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https://www.readbyqxmd.com/read/29049886/structure-activity-relationship-studies-of-pyrimido-5-4-b-indoles-as-selective-toll-like-receptor-4-ligands
#1
Michael Chan, Yuhei Kakitsubata, Tomoko Hayashi, Alast Ahmadi, Shiyin Yao, Nikunj M Shukla, Shin-Ya Oyama, Akihito Baba, Brandon Nguyen, Maripat Corr, Yasuo Suda, Dennis A Carson, Howard B Cottam, Masahiro Wakao
Previous high throughput screening studies led to the discovery of two novel, non-lipid-like chemotypes as Toll-like receptor 4 (TLR4) agonists. One of these chemotypes, the pyrimido[5,4-b]indoles, was explored for structure-activity relationship trends relative to production of TLR4 dependent cytokines/chemokines resulting in a semi-optimized lead (compound 1) that provided a starting point for further optimization studies. In this report, compounds belonging to three areas of structural modification were evaluated for biological activity using murine and human TLR4 reporter cells, primary murine bone marrow derived dendritic cells, and human peripheral blood mononuclear cells...
October 19, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29049306/protein-structural-disorder-of-the-envelope-v3-loop-contributes-to-the-switch-in-human-immunodeficiency-virus-type-1-cell-tropism
#2
Xiaowei Jiang, Felix Feyertag, David L Robertson
Human immunodeficiency virus type 1 (HIV-1) envelope gp120 is partly an intrinsically disordered (unstructured/disordered) protein as it contains regions that do not fold into well-defined protein structures. These disordered regions play important roles in HIV's life cycle, particularly, V3 loop-dependent cell entry, which determines how the virus uses two coreceptors on immune cells, the chemokine receptors CCR5 (R5), CXCR4 (X4) or both (R5X4 virus). Most infecting HIV-1 variants utilise CCR5, while a switch to CXCR4-use occurs in the majority of infections...
2017: PloS One
https://www.readbyqxmd.com/read/29049008/exogenous-murine-antimicrobial-peptide-cramp-significantly-exacerbates-ovalbumin-induced-airway-inflammation-but-ameliorates-oxazolone-induced-intestinal-colitis-in-balb-c-mice
#3
Yang Li, Xiaojie Chu, Cunbao Liu, Weiwei Huang, Yufeng Yao, Ye Xia, Pengyan Sun, Qiong Long, Xuejun Feng, Kui Li, Xu Yang, Hongmei Bai, Wenjia Sun, Yanbing Ma
Cathelicidin has been reported to be multifunctional. The current study aimed to investigate the influences of exogenous cathelicidin-related antimicrobial peptide (CRAMP) on inflammatory responses in different disease models. In OVA-induced allergic airway inflammation, CRAMP significantly enhanced the infiltration of inflammatory cells and accumulation of proinflammatory Th2 cytokine IL-13 and IL-33 in bronchial alveolar lavage fluid (BALF), exacerbated lung tissue inflammation and airway goblet cell hyperplasia, and elevated OVA-specific IgE level in serum...
October 19, 2017: Human Vaccines & Immunotherapeutics
https://www.readbyqxmd.com/read/29048484/adiponectin-suppression-of-late-inflammatory-mediator-hmgb1-induced-cytokine-expression-in-raw-264-macrophage-cells
#4
Mohamed Elfeky, Takeshi Yoneshiro, Yuko Okamatsu-Ogura, Kazuhiro Kimura
High mobility group protein B1 (HMGB1) is a late inflammatory mediator released from inflammatory cells when stimulated, resulting in exaggerating septic symptoms. We recently demonstrated that full-length adiponectin, a potent anti-inflammatory adipokine, inhibits lipopolysaccharide-induced HMGB1 release. However, the effects of adiponectin on HMGB1-induced exaggerating signals currently remain unknown. This study aimed to investigate the effects of adiponectin on the pro-inflammatory function of HMGB1 in RAW264 macrophage cells...
October 18, 2017: Journal of Biochemistry
https://www.readbyqxmd.com/read/29046677/defining-genome-wide-expression-and-phenotypic-contextual-cues-in-macrophages-generated-by-granulocyte-macrophage-colony-stimulating-factor-macrophage-colony-stimulating-factor-and-heat-killed-mycobacteria
#5
Samer Bazzi, Emale El-Darzi, Tina McDowell, Helmout Modjtahedi, Satvinder Mudan, Marcel Achkar, Charles Akle, Humam Kadara, Georges M Bahr
Heat-killed (HK) Mycobacterium obuense (NCTC13365) is currently being evaluated in the clinic as an immunotherapeutic agent for cancer treatment. Yet, the molecular underpinnings underlying immunomodulatory properties of HK M. obuense are still largely undefined. To fill this void, we sought to perform immunophenotyping, chemokine/cytokine release analysis and genome-wide characterization of monocyte-derived macrophages (MDM) in which monocytes were originally isolated from healthy donors and differentiated by HK M...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29045152/discovery-of-potent-and-orally-bioavailable-macrocyclic-peptide-peptoid-hybrid-cxcr7-modulators
#6
Markus Boehm, Kevin Beaumont, Rhys M Jones, Amit S Kalgutkar, Liying Zhang, Karen Atkinson, Guoyun Bai, Janice A Brown, Heather Eng, Gilles H Goetz, Brian R Holder, Bhagyashree Khunte, Sarah Lazzaro, Chris Limberakis, Sangwoo Ryu, Michael J Shapiro, Laurie Tylaska, Jiangli Yan, Rushia Turner, Siegfried S F Leung, Mahesh Ramaseshan, David A Price, Spiros Liras, Matthew P Jacobson, David J Earp, R Scott Lokey, Alan M Mathiowetz, Elnaz Menhaji-Klotz
The chemokine receptor CXCR7 is an attractive target for a variety of diseases. While several small molecule modulators of CXCR7 have been reported, peptidic macrocycles may provide advantages in terms of potency, selectivity, and reduced off-target activity. We produced a series of peptidic macrocycles that incorporate an N-linked peptoid functionality where the peptoid group enabled us to explore side chain diversity well beyond that of natural amino acids. At the same time, computational calculations and experimental assays were used to track and reduce polarity while closely monitoring physicochemical properties...
October 18, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29043663/nephrotoxicity-induced-by-cisplatin-intake-in-experimental-rats-and-therapeutic-approach-of-using-mesenchymal-stem-cells-and-spironolactone
#7
Mohamed M Elseweidy, Mervat E Askar, Sahar E Elswefy, Mohamed Shawky
Chronic kidney disease may lead to subsequent tissue fibrosis. However, many factors can combat injurious stimuli in these tissues aiming to repair, heal, and alleviate any disturbance. Chemokines release, migration of inflammatory cells to the affected site, and activation of fibroblasts for the production of extracellular matrix are commonly observed in this disease. In the last years, many studies have focused on spironolactone (SPL), a mineralocorticoid receptor antagonist, and its pharmacological effects...
October 17, 2017: Applied Biochemistry and Biotechnology
https://www.readbyqxmd.com/read/29042950/expression-of-ccr3-sox5-and-lc3-in-patients-with-elderly-onset-rheumatoid-arthritis-and-the-clinical-significance
#8
Jing Wang, Qing Zhao
This study investigated the expression of C-C chemokine receptor type 3 (CCR3), transcription factor SOX5 (SOX5) and microtubule-associated protein 1 light chain 3 (LC3) in patients with elderly onset rheumatoid arthritis (EORA) and the clinical significance. Ninety patients with elderly onset rheumatoid arthritis were selected in our hospital from January to December in 2016 to serve as patient group. At the same time, 50 healthy people were selected as control group. Levels of CCR3, SOX5 and LC3 in serum of two groups were detected by enzyme-linked immunosorbent assay (ELISA)...
October 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/29042208/antiallodynic-activity-of-leflunomide-is-partially-inhibited-by-naltrexone-and-glibenclamide-and-associated-with-reduced-production-of-tnf-%C3%AE-and-cxcl-1
#9
Ana Mercy S Brito, Adriana M Godin, Paulo Sérgio A Augusto, Raquel R Menezes, Ivo S F Melo, Marcela G M B Dutra, Sarah O A M Costa, Franciele A Goulart, Felipe F Rodrigues, Isis MoraisMarcela Ísis Morais, Renes R Machado, Márcio M Coelho
Leflunomide, an immunosuppressive drug approved for the treatment of patients with rheumatoid arthritis, exhibits many mechanisms which may affect the nociceptive processing. Therefore, the present study aimed to evaluate the effect induced by leflunomide on the mechanical allodynia in models of inflammatory and neuropathic pain in mice and investigate mechanisms mediating such effects. Per os (p.o.) administration of leflunomide (25, 50 or 100 mg/kg) inhibited the inflammatory edema and mechanical allodynia induced by intraplantar carrageenan...
October 14, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/29042029/ltb4-and-blt1-in-inflammatory-arthritis
#10
REVIEW
Yoshishige Miyabe, Chie Miyabe, Andrew D Luster
Inflammatory arthritis, including rheumatoid arthritis (RA), is characterized by infiltration of inflammatory cells into the joints. Biological agents targeting TNF-α and IL-6 dramatically improve RA. However, some RA patients do not respond to current treatments and these broadly active upstream biological agents increase the risk of severe infection. Therefore, there remains a need for other effective and safe treatments for RA. Many studies have implicated that blockade of leukotriene B4 (LTB4) and its high affinity receptor BLT1 dramatically suppress arthritis in animal models...
October 2017: Seminars in Immunology
https://www.readbyqxmd.com/read/29040829/soybean-derived-bowman-birk-inhibitor-bbi-blocks-hiv-entry-into-macrophages
#11
Tong-Cui Ma, Le Guo, Run-Hong Zhou, Xu Wang, Jin-Biao Liu, Jie-Liang Li, Yu Zhou, Wei Hou, Wen-Zhe Ho
Bowman-Birk inhibitor (BBI) is a soybean-derived protease inhibitor that has anti-inflammation and anti-HIV effect. Here, we further investigated the anti-HIV action of BBI in macrophages, focusing on its effect on viral entry. We found that BBI could significantly block HIV entry into macrophages. Investigation of the mechanism(s) of the BBI action on HIV inhibition showed that BBI down-regulated the expression of CD4 receptor (as much as 80%) and induced the production of the CC chemokines (up to 60 folds at protein level) in macrophages...
October 14, 2017: Virology
https://www.readbyqxmd.com/read/29040215/role-of-receptor-for-advanced-glycation-end-products-in-regulating-lung-fluid-balance-in-lipopolysaccharide-induced-acute-lung-injury-and-infection-related-acute-respiratory-distress-syndrome
#12
Hao Wang, Tao Wang, Zhicheng Yuan, Yufang Cao, Yongfang Zhou, Junyun He, Yongchun Shen, Ni Zeng, Luqi Dai, Fuqiang Wen, Lei Chen
Receptor for advanced glycation end products (RAGE) is implicated in inflammatory responses in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), but its role in pulmonary edema formation remains unclear, especially in infection-related ARDS mainly caused by pneumonia or sepsis. In this study, we investigated the role of RAGE in alveolar fluid regulation by using RAGE gene knockout (RAGE) mice in a murine ALI model induced by lipopolysaccharide (LPS), and by comparing soluble RAGE (sRAGE) levels in serum and bronchial alveolar lavage fluid (BALF) between ARDS patients and control subjects...
October 16, 2017: Shock
https://www.readbyqxmd.com/read/29040208/an-update-on-gain-of-function-mutations-in-primary-immunodeficiency-diseases
#13
Rekha D Jhamnani, Sergio D Rosenzweig
PURPOSE OF REVIEW: Most primary immunodeficiencies described since 1952 were associated with loss-of-function defects. With the advent and popularization of unbiased next-generation sequencing diagnostic approaches followed by functional validation techniques, many gain-of-function mutations leading to immunodeficiency have also been identified. This review highlights the updates on pathophysiology mechanisms and new therapeutic approaches involving primary immunodeficiencies because of gain-of-function mutations...
October 16, 2017: Current Opinion in Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/29039547/frequency-and-distribution-of-cd4-cxcr5-follicular-b-helper-t%C3%A2-cells-within-involved-tissues-in-igg4%C3%A2-related-ophthalmic-disease
#14
Huimin Yang, Ruili Wei, Qiang Liu, Yongheng Shi, Jin Li
Immonoglobulin G4‑related ophthalmic disease (IgG4‑ROD) is a IgG4‑RD and exhibits two main characteristics: Fibrosis that is not necessarily marked histopathologically; and frequent formation of germinal centers (GCs). Follicular B helper T (Tfh) cells are now recognized as the true helper cells for B cells in antibody responses. In the present study, the profile and distribution of Tfh cells in involved tissues from patients with IgG4‑ROD was compared to those of type 1 autoimmune pancreatitis (AIP) and patients with IgG4‑related lymphadenopathy (IgG4‑RL)...
October 12, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29038657/platelet-derived-chemokine-cxcl7-dimer-preferentially-exists-in-the-glycosaminoglycan-bound-form-implications-for-neutrophil-platelet-crosstalk
#15
Aaron J Brown, Krishna Mohan Sepuru, Kirti V Sawant, Krishna Rajarathnam
Platelet-derived chemokine CXCL7 (also known as NAP-2) plays a crucial role in orchestrating neutrophil recruitment in response to vascular injury. CXCL7 exerts its function by activating the CXC chemokine receptor 2 (CXCR2) receptor and binding sulfated glycosaminoglycans (GAGs) that regulate receptor activity. CXCL7 exists as monomers, dimers, and tetramers, and previous studies have shown that the monomer dominates at lower and the tetramer at higher concentrations. These observations then raise the question: what, if any, is the role of the dimer? In this study, we make a compelling observation that the dimer is actually the favored form in the GAG-bound state...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29038476/pro-angiogenic-effect-of-rantes-loaded-polysaccharide-based-microparticles-for-a-mouse-ischemia-therapy
#16
N Suffee, C Le Visage, H Hlawaty, R Aid-Launais, V Vanneaux, J Larghero, O Haddad, O Oudar, N Charnaux, A Sutton
Peripheral arterial disease results from the chronic obstruction of arteries leading to critical hindlimb ischemia. The aim was to develop a new therapeutic strategy of revascularization by using biodegradable and biocompatible polysaccharides-based microparticles (MP) to treat the mouse hindlimb ischemia. For this purpose, we deliver the pro-angiogenic chemokine Regulated upon Activation, Normal T-cell Expressed and Secreted (RANTES)/CCL5 in the mouse ischemic hindlimb, in solution or incorporated into polysaccharide-based microparticles...
October 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29038005/prednisone-alleviates-demyelination-through-regulation-of-the-nlrp3-inflammasome-in-a-c57bl-6-mouse-model-of-cuprizone-induced-demyelination
#17
Hao Yu, Mingfeng Wu, Geng Lu, Tingting Cao, Nan Chen, Yijia Zhang, Higuo Jiang, Hongbin Fan, Ruiqin Yao
Myelin abnormalities, oligodendrocyte damage, and concomitant glia activation are common in demyelinating diseases of the central nervous system (CNS). Increasing evidence has demonstrated that the inflammatory response triggers demyelination and gliosis in demyelinating disorders. Numerous clinical interventions, including those used to treat multiple sclerosis (MS), have confirmed prednisone (PDN) as a powerful anti-inflammatory drug that reduces the inflammatory response and promotes tissue repair in multiple inflammation sites...
October 13, 2017: Brain Research
https://www.readbyqxmd.com/read/29037608/chemokine-ccl8-and-its-receptor-ccr5-in-the-spinal-cord-are-involved-in-visceral-pain-induced-by-experimental-colitis-in-mice
#18
Ying Lu, Bao-Chun Jiang, De-Li Cao, Lin-Xia Zhao, You-Li Zhang
Visceral hypersensitivity induced by inflammatory bowel disease (IBD) is a clinical challenge since the underlying mechanisms remain elusive. Chemokines and their receptors have been suggested to modulate inflammatory pain and neuropathic pain. However, the exact chemokines involved in visceral pain remain to be determined. Here, we investigated the effects of spinal chemokine CCL8 and its major receptor CCR5 on the development of visceral hyperalgesia. We showed that intracolonic injection of 2,4,6-trinitrobenzene sulfonic acid (TNBS) in mice produced significant colonic inflammation and visceral hypersensitivity to colorectal distension...
October 13, 2017: Brain Research Bulletin
https://www.readbyqxmd.com/read/29036438/a-selective-sphingosine-1-phosphate-receptor-1-agonist-sew-2871-aggravates-gastric-cancer-by-recruiting-myeloid-derived-suppressor-cells
#19
Yujing Zhou, Feng Guo
The immune status of tumor microenvironment in gastric cancer is poorly understood, which limits the development of novel strategies in this field. Sphingosine-1-phosphate (S1P) acts as an immune modulator, but the role of S1P in gastric cancer is elusive. Here, we aim to investigate S1P receptor 1 (S1P1)-mediated effect of S1P in gastric cancer. We generated a xenograft mouse model and used SEW-2871, a S1P1 specific agonist to activate S1P1 signaling. Tumor-infiltrating lymphocytes (TILs) were isolated and analyzed using flow cytometry...
October 3, 2017: Journal of Biochemistry
https://www.readbyqxmd.com/read/29035436/cardioprotective-effect-of-the-sdf-1%C3%AE-cxcr4-axis-in-ischemic-postconditioning-in-isolated-rat-hearts
#20
Jeong Su Kim, Youngho Jang, June Hong Kim, Yong Hyun Park, Sun Ae Hwang, Jun Kim, Sung Ryul Lee, Zhelong Xu, Changill Ban, Kyohan Ahn, Kook Jin Chun
BACKGROUND AND OBJECTIVES: Information about the role of the stromal cell-derived factor-1α (SDF-1α)/chemokine receptor type 4 (CXCR4) axis in ischemic postconditioning (IPOC) is currently limited. We hypothesized that the SDF-1α/CXCR4 signaling pathway is directly involved in the cardioprotective effect of IPOC. METHODS: Isolated rat hearts were divided into four groups. The control group was subjected to 30-min of regional ischemia and 2-hour of reperfusion (n=12)...
September 18, 2017: Korean Circulation Journal
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