Selective inhibitors of type I receptor kinase block cellular transforming growth factor-beta signaling

Transforming growth factor (TGFbeta) is a 25-kDa dimeric polypeptide that plays a key role in a variety of physiological processes and disease states. Blocking TGFbeta signaling represents a potentially powerful and conceptually novel approach to the treatment of disorders in which the signaling pathway is constitutively activated, such as cancer, chronic inflammation with fibrosis and select immune disorders. In this paper, we describe the biological properties of a novel series of quinazoline-derived inhibitors of the type I transforming growth factor receptor kinase (TbetaKIs) that bind to the ATP-binding site and keep the kinase in its inactive conformation. These compounds effectively inhibited TGFbeta-induced Smad2 phosphorylation in cultured cells in vitro with an IC(50) between 20 and 300 nM. Moreover, TbetaKIs were able to broadly block TGFbeta-induced reporter gene activation. Finally, TbetaKIs inhibited TGFbeta-mediated growth inhibition of normal murine mammary epithelial cells (NMuMG) and mink lung epithelial cells (Mv1Lu), and TGFbeta-induced epithelial-mesenchymal transdifferentiation (EMT) of NMuMG cells. Thus, these chemical TbetaKIs have the potential to be further developed as anti-cancer and -fibrosis agents. In addition, they represent valuable new tools for dissecting the biochemical mechanisms of TGFbeta signal transduction and understanding the role of TGFbeta signaling pathways in different physiological and disease processes.     

The reimagination of sustainable integrated care in Ontario,Canada

Purpose/settingTo encourage clinical and financial efficiency, the Canadian province of Ontario initiated an integrated care program – Integrated Funding Models (IFMs) that required collaboration and coordination across acute and post-acute care sectors. This research shows how program implementers went beyond policy-makers’ original designs, to make integrated care sustainable for chronic diseases.MethodsForty-five interviews were conducted with program participants at three chronic disease programs, as well as with policymakers. Interviews were conducted over two phases; during early implementation in 2016, and as programs matured in 2018. Data were analyzed through a cultural constructivist lens to understand how participants shaped programs.FindingsParticipants desired greater accountability and control. Participants in the first program wanted localized control over decision-making. In the second, participants initiated greater control over financial uncertainty. In the third program, hospital participants sought greater control over community care. Participants across programs simultaneously wanted integrated care to be expanded holistically, spatially, and temporally for patients, extending the length of care, and expanding the spaces in which care was provided. Findings also suggest a gap between program implementers’ and policymakers’ conceptualizations of integrated care.ConclusionThis work shows how IFMs were reimagined in ways that transcended their original conceptualization as spatially and temporally delimited initiatives aimed at improving coordination and efficiency. It has practical implications for those facing sustainability challenges in other contexts.     

2-Phenylindole and Arylsulphonamide: Novel Scaffolds Bactericidal against Mycobacterium tuberculosis

相似文献   

Optimization of GPR40 Agonists for Type 2 Diabetes

相似文献   

Costs incurred and determinants of out-of-pocket payments for child delivery care in India: Evidence from a nationally representative household survey

In India, out-of-pocket (OOP) expenditure on health care services has been showing an increasing trend. The cost and willingness to pay determines the use of facility-based maternal health services. Hence, the current study was done to find the costs and determinants of OOP payments on childbirth care in India. We analyzed the most recent National Family Health Survey-4 data (NFHS-4) gathered from the Demographic Health Survey (DHS) program. Stratification and clustering in the sample design were accounted for by using the “svyset” command. Out of 43 507 women, 26 916 (61.9%) had incurred OOP expenditure during their most recent institutional delivery. The average OOP expenditure for delivery care was INR 5985 ($93.3) with median cost being INR 1000 ($15.6). About 80% of women who had OOP expenditure reported that they handled the financial situation by utilizing the money in their bank/savings account. Determinants of OOP expenses were the age of mother, education, religion, state of residence, number of antenatal visits place of delivery, and mode of delivery (P < .05). Out-of-pocket expenditure for accessing care is one of the key determinants of service utilization which, if not addressed by the health system, can deter women from having institutional deliveries in the future.     

OBG‐like ATPase 1 inhibition attenuates angiotensin II‐induced hypertrophic response in human ventricular myocytes via GSK‐3beta/beta‐catenin signalling

Obg‐like ATPase 1 (OLA1) that possesses both GTP and ATP hydrolyzing activities has been shown to be involved in translational regulation of cancer cell growth and survival. Also, GSK3β signalling has been implicated in cardiac development and disease. However, the role of OLA1 in pathological cardiac hypertrophy is unknown. We sought to understand the mechanism by which OLA1 regulates GSK3β‐β‐Catenin signalling and its functional significance in angiotensin‐II (ANG II)‐induced cardiac hypertrophic response. OLA1 function and its endogenous interaction with GSK3β/β‐catenin signalling in cultured human ventricular cardiomyocytes (AC16 cells) and mouse hearts (in vivo) was evaluated with/without ANG II‐stimulated hypertrophic response. ANG II administration in mice increases myocardial OLA1 protein expression with a corresponding increase in GSK3β phosphorylation and decrease in β‐Catenin phosphorylation. Cultured cardiomyocytes treated with ANG II show endogenous interaction between OLA1 and GSK3β, nuclear accumulation of β‐Catenin and significant increase in cell size and expression of hypertrophic marker genes such as atrial natriuretic factor (ANF; NPPA) and β‐myosin heavy chain (MYH7). Intriguingly, OLA1 inhibition attenuates the above hypertrophic response in cardiomyocytes. Taken together, our data suggest that OLA1 plays a detrimental role in hypertrophic response via GSK3β/β‐catenin signalling. Translation strategies to target OLA1 might potentially limit the underlying molecular derangements leading to left ventricular dysfunction in patients with maladaptive cardiac hypertrophy.     

Molecular Characterization of 2-Chlorobiphenyl Degrading Stenotrophomonas maltophilia GS-103

The catabolic potential of transformer oil contaminated soil bacteria in aerobic degradation of polychlorinated biphenyls (PCB) were assessed. Transformer oil contaminated soil sample was subjected to microcosm enrichment experiments (PAS medium/biphenyl as sole carbon source). PCB-degrading activity of the enrichment cultures in PAS medium with the addition of 2-chlorobiphenyl were analysed by GC–MS indicated that, although the isolates differed in PCB-degrading capabilities, all of the enrichment cultures expressed activity toward at least some of the lower chlorinated congeners. Biphenyl-utilizing bacteria isolated from the most active PCB-degrading mixed cultures showed little taxonomic diversity and identified as Stenotrophomonas maltophilia GS-103.     

Antioxidant potential of a novel tetrapeptide derivative in isoproterenol-induced myocardial necrosis in rats

A novel tetrapeptide derivative Boc-Lys(Boc)-Arg-Asp-Ser(tbu)-OtBu (PEP1261) has been tested in vivo in isoproterenol (ISO) hydrochloride (HCl)-induced myocardial necrosis in rats. ISO x HCl induces myocardial necrosis in rats which is accompanied by the distinct increase in heart weight, marked electrocardiographic changes, increase in the levels of serum marker enzymes and lipid peroxides and decrease in the levels of antioxidants. PEP1261 (5 mg/kg body weight i.p.) pre- and post-treatment effectively decreases serum marker enzyme levels, while the electrocardiographic changes get restored towards normalcy. PEP1261 also inhibits the action of the free radicals toxicity by increasing the levels of antioxidants and histological studies confirm the above findings. This study shows that PEP1261 could serve as an excellent cardioprotective agent possessing membrane-stabilizing action.     

Protection against selenite cataract in rat lens by drevogenin D, a triterpenoid aglycone from Dregea volubilis

Dregea volubilis is a woody climbing plant commonly found in the hotter parts of India. The leaves are edible and used as a green vegetable, while the plant extract has been used traditionally to treat several diseases including eye ailments. Drevogenin D is a triterpenoid aglycone that has been isolated, purified, and characterized as an active component from the leaves of D. volubilis. In this study, drevogenin D was evaluated for antioxidant and potential anticataractogenic activity in an in vitro model. 1,1-Diphenyl-2-picrylhydrazyl radical and superoxide radical scavenging activities of drevogenin D were studied and found to exhibit a 50% inhibitory concentration of 43 microg/mL and 200.6 microg/mL, respectively. Normal rat lenses cultured in 0.1 mM sodium selenite-supplemented medium were used as the experimental model for this study. Selenite-induced models are excellent mimics of oxidative stress induced cataract. Treatment with drevogenin D at a concentration of 50 microg/mL medium was found to reverse the level of activity of superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase, elevate the level of reduced glutathione and protein sulfhydryl, and lower the level of lipid peroxidation as indicated by the concentration of thiobarbituric acid-reacting substances. These results indicate good antioxidant activity and potential anticataractogenic activity for drevogenin D against selenite-induced cataractous changes, which have been reported for the first time.