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Behavioural Brain Research Mar 2022Running wheel exercise training (RWE) and skilled reaching training (SRT) are physical training approaches with positive effects on cognitive function. However, few...
Running wheel exercise training (RWE) and skilled reaching training (SRT) are physical training approaches with positive effects on cognitive function. However, few studies have compared the different effects of these exercises on long-term memory, and their mechanism remains unknown. This study investigated the effects of SRT and RWE, at the recovery stage, on the cognitive function of transient middle cerebral artery occlusion (tMCAO) rats and explored their association with NgR1/Rho-A/ROCK/LOTUS/LGI1 signaling. Adult Sprague-Dawley rats (n = 55) were divided into four groups after pretraining: SRT, RWE, tMCAO, and Sham. Rats were subjected to modified neurological severity score (mNSS) measurements and forelimb grip strength and the Morris water maze tests. Using immunofluorescence and western blotting, we evaluated axonal growth inhibitor expression in the peri-infarct cortex on days 28 and 56 after tMCAO. Results showed the mNSS reduced, whereas the grip strengths improved in RWE and SRT groups. The escape latency in the Morris water maze test was shorter, whereas the number of times of crossing the platform was higher in both the SRT and RWE groups than in the tMCAO group on day 56; furthermore, the parameters in the SRT group improved compared to those in the RWE group. Physical exercise training could improve cognitive functions by reducing the expression of the NgR1/RhoA/ROCK axon growth inhibitors and increasing the expression of the endogenous antagonists LOTUS/LGI1. Exercise training beginning at the recovery stage could improve the cognitive function in tMCAO rats through a mechanism probably associated with the axonal growth inhibitor pathway.
Topics: Animals; Axons; Behavior, Animal; Cerebral Cortex; Cognitive Dysfunction; Disease Models, Animal; Exercise Therapy; Growth Inhibitors; Ischemic Stroke; Male; Physical Conditioning, Animal; Rats; Rats, Sprague-Dawley; Signal Transduction; Stroke Rehabilitation
PubMed: 34971645
DOI: 10.1016/j.bbr.2021.113730 -
The Journal of Biological Chemistry Oct 2023After adult mammalian central nervous system injury, axon regeneration is extremely limited or absent, resulting in persistent neurological deficits. Axon regeneration...
After adult mammalian central nervous system injury, axon regeneration is extremely limited or absent, resulting in persistent neurological deficits. Axon regeneration failure is due in part to the presence of inhibitory proteins, including NogoA (Rtn4A), from which two inhibitory domains have been defined. When these inhibitory domains are deleted, but an amino-terminal domain is still expressed in a gene trap line, mice show axon regeneration and enhanced recovery from injury. In contrast, when there is no amino-terminal Nogo-A fragment in the setting of inhibitory domain deletion, then axon regeneration and recovery are indistinguishable from WT. These data indicated that an amino-terminal Nogo-A fragment derived from the gene trap might promote axon regeneration, but this had not been tested directly and production of this fragment without gene targeting was unclear. Here, we describe posttranslation production of an amino-terminal fragment of Nogo-A from the intact gene product. This fragment is created by proteolysis near amino acid G214-N215 and levels are enhanced by axotomy. Furthermore, this fragment promotes axon regeneration in vitro and acts cell autonomously in neurons, in contrast to the inhibitory extracellular action of other Nogo-A domains.Proteins interacting with the amino-terminal Nogo-A fragment by immunoprecipitation include HSPA8 (HSC70, HSP7C). Suppression of HSPA8 expression by shRNA decreases axon regeneration from cerebral cortical neurons and overexpression increases axon regeneration. Moreover, the amino-terminal Nogo-A fragment increases HSPA8 chaperone activity. These data provide an explanation for varied results in different gene-targeted Nogo-A mice, as well as revealing an axon regeneration promoting domain of Nogo-A.
Topics: Animals; Mice; Axons; Growth Inhibitors; Mammals; Myelin Proteins; Nerve Regeneration; Nogo Proteins; Proteolysis; Female; Mice, Inbred C57BL
PubMed: 37690690
DOI: 10.1016/j.jbc.2023.105232 -
Microbiology Spectrum Oct 2021Avian pathogenic Escherichia coli (APEC), a subgroup of extraintestinal pathogenic E. coli (ExPEC), causes colibacillosis in chickens and is reportedly implicated in...
Avian pathogenic Escherichia coli (APEC), a subgroup of extraintestinal pathogenic E. coli (ExPEC), causes colibacillosis in chickens and is reportedly implicated in urinary tract infections and meningitis in humans. A major limitation for the current ExPEC antibiotic therapy is the development of resistance, and antibacterial drugs that can circumvent this problem are critically needed. Here, we evaluated eight novel membrane-affecting anti-APEC small molecule growth inhibitors (GIs), identified in our previous study, against APEC infection in chickens. Among the GIs tested, GI-7 (the most effective), when administered orally (1 mg/kg of body weight), reduced the mortality (41.7%), severity of lesions (62.9%), and APEC load (2.6 log) in chickens. Furthermore, GI-7 administration at an optimized dose (60 mg/liter) in drinking water also reduced the mortality (14.7%), severity of lesions (29.5%), and APEC load (2.2 log) in chickens. The abundances of and oleate were increased in the cecum and serum, respectively, of GI-7-treated chickens. Pharmacokinetic analysis revealed that GI-7 was readily absorbed with minimal accumulation in the tissues. Earlier, we showed that GI-7 induced membrane blebbing and increased membrane permeability in APEC, suggesting an effect on the APEC membrane. Consistent with this finding, the expression of genes essential for maintaining outer membrane (OM) integrity was downregulated in GI-7-treated APEC. Furthermore, decreased levels of lipopolysaccharide (LPS) transport (Lpt) proteins and LPS were observed in GI-7-treated APEC. However, the mechanism of action of GI-7 currently remains unknown and needs further investigation. Our studies suggest that GI-7 represents a promising novel lead compound that can be developed to treat APEC infection in chickens and related human ExPEC infections. APEC is a subgroup of ExPEC, and genetic similarities of APEC with human ExPECs, including uropathogenic E. coli (UPEC) and neonatal meningitis E. coli (NMEC), have been reported. Our study identified a novel small molecule growth inhibitor, GI-7, effective in reducing APEC infection in chickens with an efficacy similar to that of the currently used antibiotic sulfadimethoxine, notably with an 8-times-lower dose. GI-7 affects the OM integrity and decreases the Lpt protein and LPS levels in APEC, an antibacterial mechanism that can overcome the antibiotic resistance problem. Overall, GI-7 represents a promising lead molecule/scaffold for the development of novel antibacterial therapies that could have profound implications for treating APEC infections in chickens, as well as human infections caused by ExPECs and other related Gram-negative bacteria. Further elucidation of the mechanism of action of GI-7 and identification of its target(s) in APEC will benefit future novel antibacterial development efforts.
Topics: Animals; Anti-Bacterial Agents; Bacterial Load; Bacterial Outer Membrane; Chickens; Disease Models, Animal; Escherichia coli Infections; Extraintestinal Pathogenic Escherichia coli; Growth Inhibitors; Humans; Poultry Diseases; Urinary Tract Infections
PubMed: 34468186
DOI: 10.1128/Spectrum.00006-21 -
Journal of Biochemistry Feb 1999A human histiocytic lymphoma cell line, U-937 cells, secretes several vascular endothelial cell growth inhibitors including leukemia inhibitory factor, oncostatin M,...
A human histiocytic lymphoma cell line, U-937 cells, secretes several vascular endothelial cell growth inhibitors including leukemia inhibitory factor, oncostatin M, tumor necrosis factor-alpha, and transforming growth factor-beta1. Characterization of partially purified fractions from the conditioned media of phorbol ester-treated U-937 cells suggested the existence of unknown endothelial growth inhibitors. Using a combination of copper affinity, heparin affinity, cation exchange, and reversed phase liquid chromatographies, a growth inhibitor for endothelial cells was purified to homogeneity from conditioned media. The purified growth inhibitor migrated as a 65 kDa band on SDS-polyacrylamide gel electrophoresis under both reducing and nonreducing conditions. Microsequencing analyses of the tryptic fragments of the growth inhibitor and a BLAST search analysis revealed a unique sequence showing no homology to known proteins. The purified protein inhibited endothelial cell growth in a dose-dependent manner, but had no effect on smooth muscle cell growth. The factor also blocked endothelial cell growth induced by both fibroblast growth factor-2 and vascular endothelial growth factor, and was additively effective in inhibiting the growth of endothelial cells by U-937 cell-derived endothelial cell growth inhibitors. Thus, this factor appears to be a novel inhibitor with specificity for vascular endothelial cells, and is tentatively called endothelial cell inhibitor (ECI) in this study.
Topics: Animals; Cattle; Endothelium, Vascular; Growth Inhibitors; Humans; Macrophages; Neovascularization, Physiologic; Sequence Analysis; Tetradecanoylphorbol Acetate; U937 Cells
PubMed: 9990136
DOI: 10.1093/oxfordjournals.jbchem.a022296 -
Molecular Endocrinology (Baltimore, Md.) Aug 2012Androgen receptor (AR) signaling exerts an antiestrogenic, growth-inhibitory influence in normal breast tissue, and this role may be sustained in estrogen receptor α... (Review)
Review
Androgen receptor (AR) signaling exerts an antiestrogenic, growth-inhibitory influence in normal breast tissue, and this role may be sustained in estrogen receptor α (ERα)-positive luminal breast cancers. Conversely, AR signaling may promote growth of a subset of ERα-negative, AR-positive breast cancers with a molecular apocrine phenotype. Understanding the molecular mechanisms whereby androgens can elicit distinct gene expression programs and opposing proliferative responses in these two breast cancer phenotypes is critical to the development of new therapeutic strategies to target the AR in breast cancer.
Topics: Androgens; Animals; Breast Neoplasms; Estrogen Receptor alpha; Female; Genes, Tumor Suppressor; Growth Inhibitors; Humans; Mammary Glands, Human; Oncogenes; Receptors, Androgen; Signal Transduction
PubMed: 22745190
DOI: 10.1210/me.2012-1107 -
Fertility and Sterility Dec 2001To describe the clinical findings, expressions, interactions, and clinical implications of leukemia inhibitory factor (LIF) in human reproduction. (Review)
Review
OBJECTIVE
To describe the clinical findings, expressions, interactions, and clinical implications of leukemia inhibitory factor (LIF) in human reproduction.
DESIGN
Review of published articles.
SETTING
Clinical development unit of biotechnology company.
INTERVENTION(S)
None.
RESULT(S)
In the endometrium, LIF is expressed in a menstrual cycle-dependent manner, with the highest level occurring at the time of implantation. LIF is also detected in uterine flushing, and its level is significantly lower in women with unexplained infertility. Likewise, endometrial explants derived from women with unexplained infertility showed reduced levels of LIF secretion. Binding of LIF to LIF receptor and gp130 activates signal transduction pathways. LIF receptor is expressed in endometrium, oocytes, and blastocysts. Cytotrophoblasts cultured in the presence of LIF differentiate toward an anchoring extravillous phenotype.
CONCLUSION(S)
On the basis of reports gathered from animal and human studies, LIF appears to play an important role in implantation and in the establishment of pregnancy.
Topics: Animals; Embryo Implantation; Embryonic and Fetal Development; Endometrium; Female; Growth Inhibitors; Humans; Interleukin-6; Leukemia Inhibitory Factor; Leukemia Inhibitory Factor Receptor alpha Subunit; Lymphokines; Pregnancy; Receptors, Cytokine; Receptors, OSM-LIF; Reproduction
PubMed: 11730732
DOI: 10.1016/s0015-0282(01)02878-3 -
Nihon Hinyokika Gakkai Zasshi. the... Oct 1993
Review
Topics: Amino Acid Sequence; Animals; Anti-Mullerian Hormone; Cattle; Glycoproteins; Growth Inhibitors; Humans; Male; Molecular Sequence Data; Mullerian Ducts; Rats; Testicular Hormones
PubMed: 8255037
DOI: No ID Found -
PloS One 2023Pancreatic cancer is one of the leading causes of cancer deaths, with pancreatic ductal adenocarcinoma (PDAC) being the most common subtype. Advanced stage diagnosis of...
Pancreatic cancer is one of the leading causes of cancer deaths, with pancreatic ductal adenocarcinoma (PDAC) being the most common subtype. Advanced stage diagnosis of PDAC is common, causing limited treatment opportunities. Gemcitabine is a frequently used chemotherapeutic agent which can be used as a monotherapy or in combination. However, tumors often develop resistance to gemcitabine. Previous studies show that the proto-oncogene PIM kinases (PIM1 and PIM3) are upregulated in PDAC compared to matched normal tissue and are related to chemoresistance and PDAC cell growth. The PIM kinases are also involved in the PI3K/AKT/mTOR pathway to promote cell survival. In this study, we evaluate the effect of the novel multikinase PIM/PI3K/mTOR inhibitor, AUM302, and commercially available PIM inhibitor, TP-3654. Using five human PDAC cell lines, we found AUM302 to be a potent inhibitor of cell proliferation, cell viability, cell cycle progression, and phosphoprotein expression, while TP-3654 was less effective. Significantly, AUM302 had a strong impact on the viability of gemcitabine-resistant PDAC cells. Taken together, these results demonstrate that AUM302 exhibits antitumor activity in human PDAC cells and thus has the potential to be an effective drug for PDAC therapy.
Topics: Humans; Phosphatidylinositol 3-Kinases; Growth Inhibitors; Pancreatic Neoplasms; Antineoplastic Agents; Carcinoma, Pancreatic Ductal; Gemcitabine; TOR Serine-Threonine Kinases; Protein Kinase Inhibitors; Phosphoinositide-3 Kinase Inhibitors; Cell Proliferation; Cell Line, Tumor
PubMed: 37943821
DOI: 10.1371/journal.pone.0294065 -
Proceedings of the National Academy of... Sep 1983Confluent African green monkey kidney (BSC-1) cells secrete a protein (Mr approximately equal to 24,000) that inhibits DNA synthesis and growth of the same cells. Using...
Rapid selective effects by a growth inhibitor and epidermal growth factor on the incorporation of [35S]methionine into proteins secreted by African green monkey (BSC-1) cells.
Confluent African green monkey kidney (BSC-1) cells secrete a protein (Mr approximately equal to 24,000) that inhibits DNA synthesis and growth of the same cells. Using [35S]methionine to metabolically label proteins, we have found that this growth inhibitor selectively induces the BSC-1 cells to synthesize and secrete another protein with a relative Mr of 48,000 on NaDodSO4/polyacrylamide gels. We have called this protein "inhibitor-inducible protein" (IIP48). The maximal increase in rate of labeling of IIP48 due to treatment with the growth inhibitor averages 12-fold over the control. IIP48 is an N-glycosidically linked glycoprotein, and it is not a major intracellular protein. This protein is maximally induced within 4 to 6 hr of adding the growth inhibitor to the cells. This is an early response of these cells to the growth inhibitor and may represent a primary response to the growth inhibitor. Epidermal growth factor (EGF) increases the rate of labeling of three other secreted proteins (MrS 28,000, 59,000, and 61,000), which we have called "mitogen-inducible proteins" (MIP28, MIP59, and MIP61). The specific effects of both EGF and the growth inhibitor on the secreted levels of these proteins are inhibited if actinomycin D is added with the growth effectors. Thus, RNA synthesis appears necessary for the inductions. EGF and the growth inhibitor induce these secreted proteins by independent and noninteracting pathways.
Topics: Animals; Cell Line; Chlorocebus aethiops; DNA Replication; Epidermal Growth Factor; Growth Inhibitors; Kidney; Methionine; Molecular Weight; Proteins
PubMed: 6604275
DOI: 10.1073/pnas.80.18.5636 -
ACS Infectious Diseases Nov 2022Metabolic profiling of the extracts from a library of actinobacteria led to the identification of a novel polyketide, demurilactone A, produced by strain DEM21308. The...
Metabolic profiling of the extracts from a library of actinobacteria led to the identification of a novel polyketide, demurilactone A, produced by strain DEM21308. The structure of the compound was assigned based on a detailed investigation of 1D/2D NMR spectra and HR-MS. Whole genome DNA sequencing, followed by bioinformatics analysis and insertional mutagenesis, identified type I polyketide synthases encoded by the gene cluster to direct the biosynthesis of this polyene macrolide. While the number of modules is consistent with the carbon backbone of the assigned structure, some discrepancies were identified in the domain organization of five modules. Close investigation of the amino acid sequences identified several mutations in the conserved motifs of nonfunctional domains. Furthermore, the absolute configuration of hydroxy-bearing stereocenters was proposed based on analyses of the ketoreductase domains. Remarkably, although demurilactone A has little detectable activity against normal-walled bacteria, it specifically inhibits the growth of cell wall-deficient "L-form" at a minimum inhibitory concentration value of 16 μg/mL. Time-lapse microscopy analyses revealed that demurilactone affects membrane dynamics, probably by reducing membrane fluidity. This compound could be a powerful reagent for studying long-standing questions about the involvement of L-forms in recurrent infection.
Topics: Bacillus subtilis; Growth Inhibitors; Polyketide Synthases; Streptomyces; Macrolides
PubMed: 36268971
DOI: 10.1021/acsinfecdis.2c00220