LncRNA MEG3 aggravates palmitate-induced insulin resistance by regulating miR-185-5p/Egr2 axis in hepatic cells.

OBJECTIVE: Long non-coding RNA (LncRNA) has been reported to play an important role in type 2 diabetes (T2D). We investigated the role of LncRNA maternally expressed gene 3 (MEG3) and its potential interaction with miR-185-5p in palmitate-induced hepatocyte insulin resistance. PATIENTS AND METHODS: High-fat diet (HFD) mice and insulin resistant hepatocyte were employed. Relative mRNA expressions of MEG3, miR-185-5p, and early growth response proteins-2 (Egr2) were measured by qRT-PCR. Western blot was performed to evaluate Egr2 protein expression levels. Glycogen contents and plasma insulin levels were tested by the corresponding assay. RESULTS: MEG3 and Egr2 were upregulated, but miR-185-5p was downregulated in palmitate-treated insulin resistance hepatocytes and HFD mice. MEG3 knockdown alleviated the influence of palmitate on insulin resistance in vitro and in vivo. miR-185-5p expression was upregulated upon MEG3 knockdown. Expression of Egr2 was positively correlated with MEG3 knockdown or overexpression, which could be negatively managed by abnormal expression of miR-185-5p. CONCLUSIONS: Our data demonstrated that LncRNA MEG3 aggravated palmitate-induced insulin resistance by regulating miR-185-5p/Egr2 axis, providing new insights into T2D therapeutic strategies.

Effects of SKI 306X, a new herbal agent, on proteoglycan degradation in cartilage explant culture and collagenase-induced rabbit osteoarthritis model.

OBJECTIVE: Protective effects of SKI 306X, a natural herbal product extracted from three herbs Clematis mandshurica, Trichosanthes kirilowii, and Prunella vulgaris, on articular cartilage was examined and compared with other osteoarthritis (OA) drugs using in vitro and in vivo models. METHODS: In vitro culture of rabbit articular cartilage explants was used as a model to measure the effects of drugs on the matrix degradation. The recombinant human interleukin-1alpha (rhIL-1alpha, 5 ng/ml) was added to induce proteoglycan (PG) degradation and the degree of PG degradation was assessed by measuring the amount of glycosaminoglycan (GAG) released into the culture medium. In in vivo experiment, collagenase was intraarticularly injected twice into the right knee joint of rabbits to induce OA-like change, and test agents were orally administered once a day for 28 days. The degrees of OA-like changes were evaluated through a histological examination. RESULTS: In vitro study revealed SKI 306X inhibited the degradation of PG in a concentration-dependent manner. Trichosanthes kirilowii, which is one of the major components of SKI 306X, also significantly inhibited the GAG release in cartilage explant culture at 0.3 and 0.1 mg/ml. Dexamethasone and NSAIDs, such as diclofenac and rofecoxib, had no significant effects on the suppression of PG degradation. In in vivo studies, OA-like degeneration of the articular cartilage and synovial tissue was induced by injecting collagenase into the right knee joint of mature rabbits. At a dose of 200 mg/kg, SKI 306X reduced the OA-like histological changes, whereas diclofenac had no effect at 10 mg/kg. CONCLUSION: These results indicate that SKI 306X inhibited PG degradation in cartilage explant culture, and its prophylactic administration significantly protected the knee joint of rabbit from OA-like change in collagenase-induced experimental OA model. This strongly suggests that SKI 306X can be a good OA agent with some cartilage protection activity.

Effect of SKI 306X, a new herbal anti-arthritic agent, in patients with osteoarthritis of the knee: a double-blind placebo controlled study.

SKI 306X is a purified extract from a mixture of three oriental herbal medicines (Clematis mandshurica, Trichosanthes kirilowii and Prunella vulgaris) that have been widely used for the treatment of inflammatory diseases such as lymphadenitis and arthritis in far East Asia. A double-blind, controlled study was performed to evaluate the efficacy and safety of SKI 306X with placebo in 96 patients with classical osteoarthritis of the knee. Patients were randomized to four treatment groups: placebo, 200 mg, 400 mg and 600 mg of SKI 306X t.i.d.. Clinical efficacy and safety were evaluated for 4 weeks continuous treatment. SKI 306X demonstrated its clinical efficacy, as assessed by 100 mm visual analogue scale (VAS), Lequesne index and patients' and investigators opinion of the therapeutic effect compared with placebo (p<0.01). No significant adverse events were observed in patients treated with SKI 306X. This study demonstrated that SKI 306X, a new herbal anti-arthritic agent provided clinical efficacy in patients with osteoarthritis.

Design and synthesis of highly potent fumagillin analogues from homology modeling for a human MetAP-2.

New fumagillin analogues were designed through structure-based molecular modeling with a human methionine aminopeptidase-2. Among the fumagillin analogues, cinnamic acid ester derivative CKD-731 showed 1000-fold more potent proliferation inhibitory activity on endothelial cell than TNP-470.

Development of three-dimensional descriptors represented by tensors: free energy of hydration density tensor.

In order to describe the degree of interaction of a molecule with its environments by descriptors, several three-dimensional descriptors have been proposed. With the physical properties calculated around a molecule, scalar, vector, and tensor (zeroth, first, and second moments) of the physical properties were calculated and were used as descriptors for calculating the similarity index between the molecules. The tensors contain the information on the spatial distribution of those physical properties around the molecule. Hydration Free Energy Density (HFED) proposed by No et al. was used to calculate HFED tensor. The descriptors were used for the similarity index calculations between substituted benzenes and between lead compounds of HIV-1 protease inhibitors. The substituted benzenes are grouped according to the similarity indices. The grouping seems reasonable from the viewpoint of a chemical sense. The lead fragments of the HIV-1 protease inhibitors have a high similarity among themselves though their chemical formulas are not very similar, the lead fragments are diverse. Although the chemical formulas are diverse, the spatial distribution of the physical properties around the molecules is similar. The descriptors have high discriminating power in the similarity calculation between the molecules.

Extracellular matrix for a rechargeable cell delivery system.

Above a critical concentration, aqueous polymer solutions of N-isopropylacrylamide copolymers with small amounts of acrylic acid, synthesized in benzene by radical polymerization, exhibited four distinct phases as the temperature increased; clear solution, opaque solution, gel and shrunken gel. The transition between the opaque solution phase and the gel phase was in the range of 30-34 degrees C and was reversible without syneresis and noticeable hysteresis under the experimental conditions used in this study. Islets of Langerhans, isolated from Sprague-Dawley rat pancreata and entrapped in the gel matrix, remained viable, with no significant decrease in insulin secretion function in vitro for one month. When islets were encapsulated with the gel matrix in hollow fibers [molecular weight cut-off (MWCO)= approximately 400000] and were exposed to dynamic changes in glucose and theophylline concentrations, their insulin secretion patterns demonstrated a smaller lag time and higher amplitude in insulin release than islets entrapped in a conventional alginate matrix under the same experimental conditions. From these two observations, i.e. gel reversibility and islet functionality in the matrix observed in in vitro experiments, the N-isopropylacrylamide copolymers with acrylic acid synthesized in this study are optimum candidates for the extracellular matrix in a diffusion chamber-type cell delivery system in order to recharge the entrapped cells when cell functionality in the system decreases.