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Abstract: Aims: The atherogenicity of chylomicron remnants has been discussed. We examined whether serum apoB48 level is associated with the presence of carotid plaque in type 2 diabetic patients. Method: Forty type 2 diabetic patients (21 males and 19 females, 52.8±11.8 years old; mean±S.D.) were divided into two groups by the presence or absence of carotid plaque. The diurnal change of serum apoB48 level was measured by enzyme-linked immunosorbent assay. Results: Fasting serum apoB48 level was higher in the subjects with carotid plaque than those without (6.5±3.8vs. 4.1±1.9μg/ml, p =0.01). Age- and gender-adjusted analysis showed that the presence of carotid plaque was associated with fasting apoB48 (OR 1.43; 95% CI, 1.07–2.09, p =0.04) and triglyceride (OR 1.14; 95% CI, 1.02–1.32, p =0.04) levels. In normal LDL-cholesterol (<140mg/dl) subjects, the presence of carotid plaque was associated with fasting apoB48 level (OR 2.16; 95% CI, 1.22–5.32, p =0.04), but not associated with fasting triglyceride level (OR 1.11; 95% CI, 0.99–1.30, p =0.13). Conclusions: Serum apoB48 level was strongly associated with the presence of carotid plaque in type 2 diabetic patients. [Copyright &y& Elsevier]

The term "cachexia" is derived from the Greek words kakos (bad) and hexis (habit). Cachexia is a malnutrition associated with chronic diseases such as cancer, chronic heart failure, chronic renal failure, and autoimmune diseases, and is characterized by decreased skeletal muscle mass. Cancer cachexia is quite common in patients with advanced cancer. Weight loss is also a characteristic symptom of cancer cachexia, along with decreased skeletal muscle mass. As nutritional supplementation alone cannot improve cachexia, cytokines and tumor-derived substances have been attracting attention as its relevant factors. Cancer cachexia can be also associated with reduced chemotherapeutic effects, increased side effects and treatment interruptions, and even poorer survival. In 2011, a consensus definition of cachexia has been proposed, and the number of relevant research reports has increased significantly. However, the pathogenesis of cachexia is not fully understood, and there are currently few regulatory-approved standard treatments for cachexia. The main reason for this is that multiple etiologies are involved in the development of cachexia. In this review, we will outline the current status of cachexia, the mechanisms of which have been elucidated in recent years, especially from the perspective of advanced cancer. [ABSTRACT FROM AUTHOR]

Abstract: Inhibition of Eg5 represents a novel approach for the treatment of cancer. Here, we report the synthesis and structure-activity relationship of S-trityl-l-cysteine (STLC) derivatives as Eg5 inhibitors. Some of these derivatives such as 4f demonstrated enhanced inhibitory activity against Eg5 and induced mitotic arrest with characteristic monoastral spindles in HeLa cells. [Copyright &y& Elsevier]

The article evaluates the apoptotic effect of peridinin, one of the most abundant carotenoids found in nature, on DLD-1 human colorectal cancer cells. According to the authors, peridinin significantly reduced the cell viability in a dose-dependent manner and induced apoptosis by activating both caspase-8 and caspase-9. They suggest that the findings could be important for the high-performance utilization of marine bioproducts.

Abstract: The first application of a combination of novel ψ[(E)-CXalkene dipeptide isosteres to conformation studies of cyclic bioactive peptides was carried out (X=H or Me). For exploration of bioactive conformations of Kessler''s cyclic RGD peptides, cyclo(-Arg-Gly-Asp-d-Phe-Val-) 1 and cyclo(-Arg-Gly-Asp-d-Phe-N-MeVal-) 2 , d-Phe-ψ[(E)-CXmall-caps>l-Val-type dipeptide isosteres were utilized having di-, tri- and tetrasubstituted alkenes containing the γ-methylated isosteres that have been reported to be potential type II′ β-turn promoters. All of the (E)-alkene pseudopeptides 3–6 exhibited higher antagonistic potency against αvβ3 integrin than 1 , although potencies were slightly lower than 2 . Detailed structural analysis using 1H NMR spectroscopy revealed that representative type II′ β/γ backbone arrangements proposed for 1 , were not observed in peptides 3–6 . Rather on the basis of 1H NMR data, the conformations of peptides 3–6 were estimated to be more analogous to those of the N-methylated peptide 2 . [Copyright &y& Elsevier]

Novel halohydrin and oxime derivatives of radicicol (1) were prepared and evaluated for their v-src tyrosine kinase inhibitory, antiproliferative, and antitumor activities. Some of the resulting derivatives showed significantly improved antitumor activities than those of 1 in vitro as tested in a cell proliferation assay and in vivo using sc-inoculated human breast carcinoma and epidermoid tumor models. Design and synthesis of radicicol-based novel affinity probes are also described. [Copyright &y& Elsevier]

Telomerase is a specialized reverse transcriptase responsible for maintaining the termini of linear chromosomes. The human enzyme is a ribonucleoprotein complex minimally comprising a catalytic protein moiety (hTERT) and an RNA subunit (hTR) which acts as the template for the reverse transcriptase reaction. Here we report expression of recombinant hTERT protein in insect cells utilizing a baculovirus expression system. The recombinant hTERT protein reconstitutes telomerase activity in the presence of hTR, either when co-expressed in insect cells or when added in vitro. Reconstitution of telomerase activity using this system will facilitate further analysis of the biochemical and biophysical properties of this enzyme. [Copyright &y& Elsevier]

Kinesin spindle protein (KSP) is expressed only in cells undergoing cell division, and hence represents an attractive target for the treatment of cancer. Several KSP inhibitors have been developed and undergone clinical trial, but their clinical use is limited by their toxicity to rapidly proliferating non - cancerous cells. To create new KSP inhibitors that are highly selective for cancer cells, we optimized the amino acid moiety of S -trityl - l - cysteine (STLC) derivative 1 using in silico modeling. Molecular docking and molecular dynamics simulation were performed to investigate the binding mode of 1 with KSP. Consistent with the structure activity relationship studies, we found that a cysteine amino moiety plays an important role in stabilizing the interaction. Based on these findings and the structure of GSH, a substrate of γ - glutamyltransferase (GGT), we designed and synthesized the prodrug N- γ - glutamylated STLC derivative 9 , which could be hydrolyzed by GGT to produce 1. The KSP ATPase inhibitory activity of 9 was lower than that of 1 , and LC - MS analysis indicated that 9 was converted to 1 only in the presence of GGT in vitro. In addition, the cytotoxic activity of 9 was significantly attenuated in GGT - knockdown A549 cells. Since GGT is overexpressed on the cell membrane of various cancer cells, these results suggest that compound 9 could be a promising prodrug that selectively inhibits the proliferation of GGT - expressing cancer cells. [Display omitted] • A series of novel S -trityl- l -cysteine derivatives as KSP inhibitors were synthesized. • Docking studies were performed to understand the pharmacophore and add new functions. • Prodrug 9 , activated by GGT and exhibiting cytotoxicity, was designed. • The correlation between cellular GGT levels and cytotoxicity treatment with 9 was investigated. • A KSP inhibitor activated by GGT was identified as a novel prodrug. [ABSTRACT FROM AUTHOR]

In this study, the effect of different periods of amoxicillin (AMPC) treatment on the eradication rate of Helicobacter pylori in 173 patients with peptic ulcers (gastric ulcer, 109; duodenal ulcer, 64) was investigated. AMPC (1.5 g/day) was administered for 2, 4, or 6 weeks with omeprazole (20mg/day) and plaunotol (240mg/day), a mucoprotective drug, for 8 weeks. The H. pylori eradication rate was 46.7% for 2 weeks' treatment, 83.4% for 4 weeks' treatment, and 100% for 6 weeks' treatment. The eradication rate had a good correlation with the period of AMPC treatment. The healing rates of peptic ulcer at 4 and 8 weeks were 93.3% and 100%, respectively, in the 2-week group, 98.0% and 99.3% in the 4-week group, and 85.7% and 100% in the 6-week group. The recurrence rate of gastric and duodenal ulcers was 3.5% and 0% respectively, in the patients in whom H. pylori was eradicated and 30.0% and 40%, respectively, in the patients in whom H. pylori was not eradicated for 12 months after the H. pylori eradication treatment. Adverse effects of this regimen were observed in 5 (2.9%) of the 173 patients. Diarrhea was observed in 3 patients and eruption in 2. These adverse effects disappeared within a few days after only AMPC was withdrawn. Therefore, these may be caused by AMPC. The eradication rate of H. pylori depends on the period of AMPC treatment. This regiment, AMPC (1.5g/day) + omeprazole (20mg/day) + plaunotol (240mg/day), is safe and well tolerated for eradication of H. pylori. [ABSTRACT FROM AUTHOR]

Rational scaffold hopping of a natural product belactosin A derivative was successfully achieved based on the pharmacophore model constructed. The peptidic scaffold was replaced by significantly simplified non-peptidic scaffolds, by which weak belactosin A (IC50 = 1440 nM) was converted into highly potent non-peptidic inhibitors (IC50 = 26–393 nM). [ABSTRACT FROM AUTHOR]

Signal transducer and activator of transcription 3 (STAT3) is a validated anticancer target due to the relationship between its constitutive activation and malignant tumors. Through a virtual screening approach on the STAT3-SH2 domain, 5,6-dimethyl-1H,3H-2,1,3-benzothiadiazole-2,2-dioxide (1) was identified as a potential STAT3 inhibitor. Some benzothiadiazole derivatives were synthesized by employing a versatile methodology, and they were tested by an AlphaScreen-based assay. Among them, benzosulfamide 1 showed a significant activity with an IC50 = 15.8 ± 0.6 µM as a direct STAT3 inhibitor. Notably, we discovered that compound 1 was also able to interact with cysteine residues located around the SH2 domain. By applying mass spectrometry, liquid chromatography, NMR, and UV spectroscopy, an in-depth investigation was carried out, shedding light on its intriguing and unexpected mechanism of interaction. [ABSTRACT FROM AUTHOR]

Abstract: Biochemical analysis of the cellular target of S-trityl-l-cysteine (STLC) derivatives was performed by using the newly synthesized STLC derivative-immobilized affinity beads (3d). The affinity beads efficiently captured KSP in HCT116 cytoplasmic cell lysate. The results obtained from pull-down and competition experiments using 3d with STLC derivatives provided the first evidence for direct interaction of these derivatives with KSP in cancer cells. Design, synthesis and application of 3d were reported. [Copyright &y& Elsevier]