Small molecule generators of biologically reactive sulfur species

Sulfur metabolism is integral to cellular growth and survival. The presence of a wide range of oxidation states of sulfur in biology coupled with its unique reactivity are some key features of the biology of this element. In particular, nearly all oxidation states of sulfur not only occur but are also inter-convertible. In order to study the chemical biology of reactive sulfur species, tools to reliably detect as well as generate these species within cells are necessary. Herein, an overview of strategies to generate certain reactive sulfur species is presented. The donors of reactive sulfur species have been organized based on their oxidation states. These interesting small molecules have helped lay a strong foundation to study the biology of reactive sulfur species and some may have therapeutic applications in the future as well.

Reactive sulfur species (RSS) are integral to cellular survival and growth. Here, small molecule generators of RSS are reviewed.     

Clinical significance of distal colon polyps for the prediction of an advanced proximal neoplasm: the KASID prospective multicenter study

Background/aims The possibility of proximal lesion without distal polyps is a weak point of sigmoidoscopic colon cancer screening, but the clinical significance of distal findings for advanced proximal neoplasm (APN) is uncertain. The aim of this study was to assess the significance of a distal finding as a predictor of APN. Materials and methods Asymptomatic patients ≥50 years old were enrolled from among patients who underwent polypectomy at 11 tertiary medical centers during the Korean Association for the Study of Intestinal Disease prospective study conducted between July 2003 and March 2004. Polyps located distal to the splenic flexure were defined as distal polyps. An advanced neoplasm was defined as a polyp of ≥10 mm in size, and/or with villous features, and/or with high-grade dysplasia, or invasive cancer. Age, gender, and distal polyp size, appearance, and histology were analyzed as risk factors of APN. The sensitivity and positive predictive value of distal polyps for APN were calculated. Results Data from 826 patients were analyzed. Mean patient age was 60.1 years (range 50–86), and 71.3% were men. APN was found in 98 patients, and 45 (45.9%) patients had no distal polyps. Risk factors of APN were a male gender, distal polyp size, and an advanced distal neoplasm. Sensitivities of a distal polyp of ≥10 mm and of an advanced distal neoplasm for APN were both 38.8% with positive predictive values of 13.3 and 14.4%, respectively. Conclusions Although distal colon findings were found to be helpful for predicting APN in asymptomatic patients aged ≥50 years, APN without distal polyps requires careful consideration.     

An integrative approach using systems biology,mutational analysis with molecular dynamics simulation to challenge the functionality of a target protein

Visceral leishmaniasis affects millions of people worldwide in areas where Leishmania donovani is endemic. The protozoan species serves a greater threat as it has gradually evolved drug resistance whereby requiring newer approaches to treat the infection. State‐of‐art techniques are mostly directed toward finding better targets extracted from the available proteome data. In light of recent computational advancements, we ascertain and validate one such target, adenylosuccinate lyase (ADSL) by implementation of in‐silico methods which led to the identification of critical amino acid residues that affects its functional attributes. Our target selection was based on comprehensive topological analysis of a knowledge‐based protein–protein interaction network. Subsequently, mutations were incorporated and the dynamic behavior of mutated and native proteins was traced using MD simulations for a total time span of 600 ns. Comparative analysis of the native and mutated structures exhibited perceptible changes in the ligand‐bound catalytic region with respect to time. The unfavorable changes in the orientations of specific catalytic residues, His118 and His196, induced by generated mutations reduce the enzyme specificity. In summary, this integrative approach is able to select a target against pathogen, identify crucial residues, and challenge its functionality through the selected mutations.     

Clinical trial: transcutaneous interferential electrical stimulation in individuals with irritable bowel syndrome - a prospective double-blind randomized study

Background: The exact etiology of irritable bowel syndrome (IBS) remains unclear. Curative treatment is not available and current treatment modalities are mainly directed against the predominant symptoms. There are a few studies reporting the beneficial effects of transcutaneous electrical stimulation in patients with chronic constipation, gastroparesis, and functional dyspepsia. Aim: To investigate whether transcutaneous electrical stimulation is an effective procedure in IBS patients. Methods: IBS patients were randomly placed in vacuum interferential current (IFC) and placebo groups. Both treatments consisted of 12 sessions administered over 4 weeks. Symptoms due to IBS were documented via questionnaires, including the IBS Global Assessment of Improvement Scale, numeric rating scales, visual analogue scale, and IBS Quality of Life Scale at the beginning of, end of, and 1 month after the treatment. Results: Patients in the therapy (29 cases) and placebo (29 cases) groups were homogeneous with respect to demographic data and gastrointestinal system symptoms. When compared to the beginning scores, severity of abdominal discomfort, bloating, and abdominal distension and rumbling improved significantly in either interference or placebo groups at both the end of treatment and 1 month after treatment. In the IFC group, severity of symptoms continued to decrease significantly at 1 month after treatment when compared to scores at just the end of treatment, whereas in the placebo group severity of these symptoms did not change significantly on numeric severity scales. Also, the visual analogue scale of the first month after treatment continued to decrease significantly when compared to the level at the end of treatment in the IFC group. Total quality score increased significantly in the IFC group. Conclusions: Vacuum IFC therapy can significantly improve symptoms and quality of life in patients with IBS. It may represent a novel treatment modality for drug-refractory IBS patients.     

Secreted protein, acidic and rich in cysteine-like 1 (SPARCL1) is down regulated in aggressive prostate cancers and is prognostic for poor clinical outcome

Prostate cancer is the second leading cause of cancer death among United States men. However, disease aggressiveness is varied, with low-grade disease often being indolent and high-grade cancer accounting for the greatest density of deaths. Outcomes are also disparate among men with high-grade prostate cancer, with upwards of 65% having disease recurrence even after primary treatment. Identification of men at risk for recurrence and elucidation of the molecular processes that drive their disease is paramount, as these men are the most likely to benefit from multimodal therapy. We previously showed that androgen-induced expression profiles in prostate development are reactivated in aggressive prostate cancers. Herein, we report the down-regulation of one such gene, Sparcl1, a secreted protein, acidic and rich in cysteine (SPARC) family matricellular protein, during invasive phases of prostate development and regeneration. We further demonstrate a parallel process in prostate cancer, with decreased expression of SPARCL1 in high-grade/metastatic prostate cancer. Mechanistically, we demonstrate that SPARCL1 loss increases the migratory and invasive properties of prostate cancer cells through Ras homolog gene family, member C (RHOC), a known mediator of metastatic progression. By using models incorporating clinicopathologic parameters to predict prostate cancer recurrence after treatment, we show that SPARCL1 loss is a significant, independent prognostic marker of disease progression. Thus, SPARCL1 is a potent regulator of cell migration/invasion and its loss is independently associated with prostate cancer recurrence.