Comparison of efficacy of eltrombopag combined with immunosuppression in the treatment of severe aplastic anemia and very severe aplastic anemia: real-world data and evidence.

Eltrombopag combined with immunosuppressive therapy (IST) was superior to IST alone for severe aplastic anemia (SAA) in the previous studies. But in China, horse antithymocyte globulin (hATG) is not available, instead, we use rabbit ATG (rATG). Here, we compared the efficacy and safety of IST (rATG combined with cyclosporine) combined with or without eltrombopag for the first-line treatment of SAA and very severe aplastic anemia (VSAA). A total of 371 patients in ten institutions in China from April 1, 2017 to December 1, 2022 were enrolled. The overall response (OR) rate at 3 months (54.2% vs. 41%; P = 0.046), the complete response (CR) (31.3% vs. 19.4%; P = 0.041) and OR (78.3% vs. 51.1%; P < 0.0001) rates at 6 months were significantly higher with IST combined with eltrombopag than with IST alone in SAA patients. While in VSAA patients, the addition of eltrombopag to IST only increased the CR rate at 6 months (29.8% vs. 9.43%; P = 0.010). Liver injury increased significantly in groups treated with IST combined with eltrombopag (P < 0.05). Serious treatment-related toxicities were similar (P > 0.05). In patients with SAA, 3-year failure-free survival (FFS) of eltrombopag combined with IST group was significantly higher than that of IST group (70.7 ± 5.3% vs. 50.3 ± 3.9%; P = 0.007). In patients with VSAA, the addition of eltrombopag significantly improved 3-year overall survival (OS) (82.2 ± 5.7% vs. 57.3 ± 7.2%; P = 0.020). Our findings suggested that IST combined with eltrombopag could improve the hematological recovery of newly diagnosed SAA without increasing severe toxicities. But in VSAA, the addition of eltrombopag seemed to show no other improvement to efficacy except the CR rate at 6 months.

Allopurinol is Associated with an Increased Risk of Cerebral Infarction: A Two-Sample Mendelian Randomization Study.

OBJECTIVE: Previous studies have reported that the inappropriate use of allopurinol may increase the risk of cerebrovascular accidents, but some studies have also confirmed that allopurinol is a protective factor against stroke. To clarify whether there is a relevant causal relationship between allopurinol and cerebral infarction, we conducted a two-sample Mendelian randomization (MR) study. METHODS: Data on single nucleotide polymorphisms (SNPs) associated with allopurinol and genome-wide association studies of cerebral infarction were obtained from the genome-wide association study (GWAS) web site. Five basic MR analyses were performed using MR-Egger regression, weighted median (WM1), inverse variance weighting (IVW), weighted mode (WM2), and simple mode. Sensitivity analysis was subsequently performed to detect horizontal pleiotropy, heterogeneity, and potential outliers. The final analysis results were mainly based on the IVW estimates. RESULTS: A total of 10 SNPs were used as instrumental variables (IVs). MR analysis [(IVW: odds ratio (OR) = 1.053, 95% confidence interval (CI): 1.019-1.088, P = 0.002), (WM1: OR = 1.053, 95% CI: 1.009-1.098, P = 0.017), (WM2: OR = 1.050, 95% CI: 1.008-1.095, P = 0.044), (MR Egger: Q = 4.285, P = 0.830)] showed a positive causal association between allopurinol and the risk of cerebral infarction. Sensitivity analysis such as horizontal pleiotropy and heterogeneity increased the reliability of this result. CONCLUSION: The results of this study provide direct evidence that there is a causal relationship between allopurinol and cerebral infarction and that allopurinol may increase the risk of cerebral infarction.

Deciphering functional groups of rumen microbiome and their underlying potentially causal relationships in shaping host traits.

Over the years, microbiome research has achieved tremendous advancements driven by culture-independent meta-omics approaches. Despite extensive research, our understanding of the functional roles and causal effects of the microbiome on phenotypes remains limited. In this study, we focused on the rumen metaproteome, combining it with metatranscriptome and metabolome data to accurately identify the active functional distributions of rumen microorganisms and specific functional groups that influence feed efficiency. By integrating host genetics data, we established the potentially causal relationships between microbes-proteins/metabolites-phenotype, and identified specific patterns in which functional groups of rumen microorganisms influence host feed efficiency. We found a causal link between Selenomonas bovis and rumen carbohydrate metabolism, potentially mediated by bacterial chemotaxis and a two-component regulatory system, impacting feed utilization efficiency of dairy cows. Our study on the nutrient utilization functional groups in the rumen of high-feed-efficiency dairy cows, along with the identification of key microbiota functional proteins and their potentially causal relationships, will help move from correlation to causation in rumen microbiome research. This will ultimately enable precise regulation of the rumen microbiota for optimized ruminant production.

Evaluation of teplizumab's efficacy and safety in treatment of type 1 diabetes mellitus: A systematic review and meta-analysis.

BACKGROUND: Islets of Langerhans beta cells diminish in autoimmune type 1 diabetes mellitus (T1DM). Teplizumab, a humanized anti-CD3 monoclonal antibody, may help T1DM. Its long-term implications on clinical T1DM development, safety, and efficacy are unknown. AIM: To assess the effectiveness and safety of teplizumab as a therapeutic intervention for individuals with T1DM. METHODS: A systematic search was conducted using four electronic databases (PubMed, Embase, Scopus, and Cochrane Library) to select publications published in peer-reviewed journals written in English. The odds ratio (OR) and risk ratio (RR) were calculated, along with their 95%CI. We assessed heterogeneity using Cochrane Q and I 2 statistics and the appropriate P value. RESULTS: There were 8 randomized controlled trials (RCTs) in the current meta-analysis with a total of 1908 T1DM patients from diverse age cohorts, with 1361 patients receiving Teplizumab and 547 patients receiving a placebo. Teplizumab was found to have a substantial link with a decrease in insulin consumption, with an OR of 4.13 (95%CI: 1.72 to 9.90). Teplizumab is associated with an improved C-peptide response (OR 2.49; 95%CI: 1.62 to 3.81) and a significant change in Glycated haemoglobin A1c (HbA1c) levels in people with type 1 diabetes [OR 1.75 (95%CI: 1.03 to 2.98)], and it has a RR of 0.71 (95%CI: 0.53 to 0.95). CONCLUSION: In type 1 diabetics, teplizumab decreased insulin consumption, improved C-peptide response, and significantly changed HbA1c levels with negligible side effects. Teplizumab appears to improve glycaemic control and diabetes management with good safety and efficacy.

A knowledge graph algorithm enabled deep recommendation system.

Personalized learning resource recommendations may help resolve the difficulties of online education that include learning mazes and information overload. However, existing personalized learning resource recommendation algorithms have shortcomings such as low accuracy and low efficiency. This study proposes a deep recommendation system algorithm based on a knowledge graph (D-KGR) that includes four data processing units. These units are the recommendation unit (RS unit), the knowledge graph feature representation unit (KGE unit), the cross compression unit (CC unit), and the feature extraction unit (FE unit). This model integrates technologies including the knowledge graph, deep learning, neural network, and data mining. It introduces cross compression in the feature learning process of the knowledge graph and predicts user attributes. Multimodal technology is used to optimize the process of project attribute processing; text type attributes, multivalued type attributes, and other type attributes are processed separately to reconstruct the knowledge graph. A convolutional neural network algorithm is introduced in the reconstruction process to optimize the data feature qualities. Experimental analysis was conducted from two aspects of algorithm efficiency and accuracy, and the particle swarm optimization, neural network, and knowledge graph algorithms were compared. Several tests showed that the deep recommendation system algorithm had obvious advantages when the number of learning resources and users exceeded 1,000. It has the ability to integrate systems such as the particle swarm optimization iterative classification, neural network intelligent simulation, and low resource consumption. It can quickly process massive amounts of information data, reduce algorithm complexity and requires less time and had lower costs. Our algorithm also has better efficiency and accuracy.

Targeting BRD4 to attenuate RANKL-induced osteoclast activation and bone erosion in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that can cause destruction of cartilage and bone's extracellular matrix. Bromodomain 4 (BRD4), as a transcriptional and epigenetic regulator, plays a key role in cancer and inflammatory diseases. While, the role of BRD4 in bone destruction in RA has not been extensively reported. Our study aimed to investigate the effect of BRD4 on the bone destruction in RA and, further, its mechanism in the pathogenesis of the disease. In this study, receiving approval from the Ethical Committee of the Affiliated Hospital of Qingdao University, we evaluated synovial tissues from patients with RA and OA for BRD4 expression through advanced techniques such as immunohistochemistry, quantitative real-time PCR (qRT-PCR), and Western blotting. We employed a collagen-induced arthritis (CIA) mouse model to assess the therapeutic efficacy of the BRD4 inhibitor JQ1 on disease progression and bone destruction, supported by detailed clinical scoring and histological examinations. Further, in vitro osteoclastogenesis assays using RAW264.7 macrophages, facilitated by TRAP staining and resorption pit assays, provided insights into the mechanistic effects of JQ1 on osteoclast function. Statistical analysis was rigorously conducted using SPSS, applying Kruskal-Wallis, one-way ANOVA, and Student's t-tests to validate the data. In our study, we found that BRD4 expression significantly increased in the synovial tissues of RA patients and the ankle joints of CIA mice, with JQ1, a BRD4 inhibitor, effectively reducing inflammation, arthritis severity (p < 0.05), and bone erosion. Treatment with JQ1 not only improved bone mass and structural integrity in CIA mice but also downregulated osteoclast-related gene expression and the RANKL/RANK signaling pathway, indicating a suppression of osteolysis. Furthermore, in vitro assays demonstrated that JQ1 markedly inhibited osteoclast differentiation and function, underscoring the pivotal role of BRD4 in osteoclastogenesis and its potential as a target for therapeutic intervention in RA-induced bone destruction. Our study concludes that targeting BRD4 with the inhibitor JQ1 significantly mitigates inflammation and bone destruction in rheumatoid arthritis, suggesting that inhibition of BRD4 may be a potential therapeutic strategy for the treatment of bone destruction in RA.

Corosolic acid attenuates cardiac ischemia/reperfusion injury through the PHB2/PINK1/parkin/mitophagy pathway.

Despite advances in treatment, myocardial infarction remains the leading cause of heart failure and death worldwide, and the restoration of coronary blood flow can also cause heart damage. In this study, we found that corosolic acid (CA), also known as plant insulin, significantly protects the heart from ischemia-reperfusion (I/R) injury. In addition, CA can inhibit oxidative stress and improve mitochondrial structure and function in cardiomyocytes. Subsequently, our study demonstrated that CA improved the expression of the mitophagy-related proteins Prohibitin 2 (PHB2), PTEN-induced putative kinase protein-1 (PINK1), and Parkin. Meanwhile, through molecular docking, we found an excellent binding between CA and PHB2 protein. Finally, the knockdown of PHB2 eliminated the protective effect of CA on hypoxia-reoxygenation in cardiomyocytes. Taken together, our study reveals that CA increases mitophagy in cardiomyocytes via the PHB2/PINK1/Parkin signaling pathway, inhibits oxidative stress response, and maintains mitochondrial function, thereby improving cardiac function after I/R.

Decoding the RNA viromes in shrew lungs along the eastern coast of China.

Shrews being insectivores, serve as natural reservoirs for a wide array of zoonotic viruses, including the recently discovered Langya henipavirus (LayV) in China in 2018. It is crucial to understand the shrew-associated virome, viral diversity, and new viruses. In the current study, we conducted high-throughput sequencing on lung samples obtained from 398 shrews captured along the eastern coast of China, and characterized the high-depth virome of 6 common shrew species (Anourosorex squamipes, Crocidura lasiura, Crocidura shantungensis, Crocidura tanakae, Sorex caecutiens, and Suncus murinus). Our analysis revealed numerous shrew-associated viruses comprising 54 known viruses and 72 new viruses that significantly enhance our understanding of mammalian viruses. Notably, 34 identified viruses possess spillover-risk potential and six were human pathogenic viruses: LayV, influenza A virus (H5N6), rotavirus A, rabies virus, avian paramyxovirus 1, and rat hepatitis E virus. Moreover, ten previously unreported viruses in China were discovered, six among them have spillover-risk potential. Additionally, all 54 known viruses and 12 new viruses had the ability to cross species boundaries. Our data underscore the diversity of shrew-associated viruses and provide a foundation for further studies into tracing and predicting emerging infectious diseases originated from shrews.

Identification of the novel HLA-B*51:413 allele by next-generation sequencing in a Chinese Han individual.

The novel allele HLA-B*51:413 differs from HLA-B*51:92:02 by one nucleotide substitution in exon 3.

WTAP/IGF2BP3 mediated m6A modification of the EGR1/PTEN axis regulates the malignant phenotypes of endometrial cancer stem cells.

Endometrial cancer (EC) stem cells (ECSCs) are pivotal in the oncogenesis, metastasis, immune escape, chemoresistance, and recurrence of EC. However, the specific mechanism of stem cell maintenance in EC cells (ECCs) has not been clarified. We found that WTAP and m6A levels decreased in both EC and ECSCs, and that knocking down WTAP promoted ECCs and ECSCs properties, including proliferation, invasion, migration, cisplatin resistance, and self-renewal. The downregulation of WTAP leads to a decrease in the m6A modification of EGR1 mRNA, and it is difficult for IGF2BP3, as an m6A reader, to recognize and bind to EGR1 mRNA that has lost m6A modification, resulting in a decrease in the stability of EGR1 mRNA. A decrease in the EGR1 level led to a decrease of in the expression tumor suppressor gene PTEN, resulting in deregulation and loss of cellular homeostasis and thereby fostering EC stem cell traits. Notably, the enforced overexpression of WTAP, EGR1, and PTEN inhibited the oncogenic effects of ECCs and ECSCs in vivo, and the combined overexpression of WTAP + EGR1 and EGR1 + PTEN further diminished the tumorigenic potential of these cells. Our findings revealed that the WTAP/EGR1/PTEN pathway is important regulator of EC stem cell maintenance, chemotherapeutic resistance, and tumorigenesis, suggesting a novel and promising therapeutic avenue for treating EC.

Global, regional, and national burden of thalassemia during 1990-2019: A systematic analysis of the Global Burden of Disease Study 2019.

INTRODUCTION: Thalassemia represents a significant public health challenge globally. However, the global burden of thalassemia and the disparities associated with it remain poorly understood. Our study aims to uncover the long-term spatial and temporal trends in thalassemia at global, regional, and national levels, analyze the impacts of age, time periods, and birth cohorts, and pinpoint the global disparities in thalassemia burden. METHODS: We extracted data on the thalassemia burden from the Global Burden of Disease Study (GBD) 2019. We employed a joinpoint regression model to assess temporal trends in thalassemia burden and an age-period-cohort model to evaluate the effects of age, period, and cohort on thalassemia mortality. RESULTS: From 1990 to 2019, the number of thalassemia incident cases, prevalent cases, mortality cases, and disability-adjusted life years (DALYs) decreased by 20.9%, 3.1%, 38.6%, and 43.1%, respectively. Age-standardized rates of incidence, prevalence, mortality, and DALY declined across regions with high, high-middle, middle, and low-middle sociodemographic index (SDI), yet remained the highest in regions with low SDI and low-middle SDI as well as in Southeast Asia, peaking among children under five years of age. The global prevalence rate was higher in males than in females. The global mortality rate showed a consistent decrease with increasing age. CONCLUSION: The global burden of thalassemia has significantly declined, yet notable disparities exist in terms of gender, age groups, periods, birth cohorts, SDI regions, and GBD regions. Systemic interventions that include early screening, genetic counseling, premarital health examinations, and prenatal diagnosis should be prioritized in regions with low, and low-middle SDI, particularly in Southeast Asia. Future population-based studies should focus specifically on thalassemia subtypes and transfusion requirements, and national registries should enhance data capture through newborn screening.

An Unusual Crystalline Porous Framework Constructed from Multitypes of Cages with Proton Conduction Property and Heterogeneous Catalytic Activity for Pyrazole Synthesis.

An unusual crystalline porous framework constructed from four types of cages, including all-inorganic Keggin-type polyoxometalate (POM) cages [H3W12O40]5-, organic hexamethylenetetramine (Hmt) cages, nanosized silver-Hmt coordination cages, and giant POM-silver-Hmt cages, was hydrothermally synthesized and structurally characterized. The framework features a highly symmetrical structure with one-dimensional nanoscale channels and holds good thermal/solvent stability, which endow it with proton conduction properties and heterogeneous catalytic activity for pyrazole. This paper not only contributes to broadening the structural diversity of cage-based crystalline porous framework materials but also sheds new light on the design of new functional framework materials.

Overview of the interplay between m6A methylation modification and non-coding RNA and their impact on tumor cells.

N6-methyladenosine (m6A) is one of the most common internal modifications in eukaryotic RNA. The presence of m6A on transcripts can affect a series of fundamental cellular processes, including mRNA splicing, nuclear transportation, stability, and translation. The m6A modification is introduced by m6A methyltransferases (writers), removed by demethylases (erasers), and recognized by m6A-binding proteins (readers). Current research has demonstrated that m6A methylation is involved in the regulation of malignant phenotypes in tumors by controlling the expression of cancer-related genes. Non-coding RNAs (ncRNAs) are a diverse group of RNA molecules that do not encode proteins and are widely present in the human genome. This group includes microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and PIWI interaction RNAs (piRNAs). They function as oncogenes or tumor suppressors through various mechanisms, regulating the initiation and progression of cancer. Previous studies on m6A primarily focused on coding RNAs, but recent discoveries have revealed the significant regulatory role of m6A in ncRNAs. Simultaneously, ncRNAs also exert their influence by modulating the stability, splicing, translation, and other biological processes of m6A-related enzymes. The interplay between m6A and ncRNAs collectively contributes to the occurrence and progression of malignant tumors in humans. This review provides an overview of the interactions between m6A regulatory factors and ncRNAs and their impact on tumors.

[The efficacy of iRoot BP plus in the treatment of adult carious pulp exposure and its impact on pulp blood flow].

PURPOSE: To explore the efficacy of iRoot BP plus in the treatment of adult carious pulp exposure and its impact on pulp blood flow. METHODS: A total of 126 cases of 156 permanent teeth from adult patients with carious pulp exposure who were treated from January 2020 to January 2022 were selected, the patients were divided into experimental group(63 cases with 79 permanent teeth) and control group(63 cases with 77 permanent teeth) by the envelope method. The experimental group was treated with iRoot BP plus, while the control group was treated with mineral trioxide polymer. The differences in treatment effectiveness, operation time, and tooth discoloration between the two groups were observed. Statistical analysis was performed with SPSS 22.0 software package. RESULTS: There was no significant difference in treatment success rates between the experimental group and the control group at 3, 6, and 12 months after surgery(P＞0.05). The operating time for each capsule in the experimental group was (2.53±0.41) min, which was significantly shorter than that in the control group(P＜0.05). The incidence of tooth discoloration in the experimental group at 12 months after surgery was 3.80%, which was significantly lower than that in the control group (P＜0.05). The bite force quotient and masticatory efficiency of the experimental group 12 months after operation were (16.65±1.14) Ibs and (94.45±5.65)%, which were significantly higher than those of the control group(P＜0.05). CONCLUSIONS: IRoot BP plus has good efficacy in the treatment of adult carious pulp exposure, with advantages such as convenient operation, less tooth discoloration, less inflammatory reactions and stable pulp blood flow after decline.

Mitochondria of Porcine Oocytes Synthesize Melatonin, Which Improves Their In Vitro Maturation and Embryonic Development.

The in vitro maturation efficiency of porcine oocytes is relatively low, and this limits the production of in vitro porcine embryos. Since melatonin is involved in mammalian reproductive physiology, in this study, we have explored whether endogenously produced melatonin can help in porcine oocyte in vitro maturation. We have found, for the first time in the literature, that mitochondria are the major sites for melatonin biosynthesis in porcine oocytes. This mitochondrially originated melatonin reduces ROS production and increases the activity of the mitochondrial respiratory electron transport chain, mitochondrial biogenesis, mitochondrial membrane potential, and ATP production. Therefore, melatonin improves the quality of oocytes and their in vitro maturation. In contrast, the reduced melatonin level caused by siRNA to knockdown AANAT (siAANAT) is associated with the abnormal distribution of mitochondria, decreasing the ATP level of porcine oocytes and inhibiting their in vitro maturation. These abnormalities can be rescued by melatonin supplementation. In addition, we found that siAANAT switches the mitochondrial oxidative phosphorylation to glycolysis, a Warburg effect. This metabolic alteration can also be corrected by melatonin supplementation. All these activities of melatonin appear to be mediated by its membrane receptors since the non-selective melatonin receptor antagonist Luzindole can blunt the effects of melatonin. Taken together, the mitochondria of porcine oocytes can synthesize melatonin and improve the quality of oocyte maturation. These results provide an insight from a novel aspect to study oocyte maturation under in vitro conditions.

Screening of Intermetallic Compounds Based on Intermediate Adsorption Equilibrium for Electrocatalytic Nitrate Reduction to Ammonia.

Electrocatalytic nitrate (NO3-) reduction reaction (NO3RR) holds great potential for the conversion of NO3- contaminants into valuable NH3 in a sustainable method. Unfortunately, the nonequilibrium adsorption of intermediates and sluggish multielectron transfer have detrimental impacts on the electrocatalytic performance of the NO3RR, posing obstacles to its practical application. Herein, we initially screen the adsorption energies of three key intermediates, i.e., *NO3, *NO, and *H2O, along with the d-band centers on 21 types of transition metal (IIIV and IB)-Sb/Bi-based intermetallic compounds (IMCs) as electrocatalysts. The results reveal that hexagonal CoSb IMCs possess the optimal adsorption equilibrium for key intermediates and exhibit outstanding electrocatalytic NO3RR performance with a Faradaic efficiency of 96.3%, a NH3 selectivity of 89.1%, and excellent stability, surpassing the majority of recently reported NO3RR electrocatalysts. Moreover, the integration of CoSb IMCs/C into a novel Zn-NO3- battery results in a high power density of 11.88 mW cm-2.

Clinical intervention effect of Xuefu Zhuyu decoction on chronic heart failure complicated with depression.

BACKGROUND: The diagnosis and treatment of depression in patients with chronic heart failure (CHF) is challenging, with no ideal treatment at present. AIM: To analyze the clinical intervention effect of Xuefu Zhuyu decoction (XFZYD) on CHF complicated with depression. METHODS: The study cohort comprised 116 patients with CHF complicated with depression who received treatment from July 2020 to July 2023, of which 55 received Western medicine (control group) and 61 received XFZYD (research group). Data on clinical effectiveness, traditional Chinese medicine (TCM) syndrome score, cardiac function, negative emotions, and serum inflammatory factors, were collected for comparative analyses. RESULTS: Compared with the control group, the research group had an evidently higher total effective rate. Furthermore, there were marked reductions in TCM symptom score, left ventricular end-diastolic diameter, left ventricular end-systolic diameter, Self-Rating Depression Scale, Hamilton Depression Scale, high-sensitivity C-reactive protein, monocyte chemoattractant protein-1, and matrix metalloproteinase-9 in the research group after treatment, and these were lower than the corresponding values in the control group. Left ventricular ejection fraction was increased and higher in the research group compared with the control group after treatment. CONCLUSION: Our findings conclusively proved that XFZYD was considerably superior to Western medicine for treating CHF complicated with depression because it significantly alleviated patients' symptoms, improved cardiac function, relieved negative emotions, and reduced the levels of serum inflammatory factors.

The cytochrome P4501A1 (CYP1A1) inhibitor bergamottin enhances host tolerance to multidrug-resistant Vibrio vulnificus infection.

PURPOSE: Vibrio vulnificus (V. Vulnificus) infection is characterized by rapid onset, aggressive progression, and challenging treatment. Bacterial resistance poses a significant challenge for clinical anti-infection treatment and is thus the subject of research. Enhancing host infection tolerance represents a novel infection prevention strategy to improve patient survival. Our team initially identified cytochrome P4501A1 (CYP1A1) as an important target owing to its negative modulation of the body's infection tolerance. This study explored the superior effects of the CYP1A1 inhibitor bergamottin compared to antibiotic combination therapy on the survival of mice infected with multidrug-resistant V. Vulnificus and the protection of their vital organs. METHODS: An increasing concentration gradient method was used to induce multidrug-resistant V. Vulnificus development. We established a lethal infection model in C57BL/6J male mice and evaluated the effect of bergamottin on mouse survival. A mild infection model was established in C57BL/6J male mice, and the serum levels of creatinine, urea nitrogen, aspartate aminotransferase, and alanine aminotransferase were determined using enzyme-linked immunosorbent assay to evaluate the effect of bergamottin on liver and kidney function. The morphological changes induced in the presence of bergamottin in mouse organs were evaluated by hematoxylin and eosin staining of liver and kidney tissues. The bacterial growth curve and organ load determination were used to evaluate whether bergamottin has a direct antibacterial effect on multidrug-resistant V. Vulnificus. Quantification of inflammatory factors in serum by enzyme-linked immunosorbent assay and the expression levels of inflammatory factors in liver and kidney tissues by real-time quantitative polymerase chain reaction were performed to evaluate the effect of bergamottin on inflammatory factor levels. Western blot analysis of IκBα, phosphorylated IκBα, p65, and phosphorylated p65 protein expression in liver and kidney tissues and in human hepatocellular carcinomas-2 and human kidney-2 cell lines was used to evaluate the effect of bergamottin on the nuclear factor kappa-B signaling pathway. One-way ANOVA and Kaplan-Meier analysis were used for statistical analysis. RESULTS: In mice infected with multidrug-resistant V. Vulnificus, bergamottin prolonged survival (p = 0.014), reduced the serum creatinine (p = 0.002), urea nitrogen (p = 0.030), aspartate aminotransferase (p = 0.029), and alanine aminotransferase (p = 0.003) levels, and protected the cellular morphology of liver and kidney tissues. Bergamottin inhibited interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α expression in serum (IL-1ß: p = 0.010, IL-6: p = 0.029, TNF-α: p = 0.025) and inhibited the protein expression of the inflammatory factors IL-1ß, IL-6, TNF-α in liver (IL-1ß: p = 0.010, IL-6: p = 0.011, TNF-α: p = 0.037) and kidney (IL-1ß: p = 0.016, IL-6: p = 0.011, TNF-α: p = 0.008) tissues. Bergamottin did not affect the proliferation of multidrug-resistant V. Vulnificus or the bacterial load in the mouse peritoneal lavage fluid (p = 0.225), liver (p = 0.186), or kidney (p = 0.637). CONCLUSION: Bergamottin enhances the tolerance of mice to multidrug-resistant V. Vulnificus infection. This study can serve as a reference and guide the development of novel clinical treatment strategies for V. Vulnificus.

The impact of female sex hormones on cardiovascular disease: from mechanisms to hormone therapy.

Cardiovascular disease remains the leading cause of mortality in women, yet it has not raised the awareness from the public. The pathogenesis of cardiovascular disease differs significantly between females and males concerning the effect of sex hormones. Estrogen and progestogen impact cardiovascular system through genomic and non-genomic effects. Before menopause, cardiovascular protective effects of estrogens have been well described. Progestogens were often used in combination with estrogens in hormone therapy. Fluctuations in sex hormone levels, particularly estrogen deficiency, were considered the specific risk factor in women's cardiovascular disease. However, considerable heterogeneity in the impact of hormone therapy was observed in clinical trials. The heterogeneity is likely closely associated with factors such as the initial time, administration route, dosage, and formulation of hormone therapy. This review will delve into the pathogenesis and hormone therapy, summarizing the effect of female sex hormones on hypertension, pre-eclampsia, coronary heart disease, heart failure with preserved ejection fraction, and cardiovascular risk factors specific to women.