Search Results (338)

Offspring of preeclamptic (PE) mothers are at increased risk of end-organ damage. Given the widespread use of NSAIDs during pregnancy and their reported ability to mitigate organ damage in PE mothers, this study examined whether prenatal naproxen modifies PE-induced lung injury in male and female offspring. PE was induced by orally administered L-nitro-arginine-methyl ester (L-NAME, 50 mg/kg/day for 7 days) to mothers prior to labor, and lung tissues were excised from 3-month-old offspring. Histopathology revealed increased interstitial inflammation and fibrosis in PE versus non-PE offspring lungs. This was more prominent in male than in female PE offspring and was coupled with more pulmonary expression of Axl tyrosine kinase receptor and downstream interleukin-1α (IL-1α) and antiangiogenic Fms-Like Tyrosine Kinase-1(sFlt1) effectors. These sex-related defects disappeared in offspring of PE dams treated prenatally with naproxen (1 mg/kg/day for 7 days). Further, PE offspring exhibited elevations in other inflammatory cytokines, IL-2 and TNFα, and apoptotic markers, caspase-3 and caspase-cleaved cytokeratin 18 (M-30) and total soluble cytokeratin 18 (M-65). The latter effects were evenly seen in both sexes and similarly offset by naproxen. These findings implicate Axl/IL-1α/sFlt1 signaling in the greater lung injury in male PE offspring and suggest a protective effect of gestational naproxen therapy. Full article

This study aimed to investigate whether hydrolyzed collagen (HC) derived from salmon skin could attenuate blood pressure and vascular damage in Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME)-induced hypertensive rats. Hypertension was induced in rats by the oral administration of L-NAME (40 mg/kg/day) for eight weeks, while HC in two doses (50, 450 mg/kg) or enalapril at 10 mg/kg dissolved in water were concurrently administered via oral gavage for the last four weeks. Treatment with HC (450 mg/kg) and enalapril resulted in a reduction in systolic blood pressure, oxidative stress markers, and inflammatory cytokines. Production of serum nitric oxide (NO) was also increased, contributing to better aortic function. Histopathological analysis confirmed these changes, showing enhanced progression in the aorta structure. Vascular function was improved, as evidenced by significantly higher relaxation responses to acetylcholine (ACh) in the presence or absence of endothelium. These findings indicate that HC effectively lowered the blood pressure in hypertensive rats, potentially through mechanisms involving the modulation of oxidative stress and the expression of nitric oxide, reducing vascular inflammation and remodeling, hence enhancing vascular function. Full article

Reactive oxygen species (ROS) are unavoidable byproducts of cellular metabolism and are normally controlled by tightly regulated antioxidant systems. Red blood cells (RBCs) are particularly susceptible to oxidative stress due to their high oxygen exposure and iron content. In sickle cell disease (SCD), this vulnerability is exacerbated, as sickled RBCs generate chronically elevated ROS that contribute directly to disease pathophysiology. This review examines emerging evidence linking oxidative stress responses to regulation of fetal hemoglobin (HbF) expression through protein arginine methyltransferases (PRMTs). PRMTs catalyze arginine methylation of histone and non-histone substrates, thereby shaping chromatin structure, transcriptional programs, and translational control. We highlight recent findings demonstrating that specific PRMTs regulate γ-globin expression through distinct mechanisms, including transcriptional repression at the β-globin locus and post-transcriptional control of γ-globin mRNA translation. We propose that oxidative stress signaling may modulate PRMT activity, creating a mechanistic link between cellular stress responses and HbF induction. Because HbF inhibits pathological hemoglobin S polymerization, PRMT-dependent pathways represent an attractive therapeutic axis for SCD and related β-hemoglobinopathies. By integrating oxidative stress biology with PRMT-mediated epigenetic and translational regulation, this review outlines a unifying framework for HbF control, identifies critical knowledge gaps, and highlights future directions for the development of targeted epigenetic therapies. Full article

Calophyllum spp. infusions are used to treat varicose veins, hemorrhoids, and hypertension. However, the chemical composition and mechanisms of action are poorly understood. Accordingly, the aim of this study was to investigate the phytochemical composition and vascular effects of hydroalcoholic extracts of Calophyllum longifolium. Phytochemical profiling was performed using ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-ESI-Q-TOF-MS). Extract effects on rat aortic rings and aortic vascular smooth muscle cells (VSMCs) were evaluated using wire myography and photometric measurement of intracellular Ca²⁺, respectively. UHPLC-ESI-Q-TOF-MS revealed the presence of coumarins, xanthones, flavonoids, triterpenes, and phenolic acids. Coumarin–resveratrol hybrids, such as gut-70 derivatives, were also abundant. In aortic rings from normotensive rats, C. longifolium induced a biphasic vascular response whereby low concentrations (1 μg/mL) produced significant vascular relaxation, whereas high concentrations (100 μg/mL) produced contraction. Blockade of ATP-sensitive (K_ATP) or voltage-gated (K_V) potassium channels attenuated these effects. Furthermore, effects were not observed in preparations preincubated with L-NG-Nitro-L-arginine methyl ester (L-NAME) or in endothelium-denuded rings. In aortic VSMCs, extracts (1 µg/mL) rapidly reduced sarcoplasmic reticulum (SR) Ca²⁺ content. This study provides the first UHPLC-ESI-Q-TOF-MS chemical profile of C. longifolium, revealing diverse bioactive metabolites. It is also the first to demonstrate that C. longifolium exerts an endothelium-dependent, nitric oxide- and Ca²⁺-mediated biphasic effect on vascular function. Taken together, these findings highlight C. longifolium as a potential novel source of vasculotropic phytopharmaceuticals. Full article

Translocator protein (TSPO) regulates mitochondrial function, inflammation, and oxidative stress; however, its role in acute myocardial injury (MI) remains incompletely understood. While previous studies have examined TSPO ligands in cardiac injury, the interplay between TSPO modulation and nitric oxide (NO) signaling in AMI has not been systematically investigated. The aim of this study was to investigate the effects of TSPO modulation by PK11195, alone or in combination with nitric oxide synthase (NOS) inhibition by Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME), on cardiometabolic, inflammatory, oxidative stress, and histopathological parameters in an experimental model of isoprenaline-induced MI in rats. Male Wistar albino rats were divided into four groups: control (C); isoprenaline + saline-treated (ISO); isoprenaline + PK11195-treated (IP); and isoprenaline + PK11195 + L-NAME-treated (IPLN) groups. Isoprenaline administration induced MI, evidenced by elevated cardiac biomarkers, electrocardiographic (ECG) alterations, and histopathological damage. PK11195 treatment significantly attenuated MI and reduced pro-inflammatory cytokine levels while increasing anti-inflammatory cytokine levels, indicating protective effects. Nevertheless, TSPO modulation was associated with adverse metabolic effects, notably elevated fibrinogen and plasma homocysteine levels. Co-administration of L-NAME mechanistically demonstrated that NO availability is essential for PK11195 cardioprotective effects, as NOS inhibition partially abolished cardioprotection and modified oxidative stress parameters. Overall, TSPO modulation exerts complex actions in acute MI through regulating mitochondrial function, inflammatory signaling, and NO pathways, suggesting that TSPO is a potential, multifaceted therapeutic target. Full article

The purpose of this study was to investigate whether quercetin, a flavonoid abundantly found in onion leaves and other plant foods, induces the dilation of retinal blood vessels in rats. The time-course changes in retinal arteriolar diameter were measured using a retinal circulation evaluation system based on a high-resolution digital fundus camera developed in our laboratory. The intravenous administration of quercetin (10–100 µg/kg/min) increased the retinal arteriolar diameter in a dose-dependent manner. This vasodilatory effect of quercetin was almost completely suppressed through an intravitreal pretreatment with N_ω-nitro-l-arginine methyl ester (l-NAME), a nitric oxide (NO) synthase inhibitor. In contrast, the systemic intravenous infusion of quercetin did not cause significant changes in the systemic blood pressure and heart rate. These results suggest that NO production plays an important role in the quercetin-induced dilation of retinal arterioles. Quercetin, which is abundantly present in several plant foods and possesses antioxidant properties, may be a useful agent for the prevention of various ocular diseases associated with visual impairment caused by reduced retinal blood flow. Full article

Methyl farnesoate (MF) is a sesquiterpenoid hormone that controls a variety of physiological processes in crustaceans, including morphogenesis, development, reproduction, and molting. MF action is mediated by a transcriptional signaling cascade consisting of Methoprene-tolerant (Met), Steroid receptor coactivator (Src), Krüppel homolog 1 (Kr-h1), and Ecdysone response gene 93 (E93) transcription factors (TFs), and transcriptional co-regulators CREB-binding protein (CBP) and C-terminal-binding protein (CtBP). Phylogenetic and sequence analyses revealed that these genes were highly conserved across pancrustacean species. Met and Src were characterized as basic helix-loop-helix, Period (Per)-Aryl Hydrocarbon Nuclear Translocator (ARNT)-Single-minded (Sim) protein (bHLH-PAS) TFs; Kr-h1 was characterized as a C₂H₂ zinc finger TF with seven zinc finger motifs; E93 was characterized as a helix-turn-helix, pipsqueak (HTH_Psq) TF. CBP was identified by several zinc finger-binding regions with Transcription Adaptor Zinc Finger 1 and 2, Really Interesting New Gene, Plant homeodomain, and Z-type zinc finger domains; the Kinase-inducible Domain Interacting-transcription factor docking site; the Bromodomain-acetylated lysine recognition and binding site; the histone acetyltransferase domain; and a C-terminal CREB-binding region containing a nuclear receptor co-activator-binding domain. CtBP had a dehydrogenase domain with arginine-glutamate-histidine catalytic triad. 81 Met contigs, 45 Src contigs, 136 Kr-h1 contigs, 66 E93 contigs, 60 CBP contigs, and 172 CtBP contigs were identified across pancrustacean taxa, including decapod crustaceans. Bioinformatic identification and annotation of these TFs and co-regulators in brachyuran Y-organ (YO) transcriptomes suggests that MF signaling influences YO ecdysteroidogenesis; functional tests in the YO are needed to establish causality. Full article

Background: Ulcerative colitis (UC) is characterized by chronic mucosal inflammation, oxidative stress, and disruption of intestinal metabolic homeostasis. Immunomodulatory nutrients such as arginine, glutamine, and β-hydroxy β-methylbutyrate (HMB) have shown potential benefits; however, their combined molecular effects on UC remain insufficiently defined. Objective: To investigate the individual and combined effects of arginine, glutamine, and HMB on inflammatory and metabolic gene expression, oxidative stress markers, and histopathological outcomes in a dextran sulfate sodium (DSS)-induced colitis model. Methods: Female Sprague Dawley rats were assigned to six groups: control, DSS, DSS + arginine, DSS + glutamine, DSS + HMB, and DSS + mixture. Colitis was induced using 3% DSS. Colon tissues were examined histologically, serum MDA, MPO, and GSH levels were quantified, and mRNA expression of IL6, IL10, COX2, NOS2, ARG2, CCR1, and ALDH4A1 was measured by RT-qPCR. Pathway enrichment analyses were performed to interpret cytokine and metabolic network regulation. Results: DSS induced severe mucosal injury, elevated MDA and MPO, reduced GSH, and significantly increased IL6, COX2, NOS2, ARG2, and CCR1 expression. Glutamine demonstrated the strongest anti-inflammatory and antioxidant effects by decreasing IL6 and COX2 and restoring GSH. Arginine primarily modulated nitric oxide–related pathways, whereas HMB increased ALDH4A1 expression and metabolic adaptation. The combination treatment produced more balanced modulation across inflammatory, chemokine, and metabolic pathways, consistent with enrichment results highlighting cytokine signaling and amino acid metabolism. Histopathological improvement was greatest in the mixture group. Conclusions: Arginine, glutamine, and HMB ameliorate DSS-induced colitis through coordinated regulation of cytokine networks, oxidative stress responses, and metabolic pathways. Their combined use yields broader and more harmonized therapeutic effects than individual administration, supporting their potential as targeted immunonutritional strategies for UC. Rather than targeting a single inflammatory mediator, this study was designed to test whether combined immunonutrient supplementation could promote coordinated regulation of cytokine signaling, oxidative stress responses, and metabolic adaptation, thereby facilitating mucosal repair in experimental colitis. Full article

Excessive oxidative stress within the renal medulla is implicated in the development of hypertension, potentially modulated by renal nerve stimulation (RNS). This study examined the effects of RNS on cortical and medullary blood perfusion in Stroke-Prone Spontaneously Hypertensive Rats (SHRSP) under both normal conditions and at varying levels of oxidative stress. Male SHRSP rats were assigned to five experimental groups and subjected to RNS at different frequencies, with infusions of vehicle, tempol, tempol plus catalase (tem + cat), diethyldithiocarbamic acid (DETC), or L-nitro-arginine methyl ester (L-NAME) at the renal cortico-medullary border (CMB). Regional blood perfusion of the renal cortex and medulla (CBP and MBP, respectively) was assessed using Laser-Doppler flowmetry. RNS significantly reduced CBP and MBP by 43 ± 8% and 23 ± 4%, respectively, at 8 Hz. Co-infusion of tempol plus catalase significantly attenuated the RNS-induced reductions in both CBP and MBP. Similarly, DETC infusion mitigated RNS-induced decreases in CBP and MBP. In contrast, tempol alone and L-NAME did not protect against the RNS-induced under-perfusion of the renal cortex and medulla. The results suggest that simultaneous removal of superoxide anion and hydrogen peroxide (H₂O₂) can alleviate the reduction in renal blood perfusion caused by RNS, emphasizing a crucial role for H₂O₂ in renal hemodynamic regulation. Interestingly, DETC, which is expected to elevate superoxide anion levels, also mitigated RNS-induced under-perfusion, suggesting the presence of a potentially novel indirect protective mechanism that warrants further investigation. Full article

Cadmium (Cd) is a persistent toxic metal that bioaccumulates in human tissues and may disrupt redox and endocrine pathways, yet the metabolic mechanisms linking Cd exposure to both endothelial and prostate dysfunctions remain insufficiently defined. This study investigated whether chronic occupational Cd exposure alters methylated arginine metabolism and prostate-specific antigen (PSA) levels, indicating a shared toxicometabolic axis. A total of 150 male workers were enrolled, including 75 metallurgical employees with documented Cd exposure and 75 matched controls. All participants were non-smokers, eliminating confounding from tobacco-related oxidative or endocrine effects. Urinary Cd concentrations were quantified using Inductively Coupled Plasma–Mass Spectrometry (ICP–MS), and serum asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), L-arginine, citrulline, and PSA were measured by Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS) and electrochemiluminescence. The use of Inductively Coupled Plasma–Mass Spectrometry for cadmium quantification and LC-MS/MS for methylated arginine profiling provided high analytical specificity and sensitivity, strengthening the validity of biomarker measurements. Correlation and multivariable analyses adjusted for age and body mass index. Cd-exposed workers demonstrated significantly elevated urinary Cd, PSA, ADMA, and SDMA levels, alongside reduced arginine/ADMA ratios, consistent with impaired nitric oxide bioavailability. Urinary Cd strongly correlated with PSA and ADMA levels. These findings indicate that Cd may disrupt the nitric oxide pathway and elevates PSA, supporting a mechanistic link between vascular and prostate stress. Combined ADMA, SDMA, and PSA profiling may serve as an early biomarker panel for Cd-related metabolic injury in occupational settings. Full article

Pulmonary carcinoma remains a highly aggressive malignancy driven by complex signaling and epigenetic dysregulation. This study investigates a novel oncogenic pathway involving the Mg^2+/Mn²⁺-dependent protein phosphatase 1B PPM1B/myosin phosphatase (MP)/protein arginine methyltransferase 5 (PRMT5) axis, which promotes carcinogenesis by symmetrically dimethylating histone H2A and suppressing tumor suppressor genes. We hypothesized that loss of PPM1B would activate this pathway and drive tumorigenesis. Western blotting, PCR, and immunohistochemistry revealed a significant reduction in PPM1B expression in both squamous cell carcinoma (SCC) and human lung adenocarcinoma (ADC) compared to normal lung tissues, which correlated with worse patient survival. Despite an increase in total MYPT1, the regulatory subunit of MP, its inhibitory phosphorylation at Thr853 was significantly elevated in both tumor types. The inactivation of MP corresponded with a significant increase in the activating phosphorylation of PRMT5 at Thr80, especially in SCC, which was linked to a particularly poor prognosis. Downstream, this resulted in a dramatic elevation in the symmetric dimethylation of histone H2A, leading to decreased expression of retinoblastoma protein. Our findings demonstrate that decreased PPM1B expression drives the oncogenic activation of the MP/PRMT5 axis. This mechanism contributes to the aggressive nature of SCC, establishing PPM1B as a promising prognostic marker in lung cancer. Full article

The relationship between the structure of walnut-derived peptides and their activity of transport efficiency across the blood–brain barrier (BBB) remains unclear. In this study, a series of walnut-derived peptides were synthesized by substituting leucine (L) with tyrosine (Y), lysine (K), or arginine (R). Three outstanding peptides—EVSGPGYSPN, TWLPYPR, and YVPFPYP—were selected based on their antioxidant capacity and BBB transport efficiency, with EVSGPGYSPN exhibiting the highest activity. Reversed-phase high-performance liquid chromatography (RP-HPLC) and Transwell assay results demonstrated that EVSGPGYSPN can remain stable during gastrointestinal digestion and penetrate the BBB. Pharmacokinetic results revealed that the cumulative concentration of EVSGPGYSPN in the brain reached 1.25 ± 0.91 µg/g at 10 h, while its plasma half-life exceeded 12 h. Furthermore, it significantly reduced reactive oxygen species (ROS) levels to 110.46 ± 15.16%. Nuclear magnetic resonance (NMR) and Fourier-transform infrared spectroscopy (FTIR) results indicated that EVSGPGYSPN is rich in aromatic hydrogen signals and exhibits low methyl signals, which may enhance its antioxidant activity. Circular dichroism (CD) spectroscopy showed that EVSGPGYSPN has the highest random coil content, which facilitates its binding to transporters on the BBB and promotes BBB permeability. This study provides valuable insights into the design of brain-targeted peptide delivery systems. Full article

Post-translational modifications (PTMs) expand the structural diversity of proteins beyond the standard amino acids, influencing protein-protein interactions. Protein methylation, a prevalent PTM, involves the transfer of methyl groups from S-adenosylmethionine (SAM) to lysine and arginine residues. Arginine methylation is catalyzed by the Protein Arginine Methyltransferase (PRMT) family to yield mono- and dimethylarginine forms. PRMT1, the isozyme responsible for the majority of asymmetric dimethylation (ADMA) is implicated in various diseases, including cancer. Here, we report the synthesis and screening of a second-generation peptide library to identify novel PRMT1 substrates. The library, based on histone peptides, incorporated varying sequences of amino acids, facilitating substrate specificity studies. Screening identified 7 peptide sequences as exceptional PRMT1 substrates, which were confirmed by kinetic analysis. Consensus sequences revealed key recognition elements for PRMT1 catalysis, suggesting roles for small non-polar side chains and specific residues near the substrate arginine. Furthermore, we developed a peptide-based PRMT1 inhibitor by substituting the substrate arginine with a chloroacetamidine warhead. The inhibitor exhibited sub-micromolar inhibitory potency against PRMT1, surpassing previous peptide-based inhibitors. Our findings contribute to understanding PRMT1 substrate specificity and provide a scaffold for developing potent inhibitors targeting PRMT1 in diseases, including cancer. Full article

Depression is a prevalent psychiatric disorder in which oxidative stress and nitric oxide (NO) signaling have been implicated. Natural compounds such as Punica granatum have shown potential antidepressant effects, but their mechanisms remain unclear. This study aimed to evaluate the antidepressant-like effects of an aqueous extract of P. granatum in male Swiss Webster mice and to explore the possible involvement of NO-related system. Acute administration of P. granatum (0.25–2 mg/kg, i.p.) was tested in the forced swim and tail suspension tests. The interaction with NO signaling was examined through co-administration with an NO donor (sodium nitroprusside, SNP) and NOS inhibitors (NG-nitro-L-arginine methyl ester, L-NAME and 7-nitroindazole, 7-NI). Biochemical markers of oxidative stress (lipid peroxidation and GSH/GSSG ratio) were also assessed. P. granatum significantly reduced immobility and increased swimming behavior, consistent with an antidepressant-like effect. SNP, L-NAME, and 7-NI induced pro-depressant effects, which were prevented by P. granatum co-administration. Treatment also attenuated oxidative stress markers in the hippocampus and prefrontal cortex. These findings suggest that the antidepressant-like effects of P. granatum may involve interactions with NO signaling, although this interpretation remains indirect, as specific NO pathway indices were not measured. Acute P. granatum administration exerts antidepressant-like and antioxidant effects in male mice. The results support its potential as a natural candidate for depression treatment, particularly in conditions associated with oxidative imbalance and possible NO dysregulation. Future studies should confirm these mechanisms using direct molecular assessments and include female cohorts. Full article

Post-translational modifications (PTMs) of proteins in eukaryotic cells are essential for regulating proteome function and maintaining cellular homeostasis. Among these, the methylation modification of arginine has received much attention in recent years. The enzymatic process of arginine methylation is catalyzed by a family of approximately nine known protein arginine methyltransferases (PRMTs) in humans, which utilize S-adenosylmethionine (SAM) as the methyl group donor. PRMTs are involved in biological processes such as gene transcription, signal transduction, and DNA damage repair. Their role in normal cellular functions and pathological disease states is becoming increasingly clear with the advancement of research. This paper provides a review of the numerous roles of members of the PRMT family in normal cellular function and disease pathophysiology, with a focus on their association with the tumor immune microenvironment (TIME), and discusses their broad impact on various physiological processes and pathological conditions. Full article