Protective Effect and Mechanism of Plant-Based Monoterpenoids in Non-alcoholic Fatty Liver Diseases.

The protective effect of plant active ingredients against non-alcoholic fatty liver disease (NAFLD) is becoming increasingly prominent, and the terpenoids have always been the main active compounds in Chinese herbal medicine exerting hepatoprotective effects. However, the related pharmacological effects, especially for monoterpenoids or iridoid glycosides, which have obvious effects on improvement of NAFLD, have not been systematically analyzed. The objective of this review is to systematically examine the molecular mechanisms of monoterpenoids in NAFLD. The signaling pathways of peroxisome proliferator-activated receptor, insulin, nuclear factor κB, toll-like receptor, adipocytokine, RAC-α serine/threonine protein kinase, mammalian target of rapamycin, 5'-AMP-activated protein kinase, and autophagy have been proven to mediate this protective effect. We further compared the experimental data from animal models, including the dosage of these monoterpenoids in detail, and demonstrated that they are effective and safe candidate drugs for NAFLD. This review provides a reference for the development of NAFLD drugs as well as a research guideline for the potential uses of plant monoterpenoids.

Mixtures of Tea and Citrus maxima (pomelo) Alleviate Lipid Deposition in HepG2 Cells Through the AMPK/ACC Signaling Pathway.

Tea and citrus maxima are natural, medicinal homologous plants, typically used for making beverages, which have anticancer, antiobesity, and antioxidation properties. Green tea, yellow tea, and black tea were combined with citrus maxima to obtain green tea and Citrus maxima (GTCM), yellow tea and Citrus maxima (YTCM), and black tea and Citrus maxima (BTCM). The biochemical components of these mixtures were analyzed, and their possible effects and mechanisms on relieving liver lipid deposition were explored. The tea polyphenols, free amino acids, phenolamine ratio, and caffeine were comparable in YTCM and GTCM, being significantly higher than those in BTCM. In addition, the content of esterified catechins, nonesterified catechins, and total catechins in YTCM was significantly higher than those in GTCM and BTCM. All three mixtures of Citrus maxima tea significantly reduced lipid deposition in HepG2 cells, with GTCM and YTCM being slightly more effective than BTCM. Regarding the possible mechanism, Western blot analysis revealed that the three Citrus maxima tea mixtures could activate the AMPK/ACC signaling pathway, upregulate the expression of p-AMPK, p-ACC, and CPT-1 proteins, and downregulate the expression of SREBP1c and fatty acid synthase proteins to inhibit fat synthesis, thereby relieving lipid deposition in liver cells. In conclusion, as a novel and healthy beverage, Citrus maxima tea has the potential to alleviate liver lipid deposition, and further could be responsible for obesity treatment.

Green tea and black tea inhibit proliferation and migration of HepG2 cells via the PI3K/Akt and MMPs signalling pathway.

BACKGROUND AND AIMS: Black tea and green tea were produced via different processing techniques from the same tea leave variety. Then, biochemical components of the two water extracts were analysed to study cell apoptosis, migration and invasion of HepG2 cells induced by black tea and green tea. METHOD: The monomer components of the black tea and green tea extracts were analysed by colorimetry and HPLC, with MTT assay and colony formation assays used to assess cell proliferation and viability. The effects of black tea and green tea on apoptosis of HepG2 cells were verified by flow cytometry, with wound healing and Transwell experiments used to detect cell invasion and metastasis. The expression of PI3K/Akt signalling and apoptosis-related proteins as well as epithelial-mesenchymal transition (EMT) regulatory factor in HepG2 cells were determined by western blotting after black tea and green tea treatment. RESULTS AND CONCLUSIONS: Black tea and green tea extracts demonstrated different degrees of inhibition of cell migration and invasion, with green tea inducing more HepG2 cell apoptosis. In addition, green tea and black tea extracts inhibited the growth of HepG2 cells and induced apoptosis via PI3K/Akt, and inhibited cell migration and invasion through the MMPs signalling pathway. This study revealed the effects of fermented (black tea) and non-fermented tea (green tea) on liver cancer cells, providing a basis for the investigation of tea extracts for their anti-tumour potential.

Theaflavin TF3 Relieves Hepatocyte Lipid Deposition through Activating an AMPK Signaling Pathway by targeting Plasma Kallikrein.

Nonalcoholic fatty liver disease (NAFLD) is rapidly becoming the leading cause of chronic liver diseases throughout the world. The deficit of pharmacotherapy for NAFLD calls for an urgent need for a new drug discovery and lifestyle management. Black tea is the most popular and functional drink consumed worldwide. Its main bioactive constituent theaflavin helps to prevent obesity-a major risk factor for NAFLD. To find new targets for the development of effective and safe therapeutic drugs from natural plants for NAFLD, we found a theaflavin monomer theaflavin-3,3'-digallate (TF3), which significantly reduced lipid droplet accumulation in hepatocytes, and directly bound and inhibited the activation of plasma kallikrein (PK), which was further proved to stimulate adenosine monophosphate activated protein kinase (AMPK) and its downstream targets. Taken together, we proposed that the TF3-PK-AMPK regulatory axis is a novel mechanism of lipid deposition mitigation, and PK could be a new target for NAFLD treatment.

A combination of Citrus reticulata peel and black tea inhibits migration and invasion of liver cancer via PI3K/AKT and MMPs signaling pathway.

Liver cancer, one of the most common malignancies, is the second leading cause of cancer death in the world. The citrus reticulate peel and black tea have been studied for their beneficial health effects. In spite of the many studies have been reported, the underlying molecular mechanisms underlying its health benefits are still not fully understood. In present study, we developed a unique citrus reticulate peel black tea (CRPBT) by combined citrus reticulate peel and black tea and assessed its active ingredients, anti-oxidant and anti-liver cancer effects in vitro. The results suggested that CRPBT exhibited antioxidant capacity and effectively inhibited proliferation and migration of liver cancer cells in a dose- and time- dependent manner. Mechanistically, CRPBT significantly down-regulated phosphorylation of PI3K and AKT, and up-regulated the ratio of Bax/Bcl-2, and suppressed the expression of MMP2/9, N-cadherin and Vimetin proteins in liver cancer cells. Taken together, CRPBT has good effect on inhibiting migration, invasion, proliferation, and inducing apoptosis in liver cancer cells.

Six types of tea reduce high-fat-diet-induced fat accumulation in mice by increasing lipid metabolism and suppressing inflammation.

A high-fat diet results in obesity because of white fat accumulation. Although tea extracts alleviate lipid metabolism disorders and decrease white fat accumulation, the mechanisms underlying the therapeutic actions of different types of Chinese tea are unclear. We established a murine model of obesity by feeding mice with a high-fat diet (HFD) and treating them with atorvastatin (positive control) or water extracts (WEATs) of different tea types. The food and water intake, body weight gain, white fat accumulation, and triglyceride (TG) and total cholesterol (TC) levels were evaluated to assess the effects of the WEATs on obesity. The levels of the lipid metabolism enzymes p-AMPK, CPT-1A and FAS and the pro-inflammatory factors iNOS and IL-6 were determined. The WEATs not only reduced the body weight and white fat accumulation in the HFD-induced obese mice, but also relieved hepatic steatosis. Comparing the effects of the six kinds of tea showed that white tea has the best anti-obesity effect. Yellow tea and raw pu-erh tea significantly up-regulated p-AMPK, green tea, white tea and raw pu-erh tea markedly inhibited FAS, and white tea, yellow tea and oolong tea up-regulated CPT-1. Therefore, it is possible that white tea, yellow tea and oolong tea inhibit obesity by increasing energy expenditure and fatty acid oxidation, while green tea, white tea and raw pu-erh tea exert their effects by inhibiting fatty acid synthesis. In addition, the WEATs also significantly decreased the levels of IL-6, while green tea, yellow tea and oolong tea significantly inhibited iNOS. Different types of tea have specific chemical compositions and can regulate different lipid metabolism related proteins. In conclusion, despite variations in its composition and mechanism of action, tea is a potent anti-obesity agent.

Tea Polypeptide Ameliorates Diabetic Nephropathy through RAGE and NF-κB Signaling Pathway in Type 2 Diabetes Mice.

Diabetic nephropathy (DN) is a major complication of type 2 diabetes (T2D), which is a key determinant of mortality in diabetic patients. Developing new therapeutic drugs which can not only control T2D but also prevent the development of DN is of great significance. We studied the therapeutic potential of Cuiyu tea polypeptides (TP), natural bioactive peptides isolated from a type of green tea, against DN and its underlying molecular mechanisms. TP (1000 mg/kg bw/day, p.o.) administration for 5 weeks significantly reduced the fasting blood glucose by 52.04 ± 9.23% in the high fat diet/streptozocin (HFD/STZ)-induced (30 mg/kg bw) diabetic mice. Compared to the model group, the serum insulin level of the TP group was decreased by 25.54 ± 6.06%, while at the same time, the HOMA-IR, HOMA-IS, and lipid levels showed different degrees of recovery ( p < 0.05). Moreover, in TP group mice the total urinary protein, creatinine, and urine nitrogen, all which can reflect the damage degree of the glomerular filtration function to a certain extent, dramatically declined by 34.51 ± 2.65%, 42.24 ± 15.24%, and 80.30 ± 6.01% compared to the model group, respectively. Mechanistically, TP stimulated the polyol PKCζ/JNK/NF-κB/TNF-α/iNOS and AGEs/RAGE/TGF-ß1 pathways, upregulated the expression of podocin in the glomeruli, and decreased the release of pro-inflammatory cytokines. These results strongly indicate the therapeutic potential of TP against DN.

Recent insights into the biological activities and drug delivery systems of tanshinones.

Tanshinones, the major lipid-soluble pharmacological constituents of the Chinese medicinal herb Tanshen (Salvia miltiorrhiza), have attracted growing scientific attention because of the prospective biomedical applications of these compounds. Numerous pharmacological activities, including anti-inflammatory, anticancer, and cardio-cerebrovascular protection activities, are exhibited by the three primary bioactive constituents among the tanshinones, ie, tanshinone I (TNI), tanshinone IIA (TNIIA), and cryptotanshinone (CPT). However, due to their poor solubility and low dissolution rate, the clinical applications of TNI, TNIIA, and CPT are limited. To solve these problems, many studies have focused on loading tanshinones into liposomes, nanoparticles, microemulsions, cyclodextrin inclusions, solid dispersions, and so on. In this review, we aim to offer an updated summary of the biological activities and drug delivery systems of tanshinones to provide a reference for these constituents in clinical applications.

Synergistic anticancer effects of triptolide and celastrol, two main compounds from thunder god vine.

Triptolide and celastrol are two main active compounds isolated from Thunder God Vine with the potent anticancer activity. However, the anticancer effect of triptolide in combination with celastrol is still unknown. In the present study, we demonstrated that the combination of triptolide with celastrol synergistically induced cell growth inhibition, cell cycle arrest at G2/M phase and apoptosis with the increased intracellular ROS accumulation in cancer cells. Pretreatment with ROS scavenger N-acetyl-L-cysteine dramatically blocked the apoptosis induced by co-treatment with triptolide and celastrol. Treatment with celastrol alone led to the decreased expressions of HSP90 client proteins including survivin, AKT, EGFR, which was enhanced by the addition of triptolide. Additionally, the celastrol-induced expression of HSP70 and HSP27 was abrogated by triptolide. In the nude mice with xenograft tumors, the lower-dose combination of triptolide with celastrol significantly inhibited the growth of tumors without obvious toxicity. Overall, triptolide in combination with celastrol showed outstanding synergistic anticancer effect in vitro and in vivo, suggesting that this beneficial combination may offer a promising treatment option for cancer patients.

In vitro and in vivo evaluations of a novel pulsed and controlled osmotic pump capsule.

OBJECTIVE: For better treatment of circadian cardiovascular events, a novel Propranolol hydrochloride (PNH) delayed-release osmotic pump capsule was developed. METHODS: The capsule body was designed of asymmetric membrane and the capsule cap was made impermeable. The physical characteristics of capsule body walls and membrane permeability were compared among different coating solutions. RESULTS: The formulation with the glycerin and diethyl phthalate (DEP) ratio of 5:4 appeared to be the best. The lag time and subsequent drug release were investigated through assembling the capsule body with capsule caps of different length. WSR N-10 was chosen as the suspending for its moderate expanding capacity. The influence of factors (WSR N-10 content, NaCl content and capsule cap length) on the responses (lag time and drug release rate) was evaluated using central composite design-response surface methodology. A second-order polynomial equation was fitted to the data and actual response values were in good accordance with the predicted ones. The optimized formulation displayed complete drug delivery, zero-order release rate with 4-h lag time. The results of in vivo pharmacokinetics in beagle dogs clearly suggested the controlled and sustained release of PNH from the system and that the relative bioavailability of this preparation was about 1.023 comparing the marketed preparation. CONCLUSIONS: These results indicate that by the adjustment of capsule cap length, PNH could be developed as a novel pulsatile and controlled drug delivery system.

Intravenous microemulsion of docetaxel containing an anti-tumor synergistic ingredient (Brucea javanica oil): formulation and pharmacokinetics.

The purpose of this study was to develop a docetaxel microemulsion containing an anti-tumor synergistic ingredient (Brucea javanica oil) and to investigate the characteristics of the microemulsion. Brucea javanica oil contains oleic acid and linoleic acids that have been shown by animal and human studies to inhibit tumor formation. The microemulsion containing Brucea javanica oil, medium-chain triglyceride, soybean lecithin, Solutol®HS 15, PEG 400, and water was developed for docetaxel intravenous administration. A formulation with higher drug content, lower viscosity, and smaller particle size was developed. The droplet size distribution of the dispersed phase of the optimized microemulsion was 13.5 nm, determined using a dynamic light scattering technique. The small droplet size enabled the microemulsion droplets to escape from uptake and phagocytosis by the reticuloendothelial system and increased the circulation time of the drug. The zeta potential was -41.3 mV. The optimized microemulsion was pale yellow, transparent, and non-opalescent in appearance. The value of the combination index was 0.58, showing that there was a synergistic effect when docetaxel was combined with Brucea javanica oil. After a single intravenous infusion dose (10 mg/kg) in male Sprague Dawley rats, the area under the curve of the microemulsion was higher and the half-time was longer compared with that of docetaxel solution alone, and showed superior pharmacokinetic characteristics. These results indicate that this preparation of docetaxel in emulsion is likely to provide an excellent prospect for clinical tumor treatment.

Mathematical Distinction in Action Potential between Primo-Vessels and Smooth Muscle.

We studied the action potential of Primo-vessels in rats to determine the electrophysiological characteristics of these structures. We introduced a mathematical analysis method, a normalized Fourier transform that displays the sine and cosine components separately, to compare the action potentials of Primo-vessels with those for the smooth muscle. We found that Primo-vessels generated two types of action potential pulses that differed from those of smooth muscle: (1) Type I pulse had rapid depolarizing and repolarizing phases, and (2) Type II pulse had a rapid depolarizing phase and a gradually slowing repolarizing phase.