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 (IC50 of 4.78 ± 0.08 µM). And a series of 4-(imidazo[1,2-a]pyrimidin-3-yl)thiazol-2-amine derivatives as novel PDE4 inhibitors starting from PTC-209 were successfully designed and synthesized using a structure-based discovery strategy. L19, the most potent inhibitor, exhibited good inhibitory activity (IC50 of 0.48 ± 0.02 µM) and remarkable metabolic stability in rat liver microsomes. Our study presents an example of discovery novel PDE4 inhibitors, which would be helpful for design and optimization of novel inhibitors in future.

Exploring the Potential Effects and Mechanism of Astragalus Membranaceus in Treating Ischemic Heart Failure Based on Network Pharmacology and Experimental Verification.

BACKGROUND: Astragalus membranaceus (AM) is a traditional Chinese medicine that has been clinically utilized as an adjunctive therapy for the treatment of myocardial ischemia and heart failure; however, its precise molecular mechanism of action remains unknown. OBJECTIVE: This study aims to investigate the potential pharmacological effects and molecular mechanism of AM in the treatment of ischemic heart failure (IHF) using network pharmacology methods, molecular docking technology, and in vitro experiments. METHODS: The active components and targets of AM were obtained from the TCMSP databases, while the disease targets of IHF were retrieved from GeneCards and OMIM databases. The analysis of overlapping targets between AM and IHF mainly included active compounds-targets network, PPI network, and GO and KEGG enrichment analysis. The association between active compounds and target proteins was verified through molecular docking. Additionally, an in vitro experimental model was used to evaluate the accuracy of the forecast results. RESULTS: The network pharmacological analysis revealed that quercetin, kaempferol, 7-Omethylisomucronulatol, formononetin, and isorhamnetin were the core active components of AM in treating IHF. The core targets included AKT1, IL6, IL1B, PTGS2, CASP3, MMP9, and HIF1A. The molecular docking results demonstrated a strong binding affinity between these active components and targets. The KEGG pathway analysis suggested that the PI3K-AKT signaling pathway might play a central role in mediating AM's therapeutic effects on IHF. In vitro experiments demonstrated that AM treatment enhanced cell viability, reduced heart failure biomarkers, and suppressed cell apoptosis. Furthermore, the western blot analyses indicated that AM treatment effectively regulated AKT1 phosphorylation in an experimental model of IHF. CONCLUSION: Through integrated network pharmacological analysis, molecular docking technology, and in vitro experimental validation, it was demonstrated that AM can effectively mitigate IHF through activating PI3K-AKT signaling pathway. These findings significantly advance our understanding of the molecular mechanisms in IHF treatment and contribute further to promoting the clinical application of AM.

Convergence-Adaptive Roundtrip Method Enables Rapid and Accurate FEP Calculations.

The free energy perturbation (FEP) method is a powerful technique for accurate binding free energy calculations, which is crucial for identifying potent ligands with a high affinity in drug discovery. However, the widespread application of FEP is limited by the high computational cost required to achieve equilibrium sampling and the challenges in obtaining converged predictions. In this study, we present the convergence-adaptive roundtrip (CAR) method, which is an enhanced adaptive sampling approach, to address the key challenges in FEP calculations, including the precision-efficiency tradeoff, sampling efficiency, and convergence assessment. By employing on-the-fly convergence analysis to automatically adjust simulation times, enabling efficient traversal of the important phase space through rapid propagation of conformations between different states and eliminating the need for multiple parallel simulations, the CAR method increases convergence and minimizes computational overhead while maintaining calculation accuracy. The performance of the CAR method was evaluated through relative binding free energy (RBFE) calculations on benchmarks comprising four diverse protein-ligand systems. The results demonstrated a significant speedup of over 8-fold compared to conventional FEP methods while maintaining high accuracy. The overall R2 values of 0.65 and 0.56 were obtained using the combined-structure FEP approach and the single-step FEP approach, respectively, in conjunction with the CAR method. In-depth case studies further highlighted the superior performance of the CAR method in terms of convergence acceleration, improved predicted correlations, and reduced computational costs. The advancement of the CAR method makes it a highly effective approach, enhancing the applicability of FEP in drug discovery.

Peteryoungia algae sp. nov. isolated from seaweeds of Gouqi Island, China, and its unique genetic features among Peteryoungia strains.

A Gram-stain-negative, light khaki, strictly aerobic, rod-shaped, motile via multiple flagella, and catalase- and oxidase-positive bacterium, designated as SSM4.3T, was isolated from the seaweed of Gouqi Island in the East China Sea. The novel isolate grows at 0-5.0% NaCl concentrations (w/v) (optimum 1%), pH 5.0-9.0 (optimum pH 7.0), and 15-37 °C (optimum 30 °C). The 16S rRNA gene sequences-based phylogeny indicates that the novel marine isolate belongs to the family Rhizobiaceae and that it shared the greatest sequence similarity (98.9%) with Peteryoungia rhizophila CGMCC 1.15691T. This classification was also supported by phylogenetic analysis using core genes. The predominant fatty acids (≥ 10%) of the strain were identified as C18:1 ω7c/C18:1 ω6c. Q-10 was identified as the major isoprenoid quinone, with trace levels of Q-9 present. The major polar lipids were identified as diphosphatidylglycerol, phosphatidylethanolamine and phosphatidylglycerol. The complete genome size of strain SSM4.3T is 4.39 Mb with a DNA G+C content of 61.3%. The average nucleotide identity, digital DNA-DNA hybridization, and average amino acid identity values between the genomes of strain SSM4.3T and its closely related representatives were 74.80-86.93%, 20.00-32.30%, and 70.30-91.52%, respectively. Phylogenetic analysis, grounded on the core genes, reveals the evolutionary relationship between SSM4.3T and other Peteryoungia strains. Pan-genomics analysis of 8 previously classified Peteryoungia species and SSM4.3T revealed their unique genetic features and functions. Overall, strain SSM4.3T was considered to be a new species of the Peteryoungia genus; the name Peteryoungia algae sp. nov. has been proposed, with type strain SSM4.3T (= LMG 32561 = MCCC 1K07170).

Effect of neoadjuvant chemoradiotherapy with or without PD-1 antibody sintilimab in pMMR locally advanced rectal cancer: A randomized clinical trial.

Neoadjuvant chemoradiotherapy (NACRT) was the standard treatment for patients with locally advanced rectal cancer (LARC) with proficient mismatch repair (pMMR) proteins. In this randomized phase 2 trial (ClinicalTrial.gov: NCT04304209), 134 pMMR LARC patients were randomly (1:1) assigned to receive NACRT or NACRT and the programmed cell death protein 1 (PD-1) antibody sintilimab. As the primary endpoint, the total complete response (CR) rate is 26.9% (18/67, 95% confidence interval [CI] 16.0%-37.8%) and 44.8% (30/67, 95% CI 32.6%-57.0%) in the control and experimental arm, respectively, with significant difference (p = 0.031 for chi-squared test). Response ratio is 1.667 (95% CI 1.035-2.683). Immunohistochemistry shows PD-1 ligand 1 (PD-L1) combined positive score is associated with the synergistic effect. The safety profile is similar between the arms. Adding the PD-1 antibody sintilimab to NACRT significantly increases the CR rate in pMMR LARC, with a manageable safety profile. PD-L1 positivity may help identify patients who might benefit most from the combination therapy.

[Study on fatigue resistance of mechanical nickel-titanium files by phase-locked infrared flaw detection method].

PURPOSE: The movement trend of the posterior teeth and the distribution of the periodontal membrane stress were studied by using three-dimensional digital technology. METHODS: CBCT data of 88 patients admitted to our hospital from June 2017 to June 2022 were selected, and input into Mimics20.0 software for preliminary extraction of all parts and stored with STL files; then the data were repaired and optimized through Geomagic Studio 2014 software. With the help of normal phase extension, the invisible appliance and periodontal membrane were constructed. Finally, the six FEM models were simulated and observed by the current teeth in different groups. Statistical analysis was performed with SPSS 21.0 software package. RESULTS: The effect force of the largest periodontal membrane was distributed in the neck of the tooth, followed by the apical area, with the maximum effect force value in the NA group. In all accessory groups, the periodontal membrane maximum paradigm isoeffect force values of all patients in the accessory vertical rectangular group were significantly smaller than the values obtained in the horizontal rectangular group. CONCLUSIONS: The design of orthodontic tooth accessories has a strong inhibition effect on the position movement of anterior teeth during recovery, which improves the accuracy of tooth three-dimensional movement to a certain extent. Meanwhile, the normal equivalent stress of the periodontal membrane of patients in the initial application of the invisible appliance without brackets is large.

Characterization and Genomic Analysis of Affinirhizobium gouqiense sp. nov. Isolated from Seawater of Gouqi Island Located in the East China Sea and Reclassification of Rhizobium lemnae to the Genus Affinirhizobium as Affinirhizobium lemnae comb. nov.

A novel bacterium designated as SSA5.23T was isolated from seawater. Cells of SSA5.23T are Gram-stain-negative, short, rod-shaped, and exhibit motility via numerous peritrichous flagella. The strain could grow at temperatures ranging from 15 to 35 °C (optimum at 25 °C), in a salinity range of 0-5.0% (w/v) NaCl, and within a pH range of 6.0-9.0 (optimum at pH 7.0). The predominant cellular fatty acid of SSA5.23T was C18:1 ω7c/C18:1 ω6c, and the major respiratory quinones were Q-9 and Q-10. Diphosphatidylglycerol, phosphatidylethanolamine, and phosphatidylglycerol were identified as the primary polar lipids. The complete genome (5.47 Mb) of SSA5.23T comprises of a circular chromosome of 3.64 Mb and three plasmids, specifically sized at 59.73 kb, 227.82 kb, and 1.54 Mb, respectively. Certain genes located on the plasmids play roles in denitrification, oxidative stress resistance, and osmotic tolerance, which likely contribute to the adaptability of this strain in marine conditions. Core-proteome average amino acid identity analysis effectively identified the strain's affiliation with the genus Affinirhizobium, showing the highest value (89.9%) with Affinirhizobium pseudoryzae DSM 19479T. This classification was further supported by the phylogenetic analysis of concatenated alignment of 170 single-copy orthologous proteins. When compared to related reference strains, SSA5.23T displayed an average nucleotide identity ranging from 74.9 to 80.3% and digital DNA-DNA hybridization values ranging from 19.9 to 23.9%. Our findings confirmed that strain SSA5.23T represents a novel species of the genus Affinirhizobium, for which the name Affinirhizobium gouqiense sp. nov. (type strain SSA5.23T = LMG 32560T = MCCC 1K07165T) was suggested.

Structural properties and antioxidant capacity of different aminated starch-phenolic acid conjugates.

Different aminated starch (AS) [EEAS (introducing ethylenediamine into starch using cross-linking-etherification-amination method (CEA)), EPAS (introducing o-phenylenediamine using CEA), OEAS (introducing ethylenediamine using cross-linking-oxidation-amination method (COA)), and OPAS (introducing o-phenylenediamine using COA)] were synthesized. The AS-phenolic acids [gallic acid (GA), syringic acid (SA), and vanillic acid (VA)] conjugates were prepared by laccase-catalyzed reaction. The grafting efficiency of EEAS on GA, SA, and VA was 36.59%, 69.71%, and 68.85%, respectively. SA reduced the maximum depolymerization rate of EEAS. The relative crystallinity of EEAS and EPAS grafted phenolic acid increased, and their particles showed severe breakage in appearance. OEAS-phenolic acid conjugates lost its granular structure and behaved as flakes and lumps, while the surface of OPAS-phenolic acid conjugates remained smooth after grafting phenolic acid. GA increased the DPPH· scavenging efficiency of EEAS from 16.12% to 79.92%. The increased antioxidant capacity of the conjugates suggested that AS-phenolic acids conjugates have high potential for applications.

Factors influencing further vertebral height loss following percutaneous vertebroplasty in osteoporotic vertebral compression fractures: A 1-year follow-up study.

BACKGROUND: Osteoporotic vertebral compression fractures (OVCFs) contribute to back pain and functional limitations in older individuals, with percutaneous vertebroplasty (PVP) emerging as a minimally invasive treatment. However, further height loss post-PVP prompts investigation into contributing factors. AIM: To investigate the factors associated with further height loss following PVP with cement augmentation in OVCF patients. METHODS: A total of 200 OVCF patients who underwent successful PVP between January 2021 and December 2022 were included in this study. "Further height loss" during 1 year of follow-up in OVCF patients with bone edema was defined as a vertical height loss of ≥ 4 mm. The study population was divided into two groups for analysis: The "No Further Height Loss group (n = 179)" and the "Further Height Loss group (n = 21)." RESULTS: In comparing two distinct groups of patients, significant differences existed in bone mineral density (BMD), vertebral compression degree, prevalence of intravertebral cleft (IVF), type of bone cement used, and cement distribution patterns. Results from binary univariate regression analysis revealed that lower BMD, the presence of IVF, cleft distribution of bone cement, and higher vertebral compression degree were all significantly associated with further height loss. Notably, the use of mineralized collagen modified-poly(methyl methacrylate) bone cement was associated with a significant reduction in the risk of further height loss. In multivariate regression analysis, lower BMD and the presence of IVF remained significantly associated with further height loss. CONCLUSION: Further height loss following PVP in OVCF patients is influenced by a complex interplay of factors, especially lower BMD and the presence of IVF. These findings underscore the importance of assessing and managing these factors when addressing height loss following PVP in OVCF patients.

Is preoperative IABP insertion significantly reducing postoperative complication in augmented high-risk coronary artery bypass grafting patients?

BACKGROUND: The aim of this study was to determine whether pre-operative intra-aortic balloon pump (IABP) insertion improves surgical outcomes in high-risk coronary artery bypass grafting (CABG) patients. METHODS: Patients with a EuroSCORE II greater than 1.2% who underwent CABG from 2009 to 2016 were included in the study, while those who utilized intra-operative or post-operative IABP were excluded. The analysis included a total of 2907 patients, with 377 patients undergoing preoperative IABP insertion (EuroSCORE II > 5.018%) and 1198 patients in the non-IABP group before matching; after propensity score matching (PSM), both groups consisted of a matched cohort of 250 patients. RESULTS: 30-day mortality events occurred in 9 (3.6%) non-IABP group and in 12 (4.8%) IABP patients (OR: 1.33 95%CI: 0.52-3.58). Kaplan-Meier survival curve analysis showed no significant differences between the two groups in mortality up to one year after the operation (p = 0.72). On multivariate analysis, IABP usage among the PSM patients was associated with lower 30-day mortality (OR: 0.28, 95%CI: 0.07-0.92, P-value = 0.043), 90-day mortality (OR: 0.26, 95%CI: 0.08-0.78, P-value = 0.022) and reduced risk of developing severe respiratory disorders (OR: 0.10, 95%CI:0.01-0.50, P-value = 0.011). CONCLUSION: Pre-operative IABP use in high-risk patients reduces 30- and 90-day mortality rates, along with a notable decrease in rates of severe respiratory disorders.

Ergone Derivatives from the Deep-Sea-Derived Fungus Aspergillus terreus YPGA10 and 25,28-Dihydroxyergone-Induced Apoptosis in Human Colon Cancer SW620 Cells.

Ten new ergone derivatives (1-10) and five known analogues (11-15) were isolated from the deep-sea-derived fungus Aspergillus terreus YPGA10. The structures including the absolute configurations were established by detailed analysis of the NMR spectroscopic data, HRESIMS, ECD calculation, and coupling constant calculation. All the structures are characterized by a highly conjugated 25-hydroxyergosta-4,6,8(14),22-tetraen-3-one nucleus. Structurally, compound 2 bearing a 15-carbonyl group and compounds 5-7 possessing a 15ß-OH/OCH3 group are rarely encountered in ergone derivatives. Bioassay results showed that compounds 1 and 11 demonstrated cytotoxic effects on human colon cancer SW620 cells with IC50 values of 8.4 and 3.1 µM, respectively. Notably, both compounds exhibited negligible cytotoxicity on the human normal lung epithelial cell BEAS-2B. Compound 11 was selected for preliminary mechanistic study and was found to inhibit cell proliferation and induce apoptosis in human colon cancer SW620 cells. In addition, compound 1 displayed cytotoxic activity against five human leukemia cell lines with IC50 values ranging from 5.7 to 8.9 µM. Our study demonstrated that compound 11 may serve as a potential candidate for the development of anticolorectal cancer agents.

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

Four new p-terphenyl derivatives, talaroterphenyls A-D (1-4), together with three biosynthetically related known ones (5-7), were obtained from the mangrove sediment-derived Talaromyces sp. SCSIO 41412. Compounds 1-3 are rare p-terphenyls, which are completely substituted on the central benzene ring by oxygen atoms; this is the first report of their isolation from natural sources. Their structures were elucidated through NMR spectroscopy, HRESIMS, and X-ray diffraction. Genome sequence analysis revealed that 1-7 were biosynthesized from tyrosine and phenylalanine, involving four key biosynthetic genes (ttpB-ttpE). These p-terphenyls (1-7) and 36 marine-derived terphenyl analogues (8-43) were screened for phosphodiesterase 4 (PDE4) inhibitory activities, and 1-5, 14, 17, 23, and 26 showed notable activities with IC50 values of 0.40-16 µM. The binding pattern of p-terphenyl inhibitors 1-3 with PDE4 were explored by molecular docking analysis. Talaroterphenyl A (1), with a low cytotoxicity, showed obvious anti-inflammatory activity in LPS-stimulated RAW264.7 cells. Furthermore, in the TGF-ß1-induced medical research council cell strain-5 (MRC-5) pulmonary fibrosis model, 1 could down-regulate the expression levels of FN1, COL1, and α-SMA significantly at concentrations of 5-20 µM. This study suggests that the oxidized p-terphenyl 1, as a marine-derived PDE4 inhibitor, could be used as a promising antifibrotic agent.

Regulation of Burkholderia cenocepacia virulence by the fatty acyl-CoA ligase DsfR as a response regulator of quorum sensing signal.

Quorum sensing (QS) is a cell-to-cell communication mechanism mediated by small diffusible signaling molecules. Previous studies showed that RpfR controls Burkholderia cenocepacia virulence as a cis-2-dodecenoic acid (BDSF) QS signal receptor. Here, we report that the fatty acyl-CoA ligase DsfR (BCAM2136), which efficiently catalyzes in vitro synthesis of lauryl-CoA and oleoyl-CoA from lauric acid and oleic acid, respectively, acts as a global transcriptional regulator to control B. cenocepacia virulence by sensing BDSF. We show that BDSF binds to DsfR with high affinity and enhances the binding of DsfR to the promoter DNA regions of target genes. Furthermore, we demonstrate that the homolog of DsfR in B. lata, RS02960, binds to the target gene promoter, and perception of BDSF enhances the binding activity of RS02960. Together, these results provide insights into the evolved unusual functions of DsfR that control bacterial virulence as a response regulator of QS signal.

Novel inflammatory and insulin resistance indices provide a clue in cerebral amyloid angiopathy.

This study investigated the correlation of newly identified inflammatory and insulin resistance indices with cerebral amyloid angiopathy (CAA), and explored their potential to differentiate CAA from hypertensive arteriopathy (HA). We retrospectively analyzed 514 consecutive patients with cerebral small vessel disease (CSVD)-related haemorrhage, comparing the differences in novel inflammatory and insulin resistance indices between patients with CAA and HA. Univariate regression, LASSO and multivariate regression were used to screen variables and construct a classification diagnosis nomogram. Additionally, these biomarkers were explored in patients with mixed haemorrhagic CSVD. Inflammatory indices were higher in CAA patients, whereas insulin resistance indices were higher in HA patients. Further analysis identified neutrophil-to-lymphocyte ratio (NLR, OR 1.17, 95% CI 1.07-1.30, P < 0.001), and triglyceride-glucose index (TyG, OR = 0.56, 95% CI 0.36-0.83, P = 0.005) as independent factors for CAA. Therefore, we constructed a CAA prediction nomogram without haemorrhagic imaging markers. The nomogram yielded an area under the curve (AUC) of 0.811 (95% CI 0.764-0.865) in the training set and 0.830 (95% CI 0.718-0.887) in the test set, indicating an ability to identify high-risk CAA patients. These results show that CSVD patients can be phenotyped using novel inflammatory and insulin resistance indices, potentially allowing identification of high-risk CAA patients without haemorrhagic imaging markers.

Functional Characterization of the MeSSIII-1 Gene and Its Promoter from Cassava.

Soluble starch synthases (SSs) play important roles in the synthesis of cassava starch. However, the expression characteristics of the cassava SSs genes have not been elucidated. In this study, the MeSSIII-1 gene and its promoter, from SC8 cassava cultivars, were respectively isolated by PCR amplification. MeSSIII-1 protein was localized to the chloroplasts. qRT-PCR analysis revealed that the MeSSIII-1 gene was expressed in almost all tissues tested, and the expression in mature leaves was 18.9 times more than that in tuber roots. MeSSIII-1 expression was induced by methyljasmonate (MeJA), abscisic acid (ABA), and ethylene (ET) hormones in cassava. MeSSIII-1 expression patterns were further confirmed in proMeSSIII-1 transgenic cassava. The promoter deletion analysis showed that the -264 bp to -1 bp MeSSIII-1 promoter has basal activity. The range from -1228 bp to -987 bp and -488 bp to -264 bp significantly enhance promoter activity. The regions from -987 bp to -747 bp and -747 bp to -488 bp have repressive activity. These findings will provide an important reference for research on the potential function and transcriptional regulation mechanisms of the MeSSIII-1 gene and for further in-depth exploration of the regulatory network of its internal functional elements.

Inhibition of SENP5 reduces brain injury in TBI rats by regulating NEDD4L/TCF3 axis.

BACKGROUND: The underlying mechanism of SENP5 influences neuronal regeneration and apoptosis in the context of TBI remains largely unexplored. METHODS: In the present study, PC12 cells treated with scratch for 24 h were regarded as a TBI cell model. The expression of SENP5 in PC12 cells was measured via Quantitative Real-Time PCR (qRT-PCR) and western blot assays. Cell Counting Kit 8 (CCK-8) and Flow cytometry assays were used to evaluate the activity of TBI cells. In addition, we assessed the effect of inhibiting SENP5 in vivo on neurological function deficits and apoptosis in the hippocampal tissues of TBI rats. The relationship between SENP5 and NEDD4L/TCF3 axis was proved via immunoprecipitation (IP) and double luciferase assays. RESULTS: Following TBI cell modeling, an increase in SENP5 expression has been found. Moreover, TBI modeling resulted in reduced cell viability and increased apoptosis, which was rescue by inhibition of SENP5. In vivo experiments demonstrated that SENP5 inhibition could mitigate TBI-induced brain injury in rats. Specifically, this inhibition led to lower neurological impairment scores, improved neuronal morphology and structure, and decreased neuronal apoptosis. In addition, NEDD4L has been proved to be relevant to the enhanced stability of the transcription factor TCF3, which in turn promoted the expression of SENP5. CONCLUSIONS: This study reveals that inhibiting SENP5 can alleviate brain injury following TBI. NEDD4L/TCF3 axis can regulate the expression of SENP5 to affect the development of TBI. However, SENP5 regulates downstream targets of TBI and important mechanisms need to be further explored.

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. And the selective PDE4 inhibitor has in vivo and in vitro anti-fibrotic effects in IPF models. But the clinical application of most PDE4 inhibitors are limited by their unexpected and severe side effects such as nausea, vomiting, and diarrhea. Herein, structure-based optimizations of the natural product Moracin M resulted in a novel a novel series of 2-arylbenzofurans as potent PDE4 inhibitors. The most potent inhibitor L13 has an IC50 of 36 ± 7 nM with remarkable selectivity across the PDE families and administration of L13·citrate (10.0 mg/kg) exhibited comparable anti-pulmonary fibrosis effects to pirfenidone (300 mg/kg) in a bleomycin-induced IPF mice model, indicate that L13 is a potential lead for the treatment of IPF.

Serum procalcitonin as a marker of neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD).

BACKGROUND: Neonatal Intrahepatic Cholestasis (NICCD), as the early-age stage of Citrin deficiency involving liver dysfunction, lacks efficient diagnostic markers. Procalcitonin (PCT) has been identified as a biomarker for infection as well as various organ damage. This study aimed to explore the potential of PCT as a biomarker for NICCD. METHODS: In a single-center retrospective case-control study. Serum PCT concentrations before and after treatment of 120 NICCD patients, as the study group, were compared to the same number of cholestatic hepatitis patients, as the control group. The potential value of PCT to discriminate NICCD from control disease was further explored using Receiver Operating Characteristic (ROC) curve analysis and compared to those of other inflammatory markers. RESULTS: There was a significantly higher level of PCT in NICCD patients than in the control group. PCT concentrations were only weakly correlated with neutrophil counts and CRP levels (p ˂ 0.05). At a cut-off value of 0.495 ng/mL, PCT exhibited a significantly higher diagnostic value compared to other inflammatory markers for discriminating NICCD from the control, with a sensitivity of 90.8 % and specificity of 98.3 %. CONCLUSION: PCT might be used as an initial biomarker to discriminate children with NICCD from another hepatitis disease.

Antifungal Activity and Mechanism of Camphor Derivatives against Rhizoctonia solani: A Promising Alternative Antifungal Agent for Rice Sheath Blight.

Rice sheath blight, caused by the fungus Rhizoctonia solani, poses a significant threat to rice cultivation globally. This study aimed to investigate the potential mechanisms of action of camphor derivatives against R. solani. Compound 4o exhibited superior fungicidal activities in vitro (EC50 = 6.16 mg/L), and in vivo curative effects (77.5%) at 500 mg/L were significantly (P < 0.01) higher than the positive control validamycin·bacillus (66.1%). Additionally, compound 4o exhibited low cytotoxicity and acute oral toxicity for adult worker honeybees of Apis mellifera L. Mechanistically, compound 4o disrupted mycelial morphology and microstructure, increased cell membrane permeability, and inhibited both PDH and SDH enzyme activities. Molecular docking and molecular dynamics analyses indicated a tight interaction of compound 4o with PDH and SDH active sites. In summary, compound 4o exhibited substantial antifungal efficacy against R. solani, serving as a promising lead compound for further optimization of antifungal agents.

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. Herein, compound AG-205/1186117 with the dihydropyrimidine scaffold was selected as the hit by virtual screening. A hit-to-lead structural modification led to a series of dihydropyrimidine derivatives. Lead 13h exhibited the IC50 of 10 nM against PDE1, high selectivity over other PDEs, as well as good safety properties. Administration of 13h exerted significant anti-liver fibrotic effects in bile duct ligation-induced fibrosis rats, which also prevented TGF-ß-induced myofibroblast differentiation in vitro, confirming that PDE1 could work as a potential target for liver fibrosis.