Mechanical stress on the periodontal ligaments, such as orthodontic force, causes the failure of homeostasis-inducing inflammation leading to inflammatory root resorption and replacement resorption. Despite these developments during orthodontic treatment, little is known about its relationship to the epithelial cell rests of Malassez (ERM) located in the periodontal ligament. To address this gap, RNA sequencing was performed on non-compression and compression forced porcine ERM groups subjected to 4.0g/cm2 for 12h. The results showed 529 upregulated and 273 downregulated genes with more than a twofold change. Pathway analyses indicated that the differentially expressed genes were significantly enriched in 13 pathways, including the TNF signaling pathway, viral protein interaction with cytokine and cytokine receptor IL-17 signaling pathway, and NF-kappa B signaling pathway. The differentially expressed genes such as BMP2, NFKBIA, CXCL8, CCL4, SOCS3, and FOS were commonly significantly upregulated within these pathways. The levels of BMP2 protein increased, while the NF-kB protein did not translocate intranuclearly, with no change in CXCL8 protein levels. Through ERM-induced mechanical compression, BPM2 can regulate root resorption and bone addition to maintain periodontal ligament homeostasis. CCL4, SOCS3, and c-fos may suppress root resorption by angiogenesis, preventing excessive osteoclast formation and inhibiting hyalinization.

The body's circadian rhythm is coordinated by core clock proteins (PER, CRY, CLOCK, and BMAL1) that function in both the central hypothalamic and peripheral tissue molecular clocks. Our recent study demonstrated that deletion of Per1 in Dahl salt-sensitive (SS) rats (SSPer1-/-) exacerbated SS hypertension (HTN), kidney injury, and disrupted blood pressure rhythms. To define time-of-day-, genotype-, and diet-dependent alterations in the renal transcriptome and proteome associated with SS HTN, kidney cortex samples were collected from SS and SSPer1-/- rats fed either a normal salt (NS, 0.4% NaCl) or high salt (HS, 4% NaCl) diet, during both the active (night) and inactive (day) periods. Dietary challenges were conducted for 3 weeks in male rats. Bulk RNA-sequencing was performed on both NS and HS-fed groups, and proteomic analyses were performed in HS-fed groups. In SS rats, HS intake blunted time-of-day-dependent transcriptional changes. Pathway analyses predicted significant stress and immune responses, as well as metabolic adaptations, induced by the HS diet. Specifically, the remodeling of the pyruvate dehydrogenase complex was identified as a key prediction in both transcriptomic and phosphoproteomic datasets. As expected, Per1 deletion further exacerbated disruptions in immune regulation and metabolic adaptation. Collectively, these findings demonstrate that numerous renal genes exhibit diurnal oscillations under physiological conditions and are profoundly disrupted in SS HTN, likely contributing to impaired kidney function and circadian misalignment of blood pressure regulation.

Vibrio cholerae, a globally significant pathogen, causes both endemic and epidemic cholera and has also been associated with sporadic gastroenteritis and foodborne infections. Shrimp exports are a key source of revenue and employment in Bangladesh. However, Vibrio outbreaks pose serious public health and socio-economic risks through seafood consumption and the spread of antibiotic-resistant genes from aquaculture. The current study investigates the genomic and pathogenic features of the V. cholerae strain associated with seafood, with particular focus on the aquaculture environment of Bangladesh. Using Oxford Nanopore long-read sequencing technology, whole-genome sequencing (WGS) was performed on V. cholerae strain SU129B isolated from pacific white shrimp in Noakhali, Bangladesh, to explore its genetic diversity, antimicrobial resistance, and virulence determinants. The assembled genome exhibited high completeness (93.08%) and contiguity (N50 = 1), along with minimal contamination (1.33%). Average nucleotide identity (ANI) analysis showed 98.13% similarity with the reference V. cholerae strain RFB16, confirming species-level identification. Functional and pathway analyses indicated that the strain possesses a complex network of genes and metabolic systems that contribute to its survival in diverse environments. Analysis of the genome also revealed several biosynthetic gene clusters associated with the production of secondary metabolites, which contribute to osmotic tolerance, and metal acquisition. The genome also harbored multiple antibiotic resistance genes, which confer resistance via efflux systems, target modification, and membrane adaptation mechanisms. Pangenome analysis revealed 8,964 genes, including 2,085 core genes, 429 soft-core genes, 1,431 shell genes, and 5,019 cloud genes, demonstrating considerable genetic diversity and adaptability. Phylogenetic analysis showed a close evolutionary relationship between the shrimp and clinical strains, suggesting possible genome conservation across environmental and clinical isolates. The findings demonstrate that V. cholerae strain SU129B can evolve in aquaculture environments and may serve as a reservoir for virulence and multidrug resistance.

The molecular details of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) and their functional significance in combating environmental stress in crop species remain inadequately elucidated. Tomato (Solanum lycopersicum) is an important crop, sensitive to temperature, and serves as a model crop plant for studying these pathways. To establish a tomato UPR transcriptome profile, we performed RNA sequencing (RNA-seq) analysis of tomato seedlings under tunicamycin (Tm)-induced ER stress. The 339 differentially expressed genes encompassed traditional ER stress markers, ER-associated degradation elements, transcription factors, and novel candidate genes. Our functional analysis of key UPR genes, viz., SlIRE1A, SlIRE1B, SlbZIP60, and SlbZIP28, using Virus-Induced Gene Silencing (VIGS) revealed differential requirements for SlIRE1A and SlIRE1B in the Tm-induced upregulation of downstream genes. Additionally, we found that the expression of most of the downstream genes we analyzed was equally dependent on both the IRE1 and bZIP28 pathways. The expression analysis of several of these genes under environmental stress conditions indicated that their expression patterns did not align with those observed during ER stress. Furthermore, our analysis of VIGS plants subjected to heat stress revealed that the regulation of reactive oxygen species (ROS) levels in tomato depends on the IRE1-bZIP60 pathway. Overall, this study provides a comprehensive analysis of UPR pathways in tomato and offers essential molecular insights for developing resilient tomato cultivars that can withstand adverse environmental conditions.

Sepsis-induced myocardial dysfunction (SIMD) is a prevalent complication among septic patients, significantly worsening patient prognosis and elevating the mortality rate. Connexin 43 (Cx43), a pivotal cardiac gap junction protein, maintains cardiac function, and its disarrangement is closely linked to cardiac diseases. However, the role of Cx43 localization changes in SIMD remains unclear. Amphiregulin (AREG) was recently reported to promote the recovery of Cx43 disarrangements. This research aimed to explore the role of Cx43 in SIMD and the preventive potential of AREG. A mouse model of SIMD was induced using lipopolysaccharide (LPS) and treated with AREG. Cardiac function and electrical conduction were assessed using echocardiography and an electrocardiogram. Inflammatory responses, Cx43 regulation, and related signaling pathways were further investigated in serum and cardiac tissues. Relevant signal pathway analysis was investigated in cultured cardiomyocytes. LPS administration significantly reduced cardiac ejection fraction and left ventricular fractional shortening, which were accompanied by disorganization, fragmentation, and lateralization of Cx43 at 6h. These pathological alterations were associated with increased phosphorylation of pS368-Cx43, mediated by p38 activation. AREG pretreatment improved cardiac function and QRS interval, and preserved Cx43 localization at intercellular discs, along with pS368-Cx43 phosphorylation with reduction of p38 inhibition. Myocardial cell studies confirmed that AREG inhibited p38 phosphorylation, independent of AKT, in LPS-induced cardiac dysfunction. This study highlights the role of Cx43 phosphorylation in SIMD and demonstrates the preventive potential of AREG in SIMD, which is associated with a reduction in p38 activation and a decrease in the phosphorylation level of pS368-Cx43. These findings may provide a novel therapeutic target for SIMD.

Modern causal methods are underutilized in occupational epidemiology, despite the development of robust methods to adequately control time-dependent confounding affected by prior exposure, the root of the healthy worker survivor effect. We demonstrate how to detect the healthy worker survivor effect empirically and explain how to interpret analyses that have not adjusted for it. For lymphohematopoietic cancer mortality and female breast cancer mortality, we performed pathway analyses assessing whether employment is a time-varying confounder affected by prior workplace exposure to ethylene oxide. These analyses ascertained whether the relevant causal relationships depicted in a directed acyclic graph were present. For both outcomes, workers employed longer were at lower risk. Workers exposed to higher levels of ethylene oxide were also more likely to leave work. Thus, employment is a time-varying confounder affected by prior exposure. The directions of these associations imply that healthy worker survivor effect is operating. Previously published estimates of health effects of workplace exposures to ethylene oxide on both lymphohematopoietic cancer mortality and female breast cancer mortality are underestimates of the true impacts. Applying these methods to other occupational cohorts can aid interpretations of analyses that have not adjusted for the healthy worker survivor effect.

Plant extracellular vesicles (EVs) serve as critical mediators of intercellular communication during plant-pathogen interactions, particularly through their cargo of regulatory small RNAs, enabling the transport of miRNAs to distant tissues during biotic stress. Potato virus Y (PVY), one of the most economically damaging plant viruses globally, poses significant threats to solanaceous crop production. However, the landscape of EV-associated miRNAs and their regulatory roles in PVY infection remain largely unexplored. In this study, we isolated and characterized EV-associated particles from the apoplastic fluid of both PVY-infected and healthy tomato leaves using differential ultracentrifugation, followed by transmission electron microscopy, nanoparticle size analysis, and western blotting. High-throughput small RNA sequencing revealed 96 significantly differentially expressed miRNAs in EV-associated particles upon viral challenge. Bioinformatic prediction revealed that 80% of these dysregulated miRNAs potentially target multiple genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses demonstrated significant overrepresentation of predicted target genes in pathways associated with transcription, ta-siRNA biogenesis involved in RNA interference, protein binding, RNAi-mediated antiviral immune response, oxidative phosphorylation, mRNA surveillance pathway, and eukaryotic ribosome biogenesis. Our findings demonstrate that PVY infection selectively modulates the miRNA composition within tomato EV-associated particles. These EV-associated particles delivered miRNAs may contribute to a sophisticated antiviral defense mechanism by co-regulating host immunity. This study provides novel insights into the role of EV-associated particles mediated RNA communication in plant immunity and lays a theoretical foundation for developing innovative miRNA- and EV-based antiviral strategies for crop protection.

Objective: To investigate the prognostic stratification value of MLH1 promoter methylation in a mismatch repair deficiency (dMMR)-type endometrioid endometrial carcinoma (EEC). Methods: A total of 338 patients with confirmed diagnosis of dMMR EEC at Third Hospital of Peking University Health Science Center, from July 2005 to June 2023 were analyzed. Based on the promoter methylation, they were classified into a dMMR methylated (dMMR MET) group (177 cases) and a dMMR nonmethylated (dMMR nonMET) group (127 cases). Somatic mutations were analyzed by targeted sequencing (196/425-gene panel), and transcriptomic differences were assessed by RNA sequencing (Master panel). We compared the clinicopathological characteristics, gene mutation/expression profiles, and molecular pathway activities systematically between the two groups. Results: Compared with the dMMR nonMET group, patients of the dMMR MET group were older significantly [(56.89±8.85) vs. (53.76±9.45) years, P=0.003] and had tumor size of larger diameters [(3.39±1.78) vs. (2.71±1.31) cm, P=0.014]. The menopausal proportion (66.9% vs. 48.8%, P=0.002) and the proportion with tumor buddings (47.5% vs. 30.4%, P=0.036) were higher. No significant differences were identified in FIGO stage, histologic grade, depth of myometrial invasion, lymphovascular invasion, or rate of lymph node metastasis (P>0.05). Mutational profiling revealed that the nonMET group had significantly higher mutation frequencies in CHD4, NF1, SMARCA4, and RET (P<0.05). Transcriptomic analysis demonstrated upregulation of immune-related genes (CCL21, CXCL2) in the MET group, and downregulation of epithelial-mesenchymal transition (EMT)-associated genes (SOX2, FOXA1). Both GO and KEGG enrichment analyses of different gene expression in the MET group demonstrated an association with the MAPK pathway. However, Hallmark pathway analysis showed no significant differences in overall pathway activity between the two groups. Survival analysis revealed no significant differences in progression-free survival (P=0.206) or overall survival (P=0.813) between the groups. Conclusions: The methylation status of the MLH1 promoter has limited value in predicting the prognosis of dMMR EEC. Molecular pathways heterogeneity between the methylated and nonmethylated subgroups suggests the necessity of integrate multi-dimensional indicators to optimize stratification strategies, instead of relying on a single epigenetic marker.

Coronary artery disease presents heterogeneous clinical manifestations ranging from stable coronary syndrome (SCS) to acute coronary syndrome (ACS). Epigenetic mechanisms, particularly DNA methylation, may contribute to both chronic disease progression and acute plaque destabilization. However, genome-wide methylation differences between ACS, SCS, and healthy individuals remain incompletely characterized. Genome-wide DNA methylation analysis was performed in patients with ACS, patients with SCS, and healthy controls using pairwise comparisons (ACS vs. control, SCS vs. control, and ACS vs. SCS). Differentially methylated regions were identified using logistic regression implemented in the methylKit package in R. Regions with a false discovery rate-adjusted q-value &lt; 0.05 and an absolute methylation difference (|Δβ|) &gt; 20% were considered significant. Unsupervised hierarchical clustering revealed clear separation between ACS, SCS, and control samples, indicating distinct epigenetic profiles. ACS showed the most pronounced methylation alterations compared to controls, whereas SCS exhibited more moderate changes consistent with chronic epigenetic remodeling. Direct comparison between ACS and SCS identified dynamic, state-dependent methylation differences. Pathway analysis demonstrated enrichment of stress response, apoptotic signaling, and cell adhesion pathways in ACS, while SCS was primarily associated with pathways related to intercellular communication and vascular signaling. Our findings demonstrate that acute and stable coronary syndromes are characterized by distinct DNA methylation landscapes and pathway signatures. Epigenetic regulation of stress, adhesion, and signaling pathways may contribute to disease acuity and progression, highlighting DNA methylation as a potential molecular marker in coronary artery disease.

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease. Recent metabolomics studies have revealed pathogenic mechanisms and provided new perspectives for diagnosis. This study aimed to analyze plasma metabolic alterations and construct a preliminary diagnostic model for HCM based on untargeted metabolomics and machine learning (ML) algorithms, in order to explore potential pathogenic pathways and improve diagnostic accuracy during screening. A total of 76 HCM patients and 35 normal participants were consecutively recruited from August, 2023 to December, 2023. Data were split into discovery and validation sets at a ratio of 7:3 and the feature combinations were selected using support vector machine (SVM) and random forest (RF). Stepwise multivariate linear regression analysis was performed to identify key metabolites associated with left ventricular wall thickness. Metabolic pathway analysis was performed using KEGG. Totally 1481 metabolites were identified with 640 differential metabolites and 240 significant differential metabolites. Multivariate statistical analysis showed that metabolism results could effectively differentiate the two cohorts (OPLS-DA positive ion mode R2Y = 0.744, Q2 = 0.456; negative ion mode R2Y = 0.611, Q2 = 0.441). SVM and RF screened the same combination of features including 7-keto-8-aminopelargonic acid (KAPA), γ-linolenoyl ethanolamid, nitrilotriacetic acid, D-quinovose and N-acetyl-l-aspartic acid (NAA), which could effectively and accurately differentiate HCM patients from normal participants (in discovery and validation sets, the SVM model AUROC was 0.996 and 0.985 with accuracies of 96.1% and 97.1%, respectively; the RF model AUROC was 1.000 with accuracies of 94.8% and 100.0%, respectively). In metabolic pathway analysis, central carbon metabolism in cancer and protein digestion and absorption were significantly upregulated in HCM patients, which were connected by alanine, aspartate and glutamate metabolism. Stepwise multivariate linear regression analysis revealed that NAA was correlated with left ventricular mass index and RV5+SV1 (P < 0.05), which may be the central target of the connecting pathway. Plasma metabolite diagnostic model including KAPA, γ-linolenoyl ethanolamid, nitrilotriacetic acid, D-quinovose and NAA can effectively and accurately screen HCM patients. Metabolomics combined with ML algorithm showed that alanine, aspartate and glutamate metabolism may be the pathogenic pathway leading to the occurrence of HCM with NAA as the central target.

Battery Electric Vehicles (BEVs) are increasingly deployed in deep underground hard-rock mining to reduce diesel emissions, ventilation demand, and heat load. However, large-format NMC lithium-ion systems introduce distinct failure modes shaped by the confined geometries, mechanical loading, and ventilation constraints of subsurface environments. This study integrates electrochemical evidence, large-scale fire-testing data, OEM design documentation, and operational observations from an anonymised deep mine to characterise the dominant risk pathways associated with BEV operation. Results show that electrical instability, mechanical degradation, thermal escalation, early toxic-gas venting, and pack-level propagation interact nonlinearly, amplifying the likelihood and consequences of failure relative to surface conditions. Ventilation patterns influence gas accumulation and dispersal, while ground-induced vibration and microseismicity elevate the probability of latent cell damage. Limitations in battery-management-system diagnostics under dynamic duty cycles further constrain early detection. The analysis demonstrates that BEV safety in deep mines is a system-level challenge that requires integrating equipment design, thermal management, ventilation engineering, maintenance practices, human factors, and emergency-response planning. The findings support a technically grounded framework for electrification and identify research priorities related to underground thermal-runaway behaviour, advanced diagnostics, multi-species gas modelling, and next-generation battery architectures.

Effective precision oncology demands integration of pharmacokinetics/pharmacodynamics (PK/PD) profiling with tumor-specific genomic features. Here, we present a personalized treatment model using a patient-derived Networking Organoid Culture System (NOCS) composed of intestinal, liver, and kidney organoids differentiated from induced pluripotent stem cells (iPSCs) of an NF1-mutant breast cancer patient. This multi-organoid system enabled individualized assessment of drug absorption, distribution, metabolism, and excretion. Integrative genomic and pathway analyses uncovered therapeutic vulnerabilities, including responsiveness to a novel exon skipping therapy targeting NF1. PK/PD-guided screening on the NOCS prioritized Paxalisib, which, when combined with the exon skipping approach, demonstrated synergistic anticancer efficacy in patient-derived tumor models. These findings establish a clinically relevant framework that integrates multi-organ PK/PD modeling with genotype-driven therapeutic strategies, highlighting the potential of combining targeted gene correction with small-molecule therapy for personalized treatment. This platform offers broad applicability in precision oncology and drug development across diverse genetic contexts.

This research investigates the molecular mechanisms of benzyl butyl phthalate (BBP) in atopic dermatitis (AD) using network toxicology and molecular dynamics simulation. The environmental toxicity of BBP was systematically predicted and assessed using ADMETlab and ProTox-II. Structural information on BBP was obtained from PubChem, and potential targets were identified using STITCH and CHEMBL. AD-related target genes were retrieved from OMIM and GeneCards. A PPI network was constructed using STRING and Cytoscape to identify key targets. GO and KEGG pathway analyses were conducted to characterize the biological functions and signaling pathways associated with the targets. Molecular docking of BBP with core targets was performed using CB-Dock2. Finally, 100 ns molecular dynamics simulations of BBP-core target complexes were conducted using Gromacs. A total of 119 potential AD-related targets were identified, with six core targets (AKT1, CASP3, KRAS, SRC, EGFR, TNF) highlighted through PPI network analysis. GO and KEGG analyses demonstrated the involvement of these targets in BP, CC, MF, and signaling pathways, with a notable focus on the PI3K-Akt signaling pathway. Molecular docking analysis revealed strong binding affinities between BBP and the core targets, while molecular dynamics simulations confirmed stable interactions between BBP and AKT1, CASP3, and KRAS. This study systematically identifies key targets and molecular mechanisms underlying BBP-induced AD by integrating network toxicology, molecular docking, and molecular dynamics simulations. The findings establish a hierarchical framework linking chemical exposure, molecular interactions, and pathological phenotypes, providing insights into the toxic mechanisms of environmental pollutants from a molecular dynamics perspective.

Neonatal hypoxic-ischemic encephalopathy (HIE) triggers systemic oxidative stress and redox imbalance, contributing to multi-organ injury. Urine is a noninvasive matrix for longitudinal profiling of molecular responses, yet time-resolved proteomic studies in HIE are limited. We performed longitudinal SWATH-MS proteomic profiling of urine from term neonates with moderate-to-severe HIE treated with therapeutic hypothermia (n = 16) and non-asphyxiated controls (n = 19) at six time points during the first eight days of life. Proteins identified in ≥ 80% of samples were quantified, and differential abundance, temporal clustering, pathway enrichment, and upstream regulatory networks were analyzed. Approximately 1,000 proteins were quantified per sample. A total of 438 proteins were differentially abundant, with most changes transient and ten persistent. Early HIE urine showed marked elevation of hemoglobin subunits and sequential induction of haptoglobin and hemopexin, indicating staged heme scavenging and oxidative stress responses. Pathway enrichment revealed inhibition of neutrophil-associated innate immunity and activation of heme detoxification, lipoprotein remodeling, and PPAR signaling. Temporal clustering demonstrated stage-specific proteomic transitions, with partial normalization toward controls by days 6-8. Ingenuity Pathway Analysis identified six upstream regulators: Interleukin-1 alpha (IL1A), Tumor Necrosis Factor (TNF), ETS Homologous Factor (EHF), Peroxisome Proliferator-Activated Receptor Delta (PPARD), Thioredoxin-Interacting Protein (TXNIP), and Solute Carrier Family 2 Member 3 (SLC2A3), coordinating inflammation, redox control, and metabolic adaptation. We identified transient and sustained proteomic shifts that trace coordinated changes in oxidative stress, heme metabolism, and metabolic adaptation, alongside key regulators such as IL1A, TNF, EHF, PPARD, and TXNIP. The progression from early injury-related divergence to partial recovery by day 8 highlights the dynamic nature of post-insult remodeling. These findings support urinary proteomics as a robust, non-invasive tool for probing HIE pathophysiology and point to promising biomarker and pathway candidates for future studies.

Phenazinoates A-E (1-5), comprising five pairs of methyl saphenate conjugates with genistein, o-aminophenol, p-acetaminophenol and glycerol, were isolated from the fermentation broth of mangrove soil-derived Streptomyces sp. OUCMDZ-4923. Their structures were determined through comprehensive one-dimensional and two-dimensional nuclear magnetic resonance spectroscopy, coupled with high-resolution electrospray ionization mass spectrometry. The absolute configurations of each isomer were established by comparing experimental electronic circular dichroism spectra with calculated counterparts. Based on the biosynthetic pathway analysis, compounds 1‒3 were semi-synthesized from the reactions of methyl (R)-saphenate with genistein, o-aminophenol, and o-formamidophenol, utilizing microwave-assisted solid acid catalysis. The compounds were resolved as enantiomerically pure forms and subsequently tested for antibacterial efficacy against six pathogenic bacteria. Phenazinoates A (1) and B (2) demonstrated bioactivity against four Gram-positive bacterial strains, with minimum inhibitory concentration values ranging from 0.78 to 3.13μg/mL.

Transcriptomic insights into the co-occurring psychological symptoms and cardiovascular risks among military service members and veterans with mild traumatic brain injury: A LIMBIC-CENC study

This study systematically analyzed research trends in aquaculture wastewater treatment from 2000 to 2024 using bibliometric methods. Through knowledge mapping and keyword co-occurrence analysis conducted with Citespace6.1 software on the Web of Science Core Collection and the CNKI (China National Knowledge Infrastructure) Core Journal Database, we aimed to elucidate the distribution characteristics, evolution of research hotspots, and differences in technological pathways within the existing research landscape, while identifying gaps in integrated knowledge synthesis and cross-regional comparative analysis. The results indicate: (1) China’s publication output in this field over the past five years has significantly surpassed international levels, reflecting an imbalance in regional research activity; (2) antibiotics, nitrogen and phosphorus, organic pollutants, and heavy metals constitute the primary pollutant categories, with increasing attention focused on antibiotic and heavy metal pollution in recent years; (3) domestic research demonstrates a preference for natural ecological treatment technologies, whereas international research is predominantly oriented toward biological treatment technologies. By integrating Chinese- and English-language literature data with visual analytics, this study addresses the existing gap in systematic knowledge mapping and comparative analysis of regional technological pathways, and highlights the ongoing paradigm shift from pollution elimination toward resource recovery. The findings provide an empirical basis for formulating differentiated regional governance policies and guiding investments in low-carbon and environmentally friendly technology research and development, thereby promoting the transition of the aquaculture industry toward green and sustainable development.

Background: Doxycycline, a tetracycline antibiotic known for inhibiting matrix metalloproteinases, has shown potential antihypertensive effects. However, its role in modulating the renin–angiotensin system remains poorly understood. This study aims to specifically evaluate Doxycycline’s effects on key RAS components and blood pressure responses to clarify its underlying mechanism and support its development as a targeted antihypertensive therapeutic candidate.Materials and Methods: This study integrated an in-silico and experimental approach to assess the antihypertensive effects of doxycycline. Bioinformatics analyses were first conducted, including target prediction, gene ontology enrichment, hub-gene identification, PPI network construction, and KEGG pathway analysis, followed by molecular docking and molecular dynamics simulations to predict doxycycline’s interactions with key RAS targets. To validate these computational findings, qRT-PCR was performed to measure the expression of selected genes in kidney tissues from hypertensive rats.Results: Bioinformatics analysis identified six key target genes, including AGT, AGTR1, AGTR2, REN, ACE, and ACE2. Molecular docking showed that doxycycline exhibited stronger binding affinity to AGTR1 (-8.346 kcal/mol) than its native ligand. Molecular dynamics confirmed the stability of the doxycycline–AGTR1 complex at 20 ns. Gene expression analysis of kidney tissues from hypertensive rats revealed a significant reduction in AGTR1 expression in the group treated with doxycycline 15 mg/kg (p&lt;0.05), while no significant change was observed at 30 mg/kg.Conclusion: Low-dose doxycycline may modulate the renin–angiotensin pathway through AGTR1 inhibition, indicating its potential as a candidate for further antihypertensive research and warranting more comprehensive in vivo evaluation.Keywords: Hypertension, doxycycline, molecular docking, gene expression, Renin-Angiotensin System

Integrative omics approaches for bioactive metabolite discovery in marine macroalgae: Recent advances and future perspectives.

Meta-analysis of differential gene expression in idiopathic pulmonary arterial hypertension.