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1.
Molecules ; 26(12)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208750

RESUMO

Entamoeba histolytica (protozoan; family Endomoebidae) is the cause of amoebiasis, a disease related to high morbidity and mortality. Nowadays, this illness is considered a significant public health issue in developing countries. In addition, parasite resistance to conventional medicinal treatment has increased in recent years. Traditional medicine around the world represents a valuable source of alternative treatment for many parasite diseases. In a previous paper, we communicated about the antiprotozoal activity in vitro of the methanolic (MeOH) extract of Ruta chalepensis (Rutaceae) against E. histolytica. The plant is extensively employed in Mexican traditional medicine. The following workup of the MeOH extract of R. chalepensis afforded the furocoumarins rutamarin (1) and chalepin (2), which showed high antiprotozoal activity on Entamoeba histolytica trophozoites employing in vitro tests (IC50 values of 6.52 and 28.95 µg/mL, respectively). Therefore, we offer a full scientific report about the bioguided isolation and the amebicide activity of chalepin and rutamarin.


Assuntos
Furocumarinas/isolamento & purificação , Ruta/metabolismo , Amebicidas/isolamento & purificação , Amebicidas/farmacologia , Antiprotozoários/farmacologia , Benzopiranos/metabolismo , Entamoeba histolytica/efeitos dos fármacos , Entamoeba histolytica/patogenicidade , Furocumarinas/farmacologia , Concentração Inibidora 50 , Medicina Tradicional , México , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia
2.
Food Chem Toxicol ; 153: 112278, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34019943

RESUMO

Bergamottin (BGM) is a major furanocoumarin constituent of grapefruit and is reported to have inhibitory effects on cytochrome P450 enzymes. This study investigated the chemical interactions between BGM and the enzyme CYP2C9. BGM exhibited time-, concentration-, and NADPH-dependent inhibition of CYP2C9. Co-incubation with diclofenac, a reversible inhibitor of CYP2C9, attenuated the time-dependent enzyme inhibition. Exhaustive dialysis did not restore enzyme activity post-inhibition. Glutathione (GSH) and catalase/superoxide dismutase failed to reverse BGM-induced CYP2C9 inactivation. A GSH trapping study suggested that BGM was metabolized to an epoxide and/or γ-ketoenal that may have been responsible for the enzyme inactivation. In conclusion, BGM can be characterized as a mechanism-based inactivator of CYP2C9 acting via the formation of an epoxide and/or γ-ketoenal.


Assuntos
Inibidores do Citocromo P-450 CYP2C9/farmacologia , Citocromo P-450 CYP2C9/metabolismo , Furocumarinas/farmacologia , Inibidores do Citocromo P-450 CYP2C9/metabolismo , Diclofenaco/farmacologia , Furocumarinas/metabolismo , Humanos , Microssomos Hepáticos/metabolismo
3.
Toxins (Basel) ; 13(4)2021 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-33920139

RESUMO

The plant kingdom has always been a treasure trove for valuable bioactive compounds, and Citrus fruits stand out among the others. Bergamottin (BRG) and 5-geranyloxy-7-methoxycoumarin (5-G-7-MOC) are two coumarins found in different Citrus species with well-acknowledged pharmacological properties. Previously, they have been claimed to be relevant in the anti-proliferative effects exerted by bergamot essential oil (BEO) in the SH-SY5Y human neuroblastoma cells. This study was designed to verify this assumption and to assess the mechanisms underlying the anti-proliferative effect of both compounds. Our results demonstrate that BRG and 5-G-7-MOC are able to reduce the proliferation of SH-SY5Y cells, inducing apoptosis and increasing cell population in sub-G0/G1 phase. Moreover, we demonstrated the pro-oxidant activity of the two coumarins that increased reactive oxygen species and impaired mitochondrial membrane potential. From a molecular point of view, BRG and 5-G-7-MOC were able to modulate apoptosis related factors at both protein and gene levels. Lastly, we evaluated the synergistic effect of their combination, finding that the highest synergy was observed at a concentration ratio similar to that occurring in the BEO, supporting our initial hypothesis. Taken together, our results deepen the knowledge regarding the effect of BRG and 5-G-7-MOC in SH-SY5Y cells, emphasizing the relevance of their cooperation in achieving this effect.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proliferação de Células/efeitos dos fármacos , Cumarínicos/farmacologia , Furocumarinas/farmacologia , Neuroblastoma/tratamento farmacológico , Óleos Vegetais/farmacologia , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sinergismo Farmacológico , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Espécies Reativas de Oxigênio/metabolismo
4.
Molecules ; 26(6)2021 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-33799365

RESUMO

Dihydrofuranocoumarin, chalepin (1) and furanocoumarin, chalepensin (2) are 3-prenylated bioactive coumarins, first isolated from the well-known medicinal plant Ruta chalepensis L. (Fam: Rutaceae) but also distributed in various species of the genera Boenminghausenia, Clausena and Ruta. The distribution of these compounds appears to be restricted to the plants of the family Rutaceae. To date, there have been a considerable number of bioactivity studies performed on coumarins 1 and 2, which include their anticancer, antidiabetic, antifertility, antimicrobial, antiplatelet aggregation, antiprotozoal, antiviral and calcium antagonistic properties. This review article presents a critical appraisal of publications on bioactivity of these 3-prenylated coumarins in the light of their feasibility as novel therapeutic agents and investigate their natural distribution in the plant kingdom, as well as a plausible biosynthetic route.


Assuntos
Furocumarinas/biossíntese , Furocumarinas/farmacologia , Animais , Clausena/química , Cumarínicos/química , Humanos , Extratos Vegetais/metabolismo , Extratos Vegetais/farmacologia , Plantas Medicinais/química , Ruta/química , Rutaceae/química
5.
Sci Rep ; 11(1): 8754, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33888745

RESUMO

Psoralen is one of the most effective ingredients extracted from the Chinese herb, Psoralea corylifolia L. Studies have found that psoralen has anti-inflammatory and estrogen-like effects; however, little research has been conducted to elucidate the mechanisms underlying these effects. Through the molecule docking assay, psoralen was found to have a better combination with ERα than ERß. In human periodontal ligament cells, psoralen was found to upregulate the estrogen target genes (e.g., CTSD, PGR, TFF1) and down-regulate the expression of inflammatory cytokines (TNF-α, IL-1ß, IL-6 and IL-8) stimulated by P. gingivalis LPS, as well as TLR4-IRAK4-NF-κb signaling pathway proteins. These effects were reversed by the ER antagonist ICI 182780. These results indicated that psoralen may exert anti-inflammatory effects as an agonist to ER, which could provide a theoretical basis for the use of psoralen for adjuvant therapy and prevention of periodontitis.


Assuntos
Anti-Inflamatórios/farmacologia , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Furocumarinas/farmacologia , Ligamento Periodontal/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Anti-Inflamatórios/metabolismo , Furocumarinas/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , NF-kappa B/metabolismo , Ligamento Periodontal/citologia , Ligamento Periodontal/metabolismo , Ligação Proteica , RNA Mensageiro/metabolismo , Receptor 4 Toll-Like/metabolismo
6.
Transfus Med ; 31(2): 136-141, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33686720

RESUMO

OBJECTIVES: Assessment of the impact of pooling five single-donor plasma (SDP) units to obtain six pathogen-reduced therapeutic plasma (PTP) units on standardisation and the retention of labile coagulation factors. BACKGROUND: SDP shows a high inter-donor variability with potential implications for the clinical treatment outcome. Additionally, there is still an existing risk for window-period transmissions of blood borne pathogens including newly emerging pathogens. METHODS/MATERIALS: Five ABO-identical SDP units were pooled, treated with the INTERTCEPT™ Blood System (Cerus Corporation, U.S.A.) and split into six PTP units which were frozen and thawed after 30 days. The variability in volume, labile coagulation factor retention and activity was assessed. RESULTS: The variability of volumes between the PTP units was reduced by 46% compared to SDP units. The variability in coagulation factor content between the PTP units was reduced by 63% compared to SDP units. Moderate, but significant losses of coagulation factors (except for vWF) were observed in PTPs compared to SDPs. CONCLUSION: The pooling of five SDP units to obtain six PTP units significantly increases product standardisation with potential implications for safety, economics as well as transfusion-transmitted pathogen safety, making it an interesting alternative to quarantine SDP (qSDP) and pathogen-reduced SDP.


Assuntos
Preservação de Sangue/métodos , Preservação de Sangue/normas , Furocumarinas/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Plasma , Raios Ultravioleta , Biomarcadores/análise , Biomarcadores/sangue , Fatores de Coagulação Sanguínea/análise , Fatores de Coagulação Sanguínea/metabolismo , Segurança do Sangue/métodos , Segurança do Sangue/normas , Humanos , Plasma/efeitos dos fármacos , Plasma/metabolismo , Plasma/microbiologia , Reprodutibilidade dos Testes
7.
Life Sci ; 274: 119291, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33667515

RESUMO

AIMS: Most therapeutic drugs of endometriosis have been contraceptives but symptoms recur in up to 75% of cases, which makes it a presses need to try to find novel and safer therapeutic drugs. Imperatorin is a furanocoumarin existing in many plants, possessing multiple activities, including anti-inflammatory. The purpose of this study was to assess the effects and mechanisms of imperatorin in endometriosis. MAIN METHODS: Ectopic endometrial volume and hematoxylin-eosin staining were used to estimate the effects of imperatorin in experimental endometriosis model rats. Potential mechanisms of imperatorin in endometriosis were systematically analyzed by network pharmacology and molecular docking. Western blotting and enzyme-linked immunosorbent assay were employed to evaluate proteins expression and cytokines levels in PI3K/Akt/NF-κB pathway. KEY FINDINGS: Imperatorin could significantly inhibit the growth and ameliorate the histopathological features of ectopic endometrium in experimental endometriosis rats. Network pharmacology approaches showed that imperatorin might regulate inflammatory response and cellular function via primarily affecting PI3K-Akt pathway, Endocrine resistance, Th17 cell differentiation in endometriosis. Moreover, 7 core targets (PIK3CA, AKT1, SRC, MAPK8, MAPK14, ERBB2 and CCND1) resulted from the intersection of KEGG and PPI network topological analysis were used to dock with imperatorin, which indicated that imperatorin could preferably fit in the binding pocket of the above target proteins, except for CCND1. Lastly, imperatorin markedly inhibited the activation of PI3K/Akt/NF-κB pathway via suppressing the phosphorylation levels of PI3K, Akt and p65 in the ectopic endometrium tissue. SIGNIFICANCE: Our findings revealed that imperatorin is a significant multi-target natural active ingredient for treatment endometriosis.


Assuntos
Endometriose/tratamento farmacológico , Furocumarinas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Fosfatidilinositol 3-Quinases/química , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Animais , Endometriose/metabolismo , Endometriose/patologia , Feminino , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
8.
Molecules ; 26(4)2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33669881

RESUMO

Ruta chalepensis L. (Rutaceae), a perennial herb with wild and cultivated habitats, is well known for its traditional uses as an anti-inflammatory, analgesic, antipyretic agent, and in the treatment of rheumatism, nerve diseases, neuralgia, dropsy, convulsions and mental disorders. The antimicrobial activities of the crude extracts from the fruits, leaves, stem and roots of R. chalepensis were initially evaluated against two Gram-positive and two Gram-negative bacterial strains and a strain of the fungus Candida albicans. Phytochemical investigation afforded 19 compounds, including alkaloids, coumarins, flavonoid glycosides, a cinnamic acid derivative and a long-chain alkane. These compounds were tested against a panel of methicillin-resistant Staphylococcus aureus (MRSA) strains, i.e., ATCC 25923, SA-1199B, XU212, MRSA-274819 and EMRSA-15. The MIC values of the active compounds, chalepin (9), chalepensin (10), rutamarin (11), rutin 3'-methyl ether (14), rutin 7,4'-dimethyl ether (15), 6-hydroxy-rutin 3',7-dimethyl ether (16) and arborinine (18) were in the range of 32-128 µg/mL against the tested MRSA strains. Compounds 10 and 16 were the most active compounds from R. chalepensis, and were active against four out of six tested MRSA strains, and in silico studies were performed on these compounds. The anti-MRSA activity of compound 16 was comparable to that of the positive control norfloxacin (MICs 32 vs 16 µg/mL, respectively) against the MRSA strain XU212, which is a Kuwaiti hospital isolate that possesses the TetK tetracycline efflux pump. This is the first report on the anti-MRSA property of compounds isolated from R. chalepensis and relevant in silico studies on the most active compounds.


Assuntos
Simulação por Computador , Furocumarinas/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Ruta/química , Ruta/crescimento & desenvolvimento , Rutina/farmacologia , Antibacterianos/química , Antibacterianos/farmacologia , Furocumarinas/química , Furocumarinas/isolamento & purificação , Ligação de Hidrogênio , Iraque , Ligantes , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Rutina/química , Rutina/isolamento & purificação
9.
Eur J Pharmacol ; 899: 174010, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33711309

RESUMO

In the present study, the therapeutic effects of imperatorin on metabolic and vascular alterations and possible underlying mechanisms were investigated in high-fat/high-fructose diet (HFFD)-fed rats. Male Sprague-Dawley rats were fed a high-fat diet plus 15% fructose in drinking water for 16 weeks. HFFD-fed rats were treated with imperatorin (15 or 30 mg/kg/day) for the last 4 weeks. In HFFD-fed rats, imperatorin significantly reduced obesity, hypertension, dyslipidemia, and insulin resistance. Imperatorin markedly improved vascular endothelial function and alleviated changes in vascular morphology. Furthermore, imperatorin treatment significantly increased the plasma levels of the nitric oxide metabolite and adiponectin, and upregulated adiponectin receptor 1 and endothelial nitric oxide synthase (eNOS) protein expression in the thoracic aorta. Imperatorin treatment decreased vascular superoxide anion production and downregulated aortic NADPH oxidase subunit p47phox protein expression. These findings indicated that imperatorin alleviates HFFD-induced metabolic and vascular alterations in rats. The possible underlying mechanism may involve the restoration of adiponectin receptor 1 and eNOS expression and suppression of p47phox expression.


Assuntos
Aorta Torácica/efeitos dos fármacos , Furocumarinas/farmacologia , Hemodinâmica/efeitos dos fármacos , Hipertensão/prevenção & controle , Síndrome Metabólica/prevenção & controle , NADPH Oxidases/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Receptores de Adiponectina/metabolismo , Animais , Aorta Torácica/metabolismo , Aorta Torácica/fisiopatologia , Dieta Hiperlipídica , Açúcares da Dieta , Modelos Animais de Doenças , Dislipidemias/enzimologia , Dislipidemias/etiologia , Dislipidemias/fisiopatologia , Dislipidemias/prevenção & controle , Frutose , Hipertensão/enzimologia , Hipertensão/etiologia , Hipertensão/fisiopatologia , Resistência à Insulina , Masculino , Síndrome Metabólica/enzimologia , Síndrome Metabólica/etiologia , Síndrome Metabólica/fisiopatologia , Óxido Nítrico/metabolismo , Obesidade/enzimologia , Obesidade/etiologia , Obesidade/fisiopatologia , Obesidade/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Transdução de Sinais
10.
Bioorg Med Chem Lett ; 37: 127839, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33556571

RESUMO

Neuraminidase (NA) is a promising target for development of anti-influenza drugs. In this study a dihydrofurocoumarin derivative ZINC05577497 was discovered as a lead NA inhibitor based on docking-based virtual screening technique. The optimization of lead ZINC05577497 led to the discovery of a series of novel NA inhibitors 5a-5j. Compound 5b has the most potent activity against NA with IC50 = 0.02 µM, which is lower than those of the reference oseltamivir carboxylate (OSC) (IC50 = 0.04 µM) and ZINC05577497 (IC50 = 0.11 µM). Other target compounds also show potential inhibition of NA activity. Molecular docking results indicate that the good potency of 5b may be attributed to the elongation of the dihydrofurocoumarin ring to the 150-cavity. The results of this paper will be useful to discover more potent NA inhibitors.


Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Furocumarinas/farmacologia , Neuraminidase/antagonistas & inibidores , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Furocumarinas/síntese química , Furocumarinas/química , Humanos , Simulação de Dinâmica Molecular , Estrutura Molecular , Neuraminidase/metabolismo , Relação Estrutura-Atividade
11.
Transfusion ; 61(3): 919-930, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33527430

RESUMO

BACKGROUND: Deterioration in quality of platelet concentrates (PCs) during storage results from the appearance of storage lesions affecting the hemostatic functions and posttransfusion survival of platelets. These lesions depend on the preparation and pathogen inactivation methods used, duration of storage, and platelet additive solutions (PASs) present in storage bags. METHODS: We investigated the effects of citrate contained in third-generation PAS (PAS-III) on storage lesions in buffy-coat PCs with or without photochemical (amotosalen-ultraviolet A) treatment over 7 days. RESULTS: Platelet counts were conserved in all groups during storage, as was platelet swirling without appearance of macroscopic aggregates. Glycoprotein (GP) IIbIIIa and GPVI expression remained stable, whereas GPIbα declined similarly in all groups during storage. Removal of citrate from PAS-III, resulting in global reduction of citrate from 11 to 5 mM, led to a significant decrease in glucose consumption, which largely countered a modest deleterious effect of photochemical treatment. Citrate reduction also resulted in decreased lactate generation and better maintenance of pH during storage, while photochemical treatment had no impact on these parameters. Moreover, citrate-free storage significantly reduced exposure of P-selectin and the apoptosis signal phosphatidylserine, thereby abolishing the activating effect of photochemical treatment on both parameters. Citrate reduction benefited platelet aggregation to various agonists up to Day 7, whereas PCT had no impact on these responses. CONCLUSION: Removal of citrate from PAS-III has a beneficial impact on platelet metabolism, spontaneous activation, and apoptosis, and improves platelet aggregation, irrespective of photochemical treatment, which should allow transfusion of platelets with better and longer-lasting functional properties.


Assuntos
Plaquetas/metabolismo , Preservação de Sangue/métodos , Ácido Cítrico/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Furocumarinas/farmacologia , Hemostasia/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Ácido Láctico/metabolismo , Selectina-P/metabolismo , Fosfatidilserinas , Contagem de Plaquetas , Testes de Função Plaquetária , Complexo Glicoproteico GPIb-IX de Plaquetas/metabolismo , Glicoproteínas da Membrana de Plaquetas/metabolismo
12.
J Nanobiotechnology ; 19(1): 8, 2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33407527

RESUMO

BACKGROUND: Non-Hodgkin's lymphoma (NHL) possesses great heterogeneity in cytogenetics, immunophenotype and clinical features, and chemotherapy currently serves as the main treatment modality. Although employing monoclonal antibody targeted drugs has significantly improved its overall efficacy, various patients continue to suffer from drug resistance or recurrence. Chinese medicine has long been used in the treatment of malignant tumors. Therefore, we constructed a low pH value sensitivity drug delivery system based on the cancer cell membrane modified mesoporous silica nanoparticles loaded with traditional Chinese medicine, which can reduce systemic toxicity and improve the therapeutic effect for the targeted drug delivery of tumor cells. RESULTS: Accordingly, this study put forward the construction of a nano-platform based on mesoporous silica nanoparticles (MSNs) loaded with the traditional Chinese medicine isoimperatorin (ISOIM), which was camouflaged by the cancer cell membrane (CCM) called CCM@MSNs-ISOIM. The proposed nano-platform has characteristics of immune escape, anti-phagocytosis, high drug loading rate, low pH value sensitivity, good biocompatibility and active targeting of the tumor site, blocking the lymphoma cell cycle and promoting mitochondrial-mediated apoptosis. CONCLUSIONS: Furthermore, this study provides a theoretical basis in finding novel clinical treatments for lymphoma.


Assuntos
Antineoplásicos/administração & dosagem , Membrana Celular , Portadores de Fármacos/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Linfoma/tratamento farmacológico , Nanopartículas/química , Animais , Apoptose/efeitos dos fármacos , Materiais Biocompatíveis , Proliferação de Células , Modelos Animais de Doenças , Furocumarinas/farmacologia , Humanos , Medicina Tradicional Chinesa , Camundongos Nus , Espécies Reativas de Oxigênio , Dióxido de Silício
13.
Molecules ; 26(2)2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33445542

RESUMO

The immunoproteasome is a multicatalytic protease that is predominantly expressed in cells of hematopoietic origin. Its elevated expression has been associated with autoimmune diseases, various types of cancer, and inflammatory diseases. Selective inhibition of its catalytic activities is therefore a viable approach for the treatment of these diseases. However, the development of immunoproteasome-selective inhibitors with non-peptidic scaffolds remains a challenging task. We previously reported 7H-furo[3,2-g]chromen-7-one (psoralen)-based compounds with an oxathiazolone warhead as selective inhibitors of the chymotrypsin-like (ß5i) subunit of immunoproteasome. Here, we describe the influence of the electrophilic warhead variations at position 3 of the psoralen core on the inhibitory potencies. Despite mapping the chemical space with different warheads, all compounds showed decreased inhibition of the ß5i subunit of immunoproteasome in comparison to the parent oxathiazolone-based compound. Although suboptimal, these results provide crucial information about structure-activity relationships that will serve as guidance for the further design of (immuno)proteasome inhibitors.


Assuntos
Furocumarinas/síntese química , Furocumarinas/farmacologia , Inibidores de Proteassoma/síntese química , Inibidores de Proteassoma/farmacologia , Furocumarinas/química , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Peptídeos/química , Peptídeos/farmacologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Inibidores de Proteassoma/química
14.
Biochem Pharmacol ; 184: 114401, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33387483

RESUMO

BACKGROUND: Allergic asthma is a common inflammatory lung disease associated with complex pathogenesis. Mast cell (MC) is one of the key drivers of allergic asthma, Mas-related G protein-coupled receptor X2 (MRGPRX2) on the MC could mediate MC activation and trigger a pseudo-allergic reaction. Imperatorin (IMP), the main active compound of Radix Angelicae Dahuricae, has been reported to exert various pharmacological effects. In this study, we focused on the therapeutical mechanism of IMP on MRGPRX2-induced pseudo-allergy and allergic asthma. METHODS: We examined the effect of IMP on MRGPRX2 related mast cell activation in mouse peritoneal MC (MPMC), Human Laboratory of Allergic Disease 2 MCs (LAD2 cells) and Mrgprx2-expressing HEK293 cells. Molecular docking and Surface plasmon resonance (SPR) were taken to reveal the binding character between IMP and MRPGRX2. MRGPRX2 downstream proteins were also detected by western blotting. IgE-independent responses was evaluated by using passive cutaneous anaphylaxis (PCA) and active systemic anaphylaxis (ASA) models. The therapeutic effect of IMP on asthma was evaluated by a lung inflammation mouse model which was induced by ovalbumin (OVA). RESULTS: IMP was found to reduce substance P (SP) induced calcium flux and suppressed degranulation of MC. SP can promote the phosphorylation of ERK and CamKII, which regulates the synthesis of inflammatory factors such as MIP-2 and TNF-α in MC. In vivo assays revealed that IMP can mitigate SP-induced mouse PCA and ASA. IMP could also mitigate lung inflammation in an OVA induced mice model by inhibiting MC activation in the lung tissue. Furthermore, IMP binds well to MRGPRX2 protein. The binding constant (KD) is 4.48 ± 0.49 × 10-7 M. The data suggeste that IMP is a novel inhibitor of MRGPRX2 to treat allergic asthma.


Assuntos
Furocumarinas/farmacologia , Hipersensibilidade/tratamento farmacológico , Mastócitos/efeitos dos fármacos , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Linhagem Celular , Furocumarinas/metabolismo , Histamina/metabolismo , Humanos , Hipersensibilidade/metabolismo , Hipersensibilidade/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Mastócitos/metabolismo , Mastócitos/patologia , Camundongos Endogâmicos C57BL , Anafilaxia Cutânea Passiva/efeitos dos fármacos , Pneumonia/tratamento farmacológico , Pneumonia/etiologia , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/metabolismo
15.
Int J Mol Sci ; 22(2)2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33430369

RESUMO

(1) Cisplatin (CDDP) is used in melanoma chemotherapy, but it has many side effects. Hence, the search for natural substances that can reduce the dose of CDDP, and CDDP-related toxicity, is highly desired. Coumarins have many biological properties, including anticancer and antiproliferative effects. (2) An in vitro 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay on two human melanoma cell lines (FM55P and FM55M2) examined the antitumor properties of CDDP and five naturally occurring coumarins (osthole, xanthotoxin, xanthotoxol, isopimpinellin, and imperatorin). The antiproliferative effects produced by combinations of CDDP with the coumarins were assessed using type I isobolographic analysis. (3) The most potent anticancer properties of coumarins were presented by osthole and xanthotoxol. These compounds were characterized by the lowest median inhibitory concentration (IC50) values relative to the FM55P and FM55M2 melanoma cells. Isobolographic analysis showed that for both melanoma cell lines, the combination of CDDP and osthole exerted synergistic and additive interactions, while the combination of CDDP and xanthotoxol exerted additive interactions. Combinations of CDDP with xanthotoxin, isopimpinellin, and imperatorin showed antagonistic and additive interactions in two melanoma cell lines. (4) The combination of CDDP and osthole was characterized by the most desirable synergistic interaction. Isobolographic analysis allows the selection of potential candidates for cancer drugs among natural substances.


Assuntos
Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Cumarínicos/farmacologia , Melanoma/tratamento farmacológico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Cisplatino/efeitos adversos , Sinergismo Farmacológico , Furocumarinas/farmacologia , Humanos , Melanoma/patologia , Metoxaleno/farmacologia
16.
Biomed Pharmacother ; 133: 110962, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33166765

RESUMO

OBJECTIVES: This study aimed at determining the synergistic effects of Yuanhu Zhitong tablets (YHZTP) on alcohol-induced conditioned place preference (CPP) in mice, in addition, the intervention mechanism was preliminarily explored based on traditional Chinese Medicine (TCM) network pharmacology on alcohol addiction. METHODS: Alcohol-induced CPP mice were used to evaluate the effects of either YHZTP or levo-tetrahydropalmatine (l-THP) plus imperatorin (IMP) administration on animal behavior. The network pharmacological strategy was used to establish the "compound-target" and "disease-drug-target" network. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed on the shared targets between the compound and the disease. Twelve algorithms on CytoHubba were used to find the hub genes that were verified by qPCR. RESULTS: Systemic administration (2 g/kg, i.p.) of ethanol (EtOH) to mice was used to induce CPP. YHZTP On its own did not induce CPP or conditioned place aversion (CPA) at the doses of 0.3 g/kg or 0.6 g/kg (i.g.), but attenuated the acquisition and expression of EtOH-induce CPP in mice. In addition, YHZTP (0.3 or 0.6 g/kg) did not exhibit any effect on the motor activity of mice. Acquisition of alcohol-induced CPP was blocked by a combination of l-THP (5 mg/kg, i.g.) + IMP (2.5 mg/kg, i.g.) or l-THP (10 mg/kg, i.g.) + IMP (5 mg/kg, i.g.). However, the combination of l-THP (2.5 mg/kg, i.g.) + IMP (1.25 mg/kg, i.g.) or mono-administration of l-THP and IMP did not exhibit any effect on alcohol-induced CPP. YHZTP was also shown to reverse the up-regulation of Gabra1, Ptgs2, Mapk1, Mapk8, Mapk14, Nr3c, Prkca and Sirt1 genes and the down-regulation of Hhtr2a and Drd2 genes in the prefrontal cortex of EtOH induced CPP mice. These genes were associated with neuroactive ligand-receptor interactions, activation of the sphingolipid, calcium, cAMP, ErbB, NF-kappa B and MAPK signaling pathways. CONCLUSION: YHZTP inhibits EtOH-induced CPP behavior in mice while a combination of l-THP and IMP exerts a synergistic effect on the reduction of EtOH-induced CPP. Possible pharmacological mechanisms include inhibition of the expression of inflammatory factors and regulation of neurotransmitter receptor levels. Therefore, YHZTP is a novel candidate for the treatment of alcohol addiction.


Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Comportamento Animal/efeitos dos fármacos , Condicionamento Psicológico/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Etanol/toxicidade , Córtex Pré-Frontal/efeitos dos fármacos , Consumo de Bebidas Alcoólicas/genética , Consumo de Bebidas Alcoólicas/metabolismo , Animais , Alcaloides de Berberina/farmacologia , Sinergismo Farmacológico , Furocumarinas/farmacologia , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Masculino , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal/metabolismo , Mapas de Interação de Proteínas , Transdução de Sinais , Biologia de Sistemas , Comprimidos
17.
J Mol Neurosci ; 71(2): 347-357, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32676972

RESUMO

Musculoskeletal pain is a widespread complex regional pain syndrome associated with altered emotional and cognitive functioning along with heightened physical disability that has become a global health concern. Effective management of this disorder and associated disabilities includes accurate diagnosis of its biomarkers and instituting mechanism-based therapeutic interventions. Herein, we explored the role of heraclin, a plant-derived molecule, in musculoskeletal pain and its underlying mechanistic approaches in an experimental mouse model. Reserpine (0.5 mg/kg) for 3 consecutive days evoked hyperalgesia, motor incoordination, lack of exploratory behavior, anxiety, and cognition lapse in mice. Reserpine-challenged mice displayed higher serum cytokine level, altered brain neurotransmitter content, elevated brain and muscle oxidative stress, and upregulated brain nerve growth factor receptor expression. Treatment with heraclin (10 mg/kg for 5 consecutive days) exerted analgesic effect and improved motor coordination and memory deficits in mice. Heraclin arrested serum cytokine rise, normalized brain neurotransmitter content, reduced tissue oxidative stress, and downregulated the nerve growth factor receptor expression. Therefore, it may be suggested that heraclin exerts beneficial effects against reserpine-induced musculoskeletal pain disorder possibly through the attenuation of NGFR-mediated pain and inflammatory signaling. Graphical Abstract.


Assuntos
Analgésicos/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Furocumarinas/uso terapêutico , Dor Musculoesquelética/tratamento farmacológico , Fator de Crescimento Neural/fisiologia , Estresse Oxidativo , Fitoterapia , Animais , Ansiedade/induzido quimicamente , Química Encefálica/efeitos dos fármacos , Transtornos Cognitivos/induzido quimicamente , Citocinas/sangue , Avaliação Pré-Clínica de Medicamentos , Comportamento Exploratório/efeitos dos fármacos , Furocumarinas/farmacologia , Gabapentina/uso terapêutico , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Hiperalgesia/fisiopatologia , Camundongos , Teste do Labirinto Aquático de Morris , Atividade Motora/efeitos dos fármacos , Dor Musculoesquelética/induzido quimicamente , Dor Musculoesquelética/fisiopatologia , Neurotransmissores/análise , Distribuição Aleatória , Reserpina/toxicidade , Substâncias Reativas com Ácido Tiobarbitúrico/análise
18.
Transfusion ; 61(1): 167-177, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33295030

RESUMO

BACKGROUND: Platelets pose the greatest transfusion-transmitted infectious risk among blood products. Refrigeration of platelets can mitigate bacterial contamination and extend platelet shelf life. Implementation of pathogen reduction technologies (PRTs) at blood banks has become increasingly popular to protect against emerging and reemerging infectious diseases. In this study, we sought to evaluate the effects of Intercept PRT on platelets collected on different platforms and cold-stored for up to 21 days in plasma and platelet additive solution (PAS). METHODS: Double-dose apheresis platelets were collected with use of a Trima or Amicus system into either 100% plasma or 65% InterSol PAS/35% plasma and split equally between two bags. One bag served as control, while the other received Intercept PRT treatment. Bags were stored unagitated in the cold and evaluated on Days 1, 7, 14, and 21 to assess platelet metabolism, activation, aggregation, and clot formation and retraction. RESULTS: By Day 14 of storage, lactate levels reached approximately 13 mmol/L for all samples irrespective of Intercept treatment. Mean clot firmness dropped from the 62.2- to 67.5-mm range (Day 1) to the 28.4- to 51.3-mm range (Day 21), with no differences observed between groups. Clot weights of Intercept-treated Trima/plasma samples were significantly higher than control by Day 14 of storage (P = .004), indicating a reduced clot retraction function. Intercept treatment caused a higher incidence of plasma membrane breakdown in plasma-stored platelets (P = .0013; Trima/plasma Day 14 Control vs Intercept). CONCLUSIONS: Intercept treatment of platelets and subsequent cold storage, in plasma or PAS, results in comparable platelet metabolism platelets for up to 14 days of storage but altered clotting dynamics. Pathogen-reduced platelets with an extended shelf life would be beneficial for the deployed setting and would greatly impact transfusion practice among civilian transfusion centers.


Assuntos
Plaquetas/metabolismo , Preservação de Sangue/métodos , Criopreservação/métodos , Plaquetoferese/métodos , Bancos de Sangue/normas , Coagulação Sanguínea/efeitos da radiação , Plaquetas/microbiologia , Plaquetas/efeitos da radiação , Patógenos Transmitidos pelo Sangue/efeitos da radiação , Citometria de Fluxo/métodos , Furocumarinas/farmacologia , Humanos , Fármacos Fotossensibilizantes/farmacologia , Plasma/efeitos da radiação , Plaquetoferese/estatística & dados numéricos , Refrigeração/métodos , Tromboelastografia/métodos
19.
Vox Sang ; 116(6): 673-681, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33277935

RESUMO

BACKGROUND AND OBJECTIVES: During the ongoing pandemic of COVID-19, SARS-CoV-2 RNA was detected in plasma and platelet products from asymptomatic blood donors, raising concerns about potential risk of transfusion transmission, also in the context of the current therapeutic approach utilizing plasma from convalescent donors. The objective of this study was to assess the efficacy of amotosalen/UVA light treatment to inactivate SARS-CoV-2 in human plasma to reduce the risk of potential transmission through blood transfusion. METHODS: Pools of three whole-blood-derived human plasma units (630-650 ml) were inoculated with a clinical SARS-CoV-2 isolate. Spiked units were treated with amotosalen/UVA light (INTERCEPT Blood System™) to inactivate SARS-CoV-2. Infectious titres and genomic viral load were assessed by plaque assay and real-time quantitative PCR. Inactivated samples were subject to three successive passages on permissive tissue culture to exclude the presence of replication-competent viral particles. RESULTS: Inactivation of infectious viral particles in spiked plasma units below the limit of detection was achieved by amotosalen/UVA light treatment with a mean log reduction of >3·32 ± 0·2. Passaging of inactivated samples on permissive tissue showed no viral replication even after 9 days of incubation and three passages, confirming complete inactivation. The treatment also inhibited NAT detection by nucleic acid modification with a mean log reduction of 2·92 ± 0·87 PFU genomic equivalents. CONCLUSION: Amotosalen/UVA light treatment of SARS-CoV-2 spiked human plasma units efficiently and completely inactivated >3·32 ± 0·2 log of SARS-CoV-2 infectivity, showing that such treatment could minimize the risk of transfusion-related SARS-CoV-2 transmission.


Assuntos
Furocumarinas/farmacologia , Plasma/virologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/efeitos da radiação , Terapia Ultravioleta , Inativação de Vírus , COVID-19/prevenção & controle , COVID-19/transmissão , Humanos , Reação Transfusional/prevenção & controle , Resultado do Tratamento
20.
Int Immunopharmacol ; 90: 107170, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33218940

RESUMO

Inflammation plays an important role in the process of atherosclerosis (AS). Inhibition of inflammation is an effective way to prevent AS. Imperatorin (IMP) is a kind of furan coumarin with various activities. In this study, the anti-inflammatory effect of IMP was explored in oxidized low-density lipoprotein (ox-LDL)-induced VSMCs and high fat diet (HFD)-induced ApoE-/- mice. The results showed that IMP attenuated the elevation of TNF-α, IL-6, MCP-1 and NO induced by ox-LDL in supernatant of VSMCs. IMP has normalized the levels of serum lipids (TC, TG, LDL-C and HDL-C) and attenuated inflammatory cytokines in serum. IMP also improved pathological changes and lipid accumulation in aorta. Matrix metalloproteinase-2 (MMP-2) expression in aorta was down-regulated by IMP. IMP could inhibit the phosphorylation of MAPKs pathway in the aorta and VSMCs, resulting in a significant decrease in the contents of p-ERK 1/2, p-JNK and p-P38. Overall, IMP could exert anti-inflammatory effects in vivo and in vitro to interfere with AS.


Assuntos
Anti-Inflamatórios/farmacologia , Aterosclerose/metabolismo , Furocumarinas/farmacologia , Inflamação/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Animais , Aorta/efeitos dos fármacos , Aorta/fisiopatologia , Citocinas/sangue , Citocinas/efeitos dos fármacos , Citocinas/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/sangue , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Animais
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