Truncated Milk Fat Globule-EGF-like Factor 8 Ameliorates Liver Fibrosis via Inhibition of Integrin-TGFß Receptor Interaction.

Milk fat globule-EGF factor 8 (MFG-E8) protein is known as an immunomodulator in various diseases, and we previously demonstrated the anti-fibrotic role of MFG-E8 in liver disease. Here, we present a truncated form of MFG-E8 that provides an advanced therapeutic benefit in treating liver fibrosis. The enhanced therapeutic potential of the modified MFG-E8 was demonstrated in various liver fibrosis animal models, and the efficacy was further confirmed in human hepatic stellate cells and a liver spheroid model. In the subsequent analysis, we found that the modified MFG-E8 more efficiently suppressed transforming growth factor ß (TGF-ß) signaling than the original form of MFG-E8, and it deactivated the proliferation of hepatic stellate cells in the liver disease environment through interfering with the interactions between integrins (αvß3 & αvß5) and TGF-ßRI. Furthermore, the protein preferentially delivered in the liver after administration, and the safety profiles of the protein were demonstrated in male and female rat models. Therefore, in conclusion, this modified MFG-E8 provides a promising new therapeutic strategy for treating fibrotic diseases.

Dose Optimization of Vancomycin Using a Mechanism-based Exposure-Response Model in Pediatric Infectious Disease Patients.

PURPOSE: This study aimed to determine the appropriate vancomycin dosage, considering patient size and organ maturation, by simulating the bacterial count and biomarker level for drug administration in pediatric patients with gram-positive bacterial (GPB) infections. METHODS: Natural language processing for n-gram analysis was used to detect appropriate pharmacodynamic (PD) markers in infectious disease patients. In addition, a mechanism-based model was established to describe the systemic exposure and evaluate the PD marker simultaneously in pediatric patients. A simulation study was then conducted by using a mechanism-based model to evaluate the optimal dose of vancomycin in pediatric patients. FINDINGS: C-reactive protein (CRP) was selected as a PD marker from an analysis of ~270,000 abstracts in PubMed. In addition, clinical results, including the vancomycin plasma concentrations and CRP levels of pediatric patients (n = 93), were collected from electronic medical records. The vancomycin pharmacokinetic model with allometric scaling and a maturation function was built as a one-compartment model, with an additional compartment for bacteria. Both the effects of vancomycin plasma concentrations on the destruction of bacteria and those of bacteria on CRP production rates were represented by using a maximum achievable effect model (Emax model). Simulation for dose optimization was conducted not only by using the final model but also by exploring the possibility of therapeutic failure based on the MICs of vancomycin for GPB. Clinical cure was defined as when the CRP level fell below the upper limit of the normal range. Our dose optimization simulations suggested a vancomycin dosage of 10 mg/kg every 8 h as the optimal maintenance dose for pediatric patients with a postconceptual age <30 weeks and 10 mg/kg every 6 h for older children, aged up to 12 years. In addition, the MIC of 3 µg/mL was assessed as the upper concentration limit associated with successful vancomycin treatment of GPB infections. IMPLICATIONS: This study confirmed that the changes in bacterial counts and CRP levels were well described with mechanistic exposure-response modeling of vancomycin. This model can be used to determine optimal empiric doses of vancomycin and to improve therapeutic outcomes in pediatric patients with GPB.

Correction to: The small molecule WNT/ß-catenin inhibitor CWP232291 blocks the growth of castration-resistant prostate cancer by activating the endoplasmic reticulum stress pathway.

In the original publication of this article [1], there are mistakes in Fig. 4d. The corrected Fig. 4 should be.

The small molecule WNT/ß-catenin inhibitor CWP232291 blocks the growth of castration-resistant prostate cancer by activating the endoplasmic reticulum stress pathway.

BACKGROUND: Androgen receptor (AR)-targeted treatments improve the survival of castration-resistant prostate cancer (CRPC) patients; however, secondary resistance to these agents ultimately occurs in virtually all patients. Therefore, alternative therapeutic targets are urgently needed. Since growing evidence demonstrates that WNT/ß-catenin signaling plays an important role in CRPC, the antitumor activity and mechanism of action of CWP232291, a small molecule ß-catenin inhibitor, were investigated in prostate cancer. METHODS: We assessed the antitumor activity of CWP232291 in prostate cancer cell lines and primary cells derived from CRPC patients. The effect of CWP232291 on apoptotic cell death, endoplasmic reticulum (ER) stress, cell viability, and WNT/ß-catenin signaling was evaluated by flow cytometry, western blotting, luciferase reporter assay, and fluorescence microscopy. Antitumor efficacy was assessed in two CRPC xenograft mouse models. RESULTS: CWP232291 induced ER stress, resulting in upregulation of the proapoptotic protein CHOP and activation of caspase-3-dependent apoptosis. In addition, CWP232291 suppressed the expression of ß-catenin by affecting WNT-dependent transcriptional activity, and downregulated AR and its splice variants in prostate cancer cells. Antitumor activity was observed in prostate cancer cells in vitro and ex vivo, and antitumor efficacy was observed in vivo. CONCLUSIONS: Beyond providing preclinical evidence of therapeutic efficacy for the novel small molecule ß-catenin inhibitor CWP232291 in CRPC, our results show that inducing ER stress and targeting WNT/ß-catenin signaling may be a novel strategy against CRPC.

Peripheral cannabinoid 1 receptor blockade mitigates adipose tissue inflammation via NLRP3 inflammasome in mouse models of obesity.

AIM: To analyze the metabolic parameters and adipose tissue inflammation via NLRP3 inflammasome following chronic treatment of mouse models of obesity with AJ5018 as the peripherally restricted cannabinoid 1 receptor (CB1R) antagonist. MATERIALS AND METHODS: The selectivity for CB1R over CB2R, brain/plasma concentration ratio, and centrally mediated neurobehavioural effects of AJ5018, were assessed. The long-term effects of AJ5018 and rimonabant on the metabolic parameters and adipose tissue inflammation were analyzed in diet-induced obese (DIO) mice and diabetic db/db mice. RESULTS: AJ5018 had a higher degree of selectivity for CB1R over CB2R and markedly reduced brain penetrance, as reflected by the lower brain/plasma concentration ratio and the attenuated centrally mediated neurobehavioural effects, compared with its brain-penetrant parent compound rimonabant. In DIO and db/db mice, AJ5018 exhibited comparable effects to rimonabant in improving metabolic abnormalities and suppressing macrophage infiltration into white adipose tissue, activation of the NLRP3 inflammasome, and production of proinflammatory cytokines. CONCLUSIONS: These results suggest that peripheral CB1R blockade improves obesity-induced insulin resistance by suppressing adipose tissue inflammation via the NLRP3 inflammasome.

Comparative studies of bioactive organosulphur compounds and antioxidant activities in garlic (Allium sativum L.), elephant garlic (Allium ampeloprasum L.) and onion (Allium cepa L.).

We evaluated organosulphur compounds in Allium vegetables, including garlic, elephant garlic and onion, using high-performance liquid chromatography. Among organosulphur compounds, elephant garlic had considerable γ-glutamyl peptides, and garlic had the highest alliin content. Onion had low level of organosulphur compounds than did elephant garlic and garlic. In addition, antioxidant capacities were evaluated by oxygen radical absorbance capacity (ORAC) values and 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azinobis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) radical scavenging assay. The results showed that garlic had the highest antioxidant capacity, followed by elephant garlic and onion. Furthermore, a positive correlation was observed between antioxidant activities and organosulphur compounds (R > 0.77). Therefore, our results indicate that there was a close relationship between antioxidant capacity and organosulphur compounds in Allium vegetables.

Dependence of interface charge trapping on channel engineering in pentacene field effect transistors.

We investigate the dependence of charge carrier mobility by trap states at various interface regions through channel engineering. Prior to evaluation of interface trap density, the electrical performance in pentaene field effect transistors (FET) with high-k gate oxide are also investigated depending on four channel engineering. As a channel engineering, gas treatment, coatings of thin polymer layer, and chemical surface modification using small molecules were carried out. After channel engineering, the performance of device as well as interface trap density calculated by conductance method are remarkably improved. It is found that the reduced interface trap density is closely related to decreasing the sub-threshold swing and improving the mobility. Particularly, we also found that performance of device such as mobility, subthreshold swing, and interface trap density after gas same is comparable to those of OTS.