Thyroid Hormone Regulates Endogenous Amyloid-β Precursor Protein Gene Expression and Processing in Both In Vitro and In Vivo Models

Thyroid ◽  
2006 ◽  
Vol 16 (12) ◽  
pp. 1207-1213 ◽  
Author(s):  
Stephen A. O'Barr ◽  
Jin S. Oh ◽  
Chan Ma ◽  
Gregory A. Brent ◽  
James J. Schultz
Keyword(s):  
Gene Expression ◽  
Thyroid Hormone ◽  
Protein Gene ◽  
Amyloid Β ◽  
Precursor Protein ◽  
In Vivo Models

scholarly journals Biophysical studies of protein misfolding and aggregation in in vivo models of Alzheimer's and Parkinson's diseases

2020 ◽  
Vol 53 ◽  
Author(s):  
Tessa Sinnige ◽  
Karen Stroobants ◽  
Christopher M. Dobson ◽  
Michele Vendruscolo
Keyword(s):  
Protein Misfolding ◽  
Molecular Mechanisms ◽  
Amyloid Β ◽  
Therapeutic Interventions ◽  
In Vivo Models ◽  
Disease Modifying Drugs ◽  
Parkinson’S Diseases ◽  
Protein Misfolding And Aggregation

Abstract Neurodegenerative disorders, including Alzheimer's (AD) and Parkinson's diseases (PD), are characterised by the formation of aberrant assemblies of misfolded proteins. The discovery of disease-modifying drugs for these disorders is challenging, in part because we still have a limited understanding of their molecular origins. In this review, we discuss how biophysical approaches can help explain the formation of the aberrant conformational states of proteins whose neurotoxic effects underlie these diseases. We discuss in particular models based on the transgenic expression of amyloid-β (Aβ) and tau in AD, and α-synuclein in PD. Because biophysical methods have enabled an accurate quantification and a detailed understanding of the molecular mechanisms underlying protein misfolding and aggregation in vitro, we expect that the further development of these methods to probe directly the corresponding mechanisms in vivo will open effective routes for diagnostic and therapeutic interventions.

scholarly journals Differential Regulation of β-Defensin Gene Expression during Cryptosporidium parvum Infection

2004 ◽  
Vol 72 (5) ◽  
pp. 2772-2779 ◽  
Author(s):  
Tarek K. Zaalouk ◽  
Mona Bajaj-Elliott ◽  
John T. George ◽  
Vincent McDonald
Keyword(s):  
Gene Expression ◽  
Cryptosporidium Parvum ◽  
Protozoan Parasite ◽  
Immune Defense ◽  
Microbial Pathogens ◽  
In Vivo Models ◽  
Defensin Gene ◽  
Intestinal Epithelia

ABSTRACT Invasion of enterocytes by pathogenic microbes evokes both innate and adaptive immune responses, and microbial pathogens have developed strategies to overcome the initial host immune defense. β-Defensins are potentially important endogenous antibiotic-like effectors of innate immunity expressed by intestinal epithelia. In this study, the interplay between the enteric protozoan parasite Cryptosporidium parvum and host epithelial β-defensin expression was investigated. Using human and murine models of infection, we demonstrated that C. parvum infection differentially regulates β-defensin gene expression. Downregulation of murine β-defensin-1 mRNA and protein was observed in both in vitro and in vivo models of infection. Infection of the human colonic HT29 cell line with the parasite resulted in differential effects on various members of the defensin gene family. Partial reduction in human β-defensin-1 (hBD-1), induction of hBD-2, and no effect on hBD-3 gene expression was observed. Recombinant hBD-1 and hBD-2 peptides exhibited significant antimicrobial activity against C. parvum sporozoites in vitro. These findings demonstrate that C. parvum infection of enterocytes may affect the expression of various defensins in different ways and suggest that the overall outcome of the effect of antimicrobial peptides on early survival of the parasite may be complex.

Inhaled nitric oxide increases surfactant protein gene expression in the intact lamb

2003 ◽  
Vol 285 (3) ◽  
pp. L628-L633 ◽  
Author(s):  
Regan B. Stuart ◽  
Boaz Ovadia ◽  
Vincent V. Suzara ◽  
Patrick A. Ross ◽  
Stephan Thelitz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nitric Oxide ◽  
Dna Content ◽  
Protein Gene ◽  
Surfactant Protein ◽  
Inhaled Nitric Oxide ◽  
Mrna Content ◽  
Lung Biopsies

Inhaled nitric oxide (iNO) is used to treat a number of disease processes. Although in vitro data suggest that nitric oxide (NO) alters surfactant protein gene expression, the effects in vivo have not been studied. The objective of this study was to evaluate the effects of iNO on surfactant protein (SP)-A, -B, and -C gene expression in the intact lamb. Thirteen 4-wk-old lambs were mechanically ventilated with 21% oxygen and received iNO at 40 ppm ( n = 7) or vehicle gas ( n = 6) for 24 h. Peripheral lung biopsies were obtained at 0, 12, and 24 h and analyzed for surfactant mRNA, protein, and total DNA content. Inhaled NO increased SP-A and SP-B mRNA content by 80% from 0 to 12 h and by 78 and 71%, respectively, from 0 to 24 h. There was an increase in SP-A and SP-B protein content by 45% from 0 to 12 h, and a decrease by 70 and 65%, respectively, from 0 to 24 h. DNA content was unchanged. The mechanisms and physiological effects of these findings warrant further investigation.

Mechanical stimuli induce vascular parathyroid hormone-related protein gene expression in vivo and in vitro.

Endocrinology ◽  
1994 ◽  
Vol 134 (5) ◽  
pp. 2230-2236 ◽  
Author(s):  
C J Pirola ◽  
H M Wang ◽  
M I Strgacich ◽  
A Kamyar ◽  
B Cercek ◽  
...  
Keyword(s):  
Gene Expression ◽  
Parathyroid Hormone ◽  
Protein Gene ◽  
Mechanical Stimuli ◽  
Related Protein ◽  
Parathyroid Hormone Related Protein

scholarly journals Amelioration of Cigarette Smoke-Induced Mucus Hypersecretion and Viscosity by Dendrobium officinale Polysaccharides In Vitro and In Vivo

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Rui Chen ◽  
Yingmin Liang ◽  
Mary Sau Man Ip ◽  
Kalin Yanbo Zhang ◽  
Judith Choi Wo Mak
Keyword(s):  
Gene Expression ◽  
Cigarette Smoke ◽  
Secretory Granules ◽  
Dendrobium Officinale ◽  
In Vivo Models ◽  
Mucus Hypersecretion ◽  
Mucin Gene ◽  
Starting Point

Chronic obstructive pulmonary disease (COPD), characterized by oxidative stress and inflammation, is one of the leading causes of death worldwide, in which cigarette smoke (CS) is the major risk factor. Dendrobium officinale polysaccharides (DOPs) are the main active ingredients extracted from Dendrobium officinale, which have been reported to have antioxidant and anti-inflammatory activity as well as inhibition of mucin gene expression. This study is aimed at investigating the effect of DOPs on CS-induced mucus hypersecretion and viscosity in vitro and in vivo. For in vitro study, primary normal human bronchial epithelial cells (HBECs) differentiated at the air-liquid interface (ALI) culture for 28 days were stimulated with cigarette smoke medium (CSM) in the absence or presence of various concentrations of DOPs or N-acetylcysteine (NAC) for 24 hours. For in vivo study, male Sprague-Dawley rats were randomized to sham air (SA) as control group or CS group for 56 days. At day 29, rats were subdivided and given water as control, DOPs, or NAC as positive control as a mucolytic drug via oral gavage for the remaining duration. Samples collected from apical washing, cell lysates, bronchoalveolar lavage (BAL), and lung tissues were evaluated for mucin gene expression, mucus secretion, and viscosity. DOPs ameliorated the CS-induced mucus hypersecretion and viscosity as shown by the downregulation of MUC5AC mRNA, MUC5AC secretary protein, and mucus viscosity via inhibition of mucus secretory granules in both in vitro and in vivo models. DOPs produced its effective effects on the CS-induced mucus hypersecretion and viscosity via the inhibition of the mucus secretory granules. These findings could be a starting point for considering the potential role of DOPs in the management of the smoking-mediated COPD. However, further research is needed.

scholarly journals Thyroid hormone receptors are down-regulated in skeletal muscle of patients with non-thyroidal illness syndrome secondary to non-septic shock

2010 ◽  
Vol 163 (5) ◽  
pp. 765-773 ◽  
Author(s):  
J Lado-Abeal ◽  
A Romero ◽  
I Castro-Piedras ◽  
A Rodriguez-Perez ◽  
J Alvarez-Escudero
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Septic Shock ◽  
Thyroid Hormone ◽  
Hormone Receptors ◽  
Serum Samples ◽  
Pathway Activation ◽  
Gene And Protein Expression

AimNon-thyroidal illness syndrome (NTIS) is related to changes in thyroid hormone (TH) physiology. Skeletal muscle (SM) plays a major role in metabolism, and TH regulates SM phenotype and metabolism. We aimed to characterize the SM of non-septic shock NTIS patients in terms of: i) expression of genes and proteins involved in TH metabolism and actions; and ii) NFKB's pathway activation, a responsible factor for some of the phenotypic changes in NTIS. We also investigated whether the patient's serum can induce in vitro the effects observed in vivo.MethodsSerum samples and SM biopsies from 14 patients with non-septic shock NTIS and 11 controls. Gene and protein expression and NFKB1 activation were analyzed by quantitative PCR and immunoblotting. Human SM cell (HSkMC) cultures to investigate the effects of patient's serum on TH action mediators.ResultsPatients with non-septic shock NTIS showed higher levels of pro-inflammatory cytokines than controls. Expression of TRβ (THRB), TRα1 (THRA), and retinoid X receptor γ (RXRG) was decreased in NTIS patients. RXRA gene expression was higher, but its protein was lower in NTIS than controls, suggesting the existence of a post-transcriptional mechanism that down-regulates protein levels. NFKB1 pathway activation was not different between NTIS and control patients. HSkMC incubated with patient's serum increased TH receptor and RXRG gene expression after 48 h.ConclusionsPatients with non-septic shock NTIS showed decreased expression of TH receptors and RXRs, which were not related to increased activation of the NFKB1 pathway. These findings could not be replicated in cultures of HSkMCs incubated in the patient's serum.

scholarly journals AB0158 IMPACT OF JAK INHIBITORS ON MACROPHAGE POLARISATION: PERSPECTIVES FOR SYSTEMIC SCLEROSIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1380.3-1380
Author(s):  
A. Lescoat ◽  
A. Ballerie ◽  
M. Lelong ◽  
C. Morzadec ◽  
S. Jouneau ◽  
...  
Keyword(s):  
Gene Expression ◽  
Systemic Sclerosis ◽  
Blood Monocytes ◽  
Jak Inhibitors ◽  
In Vivo Models ◽  
Macrophage Polarisation ◽  
Healthy Donors ◽  
The Impact

Background:Macrophage can adopt various phenotypes and activation states according to their surrounding microenvironment. M1 or inflammatory macrophages are generated under IFNɣ/LPS signaling and express the membrane marker CD86. Different subtypes of M2 macrophages are also described: M2a macrophages (generated under IL4/IL13 signaling) and characterized by a high expression of CD206 and pro-fibrotic properties and, M2c macrophages (generated under IL10 and/or glucorticoid signaling), considered as anti-inflammatory resolving macrophages. There is growing interest in the role of macrophages in the pathogenesis of Systemic Sclerosis (SSc). Recent studies highlight that macrophages from fibrotic tissues such as lung or skin from SSc patients have a M2 phenotype whereas, in blood-monocytes derived macrophages (MDM), SSc MDM have a mixed signature associating M1 and M2 characteristics. Jak inhibitors are treatments used in rheumatoid arthritis and that can variously target signals that could be involved both in M1 and in M2 polarisation.Objectives:This study evaluates the impact of three Jak inhibitors on the polarisation state of human MDM in vitro.Methods:Blood monocytes form healthy donors (HD) were differentiated with M-CSF (for 7 days) in MDM and pre-treated by ruxolitinib (Jak2-Jak1 inhibitor), tofacitinib (Jak3 inhibitor) or itacitinib (Jak1 inhibitor) (1µM for all). They were then polarised into M1i (IFNɣ, 20µg/mL), M1Li (IFNɣ+LPS, 20µg/mL), M2a (IL4+IL13; 20µg/ML), M2c (IL10, 20µg/mL) and M2c(dex) (IL10+dexamethasone, 10 nM). The impact of each Jak inhibitor on phenotype (flow cytometry), gene expression (qPCR) and cytokine secretion (ELISA) was evaluated in each polarisation state.Results:Concerning phenotypes, all Jak inhibitors reduced the expression of the M1i and M1Li marker CD86, but ruxolitinib had a higher effect. Only ruxolitinib reduced the expression of the M1i marker MHCII. All Jak inhibitors reduced the expression of CD206 in M2a. They had no impact on the expression of CD163, CD204 in any M2 conditions. Key M1 genes were repressed by all Jak inhibitors, such as CXCL10, IL6 or TNFα with a more significant effect of ruxolitinib. All Jak inhibitors reduced the gene expression of CXCL13 and SOCS3 in M2c. Secretion levels of IL6 and CCL18 were also repressed, with a more significant effect of ruxolitinib.Conclusion:Jak inhibitors can limit M1 and M2 polarisation state in vitro, with a more significant effect of the Jak2-Jak1 inhibitor ruxolitinib. The relevance of these results in MDM from SSc patients and in vivo models of SSc is still to be determined.Disclosure of Interests:Alain LESCOAT: None declared, Alice Ballerie: None declared, Marie Lelong: None declared, Claudie Morzadec: None declared, Stéphane Jouneau Grant/research support from: AIRB, Boehringer Ingelheim, LVL Medical, Novartis, Roche, Bellorophon Therapeutics, Biogen, Fibrogen, Galecto Biotech, Gilead Sciences, Pharm-Olam, Pliant Therapeutics, Savara Pharmaceuticals/Serendex Pharmaceuticals, Consultant of: Actelion, AIRB, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Chiesi, Genzyme, GlazoSmithKline, LVL Medical, Mundipharma, Novartis, Pfizer, Roche, Sanofi, Patrick Jégo: None declared, Laurent Vernhet: None declared, Olivier Fardel: None declared, Valérie Lecureur: None declared

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