Construction of ROS-Responsive Hyaluronic Acid Modified Paclitaxel and Diosgenin Liposomes and Study on Synergistic Enhancement of Anti-Ovarian Cancer Efficacy.

Purpose: Ovarian cancer is a fatal gynecologic malignancy with a high rate of abdominal metastasis. Chemotherapy still has a poor clinical prognosis for ovarian cancer patients, with cell proliferation and angiogenesis leading to invasion, migration, and recurrence. To overcome these obstacles, we constructed a novel HA-modified paclitaxel and diosgenin liposome (PEG-TK-HA-PDLPs) using two novel functional materials, DSPE-PEG2000-HA and DSPE-PEG2000-TK-PEG5000, to specifically deliver the drugs to the tumor site in order to reduce OC cell proliferation and anti-angiogenic generation, thereby inhibiting invasion and migration. Methods and Results: PEG-TK-HA-PDLPs were prepared by film dispersion, with ideal physicochemical properties and exhibits active targeting for enhanced cellular uptake. The ZIP synergy score for PTX and Dios was calculated using the online SynergyFinder software to be 3.15, indicating synergy. In vitro results showed that PEG-TK-HA-PDLPs were highly cytotoxic to ID8 cells, induced ID8 cell apoptosis, and inhibited ID8 cell migration and invasion. In vivo studies showed that PEG-TK-HA-PDLPs could prolong the circulation time in the blood, accumulate significantly in the tumor site, and effectively fight against angiogenesis with significant anti-tumor effects. Conclusion: The production of PEG-TK-HA-PDLPs is an effective strategy for the treatment of OC.

Preparation, characterization, and cytotoxicity evaluation of self-assembled nanoparticles of diosgenin-cytarabine conjugate.

Diosgenin (DG) isolated from yam roots revealed various bioactivities and applications as drug carrier. In the present study, a conjugate of DG with cytarabine (Ara-C) was used to prepare the self-assembled nanoparticles (NPs) of DG-Ara-C by a nanoprecipitation method. Dynamic light scattering (DLS) as well as transmission electron microscopy (TEM) were employed to analyze the size and the morphology of NPs, respectively. The stability and absorption of DG-Ara-C NPs were measured. Additionally, the cytotoxicity of the NPs was determined via MTT assay. The results indicated that the average particle size of DG-Ara-C NPs was around 190 nm with a narrow size distribution (PDI = 0.1). TEM showed that DG-Ara-C NPs had a spherical morphology. Compared to free DG or Ara-C, the self-assembled DG-Ara-C NPs exhibited a better anti-tumor activity against solid tumor cells as well as leukemia cells. In conclusion, DG possesses dual role in the self-assembled NPs of DG-Ara-C conjugate, being as a promising anticancer drug and drug carrier.

Diosgenin Attenuates Cognitive Impairment in Streptozotocin-Induced Diabetic Rats: Underlying Mechanisms.

OBJECTIVE: Prolonged diabetes mellitus causes impairments of cognition and attentional dysfunctions. Diosgenin belongs to a group of steroidal saponins with reported anti-diabetic and numerous protective properties. This research aimed to assess the effect of diosgenin on beneficially ameliorating learning and memory decline in a rat model of type 1 diabetes caused by streptozotocin (STZ) and to explore its modes of action including involvement in oxidative stress and inflammation. METHODS: Rats were assigned to one of four experimental groups, comprising control, control under treatment with diosgenin, diabetic, and diabetic under treatment with diosgenin. Diosgenin was given daily p.o. (40 mg/kg) for 5 weeks. RESULTS: The administration of diosgenin to the diabetic group reduced the deficits of functional performance in behavioral tests, consisting of Y-maze, passive avoidance, radial arm maze, and novel object discrimination tasks (recognitive). Furthermore, diosgenin treatment attenuated hippocampal acetylcholinesterase activity and malon-dialdehyde, along with improvement of antioxidants such as superoxide dismutase and glutathione. Meanwhile, the hippocampal levels of inflammatory indicators, namely interleukin 6, nuclear factor-κB, toll-like receptor 4, tumor necrosis factor α, and astrocyte-specific biomarker glial fibrillary acidic protein, were lower and, on the other hand, tissue levels of nuclear factor (erythroid-derived 2)-related factor 2 were elevated upon diosgenin administration. Besides, the mushroom-like spines of the pyramidal neurons of the hippocampal CA1 area decreased in the diabetic group, and this was alleviated following diosgenin medication. CONCLUSIONS: Taken together, diosgenin is capable of ameliorating cognitive deficits in STZ-diabetic animals, partly due to its amelioration of oxidative stress, inflammation, astrogliosis, and possibly improvement of cholinergic function in addition to its neuroprotective potential.

Soluplus-Mediated Diosgenin Amorphous Solid Dispersion with High Solubility and High Stability: Development, Characterization and Oral Bioavailability.

BACKGROUND AND PURPOSE: The traditional Chinese medicine, diosgenin (Dio), has attracted increasing attention because it possesses various therapeutic effects, including anti-tumor, anti-infective and anti-allergic properties. However, the commercial application of Dio is limited by its extremely low aqueous solubility and inferior bioavailability in vivo. Soluplus, a novel excipient, has great solubilization and capacity of crystallization inhibition. The purpose of this study was to prepare Soluplus-mediated Dio amorphous solid dispersions (ASDs) to improve its solubility, bioavailability and stability. METHODS: The crystallization inhibition studies were firstly carried out to select excipients using a solvent shift method. According to solubility and dissolution results, the preparation methods and the ratios of drug to excipient were further optimized. The interaction between Dio and Soluplus was characterized by differential scanning calorimetry (DSC), fourier transform infrared (FT-IR) spectroscopy, scanning electron microscopy (SEM), powder X-ray diffraction (PXRD) and molecular docking. The pharmacokinetic study was conducted to explore the potential of Dio ASDs for oral administration. Furthermore, the long-term stability of Dio ASDs was also investigated. RESULTS: Soluplus was preliminarily selected from various excipients because of its potential to improve solubility and stability. The optimized ASDs significantly improved the aqueous solubility of Dio due to its amorphization and the molecular interactions between Dio and Soluplus, as evidenced by dissolution test in vitro, DSC, FT-IR spectroscopy, SEM, PXRD and molecular docking technique. Furthermore, pharmacokinetic studies in rats revealed that the bioavailability of Dio from ASDs was improved about 5 times. In addition, Dio ASDs were stable when stored at 40°C and 75% humidity for 6 months. CONCLUSION: These results indicated that Dio ASDs, with its high solubility, high bioavailability and high stability, would open a promising way in pharmaceutical applications.

The renoprotective effect of diosgenin on aristolochic acid I-induced renal injury in rats: impact on apoptosis, mitochondrial dynamics and autophagy.

Aristolochic acid I (AA-I) remains a leading cause of aristolochic acid nephropathy (AAN), however few prevention and treatment strategies exist. In this work, the nephroprotective effect of diosgenin, a steroidal saponin distributed abundantly in several plants, on AA-I-induced renal injury and its underlying mechanism were investigated. Sprague-Dawley rats were intragastrically administered with 30 mg kg-1 d-1 diosgenin two hours before exposure to 10 mg kg-1 d-1 AA-I for consecutive four weeks, and the histological change, the renal and liver function, apoptosis, autophagy and the involved pathways were investigated. The results showed that diosgenin relieved AA-I-induced renal histological damage, including mild edematous disorder of renal tubular arrangement and widening of renal tubular lumen. No obvious changes in the hepatic tissue structure were observed in all treatment groups. Moreover, diosgenin up-regulated the expression of Bcl-2 and down-regulated Bax, and subsequently inhibited AIF expression and the cleaved form of Caspase-3, thereby alleviating apoptosis triggered by AA-I. Diosgenin also mitigated AA-I-induced renal mitochondrial dynamics disorder by increasing the expression of mitochondrial dynamics-related proteins including DRP1 and MFN2. Diosgenin inhibited AA-I-evoked autophagy via ULK1-mediated inhibition of the mTOR pathway. Overall, these results suggest that diosgenin has a protective effect against AA-I-induced renal damage and it may be a potential agent for preventing AA-I-induced AAN.

Deciphering the Role of Polyphenols in Sports Performance: From Nutritional Genomics to the Gut Microbiota toward Phytonutritional Epigenomics.

The individual response to nutrients and non-nutrient molecules can be largely affected by three important biological layers. The gut microbiome can alter the bioavailability of nutrients and other substances, the genome can influence molecule kinetics and dynamics, while the epigenome can modulate or amplify the properties of the genome. Today the use of omic techniques and bioinformatics, allow the construction of individual multilayer networks and thus the identification of personalized strategies that have recently been considered in all medical fields, including sports medicine. The composition of each athlete's microbiome influences sports performance both directly by acting on energy metabolism and indirectly through the modulation of nutrient or non-nutrient molecule availability that ultimately affects the individual epigenome and the genome. Among non-nutrient molecules polyphenols can potentiate physical performances through different epigenetic mechanisms. Polyphenols interact with the gut microbiota, undergoing extensive metabolism to produce bioactive molecules, which act on transcription factors involved in mitochondrial biogenesis, antioxidant systems, glucose and lipid homeostasis, and DNA repair. This review focuses on polyphenols effects in sports performance considering the individual microbiota, epigenomic asset, and the genomic characteristics of athletes to understand how their supplementation could potentially help to modulate muscle inflammation and improve recovery.

RPV-modified epirubicin and dioscin co-delivery liposomes suppress non-small cell lung cancer growth by limiting nutrition supply.

Chemotherapy for non-small cell lung cancer (NSCLC) is far from satisfactory, mainly due to poor targeting of antitumor drugs and self-adaptations of the tumors. Angiogenesis, vasculogenic mimicry (VM) channels, migration, and invasion are the main ways for tumors to obtain nutrition. Herein, RPV-modified epirubicin and dioscin co-delivery liposomes were successfully prepared. These liposomes showed ideal physicochemical properties, enhanced tumor targeting and accumulation in tumor sites, and inhibited VM channel formation, tumor angiogenesis, migration and invasion. The liposomes also downregulated VM-related and angiogenesis-related proteins in vitro. Furthermore, when tested in vivo, the targeted co-delivery liposomes increased selective accumulation of drugs in tumor sites and showed extended stability in blood circulation. In conclusion, RPV-modified epirubicin and dioscin co-delivery liposomes showed strong antitumor efficacy in vivo and could thus be considered a promising strategy for NSCLC treatment.

Effects of diosgenin and its derivatives on atherosclerosis.

Atherosclerosis is one of the leading causes of death in patients with cardiovascular diseases worldwide. Although some progress has been made in the treatment of cardiovascular diseases, the morbidity and mortality of cardiovascular diseases still continue to rise. At present, it is an important topic for researchers to develop safe and effective drugs from natural products to prevent and treat cardiovascular diseases. Diosgenin (DSG) is a plant sterol saponin mainly found in natural medicinal plants such as fenugreek seeds and wild yam tubers. More and more studies have reported that DSG has significant pharmacological activities such as anticancer, cardiovascular protection, hypolipidemic, anti-inflammatory, and neuroprotection. Furthermore, diosgenin is also an important basic raw material for the preparation of steroids and contraceptives in the pharmaceutical industry. Numerous preclinical studies have shown that DSG has great potential in the treatment of various cardiovascular diseases in vivo and in vitro, especially in atherosclerosis. This review mainly discusses the effects of DSG on endothelial dysfunction, lipid profile, and macrophage foam cell formation, VSMC viability, thrombosis and inflammation during the formation of atherosclerosis. Also, the mechanism of DSG on atherosclerosis was elaborated in detail. It is noteworthy that newly synthesized DSG derivatives and DSG delivery systems have good antithrombotic activity and pharmacokinetic characteristics.

Diosgenin inhibits tumor angiogenesis through regulating GRP78-mediated HIF-1α and VEGF/VEGFR signaling pathways.

The present paper describes the molecular mechanism of diosgenin on tumor microenvironment angiogenesis and the regulation of GRP78 in angiogenesis signaling pathway. CCK8 method was used to evaluate the effect of different concentrations of diosgenin on HUVEC activity in hypoxic microenvironment. Apoptosis was detected by Annexin V/PI staining. Tube Formation experiment was conducted to evaluate angiogenesis. Western Blot assay was applied to detect the expressions and phosphorylation levels of the angiogenesis-related pathways HIF-1α, GRP78, VEGF/VEGFR, PI3K/AKT, ERK, and FAK in rheumatoid HUVEC. Silencing GRP78 by siRNA interference technology was employed to investigate the mechanism of GRP78 involved in the regulation of angiogenesis. The results indicated that diosgenin can significantly inhibit the cell viability of hypoxic HUVEC and the significance is dependent on drug concentration. As the concentration increases, HUVEC activity decreases. Cell apoptosis is induced in a dose-dependent manner and angiogenesis can be significantly inhibited. The hypoxic microenvironment can significantly increase the expressions of HIF-lα, GRP78, VEGF/VEGFR, PI3K/AKT, ERK, FAK proteins in angiogenesis-related pathways, and can also enhance the phosphorylation of AKT, ERK1/2 and FAK proteins, which can be decreased by drug intervention. After silencing GRP78, the angiogenesis-related pathway proteins HIF-lα and VEGF/VEGFR are significantly reduced, thus inhibiting the activation of AKT, ERK1/2, and FAK. The anti-tumor angiogenesis mechanism of diosgenin inhibiting the expression of HIF-lα, GRP78, VEGF/VEGFR, PI3K/AKT, ERK1/2 and FAK signaling pathways may be through multiple pathways and targets, and GRP78 is involved in the regulation of angiogenesis signaling pathway.

Diosgenin Supplementation Prevents Lipid Accumulation and Induces Skeletal Muscle-Fiber Hypertrophy in Rats.

Diosgenin (Dio) is a steroid sapogenin found in plants such as Dioscorea species, and is recognized as a phytochemical against various disorders as well as a natural precursor of steroidal drugs. The present study used rats fed high-cholesterol (Chol) diets supplemented with or without 0.5% Dio for 6 wk to investigate the effects of dietary Dio on lipid metabolism. Dio supplementation significantly increased serum high-density lipoprotein Chol concentrations and fecal Chol content, and significantly decreased fecal bile acid content compared rats fed a high-Chol diet alone, showing that dietary Dio may facilitate excretion of Chol rather than bile acids. A reduction in the liver triglyceride content and intra-abdominal visceral fat was observed in Dio-supplemented rats. Interestingly, dietary Dio also significantly increased the skeletal muscle-fiber diameter and area in the thigh muscles of the rats. Mouse myoblast-derived C2C12 cells were used to examine whether Dio directly affected skeletal muscle. Dio promoted fusion of myoblasts into multinucleated cells or myotubes. Furthermore, in myotube C2C12 cells, protein levels of phosphorylated AMP-activated protein kinase (AMPK) increased with Dio treatment in a dose-dependent manner. These results indicate that Dio may not only induce myoblast fusion and enhance skeletal muscle as an energy expenditure organ, but may also activate the catabolic pathway via AMPK in skeletal muscle cells. Thus, these effects of Dio on skeletal muscles may contribute to inhibition of visceral fat accumulation.

Diosgenin exhibits tumor suppressive function via down-regulation of EZH2 in pancreatic cancer cells.

Pancreatic cancer (PC) is one of the most aggressive and lethal malignancies worldwide. Although significant progress has been made in oncology treatment, this refractory disease is still become intractable. Natural herb product diosgenin is described to exhibit vast range of pharmacological activities in preclinical studies, including anti-cancer activities. Accumulating data demonstrated that Enhancer of zeste homolog 2 (EZH2) as an oncogenic protein is over-expressed in various human cancers, including PC. However, the underlying mechanism has not been fully understood. In this study, we aim to investigate the anti-cancer properties and molecular basis of diosgenin in PC cells. Significant inhibition of cell proliferation was observed in diosgenin treated Patu8988 and Panc-1 cells in a dose- and time-dependent manner. Apoptotic cell death and G2/M phase arrest were also induced by diosgenin treatment in PC cells. Moreover, obvious inhibition of cell migration and invasive capacities was detected in diosgenin treated PC cells. Mechanistically, the expression levels of EZH2 and its target Vimentin were reduced, and PTEN was promoted after diosgenin exposure. Our results further supported that EZH2 signaling was closely associated with the anti-tumor characteristics of diosgenin in PC cells. Therefore, inhibition of EZH2 by diosgenin could be a promising therapeutic method for PC treatment.

Inhibition of tumor metastasis by targeted daunorubicin and dioscin codelivery liposomes modified with PFV for the treatment of non-small-cell lung cancer.

Background: Chemotherapy for non-small-cell lung cancer (NSCLC) still leads to unsatisfactory clinical prognosis because of poor active targeting and tumor metastasis. Purpose: The objective of this study was to construct a kind of PFV peptide modified targeted daunorubicin and dioscin codelivery liposomes, which could enhance tumor targeting and inhibit tumor cell metastasis. Methods and results: Targeted daunorubicin and dioscin codelivery liposomes were prepared by film dispersion and the ammonium sulfate gradient method. With the ideal physicochemical properties, targeted daunorubicin and dioscin codelivery liposomes exhibited enhanced cellular uptake and showed strong cytotoxicity to tumor cells. The encapsulation of dioscin increased the inhibitory effects of daunorubicin on A549 cells, vasculogenic mimicry (VM) channels and tumor metastasis. The enhanced antimetastatic mechanism of the targeted liposomes was attributed to the downregulation of matrix metalloproteinase-2 (MMP-2), vascular endothelial cadherin (VE-Cad), transforming growth factor-ß1 (TGF-ß1) and hypoxia inducible factor-1α (HIF-1α). Meanwhile, the targeted daunorubicin and dioscin codelivery liposomes exhibited significant antitumor effects in tumor-bearing mice. H&E staining, immunohistochemistry with Ki-67 and TUNEL assay also showed the promoted antitumor activity of the targeted liposomes. Conclusion: Targeted daunorubicin and dioscin codelivery liposomes may provide an effective strategy for the treatment of NSCLC.

Diosgenin and Its Fenugreek Based Biological Matrix Affect Insulin Resistance and Anabolic Hormones in a Rat Based Insulin Resistance Model.

Fenugreek is known since ancient times as a traditional herbal medicine of its multiple beneficial effects. Fenugreek's most studied and employed effect is its hypoglycemic property, but it can also be useful for the treatment of certain thyroid disorders or for the treatment of anorexia. The regulation of glucose homeostasis is a complex mechanism, dependent on the interaction of different types of hormones and neurotransmitters or other compounds. For the study of how diosgenin and fenugreek seeds modify insulin sensitivity, we used a rat insulin resistance model induced by high-fat diet. Diosgenin in three different doses (1mg/bwkg, 10mg/bwkg, and 50 mg/bwkg, respectively) and fenugreek seed (0.2 g/bwkg) were administered orally for 6 weeks. Insulin sensitivity was determined by hyperinsulinemic euglycemic glucose clamp method. Our research group found that although glucose infusion rate was not significantly modified in either group, the increased insulin sensitivity index and high metabolic clearance rate of insulin found in the 1 mg/kg diosgenin and the fenugreek seed treated group suggested an improved peripheral insulin sensitivity. Results from the 10 mg/kg diosgenin group, however, suggest a marked insulin resistance. Fenugreek seed therapy results on the investigated anabolic hormones support the theory that, besides insulin and gastrointestinal peptides, the hypothalamic-hypopituitary axis regulated hormones synchronized action with IGF-1 also play an important role in the maintaining of normal glucose levels. Both diosgenin and fenugreek seeds are capable of interacting with substrates of the above-mentioned regulatory mechanisms, inducing serious hormonal disorders. Moreover, fenugreek seeds showed the ability to reduce the thyroid hormone levels at the periphery and to modify the T4/T3 ratio. It means that in healthy people this effect could be considered a severe side effect; however, in hypothyroidism this effect represents a possibility of alternative natural therapy.

Dioscin, a Steroidal Saponin Isolated from Dioscorea nipponica, Attenuates Collagen-Induced Arthritis by Inhibiting Th17 Cell Response.

Dioscin, a steroidal saponin isolated from Dioscorea nipponica Makino, has previously been shown to possess antiarthritic effects. However, the underlying mechanism is still elusive. Herein, we investigated the therapeutic effects of dioscin on collagen-induced arthritis (CIA) in DBA/1 mice and related mechanism. Cytokine production in CII-specific immune responses were measured by enzyme-linked immunosorbent assay (ELISA); Th17 cell-related gene expression, including IL-17A, ROR γτ and IL-23p19, were detected by qPCR analysis; Surface marker, T regulatory (Treg) cells and intracellular cytokines (IL-17A and IFN- γ ) were evaluated by flow cytometry. We performed Th17 cell differentiation assay in vitro. Results showed that, in vivo, dioscin treatment significantly reduced the severity of CIA, which was accompanied by decreased Th17 response, but not Th1 and Treg response; dioscin-treated mice also showed lower percentage of CD11b + Gr-1 + neutrophils; In vitro, dioscin treatment suppressed the differentiation of naive CD4 + T cells into Th17 cell and decreased IL-17A production. Collectively, our results indicate that dioscin exerts antiarthritic effects by inhibiting Th17 cell immune response.

Cardiovascular Effect of Diosgenin in Ovariectomized Rats.

Diosgenin is a phytoestrogen and a constituent of Dioscorea. It has several biological effects, and some of them are anti-inflammatory, antidiabetic, antitumor, and vasodilatory. The present study investigated both the vasorelaxing and antioxidant mechanisms of diosgenin in isolated rat aortic rings. Female rats weighing 200-220 g were subjected to sham or OVX operations at 8 weeks of age. Ovariectomy was performed for menopause induction after anesthesia. Diosgenin (10-9 M-3 × 10-4 M) produced a concentration-dependent relaxation in aortic rings precontracted with phenylephrine (1 µM), exhibiting Emax value of 55.34% ± 7.7% (in endothelium-intact rings) and Emax value of 30.30% ± 5.7% (in endothelium-denuded rings). In the endothelium-intact rings, the vasorelaxing effect of diosgenin was reduced by NG-nitro-l-arginine methyl ester (L-NAME) (100 µM), atropine (1 µM), indomethacin (10 µM), 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ) (10 µM), 4-aminopyridine (1 mM), tetraethylammonium (3 mM), glibenclamide (10 µM), apamin (10 µM), and Tiron (1 µM). Diosgenin (10-5 M) inhibited the contractions induced by cumulative addition of phenylephrine (10-9-10-5 M). The 28-days treatment with diosgenin (50 mg/kg, v.o.) did not imply changes in the myeloperoxidase parameter, but increased significantly, levels of glutathione, superoxide dismutase, and nitric oxide, as well as reduced the concentration of malondialdehyde related to lipid peroxidation. Our results suggest that diosgenin induced relaxation in aortic rings via an endothelium-dependent pathway, which involves the EDRF, the opening of potassium channels and antioxidant action.

Combined Effect of Diosgenin Along with Ezetimibe or Atorvastatin on the Fate of Labelled Bile Acid and Cholesterol in Hypercholesterolemic Rats.

We analyzed the effect of diosgenin, administered with atorvastatin or ezetimibe, on the fate of ³H(G)-taurocholic acid or 26-14C-cholesterol in hypercholesterolemic rats. Male Wistar rats received a hypercholesterolemic diet (HD), HD + atorvastatin (HD+ATV), HD + ezetimibe (HD+EZT), HD + diosgenin (HD+DG), HD+ATV+EZT, or HD+ATV+DG for 40 days. We also included a control normal group (ND). The labelled compounds were administered on day 30. The animals were placed in metabolic cages for daily feces collection. At day 40 the rats were sacrificed. Lipid extracts from blood, liver, spinal cord, testicles, kidneys, epididymis, intestine, and feces were analyzed for radioactivity. Cholesterol activity was the highest in the liver in HD rats. DG diminished one half of this activity in HD+DG and HD+ATV+DG groups in comparison with the HD group. HD+ATV rats showed four to almost ten-fold cholesterol activity in the spinal cord compared with the ND or HD rats. Fecal elimination of neutral steroids was approximately two-fold higher in the HD+DG and HD+ATV+DG groups. Taurocholic acid activity was four to ten-fold higher in HD+DG intestine as compared to the other experimental groups. Taurocholic activity in the liver of HD and HD+DG groups was two and a half higher than in ND. Our results show that the combination of DG and ATV induced the highest cholesterol reduction in the liver and other tissues.

Anticancer activity of polyphyllin I in nasopharyngeal carcinoma by modulation of lncRNA ROR and P53 signalling.

Nasopharyngeal carcinoma (NPC) is the most common aggressive squamous cell carcinoma in head and neck cancers. Although advanced radiochemotherapy has been applied, the prognosis of NPC patients still remains poor due to the regional relapse and distant metastasis. Polyphyllin I (PP I) is extracted from natural herb Paris polyphylla that has been widely used in cancer treatment and long non-coding RNA (lncRNA) has been reported to play a key role in the anti-tumour activity of PP I. In this study, it has been found that PP I inhibited the proliferation and induced apoptosis of NPC cells in a dose-dependent manner. A higher level of lncRNA regulator of reprogramming (ROR) expression was detected in NPC cell lines compared with normal nasopharyngeal cell line and PP I must significantly down-regulate the expression level of lncRNA ROR. LncRNA ROR/P53 signalling was essential for PP I-suppressed NPC progression. These data indicated that PP I suppressed tumour growth and induced apoptosis of NPC in vitro and in vivo through down-regulation of lncRNA-ROR, subsequently upregulating of P53 signalling. LncRNA ROR may be a potential therapeutic target and PP I would be a promising candidate for NPC treatment.

Effects of Sanyaku and Its Constituent Diosgenin on the Fasted and Postprandial Hypertriacylglycerolemia in High-Fat-Diet-Fed KK- A y Mice.

In this study, we examined the fasted and postprandial triacylglycerol (TG) levels in KK- A y mice fed a high-fat diet (HFD) or a HFD containing either 500 ppm (0.05%) of diosgenin or 500 ppm (0.05%) of diosgenin-containing Chinese yam sanyaku. Oral fat tolerance tests revealed that, not only in the fasting state but also after loading of lipid emulsion, plasma levels of TG were significantly reduced in sanyaku- and diosgenin- fed mice. Levels of fat oxidation, especially in the dark phase (from 7 p.m. to 7 a.m.), were increased in the sanyaku and diosgenin groups. Moreover mRNA levels of lipoprotein lipase and peroxisome proliferator-activated receptor γ, coactivator 1α were moderately upregulated in the liver of sanyaku- and diosgenin-ingested mice. These results suggest that consecutive ingestion of diosgenin or diosgenin-containing sanyaku at the dose achievable in a human diet potentially ameliorates fasted and postprandial hypertriacylglycerolemia, which could be associated with the improvement of TG metabolism.

Diosgenin restores Aß-induced axonal degeneration by reducing the expression of heat shock cognate 70 (HSC70).

We previously found diosgenin, an herbal drug-derived steroid sapogenin, to be remarkably effective at restoring Aß-induced axonal degeneration and improving memory function in model of Alzheimer's disease (AD), 5XFAD mouse. In this study, we investigated the downstream signaling of diosgenin and explored new therapeutic targets in AD. We showed that the expression of heat shock cognate (HSC) 70 was increased in Aß-treated neurons and in 5XFAD mice but was decreased by diosgenin treatment. In addition, knockdown of HSC70 significantly promoted axonal growth in neurons. As an association molecule of HSC70 in neurons, α-tubulin was detected by immunoprecipitation. After Aß treatment, α-tubulin expression was greatly reduced in the degenerated axons, suggesting that a decline in α-tubulin may be one of the factors which correlates with axonal disruption in AD pathology. We hypothesized that the degradation of α-tubulin is triggered by the chaperone activity of HSC70. However, diosgenin significantly normalized the α-tubulin level, a potentially critical process for axonal formation. Our study indicated that reducing the HSC70 level is a new possible therapeutic target of axonal regeneration in AD.

Dioscin inhibits stem-cell-like properties and tumor growth of osteosarcoma through Akt/GSK3/ß-catenin signaling pathway.

Osteosarcoma is the most common primary bone tumor in children and adolescents. Many patients with osteosarcoma always develop drug resistance to current chemotherapy regimens, which induces a poor prognosis. And cancer stem cells (CSCs) have been reported to possess the properties to self-renew and maintain the phenotype of tumor, which may lead to clinical treatment failure. Thus, it is an urgent task to develop several potentially useful therapeutic agents, which could target CSCs in osteosarcoma. This study aims to clarify the in vitro and in vivo anti-osteosarcoma effects of dioscin, the primary component derived from Discorea nipponica Makino, and its molecular mechanism of action. In this study, all the ten human osteosarcoma cell lines were sensitive to dioscin treatment in a dose- and time-dependent manner. Dioscin inhibits proliferation and induces cell cycle arrest as well as apoptotic cell death in osteosarcoma cells. More importantly, oral administration of dioscin (60 mg/kg) showed significant therapeutic effect on osteosarcoma growth without obvious side effects in vivo. In addition, dioscin possesses the ability to suppress stem-cell-like phenotype of osteosarcoma cells. Mechanistically, dioscin inhibits osteosarcoma stem-cell-like properties and tumor growth through repression of Akt/GSK3/ß-catenin pathway. Moreover, ß-catenin expression in osteosarcoma patients was associated with clinical prognosis. Conclusively, the present study provides comprehensive evidence for the inhibition of dioscin on osteosarcoma stem-cell-like properties and tumor growth through repression of Akt/GSK3/ß-catenin pathway, which suggests dioscin as a promising therapeutic regimen. And ß-catenin may be a potential therapeutic target as well as a significant prognostic marker for osteosarcoma patients in clinic.