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Lysyl oxidase-like 2

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https://www.readbyqxmd.com/read/28683690/using-costal-chondrocytes-to-engineer-articular-cartilage-with-applications-of-passive-axial-compression-and-bioactive-stimuli
#1
Le Huwe, Gurdeep Sullan, Jerry C Hu, Kyriacos A Athanasiou
Generating neocartilage with suitable mechanical integrity from a cell source that can circumvent chondrocyte scarcity is indispensable for articular cartilage regeneration strategies. Costal chondrocytes of the rib eliminate donor site morbidity in the articular joint, but it remains unclear how neocartilage formed from these cells responds to mechanical loading, especially if the intent is to use it in a load-bearing joint. In a series of three experiments, this study sought to determine efficacious parameters of passive axial compressive stimulation that would enable costal chondrocytes to synthesize mechanically robust cartilage...
July 6, 2017: Tissue Engineering. Part A
https://www.readbyqxmd.com/read/28677767/lysyl-oxidase%C3%A2-like-2-is-expressed-in-kidney-tissue-and-is-associated-with-the-progression-of-tubulointerstitial-fibrosis
#2
Sung-Eun Choi, Nara Jeon, Hoon Young Choi, Jae Il Shin, Hyeon Joo Jeong, Beom Jin Lim
Tubulointerstitial fibrosis is a common end point of chronic kidney diseases, and preventing its progression is key to avoiding renal failure. Transforming growth factor‑β (TGF‑β) and associated molecules promote tubulointerstitial fibrosis; however, effective therapies targeting these molecules have yet to be developed. Lysyl oxidase‑like 2 (LOXL2), which is involved in invasive growth and metastasis of malignant neoplasms, has recently been reported to serve a key role in hepatic and pulmonary fibrosis...
July 4, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28638462/reorganized-collagen-in-the-tumor-microenvironment-of-gastric-cancer-and-its-association-with-prognosis
#3
Zhi-Hua Zhou, Cheng-Dong Ji, Hua-Liang Xiao, Hai-Bin Zhao, You-Hong Cui, Xiu-Wu Bian
Collagen components in the tumor microenvironment substantially influence cancer pathogenesis and progression. Nevertheless, in gastric cancer, collagen status and its prognostic role remain unclear. Using picrosirius red staining and immunohistochemistry, we found that collagen deposition was significantly increased in gastric cancer when compared with non-neoplastic tissues, and in cancer stroma, more immature collagen components were present, suggesting a qualitative change. Furthermore, the morphology of collagen fibers could be weakly, moderately or strongly changed in gastric cancer; when weakly or moderately changed, they appeared similar to normal collagen fibers, except for a higher linearization and density; when strongly changed, they were thicker and less eosinophilic, sharply differently from their normal counterparts...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/28598820/role-of-loxl2-in-the-epithelial-mesenchymal-transition-and-colorectal-cancer-metastasis
#4
Pil-Gu Park, Su Ji Jo, Min Jung Kim, Hyun Jeong Kim, Ji Hae Lee, Cheol Keun Park, Hyunki Kim, Kang Young Lee, Hoguen Kim, Jeon Han Park, Seung Myung Dong, Jae Myun Lee
Colorectal cancer (CRC) is one of the most dangerous types of malignant tumors, and cancer metastasis is a major factor in the failure of CRC therapy. Recently, LOXL2 (lysyl oxidase-like 2) has been shown to represent a regulator of epithelial-mesenchymal transition (EMT) in different cancer types. However, LOXL2 has not been reported to be involved in CRC metastasis. In this study, we demonstrated that LOXL2 expression is strongly correlated with the rate of CRC metastasis, it participates in the regulation of EMT-related molecule expression in CRC cells in vitro, and it is involved in migratory potential alterations...
May 25, 2017: Oncotarget
https://www.readbyqxmd.com/read/28592436/bladder-fibrosis-during-outlet-obstruction-is-triggered-through-the-nlrp3-inflammasome-and-the-production-of-il-1%C3%AE
#5
Francis Monty Hughes, Stephanie J Sexton, Huixia Jin, Vihasa Govada, J Todd Purves
Bladder outlet obstruction (BOO) triggers inflammation in the bladder through the NLRP3 inflammasome. BOO also activates fibrosis, which is largely responsible for the decompensation of the bladder in the chronic state. Because fibrosis can be driven by inflammation, we have explored a role for NLRP3 (and IL-1β produced by NLRP3) in the activation and progression of BOO-induced fibrosis. Female rats were divided into 5 groups: 1) control, 2) sham, 3) BOO + Vehicle, 4) BOO + the NLRP3 inhibitor glyburide or 5) BOO + the IL-1β receptor antagonist anakinra...
June 7, 2017: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/28534485/pseudoexfoliation-syndrome-associated-genetic-variants-affect-transcription-factor-binding-and-alternative-splicing-of-loxl1
#6
Francesca Pasutto, Matthias Zenkel, Ursula Hoja, Daniel Berner, Steffen Uebe, Fulvia Ferrazzi, Johannes Schödel, Panah Liravi, Mineo Ozaki, Daniela Paoli, Paolo Frezzotti, Takanori Mizoguchi, Satoko Nakano, Toshiaki Kubota, Shinichi Manabe, Erika Salvi, Paolo Manunta, Daniele Cusi, Christian Gieger, Heinz-Erich Wichmann, Tin Aung, Chiea Chuen Khor, Friedrich E Kruse, André Reis, Ursula Schlötzer-Schrehardt
Although lysyl oxidase-like 1 (LOXL1) is known as the principal genetic risk factor for pseudoexfoliation (PEX) syndrome, a major cause of glaucoma and cardiovascular complications, no functional variants have been identified to date. Here, we conduct a genome-wide association scan on 771 German PEX patients and 1,350 controls, followed by independent testing of associated variants in Italian and Japanese data sets. We focus on a 3.5-kb four-component polymorphic locus positioned spanning introns 1 and 2 of LOXL1 with enhancer-like chromatin features...
May 23, 2017: Nature Communications
https://www.readbyqxmd.com/read/28471663/identification-of-4-aminomethyl-6-trifluoromethyl-2-phenoxy-pyridine-derivatives-as-potent-selective-and-orally-efficacious-inhibitors-of-the-copper-dependent-amine-oxidase-lysyl-oxidase-like-2-loxl2
#7
Martin W Rowbottom, Gretchen Bain, Imelda Calderon, Taylor Lasof, David Lonergan, Andiliy Lai, Fei Huang, Janice Darlington, Patricia Prodanovich, Angelina M Santini, Christopher D King, Lance Goulet, Kristen E Shannon, Gina L Ma, Katherine Nguyen, Deidre A MacKenna, Jilly F Evans, John H Hutchinson
LOXL2 catalyzes the oxidative deamination of ε-amines of lysine and hydroxylysine residues within collagen and elastin, generating reactive aldehydes (allysine). Condensation with other allysines or lysines drives the formation of inter- and intramolecular cross-linkages, a process critical for the remodeling of the ECM. Dysregulation of this process can lead to fibrosis, and LOXL2 is known to be upregulated in fibrotic tissue. Small-molecules that directly inhibit LOXL2 catalytic activity represent a useful option for the treatment of fibrosis...
May 25, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28468951/insulin-resistance-promotes-lysyl-oxidase-like-2induction-and-fibrosis-accumulation-in-nonalcoholic-fatty-liver-disease
#8
Paola Dongiovanni, Marica Meroni, Guido Alessandro Baselli, Giulia Alessandra Bassani, Raffaela Rametta, Alessandro Pietrelli, Marco Maggioni, Federica Facciotti, Valentina Trunzo, Sara Badiali, Silvia Fargion, Stefano Gatti, Luca Vittorio Carlo Valenti
Background & Aims: In patients with nonalcoholic fatty liver disease (NAFLD), insulin resistance (IR) associates with fibrosis progression independently of hepatic inflammation, but the mechanisms are still unclear. Methods : We modeled the independent contribution of inflammation (steatohepatitis: NASH) by exploiting the methionine-choline deficient (MCD) diet, and that of IR by insulin receptor haploinsufficiency (InsR+/-), in the pathogenesis of liver fibrosis in C57Bl/6 mice. We confirmed study findings in 96 patients with NAFLD...
May 3, 2017: Clinical Science (1979-)
https://www.readbyqxmd.com/read/28452589/lysyl-oxidase-propeptide-promotes-adipogenesis-through-inhibition-of-fgf-2-signaling
#9
John D Griner, Carl J Rogers, Mei-Jun Zhu, Min Du
Lysyl oxidase (LOX) catalyzes the oxidative deamination of lysine residues in collagen and elastin, key components of connective tissue. LOX is synthesized as an inactive 50 kD pre-proenzyme, and secreted to the extracellular matrix where it is cleaved into an active 32 kD LOX, and an 18kD free propeptide (LOX-PP), purportedly an inhibitor of fibroblast growth factor-2 (FGF-2) signaling. Given that adipocytes are distributed inside the connective tissue, it is likely that LOX-PP has an important regulatory role in adipogenesis, which has not been studied...
January 2, 2017: Adipocyte
https://www.readbyqxmd.com/read/28449718/hif-1%C3%AE-promoted-vasculogenic-mimicry-formation-in-hepatocellular-carcinoma-through-loxl2-up-regulation-in-hypoxic-tumor-microenvironment
#10
Meili Wang, Xiulan Zhao, Dongwang Zhu, Tieju Liu, Xiaohui Liang, Fang Liu, Yanhui Zhang, Xueyi Dong, Baocun Sun
BACKGROUND: The incidence and mortality rates of hepatocellular carcinoma (HCC) have steadily increased in recent years. A hypoxic microenvironment is one of the most important characteristics of solid tumors which has been shown to promote tumor metastasis, epithelial-mesenchymal transition and angiogenesis. Epithelial-mesenchymal transition and vasculogenic mimicry have been regarded as crucial contributing factors to cancer progression. HIF-1α functions as a master transcriptional regulator in the adaptive response to hypoxia...
April 27, 2017: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/28435530/small-molecule-lysyl-oxidase-like-2-loxl2-inhibitors-the-identification-of-an-inhibitor-selective-for-loxl2-over-lox
#11
John H Hutchinson, Martin W Rowbottom, David Lonergan, Janice Darlington, Pat Prodanovich, Christopher D King, Jilly F Evans, Gretchen Bain
Two series of novel LOXL2 enzyme inhibitors are described: benzylamines substituted with electron withdrawing groups at the para-position and 2-substituted pyridine-4-ylmethanamines. The most potent compound, (2-chloropyridin-4-yl)methanamine 20 (hLOXL2 IC50 = 126 nM), was shown to be selective for LOXL2 over LOX and three other amine oxidases (MAO-A, MAO-B, and SSAO). Compound 20 is the first published small molecule inhibitor selective for LOXL2 over LOX.
April 13, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28350101/loxl3-sv2-a-novel-variant-of-human-lysyl-oxidase-like-3-loxl3-functions-as-an-amine-oxidase
#12
Chankyu Jeong, Youngho Kim
Human lysyl oxidase-like 3 (LOXL3) functions as a copper-dependent amine oxidase toward collagen and elastin. The LOXL3 protein contains four scavenger receptor cysteine-rich (SRCR) domains in the N-terminus in addition to the C-terminal characteristic domains of the lysyl oxidase (LOX) family, such as a copper-binding domain, a cytokine receptor‑like domain and residues for the lysyl-tyrosyl quinone cofactor. Using BLASTN searches, we identified a novel variant of LOXL3 (termed LOXL3-sv2), which lacked the sequences corresponding to exons 4 and 5 of LOXL3...
January 19, 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28332555/loxl2-drives-epithelial-mesenchymal-transition-via-activation-of-ire1-xbp1-signalling-pathway
#13
Eva P Cuevas, Pilar Eraso, María J Mazón, Vanesa Santos, Gema Moreno-Bueno, Amparo Cano, Francisco Portillo
Epithelial-to-Mesenchymal Transition (EMT) is a key process contributing to the aggressiveness of cancer cells. EMT is triggered by activation of different transcription factors collectively known as EMT-TFs. Different cellular cues and cell signalling networks activate EMT at transcriptional and posttranscriptional level in different biological and pathological situations. Among them, overexpression of LOXL2 (lysyl oxidase-like 2) induces EMT independent of its catalytic activity. Remarkably, perinuclear/cytoplasmic accumulation of LOXL2 is a poor prognosis marker of squamous cell carcinomas and is associated to basal breast cancer metastasis by mechanisms no yet fully understood...
March 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28325283/silencing-of-carbohydrate-sulfotransferase-15-hinders-murine-pulmonary-fibrosis-development
#14
Yoshiro Kai, Koichi Tomoda, Hiroyuki Yoneyama, Masahiro Kitabatake, Atsuhiro Nakamura, Toshihiro Ito, Masanori Yoshikawa, Hiroshi Kimura
Pulmonary fibrosis is a progressive lung disorder characterized by interstitial fibrosis, for which no effective treatments are available. Chondroitin sulfate proteoglycan (CSPG) has been shown to be a mediator, but the specific component of glycosaminoglycan chains of CSPG has not been explored. We show that chondroitin sulfate E-type (CS-E) is involved in fibrogenesis. Small interfering RNA (siRNA) targeting carbohydrate sulfotransferase 15 (CHST15) was designed to inhibit CHST15 mRNA and its product, CS-E...
March 17, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28257048/vanillin-suppresses-cell-motility-by-inhibiting-stat3-mediated-hif-1%C3%AE-mrna-expression-in-malignant-melanoma-cells
#15
Eun-Ji Park, Yoon-Mi Lee, Taek-In Oh, Byeong Mo Kim, Beong-Ou Lim, Ji-Hong Lim
Recent studies have shown that vanillin has anti-cancer, anti-mutagenic, and anti-metastatic activity; however, the precise molecular mechanism whereby vanillin inhibits metastasis and cancer progression is not fully elucidated. In this study, we examined whether vanillin has anti-cancer and anti-metastatic activities via inhibition of hypoxia-inducible factor-1α (HIF-1α) in A2058 and A375 human malignant melanoma cells. Immunoblotting and quantitative real time (RT)-PCR analysis revealed that vanillin down-regulates HIF-1α protein accumulation and the transcripts of HIF-1α target genes related to cancer metastasis including fibronectin 1 (FN1), lysyl oxidase-like 2 (LOXL2), and urokinase plasminogen activator receptor (uPAR)...
March 1, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28246207/a-phase-ii-randomized-double-blind-placebo-controlled-study-of-simtuzumab-in-combination-with-folfiri-for-the-second-line-treatment-of-metastatic-kras-mutant-colorectal-adenocarcinoma
#16
J Randolph Hecht, Al B Benson, Dmitry Vyushkov, Yingsi Yang, Johanna Bendell, Udit Verma
LESSONS LEARNED: The safety profile in the patient groups who received FOLFIRI and simtuzumab did not differ from that in the FOLFIRI and placebo group.The addition of simtuzumab to chemotherapy with FOLFIRI does not improve clinical outcomes in patients with metastatic KRAS mutant colorectal carcinoma. BACKGROUND: Simtuzumab, a humanized IgG4 monoclonal antibody to lysyl oxidase-like 2 (LOXL2), blocks desmoplastic reaction in colorectal carcinoma (CRC) cells in vitro...
March 2017: Oncologist
https://www.readbyqxmd.com/read/28246206/a-phase-ii-randomized-double-blind-placebo-controlled-study-of-simtuzumab-or-placebo-in-combination-with-gemcitabine-for-the-first-line-treatment-of-pancreatic-adenocarcinoma
#17
Al B Benson, Zev A Wainberg, J Randolph Hecht, Dmitry Vyushkov, Hua Dong, Johanna Bendell, Fred Kudrik
LESSONS LEARNED: The safety profile in the gemcitabine/simtuzumab group was similar to that in the gemcitabine/placebo group.The addition of simtuzumab to gemcitabine does not improve clinical outcomes in patients with metastatic pancreatic adenocarcinoma ABSTRACT: Background.The humanized IgG4 monoclonal antibody simtuzumab inhibits the extracellular matrix-remodeling enzyme lysyl oxidase-like 2 maintaining pathological stroma in tumors. METHODS: Adult patients with metastatic pancreatic adenocarcinoma (mPaCa) were randomly assigned to receive intravenous gemcitabine, 1,000 mg/m(2), in combination with 200 or 700 mg simtuzumab or placebo...
March 2017: Oncologist
https://www.readbyqxmd.com/read/28220932/a-phase-2-study-of-simtuzumab-in-patients-with-primary-post-polycythaemia-vera-or-post-essential-thrombocythaemia-myelofibrosis
#18
MULTICENTER STUDY
Srdan Verstovsek, Michael R Savona, Ruben A Mesa, Hua Dong, Julia D Maltzman, Shringi Sharma, Jeffrey Silverman, Stephen T Oh, Jason Gotlib
Simtuzumab, a monoclonal antibody inhibitor of extracellular matrix enzyme lysyl oxidase-like-2, showed preclinical promise and was well tolerated in clinical studies. A phase 2, open-label study of simtuzumab was conducted in patients with primary myelofibrosis (MF), post-polycythaemia vera MF and post-essential thrombocythaemia MF. Fifty-four patients were randomized to receive simtuzumab alone (200 or 700 mg [n = 12 each group]) or simtuzumab (200 or 700 mg) with ruxolitinib (n = 15 each group) for 24 weeks...
March 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28203099/a-new-dermocosmetic-containing-retinaldehyde-delta-tocopherol-glucoside-and-glycylglycine-oleamide-for-managing-naturally-aged-skin-results-from-in-vitro-to-clinical-studies
#19
Céline Rouvrais, Daniel Bacqueville, Patrick Bogdanowicz, Marie-José Haure, Laure Duprat, Christine Coutanceau, Nathalie Castex-Rizzi, Hélène Duplan, Valérie Mengeaud, Sandrine Bessou-Touya
INTRODUCTION: Natural aging of skin tissues, the addition of the cumulative action of the time and radiation exposure result in skin atrophy, wrinkles and degeneration of the extracellular matrix (ECM). The aim of the study was to investigate the beneficial effect of a combination containing retinaldehyde (RAL), delta-tocopherol glucoside (delta-TC) and glycylglycine ole-amide (GGO) and of a dermocosmetic containing the combination. MATERIALS AND METHODS: The protective effect of the combination was assessed through in vitro gene expression of ultraviolet (UV)-irradiated fibroblasts...
2017: Clinical, Cosmetic and Investigational Dermatology
https://www.readbyqxmd.com/read/28199967/pre-clinical-evaluation-of-small-molecule-loxl2-inhibitors-in-breast-cancer
#20
Joan Chang, Morghan C Lucas, Lidia E Leonte, Marc Garcia-Montolio, Lukram Babloo Singh, Alison D Findlay, Mandar Deodhar, Jonathan S Foot, Wolfgang Jarolimek, Paul Timpson, Janine T Erler, Thomas R Cox
Lysyl Oxidase-like 2 (LOXL2), a member of the lysyl oxidase family of amine oxidases is known to be important in normal tissue development and homeostasis, as well as the onset and progression of solid tumors. Here we tested the anti-tumor properties of two generations of novel small molecule LOXL2 inhibitor in the MDA-MB-231 human model of breast cancer. We confirmed a functional role for LOXL2 activity in the progression of primary breast cancer. Inhibition of LOXL2 activity inhibited the growth of primary tumors and reduced primary tumor angiogenesis...
April 18, 2017: Oncotarget
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