PAK proteins and YAP-1 signalling downstream of integrin beta-1 in myofibroblasts promote liver fibrosis

Fibrosis due to extracellular matrix (ECM) secretion from myofibroblasts complicates many chronic liver diseases causing scarring and organ failure. Integrin-dependent interaction with scar ECM promotes pro-fibrotic features. However, the pathological intracellular mechanism in liver myofibroblasts is not completely understood, and further insight could enable therapeutic efforts to reverse fibrosis. Here, we show that integrin beta-1, capable of binding integrin alpha-11, regulates the pro-fibrotic phenotype of myofibroblasts. Integrin beta-1 expression is upregulated in pro-fibrotic myofibroblasts in vivo and is required in vitro for production of fibrotic ECM components, myofibroblast proliferation, migration and contraction. Serine/threonine-protein kinase proteins, also known as P21-activated kinase (PAK), and the mechanosensitive factor, Yes-associated protein 1 (YAP-1) are core mediators of pro-fibrotic integrin beta-1 signalling, with YAP-1 capable of perpetuating integrin beta-1 expression. Pharmacological inhibition of either pathway in vivo attenuates liver fibrosis. PAK protein inhibition, in particular, markedly inactivates the pro-fibrotic myofibroblast phenotype, limits scarring from different hepatic insults and represents a new tractable therapeutic target for treating liver fibrosis

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

The metabolic organization of the adult human liver: A comparative study of normal, fibrotic, and cirrhotic liver tissue

Little is known about the alterations of metabolic organization of the human liver tissue in chronic liver diseases. We therefore compared the distribution of the following zonal metabolic markers in 10 samples of normal liver tissue, 10 samples of fibrotic tissue, and 22 samples of cirrhotic tissue: (a) the enzymatic activities of glucose-6-phosphatase (G6P), lactate dehydrogenase (LDH), succinate dehydrogenase (SDH), nicotinamide-adenine- dinucleotide-phosphate [NADPH] dehydrogenase (ND), β-hydroxybutyrate dehydrogenase (HBDH), and glutamate dehydrogenase (GDH); (b) the protein glutamine synthetase (GLS); and (c) albumin messenger RNA (mRNA). The normal human hepatic lobule was characterized by the periportal predominance of G6P and SDH enzymatic activities and albumin mRNAs, the perivenous predominance of ND and GDH, the restriction of GLS to a small perivenous compartment, and the predominance of β-HBDH at the contact of both portal tracts and centrilobular veins. In fibrosis, the overall metabolic organization of the normal liver tissue was retained. The expression of periportal markers predominated around enlarged portal tracts and that of perivenous markers around residual centrilobular veins. GLS was constantly detected at the contact of centrilobular veins. In cirrhotic nodules, no zonation was observed for most enzymatic activities or for albumin. Only G6P usually predominated at the periphery of the nodules. GLS was constantly undetectable. No difference according to the etiology of the underlying disease was observed. In conclusion, the normal human hepatic lobule presents a marked metabolic zonation, preserved in fibrotic lesions, but last in cirrhotic nodules. The alterations of the metabolic organization observed in cirrhosis might contribute to the pathogenesis of some of the metabolic disorders associated with advanced liver disease

Global network analysis of phenotypic effects: Protein networks and toxicity modulation in Saccharomyces cerevisiae

Using genome-wide information to understand holistically how cells function is a major challenge of the postgenomic era. Recent efforts to understand molecular pathway operation from a global perspective have lacked experimental data on phenotypic context, so insights concerning biologically relevant network characteristics of key genes or proteins have remained largely speculative. Here, we present a global network investigation of the genotype/phenotype data set we developed for the recovery of the yeast Saccharomyces cerevisiae from exposure to DNA-damaging agents, enabling explicit study of how protein–protein interaction network characteristics may be associated with phenotypic functional effects. We show that toxicity-modulating proteins have similar topological properties as essential proteins, suggesting that cells initiate highly coordinated responses to damage similar to those needed for vital cellular functions. We also identify toxicologically important protein complexes, pathways, and modules. These results have potential implications for understanding toxicity-modulating processes relevant to a number of human diseases, including cancer and aging

Myofibroblasts and colonic anastomosis healing in Wistar rats

<p>Abstract</p> <p>Background</p> <p>The myofibroblasts play a central role in wound healing throughout the body. The process of wound healing in the colon was evaluated with emphasis on the role of myofibroblasts.</p> <p>Methods</p> <p>One hundred male Wistar rats weighing 274 ± 9.1 g (mean age: 3.5 months) were used. A left colonic segment was transected and the colon was re-anastomosed. Animals were randomly divided into two groups. The first group experimental animals (n = 50) were sacrificed on postoperative day 3, while the second group rats (n = 50) were sacrificed on postoperative day 7. Healing of colonic anastomosis was studied in terms of anastomotic bursting pressure, as well as myofibroblastic reaction and expression of α-smooth muscle actin (α-SMA), adhesion formation, inflammatory reaction and neovascularization.</p> <p>Results</p> <p>The mean anastomotic bursting pressure increased from 20.6 ± 3.5 mmHg on the 3^rdpostoperative day to 148.8 ± 9.6 Hg on the 7^thpostoperative day. Adhesion formation was increased on the 7^thday, as compared to the 3^rdday. In addition, the myofibroblastic reaction was more profound on the 7^thpostoperative day in comparison with the 3^rdpostoperative day. The staining intensity for α-SMA was progressive from the 3rd to the 7th postoperative day. On the 7^thday the α-SMA staining in the myofibroblats reached the level of muscular layer cells.</p> <p>Conclusions</p> <p>Our study emphasizes the pivotal role of myofibroblasts in the process of colonic anastomosis healing. The findings provide an explanation for the reduction in the incidence of wound dehiscence after the 7th postoperative day.</p