Mechanical mechanism analysis of rockburst in deep-buried tunnel with high in-situ stress.

The Qinling water conveyance tunnel has a large buried depth and high in-situ stress level, and rockburst disasters frequently occurred during excavation. In order to find out the mechanical mechanism of rockburst, the research work in this paper is as follows: (1) In-situ three-dimensional hydraulic fracturing method was used to measure the in-situ stress of the deep buried tunnel crossing the ridge. (2) Based on the measured in-situ stress results, the stress distribution characteristics of the tunnel crossing the ridge were obtained by the multiple linear regression method, and the rockburst tendency during construction was predicted. (3) A three-dimensional numerical model of tunnel excavation was established to analyze the dynamic adjustment characteristics of the surrounding rock stress and elastic strain energy during TBM excavation, and to clarify the mechanical mechanism of rockburst. The research results show that the maximum principal stress of the deep-buried tunnel crossing the ridge of Qinling is 40-66 MPa, which belongs to extremely high in-situ stress level, and medium-strong rockburst may occur during excavation. In the process of TBM excavation, the stress of the surrounding rock in the range of 2.6 times the diameter of the tunnel before and after the working face is adjusted violently, and the concentrated zones after the stress redistribution are mainly distributed in the arch roof and arch bottom, and the stress concentration coefficient can reach 2.06. The arch roof, arch waist, and arch bottom are susceptible to immediate rockburst due to stress transient unloading at the moment of excavation. After the elastic strain energy of the surrounding rock at the arch roof and the arch bottom is released and accumulated, it is easy to cause time delayed rockburst, and the depth of the rockburst pit can reach 3.5 m, which is consistent with the rockburst phenomenon in the field.

Neutrophil-percentage-to-albumin ratio is associated with chronic kidney disease: Evidence from NHANES 2009-2018.

INTRODUCTION: The neutrophil-percentage-to-albumin ratio (NPAR), a novel inflammatory biomarker, has been used to predict the prognosis of patients with cancer and cardiovascular disease. However, the relationship between NPAR and chronic kidney disease (CKD) remains unknown. The purpose of this study was to investigate the possible association between NPAR and CKD. METHODS: The cross-sectional study included participants with complete information on NPAR, serum creatinine (Scr), or urinary albumin-to-creatinine ratio (UACR) from the 2009-2018 National Health and Nutrition Examination Survey (NHANES). CKD was defined as the presence of either low estimated glomerular filtration rate (eGFR) or albuminuria. Univariate and multivariate logistic regression and restricted cubic spline regression were used to assess the linear and nonlinear associations between NPAR and renal function. Subgroup and interactive analyses were performed to explore potential interactive effects of covariates. Missing values were imputed using random forest. RESULTS: A total of 25,236 participants were enrolled in the study, of whom 4518 (17.9%) were diagnosed with CKD. After adjustment for covariates, the odds ratios (ORs) for prevalent CKD were 1.19 (95% CI = 1.07-1.31, p <0.05) for the Q2 group, 1.53 (95% CI = 1.39-1.69, p < 0.001) for the Q3 group, and 2.78 (95% CI = 2.53-3.05, p < 0.001) for the Q4 group. There was a significant interaction between age and diabetes mellitus on the association between NPAR and CKD (both p for interaction < 0.05). And there was a non-linear association between NPAR levels and CKD in the whole population (p for non-linear < 0.001). All sensitivity analyses supported the positive association between NPAR and CKD. CONCLUSIONS: NPAR was positively correlated with increased risk of CKD. The NPAR may serve as an available and cost-effective tool for identifying and intervening the individuals at risk of CKD.

Serum HMGB-1 released by ferroptosis and necroptosis as a novel potential biomarker for systemic lupus erythematosus.

High mobility group box proterin-1 (HMGB-1) is a multifunctional protein that can be released by various programmed cell deaths (PCDs), such as necroptosis and ferroptosis. PCDs play a critical role in the pathogenesis of systemic lupus erythematosus (SLE). However, the role of HMGB-1 in the process of SLE remains unclear. This study aims to demonstrate the potential diagnosing role of serum HMGB-1 in SLE that released by necroptosis and ferroptosis. We found that the serum levels of HMGB-1, receptor-interacting protein kinase 3 (RIPK3) /mixed lineage kinase domain-like protein (MLKL) related with necroptosis, and metabolites associated with ferroptosis were significantly upregulated in SLE patients compared to HC individuals. These serum levels were positively correlated with SLE disease activity. Additionally, the serum level of HMGB-1 showed a strong positive correlated with the levels of RIPK3/MLKL and ferroptosis metabolites. Moreover, the serum level of HMGB-1 was correlated with renal involvement and high-antinuclear antibodies (ANA) titer. After SLE serum and interferon γ (IFN-γ) treatment in vitro, the level of necroptosis and ferroptosis markers were activated and HMGB1 was released both in HEK293 and HK2 cells. Clinically, HMGB-1 was considered as a significant independent risk factor in SLE serum by binary logistic assay. Notably, HMGB-1 exhibited outstanding diagnostic ability for SLE by the area under the curve (AUC) in receiver operating characteristic (ROC) curve analysis. Taken together, our study indicates that the serum level of HMGB-1 is a promising biomarker for the diagnosis and monitoring of SLE.

Design, synthesis and antimicrobial activity of novel berberine derivatives.

BACKGROUND: The threats to the safety of humans and the environment and the resistance of agricultural chemicals to plant pathogenic fungi and bacteria highlight an urgent need to find safe and efficient alternatives to chemical fungicides and bactericides. In this study, a series of Berberine (BBR) derivatives were designed, synthesized and evaluated for in vitro and in vivo antimicrobial activity against plant pathogenic fungi and bacteria. RESULTS: Bioassay results indicated that compounds A11, A14, A20, A21, A22, A25, A26, E1, E2, E3, Z1 and Z2 showed high inhibitory activity against Sclerotinia sclerotiorum and Botrytis cinerea. Especially, A25 showed a broad spectrum and the highest antifungal activity among these compounds. Its EC50 value against Botrytis cinerea was 1.34 µg mL-1. Compound E6 possessed high inhibitory activity against Xanthomonas oryzae and Xanthomonas Campestris, with MIC90 values of 3.12 µg mL-1 and 1.56 µg mL-1. A Topomer CoMFA model was generated for 3D-QSAR studies based on anti-B. cinerea effects, with high predictive accuracy, showed that the addition of an appropriate substituent group at the para-position of benzyl of BBR derivatives could effectively improve the anti-B. cinerea activity. In addition, compound A25 could significantly inhibit the spore germination of Botrytis cinerea at low concentration, and compound F4 exhibited remarkable curative and protective efficiencies on rice bacterial leaf blight. CONCLUSION: This study indicates that the BBR derivatives are hopeful for further exploration as the lead compound with novel antimicrobial agents. © 2024 Society of Chemical Industry.

Kidney-brain axis in the pathogenesis of cognitive impairment.

The kidney-brain axis is a bidirectional communication network connecting the kidneys and the brain, potentially affected by inflammation, uremic toxin, vascular injury, neuronal degeneration, and so on, leading to a range of diseases. Numerous studies emphasize the disruptions of the kidney-brain axis may contribute to the high morbidity of neurological disorders, such as cognitive impairment (CI) in the natural course of chronic kidney disease (CKD). Although the pathophysiology of the kidney-brain axis has not been fully elucidated, epidemiological data indicate that patients at all stages of CKD have a higher risk of developing CI compared with the general population. In contrast to other reviews, we mentioned some commonly used medicines in CKD that may play a pivotal role in the pathogenesis of CI. Revealing the pathophysiology interactions between kidney damage and brain function can reduce the potential risk of future CI. This review will deeply explore the characteristics, indicators, and potential pathophysiological mechanisms of CKD-related CI. It will provide a theoretical basis for identifying CI that progresses during CKD and ultimately prevents and treats CKD-related CI.

Efficacy of probiotics/synbiotics supplementation in patients with chronic kidney disease: a systematic review and meta-analysis of randomized controlled trials.

Background: Chronic kidney disease (CKD) is a serious and steadily growing health problem worldwide. Probiotic and synbiotic supplementation are expected to improve kidney function in CKD patients by altering imbalanced intestinal flora, regulating microbiota metabolites, modulating the brain-gut axis, and reducing inflammation. Objectives: Our aim is to report the latest and largest pooled analyses and evidence updates to explore whether probiotic and synbiotic have beneficial effects on renal function and general conditions in patients with CKD. Methods: We conducted a systematic literature search using PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials from inception until 1 December 2023. Eligible literatures were screened according to inclusion and exclusion criteria, data were extracted, and a systematic review and meta-analysis was performed. Measurements included renal function-related markers, inflammatory markers, uremic toxins, lipid metabolism-related markers and electrolytes levels. Results: Twenty-one studies were included. The results showed that probiotic/synbiotic significantly reduced blood urea nitrogen (BUN) (standardized mean difference (SMD), -0.23, 95% confidence interval (CI) -0.41, -0.04; p = 0.02, I2 = 10%) and lowered c-reactive protein level (CRP) (SMD: -0.34; 95% CI: -0.62, -0.07; p = 0.01, I2 = 37%) in CKD patients, compared with the control group. Conclusion: In summary, probiotic/synbiotic supplementation seems to be effective in improving renal function indices and inflammation indices in CKD patients. Subgroup analyses suggested that longer-term supplementation is more favorable for CKD patients, but there is a high degree of heterogeneity in the results of partial subgroup analyses. The efficacy of probiotic/synbiotic in treating CKD needs to be supported by more evidence from large-scale clinical studies. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024526836, Unique identifier: CRD42024526836.

Inhibition of OLR1 reduces SASP of nucleus pulposus cells by targeting autophagy-GATA4 axis.

Targeting cellular senescence and Senescence Associated Secretory Phenotype (SASP) through autophagy has emerged as a promising intervertebral disc (IVD) degeneration (IDD) treatment strategy in recent years. This study aimed to clarify the role and mechanism of autophagy in preventing IVD SASP. Methods involved in vitro experiments with nucleus pulposus (NP) tissues from normal and IDD patients, as well as an in vivo IDD animal model. GATA4's regulatory role in SASP was validated both in vitro and in vivo, while autophagy modulators were employed to assess their impact on GATA4 and SASP. Transcriptomic sequencing identified Oxidized low-density lipoprotein receptor 1 (OLR1) as a key regulator of autophagy and GATA4. A series of experiments manipulated OLR1 expression to investigate associated effects. Results demonstrated significantly increased senescent NP cells (NPCs) and compromised autophagy in IDD patients and animal models, with SASP closely linked to IDD progression. The aged disc milieu impeded autophagic GATA4 degradation, leading to elevated SASP expression in senescent NPCs. Restoring autophagy reversed senescence by degrading GATA4, hence disrupting the SASP cascade. Moreover, OLR1 was identified for its regulation of autophagy and GATA4 in senescent NPCs. Silencing OLR1 enhanced autophagic activity, suppressing GATA4-induced senescence and SASP expression in senescent NPCs. In conclusion, OLR1 was found to control autophagy-GATA4 and SASP, with targeted OLR1 inhibition holding promise in alleviating GATA4-induced senescence and SASP expression while delaying extracellular matrix degradation, offering a novel therapeutic approach for IDD management.

Single-Molecule Magnet Rods: Remarkably Elongated Lanthanide Phosphonate Cores with Quasilinear Hydrazones.

Large metal-phosphonate clusters typically exhibit regular polyhedral, wheel-shaped, spherical, or capsule-shaped morphologies more effectively than high-aspect ratio topologies. A system of elongated lanthanide core topologies has now been synthesized by the reaction of lanthanide 1-naphthylmethylphosphonates and four differently terminated pyrazinyl hydrazones. Four new rod-shaped dysprosium phosphonate clusters, [Dy6(O3PC11H9)4(L1)4(µ4-O)(DMF)4]·2DMF·3MeCN·3H2O (1), [Dy8(O3PC11H9)4(L2)4(µ3-O)4(CO2)4(H2O)4]·6DMF·4MeCN·3H2O (2), [Dy12Na(O3PC11H9)6(L3)6(µ3-O)2(pyr)6]·DMF·2MeCN·H2O (3), and [Dy14(O3PC11H9)12(L4)8(µ3-O)2(DMF)4(MeOH)2(H2O)4]·5DMF·2MeCN·H2O (4), were obtained. Four single-pyrazinyl hydrazones function as pentadentate bis-chelate terminal co-ligands, coordinating the periphery of dysprosium phosphonate rods. A sodium ion serves as a cation template for constructing heterobimetallic 3 by occupying the void, demonstrating the ability to reliably control cluster length by modifying the hydrazone co-ligand structure and cation template. Additionally, it was observed that the elongation of the rods has a significant directional impact on the magnetic relaxation behavior, transitioning from a one-step process in 1 to a three-step process in 2, a two-step process in 3, and finally a two-step process in 4.

Factors related to the disaster preparedness of patients on haemodialysis from Sichuan, China, during COVID-19: A cross-sectional study.

AIM: This study aimed to investigate personal preparedness among patients on haemodialysis (HD) and to examine the relationship among sociodemographic characteristics, attitudes toward disaster preparedness and personal preparedness behaviours during natural disaster incidents. DESIGN: A cross-sectional survey was conducted. METHODS: A convenience sampling method was used. A total of 446 participants from six areas of Sichuan province completed the online questionnaire study from February 27 to March 13, 2022. Sociodemographic characteristics, attitudes toward disaster preparedness and personal preparedness behaviours were measured. Descriptive statistics were used to analyse sociodemographic characteristics and attitudes toward disaster preparedness. The relationship among sociodemographic characteristics, attitudes toward disaster preparedness and personal preparedness behaviours were assessed using ordinal regression. Statistical significance was defined as p < 0.05. RESULTS: A total of 446 participants completed the survey. Of these, 42.15% (N = 188) were poorly prepared, 26.23% (N = 117) were moderately prepared and 31.61% (N = 141) were highly prepared. Ordinal regression showed that knowing about disaster preparedness (Odds Ratio (OR) = 1.691, 95% Confidence Interval (CI) = 1.081-2.644, p = 0.021), participating in disaster evacuation exercises (OR = 2.519, 95% CI = 1.595-3.977, p < 0.001) and learning about disaster preparedness (OR = 2.421, 95% CI = 1.542-3.802, p < 0.001) were associated with high preparedness. Compared to patients with a university degree or higher, patients with a junior high school education or lower (OR = 3.491, 95% CI = 1.760-6.925, p < 0.001) and senior high school degree (OR = 2.052, 95% CI = 1.038-4.057, p = 0.039) were associated with high preparedness. Patients who felt very confident and could deal with all their needs (OR = 3.878, 95% CI = 2.904-7.181, p < 0.001) or patients who felt confident and could meet some of their needs (OR = 1.949, 95% CI = 1.124-3.379, p = 0.017) had higher preparedness than those who felt less confident and were not well prepared to take care of their needs. PATIENT OR PUBLIC CONTRIBUTION: After obtaining each participant's consent, they filled out the online questionnaire using their own or a relative's cell phone while undergoing HD. IMPLICATION FOR PRACTICE: It is essential that patients should be educated not only on medical specialty topics, but also on general disaster preparedness. Medical institutions should improve and reinforce preparation training among targeted populations. The low level of preparedness is partly due to the lack of participation of patients in disaster preparedness programs. Dialysis center managers should be urged to implement such programs at their centers.

Application of Diffusion Kurtosis Imaging and Blood Oxygen Level-Dependent Magnetic Resonance Imaging in Kidney Injury Associated with ANCA-Associated Vasculitis.

OBJECTIVE: Functional magnetic resonance imaging (fMRI) has been applied to assess the microstructure of the kidney. However, it is not clear whether fMRI could be used in the field of kidney injury in patients with Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: This study included 20 patients with AAV. Diffusion kurtosis imaging (DKI) and blood oxygen level-dependent (BOLD) scanning of the kidneys were performed in AAV patients and healthy controls. The mean kurtosis (MK), mean diffusivity (MD), and fractional anisotropy (FA) parameters of DKI, the R2* parameter of BOLD, and clinical data were further analyzed. RESULTS: In AAV patients, the cortex exhibited lower MD but higher R2* values compared to the healthy controls. Medullary MK values were elevated in AAV patients. Renal medullary MK values showed a positive correlation with serum creatinine levels and negative correlations with hemoglobin levels and estimated glomerular filtration rate. To assess renal injury in AAV patients, AUC values for MK, MD, FA, and R2* in the cortex were 0.66, 0.67, 0.57, and 0.55, respectively, and those in the medulla were 0.81, 0.77, 0.61, and 0.53, respectively. CONCLUSIONS: Significant differences in DKI and BOLD MRI parameters were observed between AAV patients with kidney injuries and the healthy controls. The medullary MK value in DKI may be a noninvasive marker for assessing the severity of kidney injury in AAV patients.

Accuracy of lingual fixed retainers fabricated using a CAD/CAM bending machine.

Objective: Lingual fixed retainers, made from 0.0175-inch 3-strand twisted stainless steel wire (TW) and 0.016 × 0.022-inch straight rectangular wire (RW), are generally used in clinical practice. This study aimed to calculate their accuracy by comparing the discrepancy between computer-aided customized retainers made from these two types of wires. Methods: Eleven orthodontic patients were selected, resulting in 22 maxillary and mandibular three-dimensional printing dental models. Two types of lingual fixed retainers were bonded from canine to canine. To determine the accuracy, five points were chosen for each model, resulting in 110 selected points. The absolute values of the distances on the x-, y-, and z-axes were measured to compare the accuracy of the two types of computer-aided retainers. Results: The accuracy of the two types of retainers did not differ significantly in the x- and z-axes, but only in the y-axis (P < 0.01), where RW-fixed retainers exhibited a slightly but significantly increased distance compared to the TW. Conclusions: Both types of retainers showed high accuracy; however, RW had a slight but statistically significant difference along the y-axis compared with TW. This type of computer-aided design/computer-aided manufacturing bending machine is limited to two dimensions, and the dental arch is curved. Therefore, RW may require slight manual adjustment by the practitioner after manufacturing.

Two C-terminal isoforms of Aplysia tachykinin-related peptide receptors exhibit phosphorylation-dependent and phosphorylation-independent desensitization mechanisms.

Diversity, a hallmark of G protein-coupled receptor (GPCR) signaling, partly stems from alternative splicing of a single gene generating more than one isoform for a receptor. Additionally, receptor responses to ligands can be attenuated by desensitization upon prolonged or repeated ligand exposure. Both phenomena have been demonstrated and exemplified by the deuterostome tachykinin signaling system, although the role of phosphorylation in desensitization remains a subject of debate. Here, we describe the signaling system for tachykinin-related peptides (TKRPs) in a protostome, mollusk Aplysia. We cloned the Aplysia TKRP precursor, which encodes three TKRPs (apTKRP-1, apTKRP-2a, and apTKRP-2b) containing the FXGXR-amide motif. In situ hybridization and immunohistochemistry showed predominant expression of TKRP mRNA and peptide in the cerebral ganglia. TKRPs and their posttranslational modifications were observed in extracts of central nervous system ganglia using mass spectrometry. We identified two Aplysia TKRP receptors (apTKRPRs), named apTKRPR-A and apTKRPR-B. These receptors are two isoforms generated through alternative splicing of the same gene and differ only in their intracellular C termini. Structure-activity relationship analysis of apTKRP-2b revealed that both C-terminal amidation and conserved residues of the ligand are critical for receptor activation. C-terminal truncates and mutants of apTKRPRs suggested that there is a C-terminal phosphorylation-independent desensitization for both receptors. Moreover, apTKRPR-B also exhibits phosphorylation-dependent desensitization through the phosphorylation of C-terminal Ser/Thr residues. This comprehensive characterization of the Aplysia TKRP signaling system underscores the evolutionary conservation of the TKRP and TK signaling systems, while highlighting the intricacies of receptor regulation through alternative splicing and differential desensitization mechanisms.

Metabolic reprogramming in septic acute kidney injury: pathogenesis and therapeutic implications.

Acute kidney injury (AKI) is a frequent and severe complication of sepsis and is characterized by significant mortality and morbidity. However, the pathogenesis of septic acute kidney injury (S-AKI) remains elusive. Metabolic reprogramming, which was originally referred to as the Warburg effect in cancer, is strongly related to S-AKI. At the onset of sepsis, both inflammatory cells and renal parenchymal cells, such as macrophages, neutrophils and renal tubular epithelial cells, undergo metabolic shifts toward aerobic glycolysis to amplify proinflammatory responses and fortify cellular resilience to septic stimuli. As the disease progresses, these cells revert to oxidative phosphorylation, thus promoting anti-inflammatory reactions and enhancing functional restoration. Alterations in mitochondrial dynamics and metabolic reprogramming are central to the energetic changes that occur during S-AKI. In this review, we summarize the current understanding of the pathogenesis of metabolic reprogramming in S-AKI, with a focus on each cell type involved. By identifying relevant key regulatory factors, we also explored potential metabolic reprogramming-related therapeutic targets for the management of S-AKI.

SKLB023 protects against inflammation and apoptosis in sepsis-associated acute kidney injury via the inhibition of toll-like receptor 4 signaling.

Sepsis-associated acute kidney injury (SA-AKI) is one of common critical illnesses with high morbidity and mortality. At present, effective therapeutic drugs for SA-AKI are remain lacking. SKLB023 is a synthetic small-molecule compound which exerts potent anti-inflammatory effects in our previous studies. Here, this study aimed to characterize the protective effect of SKLB023 on SA-AKI and explore its underlying mechanism. The SA-AKI experimental models have been established by cecum ligation/puncture (CLP) and lipopolysaccharide (LPS) injection in male C57BL/6J mice. SKLB023 was administered by gavage (50 or 25 mg/kg in CLP model and 50 mg/kg in LPS model) daily 3 days in advance and 30 min earlier on the day of modeling. Our results confirmed SKLB023 treatment could improve the survival of SA-AKI mice and ameliorate renal pathological injury, inflammation, and apoptosis in the two types of septic AKI mice. Mechanically, SKLB023 deceased the expression of TLR4 in LPS-triggered renal tubular epithelial cells, and inhibited the activation of downstream pathways including NF-κB and MAPK pathways. Our study suggested that SKLB023 is expected to be a potential drug for the prevention and treatment of septic AKI.

The Time-Varying Impact of COVID-19 on the Acute Kidney Disorders: A Historical Matched Cohort Study and Mendelian Randomization Analysis.

Background: This study aimed to explore the time-varying impact of COVID-19 on acute kidney disorders, including acute kidney injury and other acute kidney diseases. Methods: From the UK Biobank, 10,121 participants with COVID-19 were matched with up to 3 historically unexposed controls by age, sex, Townsend deprivation index, and the status of hospitalization or receiving critical care. We investigated the association between COVID-19 and incidence of acute kidney disorders, within the first 4 weeks after infection, using conditional and time-varying Cox proportional hazard regression. In addition, one-sample Mendelian randomization, utilizing the polygenic risk score for COVID-19 as an instrumental variable, was conducted to explore the potential causality of the association. Results: In the matched cohort study, we observed a significant association between COVID-19 and acute kidney disorders predominantly within the first 3 weeks. The impact of COVID-19 was time dependent, peaking in the second week (hazard ratio, 12.77; 95% confidence interval, 5.93 to 27.70) and decreasing by the fourth week (hazard ratio, 2.28; 95% confidence interval, 0.75 to 6.93). In subgroup analyses, only moderate to severe COVID-19 cases were associated with acute worsening of renal function in a time-dependent pattern. One-sample Mendelian randomization analyses further showed that COVID-19 might exert a "short-term" causal effect on the risk of acute kidney disorders, primarily confined to the first week after infection. Conclusions: The risk of acute kidney disorders following COVID-19 demonstrates a time-varying pattern. Hazard effects were observed only in patients with moderate or severe but not mild COVID-19.

Chromodomain Y-like (CDYL) inhibition ameliorates acute kidney injury in mice by regulating tubular pyroptosis.

Acute kidney injury (AKI) is a common disease, but lacking effective drug treatments. Chromodomain Y-like (CDYL) is a kind of chromodomain protein that has been implicated in transcription regulation of autosomal dominant polycystic kidney disease. Benzo[d]oxazol-2(3H)-one derivative (compound D03) is the first potent and selective small-molecule inhibitor of CDYL (KD = 0.5 µM). In this study, we investigated the expression of CDYL in three different models of cisplatin (Cis)-, lipopolysaccharide (LPS)- and ischemia/reperfusion injury (IRI)-induced AKI mice. By conducting RNA sequencing and difference analysis of kidney samples, we found that tubular CDYL was abnormally and highly expressed in injured kidneys of AKI patients and mice. Overexpression of CDYL in cisplatin-induced AKI mice aggravated tubular injury and pyroptosis via regulating fatty acid binding protein 4 (FABP4)-mediated reactive oxygen species production. Treatment of cisplatin-induced AKI mice with compound D03 (2.5 mg·kg-1·d-1, i.p.) effectively attenuated the kidney dysfunction, pathological damages and tubular pyroptosis without side effects on liver or kidney function and other tissue injuries. Collectively, this study has, for the first time, explored a novel aspect of CDYL for tubular epithelial cell pyroptosis in kidney injury, and confirmed that inhibition of CDYL might be a promising therapeutic strategy against AKI.

Ultrasmall magnolol/ebselen nanomicelles for preventing renal ischemia/reperfusion injury.

Renal ischemia/reperfusion injury (RIRI) is an inevitable complication following kidney transplantation surgery, accompanied by the generation of a large amount of free radicals. A cascade of events including oxidative stress, extreme inflammation, cellular apoptosis, and thrombosis disrupts the microenvironment of renal cells and the hematological system, ultimately leading to the development of acute kidney injury (AKI). The current research primarily focuses on reducing inflammation and mitigating damage to renal cells through antioxidative approaches. However, studies on simultaneously modulating the renal hematologic system remain unreported. Herein, potent and novel drug-loaded nanomicelles can be efficiently self-assembled with magnolol (MG) and ebselen (EBS) by π-π conjugation, hydrophobic action and the surfactant properties of Tween-80. The ultrasmall MG/EBS nanomicelles (average particle size: 10-25 nm) not only fully preserve the activity of both drugs, but also greatly enhance drug utilization (encapsulation rates: MG: 90.1%; EBS: 49.3%) and reduce drug toxicity. Furthermore, EBS, as a glutathione peroxidase mimic and NO catalyst, combines with the multifunctional MG to scavenge free radicals and hydroperoxides, significantly inhibiting inflammation and thrombosis while effectively preventing apoptosis of vascular endothelial cells and renal tubular epithelial cells. This study provides a new strategy and theoretical foundation for the simultaneous regulation of kidney cells and blood microenvironment stability.

Research on coronavirus disease 2019 and the kidney: A bibliometric analysis.

Background: In addition to damage to the lungs, coronavirus disease 2019 (COVID-19) can damage multiple organs, including the kidney. Our purpose was to analyze the research hotspots and trends in COVID-19 and kidney diseases using bibliometrics to help clarify the development direction of this field. Methods: We selected and extracted all relevant publications related to COVID-19 and the kidney from the Web of Science from December 1, 2019, to July 24, 2022. VOSviewer, RStudio, CiteSpace, and other software were used to visualize keywords, publishing trends, authors and their countries, and institutions in this field and perform the statistical analysis. Results: A total of 645 articles published in 220 journals were included in this study. The United States and China contributed the most publications and were most active in international cooperation. In addition to COVID-19 and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), acute kidney injury (AKI), kidney transplant and mortality were the three keywords with the highest frequencies. In the initial stage of the COVID-19 outbreak, research focused on the clinical symptoms of COVID-19 and other macrocharacteristics, while in a later stage, the associations between SARS-CoV-2 infection and CKD and AKI, as well as the prognosis of patients with kidney disease or those who underwent kidney transplantation, gained more attention. The immune response and vaccines were also recent research hotspots. Conclusions: This bibliometric analysis provides a comprehensive overview of research on COVID-19 and kidney disease, which has received continuous, global attention. AKI, CKD, kidney transplantation, immune response and vaccines are among the hotspots in this field.

Pitavastatin sensitizes the EGFR-TKI associated resistance in lung cancer by inhibiting YAP/AKT/BAD-BCL-2 pathway.

BACKGROUND: Despite effective strategies, resistance in EGFR mutated lung cancer remains a challenge. Metabolic reprogramming is one of the main mechanisms of tumor drug resistance. A class of drugs known as "statins" inhibit lipid cholesterol metabolism and are widely used in patients with cardiovascular diseases. Previous studies have also documented its ability to improve the therapeutic impact in lung cancer patients who receive EGFR-TKI therapy. Therefore, the effect of statins on targeted drug resistance to lung cancer remains to be investigated. METHODS: Prolonged exposure to gefitinib resulted in the emergence of a resistant lung cancer cell line (PC9GR) from the parental sensitive cell line (PC9), which exhibited a traditional EGFR mutation. The CCK-8 assay was employed to assess the impact of various concentrations of pitavastatin on cellular proliferation. RNA sequencing was conducted to detect differentially expressed genes and their correlated pathways. For the detection of protein expression, Western blot was performed. The antitumor activity of pitavastatin was evaluated in vivo via a xenograft mouse model. RESULTS: PC9 gefitinib resistant strains were induced by low-dose maintenance. Cell culture and animal-related studies validated that the application of pitavastatin inhibited the proliferation of lung cancer cells, promoted cell apoptosis, and restrained the acquired resistance to EGFR-TKIs. KEGG pathway analysis showed that the hippo/YAP signaling pathway was activated in PC9GR cells relative to PC9 cells, and the YAP expression was inhibited by pitavastatin administration. With YAP RNA interference, pAKT, pBAD and BCL-2 expression was decreased, while BAX expression as increased. Accordingly, YAP down-regulated significantly increased apoptosis and decreased the survival rate of gefitinib-resistant lung cancer cells. After pAKT was increased by SC79, apoptosis of YAP down-regulated cells induced by gefitinib was decreased, and the cell survival rate was increased. Mechanistically, these effects of pitavastatin are associated with the YAP pathway, thereby inhibiting the downstream AKT/BAD-BCL-2 signaling pathway. CONCLUSION: Our study provides a molecular basis for the clinical application of the lipid-lowering drug pitavastatin enhances the susceptibility of lung cancer to EGFR-TKI drugs and alleviates drug resistance.