Translocation of IGF-1R in endoplasmic reticulum enhances SERCA2 activity to trigger Ca2+ER perturbation in hepatocellular carcinoma.

The well-known insulin-like growth factor 1 (IGF1)/IGF-1 receptor (IGF-1R) signaling pathway is overexpressed in many tumors, and is thus an attractive target for cancer treatment. However, results have often been disappointing due to crosstalk with other signals. Here, we report that IGF-1R signaling stimulates the growth of hepatocellular carcinoma (HCC) cells through the translocation of IGF-1R into the ER to enhance sarco-endoplasmic reticulum calcium ATPase 2 (SERCA2) activity. In response to ligand binding, IGF-1Rß is translocated into the ER by ß-arrestin2 (ß-arr2). Mass spectrometry analysis identified SERCA2 as a target of ER IGF-1Rß. SERCA2 activity is heavily dependent on the increase in ER IGF-1Rß levels. ER IGF-1Rß phosphorylates SERCA2 on Tyr990 to enhance its activity. Mutation of SERCA2-Tyr990 disrupted the interaction of ER IGF-1Rß with SERCA2, and therefore ER IGF-1Rß failed to promote SERCA2 activity. The enhancement of SERCA2 activity triggered Ca2+ER perturbation, leading to an increase in autophagy. Thapsigargin blocked the interaction between SERCA2 and ER IGF-1Rß and therefore SERCA2 activity, resulting in inhibition of HCC growth. In conclusion, the translocation of IGF-1R into the ER triggers Ca2+ER perturbation by enhancing SERCA2 activity through phosphorylating Tyr990 in HCC.

Discovery of Novel PTP1B Inhibitors with Once-Weekly Therapeutic Potential for Type 2 Diabetes: Design, Synthesis, and In Vitro and In Vivo Investigations of BimBH3 Peptide Analogues.

Poor medication adherence in patients with type 2 diabetes mellitus has become one of the main causes of suboptimal glycemic control. Once-weekly drugs can markedly improve the convenience, adherence, and quality of life of T2DM patients; thus, they are clinically needed and preferred. PTP1B plays a negative role in both insulin and leptin signaling pathways, which makes it an important target for diabetes. Herein, we design and synthesize 35 analogues of core BimBH3 peptide via lipidation/acylation strategy based on our previous work and evaluate their PTP1B inhibitory activity, obtaining the primary structure-activity relationship. Five compounds with good PPT1B inhibitory activity, target selectivity, and significantly improved stability were selected for molecular docking study and searching candidate molecules with long-acting antidiabetic potential. The in vivo anti-T2DM evaluation validated the once-weekly therapeutic potential of analogues 19, 26, 27, 31, and 33, which were comparable with semaglutide and therefore presented as promising drug candidates.

Comparative Pharmacokinetics and Tissue Distribution of M10 and Its Metabolite Myricetin in Normal and Dextran-Sodium-Sulfate-Induced Colitis Mice.

M10, a novel myricetin derivative, is an anti-inflammatory agent designed for treatment of colitis. Here, we aim to investigate its pharmacokinetic behavior and tissue distribution in a mouse model with colitis. Pharmacokinetics and tissue distribution of M10 and its metabolite myricetin were compared in normal mice and in dextran-sodium-sulfate (DSS)-induced colitis mice. The role of fecal microbiota was also analyzed during metabolism of M10 in vitro. After oral administration, M10 was very low in the plasma of both normal and diseased mice. However, both M10 and myricetin were mainly distributed in the gastrointestinal tract, including the stomach, colon and small intestine, in physiological and pathological conditions. Significantly, M10 and myricetin were found in higher levels in gastrointestinal tracts with inflamed tissues than in normal tissues of mice. An in vitro assay revealed that 80% of M10 was metabolized to myricetin via fecal microbiota. After oral administration, M10 was not absorbed into circulation but mainly distributed in the inflamed submucosal tissues of colitic mice, where it was metabolized into myricetin to prevent colitis development.

Discovery of Novel PTP1B Inhibitors Derived from the BH3 Domain of Proapoptotic Bcl-2 Proteins with Antidiabetic Potency.

BH3 peptide analogues are generally believed to exhibit great potency as cancer therapeutics via targeting antiapoptotic Bcl-2 proteins. Here, we describe the synthesis and identification of a new class of palmitoylated peptide BH3 analogues derived from the core region (h1-h4) of BH3 domains of proapoptotic Bcl-2 proteins and as alternative PTP1B inhibitors with antidiabetic potency in vitro and in vivo. PTP1B inhibitors are attractive for treatment of type 2 diabetes. We design the analogues using a simple lipidation approach and discovered novel lead analogues with promising antidiabetic potency in vitro and in vivo. The results presented here expanded the alternative target and function for the BH3 peptide analogues from one member Bim to other members of the proapoptotic Bcl-2 proteins and emphasize their therapeutic potential in T2DM. Furthermore, our findings may provide new proof of the regulatory function of Bcl-2 family proteins in mitochondrial nutrient and energy metabolism.

The inhibitory effects and mechanisms of polymannuroguluronate sulfate against human papillomavirus infection in vitro and in vivo.

Human papillomaviruses (HPVs) are non-enveloped DNA viruses that infect epithelia and can cause a wide variety of benign and pre-malignant epithelial tumours. The sulfated polysaccharides such as carrageenans were reported to be able to interfere with the binding process of HPV to the cell surface. In this study, brown seaweed derived polysaccharides polymannuroguluronate sulfate (PMGS) were prepared, and their anti-HPV effects were explored in vitro and in vivo. The results indicated that PMGS effectively inhibited high-risk HPV16 and HPV45 infection with very low toxicity. PMGS may inactivate HPV particles or block the binding and entry process of HPV through direct interaction with viral capsid proteins. PMGS can enter into HeLa cells and down-regulate the expression levels of viral oncogene proteins E6 and E7. In addition, PMGS also dramatically inhibited HPV infection on the skin of BALB/c Nude Mice. Thus, marine derived polysaccharide PMGS possessed anti-HPV activities in vitro and in vivo, and may block HPV infection via targeting viral capsid L1 protein, suggesting that it has great potential to be developed into a novel anti-HPV agent in the future.

Intestinal microbes influence the survival, reproduction and protein profile of Trichinella spiralis in vitro.

The interactions between intestinal microbes and parasitic worms play an essential role in the development of the host immune system. However, the effects of gut microbes on Trichinella spiralis are unknown. The aim of this work was to explore microbe-induced alterations in the survival and reproduction of T. spiralis in vitro. To further identify the proteins and genes involved in the response of nematodes to microbes, quantitative proteomic analysis of T. spiralis was conducted by iTRAQ-coupled LCMS/MS technology and quantitative real-time-PCR was used to measure changes in mRNA expression. The results showed Lactobacillus acidophilus, and especially Lactobacillus bulgaricus, significantly enhanced the survival and reproductive rates of nematodes. Salmonella enterica, and especially Escherichia coli O157:H7 (EHEC), had opposite effects. Genetic responses were activated mainly by EHEC. A total of 514 proteins were identified and quantified, and carbohydrate metabolism-related proteins existed in a higher proportion. These findings indicated that some gut bacteria are friendly or harmful to humans and in addition they may have similar beneficial or detrimental effects on parasites. This may be due to the regulation of expression of specific genes and proteins. Our studies provide a basis for developing therapies against parasitic infections from knowledge generated by studying the gut microbes of mammals.