Disruption of intermolecular disulfide bonds in PDGF-BB dimers by N-acetyl-L-cysteine does not prevent PDGF signaling in cultured hepatic stellate cells

Oxidative stress is important in the pathogenesis of liver fibrosis through its induction of hepatic stellate cell (HSC) proliferation and enhancement of collagen synthesis. Reactive oxygen species have been found to be essential second messengers in the signaling of both major fibrotic growth factors, platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta), in cultured HSC and liver fibrosis. The non-toxic aminothiol N-acetyl-L-cysteine (NAC) inhibits cellular activation and attenuates experimental fibrosis in liver. Prior reports show that NAC is capable of reducing the effects of TGF-beta in biological systems, in cultured endothelial cells, and HSC through its direct reducing activity upon TGF-beta molecules. We here analyzed the effects of NAC on PDGF integrity, receptor binding, and downstream signaling in culture-activated HSC. We found that NAC dose-dependently induces disintegration of PDGF in vitro. However, even high doses (>20mM) were not sufficient to prevent the phosphorylation of the PDGF receptor type beta, extracellular signal-regulated kinase, or protein kinase B (PKB/Akt). Therefore, we conclude that the PDGF monomer is still active. The described antifibrotic effects are therefore mainly attributable to the structural impairment of TGF-beta signaling components reported previously.     

Vascular smooth muscle cell proliferation as a therapeutic target. Part 2: Natural products inhibiting proliferation

Many natural products have been so far tested regarding their potency to inhibit vascular smooth muscle cell proliferation, a process involved in atherosclerosis, pulmonary hypertension and restenosis. Compounds studied in vitro and in vivo as VSMC proliferation inhibitors include, for example indirubin-3′-monoxime, resveratrol, hyperoside, plumericin, pelargonidin, zerumbone and apamin. Moreover, taxol and rapamycin, the most prominent compounds applied in drug-eluting stents to counteract restenosis, are natural products. Numerous studies show that natural products have proven to yield effective inhibitors of vascular smooth muscle cell proliferation and ongoing research effort might result in the discovery of further clinically relevant compounds.     

Incorporating anthropogenic effects into trophic ecology: predator–prey interactions in a human-dominated landscape

Apex predators perform important functions that regulate ecosystems worldwide. However, little is known about how ecosystem regulation by predators is influenced by human activities. In particular, how important are top-down effects of predators relative to direct and indirect human-mediated bottom-up and top-down processes? Combining data on species'' occurrence from camera traps and hunting records, we aimed to quantify the relative effects of top-down and bottom-up processes in shaping predator and prey distributions in a human-dominated landscape in Transylvania, Romania. By global standards this system is diverse, including apex predators (brown bear and wolf), mesopredators (red fox) and large herbivores (roe and red deer). Humans and free-ranging dogs represent additional predators in the system. Using structural equation modelling, we found that apex predators suppress lower trophic levels, especially herbivores. However, direct and indirect top-down effects of humans affected the ecosystem more strongly, influencing species at all trophic levels. Our study highlights the need to explicitly embed humans and their influences within trophic cascade theory. This will greatly expand our understanding of species interactions in human-modified landscapes, which compose the majority of the Earth''s terrestrial surface.     

Exploring the role of BCHE in the onset of Diabetes, Obesity and Neurological Disorders

Diabetes, Obesity and Neurological disturbances, most often show co-occurrence. There has been an extensive research in this domain, but the exact mechanism underlying the co-occurrence of the three conditions is still an enigma. The current paper is an approach to establish the role of Butyryl cholinesterase (BCHE) in Diabetes, Obesity and Neurological disorders by performing a comparative analysis with Neuroligin (NLGN2) a protein belonging to the same family. BCHE has its role in glucose regulation, Lipid metabolism and nerve signaling. Emphasis is laid on BCHE's diverse functions whose impediment affects the above mentioned metabolic pathways. Insilco techniques were employed to analyze the sequence, structural and functional similarities of the two proteins. A point mutation is focused which is common to both BCHE and Neuroligin. The mutation occurs at the homologous position in both the proteins making them deficient. This affects the three metabolic pathways leading to the respective disorders. The work describes the pathway that describes the role of BCHE in the onset of obesity mediated diabetes. The pathway further explains the association between Diabetes, Obesity and neurological disturbances.     

Isorhamnetin Inhibits Proliferation and Invasion and Induces Apoptosis through the Modulation of Peroxisome Proliferator-activated Receptor γ Activation Pathway in Gastric Cancer

Gastric cancer (GC) is a lethal malignancy and the second most common cause of cancer-related deaths. Although treatment options such as chemotherapy, radiotherapy, and surgery have led to a decline in the mortality rate due to GC, chemoresistance remains as one of the major causes for poor prognosis and high recurrence rate. In this study, we investigated the potential effects of isorhamnetin (IH), a 3′-O-methylated metabolite of quercetin on the peroxisome proliferator-activated receptor γ (PPAR-γ) signaling cascade using proteomics technology platform, GC cell lines, and xenograft mice model. We observed that IH exerted a strong antiproliferative effect and increased cytotoxicity in combination with chemotherapeutic drugs. IH also inhibited the migratory/invasive properties of GC cells, which could be reversed in the presence of PPAR-γ inhibitor. We found that IH increased PPAR-γ activity and modulated the expression of PPAR-γ regulated genes in GC cells. Also, the increase in PPAR-γ activity was reversed in the presence of PPAR-γ-specific inhibitor and a mutated PPAR-γ dominant negative plasmid, supporting our hypothesis that IH can act as a ligand of PPAR-γ. Using molecular docking analysis, we demonstrate that IH formed interactions with seven polar residues and six nonpolar residues within the ligand-binding pocket of PPAR-γ that are reported to be critical for its activity and could competitively bind to PPAR-γ. IH significantly increased the expression of PPAR-γ in tumor tissues obtained from xenograft model of GC. Overall, our findings clearly indicate that antitumor effects of IH may be mediated through modulation of the PPAR-γ activation pathway in GC.