Design and synthesis of hybrids of diarylpyrimidines and diketo acids as HIV-1 inhibitors.

Based on the strategy of molecular hybridization, diketo acid fragment as a classical phamacophore of integrase inhibitors was introduced to reverse transcriptase inhibitors diarylpyrimidines to design a series of diarylpyrimidine-diketo acid hybrids (DAPY-DKAs). The target molecules 10b and 11b showed inhibitory activities against WT HIV-1 with EC50 values of 0.18µM and 0.14µM, respectively. And the results of molecular docking demonstrated the potential binding mode and revealed that the DKA moiety and its ester could both be tolerated in the nonnucleoside binding site (NNBS) of HIV-1 RT.

Structural modifications of diarylpyrimidines (DAPYs) as HIV-1 NNRTIs: Synthesis, anti-HIV activities and SAR.

30 new analogues of diarylpyrimidines were synthesized for further structural modifications, involving not only the linker but also the wing α of DAPYs. The anti-HIV-1 activities of all target molecules were evaluated, and most of them exhibited potent anti-HIV-1 (WT) activities and low cytotoxicities. Among which, compound 4g showed excellent activities against WT HIV-1 with an EC50 value of 5.8nM and SI of up to 26,034. Another compound 4ab bearing a novel pyridinyl Wing α also displayed attractive activities. The structure-activity relationship (SAR) study was also summarized.

A Novel Antidiabetic Monomers Combination Alleviates Insulin Resistance Through Bacteria-Cometabolism-Inflammation Responses.

The present study sought to examine the therapeutic effect of a novel antidiabetic monomer combination (AMC) in treating type 2 diabetes mellitus (T2DM); while also elucidating the potential functional mechanism. Male C57BL/6J mice were fed a high-fat diet (HFD) for 12 weeks to establish T2DM. The AMC group showed significant reduction in weight, fasting blood glucose (FBG), serum total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C), and experienced reduced insulin resistance based on oral glucose tolerance testing (OGTT) and hyperinsulinemic-euglycemic clamp testing ("gold standard" for determining in vivo insulin sensitivity). Further, AMC restored the altered intestinal flora by increasing the abundance of the beneficial bacteria Akkermansia, and decreasing the number of harmful bacteria, including Bacteroides, Odoribacter, Prevotella 9, Alistipes, and Parabacteroides. Components of the host-microbial metabolome were also significantly changed in the AMC group compared to the HFD group, including hydroxyphenyllactic acid, palmitoleic acid, dodecanoic acid, linoleic acid, and erucic acid. Furthermore, AMC was found to inhibit inflammation and suppress signaling pathways related to insulin resistance. Lastly, spearman correlation analysis revealed relationships between altered microbial community and co-metabolite levels, co-metabolites and inflammatory cytokines. Hence, the potential mechanism responsible for AMC-mediated alleviation of insulin resistance was suggested to be involved in modulation of bacteria-cometabolism-inflammation responses.

Clinical anatomical study and evaluation of the use of the free anteromedial thigh perforator flaps in reconstructions of the head and neck.

The anteromedial thigh (AMT) perforator flap is usually thin, pliable, and nearly hairless, making it particularly suitable to repair defects of the head and neck. We studied the topography and outcomes of AMT perforator flaps in such defects after excision of tumours. We retrospectively reviewed the casenotes of 11 consecutive patients who had had reconstructions of the head and neck with the initial intent of using an AMT perforator flap from January 2010 to July 2011. For each patient we recorded the size and thickness of the flap; the length of the pedicle; and the number, external diameters, anatomical types, source vessels, and sites of the sizeable perforators. Of the 11 patients, 10 had successful reconstruction using AMT perforator flaps, but one had no AMT perforator big enough. The mean (range) number of sizeable perforators/flap was 1.3 (1-2), length of pedicle 10.6 (7-13) cm, and diameter of the artery 1.1(1.0-1.5) mm. Of the 13 sizeable perforators, 3 were direct and septocutaneous. The remaining ones were all musculocutaneous. Most of them were located in the middle third of the thigh. Primary closure of the donor site was achieved in all patients. One flap was successfully revised after compression of the perforator. All flaps survived with good functional and aesthetic outcomes. The free AMT perforator flap is suitable for reconstructions of the head and neck if a sizeable perforator can be found. The AMT flap may be used as a primary flap rather than as an alternative to the anterolateral thigh flap or a component of a chimeric flap.

[Preoperative Doppler evaluation of vascular perforators in the anterolateral thigh flap harvest].

OBJECTIVE: To evaluate the accuracy of Hadeco ES-1000spm hand-held doppler during the anterolateral thigh (ALT) flap harvest. METHODS: Twenty-five patients (26 sides) with ALT flaps for head and neck reconstruction between May 2005 and May 2010 received preoperative Doppler examination for the location of the cutaneous perforators of ALT flaps. The Doppler signals and body mass index (BMI) were recorded preoperatively according to ABC system. The locations of Doppler signals and of the actual cutaneous perforators at surgery were plotted and compared. The diameter of perforators was measured. RESULTS: One to three cutaneous perforators of the ALT flap were consistently found at specific locations. They were named perforators A, B, C from proximal to distal. Perforators A, B and C were present in 15 (58%), 24 (92%) and 20 (77%) cases and the diameter (> 0.5 mm) of A, B and C were 11/15, 22 (92%) and 8 (40%) respectively. The Doppler signal was within 0.5 cm of the actual perforator location in 85% flaps. The accuracy of Doppler decreased with increase of BMI. CONCLUSIONS: Preoperative assessment by hand-held Doppler is useful in predicting the perforator vessels' locations and diameter although it's accuracy is limited.