Structure and hepatoprotective activity of Usp10/NF-κB/Nrf2 pathway-related Morchella esculenta polysaccharide.

The water-soluble Morchella esculenta polysaccharide 2 (MEP2) was purified and isolated from an aqueous extract of the Morchella esculenta fruiting bodies. MEP2, having a molecular weight of 959 kDa, has a →4)-α-D-Glcp-(1→ glucan backbone, and this branch was substituted at the H-6 position by an α-D-Glcp-(1 â†’ 4)-α-D-Glcp-(1→ residue and an α-D-Glcp-(1→ residue. The hepatoprotective activity and potential mechanism of action of MEP2 were also investigated. MEP2 ameliorated severe liver damage and regulated the liver function indicators and the alcohol-related enzyme levels in chronic alcohol-induced mice. Combined with biochemical detection, the gut microbiota, metabolites, and proteomics results revealed that MEP2 regulates the levels of hepatic cytokines related to inflammatory response and oxidative stress, as well as those of intestinal Bacteroides, Oscillospira, Parabacteroides, Alistipes, and Prevotella, through the ubiquitin-specific peptidase 10 (Usp10)/nuclear factor κB (NF-κB)/nuclear factor erythroid-2 related factor 2 (Nrf2) signaling pathway in the liver of mice induced by long-term alcohol intake. These data provide experimental evidence for the application of MEP2 in chronic alcohol-induced liver injury.

The Protection of Crocin Against Ulcerative Colitis and Colorectal Cancer via Suppression of NF-κB-Mediated Inflammation.

Background: In China, the incidence of ulcerative colitis (UC) is increasing every year, but the etiology of UC remains unclear. UC is known to increase the risk of colorectal cancer (CRC). The aim of this study was to investigate the protective effects of crocin against UC and CRC in mouse models. Methods: Crocin was used to treat the dextran sodium sulfate (DSS)-induced UC mice for 3 weeks, and ApcMinC/Gpt mice with colorectal cancer for 8 weeks. Proteomics screening was used to detect changes in the protein profiles of colon tissues of UC mice. Enzyme-linked immunosorbent assays and western blot were used to verify these changes. Results: Crocin strongly reduced the disease activity index scores of UC mice, and improved the pathological symptoms of the colonic epithelium. The anti-inflammatory effects of crocin were indicated by its regulation of the activity of various cytokines, such as interleukins, via the modulation of nuclear factor kappa-B (NF-κB) signaling. Crocin significantly suppressed tumor growth in ApcMinC/Gpt mice and ameliorated pathological alterations in the colon and liver, but had no effects on spleen and kidney. Additionally, crocin significantly decreased the concentrations of interleukins and tumor necrosis factor-α in the sera and colon tissues, suggesting its anti-inflammatory effects related to NF-κB signaling. Finally, 12-h incubation of SW480 cells with crocin caused cell cycle arrest, enhanced the apoptotic rate, promoted the dissipation of mitochondrial membrane potential, and the over-accumulation of reactive oxygen species. From the theoretical analyses, phosphorylated residues on S536 may enhance the protein-protein interactions which may influence the conformational changes in the secondary structure of NF-κB. Conclusion: The protective effects of crocin on UC and CRC were due to its suppression of NF-κB-mediated inflammation.

Calf thymus polypeptide improved hematopoiesis via regulating colony-stimulating factors in BALB/c mice with hematopoietic dysfunction.

Calf thymus polypeptide (CTP) is prepared from calf thymus. It has a molecular mass of <10 kilodalton (kDa) and contains 17 types of amino acids. This study investigated the hematopoietic function-improvement effect of CTP in CHRF, K562, and bone marrow mononuclear cells; mice with immunosuppression; and with hematopoietic dysfunction. In mice with immunosuppression, CTP enhanced the cytotoxic activity of natural killer cells and the proliferation of lymphocytes and regulated the levels of immunoglobulins. It also enhanced the proliferation and differentiation of CHRF and K562 cells by upregulating the expression of proliferation- and differentiation-related proteins. In mice with hematopoietic dysfunction, CTP restored white blood cell, neutrophil, and hemoglobin proportions in the peripheral blood and enhanced the levels of B lymphocytes and hematopoietic stem cells and progenitor cells in the bone marrow. CTP effectively regulated the levels of hematopoiesis-related cytokines, such as granulocyte colony-stimulating factor (G-CSF), macrophage colony-stimulating factor (M-CSF), interleukin 2, and interferons-γ, and enhanced the expression of hematopoiesis-related proteins in both primary bone marrow cells and mice with hematopoietic dysfunction. These results indicate that CTP has hematopoietic function-improvement effect and this effect may be related to the modulation of colony-stimulating factors (CSFs) and related signaling pathways.

The Pro-Apoptotic Activity of Tamarixetin on Liver Cancer Cells Via Regulation Mitochondrial Apoptotic Pathway.

Based on the various pharmacological activities of tamarixetin, the present study investigated the cytotoxicity property of tamarixetin in human liver cancer cells including PLC/PRF/5 and HepG2 cells, and their xenografted tumor nude mice. In cells, tamarixetin incubation resulted in the suppression on cell viability; enhanced cell apoptosis rate, LDH release, caspase-3 activation, and reactive oxygen species accumulation; and decreased mitochondrial membrane potential in a dose-dependent manner. Tamarixetin inhibited the growth of PLC/PRF/5- and HepG2-xenografted tumors in BALB/c nude mice after 14-day administration without influencing their bodyweights and organ functions including liver and spleen. Tamarixetin enhanced the expression levels of pro-apoptotic proteins including Bax and cleaved caspase-3 and inhibited the expression levels of anti-apoptotic proteins including Bcl-2 and Bcl-xL in liver cancer cells and their xenografted tumor tissues. Furthermore, tamarixetin significantly suppressed the phosphorylation of ERKs and AKT in both PLC/PRF/5 and HepG2 cells, and tumor tissues. All present data suggest that tamarixetin displays pro-apoptotic properties in liver cancer cells related to the mitochondria apoptotic pathway via regulating the ERKs and AKT signaling.

The Role of AMP-Activated Protein Kinase as a Potential Target of Treatment of Hepatocellular Carcinoma.

Background: Hepatocellular carcinoma (HCC) is the fifth most frequent cancer worldwide with a very high recurrence rate and very dismal prognosis. Diagnosis and treatment in HCC remain difficult, and the identification of new therapeutic targets is necessary for a better outcome of HCC treatment. AMP-Activated Protein Kinase (AMPK) is an essential intracellular energy sensor that plays multiple roles in cellular physiology and the pathological development of chronic diseases. Recent studies have highlighted the important regulation of AMPK in HCC. This review aims to comprehensively and critically summarize the role of AMPK in HCC. Methods: Original studies were retrieved from NCBI database with keywords including AMPK and HCC, which were analyzed with extensive reading. Results: Dysregulation of the kinase activity and expression of AMPK was observed in HCC, which was correlated with survival of the patients. Loss of AMPK in HCC cells may proceed cell cycle progression, proliferation, survival, migration, and invasion through different oncogenic molecules and pathways. Conclusions: We identified several AMPK activators which may possess potential anti-HCC function, and discussed the clinical perspective on the use of AMPK activators for HCC therapy.

The Antidiabetic and Antinephritic Activities of Auricularia cornea (An Albino Mutant Strain) via Modulation of Oxidative Stress in the db/db Mice.

This study first systematically analyzed the constituents of an albino mutant strain of Auricularia cornea (AU). After 8 weeks of continuous treatment with metformin (Met) (0.1 g/kg) and AU (0.1 and 0.4 g/kg), db/db mice showed hypoglycemic functioning, indicated by reduced bodyweight, food intake, plasma glucose, serum levels of glycated hemoglobin A1c and glucagon, hepatic levels of phosphoenolpyruvate carboxykinase and lucose-6-phosphatasem, and increased serum levels of insulin. The effect of hypolipidemic functions were indicated by suppressed levels of total cholesterol and triglyceride, and enhanced levels of hepatic glycogen and high-density lipoprotein cholesterol. The renal protective effect of AU was confirmed by the protection in renal structures and the regulation of potential indicators of nephropathy. The anti-oxidative and anti-inflammatory effects of AU were verified by a cytokine array combined with an enzyme-linked immunosorbent assay. AU decreased the expression of protein kinase C α and ß2 and phosphor-nuclear factor-κB, and enhanced the expression of catalase, nuclear respiratory factor 2 (Nrf2), manganese superoxide dismutase 2, heme oxygenase-1 and-2, heat shock protein 27 (HSP27), HSP60, and HSP70 in the kidneys of db/db mice. The results confirmed that AU's anti-diabetic and anti-nephritic effects are related to its modulation on oxidative stress.

Folic acid receptor-targeted human serum albumin nanoparticle formulation of cabazitaxel for tumor therapy.

BACKGROUND: We previously developed cabazitaxel (CTX)-loaded human serum albumin nanoparticles (NPs-CTX) via a self-assembly method, and these NPs showed efficacy in prostate cancer therapy. Many studies have shown that the levels of folic acid (FA) receptor on the surface of various tumor cells are high. Therefore, FA-modified NPs-CTX may have enhanced antitumor effects compared with unmodified NPs-CTX. METHODS: NPs-CTX were first prepared via self-assembly, and FA was conjugated on the surface of NPs-CTX through the -NH2 groups of the NPs to produce FA-NPs-CTX. The FA-NPs-CTX were evaluated in tumor cells with high FA receptor (FR) expression in vitro and in vivo. RESULTS: Both NPs-CTX and FA-NPs-CTX exhibited good stability and morphology. Drug release from the NPs was not affected by FA conjugation. Compared with CTX dissolved in a mixture of Tween 80 and 13% ethanol (w/w) at a ratio of 1:4 (v/v) (Tween-CTX), the two nanoformulations had lower lytic activity against normal red blood cells. However, FA-NPs-CTX showed greater inhibition of tumor cells with overexpressed FR, compared with NPs-CTX, in the cytotoxicity experiments. Moreover, the cellular uptake of FA-NPs-CTX was enhanced through FR-mediated endocytosis in HeLa cells in vitro and HeLa xenograft tumors in vivo. Although Tween-CTX exhibited tumor growth inhibition similar to FA-NPs-CTX in vivo, this inhibition also caused adverse side effects; the median lethal dose (LD50) of Tween-CTX to mice was 5.68 mg/kg, while FA-NPs-CTX-treated mice survived at doses exceeding 400 mg/kg. CONCLUSION: The results showed that FA-NPs-CTX caused inhibition of tumor growth in a manner similar to that of Tween-CTX; however, the safety and tolerability of CTX were greatly improved by FA conjugation compared with those of Tween-CTX. In summary, FA-NPs-CTX have great potential in CTX delivery, and this formulation is a promising candidate for the treatment of cancers with high FR levels.

The Antidiabetic and Antinephritic Activities of Tuber melanosporum via Modulation of Nrf2-Mediated Oxidative Stress in the db/db Mouse.

Tuber melanosporum (TM), a valuable edible fungus, contains 19 types of fatty acid, 17 types of amino acid, 6 vitamins, and 7 minerals. The antidiabetic and antinephritic effects of TM and the underlying mechanisms related to oxidative stress were investigated in db/db mice. Eight-week oral administration of metformin (Met) at 0.1 g/kg and TM at doses of 0.2 and 0.4 g/kg decreased body weight, plasma glucose, serum levels of glycated hemoglobin, triglyceride, and total cholesterol and increased serum levels of high-density lipoprotein cholesterol in the mice, suggesting hypoglycemic and hypolipidemic effects. TM promoted glucose metabolism by increasing the levels of pyruvate kinase and hepatic glycogen. It also regulated the levels of inflammatory factors and oxidative enzymes in serum and/or the kidneys of the mice. Additionally, TM increased the expression of nuclear respiratory factor 2 (Nrf2), catalase, heme oxygenase 1, heme oxygenase 2, and manganese superoxide dismutase 2 and decreased the expression of protein kinase C alpha, phosphor-janus kinase 2, phosphor-signal transducer and activator of transcription 3, and phosphor-nuclear factor-κB in the kidneys. The results of this study reveal the antidiabetic and antidiabetic nephritic properties of TM via modulating oxidative stress and inflammation-related cytokines through improving the Nrf2 signaling pathway.

Pharmacological basis for application of scutellarin in Alzheimer's disease: Antioxidation and antiapoptosis.

Scutellarin (SC), mainly extracted from the Chinese herb Erigeron breviscapus (vant.), has been reported to possess various pharmacological activities; however, its effects on Alzheimer's disease (AD) have not been systemically reported. The protective effects of SC on AD were investigated using an L­glutamic acid (L­Glu)­damaged HT22 cell apoptosis model and an aluminum chloride plus D­galactose­induced AD mouse model. In L­Glu­damaged HT22 cells, SC significantly increased cell viability, inhibited lactate dehydrogenase release, reduced caspase­3 activity and suppressed apoptosis, which were determined via an MTT assay, an in vitro Toxicology Assay kit, a Caspase­3 activity assay kit, and propidium iodide and Annexin V staining. Furthermore, SC suppressed the accumulation of intracellular reactive oxygen species (ROS), restored the dissipation of mitochondrial membrane potential, enhanced the expression of antiapoptotic proteins and reduced the expression of pro­apoptotic proteins, as determined by immunofluorescence assays and western blotting. In AD mice, SC enhanced vertical and horizontal movements in an autonomic activity test, and reduced the escape latency time in the water maze test. SC reduced the deposition of amyloid ß1­42 (Aß1­42) and the expression of phosphorylated­Tau in the hippocampus as determined by immunohistochemistry analysis, but enhanced the serum levels of Aß1­42 of AD mice as determined by ELISA. ELISA analyses also revealed that SC enhanced the levels of acetylcholine, and superoxide dismutase in serum and brain lysate, whereas reduced the levels of ROS in brain lysate of AD mice. The present study confirmed that the protective effects of SC in AD in vitro and in vivo are associated with its antioxidant and antiapoptotic properties.

Indolyl-chalcone derivatives induce hepatocellular carcinoma cells apoptosis through oxidative stress related mitochondrial pathway in vitro and in vivo.

A facile method of assembling oxindole and phthalide units through a Lewis based catalyzed allylic alkylation reaction of Morita-Baylis-Hillman carbonates of isatins and 3-cyanophthalides was recently developed. The method efficiently delivers a hybrid of 3,3'-disubstituted oxindole with a valuable phthalide pharmacophore. In the present study, we proved the deleterious effects of 5h2c, a screened synthesis compound, against hepatocellular carcinoma (HCC) in both in vitro and in vivo models. 5h2c strongly decreased cell viability, caused over-release of lactate dehydrogenase, inhibited cell migration, and enhanced the apoptosis rate in HepG2 and PLC/PRF/5 cells. 5h2c led to an increase in intracellular reactive oxygen species levels and a decrease in mitochondrial membrane potential. In HepG2-and PLC/PRF/5-xenograft tumor mouse models, treatment with 5h2c inhibited tumor growth without affecting the animals' bodyweight or organ functions. Proteome profiling of tumor tissues after 24-h exposure to 5h2c showed significantly enhanced expression levels of Bcl-2 associated X protein, cleaved caspase -3, -8, and -9, nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), heme oxygenase-2, paraoxonase 2, catalase, and factor associated suicide ligand, and reduced the expression levels of B-cell lymphoma-2, B-cell lymphoma-extra large, heat shock protein 27, heat shock protein 60, and heat shock protein 70 in HepG2 and PLC/PRF/5 cells. All of our data confirmed that oxidative stress-mediated mitochondrial apoptosis (especially the Nrf-2/HO-1 pathway) is responsible for 5h2c-induced HCC damage.