ß-Hydroxybutyrate Protects Against Cisplatin-Induced Renal Damage via Regulating Ferroptosis.

Cisplatin is a particularly potent antineoplastic drug. However, its usefulness is restricted due to the induction of nephrotoxicity. More recent research has indicated that ß-hydroxybutyrate (ß-HB) protects against acute or chronic organ damage as an efficient healing agent. Nonetheless, the therapeutic mechanisms of ß-HB in acute kidney damage caused by chemotherapeutic drugs remain unclear. Our study developed a model of cisplatin-induced acute kidney injury (AKI), which involved the administration of a ketogenic diet or ß-HB. We analyzed blood urea nitrogen (BUN) and creatinine (Cr) levels in serum, and used western blotting and immunohistochemical staining to assess ferroptosis and the calcium/calmodulin-dependent kinase kinase 2 (Camkk2)/AMPK pathway. The mitochondrial morphology and function were examined. Additionally, we conducted in vivo and in vitro experiments using selective Camkk2 inhibitor or activator to investigate the protective mechanism of ß-HB on cisplatin-induced AKI. Exogenous or endogenous ß-HB effectively alleviated cisplatin-induced abnormally elevated levels of BUN and Cr and renal tubular necrosis in vivo. Additionally, ß-HB reduced ferroptosis biomarkers and increased the levels of anti-ferroptosis biomarkers in the kidney. ß-HB also improved mitochondrial morphology and function. Moreover, ß-HB significantly attenuated cisplatin-induced cell ferroptosis and damage in vitro. Furthermore, western blotting and immunohistochemical staining indicated that ß-HB may prevent kidney injury by regulating the Camkk2-AMPK pathway. The use of the Camkk2 inhibitor or activator verified the involvement of Camkk2 in the renal protection by ß-HB. This study provided evidence of the protective effects of ß-HB against cisplatin-induced nephrotoxicity and identified inhibited ferroptosis and Camkk2 as potential molecular mechanisms.

ß-HB protects against cisplatin-induced renal damage both in vivo and in vitro.Moreover, ß-HB is effective in attenuating cisplatin-induced lipid peroxidation and ferroptosis.The regulation of energy metabolism, as well as the treatment involving ß-HB, is associated with Camkk2.

Potato E3 ubiquitin ligase StRFP1 positively regulates late blight resistance by degrading sugar transporters StSWEET10c and StSWEET11.

Potato (Solanum tuberosum) is the fourth largest food crop in the world. Late blight, caused by oomycete Phytophthora infestans, is the most devastating disease threatening potato production. Previous research has shown that StRFP1, a potato Arabidopsis Tóxicos en Levadura (ATL) family protein, positively regulates late blight resistance via its E3 ligase activity. However, the underlying mechanism is unknown. Here, we reveal that StRFP1 is associated with the plasma membrane (PM) and undergoes constitutive endocytic trafficking. Its PM localization is essential for inhibiting P. infestans colonization. Through in vivo and in vitro assays, we investigated that StRFP1 interacts with two sugar transporters StSWEET10c and StSWEET11 at the PM. Overexpression (OE) of StSWEET10c or StSWEET11 enhances P. infestans colonization. Both StSWEET10c and StSWEET11 exhibit sucrose transport ability in yeast, and OE of StSWEET10c leads to an increased sucrose content in the apoplastic fluid of potato leaves. StRFP1 ubiquitinates StSWEET10c and StSWEET11 to promote their degradation. We illustrate a novel mechanism by which a potato ATL protein enhances disease resistance by degrading susceptibility (S) factors, such as Sugars Will Eventually be Exported Transporters (SWEETs). This offers a potential strategy for improving disease resistance by utilizing host positive immune regulators to neutralize S factors.

Gut microbiota mediates the protective effects of ß-hydroxybutyrate against cisplatin-induced acute kidney injury.

The gut microbiota has been reported to be perturbed by chemotherapeutic agents and to modulate side effects. However, the critical role of ß-hydroxybutyrate (BHB) in the regulation of the gut microbiota and the pathogenesis of chemotherapeutic agents related nephrotoxicity remains unknown. We conducted a comparative analysis of the composition and function of gut microbiota in healthy, cisplatin-challenged, BHB-treated, and high-fat diet-treated mice using 16 S rDNA gene sequencing. To understand the crucial involvement of intestinal flora in BHB's regulation of cisplatin -induced nephrotoxicity, we administered antibiotics to deplete the gut microbiota and performed fecal microbiota transplantation (FMT) before cisplatin administration. 16 S rDNA gene sequencing analysis demonstrated that both endogenous and exogenous BHB restored gut microbiota dysbiosis and cisplatin-induced intestinal barrier disruption in mice. Additionally, our findings suggested that the LPS/TLR4/NF-κB pathway was responsible for triggering renal inflammation in the gut-kidney axis. Furthermore, the ablation of the gut microbiota ablation using antibiotics eliminated the renoprotective effects of BHB against cisplatin-induced acute kidney injury. FMT also confirmed that administration of BHB-treated gut microbiota provided protection against cisplatin-induced nephrotoxicity. This study elucidated the mechanism by which BHB affects the gut microbiota mediation of cisplatin-induced nephrotoxicity by inhibiting the inflammatory response, which may help develop novel therapeutic approaches that target the composition of the microbiota.

Stable Inverted Perovskite Solar Cells with Efficiency over 23.0% via Dual-Layer SnO2 on Perovskite.

Perovskite solar cells (PSCs) have shown great potential for reducing costs and improving power conversion efficiency (PCE). One effective method to achieve the latter is to use an all-inorganic charge transport layer (ICTL). However, traditional methods for crystallizing inorganic layers often result in the formation of a powder instead of a continuous film. To address this issue, we designed a dual-layer inorganic electron transport layer (IETL). This dual-layer structure consists of a layer of SnO2 nanocrystals (SnO2 NCs) deposited via a solution process and a dense SnO2 layer deposited through atomic layer deposition (ALD SnO2) to fill the cracks and gaps between the SnO2 NCs. PSCs having these dual-layer SnO2 ETLs achieved a high efficiency of 23.0%. This efficiency surpasses the recorded performance of ICTLs deposited on the perovskite. Furthermore, the PCE is comparable to that achieved with a C60 ETL. Moreover, the high-density structure of the ALD SnO2 layer inhibits the vertical migration of ions, resulting in improved thermal stability. After continuous heating at 85 °C in 10% humidity for 1000 h, the PCE of the dual-layer SnO2 structure decreased by 18%, whereas that of the C60/BCP structure decreased by 36%. The integration of dual-layer SnO2 into PSCs represents a significant advancement in achieving high-performance, commercially viable inverted monolithic PSCs or tandem solar cells.

An antioxidant hydrogel dressing with wound pH indication function prepared based on silanized bacterial nanocellulose crosslinked with beet red pigment extract.

Maintaining wound moisture and monitoring of infection are crucial aspects of chronic wound treatment. The development of a pH-sensitive functional hydrogel dressing is an effective approach to monitor, protect, and facilitate wound healing. In this study, beet red pigment extract (BRPE) served as a native and efficient pH indicator by being grafted into silane-modified bacterial nanocellulose (BNC) to prepare a pH-sensitive wound hydrogel dressing (S-g-BNC/BRPE). FTIR confirmed the successful grafting of BRPE into the BNC matrix. The S-g-BNC/BRPE showed superior mechanical properties (0.25 MPa), swelling rate (1251 % on average), and hydrophilic properties (contact angle 21.83°). The composite exhibited a notable color change as the pH changed between 4.0 and 9.0. It appeared purple-red when the pH ranged from 4.0 to 6.0, and appeared light pink at pH 7.0 and 7.4, and appeared ginger-yellow at pH 8.0 and 9.0. Subsequently, the antioxidant activity and cytotoxicity of the composite was evaluated, its DPPH·, ABTS+, ·OH scavenging rates were 32.33 %, 19.31 %, and 30.06 %, respectively, and the cytotoxicity test clearly demonstrated the safety of the dressing. The antioxidant hydrogel dressing, fabricated with a cost-effective and easy method, not only showed excellent biocompatibility and dressing performance but could also indicated the wound state based on pH changes.

MSMTSeg: Multi-Stained Multi-Tissue Segmentation of Kidney Histology Images via Generative Self-Supervised Meta-Learning Framework.

Accurately diagnosing chronic kidney disease requires pathologists to assess the structure of multiple tissues under different stains, a process that is timeconsuming and labor-intensive. Current AI-based methods for automatic structure assessment, like segmentation, often demand extensive manual annotation and focus on single stain domain. To address these challenges, we introduce MSMTSeg, a generative self-supervised meta-learning framework for multi-stained multi-tissue segmentation in renal biopsy whole slide images (WSIs). MSMTSeg incorporates multiple stain transform models for style translation of inter-stain domains, a self-supervision module for obtaining pre-trained models with the domain-specific feature representation, and a meta-learning strategy that leverages generated virtual data and pre-trained models to learn the domain-invariant feature representation across multiple stains, thereby enhancing segmentation performance. Experimental results demonstrate that MSMTSeg achieves superior and robust performance, with mDSC of 0.836 and mIoU of 0.718 for multiple tissues under different stains, using only one annotated training sample for each stain. Our ablation study confirms the effectiveness of each component, positioning MSMTSeg ahead of classic advanced segmentation networks, recent few-shot segmentation methods, and unsupervised domain adaptation methods. In conclusion, our proposed few-shot cross-domain technology offers a feasible and cost-effective solution for multi-stained renal histology segmentation, providing convenient assistance to pathologists in clinical practice. The source code and conditionally accessible data are available at https://github.com/SnowRain510/MSMTSeg.

Expression and significance of SIRT6 in human peritoneal dialysis effluents and peritoneal mesothelial cells.

Sirtuin 6 (SIRT6) can inhibit the fibrosis of many organs. However, the relationship between SIRT6 and peritoneal fibrosis (PF) in peritoneal dialysis (PD) remains unclear. We collected 110 PD patients with a duration of PD for more than 3 months and studied the influence of PD duration and history of peritonitis on SIRT6 levels in PD effluents (PDEs). We also analyzed the relationship between SIRT6 levels in PDEs and transforming growth factor beta 1 (TGF-ß1), IL-6, PD duration, peritoneal function, PD ultrafiltration (UF), and glucose exposure. We extracted human peritoneal mesothelial cells (HPMCs) from PDEs and measured the protein and gene expression levels of SIRT6, E-cadherin, vimentin, and TGF-ß1 in these cells. Based on the clinical results, we used human peritoneal mesothelial cells lines (HMrSV5) to observe the changes in SIRT6 levels and mesothelial-to-mesenchymal transition (MMT) after intervention with PD fluid. By overexpressing and knocking down SIRT6 expression, we investigated the effect of SIRT6 expression on E-cadherin, vimentin, and TGF-ß1 expression to elucidate the role of SIRT6 in mesothelial-to-epithelial transition in PMCs. Results: (1) With the extension of PD duration, the influence of infection on SIRT6 levels in PDEs increased. Patients with the PD duration of more than 5 years and a history of peritonitis had the lowest SIRT6 levels. (2) SIRT6 levels in PDEs were negatively correlated with PD duration, total glucose exposure, TGF-ß1, IL-6 levels, and the dialysate-to-plasma ratio of creatinine (Cr4hD/P), but positively correlated with UF. This indicates that SIRT6 has a protective effect on the peritoneum. (3) The short-term group (PD ≤ 1 year) had higher SIRT6 and E-cadherin gene and protein levels than the mid-term group (1 year < PD ≤ 5 years) and long-term group (PD > 5 years) in PMCs, while vimentin and TGF-ß1 levels were lower in the mid-term group and long-term group. Patients with a history of peritonitis had lower SIRT6 and E-cadherin levels than those without such a history. (4) After 4.25% PD fluid intervention for HPMCs, longer intervention time resulted in lower SIRT6 levels. (5) Overexpressing SIRT6 can lead to increased E-cadherin expression and decreased vimentin and TGF-ß1 expression in HPMCs. Knocking down SIRT6 expression resulted in decreased E-cadherin expression and increased vimentin and TGF-ß1 expression in HPMCs. This indicates that SIRT6 expression can inhibit MMT in HPMCs, alleviate PF associated with PD, and have a protective effect on the peritoneum.

Core-shell heterostructured Ni(OH)2@activation Zn-Co-Ni layered double hydroxides electrode for flexible all-solid-state coaxial fiber-shaped asymmetric supercapacitors.

The increasing requirements for wearable and portable electronics are driving the interests of high performance fiber supercapacitor. Layered double hydroxide (LDH) is broadly used in electrode materials, owing to the adjustability of components and the unique lamellar structure. However, limited active sites and poor electrical conductivity hinder its applications. Herein, the core-shell heterostructured Ni(OH)2@activation Zn-Co-Ni layered double hydroxides (Ni(OH)2@A-ZnCoNi-LDH) electrode was fabricated by loading pseudocapacitance material on the A-ZnCoNi-LDH to improve the electrochemical performance. Significantly, benefits from the synergistic effect of the multi-metal ions and the core-shell heterostructure, the electrodes demonstrated a capacitance of 2405 mF·cm-2 at 1 mA·cm-2. Furthermore, Ni(OH)2@A-ZnCoNi-LDH was used as the core electrode and carbon nanotube (CNT) film coated with Fe2O3@reduced graphene oxide (rGO) was wrapped around the core electrode to assemble coaxial fiber asymmetric supercapacitor, which illustrated an ultrahigh energy density of 177.7 µWh·cm-2 at 0.75 mW·cm-2. In particular, after consecutive charging and discharging 7000 cycles, the capacitance retention of the device was 95 %, indicating the excellent cycling stability. Furthermore, the device with high flexibility can be woven into textiles in different shapes. The fabricated device has an excellent development prospect as an energy source in wearable electronic devices.

High-efficient removal of anionic dye from aqueous solution using metal-organic frameworks@chitosan aerogel rich in benzene structure.

With the exponentially increase of dye pollutants, the purification of dye wastewater has been an urgent ecological problem. As a novel type of porous adsorbent, metal-organic frameworks still face challenges in recyclability, agglomeration, and environmentally unfriendly synthesis. Herein, MOF-525 was in-situ growth onto the surface of the chitosan (CS) beads to fabricate MOF-525@CS aerogel. CS was utilized as substrate to uniformly disperse MOF-525, thereby significantly mitigating agglomeration and improving recyclability of MOF-525. The characterization results shown that MOF-525@CS aerogel had a high specific surface area of 103.0 m2·g-1, and MOF-525 was uniformly distributed in the 3D porous structure of CS, and the presence of benzoic acid was detected. The MOF-525@CS aerogel had a remarkable adsorption capacity of 1947 mg·g-1 for Congo red, which is greater than the sum of its parts. MOF-525@CS aerogel also inherited the rapid adsorption ability of MOF-525, removing 80 % of Congo red within 600 min. Such excellent adsorption performance can be attributed to the benzoic acid trapped by CS via CN band to enhance the π-π stacking interactions. Additionally, the utilization of benzoic acid makes the synthesis process of MOF-525@CS aerogel more environmentally friendly. The high-efficient MOF-525@CS aerogel is a competitive candidate for dye pollution adsorption.

Down-regulated TAB1 suppresses the replication of Coxsackievirus B5 via activating the NF-κB pathways through interaction with viral 3D polymerase.

Coxsackievirus Group B type 5 (CVB5), an important pathogen of hand-foot-mouth disease, is also associated with neurological complications and poses a public health threat to young infants. Among the CVB5 proteins, the nonstructural protein 3D, known as the Enteroviral RNA-dependent RNA polymerase, is mainly involved in viral genome replication and transcription. In this study, we performed immunoprecipitation coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify host proteins that interacted with CVB5 3D polymerase. A total of 116 differentially expressed proteins were obtained. Gene Ontology analysis identified that the proteins were involved in cell development and cell adhesion, distributed in the desmosome and envelope, and participated in GTPase binding. Kyoto Encyclopedia of Genes and Genomes analysis further revealed they participated in nerve diseases, such as Parkinson disease. Among them, 35 proteins were significantly differentially expressed and the cellular protein TGF-BATA-activated kinase1 binding protein 1 (TAB1) was found to be specifically interacting with the 3D polymerase. 3D polymerase facilitated the entry of TAB1 into the nucleus and down-regulated TAB1 expression via the lysosomal pathway. In addition, TAB1 inhibited CVB5 replication via inducing inflammatory factors and activated the NF-κB pathway through IκBα phosphorylation. Moreover, the 90-96aa domain of TAB1 was an important structure for the function. Collectively, our findings demonstrate the mechanism by which cellular TAB1 inhibits the CVB5 replication via activation of the host innate immune response, providing a novel insight into the virus-host innate immunity.

Energy metabolic reprogramming regulates programmed cell death of renal tubular epithelial cells and might serve as a new therapeutic target for acute kidney injury.

Acute kidney injury (AKI) induces significant energy metabolic reprogramming in renal tubular epithelial cells (TECs), thereby altering lipid, glucose, and amino acid metabolism. The changes in lipid metabolism encompass not only the downregulation of fatty acid oxidation (FAO) but also changes in cell membrane lipids and triglycerides metabolism. Regarding glucose metabolism, AKI leads to increased glycolysis, activation of the pentose phosphate pathway (PPP), inhibition of gluconeogenesis, and upregulation of the polyol pathway. Research indicates that inhibiting glycolysis, promoting the PPP, and blocking the polyol pathway exhibit a protective effect on AKI-affected kidneys. Additionally, changes in amino acid metabolism, including branched-chain amino acids, glutamine, arginine, and tryptophan, play an important role in AKI progression. These metabolic changes are closely related to the programmed cell death of renal TECs, involving autophagy, apoptosis, necroptosis, pyroptosis, and ferroptosis. Notably, abnormal intracellular lipid accumulation can impede autophagic clearance, further exacerbating lipid accumulation and compromising autophagic function, forming a vicious cycle. Recent studies have demonstrated the potential of ameliorating AKI-induced kidney damage through calorie and dietary restriction. Consequently, modifying the energy metabolism of renal TECs and dietary patterns may be an effective strategy for AKI treatment.

Diagnosis of diabetic kidney disease in whole slide images via AI-driven quantification of pathological indicators.

Diagnosis of diabetic kidney disease (DKD) mainly relies on screening the morphological variations and internal lesions of glomeruli from pathological kidney biopsy. The prominent pathological alterations of glomeruli for DKD include glomerular hypertrophy and nodular mesangial sclerosis. However, the qualitative judgment of these alterations is inaccurate and inconstant due to the intra- and inter-subject variability of pathologists. It is necessary to design artificial intelligence (AI) methods for accurate quantification of these pathological alterations and outcome prediction of DKD. In this work, we present an AI-driven framework to quantify the volume of glomeruli and degree of nodular mesangial sclerosis, respectively, based on an instance segmentation module and a novel weakly supervised Macro-Micro Aggregation (MMA) module. Subsequently, we construct classic machine learning models to predict the degree of DKD based on three selected pathological indicators via factor analysis. These corresponding modules are trained and tested on a total of 281 whole slide images (WSIs) digitized from two hospitals with different scanners. Our designed AI framework achieved inspiring results with 0.926 mIoU for glomerulus segmentation, and 0.899 F1 score for glomerulus classification in the external testing dataset. Meantime, the visualized results of the MMA module could reflect the location of the lesions. The performance of predicting disease achieved the F1 score of 0.917, which further proved the effectiveness of our AI-driven quantification of pathological indicators. Additionally, the interpretation of the machine learning model with the SHAP method showed similar accordance with the development of DKD in pathology. In conclusion, the proposed auxiliary diagnostic technologies have the feasibility for quantitative analysis of glomerular pathological tissues and alterations in DKD. Pathological quantitative indicators will also make it more convenient to provide doctors with assistance in clinical practice.

Prognostic prediction of idiopathic membranous nephropathy using interpretable machine learning.

BACKGROUND: Established prognostic models of idiopathic membranous nephropathy (IMN) were limited to traditional modeling methods and did not comprehensively consider clinical and pathological patient data. Based on the electronic medical record (EMR) system, machine learning (ML) was used to construct a risk prediction model for the prognosis of IMN. METHODS: Data from 418 patients with IMN were diagnosed by renal biopsy at the Fifth Clinical Medical College of Shanxi Medical University. Fifty-nine medical features of the patients could be obtained from EMR, and prediction models were established based on five ML algorithms. The area under the curve, recall rate, accuracy, and F1 were used to evaluate and compare the performances of the models. Shapley additive explanation (SHAP) was used to explain the results of the best-performing model. RESULTS: One hundred and seventeen patients (28.0%) with IMN experienced adverse events, 28 of them had compound outcomes (ESRD or double serum creatinine (SCr)), and 89 had relapsed. The gradient boosting machine (LightGBM) model had the best performance, with the highest AUC (0.892 ± 0.052, 95% CI 0.840-0.945), accuracy (0.909 ± 0.016), recall (0.741 ± 0.092), precision (0.906 ± 0.027), and F1 (0.905 ± 0.020). Recursive feature elimination with random forest and SHAP plots based on LightGBM showed that anti-phospholipase A2 receptor (anti-PLA2R), immunohistochemical immunoglobulin G4 (IHC IgG4), D-dimer (D-DIMER), triglyceride (TG), serum albumin (ALB), aspartate transaminase (AST), ß2-microglobulin (BMG), SCr, and fasting plasma glucose (FPG) were important risk factors for the prognosis of IMN. Increased risk of adverse events in IMN patients was correlated with high anti-PLA2R and low IHC IgG4. CONCLUSIONS: This study established a risk prediction model for the prognosis of IMN using ML based on clinical and pathological patient data. The LightGBM model may become a tool for personalized management of IMN patients.

Unveiling the potential of mitochondrial dynamics as a therapeutic strategy for acute kidney injury.

Acute Kidney Injury (AKI), a critical clinical syndrome, has been strongly linked to mitochondrial malfunction. Mitochondria, vital cellular organelles, play a key role in regulating cellular energy metabolism and ensuring cell survival. Impaired mitochondrial function in AKI leads to decreased energy generation, elevated oxidative stress, and the initiation of inflammatory cascades, resulting in renal tissue damage and functional impairment. Therefore, mitochondria have gained significant research attention as a potential therapeutic target for AKI. Mitochondrial dynamics, which encompass the adaptive shifts of mitochondria within cellular environments, exert significant influence on mitochondrial function. Modulating these dynamics, such as promoting mitochondrial fusion and inhibiting mitochondrial division, offers opportunities to mitigate renal injury in AKI. Consequently, elucidating the mechanisms underlying mitochondrial dynamics has gained considerable importance, providing valuable insights into mitochondrial regulation and facilitating the development of innovative therapeutic approaches for AKI. This comprehensive review aims to highlight the latest advancements in mitochondrial dynamics research, provide an exhaustive analysis of existing studies investigating the relationship between mitochondrial dynamics and acute injury, and shed light on their implications for AKI. The ultimate goal is to advance the development of more effective therapeutic interventions for managing AKI.

SIRT1 slows the progression of lupus nephritis by regulating the NLRP3 inflammasome through ROS/TRPM2/Ca2+ channel.

Systemic lupus erythematosus (SLE) is a chronic multisystem inflammatory disease associated with autoantibody formation. Lupus nephritis (LN) is one of the most severe organ manifestations of SLE. The inflammatory response is a key factor in kidney injury, and the NLRP3 inflammasome is frequently associated with the pathogenesis of LN. Sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD +)-dependent histone deacetylase, is a promising therapeutic target for preventing renal injury. However, the mechanism of SIRT1 in LN remains unclear. Here, we aimed to investigate the mechanism by which SIRT inhibits the NLRP3 inflammasome to slow the progression of LN. We detected the expression of SIRT1 and the infiltration of macrophages in MRL/lpr mice; the results showed that the expression of SIRT1 was decreased, and the symptoms of lupus nephritis were relieved after the use of resveratrol, which upregulated SIRT1. In vitro studies showed that after lipopolysaccharide (LPS) stimulation, SIRT1 expression decreased, and the NLRP3 inflammasome was activated. Upregulation of SIRT1 inhibits NLRP3 inflammasome activation and assembly by interfering with two signalling pathways. First, SIRT1 affects NF-κB expression, transcription, and inflammatory cytokine expression. Second, SIRT1 modulates calcium influx induced by transient receptor potential channel M2 (TRPM2), which could be partly due to the inhibition of reactive oxygen species (ROS) production. Our findings suggest that upregulated SIRT1 inhibits the NLRP3 inflammasome to slow the progression of lupus nephritis by regulating NF-κB and ROS/TRPM2/Ca2+ channels. This study reveals a new anti-inflammatory mechanism of SIRT1, suggesting that SIRT1 may be a potential therapeutic target for the prevention of LN.

Single-Cell RNA Sequencing Shows T-Cell Exhaustion Landscape in the Peripheral Blood of Patients with Hepatitis B Virus-Associated Acute-on-Chronic Liver Failure.

Background/Aims: The occurrence and development of hepatitis B virus-associated acute-on-chronic liver failure (HBV-ACLF) is closely related to the immune pathway. We explored the heterogeneity of peripheral blood T cell subsets and the characteristics of exhausted T lymphocytes, in an attempt to identify potential therapeutic target molecules for immune dysfunction in ACLF patients. Methods: A total of 83,577 T cells from HBV-ACLF patients and healthy controls were screened for heterogeneity by single-cell RNA sequencing. In addition, exhausted T-lymphocyte subsets were screened to analyze their gene expression profiles, and their developmental trajectories were investigated. Subsequently, the expression of exhausted T cells and their capacity in secreting cytokines (interleukin 2, interferon γ, and tumor necrosis factor α) were validated by flow cytometry. Results: A total of eight stable clusters were identified, among which CD4+ TIGIT+ subset and CD8+ LAG-3+ subset, with high expression of exhaust genes, were significantly higher in the HBV-ACLF patients than in normal controls. As shown by pseudotime analysis, T cells experienced a transition from naïve T cells to effector T cells and then exhausted T cells. Flow cytometry confirmed that the CD4+TIGIT+ subset and CD8+LAG-3+ subset in the peripheral blood of the ACLF patients were significantly higher than those in the healthy controls. Moreover, in vitro cultured CD8+LAG-3+ T cells were significantly fewer capable of secreting cytokines than CD8+LAG-3- subset. Conclusions: Peripheral blood T cells are heterogeneous in HBV-ACLF. The exhausted T cells markedly increase during the pathogenesis of ACLF, suggesting that T-cell exhaustion is involved in the immune dysfunction of HBV-ACLF patients.

Comprehensive pan-cancer analysis of PTGES3 and its prognostic role in hepatocellular carcinoma.

Introduction: PTGES3, also known as p23, is a molecule chaperone of Hsp90 that is involved in the pathogenesis of malignant tumors. Increasing studies have shown that PTGES3 plays a nonnegligible role in tumor development. However, analysis of PTGES3 in pan-cancer has not been performed yet. Methods: We explored the role of PTGES3 in 33 types of tumors and depicted the potentialimmune-related pathways among them. Using multiple databases includingTCGA, LinkedOmics, GDSC, and TIMER, we made a comprehensive analysis to explore whether there was an interaction between PTGES3 and prognosis, DNA methylation, copy number variation (CNV), tumor mutational burden (TMB), microsatellite instability (MSI), and tumor immune microenvironment (TME). Results: Our study revealed that PTGES3 expression level was upregulated in most cancers. PTGES3 was also associated with a positive or negative prognosis in a variety of cancers, which was mainly associated with DNA methylation, CNV, MSI, TMB, andmismatch repair-related genes. High PTGES3 expression was related to the infiltration of Th2 subsets of CD4+ T cells and immune checkpoint-related genes in most cancers, especially in hepatocellular carcinoma (HCC). Enrichment analysis demonstrated that PTGES3 was involved in cellular processes including DNA replication and spliceosome. The relationship between PTGES3 expression and HCC progression was verified at the protein level through immune histochemical analysis. Conclusions: Our research demonstrated theprognostic predictive value of PTGES3 in a wide range of cancers, which was alsoassociated with the process of tumor immune infiltration. As a result, it suggestedthat PTGES3 was a valuable prognostic biomarker in HCC treatment.

Exploratory metabolomic analysis based on UHPLC-Q-TOF-MS/MS to study hypoxia-reoxygenation energy metabolic alterations in HK-2 cells.

PURPOSE: Renal ischemia-reperfusion injury(IRI)is a major cause of acute kidney injury(AKI), the injury and repair of renal tubular epithelial cells play an important role in the pathological process of IR-AKI. Metabolomics was used to detect cell metabolism alterations and metabolic reprogramming in the initial injury, peak injury, and recovery stage of human renal proximal tubular cells (HK-2 cells) to provide insights into clinical prevention and treatment of IRI-induced AKI. METHODS: An in vitro ischemia-reperfusion (H/R) injury and the recovery model of HK-2 cells were established at different times of hypoxia/reoxygenation. Comprehensive detection of metabolic alterations in HK-2 cells after H/R induction by nontarget metabolomics. Interconversion of glycolysis and fatty acid oxidation (FAO) in HK-2 cells after H/R induction was examined by western blotting and qRT-PCR. RESULTS: Multivariate data analysis found significant differences among the groups, with significant changes in metabolites such as glutamate, malate, aspartate, and L-palmitoylcarnitine. Hypoxia-reoxygenated HK-2 cells are accompanied by altered metabolisms such as disturbance of amino acid and nucleotide metabolism, dysregulation of lipid metabolism, increased glycolysis, and metabolic reprogramming, which manifests as a shift in energy metabolism from FAO to glycolysis. CONCLUSION: The development of IRI-induced AKI in HK-2 cells is accompanied by the disturbance of amino acid, nucleotide, and tricarboxylic acid cycle metabolism and specifically metabolic reprogramming of FAO to glycolytic conversion. The timely recovery of energy metabolism in HK-2 cells is of great significance for treating and prognosis IRI-induced AKI.

Monodomain liquid crystal elastomer bionic muscle fibers with excellent mechanical and actuation properties.

Monodomain liquid crystal elastomers (m-LCEs) exhibit large reversible deformations when subjected to light and heat stimuli. Herein, we developed a new method for the large-scale continuous preparation of m-LCE fibers. These m-LCE fibers exhibit a reversible contraction ratio of 55.6%, breaking strength of 162 MPa (withstanding a load of 1 million times its weight), and maximum output power density of 1250 J/kg, surpassing those of previously reported m-LCEs. These excellent mechanical properties are mainly attributed to the formation of a homogeneous molecular network. Furthermore, the fabrication of m-LCEs with permanent plasticity using m-LCEs with impermanent instability without external intervention was realized by the synergistic effects of the self-restraint of mesogens and the prolonged relaxation process of LCEs. The designed LCE fibers, which are similar to biological muscle fibers and can be easily integrated, exhibit broad application prospects in artificial muscles, soft robots, and micromechanical systems.

Iron metabolism-related indicators as predictors of the incidence of acute kidney injury after cardiac surgery: a meta-analysis.

BACKGROUND: Some studies have found that ferroptosis plays an important role in the incidence of acute kidney injury (AKI) after cardiac surgery. However, whether iron metabolism-related indicators can be used as predictors of the incidence of AKI after cardiac surgery remains unclear. OBJECTIVES: We aimed to systematically evaluate whether iron metabolism-related indicators can be used as predictors of the incidence of AKI after cardiac surgery via meta-analysis.Search methods: The PubMed, Embase, Web of Science, and Cochrane Library databases were searched from January 1971 to February 2023 to identify prospective observational and retrospective observational studies examining iron metabolism-related indicators and the incidence of AKI after cardiac surgery among adults.Data Extraction and Synthesis: The following data were extracted by two independent authors (ZLM and YXY): date of publication, first author, country, age, sex, number of included patients, iron metabolism-related indicators, outcomes of patients, patient types, study types, sample, and specimen sampling time. The level of agreement between authors was determined using Cohen's κ value. The Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of studies. Statistical heterogeneity across the studies was measured by the I2 statistic. The standardized mean difference (SMD) and 95% confidence interval (CI) were used as effect size measures. Meta-analysis was performed using Stata 15. RESULTS: After applying the inclusion and exclusion criteria, 9 articles on iron metabolism-related indicators and the incidence of AKI after cardiac surgery were included in this study. Meta-analysis revealed that after cardiac surgery, baseline serum ferritin (µg/L) (I2 = 43%, fixed effects model, SMD = -0.3, 95% CI:-0.54 to -0.07, p = 0.010), preoperative and 6-hour postoperative fractional excretion (FE) of hepcidin (%) (I2 = 0.0%, fixed effects model, SMD = -0.41, 95% CI: -0.79 to -0.02, p = 0.038; I2 = 27.0%, fixed effects model, SMD = -0.49, 95% CI: -0.88 to -0.11, p = 0.012), 24-hour postoperative urinary hepcidin (µg/L) (I2 = 0.0%, fixed effects model, SMD = -0.60, 95% CI: -0.82 to -0.37, p < 0.001) and urine hepcidin/urine creatinine ratio (µg/mmoL) (I2 = 0.0%, fixed effects model, SMD = -0.65, 95% CI: -0.86 to -0.43, p < 0.001) were significantly lower in patients who developed to AKI than in those who did not. CONCLUSION: After cardiac surgery, patients with lower baseline serum ferritin levels (µg/L), lower preoperative and 6-hour postoperative FE of hepcidin (%), lower 24-hour postoperative hepcidin/urine creatinine ratios (µg/mmol) and lower 24-hour postoperative urinary hepcidin levels (µg/L) are more likely to develop AKI. Therefore, these parameters have the potential to be predictors for AKI after cardiac surgery in the future. In addition, there is a need for relevant clinical research of larger scale and with multiple centers to further test these parameters and prove our conclusion.Trial Registration: PROSPERO identifier: CRD42022369380.