A high-fat diet (HFD) is a well-established risk factor for coronary artery disease (CAD). Accumulating evidence indicates that maternal nutritional status before and during pregnancy critically influences long-term cardiovascular outcomes in offspring. This review systematically synthesizes current mechanistic, epidemiological, and clinical evidence regarding the impact of HFD on CAD while also examining its effects on broader cardiovascular phenotypes that are integral to CAD pathogenesis, such as endothelial dysfunction, cardiac remodeling, and metabolic derangements. A particular focus is placed on the potential effects of maternal pre-pregnancy HFD exposure on offspring CAD risk in adulthood. Existing studies suggest that HFD induces coronary injury primarily through metabolic dysregulation, endothelial dysfunction, and epigenetic reprogramming. Notably, maternal exposure to HFD during the perinatal period may predispose offspring to coronary artery disease via these mechanisms. Conversely, appropriate maternal nutritional interventions during pregnancy have shown promise in mitigating these adverse effects, although their long-term efficacy and underlying molecular mechanisms remain to be fully elucidated. Future research should prioritize large-scale prospective cohort studies with extended follow-up to determine the optimal timing, mechanisms, and efficacy of dietary interventions. Such evidence would provide a scientific foundation for developing preventive and therapeutic strategies aimed at reducing cardiovascular disease risk from the earliest developmental stages.
Repair of damaged DNA is a complex process, particularly when it is compacted into nucleosomes. There are a number of genetic disorders with deficiencies in DNA repair. Knowledge of the genes and proteins involved in these repair deficiencies is critical in developing an understanding of the molecular mechanisms utilized by proteins in the DNA repair pathways. One of these genetic disorders is xeroderma pigmentosum (XP), which is defective in nucleotide excision repair (NER). Patients in XP complementation group A (XP-A) are among the most severely affected with the lowest levels of DNA repair. The XPA protein, which is defective in these patients, plays a number of roles in the DNA repair process. One particularly important role proposed is acting as a processivity factor enabling endonucleases (XPF and XPG) and the XPB/TFIIH translocase to localize to damage sites using a processive mechanism of action. Another proposed role is in interacting with chromatin-remodeling proteins so as to enhance accessibility of lesions in nucleosomal DNA to endonucleolytic incision and other DNA repair activities. In XP-A cells, the XPA protein is proposed to be defective in ability to act as a processivity factor; endonucleases localize damage sites by a distributive mechanism and are also defective in incision of damaged nucleosomal DNA. This defect is corrected by recombinant normal human XPA. Mutations in exons 3 and 5 in the DNA binding domain of the XPA gene lead to loss of ability of XPA to act as a processivity factor. The mutation in exon 5 was found in two XP-A patients with severe XP. These studies emphasize the importance of correlating specific mutations in an XP gene and the resulting defect in a particular repair protein with the clinical severity of XP and could lead to development of novel therapeutic approaches for this disorder.
Feline Infectious Peritonitis (FIP) is a highly lethal disease in cats, and early differential diagnosis remains a significant clinical challenge. In this study, we analyzed differences in serum exosomal miRNA expression between FIP-affected cats and healthy control cats via high-throughput sequencing and identified five significantly differentially expressed miRNAs (miR-21-5p, miR-155-5p, miR-200c-3p, miR-486-5p, and miR-423-5p). A combined diagnostic model was constructed based on three key miRNAs (miR-21-5p, miR-155-5p, and miR-423-5p). ROC curve analysis showed that a combined model of these three key miRNAs had an area under the curve (AUC) of 0.93, with a sensitivity and specificity of 88.6% and 91.2%, respectively. These results indicate that the serum exosomal miRNA signature could be used as a novel biomarker for the early diagnosis of FIP, providing a non-invasive diagnostic tool in clinical practice.
Oncolytic viruses (OVs) are a class of viruses capable of specifically infecting and killing tumor cells. They exert antitumor effects through direct lysis of tumor cells, activation of the immune system, and disruption of tumor vasculature. Neutrophils, which originate from the bone marrow, are the most abundant leukocytes in peripheral blood and the immune system and play a dual regulatory role in oncolytic virotherapy. In different TME, neutrophils can polarize into two phenotypes: N1 and N2. N1 neutrophils, owing to their chemotaxis and tumor-homing capabilities, can serve as delivery vehicles for OVs, enhance the therapeutic efficacy of oncolytic virotherapy, and activate host immune responses. In contrast, N2 neutrophils impair the efficacy of OVs through their antiviral activity and immunosuppressive functions. Therefore, an in-depth understanding of the mechanisms underlying the role of neutrophils in oncolytic virotherapy is of great significance for optimizing OV-based therapies and improving their clinical application outcomes.
Clonal hematopoiesis of indeterminate potential (CHIP) causes the expansion of mutated hematopoietic stem cells and produces immunophenotypically altered leukocytes, which induce a tumor-promoting inflammatory condition. However, the causal effect of CHIP on cancer remains unclear. We assessed the relationship of genetically predicted CHIP with the risk of 18 cancer types involving 612,576 cases using two-sample Mendelian randomization (MR). Genetic instruments for overall and sub-types of CHIP were obtained from the a large-scale genome-wide association study using independent (r2 < 0.001) SNPs at genome-wide significance (p < 5.0 × 10-8). Summary statistics for 18 cancers were obtained from the FinnGen, MVP, PLCO study, and large consortia. Inverse-variance weighted random-effects models were used as the primary method for estimating causal effects. Findings from independent datasets were combined using the fixed-effect model and Bonferroni corrections were applied for multiple testing. We found genetic predicted overall and DNMT3A CHIP was significantly associated with an increased risk of thyroid cancer, lung cancer, kidney cancer, brain cancer, basal cell carcinoma, and malignant melanoma after corrections. In addition, we found the causal estimate of CHIP varied across histological sub-types of cancer. Sensitivity analyses confirmed that these findings were robust. Strong associations were found between genetic predicted CHIP and an increased risk of a broad range of cancers, highlighting the importance of timely screening for CHIP in cancer early detection and prevention.
Gastrointestinal inflammation is an inflammatory disease arising from immune imbalance in any segment of the digestive tract, triggered by various factors. Immune cells play important roles in both the onset and resolution of gastrointestinal inflammation. With the recent extensive research on extracellular vesicles, the mechanism by which immune cells regulate gastrointestinal inflammation through extracellular vesicles has gradually gained recognition within the scientific community. Extracellular vesicles derived from immune cells can communicate with other immune cells in the digestive tract and directly regulate digestive tract epithelial cells. Furthermore, with advances in biological nanotechnology, immune cell-derived extracellular vesicles may be used to treat inflammatory gastrointestinal diseases. This review focuses on delineating the role of immune cell-derived extracellular vesicles in gastrointestinal inflammation and exploring their potential applications in treating these inflammatory diseases.
Parkinson’s disease (PD) is a complex neurodegenerative disorder with diverse molecular signatures that extend beyond the central nervous system. Peripheral blood serves as a minimally invasive source of transcriptomic biomarkers reflecting systemic inflammation, mitochondrial dysfunction, lysosomal impairment, and disrupted RNA processing—key pathways involved in PD. Long-read RNA sequencing with Oxford Nanopore Technologies (ONT) offers unprecedented detail of full-length transcripts, alternative isoforms, and RNA modifications, enabling more accurate detection of disease-related transcriptional changes. We conducted high-throughput ONT long-read RNA sequencing on blood samples from 145 individuals, including PD patients and age-matched healthy controls. RNA libraries were prepared using a cDNA-based protocol optimised for high-accuracy PromethION sequencing. Transcriptomes were quantified with ONT-specific pipelines, and analyses of differential gene expression (DGE), differential transcript expression (DEX), differential transcript usage (DTU), and alternative splicing were performed using ONT-aware tools such as DRIMSeq, DEXSeq, and stageR. Pathway enrichment linked disease-related changes to mitochondrial, lysosomal, and vesicle-trafficking pathways. Our analysis identified highly significant PD-associated transcriptional signatures in peripheral blood (SNCA, VPS13C, LRRK2, GRN, STAU1, NPTN, PARK7). Long-read sequencing uncovered extensive isoform-level dysregulation, including novel transcript variants (e.g., BCL2L2-PABPN1, SQSTM1) in pathways relevant to PD, such as autophagy and endolysosomal trafficking. DTU analyses revealed shifts in isoforms of LRRK2 and GBA1, indicating widespread disturbances in RNA processing. Enrichment analysis showed activation of molecular pathways linked to neurodegeneration. This study provides the largest long-read blood transcriptomic dataset in PD to date, demonstrating that ONT sequencing can resolve isoform-level changes and reveal systemic molecular signatures of PD. Our findings support the development of blood-based RNA biomarkers and the establishment of long-read transcriptomics as a transformative approach for genomic pathology in PD.
Uric acid metabolism is associated with the development of type 2 diabetes mellitus (T2DM), cardiometabolic, and cardiovascular diseases. Additionally, T2DM patients often exhibit mild cognitive impairment (MCI). However, the underlying mechanisms remain unclear. This study aims to identify and validate biomarkers associated with uric acid metabolism in T2DM and MCI, with the goal of discovering potential diagnostic and therapeutic targets to improve the quality of life for T2DM patients. Transcriptomic data for T2DM, MCI and uric acid metabolism-related genes were sourced from public databases. Biomarkers were screened using machine learning and validated for expression. Subsequent analyses included functional enrichment, immune infiltration, subcellular localization, and drug prediction. Three biomarkers-HP, ITGB3, and SELP-were identified. All showed significantly elevated expression in the T2DM group (p < 0.05). HP and ITGB3 were primarily enriched in ribosome-related pathways, primary immunodeficiency, and adherens junction processes. Immune infiltration analysis revealed that immature B cells and plasmacytoid dendritic cells were significantly enriched in T2DM. HP showed the strongest positive correlation with plasmacytoid dendritic cells (cor = 0.65, FDR <0.05), while ITGB3 exhibited the strongest positive correlation with immature B cells (cor = 0.76, FDR <0.05). Several potential therapeutic drugs were predicted, including calcifediol (score = -99.93) and meclofenamic acid (score = -99.89). This study identified three candidate biomarkers co-dysregulated across T2DM and MCI transcriptomes and associated with uric acid metabolism. Given the exploratory sample sizes, these findings are considered hypothesis-generating and require validation in larger independent cohorts.
Mitochondrial dysfunction, driven by genetic mutations or oxidative stress, is a central contributor to the onset and progression of ophthalmic diseases. In recent years, intercellular mitochondrial transfer (MT) has emerged as a novel mechanism of cellular communication and repair in ocular tissues. MT occurs through tunneling nanotubes, extracellular vesicles (EVs), cell fusion, or transmitophagy, and has been shown to support photoreceptor survival, maintain retinal homeostasis, and protect against oxidative injury. Mesenchymal stem cells (MSCs), owing to their remarkable reparative and immunomodulatory properties, have attracted particular attention as efficient mitochondrial donors. Evidence from experimental models demonstrates that MSC-mediated MT can restore bioenergetics, mitigate oxidative stress, and rescue cellular function in inherited optic neuropathies, corneal injuries, retinal degenerative diseases, and ischemic retinopathies. This review summarizes current evidence of MT in ophthalmology, highlights the therapeutic contributions of MSCs, discusses the molecular and microenvironmental factors regulating MT efficiency, and outlines unresolved challenges. We further provide perspectives on how mitochondrial transfer may be translated into innovative therapies for ocular disorders.
Anatabine, a characteristic minor alkaloid derived from tobacco byproducts, exhibits unique structural analogy to nicotine but possesses a superior safety profile and lower addictive liability, rendering it a promising natural multi-target therapeutic candidate. Accumulating preclinical evidence has demonstrated that anatabine exerts neuroprotective, anti-inflammatory, and antioxidant effects mainly through modulating α7/α4β2 nicotinic acetylcholine receptors, suppressing NF-κB/STAT3 inflammatory signaling, and activating the Nrf2-mediated antioxidant pathway. It effectively ameliorates typical pathological alterations, including β-amyloid deposition, tau hyperphosphorylation, and microglial overactivation, thereby improving cognitive and behavioral deficits in neurodegenerative disease models. Additionally, anatabine displays broad pharmacological potentials in chronic inflammation, autoimmune thyroiditis, asthma, and hypertension. Differing from previous reviews that merely focused on single receptor regulation, the present work systematically summarizes the multi-target pharmacological characteristics of anatabine, comprehensively collates its preclinical efficacy across multiple disease categories, and highlights its advantages over nicotine in safety and addiction risk. Furthermore, we analyze the current limitations, druggability optimization challenges, and clinical translation prospects, and propose sustainable strategies for high-value utilization of tobacco byproducts. This review provides an updated and systematic theoretical basis for further mechanism exploration and therapeutic development of anatabine.
Nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) is a constitutively active enzyme that primarily produces hydrogen peroxide, a reactive oxygen species (ROS) with diverse cellular functions. While initially recognized for its role in oxidative stress, emerging evidence suggests that NOX4 plays a pivotal role in the pathogenesis of various lung diseases. This review delineates the structure characteristics of NOX4, emphasizing how its domain organization underlies a distinctive mode of molecular regulation. It further discusses current knowledge on the biological functions of NOX4-derived oxygen species, including their roles in modulating inflammation, cell death pathways, oxygen sensing, nuclear signaling, and metabolic reprogramming. Through these interconnected processes, NOX4 is positioned as a central mediator linking redox imbalance to cellular dysfunction. In addition, the contribution of NOX4 to the pathogenesis of major lung diseases, including idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), asthma, acute lung injury/acute respiratory distress syndrome (ALI/ARDS), and pulmonary hypertension are critically evaluated. Emerging therapeutic strategies targeting NOX4 are also discussed, together with key challenges associated with clinical translation, including isoform specificity, off-target effects, and tissue-selective delivery. Overall, this review provides an integrated framework for understanding NOX4 biology across multiple levels and highlights its potential as a therapeutic target in lung disease.
Open-access drug discovery platforms have accelerated hit identification and lead prioritization across multiple diseases and enable systematic repurposing of bioactive compounds beyond their original indications. However, there remains a need for new chemotypes for African trypanosomiasis with improved efficacy and resilience to emerging drug resistance. In this study, we evaluated the antitrypanosomal potential and cellular effects of two Pathogen Box compounds, MMV667494 and MMV028694. The compounds were selected through a resazurin-based in vitro phenotypic viability screen that measures metabolic activity as a proxy for parasite viability against bloodstream-form Trypanosoma brucei brucei. To explore cellular phenotypes consistent with potential mechanisms of action, we applied cytological profiling using flow cytometry- and microscopy-based assays, including Annexin V/propidium iodide staining, cell-cycle DNA-content analysis, mitochondrial membrane potential (TMRE), and mitochondrial reactive oxygen species (MitoSOX) measurements. Both MMV667494 and MMV028694 (IC50 = 0.44 ± 0.05 µM and 0.33 ± 0.03 µM, respectively) displayed sub-micromolar antitrypanosomal potency and preferential toxicity toward trypanosomes over mammalian cells (selectivity indices >10). Growth profiling demonstrated dose-dependent inhibition of parasite proliferation, with evidence of trypanocidal activity at higher concentrations and longer exposure times. Treatment resulted in increased populations of phosphatidylserine-exposed and membrane-compromised cells, which is consistent with apoptosis-like phenotypes in trypanosomes. Although both compounds induced mitochondrial membrane depolarization in treated T. b. brucei cells, this effect was observed predominantly in a subpopulation of cells and is therefore unlikely to represent the primary cause of cell death. Increased mitochondrial production of reactive oxygen species and altered cell-cycle progression were also observed, which might indicate disruption of key cellular processes. These findings shows that MMV667494 and MMV028694 are selective antitrypanosomal compounds and their activities are associated with induce apoptosis-like features, cell-cycle disruption, and mitochondrial stress signatures in bloodstream-form T. b. brucei. These findings provide phenotypic insights into the activity of the compounds, warranting further target deconvolution and optimization, although validation in human-infective subspecies and in vivo systems will be required.
High systolic blood pressure (HSBP) is a major modifiable risk factor for stroke, but trends in disease burden and causal associations related to HSBP in the United States require further investigation using multidimensional approaches. This study aims to elucidate this relationship by utilizing data from the Global Burden of Disease (GBD) database, the National Health and Nutrition Examination Survey (NHANES). This study integrated data from the GBD 2021 database and the NHANES. The GBD data provided macro-level estimates of stroke-related mortality and disability-adjusted life years (DALYs) attributable to various risk factors within the United States. By employing multivariable logistic regression models on individual-level NHANES data, the study assessed the association between HSBP history and stroke risk after adjusting for multiple confounding factors. GBD analysis revealed HSBP as the leading risk factor for U.S. stroke burden in 2021, with an increasing attributable burden since 2010, particularly among the elderly and women. NHANES analysis showed that HSBP significantly increased the risk of stroke (fully adjusted OR = 1.33, 95% CI: 1.17–1.51). Elevated SBP was additionally associated with increased all-cause mortality risk in stroke survivors (HR = 1.01). A novel U-shaped relationship emerged: stroke risk decreased below an SBP of 100 mmHg but increased sharply above this threshold. HSBP is the core driver and modifiable risk factor behind the persistently increasing stroke burden in the United States. The findings of this study highlight the critical importance of HSBP in stroke prevention and management.
The advancement in the use of all-human high content microphysiological systems (MPS) has enabled better in vitro modeling of liver function and disease progression as well as drug efficacy, metabolism and toxicity (ADME-Tox) testing. However, a continuing need in liver MPS development is balancing throughput without loss of the high-content biological complexity required for physiologically relevant modeling. Here, we present a scalable version of our well-established liver acinus microphysiological system (LAMPS). This higher-throughput format (ht-LAMPS) is designed to recapitulate the physiological complexity of the standard single-chamber LAMPS system while increasing experimental capacity through a seven-chamber microfluidic design. The ht-LAMPS is constructed using the same four key liver cell types as the LAMPS: primary hepatocytes and liver sinusoidal endothelial cells (LSECs) as well as Kupffer-like cells (THP-1) and hepatic stellate cells (LX-2). It recapitulates key physiological characteristics previously established in the LAMPS platform, including oxygen zonation-dependent liver phenotypes including model viability, secretion of functional and cytotoxicity markers, mitochondrial activity, and lipid accumulation, demonstrating reproducibility in the ht-LAMPS format. Finally, we also demonstrate that the ht-LAMPS model recapitulates key phenotypes associated with the progression of metabolic dysfunction-associated steatotic liver disease (MASLD), including increased steatosis and elevated production of inflammatory cytokines and profibrotic markers using our established MASLD media formulations. Overall, by increasing throughput while maintaining key high-content biological features of the LAMPS, ht-LAMPS provides a scalable platform for investigating liver function, modeling disease progression, and enabling downstream drug testing in MASLD and other liver-related conditions.
Retinopathy of prematurity (ROP) is a leading cause of childhood blindness that arises from disrupted retinal vascular development in premature infants. Oxygen exposure remains a central driver of treatment-warranted ROP, as higher saturation levels suppress early retinal vascular growth and later promote pathological neovascularization. Large, randomized trials of oxygen targeting show that lower oxygen saturation ranges reduce the incidence of treatment-requiring ROP, though with trade-offs in mortality. Observational cohorts, including the CRYO-ROP, ETROP, and e-ROP trials, consistently report lower rates of treatment-warranted ROP and reduced treatment need among Black infants despite similar or greater prematurity risk. Multiple explanations have been proposed to account for the paradoxically lower rates of treatment-warranted ROP observed among Black infants. Although biologic variations in angiogenic pathways have been proposed, evidence suggests that structural and clinical factors may offer an alternative explanation for these patterns. Black race is strongly correlated with residence in neighborhoods with greater socioeconomic disadvantage, which is associated with increased risk of prematurity and missed ROP follow-up visits. In addition, pulse oximeters may overestimate oxygen saturation in individuals with darker skin pigmentation, potentially altering targeted oxygen exposure. Survival-related selection bias may further contribute to this paradox, as infants at the highest risk of both mortality and treatment-warranted ROP may not survive long enough to develop treatment-requiring disease. This review examines racial differences in ROP severity and examines how oxygen exposure and structural factors may contribute to these disparities, while acknowledging the limited evidence supporting biologic explanations.
The diagnosis of amyotrophic lateral sclerosis (ALS) mainly relies on clinical symptoms and the exclusion of other diseases, with a lack of specific biomarkers, leading to delayed diagnosis and a high rate of misdiagnosis. This study aims to explore the utility of peripheral immune cells and glycosylation indices as potential diagnostic biomarkers for ALS to enhance the accuracy and efficiency of early ALS diagnosis. This retrospective study included 54 ALS patients diagnosed in our hospital from June 2023 to October 2024, along with 54 healthy controls. Blood samples and laboratory data, including levels of peripheral immune cells and glycosylation indices, were collected from both groups. Through logistic regression, random forest models, receiver operating characteristic (ROC) curve analysis, and SHAP interpretability analysis, the predictive abilities and clinical significance of each candidate indicator were screened and evaluated. Notable disparities were detected in age, leukocyte count, monocyte levels, glycated haemoglobin A1c (HbA1c), and haemoglobin glycation index (HGI) between the control and ALS groups (all P < 0.05). Logistic regression analysis revealed that age (OR = 1.114) and monocyte (OR = 3.174) were risk factors for ALS, while leukocyte (OR = 0.533) and HbA1c (OR = 0.069) were protective factors. The random forest algorithm, ranked by decreasing importance, showed that leukocyte, HGI, monocyte, and HbA1c level all influenced ALS. Using these indicators to predict ALS resulted in a false-positive rate of 18% and a false-negative rate of 6%. ROC curve analysis indicated that the combined use of leukocyte, monocyte, HbA1c level, and HGI provided the highest diagnostic value for ALS (AUC = 0.774), which was higher than that of any individual indicator (all P < 0.05). SHAP analysis visualization demonstrated that increased monocyte and decreased leukocyte, HGI, and HbA1c level were all associated with an increased risk of ALS onset, ranked in descending order of feature importance as monocyte, leukocyte, HGI, and HbA1c. Peripheral blood white blood cells, monocytes, HbA1c, and HGI can serve as potential diagnostic biomarkers for ALS. Combined detection can improve the diagnostic accuracy of ALS, facilitating early diagnosis and intervention, and ultimately improving patient prognosis. Further validation in cohorts including disease controls is required to confirm specificity.
Cardiovascular diseases represent the leading cause of global mortality and disability, posing a severe threat to human health. Accumulating evidence suggests that antigen-antibody-mediated immune responses may be involved in the pathogenesis of various cardiovascular conditions; however, whether these associations reflect causal relationships has long remained unclear. To address this question, we conducted a bidirectional two-sample Mendelian randomization study leveraging summary-level data from genome-wide association studies. In this analysis, 46 antibody-mediated immune traits were evaluated as exposures, and 11 cardiovascular outcomes, including aortic aneurysm, aortic valve stenosis, atrial fibrillation, coronary artery disease, dilated cardiomyopathy, atrioventricular block, heart failure with reduced ejection fraction, hypertrophic cardiomyopathy, infective endocarditis, myocarditis, and pericarditis, were examined as outcomes. Our results revealed several significant causal associations: genetically predicted higher levels of Epstein-Barr virus EBNA-1 antibodies were associated with increased risks of myocarditis and aortic valve stenosis, while elevated VCA p18 antibody levels were linked to a higher risk of myocarditis. Furthermore, increased antibody levels against BK polyomavirus VP1 were causally associated with greater risks of aortic valve stenosis and dilated cardiomyopathy. In contrast, higher levels of antibodies against varicella-zoster virus glycoproteins and human herpesvirus 6 IE1B were associated with reduced risks of myocarditis and aortic aneurysm, respectively. These findings not only help clarify the causal role of immune-mediated mechanisms in cardiovascular pathogenesis but also provide a theoretical foundation for the future development of immune-targeted strategies for prevention and treatment.
Current evidence supports the potential association between several common oral diseases and hypertension. The aim of the research is to clarify the causal relationship between these oral diseases and hypertension using Mendelian randomization (MR) analysis. Single nucleotide polymorphisms (SNPs) related to five oral traits (periodontitis, bleeding gums, loose teeth, periapical abscess and dental caries) were obtained from GWAS catalog, while those associated with hypertension (essential and secondary) were extracted from the FinnGen database. The SNPs were employed as instrumental variables (IVs) in the MR analysis. Assorted methods were applied, and inverse variance-weighted (IVW) analytical method was prioritized. Sensitivity analyses including MR-PRESSO method, MR Egger intercept test, Cochran's Q test, leave-one-out analysis and MR Steiger test were conducted. Our analysis identified the potential causal relationship between dental caries and essential hypertension. The forward MR analysis demonstrated a significant causal effect of dental caries on essential hypertension (OR = 1.036, 95%CI: 1.012-1.059, P = 0.003). The reverse analysis also indicated a significant causal effect (OR = 1.160, 95%CI: 1.016-1.323, P = 0.028). Additionally, we observed a causal effect of bleeding gums on essential hypertension (OR = 1.145, 95%CI: 1.019-1.288, P = 0.023). These findings support the potential causality between specific oral diseases and essential hypertension.
Doxorubicin-induced cardiotoxicity remains a leading cause of mortality among cancer patients, with oxidative stress serving as a central pathogenic mechanism. This study investigated whether combination therapy with sacubitril valsartan and bisoprolol attenuates doxorubicin-induced cardiotoxicity through modulation of oxidative stress pathways. Sixty male Sprague-Dawley rats were randomized into five groups: control, doxorubicin (DOX), bisoprolol (1.0 mg/kg/d), sacubitril valsartan (30 mg/kg/d), and combination therapy. All groups except control received intraperitoneal DOX (2.5 mg/kg weekly for 5 weeks). Cardiac function was assessed by echocardiography, myocardial injury by histopathology and enzyme levels (CK-MB, cTnI, BNP), and oxidative stress by ROS fluorescence, MDA, and SOD. Protein expression of Nrf2, HO-1, and Keap1 was analyzed by Western blot. DOX administration significantly impaired cardiac function, induced myocardial structural damage, elevated cardiac enzymes and oxidative stress markers, and downregulated Nrf2 pathway proteins compared to controls (all P < 0.05). All treatment groups significantly attenuated these abnormalities versus DOX (all P < 0.05), with combination therapy demonstrating superior cardioprotection evidenced by greatest improvement in LVEF (68.74 ± 6.87% vs. 50.26 ± 6.11%, P < 0.05), lowest cardiac enzyme levels, and most robust restoration of Nrf2 pathway expression. These findings demonstrate that sacubitril valsartan combined with bisoprolol effectively reduces doxorubicin-induced cardiotoxicity in rats by activating Nrf2-mediated antioxidant responses, providing experimental evidence for a potentially synergistic prophylactic strategy.
