Design, synthesis and evaluation of 2, 6, 8-substituted Imidazopyridine derivatives as potent PI3Kα inhibitors.

Inhibition of PI3K pathway has become a desirable strategy for cancer treatment. In this work, a series of 2, 6, 8-substituted Imidazo[1,2-a]pyridine derivatives were designed and screened for their activities against PI3Kα and a panel of PI3Kα-addicted cancer cells. Among them, compound 35 was identified as a PI3Kα inhibitor with nanomolar potency as well as acceptable antiproliferative activity. Flow cytometry analysis confirmed 35 induced cell cycle arrest and apoptosis in T47D cells. In addition, it also showed desirable in vitro ADME properties. The design, synthesis, and SAR exploration of 35 are described within.

Effects of arginine vasopressin on the transcriptome of prefrontal cortex in autistic rat model.

Our previous studies have also demonstrated that AVP can significantly improve social interaction disorders and stereotypical behaviours in rats with VPA-induced autism model. To further explore the mechanisms of action of AVP, we compared the PFC transcriptome changes before and after AVP treatment in VPA-induced autism rat model. The autism model was induced by intraperitoneally injected with VPA at embryonic day 12.5 and randomly assigned to two groups: the VPA-induced autism model group and the AVP treatment group. The AVP treatment group were treated with intranasal AVP at postnatal day 21 and for 3 weeks. The gene expression levels and function changes on the prefrontal cortex were measured by RNA-seq and bioinformatics analysis at PND42 and the mRNA expression levels of synaptic and myelin development related genes were validated by qPCR. Our results confirmed that AVP could significantly improve synaptic and axon dysplasia and promote oligodendrocyte development in the prefrontal cortex in VPA-induced autism models by regulating multiple signalling pathways.

Synthesis and biological evaluation of cajanonic acid A derivatives as potential PPARγ antagonists.

Four series of cajanonic acid A (CAA) derivatives have been designed and synthesized. The newly prepared compounds have been screened for glucose consumption activity in HepG2 cell lines and PPARγ antagonistic activity in HEK293 cell lines. Compound 26g bearing a tetrahydroisoquinolinone scaffold showed the most potent PPARγ antagonistic and hypoglycemic activities. An oral glucose tolerance test (OGTT) was performed and the results further confirmed that 26g was a potent hypoglycemic agent. In addition, the possible binding modes for compound 26g in the PPARγ protein have been investigated in this study.

ZG02 Improved Hepatic Glucose Metabolism and Insulin Sensitivity via Activation of AMPK/Sirt1 Signaling Pathways in a High-fat Diet/Streptozotocin-induced Type 2 Diabetes Model.

PURPOSE: The aim of the present study was to investigate the hypoglycemic activity and potential mechanism of tetrahydrocarbazole derivatives ZG02 in high-fat diet/streptozotocin-induced type 2 diabetes model. METHODS: C57BL/6 mice (n=30) were randomly assigned to three groups: control group (n=10) was fed with normal diet, the diabetes group (n=10) was fed with high-fat diet for eight weeks followed by intraperitoneal injection of streptozotocin (25 mg/kg) and the ZG02 group (n=10) injected intraperitoneally with ZG02 (30 mg/kg/day) for two weeks after successful modeling. The changes of weight, fasting blood glucose, oral glucose tolerance and fasting blood insulin levels in each group were evaluated. In addition, we also assessed the expression level of total AMPK, phosphorylation AMPK, SIRT1, PGC-1 and the activity of G6PC in liver. RESULTS: The results demonstrated that ZG02 could significantly antagonize the high-fat diet/streptozotocin-induced fasting hyperglycemia, restore fasting blood insulin levels and also improve activity of G6PC in liver. The results from Western blot indicated that ZG02 significantly restored the expression level of phosphorylation AMPK, Sirt1 and PGC-1. CONCLUSION: ZG02 improve hepatic glucose metabolism and insulin sensitivity via activation AMPK/Sirt1 signaling pathways in type 2 diabetes mice model.

Pharmacokinetics, Tissue Distribution, and Excretion Study of Cajanonic Acid A in Rats by UPLC-MS/MS.

Cajanonic acid A (CAA), a prenylated stilbene derivative extracted from the leaves of pigeon pea (Cajanus cajan), has been reported to possess inhibitory activity on the peroxisome proliferator-activated receptor gamma (PPARγ) and protein tyrosine phosphatase 1B (PTP1B). Its hypoglycemic activity in rats is comparable to that of the approved antidiabetic agent rosiglitazone. Therefore, CAA is a potential candidate for the treatment of type 2 diabetes and a lead compound for the discovery of novel hypoglycemic drugs. To achieve a thorough understanding of the biological behavior of CAA in vivo, our current study was designed to investigate the pharmacokinetics, bioavailability, distribution, and excretion of CAA in rats by UPLC-MS/MS. Chromatographic separation was performed on BEHC18 column (2.1 mm × 50 mm, 1.7 µm). Quantification was performed under the negative ion mode by using single reaction monitoring (SRM) of the transitions of m/z 353.14 → 309.11 for CAA and m/z 269.86 → 224.11 for genistein, respectively. Standard calibration curve showed excellent linearity (r2 > 0.99) within the range of 2 - 800 ng/mL. The accuracies and precisions were within the acceptance limits (all < 20%). CAA was quickly absorbed into bloodstream and distributed rapidly and widely to various tissues. The excretion ratio of CAA in the 3 main pathways via bile, feces, and urine was only 5.17%. These results indicate that CAA was quickly and thoroughly metabolized in vivo and excreted mainly as metabolites.

Novel berberine-based derivatives with potent hypoglycemic activity.

Four series of berberine derivatives were designed and synthesized. All the synthetic compounds were screened for in vitro glucose consumption activity in HepG2 cell lines. The results showed that most of the tested compounds exhibited potent hypoglycemic activity, and the most potent compound 20b exhibited its potency by 3.23-fold of berberine, 1.39-fold of metformin and 1.20-fold of rosiglitazone, respectively. Western blot assay indicated these novel berberine-based derivatives executed their glucose-decreasing activity via the activation of AMPK pathway.

Manufacturing a Long-Period Grating with Periodic Thermal Diffusion Technology on High-NA Fiber and Its Application as a High-Temperature Sensor.

We demonstrated a kind of long-period fiber grating (LPFG), which is manufactured with a thermal diffusion treatment. The LPFG was inscribed on an ultrahigh-numerical-aperture (UHNA) fiber, highly doped with Ge and P, which was able to easily diffuse at high temperatures within a few seconds. We analyzed how the elements diffused at a high temperature over 1300 °C in the UHNA fiber. Then we developed a periodically heated technology with a CO2 laser, which was able to cause the diffusion of the elements to constitute the modulations of an LPFG. With this technology, there is little damage to the outer structure of the fiber, which is different from the traditional LPFG, as it is periodically tapered. Since the LPFG itself was manufactured under high temperature, it can withstand higher temperatures than traditional LPFGs. Furthermore, the LPFG presents a higher sensitivity to high temperature due to the large amount of Ge doping, which is approximately 100 pm/°C. In addition, the LPFG shows insensitivity to the changing of the environment’s refractive index and strain.

Effect of Yb3+ concentration on the broadband emission intensity and peak wavelength shift in Yb/Bi ions co-doped silica-based glasses.

The effect of Yb(3+) concentration on the broadband emission intensity and peak wavelength shift in Yb/Bi ions co-doped silicate glasses is investigated. The optimal Bi(2)O(3) concentration range is about 2.0-2.5 mol% in 65SiO(2)-10Al(2)O(3)-25CaO matrix (SAC glasses). For Yb/Bi codoped SAC glasses, the maximum emission intensity excited by 980 nm LD is ~30 times and 1.5 times higher than that of single Bi-doped SAC glasses excited by 980 nm and 808 nm LD, respectively, the peak emission shows obvious red-shift from 1185 nm to 1235 nm band with the Yb(2)O(3) concentration change from 0 to 3.0 mol%. For the same Yb(2)O(3) concentration in SAC glasses, the measured fluorescence lifetime near 1020 nm of single Yb(3+)-doped glasses is longer than that of Yb/Bi codoping glasses, which implyes the efficient energy transfer from Yb(3+) to Bi(n+) in SAC glasses. The results indicate Yb(2)O(3) can be induced into the bismuth-doped silicate glasses to enhance the emission intensity and control the peak wavelength.