Modulating Inorganic Dimensionality of Ultrastable Lead Halide Coordination Polymers for Photocatalytic CO2 Reduction to Ethanol.

Lead halide hybrids have shown great potentials in CO2 photoreduction, but challenging to afford C2+ reduced products, especially using H2O as the reductant. This is largely due to the trade-off problem between instability of the benchmark 3D structures and low carrier mobility of quasi-2D analogues. Herein, the lead halide dimensionality of robust coordination polymers (CP) was modulated by organic ligands differing in a single-atom change (NH vs. CH2), in which the NH groups coordinate with interlamellar [PbI2] clusters to achieve the important 2D→3D transition. This first CP based on 3D cationic lead iodide sublattice possesses both high aqueous stability and a low exciton binding energy of 25 meV that is on the level of ambient thermal energy, achieving artificial photosynthesis of C2H5OH. Photophysical studies combined with theoretical calculations suggest the bridging [PbI2] clusters in the 3D structure not only results in enhanced carrier transport, but also promotes the intrinsic charge polarization to facilitate the C-C coupling. With trace loading of Rh cocatalyst, the apparent quantum efficiency of the 3D CP reaches 1.4 % at 400 nm with a high C2H5OH selectivity of 89.4 % (product basis), which presents one of the best photocatalysts for C2 products to date.

Cellular senescence of renal tubular epithelial cells in acute kidney injury.

Cellular senescence represents an irreversible state of cell-cycle arrest during which cells secrete senescence-associated secretory phenotypes, including inflammatory factors and chemokines. Additionally, these cells exhibit an apoptotic resistance phenotype. Cellular senescence serves a pivotal role not only in embryonic development, tissue regeneration, and tumor suppression but also in the pathogenesis of age-related degenerative diseases, malignancies, metabolic diseases, and kidney diseases. The senescence of renal tubular epithelial cells (RTEC) constitutes a critical cellular event in the progression of acute kidney injury (AKI). RTEC senescence inhibits renal regeneration and repair processes and, concurrently, promotes the transition of AKI to chronic kidney disease via the senescence-associated secretory phenotype. The mechanisms underlying cellular senescence are multifaceted and include telomere shortening or damage, DNA damage, mitochondrial autophagy deficiency, cellular metabolic disorders, endoplasmic reticulum stress, and epigenetic regulation. Strategies aimed at inhibiting RTEC senescence, targeting the clearance of senescent RTEC, or promoting the apoptosis of senescent RTEC hold promise for enhancing the renal prognosis of AKI. This review primarily focuses on the characteristics and mechanisms of RTEC senescence, and the impact of intervening RTEC senescence on the prognosis of AKI, aiming to provide a foundation for understanding the pathogenesis and providing potentially effective approaches for AKI treatment.

Efficacy and Safety of Ferric Citrate on Hyperphosphatemia among Chinese Patients with Chronic Kidney Disease Undergoing Hemodialysis: A Phase III Multicenter Randomized Open-Label Active-Drug-Controlled Study.

INTRODUCTION: Hyperphosphatemia in chronic kidney disease (CKD) patients is positively associated with mortality. Ferric citrate is a potent phosphorus binder that lowers serum phosphorus level and improves iron metabolism. We compared its efficacy and safety with active drugs in Chinese CKD patients with hemodialysis. METHODS: Chinese patients undergoing hemodialysis were randomized into two treatment groups in a 1:1 ratio, receiving either ferric citrate or sevelamer carbonate, respectively, for 12 weeks. Serum phosphorus levels, calcium concentration, and iron metabolism parameters were evaluated every 2 weeks. Frequency and severity of adverse events were recorded. RESULTS: 217 (90.4%) patients completed the study with balanced demographic and baseline characteristics between two groups. Ferric citrate decreased the serum phosphorus level to 0.59 ± 0.54 mmol/L, comparable to 0.56 ± 0.62 mmol/L by sevelamer carbonate. There was no significant difference between two groups (p > 0.05) in the proportion of patients with serum phosphorus levels reaching the target range, the response rate to the study drug, and the changes of corrected serum calcium concentrations, and intact-PTH levels at the end of treatment. The change of iron metabolism indicators in the ferric citrate group was significantly higher than those in the sevelamer carbonate group. There are 47 (40.5%) patients in the ferric citrate group, and 26 (21.3%) patients in the sevelamer carbonate group experienced drug-related treatment emergent adverse events (TEAEs); most were mild and tolerable. Common drug-related TEAEs were gastrointestinal disorders, including diarrhea (12.9 vs. 2.5%), fecal discoloration (14.7 vs. 0%), and constipation (1.7 vs. 7.4%) in ferric citrate and sevelamer carbonate group. CONCLUSION: Ferric citrate capsules have good efficacy and safety in the control of hyperphosphatemia in adult patients with CKD undergoing hemodialysis. Efficacy is not inferior to sevelamer carbonate. The TEAEs were mostly mild and tolerated by the patients.

Proteomics reveals defective peroxisomal fatty acid oxidation during the progression of acute kidney injury and repair.

Acute kidney injury (AKI) is characterized by a rapid decrease in renal function with high mortality and risk of progression to chronic kidney disease (CKD). Ischemia and reperfusion injury (IRI) is one of the major causes of AKI. However, the cellular and molecular responses of the kidney to IRI are complex and not fully understood. Herein, we conducted unbiased proteomics and bioinformatics analyses in an IRI mouse model on days 3, 7, and 21, and validated the results using IRI, unilateral ureteral obstruction (UUO), and biopsies from patients with AKI or CKD. The results indicated an obvious temporal expression profile of differentially expressed proteins and highlighted impaired lipid metabolism during the progression of AKI to CKD. Acyl-coenzyme A oxidase 1 (Acox1), the first rate-limiting enzyme of peroxisomal fatty acid beta-oxidation, was then selected, and its disturbed expression in the two murine models validated the proteomic findings. Accordingly, Acox1 expression was significantly downregulated in renal biopsies from patients with AKI or CKD, and its expression was negatively correlated with kidney injury score. Furthermore, in contrast to the decreased Acox1 expression, lipid droplet accumulation was remarkably increased in these renal tissues, suggesting dysregulation of fatty acid oxidation. In conclusion, our results suggest that defective peroxisomal fatty acid oxidation might be a common pathological feature in the transition from AKI to CKD, and that Acox1 is a promising intervention target for kidney injury and repair.

Predictors of pediatric sedation failure with initial dose of intranasal dexmedetomidine and oral midazolam.

BACKGROUND: To assess the sedative failure rate over different dose combinations of intranasal dexmedetomidine and oral midazolam for procedural sedation. METHODS: This was a retrospective study. Four groups were established according to the initial dose of sedatives. The primary outcome was the sedative failure rate for different doses of the two-drug combination. The risk factors associated with sedation failure were analyzed. RESULTS: A total of 2165 patients were included in the final analysis. Of these, 394 children were classified as sedation failure after the initial dose of a combination of intranasal dexmedetomidine and oral midazolam. Although the initial doses of intranasal dexmedetomidine and oral midazolam administered to patients varied widely, no significant differences were detected in the sedation outcomes among the groups. Multivariate analysis showed that sedation history, a history of sedation failure, and echocardiography were independent risk factors for sedation failure after an initial dose of intranasal dexmedetomidine and oral midazolam. In contrast, patients undergoing lung function and MRI were more likely to be successfully sedated. CONCLUSION: A combination of low-dose intranasal dexmedetomidine and oral midazolam provides adequate sedation efficacy without any increase in side effects, especially for patients undergoing MRI or lung function examination. IMPACT: This is an original article about the risk factors of sedation failure with an initial dose of intranasal dexmedetomidine and oral midazolam for procedure sedation. For patients undergoing echocardiogram, it is better to choose other sedatives, while a combination of intranasal dexmedetomidine and oral midazolam is a good option for patients undergoing MRI or lung function. The selection of sedative drugs should be personalized according to different procedures.

Relationship between Dialysate Bicarbonate Concentration and All-Cause Mortality in Hemodialysis Patients.

INTRODUCTION: The optimal dialysate bicarbonate concentration (DBIC) for hemodialysis (HD) remains controversial. Herein, we analyzed the effect of dialysate bicarbonate levels on mortality in HD patients. METHODS: Patients undergoing maintenance HD were recruited from the HD unit of the Daping Hospital. Patients were categorized into quartiles according to their DBIC level (quartile 1: <31.25 mmol/L, n = 77; quartile 2: 31.25-32.31 mmol/L, n = 76; quartile 3: 32.31-33.6 mmol/L; n = 81; quartile 4: ≥33.6 mmol/L, n = 79). Demographic and clinical data were collected. Survival curves were estimated using the Kaplan-Meier method. A Cox proportional hazards regression model was used to estimate the association between DBIC and all-cause mortality. RESULTS: We included 313 patients undergoing maintenance HD with a mean DBIC of 32.16 ± 1.59 mmol/L (range, 27.20-34.72 mmol/L). The patients in quartile 4 were more likely to have higher pre- and post-HD serum bicarbonate concentrations than those in other quartiles. The mortality rate was lowest in quartile 2 (10.53%). The survival time was significantly lower in the quartile 4 group than in the other quartiles (p = 0. 008, log-rank test). After full adjustment, the hazard ratio (per 3 mmol/L higher DBIC) for all-cause mortality was 4.29 (95% confidence interval, 2.11-8.47) in all patients, whereas no significant association was observed between DBIC and initial hospitalization. CONCLUSIONS: Our data indicate that DBIC is positively associated with all-cause mortality. A DBIC concentration of 31-32 mmol/L may benefit patient outcomes. This study provides an evidence-based medical basis for optimal dialysis prescription in the future.

Neutrophils promote tumor invasion via FAM3C-mediated epithelial-to-mesenchymal transition in gastric cancer.

In gastric cancer, lymph node metastasis (LNM) is the major metastasis route, and lymphatic invasion is the precursor of LNM. Tumor-associated neutrophils (TANs) promote LNM. However, the molecular mechanisms underlying TANs-mediated lymphatic invasion and/or LNM remain unclear. Herein, we revealed that high level of TANs was the independent risk factor for lymphatic invasion and LNM respectively, and lymphatic tumor cell-neutrophil clusters were positively correlated with LNM. Crosstalk between neutrophils and tumor cells was required for enhanced tumor cell invasiveness, endowing neutrophils to boost epithelial-to-mesenchymal transition (EMT) of tumor cells and in turn promoting LNM. Mechanically, tumor cells educated neutrophils via TGFß1 to produce more FAM3C through Smad2/3 signaling activation, and FAM3C promoted tumor cell EMT through JNK-ZEB1/Snail signaling pathway. The crosstalk enhanced the affinity of neutrophils with tumor cells through interaction of integrins α6ß1 and α6ß4 with CD151. Furthermore, studies using tumor-bearing mice demonstrated that neutrophils were the important driver for gastric cancer tumorigenesis and invasiveness. The study clearly identifies the functional roles of TANs in promoting tumor invasion, and facilitates a better understanding of novel mechanisms responsible for LNM of gastric cancer, which provides potential targets for developing new strategies to prevent or treat LNM in gastric cancer.

Glycolytic reprogramming controls periodontitis-associated macrophage pyroptosis via AMPK/SIRT1/NF-κB signaling pathway.

Glycolysis has been demonstrated as a crucial metabolic process in bacteria infected diseases via modulating the activity of pyroptosis. Macrophages are the most abundant immune cells that infiltrated in the infected periodontal tissues, which significantly influence the outcome of periodontitis (PD). However, the effect of glycolysis in regulating macrophage pyroptosis during PD development remains unknown. This study aimed to explore the role of glycolysis in PD-associated macrophage pyroptosis and periodontal degeneration. Clinical specimens were used to determine the emergence of macrophage pyroptosis and glycolysis in periodontal tissues by immunohistochemical analysis and western blot. For an in-depth understanding of the regulatory effect of glycolysis in the progression of macrophage pyroptosis associated periodontitis, both in vivo PD model and in vitro PD model were treated with 2-DG (2-Deoxy-d-glucose), a glycolysis inhibitor. The data showed that the blockade of glycolysis could significantly suppress the lipopolysaccharide (LPS) induced macrophage pyroptosis, resulting in an attenuation of the inflammatory response and bone resorption in periodontal lesions. Furthermore, we revealed that the regulatory effect of glycolysis on macrophage pyroptosis can be mediated via AMPK/SIRT1/NF-κB signaling pathway. Our study unveiled that suppressed glycolysis restrains the activity of PD-associated macrophage pyroptosis, osteoclastogenesis, and subsequent periodontal tissue destruction. These findings extend our knowledge of glycolysis in regulating PD-associated macrophage pyroptosis and provide a potential novel target for PD therapy.

Efficacy and Safety of Mizoribine for the Treatment of Refractory Nephrotic Syndrome: Protocol for a Multicenter, Controlled, Open-label, Randomized Controlled Trial.

BACKGROUND: Nephrotic syndrome that is resistant to steroid therapy is termed refractory nephrotic syndrome (RNS), a condition that is associated with an increased risk of end-stage renal disease. Immunosuppressants are used to treat RNS; however, prolonged use may lead to significant adverse effects. Mizoribine (MZR) is a novel agent used in long-term immunosuppressive therapy, which has few adverse effects, but data on its long-term use in patients with RNS are unavailable. OBJECTIVE: We propose a trial to examine the efficacy and safety of MZR compared with cyclophosphamide (CYC) in Chinese adult patients with RNS. METHODS: This is a multicenter, randomized, controlled interventional study with a screening phase (1 week) and a treatment phase (52 weeks). This study has been reviewed and approved by the Medical Ethics Committees of all 34 medical centers that are participating. Patients with RNS consent to participation, and are enrolled and randomized to an MZR group or a CYC group (1:1 ratio), with each group receiving tapering doses of oral corticosteroids. Participants are assessed for adverse effects, and laboratory results are collected at 8 visits during the treatment phase (weeks 4, 8, 12, 16, 20, 32, 44, and 52 [exit visit]). Participants are able to withdraw voluntarily, and investigators are required to remove patients when there are safety concerns or deviations from the protocol. RESULTS: The study started in November 2014 and was completed in March 2019. A total of 239 participants from 34 hospitals in China have been enrolled. Data analysis has been completed. The results are being finalized by the Center for Drug Evaluation. CONCLUSIONS: This study examines the safety and efficacy of MZR as a long-term treatment approach for Chinese adults with RNS. It is the longest lasting and largest randomized controlled trial to examine MZR in Chinese patients. The results can help determine whether RNS should be considered as an additional indication for MZR treatment in China. TRIAL REGISTRATION: ClinicalTrials.gov NCT02257697; https://clinicaltrials.gov/ct2/show/NCT02257697. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/46101.

Daytime Variation of Chloral Hydrate-Associated Sedation Outcomes: A Propensity-Matched Cohort Study.

BACKGROUND: Physiological processes influencing a drugs' efficacy change substantially over the course of the day. However, it is unclear whether there is an association between the sedative success rate of chloral hydrate and the time of day. We conducted a retrospective study of 41,831 cases, to determine if there was a difference in sedation success rate with chloral hydrate in children seen in the morning and afternoon. METHODS: Patients who accepted the sedation service were included. Eligible patients were divided into two cohorts of morning and afternoon cases, according to the time of day when the initial dose of chloral hydrate was administered. To ensure that the two groups were comparable, a propensity score matching method was utilized. RESULTS: The success rate with the initial dose of chloral hydrate was higher in patients who received sedation services in the afternoon. In the subgroup analysis, the afternoon cases had a higher sedation success rate compared to the morning cases in male patients; whereas, in female patients, no difference was detected between the morning versus afternoon cases. CONCLUSIONS: These results show that the afternoon cases had a higher sedation success rate than the morning cases, despite the afternoon cases receiving relatively lower initial dose than the morning cases. However, the clinical significance remains to be discussed, and further prospective studies are needed to validate the findings.

ProBDNF signaling is involved in periodontitis-induced depression-like behavior in mouse hippocampus.

OBJECTIVE: Increasing evidence supports the association between periodontitis and depression. However, the specific mechanisms remain to be further elucidated. The present study aimed to mechanistically investigate the regional roles of proBDNF (the precursor of brain-derived neurotrophic factor) in periodontitis induced depression-like behavior in mice. METHODS: Experimental periodontitis model was established by periodontal injection of Porphyromonas gingivalis lipopolysaccharide (Pg-LPS) in 8-week-old male Bdnf-HA/HA mice for 3 weeks. The depression-like behaviors, spontaneous exploratory activity and the level of anxiety were assessed by behavior tests. The activation of microglia and astrocytes, as well as the expression of Interleukin (IL)-1ß and Tumor necrosis factor (TNF)-α in the hippocampus, prefrontal cortex, and cortex were further assessed by immunofluorescence and western blots. The levels of IL-1ß in blood serum and expression of occludin as well as claudin5 in the hippocampus, prefrontal cortex, and cortex were further determined by enzyme-linked immunosorbent assay and western blot. Finally, the expression of proBDNF, its receptors, and mature BDNF (mBDNF), as well as neuronal activity were measured by western blots and immunofluorescence. RESULTS: Pg-LPS successfully induced periodontitis in mice and caused obvious depression-like behavior. Furthermore, we observed an increased activation of astrocytes and microglia, as well as a significant increase in expression of IL-1ß and TNF-α in the hippocampus of mice treated with Pg-LPS, with elevated level of IL-1ß in serum and decreased expression of occludin and claudin5 in the hippocampus. Importantly, we found that the levels of proBDNF and its receptors, SorCS2 and p75NTR, were increased significantly; however, the level of mBDNF was decreased, therefor leading to greater ratio of proBDNF/mBDNF. In addition, we also detected decreased neuronal activity in the hippocampus of mice treated with Pg-LPS. CONCLUSIONS: Our results indicate that Pg-LPS-induced periodontitis could cause depression-like behaviors in mice, and the proBDNF signaling is involved in the process.

Bone Marrow Mesenchymal Stem Cell-Derived Exosomes Alleviate Peritoneal Dialysis-Associated Peritoneal Injury.

Peritoneal fibrosis is a critical sequela that limits the application of peritoneal dialysis (PD). This study explored the role and mechanism of bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) in preventing PD-associated peritoneal injury. C57BL/6 mice were randomized into three groups: a control (saline), peritoneal injury [2.5% glucose peritoneal dialysate + lipopolysaccharide (LPS)], and peritoneal injury + exosome group. After 6 weeks, mice were dissected, and the parietal peritoneum was collected. The level of peritoneal structural and functional damage was assessed. Additionally, transcriptome analysis of the peritoneum and miRNA sequencing on BMSC-Exos were performed. The parietal peritoneum had significantly thickened, and peritoneal function was impaired in the peritoneal injury group. Peritoneal structural and functional damage was significantly reduced after exosome treatment, while peritoneal inflammation, fibrosis, angiogenesis, and mesothelial damage significantly increased. Transcriptomic analysis showed that the BMSC-Exos affected the cell cycle process, cell differentiation, and inflammatory response regulation. Significant pathways in the exosome group were enriched by inflammation, immune response, and cell differentiation, which constitute a molecular network that regulates the peritoneal protective mechanism. Additionally, inflammatory factors (TNF-α, IL-1ß), fibrosis markers (α-SMA, collagen-III, fibronectin), profibrotic cytokines (TGF-ß1), and angiogenesis-related factor (VEGF) were downregulated at the mRNA and protein levels through BMSC-Exos treatment. BMSC-Exos treatment can prevent peritoneal injury by inhibiting peritoneal fibrosis, inflammation, and angiogenesis, showing a multitarget regulatory effect. Therefore, BMSC-Exos therapy might be a new therapeutic strategy for treating peritoneal injury.

[Research Progress in Stress-Induced Senescence of Renal Tubular Cells in Diabetic Nephropathy]. / è‚¾å°ç®¡ä¸Šçš®ç»†èƒžåº”æ¿€æ€§è¡°è€åœ¨ç³–å°¿ç— è‚¾ç— ä¸­çš„ç ”ç©¶è¿›å±•.

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. Renal tubulointerstitial injury is an important pathophysiological basis that contributes to the progression of DN to end-stage renal disease. Stress-induced senescence of renal tubular epithelial cells (RTECs) forms a key link that causes tubulointerstitial injury. In recent years, it has been reported that organelles, such as endoplasmic reticulum, mitochondria, and lysosomes, in RTECs are damaged to varying degrees in DN, and that their functional imbalance may lead to stress-induced senescence of RTECs, thereby causing sustained cellular and tissue-organ damage, which in turn promotes the progression of the disease. However, the core mechanism underlying changes in the senescence microenvironment caused by stress-induced senescence of RTECs in DN is still not understood. In addition, the mechanism by which organelles lose homeostasis also needs to be further investigated. Herein, we described the specific pathophysiological mechanisms of renal tubular injury, stress-induced senescence of RTECs, and their association with organelles in the context of DN in order to provide reference for the next-step research, as well as the development of new therapeutic strategies.

Association of serum Interleukin-8 level with lymph node metastasis and tumor recurrence in gastric cancer.

The level of pretherapeutic serum interleukin-8 (sIL-8) has been demonstrated to correlate with chemoresistance in gastric cancer. However, its clinicopathological significance of sIL-8 in gastric cancer remains unknown. Herein, a total of 335 patients diagnosed with gastric adenocarcinoma were enrolled. The clinicopathological features were collected, and the sIL-8 levels were measured using enzyme-linked immunosorbent assay. The sIL-8 levels ranged from 1.48 pg/ml to 1025.22 pg/ml with > 15.41 pg/ml defined as high according to the receiver operating characteristic analysis. sIL-8 levels were strongly associated with Lauren classification and tumor recurrence. High sIL-8 correlated with lymph node metastasis (LNM) in the intestinal- and diffuse-type tumors and acted as an independent risk factor for LNM in both types. Patients with high sIL-8 levels had worse relapse-free survival than those with low sIL-8 levels. High sIL-8 level was associated with tumor relapse in the intestinal- and diffuse-type tumors, and was also an independent risk factor in the intestinal- and mixed-type tumors. Further analysis revealed that sIL-8 levels were positively associated with LNM and tumor relapse in patients with negative carcinoembryonic antigen (CEA), but not in those with elevated serum CEA levels. In conclusion, this retrospective study demonstrated that the pretherapeutic sIL-8 level has predictive value for LNM and tumor recurrence, and may serve as a potential tumor marker in gastric cancer.

VNN1 contributes to the acute kidney injury-chronic kidney disease transition by promoting cellular senescence via affecting RB1 expression.

The mechanisms underlying acute kidney injury (AKI) and chronic kidney disease (CKD) progression include interstitial inflammation, cellular senescence, and oxidative stress (OS). Although vanin-1 (VNN1) plays an important role in OS, its contribution to the AKI-CKD transition remains unknown. Here, we explored the roles and mechanisms of VNN1 in the progression of the AKI-CKD transition. We observed that VNN1 expression was upregulated after ischemia/reperfusion (I/R) injury and high VNN1 expression levels were associated with poor renal repair after I/R injury. In VNN1 knockout (KO) mice, recovery of serum creatinine and blood urea nitrogen levels after I/R injury was accelerated and renal fibrosis was inhibited after severe I/R injury. Furthermore, in VNN1 KO mice, senescence of renal tubular cells was inhibited after severe I/R injury, as assessed by P16 expression and SA-ß-Gal assays. However, our results also revealed that VNN1 KO renal tubular cells did not resist senescence when OS was blocked. To elucidate the mechanism underlying VNN1-mediated regulation of senescence during the AKI-CKD transition, retinoblastoma 1 (RB1) was identified as a potential target. Our results suggest that the reduced senescence in VNN1 KO renal tubular cells was caused by suppressed RB1 expression and phosphorylation. Collectively, our results unveil a novel molecular mechanism by which VNN1 promotes AKI-CKD transition via inducing senescence of renal tubular cells by activating RB1 expression and phosphorylation after severe renal injury. The present study proposes a new strategy for designing therapies wherein VNN1 can be targeted to obstruct the AKI-CKD transition.

Randomized Control Study on Hemoperfusion Combined with Hemodialysis versus Standard Hemodialysis: Effects on Middle-Molecular-Weight Toxins and Uremic Pruritus.

INTRODUCTION: Classic hemodialysis schedules present inadequate middle-molecular-weight toxin clearance due to limitations of membrane-based separation processes. Accumulation of uremic retention solutes may result in specific symptoms (e.g., pruritus) and may affect clinical outcome and patient's quality of life. Hemoperfusion (HP) is a blood purification modality based on adsorption that can overcome such limitations, and thus, it may be interesting to test the efficacy of at least one session per week of HP combined with hemodialysis. This is a randomized, open-label trial, controlled, multicenter clinical study to investigate the effect of long-term HP combined with hemodialysis on middle-molecular-weight toxins and uremic pruritus in maintenance hemodialysis (MHD) patients. METHODS: 438 MHD patients from 37 HD centers in China with end-stage kidney disease (63.9% males, mean age 51 years) suffering from chronic intractable pruritus were enrolled in the study. Eligible patients were randomized into four groups: low-flux hemodialysis (LFHD), high-flux hemodialysis (HFHD), HP + LFHD, and HP + HFHD at a 1:1:1:1 ratio. Beta-2 microglobulin (ß2M) and parathyroid hormone (PTH) were measured at baseline, 3-6, and 12 months. At the same time points, the pruritus score was evaluated. The primary outcome was the reduction of ß2M and PTH, while the secondary outcome was the reduction of the pruritus score. RESULTS: In the two groups HP + LFHD and HP + HFHD, there was a significant decrease of ß2M and PTH levels after 12 months compared to the control groups. No significant differences were noted between HP + LFHD and HP + HFHD. Pruritus score reduction was 63% in the HP + LFHD group and 51% in the HP + HFHD group, respectively. CONCLUSION: The long-term HP + HD can reduce ß2M and PTH levels and improve pruritus in MHD patients independently on the use of high- or low-flux dialyzers, showing that the results are linked to the effect of adsorption.

Decoy receptor 2 mediates the apoptosis-resistant phenotype of senescent renal tubular cells and accelerates renal fibrosis in diabetic nephropathy.

Apoptotic resistance leads to persistent accumulation of senescent cells and sustained expression of a senescence-associated secretory phenotype, playing an essential role in the progression of tissue fibrosis. However, whether senescent renal tubular epithelial cells (RTECs) exhibit an apoptosis-resistant phenotype, and the role of this phenotype in diabetic nephropathy (DN) remain unclear. Our previous study was the first to demonstrate that decoy receptor 2 (DcR2) is associated with apoptotic resistance in senescent RTECs and renal fibrosis. In this study, we aimed to further explore the mechanism of DcR2 in apoptosis-resistant RTECs and renal fibrosis in DN. DcR2 was co-localized with fibrotic markers (α-SMA, collagen IV, fibronectin), senescent marker p16, and antiapoptotic proteins FLIP and Bcl2 but rarely co-localized with caspase 3 or TUNEL. DcR2 overexpression promoted renal fibrosis in mice with streptozotocin (STZ)-induced DN, as evidenced by augmented Masson staining and upregulated expression of fibrotic markers. DcR2 overexpression also enhanced FLIP expression while reducing the expression of pro-apoptotic proteins (caspases 8 and 3) in senescent RTECs, resulting in apoptotic resistance. In contrast, DcR2 knockdown produced the opposite effects in vitro and in vivo. Moreover, quantitative proteomics and co-immunoprecipitation experiments demonstrated that DcR2 interacted with glucose-related protein 78 kDa (GRP78), which has been shown to promote apoptotic resistance in cancer. GRP78 exhibited co-localization with senescent and antiapoptotic markers but was rarely co-expressed with caspase 3 or TUNEL. Additionally, GRP78 knockdown decreased the apoptosis resistance of HG-induced senescent RTECs with upregulated cleaved caspase 3 and increased the percentage of apoptotic RTECs. Mechanistically, DcR2 mediated apoptotic resistance in senescent RTECs by enhancing GRP78-caspase 7 interactions and promoting Akt phosphorylation. Thus, DcR2 mediated the apoptotic resistance of senescent RTECs and renal fibrosis by interacting with GRP78, indicating that targeting the DcR2-GRP78 axis represents a promising therapeutic strategy for DN.

Analysis of Risk Factors for Chloral Hydrate Sedative Failure with Initial Dose in Pediatric Patients: a Retrospective Analysis.

BACKGROUND: Although chloral hydrate has been used as a sedative for more than 100 years, dozens of studies have reported that it has inconsistent sedative effects and high sedation failure rates with initial dose. The high failure rates may lead to repeated administration of sedatives, guardians' dissatisfaction, parental anxiety, increasing medical workload as well as leading to an increase of adverse events. Our aim is to identify the risk factors associated with chloral hydrate sedative failure with initial dose in children undergoing noninvasive diagnostic procedures. METHODS: Pediatric patients who underwent chloral hydrate sedation for noninvasive diagnostic procedures at our institution between 1 December 2019 and 1 January 2021 were retrospectively analyzed. Data collected included patients' age, gender, weight, sedation history, sedation failure history, type of procedures, initial dose of choral hydrate, sleep deprivation, sedation failure with initial dose, and sedative duration. The initial dose was classified into three levels: reduced dose (< 40 mg/kg), standard dose (40-60 mg/kg), and high dose (> 60 mg/kg). The patients were divided into three cohorts according to the different initial doses. RESULTS: A total of 15,922 patients were included in the analysis; 1928 (12.1%) were not well-sedated after administering the initial dose of chloral hydrate. The highest sedative failure was observed in the reduced dose group. By multivariate regression, we identified that heavier weight, patients with a history of sedation or a history of sedation failure, and patients who received magnetic resonance imaging (MRI) or more than one procedure simultaneously were associated with an increased odds of sedation failure at the initial dose. However, outpatients, patients undergoing hearing screening, and patients with sleep deprivation were favored regarding chloral hydrate sedative success. CONCLUSION: An alternative drug or drug combination is necessary in patients with heavier weight, those with a sedation history or sedation failure history, and those undergoing an MRI or more than one procedure simultaneously, whereas chloral hydrate is an appropriate sedation option for outpatients, patients undergoing hearing screening, and those with sleep deprivation.

Tumor-derived IL-8 facilitates lymph node metastasis of gastric cancer via PD-1 up-regulation in CD8+ T cells.

BACKGROUND: The pretherapeutic serum interleukin-8 (sIL-8) levels have been revealed to be increased in about half of patients with locally advanced gastric cancer. However, the roles of IL-8 in lymph node metastasis (LNM) and the underlying mechanisms remain unclear. METHODS: 146 patients with primary gastric carcinoma were enrolled in this study. ELISA was used to measure IL-8 levels. The CD4/CD8 ratio and programmed cell death-1 (PD-1) expression of T cells in primary tumor tissues, tumor-draining lymph nodes (TDLNs) and non-draining lymph nodes (NDLNs) were assayed with flow cytometry. Protein expression of the molecules was determined with immunohistochemistry, western blotting or immunoprecipitation. The gastric cancer mouse tumor model with LNM was utilized to determine the role of IL-8 in regulation of tumor metastasis and progression. RESULTS: The elevated sIL-8 levels were associated with LNM and poor prognosis in gastric cancer. Furthermore, sIL-8 was identified to be prominently produced by gastric cancer-associated fibroblasts (CAFs). Elevated IL-8 can up-regulate PD-1 expression in CD8+ T cells, resulting in immunosuppression in primary tumors and TDLNs, which enhances LNM of gastric cancer. Molecularly, IL-8 increases PD-1 expression through JAK2/STAT3 signaling activation, and inhibits its ubiquitination via Fbxo38 down-regulation. In addition, the in vivo studies in mouse gastric cancer model demonstrated that IL-8 promotes LNM via PD-1 up-regulation in CD8+ T cells. CONCLUSION: The present study elucidates the pro-metastatic role of elevated IL-8 in gastric cancer, and provides novel insights to enhance immune checkpoint blockade therapy for anti-PD-1 in gastric cancer.

Establishment of a novel mouse peritoneal dialysis-associated peritoneal injury model.

BACKGROUND: Peritoneal fibrosis induced by various factors during peritoneal dialysis (PD) can eventually lead to ultrafiltration failure and termination of PD treatment. The existing animal models are caused by a single stimulus, and cannot accurately simulate complex pathogenesis of peritoneal injury and fibrosis. We aim to develop an efficient and realistic mouse model of PD-associated peritoneal injury using daily intraperitoneal injection (I.P.) of human peritonitis PD effluent. METHODS: Eight-week-old male C57BL/6 mice were classified into six groups: saline control; 2.5% PD fluid; 2.5% PD fluid + lipopolysaccharide (LPS); 4.25% PD fluid; 4.25% PD fluid + LPS; and peritonitis effluent. Mice received daily I.P. for 6 weeks, and were sacrificed to determine peritoneal structural and functional damage, inflammation, and fibrosis. RESULTS: Mice in the peritonitis effluent group had low mortality. The submesothelial thickness in the peritonitis effluent group was significantly greater than that in the 2.5% PD fluid group. The peritonitis effluent group had increased expression of fibrosis markers (α-SMA, Collagen I, etc.), neutrophil granulocytes (MPO), and macrophages (CD68, F4/80) in the peritoneum based on immunohistochemical staining; and significantly higher expression of inflammation markers (IL-1ß, IL-6, etc.) and fibrosis markers (TGF-ß1, α-SMA, etc.) based on real-time qPCR. Modified peritoneal equilibration tests (PET) demonstrated that I.P. of peritonitis effluent reduced peritoneal ultrafiltration. CONCLUSION: Our novel animal model of PD-associated peritoneal injury faithfully simulates the clinical pathophysiological process. This animal model may be useful for study of the pathogenesis of PD-associated peritoneal injury and identification of novel treatments.