Oxidative Medicine and Cellular Longevity

Published by Hindawi
Online ISSN: 1942-0994
Discipline: Cell & Molecular Biology
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Aims and scope

Oxidative Medicine and Cellular Longevity is a unique peer-reviewed journal that publishes original research and review articles dealing with the cellular and molecular pathophysiological mechanisms of oxidants in health and disease. Oxidative processes influence almost all acute and chronic progressive disorders and on a cellular basis is intimately linked to cell signaling, metabolism, immune function, and senescence. The journal is an important source of information and knowledge in today's cancer, cardiovascular, immunology, and neuroscience scientific literature and serves as an international forum for the scientific community worldwide to translate pioneering “bench to bedside” research into clinical strategies.



Recent publications
  • Chen JinChen Jin
  • Bing-hao LinBing-hao Lin
  • Gang ZhengGang Zheng
  • [...]
  • Lei YangLei Yang
Bone metabolism occurs in the entire life of an individual and is required for maintaining skeletal homeostasis. The imbalance between osteogenesis and osteoclastogenesis eventually leads to osteoporosis. Oxidative stress is considered a major cause of bone homeostasis disorder, and relieving excessive oxidative stress in bone mesenchymal stem cells (BMSCs) is a potential treatment strategy for osteoporosis. Carbon monoxide releasing molecule-3 (CORM-3), the classical donor of carbon monoxide (CO), possesses antioxidation, antiapoptosis, and anti-inflammatory properties. In our study, we found that CORM-3 could reduce reactive oxygen species (ROS) accumulation and prevent mitochondrial dysfunction thereby restoring the osteogenic potential of the BMSCs disrupted by hydrogen peroxide (H2O2) exposure. The action of CORM-3 was preliminarily considered the consequence of Nrf2/HO-1 axis activation. In addition, CORM-3 inhibited osteoclast formation in mouse primary bone marrow monocytes (BMMs) by inhibiting H2O2-induced polarization of M1 macrophages and endowing macrophages with M2 polarizating ability. Rat models further demonstrated that CORM-3 treatment could restore bone mass and enhance the expression of Nrf2 and osteogenic markers in the distal femurs. In summary, CORM-3 is a potential therapeutic agent for the treatment of osteoporosis.
  • Jin HuJin Hu
  • Zhixian FangZhixian Fang
  • Xia LuXia Lu
  • [...]
  • Wenyu ChenWenyu Chen
Objective. Intravenous thrombolysis (IVT) is currently the main effective treatment for patients with ischemic stroke. This study aimed to analyze the factors affecting the early neurological recovery and prognosis of thrombolytic therapy after surgery and to construct predictive models. Materials and Methods. A total of 849 patients with ischemic stroke who received IVT treatment at six centers from June 2017 to March 2021 were included. Patients were divided into the training cohort and the validation cohort. Based on the independent factors that influence the early recovery of neurological function and the prognosis, the respective predictive nomograms were established. The predictive accuracy and discrimination ability of the nomograms were evaluated by ROC and calibration curve, while the decision curve and clinical impact curve were adopted to evaluate the clinical applicability of the nomograms. Results. The nomogram constructed based on the factors affecting the prognosis in 3 months had ideal accuracy as the AUC (95% CI) was 0.901 (0.874~0.927) in the training cohort and 0.877 (0.826~0.929) in the validation cohort. The accuracy of the nomogram is required to be improved, since the AUC (95% CI) of the training cohort and the validation cohort was 0.641 (0.597~0.685) and 0.627 (0.559~0.696), respectively. Conclusions. Based on this ideal and practical prediction model, we can early identify and actively intervene in patients with ischemic stroke after IVT to improve their prognosis. Nevertheless, the accuracy of predicting nomograms for the recovery of early neurological function after IVT still needs improvement.
APN/CPT weakens the effects of M1 macrophages on fibroblast proliferation and fibrosis. (a) HFL-1 cells were transfected with Oe-NC or Oe-CPT1A, and the mRNA level of CPT1A was measured by qRT-PCR. * * * p < 0:001 vs. Oe-NC. (b) Cell transfection was conducted to overexpress CPT1A in HFL-1 cells. Meanwhile, APN (0.5 μg/ml and 2.0 μg/ml) was introduced to HFL-1 cells. HFL-1 cells were cocultured with M1 macrophages. The protein expression of AdipoR and CPT1A in HFL-1 cells was detected using western blot. (c) The cell viability of HFL-1 cells was detected by CCK-8 assay. The level of (d) TGF-β, (e) α-SMA, and (f) Collagen I in HFL-1 cells was detected using their corresponding ELISA kits. * p < 0:05 and * * * p < 0:001 vs. HFL-1+M1; ## p < 0:01 and ### p < 0:001 vs. HFL1+M1+Oe-NC.
  • Wenjuan WuWenjuan Wu
  • Guojun ZhangGuojun Zhang
  • Lingxiao QiuLingxiao Qiu
  • [...]
  • Jizhen WuJizhen Wu
Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease that leads rapidly to death. The present study is aimed at discovering the in-depth pathogenesis of IPF, exploring the role of adiponectin/carnitine palmityl transferase 1A- (APN/CPT1A-) mediated fatty acid metabolism during the development of IPF, and excavating its potential mechanism. Here, THP-1 cells were differentiated into M0 macrophages, followed by polarization to M1 macrophages upon hypoxia. Subsequently, lung fibroblast HFL-1 cells were stimulated by M1 macrophages to simulate hypoxia-related IPF condition in vitro. It was discovered that the stimulation of M1 macrophages promoted fibroblast proliferation and fibrosis formation in vitro, accompanied with a disorder of the APN/CPT1A pathway, an overproduction of lipid peroxides, and a low level of autophagy in HFL-1 cells. Thereafter, APN treatment or CPT1A overexpression greatly suppressed above lipid peroxide accumulation, fibroblast proliferation, and fibrosis but activated autophagy in vitro. Furthermore, an in vivo IPF rat model was established by injection of bleomycin (BLM). Consistently, CPT1A overexpression exerted a protective role against pulmonary fibrosis in vivo; however, the antifibrosis property of CPT1A was partly abolished by 3-methyladenine (an autophagy inhibitor). In summary, APN/CPT1A-mediated fatty acid metabolism exerted its protective role in IPF partly through activating autophagy, shedding a new prospective for the treatment of IPF.
TRIM65 accelerates ubiquitin-mediated LATS1 protein degradation. (a) qRT-PCR results of LATS1 mRNA expression in MDA-MB-231 and MDA-MB-453 cells. (b) Co-IP demonstrated the binding of TRIM65 and LATS1 in MDA-MB-231 and MDA-MB-453 cells. (c) WB analysis and CHX release profiles of LATS1 proteins in cells treated with CHX (20 μg/mL) for 0, 2, 4, or 6 hours. (d) WB analysis of ubiquitination assays. p < 0:05, p < 0:01, and p < 0:001 were considered statistically significant. p > 0:05 was expressed by n.s.
TRIM65 promotes the malignant biological behavior by degrading the expression of LATS1 in TNBC cells. (a, b) Cell proliferation was assessed by the CCK-8 assay and colony-forming assay in MDA-MB-231 and MDA-MB-453 cells. (c) Representative images and analysis of cell invasion and migration assays in MDA-MB-231 and MDA-MB-453 cells. (d) Scientific hypothesis diagram. p < 0:05, p < 0:01, and p < 0:001 were considered statistically significant. * p < 0:05, * * p < 0:01, and * * * p < 0:001.
  • Yongbin LuYongbin Lu
  • Yi XiaoYi Xiao
  • Jingru YangJingru Yang
  • [...]
  • Tao ZhangTao Zhang
TNBC is a malignant tumor that easily relapses and metastasizes, with a poor prognosis in women. Ubiquitination plays a key role in promoting the tumor process. In various tumors, TRIM65 can affect malignant biological tumor behavior by ubiquitination of related proteins. We aimed to investigate TRIM65 expression in TNBC and whether it promotes malignant biological behavior in TNBC cells using Cell Counting Kit-8, colony formation, and transwell assays. Mechanically, we confirmed that TRIM65 promoted TNBC invasion and metastasis by ubiquitination of LATS1 protein through Co-IP, CHX, and endogenous ubiquitination experiments. The expression of TRIM65 was abnormally high and accelerated the proliferation, invasion, and migration of MDA-MB-231 and MDA-MB-453 cells. In vivo animal experiments also revealed that TRIM65 accelerated TNBC cell proliferation. Mechanistically, TRIM65 degraded LATS1 protein expression through ubiquitination in the Co-IP, CHX, and endogenous ubiquitination experiments. Rescue assays confirmed that TRIM65 degraded LATS1 protein expression, accelerating the proliferation, invasion, and migration ability of TNBC cells. Our results show that TRIM65 is upregulated in TNBC, and TRIM65 degrades LATS1 protein expression through ubiquitination and promotes malignant biological behavior in TNBC cells. TRIM65 may play an important role as a new oncogene in TNBC.
Classification statistics of KEGG channel annotation.
  • Ke-feng ZhaiKe-feng Zhai
  • Hong DuanHong Duan
  • Yan ShiYan Shi
  • [...]
  • Jun-jun WangJun-jun Wang
Circular microRNAs (miRNAs) have become central in pathophysiological conditions of atherosclerosis (AS). However, the biomarkers for diagnosis and therapeutics against AS are still unclear. The atherosclerosis models in low-density lipoprotein receptor deficiency (LDLr-/-) mice were established with a high-fat diet (HFD). The extraction kit isolated extracellular vesicles from plasma. Total RNAs were extracted from LDLr-/- mice in plasma extracellular vesicles. Significantly varying miRNAs were detected by employing Illumina HiSeq 2000 deep sequencing technology. Target gene predictions of miRNAs were employed by related software that include RNAhybrid, TargetScan, miRanda, and PITA. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) further analyzed the intersection points of predicted results. The results showed that the HFD group gradually formed atherosclerotic plaques in thoracic aorta compared with the control group. Out of 17, 8 upregulated and 9 downregulated miRNAs with a significant difference were found in the plasma extracellular vesicles that were further cross-examined by sequencing and bioinformatics analysis. Focal adhesion and Ras signaling pathway were found to be the most closely related pathways through GO and KEGG pathway analyses. The 8 most differentially expressed up- and downregulated miRNAs were further ascertained by TaqMan-based qRT-PCR. TaqMan-based qRT-PCR and in situ hybridization further validated the most differentially expressed miRNAs (miR-378d, miR-181b-5p, miR-146a-5p, miR-421-3p, miR-350-3p, and miR-184-3p) that were consistent with deep sequencing analysis suggesting a promising potential of utility to serve as diagnostic biomarkers against AS. The study gives a comprehensive profile of circular miRNAs in atherosclerosis and may pave the way for identifying biomarkers and novel targets for atherosclerosis.
Aspirin alleviates Aβ-induced senescence and mitochondrial dysfunctions via upregulation of SIRT pathway. (a-g) HMC3 cells were preincubated with aspirin for 4 h followed by treatment with 10 μM Aβ for 72 h. (a) Protein levels of SIRT1, PAI-1, and p21 were detected by western blotting. (b) The quantification of relative protein levels in (a). (c) The representative SA-β-gal staining images. (d) Quantification of the percentage of SA-β-gal cells. Scar bar, 50 μm. (e) The cells were stained with JC-1 dye and the fluorescence intensity was quantified using BioTek reader. (f) HMC3 cells were incubated with DCFH-DA and Hoechst; then, the fluorescence intensity was detected by BioTek reader. (g) The fluorescent latex beads were added to the medium and incubated at 37 ° C for 3 h. The fluorescence intensity was quantified using BioTek reader. The data are presented as mean ± SEM, n ≥ 3 independent experiments;
  • Yuqian AnYuqian An
  • Yi LiYi Li
  • Yujun HouYujun Hou
  • [...]
  • Gang PeiGang Pei
Microglia play important roles in maintenance of brain homeostasis, while due to some pathological stimuli in aging-related neurodegenerative diseases including Alzheimer’s disease, they are malfunctioning. Here, we demonstrated that amyloid-β (Aβ) accelerated cell senescence characterized by the upregulation of p21 and PAI-1 as well as senescence-associated beta-galactosidase (SA-β-gal) in human microglial cells. Consistently, Aβ induced the senescence-associated mitochondrial dysfunctions such as repression of ATP production, oxygen consumption rate (OCR), and mitochondrial membrane potential and enhancement of ROS production. Furthermore, Aβ was found to significantly suppress mRNA expression and protein level of Sirtuin-1 (SIRT1), a key regulator of senescence, and inhibit mRNA expression and translocation of NRF2, a critical transcription factor in inflammatory responses, leading to impairment of phagocytosis. Rescue of SIRT1, as expected, could counteract the pathological effects of Aβ. In summary, our findings revealed that Aβ accelerates human microglial senescence mainly through its suppression of the SIRT1/NRF2 pathway and suggested that genetic and pharmaceutical rescue of SIRT1 may provide a potential alternative treatment.
  • Lifeng LiangLifeng Liang
  • Jiayi SunJiayi Sun
  • Tianming TengTianming Teng
  • [...]
  • Wenjuan ZhangWenjuan Zhang
Background. The inflammatory response is important in dilated cardiomyopathy (DCM). However, the expression of inflammatory response genes (IRGs) and regulatory mechanisms in DCM has not been well characterized. Methods. We analyzed 27,665 cells of single-cell RNA sequencing dataset of four DCM samples and two healthy controls (HC). IRGs among differentially expressed genes (DEGs) of active cell clusters were screened from the Molecular Signatures Database (MSigDB). The bulk sequencing dataset of 166 DCM patients and 166 HC was analyzed to explore the common IRGs. The biological functions of the IRGs were analyzed according to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. IRG-related transcription factors (TFs) were determined using the TRRUST database. The protein–protein interaction (PPI) network was constructed using the STRING database. Then, we established the noncoding RNA (ncRNA) regulatory network based on the StarBase database. Finally, the potential drugs that target IRGs were explored using the Drug Gene Interaction Database (DGIdb). Results. The proportions of dendritic cells (DCs), B cells, NK cells, and T cells were increased in DCM patients, whereas monocytes were decreased. DCs expressed more IRGs in DCM. The GO and KEGG analyses indicated that the functional characteristics of active cells mainly focused on the immune response. Thirty-nine IRGs were commonly expressed among active cell cluster DEGs, bulk RNA DEGs, and inflammatory response-related genes. ETS1 plays an important role in regulation of IRG expression. The competing endogenous RNA regulatory network showed the relationship between ncRNA and IRGs. Sankey diagram showed that arachidonate 5-lipoxygenase (ALOX5) played a major role in regulation between TFs and potential drugs. Conclusion. DCs infiltrate into the myocardium and contribute to the immune response in DCM. The transcription factor ETS1 plays an important role in regulation of IRGs. Moreover, ALOX5 may be a potential therapeutic target for DCM.
Macrophage depletion reduces angiogenesis after delayed recanalization. (a) Representative images of macrophages via F4/80 immunohistochemical staining in the spleen. (b) Quantification of macrophage in each group. (c) Western blotting analysis of macrophage marker F4/80 expression. (d) Quantification of macrophage marker F4/80 expression in spleen. (e) Western blotting analyses of macrophage, neuroinflammation, and angiogenesis markers. (f-h) Quantification of related proteins in each group. (l) Representative images of microvessel density in the peri-infarction area visualized by immunohistochemical staining with lectin. Error bars represent the mean ± SD. * P < 0:05 and * * P < 0:01 vs. sham group; # P < 0:05 and ## P < 0:01 vs. rMCAO group; & P < 0:05 and && P < 0:01 vs. rMCAO+PBS (n = 5).
  • Jinwei PangJinwei Pang
  • Nathanael MateiNathanael Matei
  • Jianhua PengJianhua Peng
  • [...]
  • Yong JiangYong Jiang
Background. Recent cerebrovascular recanalization therapy clinical trials have validated delayed recanalization in patients outside of the conventional window. However, a paucity of information on the pathophysiology of delayed recanalization and favorable outcomes remains. Since macrophages are extensively studied in tissue repair, we anticipate that they may play a critical role in delayed recanalization after ischemic stroke. Methods. In adult male Sprague-Dawley rats, two ischemic stroke groups were used: permanent middle cerebral artery occlusion (pMCAO) and delayed recanalization at 3 days following middle cerebral artery occlusion (rMCAO). To evaluate outcome, brain morphology, neurological function, macrophage infiltration, angiogenesis, and neurodegeneration were reported. Confirming the role of macrophages, after their depletion, we assessed angiogenesis and neurodegeneration after delayed recanalization. Results. No significant difference was observed in the rate of hemorrhage or animal mortality among pMCAO and rMCAO groups. Delayed recanalization increased angiogenesis, reduced infarct volumes and neurodegeneration, and improved neurological outcomes compared to nonrecanalized groups. In rMCAO groups, macrophage infiltration contributed to increased angiogenesis, which was characterized by increased vascular endothelial growth factor A and platelet-derived growth factor B. Confirming these links, macrophage depletion reduced angiogenesis, inflammation, neuronal survival in the peri-infarct region, and favorable outcome following delayed recanalization. Conclusion. If properly selected, delayed recanalization at day 3 postinfarct can significantly improve the neurological outcome after ischemic stroke. The sanguineous exposure of the infarct/peri-infarct to macrophages was essential for favorable outcomes after delayed recanalization at 3 days following ischemic stroke.
  • Pan YuPan Yu
  • Yibei DaiYibei Dai
  • Tingting ZhuangTingting Zhuang
  • [...]
  • Zhihua TaoZhihua Tao
Background. The acquisition of castration resistance is lethal and inevitable in most prostate cancer patients under hormone therapy. However, effective biomarkers and therapeutic targets for castration-resistant prostate cancer remain to be defined. Methods. Comprehensive bioinformatics tools were used to screen hub genes in castration-resistant prostate cancer and were verified in androgen-dependent prostate cancer and castration-resistant prostate cancer in TCGA and the SU2C/PCF Dream Team database, respectively. Gene set enrichment analysis and in vitro experiments were performed to determine the potential functions of hub genes involved in castration-resistant prostate cancer progression. Results. Three hub genes were screened out by bioinformatics analysis: MCM4, CENPI, and KNTC1. These hub genes were upregulated in castration-resistant prostate cancer and showed high diagnostic and prognostic value. Moreover, the expression levels of the hub genes were positively correlated with neuroendocrine prostate cancer scores, which represent the degree of castration-resistant prostate cancer aggression. Meanwhile, in vitro experiments confirmed that hub gene expression was increased in castration-resistant prostate cancer cell lines and that inhibition of hub genes hindered cell cycle transition, resulting in suppression of castration-resistant prostate cancer cell proliferation, which confirmed the gene set enrichment analysis results. Conclusions. MCM4, CENPI, and KNTC1 could serve as candidate diagnostic and prognostic biomarkers of castration-resistant prostate cancer and may provide potential preventive and therapeutic targets.
Sensitive rapamycin signaling pathways and route for inhibition of the mTOR pathway. The normal mTOR signaling pathway leads to new cell development via ribosomal machinery and through the initiation of the translation process. Hence, rapamycin inhibits the mTOR pathway that leads to inhibition of cell growth, proliferation, and cell cycle progression. RTK: receptor tyrosine kinase; GPR: G-protein coupled receptor; RAS: renin angiotensin system; PIK3: phosphoinositide-3-kinase; Akt: protein kinase-B; IkB: nuclear factor; NFkB: nuclear factor kappa light chain enhancer of activated B cells; mTOR: mammalian target of rapamycin; 4E-BP1: eukaryotic translation initiation factor; p70s6k: ribosomal protein S6 kinase.
Chemical structure of curcumin.
Chemical structure of shikonin.
Glucoraphanin is hydrolyzed by myrosinase to yield glucose, sulfate, and sulforaphane.
  • Esra Küpeli AkkolEsra Küpeli Akkol
  • Hilal BardakciHilal Bardakci
  • Timur Hakan BarakTimur Hakan Barak
  • [...]
  • Yaseen HussainYaseen Hussain
Among various cancers, breast cancer is the most prevalent type in women throughout the world. Breast cancer treatment is challenging due to complex nature of the etiology of disease. Cell division cycle alterations are often encountered in a variety of cancer types including breast cancer. Common treatments include chemotherapy, surgery, radiotherapy, and hormonal therapy; however, adverse effects and multidrug resistance lead to complications and noncompliance. Accordingly, there is an increasing demand for natural products from medicinal plants and foods. This review summarizes molecular mechanisms of signaling pathways in breast cancer and identifies mechanisms by which natural compounds may exert their efficacy in the treatment of breast cancer.
Identification of differentially expressed genes (DEGs) and pathway analysis. (a) Pearson correlation between samples. (b) Hierarchical clustering diagram of DEGs in the 0-VS-1 group and 0-VS-2 group. (c) Number of DEGs in 0-VS-1 group and 0-VS-2 group. (d) Heat-map of top 20 DEGs in the 0-VS-1 group and 0-VS-2 group. (e, f) KEGG pathway enrichment of Cu-exposed C. elegans.
DAF-16 mediated Cu-induced aging and oxidative stress. (a) Expressions levels of IIS pathway related genes daf-2, age-1, and daf-16 were detected by RNA-seq and RT-qPCR. (b) Images of daf-16-GFP fusion gene in TJ356 worms, n ≥ 30/group. (c) Quantitative of DAF-16 localization. (d) H2DCFDA probe was performed to detect ROS level, n ≥ 30/condition. (e) Quantitative analysis of fluorescence intensities. (f) Representative images of SOD-3::GFP, n ≥ 30/condition. (g) Quantitative of GFP fluorescence in SOD-3::GFP worms, n ≥ 30/condition. (h) Kaplan-Meier survival curve of daf-16 (mu86) strain, 30 nematodes/plate, total 360 worms/condition. (i) mRNA level of SOD-related genes and metal detoxification genes. Scale bar is 100 μm, * P < 0:05, * * P < 0:01, and * * * P < 0:001, compared with the control. Bars represent means ± SD, n = 3 independent experiments.
Top 20 significantly DEGs of C. elegans in response to 1 mg/L Cu.
Top 20 significantly DEGs of C. elegans in response to 2 mg/L Cu.
  • Ying ZhangYing Zhang
  • Qian ZhouQian Zhou
  • Lu LuLu Lu
  • [...]
  • Lihong YinLihong Yin
Nowadays, human beings are exposed to Cu in varieties of environmental mediums, resulting in health risks needing urgent attention. Our research found that Cu shortened lifespan and induced aging-related phenotypes of Caenorhabditis elegans (C. elegans). Transcriptomics data showed differential expression genes induced by Cu were mainly involved in regulation of metabolism and longevity, especially in fatty acid metabolism. Quantitative detection of free fatty acid by GC/MS further found that Cu upregulated free fatty acids of C. elegans. A mechanism study confirmed that Cu promoted the fat accumulation in nematodes, which was owing to disorder of fatty acid desaturase and CoA synthetase, endoplasmic reticulum unfolded protein response (UPRER), mitochondrial membrane potential, and unfolded protein response (UPRmt). In addition, Cu activated oxidative stress and prevented DAF-16 translocating into nuclear with a concomitant reduction in the expression of environmental stress-related genes. Taken together, the research suggested that Cu promoted aging and induced fat deposition and oxidative damage.
  • Ming Kang QiMing Kang Qi
  • Tie Cheng SunTie Cheng Sun
  • Li Ya YangLi Ya Yang
  • [...]
  • Hui Ping WangHui Ping Wang
Objective. Premature ovarian insufficiency (POI) is a female reproductive disorder of unknown etiology with no definite pathogenesis. Melatonin (MT) is an endogenous hormone synthesized mainly by pineal cells and has strong endogenous effects in regulating ovarian function. To systematically explore the pharmacological mechanism of MT on POI therapy, a literature review approach was conducted at the signaling pathways level. Methods. Relevant literatures were searched and downloaded from databases, including PubMed and China National Knowledge Infrastructure, using the keywords “premature ovarian insufficiency,” “Hippo signaling pathways,” and “melatonin.” The search criteria were from 2010 to 2022. Text mining was also performed. Results. MT is involved in the regulation of Hippo signaling pathway in a variety of modes and has been correlated with ovarian function. Conclusions. The purpose of this review is to summarize the research progress of Hippo signaling pathways and significance of MT in POI, the potential crosstalk between MT and Hippo signaling pathways, and the prospective therapy.
PSG suppressed pyroptosis of the liver tissues in IBD mice. Effect of PSG on the levels of IL-1β (a) and IL-18 (b) in the liver tissues of IBD mice. (c) Protein expression of NLRP3 in the liver tissues was detected by IHC. Protein expressions of NLRP3, gasdermin D, caspase 1, and ASC in the liver tissues were determined by Western blot assay (d) and quantitative analysis for Western blot results (n = 3) (e). Results were expressed as the mean ± SEM. * p < 0:05 * * p < 0:01 vs. the control group; # p < 0:05 and ## p < 0:01 vs. the model group (DSS only).
Proposed mechanism of PSG in treating DSS-induced IBD and SLI of mice. Polysaccharides of garlic (PSG); interleukin-1β (IL-1β); interleukin 18 (IL-18); reactive oxygen species (ROS), malondialdehyde (MDA), alanine aminotransferase (ALT), aspartate aminotransferase (AST), Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), nuclear factor-k-gene binding (NF-κB), nuclear factor E2-related factor 2 (Nrf2), Kelch-like ECH associated protein 1 (Keap1), heme oxygenase 1 (HO1), myeloperoxidase (MPO), diamine oxidase (DAO), lipopolysaccharide (LPS), upregulation (↑), and downregulation (↓).
  • Xinyi ZhanXinyi Zhan
  • Weijie PengWeijie Peng
  • Zhuqiang WangZhuqiang Wang
  • [...]
  • Xianjing HuXianjing Hu
Inflammatory bowel disease (IBD), a widespread intestinal disease threatening human health, is commonly accompanied by secondary liver injury (SLI). Pyroptosis and oxidative stress act as an important role underlying the pathophysiology of SLI, during which a large number of proinflammatory cytokines and oxidative intermediates can be produced, thereby causing the liver severely damaged. Suppression of pyroptosis and oxidative damage can be considered one of the critical strategies for SLI therapy. Garlic, a natural food with eatable and medicinal functions, is widely used in people’s daily life. There is no study about the alleviation of garlic against IBD accompanied with SLI. This study is aimed at investigating the efficacy of the polysaccharides from garlic (PSG) in treating IBD and SLI, as well as its pharmacological mechanism. The results showed that PSG significantly alleviated dextran sulfate sodium-induced IBD determined by evaluating the bodyweight loss, disease activity index, colon length, and colonic pathological examination of mice. PSG significantly reduced the colonic inflammation by reversing the levels of myeloperoxidase, diamine oxidase activity, iNOS, and COX2 and strengthened the intestinal barrier by increasing the expressions of ZO1, occludin, and MUC2 of IBD mice. Furthermore, PSG strongly alleviated SLI determined by assessing the liver morphological change, liver index, levels of ALT and AST, and liver pathological change of mice. Mechanically, PSG reduced the high levels of LPS, IL-1β, IL18, NLRP3, gasdermin D, caspase 1, ASC, TLR4, MyD88, NF-κB, phospho-NF-κB, while it increased IL-10 in the livers of mice, indicating that PSG alleviated SLI by suppressing inflammation and pyroptosis. Additionally, PSG significantly inhibited the oxidative damage in the liver tissues of SLI mice by reducing the levels of ROS, MDA, Keap-1, 8-OHDG, and phospho-H2AX and increasing the levels of GPX4, SOD2, HO1, NQO1, and Nrf2. These findings suggested that the garlic polysaccharides could be used to treat IBD accompanied with SLI in humans.
Network pharmacology analysis of QBH in the treatment of ARIs. (a) Venn diagram showing the identified number of 65 shared targets by QBH and ARIs. (b) The PPI network constructed by 65 overlapping genes between QBH targets and ARIs targets. The nodes represented potential genes, and the edges represented protein-protein connections. (c) Horizontal stack plot showing the top 20 target genes in PPI network. (d) A drug-component-target interaction network was constructed. Each herb of QBH, active compounds of QBH, and target genes was represented by the purple, pink, and green, respectively. (e) Functional GO analysis showing the top 10 significant enrichment terms in BP, CC, and MF, respectively. (f) Functional KEGG analysis showing the top 10 enrichment signaling pathways.
Graphical representation of the main signaling pathways of QBH in the treatment of LPS-induced ALI.
  • Fangbo ZhangFangbo Zhang
  • Yu LiYu Li
  • Yujie XiYujie Xi
  • [...]
  • Hongjun YangHongjun Yang
Acute respiratory infections (ARIs) are a common public safety threat with high morbidity and mortality in pediatric patients worldwide. Qinbaohong Zhike oral liquid (QBH), a marketed traditional Chinese medicine product, has been widely used to cure respiratory diseases. QBH is reported to have antitussive, expectorant, and antiasthmatic properties. However, its treatment effect against ARIs is not elucidated. This study aimed to explore the therapeutic efficacy of QBH in the treatment of ARIs-induced pneumonia. Network pharmacology was used to predict the possible targets of QBH against ARIs. Next, the tracheal lipopolysaccharide (LPS-)-induced acute lung injury (ALI) immature rat model was constructed to evaluate the therapeutic effect of QBH. Tandem mass tag (TMT-)-based quantitative proteomics was then used to screen the in-depth disease targets of QBH. QBH exerted a protective effect against LPS-induced ALI by inhibiting pulmonary pathological damage. QBH also reduced the levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and granulocyte macrophage colony-stimulating factor (GM-CSF) in the serum and IL-1β, IL-6, IL-8, TNF-α, IFN-γ, and GM-CSF in the lung tissue. Based on proteomic data, olfactomedin 4 (OLFM4) related to immunity and inflammation was selected as a potential target. Western blot analysis further confirmed the moderating effect of QBH downregulation on OLFM4 in the lung tissue. Our findings demonstrated that QBH alleviated lung tissue damage and inflammatory reaction via inhibiting OLFM4 expression in LPS-challenged immature rats. Our research indicates that QBH may have therapeutic potential for treating ARIs-related ALI in pediatric patients, which also serves as a candidate target for drug therapy of ALI by intervening OLFM-related signaling pathways.
  • Dong PengDong Peng
  • Yi-Xue WangYi-Xue Wang
  • Tian-Hua HuangTian-Hua Huang
  • [...]
  • Shi-Jie ZhangShi-Jie Zhang
Vascular dementia (VaD), the second cause of dementia, is caused by chronic cerebral hypoperfusion, producing progressive damage to cerebral cortex, hippocampus, and white matter. Ligustilide (LIG), one of the main active ingredients of Angelica sinensis, exerts the neuroprotective effect on neurodegenerative diseases. However, the mechanism remains unclear. An in vivo model of bilateral common carotid artery occlusion and in vitro model of oxygen glucose deprivation (OGD) were employed in this study. LIG (20 or 40 mg/kg/day) was intragastrically administered to the VaD rats for four weeks. The results of the Morris water maze test demonstrated that LIG effectively ameliorated learning and memory deficiency in VaD rats. LIG obviously relieved neuronal oxidative stress damage by increasing the activities of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-PX) and decreasing the level of malondialdehyde (MDA) in VaD rats. Nissl staining showed that LIG increased the number of the Nissl body in VaD rats. After LIG administration, the apoptotic-related protein, Bax, was decreased and Bcl-2 was increased in the hippocampus of VaD rats. Moreover, the expressions of sirtuin 1 (SIRT1) and protein disulfide isomerase (PDI) were decreased, binding immunoglobulin protein (BIP) and phospho-inositol-requiring enzyme-1α (P-IRE1α), X-box binding protein 1 (XBP1s), and C/EBP-homologous protein (CHOP) were increased in VaD rats. After LIG treatment, these changes were reversed. The immunofluorescence results further showed that LIG upregulated the expression of SIRT1 and downregulated the expression of P-IRE1α in VaD rats. In addition, in vitro experiment showed that EX-527 (SIRT1 inhibitor) partly abolished the inhibitory effect of LIG on the IRE1α/XBP1s/CHOP pathway. In conclusion, these studies indicated that LIG could improve cognitive impairment by regulating the SIRT1/IRE1α/XBP1s/CHOP pathway in VaD rats.
Significance of the HDAC8/IRF1/SUCNR1 axis in CRC. (a) A box plot of the differential expression of HDAC8 in the colon adenocarcinoma (COAD) and rectum adenocarcinoma (READ) samples included in TCGA and GTEx (red box plots represent tumor samples, and gray box plots represent normal samples; in COAD, there are 275 tumor samples and 349 normal samples; in READ, there are 92 tumor samples and 318 normal samples). (b) Venn diagram of HDAC8 downstream regulatory genes and transcription factors (the left is the downstream genes of HDAC8 predicted by the starBase database, the right is the transcription factor annotation, and the center represents the intersection of the two sets of data). (c) Interaction analysis of the candidate transcription factors; each circle in the figure represents a gene, and the line between circles indicates interaction between two genes; the darker color of the circle where the gene is located reflects more interaction genes, higher core degree in the interaction network, and higher degree value. (d) Statistics of degree value of core genes in the gene interaction network (the abscissa represents the degree value and the ordinate represents the gene name). (e) KEGG enrichment analysis of the candidate transcription factors (the abscissa represents the gene ratio, the ordinate represents the KEGG entry identifier, and the histogram on the right is the color scale). (f) A box plot of the differential expression of SUCNR1 in the CRC included in TCGA and GTEx (red box plots represent tumor samples, and gray box plots represent normal samples; in COAD, there are 275 tumor samples and 349 normal samples; in READ, there are 92 tumor samples and 318 normal samples). * p < 0:05.
HDAC8 suppresses the expression of IRF1 and thus facilitates the growth and metastasis of CRC cells. (a) HDAC8 and IRF1 mRNA expression in CRC and adjacent normal tissues determined by RT-qPCR (n = 58). (b) HDAC8 and IRF1 mRNA expression in SW480, SW620, HT29, HCT-116, and FHC cell lines determined by RT-qPCR. (c) Histone acetylation levels in the IRF1 promoter region in CRC and adjacent normal tissues determined by ChIP. (d) mRNA expression of HDAC8 and IRF1 in HCT-116 cells treated with sh-HDAC8 or oe-HDAC8 determined by RT-qPCR. (e) Western blot analysis of HDAC8 and IRF1 proteins in HCT-116 cells treated with sh-HDAC8 or oe-HDAC8. (f) mRNA expression of HDAC8 and IRF1 in HCT-116 cells treated with PCI-34051 determined by RT-qPCR. (g) H3K9Ac levels in the IRF1 promoter region in HCT-116 cells treated with PCI-34051 determined by ChIP. (h) HDAC8 and IRF1 mRNA expression in HCT-116 cells treated with sh-HDAC8 or combined with sh-IRF1 determined by RT-qPCR. (i) Viability of HCT-116 cells treated with sh-HDAC8 or combined with sh-IRF1 measured by CCK-8 assay. (j) Migration of HCT-116 cells treated with sh-HDAC8 or combined with sh-IRF1 measured by Transwell assay. (k) Invasion of HCT-116 cells treated with sh-HDAC8 or combined with sh-IRF1 measured by Transwell assay. * p < 0:05, * * p < 0:01, * * * p < 0:001, and * * * * p < 0:0001, compared with adjacent normal tissues, FHC cells, or DMSO-or sh-NC-treated HCT-116 cells. # p < 0:05, ### p < 0:001, and #### p < 0:0001, compared with shHDAC8+sh-NC-treated HCT-116 cells. The experiment was conducted three times independently.
SUCNR1 promotes the migration and invasion of CRC cells by blunting tumor cell autophagy. (a) SUCNR1 mRNA expression in HCT-116 cells treated with sh-SUCNR1 determined by RT-qPCR. (b) Viability of HCT-116 cells following SUCNR1 knockdown or combined with 3-MA measured by CCK-8 assay. (c) Migration of HCT-116 cells following SUCNR1 knockdown or combined with 3-MA measured by Transwell assay. (d) Invasion of HCT-116 cells following SUCNR1 knockdown or combined with 3-MA measured by Transwell assay. (e) Flow cytometric analysis of the HCT-116 cell apoptosis following SUCNR1 knockdown or combined with 3-MA. (f) Western blot analysis of LC3-II/LC3-I ratio in HCT-116 cells following SUCNR1 knockdown or combined with 3-MA. (g) Immunofluorescence detection of the number of GFP-LC3 spots in HCT-116 cells following SUCNR1 knockdown or combined with 3-MA (scale bar = 50 μm). (h) Number of autophagic vacuoles in HCT-116 cells following SUCNR1 knockdown or combined with 3-MA under a TEM. * p < 0:05, * * p < 0:01, and * * * p < 0:001, compared with HCT-116 cells transfected with sh-NC. # p < 0:05, ## p < 0:01, and ### p < 0:001, compared with HCT-116 cells treated with sh-SUCNR1+DMSO. The experiment was conducted three times independently.
Molecular mechanism by which HDAC8 regulates the progression of CRC. Histone deacetylase HDAC8 upregulates SUCNR1 by downregulating IRF1 and consequently inhibits CRC cell autophagy, ultimately contributing to the CRC growth and liver metastasis.
  • Jierong ChenJierong Chen
  • Lixue CaoLixue Cao
  • Jianhong MaJianhong Ma
  • [...]
  • Bing GuBing Gu
Histone deacetylases (HDACs) are well-characterized for their involvement in tumor progression. Herein, the current study set out to unravel the association of HDAC8 with colorectal cancer (CRC). Bioinformatics analyses were carried out to retrieve the expression patterns of HDAC8 in CRC and the underlying mechanism. Following expression determination, the specific roles of HDAC8, IRF1, and SUCNR1 in CRC cell functions were analyzed following different interventions. Additionally, tumor formation and liver metastasis in nude mice were operated to verify the fore experiment. Bioinformatics analyses predicted the involvement of the HDAC8/IRF1/SUCNR1 axis in CRC. In vitro cell experiments showed that HDAC8 induced the CRC cell growth by reducing IRF1 expression. Meanwhile, IRF1 limited SUCNR1 expression by binding to its promoter. SUCNR1 triggered the growth and metastasis of CRC by inhibiting cell autophagy. HDAC8 blocked IRF1-mediated SUCNR1 inhibition and thereby inhibited autophagy, accelerating CRC cell growth. Lastly, HDAC8 facilitated the development of CRC and liver metastasis by regulating the IRF1/SUCNR1 axis in vivo. Taken together, our findings highlighted the critical role for the HDAC8/IRF1/SUCNR1 axis in the regulation of autophagy and the resultant liver metastasis in CRC.
Salvianolic acid A (SAA) is one of bioactive polyphenol extracted from a Salvia miltiorrhiza (Danshen), which was widely used to treat cardiovascular disease in traditional Chinese medicine. SAA has been reported to be protective in cardiovascular disease and ischemia injury, with anti-inflammatory and antioxidative effect, but its role in acute lung injury (ALI) is still unknown. In this study, we sought to investigate the therapeutic effects of SAA in a murine model of lipopolysaccharide- (LPS-) induced ALI. The optimal dose of SAA was determined by comparing the attenuation of lung injury score after administration of SAA at three different doses (low, 5 mg/kg; medium, 10 mg/kg; and, high 15 mg/kg). Dexamethasone (DEX) was used as a positive control for SAA. Here, we showed that the therapeutic effect of SAA (10 mg/kg) against LPS-induced pathologic injury in the lungs was comparable to DEX. SAA and DEX attenuated the increased W/D ratio and the protein level, counts of total cells and neutrophils, and cytokine levels in the BALF of ALI mice similarly. The oxidative stress was also relieved by SAA and DEX according to the superoxide dismutase and malondialdehyde. NET level in the lungs was elevated in the injured lung while SAA and DEX reduced it significantly. LPS induced phosphorylation of Src, Raf, MEK, and ERK in the lungs, which was inhibited by SAA and DEX. NET level and phosphorylation level of Src/Raf/MEK/ERK pathway in the neutrophils from acute respiratory distress syndrome (ARDS) patients were also inhibited by SAA and DEX in vitro, but the YEEI peptide reversed the protective effect of SAA completely. The inhibition of NET release by SAA was also reversed by YEEI peptide in LPS-challenged neutrophils from healthy volunteers. Our data demonstrated that SAA ameliorated ALI via attenuating inflammation, oxidative stress, and neutrophil NETosis. The mechanism of such protective effect might involve the inhibition of Src activation.
Background. Neuroinflammation-induced phosphorylated Tau (p-Tau) deposition in central nervous system contributes to neurodegenerative disorders. Propofol possesses neuroprotective properties. We investigated its impacts on tumor necrosis factor-α (TNF-α)-mediated p-Tau deposition in neurons. Methods. Mouse hippocampal neurons were exposed to propofol followed by TNF-α. Cell viability, p-Tau, mitophagy, reactive oxygen species (ROS), NOD-like receptor protein 3 (NLRP3), antioxidant enzymes, and p62/Keap1/Nrf2 pathway were investigated. Results. TNF-α promoted p-Tau accumulation in a concentration- and time-dependent manner. TNF-α (20 ng/mL, 4 h) inhibited mitophagy while increased ROS accumulation and NLRP3 activation. It also induced glycogen synthase kinase-3β (GSK3β) while inhibited protein phosphatase 2A (PP2A) phosphorylation. All these effects were attenuated by 25 μM propofol. In addition, TNF-α-induced p-Tau accumulation was attenuated by ROS scavenger, NLRP3 inhibitor, GSK3β inhibitor, or PP2A activator. Besides, compared with control neurons, 100 μM propofol decreased p-Tau accumulation. It also decreased ROS and NLRP3 activation, modulated GSK3β/PP2A phosphorylation, leaving mitophagy unchanged. Further, 100 μM propofol induced p62 expression, reduced Keap1 expression, triggered the nuclear translocation of Nrf2, and upregulated superoxide dismutase (SOD) and heme oxygenase-1 (HO-1) expression, which was abolished by p62 knockdown, Keap1 overexpression, or Nrf2 inhibitor. Consistently, the inhibitory effect of 100 μM propofol on ROS and p-Tau accumulation was mitigated by p62 knockdown, Keap1 overexpression, or Nrf2 inhibitor. Conclusions. In hippocampal neurons, TNF-α inhibited mitophagy, caused oxidative stress and NLRP3 activation, leading to GSK3β/PP2A-dependent Tau phosphorylation. Propofol may reduce p-Tau accumulation by reversing mitophagy and oxidative stress-related events. Besides, propofol may reduce p-Tau accumulation by modulating SOD and HO-1 expression through p62/Keap1/Nrf2 pathway.
Objective. Desmodium styracifolium is the best traditional medicine for treating kidney calculi in China. This study is aimed at increasing the carboxyl (-COOH) content of D. styracifolium polysaccharide (DSP0) and further increasing its antistone activity. Methods. DSP0 was carboxymethylated with chloroacetic acid at varying degrees. Then, oxalate-damaged HK-2 cells were repaired with modified polysaccharide, and the changes in biochemical indices before and after repair were detected. Results. Three modified polysaccharides with 7.45% (CDSP1), 12.2% (CDSP2), and 17.7% (CDSP3) -COOH are obtained. Compared with DSP0 (-COOH content = 1.17 % ), CDSPs have stronger antioxidant activity in vitro and can improve the vitality of damaged HK-2 cells. CDSPs repair the cell morphology and cytoskeleton, increase the cell healing ability, reduce reactive oxygen species and nitric oxide levels, increase mitochondrial membrane potential, limit autophagy level to a low level, reduce the eversion of phosphatidylserine in the cell membrane, weaken the inhibition of oxalate on DNA synthesis, restore cell cycle to normal state, promote cell proliferation, and reduce apoptosis/necrosis. Conclusion. The carboxymethylation modification of DSP0 can improve its antioxidant activity and enhance its ability to repair damaged HK-2 cells. Among them, CDSP2 with medium -COOH content has the highest activity of repairing cells, whereas CDSP3 with the highest -COOH content has the highest antioxidant activity. This difference may be related to the active environment of polysaccharide and conformation of the polysaccharide and cell signal pathway. This result suggests that Desmodium styracifolium polysaccharide with increased -COOH content may have improved potential treatment and prevention of kidney calculi.
Currently, Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM) are widely prevalent in the elderly population, and accumulating evidence implies a strong link between them. For example, patients with T2DM have a higher risk of developing neurocognitive disorders, including AD, but the exact mechanisms are still unclear. This time, by combining bioinformatics analysis and in vivo experimental validation, we attempted to find a common biological link between AD and T2DM. We firstly downloaded the gene expression profiling (AD: GSE122063; T2DM: GSE161355) derived from the temporal cortex. To find the associations, differentially expressed genes (DEGs) of the two datasets were filtered and intersected. Based on them, enrichment analysis was carried out, and the least absolute shrinkage and selection operator (LASSO) logistic regression and support vector machine-recursive feature elimination (SVM-RFE) algorithms were used to identify the specific genes. After verifying in the external dataset and in the samples from the AD and type 2 diabetes animals, the shared targets of the two diseases were finally determined. Based on them, the ceRNA networks were constructed. Besides, the logistic regression and single-sample gene set enrichment analysis (ssGSEA) were performed. As a result, 62 DEGs were totally identified between AD and T2DM, and the enrichment analysis indicated that they were much related to the function of synaptic vesicle and MAPK signaling pathway. Based on the evidence from external dataset and RT-qPCR, CARTPT, EPHA5, and SERPINA3 were identified as the marker genes in both diseases, and their clinical significance and biological functions were further analyzed. In conclusion, discovering and exploring the marker genes that are dysregulated in both 2 diseases could help us better comprehend the intrinsic relationship between T2DM and AD, which may inspire us to develop new strategies for facing the dilemmas of clinical or basic research in cognitive dysfunction.
Effect of H 2 O 2 on ARPE-19 cell activity and ROS production. (a) The statistical analysis of cell activity. (b) ROS production after treatment with different doses of H 2 O 2 . (c) Quantitative expression of cellular ROS. The data are shown as mean ± SD; n = 3. * P < 0:05;
Aim. Chronic inflammation is crucial for age-related macular degeneration (AMD) pathogenesis. However, the mechanism involved in activating inflammation remains unclear. This study is aimed at investigating whether nuclear factor erythrocyte-associated factor 2 (Nrf2) negatively regulated the Nod-like receptor protein 3 (NLRP3) inflammasomes through the thioredoxin 1 (Trx1)/thioredoxin interaction protein (TXNIP) complex. Methods. We determined the optimal hydrogen peroxide (H2O2) concentration, time, and changes in reactive oxygen species (ROS) levels. We also constructed animal models using blue LED irradiation. Then, the expression of Nrf2, TXNIP, Trx1, NLRP3, and inflammation-related factors and proteins, along with the changes in retinal thickness and functional status, was analyzed. Results. The oxidative stress model was established after 1 h intervention with 100 μM H2O2. Nrf2 reduced ROS production, protected the ultrastructure of mitochondria, increased the thickness of the ONL layer, and increased the amplitude of a- and b-wave amplitudes in ERG. Trx1 knockdown increased the production of ROS, damaged the ultrastructure of mitochondria, reduced the thickness of the other ONL layer, and reduced the amplitudes of a- and b-waves in the electroretinogram (ERG). Thus, TXNIP in the cytoplasm activated the inflammasomes. Conclusions. Nrf2 showed antioxidant and anti-inflammatory activity in the H2O2-induced cell stress model and blue LED-induced retinal light damage model. TXNIP transferred from the nucleus to the cytoplasm, activated NLRP3, and aggravated the retinal injury in both the cell stress model and the animal blue LED model. In contrast, Trx1 knockout promoted this process. This study revealed the possible role of the thioredoxin system in developing AMD while also providing newer insights for the future treatment of AMD.
Liver transplantation (LT) is an effective strategy for the treatment of end-stage liver disease, but immune rejection remains a significant detriment to the survival and prognosis of these LT patients. While immune rejection is closely related to cytokines, the cytokines investigated within previous studies have been limited and have not included a systematic analysis of proinflammatory cytokines. In the present study, we used a protein chip system and proteomics to detect and analyze serum proinflammatory cytokines and differentially expressed proteins in liver tissue in a mouse model of liver transplantation. In addition, bioinformatics analysis was employed to analyze the proinflammatory cytokines and differential changes in proteins in response to this procedure. With these analyses, we found that serum contents of GC-CSF, CXCL-1, MCP-5, and CXCL-2 were significantly increased after liver transplantation, while IL-5, IL-10, and IL-17 were significantly decreased. Results from Gene Ontology (GO) and KEGG pathway analyses revealed that the cytokine-cytokine receptor, Th1/Th2 cell differentiation, and JAK-STAT signaling pathway were enriched in a network associated with the activation of immune response. Results from our proteomic analysis of liver tissue samples revealed that 470 proteins are increased and 50 decreased, including Anxa1, Anxa2, Acsl4, Sirpa, S100a8, and S100a9. KEGG pathway analysis indicated that the neutrophil extracellular trap formation, NOD-like receptor signaling pathway, and leukocyte transendothelial migration were all associated with liver transplant rejection in these mice. Bioinformatics analysis results demonstrated that CXCL-1/CXCL-2 and S100a8/S100a9 were the genes most closely related to the functions of neutrophils and the mononuclear phagocyte system. These findings provide new insights into some of the critical factors associated with liver transplant rejection and thus offer new targets for the treatment and prevention of this condition.
Schisandra chinensis, as a Chinese functional food, is rich in unsaturated fatty acids, minerals, vitamins, and proteins. Hence, this study was intended to elucidate the effects and biological mechanism of Schisandrin A from Schisandra chinensis in DN. C57BL/6 mice were fed with a high-fat diet and then injected with streptozotocin (STZ). Human renal glomerular endothelial cells were stimulated with 20 mmol/L d-glucose for DN model. Schisandrin A presented acute kidney injury in mice of DN. Schisandrin A reduced oxidative stress and inflammation in model of DN. Schisandrin A reduced high glucose-induced ferroptosis and reactive oxygen species (ROS-)-mediated pyroptosis by mitochondrial damage in model of DN. Schisandrin A directly targeted AdipoR1 protein and reduced LPS+ATP-induced AdipoR1 ubiquitination in vitro model. Schisandrin A activated AdipoR1/AMPK signaling pathway and suppressed TXNIP/NLRP3 signaling pathway in vivo and in vitro model of DN. Conclusively, our study revealed that Schisandrin A from Schisandra chinensis attenuates ferroptosis and NLRP3 inflammasome-mediated pyroptosis in DN by AdipoR1/AMPK-ROS/mitochondrial damage. Schisandrin A is a possible therapeutic option for DN or other diabetes.
Anthracyclines constitute the cornerstone of numerous chemotherapy regimens for various cancers. However, the clinical application of anthracyclines is significantly limited to their dose-dependent cardiotoxicity. A comprehensive understanding of the current status of anthracycline-induced cardiotoxicity is necessary for in-depth research and optimal clinical protocols. Bibliometric analysis is widely applied in depicting development trends and tracking frontiers of a specific field. The present study is aimed at revealing the status and trends of anthracycline-induced cardiotoxicity during the past two decades by employing bibliometric software including R-bibliometric, VOSviewer, and CiteSpace. A total of 3504 publications concerning anthracycline-induced cardiotoxicity from 2002 to 2021 were collected from the Web of Science Core Collection database. Results showed significant growth in annual yields from 90 records in 2002 to 304 papers in 2021. The United States was the most productive country with the strongest collaboration worldwide in the field. Charles University in the Czech Republic was the institution that contributed the most papers, while 7 of the top 10 productive institutions were from the United States. The United States Department of Health and Human Services and the National Institutes of Health are the two agencies that provide financial support for more than 50% of sponsored publications. The research categories of included publications mainly belong to Oncology and Cardiac Cardiovascular Systems. The Journal of Clinical Oncology had a comprehensive impact on this research field with the highest IF value and many publications. Simunek Tomas from Charles University contributed the most publications, while Lipshultz Steven E. from the State University of New York possessed the highest H -index. In addition, the future research frontiers of anthracycline-induced cardiotoxicity might include early detection, pharmacogenomics, molecular mechanism, and cardiooncology. The present bibliometric analysis may provide a valuable reference for researchers and practitioners in future research directions.
Osteoporotic fracture, a major complication which is known as the outcome postmenopausal osteoporosis, seriously threatens the health of postmenopausal women. At present, the traditional osteoporotic fracture prediction methods are characterized by inconvenient application and time-consuming statistical results, while predictive serum biomarkers can make up for this shortcoming. Accurate and advanced risk prediction of osteoporotic fracture is meaningful to early prevention and intervention, effectively avoiding the risk of this disease and the secondary fracture in the surgical treatment. In this study, based on the BEYOND cohort, a 2-year follow-up study was conducted after subjects participated to survey if OF occurred. Independent sample t -test and Mann–Whitney U -test were used to analyze the differences of bone metabolism biomarkers between the OF and non-OF group. Cox proportional hazard model was used to screen the potential biomarkers might be used to predict OF risk. ROC curves and AUCs were used to analyze the predictive accuracy, and the Delong’s test was used to compare the differences between the AUCs. 15 postmenopausal women with low bone mass and OF were found, and other 60 subjects without OF were matched with 1 : 4, age, and BMI classification as control group. The serum IL-6 ( OR = 1.139 , 95 % CI = 1.058 − 1.226 ) and leptin ( OR = 0.921 , 95 % CI = 0.848 − 1.000 ) were found as OF risk predictive biomarkers for postmenopausal women with low bone mass with high accuracy ( IL − 6 = 0.871 ) ( leptin = 0.813 ) and accuracy enhanced when they were combined ( AUC = 0.898 ). The results of Delong’s test showed that the difference of AUC between leptin and IL-6&Leptin was meaningful ( P = 0.024 ) but meaningless between IL-6 and leptin ( P = 0.436 ), IL-6 and IL-6&Leptin ( P = 0.606 ). To sum up, IL-6 and leptin are the predictive biomarkers of OF for postmenopausal women with low bone mass. The IL-6 can improve the prediction accuracy of leptin ( P = 0.024 ), but not vice versa ( P = 0.606 ). Trial Information. Registered on the Chinese Clinical Trial Registry already. (Registration Number: ChiCTR-SOC-17013090).
Endothelial cell senescence is the main risk factor contributing to vascular dysfunction and the progression of aging-related cardiovascular diseases. However, the relationship between endothelial cell metabolism and endothelial senescence remains unclear. The present study provides novel insight into fatty acid metabolism in the regulation of endothelial senescence. In the replicative senescence model and H2O2-induced premature senescence model of primary cultured human umbilical vein endothelial cells (HUVECs), fatty acid oxidation (FAO) was suppressed and fatty acid profile was disturbed, accompanied by downregulation of proteins associated with fatty acid uptake and mitochondrial entry, in particular the FAO rate-limiting enzyme carnitine palmitoyl transferase 1A (CPT1A). Impairment of fatty acid metabolism by silencing CPT1A or CPT1A inhibitor etomoxir facilitated the development of endothelial senescence, as implied by the increase of p53, p21, and senescence-associated β-galactosidase, as well as the decrease of EdU-positive proliferating cells. In the contrary, rescue of FAO by overexpression of CPT1A or supplement of short chain fatty acids (SCFAs) acetate and propionate ameliorated endothelial senescence. In vivo, treatment of acetate for 4 weeks lowered the blood pressure and alleviated the senescence-related phenotypes in aortas of Ang II-infused mice. Mechanistically, fatty acid metabolism regulates endothelial senescence via acetyl-coenzyme A (acetyl-CoA), as implied by the observations that suppression of acetyl-CoA production using the inhibitor of ATP citrate lyase NDI-091143 accelerated senescence of HUVECs and that supplementation of acetyl-CoA prevented H2O2-induced endothelial senescence. Deficiency of acetyl-CoA resulted in alteration of acetylated protein profiles which are associated with cell metabolism and cell cycle. These findings thus suggest that improvement of fatty acid metabolism might ameliorate endothelial senescence-associated cardiovascular diseases.
Tubular injury has been shown to play a critical role in the morbidity of diabetic kidney disease (DKD); ferroptosis often occurs in tubules during renal disease development. This study was aimed at evaluating the inhibitory effects and potential mechanism of dapagliflozin (DAPA) against diabetic-related ferroptosis in the kidney. C57BL/6 mice were fed a high-fat diet (HFD) for 12 weeks, administered a small dose of streptozocin (STZ) for three consecutive days by intraperitoneal injection, and then orally administered dapagliflozin (10 mg/kg/day) for 8 weeks. Mouse blood and urine samples were collected, and their renal cortices were harvested for subsequent investigations. The effects of DAPA were also evaluated in HK-2 cells subjected to simulated diabetic conditions through excess glucose or palmitic acid (PA) administration. DAPA significantly ameliorated tubular injury independently of glycemic control in diabetic model mice. In vivo and in vitro investigations showed that dapagliflozin ameliorated tubular injury by inhibiting ferroptosis. Docking experiments demonstrated that dapagliflozin and SLC40A1 could bind with each other and may consequently reduce ubiquitination degradation. In conclusion, in this study, the tubular protective effects of DAPA, irrespective of glycemic control, were observed in a diabetic mouse model. DAPA ameliorated ferroptosis during diabetic tubular injury via SLC40A1 stabilization, and this may be the mechanism underlying its action. To the best of our knowledge, this is the first study to investigate the ferroptosis inhibitory effects of DAPA in the treatment of DKD.
Background. Radiation resistance of lung cancer cells is a vital factor affecting the curative effect of lung cancer. Transcription factor GATA3 is involved in cell proliferation, invasion, and migration and is significantly expressed in a variety of malignancies. However, the molecular mechanism governing GATA3 regulation in lung cancer cells’ radiation resistance is unknown. Methods. Radiation-resistant cell models (A549-RR and H1299-RR) were made using fractionated high-dose irradiation. Use clone formation, CCK-8, F-actin staining, cell cycle detection, and other experiments to verify whether the model is successfully constructed. Cells were transiently transfected with knockdown or overexpression plasmid. To explore the relationship between GATA3/H3K4me3 and target genes, we used ChIP-qPCR, ChIP-seq, and dual luciferase reporter gene experiments. Xenograft tumor models were used to evaluate the effect of GATA3 depletion on the tumorigenic behavior of lung cancer cells. Results. We report that transcription factors GATA3 and H3K4me3 coactivate NRP1 gene transcription when A549 cells develop radiation resistance. However, the mechanism of radiation resistance in H1299 cells is that GATA3 acts as a transcription inhibitor. The decrease of GATA3 will promote the increase of NRP1 transcription, in which H3K4me3 does not play a leading role. Conclusions. GATA3, an upstream transcriptional regulator of NRP1 gene, regulates the radioresistance of A549 and H1299 cells by opposite mechanisms, which provides a new target for radiotherapy of lung cancer.
Coronary heart disease (CHD) is closely related to oxidative stress and inflammatory response and is the most common cardiovascular disease (CVD). Iron is an essential mineral that participates in many physiological and biochemical reactions in the human body. Meanwhile, on the negative side, iron has an active redox capacity, which leads to the accumulation of reactive oxygen species (ROS) and lipid peroxidation. There is growing evidence that disordered iron metabolism is involved in CHD’s pathological progression. And the result of disordered iron metabolism is associated with iron overload-induced programmed cell death, often called ferroptosis. That features iron-dependent lipid peroxidation. Ferroptosis may play a crucial role in the development of CHD, and targeting ferroptosis may be a promising option for treating CHD. Here, we review the mechanisms of iron metabolism in cardiomyocytes (CMs) and explain the correlation between iron metabolism and ferroptosis. Meanwhile, we highlight the specific roles of iron metabolism and ferroptosis in the main pathological progression of CHD.
Extensive use of substances derived from natural sources has been documented in the treatment of colorectal cancer (CRC). Lysionotin (Lys) is a flavonoid present in the flowers and leaves of Gesneriaceae family plants. Despite its various pharmacological properties, which include neuroprotective, pro, antimalarial, and anticancer effects, the therapeutic advantages of Lys for CRC remain uncertain. In this present study, we demonstrated that Lys treatment successfully inhibited cell proliferation, migration, and invasion in HCT116 and SW480 CRC cells in vitro. Intriguingly, significant ferroptosis and reactive oxygen species (ROS) accumulation in CRC cells were induced by Lys treatment, whereas antagonism of ferroptosis by Liproxstatin-1 (Lip1) pretreatment retarded the anti-CRC effects of Lys. In addition, Lys reduced the amount of Nrf2 protein in CRC cells by increasing the rate at which it is degraded. Overexpression of Nrf2 rescued Lys reduced ferroptosis, suggesting the Nrf2 signaling is a crucial determinant of whether Lys induces ferroptosis in CRC cells. We also revealed that Lys suppressed tumor growth in vivo without obvious adverse effects on the main organs of mice. In conclusion, our results discovered that Lys treatment induced ferroptosis to exert antitumor effects in HCT116 and SW480 CRC cells by modulating Nrf2 signaling, providing a potential therapeutic approach for the prevention of colorectal cancer.
Stem cell-based therapeutic strategies have obtained a significant breakthrough in the treatment of cardiovascular diseases, particularly in myocardial infarction (MI). Nevertheless, limited retention and poor migration of stem cells are still problems for stem cell therapeutic development. Hence, there is an urgent need to develop new strategies that can mobilize stem cells to infarcted myocardial tissues effectively. Electroacupuncture (EA) intervention can improve cardiac function and alleviate myocardial injury after MI, but its molecular mechanism is still unclear. This study is aimed at observing the effects of EA treatment on the stem cell mobilization and revealing possible mechanisms in the MI model of mice. EA treatment at Neiguan (PC6) and Xinshu (BL15) acupoints was conducted on the second day after the ligation surgery. Then, the number of stem cells in peripheral blood after EA in MI mice and their cardiac function, infarct size, and collagen deposition was observed. We found that the number of CD34-, CD117-, Sca-1-, and CD90-positive cells increased at 6 h and declined at 24 h after EA intervention in the blood of MI mice. The expression of CXC chemokine receptor-4 (CXCR4) protein was upregulated at 6 h after EA treatment, while the ratio of LC3B II/I or p-ERK/ERK showed a reverse trend. In addition, there was obvious difference in EF and FS between wild-type mice and CXCR4+/− mice. The infarct size, collagen deposition, and apoptosis of the injured myocardium in CXCR4+/− mice increased but could be ameliorated by EA. In a word, our study demonstrates that EA alleviates myocardial injury via stem cell mobilization which may be regulated by the SDF-1/CXCR4 axis.
Objective. Ischemic cerebrovascular disease is a commonly seen vascular disorder in clinical practice. Given the difficulty of drug therapy to achieve ideal curative effects, interventional therapy has gradually become the preferred treatment for the disease. This research primarily discusses the short-term efficacy of digital subtraction angiography- (DSA-) guided neurointerventional thrombolysis for acute ischemic cerebrovascular disease (AICVD) and its influence on vascular endothelial function (VEF) and oxidative stress (OS). Methods. All the clinical data of 162 patients diagnosed with AICVD and treated between June 2019 and December 2021 were collected and analyzed retrospectively. They were assigned to two cohorts according to the difference in interventional methods: a conventional group (CG) given recombinant tissue plasminogen activator (rt-PA) therapy and an observation group (OG) intervened by DSA-guided neurointerventional thrombolysis. The two groups were compared with respect to short-term treatment efficacy, the National Institutes of Health Stroke Scale (NIHSS) score, cerebral hemodynamics, and VEF and OS indexes. Results. The short-term efficacy was better in OG (93.98%) than in CG (82.28%). After treatment, the NIHSS score decreased in both cohorts with obvious differences within the group at different time points, and the posttreatment NIHSS score was lower in OG as compared to CG. OG had higher Q m and V m while lower W v , Z cv , and R v than CG. Higher endothelial-dependent flow-mediated dilatation (FMD) was observed in OG, as well as lower ankle-brachial index (ABI) and pulse wave velocity (PWV). And the posttreatment MDA was lower while SOD, GSH-Px, and TAC were higher in OG compared with those on CG. All the above differences were of statistical significance ( P < 0.05 ). Conclusions. DSA-guided neurointerventional thrombolysis is highly effective in the treatment of AICVD, which can not only effectively improve patients’ neurological function and cerebral hemodynamics but also mitigate VEF injury and help to alleviate patients’ OS.
Many studies have found that circRNA hsa_0002360 (circ0002360) plays an important role in cancer onset and progression. However, its role in gastric cancer (GC) remains uncertain. Circ0002360 was found to be upregulated in GC cells using QRT-PCR. Furthermore, miR-629-3p, a target miRNA of circ0002360, was the most suppressed miRNA following circ0002360 overexpression. RNA immunoprecipitation (RIP), dual-luciferase reporter analyses, clone formation, transwell, DCFH-DA, and ELISA assays demonstrated that circ0002360-targeted miR-629-3p promotes cell proliferation and migration while inhibiting oxidative stress. GC-related mRNA microarrays from the GEO and TCGA databases, including GSE103236, GSE79973, GSE33429, GSE22804, GSE84437, and TCGA-STAD datasets, were used to find hub biomarkers between normal and gastric cancer samples. WGCNA and uni-Cox analysis were used to identify 27 survival-related risk genes, which were then used to build a risk model for prognosis prediction. Following that, all patients from the GSE84437 and TCGA-STAD datasets with 27 survival-related genes and enough data on survival status and time were randomly assigned to train ( n = 433 ) and test ( n = 375 ) cohorts. Furthermore, ROC and Kaplan-Meier (KM) analyses were used to validate the risk model for both cohorts. randomForest analysis indicated that PDLIM4 was the target gene of miR-629-3p, whose level was increased by circ0002360 but reversed by miR-629-3p mimics. Finally, this study confirmed that circ0002360 sponged miR-629-3p and then upregulated PDLIM4 expression. As a result, circ0002360 may be a useful marker for predicting GC prognosis and an anti-GC treatment target.
Objective. Research over the past decade has suggested important roles for pseudogenes in gliomas. Our previous study found that the RPL4P4 pseudogene is highly expressed in gliomas. However, its biological function in gliomas remains unclear. Methods. In this study, we analyzed clinical data on patients with glioma obtained from The Cancer Genome Atlas (TCGA), the Chinese Glioma Genome Atlas (CGGA), the Genotype-Tissue Expression (GTEx), and the GEPIA2 databases. We used the R language for the main analysis. Correlations among RPL4P4 expression, pathological characteristics, clinical outcome, and biological function were evaluated. In addition, the correlations of RPL4P4 expression with immune cell infiltration and glioma progression were analyzed. Finally, wound healing, Transwell, and CCK-8 assays were performed to analyze the function of RPL4P4 in glioma cells. Result. We found that RPL4P4 is highly expressed in glioma tissues and is associated with poor prognosis, IDH1 wild type, codeletion of 1p19q, and age. Multivariate analysis and the nomogram model showed that high RPL4P4 expression was an independent risk factor for glioma prognosis and had better prognostic prediction power. Moreover, high RPL4P4 expression correlated with immune cell infiltration, which showed a significant positive association with M2-type macrophages. Finally, RPL4P4 knockdown in glioma cell lines caused decreased glioma cell proliferation, invasion, and migration capacity. Conclusion. Our data suggest that RPL4P4 can function as an independent prognostic predictor of glioma. It also shows that RPL4P4 expression correlates with immune cell infiltration and that targeting RPL4P4 may be a new strategy for the treatment of glioma patients.
The regulation of collagen synthesis, which occurs in fibroblasts in the dermal layer, is a key process in dermis regeneration and skin reconstruction. Herein, we investigated whether Aronia melanocarpa extract affects the human skin condition. We focused on type I collagen synthesis using two different types of model systems: a monolayer of cells and a bioprinted 3D dermal equivalent. The Aronia extract showed no cytotoxicity and increased cell proliferation in neonatal human dermal fibroblasts. Treatment with Aronia extract increased the transcription of COL1A1 mRNA in direct proportion to the extract concentration without causing a decrease in COL1A1 mRNA degradation. Additionally, the Aronia extract inhibited the expression of MMP1 and MMP3, and an increase in type I collagen was observed along with a decrease in MMP1 protein. We also fabricated dermal equivalents from type I collagen (the major component of the dermis) and dermal fibroblasts by bioprinting. In the 3D dermis model, the compressive modulus directly affected by collagen synthesis increased in direct proportion to the Aronia extract concentration, and expression levels of MMP1 and MMP3 decreased in exactly inverse proportion to its concentration. The findings that the Aronia extract increases synthesis of type I collagen and decreases MMP1 and MMP3 expression suggest that this extract may be useful for the treatment of damaged or aged skin.
Acute kidney injury (AKI) is still a puzzling clinical problem; its pathophysiology is not completely understood. Up to now, an effective treatment for AKI is lacking. Ferroptosis is a novel form of regulated cell death characterized by the lethal accumulation of lipid hydroperoxides that are dependent on iron and reactive oxygen species and mitochondrial dysfunction. Recently, ferroptosis was shown to play a vital role in AKI such as ischemia-reperfusion kidney injury and folic acid-induced AKI. Melatonin (MT) is an antioxidant that regulates the sleep-wake cycle. While the therapeutic effect of melatonin on AKI has been reported, its mechanism for the treatment of renal ferroptosis remains unclear. We found that melatonin treatment significantly alleviated the serum biochemistry index and histopathological alterations in vivo AKI models induced by bilateral renal artery ischemia reperfusion and folic acid in mice. Ferroptosis induced by hypoxia and reoxygenation or erastin (Era) in mouse tubular epithelial cells (MTEC) was also rescued by melatonin treatment. RNA sequence analysis of ferroptosis-related genes showed that melatonin affects oxidative stress responses by inhibiting hypoxia and reoxygenation- (HR-) mediated downregulation of NRF2 and upregulation of Slc7a11 in MTEC. Specific knockdown of NRF2 increased the sensitivity of cells to ferroptosis, and melatonin failed to protect against ferroptosis in the HR condition. Together, our data indicate that melatonin prevents ferroptosis in AKI by acting on the NRF2/Slc7a11 axis.
Chronic cerebral hypoperfusion (CCH) is a cardinal risk factor for Parkinson’s disease dementia (PDD), but this potential causality lacks mechanistic evidence. We selected bilateral common carotid artery occlusion (BCCAO) to simulate chronic cerebral hypoperfusion in the rat model of PD induced by typical neurotoxin 6-hydroxy dopamine (6-OHDA). Four weeks after unilateral injection of 6-OHDA into the medial forebrain bundle, rats underwent BCCAO. Male Sprague-Dawley rats were divided into five groups of ten, including sham, PD+BCCAO 2 weeks, PD+BCCAO 1 week, PD, and BCCAO 2 weeks. Then, open field test (OFT) and Morris water maze test (MWM) were used to assess the PDD-like symptoms in rats. Also, the pathological manifestations and mechanisms of BCCAO impairing cognitive functions have been explored via hematoxylin-eosin staining, Nissl staining, immunohistochemistry, immunofluorescence, RNA sequencing analysis, lipidomics, and quantitative real-time polymerase chain reaction. In this study, we found that CCH could aggravate PDD-like cognitive symptoms (i.e., learning memory and spatial cognition) and PDD-like pathology (higher expression of α-Syn and Aβ in prefrontal cortex and striatum). Moreover, a potential relationship between differentially expressed mRNAs and lipid metabolism was revealed by RNA sequencing analysis. Lipidomics showed that CCH could affect the intensity of 5 lipids, including sphingomyelin (SM 9:0;2O/26:2; SM 8:1;2O/25:0; and SM 8:0;2O/28:4), cardiolipin, lysophosphatidylcholine, cholesteryl ester, and triacylglycerol. Interestingly, the KEGG pathway analysis of both RNA sequencing analysis and lipidomics suggested that CCH leaded to learning impairment by affecting sphingolipid metabolism. Finally, we found that CCH disrupts the sphingolipid metabolism by affecting the mRNA expression of SMPD1 and SMS2, leading to the accumulation of sphingomyelin in the prefrontal cortex. In summary, CCH, an independent exacerbating reason for impairment in learning and memory within the pathopoiesis of PD, aggravates Parkinson’s disease dementia-like symptoms and pathology in 6-OHDA-lesioned rat through interfering with sphingolipid metabolism.
Our previous studies have shown that delicaflavone (DLL), a biocomponent extracted from Selaginella doederleinii Hieron, has antitumor activity. However, the role of DLL in the antitumor immune response is unknown. In this study, we tested the potential roles of DLL in antitumor immune response. An animal tumor model with Lewis lung cancer cell line (3LL) in C57BL/6 mice was established to determine whether DLL induced the tumor-bearing host’s antitumor immune response. m6A-MeRIP-qPCR, western blot, and flow cytometry were performed to explore the underlying mechanisms. DLL inhibited the proliferation of 3LL lung cancer cells in vitro and in vivo and induced tumor cell oxidative stress. DLL significantly inhibited tumor growth in immunocompetent mice compared with nude mice. DLL treatment significantly increased Th1 cytokine production and CD8+ T cell infiltration into tumor tissues in tumor-bearing mice. DLL-mediated antitumor immune effects were reversed by overexpression of the N6-methyladenosine (m6A) transferase Mettl3/Mettl14. Mechanistically, DLL upregulated the expression of Stat1 and Irf1 and the secretion of cytokines by inhibiting Mettl3 and Mettl14 in lung cancer cells. In conclusion, DLL inhibited lung cancer cell growth by suppressing Mettl3/Mettl14 to activate antitumor immunity. These findings provided an opportunity to enhance lung cancer immunotherapy.
Aging shows a decline in overall physical function, and cellular senescence is the powerful catalyst leading to aging. Considering that aging will be accompanied with the emergence of various aging-related diseases, research on new antiaging drugs is still valuable. Extracellular vesicles (EVs), as tools for intercellular communication, are important components of the senescence-associated secretory phenotype (SASP), and they can play pathological roles in the process of cellular senescence. In addition, EVs are similar to their original cells in functions. Therefore, EVs derived from pathological tissues or body fluids may be closely related to the progression of diseases and become potential biomarkers, while those from healthy cells may have therapeutic effects. Moreover, EVs are satisfactory drug carriers. At present, numerous studies have supported the idea that engineered EVs could improve drug targeting ability and utilization efficiency. Here, we summarize the characteristics of EVs and cellular senescence and focus on the diagnostic and therapeutic potential of EVs in various aging-related diseases, including Alzheimer disease, osteoporosis, cardiovascular disease, diabetes mellitus and its complications, and skin aging.
The intestinal barrier plays a fundamental role in body health. Intracellular redox imbalance can trigger endoplasmic reticulum stress (ERS) and mitophagy, leading to intestinal barrier damage. Our previous studies demonstrated that mitophagy is closely associated with the protective effects of biogenic selenium nanoparticles (SeNPs) on intestinal epithelial barrier function. Thus, we hypothesize that ERS and mitophagy are likely involved in the regulatory effects of SeNPs on oxidative stress-induced intestinal epithelial barrier dysfunction. The results showed that oxidative stress or ERS caused the increase of intestinal epithelial permeability. SeNPs effectively alleviated hydrogen peroxide (H2O2-)-induced structural damage of endoplasmic reticulum (ER) and mitochondria of porcine jejunal epithelial cells (IPEC-J2). SeNPs significantly decreased intracellular inositol triphosphate (IP3) and Ca2+ concentration, down-regulated inositol trisphosphate receptor (IP3R) expression level, and up-regulated ER-resident selenoproteins mRNA levels in IPEC-J2 cells exposed to H2O2. In addition, SeNPs pretreatment significantly decreased the intracellular Ca2+, IP3, IP3R, and reactive oxygen species (ROS) levels; protected the structure and function of ER and mitochondria; and effectively alleviated the increase of intestinal epithelial permeability of IPEC-J2 cells exposed to tunicamycin (TM). Moreover, SeNPs significantly inhibited the colocalization of mitochondria and lysosomes. Furthermore, compared with TM model group, SeNPs significantly inhibited the activation of PERK/eIF2α/ATF4 and AMPK/mTOR/PINK1 signaling pathway. The PERK agonist (CCT020312) and the AMPK agonist (AICAR) could reverse the protective effects of SeNPs on IPEC-J2 cells. The PERK inhibitor (GSK2656157) and the AMPK inhibitor (compound C) had a similar effect on IPEC-J2 cells as that of SeNPs. In summary, the protective effects of SeNPs on intestinal barrier dysfunction are closely associated with ERS-related PERK and mitophagy-related AMPK signaling pathway.
Ocular ischemia/hypoxia is a severe problem in ophthalmology that can cause vision impairment and blindness. However, little is known about the changes occurring in the existing fully formed choroidal blood vessels. We developed a new whole organ culture model for ischemia/hypoxia in rat eyes and investigate the effects of pigment epithelium derived factor (PEDF) protein on the eye tissues. The concentration of oxygen within the vitreous was measured in the enucleated rat eyes and living rats. Then, ischemia was mimicked by incubating the freshly enucleated eyes in medium at 4°C for 14 h. Eyes were fixed immediately after enucleation or were intravitreally injected with PEDF protein or with vehicle before incubation. After incubation, light and electron microscopy (EM) as well as Tunel staining was performed. In the living rats, the intravitreal oxygen concentration was on average at 16.4% of the oxygen concentration in the air and did not change throughout the experiment whereas it was ca. 28% at the beginning of the experiment and gradually decreased over time in the enucleated eyes. EM analysis revealed that the shape of the choriocapillaris changed dramatically after 14 h incubation in the enucleated eyes. The endothelial cells made filopodia-like projections into the vessel lumen. They appeared identical to the labyrinth capillaries found in surgically extracted choroidal neovascular membranes from patients with wet age-related macular degeneration (AMD). These filopodia-like projections nearly closed the vessel lumen and showed open gaps between neighboring endothelial cells. PEDF significantly inhibited labyrinth capillary formation and kept the capillary lumen open. The number of TUNEL-positive ganglion cells and inner nuclear layer cells was significantly reduced in the PEDF-treated eyes compared to the vehicle-treated eyes. The structural changes in the chroidal vessels observed under ischemia/hypoxia conditions can mimic early changes in the process of pathological angiogenesis as observed in wet AMD patients. This new model can be used to investigate short-term drug effects on the choriocapillaris after ischemia/hypoxia and it highlighted the potential of PEDF as a promising candidate for treating wet AMD.
tRNA-derived fragments (tRFs) have been reported to have critical regulatory roles in osteoarthritis (OA). Recent studies have suggested that autophagy promotes the homeostasis of the extracellular matrix of chondrocytes in OA. However, the role of tRFs in posttranscriptional gene regulation during autophagy in OA is unknown. Therefore, we explored the role of tRF-5009A in the posttranscriptional gene regulation of autophagy and cartilage degeneration in OA. Using RNA sequencing, we identified tRF-5009A, the tRNAValCAC-derived fragment, in OA tissues and explored its expression by quantitative reverse transcription PCR and fluorescence in situ hybridization. We further investigated the relationship between the expression of tRF-5009A and clinical factors in OA. Chondrocytes were transfected with a tRF-5009A inhibitor or mimic to determine their functions, including in relation to autophagy and the cartilage phenotype. A rescue experiment and dual-luciferase reporter assay were conducted to determine whether the 3 ′ -untranslated region (UTR) of mTOR contains a tRF-5009A-binding site. tRF-5009A was downregulated in the cartilage of OA knees, especially in damaged areas. mTOR was highly expressed in damaged cartilage and negatively correlated with the expression of tRF-5009A; transfection with a tRF-5009A inhibitor promoted the expression of mTOR and suppressed autophagy, whereas transfection with a tRF-5009A mimic had the opposite effect. A dual-luciferase reporter assay showed that tRF-5009A silenced the expression of mTOR by binding to its 3 ′ -UTR. Thus, tRF-5009A regulates autophagy and cartilage degeneration in OA by targeting mTOR. In summary, these findings provide an additional tool for the clinical diagnosis and novel targeted therapy of OA.
Atherosclerosis (AS) is a chronic inflammatory disease, which has a complex interplay between altered immune metabolism and oxidative stress. Therefore, we aimed to determine the oxidative stress and immune-related biomarkers in AS. Differential gene expression analyses are based on the GSE100927 dataset in the Gene Expression Omnibus (GEO), and 389 oxidative stress (OS) genes are identified based on gene set enrichment analysis (GSEA). We identified 74 differentially expressed genes related to oxidative stress (DEOSGs). “CIBERSORT” and “WGCNA” R Packages were used to compare the differences in immune infiltration levels between AS and control samples. The DEOSGs ( N = 74 ) were intersected with the key module’s genes of WGCNA ( N = 972 ), and 27 differentially expressed immune-related oxidative stress genes (DEIOSGs) were obtained. To identify the pivotal genes, a protein-protein interaction (PPI) network was constructed using the STRING database and the Cytoscape software. MMP9, ALOX5, NCF2, NCF, and NCF4 were identified as diagnostic markers of AS, and we validated them in the GSE57691 dataset. The expression levels of the five diagnostic genes were significantly highly expressed in the AS group. Correlation analysis and single-cell analysis revealed that five diagnostic genes were mainly correlated with macrophages M1. We, respectively, intersected differentially expressed genes (DEGs) with ferroptosis gene set, necroptosis gene set, and pyroptosis gene set. The findings suggested that ALOX5 and NCF2 were differentially expressed genes of ferroptosis. High expression of five hub genes in RAW264.7 macrophages were confirmed by PCR. High ALOX5 and NCF2 expression levels in plaque tissues were confirmed by immunohistochemistry (IHC) and western blotting. Our study identified that MMP9, ALOX5, NCF2, NCF1, and NCF4 were diagnostic genes of AS and associated with oxidative stress. ALOX5 and NCF2 may be involved in the formation of the necrotic core in AS by regulating macrophage ferroptosis.
Objective. To assess the effects of dietary white meat (grass carp and chicken) and red meat (pork and beef) on metabolic parameters, including the intestinal microbiota and its metabolites (SCFAs and bile acids) in NAFLD rats induced by high-fat diet. Methods. NAFLD rats were randomly assigned to five groups: NAFLD group, grass carp group, chicken group, pork group, and beef group (10 rats in each group), and these rats were fed for 8 weeks using the high-fat diet, grass carp-based diet, chicken-based diet, pork-based diet, and beef-based diet, respectively. At the end of the intervention, NAFLD-related metabolic indexes, intestinal flora, and its metabolites were measured. Results. The grass carp-based diet significantly improved hepatic pathological changes and glycolipid metabolism, and the chicken-based diet only partially improved the metabolic parameters. However, NAFLD progression was observed in the pork group and the beef group. What is more, the white meat-based diet-mediated changes in the enrichment of beneficial bacteria (such as Lactobacillus or Akkermansia), SCFAs, and unconjugated BAs (such as UDCA) and the depletion of pathogenic bacteria (such as Bilophila and Prevotella_9) and conjugated BAs were observed, while the red meat-based diet-induced changes in the enrichment of pathogenic bacteria (Prevotella_9 or Lachnospiraceae_UCG-010) and conjugated BAs and the depletion of SCFAs and unconjugated BAs were found. Conclusion. The dietary white meat and red meat modulating gut microbiota and its metabolites may favor and aggravate NAFLD in rats, respectively.
Hypertrophic obesity, characterized by an excessive expansion of subcutaneous adipocytes, causes chronic inflammation and insulin resistance. It is the primary feature of obesity in middle-aged and elderly individuals. In the adipose microenvironment, a high level of endoplasmic reticulum (ER) stress and changes in the extracellular vesicle (EV) composition of adipocytes may cause the senescence and restrained differentiation of progenitor cells of adipose, including adipose-derived mesenchymal stem cells (ASCs). In this study, a hypertrophic obesity mouse model was established, and the effects of adipocytes on the ER stress and senescence of ASCs were observed in a coculture of control ASCs and hypertrophic obesity mouse adipocytes or their derived EVs. The adipocytes of hypertrophic obesity mice were treated with GW4869 or an iron chelation agent to observe the effects of EVs secreted by adipocytes and their iron contents on the ER stress and senescence of ASCs. Results showed higher ER stress level and senescence phenotypes in the ASCs from the hypertrophic obesity mice than in those from the control mice. The ER stress, senescence phenotypes, and ferritin level of ASCs can be aggravated by the coculture of ASCs with adipocytes or EVs released by them from the hypertrophic obesity mice. GW4869 or iron chelator treatment improved the ER stress and senescence of the ASCs cocultured with EVs released by the adipocytes of the hypertrophic obesity mice. Our findings suggest that EV-mediated transmissible ER stress is responsible for the senescence of ASCs in hypertrophic obesity mice.
Head and neck squamous carcinoma (HNSC) is the most prevalent malignancy of the head and neck regions. Long noncoding RNAs (lncRNAs) are vital in tumorigenesis regulation. However, the role of lncRNAs in HNSC requires further exploration. Herein, through bioinformatic assays using The Cancer Genome Atlas (TCGA) datasets, rapid amplification of cDNA ends (RACE) assays, and RNA-FISH, we revealed that a novel cytoplasmic transcript, HNSC-associated transcript 1 (HNSCAT1, previously recognized as linc01269), was downregulated in tumor samples and advanced tumor stages and was also associated with favorable outcomes in HNSC. Overexpression of HNSCAT1 triggered treatment efficacy in HNSCs both in vivo and in vitro. More importantly, through high-throughput transcriptome analysis (RNA-seq, in NODE database, OEZ007550), we identified KRT80, a tumor suppressor in HNSC, as the target of HNSCAT1. KRT80 expression was modulated by lncRNA HNSCAT1 and presented a positive correlation in tumor samples ( R = 0.52 , p < 0.001 ). Intriguingly, we identified that miR-1245 simultaneously interacts with KRT80 and HNSCAT1, which bridges the regulatory function between KRT80 and HNSCAT1. Conclusively, our study demonstrated that lncRNA HNSCAT1 functions as a necessary tumor inhibitor in HNSC, which provides a novel mechanism of lncRNA function and provides alternative targets for the diagnosis and treatment of HNSC.
Schematic illustration for the potential therapeutic effects of DPX on ICH and the underlying mechanism.
Deciphering the factors causing damage to white matter fiber bundles and exploring new strategies to alleviate white matter injury (WMI) is a promising treatment to improve neurological impairments after intracerebral hemorrhage (ICH). Ferroptosis usually occurs at perihematomal region and contributes to neuronal death due to reactive oxygen species (ROS) production. Dexpramipexole (DPX) easily crosses the blood brain barrier (BBB) and exerts antioxidative properties by reducing ROS production, while the role of DPX in ferroptosis after ICH remains elusive. Here, our results indicated that ferroptosis played a significant role in WMI resulting from iron and ROS accumulation around hematoma. Further evidence demonstrated that the administration of DPX decreased iron and ROS deposition to inhibit ferroptosis at perihematomal site. With the inhibition of ferroptosis, WMI was alleviated at perihematomal site, thereafter promoting locomotion and motor coordination recovery in mice after ICH. Subsequently, the results showcased that the expression of glutathione peroxidase 4 (GPX4) and ferroptosis suppressing protein 1 (FSP1) was upregulated with the administration of DPX. Collectively, the present study uncovers the underlying mechanism and elucidates the therapeutic effect of DPX on ICH, and even in other central nervous system (CNS) diseases with the presence of ferroptosis.
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12 days
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85 days
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27 days
Acceptance to publication
Acceptance rate
7.310 (2021)
Journal Impact Factor™
9.3 (2021)
Top-cited authors
Syed Ibrahim Rizvi
  • University of Allahabad
Kanti Bhooshan Pandey
  • University of Allahabad
Mario F Muñoz
  • Universidad de Sevilla
Antonio Ayala
  • Universidad de Sevilla
Sandro Argüelles
  • Universidad de Sevilla