RESUMO
Introduction: Despite years of efforts to develop new antibiotics for eradicating multidrug-resistant (MDR) and multi-virulent Methicillin-Resistant Staphylococcus aureus (MRSA) and Vancomycin-Resistant Staphylococcus aureus (VRSA) infections, treatment failures and poor prognoses in most cases have been common. Therefore, there is an urgent need for new therapeutic approaches targeting virulence arrays. Our aim is to discover new anti-virulence therapies targeting MRSA and VRSA virulence arrays. Methodology: We employed phenotypic, molecular docking, and genetic studies to screen for anti-virulence activities among selected promising compounds: Coumarin, Simvastatin, and Ibuprofen. Results: We found that nearly all detected MRSA and VRSA strains exhibited MDR and multi-virulent profiles. The molecular docking results aligned with the phenotypic and genetic assessments of virulence production. Biofilm and hemolysin productions were inhibited, and all virulence genes were downregulated upon treatment with sub-minimum inhibitory concentration (sub-MIC) of these promising compounds. Ibuprofen was the most active compound, exhibiting the highest inhibition and downregulation of virulence gene products. Moreover, in vivo and histopathological studies confirmed these results. Interestingly, we observed a significant decrease in wound area and improvements in re-epithelialization and tissue organization in the Ibuprofen and antimicrobial treated group compared with the group treated with antimicrobial alone. These findings support the idea that a combination of Ibuprofen and antimicrobial drugs may offer a promising new therapy for MRSA and VRSA infections. Conclusion: We hope that our findings can be implemented in clinical practice to assist physicians in making the most suitable treatment decisions.
Assuntos
Antibacterianos , Biofilmes , Staphylococcus aureus Resistente à Meticilina , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Infecções Estafilocócicas , Staphylococcus aureus Resistente à Vancomicina , Fatores de Virulência , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/patogenicidade , Staphylococcus aureus Resistente à Meticilina/genética , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Biofilmes/efeitos dos fármacos , Fatores de Virulência/genética , Staphylococcus aureus Resistente à Vancomicina/efeitos dos fármacos , Animais , Virulência/efeitos dos fármacos , Ibuprofeno/farmacologia , Ibuprofeno/uso terapêutico , Humanos , Cumarínicos/farmacologia , Cumarínicos/uso terapêutico , Camundongos , Modelos Animais de Doenças , Proteínas Hemolisinas/antagonistas & inibidores , Proteínas Hemolisinas/metabolismo , Proteínas Hemolisinas/genética , Farmacorresistência Bacteriana MúltiplaRESUMO
Staphylococcus aureus infections are the primary causes of morbidity, and mortality, particularly in immuno-compromised individuals. S. aureus associated infections are acquired from community, as well as hospital settings, and difficult to treat because of the emerging resistance against available antibiotics. One of the key factors of its resistance is the biofilm formation, which can be targeted to treat S. aureus-induced infections. Currently, there is no drug available that function by targeting the biofilm. This unmet need demands the discovery of drug candidates against S. aureus biofilm. The present study was designed to evaluate coumarin derivatives 1-21 against S. aureus biofilm. The 96-well plate crystal violet assay was employed for the quantification of biofilm. Results showed that the coumarin derivatives 2-4, 10, and 17 possess potent antibiofilm activity, with MBIC values between 25-100 µg/mL. The results were further confirmed through atomic force microscopy (AFM), scanning electron (SEM), and fluorescence microscopic studies. The quantitative RT-PCR analysis revealed the downregulation of biofilm associated genes, icaA and icaD. These coumarin derivatives were also found to be non-cytotoxic to fibroblasts. This study, therefore, identifies the antibiofilm potential of coumarin derivatives that will pave the way for further research on these derivatives.
Assuntos
Antibacterianos , Biofilmes , Cumarínicos , Testes de Sensibilidade Microbiana , Staphylococcus aureus , Biofilmes/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Cumarínicos/farmacologia , Cumarínicos/química , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/farmacologia , Antibacterianos/química , Humanos , Microscopia de Força AtômicaRESUMO
OBJECTIVE: To investigate the mechanism underlying the neuroprotective effect of linarin (LIN) against microglia activation-mediated inflammation and neuronal apoptosis following spinal cord injury (SCI). METHODS: Fifty C57BL/6J mice (8- 10 weeks old) were randomized to receive sham operation, SCI and linarin treatment at 12.5, 25, and 50 mg/kg following SCI (n=10). Locomotor function recovery of the SCI mice was assessed using the Basso Mouse Scale, inclined plane test, and footprint analysis, and spinal cord tissue damage and myelination were evaluated using HE and LFB staining. Nissl staining, immunofluorescence assay and Western blotting were used to observe surviving anterior horn motor neurons in injured spinal cord tissue. In cultured BV2 cells, the effects of linarin against lipopolysaccharide (LPS)induced microglia activation, inflammatory factor release and signaling pathway changes were assessed with immunofluorescence staining, Western blotting, RT-qPCR, and ELISA. In a BV2 and HT22 cell co-culture system, Western blotting was performed to examine the effect of linarin against HT22 cell apoptosis mediated by LPS-induced microglia activation. RESULTS: Linarin treatment significantly improved locomotor function (P < 0.05), reduced spinal cord damage area, increased spinal cord myelination, and increased the number of motor neurons in the anterior horn of the SCI mice (P < 0.05). In both SCI mice and cultured BV2 cells, linarin effectively inhibited glial cell activation and suppressed the release of iNOS, COX-2, TNF-α, IL-6, and IL-1ß, resulting also in reduced neuronal apoptosis in SCI mice (P < 0.05). Western blotting suggested that linarin-induced microglial activation inhibition was mediated by inhibition of the TLR4/NF- κB signaling pathway. In the cell co-culture experiments, linarin treatment significantly decreased inflammation-mediated apoptosis of HT22 cells (P < 0.05). CONCLUSION: The neuroprotective effect of linarin is medicated by inhibition of microglia activation via suppressing the TLR4/NFκB signaling pathway, which mitigates neural inflammation and reduce neuronal apoptosis to enhance motor function of the SCI mice.
Assuntos
Apoptose , Camundongos Endogâmicos C57BL , Microglia , NF-kappa B , Transdução de Sinais , Traumatismos da Medula Espinal , Receptor 4 Toll-Like , Animais , Camundongos , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/metabolismo , Microglia/efeitos dos fármacos , Microglia/metabolismo , Receptor 4 Toll-Like/metabolismo , Apoptose/efeitos dos fármacos , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Cumarínicos/farmacologia , Inflamação/metabolismo , Lipopolissacarídeos , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/etiologia , GlicosídeosRESUMO
Targeted delivery systems combined with the stimuli-responsive release of drug molecules hold noteworthy promise for precision medicine, enabling treatments with enhanced effectiveness and reduced adverse effects. An ideal drug delivery platform with versatile targeting moieties, the capability of combinational payloads, and simple preparation is highly desirable. Herein, we developed pH-sensitive fluorescent self-assembled complexes (SACs) of a galactose-functionalized G-quadruplex (G4) and a coumarin carboxamidine derivative as a targeted delivery platform through the nanoprecipitation method. These SACs selectively targeted hepatocellular carcinoma (HepG2) cells in fluorescence imaging after a short incubation and exerted specific anticancer effects in an appropriate dose range. Co-delivery of 1 µM prodrug floxuridine oligomers and 16 µg/mL SACs (minimal hemolytic effect) significantly reduced the cytotoxicity of the nucleoside anticancer drug on normal cells (NIH/3T3), kept up to 70% alive after 72-h incubation, and improved anticancer efficacy compared to SACs alone. This strategy can be extended to ratiometric multidrug delivery through self-assembly for targeted combinational therapy.
Assuntos
Quadruplex G , Humanos , Quadruplex G/efeitos dos fármacos , Células Hep G2 , Camundongos , Animais , Células NIH 3T3 , Corantes Fluorescentes/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Sistemas de Liberação de Medicamentos , Floxuridina/química , Floxuridina/farmacologia , Galactose/química , Cumarínicos/química , Cumarínicos/farmacologiaRESUMO
Leonurus japonicus Houtt is an exceptional medicinal herb used to treat obstetrical and gynecological diseases in traditional Chinese medicine, and it has significant effects on the treatment of dysmenorrhea and postpartum hemorrhage. This study investigated the effects of coumarins with diverse substituent groups from L. japonicus on isolated uterine smooth muscle and the preliminary mechanism of the most effective compound. Eight coumarins isolated from L. japonicus were assessed for their effects on the isolated uterine smooth muscle of nonpregnant rats in vitro. Coumarins 1 and 2 significantly promoted the contraction of rat uterine smooth muscle strips, whereas coumarins 3-5 showed remarkable relaxing effects against oxytocin (OT)-induced rat uterine smooth muscle contraction. Further mechanism investigations revealed that bergapten (coumarin 1) significantly increased the level of Ca2+ in uterine tissues by promoting extracellular Ca2+ influx and intracellular Ca2+ release, which were related to the activation of L-type Ca2+ channels and α-receptors. By contrast, osthole (coumarin 5), an α receptor antagonist, inhibited OT-induced uterine smooth muscle contraction by decreasing the level of Ca2+ in uterine tissues via inhibition of extracellular Ca2+ influx and intracellular Ca2+ release. This study demonstrates that the coumarins from L. japonicus are effective substances for regulating uterine smooth muscle contraction, but different coumarins with diverse substituent groups have different, even opposite effects. It can be inferred that coumarins are closely related to the efficacy of L. japonicus in the treatment of dysmenorrhea and postpartum hemorrhage.
Assuntos
Cálcio , Cumarínicos , Leonurus , Músculo Liso , Contração Uterina , Útero , Animais , Feminino , Cumarínicos/farmacologia , Cumarínicos/química , Leonurus/química , Ratos , Cálcio/metabolismo , Contração Uterina/efeitos dos fármacos , Útero/efeitos dos fármacos , Útero/metabolismo , Músculo Liso/efeitos dos fármacos , Músculo Liso/metabolismo , Contração Muscular/efeitos dos fármacos , Ratos Sprague-Dawley , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Canais de Cálcio Tipo L/metabolismo , Ocitocina/farmacologiaRESUMO
In the present study, a series of coumarins, including eight undescribed bis-isoprenylated ones Spinifoliumin A-H, were isolated and identified from the aerial parts of Zanthoxylum dimorphophyllum var. spinifolium (ZDS), a plant revered in traditional Chinese medicine, particularly for treating rheumatoid arthritis (RA). The structures of the compounds were elucidated using 1D and 2D NMR spectroscopy, complemented by ECD, [Rh2(OCOCF3)4]-induced ECD, Mo2(OAc)4 induced ECD, IR, and HR-ESI-MS mass spectrometry. A network pharmacology approach allowed for predicting their anti-RA mechanisms and identifying the MAPK and PI3K-Akt signaling pathways, with EGFR as a critical gene target. A CCK-8 method was used to evaluate the inhibition activities on HFLS-RA cells of these compounds. The results demonstrated that Spinifoliumin A, B, and D-H are effective at preventing the abnormal proliferation of LPS-induced HFLS-RA cells. The results showed that compounds Spinifoliumin A, D, and G can significantly suppress the levels of IL-1ß, IL-6, and TNF-α. Moreover, molecular docking methods were utilized to confirm the high affinity between Spinifoliumin A, D, and G and EGFR, SRC, and JUN, which were consistent with the results of network pharmacology. This study provides basic scientific evidence to support ZDS's traditional use and potential clinical application.
Assuntos
Artrite Reumatoide , Cumarínicos , Zanthoxylum , Zanthoxylum/química , Artrite Reumatoide/tratamento farmacológico , Humanos , Cumarínicos/química , Cumarínicos/farmacologia , Cumarínicos/isolamento & purificação , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular , Estrutura Molecular , Proliferação de Células/efeitos dos fármacos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Simulação de Acoplamento MolecularRESUMO
Aim: This research aims to expand the established pharmacological space of tumor-associated carbonic anhydrases (TACAs) by exploring the synthetically accessible chemical space of 3-substituted coumarins, with the help of in silico pharmacology prediction.Materials & methods: 52 novel 3-substituted coumarins were sketched, prioritizing synthetic feasibility. Their pharmacological potentials were estimated using a custom machine-learning approach. 17 compounds were predicted as cytotoxic against HeLa cells by interfering with TACAs. Those compounds were synthesized and biologically tested against HeLa cells. The three most potent compounds were assayed against multiple carbonic anhydrases, and their enzyme binding mechanism(s) were studied using molecular docking.Results: Experimental results exhibited pronounced consensus with in silico pharmacology predictions.Conclusion: Novel 3-substituted coumarins are herein dispatched to the cancer therapeutics space.
[Box: see text].
Assuntos
Antineoplásicos , Anidrases Carbônicas , Cumarínicos , Simulação de Acoplamento Molecular , Humanos , Cumarínicos/química , Cumarínicos/farmacologia , Cumarínicos/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Células HeLa , Anidrases Carbônicas/metabolismo , Descoberta de Drogas , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/farmacologia , Inibidores da Anidrase Carbônica/síntese química , Ensaios de Seleção de Medicamentos Antitumorais , Estrutura Molecular , Relação Estrutura-Atividade , Proliferação de Células/efeitos dos fármacos , Aprendizado de Máquina , Neoplasias/tratamento farmacológico , Neoplasias/patologiaRESUMO
Lamellarins are natural products with a [3,4]-fused pyrrolocoumarin skeleton possessing interesting biological properties. More than 70 members have been isolated from diverse marine organisms, such as sponges, ascidians, mollusks, and tunicates. There is a continuous interest in the synthesis of these compounds. In this review, the synthetic strategies for the synthesis of the title compounds are presented along with their biological properties. Three routes are followed for the synthesis of lamellarins. Initially, pyrrole derivatives are the starting or intermediate compounds, and then they are fused to isoquinoline or a coumarin moiety. Second, isoquinoline is the starting compound fused to an indole moiety. In the last route, coumarins are the starting compounds, which are fused to a pyrrole moiety and an isoquinoline scaffold. The synthesis of isolamellarins, azacoumestans, isoazacoumestans, and analogues is also described. The above synthesis is achieved via metal-catalyzed cross-coupling, [3 + 2] cycloaddition, substitution, and lactonization reactions. The title compounds exhibit cytotoxic, multidrug resistance (MDR), topoisomerase I-targeted antitumor, anti-HIV, antiproliferative, anti-neurodegenerative disease, and anti-inflammatory activities.
Assuntos
Cumarínicos , Cumarínicos/química , Cumarínicos/síntese química , Cumarínicos/farmacologia , Humanos , Animais , Produtos Biológicos/química , Produtos Biológicos/síntese química , Produtos Biológicos/farmacologia , Isoquinolinas/química , Isoquinolinas/síntese química , Isoquinolinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Pirróis/química , Pirróis/síntese química , Pirróis/farmacologia , Estrutura Molecular , Compostos Heterocíclicos de 4 ou mais AnéisRESUMO
BACKGROUND: Coumarins, abundantly distributed in a plethora of biologically active compounds, serve as a fundamental motif in numerous natural products, drugs, and therapeutic leads. Despite their small size, they exhibit a diverse range of biological activities, intriguing researchers with their immense pharmacological potential. PURPOSE: This study consolidates the evidence regarding the essential role of coumarins in modern drug discovery, exploring their broad-spectrum pharmaceutical effects, structural versatility, and mechanisms of action across various domains. METHODS: For literature search, we utilized PubMed, Google scholar, and SciFinder databases. Keyword and keyword combinations such as "coumarins", "natural coumarins", "specific natural coumarins for particular diseases", and "therapeutic effects" were employed to retrieve relevant studies. The search encompassed articles published between 2005 and 2023. Selection criteria included studies reporting on the pharmacological activities of natural coumarins against various diseases. RESULTS: The results highlight the therapeutic potential of natural coumarins against various diseases, demonstrating anti-cancer, anti-oxidant, and anti-inflammatory activities. They also act as monoamine oxidase inhibitors and phosphodiesterase inhibitors, and as anti-thrombotic, anti-diabetic, and hepatoprotective agents. They also show efficacy against diabetic nephropathy, neurodegenerative diseases, microbial infections and many other diseases. CONCLUSION: This review underscores the significant role of natural coumarins in medicinal chemistry and drug discovery. Their diverse biological activities and structural versatility make them promising therapeutic agents. This study serves as a catalyst for further research in the field, aiming to address emerging challenges and opportunities in drug development.
Assuntos
Cumarínicos , Cumarínicos/farmacologia , Cumarínicos/química , Humanos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Antioxidantes/farmacologia , Antioxidantes/química , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/química , Animais , Fitoterapia , Hipoglicemiantes/farmacologia , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , Descoberta de DrogasRESUMO
Understanding the spatiotemporal dynamics of formaldehyde (FA) is crucial for elucidating its pathophysiology. In this study, we designed a series of organelle-resolved probes to investigate FA dynamics. By incorporating various organelle anchors into a coumarin hydrazonate, we developed a series of probes with excellent organelle selectivity and FA specificity, enabling rapid and precise sensing of FA in an organelle-resolved way. Leveraging these probes, we captured the spatiotemporal dynamics of native FA in response to exogenous FA or oxidative stress challenges. In particular, we unveiled the distinct responses of various organelles to identical cellular stressors. Moreover, we observed the dynamic response within individual organelles when cells were exposed to stressors for varying durations. We envision these probes will serve as versatile tools for probing FA pathophysiology.
Assuntos
Formaldeído , Organelas , Formaldeído/química , Humanos , Organelas/química , Organelas/metabolismo , Células HeLa , Corantes Fluorescentes/química , Imagem Óptica , Cumarínicos/química , Cumarínicos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Estrutura MolecularRESUMO
Recent studies confirmed that pyroptosis is involved in the progression of pulmonary hypertension (PH), which could promote pulmonary artery remodeling. Urolithin A (UA), an intestinal flora metabolite of ellagitannins (ETs) and ellagic acid (EA), has been proven to possess inhibitory effects on pyroptosis under various pathological conditions. However, its role on PH remained undetermined. To investigate the potential of UA in mitigating PH, mice were exposed to hypoxia (10% oxygen, 4 weeks) to induce PH, with or without UA treatment. Moreover, in vitro experiments were carried out to further uncover the underlying mechanisms. The in vivo treatment of UA suppressed the progression of PH via alleviating pulmonary remodeling. Pyroptosis-related genes were markedly upregulated in mice models of PH and reversed after the administration of UA. In accordance with that, UA treatment significantly inhibited hypoxia-induced pulmonary arterial smooth muscle cell (PASMC) pyroptosis via the AMPK/NF-κB/NLRP3 pathway. Our results revealed that UA treatment effectively mitigated PH progression through inhibiting PASMC pyroptosis, which represents an innovative therapeutic approach for PH.
Assuntos
Proteínas Quinases Ativadas por AMP , Cumarínicos , Hipertensão Pulmonar , Hipóxia , Miócitos de Músculo Liso , NF-kappa B , Proteína 3 que Contém Domínio de Pirina da Família NLR , Artéria Pulmonar , Piroptose , Transdução de Sinais , Animais , Cumarínicos/farmacologia , Cumarínicos/uso terapêutico , Piroptose/efeitos dos fármacos , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Artéria Pulmonar/metabolismo , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Hipóxia/metabolismo , Hipóxia/complicações , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/etiologia , Masculino , Proteínas Quinases Ativadas por AMP/metabolismo , Camundongos Endogâmicos C57BL , Modelos Animais de DoençasRESUMO
Ammi majus L. is a rich source of coumarins in addition to various flavonoids, alkaloids, and terpenoids. Medicinal products of Ammi majus seed, with sunlight exposure, are worldwide used for the treatment of vitiligo (pale-white patches on the skin). To increase the content of seed-coumarins and to investigate the physiological reasons in this respect, two net-house experiments were conducted using foliar-spray treatments (0, 25, 50, 100 and 200 mg L-1) of salicylic acid (SA) (Experiment 1) and putrescine (PUT) (Experiment 2). All studied parameters were improved due to the foliar application of both growth elicitors (SA and PUT). The best outcomes for SA and PUT were obtained at 50 mg L-1 which maximally increased the growth characteristics, physiological and biochemical attributes, and seed quality parameters. In comparison to the control, 50 mg L-1 of SA and PUT increased the chlorophyll content by 26.3% and 25.5%, carotenoid content by 31.4% and 18.5%. In addition 50 mg L-1 of both SA and PUT gives the best results of FTIR (Fourier Transform Infrared Spectrophotometer) & XRD (X-ray Diffraction) analysis. In GC-MS analysis, 50 mg L-1 of SA and PUT increases the Methoxsalen content (17.44 and 16.81%) and 7H-Furo[3,2-g]. Bown (1995) [1] Benzopyran-7-one, 4,9-dimethoxy content(14.92 and 13.93%) and p-camphorene content (13.11 and 12.27%) in contrast to the control. Other important constituents were Pimpinellin (6.31 and 4.08%), Bergapten (8.72 and 6.220, Isospathulenol (7.80 and 2.47), Octadecenoic acid (5.78 and 3.59) and Vitamin E (1.48 and 0.16).
Assuntos
Carotenoides , Putrescina , Ácido Salicílico , Sementes , Ácido Salicílico/farmacologia , Putrescina/farmacologia , Sementes/química , Carotenoides/farmacologia , Clorofila , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/isolamento & purificação , Cumarínicos/farmacologia , Folhas de Planta/químicaRESUMO
Multidrug resistance (MDR) mechanisms in cancer cells are greatly influenced by glutathione transferase P1-1 (hGSTP1-1). The use of synthetic or natural compounds as hGSTP1-1 inhibitors is considered an effective approach to overcome MDR. Nine compounds consisting of coumarin-6-sulfonamide linked to chalcone derivatives were synthesized and evaluated for their ability to inhibit hGSTP1-1. Among the synthetic derivatives, compounds 5g, 5f, and 5a displayed the most potent inhibitory effect, with IC50 values of 12.2 ± 0.5 µΜ, 12.7 ± 0.7 and 16.3 ± 0.6, respectively. Kinetic inhibition analysis of the most potent molecule, 5g, showed that it behaves as a mixed-type inhibitor of the target enzyme. An in vitro cytotoxicity assessment of 5a, 5f, and 5g against the human prostate cancer cell lines DU-145 and PC3, as well as the breast cancer cell line MCF-7, demonstrated that compound 5g exhibited the most pronounced cytotoxic effect on all tested cell lines. Molecular docking studies were performed to predict the structural and molecular determinants of 5g, 5f, and 5a binding to hGSTP1-1. In agreement with the experimental data, the results revealed that 5g exhibited the lowest docking score among the three studied inhibitors as a consequence of shape complementarity, governed by van der Waals, hydrogen bonds and a π-π stacking interaction. These findings suggest that coumarin-chalcone hybrids offer new perspectives for the development of safe and efficient natural product-based sensitizers that can target hGSTP1-1 for anticancer purposes.
Assuntos
Cumarínicos , Glutationa S-Transferase pi , Simulação de Acoplamento Molecular , Sulfonamidas , Humanos , Cumarínicos/química , Cumarínicos/farmacologia , Glutationa S-Transferase pi/antagonistas & inibidores , Glutationa S-Transferase pi/metabolismo , Sulfonamidas/química , Sulfonamidas/farmacologia , Linhagem Celular Tumoral , Chalcona/química , Chalcona/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Chalconas/química , Chalconas/farmacologia , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Células MCF-7RESUMO
The inflammation causes the destroyed osseointegration at the implant-bone interface, significantly increasing the probability of implant loosening in osteoporotic patients. Currently, inhibiting the differentiation of M1 macrophages and the inflammatory response could be a solution to stabilize the microenvironment of implants. Interestingly, some natural products have anti-inflammatory and anti-polarization effects, which could be a promising candidate for stabilizing the implants' microenvironment in osteoporotic patients. This research aims to explore the inhibitory effect of Urolithin B(UB) on macrophage M1 polarization, which ameliorates inflammation, thus alleviating implant instability. We established an osteoporosis mouse model of implant loosening. The mouse tissues were taken out for morphological analysis, staining analysis, and bone metabolic index analysis. In in vitro experiments, RAW264.7 cells were polarized to M1 macrophages using lipopolysaccharide (LPS) and analyzed by immunofluorescence (IF) staining, Western blot (WB), and flow cytometry. The CSP100 plus chip experiments were used to explore the potential mechanisms behind the inhibiting effects of UB. Through observation of these experiments, UB can improve the osseointegration between the implants and femurs in osteoporotic mice and enhance the stability of implants. The UB can inhibit the differentiation of M1 macrophages and local inflammation via inhibiting the phosphorylation of VEGFR2, which can be further proved by the weakened inhibited effects of UB in macrophages with lentivirus-induced overexpression of VEGFR2. Overall, UB can specifically inhibit the activation of VEGFR2, alleviate local inflammation, and improve the stability of implants in osteoporotic mice.
Assuntos
Diferenciação Celular , Cumarínicos , Macrófagos , Osteoporose , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Animais , Camundongos , Cumarínicos/farmacologia , Cumarínicos/uso terapêutico , Macrófagos/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Diferenciação Celular/efeitos dos fármacos , Células RAW 264.7 , Fosforilação/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Osteoporose/imunologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Feminino , Camundongos Endogâmicos C57BL , Regulação para Baixo/efeitos dos fármacos , Osseointegração/efeitos dos fármacos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Humanos , Inflamação/tratamento farmacológico , Modelos Animais de Doenças , Próteses e ImplantesRESUMO
OBJECTIVES: Treatment of hemorrhagic shock (HS) induced multi-organ injury remains a challenge. Bergapten (BeG) is a bioactive coumarin-derived compound, and previous articles have suggested that BeG may serve as a prospective therapeutic modality for HS. This study was designed to investigate the efficacy of BeG in the treatment of HS and its underlying mechanisms. METHODS: In this research, we established a rat model of HS, following which we assessed the protective effects of BeG on HS induced multi-organ injury. Subsequently, we scrutinized the activation of NLRP3 inflammasomes and pyroptosis in damaged organs. Additionally, we conducted examinations of AMPK and the downstream mitophagy pathway in damaged organs. Finally, we established a hypoxia/reoxygenation (H/R) model in HK-2 cells to simulate the in vitro HS process. Following AMPK inhibition with compound C, we evaluated the levels of mitophagy and cellular pyroptosis in BeG-treated HK-2 cells subjected to H/R. RESULTS: BeG treatment alleviated HS induced multi-organ injury. Subsequent analyses indicated that the therapeutic effects of BeG were related to the attenuation of NLRP3 inflammasome activation and pyroptosis. Additionally, we found BeG treatment stimulated the phosphorylation of AMPK, thereby enhancing mitophagy. Lastly, we found that the inhibition of AMPK in vitro attenuates BeG's enhancement of mitophagy and its suppression of pyroptosis. CONCLUSION: Our research indicates that BeG has the potential to alleviate multi-organ injury induced by HS. The protective effect of BeG is likely associated with its promotion of mitophagy through AMPK activation, thereby inhibiting NLRP3 inflammasome-mediated pyroptosis.
Assuntos
Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Piroptose , Ratos Sprague-Dawley , Choque Hemorrágico , Choque Hemorrágico/tratamento farmacológico , Choque Hemorrágico/complicações , Animais , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Piroptose/efeitos dos fármacos , Humanos , Masculino , Inflamassomos/metabolismo , Linhagem Celular , Ratos , Cumarínicos/farmacologia , Cumarínicos/uso terapêutico , Mitofagia/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Modelos Animais de Doenças , Insuficiência de Múltiplos Órgãos/tratamento farmacológico , Insuficiência de Múltiplos Órgãos/prevenção & controle , Insuficiência de Múltiplos Órgãos/etiologiaRESUMO
c-MET and STAT-3 are significant targets for cancer treatments. Here, we describe a class of very effective dual STAT-3 and c-MET inhibitors with coumarin-based thiazoles (3a-o) as its scaffold. Spectroscopic evidence (NMR, HRMS, and HPLC) validated the structural discoveries of the new compounds. The cytotoxic activity of these compounds was also tested against a panel of cancer cells in accordance with US-NCI guidelines. Compound 3g proved to be active at 10 µM, thus it was automatically scheduled to be tested at five doses. Towards SNB-75 (CNS cancer cell line), compound 3g showed notable in vitro anti-cancer activity with GI50 = 1.43 µM. For the molecular targets, compound 3g displayed potent activity towards STAT-3 and c-MET having IC50 of 4.7 µM and 12.67, respectively, compared to Cabozantinib (IC50 = 15 nM of c-MET) and STAT-3-IN-3 (IC50 = 2.1 µM of STAT-3). Moreover, compound 3g significantly induced apoptosis in SNB-75 cells, causing a 3.04-fold increase in apoptotic cell death (treated cells exhibited 11.53 % overall apoptosis, against 3.04 % in reference cells) and a 3.58-fold increase in necrosis. Moreover, it arrests cells at the G2 phase. Dual inhibition of c-MET and STAT-3 protein kinase was further validated using RT-PCR. The target compound's binding mechanism was determined by the application of molecular docking.
Assuntos
Antineoplásicos , Proliferação de Células , Cumarínicos , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Proteínas Proto-Oncogênicas c-met , Fator de Transcrição STAT3 , Tiazóis , Humanos , Cumarínicos/farmacologia , Cumarínicos/química , Cumarínicos/síntese química , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/metabolismo , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Tiazóis/farmacologia , Tiazóis/química , Tiazóis/síntese química , Relação Estrutura-Atividade , Estrutura Molecular , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Apoptose/efeitos dos fármacos , Relação Dose-Resposta a Droga , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Simulação de Acoplamento MolecularRESUMO
Phytochemical characteristics and antimicrobial properties of extracts were studied in Nonea rossica Steven (Boraginaceae), which is widespread in Russia. The aerial part (herb) of N. rossica was harvested from a steppe meadow in the Novosibirsk region during flowering. The qualitative composition of biologically active compounds (BACs) was determined by thin-layer chromatography. Quantitative assays were carried out by spectrophotometry; flavonoids, hydroxycinnamic acids, and coumarin-like compounds were measured with reference to rutin, caffeic acid, and coumarin, respectively. Antimicrobial activity was determined by the serial dilution method. Gram-positive bacterial (Staphylococcus aureus ATCC 6538 FDA 209P and Bacillus cereus ATCC 10702) and fungal (Candida albicans NCTC 885-653) strains were used as test cultures. Phenolic BACs (hydroxycinnamic acids, flavonoids, and coumarins) were detected, and their quantitative contents determined. The highest yield of phenolic BACs was achieved using 40-70% ethanol as an extractant. Antimicrobial activity against S. aureus and B. cereus and antifungal activity against C. albicans were detected in N. rossica herb extracts prepared using 40-70% ethanol. The extracts were tested for the contents of caffeic acid and coumarin. Synergistic interactions of these compounds determined the bactericidal and fungistatic properties of the extracts.
Assuntos
Boraginaceae , Candida albicans , Compostos Fitoquímicos , Extratos Vegetais , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Boraginaceae/química , Candida albicans/efeitos dos fármacos , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/química , Anti-Infecciosos/farmacologia , Anti-Infecciosos/química , Staphylococcus aureus/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Cumarínicos/farmacologia , Cumarínicos/química , Bacillus cereus/efeitos dos fármacos , Antifúngicos/farmacologia , Antifúngicos/química , Flavonoides/farmacologia , Flavonoides/química , Antibacterianos/farmacologia , Antibacterianos/químicaRESUMO
Re-discovery of known metabolites is a common challenge in natural product-based drug discovery, and to avoid re-discovery, dereplication has been proposed for identifying known metabolites at the early stage of isolation. A majority of methods use LCMS to profile the extract and ignore the known mass. LC-HRMS profiling may generate a long mass list of metabolites. The identification of a new metabolite is difficult within the mass list. To overcome this, it was hypothesized that identifying a 'new metabolite' in the whole metabolome is more difficult than identifying it within the class of metabolites. A prioritization strategy was proposed to focus on the elimination of unknown and uncommon metabolites first using the designed bias filters and to prioritize the known secondary metabolites. The study employed Murraya paniculata root for the identification of new metabolites. The LC-HRMS-generated mass list of 509 metabolites was subjected to various filters, which resulted in 93 metabolites. Subsequently, it was subjected to regular dereplication, resulting in 10 coumarins, among which 3 were identified as new. Further, chromatographic efforts led to the isolation of a new coumarin, named ghosalin (1). The structure of the new compound was established through 2D NMR and X-ray crystallography. Cytotoxicity studies revealed that ghosalin has significant cytotoxicity against cancer cell lines. The proposed prioritization strategy demonstrates an alternative way for the rapid annotation of a particular set of metabolites to isolate a new metabolite from the whole metabolome of a plant extract.
Assuntos
Murraya , Extratos Vegetais , Raízes de Plantas , Raízes de Plantas/química , Raízes de Plantas/metabolismo , Humanos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Extratos Vegetais/metabolismo , Murraya/química , Cumarínicos/química , Cumarínicos/farmacologia , Cumarínicos/metabolismo , Cumarínicos/análise , Cromatografia Líquida/métodos , Linhagem Celular Tumoral , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/químicaRESUMO
In the present study, the design and synthesis of novel coumarin derivatives 8a-h, 11a-d and 16a-c as potential selective inhibitors for the tumor associated human carbonic anhydrase isoforms (hCA IX and XII) was reported. All the newly synthesized derivatives showed potent to mild activity against the targeted CA IX (KI = 0.08-9.57 µM), with selectivity indices over CA I (SI = 2.0-21.9) and over CA II (SI = 1.1-15.7). They showed similar activities against CA XII (KI = 0.06-9.48 µM) with selectivity indices over CA I (SI = 1.4-21.2) and CA II (SI = 0.9-15.5). Compound 16b featuring sulfonamide function possessed promising inhibitory activities against the targeted isoforms CA IX and XII with KI values of 0.08 and 0.06 µM, respectively. Interestingly, it was found that using compound 16b at a nontoxic concentration as an adjuvant with Doxorubicin against MCF-7 cells enhanced the cytotoxicity under hypoxia by almost 3.5 folds; IC50 decreased from 25.74 to 7.43 µM. Therefore, compound 16b restored the cytotoxicity of Doxorubicin against MCF-7 cells under hypoxia, almost as normoxia. Furthermore, flow cytometry analysis of a combination treatment of compound 16b and Doxorubicin to the MCF7 cell line revealed an increase in cell cycle arrest at the G2/M phase and a more efficient apoptotic effect than Doxorubicin alone. Furthermore, compound 16b showed no cytotoxicity against normal breast MCF-10A cell line (IC50 = 296.25 µM).
Assuntos
Anidrase Carbônica IX , Inibidores da Anidrase Carbônica , Anidrases Carbônicas , Proliferação de Células , Cumarínicos , Relação Dose-Resposta a Droga , Doxorrubicina , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Inibidores da Anidrase Carbônica/farmacologia , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/síntese química , Cumarínicos/farmacologia , Cumarínicos/química , Cumarínicos/síntese química , Anidrase Carbônica IX/antagonistas & inibidores , Anidrase Carbônica IX/metabolismo , Doxorrubicina/farmacologia , Células MCF-7 , Anidrases Carbônicas/metabolismo , Relação Estrutura-Atividade , Estrutura Molecular , Proliferação de Células/efeitos dos fármacos , Antígenos de Neoplasias/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Hipóxia Celular/efeitos dos fármacosRESUMO
Photodynamic therapy (PDT) is an effective method for treating microbial infections by leveraging the unique photophysical properties of photosensitizing agents, but issues such as fluorescence quenching and the restricted generation of reactive oxygen species (ROS) under hypoxic conditions still remain. In this study, we successfully synthesized and designed a coumarin-based aggregation-induced emission luminogen (AIEgen), called ICM, that shows a remarkable capacity for type I ROS and type II ROS generation. The 1O2 yield of ICM is 0.839. The ROS it produces include hydroxyl radicals (HOâ¢) and superoxide anions (O2â¢-), with highly effective antibacterial properties specifically targeting Staphylococcus aureus (a Gram-positive bacterium). Furthermore, ICM enables broad-spectrum fluorescence imaging and exhibits excellent biocompatibility. Consequently, ICM, as a potent type I photosensitizer for eliminating pathogenic microorganisms, represents a promising tool in addressing the threat posed by these pathogens.