RESUMO
Rationale : the proto-oncogene KRAS is frequently mutated in colorectal cancer (CRC), leading to inherent resistance against monoclonal antibodies targeting the epidermal growth factor receptor (EGFR), such as cetuximab. Therefore, addressing the primary resistance and expanding the indications for target therapy have become critical challenges. Methods : the screening of a natural product library against KRAS mutant CRC cells was conducted, leading to the discovery of a small molecule compound that sensitive to the KRASG13D mutation site. The anti-tumor activity of this small molecule compound in combination with cetuximab was evaluated using the KRASG13D mutant CRC models both in vivo and in vitro. This evaluation includes an examination of its effects on cell proliferation, viability, apoptosis, cell cycle progression, and tumor growth. Furthermore, RNA sequencing, western blot analysis, immunofluorescence, real-time quantitative PCR, and pull-down assays were employed to explore the molecular mechanisms underlying the synergistic anti-tumor effect of this small molecule compound in combination with cetuximab. Results : our study screened 882 compounds in KRAS mutant CRC cells and identified honokiol, a small molecule compound that exhibits specific sensitivity to KRASG13D mutant CRC cells. Furthermore, we revealed that the synergistic augmentation of cetuximab's sensitivity in vivo and in vitro models of KRASG13D mutant CRC in combination with honokiol. Mechanistically, honokiol suppresses SNX3-retromer mediated trafficking, thereby impeding lysosomal proteolytic capacity and inhibiting autophagy and macropinocytosis fluxes. Moreover, honokiol inhibits the conversion of RAS GDP to RAS GTP, heightening the susceptibility of KRASG13D CRC mutant cells to cetuximab. Conclusions : honokiol enhances the sensitivity of cetuximab by destroying SNX3 retromer in KRASG13D mutant CRC preclinical model. These findings present a promising strategy for expanding the indications of target therapy in KRAS mutant colorectal cancer patients.
Assuntos
Apoptose , Compostos de Bifenilo , Proliferação de Células , Cetuximab , Neoplasias Colorretais , Lignanas , Mutação , Proteínas Proto-Oncogênicas p21(ras) , Cetuximab/farmacologia , Cetuximab/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Humanos , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Animais , Lignanas/farmacologia , Lignanas/uso terapêutico , Linhagem Celular Tumoral , Compostos de Bifenilo/farmacologia , Compostos de Bifenilo/uso terapêutico , Camundongos , Proliferação de Células/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Proto-Oncogene Mas , Sinergismo Farmacológico , Camundongos Nus , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Camundongos Endogâmicos BALB C , Compostos Alílicos , FenóisRESUMO
As a continuation of our efforts to develop new agrochemicals with typical architecture and efficient bioactivity from plant natural products, natural neolignan honokiol was used as a lead compound to prepare novel analogs bearing the core 2-aminobenzoxazole scaffold. Their insecticidal potency against two representative agricultural pests, Plutella xylostella Linnaeus and Mythimna separata (Walker), were evaluated in vivo. The pesticide bioassay results revealed that compounds 7â³a, 9, 10d, and 10j exhibited prominent larvicidal activity against the larvae of P. xylostella (LC50 = 7.95, 11.85, 15.51, and 12.06 µg/mL, respectively), superior to the precursor honokiol (LC50 = 43.35 µg/mL) and two botanical insecticides, toosendanin (LC50 = 26.20 µg/mL) and rotenone (LC50 = 23.65 µg/mL). Compounds 7d, 10d, and 10j displayed a more pronounced nonchoice antifeedant effect (AFC50 = 9.48, 9.14, and 12.41 µg/mL, respectively) than honokiol (AFC50 = 54.81 µg/mL) on P. xylostella. Moreover, compounds 7b, 7â³a, 9, 10d, 10f, and 10j showed better growth inhibitory activity against M. separata (LC50 = 0.36, 0.34, 0.28, 0.16, 0.26, and 0.11 mg/mL, respectively) than honokiol, toosendanin, and rotenone (LC50 = 1.48, 0.53, and 0.46 mg/mL, respectively). A potted plant assay under greenhouse conditions illustrated that compounds 10d and 10j continued to provide good control efficacy against P. xylostella and an apparent protective effect on plants. Further cytotoxicity assay revealed that the aforementioned potent compounds showed relatively moderate toxicity and a good safety profile for non-target mammalian cells. Overall, the current work provides valuable insight into the agrochemical innovation of honokiol-derived analogs for use as natural-inspired pesticides in agricultural pest management.
Assuntos
Compostos de Bifenilo , Inseticidas , Larva , Lignanas , Mariposas , Animais , Lignanas/farmacologia , Lignanas/química , Inseticidas/química , Inseticidas/farmacologia , Mariposas/efeitos dos fármacos , Mariposas/crescimento & desenvolvimento , Larva/efeitos dos fármacos , Larva/crescimento & desenvolvimento , Compostos de Bifenilo/química , Relação Estrutura-Atividade , Benzoxazóis/química , Benzoxazóis/farmacologia , Estrutura Molecular , Compostos Alílicos , Aminas , Oxazóis , FenóisRESUMO
Objective: This study investigates the targets, pathways, and mechanisms of Schisandrin B (Sch B) in alleviating renal ischemia-reperfusion injury (RIRI) using RNA sequencing and network pharmacology. Methods: The effects of Sch B on RIRI were assessed using hematoxylin-eosin (HE) and periodic acid-Schiff (PAS) staining, along with measurements of blood creatinine and urea nitrogen (BUN). Differential gene expression in mouse models treated with RIRI and Sch B+RIRI was analyzed through RNA-Seq. Key processes, targets, and pathways were examined using network pharmacology techniques. The antioxidant capacity of Sch B was evaluated using assays for reactive oxygen species (ROS), mitochondrial superoxide, and JC-1 membrane potential. Molecular docking was employed to verify the interactions between key targets and Sch B, and the expression of these targets and pathway was confirmed using qRT-PCR, Western blot, and immunofluorescence. Results: Sch B pre-treatment significantly reduced renal pathological damage, inflammatory response, and apoptosis in a mouse RIRI model. Pathological damage scores dropped from 4.33 ± 0.33 in the I/R group to 2.17 ± 0.17 and 1.5 ± 0.22 in Sch B-treated groups (p < 0.01). Creatinine and BUN levels were also reduced (from 144.6 ± 21.05 µmol/L and 53.51 ± 2.34 mg/dL to 50.44 ± 5.61 µmol/L and 17.18 ± 0.96 mg/dL, p < 0.05). Transcriptomic analysis identified four key targets (AKT1, ALB, ACE, CCL5) and the PI3K/AKT pathway. Experimental validation confirmed Sch B modulated these targets, reducing apoptosis and oxidative stress, and enhancing renal recovery. Conclusion: Sch B reduces oxidative stress, inflammation, and apoptosis by modulating key targets such as AKT1, ALB, ACE, and CCL5, while activating the PI3K/AKT pathway, leading to improved renal recovery in RIRI.
Assuntos
Ciclo-Octanos , Lignanas , Compostos Policíclicos , Traumatismo por Reperfusão , Lignanas/farmacologia , Lignanas/química , Animais , Ciclo-Octanos/farmacologia , Ciclo-Octanos/química , Compostos Policíclicos/farmacologia , Compostos Policíclicos/química , Camundongos , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Masculino , Transcriptoma/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Substâncias Protetoras/farmacologia , Substâncias Protetoras/química , Modelos Animais de Doenças , Apoptose/efeitos dos fármacos , Farmacologia em RedeRESUMO
The natural lignan diphyllin has shown promising antitumor activity, although its clinical advancement has been impeded by challenges such as low solubility, poor metabolic stability, and limited potency. In response, we developed and synthesized two sets of diphyllin 4-C derivatives, comprising six ester derivatives and eight 1, 2, 3-triazole derivatives. Notably, among these derivatives, 1, 2, 3-triazole derivatives 7c and 7e demonstrated the most potent cytotoxic effects, with IC50 values ranging from 0.003 to 0.01 µM. Treatment with 0.2 µM of 7c and 7e resulted in a reduction of V-ATPase activity in HGC-27 cells to 23% and 29%, respectively.
Assuntos
Antineoplásicos , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Lignanas/farmacologia , Lignanas/química , Lignanas/síntese química , Relação Estrutura-Atividade , Triazóis/química , Triazóis/farmacologia , Triazóis/síntese química , ATPases Vacuolares Próton-Translocadoras/antagonistas & inibidores , ATPases Vacuolares Próton-Translocadoras/metabolismo , Azidas/síntese química , Azidas/química , Azidas/farmacologiaRESUMO
BACKGROUND: Colorectal cancer (CRC) is a significant disease worldwide, with high mortality rates. Conventional treatment methods often lead to metastasis and drug resistance, highlighting the need to explore new drugs and their potential molecular mechanisms. In this study, we investigated the effects of arctigenin on CRC cell proliferation, migration, invasion, apoptosis, and related protein expression, as well as its potential molecular mechanisms. METHODS: The CCK-8 assay, transwell migration and invasion assays, flow cytometry, immunoblotting and immunofluorescence staining, western blot and an allograft tumor transplantation model was used. RESULTS: Our study revealed that arctigenin effectively inhibited CRC cell proliferation, migration, and invasion in a dose-dependent manner, while also inducing apoptosis. At the molecular level, arctigenin significantly downregulated the expressions of PCNA, Bcl2, MMP-2, and MMP-9 and upregulated the expressions of Bax and cleaved caspase-3. Additionally, arctigenin demonstrated the ability to inhibit the epithelial-mesenchymal transition (EMT) process by upregulating E-cadherin and downregulating mesenchymal markers, such as N-cadherin, Vimentin, Snail, and Slug. Furthermore, arctigenin could inhibit the activation of the PI3K-AKT-mTOR signaling pathway, which has been implicated in cancer progression. In vivo experiments also showed that arctigenin significantly reduced tumor volume and size compared to the control group, with no significant adverse effects on the liver. CONCLUSIONS: This is the first study to elucidate the mechanism by which arctigenin inhibits colorectal cancer metastasis through the PI3K-AKT-mTOR signaling pathway by suppressing the EMT process at the molecular level.
Assuntos
Movimento Celular , Proliferação de Células , Neoplasias Colorretais , Transição Epitelial-Mesenquimal , Furanos , Lignanas , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Serina-Treonina Quinases TOR , Lignanas/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Furanos/farmacologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Serina-Treonina Quinases TOR/metabolismo , Humanos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Proliferação de Células/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Camundongos , Linhagem Celular Tumoral , Apoptose/efeitos dos fármacos , Camundongos Nus , Progressão da Doença , Camundongos Endogâmicos BALB C , Masculino , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVE: This study aims to systematically analyze the potential active components of Eucommiae cortex in the treatment of post- myocardial infarction heart failure through network analysis and molecular docking methods. In vitro experiments were conducted to verify that medioresinol, a component of Eucommiae cortex, improves oxygen-glucose deprivation-induced cell failure through its anti-inflammatory and antioxidant capacities. METHODS: Potential active components of Eucommiae cortex were screened using specific data. The targets of these components were predicted using Swiss Institute of Bioinformatics database and TargetNet, and key targets were identified by intersecting with the disease targets of myocardial infarction and heart failure. Protein-Protein Interaction analysis was performed on the key targets to screen for core targets. Genomics Institute of the Novartis Research Foundation and Human Protein Atlas were used to identify myocardial highly expressed targets. Kyoto Encyclopedia of Genes and Genomes and Gene Ontology enrichment analyses were conducted using the Database for Annotation, Visualization, and Integrated Discovery. Molecular docking was performed for the final components and target proteins. In vitro experiments were carried out using H9c2 cells subjected to oxygen and glucose deprivation conditions to validate the effects of the screened potential active components. RESULTS: Network analysis revealed that Eucommiae cortex might exert its effects through the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR), hypoxia-inducible factor 1, and Janus kinase/signal transducer and activator of transcription pathways, which are crucial for myocardial contraction, vascular tone regulation, inflammatory response, and oxidative stress. Molecular docking indicated stable binding of the selected compounds to PI3K, AKT, and mTOR. Medioresinol was selected for further study and shown to significantly improve oxidative stress and inflammatory response in myocardial ischemia-hypoxia model cells by activating the PI3K/AKT/mTOR pathway. CONCLUSION: This study confirms the role of the PI3K/AKT/mTOR pathway in the cardiovascular protective effects of Eucommiae cortex and provides evidence at the cellular level. Medioresinol demonstrated potential therapeutic effects on myocardial infarction induced heart failure by reducing oxidative stress and inflammatory responses. These findings offer a theoretical basis for the application of Eucommiae cortex in the treatment of heart failure and support the development of new therapeutic drugs for cardiovascular diseases. Future research should further validate these effects in animal models and explore the overall efficacy of Eucommiae cortex.
Assuntos
Eucommiaceae , Insuficiência Cardíaca , Simulação de Acoplamento Molecular , Infarto do Miocárdio , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Serina-Treonina Quinases TOR , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/complicações , Infarto do Miocárdio/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Eucommiaceae/química , Animais , Insuficiência Cardíaca/metabolismo , Lignanas/farmacologia , Ratos , Humanos , Linhagem Celular , Miócitos Cardíacos/metabolismo , Medicamentos de Ervas ChinesasRESUMO
Myrrh has a long tradition in the treatment of inflammatory diseases. However, many of its (active) constituents are still unknown. In the present study, secondary metabolites were isolated from an ethanolic extract by various separation methods (liquid-liquid partition, silica and RP18 flash chromatography, CPC, and preparative HPLC), their structures were elucidated with NMR spectroscopy and mass spectrometry, and the selected compounds were tested for their effect on LPS-induced NO production by RAW 264.7 murine macrophages. Among the isolated substances are 17 sesquiterpenes (1-17) including the first 4,8-cycloeudesmane (1), a triterpene (38), two phytosterols (39, 40) and one lignan (43), which were previously unknown as natural products. Numerous compounds are described for the first time for the genus Commiphora. Eight of the eleven compounds tested (1, 29, 31, 32, 34-37) showed a statistically significant, concentration-dependent weak to moderate anti-inflammatory effect on NO production in the LPS-stimulated RAW 264.7 macrophages in vitro. For the reference substance, furanoeudesma-1,3-diene, an IC50 of 46.0 µM was determined. These sesquiterpenes might therefore be part of the multi-target molecular principles behind the efficacy of myrrh in inflammatory diseases.
Assuntos
Anti-Inflamatórios , Commiphora , Lignanas , Sesquiterpenos , Esteroides , Triterpenos , Commiphora/química , Camundongos , Animais , Lignanas/farmacologia , Lignanas/química , Lignanas/isolamento & purificação , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Células RAW 264.7 , Triterpenos/farmacologia , Triterpenos/química , Triterpenos/isolamento & purificação , Sesquiterpenos/farmacologia , Sesquiterpenos/química , Sesquiterpenos/isolamento & purificação , Esteroides/farmacologia , Esteroides/química , Esteroides/isolamento & purificação , Óxido Nítrico/metabolismo , Óxido Nítrico/biossíntese , Resinas Vegetais/química , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Lipopolissacarídeos/farmacologia , Estrutura Molecular , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Espectroscopia de Ressonância MagnéticaRESUMO
Infections with methicillin-resistant Staphylococcus aureus (MRSA) are becoming increasingly serious, making the development of novel antimicrobials urgent. Here, we synthesized some amphiphilic honokiol derivatives bearing an oxazole moiety and investigated their antibacterial and hemolytic activities. Bioactivity evaluation showed that E17 possessed significant in vitro antibacterial activity against S. aureus and MRSA, along with low hemolytic activity. Moreover, E17 exhibited rapid bactericidal properties and was not susceptible to resistance. Mechanistic studies indicated that E17 interacts with phosphatidylglycerol and cardiolipin of bacterial cell membranes, leading to changes in cell membrane permeability and polarization, increased intracellular ROS, and leakage of DNA and proteins, thus accelerating bacterial death. Transcriptome analysis further demonstrated that E17 has membrane-targeting effects, affecting the expression of genes related to cell membranes and ABC transporter proteins. Notably, in vivo activity showed that E17 has prominent anti-MRSA efficacy, comparable to vancomycin, and is expected to be a new anti-MRSA drug candidate.
Assuntos
Antibacterianos , Compostos de Bifenilo , Lignanas , Staphylococcus aureus Resistente à Meticilina , Testes de Sensibilidade Microbiana , Oxazóis , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Lignanas/farmacologia , Lignanas/química , Lignanas/síntese química , Oxazóis/farmacologia , Oxazóis/química , Oxazóis/síntese química , Animais , Hemólise/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Relação Estrutura-Atividade , Humanos , Camundongos , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Compostos Alílicos , FenóisRESUMO
Arctigenin (Ar) is a promising therapeutic candidate for postmenopausal osteoporosis (PMOP). This study explores its mechanism by examining its effects on adipogenesis and osteogenesis in ovariectomized (OVX) rats. In vitro, Ar effectively suppressed the adipogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) from OVX rats, reducing lipid droplet formation and downregulating proteins associated with lipid synthesis. In vivo, Ar treatment significantly reduced bone loss, inhibited adipocyte development, improved lipid metabolism, and promoted bone formation in OVX rats. Mechanistically, Ar inhibited the phosphorylation of Mitogen-Activated Protein Kinase 1 (MEK1), downregulated Peroxisome Proliferator-Activated Receptor gamma (PPARγ), promoted the accumulation of ß-catenin in the nucleus, and prevented the direct binding of PPARγ to ß-catenin in BMSCs. This regulation of the PPARγ/Wnt signaling axis underlies its dual role in inhibiting adipogenesis and promoting osteogenesis. Notably, co-treatment with rosiglitazone (RGZ) reversed the effects of Ar on adipogenesis and osteogenesis without affecting MEK1 inhibition. These findings offer valuable insights into arctigenin's potential as a therapeutic strategy for PMOP by modulating MEK1 signaling and regulating the PPARγ/Wnt axis.
Assuntos
Adipogenia , Furanos , Lignanas , MAP Quinase Quinase 1 , Células-Tronco Mesenquimais , Osteogênese , Ovariectomia , PPAR gama , Ratos Sprague-Dawley , Via de Sinalização Wnt , beta Catenina , Animais , PPAR gama/metabolismo , Osteogênese/efeitos dos fármacos , Feminino , Adipogenia/efeitos dos fármacos , Lignanas/farmacologia , Lignanas/química , Ratos , Via de Sinalização Wnt/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/citologia , Furanos/farmacologia , Furanos/química , MAP Quinase Quinase 1/metabolismo , beta Catenina/metabolismo , Medula Óssea/metabolismo , Medula Óssea/efeitos dos fármacos , HumanosRESUMO
Objective To investigate the effects of Schisandrae Chinensis Fructus lignans on the alertness of the rats with sleep deprived by treadmill exercise and the underlying neurobiological mechanism. Methods According to the random number table method,SD male rats were assigned into control,sleep deprivation,low-,medium-,and high-dose Schisandrae Chinensis Fructus lignans,and atomoxetine hydrochloride groups,with 8 rats in each group.The rats in other groups except the control group were subjected to sleep deprivation by treadmill exercise for 3 d.During the deprivation period,each administration group was administrated with the corresponding drug by gavage,and a 5-9 hole tester was used to test the alertness performance of rats in each group. Furthermore,other SD male rats were selected and randomized into control,sleep deprivation,Schisandrae Chinensis Fructus lignans (67.2 mg/kg) and atomoxetine hydrochloride groups,with 10 rats in each group.The rats were modeled with the sleep deprivation method the same as that above and administrated with corresponding agents.ELISA was employed to measure the serum level of orexin A in each group of rats.The protein levels of c-Fos,orexin receptor 1,and orexin receptor 2 in the prefrontal cortex of rats in each group were observed by immunofluorescence and Western blotting. Results Compared with the control group,sleep deprivation reduced the choice accuracy (P<0.001) and increased the omission responses,omission percent,and mean correct response latency (P=0.002,P=0.003,P=0.020).Compared with the sleep deprivation group,medium- and high-dose Schisandrae Chinensis Fructus lignans and atomoxetine hydrochloride improved the alertness of rats,as demonstrated by the increased choice accuracy (P=0.001,P=0.006,P<0.001) and reduced omission responses (P=0.001,P=0.001,P<0.001),omission percent (P=0.001,P=0.002,P<0.001),and mean correct response latency (P=0.018,P=0.003,P=0.014).Compared with the control group,the sleep deprivation group showed elevated level of orexin A in the serum (P<0.001),up-regulated expression of c-Fos (P<0.001),and down-regulated expression of orexin receptor 1 (P=0.037) in the prefrontal cortex.Compared with the sleep deprivation group,Schisandrae Chinensis Fructus lignans (67.2 mg/kg) and atomoxetine hydrochloride lowered the orexin A level in the serum (P=0.005,P=0.029),down-regulated the expression of c-Fos (P=0.028,P=0.036),and up-regulated the expression of orexin receptor 1 (P=0.043,P=0.013) in the prefrontal cortex. Conclusion Schisandrae Chinensis Fructus lignans may antagonize the alertness decrease caused by sleep deprivation by regulating the secretion of orexin and the expression of orexin receptor 1 in the prefrontal cortex.
Assuntos
Lignanas , Ratos Sprague-Dawley , Schisandra , Privação do Sono , Animais , Lignanas/farmacologia , Schisandra/química , Masculino , Privação do Sono/metabolismo , Privação do Sono/tratamento farmacológico , Ratos , Orexinas/metabolismo , Neuropeptídeos/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismoRESUMO
The risk of ulcerative colitis (UC) is increasing worldwide with limited success using classical drugs, which has underscored the development of novel agents. Recently, carrier-free molecular assembly has been proven to be an effective drug delivery system, but it has yet to be examined for UC drug development using phytochemicals. Based on traditional Chinese medicine compatibility and potential medicinal uses, a pair of natural compounds, berberine (BBR) and magnolol (MAG), were found to self-assemble into nanostructures in aqueous solutions. Spectral analysis revealed that the assembly mechanisms of BBR and MAG were mediated through charge interactions and π-π stacking. Pharmacokinetic studies and animal imaging showed that BBR-MAG self-assembly (BM) effectively promoted the oral bioavailability and biodistribution of BBR in the colon. BM exhibited superior effects in regulating inflammatory factors, maintaining colon barrier integrity, and regulating gut microbiota in a dextran sulfate sodium salt-induced colitis mouse model. Additionally, no apparent signs of toxicity were observed, suggesting that BM has a favorable safety profile. This study presents a new strategy for UC management and highlights the cooperative effects of combined phytochemicals.
Assuntos
Berberina , Compostos de Bifenilo , Colite Ulcerativa , Lignanas , Nanoestruturas , Animais , Colite Ulcerativa/tratamento farmacológico , Berberina/química , Berberina/farmacologia , Berberina/uso terapêutico , Lignanas/química , Lignanas/farmacologia , Lignanas/uso terapêutico , Camundongos , Compostos de Bifenilo/química , Nanoestruturas/química , Masculino , Sulfato de Dextrana/química , Colo/efeitos dos fármacos , Colo/patologia , Modelos Animais de Doenças , Distribuição Tecidual , Camundongos Endogâmicos C57BL , Microbioma Gastrointestinal/efeitos dos fármacos , Disponibilidade BiológicaRESUMO
Matairesinol (MAT), a plant lignan renowned for its anticancer properties in hormone-sensitive cancers like breast and prostate cancers, presents a promising yet underexplored avenue in the treatment of metastatic prostate cancer (mPC). To elucidate its specific therapeutic targets and mechanisms, our study adopted an integrative approach, amalgamating network pharmacology (NP), bioinformatics, GeneMANIA-based functional association (GMFA), and experimental validation. By mining online databases, we identified 27 common targets of mPC and MAT, constructing a MAT-mPC protein-protein interaction network via STRING and pinpointing 11 hub targets such as EGFR, AKT1, ERBB2, MET, IGF1, CASP3, HSP90AA1, HIF1A, MMP2, HGF, and MMP9 with CytoHuba. Utilizing DAVID, Gene Ontology (GO) analysis highlighted metastasis-related processes such as epithelial-mesenchymal transition, positive regulation of cell migration, and key Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, including cancer, prostate cancer, PI3K-Akt, and MAPK signaling, while the web resources such as UALCAN and GEPIA2 affirmed the clinical significance of the top 11 hub targets in mPC patient survival analysis and gene expression patterns. Our innovative GMFA enrichment method further enriched network pharmacology findings. Molecular docking analyses demonstrated substantial interactions between MAT and 11 hub targets. Simulation studies confirmed the stable interactions of MAT with selected targets. Experimental validation in PC3 cells, employing quantitative real-time reverse-transcription PCR and various cell-based assays, corroborated MAT's antimetastatic effects on mPC. Thus, this exhaustive NP analysis, complemented by GMFA, molecular docking, molecular dynamics simulations, and experimental validations, underscores MAT's multifaceted role in targeting mPC through diverse therapeutic avenues. Nevertheless, comprehensive in vitro validation is imperative to solidify these findings.
Assuntos
Biologia Computacional , Farmacologia em Rede , Neoplasias da Próstata , Biologia de Sistemas , Masculino , Humanos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/genética , Biologia Computacional/métodos , Mapas de Interação de Proteínas/efeitos dos fármacos , Metástase Neoplásica , Linhagem Celular Tumoral , Lignanas/farmacologia , Lignanas/química , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacosRESUMO
BACKGROUND: Since the onset of the coronavirus disease 2019 (COVID-19) pandemic, remarkable advances have been made in vaccine development to reduce mortality. However, therapeutic interventions for COVID-19 are comparatively limited despite these intensive efforts. Furthermore, the rapid mutation capability of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a characteristic of its RNA structure, has led to the emergence of multiple variants, necessitating a shift from a predominantly vaccine-centric approach to one that encompasses therapeutic strategies. 6'-Hydroxy justicidin B (6'-HJB), an arylnaphthalene lignan isolated from Justicia procumbens, a traditional Chinese medicine, is known for its antiviral properties. HYPOTHESIS/PURPOSE: The aim of the present study was to assess the effectiveness and safety of 6'-HJB against SARS-CoV-2 in order to determine its potential as a therapeutic agent against COVID-19. METHODS: The efficacy of 6'-HJB was evaluated both in vitro using Vero and Calu-3 cell lines and in vivo using ferrets. The safety assessment included toxicokinetics, safety pharmacology, and Good Laboratory Practice (GLP)-compliant toxicity evaluations following single- and repeated-dose toxicity studies in dogs. RESULTS: The anti-SARS-CoV-2 efficacy of 6'-HJB was evaluated through dose-response curve (DRC) analysis using immunofluorescence; 6'-HJB demonstrated superior inhibition of SARS-CoV-2 growth and lower cytotoxicity than remdesivir. In SARS-CoV-2-infected ferret, 6'-HJB showed efficacy comparable to that of the positive control, Truvada. Further GLP toxicity studies corroborated the safety profile of 6'-HJB. Single-dose and 4-week repeated oral toxicity studies in Beagle dogs demonstrated minimal harmful effects at the highest dosages. The lethal dose of 6'-HJB exceeded 2,000 mg kg-1 in Beagle dogs. Toxicokinetic and GLP safety pharmacology studies demonstrated no adverse effects of 6'-HJB on metabolic processes, respiratory or central nervous systems, or cardiac functions. CONCLUSION: This research highlights both the antiviral efficacy and safety profile of 6'-HJB, underscoring its potential as a novel COVID-19 treatment option. The potential of 6'-HJB was demonstrated using modern scientific methodologies and standards.
Assuntos
Antivirais , Tratamento Farmacológico da COVID-19 , Justicia , SARS-CoV-2 , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Células Vero , Chlorocebus aethiops , Humanos , SARS-CoV-2/efeitos dos fármacos , Justicia/química , Furões , Masculino , Lignanas/farmacologia , Lignanas/uso terapêutico , Alanina/análogos & derivados , Alanina/farmacologia , Alanina/uso terapêutico , Feminino , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , COVID-19 , Cães , DioxolanosRESUMO
Eight novel arylnaphthalide lactone lignans, designated as diphylignan A-H (1-8), and a new dibenzyltyrolactone lignan, designated as diphylignan I (9), were isolated from the roots and rhizomes of Diphylleia sinensis, along with two additional novel natural products (11 and 14) and four known metabolites (10, 12, 13, 15). The structural and stereochemical characterization of these compounds was accomplished using NMR spectroscopy and electronic circular dichroism (ECD) analysis. The cytotoxic activities of all isolated compounds were assessed against A-549 and SMMC-7721 cell lines. Notably, compound 2 demonstrated the most significant cytotoxicity, with IC50 values of 10.27 and 11.58 µmol·L-1 against A-549 and SMMC-7721 cell lines, respectively, exhibiting greater potency than the positive control, cisplatin.
Assuntos
Antineoplásicos Fitogênicos , Lignanas , Raízes de Plantas , Rizoma , Lignanas/farmacologia , Lignanas/química , Lignanas/isolamento & purificação , Raízes de Plantas/química , Humanos , Rizoma/química , Linhagem Celular Tumoral , Estrutura Molecular , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , China , Berberidaceae/químicaRESUMO
BACKGROUND/AIM: Non-small cell lung cancer is known for its rapid growth and immune evasion, demanding effective therapies targeting both tumor cells and the microenvironment. Magnolol has shown promising anti-tumor effects in various cancers. MATERIALS AND METHODS: CL1-5-F4-bearing mice were divided into control, 40 mg/kg, and 60 mg/kg magnolol groups, once tumors reached 100 mm3 Tumor growth and body weight were monitored biweekly, and after 13 days, mice were euthanized for tumor and organ collection for subsequent staining. Histopathology and serum biochemistry assessed organ toxicity. RESULTS: Magnolol dose-dependently suppressed NSCLC progression, with no pathology alterations observed in normal organs. Magnolol-induced apoptosis and cell cycle arrest, evidenced by increased cleaved caspase-3 and decreased cyclin D1/CDK4 levels. It also down-regulated VEGF, FOXP3, and IDO-1 in tumors, implicating tumor microenvironment modulation. CONCLUSION: Magnolol exhibits significant antitumor effects in NSCLC by inducing apoptosis, inhibiting proliferation, and modulating the tumor microenvironment. These results support further investigation of magnolol as a therapeutic adjuvant to enhance NSCLC treatment outcomes.
Assuntos
Apoptose , Compostos de Bifenilo , Carcinoma Pulmonar de Células não Pequenas , Lignanas , Neoplasias Pulmonares , Microambiente Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Lignanas/farmacologia , Lignanas/uso terapêutico , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Apoptose/efeitos dos fármacos , Compostos de Bifenilo/farmacologia , Compostos de Bifenilo/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Humanos , Camundongos , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Evasão da Resposta Imune/efeitos dos fármacosRESUMO
The phytochemical investigations on the fruits of Kadsura coccinea led to the isolation of six undescribed dibenzocyclooctadiene lignans named kadcolignans B-G, together with eleven previously described analogues. The structures of these compounds were established by spectroscopic methods including NMR, HRESIMS, and CD experiments. All isolated compounds were evaluated for their hepatoprotective activity by measuring the levels of triglyceride (TG), total cholesterol (TC), and reactive oxygen species (ROS) in FFA-induced HepG2 cells. As a result, compounds 4, 5, 9, 13, and 15 showed potent inhibitory effects on hepatocyte lipid accumulation at a concentration of 100 µM. Our research not only broadens the understanding on the chemical composition of K. coccinea but also provides experimental and theoretical evidences supporting the fruit's active ingredients in alleviating nonalcoholic fatty liver disease (NAFLD).
Assuntos
Ciclo-Octanos , Frutas , Kadsura , Lignanas , Compostos Fitoquímicos , Lignanas/farmacologia , Lignanas/isolamento & purificação , Frutas/química , Humanos , Kadsura/química , Células Hep G2 , Ciclo-Octanos/farmacologia , Ciclo-Octanos/isolamento & purificação , Estrutura Molecular , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/isolamento & purificação , Substâncias Protetoras/farmacologia , Substâncias Protetoras/isolamento & purificação , Espécies Reativas de Oxigênio/metabolismo , Triglicerídeos , China , Colesterol , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológicoRESUMO
Treatment-induced ototoxicity and accompanying hearing loss are a great concern associated with chemotherapeutic or antibiotic drug regimens. Thus, prophylactic cure or early treatment is desirable by local delivery to the inner ear. In this study, we examined a novel way of intratympanically delivered sustained nanoformulation by using crosslinked hybrid nanoparticle (cHy-NPs) in a thermoresponsive hydrogel i.e. thermogel that can potentially provide a safe and effective treatment towards the treatment-induced or drug-induced ototoxicity. The prophylactic treatment of the ototoxicity can be achieved by using two therapeutic molecules, Flunarizine (FL: T-type calcium channel blocker) and Honokiol (HK: antioxidant) co-encapsulated in the same delivery system. Here we investigated, FL and HK as cytoprotective molecules against cisplatin-induced toxic effects in the House Ear Institute - Organ of Corti 1 (HEI-OC1) cells and in vivo assessments on the neuromast hair cell protection in the zebrafish lateral line. We observed that cytotoxic protective effect can be enhanced by using FL and HK in combination and developing a robust drug delivery formulation. Therefore, FL-and HK-loaded crosslinked hybrid nanoparticles (FL-cHy-NPs and HK-cHy-NPs) were synthesized using a quality-by-design approach (QbD) in which design of experiment-central composite design (DoE-CCD) following the standard least-square model was used for nanoformulation optimization. The physicochemical characterization of FL and HK loaded-NPs suggested the successful synthesis of spherical NPs with polydispersity index < 0.3, drugs encapsulation (> 75%), drugs loading (~ 10%), stability (> 2 months) in the neutral solution, and appropriate cryoprotectant selection. We assessed caspase 3/7 apopototic pathway in vitro that showed significantly reduced signals of caspase 3/7 activation after the FL-cHy-NPs and HK-cHy-NPs (alone or in combination) compared to the CisPt. The final formulation i.e. crosslinked-hybrid-nanoparticle-embedded-in-thermogel was developed by incorporating drug-loaded cHy-NPs in poloxamer-407, poloxamer-188, and carbomer-940-based hydrogel. A combination of artificial intelligence (AI)-based qualitative and quantitative image analysis determined the particle size and distribution throughout the visible segment. The developed formulation was able to release the FL and HK for at least a month. Overall, a highly stable nanoformulation was successfully developed for combating treatment-induced or drug-induced ototoxicity via local administration to the inner ear.
Assuntos
Nanopartículas , Peixe-Zebra , Animais , Nanopartículas/química , Orelha Interna/efeitos dos fármacos , Hidrogéis/química , Cisplatino/farmacologia , Cisplatino/química , Linhagem Celular , Compostos de Bifenilo/química , Sistemas de Liberação de Medicamentos/métodos , Lignanas/química , Lignanas/farmacologia , Lignanas/administração & dosagem , Camundongos , Sobrevivência Celular/efeitos dos fármacosRESUMO
Osteoarthritis (OA) is a prevalent disease of the musculoskeletal system that causes functional deterioration and diminished quality of life. Myrislignan (MRL) has a wide range of pharmacological characteristics, including an anti-inflammatory ability. Although inflammation is a major cause of OA, the role of MRL in OA treatment is still not well-understood. In this study, we analyze the anti-inflammatory and anti-ECM degradation effects of MRL both in vivo and in vitro. Rat primary chondrocytes were treated with interleukin-1ß (IL-1ß) to simulate inflammatory environmental conditions and OA in vitro. The in vivo OA rat model was established by anterior cruciate ligament transection (ACLT) on rat. Our investigation discovered that MRL lowers the IL-1ß-activated tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX2) and inducible nitric-oxide synthase (iNOS) expression in chondrocytes. Moreover, MRL effectively alleviates IL-1ß-induced extracellular matrix (ECM) degradation and promotes ECM synthesis in chondrocytes by upregulating the mRNA level expression of collagen-II and aggrecan (ACAN), downregulating the expression of matrix metalloproteinases-3,-13 (MMP-3, MMP-13), and a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5). Gene expression profiles of different groups identified DEGs that were mainly enriched in functions associated with NF-κB signaling pathway, and other highly enriched in functions related to TNF, IL-17, Rheumatoid arthritis and cytokine-cytokine receptor signaling pathways. Venn interaction of DEGs from the abovementioned five pathways showed that Nfkbia, Il1b, Il6, Nfkb1, Ccl2, Mmp3 were highly enriched DEGs. In addition, our research revealed that MRL suppresses NF-κB and modulates the Nrf2/HO-1/JNK signaling pathway activated by IL-1ß in chondrocytes. In vivo research shows that MRL slows the progression of OA in rats. Our findings imply that MRL might be a viable OA therapeutic choice.
Assuntos
Condrócitos , Interleucina-1beta , Lignanas , Osteoartrite , Ratos Sprague-Dawley , Animais , Osteoartrite/tratamento farmacológico , Osteoartrite/patologia , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Células Cultivadas , Interleucina-1beta/metabolismo , Masculino , Ratos , Lignanas/farmacologia , Lignanas/uso terapêutico , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , NF-kappa B/metabolismo , Matriz Extracelular/metabolismo , Matriz Extracelular/efeitos dos fármacos , Progressão da Doença , Fator de Necrose Tumoral alfa/metabolismo , Ciclo-Oxigenase 2/metabolismo , Ciclo-Oxigenase 2/genética , Modelos Animais de Doenças , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Transdução de Sinais/efeitos dos fármacos , Proteína ADAMTS5/metabolismo , Proteína ADAMTS5/genética , HumanosRESUMO
BACKGROUND: Schisandra chinensis lignan (SCL), a major active component of the traditional functional Chinese medicine Schisandra chinensis, has been reported to have antidepressant effects. Its mechanisms include alleviating intestinal barrier injury (IBI) by resolving intestinal microflora, anti-inflammation, and neuroprotection. SCL also regulates endogenous cannabinoid system, and it is closely related to the onset and development of depression. PURPOSE: We investigated a new treatment strategy for depression, i.e., alleviating IBI by regulating the endogenous cannabinoid system for antidepressant effects, as well as conducted in-depth research to explore the specific mechanism. METHODS: Behavioral analysis was conducted to detect the occurrence of depressive-like behavior in C57BL/6 mice. We used hematoxylin-eosin staining, periodic acid-Schiff staining, and immunofluorescence to evaluate IBI. Network pharmacology and Western blotting (WB) were used to predict and confirm that the amelioration effect of SCL was associated with anti-inflammation and anti-apoptosis. Combined with the levels of anandamide (AEA) and 2-arachidonoylglycerol (2-AG), we conducted the Pearson analysis between the AEA, 2-AG levels and the major targets identified and validated by network pharmacology and WB. Subsequently, URB-597, a fatty acid amide hydrolase (FAAH) antagonist with an AEA hydrolase-inhibiting effect, was administered to the mice, and behavioral analysis and apoptotic proteins were verified. Plasma endocannabinoid levels after URB-597 supplementation were measured via 6470 Triple Quadrupole LC/MS. Finally, the cannabinoid receptor type 2 (CB2R) antagonist AM630 was administered to mice, and immunofluorescence and WB were performed to assess the proteins of IBI and anti-inflammation. RESULTS: The study demonstrated that SCL alleviated depressive-like behaviours and ameliorated IBI. Network pharmacology and WB confirmed that the improvement of IBI was related to the anti-inflammatory and anti-apoptotic pathways. Pearson results showed that AEA levels were positively correlated with inflammation and apoptosis, with a greater contribution to apoptosis. In-depth studies validated that the URB-597 administration reversed the positive effects of SCL on depressive-like behavior and anti-apoptosis. Similarly, URB-597 counteracted AEA levels reduced by SCL and decreased 2-AG levels. Furthermore, AM630 supplementation antagonized SCL's effect of improving IBI by reactivating the MAPK/NF-κB inflammation pathway. CONCLUSION: Overall, SCL, in collaboration with the endogenous cannabinoid system regulated by SCL, alleviates depression associated IBI. The specific mechanism involes SCL decreasing AEA levels to inhibit colon tissue cell apoptosis by up-regulating FAAH. Simultaneously, it directly triggers CB2R to reduce inflammation responses, further alleviating IBI.
Assuntos
Antidepressivos , Ácidos Araquidônicos , Depressão , Endocanabinoides , Lignanas , Camundongos Endogâmicos C57BL , Alcamidas Poli-Insaturadas , Schisandra , Animais , Lignanas/farmacologia , Depressão/tratamento farmacológico , Masculino , Alcamidas Poli-Insaturadas/farmacologia , Schisandra/química , Antidepressivos/farmacologia , Camundongos , Apoptose/efeitos dos fármacos , Glicerídeos/farmacologia , Farmacologia em Rede , Amidoidrolases/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Anti-Inflamatórios/farmacologia , Benzamidas , Carbamatos , IndóisRESUMO
There has been significant global interest in respiratory health driven by the coronavirus disease (COVID-19) and severe environmental pollution. This study explored the potential of schisantherin A (SchA), a compound derived from Schisandra chinensis, to protect against acute pneumoconiosis. We assessed the effects of SchA on phorbol 12-myristate 13-acetate (PMA)-stimulated A549 alveolar epithelial cells and SiO2/TiO2-induced pulmonary injury in mice. In A549 cells, SchA significantly decreased pro-inflammatory mediators such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and interleukin (IL)-8 levels. SchA-mediated reduction in inflammatory mediators was associated with the downregulation of PMA-stimulated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK) signaling activation. In SiO2/TiO2-induced lung-injured mice, SchA administration significantly reduced MUC5AC production in lung tissue. SchA administration significantly downregulated the overexpression of NK-κB and the subsequent production of COX-2, iNOS, and NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasomes. It significantly suppressed expected increases in total cell numbers and pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and IL-1ß in the bronchoalveolar lavage fluid (BALF) in SiO2/TiO2-stimulated mice. In contrast, the SiO2/TiO2-mediated decrease in IL-10 levels was significantly improved by SchA treatment. These fundamental results can be used to develop potential treatments involving SchA for acute pneumoconiosis.