Search Results (2,783)

Background: Systemic arterial hypertension (SAH) induced by Nω-nitro-L-arginine methyl ester (L-NAME) is a well-established model characterized by nitric oxide (NO^●) synthase inhibition and vascular dysfunction. The transient receptor potential vanilloid 1 (TRPV1) regulates Ca²⁺ flux and may contribute to mitochondrial homeostasis. We hypothesized that TRPV1 activation modulates mitochondria function and attenuates cardiac damage during SAH. Methods: Hypertension was induced in Wistar rats by administration of L-NAME (200 mg/L) for 40 days. During the last four days, hypertensive animals received capsaicin (5 mg/kg/day), capsazepine (6 mg/kg/day), or their combination. Cardiac function was evaluated in isolated hearts using the Langendorff perfusion system. Myocardial tissue viability was assessed by triphenyltetrazolium chloride (TTC) staining, and mitochondrial function was evaluated by measuring respiratory control and apoptosis-related proteins. Results: Capsaicin treatment was associated with significant cardioprotective effects in hypertensive rats. Although the findings are consistent with a role of TRPV1 activation in mediating these effects, the partial protection observed with capsazepine suggests that TRPV1-independent mechanisms may also contribute. Conclusions: TRPV1 activation contributes to cardioprotection in SAH, likely through preservation of mitochondrial function and redox balance. However, additional mechanisms beyond TRPV1 modulation may also participate in the observed protective effects. Further studies—including direct assessment of mitochondrial Ca²⁺ flux and the use of more selective or genetic approaches—are currently underway to clarify the underlying mechanisms. Full article

This study aimed to investigate the selective anticancer activity of the curcumin analog PAC (3,5-Bis-4-hydroxy-3-methoxybenzylidene)-N-methyl-4-piperidone). Normal gingival epithelial cells (GECs), cancerous gingival cells (Ca9-22) and tongue squamous carcinoma cells (CAL27) were exposed to increasing concentrations of PAC (0–10 µM) for 24 h. Cell viability and cytotoxicity were evaluated using MTT and LDH assays, while apoptosis and caspase activation were analyzed by Annexin V/PI staining and flow cytometry. Gene-expression profiling was performed using RT² Profiler PCR arrays. PAC significantly inhibited Ca9-22 and CAL27 cell proliferation in a concentration-dependent manner, with an IC₅₀ value of 5 µM, while exerting no noticeable cytotoxic effects on normal GEC. PAC treatment induced significant early and late apoptosis associated with increased caspase activity in both oral cancer cell lines. Transcriptomic analyses revealed extensive modulation of apoptosis-related genes. In Ca9-22 cells, PAC predominantly suppressed anti-apoptotic and survival-associated genes, including BCL2, BIRC3, BIRC5, XIAP, CFLAR, and NFKB1. In contrast, CAL27 cells exhibited a more pronounced pro-apoptotic transcriptional profile characterized by upregulation of TP53, APAF1, CASP1, BID, and TNF. Gene interaction network analyses further demonstrated that PAC targets highly interconnected apoptotic signaling pathways. Collectively, these findings demonstrate that PAC exerts potent selective anticancer activity against OSCC cells through modulation of intrinsic and extrinsic apoptotic pathways. These results further support the therapeutic potential of PAC as a promising multitarget candidate for oral cancer treatment. Full article

This study investigates the process optimization and predictive modeling of femtosecond laser precision milling for commercial poly(methyl methacrylate) (PMMA) slices, with emphasis on surface roughness R_a and milling depth h. Three-dimensional surface morphology was measured using a laser confocal microscope, and the measurement methods for R_a and h were defined based on stable regions of interest and reference-plane correction. The effects of pulse energy, scanning line speed, scanning line spacing and pulse repetition frequency on milling quality were systematically analyzed. The results show that pulse energy and repetition frequency promoted material removal and increased milling depth, whereas scanning line speed and scanning line spacing reduced milling depth by decreasing the effective energy deposition per unit area. Surface roughness was influenced by both energy input and scanning uniformity, showing non-monotonic responses to scanning line speed and scanning line spacing. Quadratic response surface models were established using the Box–Behnken design. The ANOVA results indicate that both the R_a and h models were statistically significant, with R² values of 0.9970 and 0.9982, respectively. The validation results show that the average relative errors of the R_a and h models were 6.51% and 2.62%, respectively. These results demonstrate that the proposed models can effectively predict femtosecond laser milling quality and provide guidance for parameter selection and surface-quality control of commercial PMMA slices. Full article

Background: Pulmonary arterial hypertension (PAH) is a rare and progressive disorder characterized by increased pulmonary vascular resistance and vascular remodeling. Genetic polymorphisms, epigenetic modifications, and ion channel dysregulation are increasingly recognized as key contributors to disease pathogenesis. Anoctamin-1 (ANO1/TMEM16A), a calcium-activated chloride channel, plays a critical role in vascular tone regulation. Objective: This study aimed to investigate the association between ANO1 gene polymorphisms (rs7127129 and rs2509153), promoter methylation status, and serum chloride levels in patients with idiopathic pulmonary arterial hypertension (IPAH), congenital heart disease (CHD), and chronic thromboembolic pulmonary hypertension (CTEPH). Methods: A total of 106 IPAH patients, 40 CHD patients, and 30 CTEPH patients, together with 125 healthy controls, were included. The control group had a comparable age distribution, with a balanced sex ratio, whereas females predominated in all three PH groups. Genotyping was performed using TaqMan-based real-time PCR. Promoter methylation was analyzed using bisulfite conversion followed by quantitative real-time PCR. Serum chloride levels were measured using an ion-selective electrode method. Results: No significant association was observed between rs7127129 and rs2509153 polymorphisms and IPAH or CTEPH (p > 0.05). However, rs7127129 showed a significant association with CHD (p < 0.05). After excluding hypertensive patients, both polymorphisms remained significantly associated with CHD. Serum chloride levels differed significantly among groups (p < 0.001), with higher levels observed particularly in the CTEPH and CHD groups compared to controls, while IPAH patients exhibited intermediate but still elevated levels relative to controls. In contrast, promoter methylation levels were significantly lower in all patient groups compared to controls. An inverse relationship between chloride levels and methylation status was observed. Conclusions: ANO1 polymorphisms are not major determinants of IPAH or CTEPH but may contribute to CHD susceptibility. Increased serum chloride levels, together with decreased promoter methylation, suggest a potential mechanistic link between ion channel dysregulation and epigenetic alterations in pulmonary hypertension. Further large-scale and functional studies are warranted. Full article

Immunotherapy has transformed cancer treatment; however, clinical benefit remains limited to a subset of patients, underscoring the need for robust biomarkers that capture tumor-immune interactions across cancer types. In this study, we performed a comprehensive pan-cancer, multi-omics characterization of the immune checkpoint–related molecules CD70, CD80, and TIGIT to evaluate their diagnostic, prognostic, and immunological relevance. Using integrative analyses of transcriptomic, epigenomic, genomic, pharmacogenomic, and single-cell RNA-sequencing data from The Cancer Genome Atlas and complementary resources, we assessed expression patterns, DNA methylation, somatic mutations, copy number alterations, immune infiltration, tumor stemness, and drug sensitivity. CD70, CD80, and TIGIT were broadly dysregulated across multiple malignancies, with coordinated overexpression particularly evident in kidney renal clear-cell carcinoma. Elevated expression of these immune checkpoints was associated with advanced tumor stage, aggressive molecular subtypes, and unfavorable survival outcomes in selected cancers, including uveal melanoma and renal malignancies. Functional analyses revealed significant associations between checkpoint expression and key oncogenic pathways, including epithelial–mesenchymal transition, apoptosis, and hormone receptor signaling, suggesting links with tumor progression and immune activation states. Immune deconvolution analyses indicated that TIGIT expression is associated with a T-cell–inflamed microenvironment and reduced neutrophil infiltration, while CD80 exhibited methylation-dependent associations with immune cell composition. Genomic and epigenetic alterations were found to correlate with checkpoint expression patterns and immune phenotypes across tumor types. Pharmacogenomic profiling identified associations between checkpoint expression and sensitivity to multiple anticancer agents; however, these findings are based on cell line datasets and should be considered predictive. Single-cell transcriptomic analyses further resolved cell-type–specific expression patterns, distinguishing tumor-intrinsic from immune-restricted expression profiles. Collectively, our findings establish CD70, CD80, and TIGIT as integrative biomarkers of tumor progression, immune contexture, and therapeutic response, providing a rationale for their clinical exploitation in precision immuno-oncology. Full article

The Sugars Will Eventually be Exported Transporters (SWEET) family plays a crucial role in the carbohydrate distribution, phloem loading, and stress response of plants, yet the evolutionary characteristics and functional diversification of SWEET genes in the endangered timber species Phoebe bournei (Hemsl.) Yen C. Yang remain largely unexplored. In this study, 21 PbSWEET genes were identified and classified into four subfamilies (A-D). Subfamily A exhibited a unique lineage expansion, mainly driven by tandem and segmental duplications. The nonsynonymous-to-synonymous substitution ratio (Ka/Ks) values of all duplicate gene pairs were all less than 1, indicating a strong selective suppression effect; consistent with this evolutionary constraint, the majority of PbSWEET proteins harbor the conserved Medicago truncatula Nodulin 3/saliva (MtN3_slv) domain, with only a few exceptions lacking a complete version. Promoter and hormone response analyses revealed that under abscisic acid (ABA) stress, PbSWEET4 exhibited an immediate burst, whereas PbSWEET10 showed a delayed burst. Physiological data indicated that soluble sugars may be more dominant osmolytes than proline (Pro), a pattern that points to a potential carbon-centric regulatory strategy. PbSWEET4 showed an early burst before sugar/oxidative peaks, suggesting a possible non-canonical signaling role, whereas PbSWEET10 exhibited a late increase coinciding with sugar/malondialdehyde (MDA) peaks, suggesting potential involvement in sugar redistribution. Under methyl jasmonate (MeJA) treatment, PbSWEET10 was rapidly induced, yet sugar accumulation occurred only at 24 h, a temporal decoupling that suggests a possible transcription–metabolism decoupling. Collectively, these correlative patterns point to a possible dual-wave transcriptional mechanism and nominate PbSWEET10 as a candidate for stress response, though these inferences require functional validation. Full article

Methyl methacrylate (MMA)-based materials are widely used in temporary and permanent prosthetic dentistry; the prolonged presence of these materials in the oral cavity and potential residual monomer release can affect local biological responses. This study aimed to evaluate the biocompatibility and toxicity profiles of MMA, the monomeric unit of polymethyl methacrylate (PMMA), a key component of dental materials used in temporary prosthetic restorations. Molecular docking simulations were performed using CB-Dock2 and Autodock vina, while protein–protein interaction (PPI) analysis was performed using STRING and Cytoscape. In addition, Swiss ADME Target Prediction, toxicity prediction, and enrichment analyses were used to characterize the biological significance of selected targets in more detail. Molecular docking studies revealed promising interactions of MMA with valuable biomolecular targets relevant to biocompatibility. The toxicity profile revealed aspects of MMA that could be improved. Pharmacophore modeling, highlighting the importance of carbonyl and hydroxyl groups as pharmacophoric properties, revealed compounds with suitable biocompatibility profiles. Consequently, it emphasizes the interactions of MMA with biomolecules and safety considerations. It can guide the design and optimization of biocompatible materials as an exploratory avenue for future developments in dental biomaterials. Full article

Cadmium (Cd) is a highly toxic heavy metal that impairs plant growth, metabolism, and the accumulation of bioactive compounds. To investigate methylation-associated Cd responses in the medicinal plant Sophora tonkinensis, we integrated whole-genome bisulfite sequencing (WGBS) and transcriptome sequencing under three Cd treatments (T0, T2, and T4). Cd stress induced extensive transcriptional reprogramming and widespread DNA methylation changes, with CHH methylcytosines accounting for the largest proportion of methylated sites, whereas CG sites showed the highest average methylation level. Differentially methylated regions (DMRs) were predominantly detected in the CHH context and were frequently located in promoter and flanking regions. Integrated analysis identified 6547 and 6204 differentially methylated genes in T2 vs. T0 and T4 vs. T0, respectively, and 420 and 612 genes, respectively, showing concurrent changes in DNA methylation and transcript abundance. Genes with hypermethylation and reduced expression were more frequent than hypomethylated/upregulated genes and were mainly associated with photosynthesis, carbon fixation, fatty acid metabolism, sulfur-related metabolism, and secondary metabolic pathways potentially related to medicinal quality. Among the hypomethylated/upregulated genes, the hormone-related candidate gene StGH3.1 was selected for functional validation, and heterologous overexpression of StGH3.1 enhanced Cd tolerance in transgenic Nicotiana benthamiana. These results indicate that Cd stress is accompanied by coordinated methylome and transcriptome remodeling in S. tonkinensis and provide methylation-associated candidate genes for further investigation of Cd-responsive adaptation. Full article

Aims: Globally, cardiovascular disorders represent the foremost contributor to mortality, and elevated arterial pressure constitutes one of their principal risk determinants. Despite the availability of various treatments, optimal blood pressure control is rarely achieved. The present work was undertaken to assess the antihypertensive and vasorelaxant properties of benzaldehyde, a naturally occurring aromatic aldehyde whose role in the regulation of arterial pressure has, to our knowledge, not yet been documented. Materials and Methods: Antihypertensive activity was evaluated in normotensive Wistar rats and in animals rendered hypertensive by chronic administration of Nω-nitro-L-arginine methyl ester (L-NAME). Benzaldehyde was administered orally at doses of 20 and 40 mg/kg under both acute (6 h) and subacute (7-day) treatment protocols. Arterial pressure was recorded non-invasively by means of a tail-cuff plethysmography system. Vasorelaxant activity was examined in vitro using isolated rat aortic rings precontracted with either Epinephrine (EP, 10 μM) or potassium chloride (KCl, 80 mM). Endothelium-dependent and endothelium-independent components were dissected by pre-incubating the rings with selective pharmacological inhibitors. Additionally, the effects of benzaldehyde on both phasic and tonic contractions induced by extracellular Ca²⁺ were assessed in EP-precontracted rings in Ca²⁺-free Krebs solution. Key Findings: In hypertensive animals, benzaldehyde produced a dose-related decrease in both systolic and diastolic arterial pressure. It induced concentration-dependent vasorelaxation in both endothelium-intact and -denuded aortic rings. Relaxation was also observed in KCl-precontracted rings. Vasorelaxant responses were significantly attenuated by Indomethacin, Nifedipine, and 2-Aminoethoxydiphenyl borinate (2-APB). Significance: These findings demonstrate that benzaldehyde lowers blood pressure through both endothelium-dependent and -independent mechanisms. These include activation of the prostacyclin (PGI₂)/cAMP pathway, inhibition of L-type calcium channels, and blockade of store-operated calcium channels (SOCCs). Full article

Transfer RNAs (tRNAs) are chemically matured decoding molecules that are central to protein synthesis. Their post-transcriptional modifications, especially those in the anticodon stem-loop (ASL), shape local RNA structure, codon recognition and translational fidelity at the tRNA-mRNA decoding interface. 2′-O-methylation (Nm) is a conserved ribose modification installed at selected ASL positions, particularly positions 32 and 34, by the modular Trm7/FTSJ1 methyltransferase system. Rather than directly changing base-pairing identity, these marks help prepare the decoder for efficient translation and function within an interconnected 32–34–37 modification network, best illustrated by tRNA^Phe. Loss of Trm7/FTSJ1-mediated Nm may impair selected codon–tRNA decoding pairs; in yeast, Trm7 deficiency is additionally associated with GAAC activation and phenotypes consistent with reduced functional tRNA^Phe availability. In humans, mutations in FTSJ1 are associated with nonsyndromic X-linked intellectual disability (NSXLID), suggesting that disruption of tRNA chemical maturation can affect neuronal translation programs. In this review, we integrate anticodon-loop modifications at positions 32, 34, and 37 into a decoder-centered framework and compare the conserved enzymatic logic of yeast Trm7 and human FTSJ1 with their divergent substrate repertoires. By synthesizing structural, biochemical, genetic, and translational evidence, we distinguish established mechanisms from working models and unresolved questions concerning tRNA modification hierarchies and neuronal vulnerability. Full article

The composition of low-polarity extracts obtained by sequential extraction of the aerial parts of Rhododendron adamsii Rehd. with hexane and methyl tert-butyl ether (MTBE) was investigated using GC-MS. The hexane extract was dominated by non-polar components: squalene, n-alkanes (nonacosane, hentriacontane), sesquiterpenes (trans-nerolidol, spathulenol, β-farnesene), and β-sitosterol. The subsequent MTBE extract was enriched in more polar lipids, primarily free triterpenic acids (ursolic and oleanolic acids). A critical finding was the complete absence of diterpene grayanotoxins in all tested extracts, confirming the safety of the non-polar extraction approach. In bioactivity assays, the total hexane extract demonstrated potent inhibitory activity against the SARS-CoV-2 main protease (3CLpro) with IC₅₀ values of 0.0125–0.025 mg/mL, only one order of magnitude higher than the reference inhibitor disulfiram. Fractionation revealed that the activity was distributed among free acids, bound acids, and the unsaponifiable residue, indicating a multicomponent mechanism. Importantly, none of the samples inhibited HIV-1 protease (IC₅₀ > 0.1 mg/mL), demonstrating selectivity for the cysteine protease 3CLpro over the aspartyl protease of HIV-1. These results highlight that sequential non-polar extraction of R. adamsii provides a grayanotoxin-free lipophilic complex with selective anti-SARS-CoV-2 protease activity, paving the way for bioactivity-guided identification of individual inhibitors. Full article

Phenylalanine ammonia-lyase (PAL) is the rate-limiting enzyme in the phenylpropane metabolic pathway, which is crucial for plant disease resistance. However, the functional roles of specific PAL members in lily defense against gray mold (Botrytis elliptica) remain unclear. Using the resistant lily cultivar ‘Sorbonne’, metabolomics analysis revealed that phenylpropane metabolites were significantly induced upon pathogen infection. Combined second- and third-generation transcriptome sequencing identified eight PAL family members. Among them, LhSorPAL1 and LhSorPAL2 were strongly induced by B. elliptica and were selected for further analysis. Both recombinant proteins exhibited PAL enzymatic activity catalyzing cinnamic acid production from L-phenylalanine. Overexpression of LhSorPAL1 or LhSorPAL2 in lily via Agrobacterium-mediated transformation had no obvious effect on plant growth but significantly increased the accumulation of lignin, flavonoids, and total phenols upon pathogen challenge, leading to enhanced resistance to gray mold. Conversely, antisense expression of LhSorPAL1 or LhSorPAL2 reduced the accumulation of these metabolites. Promoter analysis revealed that both LhSorPAL1pro and LhSorPAL2pro contain methyl jasmonate (MeJA)-, abscisic acid (ABA)-, and transcription factor-binding cis-elements. Collectively, these results demonstrate that LhSorPAL1 and LhSorPAL2 positively regulate lily resistance to B. elliptica by promoting phenylpropane metabolism, providing candidate genes for molecular breeding. Full article

Psychiatric disorders represent a leading cause of disability worldwide and are characterized by substantial biological and therapeutic heterogeneity. Despite significant research efforts, peripheral biomarkers capable of guiding diagnosis, patient stratification, and personalized treatment selection are still lacking. Circulating cell-free DNA (cfDNA) has recently emerged as a promising candidate biomarker, as it may integrate signals of cellular damage, apoptotic activity, and immune activation across multiple tissues. Beyond its role as a marker, cfDNA may also actively contribute to disease processes by functioning as a damage-associated molecular pattern (DAMP), thereby perpetuating inflammatory signaling. The mitochondrial component of cfDNA (cf-mtDNA), which also possesses strong immunostimulatory properties, represents a particularly sensitive indicator of mitochondrial vulnerability to stress. In this context, the present review aims to synthesize the most recent evidence on cfDNA and cf-mtDNA in major psychiatric disorders, including major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ). Specifically, we examine their association with psychological stress exposure and childhood trauma, as well as their involvement in inflammation-related pathophysiological mechanisms such as mitochondrial dysfunction, oxidative stress, and hypothalamic–pituitary–adrenal (HPA) axis dysregulation. Available evidence suggests that alterations in cfDNA may be present in subgroups of patients with MDD, BD, and SCZ. However, findings remain heterogeneous and sometimes contradictory, partly due to methodological limitations, including the lack of standardized analytical protocols and insufficient control for potential confounders. Nevertheless, cfDNA holds promise as a tool for inflammation-based patient stratification and for informing personalized therapeutic strategies. Future research directions include the integration of cfDNA within multi-omics frameworks, the analysis of cfDNA methylation profiles to infer tissue of origin, and the exploration of pharmacological strategies aimed at modulating cfDNA as a potential therapeutic target. Full article

The influence of suspension depth and pollutant concentration on the rate and efficiency of photocatalytic degradation was investigated in aqueous TiO₂ suspensions using methyl orange (MO) as a model pollutant. Both the reaction rate and the efficiency increased by more than one order of magnitude upon a relatively small decrease in suspension layer thickness. The reaction rate exhibited a complex N-shaped dependence on dye concentration, deviating from the monotonic behavior predicted by the Eley–Rideal and Langmuir–Hinshelwood mechanisms, as well as from the relationship derived in our previous study. To elucidate the origin of this behavior, nanoparticle aggregation was examined by sedimentation kinetics, low-acceleration centrifugation, and scanning electron microscopy (SEM). The results suggest that the interplay between enhanced dye adsorption and the reduction in the available photocatalyst surface area due to aggregation leads to the appearance of a maximum in the concentration dependence of the reaction rate. The relationship between reaction rate and photocatalytic efficiency was also analyzed. Although both parameters are correlated, efficiency values strongly depend on the selected reaction time interval, which complicates direct comparison between studies employing different experimental protocols. Consequently, the reaction rate appears to be a more reliable parameter for describing photocatalytic kinetics. Full article

Background/Objectives: Heliotropium indicum (H. indicum) is a medicinal plant traditionally used for conditions associated with inflammation, but its active antinociceptive constituents remain poorly defined. This study evaluated the antinociceptive activity of the aerial parts of H. indicum through a bioassay-guided approach and explored the mechanism of action of the active compound isolated in the formalin test. Methods: Three extracts of H. indicum (hexane, dichloromethane, and methanol) were evaluated in male Swiss albino CD-1 mice using the formalin test. The most active extract was fractionated, and its major fractions were screened for antinociceptive activity. Based on the active fraction and previous phytochemical data, (E)-ethyl-12-cyclohexyl-4,5-dihydroxydodec-2-enoate (ECDE) was selected for further pharmacological evaluation in the same model. Antagonist pretreatments were used to investigate the involvement of opioid, serotonergic, gamma-aminobutyric acid (GABA_A), and Nitric Oxide (NO)–soluble Guanylyl Cyclase (sGC) pathways. Results: The three extracts reduced nociceptive behavior, mainly during phase II of the formalin test, whereas the dichloromethane extract showed the broadest activity profile and was selected for fractionation. The six fractions significantly reduced phase II nociception, and fraction F5 was selected for purification. ECDE produced a clear dose-dependent antinociceptive effect in phase II, with minimal effect on phase I, and its efficacy was compared with that of ketorolac, a standard antinociceptive drug. Dose–response analysis estimated a DE₅₀ of 0.76 mg/kg for ECDE. Pretreatment with N-nitro-L-arginine methyl ester (L-NAME) and [1,2,4]oxadiazolo [4,3-a]quinoxalin-1-one (ODQ) significantly attenuated the effect of ECDE, whereas naloxone, methiothepin, and bicuculline did not. Conclusions: ECDE was identified in H. indicum as one of the compounds contributing to this effect. Its activity appears to be directed mainly toward inflammatory nociception and to depend, at least in part, on the NO–sGC pathway. Full article