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Molecular Mechanisms of Brain Insulin Signaling 1
Published in André Kleinridders, Physiological Consequences of Brain Insulin Action, 2023
Simran Chopra, Robert Hauffe, André Kleinridders
The insulin signaling pathway is a tightly regulated molecular mechanism that controls a range of metabolically important functions in cells and generally induces energy-consuming processes, such as protein synthesis, growth, and proliferation. Moreover, it also controls both peripheral metabolic functions (e.g., glucose uptake or hepatic glucose production), as well as central metabolic functions (e.g., control of appetite and thus food intake). As such, a hyperactivation could lead to detrimental metabolic outcomes. To counteract the hyperactivation of the insulin response, the signaling pathway is subjected to a variety of negative feedback modulations on most of its protein components via posttranslational modifications, transcriptional control, and targeted protein degradation. However, if these feedback loops are continually activated, a chronic insulin-resistant state can occur.
Hyperactivated Motility of Human Spermatozoa During In Vitro Capacitation and Implications for Fertility
Published in Claude Gagnon, Controls of Sperm Motility, 2020
In 1985, two short papers were published which linked motility assessment to presumptive hyperactivation. It seems likely however, that neither study made direct observations of vigorous sperm having nonprogressive paths, high-curvature flagellation, and marked lateral head displacement. The movement characteristics of washed patient spermatozoa were evaluated by Topfer-Petersen et al.35 using the multiple-exposure (MEP) method. The sperm were classified as whiplash hyperactivated solely on the basis of an ALH value (amplitude of head displacement) that exceeded 10 μm. Their results must be read with caution, since there is doubt concerning the accuracy of Ah values obtained from the MEP method36 and there is no evidence that reliance on a single parameter will accurately identify HA sperm. Likewise, Okada et al.37 have applied the label of “hyperactivation” too freely. Although they apparently observed some star or thrashing patterns after sperm incubation in BWW medium, no details were given, nor is the relative incidence of these patterns calculated. Based on a technique called the Sperm Motile Efficiency Index (SMEI),38 which measures general invigoration of the sperm population, Okada et al. stated that fertile specimens demonstrated a marked increase in SMEI during capacitation; however, no evidence was presented that an increased SMEI is actually correlated with increases in the presumptive HA movements.
Cutaneous Manifestations of Nonantiretroviral Therapy
Published in Clay J. Cockerell, Antoanella Calame, Cutaneous Manifestations of HIV Disease, 2012
Saira B. Momin, Clay J. Cockerell
There are a number of reasons why HIV infection may be associated with an increased likelihood for the development of an ADR. Many patients are receiving chronic and multiple drugs which is a known predisposing factor. High drug dose, administration of novel agents, many with unknown biological effects, perturbation of drug metabolism, increased oxidative stress, and immune hyperactivation are other important reasons.27 HIV infection is characterized by immunodeficiency but it is also associated with chronic immune hyperactivation28 and interferon (IFN)-γ and other cytokines are elevated.29 IFN-γ increases the expression of different pro-inflammatory cytokines which plays a part in the oxidative stress seen in HIV disease.30 This may be a significant factor in the alteration in metabolism31 that in turn may lead to a shift in the balance between bioactivation and bioinactivation of drugs.4 The secretion of TNF-α, interleukin (IL)-1, IL-6 and other cytokines is induced by HIV infection. Alteration of these cytokines could contribute in enhancing susceptibility because they are critical in the activation of keratinocytes, migration of Langerhans cells to lymph nodes, and stimulation of T cell responses.32
Oxidative stress and sperm function: A systematic review on evaluation and management
Published in Arab Journal of Urology, 2019
Sulagna Dutta, Ahmad Majzoub, Ashok Agarwal
Hyperactivation is a particular state of sperm motility characterised by high amplitude, increased and asymmetric flagellar movement, elevated side-to-side sperm head displacement, along with non-linear motility [40]. It is considered to be part of capacitation and is required for successful sperm penetration of the zona pellucida and fertilisation. ROS has positive impacts on the hyperactivation processes in spermatozoa [37]. The initiation process of capacitation and hyperactivation is induced by the influx of Ca2+ and HCO3–, probably by the inactivation of an ATP-dependent Ca2+-regulatory channel (plasma membrane Ca2+-ATPase, PMCA) and alkalisation of the cytosol. Calcium ions and ROS, specifically O2–, lead to the activation of adenylate cyclase, generating cAMP. cAMP via PKA activation triggers NADPH oxidase and thereby stimulates greater ROS generation. PKA also phosphorylates serine and tyrosine residues, which can also activate protein tyrosine kinase (PTK). Consequently, PTK triggers phosphorylation of tyrosine residues in the fibrous sheath around the axoneme and the cytoskeleton of the sperm flagellum. ROS, especially H2O2, elevate tyrosine phosphorylation by inducing PTK and inhibiting phosphotyrosine phosphatase (PTPase), which leads to de-phosphorylation of tyrosine residues. The final step in the process of hyperactivation is presumably increased tyrosine phosphorylation [1]. O2– has been observed to be the major ROS contributor to this ameliorating effect [28].
Brain metastases and treatment: multiplying cognitive toxicities
Published in Expert Review of Anticancer Therapy, 2019
Elise F. Nassif, Alexandre Arsène-Henry, Youlia M. Kirova
Global brain volume decreases and white matter density and diffusivity are diminished. These radiological findings have been linked to clinical impairment [134]. Studies failed to demonstrate any hippocampal changes able to explain memory deficits. Functional imaging studies have reported cortical activation abnormalities, essentially in the prefrontal and frontal cortex and basal ganglia [135]. Some studies have reported hyperactivation, while others have reported hypoactivation. A compensatory mechanism of hyperactivation is probably initially involved [136].
Cytomegalovirus induced hemophagocytic lymphohistiocytosis: diagnostic and treatment challenges for the future
Published in Expert Review of Hematology, 2022
Linn Åsholt Rolsdorph, Knut Anders Mosevoll, Håkon Reikvam
Hemophagocytic lymphohistiocytosis (HLH) is an acute hematological condition caused by uncontrolled overactivation of the patient’s immune system. HLH is an umbrella term for conditions with similar pathophysiology, rather than a single disorder. Underlying or triggering cause, clinical presentation, and course of disease exhibit great heterogeneity. The core clinical findings of HLH are persistent fever and splenomegaly, combined with laboratory findings of cytopenias, extreme hyperferritinemia, elevated triglycerides, and low fibrinogen. Elevated serum interleukin-2 receptor (IL-2 r) is a parameter with high sensitivity for HLH [1,2]. Liver infection and elevated lactate dehydrogenase (LDH) are also commonly seen [3]. Histiocytosis and hemophagocytosis can be found in the bone marrow or in other organs. The pathogenesis of HLH is an unregulated, continuous immune activation, causing a cytokine storm and excessive macrophage activation. Interferon-γ (INF-γ), tumor necrosis factor-α (TNF-α), IL-1, IL-2, IL-6, and IL-18 are central proinflammatory cytokines in HLH pathophysiology [4,5]. Untreated, the hyperactivation causes inflammatory tissue damage (Figure 1). This can result in multiorgan failure, and untreated HLH has a high mortality rate [6]. The condition is divided into primary and secondary HLH. Primary HLH is caused by genetic mutations and often debuts within the first years of life. In secondary HLH, the immune system is triggered by exogenous factors. Infectious agents are among the most common triggers in secondary HLH, and members of the herpesvirus family are the most frequent viral agents [7]. This included Epstein-Barr virus (EBV), herpes simplex virus (HSV), and cytomegalovirus (CMV). CMV transmission often takes place early in life. Positive serology in the adult population is relatively common, as CMV infection is often asymptomatic or subclinical [8]. However, new treatment approaches in modern medicine, including immunosuppressive treatment and transplantation, have in recent decades raised concern and awareness regarding development of more severe CMV disease. One of the most feared complications is development of hyperinflammation conditions, such as HLH. Hence, HLH is a concomitant condition to CMV infection physician working with immunosuppressive patients should be aware of.