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Lihua Ni,1,* Jingyuan Cao,2,* Cheng Yuan,3 Le-Ting Zhou,4 Xiaoyan Wu1 1Department of Nephrology, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of China; 2The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, People’s Republic of China; 3Department of Gynecological Oncology, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of China; 4Department of Nephrology, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaoyan Wu; Le-Ting Zhou, Email wuxiaoyan_kid@163.com; 854597751@qq.comObjective: This study aims to explore the correlation between ferroptosis and immune microenvironment (IME) in diabetic kidney disease (DKD) to provide a new clue for exploring the underlying molecular mechanisms.Methods: Corresponding RNA data of DKD patients were downloaded from GEO databases. The weighted gene co-expression network analysis (WGCNA) was used to construct the network, and the selected hub genes, then, overlapped with ferroptosis-related genes (FRGs) from FerrDb. Consensus clustering was performed to identify new molecular subgroups. ESTIMATE, TIMER and ssGSEA analyses were applied to determinate the IME and immune status. Functional analyses including GO, KEGG and GSEA were conducted to elucidate the underlying mechanisms.Results: Two molecular subtypes were identified based on the expression of FRGs. ESTIMATE algorithm revealed that there were significant differences in ESTIMATE score between these two clusters of DKD patients, with no significant difference found in stromal score and immune score. In addition, TIMER algorithm indicated there was a significant difference in the degree of T cell infiltration. The ssGSEA algorithm showed immunity was mainly concentrated in thick ascending limb and distal convoluted tubule in adult kidney. GO, KEGG and GSEA analyses revealed that the differentially expressed genes (DEGs) were mainly enriched in immune and metabolism associated pathways.Conclusion: The ferroptosis may be induced by dysregulation of IME, thereby accelerating the progression of DKD. Our work could be applied to provide a new clue for exploring the underlying molecular mechanisms and sheds novel light on the therapy strategy of DKD.Keywords: diabetic kidney disease, DKD, ferroptosis, immune microenvironment, IME, metabolism

Zhenyu Zhang,1 Jianbing Wang,1 Mingjuan Jin,1 Mei Li,1 Litao Zhou,2 Fangyuan Jing,1 Kun Chen1 1Department of Epidemiology and Health Statistics, School of Public Health, Zhejiang University, Zhejiang, People’s Republic of China; 2Quality Control Department, Zhejiang Hospital, Zhejiang, People’s Republic of China Background: The People’s Republic of China’s population is aging rapidly, partly because of the impact of the one-child policy and improvements in the health care system. Caring for bedridden seniors can be a challenge for many families in the People’s Republic of China.Objective: To identify the inequality of income among different age groups and social statuses, and evaluate the medical burden and health insurance compensation in the People’s Republic of China.Methods: We measured income inequality and insurance compensation levels among bedridden patients in Zhejiang province, People’s Republic of China. Factor analysis and Gini coefficients were used to evaluate degree of income inequality and insurance compensation level.Results: We found distinct regional disparities in Zhejiang province, including the aspects of income, expenses, and time. Gini coefficients of older adults with long-term care needs in urban and rural areas were 0.335 and 0.602, respectively. In all age groups, Gini coefficients increased after adjustment for medical expenditures, and the inequality persisted after insurance reimbursement was taken into consideration.Conclusion: A significant income disparity between rural and urban areas was observed. Inequality increased with age, and medical expenditure is a huge burden for older people with long-term care needs. Health insurance does not play an important role in reducing inequalities among patients who need long-term care services. Keywords: Gini coefficient, bedridden, long-term care, insurance

The mechanisms contributing to age-related deterioration of the female reproductive system are complex, however aberrant protein homeostasis is a major contributor. We elucidated exceptionally stable proteins, structures, and macromolecules that persist in mammalian ovaries and gametes across the reproductive lifespan. Ovaries exhibit localized structural and cell-type-specific enrichment of stable macromolecules in both the follicular and extrafollicular environments. Moreover, ovaries and oocytes both harbor a panel of exceptionally long-lived proteins, including cytoskeletal, mitochondrial, and oocyte-derived proteins. The exceptional persistence of these long-lived molecules suggest a critical role in lifelong maintenance and age-dependent deterioration of reproductive tissues., Competing Interests: EB, KV, LZ, CG, SE, MS, JS, FD No competing interests declared, (© 2024, Bomba-Warczak, Velez et al.)

To understand the structure of the plankton community and the ecological niche characteristics of their dominant species, sampling surveys of plankton were conducted in Baiyangdian Lake in the spring （March）, summer （July）, and autumn （September） of 2022. The changes in the plankton community during the three seasons were analyzed by constructing ecological network diagrams, non-metric multidimensional scaling analysis （NMDS）, and the ecological niche width. The niche overlap of zooplankton dominant species was evaluated by the improved Levins' formula and Petraitis' index. The interspecific connectivity of dominant species was judged using the chi-square test and interspecies connectivity coefficients. The results showed that the niche width of plankton in the whole area was low. Zooplankton was dominated by rotifers, and phytoplankton was dominated by diatoms, cyanobacteria, and green algae. There were significant seasonal changes in the community structures of plankton. Compared with that in summer and autumn, there were fewer species of plankton in spring and lower interspecies connectivity. The overlap of dominant species of zooplankton was high in summer, and the interspecific competition was intensified, whereas the interspecific overlap of phytoplankton was at a low level in all three seasons. There was a significant positive correlation （ W > χ 2 0.05 ） between phytoplankton in summer and autumn, and the community structure was stable. The interdomain ecological network of zooplankton and phytoplankton showed a high negative correlation ratio in autumn, especially between copepods and cladoceras of zooplankton and chlorophyta and cyanophyta of phytoplankton. The plankton species in Baiyangdian Lake were abundant, with obvious seasonal differences. The dominant species were mainly a narrow ecological niche. The plankton community was generally in a stable state, and there was a strong predation relationship between copepods and cladoceras and green algae and cyanobacteria.

Study Question: Do the molecular signatures of cumulus cells (CCs) and follicular fluid (FF) of adolescents undergoing fertility preservation differ from that of oocyte donors?, Summary Answer: The microenvironment immediately surrounding the oocyte, including the CCs and FF, is altered in adolescents undergoing fertility preservation compared to oocyte donors., What Is Known Already: Adolescents experience a period of subfecundity following menarche. Recent evidence suggests that this may be at least partially due to increased oocyte aneuploidy. Reproductive juvenescence in mammals is associated with suboptimal oocyte quality., Study Design Size Duration: This was a prospective cohort study. Adolescents (10-19 years old, n = 23) and oocyte donors (22-30 years old, n = 31) undergoing ovarian stimulation and oocyte retrieval at a single center between 1 November 2020 and 1 May 2023 were enrolled in this study., Participants/materials Setting Methods: Patient demographics, ovarian stimulation, and oocyte retrieval outcomes were collected for all participants. The transcriptome of CCs associated with mature oocytes was compared between adolescents (10-19 years old, n = 19) and oocyte donors (22-30 years old, n = 19) using bulk RNA-sequencing. FF cytokine profiles (10-19 years old, n = 18 vs 25-30 years old, n = 16) were compared using cytokine arrays., Main Results and the Role of Chance: RNA-seq analysis revealed 581 differentially expressed genes in CCs of adolescents relative to oocyte donors, with 361 genes downregulated and 220 upregulated. Genes enriched in pathways involved in cell cycle and cell division (e.g. GO: 1903047, P  = 3.5 × 10 -43 ; GO: 0051983, P  = 4.1 × 10 -30 ; GO: 0000281, P  = 7.7 × 10 -15 ; GO: 0044839, P  = 5.3 × 10 -13 ) were significantly downregulated, while genes enriched in several pathways involved in cellular and vesicle organization (e.g. GO: 0010256, P  = 1.2 × 10 -8 ; GO: 0051129, P  = 6.8 × 10 -7 ; GO: 0016050, P  = 7.4 × 10 -7 ; GO: 0051640, P  = 8.1 × 10 -7 ) were upregulated in CCs of adolescents compared to oocyte donors. The levels of nine cytokines were significantly increased in FF of adolescents compared to oocyte donors: IL-1 alpha (2-fold), IL-1 beta (1.7-fold), I-309 (2-fold), IL-15 (1.6-fold), TARC (1.9-fold), TPO (2.1-fold), IGFBP-4 (2-fold), IL-12-p40 (1.7-fold), and ENA-78 (1.4-fold). Interestingly, seven of these cytokines have known pro-inflammatory roles. Importantly, neither the CC transcriptomes nor FF cytokine profiles were different in adolescents with or without cancer., Large Scale Data: Original high-throughput sequencing data have been deposited in Gene Expression Omnibus (GEO) database with the accession number GSE265995., Limitations Reasons for Caution: This study aims to gain insights into the associated gamete quality by studying the immediate oocyte microenvironment. The direct study of oocytes is more challenging due to sample scarcity, as they are cryopreserved for future use, but would provide a more accurate assessment of oocyte reproductive potential., Wider Implications of the Findings: Our findings have implications for the adolescent fertility preservation cycles. Understanding the expected quality of cryopreserved eggs in this age group will lead to better counseling of these patients about their reproductive potential and may help to determine the number of eggs that is recommended to be banked to achieve a reasonable chance of future live birth(s)., Study Funding/competing Interests: This project was supported by Friends of Prentice organization SP0061324 (M.M.L. and E.B.), Gesualdo Family Foundation (Research Scholar: M.M.L.), and NIH/NICHD K12 HD050121 (E.B.). The authors have declared that no conflict of interest exists., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Histone methyltransferase KMT2D is one of the most frequently mutated genes in diffuse large B-cell lymphoma (DLBCL) and has been identified as an important pathogenic factor and prognostic marker. However, the biological relevance of KMT2D mutations on tumor microenvironment remains to be determined. KMT2D mutations were assessed by whole-genome/exome sequencing (WGS/WES) in 334 patients and by targeted sequencing in 427 patients with newly diagnosed DLBCL. Among all 761 DLBCL patients, somatic mutations in KMT2D were observed in 143 (18.79%) patients and significantly associated with advanced Ann Arbor stage and MYC expression ≥ 40%, as well as inferior progression-free survival and overall survival. In B-lymphoma cells, the mutation or knockdown of KMT2D inhibited methylation of lysine 4 on histone H3 (H3K4), downregulated FBXW7 expression, activated NOTCH signaling pathway and downstream MYC/TGF-β1, resulting in alterations of tumor-induced regulatory T cell trafficking. In B-lymphoma murine models established with subcutaneous injection of SU-DHL-4 cells, xenografted tumors bearing KMT2D mutation presented lower H3K4 methylation, higher regulatory T cell recruitment, thereby provoking rapid tumor growth compared with wild-type KMT2D via FBXW7-NOTCH-MYC/TGF-β1 axis., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Ovulation is a spatiotemporally coordinated process that involves several tightly controlled events, including oocyte meiotic maturation, cumulus expansion, follicle wall rupture and repair, and ovarian stroma remodeling. To date, no studies have detailed the precise window of ovulation at single-cell resolution. Here, we performed parallel single-cell RNA-seq and spatial transcriptomics on paired mouse ovaries across an ovulation time course to map the spatiotemporal profile of ovarian cell types. We show that major ovarian cell types exhibit time-dependent transcriptional states enriched for distinct functions and have specific localization profiles within the ovary. We also identified gene markers for ovulation-dependent cell states and validated these using orthogonal methods. Finally, we performed cell-cell interaction analyses to identify ligand-receptor pairs that may drive ovulation, revealing previously unappreciated interactions. Taken together, our data provides a rich and comprehensive resource of murine ovulation that can be mined for discovery by the scientific community.

Aconitum coreanum (A. coreanum), a traditional Chinese medicine, has been proved to treat ischemic stroke (IS). However, the mechanisms of A. coreanum's anti-stroke is currently unknown. This study aimed to uncover the effect and mechanisms of A. coreanum. And study raw Aconitum coreanum (RA) and steamed Aconitum coreanum (SA) and Aconitum coreanum processed with ginger and Alumen (GA) on the mechanism of the pharmacological action of treating IS. Determining whether the efficacy is affected after processing. The right unilateral ligation of the carotid artery of gerbils was used to mimic IS. The neurological function score, infarct volume, oxidative stress level and inflammatory factor expression were measured in gerbils after IS. Western blot and immunofluorescence analyses were conducted to evaluate the expression of related proteins. Metabolomic analyzes IS-related metabolic pathways in urinary metabolites. RA, SA and GA significantly improved the infarct volume and behavioral score of IS gerbils, increased the expression of brain tissue superoxide dismutase (SOD), glutathione (GSH), nitric oxide (NO) and decreased the content of malondialdehyde (MDA), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α). Western blot and immunofluorescence analysis results showed that RA, SA and GA significantly increased the expression of P-Akt, PI3K, HO-1 and KEAP1. Metabolomic studies identified 112 differential metabolites, including L-Proline, Riboflavin, Leukotriene D4, and 7-Methylxanthine, as potential biomarkers of stroke, involving 14 metabolic pathways including riboflavin metabolism, pyrimidine metabolism, and purine metabolism. Our findings indicated that A. coreanum protected against cerebral ischemia injury probably via the PI3K/Akt and KEAP1/NRF2 pathway. A. coreanum before and after processing both had a protective effect against IS brain injury in gerbils. The A. coreanum efficacy was not reduced after processing. Even compared to RA, SA had better efficacy., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Nitrate is a common contaminant in high-salinity wastewater, which has adverse effects on both the environment and human health. However, conventional biological treatment exhibits poor denitrification performance due to the high-salinity shock. In this study, an innovative approach using an electrostimulating microbial reactor (EMR) was explored to address this challenge. With a low-voltage input of 1.2 V, the EMR reached nitrate removal kinetic parameter (k NO3-N ) of 0.0166-0.0808 h -1 under high-salinities (1.5 %-6.5 %), which was higher than that of the microbial reactor (MR) (0.0125-0.0478 h -1 ). The mechanisms analysis revealed that low-voltage significantly enhanced microbial salt-in strategy and promoted the secretion of extracellular polymeric substances. Halotolerant denitrification microorganisms (Pseudomonas and Nitratireductor) were also enriched in EMR. Moreover, the EMR achieved a NO 3 -N removal efficiency of 73.64 % in treating high-salinity wastewater (salinity 4.69 %) over 18-cycles, whereas the MR only reached 54.67 %. In summary, this study offers an innovative solution for denitrification of high-salinity wastewater., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Ethnopharmacological Relevance: Alzheimer's disease (AD) is the most prevalent neurodegenerative disease among old adults. As a traditional Chinese medicine, the herbal decoction Tian-Si-Yin consists of Morinda officinalis How. and Cuscuta chinensis Lam., which has been widely used to nourish kidney. Interestingly, Tian-Si-Yin has also been used to treat dementia, depression and other neurological conditions. However, its therapeutic potential for neurodegenerative diseases such as AD and the underlying mechanisms remain unclear., Aim of the Study: To evaluate the therapeutic effect of the herbal formula Tian-Si-Yin against AD and to explore the underlying mechanisms., Materials and Methods: The N2a cells treated with amyloid β (Aβ) peptide or overexpressing amyloid precursor protein (APP) were used to establish cellular models of AD. The in vivo anti-AD effects were evaluated by using Caenorhabditis elegans and 3 × Tg-AD mouse models. Tian-Si-Yin was orally administered to the mice for 8 weeks at a dose of 10, 15 or 20 mg/kg/day, respectively. Its protective role on memory deficits of mice was examined using the Morris water maze and fear conditioning tests. Network pharmacology, proteomic analysis and ultra-high performance liquid chromatography-mass spectrometry/mass spectrometry (UHPLC-MS/MS) were used to explore the underlying molecular mechanisms, which were further investigated by Western blotting and immunohistochemistry., Results: Tian-Si-Yin was shown to improve cell viability of Aβ-treated N2a cells and APP-expressing N2a-APP cells. Tian-Si-Yin was also found to reduce ROS level and extend lifespan of transgenic AD-like C. elegans model. Oral administration of Tian-Si-Yin at medium dose was able to effectively rescue memory impairment in 3 × Tg mice. Tian-Si-Yin was further shown to suppress neuroinflammation by inhibition of glia cell activation and downregulation of inflammatory cytokines, diminishing tau phosphoralytion and Aβ deposition in the mice. Using UHPLC-MS/MS and network pharmacology technologies, 17 phytochemicals from 68 components of Tian-Si-Yin were identified as potential anti-AD components. MAPK1, BRAF, TTR and Fyn were identified as anti-AD targets of Tian-Si-Yin from network pharmacology and mass spectrum., Conclusions: This study has established the protective effect of Tian-Si-Yin against AD and demonstrates that Tian-Si-Yin is capable of improving Aβ level, tau pathology and synaptic disorder by regulating inflammatory response., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

As an important raw material for the synthesis of chemical and pharmaceutical, hazardous carcinogen p-chloronitrobenzene (p-CNB) has been widely found in high-salinity wastewater which need to be treated carefully. Due to the high-salinity shock on microorganisms, conventional microbial treatment technologies usually show poor effluent quality. This study initially investigated the p-CNB removal performance of microorganisms stimulated by 1.2 V low-voltage in high-salinity wastewater under facultative anaerobic conditions and further revealed the enhanced mechanisms. The results showed that the p-CNB removal kinetic parameter k p-CNB in the electrostimulating microorganism reactor (EMR) increased by 104.37 % to 155.30 % compared to the microorganism reactor (MR) as the control group under the varying salinities (0-45 g/L NaCl). The secretion of extracellular polymeric substances (EPS) in halotolerant microorganisms mainly enhanced by 1.2 V voltage stimulation ranging from 0 g/L NaCl to 30 g/L NaCl. Protein concentration ratio of EMR to MR in loosely bound EPS achieved maximum value of 1.77 at the salinity of 15 g/L NaCl, and the same ratio in tightly bound EPS also peaked at 1.39 under the salinity of 30 g/L NaCl. At the salinity of 45 g/L NaCl, 1.2 V voltage stimulation mainly enhanced salt-in strategy of halotolerant microorganisms, and the intracellular Na + and K + concentration ratio of EMR to MR reached maximum and minimum values of 0.65 and 1.92, respectively. Furthermore, the results of microbial metagenomic and metatranscriptomic analysis showed the halotolerant microorganisms Pseudomonas_A and Nitratireductor with p-CNB removal ability were enriched significantly under 1.2 V voltage stimulation. And the gene expression of p-CNB removal, salt-in strategy and betaine transporter were enhanced under voltage stimulation at varying salinities. Our investigation provided a new solution which combined with 1.2 V voltage stimulation and halotolerant microorganisms for the treatment of high-salinity wastewater., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Study Question: Does a chemically defined maturation medium supplemented with FGF2, LIF, and IGF1 (FLI) improve in vitro maturation (IVM) of cumulus-oocyte complexes (COCs) obtained from children, adolescents, and young adults undergoing ovarian tissue cryopreservation (OTC)?, Summary Answer: Although FLI supplementation did not increase the incidence of oocyte meiotic maturation during human IVM, it significantly improved quality outcomes, including increased cumulus cell expansion and mitogen-activated protein kinase (MAPK) expression as well as enhanced transzonal projection retraction., What Is Known Already: During OTC, COCs, and denuded oocytes from small antral follicles are released into the processing media. Recovery and IVM of these COCs is emerging as a complementary technique to maximize the fertility preservation potential of the tissue. However, the success of IVM is low, especially in the pediatric population. Supplementation of IVM medium with FLI quadruples the efficiency of pig production through improved oocyte maturation, but whether a similar benefit occurs in humans has not been investigated., Study Design, Size, Duration: This study enrolled 75 participants between January 2018 and December 2021 undergoing clinical fertility preservation through the Fertility & Hormone Preservation & Restoration Program at the Ann & Robert H. Lurie Children's Hospital of Chicago. Participants donated OTC media, accumulated during tissue processing, for research., Participants/materials, Setting, Methods: Participants who underwent OTC and include a pediatric population that encompassed children, adolescents, and young adults ≤22 years old. All participant COCs and denuded oocytes were recovered from media following ovarian tissue processing. IVM was then performed in either a standard medium (oocyte maturation medium) or one supplemented with FLI (FGF2; 40 ng/ml, LIF; 20 ng/ml, and IGF1; 20 ng/ml). IVM outcomes included meiotic progression, cumulus cell expansion, transzonal projection retraction, and detection of MAPK protein expression., Main Results and the Role of Chance: The median age of participants was 6.3 years, with 65% of them classified as prepubertal by Tanner staging. Approximately 60% of participants had been exposed to chemotherapy and/or radiation prior to OTC. On average 4.7 ± 1 COCs and/or denuded oocytes per participant were recovered from the OTC media. COCs (N = 41) and denuded oocytes (N = 29) were used for IVM (42 h) in a standard or FLI-supplemented maturation medium. The incidence of meiotic maturation was similar between cohorts (COCs: 25.0% vs 28.6% metaphase II arrested eggs in Control vs FLI; denuded oocytes: 0% vs 5.3% in Control vs FLI). However, cumulus cell expansion was 1.9-fold greater in COCs matured in FLI-containing medium relative to Controls and transzonal projection retraction was more pronounced (2.45 ± 0.50 vs 1.16 ± 0.78 projections in Control vs FLIat 16 h). Additionally, MAPK expression was significantly higher in cumulus cells obtained from COCs matured in FLI medium for 16-18 h (chemiluminescence corrected area 621,678 vs 2,019,575 a.u., P = 0.03)., Limitations, Reasons for Caution: Our samples are from human participants who exhibited heterogeneity with respect to age, diagnosis, and previous treatment history. Future studies with larger sample sizes, including adult participants, are warranted to determine the mechanism by which FLI induces MAPK expression and activation. Moreover, studies that evaluate the developmental competence of eggs derived from FLI treatment, including assessment of embryos as outcome measures, will be required prior to clinical translation., Wider Implications of the Findings: FLI supplementation may have a conserved beneficial effect on IVM for children, adolescents, and young adults spanning the agricultural setting to clinical fertility preservation., Study Funding/competing Interest(s): This work was supported by Department of Obstetrics and Gynecology startup funds (F.E.D.), Department of Surgery Faculty Practice Plan Grant and the Fertility & Hormone Preservation & Restoration Program at the Ann & Robert H. Lurie Children's Hospital of Chicago (M.M.L. and E.E.R.). M.M.L. is a Gesualdo Foundation Research Scholar. Y.Y.'s research is supported by the internal research funds provided by Colorado Center of Reproductive Medicine. Y.Y., L.D.S., R.M.R., and R.S.P. have a patent pending for FLI. The remaining authors have no conflict of interest., Trial Registration Number: N/A., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Brominated flame-retardants (BFRs) are environmental endocrine disruptors, comprising several pollutants, which potentially affect the endocrine system and cause dysfunction and disease. Widespread BFR exposure may cause multisystem toxicity, including cardiovascular toxicity in some individuals. Studies have shown that BFRs not only increase heart rate, induce arrhythmia and cardiac hypertrophy, but also cause glycolipid metabolism disorders, vascular endothelial dysfunction, and inflammatory responses, all of which potentially induce pre-pathological changes in atherosclerosis. Experimental data indicated that BFRs disrupt gene expression or signaling pathways, which cause vascular endothelial dysfunction, lipid metabolism-related disease, inflammation, and possibly atherosclerosis. Considerable evidence now suggests that BFR exposure may be a pro-atherosclerotic risk factor. In this study, we reviewed putative BFR effects underpinning pro-atherosclerosis mechanisms, and focused on vascular endothelial cell dysfunction, abnormal lipid metabolism, pro-inflammatory cytokine production and foam cell formation. Consequently, we proposed a scientific basis for preventing atherosclerosis by BFRs and provided concepts for further research., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The aim of this study is to explore the mechanism of ligustilide, the main active constituent of essential oils of traditional Chinese medicine Angelicae Sinensis Radix, on alleviating oxygen-glucose deprivation/reperfusion(OGD/R) injury in PC12 cells from the perspective of ferroptosis. OGD/R was induced in vitro, and 12 h after ligustilide addition during reperfusion, cell viability was detected by cell counting kit-8(CCK-8) assay. DCFH-DA staining was used to detect the level of intracellular reactive oxygen species(ROS). Western blot was employed to detect the expression of ferroptosis-related proteins, glutathione peroxidase 4(GPX4), transferrin receptor 1(TFR1), and solute carrier family 7 member 11(SLC7A11), and ferritinophagy-related proteins, nuclear receptor coactivator 4(NCOA4), ferritin heavy chain 1(FTH1), and microtubule-associated protein 1 light chain 3(LC3). The fluorescence intensity of LC3 protein was analyzed by immunofluorescence staining. The content of glutathione(GSH), malondialdehyde(MDA), and Fe was detected by chemiluminescent immunoassay. The effect of ligustilide on ferroptosis was observed by overexpression of NCOA4 gene. The results showed that ligustilide increased the viability of PC12 cells damaged by OGD/R, inhibited the release of ROS, reduced the content of Fe and MDA and the expression of TFR1, NCOA4, and LC3, and improved the content of GSH and the expression of GPX4, SLC7A11, and FTH1 compared with OGD/R group. After overexpression of the key protein NCOA4 in ferritinophagy, the inhibitory effect of ligustilide on ferroptosis was partially reversed, indicating that ligustilide may alleviate OGD/R injury of PC12 cells by blocking ferritinophagy and then inhibiting ferroptosis. The mechanism by which ligustilide reduced OGD/R injury in PC12 cells is that it suppressed the ferroptosis involved in ferritinophagy.

Purpose: There has been a noted parallel rise in both the use of Assisted Reproductive Technology (ART) to conceive and childhood allergies in the last few decades. The purpose of this study was to investigate the possible association between reproductive and allergy history in parents and allergies in their children., Methods: This exploratory study used a cross-sectional study design and web-based survey to collect anonymous data on demographics, allergy, and health history from parents and about each of their children under 18 years of age. Children were stratified into two groups by allergy status (yes/no), and associations between each variable and the odds of allergies were tested using univariable and multivariable mixed logistic regression models., Results: Of the 563 children in the study, 237 were reported to have allergies whereas 326 did not. Age, residential community, household income, mode of conception, paternal age at conception, biological parental allergy status, and history of asthma and eczema were significantly associated with allergies in univariable analysis. Multivariable analysis revealed household income ($50 k to $99 k vs ≥ $200 k adj OR = 2.72, 95% CI 1.11, 6.65), biological parental allergies (mother-adj OR 2.74, 95% CI 1.59, 4.72, father-adj OR 2.06, 95% CI 1.24, 3.41) and each additional year of age of children (adj OR 1.17, CI 1.10, 1.24) were significantly associated with odds of allergies in children., Conclusion: Although the exploratory nature of this convenience, snowballing sample limited the generalizability of the findings, initial observations warrant further investigation and validation in a larger more diverse population., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The neuron-glia cross-talk is critical to brain homeostasis and is particularly affected by neurodegenerative diseases. How neurons manipulate the neuron-astrocyte interaction under pathological conditions, such as hyperphosphorylated tau, a pathological hallmark in Alzheimer's disease (AD), remains elusive. In this study, we identified excessively elevated neuronal expression of adenosine receptor 1 (Adora1 or A1R) in 3×Tg mice, MAPT P301L (rTg4510) mice, patients with AD, and patient-derived neurons. The up-regulation of A1R was found to be tau pathology dependent and posttranscriptionally regulated by Mef2c via miR-133a-3p. Rebuilding the miR-133a-3p/A1R signal effectively rescued synaptic and memory impairments in AD mice. Furthermore, neuronal A1R promoted the release of lipocalin 2 (Lcn2) and resulted in astrocyte activation. Last, silencing neuronal Lcn2 in AD mice ameliorated astrocyte activation and restored synaptic plasticity and learning/memory. Our findings reveal that the tau pathology remodels neuron-glial cross-talk and promotes neurodegenerative progression. Approaches targeting A1R and modulating this signaling pathway might be a potential therapeutic strategy for AD.

Objective: Vitamin D and Toll-like receptor-4 (TLR-4) inhibition are involved in the protection of keratinocytes. The effects of combination of 1,25(OH) 2 D 3 and TLR-4 inhibitor on the protection of keratinocytes against ultraviolet radiation B (UVB) irradiation remain unclear. This study was undertaken to explore the effects of combination of 1,25(OH) 2 D 3 and TAK-242 (TLR-4 inhibitor) on the damage to HaCaT cells caused by UVB irradiation., Methods: In vitro , HaCaT cells were treated with 1,25(OH) 2 D 3 or/and TAK-242 prior to UVB irradiation at the intensity of 20 mJ/cm 2 , then the production of reactive oxygen species (ROS), cell migration, apoptosis of cells, and the expression of oxidative stress, endoplasmic reticulum stress, and apoptosis related proteins were determined., Results: Compared with the HaCaT cells treated with 1,25(OH) 2 D 3 or TAK-242, the cells treated with both 1,25(OH) 2 D 3 and TAK-242 showed, 1) significantly lower production of ROS ( P < 0.05); 2) significantly less apoptosis of HaCaT cells ( P < 0.05); 3) significantly lower expression of NF- κ B, Caspase-8, Cyto-C, Caspase-3 ( P < 0.05)., Conclusion: The combination of 1,25(OH) 2 D 3 and TAK-242 could produce a better protection for HaCaT cells via inhibiting the oxidative stress, endoplasmic reticulum stress and apoptosis than 1,25(OH) 2 D 3 or TAK-242 alone., (Copyright © 2022 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.)

Meiotic maturation and cumulus expansion are essential for the generation of a developmentally competent gamete, and both processes can be recapitulated in vitro. We used a closed time-lapse incubator (EmbryoScope+™) to establish morphokinetic parameters of meiotic progression and cumulus expansion in mice and correlated these outcomes with egg ploidy. The average time to germinal vesicle breakdown (GVBD), time to first polar body extrusion (PBE), and duration of meiosis I were 0.91 ± 0.01, 8.82 ± 0.06, and 7.93 ± 0.06 h, respectively. The overall rate of cumulus layer expansion was 0.091 ± 0.002 μm/min, and the velocity of expansion peaked during the first 8 h of in vitro maturation (IVM) and then slowed. IVM of oocytes exposed to Nocodazole, a microtubule disrupting agent, and cumulus oocyte complexes (COCs) to 4-methylumbelliferone, a hyaluronan synthesis inhibitor, resulted in a dose-dependent perturbation of morphokinetics, thereby validating the system. The incidence of euploidy following IVM was &gt;90% for both denuded oocytes and intact COCs. No differences were observed between euploid and aneuploid eggs with respect to time to GVBD (0.90 ± 0.22 vs. 0.97 ± 0.19 h), time to PBE (8.89 ± 0.98 vs. 9.10 ± 1.42 h), duration of meiosis I (8.01 ± 0.91 vs. 8.13 ± 1.38 h), and overall rate and kinetics of cumulus expansion (0.089 ± 0.02 vs 0.088 ± 0.03 μm/min) (P &gt; 0.05). These morphokinetic parameters provide novel quantitative and non-invasive metrics for the evaluation of meiotic maturation and cumulus expansion and will enable screening compounds that modulate these processes., (© The Author(s) 2022. Published by Oxford University Press behalf of Society for the Study of Reproduction.)

Background: Postoperative cognitive dysfunction (POCD) is a common complication characterized by a significant cognitive decline. Increasing evidence suggests an association between the pathogenesis of POCD and Alzheimer's disease (AD). However, a comprehensive understanding of their relationships is still lacking., Methods: First, related databases were obtained from GEO, ArrayExpress, CNGB, and DDBJ repositories. De novo analysis was performed on the raw data using a uniform bioinformatics workflow. Then, macro- and micro-level comparisons were conducted between the transcriptomic changes associated with AD and POCD. Lastly, POCD was induced in male C57BL/6j mice and the hippocampal expression levels of mRNAs of interest were verified by PCR and compared to those in AD congenic models., Results: There was a very weak correlation in the fold-changes in protein-coding transcripts between AD and POCD. Overall pathway-level comparison suggested that AD and POCD are two disease entities. Consistently, in the classical AD pathway, the mitochondrial complex and tubulin mRNAs were downregulated in both the POCD hippocampus and cortex. POCD and AD hippocampi might share the same pathways, such as tryptophan metabolism, but undergo different pathological changes in phagosome and transferrin endocytosis pathways. The core cluster in the hippocampal network was mainly enriched in mitosis-related pathways. The hippocampal expression levels of genes of interest detected by PCR showed good consistency with those generated by high throughput platforms., Conclusion: POCD and AD are associated with different transcriptomic changes despite their similar clinical manifestations. This study provides a valuable resource for identifying biomarkers and therapeutic targets for POCD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Wang, Yuan, Zhang, Zhang and Zhou.)

Objective: To investigate the clinicopathological characteristics and prognosis of high-grade B-cell lymphoma (HGBL) involving combined rearrangements of MYC, bcl-2 and bcl-6. Methods: A total of 1 138 cases of large B cell lymphoma (LBL) that were treated at the Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine from January 2017 to September 2020 were analyzed using fluorescence in situ hybridization (FISH) with probes against MYC, bcl-2 and bcl-6. The clinical and pathological data of the 45 patients with HGBL that had rearrangements of MYC and bcl-2 and/or bcl-6 were collected and retrospectively analyzed. Results: Among the 1 138 LBL, 45 (4.0%) cases had combined rearrangements of MYC, bcl-2 and/or bcl-6 that included 6 HGBL cases with MYC, bcl-2 and bcl-6 rearrangements, 14 HGBL cases with MYC and bcl-2 rearrangements, and 25 HGBL cases with MYC and bcl-6 rearrangements. Of these 45 patients, 29 patients were male, and 16 patients were female, aged 29 to 83 years. HGBL with MYC, bcl-2 and bcl-6 rearrangements and HGBL with MYC and bcl-2 rearrangement were reclassified as the germinal center B-cell (GCB) subtype using the Hans algorithm. HGBL with MYC and bcl-6 rearrangement were reclassified as the GCB subtype (68.0%) and the non-GCB subtype (32.0%). The vast majority of HGBL cases had a high Ki-67 proliferation index. Most HGBL patients had advanced stage disease with a high IPI score and an increased LDH level. Also, some patients had clinical features including elevated plasma β2-microglobulin levels, B symptoms, and bone marrow involvement. The IPI scores and LDH levels were significantly different between the HGBL cases with MYC, bcl-2 and bcl-6 rearrangements and the HGBL cases with MYC and bcl-6 rearrangements ( P <0.05). Compared with the HGBL cases with MYC, bcl-2 and bcl-6 rearrangements, the HGBL cases with MYC and bcl-2 or bcl-6 rearrangements had a lower incidence of bone marrow involvement ( P <0.05). There were no significant differences in the prognosis among HGBL cases with MYC, bcl-2 and bcl-6 rearrangements, the cases with MYC and bcl-2 rearrangements, and the cases with MYC and bcl-6 rearrangements ( P >0.05). Conclusions: HGBL with MYC, bcl-2 and/or bcl-6 rearrangements are rare types of B-cell lymphoma with high degree of malignancy and have a short overall survival. To reduce misdiagnosis and improve diagnostic accuracy, it is necessary to assess the patients' clinical features and conduct histopathological, immunohistochemical and FISH analyses.

Objective: The present research analyzed the correlation between N6-methyladenosine (m6A) methylation and ferroptosis associated genes (FAGs) in acute kidney injury (AKI) patients., Methods: Bioinformatics analysis of microarray profiles (GSE30718) was performed to select differential expression genes (DEGs). FAGs are derived from systematic analysis of the aberrances and functional implications. The m6A methylation related genes were derived from the molecular characterization and clinical significance of m6A modulators. The multi-gene correlation of ferroptosis and M6A methylation modification was displayed. Then, the CIBERSORT algorithm was used to analyze the proportions of 22 immune cell infiltration., Results: In total, 349 DEGs were extracted between the AKI and control samples, among which 172 genes were upregulated and 177 were downregulated. FAGs (SLC1A5, CARS, SAT1, ACSL4, NFE2L2, TFRC, and MT1G) and m6A methylation related genes (YTHDF3, WTAP, and IGF2BP3) were significantly increased in AKI patients (p < 0.05). FAGs (SAT1, ACSL4, and NFE2L2) were positively correlated with the expression level of m6A methylation genes (p < 0.05). NFE2L2 has high diagnostic value, and the level of NFE2L2 was negatively correlated with the degree of follicular helper T (TFH) cell infiltration., Conclusion: Our research could provide a new theoretical basis for the pathogenesis and immune mechanism of AKI., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

As organisms age, their resistance to stress decreases while their risk of disease increases. This can be shown in patients with Werner syndrome (WS), which is a genetic disease characterized by accelerated aging along with increased risk of cancer and metabolic disease. WS is caused by mutations in WRN , a gene involved in DNA replication and repair. Recent research has shown that WRN mutations contribute to multiple hallmarks of aging including genomic instability, telomere attrition, and mitochondrial dysfunction. However, questions remain regarding the onset and effect of stress on early aging. We used a fly model of WS ( WRNexo Δ ) to investigate stress response during different life stages and found that stress sensitivity varies according to age and stressor. While larvae and young WRNexo Δ adults are not sensitive to exogenous oxidative stress, high antioxidant activity suggests high levels of endogenous oxidative stress. WRNexo Δ adults are sensitive to stress caused by elevated temperature and starvation suggesting abnormalities in energy storage and a possible link to metabolic dysfunction in WS patients. We also observed higher levels of sleep in aged WRNexo Δ adults suggesting an additional adaptive mechanism to protect against age-related stress. We suggest that stress response in WRNexo Δ is multifaceted and evokes a systemic physiological response to protect against cellular damage. These data further validate WRNexo Δ flies as a WS model with which to study mechanisms of early aging and provide a foundation for development of treatments for WS and similar diseases.

With a pot experiment, the Biolog microplate and phospholipid fatty acid (PLFA) technology were used to explore whether the application of bacteria, Bacillus amyloliquefaciens (YB706) and Burkholderia (BK8), could improve the soil nutrient, microbial community and growth of Casuarina equisetifolia . The results showed that the concentrations of soil alkali-hydrolyzed nitrogen and available phosphorus of C. equisetifolia treated with YB706 and BK8 increased significantly compared with the control (CK), but the concentrations of total nitrogen, total phosphorus, total potassium and available potassium changed little, plant height increased by 59.1% and 63.9%, respectively, and the chlorophyll content of plant treated with BK8 increased by 81.9%. The average well color development values showed a pattern of YB706>CK>BK8. The utilization rate of different carbon sources showed the same trend except the amino acids. Both YB706 and BK8 treatments significantly increased the richness and quantity of soil microorganisms. The PLFA of all kinds of microorganisms was BK8>YB706>CK except actinomycetes. The ratio of soil fungi to bacteria was increased compared with CK. The Simpson, Shannon, Brillouin and McIntosh indices of rhizosphere soil microbial community in YB706 and BK8 treatments were significantly increased. Our results suggested that application of YB706 and BK8 could improve the growth rate of C. equisetifolia seedlings, effectively increase the contents of soil available nutrients, increase soil microbial diversity, and improve soil microbial environment.

The extracellular matrix (ECM) is a major component of the ovarian stroma. Collagen and hyaluronan (HA) are critical ovarian stromal ECM molecules that undergo age-dependent changes in the mouse and human. How these matrix components are regulated and organized in other mammalian species with reproductive characteristics similar to women such as cows and pigs, has not been systematically investigated. Therefore, we performed histological, molecular, and biochemical analyses to characterize collagen and HA in these animals. Bovine ovaries had more collagen than porcine ovaries when assessed biochemically, and this was associated with species-specific differences in collagen gene transcripts: Col3a1 was predominant in cow ovaries while Col1a1 was predominant in pig ovaries. We also observed more HA in the porcine vs. bovine ovary. HA was distributed across three molecular weight ranges (<100 kDa, 100-300 kDa, and >300 kDa) in ovarian tissue and follicular fluid, with tissue having more >300 kDa HA than the other two ranges. Transcripts for HA synthesis and degradation enzymes, Has3 and Hyal2 , respectively, were predominant in cow ovaries, whereas Has2 , Kiaa1199, and Tmem2 tended to be predominant in pig ovaries. Together, our findings have implications for the composition, organization, and regulation of the ovarian ECM in large mammalian species, including humans.

Egg quality dictates fertility outcomes, and although there is a well-documented decline with advanced reproductive age, how it changes during puberty is less understood. Such knowledge is critical, since advances in Assisted Reproductive Technologies are enabling pre- and peri-pubertal patients to preserve fertility in the medical setting. Therefore, we investigated egg quality parameters in a mouse model of the pubertal transition or juvenescence (postnatal day; PND 11-40). Animal weight, vaginal opening, serum inhibin B levels, oocyte yield, oocyte diameter, and zona pellucida thickness increased with age. After PND 15, there was an age-associated ability of oocytes to resume meiosis and reach metaphase of meiosis II (MII) following in vitro maturation (IVM). However, eggs from the younger cohort (PND 16-20) had significantly more chromosome configuration abnormalities relative to the older cohorts and many were at telophase I instead of MII, indicative of a cell cycle delay. Oocytes from the youngest mouse cohorts originated from the smallest antral follicles with the fewest cumulus layers per oocyte, suggesting a more developmentally immature state. RNA Seq analysis of oocytes from mice at distinct ages revealed that the genes involved in cellular growth signaling pathways (PI3K, mTOR, and Hippo) were consistently repressed with meiotic competence, whereas genes involved in cellular communication were upregulated in oocytes with age. Taken together, these data demonstrate that gametes harvested during the pubertal transition have low meiotic maturation potential and derive from immature follicular origins., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kusuhara, Babayev, Zhou, Singh, Gerton and Duncan.)

We recently engineered the first female reproductive tract on a chip (EVATAR), to enable sex-based ex vivo research. To increase the scalability and accessibility of EVATAR, we turned to 3D printing (3DP) technologies, selecting two biocompatible 3DP resins, Dental SG (DSG) and Dental LT (DLT) to generate 3DP microphysiologic platforms. Due to the known sensitivity of reproductive cells to leachable compounds, we first screened for toxicity of these biomaterials using an in vitro mammalian oocyte maturation assay. Culture of mouse oocytes in 3DP plates using conventionally treated DSG resin resulted in rapid oocyte degeneration. Oxygen plasma treatment of the surface of printed DSG resin prevented this degeneration, and the majority of the resulting oocytes progressed through meiosis in vitro. However, 57.0% ± 37.2% of the cells cultured in the DSG resin plates exhibited abnormal chromosome morphology compared to 19.4% ± 17.3% of controls cultured in polystyrene. All tested DLT resin conditions, including plasma treatment, resulted in complete and rapid oocyte degeneration. To identify the ovo-toxic component of DLT, we analyzed DLT leachate using mass spectroscopy. We identified Tinuvin 292, a commercial light stabilizer, as a major component of the DLT leachate, which resulted in a dose-dependent disruption of meiotic progression and increase in chromosomal abnormalities with oocyte exposure, showing significant ovo-toxicity in mammals. Severe reproductive toxicity induced by in vitro exposure to these 3D-printed resins highlights potential risks of deploying insufficiently characterized materials for biomedical applications and underscores the need for more rigorous evaluation and designation of biocompatible materials., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Cholinergic degeneration is one of the key pathological hallmarks of Alzheimer's disease (AD), a condition that is characterized by synaptic disorders and memory impairments. Nerve growth factor (NGF) is secreted in brain regions that receive projections from the basal forebrain cholinergic neurons. The trophic effects of NGF rely on the appropriate maturation of NGF from its precursor, proNGF. The ratio of proNGF/NGF is known to be increased in patients with AD; however, the mechanisms that underlie this observation have yet to be elucidated. Here, we demonstrated that levels of miR-144-3p are increased in the hippocampi and the medial prefrontal cortex of an APP/PS1 mouse model of AD. These mice also exhibited cholinergic degeneration (including the loss of cholinergic fibers, the repression of choline acetyltransferase (ChAT) activity, the reduction of cholinergic neurons, and an increased number of dystrophic neurites) and synaptic/memory deficits. The elevated expression of miR-144-3p specifically targets the mRNA of tissue plasminogen activator (tPA) and reduces the expression of tPA, thus resulting in the abnormal maturation of NGF. The administration of miR-144-3p fully replicated the cholinergic degeneration and synaptic/memory deficits observed in the APP/PS1 mice. The injection of an antagomir of miR-144-3p into the hippocampi partially rescued cholinergic degeneration and synaptic/memory impairments by restoring the levels of tPA protein and by correcting the ratio of proNGF/NGF. Collectively, our research revealed potential mechanisms for the disturbance of NGF maturation and cholinergic degeneration in AD and identified a potential therapeutic target for AD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhou, Zhang, Tan, Huang, Zhou, Liu, Lu, Zhu, Yao and Liu.)

Background/aims: Diabetic nephropathy (DN) is one of the main causes of end-stage kidney disease worldwide. Emerging studies have suggested that its pathogenesis is distinct from nondiabetic renal diseases in many aspects. However, it still lacks a comprehensive understanding of the unique molecular mechanism of DN., Methods: A total of 255 Affymetrix U133 microarray datasets (Affymetrix, Santa Calra, CA, USA) of human glomerular and tubulointerstitial tissues were collected. The 22 215 Affymetrix identifiers shared by the Human Genome U133 Plus 2.0 and U133A Array were extracted to facilitate dataset pooling. Next, a linear model was constructed and the empirical Bayes method was used to select the differentially expressed genes (DEGs) of each kidney disease. Based on these DEG sets, the unique DEGs of DN were identified and further analyzed using gene ontology and pathway enrichment analysis. Finally, the protein-protein interaction networks (PINs) were constructed and hub genes were selected to further refine the results., Results: A total of 129 and 1251 unique DEGs were identified in the diabetic glomerulus (upregulated n  = 83 and downregulated n  = 203) and the diabetic tubulointerstitium (upregulated n  = 399 and downregulated n  = 874), respectively. Enrichment analysis revealed that the DEGs in the diabetic glomerulus were significantly associated with the extracellular matrix, cell growth, regulation of blood coagulation, cholesterol homeostasis, intrinsic apoptotic signaling pathway and renal filtration cell differentiation. In the diabetic tubulointerstitium, the significantly enriched biological processes and pathways included metabolism, the advanced glycation end products-receptor for advanced glycation end products signaling pathway in diabetic complications, the epidermal growth factor receptor (EGFR) signaling pathway, the FoxO signaling pathway, autophagy and ferroptosis. By constructing PINs, several nodes, such as AGR2, CSNK2A1, EGFR and HSPD1, were identified as hub genes, which might play key roles in regulating the development of DN., Conclusions: Our study not only reveals the unique molecular mechanism of DN but also provides a valuable resource for biomarker and therapeutic target discovery. Some of our findings are promising and should be explored in future work., (© The Author(s) 2021. Published by Oxford University Press on behalf of ERA-EDTA.)

Incidence of intracerebral hemorrhage (ICH) and brain iron accumulation increases with age. Excess iron accumulation in brain tissues post-ICH induces oxidative stress and neuronal damage. However, the mechanisms underlying iron deregulation in ICH, especially in the aged ICH model have not been well elucidated. Ferroportin1 (Fpn) is the only identified nonheme iron exporter in mammals to date. In our study, we reported that Fpn was significantly upregulated in perihematomal brain tissues of both aged ICH patients and mouse model. Fpn deficiency induced by injecting an adeno-associated virus (AAV) overexpressing cre recombinase into aged Fpn-floxed mice significantly worsened the symptoms post-ICH, including hematoma volume, cell apoptosis, iron accumulation, and neurologic dysfunction. Meanwhile, aged mice pretreated with a virus overexpressing Fpn showed significant improvement of these symptoms. Additionally, based on prediction of website tools, expression level of potential miRNAs in ICH tissues and results of luciferase reporter assays, miR-124 was identified to regulate Fpn expression post-ICH. Higher serum miR-124 levels were correlated with poor neurologic scores of aged ICH patients. Administration of miR-124 antagomir enhanced Fpn expression and attenuated iron accumulation in aged mice model. Both apoptosis and ferroptosis, but not necroptosis, were regulated by miR-124/Fpn signaling manipulation. Our study demonstrated the critical role of miR-124/Fpn signaling in iron metabolism and neuronal death post-ICH in aged murine model. Thus, Fpn upregulation or miR-124 inhibition might be promising therapeutic approachs for this disease., (© 2020 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) are orally active first-in-class new generation drugs for renal anemia. This extensive meta-analysis of randomized controlled trials (RCTs) was designed to provide clear information on the efficacy and safety of HIF-PHIs on anemia in chronic kidney disease (CKD) patients. Searches included PubMed, Web of Science, Ovid MEDLINE, and Cochrane Library database up to October 2019. RCTs of patients with CKD comparing HIF-PHIs with erythropoiesis-stimulating agents (ESAs) or placebo in the treatment of anemia. The primary outcome was hemoglobin change from baseline (Hb CFB); the secondary outcomes included iron-related parameters and the occurrence of each adverse event. 26 trials in 17 articles were included, with a total of 2804 dialysis or patients with CKD. HIF-PHIs treatment produced a significant beneficial effect on Hb CFB compared with the placebo group (MD, 0.69; 95% CI, 0.36 to 1.02). However, this favored effect of HIF-PHIs treatment was not observed in subgroup analysis among trials compared with ESAs (MD, 0.06; 95% CI, -0.20 to 0.31). The significant reduction in hepcidin by HIF-PHIs was observed in all subgroups when compared with the placebo group, whereas this effect was observed only in NDD-CKD patients when compared with ESAs. HIF-PHIs increased the risk of nausea (RR, 2.20; 95% CI, 1.06 to 4.53) and diarrhea (RR, 1.75; 95% CI, 1.06 to 2.92). We conclude that orally given HIF-PHIs are at least as efficacious as ESAs treatment to correct anemia short term in patients with CKD. In addition, HIF-PHIs improved iron metabolism and utilization in patients with CKD.

Fibrosis is a hallmark of aging tissues which often leads to altered architecture and function. The ovary is the first organ to show overt signs of aging, including increased fibrosis in the ovarian stroma. How this fibrosis affects ovarian biomechanics and the underlying mechanisms are unknown. Using instrumental indentation, we demonstrated a quantitative increase in ovarian stiffness, as evidenced by an increase in Young's modulus, when comparing ovaries from reproductively young (6-12 weeks) and old (14-17 months) mice. This ovarian stiffness was dependent on collagen because ex vivo enzyme-mediated collagen depletion in ovaries from reproductively old mice restored their collagen content and biomechanical properties to those of young controls. In addition to collagen, we also investigated the role of hyaluronan (HA) in regulating ovarian stiffness. HA is an extracellular matrix glycosaminoglycan that maintains tissue homeostasis, and its loss can change the biomechanical properties of tissues. The total HA content in the ovarian stroma decreased with age, and this was associated with increased hyaluronidase (Hyal1) and decreased hyaluronan synthase (Has3) expression. These gene expression differences were not accompanied by changes in ovarian HA molecular mass distribution. Furthermore, ovaries from mice deficient in HAS3 were stiffer compared to age-matched WT mice. Our results demonstrate that the ovary becomes stiffer with age and that both collagen and HA matrices are contributing mechanisms regulating ovarian biomechanics. Importantly, the age-associated increase in collagen and decrease in HA are conserved in the human ovary and may impact follicle development and oocyte quality., (© 2020 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Renal ischemia/reperfusion (I/R) injury is a major cause of acute kidney injury (AKI), characterized by tubulointerstitial inflammation. Currently, progress in developing effective therapies to prevent or ameliorate AKI by anti-inflammation remains slow. Emerging studies have suggested that NLRP3 (the NOD-, LRR- and pyrin domain-containing 3) inflammasome plays a key role in a wide spectrum of kidney disease models including I/R injury. In this study, we investigated the renal protective effects of A68930, a specific agonist for the D-1 dopamine receptor (DRD1), which was recently recognized to downregulate NLRP3 inflammasome via DRD1 signaling. AKI was induced by renal I/R injury and A68930 was intraperitoneally injected 3 times after renal reperfusion. We showed that A68930 significantly ameliorated renal dysfunction. Meanwhile, A68930 markedly reduced macrophages and T cells infiltration, renal pro-inflammatory cytokines production (TNF-α, IL-6, IL-1β), serum pro-inflammatory cytokine (TNF-α and IL-6) and NLRP3 inflammasome activation. Additionally, A68930 attenuated I/R-induced mitochondria injury, which was observed by transmission electron microscopy. In summary, our results demonstrated that activation of DRD1 by A68930 inhibited renal and systematic inflammation, and improved kidney function in I/R induced AKI model, which was probably related to the inhibition of the NLRP3 inflammasome activation., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2020 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Aging is associated with reduced tissue remodeling efficiency and increased fibrosis, characterized by excess collagen accumulation and altered matrix degradation. Ovulation, the process by which an egg is released from the ovary, is one of the most dynamic cycles of tissue wounding and repair. Because the ovary is one of the first organs to age, ovulation and ovarian wound healing is impaired with advanced reproductive age. To test this hypothesis, we induced superovulation in reproductively young and old mice and determined the numbers of eggs ovulated and corpora lutea (CLs), the progesterone producing glands formed post-ovulation. Reproductively old mice ovulated fewer eggs and had fewer CLs relative to young controls. Moreover, reproductively old mice exhibited a greater number of oocytes trapped within CLs and expanded cumulus oocyte complexes within unruptured antral follicles, indicative of failed ovulation. In addition, post-ovulatory tissue remodeling was compromised with age as evidenced by reduced CL vasculature, increased collagen, decreased hyaluronan, decreased cell proliferation and apoptosis, impaired wound healing capacity, and aberrant morphology of the ovarian surface epithelium (OSE). These findings demonstrate that ovulatory dysfunction is an additional mechanism underlying the age-related loss of fertility beyond the reduction of egg quantity and quality.

The ovarian stroma, the microenvironment in which female gametes grow and mature, becomes inflamed and fibrotic with age. Hyaluronan is a major component of the ovarian extracellular matrix (ECM), and in other aging tissues, accumulation of low molecular weight (LMW) hyaluronan fragments can drive inflammation. Thus, we hypothesized that LMW hyaluronan fragments contribute to female reproductive aging by stimulating an inflammatory response in the ovarian stroma and impairing gamete quality. To test this hypothesis, isolated mouse ovarian stromal cells or secondary stage ovarian follicles were treated with physiologically relevant (10 or 100 μg/mL) concentrations of 200 kDa LMW hyaluronan. In ovarian stromal cells, acute LMW hyaluronan exposure, at both doses, resulted in the secretion of a predominantly type 2 (Th2) inflammatory cytokine profile as revealed by a cytokine antibody array of conditioned media. Additional qPCR analyses of ovarian stromal cells demonstrated a notable up-regulation of the eotaxin receptor Ccr3 and activation of genes involved in eosinophil recruitment through the IL5-CCR3 signaling pathway. These findings were consistent with an age-dependent increase in ovarian stromal expression of Ccl11, a major CCR3 ligand. When ovarian follicles were cultured in 10 or 100 μg/mL LMW hyaluronan for 12 days, gametes with compromised morphology and impaired meiotic competence were produced. In the 100 μg/mL condition, LMW hyaluronan induced premature meiotic resumption, ultimately leading to in vitro aging of the resulting eggs. Further, follicles cultured in this LMW hyaluronan concentration produced significantly less estradiol, suggesting compromised granulosa cell function. Taken together, these data demonstrate that bioactive LMW hyaluronan fragments may contribute to reproductive aging by driving an inflammatory stromal milieu, potentially through eosinophils, and by directly compromising gamete quality through impaired granulosa cell function., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results

Background: Tuberculosis (TB) has raised major global health concerns, especially for that caused by drug-resistant Mycobacterium tuberculosis (M. tuberculosis). The control of TB was hampered by time-consuming and insensitive diagnostic methods. GeneChip analysis is a rapid method for screening and identifying the gene mutations of M. tuberculosis. However, there was little relevant information about GeneChip analysis of M. tuberculosis in China., Methods: To compare the performance of GeneChip analysis in the diagnosis of drug-resistant M. tuberculosis with traditional drug susceptibility testing (DST), 1,747 sputum specimens from 2014 to 2016 in Lianyungang of China were retrospectively analyzed., Results: GeneChip analysis showed that the gene mutation site of M. tuberculosis to RFP resistance was 46.37% in rpoB 531 (TCG→TTG), and INH resistance was 69.89% in katG 315 (AGC→ACC). There was not significant different between GeneChip analysis and DST in detecting the resistance of M. tuberculosis to RPF or INH., Conclusions: GeneChip analysis could be regarded as a rapid and recommended method for early screening and identifying the drug resistance of M. tuberculosis.

Neurotoxicity is one of the major pathological changes in multiple neurological disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD), the second popular neurodegenerative disease in aged people. It is known that the AD and PD share the similar neuropathological hallmarks, such as the oxidative stress, loss of specific neurons, and aggregation of specific proteins. However, there are no effective therapeutic drugs for both AD and PD yet. Oxytocin (OXT) is a small peptide with 9 amino acids that is neuroprotective to many neurological disorders. Whether OXT administration confers neuroprotection to 1-methyl-4-phenyl-1, 2, 3, 6- tetrahydropyridine (MPTP)-induced neurotoxicity in mice are still not known. In this study, we first found that the OXT levels are decreased in MPTP mice. Supplementation with OXT effectively rescues the locomotor disabilities and anxiety-like behaviors in MPTP mice. OXT also alleviates the hyperphosphorylation of α-synuclein at S129 site and the loss of dopaminergic neurons in the substantia nigra pars compacta, as well as the oxidative stress in the MPTP mice, and alleviates both oxidative stress and cell cytotoxicity in vitro. Furthermore, we found that OXT could inhibit the miR-26a/DAPK1 signal pathway in MPTP mice. In summary, our study demonstrates protective effects of OXT in MPTP mice and that miR-26a/DAPK1 signaling pathway may play an important role in mediating the protection of OXT.

Werner syndrome (WS) is an autosomal recessive progeroid disease characterized by patients' early onset of aging, increased risk of cancer and other age-related pathologies. WS is caused by mutations in WRN, a RecQ helicase that has essential roles responding to DNA damage and preventing genomic instability. While human WRN has both an exonuclease and helicase domain, Drosophila WRNexo has high genetic and functional homology to only the exonuclease domain of WRN. Like WRN-deficient human cells, Drosophila WRNexo null mutants (WRNexo Δ ) are sensitive to replication stress, demonstrating mechanistic similarities between these two models. Compared to age-matched wild-type controls, WRNexo Δ flies exhibit increased physiological signs of aging, such as shorter lifespans, higher tumor incidence, muscle degeneration, reduced climbing ability, altered behavior, and reduced locomotor activity. Interestingly, these effects are more pronounced in females suggesting sex-specific differences in the role of WRNexo in aging. This and future mechanistic studies will contribute to our knowledge in linking faulty DNA repair mechanisms with the process of aging., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Although glucocorticoids are the mainstays in the treatment of renal diseases for decades, the dose dependent side effects have largely restricted their clinical use. Microvesicles (MVs) are small lipid-based membrane-bound particles generated by virtually all cells. Here we show that RAW 264.7 macrophage cell-derived MVs can be used as vectors to deliver dexamethasone (named as MV-DEX) targeting the inflamed kidney efficiently. Methods : RAW macrophages were incubated with dexamethasone and then MV-DEX was isolated from the supernatants by centrifugation method. Nanoparticle tracking analysis, transmission electron microscopy, western blot and high-performance liquid chromatography were used to analyze the properties of MV-DEX. The LC-MS/MS was applied to investigate the protein compositions of MV-DEX. Based on the murine models of LPS- or Adriamycin (ADR)-induced nephropathy or in-vitro culture of glomerular endothelial cells, the inflammation-targeting characteristics and the therapeutic efficacy of MV-DEX was examined. Finally, we assessed the side effects of chronic glucocorticoid therapy in MV-DEX-treated mice. Results : Proteomic analysis revealed distinct integrin expression patterns on the MV-DEX surface, in which the integrin α L β 2 (LFA-1) and α 4 β 1 (VAL-4) enabled them to adhere to the inflamed kidney. Compared to free DEX treatment, equimolar doses of MV-DEX significantly attenuated renal injury with an enhanced therapeutic efficacy against renal inflammation and fibrosis in murine models of LPS- or ADR-induced nephropathy. In vitro , MV-DEX with about one-fifth of the doses of free DEX achieved significant anti-inflammatory efficacy by inhibiting NF-κB activity. Mechanistically, MV-DEX could package and deliver glucocorticoid receptors to renal cells, thereby, increasing cellular levels of the receptor and improving cell sensitivity to glucocorticoids. Notably, delivering DEX in MVs significantly reduced the side effects of chronic glucocorticoid therapy (e.g., hyperglycemia, suppression of HPA axis). Conclusion : In summary, macrophage-derived MVs efficiently deliver DEX into the inflamed kidney and exhibit a superior capacity to suppress renal inflammation and fibrosis without apparent glucocorticoid adverse effects. Our findings demonstrate the effectiveness and security of a novel drug delivery strategy with promising clinical applications., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Background: Reproductive aging is a robust phenotype that occurs in all females and is characterized by a significant reduction in gamete quantity and quality, which can have negative consequences on both endocrine function and fertility. Age-associated differences in the oocyte, follicle, and ovary have been well-documented, but how the broader environment changes with age is less well understood. Fat is one of the largest organs in the body, and peri-gonadal adipose tissue surrounds the rodent ovary and comprises a local ovarian environment. The goal of this study was to characterize how peri-ovarian adipose tissue changes with advanced reproductive age., Methods: We isolated peri-gonadal adipose tissue from two cohorts of CB6F1 mice: reproductively young (6-12 weeks) and reproductively old (14-17 months). A comparative histological analysis was performed to evaluate adipocyte architecture. We then extracted lipids from the tissue and performed multiple reaction monitoring (MRM)-profiling, a mass spectrometry-based method of metabolite profiling, to compare the lipid profiles of peri-gonadal adipose tissue in these age cohorts., Results: We found that advanced reproductive age was associated with adipocyte hypertrophy and a corresponding decrease in the number of adipocytes per area. Of the 10 lipid classes examined, triacylglycerols (TAGs) had significantly different profiles between young and old cohorts, despite quantitative analysis revealing a decrease in the total amount of TAGs per weight of peri-gonadal adipose tissue with age., Conclusions: These findings pinpoint age-associated physiological changes in peri-gonadal adipose tissue with respect to adipocyte morphology and lipid profiles and lay the foundation for future studies to examine how these alterations may influence both adipocyte and ovarian function.

Objective: Previous studies have indicated that the plasticizer di (2-ethylhexyl) phthalate (DEHP) affects lipid accumulation; however, its underlying mechanism remains unclear. We aim to clarify the effect of DEHP on lipid metabolism and the role of TYK2/STAT1 and autophagy., Methods: In total, 160 Wistar rats were exposed to DEHP [0, 5, 50, 500 mg/(kg•d)] for 8 weeks. Lipid levels, as well as mRNA and protein levels of TYK2, STAT1, PPARγ, AOX, FAS, LPL, and LC3 were detected., Results: The results indicate that DEHP exposure may lead to increased weight gain and altered serum lipids. We observed that DEHP exposure affected liver parenchyma and increased the volume or number of fat cells. In adipose tissue, decreased TYK2 and STAT1 promoted the expression of PPARγ and FAS. The mRNA and protein expression of LC3 in 50 and 500 mg/(kg•d) groups was increased significantly. In the liver, TYK2 and STAT1 increased compensatorily; however, the expression of FAS and AOX increased, while LPL expression decreased. Joint exposure to both a high-fat diet and DEHP led to complete disorder of lipid metabolism., Conclusion: It is suggested that DEHP induces lipid metabolism disorder by regulating TYK2/STAT1. Autophagy may play a potential role in this process as well. High-fat diet, in combination with DEHP exposure, may jointly have an effect on lipid metabolism disorder., (Copyright © 2019 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.)

Meiotic maturation and fertilization are metabolically demanding processes, and thus the mammalian oocyte is highly susceptible to changes in nutrient availability. O-GlcNAcylation-the addition of a single sugar residue (O-linked β-N-acetylglucosamine) on proteins-is a posttranslational modification that acts as a cellular nutrient sensor and likely modulates the function of oocyte proteins. O-GlcNAcylation is mediated by O-GlcNAc transferase (OGT), which adds O-GlcNAc onto proteins, and O-GlcNAcase (OGA), which removes it. Here we investigated O-GlcNAcylation dynamics in bovine and human oocytes during meiosis and determined the developmental sequelae of its perturbation. OGA, OGT, and multiple O-GlcNAcylated proteins were expressed in bovine cumulus oocyte complexes (COCs), and they were localized throughout the gamete but were also enriched at specific subcellular sites. O-GlcNAcylated proteins were concentrated at the nuclear envelope at prophase I, OGA at the cortex throughout meiosis, and OGT at the meiotic spindles. These expression patterns were evolutionarily conserved in human oocytes. To examine O-GlcNAc function, we disrupted O-GlcNAc cycling during meiotic maturation in bovine COCs using Thiamet-G (TMG), a highly selective OGA inhibitor. Although TMG resulted in a dramatic increase in O-GlcNAcylated substrates in both cumulus cells and the oocyte, there was no effect on cumulus expansion or meiotic progression. However, zygote development was significantly compromised following in vitro fertilization of COCs matured in TMG due to the effects on sperm penetration, sperm head decondensation, and pronuclear formation. Thus, proper O-GlcNAc homeostasis during meiotic maturation is important for fertilization and pronuclear stage development., (© 2019 Wiley Periodicals, Inc.)

Impairments of dendritic trees and spines have been found in many neurodegenerative diseases, including Alzheimer's disease (AD), in which the deficits of melatonin signal pathway were reported. Melatonin receptor 2 (MT2) is widely expressed in the hippocampus and mediates the biological functions of melatonin. It is known that melatonin application is protective to dendritic abnormalities in AD. However, whether MT2 is involved in the neuroprotection and the underlying mechanisms are not clear. Here, we first found that MT2 is dramatically reduced in the dendritic compartment upon the insult of oligomer Aβ. MT2 activation prevented the Aβ-induced disruption of dendritic complexity and spine. Importantly, activation of MT2 decreased cAMP, which in turn inactivated transcriptional factor CCAAT/enhancer-binding protein α(C/EBPα) to suppress miR-125b expression and elevate the expression of its target, GluN2A. In addition, miR-125b mimics fully blocked the protective effects of MT2 activation on dendritic trees and spines. Finally, injection of a lentivirus containing a miR-125b sponge into the hippocampus of APP/PS1 mice effectively rescued the dendritic abnormalities and learning/memory impairments. Our data demonstrated that the cAMP-C/EBPα/miR-125b/GluN2A signaling pathway is important to the neuroprotective effects of MT2 activation in Aβ-induced dendritic injuries and learning/memory disorders, providing a novel therapeutic target for the treatment of AD synaptopathy., (© 2019 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Artemisinin (Art) is isolated from Artemisia annua L. and known as the most effective antimalaria drugs. Previous studies demonstrated that it could exert an immune-regulatory effect on autoimmune diseases. In this study, we first investigated its potential role in tubulointerstitial inflammation and fibrosis in rats with 5/6 nephrectomy. Subtotal nephrectomized (SNx) rats were orally administered Art (100 mg·kg -1 ·d - 1) for 16 weeks. Blood and urine samples were collected for biochemical examination. Kidney tissues were collected for immunohistochemistry and Western blot analyses. Ang II-induced injury of the human kidney 2 (HK-2) cells was used for in vitro study. It was shown that Art could significantly attenuate the renal function decline in SNx rats compared with control. More importantly, Art treatment significantly reduced the tubulointerstitial inflammation and fibrosis, as demonstrated by the evaluation of renal pathology. Furthermore, Art inhibited the activation of NLRP3 inflammasome and NF-κB in the kidneys. In in vitro study, Art pretreatment could significantly prevent the activation of NLRP3 inflammasome and NF-κB in Ang II-treated HK-2 cells, while BAY11-7082 (an inhibitor of NF-κB) significantly inhibited Ang II-induced NLRP3 inflammasome activation. This study suggested that Art could provide renoprotective role by attenuating the tubulointerstitial inflammation and fibrosis in SNx rats by downregulating the NF-κB/NLRP3 signaling pathway., (© 2018 Wiley Periodicals, Inc.)

Background: Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease (ESKD) in the world. Emerging evidence has shown that urinary mRNAs may serve as early diagnostic and prognostic biomarkers of DKD. In this article, we aimed to first establish a novel bioinformatics-based methodology for analyzing the "urinary kidney-specific mRNAs" and verify their potential clinical utility in DKD., Methods: To select candidate mRNAs, a total of 127 Affymetrix microarray datasets of diabetic kidney tissues and other tissues from humans were compiled and analyzed using an integrative bioinformatics approach. Then, the urinary expression of candidate mRNAs in stage 1 study (n = 82) was verified, and the one with best performance moved on to stage 2 study (n = 80) for validation. To avoid potential detection bias, a one-step Taqman PCR assay was developed for quantification of the interested mRNA in stage 2 study. Lastly, the in situ expression of the selected mRNA was further confirmed using fluorescent in situ hybridization (FISH) assay and bioinformatics analysis., Results: Our bioinformatics analysis identified sixteen mRNAs as candidates, of which urinary BBOX1 (uBBOX1) levels were significantly upregulated in the urine of patients with DKD. The expression of uBBOX1 was also increased in normoalbuminuric diabetes subjects, while remained unchanged in patients with urinary tract infection or bladder cancer. Besides, uBBOX1 levels correlated with glycemic control, albuminuria and urinary tubular injury marker levels. Similar results were obtained in stage 2 study. FISH assay further demonstrated that BBOX1 mRNA was predominantly located in renal tubular epithelial cells, while its expression in podocytes and urothelium was weak. Further bioinformatics analysis also suggested that tubular BBOX1 mRNA expression was quite stable in various types of kidney diseases., Conclusions: Our study provided a novel methodology to identify and analyze urinary kidney-specific mRNAs. uBBOX1 might serve as a promising biomarker of DKD. The performance of the selected urinary mRNAs in monitoring disease progression needs further validation.

Hypoxia promotes tubulointerstitial inflammation in the kidney. Although hypoxia inducible factor-1α (HIF-1α) is a master regulator of the response to hypoxia, the exact mechanisms through which HIF-1α modulates the induction of tubulointerstitial inflammation are still largely unclear. We demonstrated tubulointerstitial inflammation and increased tubular HIF-1α expression in murine models of ischemia/reperfusion injury and unilateral ureteral obstruction. Increased expression of HIF-1α in tubular epithelial cells was associated with selective shedding of microRNA-23a (miRNA-23a)-enriched exosomes in vivo and systemic inhibition of miRNA-23a prior to ischemia/reperfusion injury attenuated tubulointerstitial inflammation. In vitro, uptake of miRNA-23a-enriched exosomes by macrophages triggered their reprogramming into a pro-inflammatory state via suppression of the ubiquitin editor A20. To confirm the effect of miRNA-23a-containing exosomes on tubulointerstitial inflammation, we exposed tubular epithelial cells to hypoxic conditions to promote the release of miRNA-23a-containing exosomes. Injection of these miRNA-23a-enriched exosomes into uninjured renal parenchyma resulted in increased inflammatory infiltration in vivo. Taken together, our studies demonstrate that the HIF-1α-dependent release of miRNA-23a-enriched exosomes from hypoxic tubular epithelial cells activates macrophages to promote tubulointerstitial inflammation. Blockade of exosome-mediated miRNA-23a transfer between tubular epithelial cells and macrophages may serve as a novel therapeutic approach to ameliorate tubulointerstitial inflammation., (Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Renal fibrosis is the common pathological pathway of progressive CKD. The commonly used biomarkers in clinical practice are not optimal to detect injury or predict prognosis. Therefore, it is crucial to develop novel biomarkers to allow prompt intervention. Urine serves as a valuable resource of biomarker discovery for kidney diseases. Owing to the rapid development of omics platforms and bioinformatics, research on novel urinary biomarkers for renal fibrosis has proliferated in recent years. In this chapter, we discuss the current status and provide basic knowledge in this field. We present novel promising biomarkers including tubular injury markers, proteins related to activated inflammation/fibrosis pathways, CKD273, transcriptomic biomarkers, as well as metabolomic biomarkers. Furthermore, considering the complex nature of the pathogenesis of renal fibrosis, we also highlight the combination of biomarkers to further improve the diagnostic and prognostic performance.

Objective: To observe the effect of Guben Zenggu Decoction on the expressions of calmodulin ( CaM ) and calcium/calmodulin-dependent protein kinase Ⅱ ( CaMK Ⅱ) mRNA in the hypothalamus, pituitary, spleen, adrenal gland and femur in ovariectomized rats. To explore the mechanism of Guben Zenggu Decoction regulating and controlling osteoporosis through neuro-endocrine-immune (NEI) network., Methods: The osteoporosis model was established by ovariectomy and randomly divided into model control group, Estradiol valerate group, Guben Zenggu Decoction high, medium and low concentration group. Selected the same age rats as the blank control group, after intervention, 10 rats were randomly selected at the time of 4th, 8th, 12th and 16th weeks from each group, After the success of the model and the successful intervention of Guben Zenggu Decoction for 4, 8, 12 and 16 weeks, the blood were taken from the heart, the serum bone alkaline phosphatase (BALP) levels was measured by the enzyme-linked immunosorbent assay (ELISA), and the thalamus, pituitary, spleen, adrenal, femoral tissue of rats were collected to detected the expressions of CaM and CaMKⅡ mRNA by using real-time fluorescence quantitative polymerase chain reaction (RT-PCR)., Results: At different time points (4 weeks, 8 weeks, 12 weeks, 16 weeks), the expressions of serum BALP and CaM and CaMKⅡ mRNA in NEI network in model group were significantly different from those in blank control group ( P <0.05). Compared with the model control group, serum BALP concentration and CaM mRNA expression in hypothalamus and pituitary tissue were significantly increased in estradiol valerate and Guben Zenggu Decoction groups ( P <0.05). However, the expression of CaM mRNA in adrenal gland, spleen and femur and the expression of CaMKⅡ mRNA in hypothalamus, pituitary, adrenal gland, spleen and femur were significantly decreased ( P <0.05); compared with estradiol valerate group, the effect of Guben Zenggu Decoction on the expressions of CaM mRNA and CaMKⅡ mRNA in femoral and adrenal tissues was significantly different ( P <0.05)., Conclusion: Guben Zenggu Decoction can increase the serum concentration of BALP, regulate the expression of CaM mRNA and CaMKⅡ mRNA in hypothalamus, pituitary, adrenal gland, spleen and femur, thus play a role in prevention and treatment of osteoporosis by regulating NEI network., (Copyright© by Editorial Board of Journal of Sichuan University (Medical Science Edition).)