**6. Brain hypoxia**

Molecular oxygen (O2) is required for most organisms on the planet because it supports intracellular biogenesis and is utilized by several metabolic activities. As a result, low oxygen level (hypoxia) is a crucial stress factor that usually disrupts aerobic species' lives and is a common feature of pathologic conditions such as cardiovascular abnormalities, inflammation, wounds, bacterial infection, and cancer [32]. Since it is required throughout breathing, oxygen is essential in life. In oxidative phosphorylation, O2 acts as the ultimate electron acceptor, raising the possibility of reactive oxygen species formation (ROS). ROS interact with biological macromolecules, changing their metabolic or physical characteristics and causing cell death or malfunction [33].

To sustain a wide range of cellular functions to secure life, organism cells require sufficient oxygen. The oxygen concentration in the body and localized tissues fall (hypoxia) whenever the need for oxygen increases, resulting in a physiological crisis that compromises physiological processes and survivability. Organisms have formed an effective and quick oxygen sensing system called (hypoxia-inducible factors (*HIF*s) because of the importance of oxygen in metabolism, survival, and respiration [34].

Arterial and central chemoreceptors detect changes in the oxygen content in the external environment. The brainstem's medulla, beneath the respiratory centres, contains central chemoreceptors. The carotid and aortic bodies include arterial chemoreceptors [35]. The stimulation of arterial chemoreceptors promotes neurotransmission and alters the function of neprilysin (NEP), a neutral endopeptidase that changes the biological response to hypoxia by hydrolytic component P [36]. Neuroendocrine cells in neuroepithelial bodies also govern oxygen sensing by imposing chemosensitivity, critical for oxygen sensing in the early stages of life. These exciting chemoreceptors enhance sympathetic nervous activity (SNA) and the systemic and arterial pulmonary blood flow to receive enough oxygen. Therefore, in organism cells, the expression of many adapted genes is activated to improve the oxygen supply and enable anaerobic ATP production. Hypoxia-inducible factors regulate these hypoxic responses (*HIFs*) [37].

There is a difference between sustained and intermittent hypoxia. Mitochondrial respiration utilizes more than 90% oxygen in humans during every day physiological situations [38]. The remaining (10%) oxygen is used to degrade *HIF-1*. The mitochondria use practically all oxygen or eliminate free cytosolic oxygen during the response to sustained hypoxia, enabling *HIF-1* to stabilize quickly. *HIF-1* activation causes enhanced transcription of several genes, including EPO, inducible nitric oxide synthase (iNOS), and *VEGF* [39]. These variables contribute to the recovery after early hypoxic shocks by boosting oxygenation and tissue perfusion as part of the adapted strategy to hypoxia. A free oxygen deficit is not adequately generated in intermittent hypoxia to enable *HIF-1* stabilization. Due to oxidative stress, intermittent hypoxia can cause a delayed elevation in *HIF*-1, leading to the stimulation of *NFkB*-driven inflammation [40].
