Structure-Based Optimization of Moracin M as Potent and Selective PDE4 Inhibitors with Antipsoriasis Effects.

Psoriasis is a complex chronic inflammatory disease that severely affects the quality of life of patients. However, current medications could only control the symptoms but not cure psoriasis with unmet medical needs. Herein, structure-based optimizations of natural product moracin M (IC of 2.

Hydroxychavicol derivatives from Piper betle Linn. as natural PDE4 inhibitors with anti-inflammatory effects.

PDE4 inhibitors have been developed as anti-inflammatory medications primarily used in the clinical treatment of pulmonary inflammations such as asthma, chronic obstructive pulmonary disease, and idiopathic pulmonary fibrosis. However, the application of these drugs is usually restricted by obvious side effects, such as nausea and vomiting. Our previous study found that several natural PDE4 inhibitors or their modified derivatives showed minimal side effects, particularly reduced incidence of nausea and vomiting, which aroused our interest in searching for natural PDE4 inhibitors.

Glibenclamide targets MDH2 to relieve aging phenotypes through metabolism-regulated epigenetic modification.

Mitochondrial metabolism-regulated epigenetic modification is a driving force of aging and a promising target for therapeutic intervention. Mitochondrial malate dehydrogenase (MDH2), an enzyme in the TCA cycle, was identified as an anti-aging target through activity-based protein profiling in present study. The expression level of MDH2 was positively correlated with the cellular senescence in Mdh2 knockdown or overexpression fibroblasts.

5-hydroxymethylcytosine features of portal venous blood predict metachronous liver metastases of colorectal cancer and reveal phosphodiesterase 4 as a therapeutic target.

Metachronous liver metastases (MLM) are characterised by high incidence and high mortality in clinical colorectal cancer treatment. Currently traditional clinical methods cannot effectively predict and prevent the occurrence of metachronous liver metastasis in colorectal cancer. Based on 5hmC-Seal analysis of blood and tissue samples, this study found that portal venous blood was more relevant to tumour gDNA than peripheral blood.

Inhalable Carbonyl Sulfide Donor-Hybridized Selective Phosphodiesterase 10A Inhibitor for Treating Idiopathic Pulmonary Fibrosis by Inhibiting Tumor Growth Factor-β Signaling and Activating the cAMP/Protein Kinase A/cAMP Response Element-Binding Protein (CREB)/p53 Axis.

Idiopathic pulmonary fibrosis (IPF) is a debilitating, incurable, and life-threatening disease that lacks effective therapy. The overexpression of phosphodiesterase 10A (PDE10A) plays a vital role in pulmonary fibrosis (PF). However, the impact of selective PDE10A inhibitors on the tumor growth factor-β (TGF-β)/small mother against decapentaplegic (Smad) signaling pathway remains unclear.

Discovery of highly potent phosphodiesterase-1 inhibitors by a combined-structure free energy perturbation approach.

Accurate receptor/ligand binding free energy calculations can greatly accelerate drug discovery by identifying highly potent ligands. By simulating the change from one compound structure to another, the relative binding free energy (RBFE) change can be calculated based on the theoretically rigorous free energy perturbation (FEP) method. However, existing FEP-RBFE approaches may face convergence challenges due to difficulties in simulating non-physical intermediate states, which can lead to increased computational costs to obtain the converged results.

Discovery and optimization of 4-(imidazo[1,2-a]pyrimidin-3-yl)thiazol-2-amine derivatives as novel phosphodiesterase 4 inhibitors.

Phosphodiesterases (PDEs) are important intracellular enzymes that hydrolyze the second messengers cAMP and/or cGMP. Now several studies have shown that PDE4 received particular attention due to which it represents the most prominent cAMP-metabolizing enzyme involved in many diseases. In this study, we performed prescreening of our internal compound library and discovered the compound (PTC-209) with moderate PDE4 inhibitory activity (IC of 4.

Discovery of Oxidized -Terphenyls as Phosphodiesterase 4 Inhibitors from Marine-Derived Fungi.

Four new -terphenyl derivatives, talaroterphenyls A-D (-), together with three biosynthetically related known ones (-), were obtained from the mangrove sediment-derived sp. SCSIO 41412. Compounds - are rare -terphenyls, which are completely substituted on the central benzene ring by oxygen atoms; this is the first report of their isolation from natural sources.

Structural optimization of Moracin M as novel selective phosphodiesterase 4 inhibitors for the treatment of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and high mortality lung disease. Although the antifibrotic drugs pirfenidone and nintedanib could slow the rate of lung function decline, the usual course of the condition is inexorably to respiratory failure and death. Therefore, new approaches and novel therapeutic drugs for the treatment of IPF are urgently needed.

Design, Synthesis, and Evaluation of Dihydropyrimidine Derivatives as Selective PDE1 Inhibitors for the Treatment of Liver Fibrosis.

Liver fibrosis is a common pathological feature of most chronic liver diseases with no effective drugs available. Phosphodiesterase 1 (PDE1), a subfamily of the PDE super enzyme, might work as a potent target for liver fibrosis by regulating the concentration of cAMP and cGMP. However, there are few PDE1 selective inhibitors, and none has been investigated for liver fibrosis treatment yet.

Performance of ChatGPT on the Taiwan urology board examination: insights into current strengths and shortcomings.

Purpose: To compare ChatGPT-4 and ChatGPT-3.5's performance on Taiwan urology board examination (TUBE), focusing on answer accuracy, explanation consistency, and uncertainty management tactics to minimize score penalties from incorrect responses across 12 urology domains.

Methods: 450 multiple-choice questions from TUBE(2020-2022) were presented to two models.

In Vivo Intelligent Fluorescence Endo-Microscopy by Varifocal Meta-Device and Deep Learning.

Endo-microscopy is crucial for real-time 3D visualization of internal tissues and subcellular structures. Conventional methods rely on axial movement of optical components for precise focus adjustment, limiting miniaturization and complicating procedures. Meta-device, composed of artificial nanostructures, is an emerging optical flat device that can freely manipulate the phase and amplitude of light.

Inhibition of AKR1Cs by liquiritigenin and the structural basis.

In vivo and in vitro studies have confirmed that liquiritigenin (LQ), the primary active component of licorice, acts as an antitumor agent. However, how LQ diminishes or inhibits tumor growth is not fully understood. Here, we report the enzymatic inhibition of LQ and six other flavanone analogues towards AKR1Cs (AKR1C1, AKR1C2 and AKR1C3), which are involved in prostate cancer, breast cancer, and resistance of anticancer drugs.

Bioactive Polyketides and Benzene Derivatives from Two Mangrove Sediment-Derived Fungi in the Beibu Gulf.

To discover bioactive natural products from mangrove sediment-derived microbes, a chemical investigation of the two Beibu Gulf-derived fungi strains, sp. SCSIO 41050 and sp. SCSIO 41411, led to the isolation of 23 natural products.

Lung abscess with chronic cough secondary to xanthogranulomatous pyelonephritis: A rare case report.

Rationale: Xanthogranulomatous pyelonephritis (XGPN) is a form of chronic pyelonephritis caused by chronic calculus obstruction and bacterial infection, leading to the destruction of the renal parenchyma and calyces. Conservative treatment is usually not sufficient, and surgical intervention is still the main curative approach. XGPN with transdiaphragmatic extension and lung abscess formation is a rare condition.

Preoperative hydronephrosis is an independent protective factor of renal function decline after nephroureterectomy for upper tract urothelial carcinoma.

Objectives: To evaluate the predictive role of pre-nephroureterectomy (NU) hydronephrosis on post-NU renal function (RF) change and preserved eligibility rate for adjuvant therapy in patients with upper tract urothelial carcinoma (UTUC).

Patients And Methods: This retrospective study collected data of 1018 patients from the Taiwan UTUC Collaboration Group registry of 26 institutions. The patients were divided into two groups based on the absence or presence of pre-NU hydronephrosis.

Repeated vertebral compression fractures in young adult may imply functional adrenal tumor.

Background: Patients with adrenal Cushing's syndrome (ACS) typically present with central obesity, hirsutism, hypertension, or glucose intolerance, which can be easily identified by a clinical physician. However, recognizing those with subclinical CS or those with less common symptoms and signs is challenging to the subspecialist, which can lead to delayed diagnosis and treatment. We report a case who presented with repeated vertebral fractures in 6 months.

Diabetic Patients With Rosacea Increase the Risks of Diabetic Macular Edema, Dry Eye Disease, Glaucoma, and Cataract.

Purpose: Inflammation plays a role in diabetic eye diseases, but the association between rosacea and eye diseases in patients with diabetes remains unknown.

Design: This retrospective cohort study used claims data from the National Health Insurance Research Database in Taiwan to investigate the association between rosacea and eye diseases in patients with diabetes.

Materials And Methods: Taiwanese patients diagnosed as having diabetes mellitus between January 1, 1997, and December 31, 2013, and using any hypoglycemic agents were included and divided into rosacea and nonrosacea groups.

Novel Modular Spine Blocks Affect the Lumbar Spine on Finite Element Analysis.

Introduction: There are various surgical interventions to manage osteoporotic vertebral compression fracture. Modular spine block (MSB) is a novel intravertebral fixator that can be assembled. This study aimed to quantitatively investigate the force distribution in vertebrae with the various structural designs and implantation methods by finite element analysis (FEA).

Diffused bladder wall calcification in a survivor with severe coronavirus disease 2019: A case report.

Rationale: Bladder calcification is a rare presentation that was first interpreted to be related to a urea-splitting bacterial infection. Aside from infection, other hypotheses such as schistosomiasis, tuberculosis, cancer, and cytokine-induced inflammatory processes have also been reported. Severe coronavirus disease 2019 (COVID-19) is known for its provoking cytokine storm and uninhibited systematic inflammation, and calcification over the coronary artery or lung has been reported as a long-term complication.

Finite element analysis after rod fracture of the spinal hybrid elastic rod system.

Background: The spinal hybrid elastic (SHE) rod dynamic stabilization system can provide sufficient spine support and less adjacent segment stress. This study aimed to investigate the biomechanical effects after the internal fracture of SHE rods using finite element analysis.

Methods: A three-dimensional nonlinear finite element model was developed.

Discovery of novel PDE4 inhibitors targeting the M-pocket from natural mangostanin with improved safety for the treatment of Inflammatory Bowel Diseases.

Inflammatory Bowel Diseases (IBDs) are chronic disorders with iterative intestinal mucosal inflammation which remain unmet medical needs. PDE4 inhibitors were reported to be novel anti-IBD agents, but their clinical use was hampered by side effects such as emesis and nausea. Herein, structure-based discovery of natural mangostanin (1) targeting the M-pocket resulted in the novel and potent PDE4 inhibitor 22d (IC = 3.

Structure-based optimization of Toddacoumalone as highly potent and selective PDE4 inhibitors with anti-inflammatory effects.

Phosphodiesterase-4 (PDE4) is an important drug target for inflammatory diseases. Previously, we identified a series of novel PDE4 inhibitors derived from the natural Toddacoumalone, among which the hit compound 2 with a naphthyridine scaffold showed moderate potency with the IC value of 400 nM. Based on the co-crystal structure of PDE4D-2, further structural optimizations and structure-activity relationship studies led to a highly potent PDE4 inhibitor 23a with the IC value of 0.

Free energy perturbation (FEP)-guided scaffold hopping.

Scaffold hopping refers to computer-aided screening for active compounds with different structures against the same receptor to enrich privileged scaffolds, which is a topic of high interest in organic and medicinal chemistry. However, most approaches cannot efficiently predict the potency level of candidates after scaffold hopping. Herein, we identified potent PDE5 inhibitors with a novel scaffold a free energy perturbation (FEP)-guided scaffold-hopping strategy, and FEP shows great advantages to precisely predict the theoretical binding potencies Δ between ligands and their target, which were more consistent with the experimental binding potencies Δ (the mean absolute deviations  < 2 kcal/mol) than those Δ or Δ predicted by the MM-PBSA or MM-GBSA method.

Discovery of catalytic-site-fluorescent probes for tracing phosphodiesterase 5 in living cells.

Small molecule fluorescent probes provide a powerful labelling technology to enhance our understanding of particular proteins. However, the discovery of a proper fluorescent probe for detecting PDE5 is still a challenge due to the highly conservative structure of the catalytic domain in the phosphodiesterase (PDE) families. Herein, we identified probes based on the key amino residues in the ligand binding pocket of PDE5 and catalytic-site-fluorescent probes PCO2001-PCO2003 were well designed and synthesized.