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1.
J Ethnopharmacol ; 336: 118743, 2025 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-39209000

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver-related morbidity and mortality, with hepatic steatosis being the hallmark symptom. Salvia miltiorrhiza Bunge (Smil, Dan-Shen) and Ligusticum striatum DC (Lstr, Chuan-Xiong) are commonly used to treat cardiovascular diseases and have the potential to regulate lipid metabolism. However, whether Smil/Lstr combo can be used to treat NAFLD and the mechanisms underlying its lipid-regulating properties remain unclear. PURPOSE: To assess the feasibility and reliability of a short-term high-fat diet (HFD) induced zebrafish model for evaluating hepatic steatosis phenotype and to investigate the liver lipid-lowering effects of Smil/Lstr, as well as its active components. METHODS: The phenotypic alterations of liver and multiple other organ systems were examined in the HFD zebrafish model using fluorescence imaging and histochemistry. The liver-specific lipid-lowering effects of Smil/Lstr combo were evaluated endogenously. The active molecules and functional mechanisms were further explored in zebrafish, human hepatocytes, and hamster models. RESULTS: In 5-day HFD zebrafish, significant lipid accumulation was detected in the blood vessels and the liver, as evidenced by increased staining with Oil Red O and fluorescent lipid probes. Hepatic hypertrophy was observed in the model, along with macrovesicular steatosis. Smil/Lstr combo administration effectively restored the lipid profile and alleviated hepatic hypertrophy in the HFD zebrafish. In oleic-acid stimulated hepatocytes, Smil/Lstr combo markedly reduced lipid accumulation and cell damage. Subsequently, based on zebrafish phenotypic screening, the natural phthalide senkyunolide I (SEI) was identified as a major molecule mediating the lipid-lowering activities of Smil/Lstr combo in the liver. Moreover, SEI upregulated the expression of the lipid metabolism regulator PPARα and downregulated fatty acid translocase CD36, while a PPARα antagonist sufficiently blocked the regulatory effect of SEI on hepatic steatosis. Finally, the roles of SEI on hepatic lipid accumulation and PPARα signaling were further verified in the hamster model. CONCLUSIONS: We proposed a zebrafish-based screening strategy for modulators of hepatic steatosis and discovered the regulatory roles of Smil/Lstr combo and its component SEI on liver lipid accumulation and PPARα signaling, suggesting their potential value as novel candidates for NAFLD treatment.


Assuntos
Modelos Animais de Doenças , PPAR alfa , Transdução de Sinais , Peixe-Zebra , Animais , Transdução de Sinais/efeitos dos fármacos , PPAR alfa/metabolismo , Humanos , Masculino , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Dieta Hiperlipídica , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Cricetinae , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Mesocricetus , Células Hep G2 , Benzofuranos/farmacologia , Fígado Gorduroso/tratamento farmacológico
2.
Biomaterials ; 313: 122766, 2025 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-39180916

RESUMO

The immune resistance of tumor microenvironment (TME) causes immune checkpoint blockade therapy inefficient to hepatocellular carcinoma (HCC). Emerging strategies of using chemotherapy regimens to reverse the immune resistance provide the promise for promoting the efficiency of immune checkpoint inhibitors. The induction of cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) in tumor cells evokes the adaptive immunity and remodels the immunosuppressive TME. In this study, we report that mitoxantrone (MIT, a chemotherapeutic drug) activates the cGAS-STING signaling pathway of HCC cells. We provide an approach to augment the efficacy of MIT using a signal transducer and activator of transcription 3 (STAT3) inhibitor called napabucasin (NAP). We prepare an aminoethyl anisamide (AEAA)-targeted polyethylene glycol (PEG)-modified poly (lactic-co-glycolic acid) (PLGA)-based nanocarrier for co-delivery of MIT and NAP. The resultant co-nanoformulation can elicit the cGAS-STING-based immune responses to reshape the immunoresistant TME in the mice orthotopically grafted with HCC. Consequently, the resultant co-nanoformulation can promote anti-PD-1 antibody for suppressing HCC development, generating long-term survival, and inhibiting tumor recurrence. This study reveals the potential of MIT to activate the cGAS-STING signaling pathway, and confirms the feasibility of nano co-delivery for MIT and NAP on achieving HCC chemo-immunotherapy.


Assuntos
Carcinoma Hepatocelular , Imunoterapia , Neoplasias Hepáticas , Proteínas de Membrana , Mitoxantrona , Nucleotidiltransferases , Fator de Transcrição STAT3 , Mitoxantrona/farmacologia , Mitoxantrona/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Animais , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Humanos , Nucleotidiltransferases/metabolismo , Proteínas de Membrana/metabolismo , Fator de Transcrição STAT3/metabolismo , Camundongos , Imunoterapia/métodos , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Benzofuranos , Naftoquinonas
3.
J Ethnopharmacol ; 336: 118711, 2025 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-39181286

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: According to the theory of Qi and blood in Traditional Chinese Medicine (TCM), the combination of Qi-reinforcing herbs and blood-activating herbs has a synergistic effect in improving blood stasis syndrome, especially in tumor treatment. The classic "Radix Astragali - Salvia miltiorrhiza" duo exemplifies this principle, renowned for invigorating Qi and activating blood flow, employed widely in tumor therapies. Our prior research underscores the potent inhibition of pancreatic tumor xenografts by the combination of Formononetin (from Radix Astragali) and Salvianolic acid B (from Salvia miltiorrhiza) in vitro. However, it remains unclear whether this combination can inhibit the abnormal vascularization of pancreatic tumors to achieve its anti-cancer effect. AIM OF THE STUDY: Abnormal vasculature, known to facilitate tumor growth and metastasis. Strategies to normalize tumor-associated blood vessels provide a promising avenue for anti-tumor therapy. This study aimed to unravel the therapeutic potential of Formononetin combined with Salvianolic acid B (FcS) in modulating pancreatic cancer's impact on endothelial cells, illuminate the underlying mechanisms that govern this therapeutic interaction, thereby advancing strategies to normalize tumor vasculature and combat cancer progression. MATERIALS AND METHODS: A co-culture system involving Human Umbilical Vein Endothelial Cells (HUVECs) and PANC-1 cells was established to investigate the potential of targeting abnormal vasculature as a novel anti-tumor therapeutic strategy. We systematically compared HUVEC proliferation, migration, invasion, and lumenogenesis in both mono- and co-culture conditions with PANC-1 (H-P). Subsequently, FcS treatment of the H-P system was evaluated for its anti-angiogenic properties. Molecular docking was utilized to predict the interactions between Formononetin and Salvianolic acid B with RhoA, and the post-treatment expression of RhoA in HUVECs was assessed. Furthermore, we utilized shRhoA lentivirus to elucidate the role of RhoA in FcS-mediated effects on HUVECs. In vivo, a zebrafish xenograft tumor model was employed to assess FcS's anti-tumor potential, focusing on cancer cell proliferation, migration, apoptosis, and vascular development. RESULTS: FcS treatment demonstrated a significant, dose-dependent inhibition of PANC-1-induced alterations in HUVECs, including proliferation, migration, invasion, and tube formation capabilities. Molecular docking analyses indicated potential interactions between FcS and RhoA. Further, FcS treatment was found to downregulate RhoA expression and modulated the PI3K/AKT signaling pathway in PANC-1-induced HUVECs. Notably, the phenotypic inhibitory effects of FcS on HUVECs were attenuated by RhoA knockdown. In vivo zebrafish studies validated FcS's anti-tumor activity, inhibiting cancer cell proliferation, metastasis, and vascular sprouting, while promoting tumor cell apoptosis. CONCLUSIONS: This study underscores the promising potential of FcS in countering pancreatic cancer-induced endothelial alterations. FcS exhibits pronounced anti-abnormal vasculature effects, potentially achieved through downregulation of RhoA and inhibition of the PI3K/Akt signaling pathway, thereby presenting a novel therapeutic avenue for pancreatic cancer management.


Assuntos
Benzofuranos , Movimento Celular , Células Endoteliais da Veia Umbilical Humana , Isoflavonas , Neoplasias Pancreáticas , Proteína rhoA de Ligação ao GTP , Isoflavonas/farmacologia , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Animais , Benzofuranos/farmacologia , Proteína rhoA de Ligação ao GTP/metabolismo , Linhagem Celular Tumoral , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Neovascularização Patológica/tratamento farmacológico , Peixe-Zebra , Proliferação de Células/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Antineoplásicos Fitogênicos/farmacologia , Depsídeos
4.
AAPS PharmSciTech ; 25(7): 204, 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-39237789

RESUMO

Benign hyperplasia (BHP) is a common disorder that affects men over the age of 60 years. Transurethral resection of the prostate (TURP) is the gold standard for operative treatment, but a range of drugs are also available to improve quality of life and to reduce BHP-associated urinary tract infections and complications. Darifenacin, an anti-muscarinic agent, has been found effective for relieving symptoms of overactive bladder associated with BHP, but the drug has poor solubility and bioavailability, which are major challenges in product development. An inorganic/organic bio-composite with gastric pH-resistant property was synthesized for the targeted oral delivery of Darifenacin to the lower gastrointestinal tract (GIT). This development was accomplished through co-precipitation of calcium carbonate in quince seed-based mucilage. The FTIR, XRD, DSC, and TGA results showed good drug-polymer compatibility, and the SEM images showed calcite formation in the quince hydrogel system. After 72 h, the drug release of 34% and 75% were observed in acidic (0.1N HCl) and 6.8 pH phosphate buffer, respectively. A restricted/less drug was permeated through gastric membrane (21.8%) as compared to permeation through intestinal membrane (65%.) The developed composite showed significant reduction in testosterone-induced prostatic hyperplasia (2.39 ± 0.12***) as compared to untreated diseased animal group. No sign of organ toxicity was observed against all the developed composites. In this study, we developed an inorganic-organic composite system that is highly biocompatible and effective for targeting the lower GIT, thereby avoiding the first-pass metabolism of darifenacin.


Assuntos
Benzofuranos , Pirrolidinas , Solubilidade , Administração Oral , Animais , Benzofuranos/administração & dosagem , Benzofuranos/farmacocinética , Benzofuranos/química , Benzofuranos/farmacologia , Masculino , Pirrolidinas/química , Pirrolidinas/administração & dosagem , Liberação Controlada de Fármacos , Sistemas de Liberação de Medicamentos/métodos , Ratos , Hiperplasia Prostática/tratamento farmacológico , Antagonistas Muscarínicos/administração & dosagem , Antagonistas Muscarínicos/farmacocinética , Disponibilidade Biológica , Carbonato de Cálcio/química , Concentração de Íons de Hidrogênio , Hidrogéis/química , Polímeros/química
5.
Molecules ; 29(17)2024 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-39274864

RESUMO

The root of Salvia miltiorrhiza Bunge (SMB) has been widely used to treat cardiovascular diseases. However, the contents of secondary metabolites in the roots from different production areas are significantly different, and the impact of soil factors on this accumulation remains unclear. Therefore, this study aimed to elucidate the regularity of variation between the active components and soil factors through targeted metabolomics and chemical dosimetry. Soils were collected from five different cities (A, B, C, D, and E) and transplanted into the study area. The results showed that there were significant differences in the soil fertility characteristics and heavy metal pollution levels in different soils. Ten water- and twelve lipid-soluble metabolites were identified in SMBs grown in all soil types. SMBs from D cities exhibited the highest total tanshinone content (p < 0.05). The salvianolic acid B content in SMBs from E cities was the highest (p < 0.05). Interestingly, correlation analysis revealed a significant negative correlation between the accumulation of lipid-soluble and water-soluble metabolites. Double-matrix correlation analysis demonstrated that available potassium (AK) was significantly negatively correlated with salvianolic acid B (r = -0.80, p = 0.0004) and positively correlated with tanshinone IIA (r = 0.66, p = 0.008). Conversely, cadmium (Cd) and cuprum (Cu) were significantly positively and negatively correlated with salvianolic acid B (r = 0.96, p < 0.0001 and r = 0.72, p = 0.0024) and tanshinone IIA (r = 0.40, p = 0.14 and r = 0.73, p = 0.0018), respectively. Mantel's test indicated that AK (r > 0.52, p < 0.001), Cu (r > 0.60, p < 0.005), and Cd (r > 0.31, p < 0.05) were the primary drivers of the differences in the active components of SMBs. These findings provide a theoretical framework for modulating targeted metabolites of SMB through soil factors, with significant implications for the cultivation and quality control of medicinal plants.


Assuntos
Metabolômica , Salvia miltiorrhiza , Solo , Salvia miltiorrhiza/química , Salvia miltiorrhiza/metabolismo , Metabolômica/métodos , Solo/química , Cromatografia Líquida de Alta Pressão/métodos , Raízes de Plantas/metabolismo , Raízes de Plantas/química , Abietanos , Benzofuranos/análise , Benzofuranos/metabolismo , Depsídeos
6.
Physiol Res ; 73(4): 529-541, 2024 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-39264076

RESUMO

While 3-N-butylphthalide (NBP) has demonstrated notable cardioprotective effects, its precise role in mitigating myocardial arrhythmia following ischemia/reperfusion (IR) injury in diabetes remains unclear. This study aimed to explore the potential mechanisms through which NBP mitigates reperfusion-induced myocardial arrhythmia in diabetic rats, with a particular focus on mitochondrial function and biogenesis, endoplasmic reticulum (ER) stress, and oxidative/inflammatory responses. Sixty Sprague-Dawley rats were divided into non-diabetic and diabetic groups, subjected to in-vivo myocardial IR injury, and treated with NBP (100 mg/kg, intraperitoneally) through different modalities: preconditioning, postconditioning, or a combination of both. Electrocardiography (ECG) was employed to assess the incidence and severity of arrhythmia. Fluorometric, Western blotting and ELISA analyses were utilized to measure the mitochondrial, ER stress, and cellular outcomes. Treatment of non-diabetic rats with NBP in preconditioned, postconditioned, and combined approaches significantly reduced cardiotroponin-I and the frequency and severity of arrhythmias induced by IR injury. However, only the combined preconditioning plus postconditioning approach of NBP had protective and antiarrhythmic effects in diabetic rats, in an additive manner. Moreover, the NBP combined approach improved mitochondrial function and upregulated the expression of PGC-1?, Sirt1, and glutathione while concurrently downregulating ER stress and oxidative and pro-inflammatory-related proteins in diabetic rats. In conclusion, the combined approach of NBP treatment was effective in mitigating myocardial arrhythmia in diabetic rats. This approach coordinates interactions within the mitochondria-endoplasmic reticulum network and inhibits oxidative and inflammatory mediators, offering a promising strategy for managing myocardial arrhythmia in diabetic patients. Key words: Myocardial Infarction, Mitochondria, Arrhythmia, Reperfusion, Diabetes, Ischemia.


Assuntos
Arritmias Cardíacas , Benzofuranos , Diabetes Mellitus Experimental , Estresse do Retículo Endoplasmático , Traumatismo por Reperfusão Miocárdica , Estresse Oxidativo , Ratos Sprague-Dawley , Animais , Estresse Oxidativo/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Benzofuranos/farmacologia , Benzofuranos/uso terapêutico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/complicações , Masculino , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/prevenção & controle , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/tratamento farmacológico , Ratos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Antiarrítmicos/farmacologia , Antiarrítmicos/uso terapêutico , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/efeitos dos fármacos , Inflamação/metabolismo , Inflamação/tratamento farmacológico
7.
Sci Rep ; 14(1): 20123, 2024 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-39209951

RESUMO

Modulation of the Nrf2 pathway, a master regulator of the antioxidant response and cellular metabolism, has been suggested as a promising therapeutic strategy in tauopathies, a heterogeneous group of neurodegenerative disorders characterized by intracellular proteinaceous inclusions of abnormally phosphorylated tau. Here, we explored the neuroprotective potential of different Nrf2-pathway activators in human immortalized dopaminergic neurons against annonacin-induced toxicity, a mitochondrial inhibitor associated with a PSP-like syndrome and capable of mimicking tauopathy-like features. Interestingly, we observed heterogenous and compound-dependent neuroprotective effects among the different Nrf2-pathway activators. With the exception of Fyn inhibitors, all the selected Nrf2-pathway activators improved cell viability and the oxidative status, and reduced the annonacin-induced tau hyperphosphorylation and neurite degeneration, particularly the p62-activators. However, improvement of the impaired mitochondrial function was only observed by the Bach-1 inhibitor. Surprisingly, we found evidence that ezetimibe, an approved drug for hypercholesterolemia, prevents the transcriptional upregulation of 4R-tau triggered by annonacin insult. Overall, our results suggest that the neuroprotective effects of the Nrf2-pathway activators against annonacin toxicity may rely on the specific mechanism of action, intrinsic to each compound, and possibly on the concomitant modulation of additional signaling pathways. Further research will be needed to fully understand how synergistic modulation of metabolic adaptation and cell survival can be exploit to develop new therapeutical strategies for tauopathies and eventually other neurodegenerative diseases.


Assuntos
Sobrevivência Celular , Fator 2 Relacionado a NF-E2 , Fármacos Neuroprotetores , Transdução de Sinais , Fator 2 Relacionado a NF-E2/metabolismo , Humanos , Fármacos Neuroprotetores/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Proteínas tau/metabolismo , Fosforilação/efeitos dos fármacos , Linhagem Celular , Benzofuranos/farmacologia , Furanos , Lactonas
8.
ACS Chem Neurosci ; 15(17): 3152-3167, 2024 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-39145537

RESUMO

Preclinical and clinical studies have indicated that compromised blood-brain barrier (BBB) function contributes to Alzheimer's disease (AD) pathology. BBB breakdown ranged from mild disruption of tight junctions (TJs) with increased BBB permeability to chronic integrity loss, affecting transport across the BBB, reducing brain perfusion, and triggering inflammatory responses. We recently developed a high-throughput screening (HTS) assay to identify hit compounds that enhance the function of a cell-based BBB model. The HTS screen identified (S,E)-2-acetyl-6-[3-(4'-fluorobiphenyl-4-yl)acryloyl]-3,7,9-trihydroxy-8,9b-dimethyldibenzo-[b,d]furan-1(9bH)-one (4-FPBUA), a semisynthetic analogue of naturally occurring usnic acid, which protected the in vitro model against Aß toxicity. Usnic acid is a lichen-derived secondary metabolite with a unique dibenzofuran skeleton that is commonly found in lichenized fungi of the genera Usnea. In this study, we aimed to evaluate the effect of 4-FPBUA in vitro on the cell-based BBB model function and its in vivo ability to rectify BBB function and reduce brain Aß in two AD mouse models, namely, 5xFAD and TgSwDI. Our findings demonstrated that 4-FPBUA enhanced cell-based BBB function, increased Aß transport across the monolayer, and reversed BBB breakdown in vivo by enhancing autophagy as an mTOR inhibitor. Induced autophagy was associated with a significant reduction in Aß accumulation and related pathologies and improved memory function. These results underscore the potential of 4-FPBUA as a candidate for further preclinical exploration to better understand its mechanisms of action and to optimize dosing strategies. Continued research may also elucidate additional pathways through which 4-FPBUA contributed to the amelioration of BBB dysfunction in AD. Collectively, our findings supported the development of 4-FPBUA as a therapeutic agent against AD.


Assuntos
Doença de Alzheimer , Autofagia , Benzofuranos , Barreira Hematoencefálica , Modelos Animais de Doenças , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Benzofuranos/farmacologia , Autofagia/efeitos dos fármacos , Autofagia/fisiologia , Camundongos , Peptídeos beta-Amiloides/metabolismo , Camundongos Transgênicos , Humanos
9.
Environ Health Perspect ; 132(8): 87005, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39140734

RESUMO

BACKGROUND: Exposure to persistent organic pollutants (POPs) and disruptions in the gastrointestinal microbiota have been positively correlated with a predisposition to factors such as obesity, metabolic syndrome, and type 2 diabetes; however, it is unclear how the microbiome contributes to this relationship. OBJECTIVE: This study aimed to explore the association between early life exposure to a potent aryl hydrocarbon receptor (AHR) agonist and persistent disruptions in the microbiota, leading to impaired metabolic homeostasis later in life. METHODS: This study used metagenomics, nuclear magnetic resonance (NMR)- and mass spectrometry (MS)-based metabolomics, and biochemical assays to analyze the gut microbiome composition and function, as well as the physiological and metabolic effects of early life exposure to 2,3,7,8-tetrachlorodibenzofuran (TCDF) in conventional, germ-free (GF), and Ahr-null mice. The impact of TCDF on Akkermansia muciniphila (A. muciniphila) in vitro was assessed using optical density (OD 600), flow cytometry, transcriptomics, and MS-based metabolomics. RESULTS: TCDF-exposed mice exhibited lower abundances of A. muciniphila, lower levels of cecal short-chain fatty acids (SCFAs) and indole-3-lactic acid (ILA), as well as lower levels of the gut hormones glucagon-like peptide 1 (GLP-1) and peptide YY (PYY), findings suggestive of disruption in the gut microbiome community structure and function. Importantly, microbial and metabolic phenotypes associated with early life POP exposure were transferable to GF recipients in the absence of POP carry-over. In addition, AHR-independent interactions between POPs and the microbiota were observed, and they were significantly associated with growth, physiology, gene expression, and metabolic activity outcomes of A. muciniphila, supporting suppressed activity along the ILA pathway. CONCLUSIONS: These data obtained in a mouse model point to the complex effects of POPs on the host and microbiota, providing strong evidence that early life, short-term, and self-limiting POP exposure can adversely impact the microbiome, with effects persisting into later life with associated health implications. https://doi.org/10.1289/EHP13356.


Assuntos
Benzofuranos , Microbioma Gastrointestinal , Homeostase , Camundongos Endogâmicos C57BL , Receptores de Hidrocarboneto Arílico , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/fisiologia , Receptores de Hidrocarboneto Arílico/metabolismo , Camundongos , Homeostase/efeitos dos fármacos , Poluentes Orgânicos Persistentes , Masculino , Ligantes
10.
Phytomedicine ; 133: 155925, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39173278

RESUMO

BACKGROUND: Nur77, an orphan member of the nuclear receptor superfamily, regulates inflammatory diseases and is a therapeutic target for treating inflammation. Phthalides in Angelica sinensis exhibit anti-inflammatory activity. PURPOSE: This study aimed to screen compounds from A. sinensis phthalide extract that could exert anti-inflammatory activity by targeting Nur77. To provide new theoretical support for better elucidation of Chinese medicine targeting mitochondria to achieve multiple clinical efficacies. METHODS: The anti-inflammatory capacity of phthalides was assessed in tumor necrosis factor-alpha (TNF-α)-stimulated HepG2 cells using western blotting. The interaction between phthalides and Nur77 was verified by molecular docking, surface plasmon resonance, and cellular thermal shift assay. Co-immunoprecipitation, western blotting, and immunostaining were performed to determine the molecular mechanisms. The in vivo anti-inflammatory activity of the phthalides was evaluated in a lipopolysaccharide (LPS)/d-galactosamine (d-GalN)-induced acute hepatitis and liver injury mouse model of acute hepatitis and liver injury. Finally, the toxicity of phthalide toxicity was assessed in zebrafish experiments. RESULTS: Among the 27 phthalide compounds isolated from A. sinensis, tokinolide B (TB) showed the best Nur77 binding capacity and, the best anti-inflammatory activity, which was induced without apoptosis. In vivo and in vitro experiments showed that TB promoted Nur77 translocation from the nucleus to the mitochondria and interacted with tumor necrosis factor receptor-associated factor 2 (TRAF2) and sequestosome 1 (p62) to induce mitophagy for anti-inflammatory functions. TB substantially inhibited LPS/d-GalN-induced acute hepatitis and liver injury in mice. TB also exhibited significantly lower toxicity than celastrol in zebrafish experiments. CONCLUSION: These findings suggested that TB inhibits inflammation by promoting Nur77 interaction with TRAF2 and p62, thereby inducing mitophagy. These findings offer promising directions for developing novel anti-inflammatory agents, enhance the understanding of phthalide compounds, and highlight the therapeutic potential of traditional Chinese herbs.


Assuntos
Angelica sinensis , Anti-Inflamatórios , Benzofuranos , Simulação de Acoplamento Molecular , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares , Peixe-Zebra , Animais , Angelica sinensis/química , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Humanos , Anti-Inflamatórios/farmacologia , Benzofuranos/farmacologia , Camundongos , Células Hep G2 , Masculino , Lipopolissacarídeos , Fator de Necrose Tumoral alfa/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Modelos Animais de Doenças
11.
J Pineal Res ; 76(5): e13002, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39119925

RESUMO

Parkinson's disease affects millions of people worldwide, and without significant progress in disease prevention and treatment, its incidence and prevalence could increase by more than 30% by 2030. Researchers have focused on targeting sleep and the circadian system as a novel treatment strategy for Parkinson's disease. This study investigated the association between melatonin receptor agonists and Parkinson's disease, using the Food and Drug Administration (FDA) Adverse Events Reporting System (FAERS). The target drugs were melatonin receptor agonists including ramelteon, tasimelteon, and agomelatine. Parkinson's disease cases were defined according to the Medical Dictionary for Regulatory Activities (MedDRA) 25.0; Standardized MedDRA Query (SMQ) using both the "narrow" and "broad" preferred terms (PTs) associated with Parkinson's disease. The association between melatonin receptor agonists (ramelteon, tasimelteon, and agomelatine) and Parkinson's disease was evaluated by the reporting odds ratio. Upon analyzing the data from all patients registered in the FAERS, ramelteon (ROR: 0.66, 95% confidence interval [95% CI]: 0.51-0.84) and tasimelteon (ROR: 0.49, 95% CI: 0.38-0.62) showed negative correlations with Parkinson's disease. Conversely, only agomelatine was positively correlated with Parkinson's disease (ROR: 2.63, 95% CI: 2.04-3.40). These results suggest that among the melatonin receptor agonists, ramelteon and tasimelteon are negatively correlated with Parkinson's disease. In contrast, agomelatine was shown to be positively correlated with Parkinson's disease. These results should be used in research to develop drugs for the treatment of Parkinson's disease, fully considering the limitations of the spontaneous reporting system.


Assuntos
Acetamidas , Indenos , Doença de Parkinson , Receptores de Melatonina , Doença de Parkinson/tratamento farmacológico , Humanos , Indenos/uso terapêutico , Acetamidas/uso terapêutico , Receptores de Melatonina/agonistas , Masculino , Feminino , Idoso , Tetra-Hidronaftalenos/uso terapêutico , Pessoa de Meia-Idade , Benzofuranos , Ciclopropanos , Naftalenos
12.
Int J Mol Sci ; 25(15)2024 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-39125602

RESUMO

The benzofuran core inhibitors HCV-796, BMS-929075, MK-8876, compound 2, and compound 9B exhibit good pan-genotypic activity against various genotypes of NS5B polymerase. To elucidate their mechanism of action, multiple molecular simulation methods were used to investigate the complex systems of these inhibitors binding to GT1a, 1b, 2a, and 2b NS5B polymerases. The calculation results indicated that these five inhibitors can not only interact with the residues in the palm II subdomain of NS5B polymerase, but also with the residues in the palm I subdomain or the palm I/III overlap region. Interestingly, the binding of inhibitors with longer substituents at the C5 position (BMS-929075, MK-8876, compound 2, and compound 9B) to the GT1a and 2b NS5B polymerases exhibits different binding patterns compared to the binding to the GT1b and 2a NS5B polymerases. The interactions between the para-fluorophenyl groups at the C2 positions of the inhibitors and the residues at the binding pockets, together with the interactions between the substituents at the C5 positions and the residues at the reverse ß-fold (residues 441-456), play a key role in recognition and the induction of the binding. The relevant studies could provide valuable information for further research and development of novel anti-HCV benzofuran core pan-genotypic inhibitors.


Assuntos
Antivirais , Benzofuranos , Genótipo , Hepacivirus , Proteínas não Estruturais Virais , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/metabolismo , Proteínas não Estruturais Virais/química , Benzofuranos/química , Benzofuranos/farmacologia , Hepacivirus/efeitos dos fármacos , Hepacivirus/enzimologia , Hepacivirus/genética , Antivirais/farmacologia , Antivirais/química , Simulação de Dinâmica Molecular , Simulação de Acoplamento Molecular , Sítios de Ligação , Ligação Proteica , Humanos , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , RNA Polimerase Dependente de RNA
13.
Int J Mol Sci ; 25(15)2024 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-39126007

RESUMO

Diabetic retinopathy (DR) is one of the most prevalent secondary complications associated with diabetes. Specifically, Type 1 Diabetes Mellitus (T1D) has an immune component that may determine the evolution of DR by compromising the immune response of the retina, which is mediated by microglia. In the early stages of DR, the permeabilization of the blood-retinal barrier allows immune cells from the peripheral system to interact with the retinal immune system. The use of new bioactive molecules, such as 3-(2,4-dihydroxyphenyl)phthalide (M9), with powerful anti-inflammatory activity, might represent an advance in the treatment of diseases like DR by targeting the immune systems responsible for its onset and progression. Our research aimed to investigate the molecular mechanisms involved in the interaction of specific cells of the innate immune system during the progression of DR and the reduction in inflammatory processes contributing to the pathology. In vitro studies were conducted exposing Bv.2 microglial and Raw264.7 macrophage cells to proinflammatory stimuli for 24 h, in the presence or absence of M9. Ex vivo and in vivo approaches were performed in BB rats, an animal model for T1D. Retinal explants from BB rats were cultured with M9. Retinas from BB rats treated for 15 days with M9 via intraperitoneal injection were analyzed to determine survival, cellular signaling, and inflammatory markers using qPCR, Western blot, or immunofluorescence approaches. Retinal structure images were acquired via Spectral-Domain-Optical Coherence Tomography (SD-OCT). Our results show that the treatment with M9 significantly reduces inflammatory processes in in vitro, ex vivo, and in vivo models of DR. M9 works by inhibiting the proinflammatory responses during DR progression mainly affecting immune cell responses. It also induces an anti-inflammatory response, primarily mediated by microglial cells, leading to the synthesis of Arginase-1 and Hemeoxygenase-1(HO-1). Ultimately, in vivo administration of M9 preserves the retinal integrity from the degeneration associated with DR progression. Our findings demonstrate a specific interaction between both retinal and systemic immune cells in the progression of DR, with a differential response to treatment, mainly driven by microglia in the anti-inflammatory action. In vivo treatment with M9 induces a switch in immune cell phenotypes and functions that contributes to delaying the DR progression, positioning microglial cells as a new and specific therapeutic target in DR.


Assuntos
Diabetes Mellitus Tipo 1 , Retinopatia Diabética , Modelos Animais de Doenças , Microglia , Animais , Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/patologia , Retinopatia Diabética/imunologia , Ratos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/complicações , Camundongos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Retina/efeitos dos fármacos , Retina/patologia , Retina/metabolismo , Células RAW 264.7 , Masculino , Benzofuranos/farmacologia , Benzofuranos/uso terapêutico , Imunomodulação/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inflamação/patologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/complicações , Ratos Endogâmicos BB
14.
J Integr Neurosci ; 23(8): 158, 2024 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-39207079

RESUMO

BACKGROUND: Most acute cerebral infarctions (ACI) may develop vascular dementia (VD), which involves almost all types of cognitive impairment. Unfortunately, there is currently no effective treatment for VD. Most patients exhibit mild cognitive impairment (MCI) before the development of VD. N-butyl-phthalide (NBP) is used to treat ACI and improve cognitive function. The oxygen and glucose deprivation (OGD) model of neurons is an in vitro model of ischemia, hypoxia, and cognitive dysfunction. METHODS: We conducted clinical studies and in vitro experiments to investigate the clinical efficacy and mechanism of action of NBP for treating ACI-induced MCI. Patients with ACI-induced MCI were randomly divided into control (Ctrl) and NBP groups. We assessed various indicators, such as clinical efficacy, montreal cognitive assessment scale (MOCA), activities of daily living (ADL), and cerebral infarct size in both groups before and after treatment. We observed the morphology of neurons and detected the survival rate, action potentials (APs), expression of high mobility group box 1 (HMGB1), toll-like receptor 4 (TLR4), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), and the interaction between TLR4 and HMGB1. RESULTS: The MOCA and ADL scores increased significantly after treatment in the NBP group. A OGD model of neurons was established, and the neurons were divided into Ctrl and NBP groups. We observed that the survival rate and APs amplitude of the neurons were significantly increased in the NBP group, whereas TNF-α expression was decreased. Furthermore, the interaction between TLR4 and HMGB1 decreased in the NBP group. CONCLUSION: NBP plays a neuroprotective role by inhibiting the TLR4/HMGB1 pathway and ameliorating ACI-induced MCI.


Assuntos
Benzofuranos , Infarto Cerebral , Disfunção Cognitiva , Proteína HMGB1 , Fármacos Neuroprotetores , Receptor 4 Toll-Like , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/metabolismo , Proteína HMGB1/metabolismo , Proteína HMGB1/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo , Receptor 4 Toll-Like/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/administração & dosagem , Benzofuranos/farmacologia , Benzofuranos/administração & dosagem , Humanos , Infarto Cerebral/tratamento farmacológico , Masculino , Idoso , Animais , Feminino , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Pessoa de Meia-Idade
15.
J Med Econ ; 27(1): 1076-1085, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39102473

RESUMO

AIMS: Fruquintinib is a selective small molecule tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR)-1, -2, and -3 recently approved in the United States (US) for the treatment of adult patients with metastatic colorectal cancer (CRC) who have previously been treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type and medically appropriate, anti-epidermal growth factor receptor therapy. This study aimed to estimate the 5-year budget impact of fruquintinib from a US payer perspective (commercial and Medicare). MATERIALS AND METHODS: A budget impact model was developed to compare two scenarios: a reference scenario in which patients received regorafenib, trifluridine/tipiracil, or trifluridine/tipiracil with bevacizumab and an alternative scenario in which patients received reference scenario treatments or fruquintinib. Market shares were evenly divided across available options. A 5-year time horizon and a hypothetical health plan of 1 million members was assumed. The model included epidemiological inputs to estimate the eligible population; clinical inputs for treatment duration, progression-free survival, overall survival, and adverse event (AE) frequency; and cost inputs for treatment, AEs, disease management, subsequent therapy, and terminal care costs. Budget impact was reported as total, per member per year (PMPY), and per member per month (PMPM). RESULTS: The model estimated an eligible population of 194 patients (39 per year) over 5 years. In the base case, the estimated 5-year budget impact of fruquintinib was $4,077,073 ($0.82 PMPY and 0.07 PMPM) for a commercial health plan. During the first year, the estimated budget impact was $627,570 ($0.63 PMPY and 0.05 PMPM). Results were robust across sensitivity analyses. PMPM costs from the Medicare perspective were greater than the base-case (commercial) ($0.17 vs. $0.07) due to higher incidence of CRC in that population. CONCLUSIONS: Fruquintinib is associated with a low budget impact for payers based on proposed thresholds in the US.


Fruquintinib is a treatment for metastatic colorectal cancer that has progressed after or not responded to multiple guideline-recommended therapies. This budget impact analysis was conducted to estimate the added costs a health plan would incur over a 5-year period if it chose to cover this therapy. The analysis found that the per plan member per month cost of covering fruquintinib was $0.07 for a United States commercial health plan and $0.17 for Medicare.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Benzofuranos , Bevacizumab , Neoplasias Colorretais , Piridinas , Timina , Humanos , Neoplasias Colorretais/tratamento farmacológico , Benzofuranos/uso terapêutico , Benzofuranos/economia , Estados Unidos , Bevacizumab/uso terapêutico , Bevacizumab/economia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/economia , Piridinas/uso terapêutico , Piridinas/economia , Trifluridina/uso terapêutico , Trifluridina/economia , Orçamentos , Quinazolinas/uso terapêutico , Quinazolinas/economia , Compostos de Fenilureia/uso terapêutico , Compostos de Fenilureia/economia , Uracila/análogos & derivados , Uracila/uso terapêutico , Uracila/economia , Compostos Organoplatínicos/uso terapêutico , Compostos Organoplatínicos/economia , Análise Custo-Benefício , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Camptotecina/economia , Antineoplásicos/economia , Antineoplásicos/uso terapêutico , Irinotecano/uso terapêutico , Irinotecano/economia , Medicare , Fluoruracila/uso terapêutico , Fluoruracila/economia , Oxaliplatina/uso terapêutico , Oxaliplatina/economia , Receptores de Fatores de Crescimento do Endotélio Vascular , Modelos Econômicos , Combinação de Medicamentos , Pirrolidinas
16.
Sci Rep ; 14(1): 19349, 2024 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-39164287

RESUMO

Inhibition of translation initiation using eIF4A inhibitors like (-)-didesmethylrocaglamide [(-)-DDR] and (-)-rocaglamide [(-)-Roc] is a potential cancer treatment strategy as they simultaneously diminish multiple oncogenic drivers. We showed that human and dog osteosarcoma cells expressed higher levels of eIF4A1/2 compared with mesenchymal stem cells. Genetic depletion of eIF4A1 and/or 2 slowed osteosarcoma cell growth. To advance preclinical development of eIF4A inhibitors, we demonstrated the importance of (-)-chirality in DDR for growth-inhibitory activity. Bromination of DDR at carbon-5 abolished growth-inhibitory activity, while acetylating DDR at carbon-1 was tolerated. Like (-)-DDR, (±)-DDR, and (-)-Roc, (±)-DDR-acetate increased γH2A.X levels and induced G2/M arrest and apoptosis. Consistent with translation inhibition, these rocaglates decreased the levels of several mitogenic kinases, the STAT3 transcription factor, and the stress-activated protein kinase p38. However, phosphorylated p38 was greatly enhanced in treated cells, suggesting activation of stress response pathways. RNA sequencing identified RHOB as a top upregulated gene in both (-)-DDR- and (-)-Roc-treated osteosarcoma cells, but the Rho inhibitor Rhosin did not enhance the growth-inhibitory activity of (-)-DDR or (-)-Roc. Nonetheless, these rocaglates potently suppressed tumor growth in a canine osteosarcoma patient-derived xenograft model. These results suggest that these eIF4A inhibitors can be leveraged to treat both human and dog osteosarcomas.


Assuntos
Fator de Iniciação 4A em Eucariotos , Osteossarcoma , Cães , Animais , Humanos , Osteossarcoma/tratamento farmacológico , Osteossarcoma/patologia , Osteossarcoma/metabolismo , Linhagem Celular Tumoral , Fator de Iniciação 4A em Eucariotos/antagonistas & inibidores , Fator de Iniciação 4A em Eucariotos/metabolismo , Camundongos , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/patologia , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Proliferação de Células/efeitos dos fármacos , Benzofuranos/farmacologia
17.
J Agric Food Chem ; 72(36): 19594-19603, 2024 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-39214614

RESUMO

The Dothideomycete fungal pathogen Pyrenophora tritici-repentis (Ptr) is the causal agent of the tan spot disease of wheat. The proteinaceous necrotrophic effectors ToxA and ToxB are well characterized. A nonproteinaceous effector called ToxC has also been partially characterized. Ptr produces a number of other small molecular weight compounds, but these remain poorly characterized. In this study, two novel compounds, designated ToxE1 and ToxE2, capable of inducing chlorotic symptoms on wheat leaves in a cultivar-specific manner, were purified from Ptr liquid cultures. There is no evidence that these compounds correspond to ToxC. Most isolates produced ToxE1, ToxE2, or both, and both compounds were detected in infected wheat leaves. The structures of both analogues were elucidated by NMR spectroscopy and comprise a phthalide core structure with an amide moiety. We postulate that these compounds have a general phytotoxic effect and may have an ancillary role in disease development.


Assuntos
Ascomicetos , Benzofuranos , Micotoxinas , Doenças das Plantas , Triticum , Triticum/microbiologia , Triticum/química , Ascomicetos/química , Ascomicetos/metabolismo , Doenças das Plantas/microbiologia , Micotoxinas/química , Micotoxinas/metabolismo , Micotoxinas/toxicidade , Benzofuranos/química , Benzofuranos/farmacologia , Folhas de Planta/química , Folhas de Planta/microbiologia , Estrutura Molecular
18.
Antiviral Res ; 230: 105976, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39117283

RESUMO

Coronaviruses are highly transmissible respiratory viruses that cause symptoms ranging from mild congestion to severe respiratory distress. The recent outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has underscored the need for new antivirals with broad-acting mechanisms to combat increasing emergence of new variants. Currently, there are only a few antivirals approved for treatment of SARS-CoV-2. Previously, the rocaglate natural product silvestrol and synthetic rocaglates such as CR-1-31b were shown to have antiviral effects by inhibiting eukaryotic translation initiation factor 4A1 (eIF4A) function and virus protein synthesis. In this study, we evaluated amidino-rocaglates (ADRs), a class of synthetic rocaglates with the most potent eIF4A-inhibitory activity to-date, for inhibition of SARS-CoV-2 infection. This class of compounds showed low nanomolar potency against multiple SARS-CoV-2 variants and in multiple cell types, including human lung-derived cells, with strong inhibition of virus over host protein synthesis and low cytotoxicity. The most potent ADRs were also shown to be active against two highly pathogenic and distantly related coronaviruses, SARS-CoV and MERS-CoV. Mechanistically, cells with mutations of eIF4A1, which are known to reduce rocaglate interaction displayed reduced ADR-associated loss of cellular function, consistent with targeting of protein synthesis. Overall, ADRs and derivatives may offer new potential treatments for SARS-CoV-2 with the goal of developing a broad-acting anti-coronavirus agent.


Assuntos
Antivirais , Biossíntese de Proteínas , SARS-CoV-2 , Replicação Viral , SARS-CoV-2/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Antivirais/farmacologia , Antivirais/síntese química , Antivirais/química , Humanos , Chlorocebus aethiops , Animais , Biossíntese de Proteínas/efeitos dos fármacos , Células Vero , Tratamento Farmacológico da COVID-19 , Benzofuranos/farmacologia , Benzofuranos/síntese química , Benzofuranos/química , COVID-19/virologia , Proteínas Virais/antagonistas & inibidores , Proteínas Virais/metabolismo , Proteínas Virais/genética , Fator de Iniciação 4A em Eucariotos/antagonistas & inibidores , Fator de Iniciação 4A em Eucariotos/metabolismo
19.
Microb Pathog ; 195: 106892, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39216611

RESUMO

The highly pathogenic Marburg virus (MARV) is a member of the Filoviridae family, a non-segmented negative-strand RNA virus. This article represents the computer-aided drug design (CADD) approach for identifying drug-like compounds that prevent the MARV virus disease by inhibiting nucleoprotein, which is responsible for their replication. This study used a wide range of in silico drug design techniques to identify potential drugs. Out of 368 natural compounds, 202 compounds passed ADMET, and molecular docking identified the top two molecules (CID: 1804018 and 5280520) with a high binding affinity of -6.77 and -6.672 kcal/mol, respectively. Both compounds showed interactions with the common amino acid residues SER_216, ARG_215, TYR_135, CYS_195, and ILE_108, which indicates that lead compounds and control ligands interact in the common active site/catalytic site of the protein. The negative binding free energies of CID: 1804018 and 5280520 were -66.01 and -31.29 kcal/mol, respectively. Two lead compounds were re-evaluated using MD modeling techniques, which confirmed CID: 1804018 as the most stable when complexed with the target protein. PC3 of the (Z)-2-(2,5-dimethoxybenzylidene)-6-(2-(4-methoxyphenyl)-2-oxoethoxy) benzofuran-3(2H)-one (CID: 1804018) was 8.74 %, whereas PC3 of the 2'-Hydroxydaidzein (CID: 5280520) was 11.25 %. In this study, (Z)-2-(2,5-dimethoxybenzylidene)-6-(2-(4-methoxyphenyl)-2-oxoethoxy) benzofuran-3(2H)-one (CID: 1804018) unveiled the significant stability of the proteins' binding site in ADMET, Molecular docking, MM-GBSA and MD simulation analysis studies, which also showed a high negative binding free energy value, confirming as the best drug candidate which is found in Angelica archangelica which may potentially inhibit the replication of MARV nucleoprotein.


Assuntos
Antivirais , Benzofuranos , Marburgvirus , Simulação de Acoplamento Molecular , Replicação Viral , Antivirais/farmacologia , Antivirais/química , Antivirais/metabolismo , Marburgvirus/efeitos dos fármacos , Marburgvirus/metabolismo , Benzofuranos/farmacologia , Benzofuranos/química , Benzofuranos/metabolismo , Replicação Viral/efeitos dos fármacos , Quimioinformática/métodos , Desenho de Fármacos , Ligação Proteica , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/química , Sítios de Ligação , Ligantes
20.
Toxicol Appl Pharmacol ; 491: 117072, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39153513

RESUMO

AIMS: Septic cardiomyopathy is characterized by impaired contractile function and mitochondrial activity dysregulation. Salvianolic acid B (Sal B) is a potent therapeutic compound derived from the traditional Chinese medicine Salvia miltiorrhiza. This study explored the protective effects of Sal B on septic heart injury, emphasizing the mitochondrial unfolded protein response (UPRmt). MATERIALS AND METHODS: An in vivo mouse model of lipopolysaccharide (LPS)-induced heart injury was utilized to assess Sal B's protective role in septic cardiomyopathy. Additionally, cell models stimulated by LPS were developed to investigate the mechanisms of Sal B on UPRmt. Quantitative polymerase chain reaction, western blotting, immunohistochemistry, and immunofluorescence were employed for molecular analysis. RESULTS: Sal B, administered at doses of 10, 30, and 60 mg/kg, demonstrated protective effects on cardiac contractile function, reduced heart inflammation, and mitigated cardiac injury in LPS-exposed mice. In cardiomyocytes, LPS induced apoptosis, elevated mitochondrial ROS levels, promoted mitochondrial fission, and decreased mitochondrial membrane potential, all of which were alleviated by Sal B. Mechanistically, Sal B was found to induce UPRmt both in vivo and in vitro. ATF5, identified as a UPRmt activator, was modulated by LPS and Sal B, resulting in increased ATF5 expression and its translocation from the cytosol to the nucleus. ATF5-siRNA delivery reversed UPRmt upregulation, exacerbating mitochondrial dysfunction in LPS-stimulated cardiomyocytes and counteracting the mitochondrial function enhancement in Sal B-treated cardiomyocytes. CONCLUSIONS: This study provides evidence that Sal B confers cardiac protection by enhancing UPRmt, highlighting its potential as a therapeutic approach for mitigating mitochondrial dysfunction in septic cardiomyopathy.


Assuntos
Benzofuranos , Cardiomiopatias , Camundongos Endogâmicos C57BL , Mitocôndrias Cardíacas , Miócitos Cardíacos , Resposta a Proteínas não Dobradas , Animais , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/metabolismo , Benzofuranos/farmacologia , Camundongos , Masculino , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Lipopolissacarídeos/toxicidade , Sepse/tratamento farmacológico , Sepse/complicações , Sepse/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Depsídeos
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