1,720,999 research outputs found
ARHGEF3 controls HDACi-induced differentiation via RhoA-dependent pathways in acute myeloid leukemias.
No full textAltered expression and activity of histone deacetylases (HDACs) have been correlated with tumorigenesis. Inhibitors of HDACs (HDACi) induce acetylation of histone and non-histone proteins affecting gene expression, cell cycle progression, cell migration, terminal differentiation and cell death. Here, we analyzed the regulation of ARHGEF3, a RhoA-specific guanine nucleotide exchange factor, by the HDACi MS275 (entinostat). MS275 is a well-known benzamide-based HDACi, which induces differentiation of the monoblastic-like human histiocytic lymphoma cell line U937 to monocytes/macrophages. Incubation of U937 cells with MS275 resulted in an up regulation of ARHGEF3, followed by a significant enhancement of the marker of macrophage differentiation CD68. ARHGEF3 protein is primarily nuclear, but MS275 treatment rapidly induced its translocation into the cytoplasm. ARHGEF3 cytoplasmic localization is associated with activation of the RhoA/Rho-associated Kinase (ROCK) pathway. In addition to cytoskeletal rearrangements orchestrated by RhoA, we showed that ARHGEF3/RhoA-dependent signals involve activation of SAPK/JNK and then Elk1 transcription factor. Importantly, MS275-induced CD68 expression was blocked by exposure of U937 cells to exoenzyme C3 transferase and Y27632, inhibitors of Rho and ROCK respectively. Moreover, ARHGEF3 silencing prevented RhoA activation leading to a reduction in SAPK/JNK phosphorylation, Elk1 activation and CD68 expression, suggesting a crucial role for ARHGEF3 in myeloid differentiation. Taken together, our results demonstrate that ARHGEF3 modulates acute myeloid leukemia differentiation through activation of RhoA and pathways directly controlled by small GTPase family proteins. The finding that GEF protein modulation by HDAC inhibition impacts on cell differentiation may be important for understanding the antitumor mechanism(s) by which HDACi treatment stimulates differentiation in cancer
miR-21 in Human Cardiomyopathies
No full textmiR-21 is a 22-nucleotide long microRNA that matches target mRNAs in a complementary base pairing fashion and regulates gene expression by repressing or degrading target mRNAs. miR-21 is involved in various cardiomyopathies, including heart failure, dilated cardiomyopathy, myocardial infarction, and diabetic cardiomyopathy. Expression levels of miR-21 notably change in both heart and circulation and provide cardiac protection after heart injury. In the meantime, miR-21 also tightly links to cardiac dysfunctions such as cardiac hypertrophy and fibrosis. This review focuses on the miR-21 expression pattern and its functions in diseased-heart and further discusses the feasibility of miR-21 as a biomarker and therapeutic target in cardiomyopathies
Potential Role of Lisinopril in Reducing Atherosclerotic Risk: Evidence of an Antioxidant Effect in Human Cardiomyocytes Cell Line
No full textThe cellular mechanisms involved in myocardial ischemia/reperfusion injury (I/R) pathogenesis are complex but attributable to reactive oxygen species (ROS) production. ROS produced by coronary endothelial cells, blood cells (e.g., leukocytes and platelets), and cardiac myocytes have the potential to damage vascular cells directly and cardiac myocytes, initiating mechanisms that induce apoptosis, inflammation, necrosis, and fibrosis of myocardial cells. In addition to reducing blood pressure, lisinopril, a new non-sulfhydryl angiotensin-converting enzyme (ACE) inhibitor, increases the antioxidant defense in animals and humans. Recently, it has been shown that lisinopril can attenuate renal oxidative injury in the l-NAME-induced hypertensive rat and cause an impressive improvement in the antioxidant defense system of Wistar rats treated with doxorubicin. The potential effect of lisinopril on oxidative damage and fibrosis in human cardiomyocytes has not been previously investigated. Thus, the present study aims to investigate the effect of different doses of lisinopril on oxidative stress and fibrotic mediators in AC16 human cardiomyocytes, along with a 7-day presence in the culture medium. The results revealed that AC16 human cardiomyocytes exposed to lisinopril treatment significantly showed an upregulation of proteins involved in protecting against oxidative stress, such as catalase, SOD2, and thioredoxin, and a reduction of osteopontin and Galectin-3, critical proteins involved in cardiac fibrosis. Moreover, lisinopril treatment induced an increment in Sirtuin 1 and Sirtuin 6 protein expression. These findings demonstrated that, in AC16 human cardiomyocytes, lisinopril could protect against oxidative stress and fibrosis via the activation of Sirtuin 1 and Sirtuin 6 pathways
Circulating biomarkers of inflammaging and Alzheimer’s disease to track age-related trajectories of dementia: Can we develop a clinically relevant composite combination?
Get PDF: Alzheimer's disease (AD) is a rapidly growing global concern due to a consistent rise of the prevalence of dementia which is mainly caused by the aging population worldwide. An early diagnosis of AD remains important as interventions are plausibly more effective when started at the earliest stages. Recent developments in clinical research have focused on the use of blood-based biomarkers for improve diagnosis/prognosis of neurodegenerative diseases, particularly AD. Unlike invasive cerebrospinal fluid tests, circulating biomarkers are less invasive and will become increasingly cheaper and simple to use in larger number of patients with mild symptoms or at risk of dementia. In addition to AD-specific markers, there is growing interest in biomarkers of inflammaging/neuro-inflammaging, an age-related chronic low-grade inflammatory condition increasingly recognized as one of the main risk factor for almost all age-related diseases, including AD. Several inflammatory markers have been associated with cognitive performance and AD development and progression. The presence of senescent cells, a key driver of inflammaging, has also been linked to AD pathogenesis, and senolytic therapy is emerging as a potential treatment strategy. Here, we describe blood-based biomarkers clinically relevant for AD diagnosis/prognosis and biomarkers of inflammaging associated with AD. Through a systematic review approach, we propose that a combination of circulating neurodegeneration and inflammatory biomarkers may contribute to improving early diagnosis and prognosis, as well as providing valuable insights into the trajectory of cognitive decline and dementia in the aging population
On the wake of metformin: do anti-diabetic SGLT2 inhibitors exert anti-aging effects?
Get PDFHere we propose that SGLT2 inhibitors (SGLT2i), a class of drugs primarily used to treat type 2 diabetes, could also be repositioned as anti-aging senomorphic drugs (agents that prevent the extrinsic harmful effects of senescent cells). As observed for metformin, another anti-diabetic drug with established anti-aging potential, increasing evidence suggests that SGLT2i can modulate some relevant pathways associated with the aging process, such as free radical production, cellular energy regulation through AMP-activated protein kinase (AMPK), autophagy, and the activation of nuclear factor (NF)-kB/inflammasome. Some interesting pro-healthy effects were also observed on human microbiota. All these mechanisms converge on fueling a systemic proinflammatory condition called inflammaging, now recognized as the main risk factor for accelerated aging and increased risk of age-related disease development and progression. Inflammaging can be worsened by cellular senescence and immunosenescence, which contributes to the increased burden of senescent cells during aging, perpetuating the proinflammatory condition. Interestingly, increasing evidence suggested the direct effects of SGLT-2i against senescent cells, chronic activation of immune cells, and metabolic alterations induced by overnutrition (meta-inflammation). In this framework, we analyzed and discussed the multifaceted impact of SGLT2i, compared with metformin effects, as a potential anti-aging drug beyond diabetes management. Despite promising results in experimental studies, rigorous investigations with well-designed cellular and clinical investigations will need to validate SGLT2 inhibitors' anti-aging effects
Sarcopenia and Cognitive Function: Role of Myokines in Muscle Brain Cross-Talk
No full textSarcopenia is a geriatric syndrome characterized by the progressive degeneration of muscle mass and function, and it is associated with severe complications, which are falls, functional decline, frailty, and mortality. Sarcopenia is associated with cognitive impairment, defined as a decline in one or more cognitive domains as language, memory, reasoning, social cognition, planning, making decisions, and solving problems. Although the exact mechanism relating to sarcopenia and cognitive function has not yet been defined, several studies have shown that skeletal muscle produces and secrete molecules, called myokines, that regulate brain functions, including mood, learning, locomotor activity, and neuronal injury protection, showing the existence of muscle-brain cross-talk. Moreover, studies conducted on physical exercise supported the existence of muscle-brain cross-talk, showing how physical activity, changing myokines' circulating levels, exerts beneficial effects on the brain. The review mainly focuses on describing the role of myokines on brain function and their involvement in cognitive impairment in sarcopenia
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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