Despite intensive clinical and scientific efforts, the mortality rate of sepsis remains high due to lack precise biomarkers for patient stratification therapeutic guidance. Interleukin 40 (IL-40), a novel cytokine with immune regulatory functions in human diseases, was elevated at admission two independent cohorts patients sepsis. High levels secreted IL-40 septic were positively correlated PCT, CRP, lactate (LDH), Sequential Organ Failure Assessment (SOFA) scores, which used stratify early...

Highlights•The gut Actinobacterium Eggerthella lenta increases drug absorption in mice•A secreted factor produced by E. inhibits P-glycoprotein ATPase activity•P-glycoprotein inhibition is conserved within the Eggerthellaceae family•Activity-guided fractionation implicated a group of small polar metabolitesSummaryDrug efflux transporters are major determinant efficacy and toxicity. A canonical example (P-gp), an transporter that controls intestinal diverse compounds. Despite rich literature...

Our recent studies demonstrated that the natural product nobiletin (NOB) served as a promising multidrug resistance (MDR) reversal agent and improved effectiveness of cancer chemotherapy in vitro. However, low aqueous solubility difficulty total synthesis limited its application therapeutic agent. To tackle these challenges, NOB was synthesized high yield by concise route six steps fourteen derivatives were with remarkable efficacy. All compounds showed sensitivity to paclitaxel (PTX)...

Pulmonary arterial hypertension (PAH) causes pathological increase in pulmonary vascular resistance, leading to right-heart failure and eventual death. Previously, phosphodiesterase-10 (PDE10) was reported be a promising target for PAH based on the studies with nonselective PDE inhibitor papaverine, but little progress has been made confirm practical application of PDE10 inhibitors. To validate whether is ameliorated by inhibition rather than other isoforms, here we report an integrated...

Alzheimer’s disease (AD) is a widely recognized type of dementia that leads to progressive cognitive decline and memory loss, affecting significant number people their families worldwide. Given the multifactorial nature AD, multitarget-directed ligands (MTDLs) hold promise in developing effective drugs for AD. Phosphodiesterase-9 (PDE9) emerging as promising target AD therapy. In this study, by combining PDE9 inhibitor C33 with antioxidant melatonin, we designed discovered series...

Phosphodiesterase-5 (PDE5) is a potent therapeutic target for the treatment of male erectile dysfunction and pulmonary arterial hypertension with several drugs available on market. However, most reported PDE5 inhibitors lack specificity over PDE6, holoenzyme in eleven PDE families, which may cause various adverse effects. Targeting unique allosteric pocket has proved to be an effective approach designing selective inhibitors. In present study, integrated virtual screening procedure...

Aims The purpose of this study was to explore the relationship between blood urea nitrogen serum albumin ratio and 28-day in-hospital mortality in patients with chronic heart failure complicated by sepsis admitted intensive care unit (ICU). Methods This retrospective included 723 from eICU database. Smooth curve fitting assessed association BAR mortality. Multivariable Cox regression analysis conducted calculate adjusted hazard (HR) 95% confidence interval (CI). Kaplan–Meier curves compared...

Phosphodiesterase-2A (PDE2A) is a potential therapeutic target for treatment of Alzheimer's disease and pulmonary hypertension. However, most the current PDE2A inhibitors have moderate selectivity over other PDEs. In present study, we described discovery novel by structure-based virtual screening combining pharmacophore model screening, molecular docking, dynamics simulations, bioassay validation. Nine hits out 30 molecules from SPECS database (a hit rate 30%) inhibited with affinity less...

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and devastating lung disease lacking effective therapy. To identify whether phosphodiesterase-1 (PDE1) inhibition could act as novel target for the treatment of IPF, hit-to-lead structural optimizations were performed on PDE9/PDE1 dual inhibitor (R)-C33, leading to compound 3m with an IC50 2.9 nM against PDE1C, excellent selectivity across PDE subfamilies, reasonable drug-like properties, remarkable pharmacodynamic effects...

Dearomatization reactions provide a rapid approach to construct complicated molecules that are difficult synthesize by traditional methods from simple aromatic compounds. Herein, we report an efficient dearomative [3+2] cycloaddition reaction of 2-alkynyl pyridines with diarylcyclopropenones, leading the synthesis densely functionalized indolizinones in moderate good yields under metal-free conditions. In addition, this strategy can also be employed cyclization isoquinolines access variety...

Phosphodiesterase 5 (PDE5) inhibitors have been used as clinical agents to treat erectile dysfunction and pulmonary arterial hypertension (PAH). Herein, we detail the discovery of a novel series chromeno[2,3-c]pyrrol-9(2H)-one derivatives selective orally bioavailable against phosphodiesterase 5. Medicinal chemistry optimization resulted in 2, which exhibits desirable inhibitory potency 5.6 nM with remarkable selectivity well excellent pharmacokinetic properties an oral bioavailability...

Discovery of multitarget-directed ligands (MTDLs), targeting different factors simultaneously to control the complicated pathogenesis Alzheimer's disease (AD), has become an important research area in recent years. Both phosphodiesterase 9A (PDE9A) and butyrylcholinesterase (BuChE) inhibitors could participate processes AD attenuate neuronal injuries improve cognitive impairments. However, on MTDLs combining inhibition PDE9A BuChE not been reported yet. In this study, a series novel...

Liver fibrosis is a common pathological feature of most chronic liver diseases with no effective drugs available. Phosphodiesterase 1 (PDE1), subfamily the PDE super enzyme, might work as potent target for by regulating concentration cAMP and cGMP. However, there are few PDE1 selective inhibitors, none has been investigated treatment yet. Herein, compound AG-205/1186117 dihydropyrimidine scaffold was selected hit virtual screening. A hit-to-lead structural modification led to series...

Optimization efforts were devoted to discover novel PDE10A inhibitors in order improve solubility and pharmacokinetics properties for a long-term therapy against pulmonary arterial hypertension (PAH) starting from the previously synthesized inhibitor A. As result, potent highly selective inhibitor, 14·3HCl (half maximal inhibitory concentration, IC50 = 2.8 nmol/L >3500-fold selectivity) exhibiting desirable metabolic stability with remarkable bioavailability of 50% was identified aid...

To further explore the structure–activity relationship around chromeno[2,3-c]pyrrol-9(2H)-one scaffold, 19 derivatives as inhibitors against PDE5 were discovered. The most potent inhibitor 3 has an IC50 of 0.32 nM with remarkable selectivity and druglike profile. Oral administration (1.25 mg/kg) caused comparable therapeutic effects to sildenafil (10.0 pulmonary arterial hypertension. Further, different binding patterns from revealed in cocrystal structures, which provide structural...

In patients with mild osteoarthritis (OA), two to four monthly injections are required for 6 months due the degradation of hyaluronic acid (HA) by peroxidative cleavage and hyaluronidase. However, frequent may lead local infection also cause inconvenience during COVID-19 pandemic. Herein, we developed a novel HA granular hydrogel (n-HA) improved resistance. The chemical structure, injectable capability, morphology, rheological properties, biodegradability, cytocompatibility n-HA were...

Phosphodiesterase-9 (PDE9) is a promising target for treatment of Alzheimer's disease (AD). To discover multifunctional anti-AD agents with capability PDE9 inhibition and antioxidant activity, series novel pyrazolopyrimidinone derivatives, coupling the pharmacophore antioxidants such as ferulic lipolic acids have been designed assistance molecular docking dynamics simulations. Twelve out 14 synthesised compounds inhibited PDE9A IC50 below 200 nM, showed good capacities in ORAC assay....

The pathological processes of Alzheimer's disease and type 2 diabetes mellitus have been demonstrated to be linked together. Both PDE9 inhibitors PPARγ agonists such as rosiglitazone exhibited remarkable preclinical clinical treatment effects for these two diseases. In this study, a series combining the pharmacophore were discovered. All compounds possessed affinities towards four them IC50 values <5 nmol/L. addition, showed low cell toxicity in human SH-SY5Y neuroblastoma cells. Compound...