WWC1 upregulation accelerates hyperuricemia by reduction in renal uric acid excretion through Hippo signaling pathway.

Hyperuricemia (HUA) is a metabolic disorder characterized by elevated serum uric acid (UA), primarily attributed to the hepatic overproduction and renal underexcretion of UA. Despite the elucidation of molecular pathways associated with this underexcretion, the etiology of HUA remains largely unknown. In our study, using by Uox knockout rats, HUA mouse, and cell line models, we discovered that the increased WWC1 levels were associated with decreased renal UA excretion. Additionally, using knockdown and overexpression approaches, we found that WWC1 inhibited UA excretion in renal tubular epithelial cells. Mechanistically, WWC1 activated the Hippo pathway, leading to phosphorylation and subsequent degradation of the downstream transcription factor YAP1, thereby impairing the ABCG2 and OAT3 expression through transcriptional regulation. Consequently, this reduction led to a decrease in UA excretion in renal tubular epithelial cells. In conclusion, our study has elucidated the role of upregulated WWC1 in renal tubular epithelial cells inhibiting the excretion of UA in the kidneys and causing HUA.

The correlation between serum angiopoietin-2 levels and acute kidney injury (AKI): a meta-analysis.

INTRODUCTION: The correlation between serum angiopoietin-2 levels and acute kidney injury (AKI) is a topic of significant clinical interest. This meta-analysis aims to provide a comprehensive evaluation of this relationship. CONTENT: A systematic search was conducted in PubMed, Embase, Web of Science, and Cochrane databases up to October 11, 2023. The included studies were evaluated using the Newcastle-Ottawa Scale (NOS) and Methodological Index for Non-Randomized Studies (MINORS). Weighted mean differences (WMD) and odds ratios (OR) were calculated using random-effects models. Sensitivity analysis, funnel plots, and Egger's test were used to assess the robustness and publication bias of the findings. Subgroup analyses were performed to explore potential variations between adults and children. SUMMARY: Eighteen studies encompassing a total of 7,453 participants were included. The analysis revealed a significant elevation in serum angiopoietin-2 levels in patients with AKI compared to those without (WMD: 4.85; 95 % CI: 0.75 to 0.27; I²=93.2 %, p<0.001). Subgroup analysis indicated significantly higher angiopoietin-2 levels in adults with AKI (WMD: 5.17; 95 % CI: 3.51 to 6.83; I²=82.6 %, p<0.001), but not in children. Additionally, high serum angiopoietin-2 levels were associated with an increased risk of AKI (OR: 1.58; 95 % CI: 1.39 to 1.8; I²=89.1 %, p<0.001). Sensitivity analysis validated the robustness of these results, showing no substantial change in the overall effect size upon the exclusion of individual studies. OUTLOOK: This meta-analysis supports a significant association between elevated serum angiopoietin-2 levels and increased risk of AKI. The observed differential association between adults and children highlights the need for further targeted research to understand these age-specific variations.

The hepatoprotective effects of Herbt Tea Essences on phenanthrene-induced liver damage in mice.

Phenanthrene (Phe), one of the most frequently occurring pollutants in nature, can cause substantial damage to the human liver. Herbt Tea Essences (HTE), a kind of black tea extract with strong anti-inflammatory activity, can protect humans against disease. Currently, whether HTE can protect the liver from Phe-induced hepatotoxicity remains unclear. Herein, we explore the protective effects of HTE against Phe-induced hepatotoxicity. Our results showed that Phe exposure could significantly induce liver damage and increase serum hepatic enzyme levels in mice. HTE could prevent liver damage and recover the expression levels of inflammatory factors. Furthermore, we found that HTE suppressed the excessive activation of the nuclear transcription factor kappa-B and transforming growth factor-ß/SMAD signaling pathways to alleviate Phe-induced liver inflammation and fibrosis. Overall, our data showed that HTE treatment could be a new preventive means for Phe-induced liver disease.

Estradiol protects female mice from hyperuricemia induced by PCB138 exposure.

Polychlorinated biphenyls (PCBs) are a type of persistent organic pollutant (POP). Our previous study demonstrated that exposure to 0.5-50 µg/kg bw PCB138 during postnatal days (PND) 3-21 led to elevated serum uric acid (UA) levels and kidney injury in adult male mice. Given that the prevalence of hyperuricemia (HUA) is significantly lower in women than in men, it is worth investigating whether POP-induced HUA and its secondary kidney injury have sexual dimorphism. Herein, we exposed female mice to 0.5-50 µg/kg bw PCB138 during PND 3-21, resulting in elevated serum UA levels, but without causing significant kidney damage. Concurrently, we found a negative correlation between serum 17ß-estradiol (E2) and serum UA levels. We also observed down-regulation of estrogen receptor (ER) protein levels in the kidneys of the PCB138-exposed groups. Furthermore, our study showed that E2 rescued the increased UA level and cytotoxicity caused by HUA in human renal tubular epithelial (HK-2) cells. Collectively, our findings suggest that E2 likely plays a crucial protective role in PCB138-induced HUA and kidney injury in female mice. Our research highlights the existence of sexual dimorphism in kidney injury secondary to HUA induced by POPs, which could provide guidance for individuals of different genders in preventing kidney injury caused by environmental factors.

Tissue expression of the SARS-CoV-2 cell receptor gene ACE2 in children.

Coronavirus disease 2019 (COVID-19) has become a significant global public health problem. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which causes the disease, utilizes angiotensin-converting enzyme II (ACE2) as a major functional receptor to enter host cells. No study has systematically assessed ACE2 expression in multiple tissues in children. This study investigated ACE2 expression and ACE2 protein's histological distribution in various organs in paediatric patients (the small intestine, thymus, heart and lungs). Our study revealed that ACE2 was highly expressed in enterocytes of the small intestine and widely expressed in the myocardium of heart tissues. The most notable finding was the positive staining of ACE2 in the Hassall's corpuscles epithelial cells. Negligible ACE2 expression in the lung tissues may contribute to a lower risk of infection and fewer symptoms of pneumonia in children than in adults with COVID-19 infection. These findings provide initial evidence for understanding SARS-CoV-2 pathogenesis and prevention strategies in paediatric clinical practice, which should be applicable for all children worldwide.

Luteoloside attenuates anoxia/reoxygenation-induced cardiomyocytes injury via mitochondrial pathway mediated by 14-3-3η protein.

Ischemia/reperfusion (I/R) injury is the major cause of acute cardiovascular disease worldwide. 14-3-3η protein has been demonstrated to protect myocardium against I/R injury. Luteoloside (Lut), a flavonoid found in many Chinese herbs, exerts myocardial protection effects. However, the mechanism remains unclear. We hypothesize that the cardioprotective role of Lut is exerted by regulating the 14-3-3η signal pathway. To investigate our hypothesis, an in vitro I/R model was generated in H9C2 cardiomyocytes by anoxia/reoxygenation (A/R) treatment. The effects of Lut on cardiomyocytes with A/R injury were assessed by determining the cell viability, lactate dehydrogenase levels, intracellular reactive oxygen species levels, mitochondrial permeability transition pores (mPTP) openness, caspase-3 activity, and apoptosis rate. The effects on protein expression were tested using western blot analysis. Lut attenuated A/R-induced injury to cardiomyocytes by increasing the expression of 14-3-3η protein and cell viability; decreasing levels of lactate dehydrogenase, reactive oxygen species, mPTP openness, caspase-3 activity, and low apoptosis rate were observed. However, the cardioprotective effects of Lut were blocked by AD14-3-3ηRNAi, an adenovirus knocking down the intracellular 14-3-3η expression. In conclusion, to our knowledge, this is the first study to demonstrate that Lut protected cardiomyocytes from A/R-induced injury via the regulation of 14-3-3η signaling pathway.

A nanohybrid composed of Prussian Blue and graphitic C3N4 nanosheets as the signal-generating tag in an enzyme-free electrochemical immunoassay for the neutrophil gelatinase-associated lipocalin.

An enzyme-free electrochemical immunoassay is described for the neutrophil gelatinase-associated lipocalin (NGAL; a biomarker of kidney disease). Prussian Blue (PB) nanoparticles with redox activity were deposited on graphitic C3N4 nanosheets (g-C3N4) by in-situ reduction. A screen printed electrode (SPCE) was modified with antibody against NGAL, and the PB-g-C3N4 nanohybrid was used as the signal-generating tag for the secondary antibody against NGAL. Upon addition of target NGAL and of secondary antibody, a sandwich is formed on the SPCE. At an applied potential of typically 0.13 V (vs. Ag/AgCl), a well-defined voltammetric peak is observed that results from the presence of PB on the secondary antibody. Under optimal conditions, the peak current increases linearly in the 0.01 to 10 ng·mL-1 NGAL concentration range, and the detection limit is 2.8 pg·mL-1. An average precision of <12% was accomplished in the batch-to-batch mode. Other disease-related biomarkers do not interfere. The accuracy and inter-laboratory validation of this method were evaluated for target NGAL detection in spiked human serum by using a commercial ELISA. The results obtained by the two methods are in good accordance. Graphical abstract An enzyme-free electrochemical immunoassay was used for detection of neutrophil gelatinase-associated lipocalin by Prussian blut/graphitic-C3N4 nanohybrids as the signal-generation tags.

An machine learning model to predict quality of life subtypes of disabled stroke survivors.

OBJECTIVE: Stroke causes serious physical disability with impaired quality of life (QoL) and heavy burden on health. The goal of this study is to explore the impaired QoL typologies and their predicting factors in physically disabled stroke survivors with machine learning approach. METHODS: Non-negative matrix factorization (NMF) was applied to clustering 308 physically disabled stroke survivors in rural China based on their responses on the short form 36 (SF-36) assessment of quality of life. Principal component analysis (PCA) was conducted to differentiate the subtypes, and the Boruta algorithm was used to identify the variables relevant to the categorization of two subtypes. A gradient boosting machine(GBM) and local interpretable model-agnostic explanation (LIME) algorithms were used to apply to interpret the variables that drove subtype predictions. RESULTS: Two distinct subtypes emerged, characterized by short form 36 (SF-36) domains. The feature difference between worsen QoL subtype and better QoL subtype was as follows: role-emotion (RE), body pain (BP) and general health (GH), but not physical function (PF); the most relevant predictors of worsen QoL subtypes were help from others, followed by opportunities for community activity and rehabilitation needs, rather than disability severity or duration since stroke. INTERPRETATION: The results suggest that the rehabilitation programs should be tailored toward their QoL clustering feature; body pain and emotional-behavioral problems are more crucial than motor deficit; stroke survivors with worsen QoL subtype are most in need of social support, return to community, and rehabilitation.

Inflammatory response-based prognostication and personalized therapy decisions in clear cell renal cell cancer to aid precision oncology.

OBJECTIVE: The impact of inflammatory response on tumor development and therapeutic response is of significant importance in clear cell renal cell carcinoma (ccRCC). The customization of specialized prognostication approaches and the exploration of supplementary treatment options hold critical clinical implications in relation to the inflammatory response. METHODS: In the present study, unsupervised clustering was implemented on TCGA-KIRC tumors using transcriptome profiles of inflammatory response genes, which was then validated in two ccRCC datasets (E-MATB-1980 and ICGC) and two immunotherapy datasets (IMvigor210 and Liu et al.) via SubMap and NTP algorithms. Combining co-expression and LASSO analyses, inflammatory response-based scoring system was defined, which was evaluated in pan-cancer. RESULTS: Three reproducible inflammatory response subtypes (named IR1, IR2 and IR3) were determined and independently verified, each exhibiting distinct molecular, clinical, and immunological characteristics. Among these subtypes, IR2 had the best OS outcomes, followed by IR3 and IR1. In terms of anti-angiogenic agents, sunitinib may be appropriate for IR1 patients, while axitinib and pazopanib may be suitable for IR2 patients, and sorafenib for IR3 patients. Additionally, IR1 patients might benefit from anti-CTLA4 therapy. A scoring system called IRscore was defined for individual ccRCC patients. Patients with high IRscore presented a lower response rate to anti-PD-L1 therapy and worse prognostic outcomes. Pan-cancer analysis demonstrated the immunological features and prognostic relevance of the IRscore. CONCLUSION: Altogether, characterization of inflammatory response subtypes and IRscore provides a roadmap for patient risk stratification and personalized treatment decisions, not only in ccRCC, but also in pan-cancer.

After-effects of repetitive transcranial magnetic stimulation with parameter dependence on long-term potentiation-like plasticity and object recognition memory in rats.

Objective: To investigate the after-effects of 25-Hz repetitive transcranial magnetic stimulation (rTMS) at 60, 100, and 120% resting motor threshold (rMT) on long-term potentiation (LTP) in the rat hippocampus, to clarify the intensity dependence of rTMS, and to determine whether it simultaneously affects learning and memory ability. Methods: Five rats were randomly selected from 70 male Wistar rats, and evoked rMT potentials were recorded in response to magnetic stimulation. The remaining 65 rats were randomly assigned to five groups (n = 13), including sham rTMS, 1 Hz 100% rMT, and 25 Hz rTMS groups with 3 subgroups of 60% rMT, 100% rMT, and 120% rMT. Five rats in each group were anesthetized and induced by a priming TMS-test design for population spike (PS) response of the perforant path-dentate gyrus in the hippocampus; the remaining eight rats in each group were evaluated for object recognition memory in the novel object recognition (NOR) task after the different rTMS protocols. Results: Forty-five percent (approximately 1.03 T) of the magnetic stimulator output was confirmed as rMT in the biceps femoris muscle. The PS ratio was ranked as follows: 25 Hz 100% rMT (267.78 ± 25.71%) > sham rTMS (182 ± 9.4%) >1 Hz 100% rMT (102.69 ± 6.64%) > 25 Hz 120% rMT (98 ± 11.3%) > 25 Hz 60% rMT (36 ± 8.5%). Significant differences were observed between the groups, except for the difference between the 25 Hz 120% rMT and the 1 Hz 100% rMT groups (p = 0.446). LTP was successfully induced over the 60-min recording period only in the sham rTMS and 25 Hz 100% rMT groups. Moreover, these two groups spent more time exploring a novel object than a familiar object during the NOR task (p < 0.001), suggesting long-term recognition memory retention. In the between-group analysis of the discrimination index, the following ranking was observed: 25 Hz 100% rMT (0.812 ± 0.158) > sham rTMS (0.653 ± 0.111) > 25 Hz 120% rMT (0.583 ± 0.216) >1 Hz 100% rMT (0.581 ± 0.145) > 25 Hz 60% rMT (0.532 ± 0.220). Conclusion: The after-effect of 25-Hz rTMS was dependent on stimulus intensity and provided an inverted (V-shaped) bidirectional modulation on hippocampal plasticity that involved two forms of metaplasticity. Furthermore, the effects on the recognition memory ability were positively correlated with those on LTP induction in the hippocampus in vivo.