Nashstone1437

ZNF667-AS1 gene, located in the human chromosome region 19q13.43, has been shown to be silenced by DNA hypermethylation in several cancers. In this review, we report on the biological functions of ZNF667-AS1 from recent studies and describe the regulatory functions of ZNF667-AS1 in human disease, including cancer. Furthermore, we discuss the emerging insights into the potential role of ZNF667-AS1 as a biomarker and novel therapeutic target in cancer, including GCs (ovarian, cervical, and endometrial cancers).Toxoplasma gondii is a protozoan parasite that causes toxoplasmosis and infects almost one-third of the global human population. A lack of effective drugs and vaccines and the emergence of drug resistant parasites highlight the need for the development of new drugs. The mitochondrial electron transport chain (ETC) is an essential pathway for energy metabolism and the survival of T. gondii. In apicomplexan parasites, malatequinone oxidoreductase (MQO) is a monotopic membrane protein belonging to the ETC and a key member of the tricarboxylic acid cycle, and has recently been suggested to play a role in the fumarate cycle, which is required for the cytosolic purine salvage pathway. In T. gondii, a putative MQO (TgMQO) is expressed in tachyzoite and bradyzoite stages and is considered to be a potential drug target since its orthologue is not conserved in mammalian hosts. As a first step towards the evaluation of TgMQO as a drug target candidate, in this study, we developed a new expression system for TgMQO in FN102(DE3)TAO, a strain deficient in respiratory cytochromes and dependent on an alternative oxidase. This system allowed, for the first time, the expression and purification of a mitochondrial MQO family enzyme, which was used for steady-state kinetics and substrate specificity analyses. Ferulenol, the only known MQO inhibitor, also inhibited TgMQO at IC50 of 0.822 μM, and displayed different inhibition kinetics compared to Plasmodium falciparum MQO. Furthermore, our analysis indicated the presence of a third binding site for ferulenol that is distinct from the ubiquinone and malate sites.Twenty-one human genes encode connexins, a family of homologous proteins making gap junction (GJ) channels, which mediate direct intercellular communication to synchronize tissue/organ activities. Genetic variants in more than half of the connexin genes are associated with dozens of different Mendelian inherited diseases. With rapid advances in DNA sequencing technology, more variants are being identified not only in families and individuals with diseases but also in people in the general population without any apparent linkage to Mendelian inherited diseases. Nevertheless, it remains challenging to classify the pathogenicity of a newly identified connexin variant. Here, we analyzed the disease- and Genome Aggregation Database (gnomAD, as a proxy of the general population)-linked variants in the coding region of the four disease-linked α connexin genes. We found that the most abundant and position-sensitive missense variants showed distinct domain distribution preference between disease- and gnomAD-linked variants. Plotting missense variants on topological and structural models revealed that disease-linked missense variants are highly enriched on the structurally stable/resolved domains, especially the pore-lining domains, while the gnomAD-linked missense variants are highly enriched in the structurally unstable/unresolved domains, especially the carboxyl terminus. In addition, disease-linked variants tend to be on highly conserved residues and those positions show evolutionary co-variation, while the gnomAD-linked missense variants are likely on less conserved residue positions and on positions without co-variation. Collectively, the revealed distribution patterns of disease- and gnomAD-linked missense variants further our understanding of the GJ structure-biological function relationship, which is valuable for classifying the pathogenicity of newly identified connexin variants.After myocardial infarction (MI), a strong inflammatory response takes place in the heart to remove the dead tissue resulting from ischemic injury. A growing body of evidence suggests that timely resolution of this inflammatory process may aid in the prevention of adverse cardiac remodeling and heart failure post-MI. The present challenge is to find a way to stimulate this process without interfering with the reparative role of the immune system. Extracellular vesicles (EVs) are natural membrane particles that are released by cells and carry different macromolecules, including proteins and non-coding RNAs. In recent years, EVs derived from various stem and progenitor cells have been demonstrated to possess regenerative properties. They can provide cardioprotection via several mechanisms of action, including immunomodulation. In this review, we summarize the role of the innate immune system in post-MI healing. We then discuss the mechanisms by which EVs modulate cardiac inflammation in preclinical models of myocardial injury through regulation of monocyte influx and macrophage function. Finally, we provide suggestions for further optimization of EV-based therapy to improve its potential for the treatment of MI.Glucocorticoids provide indispensable anti-inflammatory therapies. However, metabolic adverse effects including muscle wasting restrict their use. The enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) modulates peripheral glucocorticoid responses through pre-receptor metabolism. This study investigates how 11β-HSD1 influences skeletal muscle responses to glucocorticoid therapy for chronic inflammation. We assessed human skeletal muscle biopsies from patients with rheumatoid arthritis and osteoarthritis for 11β-HSD1 activity ex vivo. Using the TNF-α-transgenic mouse model (TNF-tg) of chronic inflammation, we examined the effects of corticosterone treatment and 11β-HSD1 global knock-out (11βKO) on skeletal muscle, measuring anti-inflammatory gene expression, muscle weights, fiber size distribution, and catabolic pathways. Muscle 11β-HSD1 activity was elevated in patients with rheumatoid arthritis and correlated with inflammation markers. In murine skeletal muscle, glucocorticoid administration suppressed IL6 expression in TNF-tg mice but not in TNF-tg11βKO mice. TNF-tg mice exhibited reductions in muscle weight and fiber size with glucocorticoid therapy. In contrast, TNF-tg11βKO mice were protected against glucocorticoid-induced muscle atrophy. Glucocorticoid-mediated activation of catabolic mediators (FoxO1, Trim63) was also diminished in TNF-tg11βKO compared to TNF-tg mice. In summary, 11β-HSD1 knock-out prevents muscle atrophy associated with glucocorticoid therapy in a model of chronic inflammation. Targeting 11β-HSD1 may offer a strategy to refine the safety of glucocorticoids.Water transport in epithelia occurs transcellularly (aquaporins) and paracellularly (claudin-2, claudin-15). Recently, we showed that downregulated tricellulin, a protein of the tricellular tight junction (tTJ, the site where three epithelial cells meet), increased transepithelial water flux. We now check the hypothesis that another tTJ-associated protein, angulin-1 (alias lipolysis-stimulated lipoprotein receptor, LSR) is a direct negative actuator of tTJ water permeability depending on the tightness of the epithelium. For this, a tight and an intermediate-tight epithelial cell line, MDCK C7 and HT-29/B6, were stably transfected with CRISPR/Cas9 and single-guide RNA targeting angulin-1 and morphologically and functionally characterized. Water flux induced by an osmotic gradient using 4-kDa dextran caused water flux to increase in angulin-1 KO clones in MDCK C7 cells, but not in HT-29/B6 cells. In addition, we found that water permeability in HT-29/B6 cells was not modified after either angulin-1 knockout or tricellulin knockdown, which may be related to the presence of other pathways, which reduce the impact of the tTJ pathway. In conclusion, modulation of the tTJ by knockout or knockdown of tTJ proteins affects ion and macromolecule permeability in tight and intermediate-tight epithelial cell lines, while the transepithelial water permeability was affected only in tight cell lines.The metabotropic glutamate receptor type 5 (mGluR5) has been proposed to play a crucial role in the selection and regulation of cognitive, affective, and emotional behaviors. EGFR inhibitors cancer However, the mechanisms by which these receptors mediate these effects remain largely unexplored. Here, we studied the role of mGluR5 located in D1 receptor-expressing (D1) neurons in the manifestation of different behavioral expressions. Mice with conditional knockout (cKO) of mGluR5 in D1 neurons (mGluR5D1 cKO) and littermate controls displayed similar phenotypical profiles in relation to memory expression, anxiety, and social behaviors. However, mGluR5D1 cKO mice presented different coping mechanisms in response to acute escapable or inescapable stress. mGluR5D1 cKO mice adopted an enhanced active stress coping strategy upon exposure to escapable stress in the two-way active avoidance (TWA) task and a greater passive strategy upon exposure to inescapable stress in the forced swim test (FST). In summary, this work provides evidence for a functional integration of the dopaminergic and glutamatergic system to mediate control over internal states upon stress exposure and directly implicates D1 neurons and mGluR5 as crucial mediators of behavioral stress responses.FREM1 (Fras-related extracellular matrix 1) and its splice variant TILRR (Toll-like interleukin-1 receptor regulator) have been identified as integral components of innate immune systems. The potential involvement of FREM1 in HIV-1 (human immunodeficiency virus 1) acquisition was suggested by a genome-wide SNP (single nucleotide polymorphism) analysis of HIV-1 resistant and susceptible sex workers enrolled in the Pumwani sex worker cohort (PSWC) in Nairobi, Kenya. The studies showed that the minor allele of a FREM1 SNP rs1552896 is highly enriched in the HIV-1 resistant female sex workers. Subsequent studies showed that FREM1 mRNA is highly expressed in tissues relevant to mucosal HIV-1 infection, including cervical epithelial tissues, and TILRR is a major modulator of many genes in the NF-κB signal transduction pathway. In this article, we review the role of FREM1 and TILRR in modulating inflammatory responses and inflammation, and how their influence on inflammatory responses of cervicovaginal tissue could enhance the risk of vaginal HIV-1 acquisition.Poor sleep quality and disrupted circadian behavior are a normal part of aging and include excessive daytime sleepiness, increased sleep fragmentation, and decreased total sleep time and sleep quality. Although the neuronal decline underlying the cellular mechanism of poor sleep has been extensively investigated, brain function is not fully dependent on neurons. A recent antemortem autographic study and postmortem RNA sequencing and immunohistochemical studies on aged human brain have investigated the relationship between sleep fragmentation and activation of the innate immune cells of the brain, microglia. In the process of aging, there are marked reductions in the number of brain microglial cells, and the depletion of microglial cells disrupts circadian rhythmicity of brain tissue. We also showed, in a previous study, that pharmacological suppression of microglial function induced sleep abnormalities. However, the mechanism underlying the contribution of microglial cells to sleep homeostasis is only beginning to be understood.