ABSTRACT
Background: Diabetic osteoporosis (DOP) is a progressive osteoblast dysfunction induced by high glucose, which has negative impacts on bone homeostasis. Qizhi Kebitong formula (QKF) is a traditional Chinese medicine (TCM) formula for treating DOP. However, its role in the protection of DOP has not been clarified yet. Here, we aimed to explore the potential mechanisms of QKF on DOP development via in vivo experiment. Methods: Network pharmacology was used to detect the key targets and signaling pathways of QKF on DOP. The effects of QKF on DOP were examined by the phenotypic characteristics, micro-CT, and hematoxylin-eosin (H&E) staining. The predicted targets and pathways were validated by a streptozocin- (STZ-) induced mouse model. Subsequently, the levels of the selected genes and proteins were analyzed using qRT-PCR and Western blot. Finally, AutoDock and PyMOL were used for molecular docking. Results: In this study, 90 active compounds and 2970 related disease targets have been found through network pharmacology. And QKF could improve the microstructures of femur bone mass, reduce inflammatory cell infiltration, and downregulate the levels of TNF-α, IKBKB, IL-6, and IL-1ß. Moreover, the underlying effect of PI3K/Akt/NF-κB pathways was also recommended in the treatment. Conclusion: Altogether, our findings suggested that QKF could markedly alleviate osteoblast dysfunction by modulating the key targets and PI3K/Akt/NF-κB signaling pathway.
Subject(s)
Diabetes Mellitus , Drugs, Chinese Herbal , Osteoporosis , Animals , Drugs, Chinese Herbal/pharmacology , Mice , Molecular Docking Simulation , NF-kappa B/metabolism , Osteoporosis/drug therapy , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , StreptozocinABSTRACT
Vascular dysfunction can lead to a variety of fatal diseases, including cardiovascular and cerebrovascular diseases, metabolic syndrome, and cancer. Although a large number of studies have reported the therapeutic effects of natural compounds on vascular-related diseases, ginseng is still the focus of research. Ginseng and its active substances have bioactive effects against different diseases with vascular dysfunction. In this review, we summarized the key molecular mechanisms and signaling pathways of ginseng, its different active ingredients or formula in the prevention and treatment of vascular-related diseases, including cardiac-cerebral vascular diseases, hypertension, diabetes complications, and cancer. Moreover, the bidirectional roles of ginseng in promoting or inhibiting angiogenesis have been highlighted. We systematically teased out the relationship between ginseng and vascular dysfunction, which could provide a basis for the clinical application of ginseng in the future.
Subject(s)
Hypertension , Panax , Humans , Hypertension/drug therapy , Signal TransductionABSTRACT
INTRODUCTION: The roots of Stephania succifera are used in traditional medicine for the treatment of several diseases. Research on this plant has mainly focused on bioactive alkaloids from the roots, and no previous work on compounds from the abundant leaves has yet been reported. OBJECTIVE: To identify and compare alkaloidal compounds in S. succifera roots and leaves and to predict the potential bioactivity of some alkaloids. METHODS: High-performance liquid chromatography with quadrupole time-of-flight tandem mass spectrometry (HPLC-QTOF-MS/MS) was employed to identify alkaloidal compounds from S. succifera. The potential targets and bioactivities of most alkaloids were predicted using the PharmMapper server. RESULTS: Fifty-six alkaloidal compounds, including protoberberine-, aporphine-, proaporphine-, benzylisoquinoline-, and lactam-type alkaloids, were identified or tentatively identified in S. succifera roots and leaves based on the HPLC-MS data. Forty-one compounds have not been previously reported in S. succifera and eight of them have not been previously reported in the literature. Twenty-four alkaloidal compounds were found in both roots and leaves. Twelve potential targets with different indications were predicted for some alkaloids. CONCLUSION: Comparison of chemical constituents and their potential bioactivities for S. succifera roots and leaves indicated that diverse bioactive alkaloids were present in the leaves as well as the roots. PharmMapper provided new directions for bioactivity screening. This study will be helpful for further understanding the medicinal components of S. succifera and the rational utilisation of plant resources.
Subject(s)
Alkaloids , Stephania , Alkaloids/analysis , Chromatography, High Pressure Liquid/methods , Plant Extracts/chemistry , Plant Leaves/chemistry , Stephania/chemistry , Tandem Mass Spectrometry/methodsABSTRACT
Vascular calcification (VC) is characterized by pathological depositions of calcium and phosphate in the arteries and veins via an active cell-regulated process, in which vascular smooth muscle cells (VSMCs) transform into osteoblast/chondrocyte-like cells as in bone formation. VC is associated with significant morbidity and mortality in chronic kidney disease (CKD) and cardiovascular disease, but the underlying mechanisms remain unclear. In this study we investigated the role of large-conductance calcium-activated potassium (BK) channels in 3 experimental VC models. VC was induced in vascular smooth muscle cells (VSMCs) by ß-glycerophosphate (ß-GP), or in rats by subtotal nephrectomy, or in mice by high-dosage vitamin D3. We showed that the expression of BK channels in the artery of CKD rats with VC and in ß-GP-treated VSMCs was significantly decreased, which was functionally confirmed by patch-clamp recording. In ß-GP-treated VSMCs, BK channel opener NS1619 (20 µM) significantly alleviated VC by decreasing calcium content and alkaline phosphatase activity. Furthermore, NS1619 decreased mRNA expression of ostoegenic genes OCN and OPN, as well as Runx2 (a key transcription factor involved in preosteoblast to osteoblast differentiation), and increased the expression of α-SMA protein, whereas BK channel inhibitor paxilline (10 µM) caused the opposite effects. In primary cultured VSMCs from BK-/- mice, BK deficiency aggravated calcification as did BK channel inhibitor in normal VSMCs. Moreover, calcification was more severe in thoracic aorta rings of BK-/- mice than in those of wild-type littermates. Administration of BK channel activator BMS191011 (10 mg· kg-1 ·d-1) in high-dosage vitamin D3-treated mice significantly ameliorated calcification. Finally, co-treatment with Akt inhibitor MK2206 (1 µM) or FoxO1 inhibitor AS1842856 (3 µM) in calcified VSMCs abrogated the effects of BK channel opener NS1619. Taken together, activation of BK channels ameliorates VC via Akt/FoxO1 signaling pathways. Strategies to activate BK channels and/or enhance BK channel expression may offer therapeutic avenues to control VC.
Subject(s)
Large-Conductance Calcium-Activated Potassium Channels/drug effects , Muscle, Smooth, Vascular/drug effects , Proto-Oncogene Proteins c-akt/drug effects , Vascular Calcification/pathology , Alkaline Phosphatase/drug effects , Animals , Aorta, Thoracic/drug effects , Benzimidazoles/pharmacology , Cholecalciferol/pharmacology , Disease Models, Animal , Glycerophosphates/pharmacology , Male , Mice , Mice, Inbred C57BL , Nephrectomy , Osteocalcin/drug effects , Osteopontin/drug effects , Peptide Fragments/drug effects , RNA, Messenger/drug effects , Random Allocation , Rats , Rats, Sprague-DawleyABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Trillium tschonoskii Maxim, a perennial herb of the Trilliaceae, has been widely used to treat inflammation, hypertension and cancer. We investigated Paris saponin VII's (PS VII), isolated from Trillium tschonoskii Maxim, function in mediating autophagy and apoptosis in NSCLC cells. MATERIALS AND METHODS: We treated various NSCLC cells with different concentrations of PS â ¦ and then measure the cell apoptosis by using flow cytometry assays and western blot. Autophagy were investigated by using western blot, transmission electron microscopy and immunofluorescence analysis. We also use a xenograft model of nude mice to measure the effect of PS â ¦ in vivo. RESULTS: Treatment with PS â ¦ significantly inhibit NSCLC cell growth, especially for A549 (IC50â¯=â¯1.53⯵M). Moreover, PS VII induces caspase-dependent apoptosis and autophagy through AMPK-ULK1 pathway. After blocking autophagy by 3-methyladenine (3-MA), PS VII induced cell death was significantly increased. In vivo, the co-treatment with PS VII and 3-MA dramatically inhibited A549 tumor growth in immune deficient mice and has similar inhibition rates as cisplatin group. CONCLUSION: Our results suggest that a combination of PS VII and autophagy inhibitor may be a potential anticancer strategy in the NSCLC therapy.
Subject(s)
Antineoplastic Agents, Phytogenic/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Saponins/therapeutic use , Animals , Antineoplastic Agents, Phytogenic/pharmacology , Apoptosis/drug effects , Autophagy/drug effects , Cell Line, Tumor , Humans , Mice, Inbred BALB C , Mice, Nude , Saponins/pharmacology , TrilliumABSTRACT
The intestinal permeability of forskolin was investigated using a single pass intestinal perfusion (SPIP) technique in rats. SPIP was performed in different intestinal segments (duodenum, jejunum, ileum, and colon) with three concentrations of forskolin (11.90, 29.75, and 59.90 µg/mL). The investigations of adsorption and stability were performed to ensure that the disappearance of forskolin from the perfusate was due to intestinal absorption. The results of the SPIP study indicated that forskolin could be absorbed in all segments of the intestine. The effective permeability (P (eff)) of forskolin was in the range of drugs with high intestinal permeability. The P (eff) was highest in the duodenum as compared to other intestinal segments. The decreases of P (eff) in the duodenum and ileum at the highest forskolin concentration suggested a saturable transport process. The addition of verapamil, a P-glycoprotein inhibitor, significantly enhanced the permeability of forskolin across the rat jejunum. The absorbed fraction of dissolved forskolin after oral administration in humans was estimated to be 100 % calculated from rat P (eff). In conclusion, dissolved forskolin can be absorbed readily in the intestine. The low aqueous solubility of forskolin might be a crucial factor for its poor oral bioavailability.