Network pharmacology, molecular docking, combined with experimental verification to explore the role and mechanism of shizhifang decoction in the treatment of hyperuricemia.

Ethnopharmacological relevance: Shizhifang Decoction, a traditional Chinese medicine prescription formulated by Professor Zheng Pingdong of Shuguang Hospital, has been widely utilized in clinical settings for the treatment of hyperuricemia due to its proven safety and efficacy. Objective: In this study, we used network pharmacology, molecular docking technology, and experimental validation to elucidate the therapeutic effects and underlying mechanisms of Shizhifang Decoction in managing hyperuricemia. Methods: Quality control and component identification of the freeze-dried powder of Shizhifang Decoction were conducted using ultra-high performance liquid chromatography-tandem quadrupole time-of-flight mass spectrometry. Active ingredients and their corresponding targets were obtained from Traditional Chinese Medicine Systems Pharmacology, Traditional Chinese Medicine Information Database, The Encyclopedia of Traditional Chinese Medicine, and other databases. Disease-related targets for hyperuricemia were collected from GeneCards and DisGeNET databases. The Venny platform is used to screen common targets for drug active ingredients and diseases. Subsequently, we constructed an active component-target-disease interaction network using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database, create a component disease common target network using Cytoscape 3.9.1 software, from which core targets were selected. Import common targets into the Database for Annotation, Visualization and Integrated Discovery (DAVID) for Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analysis. Molecular docking was then conducted to validate the binding capacity of key active ingredients and their associated targets in Shizhifang Decoction. The theoretical predictions were further confirmed through in vitro and in vivo experiments. Result: A total of 35 active ingredients and 597 action targets were identified, resulting in 890 disease-related targets for hyperuricemia. After comprehensive analysis, 99 common targets were determined. Protein-protein interaction network analysis revealed crucial relationships between these targets and hyperuricemia. Among them, 12 core targets (CASP3, IL1B, IL6, TNF, TP53, GAPDH, PTGS2, MYC, INS, VEGFA, ESR1, PPARG) were identified. Gene Ontology enrichment analysis demonstrated significant associations with the regulation of inflammatory response, cell apoptosis, and the positive regulation of extracellular regulated protein kinases 1 and extracellular regulated protein kinases 2 cascades. Kyoto Encyclopedia of Genes and Genomes pathway analysis highlighted inflammation and apoptosis-related pathways as critical mediators of Shizhifang Decoction's effects on hyperuricemia. Molecular docking studies further supported the interactions between apoptosis-related proteins and active ingredients in the extracellular regulated protein kinases 1/2 signaling pathway. In vitro experiments confirmed the downregulation of apoptosis-related proteins (caspase-3, Bax, Bcl-2) and the inhibition of the extracellular regulated protein kinases 1/2 signaling pathway by Shizhifang Decoction. These findings were also validated in animal models, demonstrating the potential of Shizhifang Decoction to mitigate renal injury induced by hyperuricemia through extracellular regulated protein kinases 1/2-mediated inhibition of renal tubular epithelial cell apoptosis. Conclusion: Our study provides valuable insights into the main mechanism by which Shizhifang Decoction ameliorates hyperuricemia. By targeting the ERK1/2 signaling pathway and modulating cell apoptosis, Shizhifang Decoction exhibits promising therapeutic potential for the treatment of hyperuricemia. These findings support the continued exploration and development of Shizhifang Decoction as a potential herbal remedy for hyperuricemia management.

Risk-prediction model for incident hypertension in patients with obstructive sleep apnea based on SpO2 signals.

This work proposes a method utilizing oxygen saturation (SpO2) for predicting incident hypertension in patients with obstructive sleep apnea (OSA). We extracted time domain features and frequency domain features from the SpO2 signal. For prediction, we employed several machine learning algorithms to establish the 3-year risk prediction model in the Chinese Sleep Health Study, including 250 subjects without baseline hypertension who underwent sleep monitoring. The proposed random forest model achieved an accuracy of 84.4%, a sensitivity of 77.0%, a specificity of 91.5% and an area under the receiver operator characteristic of 84.3% using 10-fold crossvalidation. We show that the model outperformed two sleep medicine specialists using clinical experience to predict hypertension. Furthermore, we applied the prediction results in the public Sleep Heart Health Study database and showed the subjects who were predicted to have hypertension would be at a higher risk in 4-6 years. This work shows the potential of SpO2 signal during sleep for the prediction of hypertension and could be beneficial to the early detection and timely treatment of hypertension in OSA patients.Clinical Relevance-There is no prediction model for incident hypertension in OSA patients in clinical practice. Most patients are unaware of health complexity, symptoms and risk factors before hypertension. Establishing an accurate prediction model can effectively provide early intervention for OSA patients and reduce the prevalence of hypertension.

Shizhifang ameliorates pyroptosis of renal tubular epithelial cells in hyperuricemia through inhibiting NLRP3 inflammasome.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese Medicine (TCM) Compound Shizhifang (SZF), consisting of the seeds of four Chinese herbs, has been used in Shanghai Shuguang Hospital in China for more than 20 years and has proven its clinical safety and efficacy in lowering uric acid and protecting kidney function. AIM OF THE STUDY: Hyperuricemia (HUA)-induced pyroptosis of renal tubular epithelial cells serves as a significant cause of tubular damage. SZF proves to be effective in alleviating renal tubular injury and inflammation infiltration of HUA. However, the inhibiting effect of SZF on pyroptosis in HUA still remains elusive. This study aims to verify whether SZF could ameliorate pyroptosis in tubular cells induced by uric acid (UA). MATERIALS AND METHODS: Quality control analysis and chemical and metabolic identification for SZF and SZF drug serum were performed by using UPLC-Q-TOF-MS. In vitro, human renal tubular epithelial cells (HK-2) stimulated by UA were treated with SZF or NLRP3 inhibitor (MCC950). HUA mouse models were induced by intraperitoneal injection of potassium oxonate (PO). Mice were treated with SZF, allopurinol or MCC950. We focused on evaluated the effect of SZF on the NLRP3/Caspase-1/GSDMD pathway, renal function, pathologic structure and inflammation. RESULTS: SZF significantly restrained the activation of the NLRP3/Caspase-1/GSDMD pathway in vitro and in vivo induced by UA. SZF was better than allopurinol and MCC950 in reducing pro-inflammatory cytokine levels, attenuating tubular inflammatory injury, inhibiting interstitial fibrosis and tubular dilation, maintaining tubular epithelial cell function, and protecting kidney. Furthermore, 49 chemical compounds of SZF and 30 metabolites in serum after oral administration were identified. CONCLUSIONS: SZF inhibits UA-induced renal tubular epithelial cell pyroptosis via by targeting NLRP3 to inhibit tubular inflammatory and prevent the progression of HUA-induced renal injury effectively.

Evaluation the effectiveness of the Jiangniaosuan formulation in the treatment of hyperuricemic nephropathy in patients with chronic kidney disease stages 3-4: Study protocol of a randomized controlled trial.

Background: Hyperuricemic nephropathy is a highly prevalent kidney disease induced by excessive accumulation and deposition of monosodium urate in kidney, which contributes to the loss of kidney function. The Jiangniaosuan formulation (JNSF) is a Chinese herbal medicine treatment. The aim of this study is to evaluate its efficacy and safety among patients with hyperuricemic nephropathy at chronic kidney disease (CKD) stages 3-4 and with obstruction of phlegm turbidity and blood stasis syndrome. Methods: Our research is designed as a single-centre, double-blinded, randomized, placebo-controlled trial for 118 patients diagnosed with hyperuricemic nephropathy at CKD stages 3-4 and with obstruction of phlegm turbidity and blood stasis syndrome in mainland China. Patients are to be randomized into two groups: either the intervention group which receives JNSF 20.4 g/day combined with febuxostat 20-40 mg/day, or the control group which receives JNSF placebo 20.4 g/day combined with febuxostat 20-40 mg/day. The intervention will be carried on for 24 weeks. The change in estimated glomerular filtration rate (eGFR) is set as the primary outcome. Secondary outcomes include changes in serum uric acid, serum nitric oxide, urinary albumin/creatinine ratio, urinary N-acetyl-ß-D glucosaminidase, urinary ß2 microglobulin, urinary retinol binding protein and TCM syndromes in 24 weeks. Statistical analysis will be formulated by SPSS 24.0. Discussion: The trial will conduce to the comprehensive assessment in the efficacy and safety of JNSF among patients diagnosed with hyperuricemic nephropathy at CKD stages 3-4, and provide a clinical method available on systems of the combination of modern medicine and TCM.

Relative spectral power quantifying the distribution of intermittent hypoxemia in obstructive sleep apnea is strongly associated with hypertension.

STUDY OBJECTIVES: To investigate the association between the periodicity of distribution of intermittent hypoxemia (IH) and hypertension in adults with obstructive sleep apnea (OSA) and search for an index to quantify the association. METHODS: Samples were derived from two cross-sectional studies: The Sleep Heart Health Study (SHHS) including 3991 adults with age 64.7 ± 10.9 years; and the Chinese Changgung Sleep Health Study (CSHS) including 906 adults with age 59.5 ± 12.4 years. Spectral analysis of peripheral oxygen saturation (SpO2) was performed and the relative spectral power (PFR) in the frequency band of 0.011-0.037 Hz (PFR0.011-0.037Hz) was extracted to quantify the periodic distribution of IH. Multiple logistic regression models were used to calculate the partially and fully adjusted odd ratios for PFR0.011-0.037Hz. RESULTS: PFR0.011-0.037Hz was significantly higher in the hypertension group than non-hypertension group (44.4% ± 0.3% vs. 42.1% ± 0.3%, p < 0.001 in SHHS and 57.4% ± 0.7% vs. 50.5% ± 0.8%, p < 0.001 in CSHS). In the fully adjusted model, individuals in the SHHS with PFR0.011-0.037Hz in the highest quintiles had an odd ratio of 1.33 [95% confidence interval (CI) 1.06-1.67]. Similarly, the group in the CSHS with PFR0.011-0.037Hz in the highest quintile had an odd ratio of 3.08 (95% CI 1.80-5.28). CONCLUSIONS: We developed an IH distribution measure which is strongly associated with hypertension independent of multiple confounding variables. The finding suggests that the periodic distribution of sleep related upper airway obstructions is an essential hypertension characterizing feature.

Minimal change disease caused by polycythemia vera: A case report.

BACKGROUND: Polycythemia vera (PV), often attributed to the JAK2 V617F mutation, is characterized by enhanced red blood cell counts in the peripheral blood. PV-associated renal disease is clinically rare; to date, there have been reports of other chronic kidney diseases related to PV, but no reports on PV-associated minimal change disease. CASE SUMMARY: A 37-year-old man presented with proteinuria and high red blood cell count on January 4, 2021. The patient underwent bone marrow and renal biopsies, then was subsequently diagnosed with PV and minimal change in disease. Hydroxyurea was administered and proteinuria remission was achieved. The patient's last visit was on April 14, 2022. CONCLUSION: We inferred that there may be a causal relationship between PV and minimal change disease.

Endothelial injury and inflammation in patients with hyperuricemic nephropathy at chronic kidney disease stages 1-2 and 3-4.

BACKGROUND: Endothelial injury and inflammation are the main pathological changes in hyperuricemic nephropathy (HN); however, they have not been assessed in patients in the early, middle, and late phases of HN. AIM: To investigate endothelial injury and inflammatory conditions between patients with HN at chronic kidney disease (CKD) stages 3-4 and CKD 1-2. METHODS: This study enrolled 80 patients (49 and 31 with HN at CKD stage 1-2 and 3-4, respectively) from the Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine between July 2021 and January 2022. Plasma levels of heparan sulfate, endocan, oxidized low-density lipoprotein (Ox-LDL), E-selectin, soluble intercellular adhesion molecule-1 (slCAM1), interleukin (IL)-1ß, and IL-6 and urine levels of lipocalin-type prostaglandin D synthase (L-PGDS), IL-1ß, and IL-6 were measured using enzyme-linked immunosorbnent assay. RESULTS: Comparison between patients with HN at CKD 1-2 and those with HN at CKD 3-4 showed that age and disease course were significant factors (P < 0.001 and P < 0.010, respectively). There were no statistical differences in sex, heart rate, body mass index, and systolic and diastolic blood pressures. The incidence of hypertension was also significant (P = 0.03). Plasma levels of heparin sulfate (P < 0.001), endocan (P = 0.034), E-selectin (P < 0.001), slCAM1 (P < 0.001), IL-1ß (P = 0.006), and IL-6 (P = 0.004) and the urine levels of L-PGDS (P < 0.001), IL-1ß (P = 0.003), and IL-6 (P < 0.001) were high in patients with HN at CKD 3-4 than in those with HN at CKD 1-2. The difference in plasma Ox-LDL levels was not significant (P = 0.078). CONCLUSION: Vascular endothelial injury and inflammation were higher in patients with HN at CKD3-4 than at CKD 1-2. Plasma heparin sulfate and slCAM1 levels are synergistic factors for CKD staging in HN.

TNF-α-mediated podocyte injury via the apoptotic death receptor pathway in a mouse model of IgA nephropathy.

BACKGROUND: IgA nephropathy (IgAN) is the most common primary glomerular disease worldwide and it is characterized by mesangial IgA deposits. Proteinuria is a common clinical feature of IgAN, which has a critical connection to podocyte injury and has been used as a clinical prognostic factor for IgAN. Evidence has shown that TNF-α released from mesangial cells may lead to podocyte apoptosis. METHODS: Forty male BALB/c mouse were randomly divided into the control group and IgAN group. A mice model of IgAN was developed by oral administration of bovine serum albumin (BSA) combined with Staphylococcus Enterotoxin B (SEB) tail vein injection. Urinary protein concentrations, renal function, renal morphological, IgA deposition, apoptosis situation, and the mRNA and protein expression of nephrin, podocin, TNF-α, TNFR1, caspase-8 and caspase-3, were detected after 12 weeks. RESULTS: BSA and SEB can successfully establish an IgAN mouse model, and the main pathological changes are the IgA immune complex deposition in the mesangial area. The gene and protein expression levels of nephrin and podocin were found to be downregulated, and death receptor pathway-related indicators were upregulated, and they were involved in TNF-α-activated podocyte injury and apoptosis in IgAN mice. CONCLUSION: TNF-α may play an important role in the pathogenesis of podocyte apoptosis in IgAN, and its effects may be mediated through the apoptotic death receptor pathway.

Calycosin plays a protective role in diabetic kidney disease through the regulation of ferroptosis.

CONTEXT: Diabetic kidney disease (DKD) is a devastating complication of diabetes. Renal functional deterioration caused by tubular injury is the primary change associated with this disease. Calycosin shows protective roles in various diseases. OBJECTIVES: This study explored the function and underlying mechanism of calycosin in DKD. MATERIALS AND METHODS: HK-2 cells were treated with 25 mM high glucose (HG) to establish a renal tubule injury cell model. Then, the viability of cells treated with 0, 5, 10, 20, 40 and 80 µM of calycosin was measured using Cell Counting Kit-8. For the in vivo model, db/db mice were treated with 10 and 20 mg/kg/day of calycosin; db/m mice served as controls. The histomorphology was analyzed via haematoxylin and eosin staining. RESULTS: HG-induced decreased expression of glutathione (491.57 ± 33.56 to 122.6 ± 9.78 µmol/mL) and glutathione peroxidase 4 (inhibition rate 92.3%) and increased expression of lactate dehydrogenase (3.85 ± 0.89 to 16.84 ± 2.18 U/mL), malondialdehyde (3.72 ± 0.66 to 18.2 ± 1.58 nmol/mL), lipid ROS (4.31-fold increase) and NCOA4 (7.69-fold increase). The effects induced by HG could be blocked by calycosin. Moreover, calycosin alleviated the HG-induced decrease of cell viability and the increase of lipid ROS, but erastin could block the effects caused by calycosin. The in vivo model showed that calycosin alleviated the renal injury caused by diabetes. DISCUSSION AND CONCLUSION: Calycosin has a protective effect on diabetic kidney disease; ferroptosis may be involved in this process.

Effect of Baihu and Guizhi decoction in acute gouty arthritis: study protocol for a randomized controlled trial.

BACKGROUND: The prevalence rates of gout worldwide have increased annually. Acute gouty arthritis (AGA) accounts for a large proportion of gout patients and causes severe physical and mental pain in patients. Controlling the occurrence and development of gout inflammation is the first step in the treatment of gout. The main treatment drugs in gout are non-steroid anti-inflammatory drugs (NSAIDs), colchicine, and glucocorticoids, but these treatments have many adverse reactions which limit their clinical application. Baihu and Guizhi decoction (BHGZ) is one of the classic prescriptions in the Synopsis of the Golden Chamber and is a good prescription for AGA. Previous clinical studies have shown that BHGZ confers a strong benefit for treating AGA. However, the literature shows a lack of high-quality RCT research on BHGZ with respect to AGA. Therefore, in this study, we use a randomized, double-blind, controlled study with a placebo to evaluate the clinical efficacy and safety of BHGZ on the AGA of moist heat arthralgia spasm syndrome. METHODS: This study is a randomized, double-blind, controlled clinical trial. A total of 102 adult participants with AGA of moist heat arthralgia spasm syndrome will be enrolled, with balanced treatment allocation (1:1). The experimental intervention will be BHGZ plus the low-dose colchicine, and the control intervention will be placebo plus the low-dose colchicine for 10 days. To study the clinical efficacy (including VAS score; joint tenderness, joint swelling, joint movement disorder; TCM evidence efficacy score) and the changes of inflammatory indexes. At the same time, the improvement of joint inflammation in patients with AGA will be observed from musculoskeletal ultrasound imaging, and the safety evaluation will be carried out. DISCUSSION: This study will be the first placebo-controlled RCT to assess whether BHGZ plus low-dose colchicine have beneficial effects on changing reducing inflammation of joints for patients with AGA of moist heat arthralgia spasm syndrome. The results of this trial will help to provide evidence-based recommendations for clinicians. TRIAL REGISTRATION: Chinese Clinical Trials Register ChiCTR1900024974 . Registered on 5 August 2019.

Efficacy of Chinese herbal medicine Jiangniaosuan formula for treatment of hyperuricemia: study protocol for a double-blinded non-inferiority randomized controlled clinical trial.

BACKGROUND: Jiangniaosuan formula (JNSF) is commonly used in China for treating hyperuricemia, but there is little research-based evidence to support its use. This randomized controlled trial aims to assess the efficacy and safety of JNSF. METHODS: A total of 72 patients with hyperuricemia will be selected and randomly assigned in a ratio of 1:2 to receive either Western medicine, i.e., febuxostat 40 mg (WG group; n = 24), or Chinese herbal medicine, i.e., Jiangniaosuan formula + febuxostat 20 mg (WJNSG group; n = 48). After 12 weeks, the WJNSG will be randomly divided into two groups of 24 patients each; one group (WJNSG; n = 24) still will receive febuxostat 20 mg + Jiangniaosuan formula, and the other group (JNSG; n = 24) will continue to receive Jiangniaosuan formula + placebo. Participants will be followed up at 4-week intervals. The primary outcome will be the change in serum uric acid level, and the secondary outcome will be the change in traditional Chinese medicine (TCM) syndrome scores. Serum creatinine, blood glucose, and insulin levels will also be measured. DISCUSSION: We hypothesize that patients with hyperuricemia will benefit from JNSF. This study will provide evidence-based recommendations for clinicians. DISSEMINATION: The results will be published in a peer-reviewed journal and disseminated by academic conferences. The datasets analyzed during the current study are available from the corresponding author on reasonable request. TRIAL REGISTRATION: Chinese Clinical Trials Register ChiCTR2000041083 . Registered on 3 May 2021. The protocol version number is V3.0, 20210301.

Selection of OSA-specific pronunciations and assessment of disease severity assisted by machine learning.

STUDY OBJECTIVES: To screen all of the obstructive sleep apnea (OSA)-characteristic pronunciations, explore the pronunciations which provide a better OSA classification effect than those used previously, and further clarify the correlation between speech signals and OSA. METHODS: A total of 158 adult male Mandarin native speakers who completed polysomnography at the Sleep Medicine Center of Beijing Tongren Hospital from November 15, 2019, to January 19, 2020, were enrolled in this study. All Chinese syllables were collected from each participant in the sitting position. The syllables, vowels, consonants, and tones were screened to identify the pronunciations that were most effective for OSA classification. RESULTS: The linear prediction coefficients of Chinese syllables were extracted as features and mathematically modeled using a decision tree model to dichotomize participants with apnea-hypopnea index thresholds of 10 and 30 events/h, and the leave-one-out method was used to verify the classification performance of Chinese syllables for OSA. Chinese syllables such as [leng] and [jue], consonant pronunciations such as [zh] and [f], and vowel pronunciations such as [ing] and [ai] were the most suitable pronunciations for classification of OSA. An OSA classification model consisting of several syllable combinations was constructed, with areas under curve of 0.83 (threshold of apnea-hypopnea index = 10) and 0.87 (threshold of apnea-hypopnea index = 30), respectively. CONCLUSIONS: This study is the first comprehensive screening of OSA-characteristic pronunciations and can act as a guideline for the construction of OSA speech corpora in other languages. CITATION: Ding Y, Sun Y, Li Y, et al. Selection of OSA-specific pronunciations and assessment of disease severity assisted by machine learning. J Clin Sleep Med. 2022;18(11):2663-2672.

Effects of resveratrol on renal ischemia-reperfusion injury: A systematic review and meta-analysis.

Renal ischemia-reperfusion (I/R) injury may lead to acute kidney injury, which is characterized by high morbidity and mortality rates. Resveratrol (RSV) can be extracted from Chinese herbs, and multiple animal experiments have demonstrated its potential for renal protection. This systematic review evaluates the protective effect of RSV against renal I/R injury in animal models. The PubMed, Embase, Web of Science, and Science Direct databases were searched for animal experiments related to RSV in renal I/R injury from their establishment to June 2022. In total, 19 studies were included with 249 animals (129 treated with RSV and 120 as controls). The pooled analysis revealed that RSV administration significantly decreased serum creatinine (SCr) levels (16 studies, n = 243, WMD = -58.13, 95% CI = -79.26 to -37.00, p < 0.00001) and blood urea nitrogen (BUN) levels (12 studies, n = 163, WMD = -34.37, 95% CI = -46.70 to -22.03, p < 0.00001) in the renal I/R injury model. The level of malondialdehyde (MDA), an oxidative stress index, was alleviated [7 studies, n = 106, standardized mean difference (SMD) = -6.05, 95% CI = -8.90 to -3.21, p < 0.0001] and antioxidant enzymes such as glutathione (GSH) (7 studies, n = 115, SMD = 9.25, 95% CI = 5.51-13.00, p < 0.00001) and catalase (CAT) (4 studies, n = 59, SMD = 8.69, 95% CI = 4.35-13.03, p < 0.0001) were increased after treatment of RSV. The subgroup analysis suggested that 5-10 mg/kg of RSV optimally protects against renal I/R injury as both the BUN and SCr levels were significantly decreased at this dosage. The protective effects of RSV against renal I/R injury might be attributed to multiple mechanisms, such as inhibiting oxidative stress, apoptosis, inflammation, fibrillation, and promoting autophagy. For a deeper understanding of the protective effects of RSV, experimental studies on animal models and large randomized controlled trials in humans are needed.

Development and validation of a practical machine-learning triage algorithm for the detection of patients in need of critical care in the emergency department.

Identifying critically ill patients is a key challenge in emergency department (ED) triage. Mis-triage errors are still widespread in triage systems around the world. Here, we present a machine learning system (MLS) to assist ED triage officers better recognize critically ill patients and provide a text-based explanation of the MLS recommendation. To derive the MLS, an existing dataset of 22,272 patient encounters from 2012 to 2019 from our institution's electronic emergency triage system (EETS) was used for algorithm training and validation. The area under the receiver operating characteristic curve (AUC) was 0.875 ± 0.006 (CI:95%) in retrospective dataset using fivefold cross validation, higher than that of reference model (0.843 ± 0.005 (CI:95%)). In the prospective cohort study, compared to the traditional triage system's 1.2% mis-triage rate, the mis-triage rate in the MLS-assisted group was 0.9%. This MLS method with a real-time explanation for triage officers was able to lower the mis-triage rate of critically ill ED patients.

Huangqi Guizhi Wuwu Decoction attenuates Podocyte cytoskeletal protein damage in IgA nephropathy rats by regulating AT1R/Nephrin/c-Abl pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Huangqi Guizhi Wuwu Decoction(HQGZWWD) is a Traditional Chinese Medicine formula from Synopsis of Golden Chamber used to treat blood arthralgia. According to the principle that the same treatment can be used for different diseases, HQGZWWD has proven effective for IgA nephropathy (IgAN) associated with spleen and kidney yang deficiency. AIM OF THE STUDY: In this study, we investigated the mechanism by which HQGZWWD alleviates proteinuria and protects renal function in rats with IgAN by regulating the AT1R/Nephrin/c-Abl pathway. METHODS: Rats were randomly divided into six groups: control, IgAN model, IgAN model treated with low-dose HQGZWWD, IgAN model treated with medium-dose HQGZWWD, IgAN model treated with high-dose HQGZWWD, and IgAN model treated with valsartan. IgAN was induced using bovine γ-globulin. We evaluated the mediating effects of HQGZWWD on podocyte cytoskeletal proteins, the AT1R/Nephrin/c-Abl pathway, upstream tumor necrosis factor-α (TNF-α), and TNF-α receptor-1 (TNFR1). RESULTS: The IgAN rats displayed proteinuria, IgA deposition in the mesangial region, and podocyte cytoskeletal protein damage. The expression of TNF-α, TNFR1, AT1R, and c-Abl was increased in the IgAN rat kidney, whereas the expression of nephrin, podocin, ACTN4, and phosphorylated nephrin (p-nephrin) was reduced. HQGZWWD treatment significantly alleviated podocyte cytoskeletal protein damage in the IgAN rats, upregulated the expression of nephrin, podocin, and ACTN4, and the colocalized expression of F-actin and nephrin. This study demonstrates that HQGZWWD attenuates podocyte cytoskeletal protein damage by regulating the AT1R-nephrin- c-Abl pathway, upregulating the expression of p-nephrin, and downregulating the expression of AT1R and c-Abl. CONCLUSIONS: These results indicate that HQGZWWD attenuates podocyte cytoskeletal protein damage in IgAN rats by regulating the AT1R/Nephrin/c-Abl pathway, providing a potential therapeutic approach for IgAN.

Reactive oxygen species induced by uric acid promote NRK­52E cell apoptosis through the NEK7­NLRP3 signaling pathway.

Increasing uric acid (UA) could induce renal tubular epithelial cell (NRK­52E) injury. However, the specific mechanism by which UA induces renal tubular epithelial cell injury remains unknown. It was hypothesized that UA induces renal tubular epithelial cell injury through reactive oxygen species (ROS) and the Never in mitosis gene A (NIMA)­related kinase 7 (NEK7)/NLR family pyrin domain containing 3 (NLRP3) signaling pathway. TUNEL assay and flow cytometry were applied to measure apoptosis, and the results of the present study showed that UA treatment induced apoptosis of NRK­52E cells in a concentration­dependent manner. Western blotting was performed to determine the expression levels of cleaved caspase­3, Bax and Bcl­xl, it was found that levels were significantly increased after UA treatment in NRK­52E cells. ROS and apoptosis were predominantly induced in NRK­52E cells and there was an association between ROS and apoptosis. Enhanced expression of NEK7, NLRP3, apoptosis­associated speck­like and caspase­1 were observed in NRK­52E cells treated with UA. The ROS inhibitor, N­acetyl­l­cysteine, exerted a protective effect on the UA­induced apoptosis of tubular epithelial cells by reducing excess ROS production, which significantly inhibited NEK7 and NLRP3 inflammasome activation. These results indicated that UA activates ROS and induces apoptosis of NRK­52E cells. The mechanism might be related to the regulation of the NEK7/NLRP3 signaling pathway.

Impact of preoperative body mass index on perioperative outcomes is optimized by enhanced recovery protocols in laparoscopic radical cystectomy with intracorporeal urinary diversion.

BACKGROUND: We aimed to examine whether body mass index (BMI) had an impact on clinical outcomes of laparoscopic radical cystectomy with intracorporeal urinary diversion. Furthermore, we analyzed the optimization of enhanced recovery protocols (ERPs) on the impact of BMI on clinical outcomes. METHODS: By searching our database, data of 83 consecutive patients were retrospectively collected, including 37 patients with a BMI <24 kg/m2 (group A) and 46 patients with a BMI ≥24 kg/m2 (group B). The baseline and peri-operative variables of the two groups were compared. Subgroup analysis was conducted for ERPs (11 patients in group A1, 18 patients in group B1) and conventional recovery protocols (CRPs; 26 patients in group A2, 28 patients in group B2). The primary outcomes were 30-day overall complication rate and ΔALBmin (reduction proportion of minimum albumin). The secondary outcomes were operative time and length of stay. RESULTS: The baseline variables were similar between the two groups (P>0.05). The 30-day overall complication rate, operative time, and length of stay were similar between the two groups (P>0.05). But post-operative nausea and vomiting (PONV) was higher in group A than in group B (32.4% vs. 8.7%, P=0.014). Group A was associated with lower serum albumin level pre-operatively and on post-operative days 1-3. ΔALBmin was higher in group A than in group B (33.08%±9.88% vs. 27.92%±8.52%, P<0.05). In the subgroup analysis, the CRPs group presented similar results, with group A2 showing higher PONV rate, lower albumin level pre- and post-operatively, and higher level of reduction proportion (P<0.05). For the ERPs group, the PONV rate, pre-operative albumin level, and reduction proportion were similar between group A1 and B1 (P>0.05). Multivariable analysis showed that PONV and CRPs were independently associated with ΔALBmin ≥34% (P<0.05). CONCLUSIONS: BMI had no impact on the 30-day overall complication rate, operative time, and length of stay of patients who underwent laparoscopic radical cystectomy with intracorporeal urinary diversion. BMI <24 kg/m2 was associated with higher PONV rate and more albumin loss, both of which could be optimized by ERPs.

The Association of Insomnia with Depression and Anxiety Symptoms in Patients Undergoing Noncardiac Surgery.

OBJECTIVE: Insomnia is common in patients undergoing surgery. It can increase the rate of postoperative complications, interfere with patient recovery, and decrease hospital satisfaction. However, there are few studies on perioperative insomnia. This study was conducted to investigate the differences in the demographic, health status, and clinical characteristics of patients with and without insomnia postoperatively, and to identify the potential risk factors of insomnia. METHODS: There were 299 non-cardiac surgery patients, 165 females, and 134 males, with a mean age of 55 years, enrolled in the study. The Insomnia Severity Index (ISI), Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder 7 (GAD-7), and Montreal Cognitive Assessment (MoCA) were administered to all the patients preoperatively. The Visual Analogue Scale (VAS) was used preoperatively, and at the end of the surgery, and then one day, two days, and three days after surgery. The PHQ-9, the GAD-7, and the ISI were repeated three days after surgery. Insomnia was diagnosed by the ISI as being a score of 8-28 (mild: 8-14; moderate-severe: 15-21; severe: 22-28). The patients were divided into group A (with insomnia, N=78) and group B (without insomnia, N=221) according to their ISI score three days after surgery. The general clinical data of the two groups were analyzed first, and then binary logistic regression analysis was conducted to assess the risk factors of insomnia. RESULTS: A total of 299 non-cardiac surgery patients with a mean age of 55 years were enrolled in the study. Of the included patients, the number of females was 165 and the number of the male was 134. The incidence of insomnia at 3 days postoperatively was 26.1% (78/299). The average points that group A patients scored in the ISI, PHQ-9, and the GAD-7 were significantly higher than those in group B. The VAS score three days after surgery was significantly higher in group A. The PHQ-9 and the GAD-7 three days after surgery showed significantly higher depression and anxiety scores in group A. Logistic regression showed that the ISI (p<0.001, 95% CI=1.218-1.500) and the GAD-7 (p=0.003, 95% CI=1.041-1.218) preoperatively, and the PHQ-9 postoperatively (p<0.001, 95% CI=1.226-1.555), were risk factors of insomnia. CONCLUSION: Insomnia is common and can worsen after surgery. The present study suggests that depression and anxiety are risk factors for insomnia after surgery. There is a need for further research and the development of strategies for depression and anxiety management to ensure better sleep quality for patients, which will be of significant benefit to their health. CLINICAL TRIAL REGISTRATION: The study was registered at clinical trial (NCT04027751); Trial registration: clinical trial, NCT04027751. Registered 22 July 2019; https://clinicaltrials.gov/ct2/show/NCT04027751?cond=NCT04027751&cntry=CN&draw=2&rank=1.

Real-time prediction of upcoming respiratory events via machine learning using snoring sound signal.

STUDY OBJECTIVES: The aim of the study was to inspect the acoustic properties and sleep characteristics of a preapneic snoring sound. The feasibility of forecasting upcoming respiratory events by snoring sound was also investigated. METHODS: Participants with habitual snoring or a heavy breathing sound during sleep were recruited consecutively. Polysomnography was conducted, and snoring-related breathing sound was recorded simultaneously. Acoustic features and sleep features were extracted from 30-second samples, and a machine learning algorithm was used to establish 2 prediction models. RESULTS: A total of 74 eligible participants were included. Model 1, tested by 5-fold cross-validation, achieved an accuracy of 0.92 and an area under the curve of 0.94 for respiratory event prediction. Model 2, with acoustic features and sleep information tested by Leave-One-Out cross-validation, had an accuracy of 0.78 and an area under the curve of 0.80. Sleep position was found to be the most important among all sleep features contributing to the performance of the 2 models. CONCLUSIONS: Preapneic sound presented unique acoustic characteristics, and snoring-related breathing sound could be deployed as a real-time apneic event predictor. The models, combined with sleep information, serve as a promising tool for an early warning system to forecast apneic events. CITATION: Wang B, Yi X, Gao J, et al. Real-time prediction of upcoming respiratory events via machine learning using snoring sound signal. J Clin Sleep Med. 2021;17(9):1777-1784.