Bioinformatics and experimental studies jointly reveal that Sacubitril Valsartan improves myocardial oxidative stress and inflammation by regulating the MAPK signaling pathway to treat chemotherapy related cardiotoxicity.

BACKGROUND: CRC is a common but serious complication or sequela of tumor treatment, and new coping strategies are urgently needed. SV is a classic clinical cardiovascular protective drug, which has been widely used in the treatment of heart failure, hypertension and other diseases. It has good therapeutic effect in other cardiovascular diseases such as diabetes cardiomyopathy, ischemic cardiomyopathy and vascular disease, but it has not been proved by research that SV can prevent and treat CRC. METHOD: In this study, DOX was used to induce a rat CRC model and evaluate the therapeutic effect of SV on it. Subsequently, R software was applied to analyze the control group, SV group, and DOX group in databases GSE207283 and GSE22369, and to screen for common differentially expressed genes. Use the DAVID website for enrichment analysis and visualization. Use STRING website to analyze and visualize protein interaction networks of key genes. Finally, experimental verification was conducted on key genes. RESULT: Our research results show that SV has a protective effect on DOX induced myocardial injury by alleviating Weight loss, increasing Ejection fraction, and reducing the level of biomarkers of myocardial injury. Meanwhile, SV can effectively alleviate the above abnormalities. Bioinformatics and KEGG pathway analysis showed significant enrichment of metabolic and MAPK signaling pathways, suggesting that they may be the main regulatory pathway for SV treatment of CRC. Subsequent studies have also confirmed that SV can inhibit DOX induced myocardial injury through the MAPK signaling pathway, and alleviate DOX induced oxidative stress and inflammatory states. CONCLUSION: Our research indicates that SV is a potential drug for treating CRC and preliminarily elucidates its molecular mechanism of regulating the MAPK pathway to improve oxidative stress and inflammation.

Research Progress on Flavonoids in Traditional Chinese Medicine to Counteract Cardiotoxicity Associated with Anti-Tumor Drugs.

The development of anti-tumor drugs has notably enhanced the survival rates and quality of life for patients with malignant tumors. However, the side effects of these drugs, especially cardiotoxicity, significantly limit their clinical application. The cardiotoxicity associated with anti-tumor drugs has been a subject of extensive attention and research. Traditional to mitigate these side effects have included reducing drug dosages, shortening treatment duration, modifying administration methods, and opting for drugs with lower toxicity. However, either approach may potentially compromise the anti-tumor efficacy of the medications. Therefore, exploring other effective methods for anti-cardiotoxicity will be the focus of future research. The potential of traditional Chinese medicine (TCM) in managing cardiovascular diseases and cancer treatment has gained widespread recognition. TCM is valued for its minimal side effects, affordability, and accessibility, offering promising avenues in the prevention and treatment of cardiotoxicity caused by anti-tumor drugs. Among its constituents, flavonoids, which are present in many TCMs, are particularly notable. These monomeric compounds with distinct structural components have been shown to possess both cardiovascular protective properties and anti-tumor capabilities. In this discussion, we will delve into the classification of anti-tumor drugs and explore the underlying mechanisms of their associated cardiotoxicity. Additionally, we will examine flavonoids found in TCM and investigate their mechanisms of cardiovascular protection. This will include an analysis of how these natural compounds can mitigate the cardiac side effects of anti-tumor therapies while potentially enhancing overall patient health and treatment outcomes.

Effects of warming at embryonic and larval stages on tadpole fitness in high-altitude Rana kukunoris.

Global warming may affect the early developmental stages of high-altitude amphibians, thereby influencing their later fitness. Yet, this has been largely unexplored. To investigate whether and how the temperatures experienced by embryonic and larval stages affect their fitness at later developmental stages, we designed two experiments in which the embryos and larvae were treated with three temperatures (24, 18 and 12 °C), respectively. Then, the life history traits of the tadpoles during the metamorphotic climax in all treatments were evaluated, including growth rate, survival rate, morphology, thermal physiology, swimming performance, standard metabolic rate (SMR), oxidative and antioxidative system, and metabolic enzyme activities. The results revealed that elevated temperature accelerated metamorphosis but decreased body size at metamorphosis. Additionally, warming during the embryonic and larval stages decreased the thermal tolerance range and induced increased oxidative stress. Furthermore, high embryonic temperature significantly decreased the hatching success, but had no significant effect on swimming performance and SMR. Warming during larval periods was harmful to the survival and swimming performance of tadpoles. The effect size analysis revealed that the negative impacts of embryonic temperature on certain physiological traits, such as growth and development, survival and swimming performance, were more pronounced than those of larval temperature. Our results highlight the necessity for particular attention to be paid to the early stages of amphibians, notably the embryonic stages when evaluating the impact of global warming on their survival.

Potential Effects of High Temperature and Heat Wave on Nanorana pleskei Based on Transcriptomic Analysis.

In the context of climate change, understanding how indigenous amphibians of the Qinghai-Tibet plateau react to stresses and their coping mechanisms could be crucial for predicting their fate and successful conservation. A liver transcriptome for Nanorana pleskei was constructed using high-throughput RNA sequencing, and its gene expression was compared with frogs acclimated under either room temperature or high temperature and also heat wave exposed ones. A total of 126,465 unigenes were produced, with 66,924 (52.92%) of them being annotated. Up to 694 genes were found to be differently regulated as a result of abnormal temperature acclimatization. Notably, genes belonging to the heat shock protein (HSP) family were down-regulated in both treated groups. Long-term exposure to high-temperature stress may impair the metabolic rate of the frog and trigger the body to maintain a hypometabolic state in an effort to survive challenging times. During heat waves, unlike the high-temperature group, mitochondrial function was not impaired, and the energy supply was largely normal to support the highly energy-consuming metabolic processes. Genes were more transcriptionally suppressed when treated with high temperatures than heat waves, and the body stayed in low-energy states for combating these long-term adverse environments to survive. It might be strategic to preserve initiation to executive protein activity under heat wave stress. Under both stress conditions, compromising the protection of HSP and sluggish steroid activity occurred in frogs. Frogs were more affected by high temperatures than by heat waves.

Ring finger protein 10 improves pirarubicin-induced cardiac inflammation by regulating the AP-1/Meox2 signaling pathway.

OBJECTIVES: Pirarubicin (THP) is widely used in clinical antitumor therapy, but its cardiotoxicity seriously affects the therapeutic effect in patients. In the study, we investigated the role of ring finger protein 10 (RNF10) in cardiotoxicity induced by THP. MATERIALS AND METHODS: A cardiac toxicity model in Sprague-Dawley (SD) rats induced by THP was established. Changes in diet, weight, electrocardiogram (ECG), and echocardiography were observed. Serum levels of brain natriuretic peptide (BNP), creatine kinase MB (CK-MB), cardiac troponin T (cTnT), and lactate dehydrogenase (LDH) were measured. The expression of RNF10 in myocardium was observed by immunohistochemistry. The expressions of RNF10, activator protein-1 (AP-1), mesenchyme homeobox 2 (Meox2), total nuclear factor (NF)-κB p65 (T-P65), phosphorylated NF-κB p65 (PP65), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor (TNF)-α, interleukin (IL)-6, and mature IL-1ß were detected by Western blot. A THP-induced H9c2 myocardial cell injury model was established. RNF10 was downregulated or overexpressed by RNF10 siRNA and a RNF10 lentiviral vector, respectively. Then, cell viability was measured. The expression of RNF10 in H9c2 cells was observed by immunofluorescence. All of the above signaling pathways were verified by Western blots. FINDINGS: THP caused a series of cardiotoxic manifestations in SD rats. Our studies suggested that THP caused cardiac inflammation by inhibiting the expression of RNF10, while overexpression of RNF10 antagonized the cardiotoxicity induced by THP. SIGNIFICANCE: Our study showed RNF10 improved THP-induced cardiac inflammation by regulating the AP-1/Meox2 signaling pathway. RNF10 may be a new target to treat THP-induced cardiotoxicity.

The 'diamond' approach to personalized drug treatment of heart failure with reduced ejection fraction.

Heart failure (HF) is a complex clinical syndrome with symptoms and signs due to cardiac dysfunction, leading to high hospitalization and morbidity. HF treatment has rapidly developed in recent decades, and breakthroughs have been made. Although conventional neurohormonal blockade therapies, including ß-blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and mineralocorticoid receptor antagonists (MRAs), significantly improve the prognosis of patients with heart failure with reduced ejection fraction (HFrEF), mortality and rehospitalization remain high. Therefore, new therapies are needed. Previous studies demonstrated that ivabradine, angiotensin receptor-neprilysin inhibitor (ARNI), sodium-glucose cotransporter 2 (SGLT2) inhibitor, vericiguat, and omecamtiv mecarbil (OM) are beneficial for HFrEF. However, there is a lack of systematic review of the most optimal manner to use under various clinical conditions. This review summarizes the current knowledge regarding these therapies to give suggestions regarding clinical use timing, application scope, and optimal therapies under various conditions. Most importantly, we propose the HF diamond approach to express the necessity of conjunction of therapies. Different from the current guidelines, we suggest to use the diamond approach in an early and comprehensive manner at the beginning of ventricular remodeling in HFrEF to prevent further deterioration of HF and maximize the prognosis of patients.

Sulfur application reduces cadmium uptake in edible parts of pakchoi (Brassica chinensis L.) by cadmium chelation and vacuolar sequestration.

Sulfur (S) application in pakchoi (Brassica chinensis L.) cultivation is vital for reducing cadmium (Cd) accumulation in the plants. However, the mechanism of S application on Cd uptake and translocation in pakchoi is unclear. In this study, a hydroponic experiment was performed to investigate the effects of S application on Cd accumulation in pakchoi at one Cd concentration (50 µM, in comparison to the control condition, 0 µM) and three S levels (0, 2, 4 mM). The results showed that excessive S application (4 mM) reduced Cd accumulation and alleviated pakchoi growth inhibition caused by Cd stress in shoots and roots. With increased S application, the proportion of Cd in the vacuolar fraction and the proportion of NaCl-extractable Cd increased in roots. Additionally, S application increased the content of glutathione (GSH) and phytochelatins (PCs). The reduced Cd uptake and accumulation in pakchoi shoots could have been due to increased Cd chelation and vacuolar sequestration in roots. In addition, sufficient S application (2 mM) increased the expression of γ-glutamylcysteine synthetase (GSH1) and nicotinamide synthase (NAS) in roots, and excessive S application upregulated the expression of ATP sulfurylase (ATPS) and phytochelatin synthase (PCs). This study provides evidence for the mechanism of mitigating Cd toxicity in pakchoi and will be helpful for developing strategies to reduce Cd accumulation in the edible parts of pakchoi through S fertilizer application.

RING finger protein 10 attenuates vascular restenosis by inhibiting vascular smooth muscle cell hyperproliferation in vivo and vitro.

Vascular smooth muscle cell (VSMC) hyperproliferation is the main pathological process in various cardiovascular diseases, such as vascular restenosis. This process may be repressed by RING finger protein 10 (RNF10) in metabolic syndrome (MetS) rats. The aim of this study is to evaluate the inhibitory effects and molecular mechanisms of RNF10 on VSMC hyperproliferation. Neointimal hyperplasia in MetS and high-glucose-induced VSMC hyperproliferation were measured after infection with adenoviruses encoding RNF10 (Ad-RNF10), short hairpin RNF10 (Ad-shRNF10), or green fluorescent protein (Ad-GFP). In vivo and in vitro, we found that overexpression of RNF10 significantly affected neointima formation and VSMC proliferation, and displayed further inhibitory activity by promoting mesenchyme homeobox 2 (Meox2) and suppressing activating protein 1 (AP-1). In contrast, Ad-shRNF10 had an opposite effect on neointimal hyperplasia and VSMC hyperproliferation in vivo and in vitro. Our study indicated that RNF10 inhibited the hyperproliferation with the activities of Meox2 and AP-1 proteins. RNF10 may be a next drug target for treating vascular restenosis and other related cardiovascular diseases. © 2018 IUBMB Life, 71(5):632-642, 2019.

Oxygenation properties and underlying molecular mechanisms of hemoglobins in plateau zokor (Eospalax baileyi).

The plateau zokor (Eospalax baileyi) is a species of subterranean rodent endemic to the Tibetan Plateau. It is well adapted to the cold and hypoxic and hypercapnic burrow. To study the oxygenation properties of plateau zokor hemoglobins (Hbs), we measured intrinsic Hb-O2 affinities and their sensitivities to pH (Bohr effect); CO2; Cl-, 2,3-diphosphoglycerate (DPG); and temperature using purified Hbs from zokor and mouse. The optimal deoxyHb model of plateau zokor was constructed and used to study its structural characteristics by molecular dynamics simulations. O2 binding results revealed that plateau zokor Hbs exhibit remarkably high intrinsic Hb-O2 affinity, low CO2 effects compared with human and the relatively low anion allosteric effector sensitivities (DPG and Cl-) at normal temperature, which would safeguard the pulmonary Hb-O2 loading under hypoxic and hypercapnic conditions. Furthermore, the high anion allosteric effector sensitivities at low temperature and low temperature sensitivities of plateau zokor Hbs would facilitate the releasing of O2 in cold extremities and metabolic tissues. However, the high Hb-O2 affinity of plateau zokor is not compensated by high pH sensitivity as the Bohr factors of plateau zokor Hbs were as low as those of mouse. The results of molecular dynamics simulations revealed the reduced hydrogen bonding between the α1ß1- and α2ß2-dimer interface of deoxyHb in zokor compared with mouse. It may be the primary mechanism of the high intrinsic Hb-O2 affinities in zokor. Specifically, substitution of the 131Ser→Asn in the α2-chain weakened the connection between α1- and ß2-subunit.

[Protection mechanisms of hesperidin on mouse with insulin resistance].

To explore the effects of hesperidin on glycolipid metabolic disorders and its mechanism in mice induced by high-fat diet, 40 male C57 mice were randomly divided into control group, OB group, low dose group (OB+ hes-low) and high dose group (OB+ hes-high) according to the diet. After 16 weeks, the body weight, liver index and visceral fat index in all mice were detected. The glucose metabolism indications (blood glucose, insulin levels and HOMA-IR) and serum lipid levels were evaluated. The mRNA expression of insulin signaling pathway genes(IR, IRS1, Glut2, Glut4), lipid metabolism pathway genes(SREBP-1c, FAS, ACC, PPARα) and AMPK were analyzed by Real-time PCR. After 16-week feeding, the indicators in OB group were higher than those in control group, including body weight, body fat deposition, serum glucose, serum lipid, serum insulin and HOMA-IR index (P<0.05). And impaired glucose tolerance occurred in the OB group (P<0.05). Treating with hesperidin, whether in low or high dose, attenuated these changes (P<0.05), especially in high dose group(P<0.05). Hesperidin, especially in high dose, upregulated the mRNA expressions of AMPK (P<0.05), which had impact on the gene expressions of insulin signaling pathway (IR, IRS-1, Glut2/4) (P<0.05) and lipid metabolism related genes (SREBP-1c and Fas and ACC) (P<0.05). The activatory effect of hesperidin on the mRNA expressions of PPARα was also observed (P<0.05), especially in high dose group (P<0.05). Hesperidin inhibits obesity, hyperglycemia, hyperlipemia and attenuates insulin resistance. These effects might be closed related to the activation of AMPK, which regulate the insulin signaling pathway and lipid metabolism.

Suv39h1 protects from myocardial ischemia-reperfusion injury in diabetic rats.

BACKGROUND: Patients with diabetes are at increased risk of ischemic events. Suv39h1 is a histone methyltransferase that catalyzes the methylation of histone 3 lysine 9, which is associated with the suppression of inflammatory genes in diabetes. However, the role of Suv39h1 in myocardial ischemia/reperfusion (I/R) injury under diabetic condition has not been evaluated. METHODS: To generate diabetic model, male SD rats were fed with 60% fat diet followed by intraperitoneal injection with 40mg/kg streptozotocin. Adenovirus encoding Suv39h1 gene was used for Suv39h1 overexpression. Each rat received injections of adenovirus at five myocardial sites. Three days after gene transfection, each rat was subjected to left main coronary artery occlusion and reperfusion. After 30 min ischemia and reperfusion for 4 h, the rats were euthanized for real-time PCR, Western blot, immunohistochemical staining, and morphometric analysis. RESULTS: Delivery of Ad-Suv39h1 into the hearts of diabetic rats could markedly increase Suv39h1 expression. Up-regulation of Suv39h1 significantly reduced infarct size and tissue damage after I/R injury, which was associated with protection from apoptosis of cardiac myocytes and reduction of inflammatory response. In addition, compared with injury group, Ad-Suv39h1 led to a decreased activity of mitogen-activated protein kinase family and its down-steam transcriptional factor NF-κB. CONCLUSION: Overexpression of Suv39h1 results in the de-activation of proinflammatory pathways and reduced apoptosis and myocardial injury. Therefore, Suv39h1 might represent a novel therapeutic strategy to reduce I/R injury under diabetic condition.

Food therapy of scutellarein ameliorates pirarubicin­induced cardiotoxicity in rats by inhibiting apoptosis and ferroptosis through regulation of NOX2­induced oxidative stress.

Pirarubicin (THP) is one of the most commonly used antineoplastic drugs in clinical practice. However, its clinical application is limited due to its toxic and heart­related side effects. It has been reported that oxidative stress, inflammation and apoptosis are closely associated with cardiotoxicity caused by pirarubicin (CTP). Additionally, it has also been reported that scutellarein (Sc) exerts anti­inflammatory, antioxidant, cardio­cerebral vascular protective and anti­apoptotic properties. Therefore, the present study aimed to investigate the effect of food therapy with Sc on CTP and its underlying molecular mechanism using echocardiography, immunofluorescence, western blot, ROS staining, and TUNEL staining. The in vivo results demonstrated that THP was associated with cardiotoxicity. Additionally, abnormal changes in the expression of indicators associated with oxidative stress, ferroptosis and apoptosis were observed, which were restored by Sc. Therefore, it was hypothesized that CTP could be associated with oxidative stress, ferroptosis and apoptosis. Furthermore, the in vitro experiments showed that Sc and the NADPH oxidase 2 (NOX2) inhibitor, GSK2795039 (GSK), upregulated glutathione peroxidase 4 (GPX4) and inhibited THP­induced oxidative stress, apoptosis and ferroptosis. However, cell treatment with the ferroptosis inhibitor, ferrostatin­1, or inducer, erastin, could not significantly reduce or promote, respectively, the expression of NOX2. However, GSK significantly affected ferroptosis and GPX4 expression. Overall, the results of the present study indicated that food therapy with Sc ameliorated CTP via inhibition of apoptosis and ferroptosis through regulation of NOX2­induced oxidative stress, thus suggesting that Sc may be a potential therapeutic drug against CTP.

Convergent High O2 Affinity but Distinct ATP-Mediated Allosteric Regulation of Hemoglobins in Oviparous and Viviparous Eremias Lizards from the Qinghai-Tibet Plateau.

The functional adaptation and underlying molecular mechanisms of hemoglobins (Hbs) have primarily concentrated on mammals and birds, with few reports on reptiles. This study aimed to investigate the convergent and species-specific high-altitude adaptation mechanisms of Hbs in two Eremias lizards from the Qinghai-Tibet Plateau. The Hbs of high-altitude E. argus and E. multiocellata were characterized by significantly high overall and intrinsic Hb-O2 affinity compared to their low-altitude populations. Despite the similarly low Cl- sensitivities, the Hbs of high-altitude E. argus exhibited higher ATP sensitivity and ATP-dependent Bohr effects than that of E. multiocellata, which could facilitate O2 unloading in respiring tissues. Eremias lizards Hbs exhibited similarly low temperature sensitivities and relatively high Bohr effects at lower temperatures, which could help to stably deliver and release O2 to cold extremities at low temperatures. The oxygenation properties of Hbs in high-altitude populations might be attributed to varying ratios of ß2/ß1 globin and substitutions on the ß2-type globin. Notably, the Asn12Ala in lowland E. argus could cause localized destabilization of the E-helix in the tetrameric Hb by elimination of hydrogen bonds, thereby resulting in its lowest O2 affinity. This study provides a valuable reference for the high-altitude adaptation mechanisms of hemoglobins in reptiles.

Associations of educational attainment with Sepsis mediated by metabolism traits and smoking: a Mendelian randomization study.

Objective: Sepsis constitutes a significant global healthcare burden. Studies suggest a correlation between educational attainment and the likelihood of developing sepsis. Our goal was to utilize Mendelian randomization (MR) in order to examine the causal connection between educational achievement (EA) and sepsis, while measuring the mediating impacts of adjustable variables. Methods: We collected statistical data summarizing educational achievement (EA), mediators, and sepsis from genome-wide association studies (GWAS). Employing a two-sample Mendelian randomization (MR) approach, we calculated the causal impact of education on sepsis. Following this, we performed multivariable MR analyses to assess the mediation proportions of various mediators, including body mass index (BMI), smoking, omega-3 fatty acids, and apolipoprotein A-I(ApoA-I). Results: Genetic prediction of 1-SD (4.2 years) increase in educational attainment (EA) was negatively correlated with sepsis risk (OR = 0.83, 95% CI 0.71 to 0.96). Among the four identified mediators, ranked proportionally, they including BMI (38.8%), smoking (36.5%), ApoA-I (6.3%) and omega-3 (3.7%). These findings remained robust across a variety of sensitivity analyses. Conclusion: The findings of this study provided evidence for the potential preventive impact of EA on sepsis, which may be influenced by factors including and metabolic traits and smoking. Enhancing interventions targeting these factors may contribute to reducing the burden of sepsis.

Correlation and predictive value of pathological complete response and ultrasound characteristic parameters in neoadjuvant chemotherapy for breast.

BACKGROUND: Breast cancer ranks as one of the most prevalent malignant tumors among women, significantly endangering their health and lives. While radical surgery has been a pivotal method for halting disease progression, it alone is insufficient for enhancing the quality of life for patients. AIM: To investigate the correlation between ultrasound characteristic parameters of breast cancer lesions and clinical efficacy in patients undergoing neoadjuvant chemotherapy (NAC). METHODS: Employing a case-control study design, this research involved 178 breast cancer patients treated with NAC at our hospital from July 2019 to June 2022. According to the Miller-Payne grading system, the pathological response, i.e. efficacy, of the NAC in the initial breast lesion after NAC was evaluated. Of these, 59 patients achieved a pathological complete response (PCR), while 119 did not (non-PCR group). Ultrasound characteristics prior to NAC were compared between these groups, and the association of various factors with NAC efficacy was analyzed using univariate and multivariate approaches. RESULTS: In the PCR group, the incidence of posterior echo attenuation, lesion diameter ≥ 2.0 cm, and Alder blood flow grade ≥ II were significantly lower compared to the non-PCR group (P < 0.05). The area under the curve values for predicting NAC efficacy using posterior echo attenuation, lesion diameter, and Alder grade were 0.604, 0.603, and 0.583, respectively. Also, rates of pathological stage II, lymph node metastasis, vascular invasion, and positive Ki-67 expression were significantly lower in the PCR group (P < 0.05). Logistic regression analysis identified posterior echo attenuation, lesion diameter ≥ 2.0 cm, Alder blood flow grade ≥ II, pathological stage III, vascular invasion, and positive Ki-67 expression as independent predictors of poor response to NAC in breast cancer patients (P < 0.05). CONCLUSION: While ultrasound characteristics such as posterior echo attenuation, lesion diameter ≥ 2.0 cm, and Alder blood flow grade ≥ II exhibit limited predictive value for NAC efficacy, they are significantly associated with poor response to NAC in breast cancer patients.

GPRC5A promotes gallbladder cancer metastasis by upregulating TNS4 via the JAK2-STAT3 pathway.

Aberrant expression of G protein-coupled receptor class C group 5 member A (GPRC5A) has been reported in multiple cancers and is closely related to patient prognosis. However, the mechanistic role of GPRC5A in gallbladder cancer (GBC) remains unclear. Here, we determined tumor expression levels of GPRC5A and the molecular mechanisms by which GPRC5A regulates gallbladder cancer metastasis. We found that GPRC5A was significantly upregulated in GBC, correlating with poorer patient survival. Knocking down GPRC5A inhibited GBC cell metastasis both in vitro and in vivo. GRPRC5A knockdown resulted in downregulation of TNS4 expression through the JAK2-STAT3 axis. Clinically, GPRC5A expression positively correlated with TNS4. Finally, STAT3 bound to TNS4's promoter region, inducing its expression. Overall, GPRC5A showed high expression in GBC tissues, associated with poor patient prognosis. Our findings first demonstrate that the GPRC5A-JAK2-STAT3-TNS4 pathway promotes GBC cell metastasis, suggesting potential therapy targets.

Topological reorganization and functional alteration of distinct genomic components in gallbladder cancer.

Altered three-dimensional architecture of chromatin influences various genomic regulators and subsequent gene expression in human cancer. However, knowledge of the topological rearrangement of genomic hierarchical layers in cancer is largely limited. Here, by taking advantage of in situ Hi-C, RNA-sequencing, and chromatin immunoprecipitation sequencing (ChIP-seq), we investigated structural reorganization and functional changes in chromosomal compartments, topologically associated domains (TADs), and CCCTC binding factor (CTCF)-mediated loops in gallbladder cancer (GBC) tissues and cell lines. We observed that the chromosomal compartment A/B switch was correlated with CTCF binding levels and gene expression changes. Increased inter-TAD interactions with weaker TAD boundaries were identified in cancer cell lines relative to normal controls. Furthermore, the chromatin short loops and cancer unique loops associated with chromatin remodeling and epithelial-mesenchymal transition activation were enriched in cancer compared with their control counterparts. Cancer-specific enhancer-promoter loops, which contain multiple transcription factor binding motifs, acted as a central element to regulate aberrant gene expression. Depletion of individual enhancers in each loop anchor that connects with promoters led to the inhibition of their corresponding gene expressions. Collectively, our data offer the landscape of hierarchical layers of cancer genome and functional alterations that contribute to the development of GBC.

Bilateral superselective adrenal artery embolization for bilateral primary aldosteronism: a novel approach in an efficacy and safety proof-of-principle trial.

Superselective adrenal artery embolization (SAAE) offers a novel approach for treating primary aldosteronism (PA). In this study, we aimed to assess the efficacy and safety of SAAE for the treatment of PA based on the lateralization results obtained from adrenal vein sampling (AVS).In this prospective study, we enrolled 40 patients with PA who underwent SAAE. The patients were categorized into two groups, unilateral PA and bilateral PA, based on AVS results. Clinical parameters and biochemical markers were assessed at 3 and 12 months postoperatively. The primary outcomes were changes in blood pressure and defined daily dose (DDD) of antihypertensive medications compared to baseline. Thirty-eight patients achieved technical success, with favorable clinical and biochemical efficacy rates. At three months postoperatively, the clinical efficacy rates were 79.2% and 78.6% for the UPA and BPA groups, respectively. At 12 months, the rates were 83.3% and 71.4%, respectively. Both groups exhibited a significant decrease in average blood pressure at 3 and 12 months compared with baseline (P < 0.001), and there was also a notable reduction in DDD (P < 0.05). At three months, the biochemical efficacy rates were 61.9% and 58.3% in the UPA and BPA groups, respectively. Due to loss to follow-up, biochemical indicators were not assessed at 12 months postoperatively. No severe adverse reactions occurred during or after SAAE. Patients with both UPA and BPA can benefit from SAAE. The superiority of bilateral adrenal artery embolization in the treatment of BPA over unilateral adrenal artery embolization requires further investigation.

Multi-omic Analyses Shed Light on The Genetic Control of High-altitude Adaptation in Sheep.

Sheep were domesticated in the Fertile Crescent and then spread globally, where they have been encountering various environmental conditions. The Tibetan sheep has adapted to high altitudes on the Qinghai-Tibet Plateau over the past 3000 years. To explore genomic variants associated with high-altitude adaptation in Tibetan sheep, we analyzed Illumina short-reads of 994 whole genomes representing ∼ 60 sheep breeds/populations at varied altitudes, PacBio High fidelity (HiFi) reads of 13 breeds, and 96 transcriptomes from 12 sheep organs. Association testing between the inhabited altitudes and 34,298,967 variants was conducted to investigate the genetic architecture of altitude adaptation. Highly accurate HiFi reads were used to complement the current ovine reference assembly at the most significantly associated ß-globin locus and to validate the presence of two haplotypes A and B among 13 sheep breeds. The haplotype A carried two homologous gene clusters: (1) HBE1, HBE2, HBB-like, and HBBC, and (2) HBE1-like, HBE2-like, HBB-like, and HBB; while the haplotype B lacked the first cluster. The high-altitude sheep showed highly frequent or nearly fixed haplotype A, while the low-altitude sheep dominated by haplotype B. We further demonstrated that sheep with haplotype A had an increased hemoglobin-O2 affinity compared with those carrying haplotype B. Another highly associated genomic region contained the EGLN1 gene which showed varied expression between high-altitude and low-altitude sheep. Our results provide evidence that the rapid adaptive evolution of advantageous alleles play an important role in facilitating the environmental adaptation of Tibetan sheep.

Resveratrol attenuates oxidative stress induced by balloon injury in the rat carotid artery through actions on the ERK1/2 and NF-kappa B pathway.

BACKGROUND/AIM: Oxidative stress plays a critical role in pathogenesis of the neointimal arterial hyperplasia. The aim of the study was to evaluate effects of resveratrol (RSV) on the vascular hyperplasia stimulated by oxidative damage. METHODS: Balloon vascular injury was induced in rats that were intraperitonealy exposed to resveratrol (1 mg/kg) on 7 or 14 days after surgical procedure. Animals were euthanized on 7 or 14 days after operation. The blood level of 8-iso-prostaglandin F2α, arterial morphology as well as expression of monocyte chemotactic protein-1 and interleukin-6 in carotid wall were measured. Vascular smooth muscle cells (VSMCs) were isolated from the thoracic aorta. Cellular proliferation and migration assays, reactive oxygen species (ROS), superoxide dismutase (SOD) and NADPH oxidative activity, protein level of ß-actin, histone H3, NF-ĸB p65, IĸB, ERK1/2, phospho-ERK1/2, phospho-p38 as well as NF-ĸB transcription activity were evaluated in-vitro after angiotensin II stimulation and resveratrol (50-200 µmol/L) treatment. RESULTS: Significant decreases in neointimal/medial area, serum prostaglandin level and genes expression were found in rats treated with resveratrol, when compared to the control group. Significant changes were also revealed for proliferation and migration rates, ROS level, as well as SOD, NADPH oxidase, ERK1/2 phosphorylation and NF-ĸB transcriptional activity in cell cultures exposed to highest dose of resveratrol. Insignificant changes were observed for NF-kappaB p65 translocation and IĸB degradation, p38 phosphorylation in MAPK pathway. CONCLUSION: Resveratrol significantly suppressed the neointimal hyperplasia after balloon injury through inhibition of oxidative stress and inflammation by blocking the ERK1/2/NF-kappa B pathway.