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Journal of Molecular Medicine
Journal Prestige (SJR): 2.177
Citation Impact (citeScore): 5
Number of Followers: 11  
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 1432-1440 - ISSN (Online) 0946-2716
Published by Springer-Verlag Homepage  [2352 journals]
  • Approaches to therapeutic angiogenesis for ischemic heart disease
    • Authors: Takerra Johnson; Lina Zhao; Gygeria Manuel; Herman Taylor; Dong Liu
      Pages: 141 - 151
      Abstract: Ischemic heart disease (IHD) is caused by the narrowing of arteries that work to provide blood, nutrients, and oxygen to the myocardial tissue. The worldwide epidemic of IHD urgently requires innovative treatments despite the significant advances in medical, interventional, and surgical therapies for this disease. Angiogenesis is a physiological and pathophysiological process that initiates vascular growth from pre-existing blood vessels in response to a lack of oxygen. This process occurs naturally over time and has encouraged researchers and clinicians to investigate the outcomes of accelerating or enhancing this angiogenic response as an alternative IHD therapy. Therapeutic angiogenesis has been shown to revascularize ischemic heart tissue, reduce the progression of tissue infarction, and evade the need for invasive surgical procedures or tissue/organ transplants. Several approaches, including the use of proteins, genes, stem/progenitor cells, and various combinations, have been employed to promote angiogenesis. While clinical trials for these approaches are ongoing, microvesicles and exosomes have recently been investigated as a cell-free approach to stimulate angiogenesis and may circumvent limitations of using viable cells. This review summarizes the approaches to accomplish therapeutic angiogenesis for IHD by highlighting the advances and challenges that addresses the applicability of a potential pro-angiogenic medicine.
      PubDate: 2019-02-01
      DOI: 10.1007/s00109-018-1729-3
      Issue No: Vol. 97, No. 2 (2019)
  • Coexpression of FOXK1 and vimentin promotes EMT, migration, and invasion
           in gastric cancer cells
    • Authors: Hui Zhang; Xiaosheng Wu; Yizhi Xiao; Liqing Wu; Ying Peng; Weimei Tang; Guangnan Liu; Yong Sun; Jing Wang; Huiqiong Zhu; Mengwei Liu; Wenjing Zhang; Weiyu Dai; Ping Jiang; Aimin Li; Guoxin Li; Li Xiang; Side Liu; Jide Wang
      Pages: 163 - 176
      Abstract: In human gastric cancer (GC), the upregulation of FOXK1 and vimentin is frequently observed in cancer cells and correlates with increased malignancy. We report that FOXK1 synergizes with vimentin to promote GC invasion and metastasis via the induction of epithelial-mesenchymal transition (EMT). We showed that higher expression levels of FOXK1 were significantly associated with GC development. FOXK1 can physically interact with and stabilize vimentin. Moreover, a positive correlation between the expression of FOXK1 and vimentin was found in GC cells. Higher expression levels of these two proteins were significantly associated with differentiation, lymph node metastasis, AJCC stage, and poorer prognosis. Furthermore, the coexpression of FOXK1 and vimentin enhances cell metastasis through the induction of EMT in GC cells. However, the siRNA-mediated repression of vimentin in FOXK1-overexpressing cells reversed the EMT-like phenotype and reduced GC cell migration and invasion in vitro and in vivo. Altogether, our findings suggest that the vimentin-FOXK1 axis provides new insights into the molecular mechanisms underlying EMT regulation during GC progression and metastasis.
      PubDate: 2019-02-01
      DOI: 10.1007/s00109-018-1720-z
      Issue No: Vol. 97, No. 2 (2019)
  • Interleukin-23 receptor signaling mediates cancer dormancy and
           radioresistance in human esophageal squamous carcinoma cells via the
           Wnt/Notch pathway
    • Authors: Yuepeng Zhou; Yuting Su; Haitao Zhu; Xuefeng Wang; Xiaoqin Li; Chunhua Dai; Chengcheng Xu; Tingting Zheng; Chaoming Mao; Deyu Chen
      Pages: 177 - 188
      Abstract: In the tumor microenvironment, inflammatory cells and molecules influence almost every process; among them, interleukin-23 (IL-23) is a pro-inflammatory molecule that exhibits pro- or anti-tumor properties, but both activities remain poorly understood. In this study, we investigated the effect of extracellular IL-23 in IL-23 receptor-positive (IL-23R+) esophageal squamous cell carcinoma (ESCC) and explored the mechanisms underlying this effect. We analyzed ESCC tumor tissues by immunohistochemical and immunofluorescence staining and found that IL-23, which was highly expressed, co-localized with Oct-4A in IL-23R+ ESCC cells. In addition, IL-23 treatment significantly increased the accumulation of CD133+ cells and activated the Wnt and Notch signaling pathways in CD133−IL-23R+ ESCC cell lines. Consistently, CD133−IL-23R+ cells pretreated with IL-23 showed stronger anti-apoptosis activity when exposed to radiation and higher survival than untreated groups. Moreover, the inhibition of Wnt/Notch signaling by a small-molecule inhibitor or siRNA abolished the effect of IL-23-induced dormancy and consequent radioresistance. Taken together, these results suggested that IL-23 facilitates radioresistance in ESCC by activating Wnt/Notch-mediated G0/1 phase arrest, and attenuating these detrimental changes by blocking the formation of dormancy may prove to be an effective pretreatment for radiotherapy. Key messages IL-23/IL-23R is correlated with the acquisition of stem-like potential in ESCC. CD133−IL-23R+ ESCCs acquired dormancy via IL-23. Radioresistance depends on IL-23-mediated Wnt/Notch pathway activation in vitro and vivo.
      PubDate: 2019-02-01
      DOI: 10.1007/s00109-018-1724-8
      Issue No: Vol. 97, No. 2 (2019)
  • Effect of DJ-1 on the neuroprotection of astrocytes subjected to cerebral
           ischemia/reperfusion injury
    • Authors: Li Peng; Yipeng Zhao; Yixin Li; Yang Zhou; Linyu Li; Shipeng Lei; Shanshan Yu; Yong Zhao
      Pages: 189 - 199
      Abstract: Astrocytes are involved in neuroprotection, and DJ-1 is an important antioxidant protein that is abundantly expressed in reactive astrocytes. However, the role of DJ-1 in astrocytes’ neuroprotection in cerebral ischemia/reperfusion injury and its potential mechanism is unclear. Thus, to explore effects and mechanisms of DJ-1 on the neuroprotection of astrocytes, we used primary co-cultures of neurons and astrocytes under oxygen and glucose deprivation/reoxygenation in vitro and transient middle cerebral artery occlusion/reperfusion in vivo to mimic ischemic reperfusion insult. Lentiviral was used to inhibit and upregulate DJ-1 expression in astrocytes, and DJ-1 siRNA blocked DJ-1 expression in rats. Inhibiting DJ-1 expression led to decreases in neuronal viability. DJ-1 knockdown also attenuated total and nuclear Nrf2 and glutathione (GSH) levels in vitro and vivo. Similarly, loss of DJ-1 decreased Nrf2/ARE-binding activity and expression of Nrf2/ARE pathway-driven genes. Overexpression of DJ-1 yielded opposite results. This suggests that the mechanism of action of DJ-1 in astrocyte-mediated neuroprotection may involve regulation of the Nrf2/ARE pathway to increase GSH after cerebral ischemia/reperfusion injury. Thus, DJ-1 may be a new therapeutic target for treating ischemia/reperfusion injury. Key Messages Astrocytes protect neurons in co-culture after OGD/R DJ-1 is upregulated in astrocytes and plays an important physiological roles in neuronal protection under ischemic conditions DJ-1 protects neuron by the Nrf2/ARE pathway which upregulates GSH
      PubDate: 2019-02-01
      DOI: 10.1007/s00109-018-1719-5
      Issue No: Vol. 97, No. 2 (2019)
  • Treprostinil reduces endothelial damage in murine sinusoidal obstruction
    • Authors: Madeleine Themanns; Florian Koban; Christian Bergmayr; Alicja Chrzan; Wolfgang Strohmaier; Johannes Haybaeck; Michael Freissmuth; Eva Zebedin-Brandl
      Pages: 201 - 213
      Abstract: Sinusoidal obstruction syndrome (SOS) is a major complication after hematopoietic stem cell transplantation and belongs to a group of diseases increasingly identified as transplant-related systemic endothelial disease. Administration of defibrotide affords some protection against SOS, but the effect is modest. Hence, there is unmet medical need justifying the preclinical search for alternative approaches. Prostaglandins exert protective actions on endothelial cells of various vascular beds. Here, we explored the therapeutic potential of the prostacyclin analog treprostinil to prevent SOS. Treprostinil acts via stimulation of IP, EP2, and EP4 receptors, which we detected in murine liver sinusoidal endothelial cells (LSECs). Busulfan-induced cell death was reduced when pretreated with treprostinil in vitro. In a murine in vivo model of SOS, concomitantly administered treprostinil caused lower liver weight-to-body weight ratios indicating liver protection. Histopathological changes were scored to assess damage to liver sinusoidal endothelial cells, to hepatocytes, and to the incipient fibrotic reaction. Treprostinil indeed reduced sinusoidal endothelial cell injury, but this did not translate into reduced liver cell necrosis or fibrosis. In summary, our observations provide evidence for a beneficial effect of treprostinil on damage to LSECs but unexpectedly treprostinil was revealed as a double-edged sword in SOS. Key messages Murine liver sinusoidal endothelial cells (LSECs) express prostanoid receptors. Treprostinil reduces busulfan-induced cell death in vitro. Treprostinil lowers liver weight-to-body weight ratios in mice. Treprostinil positively affects LSECs in mice but not hepatic necrosis/fibrosis.
      PubDate: 2019-02-01
      DOI: 10.1007/s00109-018-1726-6
      Issue No: Vol. 97, No. 2 (2019)
  • Connexin43 hemichannel block protects against the development of diabetic
           retinopathy signs in a mouse model of the disease
    • Authors: Odunayo O. Mugisho; Colin R. Green; David M. Squirrell; Sarah Bould; Helen V. Danesh-Meyer; Jie Zhang; Monica L. Acosta; Ilva D. Rupenthal
      Pages: 215 - 229
      Abstract: Diabetic retinopathy (DR) is a vascular disease of the neuroretina characterised by hyperglycaemia and inflammation. Current DR therapies target late-stage vascular defects and there is evidence to suggest that they contribute to geographic atrophy and retinal ganglion cell death long term. Therefore, alternative treatments that target common upstream disease mechanisms are needed. Recent studies have shown that connexin43 hemichannel blockers can reduce inflammation and prevent vessel leak in brain and spinal cord lesions. The aim of this study was to evaluate the effectiveness of a connexin43 hemichannel blocker (Peptide5) in a mouse model of DR in which pro-inflammatory cytokines, IL-1β and TNF-α, were intravitreally injected into non-obese diabetic (NOD, hyperglycaemic) mice. Fundus and optical coherence tomography images were taken to evaluate vessel dilation and beading as well as retinal and vitreous hyper-reflective foci (HRF). Immunohistochemistry was performed to assess levels of astrogliosis, microgliosis and inflammasome activation. Results showed that Peptide5 injection lowered the incidence of vessel dilation and beading, decreased the severity of vitreous and retinal HRF, and reduced sub-retinal fluid accumulation compared to the vehicle group. Furthermore, Peptide5 led to reduced connexin43 and GFAP upregulation, inhibited microglial infiltration into the outer nuclear layer and prevented upregulation of inflammasome markers compared to vehicle. The present study provides evidence in support of Peptide5, and connexin43 hemichannel block in general, as a potential upstream approach for the treatment of DR. Key messages Connexin43 is upregulated in a novel mouse model of diabetic retinopathy (DR). Connexin43 hemichannel block inhibits inflammation and inflammasome activation. Connexin43 hemichannel block prevents the development of clinical DR signs. Connexin43 hemichannel block is a potential upstream approach for DR treatment.
      PubDate: 2019-02-01
      DOI: 10.1007/s00109-018-1727-5
      Issue No: Vol. 97, No. 2 (2019)
  • The FAK inhibitor BI 853520 inhibits spheroid formation and orthotopic
           tumor growth in malignant pleural mesothelioma
    • Authors: Viktoria Laszlo; Zsuzsanna Valko; Judit Ozsvar; Ildiko Kovacs; Tamas Garay; Mir Alireza Hoda; Thomas Klikovits; Paul Stockhammer; Clemens Aigner; Marion Gröger; Walter Klepetko; Walter Berger; Michael Grusch; Jozsef Tovari; Irene C. Waizenegger; Balazs Dome; Balazs Hegedus
      Pages: 231 - 242
      Abstract: No tyrosine kinase inhibitors are approved for malignant pleural mesothelioma (MPM). Preclinical studies identified focal adhesion kinase (FAK) as a target in MPM. Accordingly, we assessed the novel, highly selective FAK inhibitor (BI 853520) in 2D and 3D cultures and in vivo. IC50 values were measured by adherent cell viability assay. Cell migration and 3D growth were quantified by video microscopy and spheroid formation, respectively. Phosphorylation of FAK, Akt, S6, and Erk was measured by immunoblot. The mRNA expression of the putative tumor stem cell markers SOX2, Nanog, CD44, ALDH1, c-myc, and Oct4 was analyzed by qPCR. Cell proliferation, apoptosis, and tumor tissue microvessel density (MVD) were investigated in orthotopic MPM xenografts. In all 12 MPM cell lines, IC50 exceeded 5 μM and loss of NF2 did not correlate with sensitivity. No synergism was found with cisplatin in adherent cells. BI 853520 decreased migration in 3 out of 4 cell lines. FAK phosphorylation was reduced upon treatment but activation of Erk, Akt, or S6 remained unaffected. Nevertheless, BI 853520 inhibited spheroid growth and significantly reduced tumor weight, cell proliferation, and MVD in vivo. BI 853520 has limited effect in adherent cultures but demonstrates potent activity in spheroids and in orthotopic tumors in vivo. Based on our findings, further studies are warranted to explore the clinical utility of BI 853520 in human MPM. Key messages Response to FAK inhibition in MPM is independent of NF2 expression or histotype. FAK inhibition strongly interfered with MPM spheroid formation. BI 853520 has been shown to exert anti-tumor effect in MPM.
      PubDate: 2019-02-01
      DOI: 10.1007/s00109-018-1725-7
      Issue No: Vol. 97, No. 2 (2019)
  • Cancer-associated fibroblasts promote the stemness of CD24 + liver cells
           via paracrine signaling
    • Authors: Yawen Li; Ronghua Wang; Si Xiong; Xiju Wang; Zhenxiong Zhao; Shuya Bai; Yun Wang; Yuchong Zhao; Bin Cheng
      Pages: 243 - 255
      Abstract: Cancer stem cells (CSCs), which support tumor progress in hepatocellular carcinoma (HCC) developed in fibrotic or cirrhotic livers, are regulated by the tumor microenvironment. Cancer-associated fibroblasts (CAFs) are the major component of the tumor stroma in HCC; however, the mechanisms by which CAFs contribute to stemness maintenance remain largely unknown. Here, we found that the expression of CD24 was high in HCC tissues compared with adjacent normal liver tissues, and positively correlated with the poor prognosis and α-SMA expression in CAFs. CD24+ cells isolated from HCC cell lines exhibited stemness properties of self-renewal, chemotherapy resistance, metastasis, and tumorigenicity in NOD/SCID mice. Moreover, CAF-derived HGF and IL6 enhanced the stemness properties of CD24+ cells via activating STAT3 Tyr705 phosphorylation. Blockade of HGF/c-Met or IL6/IL6R signaling significantly abolished the effect of CAFs on stemness properties, which compromised the activation of STAT3 pathway in CD24+ cells. Meanwhile, knockdown of STAT3 in CD24+ cells notably attenuated CAF-induced stemness characteristics of CD24+ cells. Furthermore, in HCC patients, higher expression of phospho-STAT3 was also demonstrated to be positively correlated with poor clinical outcomes. In summary, HGF and IL6 secreted by CAFs promoted the stemness properties of CD24+ cells through the phosphorylation of STAT3 signaling, and targeting the paracrine pathways may provide a new therapeutic strategy for HCC. Key messages CD24, identified as a marker for HCC CSCs, was positively correlated with the poor prognosis and α-SMA expression in CAFs. CAFs promoted self-renewal, chemotherapy resistance, metastasis, and tumorigenicity of CD24+ HCC cells. HGF and IL6 secreted by CAFs promoted the stemness properties of CD24+ HCC cells through the phosphorylation of STAT3.
      PubDate: 2019-02-01
      DOI: 10.1007/s00109-018-1731-9
      Issue No: Vol. 97, No. 2 (2019)
  • Correction to: Trichostatin A, a histone deacetylase inhibitor, induces
           synergistic cytotoxicity with chemotherapy via suppression of Raf/MEK/ERK
           pathway in urothelial carcinoma
    • Authors: Wei-Chou Lin; Fu-Shun Hsu; Kuan-Lin Kuo; Shing-Hwa Liu; Chia-Tung Shun; Chung-Sheng Shi; Hong-Chiang Chang; Yu-Chieh Tsai; Ming-Chieh Lin; June-Tai Wu; Yu Kuo; Po-Ming Chow; Shih-Ming Liao; Shao-Ping Yang; Jo-Yu Hong; Kuo-How Huang
      Abstract: In Fig. 1b, upper part, the cell viability counts after treatment with cisplatin and TSA in T24 cells was by mistake a duplication of the image for NTUB1 on the left. In the corrected version of Fig. 1, the image was replaced appropriately.
      PubDate: 2019-02-11
      DOI: 10.1007/s00109-019-01748-2
  • Efficacy of novel selective NLRP3 inhibitors in human and murine retinal
           pigment epithelial cells
    • Authors: Luping Wang; Sarah Schmidt; Petra P. Larsen; Johanna H. Meyer; William R. Roush; Eicke Latz; Frank G. Holz; Tim U. Krohne
      Abstract: NLRP3 inflammasome activation in the retinal pigment epithelium (RPE) is observed in atrophic age-related macular degeneration (AMD), and pharmacological NLRP3 inhibition may provide a therapeutic strategy to halt disease progression. We tested selective NLRP3 inhibitors (IFM-514, IFM-632, and CRID3) for their efficacy in human and murine RPE cells. Inflammasome activation was induced in primary human RPE cells and ARPE-19 cells following priming with IL-1α by different stimuli, including lysosomal membrane permeabilization by leucyl-leucine methyl ester (Leu-Leu-OMe), oxidative damage induced by hydrogen peroxide, lipofuscin-mediated photooxidative damage induced by incubation with 4-hydroxynonenal-modified photoreceptor outer segments and subsequent blue light irradiation, and P2X7 receptor activation by benzoylbenzoyl-ATP. Independent of the applied activation mechanism, treatment with the NLRP3 inhibitors IFM-632, IFM-514, and CRID3 resulted in a significant suppression of inflammasome activation as assessed by IL-1β and LDH release. Likewise, inflammasome activation in blue light-irradiated Abca4−/− mouse and Leu-Leu-OMe-treated wild-type mouse RPE/choroid/sclera eye cups was significantly reduced by treatment with the NLRP3 inhibitors. These results indicate that the investigated selective NLRP3 inhibitors are effective in human and murine RPE cells, thus representing promising agents for the future evaluation of inflammasome inhibition as a therapeutic strategy in atrophic AMD. Key messages • NLRP3 inhibitors suppress inflammasome activation in human RPE cells independent of trigger. • Light-induced inflammasome activation in Abca4−/− mouse eye cups is reduced by NLRP3 inhibitors. • Novel selective NLRP3 inhibitors are effective in human and murine RPE cells. • Promising compounds for pharmaceutical intervention in atrophic AMD.
      PubDate: 2019-02-10
      DOI: 10.1007/s00109-019-01753-5
  • FOXM1 plays a role in autophagy by transcriptionally regulating Beclin-1
           and LC3 genes in human triple-negative breast cancer cells
    • Authors: Zuhal Hamurcu; Nesrin Delibaşı; Ufuk Nalbantoglu; Elif Funda Sener; Nursultan Nurdinov; Bayram Tascı; Serpil Taheri; Yusuf Özkul; Hamiyet Donmez-Altuntas; Halit Canatan; Bulent Ozpolat
      Abstract: Triple-negative breast cancer (TNBC) is associated with poor prognosis owing to its aggressive and heterogeneous nature, and the lack of therapeutic targets. Although Forkhead Box M1 (FOXM1) is one of the most important oncogenes contributing to tumorigenesis, progression, and drug resistance in TNBC, the underlying molecular mechanisms are not well understood. Emerging evidence indicates that autophagy plays a critical role in cell survival and protective mechanism in TNBC. However, signaling pathways that are involved in the regulation of autophagy remain to be elucidated. In the present study, we examined the role of FOXM1 in regulating autophagy in TNBC cells and found that FOXM1 is upregulated during induction of autophagy. We found that inhibition of FOXM1 suppressed starvation and rapamycin-induced autophagy and expression of the major autophagy regulators, LC3 and Beclin-1. Further studies demonstrated that FOXM1 directly binds to the promotors of LC3 and Beclin-1 genes and transcriptionally regulates their expression by chromatin immunoprecipitation (ChIP) and luciferase gene reporter assays. In conclusion, our study provides the first evidence about the role of FOXM1 in regulating expression of LC3 and Beclin-1 and autophagy in TNBC cells. Our findings provide novel insight into the role of FOXM1 regulation of the autophagic survival pathway and potential molecular target for treating TNBC. Key messages • FOXM1 promotes tumorigenesis and progression of TNBC. However, the underlying molecular mechanism by which FOXM1 promotes TNBC tumorigenesis is unclear. The goal of our study was to determine the role of FOXM1 in the regulation of autophagy that plays a role in TNBC progression. Our findings show that FOXM1 binds to promoters of the genes encoding the major autophagy proteins, Beclin and LC3, and provide new insights into the regulation of autophagy, which is being targeted in many clinical trials.
      PubDate: 2019-02-07
      DOI: 10.1007/s00109-019-01750-8
  • Exploring the roles of MSCs in infections: focus on bacterial diseases
    • Authors: Pasquale Marrazzo; Annunziata Nancy Crupi; Francesco Alviano; Laura Teodori; Laura Bonsi
      Abstract: Despite human healthcare advances, some microorganisms continuously react evolving new survival strategies, choosing between a commensal fitness and a pathogenic attitude. Many opportunistic microbes are becoming an increasing cause of clinically evident infections while several renowned infectious diseases sustain a considerable number of deaths. Besides the primary and extensively investigated role of immune cells, other cell types are involved in the microbe-host interaction during infection. Interestingly, mesenchymal stem cells (MSCs), the current leading players in cell therapy approaches, have been suggested to contribute to tackling pathogens and modulating the host immune response. In this context, this review critically explores MSCs’ role in E. coli, S. aureus, and polymicrobial infections. Summarizing from various studies, in vitro and in vivo results support the mechanistic involvement of MSCs and their derivatives in fighting infection and in contributing to microbial spreading. Our work outlines the double face of MSCs during infection, disease, and sepsis, highlighting potential pitfalls in MSC-based therapy due to the MSCs’ susceptibility to pathogens’ weapons. We also identify potential targets to improve infection treatments, and propose the potential applications of MSCs for vaccine research.
      PubDate: 2019-02-07
      DOI: 10.1007/s00109-019-01752-6
  • MicroRNA-145 targets Smad1 in endometrial stromal cells and regulates
           decidualization in rat
    • Authors: Vijay K. Sirohi; Kanchan Gupta; Radhika Kapoor; Anila Dwivedi
      Abstract: Decidualization of endometrial stromal cells is the pre-requisite for the embryo implantation and establishment of pregnancy. Although known to be regulated by several factors, the process of regulation of decidualization by miRNAs is largely unknown. Previous reports suggest that the upregulated expression of miR-145 is associated with repeated implantation failure. The current study was aimed to identify and validate the role of miR-145 in regulating stromal cell decidualization and the mechanism involved therein. Expression of miR-145 was found to be downregulated during the decidualization period of early pregnancy and also in artificially induced decidualization in rat uterus. During in vitro decidualization in rat endometrial stromal cells (ESCs), the overexpression of mimic miR-145 attenuated the progression of decidualization. Biochemical marker alkaline phosphatase and protein markers (insulin-like growth factor binding protein, cyclin D3) were also suppressed in miR-145 mimic-transfected cells as compared to normal decidualized cells. Bioinformatic analysis and luciferase reporter assay confirmed that Smad1 is the direct target of miR-145. Differentiation of ESCs was inhibited in miR-145 mimic-transfected cells which occurred via downregulating the target Smad1 along with its downstream p-Smad1/5/8 and Wnt-4. Pre-treatment of ESCs with Smad1 siRNA resulted in downregulated expression of p-Smad1/5/8, Wnt-4, Cox-2, and VEGF. In addition, miR-145 overexpression resulted in the loss of angiogenic factors Cox-2, MMP-9, and VEGF, indicating suppression of the process of angiogenesis. Migration of human umbilical vein endothelial cells was also attenuated in the presence of conditioned media obtained from miR-145-transfected decidualizing cells. In conclusion, the study demonstrated the role of miR-145 in regulation of progression of decidualization which is mediated through inhibition of Smad1. Key messages MiR-145 expression is downregulated during decidualization in the rat uterus. Overexpression of miR-145 inhibited the decidualization progression. MiR-145 suppressed the migration and invasion of HUVECs. MiR-145 downregulated Smad1 which suppresses Smad1/5/8, Wnt-4, MMP-9, Cox-2, and VEGF.
      PubDate: 2019-02-07
      DOI: 10.1007/s00109-019-01744-6
  • MOTS-c peptide regulates adipose homeostasis to prevent
           ovariectomy-induced metabolic dysfunction
    • Authors: Huanyu Lu; Ming Wei; Yue Zhai; Qingyang Li; Zichen Ye; Li Wang; Wenjing Luo; Jingyuan Chen; Zifan Lu
      Abstract: The postmenopausal state is associated with an increased risk of metabolic disorder including reduced energy expenditure and weight gain, leading to higher cardiovascular and cancer risks among other diseases. Mitochondrial-derived peptide (MOTS-c) is a 16–amino acid peptide encoded by mitochondrial DNA. Here, we showed that MOTS-c treatment in mice prevented ovariectomy-induced obesity and insulin resistance. After ovariectomy, low levels of estrogens increased fat mass overload and disturbed normal adipose function, forcing the development of insulin resistance. MOTS-c treatment increased brown fat activation and reduced OVX-induced fat accumulation and inflammatory invasion in white adipose tissue, which contributes to the lower level of fatty acid in serum and liver. Moreover, MOTS-c activated AMPK pathway to improve energy dissipation and insulin sensitivity. And a blocker of AMPK pathway was found to attenuate the role of MOTS-c in the regulation of adipocyte lipid metabolism. In conclusion, MOTS-c is a high potential candidate for chronic treatment of menopausal induced metabolic dysfunction. Key messages • MOTS-c prevents ovariectomy (OVX)-induced body weight gain and insulin resistance. • MOTS-c reduces fat mass and suppresses inflammatory response under OVX condition. • MOTS-c sustains the activity of the brown adipose under OVX condition. • MOTS-c mediates AMPK pathway activation to control adipose metabolic homeostasis.
      PubDate: 2019-02-06
      DOI: 10.1007/s00109-018-01738-w
  • AMPK agonist AICAR ameliorates portal hypertension and liver cirrhosis via
           NO pathway in the BDL rat model
    • Authors: Liangshuo Hu; Lin Su; Zhixia Dong; Yunhua Wu; Yi Lv; Jacob George; Jianhua Wang
      Abstract: Recent studies have indicated that the Adenosine 5‘-monophosphate (AMP)-activated protein kinase (AMPK) pathway is closely involved in liver fibrosis and other fibrotic diseases. However, whether targeting the AMPK pathway can rescue liver fibrosis and its complications, such as portal hypertension, is unknown. This study aimed to explore the therapeutic value of AICAR (5-aminoimidazole-4-carboxyamide ribonucleoside), an agonist of the AMPK pathway, on liver fibrosis and portal hypertension in bile duct ligation (BDL) rats. In vitro experiments showed that the gene expression levels of TGF-b, a-SMA, and collagen 1 in primary rat hepatic stellate cells (HSCs) were significantly decreased after AICAR treatment. The p-eNOS expression and nitric oxide (NO) production were increased by AICAR administration in sinusoidal endothelial cells (SECs). For in vivo animal studies, AICAR acutely decreased portal pressure in the BDL and CCL4 fibrotic rats, but not in the partial portal vein ligation (PVL) rats, without changes in systemic hemodynamics. It was also observed by using intravital fluorescence microscopy that AICAR led to sinusoidal vasodilation in situ experiment. We propose that the relevant mechanisms may be related to the activation of the AMPK/NO pathway in SECs and that this activation promoted NO production in the liver, thereby promoting hepatic sinusoid microcirculation and decreased intrahepatic resistance. The results were verified using the NO inhibitor L-NAME. Chronic AICAR treatment also showed profound beneficial effects on the BDL model rats. The hemodynamic condition was greatly improved, but the positive effect could be partially blocked by L-NAME. Moreover, AICAR also decreased hepatic fibrogenesis in the BDL rats. Key messages Acute and chronic use of AICAR could alleviate portal pressure without changing systemic hemodynamics. AICAR induced sinusoidal vasodilation by improving NO bioavailability and ameliorating endothelial dysfunction in vivo and in vitro. AICAR could alleviate liver cirrhosis in the BDL model rats.
      PubDate: 2019-02-05
      DOI: 10.1007/s00109-019-01746-4
  • MiR-449a-5p mediates mitochondrial dysfunction and phenotypic transition
           by targeting Myc in pulmonary arterial smooth muscle cells
    • Authors: Chen Zhang; Cui Ma; Lixin Zhang; Linlin Zhang; Fengying Zhang; Mingfei Ma; Xiaodong Zheng; Min Mao; Tingting Shen; Daling Zhu
      Abstract: MicroRNAs have been considered to participate in pulmonary arterial hypertension (PAH) and regulate numerous disease pathways in pulmonary vasculature. However, the molecular role in the pathologies has not yet been fully uncovered, particularly in the view of energy metabolism and vascular smooth muscle cell phenotypic regulation. Here, several altered miRNAs are founded in genome-wide miRNA sequencing analysis, in which miR-449a-5p was identified as a probable candidate in hypoxic PAH and verified such a decreasing trend. Moreover, we identify that miR-449a-5p plays critical role in both mitochondria metabolic dysfunction and phenotype transformation of pulmonary arterial smooth muscle cells. Subsequently, we initiate that the transcription factor Myc, which is negatively regulated by miR-449a-5p, results in the aberrant effects contributing to pulmonary arterial smooth muscle cell proliferation. Taken together, we demonstrated that the miR-449a-5p/Myc axis is indispensable for the development and progression of PAH. These results may serve as a significant implication for understanding and treatment of PAH. Key messages • The downregulation of miR-449a-5p occurs in both PAH-PAs and hypoxic PASMCs. • MiR-449a-5p is involved in hypoxia-induced mitochondria dysfunction of PASMCs. • MiR-449a-5p inhibits hypoxic phenotypic transition and proliferation of PASMCs. • The aberrant effects of MiR-449a-5p depend on downstream transcription factor Myc. • Myc contributes to mitochondria dysfunction and phenotype transformation in PAH.
      PubDate: 2019-02-04
      DOI: 10.1007/s00109-019-01751-7
  • Role of sirtuin-1 in diabetic nephropathy
    • Authors: Wanning Wang; Weixia Sun; Yanli Cheng; Zhonggao Xu; Lu Cai
      Abstract: Diabetic nephropathy (DN) is a research priority for scientists around the world because of its high prevalence and poor prognosis. Although several mechanisms have been shown to be involved in its pathogenesis and many useful drugs have been developed, the management of DN remains challenging. Increasing amounts of evidence show that silent information regulator 2 homolog 1 (sirtuin-1), a nicotinamide adenine dinucleotide (NAD+)–dependent protein deacetylase, plays a crucial role in the pathogenesis and development of DN. Clinical data show that gene polymorphisms of sirtuin-1 affect patient vulnerability to DN. In addition, upregulation of sirtuin-1 attenuates DN in various experimental models of diabetes and in renal cells, including podocytes, mesangial cells, and renal proximal tubular cells, incubated with high concentrations of glucose or advanced glycation end products. Mechanistically, sirtuin-1 has its renoprotective effects by modulating metabolic homeostasis and autophagy, resisting apoptosis and oxidative stress, and inhibiting inflammation through deacetylation of histones and the transcription factors p53, forkhead box group O, nuclear factor-κB, hypoxia-inducible factor-1α, and others. Furthermore, some microRNAs have been implicated in the progression of DN because they target sirtuin-1 mRNA. Several synthetic drugs and natural compounds have been identified that upregulate the expression and activity of sirtuin-1, which protects against DN. The present review will summarize advances in knowledge regarding the role of sirtuin-1 in the pathogenesis of DN. The available evidence implies that sirtuin-1 has great potential as a clinical target for the prevention and treatment of diabetes.
      PubDate: 2019-02-01
      DOI: 10.1007/s00109-019-01743-7
  • Pathological role of apoptosis signal-regulating kinase 1 in human
           diseases and its potential as a therapeutic target for cognitive disorders
    • Abstract: Cognitive disorders are among the leading causes of health and social issues, as well as socioeconomic burden. Cognitive dysfunction associated with diseases including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, diabetes, and stroke can lead to dementia. Despite extensive efforts, strategies for the prevention and treatment of cognitive dysfunction are scarce. Apoptosis signal-regulating kinase 1 (ASK1) participates in diverse biological pathological processes, such as cell death, survival, and differentiation, and it has been suggested as a therapeutic target in various diseases. However, the role of ASK1 in cognitive dysfunction has not been clearly examined yet. In addition, only a few studies have reported a possible relationship between ASK1 signaling and cognitive deficits. In this review, we summarized experimental evidences regarding the association between ASK1 and the pathogenesis of various diseases. Furthermore, we reviewed preclinical studies supporting the possibility that ASK1 regulation is a promising target for the prevention/treatment of cognitive disorders. Nevertheless, future studies are necessary to investigate the role of ASK1 in the pathogenic mechanisms underlying cognitive dysfunctions, for the translation of preclinical information into clinical application.
      PubDate: 2019-01-07
      DOI: 10.1007/s00109-018-01739-9
  • Nuclear localization of LDL receptor-related protein 1B in mammary gland
    • Authors: Yoshimi Asano; Tamotsu Takeuchi; Hiroshi Okubo; Chiemi Saigo; Yusuke Kito; Yoshinori Iwata; Manabu Futamura; Kazuhiro Yoshida
      Abstract: LRP1B intracellular domain is released and transported to the nucleus; however, pathological consequences of this nuclear transport are largely unclear. We aimed to unravel the pathobiological significance of nuclear localization of LRP1B intracellular domain in mammary gland carcinogenesis. Immunohistochemical staining using antibodies for LRP1B intracellular domain was performed to determine LRP1B expression in 92 invasive ductal breast carcinomas. LRP1B immunoreactivity was detected in the surface membrane and cytoplasm of 60 of 92 invasive ductal carcinomas and in the nucleus of 15 of 92 carcinomas. Nuclear LRP1B was significantly associated with poor patient prognosis, particularly luminal A type breast cancer, where it was significantly related to nodal metastasis. Doxycycline-dependent nuclear expression of LRP1B intracellular domain was established in cultured breast cancer cells. Enforced nuclear expression significantly increased Matrigel invasion activity in MCF-7 and T47D luminal A breast cancer cells. Moreover, enforced nuclear expression of LRP1B intracellular domain facilitated MCF-7 cells growth in mammary fat pad of nude mice, which was supplemented with estrogen. Comprehensive microarray-based analysis demonstrated that nuclear expression of LRP1B intracellular domain significantly increased long non-coding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) expression, which facilitates breast cancer invasion with poor prognosis. Nuclear-localized LRP1B intracellular domain promoted breast cancer progression with poor prognosis, possibly through the NEAT1 pathway. Nuclear transport of LRP1B intracellular domain could be a therapeutic target for breast cancer patients. Key messages Nuclear LRP1B was significantly associated with poor patient prognosis. Nuclear LRP1B increased Matrigel invasion activity of breast cancer cells. Nuclear expression of LRP1B intracellular domain increased NEAT1 expression.
      PubDate: 2019-01-03
      DOI: 10.1007/s00109-018-01732-2
  • Overexpression of branched-chain amino acid aminotransferases rescues the
           growth defects of cells lacking the Barth syndrome-related gene TAZ1
    • Authors: Diana Antunes; Arpita Chowdhury; Abhishek Aich; Sreedivya Saladi; Nofar Harpaz; Mark Stahl; Maya Schuldiner; Johannes M. Herrmann; Peter Rehling; Doron Rapaport
      Abstract: The yeast protein Taz1 is the orthologue of human Tafazzin, a phospholipid acyltransferase involved in cardiolipin (CL) remodeling via a monolyso CL (MLCL) intermediate. Mutations in Tafazzin lead to Barth syndrome (BTHS), a metabolic and neuromuscular disorder that primarily affects the heart, muscles, and immune system. Similar to observations in fibroblasts and platelets from patients with BTHS or from animal models, abolishing yeast Taz1 results in decreased total CL amounts, increased levels of MLCL, and mitochondrial dysfunction. However, the biochemical mechanisms underlying the mitochondrial dysfunction in BTHS remain unclear. To better understand the pathomechanism of BTHS, we searched for multi-copy suppressors of the taz1Δ growth defect in yeast cells. We identified the branched-chain amino acid transaminases (BCATs) Bat1 and Bat2 as such suppressors. Similarly, overexpression of the mitochondrial isoform BCAT2 in mammalian cells lacking TAZ improves their growth. Elevated levels of Bat1 or Bat2 did not restore the reduced membrane potential, altered stability of respiratory complexes, or the defective accumulation of MLCL species in yeast taz1Δ cells. Importantly, supplying yeast or mammalian cells lacking TAZ1 with certain amino acids restored their growth behavior. Hence, our findings suggest that the metabolism of amino acids has an important and disease-relevant role in cells lacking Taz1 function. Key messages Bat1 and Bat2 are multi-copy suppressors of retarded growth of taz1Δ yeast cells. Overexpression of Bat1/2 in taz1Δ cells does not rescue known mitochondrial defects. Supplementation of amino acids enhances growth of cells lacking Taz1 or Tafazzin. Altered metabolism of amino acids might be involved in the pathomechanism of BTSH.
      PubDate: 2019-01-03
      DOI: 10.1007/s00109-018-1728-4
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