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1.
Arch Dermatol Res ; 316(9): 668, 2024 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-39382722

RESUMO

There are significant psychosocial burdens in patients with hyperpigmentation, which emphasizes the importance of treatment. Current gold standard for treatment is hydroquinone; however, alternatives have been developed given the concern for side effects of hydroquinone. Melanogenesis is responsible for the production of eumelanin and pheomelanin; there are many factors that will determine whether eumelanin or pheomelanin will be produced. Eumelanin is known for its photoprotective qualities, while pheomelanin is implicated in photocarcinogenesis and photoaging. Multiple treatment modalities for hyperpigmentation that shift eumelanin to pheomelanin synthesis exist. Cysteamine, glutathione, kojic acid, and methyl sulfonyl methane are four agents used to treat hyperpigmentation by shifting the production of eumelanin to pheomelanin. It is critical to discuss photoprotection with patients to help reduce the potential impact of increased pheomelanin production and to expand research in this area.


Assuntos
Hiperpigmentação , Melaninas , Pironas , Humanos , Melaninas/biossíntese , Melaninas/metabolismo , Hiperpigmentação/tratamento farmacológico , Hiperpigmentação/metabolismo , Pironas/uso terapêutico , Glutationa/metabolismo , Hidroquinonas/administração & dosagem
2.
Fungal Biol ; 128(7): 2094-2101, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39384279

RESUMO

Fusarium verticillioides is both an endophyte and pathogen of maize. During growth on maize, the fungus often synthesizes the mycotoxins fumonisins, which have been linked to a variety of diseases, including cancer in some animals. How F. verticillioides responds to other fungi, such as Fusarium proliferatum, Aspergillus flavus, Aspergillus niger, and Penicillium oxalicum, that coinfect maize, has potential to impact mycotoxin synthesis and disease. We hypothesize that low molecular weight acids produced by these fungi play a role in communication between the fungi in planta/nature. To address this hypothesis, we exposed 48-h maize kernel cultures of F. verticillioides to oxalic acid, citric acid, fusaric acid, or kojic acid and then compared transcriptomes after 30 min and 6 h. Transcription of some genes were affected by multiple chemicals and others were affected by only one chemical. The most significant positive response was observed after exposure to fusaric acid which resulted in >2-fold upregulation of 225 genes, including genes involved in fusaric acid synthesis. Exposure of cultures to the other three chemicals increased expression of only 3-15 genes. The predicted function and frequent co-localization of three sets of genes support a role in protecting the fungus from the chemical or a role in catabolism. These unique transcriptional responses support our hypothesis that these chemicals can act as signaling molecules. Studies with gene deletion mutants will further indicate if the initial transcriptional response to the chemicals benefit F. verticillioides.


Assuntos
Ácido Fusárico , Fusarium , Zea mays , Fusarium/genética , Fusarium/metabolismo , Fusarium/efeitos dos fármacos , Fusarium/crescimento & desenvolvimento , Zea mays/microbiologia , Ácido Fusárico/farmacologia , Ácido Fusárico/metabolismo , Regulação Fúngica da Expressão Gênica/efeitos dos fármacos , Pironas/farmacologia , Pironas/metabolismo , Ácido Cítrico/metabolismo , Ácido Cítrico/farmacologia , Ácido Oxálico/metabolismo , Perfilação da Expressão Gênica , Transcrição Gênica
3.
Pestic Biochem Physiol ; 204: 106072, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39277417

RESUMO

The synthetic auxin 2,4-D and the 4-hydroxyphenylpyruvate dioxygenase inhibitor pyrasulfotole are phloem-mobile post-emergence herbicides, the latter applied in co-formulation with either bromoxynil (a contact herbicide causing leaf desiccation) or MCPA (another synthetic auxin). Previous studies have shown a wide range of 2,4-D translocation phenotypes in resistant populations of the agricultural weed Raphanus raphanistrum, but it was hypothesised that enhanced movement out of the apical meristem could contribute to resistance. Little is known about pyrasulfotole translocation or the effect of bromoxynil on pyrasulfotole movement. Therefore, the behaviour of pyrasulfotole and 2,4-D applied to the growing point of susceptible and resistant R. raphanistrum seedlings was assessed, along with the effect of bromoxynil on pyrasulfotole translocation. The small amount of herbicide directly contacting the growing point after spraying was sufficient to induce herbicide symptoms, and there was no enhancement of translocation away from the growing point in either pyrasulfotole- or 2,4-D-resistant populations. Bromoxynil had a slightly inhibitory effect on pyrasulfotole translocation in some populations, somewhat negating the minor differences observed among populations when pyrasulfotole was applied alone. Resistance to pyrasulfotole could not explained by enhanced metabolism or vacuolar sequestration of the herbicide. Overall, differential translocation in either the treated leaves or apical meristems does not appear to be a major determinant of resistance to pyrasulfotole or 2,4-D.


Assuntos
Ácido 2,4-Diclorofenoxiacético , Resistência a Herbicidas , Herbicidas , Raphanus , Herbicidas/farmacologia , Ácido 2,4-Diclorofenoxiacético/farmacologia , Raphanus/efeitos dos fármacos , Raphanus/metabolismo , Plântula/efeitos dos fármacos , Plântula/metabolismo , Pironas/farmacologia , Transporte Biológico , Ácidos Indolacéticos/metabolismo , Ácidos Indolacéticos/farmacologia , Isoxazóis , Nitrilas , Sulfonas
4.
Enzymes ; 56: 261-280, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39304289

RESUMO

Tyrosinase is involved in several human diseases, among which hypopigmentation and depigmentation conditions (vitiligo, idiopathic guttate hypomelanosis, pityriasis versicolor, pityriasis alba) and hyperpigmentations (melasma, lentigines, post-inflammatory and periorbital hyperpigmentation, cervical idiopathic poikiloderma and acanthosis nigricans). There are increasing evidences that tyrosinase plays a relevant role in the formation and progression of melanoma, a difficult to treat skin tumor. Hydroquinone, azelaic acid and tretinoin (all-trans-retinoic acid) are clinically used in the management of some hyperpigmentations, whereas many novel chemotypes acting as tyrosinase inhibitors with potential antimelanoma action are being investigated. Kojic acid, hydroquinone, its glycosylated derivative arbutin, or the resorcinol derivative rucinol are used in cosmesis in creams as skin whitening agents, whereas no antimelanoma tyrosinase inhibitor reached clinical trials so far, although thiamidol is a recently approved new tyrosinase inhibitor for the treatment of melasma. Kojic acid and vitamin C are used for avoiding vegetable/food oxidative browning due to the tyrosinase-catalyzed reactions, whereas bacterial enzymes show potential in biotechnological applications, for the production of mixed melanins, for protein cross-linking reactions, for producing phenol(s) biosensors, of for the production of L-DOPA, an anti-Parkinson's disease drug.


Assuntos
Inibidores Enzimáticos , Monofenol Mono-Oxigenase , Monofenol Mono-Oxigenase/antagonistas & inibidores , Monofenol Mono-Oxigenase/metabolismo , Humanos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Animais , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Melanoma/tratamento farmacológico , Pironas
5.
Sci Rep ; 14(1): 21144, 2024 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-39256396

RESUMO

Kojic acid (KA) has gained significant attention due to its widespread use in the food and cosmetics industries. However, concerns about its potential carcinogenic effects have heightened the need for sensitive detection methods. This study introduces a fluorescence-based optical sensor for the quantification of KA in food samples, utilizing fluorescent carbon dots (CDs) synthesized from pomegranate peel via a hydrothermal method. The Stern-Volmer plot demonstrated a linear response for KA in the range of 120 to 1200 µM, with a Pearson correlation coefficient (r) of 0.9999 and. The sensor exhibited a detection limit of 30 ± 0.04 µM and a limit of quantification (LOQ) of 90 ± 0.14 µM. Application of the developed method to soy sauce and vinegar samples yielded accurate KA determinations, with recoveries of 103.11 ± 0.96% and 104.45 ± 2.15%, respectively. These findings highlight the potential of the proposed sensor for practical applications in food quality and safety assessment, offering valuable insights into the presence of KA in food products.


Assuntos
Carbono , Análise de Alimentos , Punica granatum , Pironas , Pontos Quânticos , Punica granatum/química , Pironas/análise , Pironas/química , Carbono/química , Pontos Quânticos/química , Análise de Alimentos/métodos , Limite de Detecção , Corantes Fluorescentes/química , Contaminação de Alimentos/análise , Espectrometria de Fluorescência/métodos
6.
Nutrients ; 16(18)2024 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-39339761

RESUMO

BACKGROUND: Hispidin, a polyphenol component mainly derived from the medicinal mushroom species Phellinus and Inonotus, shows promise for biomedical applications, yet its potential in wound healing remains largely unexplored. This research investigates the wound healing effects of hispidin through in vitro and in vivo experiments, while also evaluating its antimicrobial properties and safety profile. METHODS: In vitro scratch assays were conducted to evaluate the impact of hispidin on the migration of NIH-3T3 cells. The wound healing potential of hispidin was assessed in rats using excision wounds, dead space wounds, and linear incisions, treated with various topical ointments including a simple ointment, 2.5% (w/w) and a 5% (w/w) hispidin ointment, and a 0.2% (w/w) nitrofurazone ointment, administered at 0.2 g daily for 14 days. RESULTS: Hispidin demonstrated antimicrobial properties and was particularly effective against Staphylococcus epidermidis. Hispidin enhanced NIH-3T3 cell viability, and promoted wound closure in scratch assays, correlating with increased levels of FGF21, TGF-ß1, EGF, and VEGF. In excision wound models, the 5% (w/w) hispidin ointment improved wound contraction, epithelialization, tissue regeneration, fibroblast activity, and angiogenesis. In the granulation tissue from dead space wound models, hispidin reduced pro-inflammatory cytokines (TNF-α, IL-6, IL-1ß) and lipid peroxidation, while increasing anti-inflammatory cytokines (IL-10) and antioxidant activities (SOD, GPx, CAT), along with connective tissue markers like hydroxyproline, hexosamine, and hexuronic acid. Hispidin also enhanced wound breaking strength in incision models. Acute dermal toxicity studies indicated no adverse effects at 2000 mg/kg. CONCLUSIONS: These findings highlight hispidin's potential in wound care, demonstrating its antimicrobial, regenerative, and safety properties.


Assuntos
Cicatrização , Animais , Cicatrização/efeitos dos fármacos , Células NIH 3T3 , Camundongos , Ratos , Masculino , Pomadas , Pironas/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Ratos Sprague-Dawley , Staphylococcus epidermidis/efeitos dos fármacos , Pele/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Modelos Animais de Doenças , Anti-Infecciosos/farmacologia , Antibacterianos/farmacologia
7.
Molecules ; 29(17)2024 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-39275009

RESUMO

Inspired by the potent tyrosinase inhibitory activity of phenolic compounds with a 2-phenylbenzo[d]thiazole scaffold, we explored phenolic compounds 1-15 with 2-phenylbenzo[d]oxazole, which is isosterically related to 2-phenylbenzo[d]thiazole, as novel tyrosinase inhibitors. Among these, compounds 3, 8, and 13, featuring a resorcinol structure, exhibited significantly stronger mushroom tyrosinase inhibition than kojic acid, with compound 3 showing a nanomolar IC50 value of 0.51 µM. These results suggest that resorcinol plays an important role in tyrosinase inhibition. Kinetic studies using Lineweaver-Burk plots demonstrated the inhibition mechanisms of compounds 3, 8, and 13, while docking simulation results indicated that the resorcinol structure contributed to tyrosinase binding through hydrophobic and hydrogen bonding interactions. Additionally, these compounds effectively inhibited tyrosinase activity and melanin production in B16F10 cells and inhibited B16F10 tyrosinase activity in situ in a concentration-dependent manner. As these compounds showed no cytotoxicity to epidermal cells, melanocytes, or keratinocytes, they are appropriate for skin applications. Compounds 8 and 13 demonstrated substantially higher depigmentation effects on zebrafish larvae than kojic acid, even at 800- and 400-times lower concentrations than kojic acid, respectively. These findings suggest that 2-phenylbenzo[d]oxazole is a promising candidate for tyrosinase inhibition.


Assuntos
Melaninas , Simulação de Acoplamento Molecular , Monofenol Mono-Oxigenase , Preparações Clareadoras de Pele , Animais , Humanos , Camundongos , Agaricales/enzimologia , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Melaninas/biossíntese , Melaninas/antagonistas & inibidores , Estrutura Molecular , Monofenol Mono-Oxigenase/antagonistas & inibidores , Monofenol Mono-Oxigenase/metabolismo , Oxazóis/química , Oxazóis/farmacologia , Pironas , Resorcinóis/química , Resorcinóis/farmacologia , Preparações Clareadoras de Pele/farmacologia , Preparações Clareadoras de Pele/química , Relação Estrutura-Atividade , Peixe-Zebra
8.
Appl Microbiol Biotechnol ; 108(1): 471, 2024 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-39316232

RESUMO

The Streptomyces sp. is considered the vast reservoir of bioactive natural products belonging to different classes like polyketides, terpenoids, lanthipeptides, and non-ribosomal peptides to name a few. The ubiquitous distribution of the genus makes them capable of producing distinct compounds. Many of those compounds contain a unique γ-pyrone with various chemical structures and exhibit different bioactivities. One such class, nitrophenyl-γ-pyrone, constitutes different bioactive compounds isolated from Streptomyces sp. from different sources ranging from soil to marine environments. In addition, such compounds have antinematodal, cytotoxicity activities, and inhibition of adipogenesis. These compounds include aureothin (3), spectinabilin (7), and their derivatives. Moreover, there are other compounds like actinopyrones (11-16), benwamycins (22-23), and peucemycin and its derivatives (24-26) that also have antibacterial and anticancer activities. The other group classified as anthra-γ-pyrone has various bioactive natural products. For instance, tetrahydroanthra-γ-pyrone, shellmycin A-D (27-30) possess antibacterial as well as anticancer activities. In addition, the pluramycin family compounds belonging to anthra-γ-pyrone group also possess cytotoxic activity, for instance, kidamycin (31), rubiflavin, and their derivatives (33-37). Xanthones are another important group of natural products that also contain γ-pyrone ring producing different bioactivities. Albofungin (42) and its derivatives (43-46) belong to subgroup polycyclic tetrahydro xanthones that possess antibacterial, anticancer, and antibiofilm, antimacrofouling activities. Similarly, other compounds, belonging to this subgroup, exhibit different bioactivities like antifungal, antimalarial, and antibacterial activities and block transient receptor potential vanilloid 1 (TRPV1). These compounds include cervinomycins (48-55), citreamycins (56-57), sattahipmycin (59), and chrexanthomycins (60-63). This review gives succinct information on the γ-pyrone containing natural products isolated from Streptomyces sp. focusing on their structure and bioactivities. KEY POINTS: • The Streptomyces sp. is the producer of various bioactive natural products including the one with γ-pyrone ring. • These γ-pyrone compounds are structurally different and possess different bioactivities. • The Streptomyces has the potential to produce such compounds and the reservoir of these compounds is expected to increase in the future.


Assuntos
Antibacterianos , Produtos Biológicos , Pironas , Streptomyces , Streptomyces/química , Pironas/química , Pironas/farmacologia , Produtos Biológicos/farmacologia , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Antibacterianos/farmacologia , Antibacterianos/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Humanos
9.
Int J Biol Macromol ; 277(Pt 4): 134514, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39111504

RESUMO

The current environmental consciousness of the world's population encourages researchers to work on new materials that are environmentally benign and able to display the appropriate features for the needed application. To develop high-performing, inexpensive eco-materials, scientists have frequently turned to nature, attempting to mimic its processes' excellent performance at a reasonable price. In this regard, we decided to focus on alginic acid (AA), a polysaccharide widely found in brown algae, and kojic acid (KA), a chelating agent fungi produces. This study proposes rapidly synthesizing a sustainable, biocompatible material (AK) based on AA and KA, employing chlorokojic acid (CKA). The material has a dual function: antibacterial activity on both Gram-positive and Gram-negative bacteria, without any cytotoxic action on human cells in vitro, and catalytic ability to convert CO2 into cyclic carbonates at atmospheric pressure, without solvents, with high yields, and without the use of metals. Furthermore, the material's insolubility in organic solvents allows it to be easily separated from the reaction product and reused for other catalytic cycles. Both applications have a key role in the medical and environmental fields, combating the outbreak of infections and providing an innovative methodology to fix the CO2 on specific substrates.


Assuntos
Ácido Algínico , Antibacterianos , Dióxido de Carbono , Pironas , Pironas/química , Pironas/farmacologia , Antibacterianos/química , Antibacterianos/farmacologia , Dióxido de Carbono/química , Ácido Algínico/química , Humanos , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Catálise , Testes de Sensibilidade Microbiana , Alginatos/química
10.
Free Radic Biol Med ; 223: 263-280, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39117049

RESUMO

Given the substantial risks associated with ultraviolet B (UVB) radiation-induced solar dermatitis, enhancing current strategies to combat UVB regarding skin diseases is imperative. The cross-talk between ferroptosis and inflammation has been proven to be an essential factor in UVB-induced solar dermatitis, whereas detailed process of how their interaction contributes to this remains unclear. Therefore, further investigation of ferroptosis-mediated processes and identification of corresponding inhibitory approaches hold promise for repairing skin damage. Senkyunolide I (Sen I), a bioactive component mainly extracted from the traditional Chinese medicinal plants, Ligusticum chuanxiong Hort. and Angelica sinensis (Oliv.) Diels, has demonstrated efficacy in combating oxidative stress and inflammation. In this study, we utilized UVB-irradiated HaCaT cells as an in vitro model and C57BL/6J mice as an in vivo model of solar dermatitis. Our findings revealed the pivotal roles of autophagy and ferroptosis in inducing skin inflammation, particularly emphasizing the activation of ferroptosis through macroautophagy. Surprisingly, this mechanism operated independently of ferritinophagy, a classical autophagy-driven ferroptosis pathway. Instead, our results highlighted Transferrin Receptor 1 (TfR1), tightly controlled by autophagy, as a crucial mediator of ferroptosis execution and amplifier of subsequent lethal signals. Furthermore, extracellular High Mobility Group Box 1 protein (HMGB1), released following UVB-induced ferroptotic cells from activated autophagic flux, initiated a feedback loop with TfR1, propagating ferroptosis to neighboring cells and exacerbating damage. Remarkably, Sen I administration showed a significant protective effect against UVB damage in both in vitro and in vivo models by interrupting this cascade. Consequently, we have illuminated a novel therapeutic pathway post-UVB exposure and identified Sen I as a potent natural molecule that safeguarded against UVB-induced solar dermatitis by suppressing the autophagy-ferroptosis-HMGB1-TfR1 axis, highlighting a new frontier in photoprotection.


Assuntos
Autofagia , Ferroptose , Proteína HMGB1 , Raios Ultravioleta , Ferroptose/efeitos dos fármacos , Animais , Autofagia/efeitos dos fármacos , Humanos , Camundongos , Proteína HMGB1/metabolismo , Raios Ultravioleta/efeitos adversos , Camundongos Endogâmicos C57BL , Células HaCaT , Dermatite/metabolismo , Dermatite/tratamento farmacológico , Dermatite/patologia , Pironas/farmacologia , Retroalimentação Fisiológica , Estresse Oxidativo/efeitos dos fármacos
11.
Phytochem Anal ; 35(7): 1674-1687, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39099156

RESUMO

INTRODUCTION: Catnip (Nepeta cataria, L.) has well-documented applications in arthropod repellency because of its bioactive iridoids. Long-term stability of nepetalactones and other iridoids in N. cataria are needed to develop as effective pest repellents. OBJECTIVES: The present work intends to measure iridoid concentration over time in biomass, plant extracts, and extract solution while identifying degradative byproducts under different storage conditions. METHODOLOGY: Samples of desiccated biomass, ethanol extract, and extract in ethanol solution were stored in ambient light or darkness. Through UHPLC-QTOF/MS or UHPLC-QQQ/MS, the concentration of Z,E-nepetalactone, E,Z-nepetalactone, nepetalic acid, and dihydronepetalactone were examined over 2 years and statistically analyzed for determination of best storage practices. Degradation kinetics were applied to each analyte using graphical estimation. With targeted formula searching, degradative byproducts were identified and quantified. RESULTS: Light exposure caused significant decreases in E,Z-nepetalactone concentration in all sample types, while having no effect on Z,E-nepetalactone as it decayed more rapidly. Extract samples lost nepetalactone content faster than biomass or extract solution. Dihydronepetalactone levels were low, but never declined over 2 years. Nepetalic acid increased over some periods, depending on sample type, indicating a relationship between the acid and nepetalactone. Four degradative byproducts-nepetonic acid, dehydronepetalactone, an anhydride, and an ethanolic ester-were identified, with variable responses to light exposure. CONCLUSIONS: Protecting catnip products from light is necessary to preserve nepetalactones, and a discernable difference in nepetalactone isomer stability was discovered. Identifying Nepeta chemotypes rich in dihydronepetalactone may provide more resilient botanicals as starting materials for processing.


Assuntos
Iridoides , Nepeta , Nepeta/química , Iridoides/análise , Iridoides/química , Cromatografia Líquida de Alta Pressão/métodos , Extratos Vegetais/química , Extratos Vegetais/análise , Espectrometria de Massas/métodos , Espectrometria de Massas em Tandem/métodos , Estabilidade de Medicamentos , Biomassa , Monoterpenos Ciclopentânicos , Pironas
12.
J Org Chem ; 89(17): 12432-12438, 2024 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-39178422

RESUMO

Substituted 5-hydroxy γ-pyrones have shown promise as covalent inhibitor leads against cysteine proteases and transcription factors, but their hydrolytic instability has hindered optimization efforts. Previous mechanistic proposals have suggested that these molecules function as Michael acceptor prodrugs, releasing a leaving group to generate an o-quinone methide-like structure. Addition to this electrophile of either water or an active site cysteine was purported to lead to inhibitor hydrolysis or enzyme inhibition, respectively. Through the use of kinetic nuclear magnetic resonance experiments, Hammett analysis, kinetic isotope effect studies, and density functional theory calculations, our findings suggest that enzyme inhibition and hydrolysis proceed by distinct pathways and are differentially influenced by substituent electronics. This mechanistic revision helps enable a more rational optimization for this class of promising compounds.


Assuntos
Pró-Fármacos , Pironas , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Pironas/química , Pironas/farmacologia , Estrutura Molecular , Teoria da Densidade Funcional , Cinética , Hidrólise , Cisteína Proteases/química , Cisteína Proteases/metabolismo
13.
Int J Biol Macromol ; 278(Pt 2): 134854, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39168223

RESUMO

Bioactivity screening revealed that the EtOAc extract from the culture broth of Phellinus igniarius SY489 exhibited remarkable α-glucosidase inhibitory activity, with an IC50 value of 1.92 µg/mL. Activity- and ultraviolet (UV) profile-guided isolation led to the discovery of four anti-diabetic styrylpyrones (1-4), including two novel compounds, phelignidins A (1) and B (2). Compounds 1 and 2 represent a rare structural type of styrylpyrone dimer, in which one of the pyrone moieties exists in an open-ring state. The absolute configurations of the new compounds 1 and 2, as well as the previously unresolved compound 3, were established. Compounds 1-4 were effective in α-glucosidase inhibition, anti-glycation, and antioxidant assays, surpassing or being comparable to the positive control drugs, with minimal cytotoxicity. Furthermore, studies on α-glucosidase inhibition mechanisms suggested that these compounds interact with α-glucosidase at a single binding site, causing secondary structure unfolding and exerting inhibitory activity via a mixed-type mechanism. These results provide an important basis for developing novel, low-toxicity, multi-target anti-diabetic drugs from edible and medicinal fungi.


Assuntos
Inibidores de Glicosídeo Hidrolases , Hipoglicemiantes , Estresse Oxidativo , Pironas , alfa-Glucosidases , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/química , Pironas/química , Pironas/farmacologia , alfa-Glucosidases/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/química , Basidiomycota/química , Antioxidantes/farmacologia , Antioxidantes/química , Glicosilação/efeitos dos fármacos , Humanos
14.
Anal Chim Acta ; 1320: 343026, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-39142791

RESUMO

BACKGROUND: As a significant biomarker of melanocytic lesions, tyrosinase (TYR) plays an essential role in the clinical diagnosis and treatment of melanin-related diseases. Thus, it is important to develop robust methods for assessing TYR activity. Covalent organic frameworks (COFs) have garnered considerable attention owing to their unique properties, including high chemical stability, good biocompatibility, and large surface area compared with organic dyes, noble metal nanoclusters, and semiconductor quantum dots. However, most COFs are insoluble in water and exhibit weak or no fluorescence emission. Therefore, the development of a water-soluble fluorescent COF for detecting TYR activity in biological samples remains highly desired. RESULTS: In this work, a sensitive and facile fluorometric method based on fluorescent COF was constructed for the detection of TYR activity in human serum samples. The water-soluble COF was fabricated through the condensation polymerization of 4',4‴,4''''',4'''''''-(1,2-ethene-diylidene) tetrakis [1,1'-biphenyl]-4-carboxaldehyde and 2,4,6-tris-(4-aminophenyl)-triazine. The resulting COF displayed yellow-green fluorescence with a maximum emission peak at 560 nm. Tyrosine was catalyzed by TYR to produce melanin-like polymers which formed a coating on the surface of COF and effectively quenched its fluorescence due to fluorescence resonance energy transfer. The proposed approach demonstrated a strong linear correlation in the range of 0.5-80 U/L with a low detection limit of 0.09 U/L. Additionally, the limit of detection for kojic acid, serving as a representative TYR inhibitor, was determined to be 0.0004 µg/mL. SIGNIFICANCE: Our proposed fluorometric sensing platform exhibited exceptional selectivity, sensitivity, and satisfactory recoveries in human serum samples, which is of paramount importance for the clinical diagnostics of melanin-related diseases. Furthermore, the proposed approach was further employed for the screening of TYR inhibitors, suggesting the potential applications in clinical treatment and pharmaceutical research.


Assuntos
Inibidores Enzimáticos , Corantes Fluorescentes , Estruturas Metalorgânicas , Monofenol Mono-Oxigenase , Monofenol Mono-Oxigenase/antagonistas & inibidores , Monofenol Mono-Oxigenase/metabolismo , Estruturas Metalorgânicas/química , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Humanos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Espectrometria de Fluorescência , Limite de Detecção , Ensaios Enzimáticos/métodos , Pironas
15.
Bioorg Med Chem ; 111: 117848, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-39067378

RESUMO

A new total synthesis of the natural δ-lactone cleistenolide (1) and its (6S)-stereoisomer 2 was achieved starting from d-glucose. Key steps in the synthesis of 1 involved: oxidative cleavage of the C1-C2 bond in partially protected d-glucose derivative (20), and chain extension of resulting aldehyde 20a with a single C2 fragment using (Z)-selective Wittig olefination. Synthesis of 2 involves the following key steps: periodate cleavage of the C5-C6 bond in the commercially available monoacetone d-glucose (24), followed by C2 chain elongation by using the (Z)-selective Wittig olefination. This new approach is also applied to prepare a few new 4-substituted cleistenolide analogues (3 - 18). Compounds 3 - 7 were designed using molecular hybridization, while the remaining eleven analogues were designed using the bioisosterism method. MTT assay showed that most analogues were more active than lead 1 against several malignant cells, but were completely inactive in the culture of normal foetal lung fibroblasts (MRC-5). The K562 cells appeared to be the most sensitive to the synthesized analogues. The strongest antiproliferative activity against this cell line was shown by 4-O-cinnamoyl derivative 3 and 4,6-di-O-benzyl derivative 17, with submicromolar IC50 values (0.76 and 0.67 µM, respectively). Structural features important for the activity of this class of compounds were identified by SAR analysis.


Assuntos
Antineoplásicos , Proliferação de Células , Humanos , Proliferação de Células/efeitos dos fármacos , Relação Estrutura-Atividade , Estereoisomerismo , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Ensaios de Seleção de Medicamentos Antitumorais , Linhagem Celular Tumoral , Estrutura Molecular , Relação Dose-Resposta a Droga , Furanos/química , Furanos/farmacologia , Furanos/síntese química , Pironas
16.
Bioprocess Biosyst Eng ; 47(10): 1633-1645, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38970656

RESUMO

This work aimed to define strategies to increase the bioproduction of 6 pentyl-α-pyrone (bioaroma). As first strategy, fermentations were carried out in the solid state, with agro-industrial residues: Mauritia flexuosa Liliopsida. and Manihot esculenta Crantz in isolation, conducting them with different nutrient solutions having Trichoderma harzianum as a fermenting fungus. Physicochemical characterizations, centesimal composition, lignocellulosic and mineral content and antimicrobial activity were required. Fermentations were conducted under different humidification conditions (water, nutrient solution without additives and nutrient solutions with glucose or sucrose) for 9 days. Bioaroma was quantified by gas chromatography, assisted by solid-phase microextraction. The results showed the low production of this compound in fermentations conducted with sweet cassava (around 6 ppm (w/w)). The low bioproduction with sweet cassava residues can probably be related to its starch-rich composition, homogeneous substrate, and low concentration of nutrients. Already using buriti, the absence of aroma production was detected. Probably the presence of silicon and high lignin content in buriti minimized the fungal activity, making it difficult to obtain the aroma of interest. Given the characteristics presented by the waste, a new strategy was chosen: mixing waste in a 1:1 ratio. This fermentation resulted in the production of 156.24 ppm (w/w) of aroma using the nutrient solution added with glucose. This combination, therefore, promoted more favorable environment for the process, possibly due to the presence of fermentable sugars from sweet cassava and fatty acids from the buriti peel, thus proving the possibility of an increase of around 2500% in the bioproduction of coconut aroma.


Assuntos
Manihot , Pironas , Manihot/química , Manihot/metabolismo , Pironas/metabolismo , Pironas/química , Cocos/química , Odorantes/análise , Hypocreales/metabolismo , Fermentação
17.
Planta Med ; 90(10): 792-800, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39013429

RESUMO

This work investigated interactions ascribed to the administration of phytomedicines containing Valeriana officinalis and Piper methysticum with conventional drugs. The phytomedicines were characterized by HPLC and administered per os to male Wistar rats, either concomitantly or not with the CYP3A substrate midazolam. To distinguish between the presystemic or systemic effect, midazolam was given orally and intravenously. The effects on the P-gp substrate fexofenadine uptake by Caco-2 cells were examined. The valerenic acid content was 1.6 ± 0.1 mg per tablet, whereas kavain was 13.7 ± 0.3 mg/capsule. Valerian and kava-kava extracts increased the maximum plasma concentration (Cmax) of midazolam 2- and 4-fold compared to the control, respectively. The area under the plasma concentrations versus time curve (AUC(0-∞)) was enhanced from 994.3 ± 152.3 ng.h/mL (control) to 3041 ± 398 ng.h/mL (valerian) and 4139 ± 373 ng.h/mL (kava-kava). The half-life of midazolam was not affected. These changes were attributed to the inhibition of midazolam metabolism by the enteric CYP3A since the i. v. pharmacokinetic of midazolam remained unchanged. The kava-kava extract augmented the uptake of fexofenadine by 3.5-fold compared to the control. Although Valeriana increased the uptake of fexofenadine, it was not statistically significant to that of the control (12.5 ± 3.7 ng/mg protein vs. 5.4 ± 0.3 ng/mg protein, respectively). Therefore, phytomedicines containing V. officinalis or P. methysticum inhibited the intestinal metabolism of midazolam in rats. Conversely, the P-gp-mediated transport of fexofenadine was preferably affected by kava-kava.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Citocromo P-450 CYP3A , Kava , Midazolam , Extratos Vegetais , Ratos Wistar , Terfenadina , Valeriana , Animais , Valeriana/química , Midazolam/farmacocinética , Midazolam/farmacologia , Masculino , Citocromo P-450 CYP3A/metabolismo , Citocromo P-450 CYP3A/efeitos dos fármacos , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/efeitos dos fármacos , Terfenadina/análogos & derivados , Terfenadina/farmacocinética , Humanos , Células CACO-2 , Ratos , Kava/química , Interações Ervas-Drogas , Piper/química , Indenos , Pironas , Sesquiterpenos
18.
Int J Mol Sci ; 25(13)2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-39000492

RESUMO

Oxidative stress can damage neuronal cells, greatly contributing to neurodegenerative diseases (NDs). In this study, the protective activity of arzanol, a natural prenylated α-pyrone-phloroglucinol heterodimer, was evaluated against the H2O2-induced oxidative damage in trans-retinoic acid-differentiated (neuron-like) human SH-SY5Y cells, widely used as a neuronal cell model of neurological disorders. The pre-incubation (for 2 and 24 h) with arzanol (5, 10, and 25 µM) significantly preserved differentiated SH-SY5Y cells from cytotoxicity (MTT assay) and morphological changes induced by 0.25 and 0.5 mM H2O2. Arzanol reduced the generation of reactive oxygen species (ROS) induced by 2 h oxidation with H2O2 0.5 mM, established by 2',7'-dichlorodihydrofluorescein diacetate assay. The 2 h incubation of differentiated SH-SY5Y cells with H2O2 determined a significant increase in the number of apoptotic cells versus control cells, evaluated by propidium iodide fluorescence assay (red fluorescence) and NucView® 488 assay (green fluorescence). Arzanol pre-treatment (2 h) exerted a noteworthy significant protective effect against apoptosis. In addition, arzanol was tested, for comparison, in undifferentiated SH-SY5Y cells for cytotoxicity and its ability to protect against H2O2-induced oxidative stress. Furthermore, the PubChem database and freely accessible web tools SwissADME and pkCSM-pharmacokinetics were used to assess the physicochemical and pharmacokinetic properties of arzanol. Our results qualify arzanol as an antioxidant agent with potential neuroprotective effects against neuronal oxidative stress implicated in NDs.


Assuntos
Apoptose , Diferenciação Celular , Peróxido de Hidrogênio , Estresse Oxidativo , Espécies Reativas de Oxigênio , Humanos , Estresse Oxidativo/efeitos dos fármacos , Peróxido de Hidrogênio/toxicidade , Peróxido de Hidrogênio/farmacologia , Diferenciação Celular/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Linhagem Celular Tumoral , Apoptose/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Antioxidantes/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Pironas/farmacologia
19.
Zhongguo Zhong Yao Za Zhi ; 49(11): 2965-2972, 2024 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-39041156

RESUMO

This study developed a UPLC-PDA wavelength switching method to simultaneously determine the content of maltol and seventeen saponins in red and black ginseng and compared the quality differences of two different processed products of red and black ginseng. A Waters HSS T3 column(2. 1 mm×100 mm, 1. 8 µm) at 30 ℃ was adopted, with the mobile phase of acetonitrile(A) and water containing 0. 1% phosphoric acid(B) under gradient elution, the flow rate of 0. 3 m L·min~(-1), and the injection volume of 2 µL.The wavelength switching was set at 273 nm within 0-11 min and 203 nm within 11-60 min. The content results of multiple batches of red and black ginseng samples were analyzed by the hierarchical cluster analysis(HCA) and principal component analysis(PCA) to evaluate the quality difference. The results showed that the 18 constituents exhibited good linear relationships within certain concentration ranges, with the correlation coefficients(r) greater than 0. 999 1. The relative standard deviations(RSDs) of precision,repeatability, and stability were all less than 5. 0%. The average recoveries ranged from 95. 93% to 104. 2%, with an RSD of 1. 8%-4. 2%. The content determination results showed that the quality of red and black ginseng samples was different, and the two types of processed products were intuitively distinguished by HCA and PCA. The method is accurate, reliable, and reproducible. It can be used to determine the content of maltol and seventeen saponins in red and black ginseng and provide basic information for the quality evaluation and comprehensive utilization of red and black ginseng.


Assuntos
Panax , Pironas , Saponinas , Panax/química , Saponinas/análise , Saponinas/química , Cromatografia Líquida de Alta Pressão/métodos , Pironas/análise , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/análise
20.
Ecotoxicol Environ Saf ; 282: 116734, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-39024951

RESUMO

Hepatic diseases pose a significant threat to community health, impacting the quality of life and longevity of millions worldwide. Despite revolutionary advancements in treatment, liver diseases remain a pressing issue, necessitating the development of more effective therapeutic approaches. Here, we conducted a comprehensive multi-omics analysis to investigate the underlying mechanism of Swertiamarin in alleviating hepatic injuries induced by CCl4 in mice. We divided 100 Kunming mice into five groups: RC (control), RM (CCl4), RD (15 mg/Kg Swertiamarin), RZ (30 mg/Kg Swertiamarin), and RG (60 mg/Kg Swertiamarin). Animals in groups RD, RZ, and RG received daily Swertiamarin via gavage, while those in groups RM, RD, RZ, and RG were treated with CCl4 solution intraperitoneally every four days, nine times in total. Our findings revealed that mice in the RM group exhibited slightly lower average weights compared to other groups, along with significantly higher liver weight (p<0.0001) and liver index (p<0.0001). Pathological analysis indicated liver damage characterized by cell degeneration, inflammatory cell infiltration, and hepatic fibrosis in the CCl4-induced group. In contrast, Swertiamarin supplementation mitigated these effects, reducing denatured cells, inflammatory cells, and collagenous fibers in the liver. Serum analysis showed elevated levels of TNF-α (p<0.001), IL-6 (p<0.05), ALT (p<0.001), AST (p<0.0001), MDA (p<0.001), and Hyp (p<0.001) in CCl4-induced animals, along with lower levels of T-AOC (p<0.001), GSH-px (p<0.0001), SOD (p<0.001), and CAT (p<0.01). Microbiome analysis revealed significant differences among groups, with pathogenic taxa such as Arthrinium and Aureobasidium, and probiotic Saccharomyces showing notable variations. Metabolomics analysis identified numerous differentially abundant metabolites, with Swertiamarin-treated animals exhibiting distinct profiles. Our findings highlight the potential of Swertiamarin ameliorating CCl4-induced liver toxicity through modulation of antioxidant capacity, inflammatory response, gut microbiota, and metabolites. These insights may inform the development of novel therapies for liver injury.


Assuntos
Tetracloreto de Carbono , Doença Hepática Induzida por Substâncias e Drogas , Glucosídeos Iridoides , Fígado , Pironas , Animais , Pironas/farmacologia , Glucosídeos Iridoides/farmacologia , Camundongos , Fígado/efeitos dos fármacos , Fígado/patologia , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Masculino , Metabolômica , Estresse Oxidativo/efeitos dos fármacos , Multiômica , Animais não Endogâmicos
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