The change of non-alcoholic fatty liver disease is associated with risk of incident diabetes.

Background & aims: The effect of change in non-alcoholic fatty liver disease (NAFLD) status on incident diabetes has not been well studied. We aimed to investigate the association of NAFLD development and remission with the risk of incident diabetes during a median of 3.5-year follow-up. Methods: A total of 2690 participants without diabetes were recruited in 2011-2012 and assessed for incident diabetes in 2014. Abdominal ultrasonography was used to determine the change of NAFLD. 75 g oral glucose tolerance test (OGTT) was performed to determine diabetes. NAFLD severity was assessed using Gholam's model. The odds ratios (ORs) for incident diabetes were estimated by logistic regression models. Results: NAFLD was developed in 580 (33.2%) participants and NAFLD remission occurred in 150 (15.9%) participants during a median of 3.5-year follow-up. A total of 484 participants developed diabetes during follow-up, including 170 (14.6%) in consistent non-NAFLD group, 111 (19.1%) in NAFLD developed group, 19 (12.7%) in NAFLD remission group, and 184 (23.2%) in sustained NAFLD group. The development of NAFLD increased the risk of incident diabetes by 43% (OR, 1.43; 95%CI, 1.10-1.86) after adjustment for multiple confounders. Compared with sustained NAFLD group, remission of NAFLD reduced the risk of incident diabetes by 52% (OR, 0.48; 95%CI, 0.29-0.80). The effect of NAFLD alteration on incident diabetes was not changed after adjustment for body mass index or waist circumference, change of body mass index or waist circumference. In NAFLD remission group, participants with non-alcoholic steatohepatitis (NASH) at baseline were more likely to develop diabetes (OR, 3.03; 95%CI, 1.01-9.12). Conclusions: NAFLD development increases the risk of incident diabetes, whereas NAFLD remission reduces the risk of incident diabetes. Moreover, presence of NASH at baseline could attenuate the protective effect of NAFLD remission on incident diabetes. Our study suggests that early intervention of NAFLD and maintenance of non-NAFLD are important for prevention of diabetes.

Novel inhibitors of Rickettsia prowazekii methionine aminopeptidase from the Malaria Box.

Methionine aminopeptidases (MetAp) are dinuclear metalloenzymes found in both prokaryotes and eukaryotes that catalyze the hydrolysis of the N-terminal methionine residue from nascent proteins, an important post-translational modification, which makes it an attractive target for drug discovery. Rickettsia prowazekii (Rp) is an obligate pathogen and causative agent of epidemic typhus and typhus fever. In our ongoing search for anti-rickettsial agents we screened 400 compounds from the Malaria Box for inhibition of RpMetAp1 and discovered 12 compounds that inhibited the enzyme with IC50 values ranging from 800 nM to 22 µM. These inhibitors are from eleven different chemical series and represent leads that can be used to discover more potent and efficacious anti-rickettsial agents.

Fasting serum fructose is associated with metabolic dysfunction-associated fatty liver disease: A prospective study.

AIM: The association between sugar-sweetened beverages and metabolic disorders has been well studied. However, it has not been determined whether fasting serum fructose is associated with metabolic dysfunction-associated fatty liver disease (MAFLD). METHODS: Participants were enrolled from 2011 to 2012 in Shanghai. Fasting serum fructose concentration was measured with a validated liquid chromatography-tandem mass spectrometry method. RESULTS: A total of 954 participants without diabetes were included. They were followed for an average of 3.5 years. A total of 320 (33.5%) participants had MAFLD at baseline. With the increase in fasting serum fructose level by quartile, the MAFLD prevalence was increased by 27.0%, 25.0%, 37.4%, and 44.5%, respectively (p < 0.001). Each SD increase in fasting serum fructose level was associated with a 60% increased risk of MAFLD (odds ratio 1.60; 95% confidence interval [CI], 1.36-1.88; p < 0.001). Fasting serum fructose levels were more closely associated with four components of MAFLD (hepatic steatosis, prediabetes, insulin resistance, and low high-density lipoprotein). We built a diagnostic model named the fructose fat index (FFI). The area under the receiver operating characteristic curve of the FFI was 0.879 (95% CI, 0.850-0.908) in the derivation cohort and 0.827 (95% CI, 0.776-0.878) in the validation cohort. Subsequent prospective studies found that the incidence risk of MAFLD was 2.26 times higher in the high-fructose group than in the low-fructose group among female participants (95% CI, 1.46-3.49; p < 0.001). CONCLUSION: Fasting serum fructose concentration, which mostly reflects endogenous fructose, was associated with a higher risk of MAFLD. The FFI derived from fasting serum fructose could be used to predict MAFLD.

Identification of a Wells-Dawson polyoxometalate-based AP-2γ inhibitor with pro-apoptotic activity.

AP-2 gamma (AP-2γ) is a transcription factor that plays pivotal roles in breast cancer biology. To search for small molecule inhibitors of AP-2γ, we performed a high-throughput fluorescence anisotropy screen and identified a polyoxometalate compound with Wells-Dawson structure K6[P2Mo18O62] (Dawson-POM) that blocks the DNA-binding activity of AP-2γ. We showed that this blocking activity is due to the direct binding of Dawson-POM to AP-2γ. We also provided evidence to show that Dawson-POM decreases AP-2γ-dependent transcription similar to silencing the gene. Finally, we demonstrated that Dawson-POM contains anti-proliferative and pro-apoptotic effects in breast cancer cells. In summary, we identified the first small molecule inhibitor of AP-2γ and showed Dawson-POM-mediated inhibition of AP-2γ as a potential avenue for cancer therapy.

The identification of inhibitory compounds of Rickettsia prowazekii methionine aminopeptidase for antibacterial applications.

Methionine aminopeptidase (MetAP) is a dinuclear metalloprotease responsible for the cleavage of methionine initiator residues from nascent proteins. MetAP activity is necessary for bacterial proliferation and is therefore a projected novel antibacterial target. A compound library consisting of 294 members containing metal-binding functional groups was screened against Rickettsia prowazekii MetAP to determine potential inhibitory motifs. The compounds were first screened against the target at a concentration of 10 µM and potential hits were determined to be those exhibiting greater than 50% inhibition of enzymatic activity. These hit compounds were then rescreened against the target in 8-point dose-response curves and 11 compounds were found to inhibit enzymatic activity with IC50 values of less than 10 µM. Finally, compounds (1-5) were docked against RpMetAP with AutoDock to determine potential binding mechanisms and the results were compared with crystal structures deposited within the PDB.

Rickettsia prowazekii methionine aminopeptidase as a promising target for the development of antibacterial agents.

Methionine aminopeptidase (MetAP) is a class of ubiquitous enzymes essential for the survival of numerous bacterial species. These enzymes are responsible for the cleavage of N-terminal formyl-methionine initiators from nascent proteins to initiate post-translational modifications that are often essential to proper protein function. Thus, inhibition of MetAP activity has been implicated as a novel antibacterial target. We tested this idea in the present study by targeting the MetAP enzyme in the obligate intracellular pathogen Rickettsia prowazekii. We first identified potent RpMetAP inhibitory species by employing an in vitro enzymatic activity assay. The molecular docking program AutoDock was then utilized to compare published crystal structures of inhibited MetAP species to docked poses of RpMetAP. Based on these in silico and in vitro screens, a subset of 17 compounds was tested for inhibition of R. prowazekii growth in a pulmonary vascular endothelial cell (EC) culture infection model system. All compounds were tested over concentration ranges that were determined to be non-toxic to the ECs and 8 of the 17 compounds displayed substantial inhibition of R. prowazekii growth. These data highlight the therapeutic potential for inhibiting RpMetAP as a novel antimicrobial strategy and set the stage for future studies in pre-clinical animal models of infection.