An Increase in TNF-α Levels in Fetus due to Prenatal Ischemic Hypoxia

BACKGROUND: Prenatal ischemic hypoxia can increase mortality and morbidity and affect the immune system. One of the immune responses is tumor necrosis factor-α (TNF-α) levels. However, the cellular mechanism of immune response abnormalities due to prenatal hypoxia remains unclear. An 11–17-day-old fetus is a sensitive period of neural development. Brain ischemia will cause cell dysfunction and can even affect TNF-α levels. Thus, how prenatal ischemic hypoxia increases TNF-α levels in the fetus remains unclear. AIM: This study aims to examine the effect of the onset and duration of prenatal ischemic hypoxia on TNF-α levels. METHODOLOGY: An experimental study with a post-test control design was conducted. Thirty Rattus norvegicus were induced with prenatal ischemic hypoxia (embryos aged 7, 12, and 17 days). The independent variable was prenatal ischemic hypoxia, while the dependent variable was TNF-α levels. TNF-α was measured using the ELISA technique and was carried out when the fetus was 19 days old (E19). The TNF-α was analyzed using ANOVA, and the limit of significance was set at p < 0.05. RESULTS: The TNF-α levels in the prenatal ischemic hypoxia group were statistically higher than in the control group (p < 0.05). The more the onset and the longer the ischemic hypoxia is, the higher the TNF-level (p < 0.05). CONCLUSION: The prenatal ischemic hypoxia increased TNF-α levels in the fetus.

Nitric Oxide-Dependent Pathways as Critical Factors in the Consequences and Recovery after Brain Ischemic Hypoxia

Brain ischemia is one of the leading causes of disability and mortality worldwide. Nitric oxide (NO•), a molecule that is involved in the regulation of proper blood flow, vasodilation, neuronal and glial activity constitutes the crucial factor that contributes to the development of pathological changes after stroke. One of the early consequences of a sudden interruption in the cerebral blood flow is the massive production of reactive oxygen and nitrogen species (ROS/RNS) in neurons due to NO• synthase uncoupling, which leads to neurotoxicity. Progression of apoptotic or necrotic neuronal damage activates reactive astrocytes and attracts microglia or lymphocytes to migrate to place of inflammation. Those inflammatory cells start to produce large amounts of inflammatory proteins, including pathological, inducible form of NOS (iNOS), which generates nitrosative stress that further contributes to brain tissue damage, forming vicious circle of detrimental processes in the late stage of ischemia. S-nitrosylation, hypoxia-inducible factor 1α (HIF-1α) and HIF-1α-dependent genes activated in reactive astrocytes play essential roles in this process. The review summarizes the roles of NO•-dependent pathways in the early and late aftermath of stroke and treatments based on the stimulation or inhibition of particular NO• synthases and the stabilization of HIF-1α activity.

Cerebral ischemia induces TRPC6 via HIF1α/ZEB2 axis in the glomerular podocytes and contributes to proteinuria

Podocytes are specialized cells of the glomerulus and key component of the glomerular filtration apparatus (GFA). GFA regulates the permselectivity and ultrafiltration of blood. The mechanism by which the integrity of the GFA is compromised and manifest in proteinuria during ischemic stroke remains enigmatic. We investigated the mechanism of ischemic hypoxia-induced proteinuria in a middle cerebral artery occlusion (MCAO) model. Ischemic hypoxia resulted in the accumulation of HIF1α in the podocytes that resulted in the increased expression of ZEB2 (Zinc finger E-box-binding homeobox 2). ZEB2, in turn, induced TRPC6 (transient receptor potential cation channel, subfamily C, member 6), which has increased selectivity for calcium. Elevated expression of TRPC6 elicited increased calcium influx and aberrant activation of focal adhesion kinase (FAK) in podocytes. FAK activation resulted in the stress fibers reorganization and podocyte foot process effacement. Our study suggests overactive HIF1α/ZEB2 axis during ischemic-hypoxia raises intracellular calcium levels via TRPC6 and consequently altered podocyte structure and function thus contributes to proteinuria.

Physiological interpretation of almost loss of consciousness

Background: The phenomenon of almost loss of consciousness (A-LOC) is although known to the aviation fraternity since the 1980s, it is not well researched. Very few studies have attempted to elaborate the characteristics of A-LOC. The present study is a retrospective analysis which has endeavored to address the lacunae in literature. Materials and Methods: A retrospective analysis of the G training data in high-performance human centrifuge for a time span of 4 years (2009–2013) was carried out. Results: A total of 71 A-LOC incidents were reported and were analyzed for better understanding of A-LOC. On the basis of findings such as nystagmus, maintenance of postural tone, convulsions, amnesia, and dreams during A-LOC, neurophysiology of A-LOC has been hypothesized. Conclusion: The presence of nystagmus and maintenance of body posture suggest intact vestibulo-ocular reflex and sensory-motor tract, respectively. Non-recollection of dreams, amnesia suggests breach in memory and/ or information processing for higher functions. The mechanism of A-LOC in toto can be explained by regional differences in blood flow and vulnerability of cerebral centers to ischemic hypoxia. Convulsions in A-LOC could be attributed to hyperexcitability of nerve fibers due to hypoxia.

Cerebral ischemia induces TRPC6 in the glomerular podocytes: A novel role for HIF1α/ZEB2 axis in the pathogenesis of stroke-induced proteinuria

Glomerular filtration apparatus (GFA) regulates the glomerular permselectivity and ultrafiltration of urine. Podocytes are specialized cells and a key component of the GFA. The mechanism by which the integrity of the GFA is compromised and manifest in proteinuria during ischemic stroke remains enigmatic. Hypoxia is a determining factor in the pathophysiology of ischemia. We investigated the mechanism of ischemic-hypoxia induced proteinuria in a middle cerebral artery occlusion (MCAO) model. Ischemic hypoxia resulted in the accumulation of HIF1α in the glomerular podocytes that resulted in the increased expression of ZEB2. ZEB2, in turn, induced TRPC6 (transient receptor potential cation channel, subfamily C, member 6), which has increased selectivity for calcium. Elevated expression of TRPC6 elicited increased calcium influx and aberrant activation of focal adhesion kinase (FAK) in podocytes. FAK activation resulted in the stress fibers reorganization and podocyte foot process effacement. Our study suggests overactive HIF1α/ZEB2 axis during ischemic-hypoxia induces intracellular calcium levels via TRPC6 and consequently altered podocyte integrity and permselectivity.

Peptidomic Analysis of Cultured Cardiomyocytes Exposed to Acute Ischemic-Hypoxia

Background: Acute Myocardial Infarction (AMI) is a life-threatening cardiovascular disease involving disruption of blood flow to the heart, consequent tissue damage, and sometimes death. Peptidomics, an emerging branch of proteomics, has attracted wide attention. Methods: A comparative peptidomic profiling was used to explore changes induced by acute ischemic-hypoxia in primary cultured neonatal rat myocardial cells. Analysis of six-plex tandem mass tag (TMT) labelled peptides was performed using nanoflow liquid chromatography coupled online with an LTQ-Orbitrap Velos mass spectrometer. Results: A total of 220 differentially expressed peptides originating from 119 proteins were identified, of which 37 were upregulated and 183 were downregulated in cardiomyocytes exposed to hypoxia/ischemia conditions. Many of the identified peptides were derived from functional domains of proteins closely associated with cardiomyocyte structure or AMI. Conclusion: Numerous peptides may be involved in process of AMI. These results pave the way for future functional studies of the identified peptides.