Mediating effect of gestational weight gain on the preventive effect of exercise during pregnancy on macrosomia: a randomized clinical trial.

OBJECTIVE: We sought to investigate the impact of individualized exercise guidance during pregnancy on the incidence of macrosomia and the mediating effect of gestational weight gain (GWG). DESIGN: A prospective randomized clinical trial. SETTING: A Hospital in Xingtai District, Hebei Province. POPULATION: Older than 20 years of age, mid-pregnancy, and singleton pregnant women without contraindications to exercise during pregnancy. METHODS: A randomized clinical trial was conducted from December 2021 to September 2022 to compare the effects of standard prenatal care with individualized exercise guidance on the incidence of macrosomia. MAIN OUTCOME MEASURE: Incidence of macrosomia. RESULTS: In all, 312 singleton women were randomized into an intervention group (N = 162) or a control group (N = 150). Participants who received individualized exercise guidance had a significantly lower incidence of macrosomia (3.73% vs. 13.61%, P = 0.002) and infants large for gestational age (9.94% vs. 19.73%, P = 0.015). However, no differences were observed in the rate of preterm birth (1.86% vs. 3.40%, P = 0.397) or the average gestational age at birth (39.14 ± 1.51 vs. 38.69 ± 1.85, P = 0.258). Mediation analysis revealed that GWG mediated the effect of exercise on reducing the incidence of macrosomia. CONCLUSION: Individualized exercise guidance may be a preventive tool for macrosomia, and GWG mediates the effect of exercise on reducing the incidence of macrosomia. However, evidence does not show that exercise increases the rate of preterm birth or affects the average gestational age at birth. TRIAL REGISTRATION: The trial is registered at www.clinicaltrails.gov [registration number: NCT05760768; registration date: 08/03/2023 (retrospectively registered)].

Identification of membrane curvature sensing motifs essential for VPS37A phagophore recruitment and autophagosome closure.

VPS37A, an ESCRT-I complex component, is required for recruiting a subset of ESCRT proteins to the phagophore for autophagosome closure. However, the mechanism by which VPS37A is targeted to the phagophore remains obscure. Here, we demonstrate that the VPS37A N-terminal domain exhibits selective interactions with highly curved membranes, mediated by two membrane-interacting motifs within the disordered regions surrounding its Ubiquitin E2 variant-like (UEVL) domain. Site-directed mutations of residues in these motifs disrupt ESCRT-I localization to the phagophore and result in defective phagophore closure and compromised autophagic flux in vivo, highlighting their essential role during autophagy. In conjunction with the UEVL domain, we postulate that these motifs guide a functional assembly of the ESCRT machinery at the highly curved tip of the phagophore for autophagosome closure. These results advance the notion that the distinctive membrane architecture of the cup-shaped phagophore spatially regulates autophagosome biogenesis.

Age-Related Changes in Urethral Structure and Responds to Injury: Single-Cell Atlas of a Rat Model of Vaginal Birth Injury induced Stress Urinary Incontinence.

Stress urinary incontinence (SUI) greatly affects the daily life of numerous women and is closely related to a history of vaginal delivery and aging. We used vaginal balloon dilation to simulate vaginal birth injury in young and middle-aged rats to produce a SUI animal model, and found that young rats restored urethral structure and function well, but not the middle-aged rats. To identify the characteristics of cellular and molecular changes in the urethral microenvironment during the repair process of SUI. We profiled 51,690 individual female rat urethra cells from 24 and 48 weeks old, with or without simulated vaginal birth injury. Cell interaction analysis showed that signal networks during repair process changed from resting to active, and aging altered the distribution but not the overall level of cell interaction in the repair process. Similarity analysis showed that muscle, fibroblasts, and immune cells underwent large transcriptional changes during aging and repair. In middle-aged rats, cell senescence occurs mainly in the superficial and middle urothelium due to cellular death and shedding, and the basal urothelium expressed many Senescence-Associated Secretory Phenotype (SASP) genes. In conclusion, we established the aging and vaginal balloon dilation (VBD) model of female urethral cell anatomy and the signal network landscape, which provides an insight into the normal or disordered urethra repair process and the scientific basis for developing novel SUI therapies.

Unlocking digital potential: Exploring the drivers of employee dynamic capability on employee digital performance in Chinese SMEs-moderation effect of competitive climate.

While dynamic capabilities have been described as crucial for achieving organizational performance in dynamic environments, there has been limited scholarly distinction between dynamic capabilities and employee dynamic capabilities (EDC), especially in the digital era. Consequently, a knowledge gap has emerged. To address this void, this paper aims to investigate the driving factors of EDC and their impact on employee digital performance (EDP). Simultaneously, incorporating the competitive climate (CC) as a moderating variable between employee dynamic capabilities and employee digital performance addresses theoretical gaps in specific regions in China, particularly in small and medium-sized enterprises (SMEs). This study utilizes survey data from SMEs in four Chinese provinces: Shanghai, Guizhou, Guangdong, and Anhui. It employs CB-SEM (AMOS) to analyze the new conceptual framework. Firstly, the research uncovers that the positive relationship between digital capabilities and employee digital performance necessitates employee dynamic capabilities as a mediator. Secondly, there exists a direct and indirect relationship between organizational learning and employee digital performance. Finally, this study discerns that the competitive climate moderates the relationship between employee dynamic capabilities and employee digital performance. This finding demonstrates remarkable alignment with the competitive culture in specific regions of China. The research results encourage SMEs to seize the opportunities presented by emerging digital technologies and industry digitization trends. They should commit to embracing new digital technologies, enhancing digital capability, strengthening organizational learning, fostering a positive competitive climate, and focusing on the development of employee dynamic capability to enhance their competitive edge. The findings of this research contribute not only to academic inquiry but also furnish pertinent decision-making references for relevant departments.

Study on the relationship between the fitness of three types of N95 respirators and facial dimensions.

N95 respirators are the core equipment used by healthcare workers to prevent the spread of respiratory diseases. The protective effect of N95 against infection spread depends on the fit of the N95 to the wearer, which is related to the wearer's facial dimensions. The purpose of this cross-sectional study was to assess the relationship between the fit of three types of N95 and facial dimensions. A total of 305 healthcare workers from ten hospitals in Beijing were recruited for this study. Facial dimensions of workers were measured using Intel RealSense Depth Camera D435. Fit testing was conducted on three types of N95 using the TSI-8038 Porta Count Pro + Respirator Fit Tester. Possible associations between the fit test results and facial dimension data were examined. A Porta Count reading of 100 was used as the criterion for an acceptable fit. The fit of the folding respirators was positively correlated with nose length (r = 0.13, p = 0.02), nose height (r = 0.14, p = 0.02), and face width (r = 0.12, p = 0.03), whereas that of flat respirators was correlated with nose width (r = 0.16, p < 0.01), chin length (r = 0.18, p < 0.01), and pro-face width (r = 0.13, p = 0.02), and that of arched respirators was correlated with the nose length (r = 0.13, p = 0.03). The fit of N95 for wearers depends on their facial features. The results of this study can provide advice for medical workers to choose the appropriate N95. Medical staff should fully consider their facial dimensions when choosing an appropriate N95 to improve the protective efficacy of respirators and to reduce the risk of infection by respiratory diseases.

High-Performance Hydrogel-Encapsulated Engineered Exosomes for Supporting Endoplasmic Reticulum Homeostasis and Boosting Diabetic Bone Regeneration.

The regeneration of bone defects in diabetic patients still faces challenges, as the intrinsic healing process is impaired by hyperglycemia. Inspired by the discovery that the endoplasmic reticulum (ER) is in a state of excessive stress and dysfunction under hyperglycemia, leading to osteogenic disorder, a novel engineered exosome is proposed to modulate ER homeostasis for restoring the function of mesenchymal stem cells (MSCs). The results indicate that the constructed engineered exosomes efficiently regulate ER homeostasis and dramatically facilitate the function of MSCs in the hyperglycemic niche. Additionally, the underlying therapeutic mechanism of exosomes is elucidated. The results reveal that exosomes can directly provide recipient cells with SHP2 for the activation of mitophagy and elimination of mtROS, which is the immediate cause of ER dysfunction. To maximize the therapeutic effect of engineered exosomes, a high-performance hydrogel with self-healing, bioadhesive, and exosome-conjugating properties is applied to encapsulate the engineered exosomes for in vivo application. In vivo, evaluation in diabetic bone defect repair models demonstrates that the engineered exosomes delivering hydrogel system intensively enhance osteogenesis. These findings provide crucial insight into the design and biological mechanism of ER homeostasis-based tissue-engineering strategies for diabetic bone regeneration.

Sex-specific association between monocyte to high-density lipoprotein cholesterol and extensive abdominal aortic calcification in humans.

Recent studies have identified monocyte-to-high-density lipoprotein cholesterol ratio (MHR) as a simple marker of atherosclerosis. Abdominal aortic calcification (AAC) is a direct result of vascular atherosclerosis. Our study aims to investigate the association between MHR and the prevalent extensive AAC and assess the value of MHR for identifying prevalent extensive AAC. 2857 subjects (28.07%) from the cross-sectional National Health and Nutrition Examination Survey 2013-2014 were included in our study. AAC was detected through dual-energy x-ray absorptiometry and quantified by Kauppila score. Extensive AAC was identified in 153 (10.44% of 1465) females and 146 (10.49% of 1392) males. With the full adjustment, each SD increase of MHR resulted in an 87.3% additional risk for extensive AAC in females. When dividing into quartiles, the top quartile had a 3.472 times risk of prevalent extensive AAC than the bottom quartile. However, no significant association was observed in males. Furthermore, smooth curve fitting implicated that the significant association was linear in the whole range of MHR among females. Additionally, ROC demonstrated an improvement in the identification of extensive AAC only among females when introducing MHR into established risk factors of atherosclerosis (0.808 vs. 0.864, p < 0.001). Finally, category-free net reclassification index and integrated discrimination index also supported the improvement by MHR in females. Our study revealed a linear association between MHR and prevalent extensive AAC in females. Moreover, our results implicated the potential value of MHR to refine the identification of prevalent extensive AAC in females.

The soil microbial necromass carbon and the carbon pool stability drive a stronge priming effect following vegetation restoration.

The priming effect stands as a critical factor influencing the balance of soil organic carbon (SOC). Following vegetation restoration, the carbon (C) pool stability in Platycladus orientalis forests (PO) varies, and the priming effect resulting from exogenous C addition also differs significantly. Here, we selected PO with restoration ages of 10, 15, and 30 years in the rocky mountainous area in northern China and conducted measurements of soil properties, microbial communities, microbial necromass C (MNC), SOC fractions, and the priming effect characteristics to explore the main influencing factors of the priming effect, especially the microbiological mechanisms. Our results showed that the ratio of mineral-associated organic C to particulate organic C increased. The characteristics of the priming effect showed the same pattern, and there was a significant positive correlation between the C pool stability and the priming effect. The diversity of the fungal communities increased with increasing vegetation restoration age, and the content and proportion of fungal necromass C (FNC) also increased synchronously, reaching the maximum value in the soil of PO that had been restored for 30 years. In addition, the soil water content and total nitrogen indirectly affected the priming effect by influencing the microbial communities. In summary, the results suggested that vegetation restoration can enhance the C pool stability by promoting an increase in soil FNC, thereby producing a positive priming effect. This can help deepen our understanding of the SOC mineralization changes induced by fresh C input following vegetation restoration and provides a theoretical basis for better explaining the C cycle between soil and atmosphere under the vegetation restoration models in the future.

Significance of fatty liver index to detect prevalent ischemic heart disease: evidence from national health and nutrition examination survey 1999-2016.

Background: Non-alcoholic fatty liver disease (NAFLD) contributes to the development of ischemic heart disease via multiple mechanisms. Fatty liver index (FLI) has been proposed as an accurate, convenient, and economic surrogate of the severity of NAFLD. Our present study aims to assess the association between FLI and the prevalent IHD and to evaluate the potential value of FLI to refine the detection of prevalent IHD in the general population. Methods: Our work recruited 32,938 subjects from the National Health and Nutrition Examination Survey 1999-2016. IHD was diagnosed according to the subjects' self-report. FLI was determined based on triglycerides, BMI, γ-glutamyltransferase, and waist circumference. Results: 2,370 (7.20%) subjects were diagnosed with IHD. After adjustment of age, sex, race, current smoking, current drinking, PIR, BMI, WC, TC, TG, GGT, Scr, FPG, SBP, anti-hypertensive therapy, anti-diabetic therapy, and lipid-lowering therapy, one standard deviation increase of FLI resulted in a 27.0% increment of the risk of prevalent IHD. In the quartile analysis, we observed a 1.684 times risk of prevalent IHD when comparing the fourth quartile with the first quartile, and there was a trend towards higher risk across the quartiles. The smooth curve fitting displayed a linear relationship between FLI and the presence of IHD without any threshold or saturation effect. Subgroup analysis revealed a robust association in conventional cardiovascular subpopulations, and the association could be more prominent in female subjects and diabetes patients. ROC analysis demonstrated an incremental value of FLI for detecting prevalent IHD after introducing it to conventional cardiovascular risk factors (AUC: 0.823 vs. 0.859, P for comparison <0.001). Also, results from reclassification analysis implicated that more IHD patients could be correctly identified by introducing FLI into conventional cardiovascular risk factors (continuous net reclassification index: 0.633, P < 0.001; integrated discrimination index: 0.034, P < 0.001). Conclusion: The current analysis revealed a positive and linear relationship between FLI and the prevalent IHD. Furthermore, our findings suggest the incremental value of FLI to refine the detection of prevalent IHD in the general population.

Application of common industrial solid waste in water treatment: a review.

Industrial solid waste has a wide range of impacts, and it is directly or indirectly related to land, atmosphere, water, and other resources. Industrial solid waste has a large amount of production, complex and diverse components and contains a variety of harmful substances. However, as industrial by-products, it also has a lot of available value. Industrial solid waste has been continuously studied in water treatment due to its special composition and porous and loose structure. It is known that there are few reviews of various industrial solid wastes in the field of wastewater treatment, and most of them only discuss single industrial solid waste. This paper aims to sort out the different studies on various solid wastes such as fly ash, red mud, wastewater sludge, blast furnace slag and steel slag in dyeing, heavy metal, and phosphorus-containing wastewater. Based on the modification of industrial solid waste and the preparation of composite materials, adsorbents, coagulants, catalysts, filtration membranes, geological polymers, and other materials with high adsorption properties for pollutants in wastewater were formed; the prospect and development of these materials in the field of wastewater were discussed, which provides some ideas for the mutual balance of environment and society. Meanwhile, some limitations of solid waste applications for wastewater treatment have been put forward, such as a lack of further researches about environment-friendly modification methods, application costs, the heavy metal leaching, and toxicity assessment of industrial solid waste.

Accelerating Wound Closure With Metrnl in Normal and Diabetic Mouse Skin.

Impaired wound healing and ulcer complications are major causes of morbidity in patients with diabetes. Impaired wound healing is associated with increased inflammation and poor angiogenesis in diabetes patients. Here, we demonstrate that topical administration of a secreted recombinant protein (Meteorin-like [Metrnl]) accelerates wound epithelialization and angiogenesis in mice. We observed a significant increase in Metrnl expression during physiological wound healing; however, its expression remained low during diabetic wound healing. Functionally, the recombinant protein Metrnl significantly accelerated wound closure in normal and diabetic mice models including db/db, high-fat diet/streptozotocin (HFD/STZ), and STZ mice. Mechanistically, keratinocytes secrete quantities of Metrnl to promote angiogenesis; increase endothelial cell proliferation, migration, and tube formation; and enhance macrophage polarization to the M2 type. Meanwhile, M2 macrophages secrete Metrnl to further stimulate angiogenesis. Moreover, the keratinocyte- and macrophage-produced cytokine Metrnl drives postinjury angiogenesis and reepithelialization through activation of AKT phosphorylation (S473) in a KIT receptor tyrosine kinase (c-Kit)-dependent manner. In conclusion, our study suggests that Metrnl has a biological effect in accelerating wound closure through c-Kit-dependent angiogenesis and epithelialization.

Multifaceted membrane interactions of human Atg3 promote LC3-phosphatidylethanolamine conjugation during autophagy.

Autophagosome formation, a crucial step in macroautophagy (autophagy), requires the covalent conjugation of LC3 proteins to the amino headgroup of phosphatidylethanolamine (PE) lipids. Atg3, an E2-like enzyme, catalyzes the transfer of LC3 from LC3-Atg3 to PEs in targeted membranes. Here we show that the catalytically important C-terminal regions of human Atg3 (hAtg3) are conformationally dynamic and directly interact with the membrane, in collaboration with its N-terminal membrane curvature-sensitive helix. The functional relevance of these interactions was confirmed by in vitro conjugation and in vivo cellular assays. Therefore, highly curved phagophoric rims not only serve as a geometric cue for hAtg3 recruitment, but also their interaction with hAtg3 promotes LC3-PE conjugation by targeting its catalytic center to the membrane surface and bringing substrates into proximity. Our studies advance the notion that autophagosome biogenesis is directly guided by the spatial interactions of Atg3 with highly curved phagophoric rims.

Boosting the Cell Performance of the SiO/Cu and SiO/PPy Anodes via In-Situ Reduction/Oxidation Coating Strategies.

Silicon monoxide (SiO) has attracted great attention due to its high theoretical specific capacity as an alternative material for conventional graphite anode, but its poor electrical conductivity and irreversible side reactions at the SiO/electrolyte interface seriously reduce its cycling stability. Here, to overcome the drawbacks, the dicharged SiO anode coated with Cu coating layer is elaborately designed by in-situ reduction method. Compared with the pristine SiO anode of lithium-ion battery (293 mAh g-1 at 0.5 A g-1 after 200 cycles), the obtained SiO/Cu composite presents superior cycling stability (1206 mAh g-1 at 0.5 A g-1 after 200 cycles). The tight combination of Cu particles and SiO significantly improves the conductivity of the composite, effectively inhibits the side-reaction between the active material and electrolyte. In addition, polypyrrole-coated SiO composites are further prepared by in-situ oxidation method, which delivers a high reversible specific capacity of 1311 mAh g-1 at 0.5 A g-1 after 200 cycles. The in-situ coating strategies in this work provide a new pathway for the development and practical application of high-performance silicon-based anode.

CGRP-Loaded Porous Microspheres Protect BMSCs for Alveolar Bone Regeneration in the Periodontitis Microenvironment.

Periodontitis is a prevalent dental disease marked by progressive destruction of tooth-supporting tissues, and the recovery of bone defects after periodontitis remains challenging. Although stem cell-based therapy is a promising treatment for periodontal tissue regeneration, the function of mesenchymal stem cells is constantly impaired by the inflammatory microenvironment, leading to compromised treatment outcomes. Herein, calcitonin gene-related peptide (CGRP)-loaded porous microspheres (PMs) are prepared to protect bone marrow mesenchymal stem cells (BMSCs) against inflammatory mediators in periodontitis. The released CGRP can effectively ameliorate the inflammation-induced dysfunction of BMSCs, which may involve suppressing the ROS (reactive oxygen species)/NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3)/Caspase-1 (CASP1) pathway. Moreover, the porous architecture of PMs provides effective cell-carrying capacity and physical protection for BMSCs during transplantation. In vivo experiments demonstrate that CGRP/BMSC-loaded PMs can effectively inhibit inflammation and improve osteogenic activity, resulting in better periodontal bone regeneration. This study focuses on the protection of stem cell function in the inflammatory microenvironment, which is important for stem cell-mediated tissue regeneration and repair under inflammatory conditions.

Integration of GWAS and RNA-Seq Analysis to Identify SNPs and Candidate Genes Associated with Alkali Stress Tolerance at the Germination Stage in Mung Bean.

Soil salt-alkalization seriously impacts crop growth and productivity worldwide. Breeding and applying tolerant varieties is the most economical and effective way to address soil alkalization. However, genetic resources for breeders to improve alkali tolerance are limited in mung bean. Here, a genome-wide association study (GWAS) was performed to detect alkali-tolerant genetic loci and candidate genes in 277 mung bean accessions during germination. Using the relative values of two germination traits, 19 QTLs containing 32 SNPs significantly associated with alkali tolerance on nine chromosomes were identified, and they explained 3.6 to 14.6% of the phenotypic variance. Moreover, 691 candidate genes were mined within the LD intervals containing significant trait-associated SNPs. Transcriptome sequencing of alkali-tolerant accession 132-346 under alkali and control conditions after 24 h of treatment was conducted, and 2565 DEGs were identified. An integrated analysis of the GWAS and DEGs revealed six hub genes involved in alkali tolerance responses. Moreover, the expression of hub genes was further validated by qRT-PCR. These findings improve our understanding of the molecular mechanism of alkali stress tolerance and provide potential resources (SNPs and genes) for the genetic improvement of alkali tolerance in mung bean.

Control of the electron dynamics in solid-state high harmonic generation on ultrafast time scales by a polarization-skewed laser pulse.

Since high-order harmonic generation (HHG) from atoms depends sensitively on the polarization of the driving laser field, the polarization gating (PG) technique was developed and applied successfully to generate isolated attosecond pulses from atomic gases. The situation is, however, different in solid-state systems as it has been demonstrated that due to collisions with neighboring atomic cores of the crystal lattice strong HHG can be generated even by elliptically- and circularly-polarized laser fields. Here we apply PG to solid-state systems and find that the conventional PG technique is inefficient for the generation of isolated ultrashort harmonic pulse bursts. In contrast, we demonstrate that a polarization-skewed laser pulse is able to confine the harmonic emission to a time window of less than one-tenth of the laser cycle. This method provides a novel way to control HHG and to generate isolated attosecond pulses in solids.

Stabilization of Bio-Oss® particulates using photocurable hydrogel to enhance bone regeneration by regulating macrophage polarization.

Bone substitutes are widely used in maxillofacial and oral surgeries. However, in clinical practice, bone substitutes with various forms, including separated particulates, powders, and blocks, have exhibited poor handling properties and space maintenance characteristics, resulting in long surgery procedures and unstable volume of the newly formed bone. Movable separated particulates with high stiffness have induced local inflammatory responses that hinder bone regeneration. The present study aimed to develop a new method to enhance the stability and operability of bone substitutes commonly used in dentistry by premixing with photocurable hydrogel GelMA. The GelMA-encapsulated particulate had a strong capacity to aggregate separated particulates and firmly attach to the host bone defect after photocuring compared to particulates alone. Additionally, macrophages at the surface of the GelMA-stabilized particulates tended to present a more M2-like phenotype than those at the surface of Bio-Oss®, leading to more MMR+ multinucleated giant cell formation and the induction of blood vessel invasion and new bone formation. In conclusion, this hydrogel-coated bone substitute strategy facilitates bone regeneration with increased operability, a stable volume of osteogenic space, and a favorable osteogenic microenvironment, indicating its potential value in the field of maxillofacial and oral surgeries when bone substitutes are needed.

Extracellular vesicles derived from mouse adipose-derived mesenchymal stem cells promote diabetic corneal epithelial wound healing through NGF/TrkA pathway activation involving dendritic cells.

Diabetic keratopathy (DK) is a common ocular complication of diabetes in which the dendritic cells (DCs)-mediated inflammatory response plays an important role. Nerve growth factor (NGF)/Tropomyosin receptor kinase A (TrkA)-mediated inhibition of the nuclear factor kappa B (NF-κB) pathway can reduce inflammatory cytokine production. Extracellular vesicles (EVs) derived from mouse adipose-derived mesenchymal stem cells (mADSC-EVs) have been explored extensively as treatments for degenerative eye disease. However, mADSC-EVs is poorly studied in the DK models. In this study, we investigated the anti-inflammatory effects of mADSC-EVs and explored the underlying mechanisms in vitro and in vivo DK models. Our results showed that mADSC-EVs have significant therapeutic effects including increasing tear volume and the ratio of lacrimal gland/body weight, promoting corneal nerve regeneration, and sensation recovery in streptozotocin (STZ)-induced DK mice. In addition, mADSC-EVs significantly reduced the inflammatory response involving DCs, consistently up-regulated protein expression of the NGF/TrkA pathway, and importantly, reduced lipopolysaccharide (LPS)-mediated IL-6 and TNF-α expression and directly dependent on TrkA in the induced culture of bone marrow-derived DCs (BMDCs). Taken together, our findings revealed that mADSC-EVs promoted diabetic corneal epithelial wound healing through NGF/TrkA pathway activation involving DCs. Given the significant therapeutic efficacy of mADSC-EVs and its clinical application, mADSC-EVs appears to be a promising new therapy for DK.

The UDPase ENTPD5 regulates ER stress-associated renal injury by mediating protein N-glycosylation.

Impaired protein N-glycosylation leads to the endoplasmic reticulum (ER) stress, which triggers adaptive survival or maladaptive apoptosis in renal tubules in diabetic kidney disease (DKD). Therapeutic strategies targeting ER stress are promising for the treatment of DKD. Here, we report a previously unappreciated role played by ENTPD5 in alleviating renal injury by mediating ER stress. We found that ENTPD5 was highly expressed in normal renal tubules; however, ENTPD5 was dynamically expressed in the kidney and closely related to pathological DKD progression in both human patients and mouse models. Overexpression of ENTPD5 relieved ER stress in renal tubular cells, leading to compensatory cell proliferation that resulted in hypertrophy, while ENTPD5 knockdown aggravated ER stress to induce cell apoptosis, leading to renal tubular atrophy and interstitial fibrosis. Mechanistically, ENTPD5-regulated N-glycosylation of proteins in the ER to promote cell proliferation in the early stage of DKD, and continuous hyperglycemia activated the hexosamine biosynthesis pathway (HBP) to increase the level of UDP-GlcNAc, which driving a feedback mechanism that inhibited transcription factor SP1 activity to downregulate ENTPD5 expression in the late stage of DKD. This study was the first to demonstrate that ENTPD5 regulated renal tubule cell numbers through adaptive proliferation or apoptosis in the kidney by modulating the protein N-glycosylation rate in the ER, suggesting that ENTPD5 drives cell fate in response to metabolic stress and is a potential therapeutic target for renal diseases.

Metrnl Alleviates Lipid Accumulation by Modulating Mitochondrial Homeostasis in Diabetic Nephropathy.

Ectopic lipid accumulation in renal tubules is closely related to the pathogenesis of diabetic kidney disease (DKD), and mitochondrial dysfunction is thought to play a key role in lipid accumulation. Therefore, maintaining mitochondrial homeostasis holds considerable promise as a therapeutic strategy for the treatment of DKD. Here, we report that the Meteorin-like (Metrnl) gene product mediates lipid accumulation in the kidney and has therapeutic potential for DKD. We confirmed the reduced expression of Metrnl in renal tubules, which was inversely correlated with DKD pathological changes in human patients and mouse models. Functionally, pharmacological administration of recombinant Metrnl (rMetrnl) or Metrnl overexpression could alleviate lipid accumulation and inhibit kidney failure. In vitro, rMetrnl or Metrnl overexpression attenuated palmitic acid-induced mitochondrial dysfunction and lipid accumulation in renal tubules accompanied by maintained mitochondrial homeostasis and enhanced lipid consumption. Conversely, shRNA-mediated Metrnl knockdown diminished the protective effect on the kidney. Mechanistically, these beneficial effects of Metrnl were mediated by the Sirt3-AMPK signaling axis to maintain mitochondrial homeostasis and through Sirt3-uncoupling protein-1 to promote thermogenesis, consequently alleviating lipid accumulation. In conclusion, our study demonstrates that Metrnl regulated lipid metabolism in the kidney by modulating mitochondrial function and is a stress-responsive regulator of kidney pathophysiology, which sheds light on novel strategies for treating DKD and associated kidney diseases. ARTICLE HIGHLIGHTS: Metrnl is expressed in renal tubules and is reduced under diabetic conditions. The concentration of Metrnl in the kidney is correlated with lipid accumulation and serum creatinine. Metrnl-specific overexpression in the kidney or recombinant Metrnl administration alleviates renal injuries in diabetic mice. Metrnl regulates renal tubules lipid metabolism through Sirt3-AMPK/UCP1 signaling axis-mediated mitochondrial homeostasis.