Chronic (continuous, non-interrupted) hypoxia and cycling (intermittent, transient) hypoxia are two types of hypoxia occurring in malignant tumors. They are both associated with the activation of hypoxia-inducible factor-1 (HIF-1) and nuclear factor κB (NF-κB), which induce changes in gene expression. This paper discusses in detail the mechanisms of activation of these two transcription factors in chronic and cycling hypoxia and the crosstalk between both signaling pathways. In particular, it focuses on the importance of reactive oxygen species (ROS), reactive nitrogen species (RNS) together with nitric oxide synthase, acetylation of HIF-1, and the action of MAPK cascades. The paper also discusses the importance of hypoxia in the formation of chronic low-grade inflammation in cancerous tumors. Finally, we discuss the effects of cycling hypoxia on the tumor microenvironment, in particular on the expression of VEGF-A, CCL2/MCP-1, CXCL1/GRO-α, CXCL8/IL-8, and COX-2 together with PGE₂. These factors induce angiogenesis and recruit various cells into the tumor niche, including neutrophils and monocytes which, in the tumor, are transformed into tumor-associated neutrophils (TAN) and tumor-associated macrophages (TAM) that participate in tumorigenesis.

Cyclin-dependent kinase 5 (Cdk5) belongs to the family of proline-directed serine/threonine kinases and plays a critical role in neuronal differentiation, migration, synaptogenesis, plasticity, neurotransmission and apoptosis. The deregulation of Cdk5 activity was observed in post mortem analysis of brain tissue of Alzheimer’s disease (AD) patients, suggesting the involvement of Cdk5 in the pathomechanism of this neurodegenerative disease. However, our recent study demonstrated the important function of Cdk5 in regulating inflammatory reaction. Since the role of Cdk5 in regulation of inflammatory signalling in AD is unknown, we investigated the involvement of Cdk5 in neuroinflammation induced by single intracerebroventricular (icv) injection of amyloid beta protein (Aβ) oligomers in mouse. The brain tissue was analysed up to 35 days post injection. Roscovitine (intraperitoneal administration) was used as a potent Cdk5 inhibitor. The experiments were also performed on human neuroblastoma SH-SY5Y as well as mouse BV2 cell lines treated with exogenous oligomeric Aβ. Our results demonstrated that single injection of Aβ oligomers induces long-lasting activation of microglia and astrocytes in the hippocampus. We observed also profound, early inflammatory response in the mice hippocampus, leading to the significant elevation of pro-inflammatory cytokines expression (e.g. TNF-α, IL-1β, IL-6). Moreover, Aβ oligomers elevated the formation of truncated protein p25 in mouse hippocampus and induced overactivation of Cdk5 in neuronal cells. Importantly, administration of roscovitine reduced the inflammatory processes evoked by Aβ in the hippocampus, leading to the significant decrease of cytokines level. These studies clearly show the involvement of Cdk5 in modulation of brain inflammatory response induced by Aβ and may indicate this kinase as a novel target for pharmacological intervention in AD.

Extracellular matrix (ECM) molecules that are released by neurons and glial cells form perineuronal nets (PNNs) and modulate many neuronal and glial functions. PNNs, whose structure is still not known in detail, surround cell bodies and dendrites, which leaves free space for synapses to come into contact. A reduction in the expression of many neuronal ECM components adversely affects processes that are associated with synaptic plasticity, learning, and memory. At the same time, increased ECM activity, e.g., as a result of astrogliosis following brain damage or in neuroinflammation, can also have harmful consequences. The therapeutic use of enzymes to attenuate elevated neuronal ECM expression after injury or in Alzheimer’s disease has proven to be beneficial by promoting axon growth and increasing synaptic plasticity. Yet, severe impairment of ECM function can also lead to neurodegeneration. Thus, it appears that to ensure healthy neuronal function a delicate balance of ECM components must be maintained. In this paper we review the structure of PNNs and their components, such as hyaluronan, proteoglycans, core proteins, chondroitin sulphate proteoglycans, tenascins, and Hapln proteins. We also characterize the role of ECM in the functioning of the blood-brain barrier, neuronal communication, as well as the participation of PNNs in synaptic plasticity and some clinical aspects of perineuronal net impairment. Furthermore, we discuss the participation of PNNs in brain signaling. Understanding the molecular foundations of the ways that PNNs participate in brain signaling and synaptic plasticity, as well as how they change in physiological and pathological conditions, may help in the development of new therapies for many degenerative and inflammatory diseases of the brain.

This review describes the role of CXCL1, a chemokine crucial in inflammation as a chemoattractant for neutrophils, in physiology and in selected major non-cancer diseases. Due to the vast amount of available information, we focus on the role CXCL1 plays in the physiology of bones, bone marrow, muscle and the nervous system. For this reason, we describe its effects on hematopoietic stem cells, myoblasts, oligodendrocyte progenitors and osteoclast precursors. We also present the involvement of CXCL1 in diseases of selected tissues and organs including Alzheimer’s disease, epilepsy, herpes simplex virus type 1 (HSV-1) encephalitis, ischemic stroke, major depression, multiple sclerosis, neuromyelitis optica, neuropathic pain, osteoporosis, prion diseases, rheumatoid arthritis, tick-borne encephalitis (TBE), traumatic spinal cord injury and West Nile fever.