Journal of molecular medicine (Berlin, Germany)最新文献

{"title":"The acidic tumor microenvironment drives a stem-like phenotype in melanoma cells.","authors":"Elena Andreucci,&nbsp;Silvia Peppicelli,&nbsp;Jessica Ruzzolini,&nbsp;Francesca Bianchini,&nbsp;Alessio Biagioni,&nbsp;Laura Papucci,&nbsp;Lucia Magnelli,&nbsp;Benedetta Mazzanti,&nbsp;Barbara Stecca,&nbsp;Lido Calorini","doi":"10.1007/s00109-020-01959-y","DOIUrl":"https://doi.org/10.1007/s00109-020-01959-y","url":null,"abstract":"<p><p>Acidosis characterizes the microenvironment of most solid tumors and is considered a new hallmark of cancer. It is mainly caused by both \"aerobic\" and \"anaerobic\" glycolysis of differently adapted cancer cells, with the final product lactic acid being responsible of the extracellular acidification. Many evidences underline the role of extracellular acidosis in tumor progression. Among the different findings, we demonstrated that acidosis-exposed cancer cells are characterized by an epithelial-to-mesenchymal transition phenotype with high invasive ability, high resistance to apoptosis, anchorage-independent growth, and drug therapy. Acidic melanoma cells over-express SOX2, which is crucial for the maintenance of their oxidative metabolism, and carbonic anhydrase IX, that correlates with poor prognosis of cancer patients. Considering these evidences, we realized that the profile outlined for acid cancer cells inevitably remind us the stemness profile. Therefore, we wondered whether extracellular acidosis might induce in cancer cells the acquisition of stem-like properties and contribute to the expansion of the cancer stem cell sub-population. We found that a chronic adaptation to acidosis stimulates in cancer cells the expression of stem-related markers, also providing a high in vitro/in vivo clonogenic and trans-differentiating ability. Moreover, we observed that the acidosis-induced stem-like phenotype of melanoma cells was reversible and related to the EMT induction. These findings help to characterize a further aspect of stem cell niche, contributing to the sustainment and expansion of cancer stem cell subpopulation. Thus, the usage of agents controlling tumor extracellular acidosis might acquire great importance in the clinic for the treatment of aggressive solid tumor. KEY MESSAGES: • Extracellular acidosis up-regulates EMT and stem-related markers in melanoma cells • Acidic medium up-regulates in vitro self-renewal capacity of melanoma cells • Chronic acidosis adaptation induces trans-differentiation ability in melanoma cells • Melanoma cells adapted to acidosis show higher tumor-initiating potential than control cells • Extracellular acidosis promotes a stem-like phenotype in prostate and colorectal carcinoma cells.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":" ","pages":"1431-1446"},"PeriodicalIF":4.7,"publicationDate":"2020-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s00109-020-01959-y","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38279808","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Revisiting lactate dynamics in cancer-a metabolic expertise or an alternative attempt to survive?","authors":"Cindy Mendes,&nbsp;Jacinta Serpa","doi":"10.1007/s00109-020-01965-0","DOIUrl":"https://doi.org/10.1007/s00109-020-01965-0","url":null,"abstract":"<p><p>Cancer cells are able to rewire their metabolism in order to support and allow rapid proliferation, continuous growth, and survival in hostile conditions, such as acidosis and hypoxia. Lactate is the final product of anaerobic glycolysis in several organisms being considered during most of the last century a dead-end waste product. In cancer context, the majority of studies on lactate have focused on its production rather than on its consumption. However, lactate has been currently proposed as a unique source of energy, a signalling molecule, and a target for cancer therapy. Cancer cells are capable of importing lactate and utilising it for energetic purposes. Indeed, lactate is a crucial substrate that fuels the oxidative metabolism of oxygenated cancer cells. In this review, we discuss the role of lactate as a key molecule in carcinogenesis, acting as a fuel for cancer cell survival, growth, and proliferation, and we describe potential therapeutic approaches to target lactate metabolism in cancer.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":" ","pages":"1397-1414"},"PeriodicalIF":4.7,"publicationDate":"2020-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s00109-020-01965-0","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38291693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Need for a precise molecular diagnosis in Beckwith-Wiedemann and Silver-Russell syndrome: what has to be considered and why it is important.","authors":"Thomas Eggermann,&nbsp;Johanna Brück,&nbsp;Cordula Knopp,&nbsp;György Fekete,&nbsp;Christian Kratz,&nbsp;Velibor Tasic,&nbsp;Ingo Kurth,&nbsp;Miriam Elbracht,&nbsp;Katja Eggermann,&nbsp;Matthias Begemann","doi":"10.1007/s00109-020-01966-z","DOIUrl":"https://doi.org/10.1007/s00109-020-01966-z","url":null,"abstract":"<p><p>Molecular diagnostic testing of the 11p15.5-associated imprinting disorders Silver-Russell and Beckwith-Wiedemann syndrome (SRS, BWS) is challenging due to the broad spectrum of molecular defects and their mosaic occurrence. Additionally, the decision on the molecular testing algorithm is hindered by their clinical heterogeneity. However, the precise identification of the type of defect is often a prerequisite for the clinical management and genetic counselling. Four major molecular alterations (epimutations, uniparental disomies, copy number variants, single nucleotide variants) have been identified, but their frequencies vary between SRS and BWS. Due to their molecular aetiology, epimutations in both disorders as well as upd(11)pat in BWS are particular prone to mosaicism which might additionally complicate the interpretation of testing results. We report on our experience of molecular analysis in a total cohort of 1448 patients referred for diagnostic testing of BWS and SRS, comprising a dataset from 737 new patients and from 711 cases from a recent study. Though the majority of positively tested patients showed the expected molecular results, we identified a considerable number of clinically unexpected molecular alterations as well as not yet reported changes and discrepant mosaic distributions. Additionally, the rate of multilocus imprinting disturbances among the patients with epimutations and uniparental diploidies could be further specified. Altogether, these cases show that comprehensive testing strategies have to be applied in diagnostic testing of SRS and BWS. The precise molecular diagnosis is required as the basis for a targeted management (e.g. ECG (electrocardiogram) and tumour surveillance in BWS, growth treatment in SRS). The molecular diagnosis furthermore provides the basis for genetic counselling. However, it has to be considered that recurrence risk calculation is determined by the phenotypic consequences of each molecular alteration and mechanism by which the alteration arose. KEY MESSAGES: The detection rates for the typical molecular defects of Beckwith-Wiedemann syndrome or Silver-Russell syndrome (BWS, SRS) are lower in routine cohorts than in clinically well-characterised ones. A broad spectrum of (unexpected) molecular alterations in both disorders can be identified. Multilocus imprinting disturbances (MLID) are less frequent in SRS than expected. The frequency of MLID and uniparental diploidy in BWS is confirmed. Mosaicism is a diagnostic challenge in BWS and SRS. The precise determination of the molecular defects affecting is the basis for a targeted clinical management and genetic counselling.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":" ","pages":"1447-1455"},"PeriodicalIF":4.7,"publicationDate":"2020-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s00109-020-01966-z","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38400288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MicroRNA-181a regulates IFN-γ expression in effector CD8⁺ T cell differentiation.","authors":"Tiago Amado,&nbsp;Ana Amorim,&nbsp;Francisco J Enguita,&nbsp;Paula V Romero,&nbsp;Daniel Inácio,&nbsp;Marta Pires de Miranda,&nbsp;Samantha J Winter,&nbsp;J Pedro Simas,&nbsp;Andreas Krueger,&nbsp;Nina Schmolka,&nbsp;Bruno Silva-Santos,&nbsp;Anita Q Gomes","doi":"10.1007/s00109-019-01865-y","DOIUrl":"https://doi.org/10.1007/s00109-019-01865-y","url":null,"abstract":"<p><p>CD8⁺ T cells are key players in immunity against intracellular infections and tumors. The main cytokine associated with these protective responses is interferon-γ (IFN-γ), whose production is known to be regulated at the transcriptional level during CD8⁺ T cell differentiation. Here we found that microRNAs constitute a posttranscriptional brake to IFN-γ expression by CD8⁺ T cells, since the genetic interference with the Dicer processing machinery resulted in the overproduction of IFN-γ by both thymic and peripheral CD8⁺ T cells. Using a gene reporter mouse for IFN-γ locus activity, we compared the microRNA repertoires associated with the presence or absence of IFN-γ expression. This allowed us to identify a set of candidates, including miR-181a and miR-451, which were functionally tested in overexpression experiments using synthetic mimics in peripheral CD8⁺ T cell cultures. We found that miR-181a limits IFN-γ production by suppressing the expression of the transcription factor Id2, which in turn promotes the Ifng expression program. Importantly, upon MuHV-4 challenge, miR-181a-deficient mice showed a more vigorous IFN-γ⁺ CD8⁺ T cell response and were able to control viral infection significantly more efficiently than control mice. These data collectively establish a novel role for miR-181a in regulating IFN-γ-mediated effector CD8⁺ T cell responses in vitro and in vivo.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":" ","pages":"309-320"},"PeriodicalIF":4.7,"publicationDate":"2020-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s00109-019-01865-y","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37596407","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sphingosine is able to prevent and eliminate Staphylococcus epidermidis biofilm formation on different orthopedic implant materials in vitro.","authors":"Sascha Beck,&nbsp;Carolin Sehl,&nbsp;Sylvia Voortmann,&nbsp;Hedda Luise Verhasselt,&nbsp;Michael J Edwards,&nbsp;Jan Buer,&nbsp;Mike Hasenberg,&nbsp;Erich Gulbins,&nbsp;Katrin Anne Becker","doi":"10.1007/s00109-019-01858-x","DOIUrl":"https://doi.org/10.1007/s00109-019-01858-x","url":null,"abstract":"<p><p>Periprosthetic infection (PPI) is a devastating complication in joint replacement surgery. On the background of an aging population, the number of joint replacements and associated complications is expected to increase. The capability for biofilm formation and the increasing resistance of different microbes to antibiotics have complicated the treatment of PPI, requiring the need for the development of alternative treatment options. The bactericidal effect of the naturally occurring amino alcohol sphingosine has already been reported. In our study, we demonstrate the antimicrobial efficacy of sphingosine on three different strains of biofilm producing Staphylococcus epidermidis, representing one of the most frequent microbes involved in PPI. In an in vitro analysis, sphingosine's capability for prevention and treatment of biofilm-contamination on different common orthopedic implant surfaces was tested. Coating titanium implant samples with sphingosine not only prevented implant contamination but also revealed a significant reduction of biofilm formation on the implant surfaces by 99.942%. When testing the antimicrobial efficacy of sphingosine on sessile biofilm-grown Staphylococcus epidermidis, sphingosine solution was capable to eliminate 99.999% of the bacteria on the different implant surfaces, i.e., titanium, steel, and polymethylmethacrylate. This study provides evidence on the antimicrobial efficacy of sphingosine for both planktonic and sessile biofilm-grown Staphylococcus epidermidis on contaminated orthopedic implants. Sphingosine may provide an effective and cheap treatment option for prevention and reduction of infections in joint replacement surgery. KEY MESSAGES: • Here we established a novel technology for prevention of implant colonization by sphingosine-coating of orthopedic implant materials. • Sphingosine-coating of orthopedic implants prevented bacterial colonization and significantly reduced biofilm formation on implant surfaces by 99.942%. • Moreover, sphingosine solution was capable to eliminate 99.999% of sessile biofilm-grown Staphylococcus epidermidis on different orthopedic implant surfaces.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":" ","pages":"209-219"},"PeriodicalIF":4.7,"publicationDate":"2020-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s00109-019-01858-x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37479754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regimen-dependent synergism and antagonism of treprostinil and vildagliptin in hematopoietic cell transplantation.","authors":"Eva Zebedin-Brandl,&nbsp;Madeleine Themanns,&nbsp;Zahra Kazemi,&nbsp;Shahrooz Nasrollahi-Shirazi,&nbsp;Marion Mussbacher,&nbsp;Elizabeth Heyes,&nbsp;Katrin Meissl,&nbsp;Michaela Prchal-Murphy,&nbsp;Wolfgang Strohmaier,&nbsp;Guenther Krumpl,&nbsp;Michael Freissmuth","doi":"10.1007/s00109-019-01869-8","DOIUrl":"https://doi.org/10.1007/s00109-019-01869-8","url":null,"abstract":"<p><p>The cell dose in umbilical cord blood units is a major determinant for the outcome of hematopoietic cell transplantation. Prostaglandin analogs and dipeptidylpeptidase-4 (DPP4/CD26)-inhibitors enhance the ability of hematopoietic stem cells (HSCs) to reconstitute hematopoiesis. Here we explored the synergism between treprostinil, a stable prostaglandin agonist, and the DPP4/CD26-inhibitor vildagliptin. The combination of treprostinil and forskolin caused a modest but statistically significant increase in the surface levels of DPP4/CD26 on hematopoietic stem and progenitor cells (HSPCs) derived from murine bone and human cord blood. Their migration towards stromal cell-derived factor-1 (SDF-1/CXCL12) was enhanced, if they were pretreated with treprostinil and forskolin, and further augmented by vildagliptin. Administration of vildagliptin rescued 25% of lethally irradiated recipient mice injected with a limiting number of untreated HSPCs, but 90 to 100% of recipients injected with HSPCs preincubated with treprostinil and forskolin. The efficacy of vildagliptin surpassed that of treprostinil (60% rescue). Surprisingly, concomitant administration of vildagliptin and treprostinil resulted in poor survival of recipients indicating mutual antagonism, which was recapitulated when homing of and colony formation by HSPCs were assessed. These observations of regimen-dependent synergism and antagonism of treprostinil and vildagliptin are of translational relevance for the design of clinical trials. KEY MESSAGES: Pretreatment with treprostinil increases surface levels of DPP4/CD26 in HSPCs. Vildagliptin enhances in vitro migration of pretreated HSPCs. Vildagliptin enhances in vivo homing and engraftment of pretreated HSPCs. Unexpected mutual antagonism in vivo by concomitant administration of vildagliptin and treprostinil.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":" ","pages":"233-243"},"PeriodicalIF":4.7,"publicationDate":"2020-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s00109-019-01869-8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37487369","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NOD1 inhibits proliferation and enhances response to chemotherapy via suppressing SRC-MAPK pathway in hepatocellular carcinoma.","authors":"Xiaomin Ma,&nbsp;Yumin Qiu,&nbsp;Lihui Zhu,&nbsp;Yunxue Zhao,&nbsp;Yueke Lin,&nbsp;Dapeng Ma,&nbsp;Zhenzhi Qin,&nbsp;Caiyu Sun,&nbsp;Xuecheng Shen,&nbsp;Tao Li,&nbsp;Lihui Han","doi":"10.1007/s00109-019-01868-9","DOIUrl":"https://doi.org/10.1007/s00109-019-01868-9","url":null,"abstract":"<p><p>NOD1 is an innate immune sensor playing an important role in fighting against infection. However, its role in cancer is far from being clarified, and whether NOD1 plays a role in the progression of hepatocellular carcinoma (HCC) has never been reported. Here, we found that NOD1 expression was significantly decreased in hepatocellular carcinoma tissues and overexpression of NOD1 significantly inhibited tumorigenesis in vivo. In vitro experiments demonstrated that NOD1 inhibited proliferation of HCC cells by directly targeting proto-oncogene SRC and inducing cell cycle arrest at G1 phase. Further investigation showed that NOD1 exerted its antitumor effect by inhibiting SRC activation and further suppressing SRC/MAPK axis in hepatocellular carcinoma cells. Moreover, NOD1 dramatically enhanced the response of HCC cells to chemotherapy via inhibition of SRC-MAPK axis both in vitro and in vivo. Collectively, these data indicated that NOD1 suppressed proliferation and enhanced response to sorafenib or 5-FU treatment through inhibiting SRC-MAPK axis in hepatocellular carcinoma. KEY MESSAGES: NOD1 significantly inhibited tumorigenesis of HCC in cellular and animal models. NOD1 inhibited proliferation of HCC cells by inducing cell cycle arrest. NOD1 exerted its antitumor effect on HCC by directly interacting with SRC and inhibiting SRC-MAPK axis. NOD1 significantly enhanced the chemosensitivity of HCC cells to chemotherapeutic drugs.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":" ","pages":"221-232"},"PeriodicalIF":4.7,"publicationDate":"2020-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s00109-019-01868-9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37487430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ACT001 modulates the NF-κB/MnSOD/ROS axis by targeting IKKβ to inhibit glioblastoma cell growth.","authors":"Qiuying Li,&nbsp;Yu Sun,&nbsp;Bowen Liu,&nbsp;Jiabo Li,&nbsp;Xin Hao,&nbsp;Weizhi Ge,&nbsp;Xuemei Zhang,&nbsp;Shiqi Bao,&nbsp;Jianmiao Gong,&nbsp;Zhenhuan Jiang,&nbsp;Chuanjiang Qiu,&nbsp;Liqing Zhao,&nbsp;Yapu Zhao,&nbsp;Yue Chen,&nbsp;Xuejun Yang,&nbsp;Yahui Ding,&nbsp;Zhenzhou Wu","doi":"10.1007/s00109-019-01839-0","DOIUrl":"https://doi.org/10.1007/s00109-019-01839-0","url":null,"abstract":"<p><p>Glioblastomas are high-grade brain tumors with poor prognoses, and new therapeutic approaches for these tumors are critically needed. This study revealed the underlying mechanisms of a new orphan drug, ACT001, that is currently in clinical trials for the treatment of advanced glioblastoma in Australia and China. ACT001 significantly suppressed glioma cell proliferation and induced apoptosis and cell cycle arrest in vitro, as determined by Cell Counting Kit-8 assays and flow cytometry. In addition, U-118 MG cells with high expression of p-IKKβ were sensitive to ACT001. Changes in the oxidative stress pathway in U-118 MG cells were detected with the isobaric tags for relative and absolute quantitation (iTRAQ) method. We further verified that ACT001 elevated the levels of reactive oxygen species (ROS) by regulating NF-κB-targeted MnSOD. ACT001 markedly inhibited NF-κB activation by directly binding IKKβ and inhibiting its phosphorylation. Overexpression of IKKβ markedly attenuated the changes in MnSOD and NOX1, indicating that ACT001 increased the levels of ROS by reducing the protein expression of p-IKKβ. Furthermore, ACT001 reduced cyclin B1/CDC2 expression and triggered G₂/M phase arrest by increasing ROS production. ACT001 also upregulated the expression of Bax and Bim and induced apoptosis in a ROS-dependent manner. ACT001 effectively suppressed the growth of U-118 MG tumors in BALB/c nude mice and GL-261-luciferase tumors in C57BL/6 J mice. Finally, ACT001 downregulated the expression of p-p65, MnSOD, cyclin B1, CDC2, and Ki67 in U-118 MG tumor tissues. Patients with activated NF-κB signaling should thus be given priority for enrollment in future phase II clinical trials. KEY MESSAGES: ACT001 directly bind to IKKβ and inhibited its phosphorylation. The inhibition of p-IKKβ induced the generation of ROS. ACT001 promoted the generation of ROS by regulating MnSOD expression to induce G₂/M phase arrest.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":" ","pages":"263-277"},"PeriodicalIF":4.7,"publicationDate":"2020-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s00109-019-01839-0","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37511292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deletion of FHL2 in fibroblasts attenuates fibroblasts activation and kidney fibrosis via restraining TGF-β1-induced Wnt/β-catenin signaling.","authors":"Ying Duan,&nbsp;Yumei Qiu,&nbsp;Xiaowen Huang,&nbsp;Chunsun Dai,&nbsp;Junwei Yang,&nbsp;Weichun He","doi":"10.1007/s00109-019-01870-1","DOIUrl":"https://doi.org/10.1007/s00109-019-01870-1","url":null,"abstract":"<p><p>Four-and-a-half LIM domains protein 2 (FHL2) has been proposed involving in β-catenin activity. We previously reported that FHL2 mediates TGF-β1-induced tubular epithelial-to-mesenchymal transition through activating Wnt/β-catenin signaling. However, the potential role and mechanism for FHL2 in TGF-β1-induced fibroblast activation and kidney fibrosis remains unknown. Here, we initially observed higher levels of FHL2 expression in fibrotic kidneys from both patients and mice, especially in α-smooth muscle actin (α-SMA)-positive cells in the interstitium. In cultured interstitial fibroblasts, FHL2 expression was induced by TGF-β1. Knockdown of FHL2 remarkably suppressed TGF-β1-induced α-SMA, type I collagen, and fibronectin expression, while overexpression of FHL2 was sufficient to activate fibroblasts. In mice, fibroblast-specific deletion of FHL2 diminished renal induction of α-SMA, type I collagen, and fibronectin and interstitial extracellular matrix deposition at 2 weeks after ureteral obstruction. We next investigated Wnt/β-catenin activity and found that β-catenin was activated in most FHL2-positive cells in renal interstitium from mice with obstructive nephropathy. In vitro, TGF-β1 induced a physical interaction between FHL2 and β-catenin, especially in the nucleus. Downregulation of FHL2 inhibited TGF-β1-induced active β-catenin upregulation, β-catenin nuclear translocation, and β-catenin-mediated transcription, whereas overexpression of FHL2 was able to activate Wnt/β-catenin signaling. FHL2 overexpression-induced β-catenin-mediated gene transcription could be hindered by ICG-001, but FHL2 overexpression-induced upregulation of active β-catenin could not be. Collectively, this study reveals that the signal regulatory effect of FHL2 on β-catenin plays an important role in TGF-β1-induced fibroblast activation and kidney fibrosis.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":" ","pages":"291-307"},"PeriodicalIF":4.7,"publicationDate":"2020-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s00109-019-01870-1","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37533363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exercise enhances cardiac function by improving mitochondrial dysfunction and maintaining energy homoeostasis in the development of diabetic cardiomyopathy.","authors":"Shawn Yongshun Wang,&nbsp;Siyu Zhu,&nbsp;Jian Wu,&nbsp;Maomao Zhang,&nbsp;Yousheng Xu,&nbsp;Wei Xu,&nbsp;Jinjin Cui,&nbsp;Bo Yu,&nbsp;Wei Cao,&nbsp;Jingjin Liu","doi":"10.1007/s00109-019-01861-2","DOIUrl":"https://doi.org/10.1007/s00109-019-01861-2","url":null,"abstract":"<p><p>Diabetic cardiomyopathy (DCM) is a major cause of morbidity and mortality in diabetic patients. Reactive oxygen species (ROS) produced by oxidative stress play an important role in the development of DCM. DCM involves abnormal energy metabolism, thereby reducing energy production. Exercise has been reported to be effective in protecting the heart against ROS accumulation during the development of DCM. We hypothesize that the AMPK/PGC-1α axis may play a crucial role in exercise-induced bioenergetic metabolism and aerobic respiration on oxidative stress parameters in the development of diabetic cardiomyopathy. Using a streptozotocin/high-fat diet mouse to generate a diabetic model, our aim was to evaluate the effects of exercise on the cardiac function, mitochondrial oxidative capacity, mitochondrial function, and cardiac expression of PGC-1α. Mice fed a high-fat diet were given MO-siPGC-1α or treated with AMPK inhibitor. Mitochondrial structure and effects of switching between the Warburg effect and aerobic respiration were analysed. Exercise improved blood pressure and systolic dysfunction in diabetic mouse hearts. The beneficial effects of exercise were also observed in a mitochondrial function study, as reflected by an enhanced oxidative phosphorylation level, increased membrane potential, and decreased ROS level and oxygen consumption. On the other hand, depletion of PGC-1α attenuated the effects of exercise on the enhancement of mitochondrial function. In addition, PGC-1α may be responsible for reversing the Warburg effect to aerobic respiration, thus enhancing mitochondrial metabolism and energy homoeostasis. In this study, we demonstrate the protective effects of exercise on shifting energy metabolism from fatty acid oxidation to glucose oxidation in an established diabetic stage. These data suggest that exercise is effective at ameliorating diabetic cardiomyopathy by improving mitochondrial function and reducing metabolic disturbances.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":" ","pages":"245-261"},"PeriodicalIF":4.7,"publicationDate":"2020-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s00109-019-01861-2","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37508515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}