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21.
Harston RK McKillop JC Moschella PC Van Laer A Quinones LS Baicu CF Balasubramanian S Zile MR Kuppuswamy D 《American journal of physiology. Heart and circulatory physiology》2011,300(5):H1696-H1706
Ubiquitin-mediated protein degradation is necessary for both increased ventricular mass and survival signaling for compensated hypertrophy in pressure-overloaded (PO) myocardium. Another molecular keystone involved in the hypertrophic growth process is the mammalian target of rapamycin (mTOR), which forms two distinct functional complexes: mTORC1 that activates p70S6 kinase-1 to enhance protein synthesis and mTORC2 that activates Akt to promote cell survival. Independent studies in animal models show that rapamycin treatment that alters mTOR complexes also reduces hypertrophic growth and increases lifespan by an unknown mechanism. We tested whether the ubiquitin-mediated regulation of growth and survival in hypertrophic myocardium is linked to the mTOR pathway. For in vivo studies, right ventricle PO in rats was conducted by pulmonary artery banding; the normally loaded left ventricle served as an internal control. Rapamycin (0.75 mg/kg per day) or vehicle alone was administered intraperitoneally for 3 days or 2 wk. Immunoblot and immunofluorescence imaging showed that the level of ubiquitylated proteins in cardiomyocytes that increased following 48 h of PO was enhanced by rapamycin. Rapamycin pretreatment also significantly increased PO-induced Akt phosphorylation at S473, a finding confirmed in cardiomyocytes in vitro to be downstream of mTORC2. Analysis of prosurvival signaling in vivo showed that rapamycin increased PO-induced degradation of phosphorylated inhibitor of κB, enhanced expression of cellular inhibitor of apoptosis protein 1, and decreased active caspase-3. Long-term rapamycin treatment in 2-wk PO myocardium blunted hypertrophy, improved contractile function, and reduced caspase-3 and calpain activation. These data indicate potential cardioprotective benefits of rapamycin in PO hypertrophy. 相似文献
22.
Ahmet Sinan SARI Emre DEMRAY Ahmet
ZTÜRK Ayen TERZ Erdal KARA
Z 《Turkish Journal of Biology》2021,45(3):301
Selective targeting of transfected mesenchymal stem cells (MSCs) carrying specific antioncogenes to the tumor was suggested as a treatment option. Bone morphogenetic protein-2 (BMP2) was shown to inhibit the proliferation and aggressiveness of osteosarcoma (OS) cells. Here, we aimed to assess the homing efficiency of intraperitoneally administered hMSCs transfected with BMP2 to the tumoral site and their effects on OS using an orthotopic xenograft murine model. Orthotopic xenograft murine model of OS in six-week-old female NOD/SCID mice using 143B cells was established. hMSCs transfected with BMP2 (BMP2+hMSC) were used. In vivo experiments performed on four groups of mice that received no treatment, or intraperitoneally administered BMP2, hMSCs, and BMP2+hMSCs. Histopathological and immunohistochemical studies were used to evaluate the pathological identification and to assess the dimensions and necrotic foci of the tumor, the features of lung metastases, and immunostaining against p27, Ki-67, and caspase-3 antibodies. The osteogenic differentiation markers BMP2, BMP4, COL1A1, OPN, OCN and PF4 evaluated using RT-PCR. The tumor dimensions in the hMSCs group were significantly higher than those of the remaining groups (p < 0.01). The number of metastatic foci in the BMP2+hMSCs group was significantly lower than those of the other groups (p < 0.01). The current results showed that the intraperitoneal route could be efficiently used for targeting hMSCs to the tumoral tissues for effective BMP2 delivery. In this study, the effects of BMP2 transfected hMSCs on human OS and metastasis were promising for achieving osteogenic differentiation and reduced metastatic process. 相似文献
23.
Opportunistic fungal infections increase morbidity and mortality in COVID-19 patients monitored in intensive care units (ICU). As patients’ hospitalization days in the ICU and intubation period increase, opportunistic infections also increase, which prolongs hospital stay days and elevates costs. The study aimed to describe the profile of fungal infections and identify the risk factors associated with mortality in COVID-19 intensive care patients. The records of 627 patients hospitalized in ICU with the diagnosis of COVID-19 were investigated from electronic health records and hospitalization files. The demographic characteristics (age, gender), the number of ICU hospitalization days and mortality rates, APACHE II scores, accompanying diseases, antibiotic-steroid treatments taken during hospitalization, and microbiological results (blood, urine, tracheal aspirate samples) of the patients were recorded. Opportunistic fungal infection was detected in 32 patients (5.10%) of 627 patients monitored in ICU with a COVID-19 diagnosis. The average APACHE II score of the patients was 28 ± 6. While 25 of the patients (78.12%) died, seven (21.87%) were discharged from the ICU. Candida parapsilosis (43.7%) was the opportunistic fungal agent isolated from most blood samples taken from COVID-19 positive patients. The mortality rate of COVID-19 positive patients with candidemia was 80%. While two out of the three patients (66.6%) for whom fungi were grown from their tracheal aspirate died, one patient (33.3%) was transferred to the ward. Opportunistic fungal infections increase the mortality rate of COVID-19-positive patients. In addition to the risk factors that we cannot change, invasive procedures should be avoided, constant blood sugar regulation should be applied, and unnecessary antibiotics use should be avoided. 相似文献
24.
Steven M. Sparks Paul K. Spearing Caroline J. Diaz David J. Cowan Channa Jayawickreme Grace Chen Thomas J. Rimele Claudia Generaux Lindsey T. Harston Shane G. Roller 《Bioorganic & medicinal chemistry letters》2017,27(20):4673-4677
Modulation of gastrointestinal nutrient sensing pathways provides a promising a new approach for the treatment of metabolic diseases including diabetes and obesity. The calcium-sensing receptor has been identified as a key receptor involved in mineral and amino acid nutrient sensing and thus is an attractive target for modulation in the intestine. Herein we describe the optimization of gastrointestinally restricted calcium-sensing receptor agonists starting from a 3-aminopyrrolidine-containing template leading to the identification of GI-restricted agonist 19 (GSK3004774). 相似文献
25.
Kuzoff RK; Sweere JA; Soltis DE; Soltis PS; Zimmer EA 《Molecular biology and evolution》1998,15(3):251-263
18S ribosomal RNA genes are the most widely used nuclear sequences for
phylogeny reconstruction at higher taxonomic levels in plants. However, due
to a conservative rate of evolution, 18S rDNA alone sometimes provides too
few phylogenetically informative characters to resolve relationships
adequately. Previous studies using partial sequences have suggested the
potential of 26S or large-subunit (LSU) rDNA for phylogeny retrieval at
taxonomic levels comparable to those investigated with 18S rDNA. Here we
explore the patterns of molecular evolution of entire 26S rDNA sequences
and their impact on phylogeny retrieval. We present a protocol for PCR
amplification and sequencing of entire (approximately 3.4 kb) 26S rDNA
sequences as single amplicons, as well as primers that can be used for
amplification and sequencing. These primers proved useful in angiosperms
and Gnetales and likely have broader applicability. With these protocols
and primers, entire 26S rDNA sequences were generated for a diverse array
of 15 seed plants, including basal eudicots, monocots, and higher eudicots,
plus two representatives of Gnetales. Comparisons of sequence dissimilarity
indicate that expansion segments (or divergence domains) evolve 6.4 to 10.2
times as fast as conserved core regions of 26S rDNA sequences in plants.
Additional comparisons indicate that 26S rDNA evolves 1.6 to 2.2 times as
fast as and provides 3.3 times as many phylogenetically informative
characters as 18S rDNA; compared to the chloroplast gene rbcL, 26S rDNA
evolves at 0.44 to 1.0 times its rate and provides 2.0 times as many
phylogenetically informative characters. Expansion segment sequences
analyzed here evolve 1.2 to 3.0 times faster than rbcL, providing 1.5 times
the number of informative characters. Plant expansion segments have a
pattern of evolution distinct from that found in animals, exhibiting less
cryptic sequence simplicity, a lower frequency of insertion and deletion,
and greater phylogenetic potential.
相似文献
26.
27.
Background
Inbreeding can slow population growth and elevate extinction risk. A small number of unrelated immigrants to an inbred population can substantially reduce inbreeding and improve fitness, but little attention has been paid to the sex-specific effects of immigrants on such "genetic rescue". We conducted two subsequent experiments to investigate demographic consequences of inbreeding and genetic rescue in guppies. 相似文献28.
Diabetes mellitus is a heterogeneous metabolic disorder characterized by hyperglycaemia resulting in defective insulin secretion,
resistance to insulin action or both. The use of biguanides, sulphonylurea and other drugs are valuable in the treatment of
diabetes mellitus; their use, however, is restricted by their limited action, pharmaco-kinetic properties, secondary failure
rates and side effects. Trigonella foenum-graecum, commonly known as fenugreek, is a plant that has been extensively used as a source of antidiabetic compounds from its seeds
and leaf extracts. Preliminary human trials and animal experiments suggest possible hypoglycaemic and anti-hyperlipedemic
properties of fenugreek seed powder taken orally. Our results show that the action of fenugreek in lowering blood glucose
levels is almost comparable to the effect of insulin. Combination with trace metal showed that vanadium had additive effects
and manganese had additive effects with insulin on in vitro system in control and diabetic animals of young and old ages using adipose tissue. The Trigonella and vanadium effects were studied in a number of tissues including liver, kidney, brain peripheral nerve, heart, red blood
cells and skeletal muscle. Addition of Trigonella to vanadium significantly removed the toxicity of vanadium when used to reduce blood glucose levels. Administration of the
various combinations of the antidiabetic compounds to diabetic animals was found to reverse most of the diabetic effects studied
at physiological, biochemical, histochemical and molecular levels. Results of the key enzymes of metabolic pathways have been
summarized together with glucose transporter, Glut-4 and insulin levels. Our findings illustrate and elucidate the antidiabetic/insulin
mimetic effects of Trigonella, manganese and vanadium. 相似文献
29.
Marije Oosting Kathrin Buffen Subbarao RK Malireddi Patrick Sturm Ineke Verschueren Marije I Koenders Frank L van de Veerdonk Jos WM van der Meer Mihai G Netea Thirumala-Devi Kanneganti Leo AB Joosten 《Arthritis research & therapy》2012,14(6):R247
Introduction
The protein platform called the NOD-like-receptor -family member (NLRP)-3 inflammasome needs to be activated to process intracellular caspase-1. Active caspase-1 is able to cleave pro-Interleukin (IL)-1β, resulting in bioactive IL-1β. IL-1β is a potent proinflammatory cytokine, and thought to play a key role in the pathogenesis of Lyme arthritis, a common manifestation of Borrelia burgdorferi infection. The precise pathways through which B. burgdorferi recognition leads to inflammasome activation and processing of IL-1β in Lyme arthritis has not been elucidated. In the present study, we investigated the contribution of several pattern recognition receptors and inflammasome components in a novel murine model of Lyme arthritis.Methods
Lyme arthritis was elicited by live B. burgdorferi, injected intra-articularly in knee joints of mice. To identify the relevant pathway components, the model was applied to wild-type, NLRP3-/-, ASC-/-, caspase-1-/-, NOD1-/-, NOD2-/-, and RICK-/- mice. As a control, TLR2-/-, Myd88-/- and IL-1R-/- mice were used. Peritoneal macrophages and bone marrow-derived macrophages were used for in vitro cytokine production and inflammasome activation studies. Joint inflammation was analyzed in synovial specimens and whole knee joints. Mann-Whitney U tests were used to detect statistical differences.Results
We demonstrate that ASC/caspase-1-driven IL-1β is crucial for induction of B. burgdorferi-induced murine Lyme arthritis. In addition, we show that B. burgdorferi-induced murine Lyme arthritis is less dependent on NOD1/NOD2/RICK pathways while the TLR2-MyD88 pathway is crucial.Conclusions
Murine Lyme arthritis is strongly dependent on IL-1 production, and B. burgdorferi induces inflammasome-mediated caspase-1 activation. Next to that, murine Lyme arthritis is ASC- and caspase-1-dependent, but NLRP3, NOD1, NOD2, and RICK independent. Also, caspase-1 activation by B. burgdorferi is dependent on TLR2 and MyD88. Based on present results indicating that IL-1 is one of the major mediators in Lyme arthritis, there is a rationale to propose that neutralizing IL-1 activity may also have beneficial effects in chronic Lyme arthritis. 相似文献30.