Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pulmonary arterial hypertension (PAH) is a progressive and fatal lung disease of multifactorial etiology. Most of the available drugs and FDA-approved therapies for treating pulmonary hypertension attempt to overcome the imbalance between vasoactive and vasodilator mediators, and restore the endothelial cell function. Traditional medications for treating PAH include the prostacyclin analogs and receptor agonists, phosphodiesterase 5 inhibitors, endothelin-receptor antagonists, and cGMP activators. While the current FDA-approved drugs showed improvements in quality of life and hemodynamic parameters, they have shown only very limited beneficial effects on survival and disease progression. None of them offers a cure against PAH, and the median survival rate remains less than three years from diagnosis. Extensive research efforts have led to the emergence of innovative therapeutic approaches in the area of PAH. In this review, we provide an overview of the current FDA-approved therapies in PAH and discuss the associated clinical trials and reported-side effects. As recent studies have led to the emergence of innovative therapeutic approaches in the area of PAH, we also focus on the latest promising therapies in preclinical studies such as stem cell-based therapies, gene transfer, and epigenetic therapies.
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PMID:Current and emerging therapeutic approaches to pulmonary hypertension. 3270 6

Pulmonary hypertension (PH) is classified into 5 clinical subgroups: pulmonary arterial hypertension (PAH), PH due to left-sided heart disease, PH due to chronic lung disease, chronic thromboembolic PH (CTEPH), and PH with an unclear and/or multifactorial mechanisms. A range of underlying conditions can lead to these disorders. Overall, PH affects approximately 1% of the global population, and over half of patients with heart failure may be affected. Cardiologists are therefore likely to encounter PH in their practice. Routine tests in patients with symptoms and physical findings suggestive of PH include electrocardiography, chest radiography, and pulmonary function tests. Transthoracic echocardiography is used to estimate the probability of PH. All patients with suspected or confirmed PH, without confirmed left-sided heart or lung diseases, should have a ventilation-perfusion scan to exclude CTEPH. Right-sided heart catheterization is essential for accurate diagnosis and classification. All patients with PAH or CTEPH must be referred to a specialist center. Surgical pulmonary endarterectomy is the treatment of choice for eligible patients with CTEPH. Targeted treatments (phosphodiesterase type 5 inhibitors, soluble guanylate cyclase stimulators, endothelin receptor antagonists, prostacyclin analogues, and prostacyclin receptor agonists) are licensed for patients with PAH. The soluble guanylate cyclase stimulator riociguat is the only licensed targeted therapy for patients with inoperable or persistent/recurrent CTEPH. Management of PH resulting from left-sided heart disease primarily involves treatment of the underlying condition.
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PMID:Pulmonary Hypertension: A Brief Guide for Clinicians. 3286 39

Background: In COVID 19 related lung disease, which is a leading cause of death from this disease, cytokines like tumor necrosis factor-alpha (TNF alpha) may be pivotal in the pathogenesis. TNF alpha reduces fluid absorption due to impairment of sodium and chloride transport required for building an osmotic gradient across epithelial cells, which in the airways maintains airway surface liquid helping to keep airways open and enabling bacterial clearance and aids water absorption from the alveolar spaces. TNF alpha can, through Rho-kinase, disintegrate the endothelial and epithelial cytoskeleton, and thus break up intercellular tight junctional proteins, breaching the intercellular barrier, which prevents flooding of the interstitial and alveolar spaces with fluid. Hypotheses: (1) Preservation and restoration of airway and alveolar epithelial sodium and chloride transport and the cytoskeleton dependent integrity of the cell barriers within the lung can prevent and treat COVID 19 lung disease. (2) TNF alpha is the key mediator of pulmonary edema in COVID 19 lung disease. Confirmation of hypothesis and implications: The role of a reduction in the function of epithelial sodium and chloride transport could with regards to chloride transport be tested by analysis of chloride levels in exhaled breath condensate and levels correlated with TNF alpha concentrations. Reduced levels would indicate a reduction of the function of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel and a correlation with TNF alpha levels indicative of its involvement. Anti-TNF alpha treatment with antibodies is already available and needs to be tested in randomized controlled trials of COVID 19 lung disease. TNF alpha levels could also be reduced by statins, aspirin, and curcumin. Chloride transport could be facilitated by CFTR activators, including curcumin and phosphodiesterase-5 inhibitors. Sodium and chloride transport could be further regulated to prevent accumulation of alveolar fluid by use of Na(+)/K(+)/2Cl(-) cotransporter type 1 inhibitors, which have been associated with improved outcome in adults ventilated for acute respiratory distress syndrome (ARDS) in randomized controlled trials. Primary prevention of coronavirus infection and TNF alpha release in response to it could be improved by induction of antimicrobial peptides LL-37 and human beta defensin-2 and reduction of TNF alpha production by vitamin D prophylaxis for the population as a whole.
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PMID:Pathways in the Pathophysiology of Coronavirus 19 Lung Disease Accessible to Prevention and Treatment. 3292 1

Tuberculosis, a lung disease caused by Mycobacterium tuberculosis (Mtb), is one of the ten leading causes of death worldwide affecting mainly developing countries. Mtb can persist and survive inside infected cells through modulation of host antibacterial attack, i.e., by avoiding the maturation of phagosome containing mycobacteria to more acidic endosomal compartment. In addition, bacterial phosphatases play a central role in the interplay between host cells and Mtb. In this study, we characterized the Rv2577 of Mtb as a potential alkaline phosphatase/phosphodiesterase enzyme. By an in vitro kinetic assay, we demonstrated that purified Rv2577 expressed in Mycobacterium smegmatis displays both enzyme activities, as evidenced by using the artificial substrates p-NPP and bis-(p-NPP). In addition, a three-dimensional model of Rv2577 allowed us to define the catalytic amino acid residues of the active site, which were confirmed by site-directed mutagenesis and enzyme activity analysis, being characteristic of a member of the metallophosphatase superfamily. Finally, a mutation introduced in Rv2577 reduced the replication of Mtb in mouse organs and impaired the arrest of phagosomes containing mycobacteria in early endosomes; which indicates Rv2577 plays a role in Mtb virulence.
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PMID:Rv2577 of Mycobacterium tuberculosis Is a Virulence Factor With Dual Phosphatase and Phosphodiesterase Functions. 3319 64


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