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1.
Bratisl Lek Listy ; 122(10): 748-752, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34570578

RESUMO

BACKGROUND: Thymoquinone (TQ) is the active compound extracted from Nigella sativa which has been reported to possess various pharmacological attributes. This study shows that Thymoquinone (TQ) is an Alzheimer's disease (AD) model cell line on amyloid-beta (Aß) -induced U87 (human astrocytoma cell line) in ß-amyloid (Aß)-induced in vitro Alzheimer's Disease (AD) model. AIM: We aimed to investigate the effects on antioxidant and apoptotic pathways. METHODS: In the study three groups were formed, the control group, the Aß group, and the Aß+TQ group obtained by adding TQ to the Aß group. Firstly, the cytotoxic potential of TQ in U87 cells was investigated by the colorimetric MTT (3-4,5-dimethyl-thiazolyl-2,5 diphenyltetrazolium bromide) test. To determine the antioxidant status in the cell line treated with Thymoquinone, to examine the effects of superoxide dismutase (SOD) and catalase (CAT) activities, on apoptosis Caspase-3 protein levels were measured by ELISA method. RESULTS: When compared to the control group, the SOD and CAT levels were significantly decreased in the U87 cell line exposed to Aß; Caspase-3 levels were found to increase significantly. However, application of TQ to the Aß-U87 cell line significantly increased SOD and CAT levels; it was found that it decreased the caspase-3 level. CONCLUSION: In in vitro experiments, we determined that TQ has a protective effect by increasing antioxidant parameters in the amyloid beta-induced cell line (Fig. 4, Ref. 41). Text in PDF www.elis.sk Keywords: thymoquinone, amyloid-beta, U87, SOD, CAT, caspase-3.


Assuntos
Peptídeos beta-Amiloides , Nigella sativa , Peptídeos beta-Amiloides/toxicidade , Antioxidantes/farmacologia , Benzoquinonas/farmacologia
2.
Molecules ; 26(17)2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34500570

RESUMO

Thymoquinone (TQ) is the main biologically active constituent of Nigella sativa. Many studies have confirmed its anticancer actions. Herein, we investigated the different anticancer activities of, and considered resistance mechanisms to, TQ. MTT and clonogenic data showed TQ's ability to suppress breast MDA-MB-468 and T-47D proliferation at lower concentrations compared to other cancer and non-transformed cell lines tested (GI50 values ≤ 1.5 µM). Flow-cytometric analyses revealed that TQ consistently induced MDA-MB-468 and T-47D cell-cycle perturbation, specifically inducing pre-G1 populations. In comparison, less sensitive breast MCF-7 and colon HCT-116 cells exhibited only transient increases in pre-G1 events. Annexin V/PI staining confirmed apoptosis induction in MDA-MB-468 and HCT-116 cells, which was continuous in the former and transient in the latter. Experiments revealed the role of reactive oxygen species (ROS) generation and aneuploidy induction in MDA-MB-468 cells within the first 24 h of treatment. The ROS-scavenger NAD(P)H dehydrogenase (quinone 1) (NQO1; DT-diaphorase) and glutathione (GSH) were implicated in resistance to TQ. Indeed, western blot analyses showed that NQO1 is expressed in all cell lines in this study, except those most sensitive to TQ-MDA-MB-468 and T-47D. Moreover, TQ treatment increased NQO1 expression in HCT-116 in a concentration-dependent fashion. Measurement of GSH activity in MDA-MB-468 and HCT-116 cells found that GSH is similarly active in both cell lines. Furthermore, GSH depletion rendered these cells more sensitive to TQ's antiproliferative actions. Therefore, to bypass putative inactivation of the TQ semiquinone metabolite, the benzylamine analogue was designed and synthesised following modification of TQ's carbon-3 atom. However, the structural modification negatively impacted potency against MDA-MB-468 cells. In conclusion, we disclose the following: (i) The anticancer activity of TQ may be a consequence of ROS generation and aneuploidy; (ii) Early GSH depletion could substantially enhance TQ's anticancer activity; (iii) Benzylamine substitution at TQ's carbon-3 failed to enhance anticancer activity.


Assuntos
Antineoplásicos/farmacologia , Benzoquinonas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Aneuploidia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células HCT116 , Humanos , Células MCF-7 , NAD(P)H Desidrogenase (Quinona)/metabolismo , Nigella sativa/química
3.
J Enzyme Inhib Med Chem ; 36(1): 1898-1904, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34344239

RESUMO

Geldanamycin (GDM) has been modified by different type neutral/acidic/basic substituents (1-7) and by quinuclidine motif (8), transformed into ammonium salts (9-13) at C(17). These compounds have been characterised by spectroscopic and x-ray methods. Derivative 8 shows better potency than GDM in MCF-7, MDA-MB-231, A549 and HeLa (IC50s = 0.09-1.06 µM). Transformation of 8 into salts 9-13 reduces toxicity (by 11-fold) at attractive potency, e.g. MCF-7 cell line (IC50∼2 µM). Our studies show that higher water solubility contributes to lower toxicity of salts than GDM in healthy CCD39Lu and HDF cells. The use of 13 mixtures with potentiators PEI and DOX enhanced anticancer effects from IC50∼2 µM to IC50∼0.5 µM in SKBR-3, SKOV-3, and PC-3 cancer cells, relative to 13. Docking studies showed that complexes between quinuclidine-bearing 8-13 and Hsp90 are stabilised by extra hydrophobic interactions between the C(17)-arms and K58 or Y61 of Hsp90.


Assuntos
Antineoplásicos/farmacologia , Benzoquinonas/farmacologia , Lactamas Macrocíclicas/farmacologia , Compostos de Amônio Quaternário/química , Antineoplásicos/química , Benzoquinonas/química , Linhagem Celular , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Humanos , Lactamas Macrocíclicas/química , Estrutura Molecular , Sais/química , Análise Espectral/métodos
4.
Andrologia ; 53(10): e14130, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34414592

RESUMO

In this study, it was aimed to investigate possible ameliorating effects of thymoquinone on testicular damage in an epilepsy model. Adult male Wistar rats were divided into 4 groups. The animals in sham-operated groups were given saline or thymoquinone (s.c.); and the animals in pentylenetetrazole (PTZ) group were applied PTZ. The animals in PTZ+thymoquinone group were given thymoquinone (i.p) for 6 days after applying PTZ. Hematoxylin-eosin, periodic acid-Schiff and TUNEL staining and PCNA, StAR, inhibin ß-B immunohistochemistry and ZO-1 immunofluorescence methods were applied. Staining intensity and cell numbers were determined. Degeneration of seminiferous tubules was observed in PTZ group. Most of the tubules showed normal morphology in the PTZ+thymoquinone group. Apoptotic cell index was found to be increased and proliferative index decreased in PTZ group. Thymoquinone administration decreased apoptotic index and increased proliferation index. In PTZ group, ZO-1, StAR and inhibin ß-B immunohistochemical staining intensity was observed to be decreased and after thymoquinone application, ZO-1 was increased. StAR and inhibin ß-B-positive cell numbers were decreased in PTZ group and increased in the PTZ +thymoquinone group. In this study, it was observed that PTZ-induced epileptic seizures caused testicular damage in the rat and thymoquinone ameliorated these effects.


Assuntos
Epilepsia do Lobo Temporal , Pentilenotetrazol , Animais , Benzoquinonas/farmacologia , Masculino , Pentilenotetrazol/toxicidade , Ratos , Ratos Wistar
5.
Int J Mol Sci ; 22(16)2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34445781

RESUMO

The prevalence of chronic kidney disease (CKD) is increasing worldwide, and a close association between acute kidney injury (AKI) and CKD has recently been identified. Black cumin (Nigella sativa) has been shown to be effective in treating various kidney diseases. Accumulating evidence shows that black cumin and its vital compound, thymoquinone (TQ), can protect against kidney injury caused by various xenobiotics, namely chemotherapeutic agents, heavy metals, pesticides, and other environmental chemicals. Black cumin can also protect the kidneys from ischemic shock. The mechanisms underlying the kidney protective potential of black cumin and TQ include antioxidation, anti-inflammation, anti-apoptosis, and antifibrosis which are manifested in their regulatory role in the antioxidant defense system, NF-κB signaling, caspase pathways, and TGF-ß signaling. In clinical trials, black seed oil was shown to normalize blood and urine parameters and improve disease outcomes in advanced CKD patients. While black cumin and its products have shown promising kidney protective effects, information on nanoparticle-guided targeted delivery into kidney is still lacking. Moreover, the clinical evidence on this natural product is not sufficient to recommend it to CKD patients. This review provides insightful information on the pharmacological benefits of black cumin and TQ against kidney damage.


Assuntos
Injúria Renal Aguda/tratamento farmacológico , Benzoquinonas/farmacologia , Rim/efeitos dos fármacos , Nigella sativa/química , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Insuficiência Renal Crônica/tratamento farmacológico , Animais , Humanos , Transdução de Sinais/efeitos dos fármacos
6.
Phytomedicine ; 91: 153658, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34332284

RESUMO

BACKGROUND: 2,6-Dimethoxy-1,4-benzoquinone (DMBQ), a natural phytochemical present in fermented wheat germ, has been reported to exert anti-cancer, anti-inflammatory, and anti-adipogenic effects. However, the effect of DMBQ on muscle hypertrophy and myoblast differentiation has not been elucidated. PURPOSE: We investigated the effect of DMBQ on skeletal muscle mass and muscle function and then determined the possible mechanism of DMBQ. METHODS: To examine myogenic differentiation and hypertrophy, confluent C2C12 cells were incubated in differentiation medium with or without various concentrations of DMBQ for 4 days. In animal experiments, C57BL/6 mice were fed DMBQ-containing AIN-93 diet for 7 weeks. Grip strength, treadmill, microscopic evaluation of muscle tissue, western blotting, and quantitative real-time PCR were performed. RESULTS: DMBQ significantly increased fusion index, myotube size, and the protein expression of myosin heavy chain (MHC). DMBQ increased the phosphorylation of protein kinase B (AKT) and p70 ribosomal protein S6 kinase (S6K), whereas the phosphorylation of these proteins was abolished by the phosphoinositide 3-kinase inhibitor LY294002 in C2C12 cells. In addition, DMBQ treatment increased peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α), which programs mitochondrial biogenesis, protein levels compared with control C2C12 cells. DMBQ significantly increased maximal respiration and spare respiratory capacity in C2C12 cells. In animal experiments, DMBQ increased skeletal muscle weights and skeletal muscle fiber size compared with the control group values. In addition, the DMBQ group showed increased grip strength and running distance on an accelerating treadmill. The protein expression of total MHC, MHC1, MHC2A, and MHC2B in skeletal muscle was upregulated by DMBQ supplementation. We found that DMBQ increased the phosphorylation of AKT and mammalian target of rapamycin (mTOR), as well as downstream S6K and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) in skeletal muscle. DMBQ also stimulated mRNA expression of PGC1α, accompanied by an increase in mitochondrial DNA content, oxidative phosphorylation (OXPHOS) proteins, and oxidative enzyme activity. CONCLUSION: Collectively, DMBQ was shown to increase skeletal muscle mass and performance by regulating the AKT/mTOR signaling pathway and enhancing mitochondrial function, which might be useful for the treatment and prevention of skeletal muscle atrophy.


Assuntos
Benzoquinonas/farmacologia , Mitocôndrias/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Transdução de Sinais , Animais , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Fibras Musculares Esqueléticas/fisiologia , Músculo Esquelético/fisiologia , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo
7.
Molecules ; 26(14)2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34299454

RESUMO

In this study, a new broth macrodilution volatilization method for the simple and rapid determination of the antibacterial effect of volatile agents simultaneously in the liquid and vapor phase was designed with the aim to assess their therapeutic potential for the development of new inhalation preparations. The antibacterial activity of plant volatiles (ß-thujaplicin, thymohydroquinone, thymoquinone) was evaluated against bacteria associated with respiratory infections (Haemophilus influenzae, Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes) and their cytotoxicity was determined using a modified thiazolyl blue tetrazolium bromide assay against normal lung fibroblasts. Thymohydroquinone and thymoquinone possessed the highest antibacterial activity against H. influenzae, with minimum inhibitory concentrations of 4 and 8 µg/mL in the liquid and vapor phases, respectively. Although all compounds exhibited cytotoxic effects on lung cells, therapeutic indices (TIs) suggested their potential use in the treatment of respiratory infections, which was especially evident for thymohydroquinone (TI > 34.13). The results demonstrate the applicability of the broth macrodilution volatilization assay, which combines the principles of broth microdilution volatilization and standard broth macrodilution methods. This assay enables rapid, simple, cost- and labor-effective screening of volatile compounds and overcomes the limitations of assays currently used for screening of antimicrobial activity in the vapor phase.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Óleos Voláteis/farmacologia , Administração por Inalação , Antibacterianos/análise , Bactérias/efeitos dos fármacos , Benzoquinonas/administração & dosagem , Benzoquinonas/farmacologia , Haemophilus influenzae/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Monoterpenos/administração & dosagem , Monoterpenos/farmacologia , Óleos Voláteis/química , Staphylococcus aureus/efeitos dos fármacos , Streptococcus pneumoniae/efeitos dos fármacos , Streptococcus pyogenes/efeitos dos fármacos , Timol/administração & dosagem , Timol/análogos & derivados , Timol/farmacologia , Tropolona/administração & dosagem , Tropolona/análogos & derivados , Tropolona/farmacologia , Compostos Orgânicos Voláteis/química , Compostos Orgânicos Voláteis/farmacologia , Volatilização
8.
Clin Exp Pharmacol Physiol ; 48(11): 1445-1453, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34297870

RESUMO

Nigella sativa (N. sativa) is an annual flowering plant that has been used as a traditional remedy for many centuries. The seed possesses a large variety of compounds with thymoquinone (TQ) considered its major but not sole bioactive constituent. Supercritical fluid extraction, geographical location, and oxidative status of N. sativa produces the highest yield of essential oil content including TQ. Thymoquinone is lipophilic, heat and light sensitive with low oral bioavailability and rapid elimination that have significantly inhibited its pharmacological development. Novel developments in nanoparticulate-based oral administration, nasal spray and transdermal delivery may allow the clinical development of N. sativa and TQ as therapeutic agents. Animal and human studies indicate a potential role of N. sativa seed oil and TQ for a diverse range of disease processes including hypertension, dyslipidaemia, type 2 diabetes mellitus, arthritis, asthma, bacterial and viral infections, neurological and dermatological disorders, as it belongs to the group of pan-assay interference compounds. This review outlines the pharmacological properties of N. sativa and TQ and their potential wide application for a large variety of human diseases. The paper will focus on recent studies of the anti-inflammatory and antiviral properties that make N. sativa and TQ promising therapeutic agents targeting contemporary inflammatory and infectious diseases including Covid 19.


Assuntos
Benzoquinonas/farmacologia , Doenças Transmissíveis/tratamento farmacológico , Inflamação/tratamento farmacológico , Nigella sativa/química , Animais , Benzoquinonas/uso terapêutico , Humanos
9.
Int J Mol Sci ; 22(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202112

RESUMO

D-galactose (D-gal) administration causes oxidative disorder and is widely utilized in aging animal models. Therefore, we subcutaneously injected D-gal at 200 mg/kg BW dose to assess the potential preventive effect of thymoquinone (TQ) and curcumin (Cur) against the oxidative alterations induced by D-gal. Other than the control, vehicle, and D-gal groups, the TQ and Cur treated groups were orally supplemented at 20 mg/kg BW of each alone or combined. TQ and Cur effectively suppressed the oxidative alterations induced by D-gal in brain and heart tissues. The TQ and Cur combination significantly decreased the elevated necrosis in the brain and heart by D-gal. It significantly reduced brain caspase 3, calbindin, and calcium-binding adapter molecule 1 (IBA1), heart caspase 3, and BCL2. Expression of mRNA of the brain and heart TP53, p21, Bax, and CASP-3 were significantly downregulated in the TQ and Cur combination group along with upregulation of BCL2 in comparison with the D-gal group. Data suggested that the TQ and Cur combination is a promising approach in aging prevention.


Assuntos
Benzoquinonas/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Curcumina/farmacologia , Galactose/farmacologia , Miocárdio/metabolismo , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Benzoquinonas/química , Curcumina/química , Imuno-Histoquímica , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Especificidade de Órgãos , Ratos , Relação Estrutura-Atividade
10.
Molecules ; 26(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202733

RESUMO

Thymoquinone is a natural bioactive with significant therapeutic activity against multiple ailments including wound healing. The poor aqueous solubility and low skin permeability limit its therapeutic efficacy. The present investigation aimed to improve the biopharmaceutical attributes of thymoquinone to enhance its topical efficacy in wound healing. A nanoemulsion-based hydrogel system was designed and characterized as a nanotechnology-mediated drug delivery approach to improve the therapeutic efficacy of thymoquinone, utilizing a high-energy emulsification technique. The black seed oil, as a natural home of thymoquinone, was utilized to improve the drug loading capacity of the developed nanoemulsion system and reduced the oil droplet size to <100 nm through ultrasonication. The influence of formulation composition, and the ultrasonication process conditions, were investigated on the mean globule size and polydispersity index of the generated nanoemulsion. Irrespective of surfactant/co-surfactant ratio and % concentration of surfactant/co-surfactant mixture, the ultrasonication time had a significant (p < 0.05) influence on the mean droplet size and polydispersity index of the generated nanoemulsion. The developed nanoemulgel system of thymoquinone demonstrated the pseudoplastic behavior with thixotropic properties, and this behavior is desirable for topical application. The nanoemulgel system of thymoquinone exhibited significant enhancement (p < 0.05) in skin penetrability and deposition characteristics after topical administration compared to the conventional hydrogel system. The developed nanoemulgel system of thymoquinone exhibited quicker and early healing in wounded Wistar rats compared to the conventional hydrogel of thymoquinone, while showing comparable healing efficacy with respect to marketed silver sulfadiazine (1%) cream. Furthermore, histopathology analysis of animals treated with a developed formulation system demonstrated the formation of the thick epidermal layer, papillary dermis along with the presence of extensive and organized collagen fibers in newly healed tissues. The outcome of this investigation signifies that topical delivery of thymoquinone through nanoemulgel system is a promising candidate which accelerates the process of wound healing in preclinical study.


Assuntos
Benzoquinonas , Sistemas de Liberação de Medicamentos , Nanopartículas , Absorção Cutânea/efeitos dos fármacos , Pele/metabolismo , Cicatrização/efeitos dos fármacos , Administração Tópica , Animais , Benzoquinonas/química , Benzoquinonas/farmacocinética , Benzoquinonas/farmacologia , Emulsões , Nanopartículas/química , Nanopartículas/uso terapêutico , Ratos , Ratos Wistar , Pele/patologia
11.
Int J Mol Sci ; 22(11)2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-34070744

RESUMO

The ClC-2 channel plays a critical role in maintaining ion homeostasis in the brain and the testis. Loss-of-function mutations in the ClC-2-encoding human CLCN2 gene are linked to the white matter disease leukodystrophy. Clcn2-deficient mice display neuronal myelin vacuolation and testicular degeneration. Leukodystrophy-causing ClC-2 mutant channels are associated with anomalous proteostasis manifesting enhanced endoplasmic reticulum (ER)-associated degradation. The molecular nature of the ER quality control system for ClC-2 protein remains elusive. In mouse testicular tissues and Leydig cells, we demonstrated that endogenous ClC-2 co-existed in the same protein complex with the molecular chaperones heat shock protein 90ß (Hsp90ß) and heat shock cognate protein (Hsc70), as well as the associated co-chaperones Hsp70/Hsp90 organizing protein (HOP), activator of Hsp90 ATPase homolog 1 (Aha1), and FK506-binding protein 8 (FKBP8). Further biochemical analyses revealed that the Hsp90ß-Hsc70 chaperone/co-chaperone system promoted mouse and human ClC-2 protein biogenesis. FKBP8 additionally facilitated membrane trafficking of ClC-2 channels. Interestingly, treatment with the Hsp90-targeting small molecule 17-allylamino-17-demethoxygeldanamycin (17-AAG) substantially boosted ClC-2 protein expression. Also, 17-AAG effectively increased both total and cell surface protein levels of leukodystrophy-causing loss-of-function ClC-2 mutant channels. Our findings highlight the therapeutic potential of 17-AAG in correcting anomalous ClC-2 proteostasis associated with leukodystrophy.


Assuntos
Encéfalo/metabolismo , Canais de Cloreto/genética , Células Intersticiais do Testículo/metabolismo , Neurônios/metabolismo , Doença de Pelizaeus-Merzbacher/genética , Proteostase/genética , Animais , Benzoquinonas/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Células CHO , Canais de Cloreto/deficiência , Cricetulus , Modelos Animais de Doenças , Degradação Associada com o Retículo Endoplasmático/efeitos dos fármacos , Regulação da Expressão Gênica , Células HEK293 , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/metabolismo , Proteínas de Choque Térmico HSP90/genética , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Lactamas Macrocíclicas/farmacologia , Células Intersticiais do Testículo/efeitos dos fármacos , Células Intersticiais do Testículo/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/patologia , Doença de Pelizaeus-Merzbacher/tratamento farmacológico , Doença de Pelizaeus-Merzbacher/metabolismo , Doença de Pelizaeus-Merzbacher/patologia , Isoformas de Proteínas/deficiência , Isoformas de Proteínas/genética , Transdução de Sinais , Proteínas de Ligação a Tacrolimo/genética , Proteínas de Ligação a Tacrolimo/metabolismo
12.
Pharm Biol ; 59(1): 696-703, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34110959

RESUMO

CONTEXT: COVID-19 is a novel coronavirus that causes a severe infection in the respiratory system. Nigella sativa L. (Ranunculaceae) is an annual flowering plant used traditionally as a natural food supplement and multipurpose medicinal agent. OBJECTIVE: The possible beneficial effects of N. sativa, and its constituent, thymoquinone (TQ) on COVID-19 were reviewed. METHODS: The key words including, COVID-19, N. sativa, thymoquinone, antiviral effects, anti-inflammatory and immunomodulatory effects in different databases such as Web of Science (ISI), PubMed, Scopus, and Google Scholar were searched from 1990 up to February 2021. RESULTS: The current literature review showed that N. sativa and TQ reduced the level of pro-inflammatory mediators including, IL-2, IL-4, IL-6, and IL-12, while enhancing IFN-γ. Nigella sativa and TQ increased the serum levels of IgG1 and IgG2a, and improved pulmonary function tests in restrictive respiratory disorders. DISCUSSION AND CONCLUSIONS: These preliminary data of molecular docking, animal, and clinical studies propose N. sativa and TQ might have beneficial effects on the treatment or control of COVID-19 due to antiviral, anti-inflammatory and immunomodulatory properties as well as bronchodilatory effects. The efficacy of N. sativa and TQ on infected patients with COVID-19 in randomize clinical trials will be suggested.


Assuntos
Anti-Inflamatórios/farmacologia , Antivirais/farmacologia , Benzoquinonas/farmacologia , COVID-19/tratamento farmacológico , Nigella sativa , Extratos Vegetais/farmacologia , SARS-CoV-2/efeitos dos fármacos , Animais , Anti-Inflamatórios/isolamento & purificação , Antivirais/isolamento & purificação , Benzoquinonas/isolamento & purificação , COVID-19/imunologia , COVID-19/metabolismo , COVID-19/virologia , Citocinas/metabolismo , Humanos , Sistema Imunitário/efeitos dos fármacos , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Sistema Imunitário/virologia , Mediadores da Inflamação/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/virologia , Nigella sativa/química , Extratos Vegetais/isolamento & purificação , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade
13.
Int J Mol Sci ; 22(9)2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-34062977

RESUMO

Chronic inflammation has been associated with several chronic diseases, such as age-related macular degeneration (AMD). The NLRP3 inflammasome is a central proinflammatory signaling complex that triggers caspase-1 activation leading to the maturation of IL-1ß. We have previously shown that the inhibition of the chaperone protein, Hsp90, prevents NLRP3 activation in human retinal pigment epithelial (RPE) cells; these are cells which play a central role in the pathogenesis of AMD. In that study, we used a well-known Hsp90 inhibitor geldanamycin, but it cannot be used as a therapy due to its adverse effects, including ocular toxicity. Here, we have tested the effects of a novel Hsp90 inhibitor, TAS-116, on NLRP3 activation using geldanamycin as a reference compound. Using our existing protocol, inflammasome activation was induced in IL-1α-primed ARPE-19 cells with the proteasome and autophagy inhibitors MG-132 and bafilomycin A1, respectively. Intracellular caspase-1 activity was determined using a commercial caspase-1 activity kit and the FLICA assay. The levels of IL-1ß were measured from cell culture medium samples by ELISA. Cell viability was monitored by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test and lactate dehydrogenase (LDH) measurements. Our findings show that TAS-116 could prevent the activation of caspase-1, subsequently reducing the release of mature IL-1ß. TAS-116 has a better in vitro therapeutic index than geldanamycin. In summary, TAS-116 appears to be a well-tolerated Hsp90 inhibitor, with the capability to prevent the activation of the NLRP3 inflammasome in human RPE cells.


Assuntos
Benzamidas/farmacologia , Células Epiteliais/metabolismo , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pirazóis/farmacologia , Epitélio Pigmentado da Retina/patologia , Benzoquinonas/farmacologia , Caspase 1/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Proteínas de Choque Térmico HSP70/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Interleucina-1beta/metabolismo , Interleucina-8/metabolismo , Lactamas Macrocíclicas/farmacologia
14.
Molecules ; 26(11)2021 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-34072086

RESUMO

Benzopyrene [B(a)P] is a well-recognized environmental carcinogen, which promotes oxidative stress, inflammation, and other metabolic complications. In the current study, the therapeutic effects of thymoquinone (TQ) against B(a)P-induced lung injury in experimental rats were examined. B(a)P used at 50 mg/kg b.w. induced lung injury that was investigated via the evaluation of lipid profile, inflammatory markers, nitric oxide (NO), and malondialdehyde (MDA) levels. B(a)P also led to a decrease in superoxide dismutase (SOD) (34.3 vs. 58.5 U/mg protein), glutathione peroxidase (GPx) (42.4 vs. 72.8 U/mg protein), catalase (CAT) (21.2 vs. 30.5 U/mg protein), and total antioxidant capacity compared to normal animals. Treatment with TQ, used at 50 mg/kg b.w., led to a significant reduction in triglycerides (TG) (196.2 vs. 233.7 mg/dL), total cholesterol (TC) (107.2 vs. 129.3 mg/dL), and inflammatory markers and increased the antioxidant enzyme level in comparison with the group that was administered B(a)P only (p < 0.05). B(a)P administration led to the thickening of lung epithelium, increased inflammatory cell infiltration, damaged lung tissue architecture, and led to accumulation of collagen fibres as studied through haematoxylin and eosin (H&E), Sirius red, and Masson's trichrome staining. Moreover, the recognition of apoptotic nuclei and expression pattern of NF-κB were evaluated through the TUNEL assay and immunohistochemistry, respectively. The histopathological changes were found to be considerably low in the TQ-treated animal group. The TUNEL-positive cells increased significantly in the B(a)P-induced group, whereas the TQ-treated group showed a decreased apoptosis rate. Significantly high cytoplasmic expression of NF-κB in the B(a)P-induced group was seen, and this expression was prominently reduced in the TQ-treated group. Our results suggest that TQ can be used in the protection against benzopyrene-caused lung injury.


Assuntos
Benzo(a)pireno/química , Benzoquinonas/análise , Benzoquinonas/farmacologia , Inflamação , Lipídeos/química , Lesão Pulmonar/induzido quimicamente , Pulmão/efeitos dos fármacos , Nigella sativa/metabolismo , Óxido Nítrico/química , Estresse Oxidativo , Fibrose Pulmonar/induzido quimicamente , Animais , Antioxidantes/química , Colesterol/química , Fragmentação do DNA , Molécula 1 de Adesão Intercelular/biossíntese , Interleucina-1beta/biossíntese , Interleucina-6/biossíntese , Pulmão/patologia , Masculino , Fibrose Pulmonar/fisiopatologia , Ratos , Resultado do Tratamento , Fator de Necrose Tumoral alfa/biossíntese
15.
Drug Des Devel Ther ; 15: 1819-1833, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33976534

RESUMO

COVID-19 has caused a major global health crisis, as excessive inflammation, oxidation, and exaggerated immune response in some sufferers can lead to a condition known as cytokine storm, which may progress to acute respiratory distress syndrome (ARDs), which can be fatal. So far, few effective drugs have emerged to assist in the treatment of patients with COVID-19, though some herbal medicine candidates may assist in the fight against COVID-19 deaths. Thymoquinone (TQ), the main active ingredient of black seed oil, possesses antioxidant, anti-inflammatory, antiviral, antimicrobial, immunomodulatory and anticoagulant activities. TQ also increases the activity and number of cytokine suppressors, lymphocytes, natural killer cells, and macrophages, and it has demonstrated antiviral potential against a number of viruses, including murine cytomegalovirus, Epstein-Barr virus, hepatitis C virus, human immunodeficiency virus, and other coronaviruses. Recently, TQ has demonstrated notable antiviral activity against a SARSCoV-2 strain isolated from Egyptian patients and, interestingly, molecular docking studies have also shown that TQ could potentially inhibit COVID-19 development through binding to the receptor-binding domain on the spike and envelope proteins of SARS-CoV-2, which may hinder virus entry into the host cell and inhibit its ion channel and pore forming activity. Other studies have shown that TQ may have an inhibitory effect on SARS CoV2 proteases, which could diminish viral replication, and it has also demonstrated good antagonism to angiotensin-converting enzyme 2 receptors, allowing it to interfere with virus uptake into the host cell. Several studies have also noted its potential protective capability against numerous chronic diseases and conditions, including diabetes, hypertension, dyslipidemia, asthma, renal dysfunction and malignancy. TQ has recently been tested in clinical trials for the treatment of several different diseases, and this review thus aims to highlight the potential therapeutic effects of TQ in the context of the COVID-19 pandemic.


Assuntos
Benzoquinonas/uso terapêutico , COVID-19/tratamento farmacológico , SARS-CoV-2 , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Benzoquinonas/farmacologia , COVID-19/prevenção & controle , Comorbidade , Epigênese Genética , Humanos , Simulação de Acoplamento Molecular , SARS-CoV-2/química
16.
DNA Repair (Amst) ; 103: 103117, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33990030

RESUMO

INTRODUCTION: Hepatocellular carcinoma (HCC) remains one of the most predominant types of digestive system malignancies worldwide. TNF-related apoptosis-inducing ligand (TRAIL) is a biological cytokine with the mentioned specificity, but some tumor cells' resistance limits its use as a therapeutic approach. The present study aimed to investigate thymoquinone (TQ) and TRAIL's combined effect and the potential mechanisms in human hepatic HepG2 carcinoma cells. METHODS: Cell viability and IC50 dose for TQ and TRAIL, alone and in combination, were determined using the MTT method. ELISA evaluated the expression levels of 8-Hydroxy-2'-deoxyguanosine. The apoptosis rate was assessed by flow cytometry, ELISA cell death assay, and caspase 8 activity assays. The mRNA and protein evaluation of candidate genes, including survivin, Bcl-2, XIAP, c-IAP1, c-IAP2, and c-FLIP, were accomplished before and after the treatment using qRT-PCR and Western blot analysis, respectively. RESULTS: Our results showed that TQ synergistically increased TRAIL's cell toxic effects as follows: TQ plus TRAIL > TRAIL > TQ. TQ could sensitize the HepG2 cells against the TRAIL-induced apoptosis and amplify the caspase 8 activity. This outcome is achieved by decreasing the mRNA and protein expression levels of anti-apoptotic genes. CONCLUSIONS: Our findings suggest that TQ can sensitize the human HCC cell line HepG2 against TRAIL by inducing the death receptor pathway. Moreover, these agents' combinational therapy might promise a therapeutic regimen for improving the clinical efficacy of TRAIL-induced apoptosis in patients with HCC.


Assuntos
Apoptose , Benzoquinonas/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Dano ao DNA , Neoplasias Hepáticas/tratamento farmacológico , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Benzoquinonas/uso terapêutico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/fisiopatologia , DNA/efeitos dos fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/fisiopatologia , Estresse Oxidativo
17.
Appl Microbiol Biotechnol ; 105(11): 4709-4718, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34014346

RESUMO

Shigella flexneri (Sh. flexneri), a common foodborne pathogen, has become one of the main threats to food safety and human health due to its high pathogenicity and persistent infection. The objective of this study was to explore the antimicrobial and anti-biofilm activities and the possible mechanism of thymoquinone (TQ) against Sh. flexneri. The minimum inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) of TQ against Sh. flexneri were 0.4 and 0.5 mg/mL, respectively. TQ showed bactericidal activity against Sh. flexneri in culture medium and milk system. Scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM) observations demonstrated that TQ could induce abnormal cell morphology and destroy cell membrane. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) analysis suggested that TQ could inhibit protein synthesis in Sh. flexneri. Also, at sub-inhibitory concentrations (SICs), TQ exhibited an inhibitory effect on Sh. flexneri biofilm formation, which was confirmed by crystal violet quantitative analysis and SEM observation. Real-time quantitative PCR (RT-qPCR) analyses revealed that TQ downregulated the expression of genes involved in Sh. flexneri biofilm formation. Thus, TQ has potential as a natural antimicrobial and anti-biofilm agent to address the contamination and infection caused by Sh. flexneri. KEY POINTS: • Antimicrobial and anti-biofilm activity of TQ on Shigella flexneri were investigated. • TQ inhibited biofilm formation by Shigella flexneri. • TQ provided a new strategy for Shigella flexneri control.


Assuntos
Biofilmes , Shigella flexneri , Antibacterianos/farmacologia , Benzoquinonas/farmacologia , Humanos
18.
Molecules ; 26(8)2021 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-33920728

RESUMO

The aim of the present study was to assess the short-term effects of Thymoquinone (TQ) on oxidative stress, glycaemic control, and renal functions in diabetic rats. DM was induced in groups II and III with a single dose of streptozotocin (STZ), while group I received no medication (control). The rats in groups I and II were then given distilled water, while the rats in group III were given TQ at a dose of 50 mg/kg body weight/day for 4 weeks. Lipid peroxidase, nitric oxide (NO), total antioxidant capacity (TAC), glycated haemoglobin (HbA1c), lipid profiles, and renal function were assessed. Moreover, the renal tissues were used for histopathological examination. STZ increased the levels of HbA1c, lipid peroxidase, NO, and creatinine in STZ-induced diabetic rats in comparison to control rats. TAC was lower in STZ-induced diabetic rats than in the control group. Furthermore, rats treated with TQ exhibited significantly lower levels of HbA1c, lipid peroxidase, and NO than did untreated diabetic rats. TAC was higher in diabetic rats treated with TQ than in untreated diabetic rats. The histopathological results showed that treatment with TQ greatly attenuated the effect of STZ-induced diabetic nephropathy. TQ effectively adjusts glycaemic control and reduces oxidative stress in STZ-induced diabetic rats without significant damaging effects on the renal function.


Assuntos
Benzoquinonas/farmacologia , Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Animais , Antioxidantes/farmacologia , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/patologia , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/patologia , Modelos Animais de Doenças , Humanos , Hipoglicemia/sangue , Hipoglicemia/tratamento farmacológico , Hipoglicemia/patologia , Rim/efeitos dos fármacos , Rim/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos
19.
Int J Mol Sci ; 22(5)2021 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-33802613

RESUMO

This study demonstrates the rational fabrication of a magnetic composite nanofiber mesh that can achieve mutual synergy of hyperthermia, chemotherapy, and thermo-molecularly targeted therapy for highly potent therapeutic effects. The nanofiber is composed of biodegradable poly(ε-caprolactone) with doxorubicin, magnetic nanoparticles, and 17-allylamino-17-demethoxygeldanamycin. The nanofiber exhibits distinct hyperthermia, owing to the presence of magnetic nanoparticles upon exposure of the mesh to an alternating magnetic field, which causes heat-induced cell killing as well as enhanced chemotherapeutic efficiency of doxorubicin. The effectiveness of hyperthermia is further enhanced through the inhibition of heat shock protein activity after hyperthermia by releasing the inhibitor 17-allylamino-17-demethoxygeldanamycin. These findings represent a smart nanofiber system for potent cancer therapy and may provide a new approach for the development of localized medication delivery.


Assuntos
Benzoquinonas/farmacologia , Preparações de Ação Retardada/farmacologia , Doxorrubicina/farmacologia , Hipertermia/tratamento farmacológico , Lactamas Macrocíclicas/farmacologia , Nanofibras/química , Neoplasias/tratamento farmacológico , Benzoquinonas/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Preparações de Ação Retardada/química , Doxorrubicina/química , Liberação Controlada de Fármacos , Sinergismo Farmacológico , Compostos Férricos/química , Humanos , Lactamas Macrocíclicas/química , Células MCF-7 , Magnetismo/métodos , Nanopartículas de Magnetita/química
20.
Molecules ; 26(6)2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33805696

RESUMO

Experimental evidence indicates that the activation of ionotropic glutamate receptors plays an important role in neurological disorders' models such as epilepsy, cerebral ischemia and trauma. The glutamate receptor agonist kainic acid (KA) induces seizures and excitotoxic cell death in the CA3 region of the hippocampus. Thymoquinone (TQ) is the most important component of the essential oil obtained from black cumin (Nigella sativa L.) seeds. It has many pharmacological actions including antioxidant, anti-inflammatory, and anti-apoptotic effects. TQ was used in an in vitro experimental model of primary cultures where excitotoxicity was induced. Briefly, rat organotypic hippocampal slices were exposed to 5 µM KA for 24 h. Cell death in the CA3 subregions of slices was quantified by measuring propidium iodide fluorescence. The cross-talk between TQ, ER stress and apoptotic pathways was investigated by Western blot. In untreated slices TQ (10 µM) induced a significant increase on the PSD95 levels and it decreased the excitotoxic injury induced by KA. Additionally, TQ was able to ameliorate the KA-induced increase in unfolded proteins GRP78 and GRP94 expression. Finally, TQ was able to partially rescue the reduction of the KA-induced apoptotic pathway activation. Our results suggest that TQ modulates the processes leading to post-kainate neuronal death in the CA3 hippocampal area.


Assuntos
Benzoquinonas/farmacologia , Região CA3 Hipocampal/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Região CA3 Hipocampal/patologia , Região CA3 Hipocampal/fisiopatologia , Modelos Animais de Doenças , Proteína 4 Homóloga a Disks-Large/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Epilepsia/induzido quimicamente , Epilepsia/tratamento farmacológico , Epilepsia/fisiopatologia , Agonistas de Aminoácidos Excitatórios/toxicidade , Feminino , Técnicas In Vitro , Ácido Caínico/toxicidade , Masculino , Plasticidade Neuronal/efeitos dos fármacos , Ratos , Ratos Wistar
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