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ETHNOPHARMACOLOGICAL RELEVANCE: Hai-Honghua medicinal liquor (HHML), an external Chinese herbal formula preparation, is often applied to treat freshly closed tibia/fibular fractures, ankle fractures, and other bone-related disorders, but the related molecular mechanism is unclear. AIM OF THE STUDY: To evaluate the therapeutic effect of HHML in patients with tibial/fibular and ankle fractures, and to explore its related possible mechanism. METHODS AND MATERIALS: A total of 182 patients with tibia/fibular fractures and 183 patients with ankle fractures were enrolled in this study. A randomized, controlled, unblinded clinical trial was designed to evaluate the therapeutic effect of HHML on tibial/fibular and ankle fractures. The chemical compositions of HHML were analyzed by the HPLC-Q-Extractive MS/MS. Furthermore, a rat tibial fracture model was established to evaluate the therapeutic effects of HHML in promoting fracture healing, and the mouse embryonic osteoblasts cell line of MC3T3-E1 was further carried out to explore the mechanisms of HHML on osteoblast differentiation. RESULTS: In the clinical evaluation, HHML treatment significantly shortened the time for pain and swelling in patients with tibial/fibular fractures (P < 0.01) and ankle fractures (P < 0.01), and the incidence of complications was significantly reduced as well. Subsequently, 116 constituents were identified from HHML via HPLC-Q-TOF-MS/MS analysis. In vivo, no obvious changes in weight were observed in HHML-treated rats. Moreover, the levels of bone formation markers (including osteocalcin (OCN), N-terminal propeptide of type I procollagen (PINP), alkaline phosphatase (ALP), calcium (Ca) and substance P) in rat serum were significantly increased in HHML-treated rats compared with model rats (P < 0.05). Micro-CT analysis showed bone mineral density (BMD), bone volume fraction (BV/TV), trabecular thickness (Tb.Th) of the HHML-treated rats were significantly increased (P < 0.05, vs. Model) while trabecular separation (Tb.Sp) and structure model index (SMI) values were significantly reduced (P < 0.05, vs. Model). Histological analysis showed that HHML treatment promoted the healing of fractures and cartilage repair, and increased the osteoblasts and collagen fibers. Furthermore, our results also revealed HHML could promote MC3T3-E1 cells proliferation and osteoblast differentiation via regulation of the runt-related transcription factor 2 (RUNX2), bone alkaline phosphatase (BALP), and OCN by activating phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathway, which confirmed by adding PI3K chemical inhibitor of LY294002. CONCLUSION: HHML treatment is a reliable remedy for fractures in tibial and ankle by promotion of osteogenic differentiation via activation of PI3K/Akt pathway.
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Diferenciación Celular , Medicamentos Herbarios Chinos , Osteoblastos , Osteogénesis , Proteínas Proto-Oncogénicas c-akt , Ratas Sprague-Dawley , Animales , Medicamentos Herbarios Chinos/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Masculino , Osteogénesis/efectos de los fármacos , Humanos , Ratones , Diferenciación Celular/efectos de los fármacos , Femenino , Persona de Mediana Edad , Adulto , Ratas , Osteoblastos/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Curación de Fractura/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Fracturas Óseas/tratamiento farmacológico , Anciano , Adulto Joven , Modelos Animales de EnfermedadRESUMEN
Hydroxy-α-sanshool (HAS) is the predominant active compound in Zanthoxylum bungeanum Maxim (ZBM). Our present work was aimed to explore the in vitro metabolism characteristics, and in vivo pharmacokinetic (PK) profile of HAS. Plasma (human), liver microsomes, and hepatocytes (human, monkey, dog, mouse, and rat) were collected for HAS metabolism studies in vitro and HAS elimination rates in liver microsomes and hepatocytes of different species were investigated. In addition, five recombinant human CYP enzymes were used to identify CYP isoforms of HAS. Finally, the PK properties of HAS in rats in vivo were studied by oral administration (p.o.). The results showed that HAS stably metabolized in human and rat liver microsomes and human hepatocytes, and the binding of HAS to human plasma proteins was nonspecific; HAS has strong inhibitory effects on CYP2C9 and CYP2D6 of human liver microsomes. In addition, in vivo PK study, HAS is rapidly absorbed in rats after oral administration. In conclusion, the in vivo and in vitro metabolic studies of HAS in this study provide data support for its further development and application, and the metabolic profiles of different species can be used as a reference for its safety evaluation.
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BACKGROUND: Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease characterized by hyperglycemia and insulin resistance. Mung bean sprouts are traditionally considered a "folk" hypoglycemic food and their pharmacological effects and underlying mechanisms warrant further investigation. PURPOSE: This study aimed to investigate the anti-diabetic effects of the exosomes-like nanoparticles in mung bean sprouts (MELNs) and explore the related molecular mechanisms. RESULTS: MELNs were isolated using a differential centrifugation-polyethylene glycol (PEG) method, and the identification of MELNs were confirmed by PAGE gel electrophoresis, agarose gel electrophoresis, thin-layer chromatography (TLC), and transmission electron microscopy (TEM). In the high-fat diet/streptozotocin (HFD/STZ) mouse model, MELNs ameliorated the progression of T2DM by increasing oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) results, decreasing the fasting blood glucose level, and reducing the serum triglycerides (TG) and total cholesterol (TC). Histopathological examinations indicated MELNs diminished inflammatory infiltration of hepatocytes and amplified the area of islet B cells. In addition, MELNs decreased the oxidative stress levels in liver tissue and had good biocompatibility. In vitro experiments verified that MELNs improved the viability of glucosamine (GlcN) induced insulin-resistant hepatocytes. Furthermore, this study also revealed that MELNs upregulated GLUT4 & Nrf2 and down-regulated GSK-3ß via activating the PI3K/Akt signaling pathway, promoting the production of antioxidant enzymes, such as HO-1 and SOD, to reduce oxidative stress. CONCLUSION: MELNs mitigated the progression of type 2 diabetes in HFD/STZ mouse model. The underlying molecular mechanism is related to PI3K/Akt/GLUT4/GSK-3ß signaling pathway.
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Diabetes Mellitus Tipo 2 , Exosomas , Nanopartículas , Vigna , Animales , Ratones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucógeno Sintasa Quinasa 3 beta , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Insulina , Modelos Animales de Enfermedad , Transducción de SeñalRESUMEN
BACKGROUND: Accumulating evidence suggested increasing energy expenditure is a feasible strategy for combating obesity, and browning of white adipose tissue (WAT) to promote thermogenesis might be one of the attractive ways. Hydroxy-α-sanshool (HAS), a natural amide alkaloid extracted from the fruits of Zanthoxylum bungeanum Maxim, possesses lots of benefits in lipid metabolism regulation. METHODS: The anti-obesity effect of HAS was investigated by establishing an animal model of obesity and a 3T3-L1 differentiation cell model. Effects of HAS on the whole-body fat and liver of obese mice, and the role of HAS in inducing browning of white fat were studied by Micro CT, Metabolic cage detection, Cell mitochondrial pressure detection, transmission electron microscopy and cold exposure assays. Furthermore, the Real-time PCR (qPCR), digital PCR (dPCR), western blot, Co-immunoprecipitation (Co-IP), molecular docking, drug affinity responsive target stability (DARTS), Cellular thermal shift assay (CETSA) and other methods were used to investigate the target and mechanisms of HAS. RESULTS: We found that treatment with HAS helped mice combat obesity caused by a high fat diet (HFD) and improve metabolic characteristics. In addition, our results suggested that the anti-obesity effect of HAS is related to increase energy consumption and thermogenesis via induction of browning of WAT. The further investigations uncovered that HAS can up-regulate UCP-1 expression, increase mitochondria number, and elevate the cellular oxygen consumption rates (OCRs) of white adipocytes. Importantly, the results indicated that browning effects of HAS is closely associated with SIRT1-dependent PPAR-γ deacetylation through activating the TRPV1/AMPK pathway, and TRPV1 is the potential drug target of HAS for the browning effects of WAT. CONCLUSIONS: Our results suggested the HAS can promote browning of WAT via regulating AMPK/SIRT-1/PPARγ signaling, and the potential drug target of HAS is the membrane receptor of TRPV1.
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PPAR gamma , Zanthoxylum , Ratones , Animales , PPAR gamma/metabolismo , Frutas , Simulación del Acoplamiento Molecular , Proteínas Quinasas Activadas por AMP/metabolismo , Tejido Adiposo Blanco , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Alcamidas Poliinsaturadas/farmacología , Dieta Alta en Grasa/efectos adversos , Células 3T3-L1 , Canales Catiónicos TRPV/metabolismo , Canales Catiónicos TRPV/farmacologíaRESUMEN
Licochalcone A (LCA) is a flavonoid isolated from Glycyrrhiza uralensis Fisch that has shown promising therapeutic effects in various cancers. This study attempted to analyze its therapeutic potential for esophageal cancer (EC). Combining multiple databases and network pharmacology, we found that the mechanism of LCA inhibiting EC may be closely related to p53 signaling pathway, cell cycle regulation and apoptosis. Molecular docking was then used to predict the affinity between LCA and key targets. Subsequently, we selected three common EC cell lines for in vitro validation. LCA treatment significantly inhibited EC cell proliferation and colony formation. Wound healing and transwell assay showed that LCA can reduce the migration and invasion of EC cells, and down-regulated the expression of matrix metalloproteinases (MMP). LCA promoted excessive ROS production, decreased mitochondrial membrane potential, and upregulated the expression of Bax, Caspase3 and Caspase-9, all of which are involved in apoptosis. LCA treatment blocked the cell cycle in G2/M phase and decreased the expression of cyclin D1, cyclin B1, and CDK1. LCA significantly up-regulated p53 protein and gene expression, thereby inducing apoptosis and cycle arrest. Finally, the xenograft tumor model was established by subcutaneous injection of Eca-109 cells. LCA administration inhibited tumor growth by activating p53 signaling pathways and apoptosis. Meanwhile, there was no significant weight loss and few major organotoxicity and hematotoxicity. In conclusion, LCA is an excellent candidate for EC treatment by regulating p53 pathway to induce G2/M phase arrest and apoptosis.
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Neoplasias Esofágicas , Proteína p53 Supresora de Tumor , Humanos , Proteína p53 Supresora de Tumor/metabolismo , Simulación del Acoplamiento Molecular , Apoptosis , Proliferación Celular , Mitosis , Neoplasias Esofágicas/tratamiento farmacológico , Línea Celular TumoralRESUMEN
As the common pathological basis of various cardiovascular diseases, the morbidity and mortality of atherosclerosis (AS) have increased in recent years. Unfortunately, there are still many problems in the treatment of AS, and the prevention and treatment of the disease is not ideal. Up to now, the occurrence and development of AS can roughly include endothelial cell dysfunction, vascular smooth muscle cell proliferation, inflammation, foam cell production, and neoangiogenesis. Among them, endothelial dysfunction, as an early event of AS, plays a particularly important role in promoting the development of AS. In addition, oxidative stress occurs throughout the causes of endothelial dysfunction. Some previous studies have shown that flavonoids derived from herbal medicines are typical secondary metabolites. Due to its structural presence of multiple active hydroxyl groups, it is able to exert antioxidant activity in diseases. Therefore, in this review, we will search PubMed, Web of Science, Elesvier, Wliey, Springer for relevant literature, focusing on flavonoids extracted from herbal medicines, and summarizing how they can prevent endothelial dysfunction by inhibiting oxidative stress. Meanwhile, in our study, we found that flavonoid represented by quercetin and naringenin showed superior protective effects both in vivo and in vitro, suggesting the potential of flavonoid compounds in the treatment of AS.
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Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease characterized by hyperglycemia. The fruits of Zanthoxylum bungeanum Maxim. is a common spice and herbal medicine in China, and hydroxy-α-sanshool (HAS) is the most abundant amide in Z. bungeanum and reported to have significant hypoglycemic effects. The purpose of this study was to evaluate the ameliorative effects of HAS on T2DM and the potential mechanisms responsible for those effects. An acute toxicity test revealed the median lethal dose (LD50) of HAS is 73 mg/kg. C57BL/6 J mice were fed a high-fat diet and given an intraperitoneal injection of streptozotocin (STZ) to induce T2DM in mice to evaluate the hypoglycemic effects of HAS. The results showed that HAS significantly reduced fasting blood glucose, reduced pathological changes in the liver and pancreas, and increased liver glycogen content. In addition, glucosamine (GlcN)-induced HepG2 cells were used to establish an insulin resistance cell model and explore the molecular mechanisms of HAS activity. The results demonstrated that HAS significantly increases glucose uptake and glycogen synthesis in HepG2 cells and activates the PI3K/Akt pathway in GlcN-induced cells, as well as increases GSK-3ß phosphorylation, suppresses phosphorylation of glycogen synthase (GS) and increases glycogen synthesis in liver cells. Furthermore, these effects of HAS were blocked by the PI3K inhibitor LY294002. The results of our study suggest that HAS reduces hepatic insulin resistance and increases hepatic glycogen synthesis by activating the PI3K/Akt/GSK-3ß/GS signaling pathway.
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Backgroud: Alzheimer's disease (AD) is a typical neurodegenerative disease, which occurs in the elderly population. Alpiniae oxyphyllae Fructus (AOF) is a traditional Chinese medicine that has potential therapeutic effect on AD, but the mechanism behind it is unclear. Methods: Firstly, the main chemical components of AOF were identified by LC-MS, while the main active ingredients and targets were screened by TCMSP database. At the same time, AD-related target proteins were obtained using Genecards and OMIM databases. PPI was constructed by cross-linking AOF and AD targets, and GO enrichment analysis and KEGG pathway enrichment analysis were performed to identify the relevant biological processes and signaling pathways. Finally, based on the H2O2-stimulated PC12 cell, flow cytometry, WB and immunofluorescence experiments were performed to verify the protective effect of AOF on AD. Results: We identified 38 active ingredients with 662 non-repetitive targets in AOF, of which 49 were potential therapeutic AD targets of AOF. According to the GO and KEGG analysis, these potential targets are mainly related to oxidative stress and apoptosis. The role of AOF in the treatment of AD is mainly related to the PI3K/AKT signaling pathway. Protocatechuic acid and nootkatone might be the main active ingredients of AOF. In subsequent experiments, the results of CCK-8 showed that AOF mitigated PC12 cell damage induced by H2O2. Kits, flow cytometry, and laser confocal microscopy indicated that AOF could decrease ROS and increase the activity of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px), while AOF could also increase mitochondrial membrane potential (MMP), thereby inhibiting apoptosis. Finally, immunofluorescence and WB results showed that AOF inhibited the expression of BAX and caspase-3 in PC12 cells, and promoted the expression of Bcl-2. At the same time, the phosphorylation levels of PI3K and Akt proteins were also significantly increased. Conclusion: This study suggests that AOF had the potential to treat AD by suppressing apoptosis induced by oxidative stress via the PI3K/Akt pathway.
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Hepatic fibrosis (HF) refers to the pathophysiological process of connective tissue dysplasia in the liver caused by various pathogenic factors. Nowadays, HF is becoming a severe threat to the health of human being. However, the drugs available for treating HF are limited. Currently, increasing natural agents derived from traditional Chinese medicines (TCMs) have been found to be beneficial for HF. A systemic literature search was conducted from PubMed, GeenMedical, Sci-Hub, CNKI, Google Scholar and Baidu Scholar, with the keywords of "traditional Chinese medicine," "herbal medicine," "natural agents," "liver diseases," and "hepatic fibrosis." So far, more than 76 natural monomers have been isolated and identified from the TCMs with inhibitory effect on HF, including alkaloids, flavones, quinones, terpenoids, saponins, phenylpropanoids, and polysaccharides, etc. The anti-hepatic fibrosis effects of these compounds include hepatoprotection, inhibition of hepatic stellate cells (HSC) activation, regulation of extracellular matrix (ECM) synthesis & secretion, regulation of autophagy, and antioxidant & anti-inflammation, etc. Natural compounds and extracts from TCMs are promising agents for the prevention and treatment of HF, and this review would be of great significance to development of novel drugs for treating HF.
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Cancer, a common malignant disease, is one of the predominant causes of diseases that lead to death. Additionally, cancer is often detected in advanced stages and cannot be radically cured. Consequently, there is an urgent need for reliable and easily detectable markers to identify and monitor cancer onset and progression as early as possible. Our aim was to systematically review the relevant roles of cathepsin K (CTSK) in various possible cancers in existing studies. CTSK, a well-known key enzyme in the bone resorption process and most studied for its roles in the effective degradation of the bone extracellular matrix, is expressed in various organs. Nowadays, CTSK has been involved in various cancers such as prostate cancer, breast cancer, bone cancer, renal carcinoma, lung cancer and other cancers. In addition, CTSK can promote tumor cells proliferation, invasion and migration, and its mechanism may be related to RANK/RANKL, TGF-ß, mTOR and the Wnt/ß-catenin signaling pathway. Clinically, some progress has been made with the use of cathepsin K inhibitors in the treatment of certain cancers. This paper reviewed our current understanding of the possible roles of CTSK in various cancers and discussed its potential as a biomarker and/or novel molecular target for various cancers.
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Neoplasias , Biomarcadores , Catepsina K/metabolismo , Humanos , Masculino , Neoplasias/tratamiento farmacológicoRESUMEN
Glabridin (Gla) is a typical flavonoid isolated from the Glycyrrhiza glabra with various bioactivities and is a common additive in many cosmetics. In our study, we evaluated the antiscarring effect of Gla from G. glabra in a rabbit ear hyperplastic scar model. Hematoxylin and eosin staining and Masson staining were applied to determine the pathological changes and collagen fibers of scar tissue in rabbits. The results suggested that Gla could reduce rabbit ear scar hyperplasia, inhibit inflammation, and decrease collagen production. Furthermore, the in vitro cell experiments were applied to determine the effects of Gla on human keloid fibroblasts (HKFs), and we observed that Gla suppressed the HKF cells' proliferation via inducing apoptosis. Subsequently, we found that Gla reduced collagen production in HKF cells. The further molecular mechanisms investigations suggested that Gla played a therapeutic role against keloid by attenuating PI3K/Akt and TGFß1/SMAD pathways. Our study would be beneficial for extending the applications of the known sweet plant of G. glabra.
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Glycyrrhiza , Queloide , Animales , Colágeno/metabolismo , Fibroblastos , Glycyrrhiza/metabolismo , Humanos , Isoflavonas , Queloide/tratamiento farmacológico , Queloide/metabolismo , Queloide/patología , Fenoles , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Conejos , Transducción de Señal , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
Cancers are generally recognized as the leading cause of death and a predominant barrier to prolonging life expectancy in both developed and developing countries. Emodin is a typical anthraquinone derivative from various plants that exhibits a wide spectrum of biological activities, such as anticancer, antibacterial, hepatoprotective and anti-inflammatory activities. Much previous preclinical evidence has demonstrated that emodin exhibits reliable effects on several cancer types, including lung cancer, liver cancer, colon cancer, breast cancer, pancreatic cancer, leukemia, cervical cancer, and ovarian cancer, etc. The related molecular mechanisms corresponding to the anticancer activities of emodin are involved in the induction of apoptosis, inhibition of cell proliferation, enhanced reactive oxygen species (ROS) accumulation, and induction of autophagy, etc. In the present review, we summarized the sources, anticancer properties in vitro and in vivo, molecular mechanisms, metabolic transformation and toxicities of emodin. In addition, we also discussed the limitations of the present investigations of emodin against cancers and gave some perspectives for them, which would be beneficial for the further exploration and development of this natural compound as a clinical cancer drug.
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Antineoplásicos , Neoplasias del Colon , Emodina , Antraquinonas/farmacología , Antraquinonas/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis , Emodina/farmacología , Emodina/uso terapéutico , HumanosRESUMEN
Pancreatic cancer, a poor prognosis and high morbidity and mortality cancer, is a malignant tumor occurring in pancreatic exocrine glands. Currently, surgery and gemcitabine (Gem) are commonly used to treat pancreatic cancers. However, the high recurrence rate and resistance makes the therapeutic effects still unsatisfied. Apoptosis is comprehensively recognized as one of the major ways of the programmed cell death, refers to the autonomous and orderly death process of cells in order to maintain the stability of the body's environment after receiving a certain signal or stimulation. Currently, it has also been proven to be a promising way for the treatment of pancreatic cancer. Nowadays, some active ingredients from herbal medicine have been reported to be effective for the treatment of pancreatic cancer via inducing cells apoptosis. Therefore, this article reviews the current references regarding anti pancreatic cancer effects of natural products derived from herbal medicines via triggering apoptosis, and summarizes the related potential signal pathways, including death receptors mediated apoptotic pathway, mitochondrial dependent apoptotic pathway, NF-κB mediated apoptotic pathways, MAPK mediated apoptotic pathway, ERS mediated apoptotic pathway, PI3K-Akt mediated apoptotic pathway, and other pathways such as JAK-STAT signal pathway, which can lay a certain foundation for the research and development of new natural products against pancreatic cancer.