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https://www.readbyqxmd.com/read/29150704/evaluation-of-immune-mediated-idiosyncratic-drug-toxicity-using-chimeric-hla-transgenic-mice
#1
Takeshi Susukida, Shigeki Aoki, Kotaro Kogo, Sota Fujimori, Binbin Song, Cong Liu, Shuichi Sekine, Kousei Ito
Immune-mediated idiosyncratic drug toxicity (IDT) is a rare adverse drug reaction, potentially resulting in death. Although genome-wide association studies suggest that the occurrence of immune-mediated IDT is strongly associated with specific human leukocyte antigen (HLA) allotypes, these associations have not yet been prospectively demonstrated. In this study, we focused on HLA-B*57:01 and abacavir (ABC)-induced immune-mediated IDT, and constructed transgenic mice carrying chimeric HLA-B*57:01 (B*57:01-Tg) to determine if this in vivo model may be useful for evaluating immune-mediated IDT...
November 17, 2017: Archives of Toxicology
https://www.readbyqxmd.com/read/29150565/the-role-of-macrophages-in-the-response-to-tnf-inhibition-in-experimental-arthritis
#2
Qi-Quan Huang, Robert Birkett, Renee Doyle, Bo Shi, Elyssa L Roberts, Qinwen Mao, Richard M Pope
The reduction of synovial tissue macrophages is a reliable biomarker for clinical improvement in patients with rheumatoid arthritis (RA), and macrophages are reduced in synovial tissue shortly after initiation of TNF inhibitors. The mechanism for this initial response is unclear. These studies were performed to identify the mechanisms responsible for the initial reduction of macrophages following TNF inhibition, positing that efflux to draining lymph nodes was involved. RA synovial tissue and synovial fluid macrophages expressed CCR7, which was increased in control macrophages following incubation with TNF-α...
November 17, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29149759/dusp1-alleviates-cardiac-ischemia-reperfusion-injury-by-suppressing-the-mff-required-mitochondrial-fission-and-bnip3-related-mitophagy-via-the-jnk-pathways
#3
Qinhua Jin, Ruibing Li, Nan Hu, Ting Xin, Pingjun Zhu, Shunying Hu, Sai Ma, Hong Zhu, Jun Ren, Hao Zhou
Mitochondrial fission and selective mitochondrial autophagy (mitophagy) form an essential axis of mitochondrial quality control that plays a critical role in the development of cardiac ischemia-reperfusion (IR) injury. However, the precise upstream molecular mechanism of fission/mitophagy remains unclear. Dual-specificity protein phosphatase1 (DUSP1) regulates cardiac metabolism, but its physiological contribution in the reperfused heart, particularly its influence on mitochondrial homeostasis, is unknown. Here, we demonstrated that cardiac DUSP1 was downregulated following acute cardiac IR injury...
November 6, 2017: Redox Biology
https://www.readbyqxmd.com/read/29149648/dried-plum-alleviates-symptoms-of-inflammatory-arthritis-in-tnf-transgenic-mice
#4
Faryal Mirza, Joseph Lorenzo, Hicham Drissi, Francis Y Lee, Do Y Soung
Dried plum (DP), a rich source of polyphenols has been shown to have bone-preserving properties in both animal models of osteoporosis and postmenopausal women. We evaluated if DP alleviated the destruction of joints in transgenic mice (TG) that overexpress human tumor necrosis factor (TNF), a genetic model of rheumatoid arthritis (RA). A four-week treatment of 20% DP diet in TG slowed the onset of arthritis and reduced bone erosions in the joints compared to TG on a regular diet. This was associated with fewer tartrate-resistant acid phosphatase (TRAP) positive cells, suggesting decreased osteoclastogenesis...
October 16, 2017: Journal of Nutritional Biochemistry
https://www.readbyqxmd.com/read/29146922/molecular-definition-of-multiple-sites-of-antibody-inhibition-of-malaria-transmission-blocking-vaccine-antigen-pfs25
#5
Stephen W Scally, Brandon McLeod, Alexandre Bosch, Kazutoyo Miura, Qi Liang, Sean Carroll, Sini Reponen, Ngan Nguyen, Eldar Giladi, Sebastian Rämisch, Vidadi Yusibov, Allan Bradley, Franck Lemiale, William R Schief, Daniel Emerling, Paul Kellam, C Richter King, Jean-Philippe Julien
The Plasmodium falciparum Pfs25 protein (Pfs25) is a leading malaria transmission-blocking vaccine antigen. Pfs25 vaccination is intended to elicit antibodies that inhibit parasite development when ingested by Anopheles mosquitoes during blood meals. The Pfs25 three-dimensional structure has remained elusive, hampering a molecular understanding of its function and limiting immunogen design. We report six crystal structures of Pfs25 in complex with antibodies elicited by immunization via Pfs25 virus-like particles in human immunoglobulin loci transgenic mice...
November 16, 2017: Nature Communications
https://www.readbyqxmd.com/read/29146611/smooth-muscle-selective-nuclear-factor-%C3%AE%C2%BAb-inhibition-reduces-phosphate-induced-arterial-medial-calcification-in-mice-with-chronic-kidney-disease
#6
Tadashi Yoshida, Maho Yamashita, Chihiro Horimai, Matsuhiko Hayashi
BACKGROUND: Hyperphosphatemia is a major factor promoting the formation of arterial medial calcification in chronic kidney disease (CKD). However, arterial medial calcification begins to occur during the early stages of CKD, when hyperphosphatemia is not yet apparent. It is predicted that other factors also play a role. The aim of the present study was to determine the role of pro-inflammatory nuclear factor-κB (NF-κB) signaling in smooth muscle cells (SMCs) for phosphate-induced arterial medial calcification in CKD mice...
November 16, 2017: Journal of the American Heart Association
https://www.readbyqxmd.com/read/29146302/mechanisms-involved-in-bone-resorption-regulated-by-vitamin-d
#7
REVIEW
Yuko Nakamichi, Nobuyuki Udagawa, Tatsuo Suda, Naoyuki Takahashi
Active forms of vitamin D enhance osteoclastogenesis in vitro and in vivo through the vitamin D receptor (VDR) in osteoblast-lineage cells consisting of osteoblasts and osteocytes. This pro-resorptive activity was evident basically with higher concentrations of active vitamin D than those expected in physiological conditions. Nevertheless, vitamin D compounds have been used in Japan for treating osteoporosis to increase bone mineral density (BMD). Of note, the increase in BMD by long-term treatment with pharmacological (=near-physiological) doses of vitamin D compounds was caused by the suppression of bone resorption...
November 13, 2017: Journal of Steroid Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/29146238/ccr5-mediates-hiv-1-tat-induced-neuroinflammation-and-influences-morphine-tolerance-dependence-and-reward
#8
Maciej Gonek, Virginia D McLane, David L Stevens, Kumiko Lippold, Hamid I Akbarali, Pamela E Knapp, William L Dewey, Kurt F Hauser, Jason J Paris
The HIV-1 regulatory protein, trans-activator of transcription (Tat), interacts with opioids to potentiate neuroinflammation and neurodegeneration within the CNS. These effects may involve the C-C chemokine receptor type 5 (CCR5); however, the behavioral contribution of CCR5 on Tat/opioid interactions is not known. Using a transgenic murine model that expresses HIV-1 Tat protein in a GFAP-regulated, doxycycline-inducible manner, we assessed morphine tolerance, dependence, and reward. To assess the influence of CCR5 on these effects, mice were pretreated with oral vehicle or the CCR5 antagonist, maraviroc, prior to morphine administration...
November 13, 2017: Brain, Behavior, and Immunity
https://www.readbyqxmd.com/read/29145710/testosterone-replacement-in-transgenic-sickle-cell-mice-controls-priapic-activity-and-upregulates-pde5-expression-and-enos-activity-in-the-penis
#9
B Musicki, S Karakus, W Akakpo, F H Silva, J Liu, H Chen, B R Zirkin, A L Burnett
Sickle cell disease (SCD)-associated priapism is characterized by decreased nitric oxide (NO) signaling and downregulated phosphodiesterase (PDE)5 protein expression and activity in the penis. Priapism is also associated with testosterone deficiency, but molecular mechanisms underlying testosterone effects in the penis in SCD are not known. Given the critical role of androgens in erection physiology and NO synthase (NOS)/PDE5 expression, we hypothesized that testosterone replacement to eugonadal testosterone levels reduces priapism by reversing impaired endothelial (e)NOS activity and molecular abnormalities involving PDE5...
November 16, 2017: Andrology
https://www.readbyqxmd.com/read/29145462/circulating-soluble-endoglin-modifies-the-inflammatory-response-in-mice
#10
Laura Ruiz-Remolina, Claudia Ollauri-Ibáñez, Lucía Pérez-Roque, Elena Núñez-Gómez, Fernando Pérez-Barriocanal, José Miguel López-Novoa, Miguel Pericacho, Alicia Rodríguez-Barbero
Inflammation is associated with every health condition, and is an important component of many pathologies such as cardiovascular diseases. Circulating levels of soluble endoglin have been shown to be higher in the serum of patients with cardiovascular diseases with a significant inflammatory component. The aim of this study was to evaluate the implication of circulating soluble endoglin in the inflammatory response. For this purpose, a transgenic mouse expressing human soluble endoglin (sEng+) was employed, and three different inflammatory approaches were used to mimic inflammatory conditions in different tissues...
2017: PloS One
https://www.readbyqxmd.com/read/29145399/point-mutation-in-d8c-domain-of-tamm-horsfall-protein-uromodulin-in-transgenic-mice-causes-progressive-renal-damage-and-hyperuricemia
#11
Lijie Ma, Yan Liu, Nichole K Landry, Tarek M El-Achkar, John C Lieske, Xue-Ru Wu
Hereditary mutations in Tamm-Horsfall protein (THP/uromodulin) gene cause autosomal dominant kidney diseases characterized by juvenile-onset hyperuricemia, gout and progressive kidney failure, although the disease pathogenesis remains unclear. Here we show that targeted expression in transgenic mice of a mutation within the domain of 8 cysteines of THP in kidneys' thick ascending limb (TAL) caused unfolded protein response in younger (1-month old) mice and apoptosis in older (12-month old) mice. While the young mice had urine concentration defects and polyuria, such defects progressively reversed in the older mice to marked oliguria, highly concentrated urine, fibrotic kidneys and reduced creatinine clearance...
2017: PloS One
https://www.readbyqxmd.com/read/29145032/intravenous-immunoglobulin-improves-glucose-control-and-%C3%AE-cell-function-in-human-iapp-transgenic-mice-by-attenuating-islet-inflammation-and-reducing-iapp-oligomers
#12
Yue Zhang, Xiao-Lin Yu, Jie Zhu, Shu-Ying Liu, Xiang-Meng Liu, Quan-Xiu Dong, Jia-Qian Chai, Rui-Tian Liu
Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by β-cell loss, insulin resistance, islet inflammation and amyloid deposits derived from islet amyloid polypeptide (IAPP). Reducing toxic IAPP oligomers and inhibiting islet inflammation may provide therapeutic benefit in treating T2DM. Intravenous immunoglobulin (IVIg) is an efficient anti-inflammatory and immunomodulatory agent for the treatment of several autoimmune or inflammatory neurological diseases. However, whether IVIg has therapeutic potential on T2DM remains unclear...
November 13, 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/29143286/doxycycline-inducible-and-astrocyte-specific-hiv-1-tat-transgenic-mice-itat-as-an-hiv-neuroaids-model
#13
Dianne Langford, Byung Oh Kim, Wei Zou, Yan Fan, Pejman Rahimain, Ying Liu, Johnny J He
HIV-1 Tat is known to be neurotoxic and important for HIV/neuroAIDS pathogenesis. However, the overwhelming majority of the studies involved use of recombinant Tat protein. To understand the contributions of Tat protein to HIV/neuroAIDS and the underlying molecular mechanisms of HIV-1 Tat neurotoxicity in the context of a whole organism and independently of HIV-1 infection, a doxycycline-inducible astrocyte-specific HIV-1 Tat transgenic mouse (iTat) was created. Tat expression in the brains of iTat mice was determined to be in the range of 1-5 ng/ml and led to astrocytosis, loss of neuronal dendrites, and neuroinflammation...
November 15, 2017: Journal of Neurovirology
https://www.readbyqxmd.com/read/29143114/cancer-vaccine-strategies-translation-from-mice-to-human-clinical-trials
#14
REVIEW
Jay A Berzofsky, Masaki Terabe, Jane B Trepel, Ira Pastan, David F Stroncek, John C Morris, Lauren V Wood
We translated two cancer vaccine strategies from mice into human clinical trials. (1) In preclinical studies on TARP, an antigen expressed in most prostate cancers, we mapped epitopes presented by HLA-A*0201, modified them to increase affinity and immunogenicity in HLA transgenic mice, and induced human T cells that killed human cancer cells ("epitope enhancement"). In a clinical trial, HLA-A2(+) prostate cancer patients with PSA biochemical recurrence (Stage D0) were vaccinated with two peptides either in Montanide-ISA51 or on autologous dendritic cells (DCs)...
November 15, 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/29142275/nf-%C3%AE%C2%BAb-protects-nkt-cells-from-tumor-necrosis-factor-receptor-1-induced-death
#15
Amrendra Kumar, Laura E Gordy, Jelena S Bezbradica, Aleksandar K Stanic, Timothy M Hill, Mark R Boothby, Luc Van Kaer, Sebastian Joyce
Semi-invariant natural killer T (NKT) cells are innate-like lymphocytes with immunoregulatory properties. NKT cell survival during development requires signal processing by activated RelA/NF-κB. Nonetheless, the upstream signal(s) integrated by NF-κB in developing NKT cells remains incompletely defined. We show that the introgression of Bcl-xL-coding Bcl2l1 transgene into NF-κB signalling-deficient IκBΔN transgenic mouse rescues NKT cell development and differentiation in this mouse model. We reasoned that NF-κB activation was protecting developing NKT cells from death signals emanating either from high affinity agonist recognition by the T cell receptor (TCR) or from a death receptor, such as tumor necrosis factor receptor 1 (TNFR1) or Fas...
November 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29141991/human-sex-hormone-binding-globulin-does-not-provide-metabolic-protection-against-dysglycemia-in-mice
#16
Yael Sofer, Nava Nevo, Michal Vechoropulus, Gabi Shefer, Esther Osher, Nathan Landis, Geoffrey L Hammond, Naftali Stern
BACKGROUND: Sex hormone binding globulin (SHBG) is the main transporter of sex hormones in most vertebrates. Low SHBG levels have been linked to increased propensity for diabetes and metabolic syndrome. Polymorphisms of the SHBG gene linked to low SHBG protein levels, also strongly predicted increased risk of type 2 diabetes, thus raising the possibility that SHBG may play a role in the in the pathogenesis of insulin resistance and diabetes. AIM: To examine whether expression of human SHBG in mice may ameliorate the development of diabetes and metabolic syndrome in response to a high fat diet...
November 15, 2017: Endocrine Connections
https://www.readbyqxmd.com/read/29141888/lung-cancer-associated-pulmonary-hypertension-role-of-microenvironmental-inflammation-based-on-tumor-cell-immune-cell-cross-talk
#17
Soni Savai Pullamsetti, Baktybek Kojonazarov, Samantha Storn, Henning Gall, Ylia Salazar, Janine Wolf, Andreas Weigert, Nefertiti El-Nikhely, Hossein Ardeschir Ghofrani, Gabriele A Krombach, Ludger Fink, Stefan Gattenlöhner, Ulf R Rapp, Ralph Theo Schermuly, Friedrich Grimminger, Werner Seeger, Rajkumar Savai
Dyspnea is a frequent, devastating, and poorly understood symptom of advanced lung cancer. In our cohort, among 519 patients who underwent a computed tomography scan for the diagnosis of lung cancer, 250 had a mean pulmonary artery diameter of >28 mm, indicating pulmonary hypertension (PH). In human lung cancer tissue, we consistently observed increased vascular remodeling and perivascular inflammatory cell accumulation (macrophages/lymphocytes). Vascular remodeling, PH, and perivascular inflammatory cell accumulation were mimicked in three mouse models of lung cancer (LLC1, KRas(LA2) , and cRaf-BxB)...
November 15, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/29141186/hyperbaric-oxygen-therapy-ameliorates-pathophysiology-of-3xtg-ad-mouse-model-by-attenuating-neuroinflammation
#18
Ronit Shapira, Beka Solomon, Shai Efrati, Dan Frenkel, Uri Ashery
There is a real need for new interventions for Alzheimer's disease (AD). Hyperbaric oxygen therapy (HBOT), the medical administration of 100% oxygen at conditions greater than 1 atmosphere absolute, has been used successfully to treat several neurological conditions, but its effects on AD pathology have never been thoroughly examined. Therefore, we exposed old triple-transgenic (3xTg) and non-transgenic mice to HBOT followed by behavioral, histological, and biochemical analyses. HBOT attenuated neuroinflammatory processes by reducing astrogliosis, microgliosis, and the secretion of proinflammatory cytokines (IL-1β and TNFα) and increasing expression of scavenger receptor A, arginase1, and antiinflammatory cytokines (IL-4 and IL-10)...
October 20, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/29140847/overexpressed-wild-type-superoxide-dismutase-1-exhibits-amyotrophic-lateral-sclerosis-related-misfolded-conformation-in-induced-pluripotent-stem-cell-derived-spinal-motor-neurons
#19
Kenichi Komatsu, Keiko Imamura, Hirofumi Yamashita, Jean-Pierre Julien, Ryosuke Takahashi, Haruhisa Inoue
Amyotrophic lateral sclerosis (ALS) is a late-onset, fatal disorder in which motor neurons selectively degenerate. Superoxide dismutase 1 (SOD1) was found to be a causative gene of familial ALS, and mutant SOD1 transgenic mice recapitulated ALS phenotypes. Analysis of these mice showed accumulation of misfolded SOD1 protein in motor neurons. Misfolded SOD1 accumulation was found in spinal motor neurons of both familial ALS patients with the SOD1 mutation and sporadic ALS patients. However, it is unclear what condition causes wild-type SOD1 misfolding in patients without the SOD1 mutation...
November 14, 2017: Neuroreport
https://www.readbyqxmd.com/read/29139538/limitations-of-the-pax7-creer-t2-transgene-for-driving-deletion-of-nf1-in-adult-mouse-muscle
#20
Matthew A Summers, Kathy Mikulec, Lauren Peacock, David G Little, Aaron Schindeler
Neurofibromatosis Type 1 (NF1) is an autosomal dominant genetic disorder that results in a variety of characteristic manifestations. Prior studies have shown reduced muscle size and global skeletal muscle weakness in children with NF1. This associated weakness can lead to significant challenges impacting on quality of life. Pre-clinical studies using a muscle-specific NF1 knockout mouse have linked this weakness to an underlying primary metabolic deficiency in the muscle. However, the neonatal lethality of this strain prevents analysis of the role of NF1 in adult muscle...
2017: International Journal of Developmental Biology
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