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1.
Sci Rep ; 14(1): 13016, 2024 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-38844763

RESUMO

Diabetes mellitus (DM) is a complex metabolic condition that causes organ dysfunction. The current experiment sought to determine the effect of thymoquinone (TQ) on hyperglycemia, hyperlipidemia, oxidative/nitrosative stress, inflammation, and apoptosis in diabetic rats prompted by streptozotocin (STZ) (55 mg/kg body weight i/p). The animals were allocated into control, TQ (50 mg/kg B.W. orally administered for 4 succeeding weeks), Diabetic, and Diabetic + TQ groups. This study confirmed that TQ preserves the levels of insulin, fasting blood glucose, HOMA ß-cell indices, HbA1c %, body weight, and lipid profile substantially relative to the DC group. Furthermore, hepatic antioxidant (CAT, GSH, and T-SOD) values were reduced. Conversely, the enzymatic activity of liver functions (AST, ALT, ALP, cytochrome P450, and hepatic glucose-6-phosphatase), lipid peroxidation (MDA), pro-inflammatory cytokines (IL-1ß, TNF-α, and IL-6), nitric oxide (NO) and inflammatory marker (CRP) enhanced with STZ administration, which is substantially restored after TQ treatment. Relative to the diabetic rats, TQ reestablished the hepatic architectural changes and collagen fibers. Additionally, TQ downregulated the intensity of the immunohistochemical staining of pro-apoptotic marker (caspase-3), p53, and tumor necrosis factor-alpha (TNF-α) proteins in hepatic tissues. Furthermore, TQ displayed abilities to interact and inhibit the binding site of caspase-3, interleukin-6 receptor, interleukin-1 receptor type 1, TNF receptor superfamily member 1A, and TNF receptor superfamily member 1B in rats following the molecular docking modeling. All these data re-establish the liver functions, antioxidant enzymes, anti-inflammatory markers, and anti-apoptotic proteins impacts of TQ in STZ-induced DM rats. Founded on these outcomes, the experiment proposes that TQ is a novel natural supplement with various clinical applications, including managing DM, which in turn is recommended to play a pivotal role in preventing the progression of diabetes mellitus.


Assuntos
Apoptose , Benzoquinonas , Diabetes Mellitus Experimental , Fígado , Simulação de Acoplamento Molecular , Estresse Nitrosativo , Estresse Oxidativo , Animais , Benzoquinonas/farmacologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Ratos , Apoptose/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Masculino , Estresse Nitrosativo/efeitos dos fármacos , Fígado/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Inflamação/metabolismo , Inflamação/tratamento farmacológico , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Glicemia/metabolismo , Ratos Wistar , Estreptozocina
2.
Nat Commun ; 15(1): 4943, 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38858372

RESUMO

The development of Type I photosensitizers (PSs) is of great importance due to the inherent hypoxic intolerance of photodynamic therapy (PDT) in the hypoxic microenvironment. Compared to Type II PSs, Type I PSs are less reported due to the absence of a general molecular design strategy. Herein, we report that the combination of typical Type II PS and natural substrate carvacrol (CA) can significantly facilitate the Type I pathway to efficiently generate superoxide radical (O2-•). Detailed mechanism study suggests that CA is activated into thymoquinone (TQ) by local singlet oxygen generated from the PS upon light irradiation. With TQ as an efficient electron transfer mediator, it promotes the conversion of O2 to O2-• by PS via electron transfer-based Type I pathway. Notably, three classical Type II PSs are employed to demonstrate the universality of the proposed approach. The Type I PDT against S. aureus has been demonstrated under hypoxic conditions in vitro. Furthermore, this coupled photodynamic agent exhibits significant bactericidal activity with an antibacterial rate of 99.6% for the bacterial-infection female mice in the in vivo experiments. Here, we show a simple, effective, and universal method to endow traditional Type II PSs with hypoxic tolerance.


Assuntos
Benzoquinonas , Fotoquimioterapia , Fármacos Fotossensibilizantes , Staphylococcus aureus , Benzoquinonas/química , Benzoquinonas/farmacologia , Benzoquinonas/metabolismo , Fármacos Fotossensibilizantes/farmacologia , Animais , Camundongos , Feminino , Fotoquimioterapia/métodos , Transporte de Elétrons/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Cimenos/farmacologia , Cimenos/química , Antibacterianos/farmacologia , Oxigênio Singlete/metabolismo , Superóxidos/metabolismo , Infecções Estafilocócicas/tratamento farmacológico , Humanos , Luz , Camundongos Endogâmicos BALB C
3.
Anal Chim Acta ; 1312: 342755, 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38834267

RESUMO

BACKGROUND: Identifying drug-binding targets and their corresponding sites is crucial for drug discovery and mechanism studies. Limited proteolysis-coupled mass spectrometry (LiP-MS) is a sophisticated method used for the detection of compound and protein interactions. However, in some cases, LiP-MS cannot identify the target proteins due to the small structure changes or the lack of enrichment of low-abundant protein. To overcome this drawback, we developed a thermostability-assisted limited proteolysis-coupled mass spectrometry (TALiP-MS) approach for efficient drug target discovery. RESULTS: We proved that the novel strategy, TALiP-MS, could efficiently identify target proteins of various ligands, including cyclosporin A (a calcineurin inhibitor), geldanamycin (an HSP90 inhibitor), and staurosporine (a kinase inhibitor), with accurately recognizing drug-binding domains. The TALiP protocol increased the number of target peptides detected in LiP-MS experiments by 2- to 8-fold. Meanwhile, the TALiP-MS approach can not only identify both ligand-binding stability and destabilization proteins but also shows high complementarity with the thermal proteome profiling (TPP) and machine learning-based limited proteolysis (LiP-Quant) methods. The developed TALiP-MS approach was applied to identify the target proteins of celastrol (CEL), a natural product known for its strong antioxidant and anti-cancer angiogenesis effect. Among them, four proteins, MTHFD1, UBA1, ACLY, and SND1 were further validated for their strong affinity to CEL by using cellular thermal shift assay. Additionally, the destabilized proteins induced by CEL such as TAGLN2 and CFL1 were also validated. SIGNIFICANCE: Collectively, these findings underscore the efficacy of the TALiP-MS method for identifying drug targets, elucidating binding sites, and even detecting drug-induced conformational changes in target proteins in complex proteomes.


Assuntos
Proteólise , Humanos , Espectrometria de Massas/métodos , Lactamas Macrocíclicas/farmacologia , Lactamas Macrocíclicas/química , Benzoquinonas/química , Benzoquinonas/farmacologia , Temperatura , Triterpenos Pentacíclicos/química , Ciclosporina/farmacologia , Ciclosporina/química , Ciclosporina/metabolismo , Estaurosporina/farmacologia , Estaurosporina/metabolismo , Ligantes , Descoberta de Drogas , Sítios de Ligação
4.
J Enzyme Inhib Med Chem ; 39(1): 2339901, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38864175

RESUMO

The spices and aromatic herbs were used not only in cooking to add flavour and smell to dishes but also for medicinal use. Nigella sativa, also called black cumin, is one of the species that contains an important bioactive component, thymoquinone (TQ), which has antioxidant, anti-inflammatory, antimicrobial, and antidiabetic effects. Curcuma longa, which also includes curcumin, has numerous anti-cancer properties. However, the bioavailability of curcumin is lower than that of its analogs. An analog of curcumin (EF-24), which has better bioavailability than curcumin, is capable of exerting a high anti-cancer effect. In our study, we determined the effects of PON1 enzyme activity on the proliferation and aggressiveness of glioblastoma cancer treated with TQ and EF-24 from lysates of the glioblastoma cell line U87MG. The results were determined as increased PON1 activity after treatment with TQ and EF-24 in the U87MG cell line (p < 0.0001).


Assuntos
Arildialquilfosfatase , Benzoquinonas , Proliferação de Células , Curcumina , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Glioblastoma , Humanos , Arildialquilfosfatase/metabolismo , Arildialquilfosfatase/antagonistas & inibidores , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Benzoquinonas/farmacologia , Benzoquinonas/química , Curcumina/farmacologia , Curcumina/química , Curcumina/síntese química , Proliferação de Células/efeitos dos fármacos , Estrutura Molecular , Relação Estrutura-Atividade , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Células Tumorais Cultivadas
5.
Toxicon ; 244: 107754, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38761922

RESUMO

Thymoquinone (TQ) is one of the main phytochemical bioactive ingredients in Nigella sativa, with reported immunity-boosting properties. The current study evaluated the anti-inflammatory effect of TQ against inflammation brought on by free fatty acid Palmitate (PA) using macrophages raw 264.7 cell line. Data revealed that TQ significantly improved the viability of basal and PA stimulated Macrophages at concentrations of 50 and 100 µg/mL. Also, TQ significantly reduced nitric oxide and triglyceride levels in PA-stimulated macrophages at concentrations of 50 and 100 µg/mL. The pro-inflammatory cytokines studies revealed that PA significantly increased the release of the cytokines TNF-α, MHGB-1, IL-1ß, and IL-6. TQ at concentrations 25, 50, and 100 µg/ml significantly decreases the release of the studied cytokines in PA-stimulated macrophages to variable extents with parallel inhibition to their corresponding gene expression. Bioenergetic assays showed that PA significantly decreased cellular ATP, mitochondrial complexes I and III activities and mitochondrial membrane potential with a subsequent significant increase in lactate production. At the same time, TQ can alleviate the effect of PA on macrophages' bioenergetics parameters to variable extent based on TQ concentration. To conclude, TQ could mitigate palmitate-induced inflammation and cytotoxicity in macrophages by improving macrophage viability and controlling cytokine release with improved PA-induced bioenergetics disruption.


Assuntos
Benzoquinonas , Inflamação , Macrófagos , Nigella sativa , Palmitatos , Benzoquinonas/farmacologia , Animais , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Nigella sativa/química , Células RAW 264.7 , Palmitatos/toxicidade , Palmitatos/farmacologia , Inflamação/tratamento farmacológico , Citocinas/metabolismo , Metabolismo Energético/efeitos dos fármacos , Anti-Inflamatórios/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Óxido Nítrico/metabolismo
6.
Am J Chin Med ; 52(3): 775-797, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38715182

RESUMO

Kidney disease is a common health problem worldwide. Acute or chronic injuries may interfere with kidney functions, eventually resulting in irreversible kidney damage. A number of recent studies have shown that the plant-derived natural products have an extensive potential for renal protection. Thymoquinone (TQ) is an essential compound derived from Nigella Sativa (NS), which is widely applied in the Middle East as a folk medicine. Previous experiments have demonstrated that TQ has a variety of potential pharmacological effects, including anti-oxidant, antibacterial, antitumor, immunomodulatory, and neuroprotective activities. In particular, the prominent renal protective efficacy of TQ has been demonstrated in both in vivo and in vitro experiments. TQ can prevent acute kidney injuries from various xenobiotics through anti-oxidation, anti-inflammatory, and anti-apoptosis effects. In addition, TQ exhibited significant pharmacological effects on renal cell carcinoma, renal fibrosis, and urinary calculi. The essential mechanisms involve scavenging ROS and increasing anti-oxidant activity, decreasing inflammatory mediators, inducing apoptosis, and inhibiting migration and invasion. The purpose of this review is to conclude the pharmacological effects and the potential mechanisms of TQ in renal protection, shedding new light on the exploration of medicinal phyto-protective agents targeting kidneys.


Assuntos
Antioxidantes , Apoptose , Benzoquinonas , Nigella sativa , Fitoterapia , Benzoquinonas/farmacologia , Humanos , Nigella sativa/química , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Animais , Nefropatias/prevenção & controle , Nefropatias/tratamento farmacológico , Rim/efeitos dos fármacos , Anti-Inflamatórios , Injúria Renal Aguda/prevenção & controle , Injúria Renal Aguda/tratamento farmacológico , Carcinoma de Células Renais/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Substâncias Protetoras/farmacologia
7.
Eur J Med Chem ; 272: 116479, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38733886

RESUMO

Through a comprehensive molecular docking study, a unique series of naphthoquinones clubbed azetidinone scaffolds was arrived with promising binding affinity to Mycobacterial Cytbc1 complex, a drug target chosen to kill multi-drug resistant Mycobacterium tuberculosis (MDR-Mtb). Five compounds from series-2, 2a, 2c, 2g, 2h, and 2j, showcased significant in vitro anti-tubercular activities against Mtb H37Rv and MDR clinical isolates. Further, synergistic studies of these compounds in combination with INH and RIF revealed a potent bactericidal effect of compound 2a at concentration of 0.39 µg/mL, and remaining (2c, 2g, 2h, and 2j) at 0.78 µg/mL. Exploration into the mechanism study through chemo-stress assay and proteome profiling uncovered the down-regulation of key proteins of electron-transport chain and Cytbc1 inhibition pathway. Metabolomics corroborated these proteome findings, and heightened further understanding of the underlying mechanism. Notably, in vitro and in vivo animal toxicity studies demonstrated minimal toxicity, thus underscoring the potential of these compounds as promising anti-TB agents in combination with RIF and INH. These active compounds adhered to Lipinski's Rule of Five, indicating the suitability of these compounds for drug development. Particular significance of molecules NQ02, 2a, and 2h, which have been patented (Published 202141033473).


Assuntos
Antituberculosos , Complexo III da Cadeia de Transporte de Elétrons , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis , Tuberculose Resistente a Múltiplos Medicamentos , Mycobacterium tuberculosis/efeitos dos fármacos , Antituberculosos/farmacologia , Antituberculosos/química , Antituberculosos/síntese química , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Complexo III da Cadeia de Transporte de Elétrons/antagonistas & inibidores , Complexo III da Cadeia de Transporte de Elétrons/metabolismo , Relação Estrutura-Atividade , Estrutura Molecular , Simulação de Acoplamento Molecular , Benzoquinonas/química , Benzoquinonas/farmacologia , Animais , Humanos , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Sinergismo Farmacológico
8.
Environ Sci Technol ; 58(21): 9113-9124, 2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38743028

RESUMO

The antioxidant N-(1,3-Dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD) and its oxidized quinone product 6PPD-quinone (6PPD-Q) in rubber have attracted attention due to the ecological risk that they pose. Both 6PPD and 6PPD-Q have been detected in various environments that humans cohabit. However, to date, a clear understanding of the biotransformation of 6PPD-Q and a potential biomarker for exposure in humans are lacking. To address this issue, this study presents a comprehensive analysis of the extensive biotransformation of 6PPD-Q across species, encompassing both in vitro and in vivo models. We have tentatively identified 17 biotransformation metabolites in vitro, 15 in mice in vivo, and confirmed the presence of two metabolites in human urine samples. Interestingly, different biotransformation patterns were observed across species. Through semiquantitative analysis based on peak areas, we found that almost all 6PPD-Q underwent biotransformation within 24 h of exposure in mice, primarily via hydroxylation and subsequent glucuronidation. This suggests a rapid metabolic processing of 6PPD-Q in mammals, underscoring the importance of identifying effective biomarkers for exposure. Notably, monohydroxy 6PPD-Q and 6PPD-Q-O-glucuronide were consistently the most predominant metabolites across our studies, highlighting monohydroxy 6PPD-Q as a potential key biomarker for epidemiological research. These findings represent the first comprehensive data set on 6PPD-Q biotransformation in mammalian systems, offering insights into the metabolic pathways involved and possible exposure biomarkers.


Assuntos
Benzoquinonas , Biomarcadores , Biotransformação , Exposição Ambiental , Poluentes Ambientais , Fenilenodiaminas , Animais , Camundongos , Exposição Ambiental/análise , Fenilenodiaminas/sangue , Fenilenodiaminas/metabolismo , Fenilenodiaminas/urina , Benzoquinonas/sangue , Benzoquinonas/metabolismo , Benzoquinonas/urina , Hidroxilação , Biomarcadores/metabolismo , Biomarcadores/urina , Borracha/química , Masculino , Adulto Jovem , Adulto , Ratos , Microssomos Hepáticos/metabolismo , Feminino , Poluentes Ambientais/sangue , Poluentes Ambientais/metabolismo , Poluentes Ambientais/urina
9.
Int Immunopharmacol ; 135: 112249, 2024 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-38772297

RESUMO

Interleukin-35 (IL-35) is a novel anti-inflammatory component, and its role in protecting against acute kidney disease (AKD) has not been explored. Thymoquinone (TQ) has been widely used for many therapeutic targets. Inflammation/oxidative signaling plays essential roles in the pathogenesis of diverse disorders, such as AKD, cancer, cardiac disease, aging, and metabolic and neurodegenerative disorders. The objective of the investigation was to evaluate how IL-35 prevents inflammation and oxidative stress indicators in the kidneys of rats caused by lipopolysaccharide (LPS). The experimental rats were allocated into six groups: control (0.5 mL saline); TQ (0.5 mg/kg, b.w. IP), IL-35 (100 µg of IL-35 /kg, b.w. IP), LPS (500 µg/kg b.w. IP), LPS + IL-35, and LPS + TQ. Results indicate that the hematological and blood biochemical parameters were substantially restored by TQ or IL-35 therapy. The elevation of kidney function (uric acid, creatinine, and cystatin C) and oxidative related biomarkers (MDA, PC, and MYO) in rat kidneys was significantly restored by the TQ and IL-35 therapies after LPS administration (P < 0.05). Serum immunological variables IgM and IgG were significantly restored by TQ and IL-35 in LPS-treated rats. Both IL-35 and TQ markedly mitigated the decrease antioxidant related biomarkers (SOD, GSH, CAT and TAC) triggered by LPS. The IL-35 and TQ treatments significantly diminished serum levels of inflammatory responses such as TNF-α, NF-κB, IL-6 and IFN-γ, and significantly increased IL-10 in LPS-treated rats. Additionally, serum levels of MCP, Caspase-3, andBcl-2 were significantly diminished by TQ or IL-35 therapy. The histopathology and immunohistochemistry for NF-kB, PCNA and TNF-α cytokines revealedremodeling when treated with TQ and IL-35. In summary, administration of IL-35 or TQ can attenuateLPS-induced renal damage by extenuatingoxidative stress, tissue impairment, apoptosis, and inflammation, implicating IL-35 as a promising therapeutic agent in acute-related renal injury.


Assuntos
Injúria Renal Aguda , Anti-Inflamatórios , Benzoquinonas , Interleucinas , Rim , Lipopolissacarídeos , Nanopartículas , Estresse Oxidativo , Animais , Benzoquinonas/farmacologia , Benzoquinonas/uso terapêutico , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/patologia , Injúria Renal Aguda/imunologia , Ratos , Masculino , Interleucinas/metabolismo , Interleucinas/sangue , Rim/efeitos dos fármacos , Rim/patologia , Rim/metabolismo , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Citocinas/metabolismo , Citocinas/sangue
10.
Biomed Pharmacother ; 175: 116692, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38701569

RESUMO

CCl4 toxicity is a fatal condition that can cause numerous organ dysfunctions. We evaluated and compared the protective effects of cuminaldehyde (CuA), thymoquinone (TQ), and gallic acid (GA) on CCl4-induced pulmonary and renal toxicity in rats. The impacts of these compounds on CCl4-induced oxidative stress, inflammation, and morphological alterations were examined. The results showed that the compounds under investigation prevented CCl4 from significantly increasing pulmonary and renal lipid peroxidation and NO levels, as well as massively depleting GSH levels and GPX and SOD activities. Moreover, they suppressed the CCl4-induced increase in mucus secretion in the lung and upregulated the gene expression of pulmonary and renal NF-Ò¡B, iNOS, TNF-α, and COX-2. The heatmap cluster plots showed that GA and TQ had better protective potencies than CuA. The external organ morphology, histopathological results, and chest X-ray analysis confirmed the toxicity of CCl4 and the protective influences of the tested compounds in both the lungs and kidneys of rats. These compounds displayed predicted competitive inhibitory effects on iNOS activity and may block the IL-13α2 receptor, as revealed by molecular docking analysis. Thus, CuA, TQ, and GA, particularly the latter two, are prospective protective compounds against the pulmonary and renal toxicity caused by CCl4.


Assuntos
Benzaldeídos , Benzoquinonas , Tetracloreto de Carbono , Ácido Gálico , Rim , Pulmão , NF-kappa B , Estresse Oxidativo , Espécies Reativas de Oxigênio , Transdução de Sinais , Animais , Ácido Gálico/farmacologia , Benzoquinonas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Masculino , NF-kappa B/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Ratos , Tetracloreto de Carbono/toxicidade , Rim/efeitos dos fármacos , Rim/patologia , Rim/metabolismo , Benzaldeídos/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Simulação de Acoplamento Molecular , Cimenos/farmacologia , Substâncias Protetoras/farmacologia , Antioxidantes/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Ratos Wistar , Ratos Sprague-Dawley
11.
J Agric Food Chem ; 72(23): 13164-13174, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38819965

RESUMO

Obtaining a microorganism strain with a broad-spectrum resistance property and highly efficient antifungal activity is important to the biocontrol strategy. Herein, a marine Streptomyces sp. HNBCa1 demonstrated a broad-spectrum resistance to 17 tested crop pathogenic fungi and exhibited a high biocontrol efficiency against mango anthracnose and banana fusarium wilt. To uncover the critical bioactive secondary metabolites basis, genome assembly and annotation, metabolomic analysis, and a semipreparative HPLC-based activity-guide method were employed. Finally, geldanamycin and ectoine involved in codifferential secondary metabolites were also found to be related to biosynthetic gene clusters in the genome of HNBCa1. Reblastatin and geldanamycin were uncovered in response to broad-spectrum resistance to the 17 crop pathogenic fungi. Our results suggested that reblastatin and geldanamycin were critical to maintaining the broad-spectrum resistance property and highly efficient antifungal activity of HNBCa1, which could be further developed as a biological control agent to control crop fungal diseases.


Assuntos
Fusarium , Lactamas Macrocíclicas , Doenças das Plantas , Metabolismo Secundário , Streptomyces , Streptomyces/genética , Streptomyces/metabolismo , Streptomyces/química , Doenças das Plantas/microbiologia , Lactamas Macrocíclicas/farmacologia , Lactamas Macrocíclicas/metabolismo , Lactamas Macrocíclicas/química , Fusarium/efeitos dos fármacos , Benzoquinonas/farmacologia , Benzoquinonas/metabolismo , Benzoquinonas/química , Fungos/genética , Antifúngicos/farmacologia , Antifúngicos/metabolismo , Antifúngicos/química
12.
J Pharm Biomed Anal ; 246: 116223, 2024 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-38763108

RESUMO

The utilization of Hydroquinone (HQ) in over-the-counter skincare items is subject to restrictions. Consequently, Arbutin (AR) serves as a reliable alternative for addressing hyperpigmentation in non-prescription topical formulations. Nevertheless, AR undergoes decomposition into HQ and p-Benzoquinone (BZ) when exposed to temperature stress, ultraviolet light, or dilution in an acidic environment, all of which can induce skin toxicity. The intention of this paper is to investigate the effect of extraction procedure on the conversion of AR to HQ and or BZ and to evaluate kinetics of AR hydrolysis to HQ. Meanwhile this study aims to evaluate AR and BZ interference with the United States Pharmacopoeia (USP) identification and assessment method for HQ Hydrolytic stress during extraction conditions underwent optimization through systematic screening tests. Subsequent assessment of the residual drug and its degradation products were achieved by HPLC method. The resulting data were meticulously fitted to various kinetic models. To analyze the potential interference of AR in HQ measurement using USP method, the standard concentrations of AR and HQ were analyzed through UV-VIS spectrophotometry. For enhanced certainty, a validated HPLC method analysis was also conducted. Notably, the acid hydrolysis of AR exhibited independence from its initial concentration. So, the hydrolytic degradation of AR exhibited a Zero-order kinetic profile. Furthermore, the proven interference of AR in the UV-VIS spectrophotometry method was identified within the context of the USP method. This study successfully utilized an adopted HPLC method for the concurrent quantification of AR, HQ, and BZ. The potential interference of AR in the UV-VIS spectrophotometric assay for HQ may lead to false results especially for regulatory purposes.


Assuntos
Arbutina , Benzoquinonas , Hidroquinonas , Hiperpigmentação , Arbutina/análise , Arbutina/química , Hidroquinonas/análise , Hidroquinonas/química , Benzoquinonas/química , Benzoquinonas/análise , Cromatografia Líquida de Alta Pressão/métodos , Hidrólise , Preparações Clareadoras de Pele/química , Preparações Clareadoras de Pele/análise , Cinética , Administração Tópica , Espectrofotometria Ultravioleta/métodos
13.
Life Sci ; 348: 122699, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38718854

RESUMO

AIMS: Azoles have been widely employed for the treatment of invasive fungal diseases; however, their efficacy is diminished as pathogenic fungi tolerate them due to their fungistatic properties. Geldanamycin (GdA) can render azoles fungicidal by inhibiting the ATPase and molecular chaperone activities of heat shock protein 90 (Hsp90). Nonetheless, the clinical applicability of GdA is restricted due to its cytotoxic ansamycin scaffold structure, its induction of cytoprotective heat shock responses, and the conservative nature of Hsp90. Hence, it is imperative to elucidate the mechanism of action of GdA to confer fungicidal properties to azoles and mitigate the toxic adverse effects associated with GdA. MATERIALS AND METHODS: Through various experimental methods, including the construction of gene-deleted Candida albicans mutants, in vitro drug sensitivity experiments, Western blot analysis, reactive oxygen species (ROS) assays, and succinate dehydrogenase activity assays, we identified Hsp90 client proteins associated with the tolerance of C. albicans to azoles. KEY FINDINGS: It was observed that GdA effectively hindered the entry of Hsp90 into mitochondria, resulting in the alleviation of inhibitory effect of Hsp90 on succinate dehydrogenase. Consequently, the activation of succinate dehydrogenase led to an increased production of ROS. within the mitochondria, thereby facilitating the antifungal effects of azoles against C. albicans. SIGNIFICANCE: This research presents a novel approach for conferring fungicidal properties to azoles, which involves specifically disrupting the interaction of between Hsp90 and succinate dehydrogenase rather than employing a non-specific inhibition of ATPase activity of Hsp90.


Assuntos
Antifúngicos , Azóis , Benzoquinonas , Candida albicans , Proteínas de Choque Térmico HSP90 , Lactamas Macrocíclicas , Espécies Reativas de Oxigênio , Succinato Desidrogenase , Benzoquinonas/farmacologia , Lactamas Macrocíclicas/farmacologia , Candida albicans/efeitos dos fármacos , Antifúngicos/farmacologia , Proteínas de Choque Térmico HSP90/metabolismo , Succinato Desidrogenase/metabolismo , Succinato Desidrogenase/antagonistas & inibidores , Azóis/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Testes de Sensibilidade Microbiana , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/genética , Farmacorresistência Fúngica/efeitos dos fármacos
14.
Eur J Pharm Biopharm ; 200: 114312, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38735345

RESUMO

BACKGROUND: Nanomedicine, as the combination of radiopharmaceutical and nanocarrier (QDs), is developed for treating cancer. Gallic acid is antimutagenic, anti-inflammatory, and anti-carcinogenic. Typical retention time of gallic acid is approximately 4 to 8 h. To increase the retention time gallic acid is converted to prodrug by adding lipophilic moieties, encapsulating in lipophilic nanoparticles, or liposome formation. Similarly, thymoquinone is powerful antioxidant, anti-apoptotic, and anti-inflammatory effect, with reduced DNA damage. METHODS: In this study, a hydrophilic drug (gallic acid) is chemically linked to the hydrophobic drug (thymohydroquinone) to overcome the limitations of co-delivery of drugs. Thymohydroquinone (THQG) as the combination of gallic acid (GA) and thymoquinone (THQ) is loaded onto the PEI functionalized antimonene quantum dots (AM-QDs) and characterized by FTIR, UV-visible spectroscopy, X-ray powder diffraction, Zeta sizer, SEM and AFM, in-vitro and in-vivo assay, and hemolysis. RESULTS: The calculated drug loading efficiency is 90 %. Drug release study suggests the drug combination is pH sensitive and it can encounters acidic pH, releasing the drug from the nanocarrier. The drug and drug-loaded nanocarrier possesses low cytotoxicity and cell viability on MCF-7 and Cal-27 cell lines. The proposed drug delivery system is radiolabeled with Iodine-131 (131I) and Technetium (99mTc) and its deposition in various organs of rats' bodies is examined by SPECT-CT and gamma camera. Hemolytic activity of 2, 4, 6, and 8 µg/mL is 1.78, 4.16, 9.77, and 15.79 %, respectively, reflecting low levels of hemolysis. The system also sustains oxidative stress in cells and environment, decreasing ROS production to shield cells and keep them healthy. CONCLUSIONS: The results of this study suggest that the proposed drug carrier system can be used as a multi-modal theragnostic agent in cancer treatment.


Assuntos
Ácido Gálico , Pontos Quânticos , Animais , Ratos , Ácido Gálico/química , Ácido Gálico/farmacologia , Pontos Quânticos/química , Humanos , Concentração de Íons de Hidrogênio , Benzoquinonas/química , Benzoquinonas/administração & dosagem , Benzoquinonas/farmacologia , Neoplasias/tratamento farmacológico , Antineoplásicos/farmacologia , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Nanomedicina Teranóstica/métodos , Linhagem Celular Tumoral , Masculino , Células MCF-7 , Nanopartículas/química , Sobrevivência Celular/efeitos dos fármacos
15.
Chem Res Toxicol ; 37(6): 1035-1043, 2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38771972

RESUMO

Chlorobenzoquinones (CBQs) are a class of emerging water disinfection byproducts that pose significant risks to public health. In this study, we found that three CBQs (tetrachloro-1,4-benzoquinone, 2,5-dichloro-1,4-benzoquinone, and 2-chloro-1,4-benzoquinone) can significantly aggravate cell death caused by Ras-selective lethal small molecule 3 (RSL3). Further study showed that the cell death caused by CBQs, either alone or in combination with RSL3, was related to iron accumulation and GPX4 inactivation, suggesting the occurrence of ferroptosis. Furthermore, reactive oxygen species are found to play a potential key role in mediating the toxicity of CBQs in CBQs and RSL3-induced ferroptosis. These findings will be helpful in understanding the toxic mechanism of CBQs to mammalian cells.


Assuntos
Benzoquinonas , Ferroptose , Espécies Reativas de Oxigênio , Ferroptose/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Benzoquinonas/química , Benzoquinonas/farmacologia , Humanos , Estrutura Molecular , Hidrocarbonetos Clorados/química , Hidrocarbonetos Clorados/farmacologia , Hidrocarbonetos Clorados/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Carbolinas
16.
Anticancer Res ; 44(6): 2555-2565, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38821604

RESUMO

BACKGROUND/AIM: Breast cancer is the most prevalent form of cancer among women worldwide, with a high mortality rate. While the most common cause of breast cancer death is metastasis, there is currently no potential treatment for patients at the metastatic stage. The present study investigated the potential of using a combination of HSP90 and mTOR inhibitor in the treatment of breast cancer cell growth, migration, and invasion. MATERIALS AND METHODS: Gene Expression Profiling Interactive Analysis (GEPIA) was used to investigate the gene expression profiles. Western blot analysis and fluorescence staining were used for protein expression and localization, respectively. MTT, wound healing, and transwell invasion assays were used for cell proliferation, migration, and invasion, respectively. RESULTS: GEPIA demonstrated that HSP90 expression was significantly higher in breast invasive carcinoma compared to other tumor types, and this expression correlated with mTOR levels. Treatment with 17-AAG, an HSP90 inhibitor, and Torkinib, an mTORC1/2 inhibitor, significantly inhibited cell proliferation. Moreover, combination treatment led to down-regulation of AKT. Morphological changes revealed a reduction in F-actin intensity, a marked reduction of YAP, with interference in nuclear localization. CONCLUSION: Targeting HSP90 and mTOR has the potential to suppress breast cancer cell growth and progression by disrupting AKT signaling and inhibiting F-actin polymerization. This combination treatment may hold promise as a therapeutic strategy for breast cancer treatment that ameliorates adverse effects of a single treatment.


Assuntos
Actinas , Neoplasias da Mama , Movimento Celular , Proliferação de Células , Proteínas de Choque Térmico HSP90 , Proteínas Proto-Oncogênicas c-akt , Serina-Treonina Quinases TOR , Humanos , Proteínas de Choque Térmico HSP90/metabolismo , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Feminino , Serina-Treonina Quinases TOR/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proliferação de Células/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Actinas/metabolismo , Actinas/genética , Linhagem Celular Tumoral , Invasividade Neoplásica , Transdução de Sinais/efeitos dos fármacos , Lactamas Macrocíclicas/farmacologia , Benzoquinonas/farmacologia , Inibidores de MTOR/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
17.
Environ Res ; 252(Pt 3): 119043, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38692422

RESUMO

It is of great significance to establish an effective method for removing Cr(VI) from wastewater. Herein, Fe-doped g-C3N4 (namely Fe-g-C3N4-2) was synthesized and then employed as photocatalyst to conduct the test of Cr(VI) reduction. Notably, the embedding of Fe ion in g-C3N4 can offer the Fe2+/Fe3+ redox couples, so reducing the interfacial resistance of charge transfer and suppressing the recombination of photogenerated electrons and holes. The impurity energy levels will form in g-C3N4 after the introduction of Fe ion, thereby boosting the light absorption capacity of catalyst. Thus, Fe-g-C3N4-2 showed good performance in photocatalytic Cr(VI) reduction, and the reduction efficiency of Cr(VI) can reach 39.9% within 40 min. Different with many previous studies, current work unexpectedly found that the addition of p-benzoquinone (BQ) can promote the Cr(VI) reduction, and the reduction efficiency of Cr(VI) over Fe-g-C3N4-2 was as high as 93.2% in the presence of BQ (1.5 mM). Further analyses showed that BQ can be reduced to hydroquinone (HQ) by photogenerated electrons, and UV light can also directly induce BQ to generate HQ by using H2O as the hydrogen donor. The HQ with reducing ability can accelerate the Cr(VI) reduction. In short, current work shared some novel insights into photocatalytic Cr(VI) reduction in the presence of BQ. Future research should consider possible reactions between photogenerated electrons and BQ. For the UV-induced photocatalysis, the suitability of BQ as the scavenger of O2•‒ must be given carefully consideration.


Assuntos
Benzoquinonas , Cromo , Ferro , Oxirredução , Benzoquinonas/química , Cromo/química , Catálise , Ferro/química , Poluentes Químicos da Água/química , Poluentes Químicos da Água/efeitos da radiação , Processos Fotoquímicos , Compostos de Nitrogênio/química , Compostos de Nitrogênio/efeitos da radiação , Grafite
18.
J Pharmacol Toxicol Methods ; 127: 107519, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38797368

RESUMO

Thymoquinone (TH) has been one of the major phytochemical used in the treatment of cancers since long time, especially in the management of glioblastoma multiforme (GBM). The formulation of lipo-polymeric nanoshells (LPNs) and their nasal delivery are fascinating approaches for overcoming the drawbacks of low solubility and poor bioavailability of TH. Hence targeting LPNs to the brain requires a validated bioanalytical method for the assessment of TH concentration in Cerebrospinal fluid (CSF) and brain tissue homogenates (BTH). Therefore, the current work focuses on the development and validation of high-performance liquid chromatography (HPLC) method in CSF by employing nasal simulated fluid (NSF) as one of the major components of the mobile phase. The developed method was checked for linearity in the range of 0.05 to 1.6 µg/mL, having an r2 value of 0.999 with mean % recovery >95% and % RSD values below <2.0%. The developed method gave a clear separation of TH at 6.021 ± 0.17 min with an internal standard at 4.102 ± 0.09 min and a CSF spike at 2.170 ± 0.12 min. The developed method assisted in determining the in-vitro and in-vivo drug release study of LPNs, pharmacokinetic profiling, qualitative in-vivo brain uptake study, in-vitro cellular uptake, and generating stability data of formulated LPNs proposed for intranasal administration in rats.


Assuntos
Administração Intranasal , Benzoquinonas , Encéfalo , Nanoconchas , Animais , Benzoquinonas/farmacocinética , Benzoquinonas/administração & dosagem , Benzoquinonas/líquido cefalorraquidiano , Benzoquinonas/química , Ratos , Cromatografia Líquida de Alta Pressão/métodos , Encéfalo/metabolismo , Masculino , Nanoconchas/química , Ratos Wistar , Disponibilidade Biológica
19.
Enzyme Microb Technol ; 178: 110455, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38723387

RESUMO

Thymoquinone, extracted from the black seeds of Nigella sativa, is a natural substance with highly beneficial effects against various human diseases. In this study, we aimed to construct a Saccharomyces cerevisiae strain that, produce thymoquinone from thymol, a relatively inexpensive substrate. To achieve this, cytochrome P450 from Origanum vulgare was expressed in S. cerevisiae for the bioconversion of thymol to thymoquinone, with the co-expression of cytochrome P450 reductase (CPR) from Arabidopsis thaliana, ATR1. Additionally, flexible linkers were used to connect these two enzymes. Furthermore, modifications were performed to expand the endoplasmic reticulum (ER) space, leading to increased thymoquinone production. After integrating the genes into the chromosome and optimizing the media components, a significant improvement in the thymol-to-thymoquinone conversion rate and yield were achieved. This study represents a possibility of the production of thymoquinone, a bioactive ingredient of a plant, using an engineered microbial cell.


Assuntos
Benzoquinonas , Engenharia Metabólica , Saccharomyces cerevisiae , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/enzimologia , Benzoquinonas/metabolismo , Timol/metabolismo , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo
20.
Sci Rep ; 14(1): 11103, 2024 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-38750093

RESUMO

Safe and effective pain management is a critical healthcare and societal need. The potential for acute liver injury from paracetamol (ApAP) overdose; nephrotoxicity and gastrointestinal damage from chronic non-steroidal anti-inflammatory drug (NSAID) use; and opioids' addiction are unresolved challenges. We developed SRP-001, a non-opioid and non-hepatotoxic small molecule that, unlike ApAP, does not produce the hepatotoxic metabolite N-acetyl-p-benzoquinone-imine (NAPQI) and preserves hepatic tight junction integrity at high doses. CD-1 mice exposed to SRP-001 showed no mortality, unlike a 70% mortality observed with increasing equimolar doses of ApAP within 72 h. SRP-001 and ApAP have comparable antinociceptive effects, including the complete Freund's adjuvant-induced inflammatory von Frey model. Both induce analgesia via N-arachidonoylphenolamine (AM404) formation in the midbrain periaqueductal grey (PAG) nociception region, with SRP-001 generating higher amounts of AM404 than ApAP. Single-cell transcriptomics of PAG uncovered that SRP-001 and ApAP also share modulation of pain-related gene expression and cell signaling pathways/networks, including endocannabinoid signaling, genes pertaining to mechanical nociception, and fatty acid amide hydrolase (FAAH). Both regulate the expression of key genes encoding FAAH, 2-arachidonoylglycerol (2-AG), cannabinoid receptor 1 (CNR1), CNR2, transient receptor potential vanilloid type 4 (TRPV4), and voltage-gated Ca2+ channel. Phase 1 trial (NCT05484414) (02/08/2022) demonstrates SRP-001's safety, tolerability, and favorable pharmacokinetics, including a half-life from 4.9 to 9.8 h. Given its non-hepatotoxicity and clinically validated analgesic mechanisms, SRP-001 offers a promising alternative to ApAP, NSAIDs, and opioids for safer pain treatment.


Assuntos
Acetaminofen , Analgésicos , Ácidos Araquidônicos , Substância Cinzenta Periaquedutal , Transcriptoma , Animais , Masculino , Camundongos , Acetaminofen/efeitos adversos , Amidoidrolases/metabolismo , Amidoidrolases/genética , Analgésicos/farmacologia , Ácidos Araquidônicos/farmacologia , Benzoquinonas/farmacologia , Glicerídeos , Substância Cinzenta Periaquedutal/metabolismo , Substância Cinzenta Periaquedutal/efeitos dos fármacos
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