Search Results (123)

Traumatic injury remains a critical global health challenge, with polytrauma frequently leading to multi-organ failure and mortality. A severe complication of polytrauma is acute kidney injury (AKI), which is driven by a massive systemic inflammatory response following the initial insult. This inflammation is exacerbated by the upregulation of phosphodiesterase 4 (PDE4) enzymes; therefore, PDE4 inhibition represents a rational therapeutic strategy. Roflumilast is an FDA-approved PDE4 inhibitor currently used for chronic obstructive pulmonary disease (COPD). This study evaluated the hypothesis that roflumilast can mitigate inflammation and prevent AKI in a polytrauma rat model. Anesthetized male Sprague–Dawley rats were randomly assigned to either a vehicle control group (n = 9) or a roflumilast treatment group (0.2 mg/kg, n = 10). All animals underwent a polytrauma protocol—including soft tissue injury, fibula fracture, and pressure-controlled hemorrhage—followed by whole blood resuscitation and a 72-h observation period. Rats treated with roflumilast demonstrated higher survival rates compared to injury controls (70% vs. 33%). Furthermore, roflumilast treatment significantly lowered blood urea nitrogen (BUN, p < 0.05) and renal levels of Kidney Injury Molecule-1 (KIM-1, p < 0.05). Roflumilast also significantly reduced levels of circulating High Mobility Group Box 1 (HMGB1) (p < 0.05) and the proinflammatory cytokine macrophage inflammatory protein-1 alpha (MIP-1α) (p < 0.05). These findings suggest that roflumilast is a promising therapeutic agent for mitigating trauma-induced AKI. Full article

Physics-informed neural networks (PINNs) approximate partial differential equations (PDEs) by enforcing governing equations and boundary conditions during training, but their accuracy depends on how collocation points are distributed and updated. We propose spatiotemporal compositional active sampling (STCAS), a reference-assisted offline configuration procedure that uses an analytic or high-accuracy numerical solution to rank complete three-stage sampling plans. It screens eight fixed rules, forms a task-specific shortlist, and evaluates bounded fixed, switched, and locally blended plans with independent selection sets and a composition guard. A safety-anchor decision retains the standard PINN unless the selected candidate is at least 5% better. Across five evaluations on 18 analytically specified two-dimensional Poisson tasks, this protocol improves 16 task means and ties two, reducing aggregate relative-$L_2$ error by 12.8% (hierarchical-bootstrap 95% interval $[6.78\%,19.32\%]$; one-sided paired Wilcoxon $p=2.19\times {10}^{-4}$). Against the confirmed fixed plan, aggregate error decreases by 8.2%. In comparison experiments designed for two transfer tasks and matched for main PINN training budgets, STCAS achieves the lowest aggregate mean reported error among the compared methods for both a steady convection–diffusion equation and a nonlinear time-dependent Burgers equation; its offline search cost is additional. Full article

Organic phosphorus (OP) transformation in perennial orchard soils is strongly regulated by planting duration. However, the pathways of soil OP turnover in the orchards with different planting years remain largely unknown. This study was conducted in Penglai District, Shandong Province, China, characterized by a warm-temperate continental monsoon climate and brown sandy loam soil. Soil samples were collected from the 0–20 cm layer of vineyards established for 0.5, 4, 16, and 22 years (Y0.5, Y4, Y16, and Y22, respectively). Soil P pools, OP forms determined by solution ³¹P nuclear magnetic resonance spectroscopy, acid and alkaline phosphomonoesterase (ACP and ALP), phosphodiesterase (PDE) activities, and the diversity and composition of phoC- and phoD-harboring bacterial communities were analyzed. Differences among vineyard ages were assessed using one-way ANOVA, while principal coordinate analysis, canonical correlation analysis, and structural equation modeling were employed to evaluate microbial community variation and the relationships among soil properties, functional bacterial communities, phosphatase activities, and OP forms. We observed that compared with that in Y0.5, total P content in Y4 was significantly lower, whereas available P (AP) content in Y16, and OP content in both Y16 and Y22, were significantly higher. The contents of orthophosphate, myo-inositol hexakisphosphate (myo-IHP), scyllo-IHP, choline phosphate and corrected monoester (cMonoester) in Y16 and Y22 were significantly higher than that in Y0.5. Soil ACP activity in Y16 was significantly higher than that in Y4, but ALP and PDE activities in Y16 were significantly lower than those in other planting years. The phoC- and phoD-harboring community composition in Y16 was significantly altered, with phoC- and phoD-harboring community α-diversity remarkably increased and decreased, respectively. The phoC- and phoD-harboring community composition was driven by soil pH, AP and cMonoester, with phoD-harboring community composition predicted by the soil C:P ratio. Soil OP transformation is mainly regulated by the activity of PDE and ACP, and the diversity and composition of phoC-harboring communities, in orchards with different planting years. Full article

The lack of effective anti-fibrotic agents remains a significant unmet need in the treatment of intestinal fibrosis, a condition largely driven by transforming growth factor-β1 (TGF-β1)-mediated myofibroblast activation. Phosphodiesterase 4 (PDE4) inhibitors, known to increase intracellular cAMP levels, exhibit anti-inflammatory and potential anti-fibrotic properties, though their efficacy in intestinal fibrosis is poorly defined. In this study, we investigated the anti-fibrotic effects and underlying mechanisms of PDE4 inhibitors (rolipram, roflumilast, piclamilast, and mesopram) in human intestinal myofibroblasts (HIMFs) stimulated with TGF-β1. All PDE4 inhibitors significantly reduced TGF-β1-induced mRNA expression of collagen1A1 (COL1A1) and fibronectin (FN1), with mesopram additionally reducing α-smooth muscle actin (ACTA2) mRNA expression. At the protein level, however, only roflumilast significantly decreased procollagen1A1 (Procol1A1) and FN expression. Mechanistically, roflumilast, rolipram, and mesopram significantly reduced serum response factor (SRF) mRNA expression, whereas piclamilast and mesopram significantly inhibited myocardin-related transcription factor A (MRTFA) mRNA expression. Rolipram and roflumilast exhibited a decreasing trend in MRTFA mRNA expression without statistical significance. Notably, roflumilast demonstrated superior inhibitory effects, significantly decreasing both MRTF-A and SRF protein expression and effectively reducing nuclear localization of MRTF-A. Additionally, rolipram and roflumilast significantly attenuated TGF-β1-induced phosphorylation of Smad2. These findings indicate that PDE4 inhibitors, particularly roflumilast, effectively suppress TGF-β1-induced fibrogenic activation in HIMFs by modulating MRTF/SRF and Smad-dependent pathways, highlighting the value of roflumilast for further preclinical investigation as a potential therapeutic strategy for intestinal fibrosis. Full article

A novel class of resveratrol derivatives as dual PDE4 (Phosphodiesterase 4) inhibitors and free radical scavengers for the treatment of COPD (chronic obstructive pulmonary disease) was developed in this study. In vitro, the most promising compound WYZ69 showed similar PDE4 inhibitory activity and anti-inflammatory activity to rolipram and better DPPH free radical scavenging ability and anti-lipid peroxidative activity than edaravone. In addition, compound WYZ69 turned out to be a novel ferroptosis inhibitor, which significantly inhibited ferroptosis as a free radical scavenger, decreased the levels of ROS (reactive oxygen species), increased the expression of GPX4 (Glutathione peroxidase 4), and decreased the expression of transferrin in A549 cells induced by a ferroptosis activator, RSL3 ((1S,3R)-RSL3). In vivo, it exhibited a half-life of 1.63 h in mice and moderate anti-inflammatory activity in mice induced by LPS (Lipopolysaccharide). Hence, these findings suggest that compound WYZ69 is a promising dual PDE4 inhibitor and free radical scavenger with anti-inflammatory and anti-ferroptosis activities for the treatment of COPD. Full article

We study a special case of the extended Korteweg–de Vries (eKdV) equation, arising in the description of weakly nonlinear long waves with higher-order dispersive effects. The model incorporates both third- and fifth-order dispersion and quadratic nonlinearity and describes steeper and shorter waves than the classical KdV equation. First, we determine the Lie point symmetry algebra of the equation and show that it reduces to space–time translations, which in turn motivates a traveling-wave reduction. The reduced fifth-order ODE is then analyzed by means of a calibrated $(G^{\prime }/G)$-expansion ansatz. Although homogeneous balance suggests a degree $M=4$ for exact solutions, a degree-$M=2$ truncation already yields three coherent families of traveling waves—hyperbolic (solitary), trigonometric (periodic), and rational—distinguished by the discriminant of the auxiliary linear equation. Using the direct multiplier method, we construct four conservation laws, corresponding to mass, momentum, energy, and a higher-order dispersion invariant, with all ${\alpha }^2$ contributions retained. Direct substitution and numerical diagnostics demonstrate that, once the algebraic wave speed is imposed, the $M=2$ profiles satisfy the PDE with residuals of order ${10}^{-3}$ and preserve the conserved quantities to machine precision (below ${10}^{-13}\%$ relative variation) over extended integration domains. These results extend the known solution structure of the special eKdV equation and illustrate the effectiveness of the $(G^{\prime }/G)$ framework for higher-order dispersive models. Full article

Background: Sport-related injuries are common, and often recurrent, among female college soccer players. This exploratory cohort study investigated whether perceptual decision efficiency and sleep quality could discriminate between injured and uninjured players. Methods: Twenty-seven NCAA Division I women’s soccer players (19.5 ± 1.3 years) completed a perceptual response training program, administered through an immersive virtual reality system, across a 13-week season. Players completed 11 training sessions progressing through four levels of task difficulty, with conjugate eye movements, neck rotation, and whole-body lunge-reach responses measured for each trial. Four metrics, elapsed time, rate correct per second, across-trials variability, and an efficiency index, were calculated for each of three defined time segments: perceptual decision, action initiation, and perceptual–motor response. The Pittsburgh Sleep Quality Index (PSQI) and Global Well-Being Index (GWBI) were administered prior to the first practice session, and all subsequent time-loss injuries were documented. Receiver operating characteristic analyses, Kaplan–Meier survival analysis, and classification tree modeling were used to evaluate injury discrimination. Results: Twelve time-loss injuries, including five concussions and seven lower extremity musculoskeletal injuries, were sustained by 10 of the 27 players. Optimal discrimination between injured and uninjured players was derived from the perceptual decision efficiency (PDE) metric for the most difficult perceptual response training task (AUC = 0.682–0.794), with a binary cut point of ≤6.02 yielding an odds ratio of 5.60 (95% CI: 1.02, 30.90; Mantel–Cox log rank p = 0.025). All five concussions occurred in players classified as high-risk by a suboptimal PDE value. Pre-participation PSQI demonstrated an AUC of 0.735. Notably, no player with both an optimal PDE value and a favorable sleep quality score (PSQI < 4) sustained a time-loss injury. Moderate-to-large training-related improvements in perceptual decision metrics were observed for the least challenging task from early- to late-season sessions. Conclusions: Optimal values for PDE and sleep quality together characterized female college soccer players who avoided injury. Both factors appear to be modifiable, suggesting that perceptual response training combined with interventions to enhance sleep quality may enhance injury resistance. Independent validation in larger, diverse athlete cohorts is warranted. Full article

Background: Non-syndromic retinitis pigmentosa (RP) is characterized by rod–cone degeneration, resulting in night blindness, visual field constriction, and eventual blindness. Recessively inherited RP is predominantly exacerbated in consanguineous populations, such as Pakistan. This study aimed to perform the genetic analysis of sixteen non-syndromic RP segregating Pakistani families, and to summarize the mutation spectrum of non-syndromic RP in our population by reviewing related literature. Methods: We screened 16 non-syndromic RP families using targeted capture panel sequencing of 344 genes related to inherited retinal dystrophies. Variants were prioritized based on rarity (minor allele frequency (MAF) < 0.001 in the gnomAD South Asian subset), pathogenicity assessments using ACMG/AMP criteria, and REVEL scores (>0.5). Candidate variants were validated for familial segregation through Sanger sequencing. Results: We identified 15 distinct variants across 14 genes associated with non-syndromic retinitis pigmentosa, comprising 6 missense, 7 nonsense, 1 frameshift, and 2 splice-site variants, including 4 novel variants, i.e., p.(Val220Met) and p.(Pro1282SerfsTer2) in RP1, 1 each in PDE6B (c.2021+5G>A), and PRCD p.(Ser38Ter). Homozygosity predominated, underscoring the impact of consanguinity on the burden of autosomal recessive disease in the present cohort, while the CERKL disease-causing mutation, i.e., p.(Arg257Ter), recurred in two families. Conclusions: This study expands Pakistan’s non-syndromic RP mutational spectrum by identifying novel variants in RP1, PDE6B, and PRCD, alongside recurrent CERKL and RHO mutations of the local population. The literature review suggests that RP1, TULP1, and PDE6B are among the most mutated genes in our population, supporting the value of population-specific genetic panels to enhance diagnostics and carrier screening. Full article

Alzheimer’s disease (AD) is characterized by amyloid-β deposition, neuroinflammation, and mitochondrial dysfunction. Phosphodiesterase 4 (PDE4), a key regulator of cyclic nucleotides in neurons, represents a promising therapeutic target for AD. In this study, we performed a PDE4 inhibition-guided screen of an in-house marine natural product library derived from marine fungi, leading to the identification of a sesterterpenoid variecolactone (VLT) as a potent PDE4 inhibitor. VLT exhibited selective PDE4D inhibition (IC₅₀ = 2.302 μM) with minimal activity against other PDE subtypes. Further mechanical investigation revealed that VLT treatment elevated cAMP and p-CREB levels, reduced amyloid-β (Aβ) accumulation, promoted synaptic function, and ameliorated mitochondrial fragmentation, along with mtDNA homeostasis in the AD cell model. Moreover, under conditions of mtDNA depletion or Drp1 overexpression, VLT exerted neuroprotective effects and maintained mtDNA homeostasis via the cAMP-PKA-CREB signaling pathway. These results demonstrate that PDE4 inhibition by VLT represents a promising therapeutic strategy for AD and related neurodegenerative disorders. Full article

Peripheral arterial disease is a leading cause of amputation and/or death worldwide. Phosphodiesterase 4 (PDE 4) inhibitors demonstrated beneficial effects in ischemia–reperfusion (IR) settings, but whether PDE 4 inhibition protects skeletal muscle against IR deleterious effects is unknown. We therefore performed limb IR (two hours each) in twenty-one male Swiss mice (12–16-week-old) treated or not with Rolipram (1 mg/kg i.p. 30 min before ischemia and 5 min before reperfusion). The muscles were analyzed 4 h after the onset of ischemia. IR significantly increased leucocyte infiltration (93.13 ± 6.886 vs. 150.1 ± 18.38 cells/mg of muscle, p < 0.05) and apoptosis (Bax/Bcl2 ratio, +239%, p < 0.05), together with enhanced mitochondrial fission transcripts (+224% for Drp1, p < 0.01 and +368%, p < 0.0001 for Fis1), and decreased mitochondrial respiration and antioxidant defense. PDE 4 inhibition reduced leucocyte infiltration (150.1 ± 18.38 vs. 55.58 ± 13.83; p < 0.01) and apoptosis (+67%, NS) in association with reduced fission markers (+91% for Drp 1 and +111%, p < 0.05, for Fis 1). Muscle mitochondrial respiration did not improve. In conclusion, PDE 4 inhibition using Rolipram partly protected skeletal muscles against IR-induced deleterious effects. These data support further studies investigating the usefulness of leucocytes modulation in lower-limb IR and a potential beneficial effect of PDE 4 inhibition in peripheral arterial disease. Full article

Elateridae (Coleoptera: Elateroidea) are renowned for their clicking mechanism. However, several lineages exhibit body softening that compromises this mechanism, particularly within Plastocerini, Drilini, and Omalisinae. It remains unclear how this body softening is anatomically achieved and which specific structures are degraded in relation to the loss of clicking function. To elucidate the internal morphological adaptations and distinguish them from hard-bodied clicking elateroids, we employed micro-CT to scan Plastocerus thoracicus and reconstruct its thoracic morphology in 3D and quantified key muscle ratios (e.g., M2/M60, M4/M60). Based on our study of P. thoracicus, a detailed comparison was made with previously reported data on Campsosternus auratus (Elateridae) and Cerophytum lii (Cerophytidae). Three-dimensional reconstructions revealed significant structural divergences in P. thoracicus: (1) the clicking-related muscles M4 are markedly weaker than those in Ca. auratus and Ce. Lii. (2) the prosternal process (PP) is extremely narrow. The posterior part of the pronotum exhibits underdeveloped regions, including the posterodorsal evagination (PdE) and the posteromedial process (PmPr). (3) the mesonotum (i.e., the “biological spring” identified in previous studies) is greatly flattened and weakened. (4) the flight muscles (M60, M64) and walking muscles (M74, M75) exhibited significantly bigger volume than Ca. auratus and Ce. lii. These findings provide critical data for understanding the morphological evolution of Elateridae and offer insights into the functional adaptations of the clicking mechanism through comparative anatomy. Full article

Phospodiesterase 4 (PDE4) has long been an attractive target not only for the anti-inflammatory therapy in respiratory diseases, but also for other pathologies such as psoriatic arthritis and atopic dermatitis. In this study, we report the synthesis of 5-acetyl-2-ethyl-6-phenyl-3(2H)-pyridazinones differently substituted at position 4 with a variety of aryl/alkylamines, which act as potent PDE4B1 inhibitors in the low nanomolar range. The selectivity toward PDE4A4, PDE4D3 and HARBS, as well as the ability to inhibit TNFα production in human whole blood (hWB), was also evaluated for the most potent products, resulting in a small cluster of compounds with an interesting profile and two selected products (3a and 3k) have been in depth investigated with additional in vitro tests on metabolism and in vivo studies. Finally, molecular docking and minimization of the ligand-enzyme complexes were carried out. Full article

Background/Objectives: Taiwan cinnamon leaves have been reported to be effective in improving chronic diseases. Herein, cinnamon leaf extract (CLE) and nanoemulsion (CLEN) were prepared to explore their effects in improving sexual dysfunction in rats. Methods: Following extraction with 80% ethanol and analysis by UPLC-MS/MS, CLEN was prepared using an optimal ratio of soybean oil, lecithin, Tween 80, deionized water, and CLE. A total of 48 male rats and 48 female rats were used, with the former being induced with erectile dysfunction, followed by treatment with CLEN or CLE at two doses (100 mg/kg and 50 mg/kg) for 4 weeks. After conducting the penile reflex test, male rats were paired with female rats for measurement of sexual behavior and ICP/MAP. Following sacrifice, α-SMA, nNOS, and β-III tubulin expression areas were measured by histochemical analyses; SMC/collagen ratio by Masson’s trichrome staining; and NO, cGMP, and PDE5 levels by ELISA kits. Results: CLEN was more effective than CLE in increasing intromission frequency, decreasing intromission and ejaculation latency, and recovering erectile response for improving copulatory and ejaculatory performances. A higher maximum ICP/MAP ratio was shown for CLEN through elevation of neurovascular function and erectile capacity. Additionally, CLEN efficiently reduced fibrosis, enhanced neuronal marker expression, and increased the SMC/collagen ratio, leading to penile tissue protection and neural regeneration. Both treatments showed elevated levels of NO and cGMP with a reduction in PDE5, probably through modulation of the NO-cGMP signaling pathway. Conclusions: CLEN was more effective than CLE in restoring erectile function in rats. Some more clinical trials are needed to verify this finding. Full article

Background: Inherited retinal dystrophies are a heterogeneous group of progressive disorders impacting photoreceptor function, often limiting the usefulness of standard electroretinography in advanced cases. Full-field stimulus test (FST) testing has become a sensitive psychophysical technique for detecting residual visual function when traditional electrophysiology is non-recordable. This study evaluated the ability of chromatic FST to differentiate rod–cone from cone photoreceptor dysfunction in patients with genetically confirmed inherited retinal dystrophies. Methods: Cross-sectional FST data were analyzed from 39 patients (mean age 45.7 ± 20.0 years) with genetically confirmed inherited retinal dystrophies at a tertiary academic center. All participants underwent standardized FST testing using white, red, and blue stimuli. Patients were classified into rod–cone dystrophy (n = 27) or cone dystrophy (n = 12) groups based on genetic and clinical criteria. Group comparisons focused on FST thresholds and especially blue–red threshold differences as markers of photoreceptor-mediated function. Bonferroni correction was applied to adjust for multiple comparisons across four primary FST parameters. Additional analyses by genotype were performed with nonparametric tests. Results: Eight different genetic mutations were represented, including Phosphodiesterase 6A (PDE6A) (n = 10), Rhodopsin (RHO) (n = 7), Phosphodiesterase 6B (PDE6B) (n = 6), Cyclic Nucleotide-Gated Channel Beta 1 (CNGB1) (n = 4), Cyclic Nucleotide-Gated Channel Alpha 3 (CNGA3) (n = 4), Nuclear Receptor Subfamily 2 Group E Member 3 (NR2E3) (n = 4), Guanylate Cyclase 2D (GUCY2D) (n = 2), and Cyclic Nucleotide-Gated Channel Beta 3 (CNGB3) (n = 2). Blue–red FST threshold differences exhibited moderate group discrimination in uncorrected analysis, with rod–cone dystrophies averaging −8.35 ± 10.37 dB and cone dystrophies −11.20 ± 14.60 dB. The area under the receiver operating characteristic curve for blue–red difference was 0.74 (95% CI: 0.59–0.90), with 75% sensitivity and 70.4% specificity at a −10 dB cutoff. However, no chromatic FST parameter maintained statistical significance between groups after Bonferroni correction. Inter-eye FST correlation was high (r = 0.758, p < 0.001), supporting test reliability. Conclusions: Chromatic FST testing provides a practical and sensitive means to assess photoreceptor function in advanced inherited retinal dystrophies, particularly when standard electrophysiologic methods are uninformative. Although the blue–red threshold difference offers moderate discrimination between rod–cone and cone dystrophies in uncorrected analysis, no chromatic parameter reached statistical significance after adjustment for multiple testing. Chromatic FST should be considered a supplementary approach for clinical monitoring and therapeutic studies in advanced retinal dystrophies, with further validation needed in larger cohorts. Full article

Phytochemical investigation of the ethyl acetate extract from the aerial parts of Pouzolzia pentandra led to the isolation and identification of fourteen compounds (1–14). These include known compounds such as β-sitosterol (1), bauerenol (2), oleanolic acid (3), 3β-friedelanol (4), kaempferol (5), quercetin (6), 2′,6′-dihydroxy-3′,4′-dimethoxychalcone (7), friedelan-3-one (8), dipterocarpol (9), 3β-hydroxyolean-12-en-28-one 3-p-coumarate (10), daucosterol (11), astilbin (12), 3-methoxy-4-hydroxybenzoic acid (13), and pouzolignan F (14). Among these, compound 14 displayed the most potent inhibitory activity on nitric oxide (NO) production in LPS-stimulated RAW264.7 macrophages, with an IC₅₀ value of 10.54 ± 0.4 µM. Mechanistic studies further revealed that compound 14 significantly suppressed the LPS-induced release of key pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). Furthermore, it inhibited the activation of the nuclear factor-kappa B (NF-κB) signaling pathway by preventing the nuclear translocation of its p65 subunit. Molecular docking studies were performed to evaluate the anti-inflammatory potential of compound 14 against cyclooxygenase-2 (COX-2) and phosphodiesterase-4 (PDE4). The compound exhibited binding affinities of −6.138 kcal/mol and −9.361 kcal/mol for COX-2 and PDE4, respectively. Subsequent molecular dynamics (MD) simulations confirmed the formation of a stable complex with the active site of PDE4. Collectively, these integrated in vitro and in silico findings demonstrate that pouzolignan F acts as a multi-target anti-inflammatory agent, likely through the inhibition of inflammatory mediators, cytokines, and the NF-κB pathway. Full article