fungus Dichotomomyces cejpii F31-1, hydrogen peroxide (H2O2) was added to the GPY culture medium. The HPLC chromatogram of the EtOAc extract of the culture broth was distinct from that of the H2O2 free GPY medium. Further study of the metabolites in the GPY medium with H2O2 resulted in the discovery of eight known compounds. Among them, (22E)-5α, 8α-epidioxyergosta-6, 22-dien-3ß-ol (2) and ergosta-4,6,8(14),22-tetraene-3-one (3) were present in the highest concentration, while ergosterol and diketopiperazines are abundant in the H2O2 free medium. Additionally, a new compound, dichocetide D (1) containing a chlorine element and a known ergosterol (10) were isolated from the H2O2 free medium. (22E)-5α, 8α-epidioxyergosta-6, 22-dien-3ß-ol (2) exhibited moderate cytotoxic activity against human prostate cancer cell line LNCaP-C4-2B.


Assuntos
Antineoplásicos/farmacologia , Aspergillus/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Aspergillus/efeitos dos fármacos , Meios de Cultura/química , Dicetopiperazinas/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Ergosterol/isolamento & purificação , Ergosterol/metabolismo , Ergosterol/farmacologia , Humanos , Peróxido de Hidrogênio/farmacologia , Indóis/química , Indóis/metabolismo , Indóis/farmacologia , Masculino , Melanoma/tratamento farmacológico , Camundongos , Estrutura Molecular , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Quinazolinas/química , Quinazolinas/metabolismo , Quinazolinas/farmacologia , Metabolismo Secundário
16.
Molecules ; 25(24)2020 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-33339401

RESUMO

OBJECTIVE: This study evaluated the antifungal activity of cinnamaldehyde on Candida spp. In vitro and in situ assays were carried out to test cinnamaldehyde for its anti-Candida effects, antibiofilm activity, effects on fungal micromorphology, antioxidant activity, and toxicity on keratinocytes and human erythrocytes. Statistical analysis was performed considering α = 5%. RESULTS: The minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) of cinnamaldehyde ranged from 18.91 µM to 37.83 µM. MIC values did not change in the presence of 0.8 M sorbitol, whereas an 8-fold increase was observed in the presence of ergosterol, suggesting that cinnamaldehyde may act on the cell membrane, which was subsequently confirmed by docking analysis. The action of cinnamaldehyde likely includes binding to enzymes involved in the formation of the cytoplasmic membrane in yeast cells. Cinnamaldehyde-treated microcultures showed impaired cellular development, with an expression of rare pseudo-hyphae and absence of chlamydoconidia. Cinnamaldehyde reduced biofilm adherence by 64.52% to 33.75% (p < 0.0001) at low concentrations (378.3-151.3 µM). Cinnamaldehyde did not show antioxidant properties. CONCLUSIONS: Cinnamaldehyde showed fungicidal activity through a mechanism of action likely related to ergosterol complexation; it was non-cytotoxic to keratinocytes and human erythrocytes and showed no antioxidant activity.


Assuntos
Acroleína/análogos & derivados , Antifúngicos/farmacologia , Biofilmes/efeitos dos fármacos , Candida/fisiologia , Acroleína/química , Acroleína/metabolismo , Acroleína/farmacologia , Antifúngicos/química , Antifúngicos/metabolismo , Antioxidantes/química , Sítios de Ligação , Candida/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ergosterol/química , Ergosterol/farmacologia , Humanos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Sorbitol/química , Sorbitol/farmacologia , Esqualeno Mono-Oxigenase/química , Esqualeno Mono-Oxigenase/metabolismo
17.
Int J Mol Sci ; 21(24)2020 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-33317048

RESUMO

Lumisterol (L3) is a stereoisomer of 7-dehydrocholesterol and is produced through the photochemical transformation of 7-dehydrocholesteol induced by high doses of UVB. L3 is enzymatically hydroxylated by CYP11A1, producing 20(OH)L3, 22(OH)L3, 20,22(OH)2L3, and 24(OH)L3. Hydroxylumisterols function as reverse agonists of the retinoic acid-related orphan receptors α and γ (RORα/γ) and can interact with the non-genomic binding site of the vitamin D receptor (VDR). These intracellular receptors are mediators of photoprotection and anti-inflammatory activity. In this study, we show that L3-hydroxyderivatives significantly increase the expression of VDR at the mRNA and protein levels in keratinocytes, both non-irradiated and after UVB irradiation. L3-hydroxyderivatives also altered mRNA and protein levels for RORα/γ in non-irradiated cells, while the expression was significantly decreased in UVB-irradiated cells. In UVB-irradiated keratinocytes, L3-hydroxyderivatives inhibited nuclear translocation of NFκB p65 by enhancing levels of IκBα in the cytosol. This anti-inflammatory activity mediated by L3-hydroxyderivatives through suppression of NFκB signaling resulted in the inhibition of the expression of UVB-induced inflammatory cytokines, including IL-17, IFN-γ, and TNF-α. The L3-hydroxyderivatives promoted differentiation of UVB-irradiated keratinocytes as determined from upregulation of the expression at the mRNA of involucrin (IVL), filaggrine (FLG), and keratin 14 (KRT14), downregulation of transglutaminase 1 (TGM1), keratins including KRT1, and KRT10, and stimulation of ILV expression at the protein level. We conclude that CYP11A1-derived hydroxylumisterols are promising photoprotective agents capable of suppressing UVB-induced inflammatory responses and restoring epidermal function through targeting the VDR and RORs.


Assuntos
Ergosterol/farmacologia , Queratinócitos/efeitos dos fármacos , Provitaminas/farmacologia , Tolerância a Radiação , Raios Ultravioleta , Células Cultivadas , Enzima de Clivagem da Cadeia Lateral do Colesterol/metabolismo , Ergosterol/análogos & derivados , Humanos , Interferon gama/genética , Interferon gama/metabolismo , Queratinócitos/metabolismo , Queratinócitos/efeitos da radiação , Queratinas/genética , Queratinas/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Transglutaminases/genética , Transglutaminases/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
18.
PLoS One ; 15(11): e0243066, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33253287

RESUMO

Candidiasis causes high morbidity and mortality among immunocompromised patients. Antifungal drug resistance and cytotoxicity highlight the need of effective antifungal therapeutics. In this study, we found that kalopanaxsaponin A (KPA), a triterpenoid saponin natural product, could inhibit the proliferation of various Candida species, and exerted a fungicidal effect against C. albicans. To further explore its antifungal action mode, spectrofluorophotometer, fluorescence microscopy and transmission electron microscopy were performed, showing that KPA treatment induced the accumulation of intracellular reactive oxygen species (ROS), resulting in mitochondrial dysfunction. Meanwhile, KPA treatment also broke down the membrane barrier of C. albicans causing the leakage of intracellular trehalose, the entrance of extracellular impermeable substance and the decrease of ergosterol content. Both ROS accumulation and membrane destruction contributed to the death of C. albicans cells. Our work preliminarily elucidated the potential mechanisms of KPA against C. albicans on a cellular level, and might provide a potential option for the treatment of clinical candidiasis.


Assuntos
Candida albicans/efeitos dos fármacos , Candidíase/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Ácido Oleanólico/análogos & derivados , Saponinas/farmacologia , Antifúngicos/farmacologia , Candida albicans/patogenicidade , Candidíase/microbiologia , Candidíase/patologia , Membrana Celular/efeitos dos fármacos , Farmacorresistência Fúngica/efeitos dos fármacos , Farmacorresistência Fúngica/genética , Ergosterol/farmacologia , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Potencial da Membrana Mitocondrial/genética , Mitocôndrias/genética , Ácido Oleanólico/farmacologia , Espécies Reativas de Oxigênio/metabolismo
19.
Pak J Pharm Sci ; 33(3): 997-1003, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-33191223

RESUMO

In the present study, ergosteryl-ferulate (5), oryzanol analog was evaluated for its possibility as the inhibitor of hmg-coa reductase (hmgr), through in silico and in vitro approach. firstly, the study was conducted through molecular docking simulation using autodock tools software to predict the interaction of 5 in complexes with hmgr. in addition, four major compounds of oryzanol (1-4) were employed as a comparison. secondly, 5 was synthesized through esterification using thionyl chloride as an activator. lastly, 5 was evaluated for its capacity to inhibit hmgr activity using hmgr assay kit. molecular docking simulation results suggest that oryzanol (1-4) and 5 exhibited a binding affinity against hmgr. the activity of 5 was predicted to be the best among the oryzanol compounds (1-4), in which, the free binding energy and inhibition constant were -4.17 kcal/mol and 0.88mm. the in vitro assay showed that 5 had inhibitory activity against hmgr 1.93 times higher than oryzanol. in summary, 5 has more potential candidates for hmgr inhibitor than oryzanol.


Assuntos
Ergosterol/farmacologia , Hidroximetilglutaril-CoA Redutases/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Simulação de Acoplamento Molecular , Sítios de Ligação , Domínio Catalítico , Ergosterol/análogos & derivados , Ergosterol/síntese química , Inibidores de Hidroximetilglutaril-CoA Redutases/síntese química , Cinética , Ligação Proteica
20.
J Mycol Med ; 30(4): 101038, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33069573

RESUMO

Unbalanced lipid peroxidation damages the human body, and is associated with the formation of tumors, infections, inflammations, autoimmune diseases, and cardiovascular and cerebrovascular diseases. However, food and drugs that contain anti-lipid peroxidation active substances, can help to protect against these negative health impacts. We observed lipid peroxidation inhibition in the metabolites of fermented Monascus anka, in media with Dendrobium nobile Lindl. The anti-lipid peroxidation ability of the extracts was strongest in ethyl acetate, so this was selected for further purifications. A crystal with strong antioxidant properties was obtained by column chromatography. Based on its spectroscopic analysis by Electron Bombardment Ion Source and Mass Spectrometry (EI-MS), 1H-Nuclear Magnetic Resonance (1H-NMR), and 13C-Nuclear Magnetic Resonance (13C-NMR), the isolated crystal was identified as ergosterol. The inhibition rates of the lipid peroxide due to the ergosterol were 57.42%, at 2µg/mL in vitro. Simultaneously, the survival rates of the damaged cells treated with 0.3mmol/L H2O2 were significantly improved with the ergosterol, up to 43.88% (200µg/mL) and 46.64% (400µg/mL), compared to 36.47% for the injured cells. The survival rate of the cells was 78.32% (400µg/mL), with ergosterol as a prevention. Cell injury can increase the level of intracellular ROS, but its levels in the damaged cells were reduced after the ergosterol treatments, and the reduction increased with the increasing concentrations. A 400µg/mL concentration resulted in the lowest fluorescence intensity; 33421.11 AU below the normal level. Ergosterol significantly reduced the ROS levels, to reduce the cell damage. Ergosterol from Monascus anka was thus found to have strong anti-lipid peroxidation and antioxidant capabilities, and the ability to protect and repair damaged cells. It may consequently serve as a potential natural antioxidant and will play an important role in human anti-lipid peroxide.


Assuntos
Antioxidantes , Ergosterol/isolamento & purificação , Ergosterol/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Monascus/química , Antioxidantes/isolamento & purificação , Antioxidantes/farmacologia , Células Cultivadas , Fracionamento Químico/métodos , Ergosterol/análise , Etanol/química , Fermentação , Humanos , Peróxido de Hidrogênio/metabolismo , Ressonância Magnética Nuclear Biomolecular , Espécies Reativas de Oxigênio/metabolismo , Solventes/química , Espectrometria de Massas por Ionização por Electrospray , Água/química
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...