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Jingjiang Pi, Jie Liu, Tao Zhuang, Lin Zhang, Huimin Sun, Xiaoli Chen, Qian Zhao, Yashu Kuang, Sheng Peng, Xiaohui Zhou, Zuoren Yu, Ting Tao, Brian Tomlinson, Paul Chan, Ying Tian, Huimin Fan, Zhongmin Liu, Xiangjian Zheng, Edward Morrisey, Yuzhen Zhang
Rationale: Angiogenesis is critical for embryonic development and microRNAs fine-tune this process, but the underlying mechanisms remain incompletely understood. Methods: Endothelial cell (EC) specific miR302-367 line was used as gain-of-function and anti-miRs as loss-of-function models to investigate the effects of miR302-367 on developmental angiogenesis with embryonic hindbrain vasculature as an in vivo model and fibrin gel beads and tube formation assay as in vitro models. Cell migration was evaluated by Boyden chamber and scratch wound healing assay and cell proliferation by cell count, MTT assay, Ki67 immunostaining and PI cell cycle analysis...
2018: Theranostics
Hao Zhuang, Qiang Li, Xinran Zhang, Xuda Ma, Zun Wang, Yun Liu, Xianfu Yi, Ruibing Chen, Feng Han, Ning Zhang, Yongmei Li
Metabolic reprogramming is a hallmark of cancer. Glycine decarboxylase (GLDC), an oxidoreductase, plays an important role in amino acid metabolism. While GLDC promotes tumor initiation and proliferation in non-small cell lung cancer and glioma and it was reported as a putative tumor suppressor gene in gastric cancer, the role of GLDC in hepatocellular carcinoma (HCC) is unknown. In the current study, microarray-based analysis suggested that GLDC expression was low in highly malignant HCC cell lines, and clinicopathological analysis revealed a decrease in GLDC in HCC tumor samples...
March 7, 2018: Free Radical Biology & Medicine
Aijaz A John, Ravi Prakash, Jyoti Kureel, Divya Singh
We report the role of miR-1187 in regulation of osteoblast functions. Over-expression of miR-1187 inhibited osteoblast differentiation. Target prediction analysis tools and experimental validation by luciferase 3' UTR reporter assay identified BMPR-II and ArhGEF-9 as direct targets of miR-1187. ArhGEF-9 activates Cdc42 which has a major role in actin reorganization. BMP-2 also induces actin polymerization. Role of miR-1187 in actin reorganization was determined by western blotting, immunofluorescence, and in vivo gene silencing studies...
March 9, 2018: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
Juhyun Park, Sung Yong Cho, Kwanjin Park, Ji Sun Chai, Hwancheol Son, Soo Woong Kim, Jae-Seung Paick, Min Chul Cho
We evaluated whether LIM-kinase 2 inhibitor (LIMK2i) could improve erectile function by suppressing corporal fibrosis through the normalization of the Rho-associated coiled-coil protein kinase 1 (ROCK1)/LIMK2/Cofilin pathway in a rat model of cavernous nerve crush injury (CNCI). Sixty 11-week-old male Sprague-Dawley rats were divided equally into five groups: sham surgery (S), CNCI (I), and CNCI treated with low-dose (L), medium-dose (M), and high-dose (H) LIMK2i. The L, M, and H groups were treated with a daily intraperitoneal injection of LIMK2i (2...
March 6, 2018: Asian Journal of Andrology
Zhen Zhong, Laura Grasso, Caroline Sibilla, Tim J Stevens, Nicholas Barry, Anne Bertolotti
Protein aggregation is a hallmark of diverse neurodegenerative diseases. Multiple lines of evidence have revealed that protein aggregates can penetrate inside cells and spread like prions. How such aggregates enter cells remains elusive. Through a focused siRNA screen targeting genes involved in membrane trafficking, we discovered that mutant SOD1 aggregates, like viruses, exploit cofilin-1 to remodel cortical actin and enter cells. Upstream of cofilin-1, signalling from the RHO GTPase and the ROCK1 and LIMK1 kinases controls cofilin-1 activity to remodel actin and modulate aggregate entry...
March 15, 2018: EMBO Journal
Kijung Sung, Luiz F Ferrari, Wanlin Yang, ChiHye Chung, Xiaobei Zhao, Yingli Gu, Suzhen Lin, Kai Zhang, Bianxiao Cui, Matthew L Pearn, Michael T Maloney, William C Mobley, Jon D Levine, Chengbiao Wu
Nerve growth factor (NGF) exerts multiple functions on target neurons throughout development. The recent discovery of a point mutation leading to a change from arginine to tryptophan at residue 100 in the mature NGFβ sequence (NGFR100W ) in patients with hereditary sensory and autonomic neuropathy, type V (HSAN V), made it possible to distinguish the signaling mechanisms that lead to two functionally different outcomes of NGF: trophic versus nociceptive. We performed extensive biochemical, cellular and live imaging experiments to examine the binding and signaling properties of NGFR100W Our results show that, similar to the wildtype NGF (wtNGF), the naturally occurring NGFR100W mutant was capable of binding to and activating the TrkA receptor and its downstream signaling pathways to support neuronal survival and differentiation...
February 24, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Zhongyi Lu, Xiaodong Jia, Yong Chen, Xuelin Han, Fangyan Chen, Shuguang Tian, Xueting Su, Zongwei Li, Jingya Zhao, Xi Zhang, Mandong Hu, Liuyu Huang, Li Han
Through some specific amino acid residues, Cofilin, a ubiquitous actin depolymoerization factor, can significantly affect mitochondrial function related to drug resistance and apoptosis in Saccharomyces cerevisiae ; however, this modulation in a major fungal pathogen, A. fumigatus was still unclear. Hereby, it was found firstly that mutations on several charged residues in cofilin to alanine, D19A;R21A, E48A, and K36A increased the formation of reactive oxygen species and induced apoptosis along with typical hallmarks including mitochondrial membrane potential depolarization, the cytochrome c release, upregulation of metacaspases, and DNA cleavage in A...
February 26, 2018: Antimicrobial Agents and Chemotherapy
M Shin, M B Chavez, A Ikeda, B L Foster, J D Bartlett
Ameloblasts responsible for enamel formation express matrix metalloproteinase 20 (MMP20), an enzyme that cleaves enamel matrix proteins, including amelogenin (AMELX) and ameloblastin (AMBN). Previously, we showed that continuously erupting incisors from transgenic mice overexpressing active MMP20 had a massive cell infiltrate present within their enamel space, leading to enamel mineralization defects. However, effects of MMP20 overexpression on mouse molars were not analyzed, although these teeth more accurately represent human odontogenesis...
February 1, 2018: Journal of Dental Research
Marina Mikhaylova, Julia Bär, Bas van Bommel, Philipp Schätzle, PingAn YuanXiang, Rajeev Raman, Johannes Hradsky, Anja Konietzny, Egor Y Loktionov, Pasham Parameshwar Reddy, Jeffrey Lopez-Rojas, Christina Spilker, Oliver Kobler, Syed Ahsan Raza, Oliver Stork, Casper C Hoogenraad, Michael R Kreutz
Compartmentalization of calcium-dependent plasticity allows for rapid actin remodeling in dendritic spines. However, molecular mechanisms for the spatio-temporal regulation of filamentous actin (F-actin) dynamics by spinous Ca2+ -transients are still poorly defined. We show that the postsynaptic Ca2+ sensor caldendrin orchestrates nano-domain actin dynamics that are essential for actin remodeling in the early phase of long-term potentiation (LTP). Steep elevation in spinous [Ca2+ ]i disrupts an intramolecular interaction of caldendrin and allows cortactin binding...
February 20, 2018: Neuron
Matteo Zampini, Claudia Tregnago, Valeria Bisio, Luca Simula, Giulia Borella, Elena Manara, Carlo Zanon, Francesca Zonta, Valentina Serafin, Benedetta Accordi, Silvia Campello, Barbara Buldini, Andrea Pession, Franco Locatelli, Giuseppe Basso, Martina Pigazzi
The somatic translocation t(8;21)(q22;q22)/RUNX1-RUNX1T1 is one of the most frequent rearrangements found in children with standard-risk acute myeloid leukemia (AML). Despite the favorable prognostic role of this aberration, we recently observed a higher than expected frequency of relapse. Here, we employed an integrated high-throughput approach aimed at identifying new biological features predicting relapse among 34 t(8;21)-rearranged patients. We found that the DNA methylation status of patients who suffered from relapse was peculiarly different from that of children maintaining complete remission...
February 2, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Andrew Huehn, Wenxiang Cao, W Austin Elam, Xueqi Liu, Enrique M De La Cruz, Charles V Sindelar
Cofilin/ADF proteins are actin-remodeling proteins, essential for actin disassembly in various cellular processes, including cell division, intracellular transport, and motility. Cofilins bind actin filaments cooperatively and sever them preferentially at boundaries between bare and cofilin-decorated (cofilactin) segments. The cooperative binding to actin has been proposed to originate from conformational changes that propagate allosterically from clusters of bound cofilin to bare actin segments. Estimates of the lengths over which these cooperative conformational changes propagate vary dramatically, ranging from 2 to >100 subunits...
February 20, 2018: Journal of Biological Chemistry
Richard W Smith, Richard D Moccia, Colin B Seymour, Carmel E Mothersill
Exposure to a single 0.5 Gy X-ray dose of eggs at 48 h after fertilisation (48 h egg), eyed eggs, yolk sac larvae (YSL) and first feeders induces a legacy effect in adult rainbow trout. This includes the transmission of a bystander effect to non-irradiated adult trout which had swam with the irradiated fish. The aim of this study was to investigate this legacy by analysing the gill proteome of these irradiated and bystander fish. Irradiation at all of the early life stages resulted in changes to proteins which play a key role in development but are also known to be anti-tumorigenic and anti-oxidant: upregulation of haemoglobin subunit beta (48 h egg), haemoglobin, serum albumin 1 precursor (eyed eggs), clathrin heavy chain 1 isoform X10 (eyed eggs and first feeders), and actin-related protein 2/3 complex subunit 4 (first feeders), downregulation of pyruvate dehydrogenase, histone 1 (48 h egg), triosephosphate isomerase (TPI), collagen alpha-1(1) chain like proteins (YSL), pyruvate kinase PKM-like protein (YSL and first feeders), ubiquitin-40S ribosomal proteins S27 and eukaryotic translation initiation factor 4 A isoform 1B (first feeders)...
February 17, 2018: Environmental Research
F Fattori, C Fiorillo, C Rodolico, G Tasca, M Verardo, E Bellacchio, S Pizzi, A Ciolfi, G Fagiolari, A Lupica, P Broda, M Pedemonte, M Moggio, C Bruno, M Tartaglia, E Bertini, A D'Amico
Congenital myopathies (CMs) caused by mutation in cofilin-2 gene (CFL2) show phenotypic heterogeneity ranging from early onset and rapid progressive forms to milder myopathy. Muscle histology is also heterogeneous showing rods and /or myofibrillar changes. Here, we report on three new cases, from two unrelated families, of severe CM related to novel homozygous or compound heterozygous loss-of-function mutations in CFL2. Peculiar histopathological changes showed nemaline bodies and thin filaments accumulations together to myofibrillar changes, which were evocative of the muscle findings observed in Cfl2-/- knockout mouse model...
February 19, 2018: Clinical Genetics
Mingyue Li, Grace Gar-Lee Yue, Li-Hua Song, Mao-Bo Huang, Julia Kin-Ming Lee, Stephen Kwok-Wing Tsui, Kwok-Pui Fung, Ning-Hua Tan, Clara Bik-San Lau
Bigelovin, a sesquiterpene lactone, has been demonstrated to induce apoptosis, inhibit inflammation and angiogenesis in vitro, but its potential anti-metastatic activity remains unclear. In the present study, two colon cancer mouse models, orthotopic tumor allografts and experimental metastatic models were utilized to investigate the progression and metastatic spread of colorectal cancer after bigelovin treatments. Results showed that bigelovin (intravenous injection; 0.3-3 mg/kg) significantly suppressed tumor growth and inhibited liver/lung metastasis with modulation of tumor microenvironment (e...
February 15, 2018: Biochemical Pharmacology
Jung-Hyun Choi, Wei Wang, Dongkeun Park, Sung-Hoon Kim, Kyong-Tai Kim, Kyung-Tai Min
In neuronal development, dynamic rearrangement of actin promotes axonal growth cone extension, and spatiotemporal translation of local mRNAs in response to guidance cues directs axonal growth cone steering, where cofilin plays a critical role. While regulation of cofilin activity is well studied, regulatory mechanism for cofilin mRNA translation in neurons is unknown. In eukaryotic cells, proteins can be synthesized by cap-dependent or cap-independent mechanism via internal ribosome entry site (IRES)-mediated translation...
February 12, 2018: EMBO Journal
Dawei Mu, Gaobiao Zhou, Jianye Li, Bin Su, Heqing Guo
Ursolic acid has various pharmacological activities, and can reduce blood fat as well as having antihepatic, antitumoral, anti-inflammatory and antiviral properties. However, the pro-apoptotic mechanism by which ursolic acid influences human prostate cancer requires additional study. The aim of the present study was to assess whether ursolic acid activates the apoptosis of prostate cancer and to investigate the mechanism by which the Rho-associated protein kinase 1 (ROCK1)/phosphatase and tensin homolog (PTEN) signaling pathway performs a role in ursolic acid-mediated cofilin-1 to induce apoptosis in human prostate cancer...
March 2018: Oncology Letters
Yue Zhang, Yaoyi Wang, Jun Xue
The main problem in breast cancer treatment is the recurrence of tumor growth and metastases. Previous studies have suggested that Paclitaxel is widely used to treat various cancers. The present study analyzed the potential signaling pathway of Paclitaxel-inhibited breast cancer metastasis. It was demonstrated that Paclitaxel treatment significantly inhibited growth of breast cancer cell lines including MCF-7 and SKBR3 cells. Results demonstrated that Paclitaxel significantly inhibited breast cancer cell migration and invasion...
February 2018: Experimental and Therapeutic Medicine
Markku Hakala, Maria Kalimeri, Giray Enkavi, Ilpo Vattulainen, Pekka Lappalainen
Membrane phosphoinositides control organization and dynamics of the actin cytoskeleton by regulating the activities of several key actin-binding proteins. Twinfilin is an evolutionarily conserved protein, which contributes to cytoskeletal dynamics by interacting with actin monomers, filaments, and the heterodimeric capping protein. Twinfilin also binds phosphoinositides, which inhibit its interactions with actin, but the underlying mechanism has remained unknown. Here we show that the high-affinity binding site of twinfilin for phosphoinositides is located at the carboxy-terminal tail-region, while the two ADF/cofilin like ADF-H domains of twinfilin bind phosphoinositides only with low affinity...
February 7, 2018: Journal of Biological Chemistry
Hao Zhou, Jin Wang, Pingjun Zhu, Shunying Hu, Jun Ren
Ripk3-mediated cellular apoptosis is a major contributor to the pathogenesis of myocardial ischemia reperfusion (IR) injury. However, the mechanisms by which Ripk3 influences microvascular homeostasis and endothelial apoptosis are not completely understood. In this study, loss of Ripk3 inhibited endothelial apoptosis, alleviated luminal swelling, maintained microvasculature patency, reduced the expression of adhesion molecules and limited the myocardial inflammatory response. In vitro, Ripk3 deficiency protected endothelial cells from apoptosis and migratory arrest induced by HR injury...
January 27, 2018: Cellular Signalling
Bruno K Rodiño-Janeiro, Cristina Martínez, Marina Fortea, Beatriz Lobo, Marc Pigrau, Adoración Nieto, Ana María González-Castro, Eloísa Salvo-Romero, Danila Guagnozzi, Cristina Pardo-Camacho, Cristina Iribarren, Fernando Azpiroz, Carmen Alonso-Cotoner, Javier Santos, Maria Vicario
Disturbed intestinal epithelial barrier and mucosal micro-inflammation characterize irritable bowel syndrome (IBS). Despite intensive research demonstrating ovarian hormones modulation of IBS severity, there is still limited knowledge on the mechanisms underlying female predominance in this disorder. Our aim was to identify molecular pathways involved in epithelial barrier dysfunction and female predominance in diarrhea-predominant IBS (IBS-D) patients. Total RNA and protein were obtained from jejunal mucosal biopsies from healthy controls and IBS-D patients meeting the Rome III criteria...
February 2, 2018: Scientific Reports
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