Gut microbiota plays a significant role in gout.

With the development of social economy, the incidence of gout is increasing, which is closely related to people's increasingly rich diet. Eating a diet high in purine, fat, sugar and low-fibre for a long time further aggravates gout by affecting uric acid metabolism. The renal metabolism mechanism of uric acid has been thoroughly studied. To find a new treatment method for gout, increasing studies have recently been conducted on the mechanism of intestinal excretion, metabolism and absorption of uric acid. The most important research is the relationship between intestinal microbiota and the risk of gout. Gut microbiota represent bacteria that reside in a host's gastrointestinal tract. The composition of the gut microbiota is associated with protection against pathogen colonization and disease occurrence. This review focuses on how gut microbiota affects gout through uric acid and discusses the types of bacteria that may be involved in the occurrence and progression of gout. We also describe potential therapy for gout by restoring gut microbiota homeostasis and reducing uric acid levels. We hold the perspective that changing intestinal microbiota may become a vital method for effectively preventing or treating gout.

Recent Advances on the Molecular Mechanism and Clinical Trials of Venous Thromboembolism.

Venous thromboembolism is a condition that includes deep vein thrombosis and pulmonary embolism. It is the third most common cardiovascular disease behind acute coronary heart disease and stroke. Over the past few years, growing research suggests that venous thrombosis is also related to the immune system and inflammatory factors have been confirmed to be involved in venous thrombosis. The role of inflammation and inflammation-related biomarkers in cerebrovascular thrombotic disease is the subject of ongoing debate. P-selectin leads to platelet-monocyte aggregation and stimulates vascular inflammation and thrombosis. The dysregulation of miRNAs has also been reported in venous thrombosis, suggesting the involvement of miRNAs in the progression of venous thrombosis. Plasminogen activator inhibitor-1 (PAI-1) is a crucial component of the plasminogen-plasmin system, and elevated levels of PAI-1 in conjunction with advanced age are significant risk factors for thrombosis. In addition, it has been showed that one of the ways that neutrophils promote venous thrombosis is the formation of neutrophil extracellular traps (NETs). In recent years, the role of extracellular vesicles (EVs) in the occurrence and development of VTE has been continuously revealed. With the advancement of research technology, the complex regulatory role of EVs on the coagulation process has been gradually discovered. However, our understanding of the causes and consequences of these changes in venous thrombosis is still limited. Therefore, we review our current understanding the molecular mechanisms of venous thrombosis and the related clinical trials, which is crucial for the future treatment of venous thrombosis.

MMDAE-HGSOC: A novel method for high-grade serous ovarian cancer molecular subtypes classification based on multi-modal deep autoencoder.

High-grade serous ovarian cancer (HGSOC) is a type of ovarian cancer developed from serous tubal intraepithelial carcinoma. The intrinsic differences among molecular subtypes are closely associated with prognosis and pathological characteristics. At present, multi-omics data integration methods include early integration and late integration. Most existing HGSOC molecular subtypes classification methods are based on the early integration of multi-omics data. The mutual interference among multi-omics data is ignored, which affects the effectiveness of feature learning. High-dimensional multi-omics data contains genes unassociated with HGSOC molecular subtypes, resulting in redundant information, which is not conducive to model training. In this paper, we propose a multi-modal deep autoencoder learning method, MMDAE-HGSOC. MiRNA expression, DNA methylation, and copy number variation (CNV) are integrated with mRNA expression data to construct a multi-omics feature space. The multi-modal deep autoencoder network is used to learn the high-level feature representation of multi-omics data. The superposition LASSO (S-LASSO) regression algorithm is proposed to fully obtain the associated genes of HGSOC molecular subtypes. The experimental results show that MMDAE-HGSOC is superior to the existing classification methods. Finally, we analyze the enrichment gene ontology (GO) terms and biological pathways of these significant genes, which are discovered during the gene selection process.

Resveratrol in the Hypothalamic Paraventricular Nucleus Attenuates Hypertension by Regulation of ROS and Neurotransmitters.

BACKGROUND: The hypothalamic paraventricular nucleus (PVN) is an important nucleus in the brain that plays a key role in regulating sympathetic nerve activity (SNA) and blood pressure. Silent mating-type information regulation 2 homolog-1 (sirtuin1, SIRT1) not only protects cardiovascular function but also reduces inflammation and oxidative stress in the periphery. However, its role in the central regulation of hypertension remains unknown. It is hypothesized that SIRT1 activation by resveratrol may reduce SNA and lower blood pressure through the regulation of intracellular reactive oxygen species (ROS) and neurotransmitters in the PVN. METHODS: The two-kidney one-clip (2K1C) method was used to induce renovascular hypertension in male Sprague-Dawley rats. Then, bilaterally injections of vehicle (artificial cerebrospinal fluid, aCSF, 0.4 µL) or resveratrol (a SIRT1 agonist, 160 µmol/L, 0.4 µL) into rat PVN were performed for four weeks. RESULTS: PVN SIRT1 expression was lower in the hypertension group than the sham surgery (SHAM) group. Activated SIRT1 within the PVN lowered systolic blood pressure and plasma norepinephrine (NE) levels. It was found that PVN of 2K1C animals injected with resveratrol exhibited increased expression of SIRT1, copper-zinc superoxide dismutase (SOD1), and glutamic acid decarboxylase (GAD67), as well as decreased activity of nuclear factor-kappa B (NF-κB) p65 and NAD(P)H oxidase (NOX), particularly NOX4. Treatment with resveratrol also decreased expression of ROS and tyrosine hydroxylase (TH). CONCLUSION: Resveratrol within the PVN attenuates hypertension via the SIRT1/NF-κB pathway to decrease ROS and restore the balance of excitatory and inhibitory neurotransmitters.

The development of a nomogram model for predicting left recurrent laryngeal nerve lymph node metastasis in esophageal cancer based on radiomics and clinical factors.

Background: The lymph node dissection for esophageal cancer is controversial. Some prediction models of lymph node metastasis (LNM) use the short diameter of lymph nodes measured by computed tomography (CT) examination as a predictor, but the size of that for judging metastasis is still controversial. However, radiomics can extract some features in tumors that cannot be obtained by naked eyes, which may have a higher value in predicting LNM. In this study, a nomogram was developed based on radiomics and clinical factors to predict left recurrent laryngeal nerve lymph node (RLNN) metastasis in patients with esophageal squamous cell carcinoma (ESCC). Methods: There were 350 patients included in this retrospective study. And the postoperative pathological results determined whether there was left RLNN metastasis. A univariate analysis was conducted of the clinical data. The least absolute shrinkage and selection operator regression analysis was conducted to filter the radiomics features extracted from CT images. The multivariate logistic regression equation was used to construct a nomogram. The area under the curve (AUC) was used to evaluate the predictive ability. Due to the small sample size, we chose to perform internal validation after the model was established by 10-fold cross-validation, Harrell's concordance index (C-index), bootstrap validation and calibration. Results: Ultimately, 3 indicators were screened out; that is, tumor location, surface volume ratio, and run-length non-uniformity. We then constructed the nomogram using these 3 indicators. The model had good accuracy and calibration performance. It has an AUC of 0.903 (95% confidence interval: 0.861-0.945), a sensitivity of 0.873, and a specificity of 0.756. Ten-fold cross-validation showed that the sensitivity and specificity of the training set were 88.08% and 75.81%, and the validation set had a sensitivity of 85.08% and a specificity of 75.49%. The Brier score was 0.074, and C-index was 0.904, which indicated good consistency between the actual and predicted results. Conclusions: A nomogram constructed based on radiomics features and clinical factors can be used to predict the metastasis of left RLNN in patients with ESCC in a non-invasive way, which provided a reference for clinicians to formulate individualized lymph node dissection plans.

Gut microbiota homeostasis restoration may become a novel therapy for breast cancer.

Breast cancer is the most diagnosed cancer in women. It significantly impairs a patient's physical and mental health. Gut microbiota comprise the bacteria residing in a host's gastrointestinal tract. Through studies over the last decade, we now know that alterations in the composition of the gut microbiome are associated with protection against colonization by pathogens and other diseases, such as diabetes and cancer. This review focuses on how gut microbiota can affect breast cancer development through estrogen activity and discusses the types of bacteria that may be involved in the onset and the progression of breast cancer. We also describe potential therapies to curtail the risk of breast cancer by restoring gut microbiota homeostasis and reducing systemic estrogen levels. This review will further explore the relationship between intestinal microbes and breast cancer and propose a method to treat breast cancer by improving intestinal microbes. We aimed at discovering new methods to prevent or treat BC by changing intestinal microorganisms.

Effects of Irbesartan and Amlodipine Besylate Tablets on the Intestinal Microflora of Rats With Hypertensive Renal Damage.

Objective: The present study aimed to investigate the effects of irbesartan and amlodipine besylate tablets on the intestinal microflora of rats with hypertensive renal damage. Methods: Eighteen 12-week-old male spontaneous hypertensive rats were randomly divided into three groups. The Ai-HDG group was given irbesartan at 15 mg/kg per day by gavage, the Ci-HDG group was given amlodipine besylate tablets at 1 mg/kg per day by gavage, and the Wi-HDG group, i.e., the control, was given the same dose of distilled water per day by gavage. The treatment lasted for 6 weeks. Six 12-week-old male Wistar-Kyoto rats were used as the reference group. Bacterial DNA was extracted from the feces of all the rats for high-throughput sequencing before and after the experiment. Operational taxonomic units were used to analyze the species of the intestinal flora, and the alpha diversity index was used to analyze the diversity. The relative abundance of the intestinal microflora in each group of rats was therefore analyzed at the phylum and genus levels. Results: Compared with the Wi-HDG group, the alpha diversity of the Ai-HDG group increased (p < 0.05), while in the Ci-HDG group, only the Shannon index increased significantly. At the phylum level, compared with the control group, in the Ai-HDG and Ci-HDG groups, Firmicutes (F) decreased, Bacteroides (B) increased, and the F/B ratio decreased (p < 0.05). At the genus level, compared with the Wi-HDG group, the Ai-HDG and Ci-HDG groups did not show a significantly delayed decline in lactic acid bacteria. However, in the Ai-HDG group, the relative abundance of Bifidobacteria increased. Conclusion: After the administration of irbesartan and amlodipine besylate, the disorder of intestinal flora in the rats with hypertensive renal damage improved. However, irbesartan was better than amlodipine besylate at improving the diversity of the intestinal flora in these rats.

PVN Blockade of p44/42 MAPK Pathway Attenuates Salt-induced Hypertension through Modulating Neurotransmitters and Attenuating Oxidative Stress.

The imbalance of neurotransmitters and excessive oxidative stress responses contribute to the pathogenesis of hypertension. In this study, we determined whether blockade of p44/42 MAPK pathway in the hypothalamic paraventricular nucleus (PVN) ameliorates the development of hypertension through modulating neurotransmitters and attenuating oxidative stress. Dahl salt-sensitive (S) rats received a high-salt diet (HS, 8% NaCl) or a normal-salt diet (NS, 0.3% NaCl) for 6 weeks and were treated with bilateral PVN infusion of PD-98059 (0.025 µg/h), a p44/42 MAPK inhibitor, or vehicle via osmotic minipump. HS resulted in higher mean arterial pressure (MAP) and Fra-like (Fra-LI) activity, and plasma and PVN levels of norepinephrine (NE), tyrosine hydroxylase (TH), NOX2 and NOX4, lower PVN levels of gamma-aminobutyric acid (GABA), copper/zinc superoxide dismutase (Cu/Zn-SOD) and the 67-kDa isoform of glutamate decarboxylase (GAD67), as compared with NS group. PD-98059 infusion reduced NE, TH, NOX2 and NOX4 in the PVN, and induced Cu/Zn-SOD and GAD67 in the PVN. It suggests that PVN blockade of p44/42 MAPK attenuates hypertension through modulating neurotransmitters and attenuating oxidative stress.

Paraventricular Nucleus Infusion of Epigallocatechin-3-O-Gallate Improves Renovascular Hypertension.

Oxidative stress plays an important role in the pathogenesis of hypertension. Epigallocatechin-3-O-gallate (EGCG) is the main polyphenol present in green tea and is known for its potent antioxidant and anti-inflammatory properties. In the present study, we hypothesize that EGCG attenuates oxidative stress in the paraventricular nucleus of hypothalamus (PVN), thereby decreasing the blood pressure and sympathetic activity in renovascular hypertensive rats. After renovascular hypertension was induced in male Sprague-Dawley rats by the two-kidney one-clip (2K-1C) method, the rats received bilateral PVN infusion of EGCG (20 µg/h) or vehicle via osmotic minipump for 4 weeks. Our results were shown as follows: (1) Hypertension induced by 2K-1C was associated with the production of reactive oxygen species in the PVN; (2) chronic infusion of EGCG in the PVN decreased stress-related NAD(P)H oxidase subunit gp91(phox) and NOX-4 and increased the activity of antioxidant enzymes (SOD-1), also balanced the content of cytokines (IL-1ß, IL-6, IL-10 and MCP-1) in the PVN, and attenuated the level of norepinephrine in plasma of 2K-1C rats. Our findings provide strong evidence that PVN infusion of EGCG inhibited renovascular hypertension progression through its potent anti-oxidative and anti-inflammatory activity in the PVN.

Targeting Interleukin-1 beta to Suppress Sympathoexcitation in Hypothalamic Paraventricular Nucleus in Dahl Salt-Sensitive Hypertensive Rats.

Findings from our laboratory indicate that expressions of some proinflammatory cytokines such as tumor necrosis factor, interleukin-6 and oxidative stress responses are increased in the hypothalamic paraventricular nucleus (PVN) and contribute to the progression of salt-sensitive hypertension. In this study, we determined whether interleukin-1 beta (IL-1ß) activation within the PVN contributes to sympathoexcitation during development of salt-dependent hypertension. Eight-week-old male Dahl salt-sensitive (S) rats received a high-salt diet (HS, 8 % NaCl) or a normal-salt diet (NS, 0.3 % NaCl) for 6 weeks, and all rats were treated with bilateral PVN injection of gevokizumab (IL-1ß inhibitor, 1 µL of 10 µg) or vehicle once a week. The mean arterial pressure (MAP), heart rate (HR) and plasma norepinephrine (NE) were significantly increased in high-salt-fed rats. In addition, rats with high-salt diet had higher levels of NOX-2, NOX-4 [subunits of NAD (P) H oxidase], IL-1ß, NLRP3 (NOD-like receptor family pyrin domain containing 3), Fra-LI (an indicator of chronic neuronal activation) and lower levels of IL-10 in the PVN than normal-diet rats. Bilateral PVN injection of gevokizumab decreased MAP, HR and NE, attenuated the levels of oxidative stress and restored the balance of cytokines. These findings suggest that IL-1ß activation in the PVN plays a role in salt-sensitive hypertension.

Endogenous hydrogen peroxide in the hypothalamic paraventricular nucleus regulates neurohormonal excitation in high salt-induced hypertension.

Reactive oxygen species (ROS) in the brain plays an important role in the progression of hypertension and hydrogen peroxide (H2O2) is a major component of ROS. The aim of this study is to explore whether endogenous H2O2 changed by polyethylene glycol-catalase (PEG-CAT) and aminotriazole (ATZ) in the hypothalamic paraventricular nucleus (PVN) regulates neurotransmitters, renin-angiotensin system (RAS), and cytokines, and whether subsequently affects the renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) in high salt-induced hypertension. Male Sprague-Dawley rats received a high-salt diet (HS, 8% NaCl) or a normal-salt diet (NS, 0.3% NaCl) for 10 weeks. Then rats were treated with bilateral PVN microinjection of PEG-CAT (0.2 i.u./50nl), an analog of endogenous catalase, the catalase inhibitor ATZ (10nmol/50nl) or vehicle. High salt-fed rats had significantly increased MAP, RSNA, plasma norepinephrine (NE) and pro-inflammatory cytokines (PICs). In addition, rats with high-salt diet had higher levels of NOX-2, NOX-4 (subunits of NAD(P)H oxidase), angiotensin-converting enzyme (ACE), interleukin-1beta (IL-1ß), glutamate and NE, and lower levels of gamma-aminobutyric acid (GABA) and interleukin-10 (IL-10) in the PVN than normal diet rats. Bilateral PVN microinjection of PEG-CAT attenuated the levels of RAS and restored the balance of neurotransmitters and cytokines, while microinjection of ATZ into the PVN augmented those changes occurring in hypertensive rats. Our findings demonstrate that ROS component H2O2 in the PVN regulating MAP and RSNA are partly due to modulate neurotransmitters, renin-angiotensin system, and cytokines within the PVN in salt-induced hypertension.