RLA8-A New and Highly Effective Quadruple PPAR-α/γ/δ and GPR40 Agonist to Reverse Nonalcoholic Steatohepatitis and Fibrosis.

Nonalcoholic fatty liver disease (NAFLD) is a very common chronic hepatic disease, with nonalcoholic steatohepatitis (NASH) as a major and severe subcategory that can lead to cirrhosis and hepatocellular carcinoma, and thereby to a high mortality rate. Currently, there has been no approved drug to treat NAFLD or NASH. The current study has presented RLA8, a novel and balanced quadruple agonist for hepatic lipid metabolism and inflammation-related peroxisome proliferator-activated receptors (PPARs)-α/γ/δ and G protein-coupled receptor 40 (GPR40), as a NASH drug candidate. The efficacy of RLA8 to treat NASH was evaluated in vivo using two mouse models induced by methionine/choline-deficient diet or by high-fat diet, respectively. RLA8 was shown to improve serum alanine aminotransferase and high-density lipoprotein cholesterol levels, reduce hepatic free fatty acid and triglyceride levels, and alleviate insulin resistance. Cytokine and lipoperoxide analysis revealed that RLA8 could reduce oxidative stress and inflammation. Histochemical and morphologic examination of mouse livers showed that RLA8 could improve pathologic changes such as steatosis, ballooning, collagen fiber, and inflammation. Polymerase chain reaction and Western blot analyses proved that RLA8 could result in PPARs and GPR40 activation, accompanied by upregulation of the 5'AMP-activated protein kinase-acetyl-CoA carboxylase pathway and inhibition of the expression of lipogenic genes and proteins, which provided more insights into its action mechanisms. In summary, RLA8 has significantly better efficacy to improve NASH-induced liver damage such as steatosis, inflammation, and fibrosis, and, consequently, it represents a new and highly promising NASH drug candidate that is worthy of further investigation and development.

Enhanced interferon-gamma secretion and antitumor activity of T-lymphocytes activated by dendritic cells loaded with glycoengineered myeloma antigens.

BACKGROUND: Immunotherapy is emerging as a promising cure for cancer. However, a severe problem in this area is the immune tolerance to tumor cells and tumor-associated antigens, as evidenced by the ability of cancer to escape immune surveillance. To overcome this problem this work examined the potential of improving the antigenicity of myeloma by metabolic engineering of its cell surface carbohydrate antigens (i.e., glycoengineering) and presentation of the modified tumor antigens by dendritic cells (DCs) to generate cytotoxic T-lymphocytes (CTLs). METHODS: CD138+ myeloma cells were isolated from 11 multipe myeloma (MM) patients by the immunomagnetic bead method. The MM cells were treated with N-propionyl-D-mannosamine (ManNPr), a synthetic analog of N-acetyl-D-mannosamine (ManNAc), the natural biosynthetic precursor of N-acetyl sialic acid (NeuNAc), to express unnatural N-propionylated sialoglycans. The glycoengineered cells were then induced to apoptosis, and the apoptotic products were added to cultured functional DCs that could present the unnatural carbohydrate antigens to autologous T-lymphocytes. RESULTS: It was found that the resultant DCs could activate CD4+ and CD8+ T-lymphocytes, resulting in increased expression of T cell surface markers, including CD8CD28 and CD4CD29. Moreover, upon stimulation by glycoengineered MM cells, these DC-activated T-lymphocytes could release significantly higher levels of IFN-gamma (P < 0.05). Lactate dehydrogenase (LDH) assays further showed that the stimulated T-lymphocytes were cytotoxic to glycoengineered MM cells. CONCLUSIONS: This work demonstrated that glycoengineered myeloma cells were highly antigenic and the CTLs induced by the DCs loaded with the unnatural myeloma antigens were specifically cytotoxic to the glycoengineered myeloma. This may provide a new strategy for overcoming the problem of immune tolerance for the development of effective immunotherapies for MM.

[Measurement and statistical analysis of the vertical force in normal young people's gait].

OBJECTIVE: To find a method for evaluating the relationship between mechanical data and gait efficiently. METHOD: Gait mechanical data of 27 young men (20-22 years) without history of the kinetic diseases were collected using a force-measuring system. The data were transformed into characteristic two-peak curves in vertical direction (z-axis). Seven characteristic parameters were distilled. The coefficient of variation (CV) and the absolute symmetry index (ASI) of the parameters between left foot and right foot were analyzed. RESULT: It was found that CV of the first temporal parameter of gait (T(Z1)) is equal to 14.49%, which corresponds to larger dispersion. The values of ASI are all lower than 12.5%, which means the symmetry between left and right feet meets general requirement. But the P value (result of t-test) of F(Z2) is 0.0368 (lower than 0.05), which means that there is obvious differentia between F(Z2) of left and right feet, while no such differentiae were found for the other six characteristic parameters. t-test was also used to analyze the differentia between the gait of male and female. It is still found that p value of F(Z2) is lower than 0.01, which corresponds to a great differentia on F(Z2) between male and female. CONCLUSION: Some significant conclusions of the repetition, dispersion, symmetry and differentia of gait data have been obtained by the analysis.

[A gait analysis system based on digital video and digital image processing].

OBJECTIVE: To provide a gait analysis system. METHOD: The system is composed of general video devices and personal computer hardware. The techniques of digital video and digital image processing such as template matching, sub-pixel and motion estimate etc were employed to identify and trace the markers. RESULT: A gait result of a cerebral palsy object, which consists of bar-figure, data, and video was provided. CONCLUSION: The gait analysis system based on digital video and digital image processing is easy to use, and can provide visual result, which is easy to understand.

Total Synthesis of Tricolorin A.

Tricolorin A (1), a structurally amazing resin glycoside with promising bioactivities from Ipomoea tricolor cav. (convolvulaceae), was synthesized in a total of 45 steps, with the longest linear sequence of 20 steps and overall yield of 0.65% from D-mannitol. The AB disaccharide 19-membered lactone 2 was constructured by a regioselective macrolactonization using Corey-Nicolaou protocol. The macrolactone tetrasaccharide 33 was realized either by "one-pot two-step" glycosylation procedure or by a stepwise assembly employing the "armed-disarmed" glycosylation strategy.