Dietary glucosamine overcomes the defects in αß-T cell ontogeny caused by the loss of de novo hexosamine biosynthesis.

T cell development requires the coordinated rearrangement of T cell receptor (TCR) gene segments and the expression of either αß or γδ TCR. However, whether and how de novo synthesis of nutrients contributes to thymocyte commitment to either lineage remains unclear. Here, we find that T cell-specific deficiency in glutamine:fructose-6-phosphate aminotransferase 1 (GFAT1), the rate-limiting enzyme of the de novo hexosamine biosynthesis pathway (dn-HBP), attenuates hexosamine levels, blunts N-glycosylation of TCRß chains, reduces surface expression of key developmental receptors, thus impairing αß-T cell ontogeny. GFAT1 deficiency triggers defects in N-glycans, increases the unfolded protein response, and elevates  γδ-T cell numbers despite reducing γδ-TCR diversity. Enhancing TCR expression or PI3K/Akt signaling does not reverse developmental defects. Instead, dietary supplementation with the salvage metabolite, glucosamine, and an α-ketoglutarate analogue partially restores αß-T cell development in GFAT1T-/- mice, while fully rescuing it in ex vivo fetal thymic organ cultures. Thus, dn-HBP fulfils, while salvage nutrients partially satisfy, the elevated demand for hexosamines during early T cell development.

Citrus depressa Hayata peel ameliorates nonalcoholic fatty liver and modulates the activity of hepatic drug-metabolizing enzymes and transporters in rats fed a high-fat diet.

Citrus depressa Hayata is a small, green citrus fruit native to Taiwan and Japan. Citrus peel contains polymethoxylated flavones, including nobiletin and tangeretin, and may exhibit strong antioxidant and anti-inflammatory activities. A preliminary study revealed that Citrus depressa Hayata peel (CDHP) ethanolic extract reduced fat accumulation and the concentration of reactive oxygen species in human HepG2 cells exposed to oleic acid. The effects of CDHP on the activity of hepatic drug-metabolizing enzymes and membrane transporters in high-fat (HF) diet-induced fatty liver were investigated. Male rats were fed a low-fat diet, a HF diet, and a HF diet containing 4% CDHP for 11 weeks. The low-fat and HF diet respectively contained 13.5% and 38.1% of daily total calories from dietary fat. CDHP supplementation reduced the HF diet-induced accumulation of triglycerides in the liver and lowered hepatic fatty acid synthase activity. Higher faecal excretions of cholesterol, triglycerides, and total bile acids were observed after CDHP treatment. CDHP lowered the HF diet-induced increase in the mRNA expressions of nuclear factor erythroid 2-related factor 2, aryl hydrocarbon receptor, pregnane X receptor, and peroxisome proliferator-activated receptor-α and the activities of cytochrome P-450 (CYP)1A1, 1A2, 2B, and 2E1. However, increased hepatic CYP3A activity was observed in rats fed the HF diet containing CDHP. A higher hepatic multidrug resistance-associated protein 2 level was observed after CDHP treatment. After CDHP administration (1 g per kg body weight) for 1 h, nobiletin was found in plasma and various tissues and was abundant in the liver. An in vitro study revealed that the activity of various CYP enzymes in liver microsomes was inhibited by CDHP ethanolic extract and nobiletin, with IC50 values ranging from 18.5 to 54.4 µg ml-1 and from 13.0 to 33.2 µM, respectively. The results of this study suggest that CDHP might reduce hepatic steatosis and alter drug-metabolizing enzymes and transporters in HF diet-induced nonalcoholic fatty liver diseases.

Shenqi Fuzheng Injection () Combined with Chemotherapy for Acute Leukemia: A Meta-Analysis.

OBJECTIVE: To evaluate to the efficacy and safety of Shenqi Fuzheng Injection (, SFI) combined with chemotherapy in the treatment of acute leukemia (AL) by meta-analysis. METHODS: PubMed, Cochrane library, Embase, SinoMed, China National Knowledge Infrastructure (CNKI), VIP Journal Integration Platform, Wanfang Database were searched from establishment to November 1, 2018. The randomized controlled trials (RCTs) of SFI combined with chemotherapy in the treatment of AL were included. The Cochrane risk assessment form (RevMan 5.1) was used to evaluate the quality of included studies. RESULTS: A total of 14 RCTs and 1,088 patients was included. The quality evaluation were mostly low risk or unclear. Meta-analysis showed that compared with chemotherapy alone, SFI combined with chemotherapy can improve the total clinical effective rate in patients with AL (RR=1.15, 95% CI: 1.056-1.177; P=0.0001), and relieve adverse reactions caused by chemotherapy drugs, including infection (RR=0.561, 95% CI: 0.397-0.792; P=0.001), nausea and vomiting (RR=0.662, 95% CI: 0.524-0.835; P=0.001), bleeding (RR=0.548, 95% CI: 0.39-0.768; P=0.0001), cardiotoxicity (RR=0.230, 95% CI: 0.080-0.660; P=0.006) and hyperhidrosis (RR=0.348, 95% CI: 0.208-0.581; P=0.0001). The incidence rates of adverse reactions in SFI combined with chemotherapy group were significantly lower than that of the chemotherapy alone group (P<0.01). CONCLUSIONS: Shenqi Fuzheng Injection combined with chemotherapy has good efficacy and safety for AL, and it can alleviate the adverse reactions caused by chemotherapy. However, subject to the limitations of the methodological quality of the literature, the conclusions of this study need to be further verified by large-scale and multi-center RCTs.

Qing-Yu-Mu, an Herbal Formula, Reduces Hepatic Oxidative Stress in Rats Fed a High-Frying Oil Diet and Ameliorates Carbon Tetrachloride-Induced Liver Injury.

Qing-Yu-Mu (QYM) is an herbal formula used to prevent and treat liver disease in Taiwan. In this study, the hepatoprotective effects of QYM were evaluated in two experimental models. First, rats were fed a high-frying oil (FO) diet containing 1.25% QYM for 5 weeks to investigate effects of QYM on hepatic oxidative stress and antioxidant enzyme activities. Then, protective effects of QYM on carbon tetrachloride (CCl4)-induced chronic liver injury were evaluated. Results show that QYM treatment reduced FO diet-induced hepatic lipid peroxidation and reactive oxygen species levels and increased glutathione (GSH) S-transferase activity. A higher reduced GSH/oxidized GSH (GSSG) ratio was observed after QYM treatment. Furthermore, QYM ameliorated CCl4-induced liver injury by reducing the activity of plasma alanine aminotransferase and histological lesions in the liver. QYM also increased the level of hepatic GSH and activities of GSH peroxidase and superoxide dismutase. Finally, chlorogenic acid, chrysophanol, and apigenin were found to be present in relative abundance in QYM. Results show that QYM may exhibit a hepatoprotective effect by reducing oxidative stress and increasing antioxidant activity in the liver.

A Diterpenoid, 14-Deoxy-11, 12-Didehydroandrographolide, in Andrographis paniculata Reduces Steatohepatitis and Liver Injury in Mice Fed a High-Fat and High-Cholesterol Diet.

14-Deoxy-11,12-didehydroandrographolide (deAND), a diterpenoid in Andrographis paniculata (Burm. f.) Nees, acts as a bioactive phytonutrient that can treat many diseases. To investigate the protective effects of deAND on reducing fatty liver disease, male mice were fed a high-fat and high-cholesterol (HFHC) diet without or with 0.05% and 0.1% deAND supplementation. Cholesterol accumulation, antioxidant, and anti-inflammatory activities in liver and liver injury were evaluated after deAND treatment. The results show that deAND treatment for seven weeks reduced plasma alanine aminotransferase activity and lowered hepatic cholesterol accumulation, tumor nuclear factor-α, and histological lesions. The 0.1% deAND treatment reduced HFHC diet-induced apoptosis by lowering the caspase 3/pro-caspase 3 ratio. After 11 weeks of deAND treatment, increased NOD-like receptor protein 3 (NLRP3), capase-1, and interleukin-1ß protein levels in liver were suppressed by deAND treatment. In addition, nuclear factor erythroid 2-related factor 2 (Nrf2) mRNA expression, heme oxygenase-1 protein expression, and the activities of glutathione peroxidase and glutathione reductase were increased in mice fed the HFHC diet. However, those activities of antioxidant enzymes or proteins were also upregulated by 0.1% deAND treatment. Furthermore, deAND treatment tended to lower hepatic lipid peroxides. Finally, deAND treatment reversed the depletion of hepatic glutamate level induced by the HFHC diet. These results indicate that deAND may ameliorate HFHC diet-induced steatohepatitis and liver injury by increasing antioxidant and anti-inflammatory activities.

Food-Drug Interaction between the Adlay Bran Oil and Drugs in Rats.

Adlay (Coix lachryma-jobi L. var. ma-yuen Stapf) contains various phytonutrients for treating many diseases in Asia. To investigate whether orally administered adlay bran oil (ABO) can cause drug interactions, the effects of ABO on the pharmacokinetics of five cytochrome P450 (CYP) probe drugs were evaluated. Rats were given a single oral dose (2.5 mL/kg BW) of ABO 1 h before administration of a drug cocktail either orally or intravenously, and blood was collected at various time points. A single oral dose of ABO administration did not affect the pharmacokinetics of five probe drugs when given as a drug cocktail intravenously. However, ABO increased plasma theophylline (+28.4%), dextromethorphan (+48.7%), and diltiazem (+46.7%) when co-administered an oral drug cocktail. After 7 days of feeding with an ABO-containing diet, plasma concentrations of theophylline (+45.4%) and chlorzoxazone (+53.6%) were increased after the oral administration of the drug cocktail. The major CYP enzyme activities in the liver and intestinal tract were not affected by ABO treatment. Results from this study indicate that a single oral dose or short-term administration of ABO may increase plasma drug concentrations when ABO is given concomitantly with drugs. ABO is likely to enhance intestinal drug absorption. Therefore, caution is needed to avoid food-drug interactions between ABO and co-administered drugs.

Ganoderma tsugae induced ROS-independent apoptosis and cytoprotective autophagy in human chronic myeloid leukemia cells.

The medicinal fungus Ganoderma, known in Chinese as Lingzhi or Reishi, traditionally has various medicinal uses and has been employed in cancer treatment in Asia for centuries. This study used ethanol-extracted Ganoderma tsugae (GT) and examined its antitumor activities on human chronic myeloid leukemia cells as well as its molecular mechanism of action. Treatment with GT (200-400 µg/mL) significantly reduced cell viability and caused G2/M arrest in K562 cells. In addition, GT induced mitochondrial and death receptor mediated apoptosis, correlated with DNA fragmentation, followed by cytochrome c release, caspase-3/8/9 activation, PARP cleavage, Fas activation, Bid cleavage, and Bax/Bcl-2 dysregulation. Cytoprotective autophagy was found to be induced by GT, as was revealed by increased LC3-II accumulation, Beclin-1/Bcl-2 dysregulation, acidic vesicular organelle formation, and p62/SQSTM1 activation. Notably, pretreatment of cells with the autophagy inhibitors 3-MA and CQ enhanced GT-induced apoptosis. Interestingly, reactive oxygen species production in cells was not triggered by GT administration; equally, the antioxidant N-acetylcysteine was found to be incapable of preventing apoptosis and autophagy induced by GT treatment. Finally, this study discovered that cytoprotective autophagy induced by GT was associated with EGFR and PI3K/AKT/mTOR signaling cascade suppression. In summary, GT demonstrated antitumor activity against human chronic myeloid leukemia.