Phosphodiesterase 10A Upregulation Contributes to Pulmonary Vascular Remodeling

Phosphodiesterases (PDEs) modulate the cellular proliferation involved in the pathophysiology of pulmonary hypertension (PH) by hydrolyzing cAMP and cGMP. The present study was designed to determine whether any of the recently identified PDEs (PDE7-PDE11) contribute to progressive pulmonary vascular remodeling in PH. All in vitro experiments were performed with lung tissue or pulmonary arterial smooth muscle cells (PASMCs) obtained from control rats or monocrotaline (MCT)-induced pulmonary hypertensive (MCT-PH) rats, and we examined the effects of the PDE10 inhibitor papaverine (Pap) and specific small interfering RNA (siRNA). In addition, papaverine was administrated to MCT-induced PH rats from day 21 to day 35 by continuous intravenous infusion to examine the in vivo effects of PDE10A inhibition. We found that PDE10A was predominantly present in the lung vasculature, and the mRNA, protein, and activity levels of PDE10A were all significantly increased in MCT PASMCs compared with control PASMCs. Papaverine and PDE10A siRNA induced an accumulation of intracellular cAMP, activated cAMP response element binding protein and attenuated PASMC proliferation. Intravenous infusion of papaverine in MCT-PH rats resulted in a 40%–50% attenuation of the effects on pulmonary hypertensive hemodynamic parameters and pulmonary vascular remodeling. The present study is the first to demonstrate a central role of PDE10A in progressive pulmonary vascular remodeling, and the results suggest a novel therapeutic approach for the treatment of PH

Curcuma longa L. Zingiberaceae

Amomum curcuma Jacg. (1776); Curcuma domestica Val. (1918

Urban water security in South Asia: Crucial policy lessons from the Nepalese town of Bidur

The rapidly urbanizing and highly populated South Asian region is facing a water crisis. As a key response, large centralized water systems are being put in place, replacing small and community-based systems. In this discussion note, we present the case of Nepal's town of Bidur to show that Himalayan South Asian towns cannot ensure water supply by neglecting community-based and small-scale water supply systems. Using insights from qualitative and quantitative data collected during 2014–2019, we argue that decentralized and community-based urban water systems are more resilient than large ones during disasters. Our argument is based on the analysis of Bidur's response to the 2015 earthquake as well as the COVID-19 pandemic. We show that a mixed approach of large and small water supply schemes provides a promising solution to water insecurity in the South Asian towns. This approach can be realized by promoting diversity of water management strategies and creating research-informed planning and discussion forums at the community and municipality levels. We also recommend municipalities to formulate a comprehensive water security strategy, considering the current and future scenarios of water demand and supply