Developing a Deeper Understanding of Autism: Connecting Knowledge through Literature Mining

Table 2

Potential hypotheses for the relationship between autism and NF-kappaB.

Autism literature	NF-kappaB literature
Araghi-Niknam and Fatemi [63] showed a reduction of Bcl-2, an important marker of apoptosis, in the frontal, parietal, and cerebellar cortices of autistic individuals.	Mattson [29] reported that activation of NF-kappaB in neurons can promote their survival by inducing the expression of genes encoding antiapoptotic proteins such as Bcl-2 and the antioxidant enzyme Mn-superoxide dismutase.
Vargas et al. [37] reported altered cytokine expression profiles in brain tissue and cerebrospinal fluid of patients with autism.	Ahn and Aggarwal [40] reported that, on activation, NF-kappaB regulates the expression of almost 400 different genes, which include enzymes, cytokines (such as TNF, IL-1, IL-6, IL-8, and chemokines), adhesion molecules, cell cycle regulatory molecules, viral proteins, and angiogenic factors.
Vargas et al. [37] also indicated that macrophage chemoattractant protein MCP-1 and tumor growth factor-beta1 were the most prevalent cytokines in the brain tissue of patients with autism.	Thibeault et al. [41] showed that the MCP-1 gene is expressed within particular populations of cells in response to inflammatory molecules that employ NF-kappaB as an intracellular signaling mechanism.
Ming et al. [46] reported on increased urinary excretion of an oxidative stress biomarker—8-iso-PGF2alpha in autism.	Zou and Crews [64] reported an increase in NF-kappaB DNA binding following oxidative stress neurotoxicity.
Yoo et al. [65] observed statistically significant associations between polymorphisms of PTGS2, the gene encoding cyclooxygenase-2, and autism spectrum disorders.	Lee et al. [66] elucidated the role of spinal NF-kappaB in the cyclooxygenase-2 upregulation and pain hypersensitivity following peripheral inflammation.
Ma et al. [67] performed a genome-wide linkage analysis on 26 extended autism families and found significant linkage to chromosome 12q14.	Weersma et al. [68] mentioned chromosome 12q14 as a region of IRAK-M gene, which is an NF-kappaB-mediated negative regulator of the toll-like receptor/IL-1R pathways.
Steele et al. [69] demonstrated spatial memory deficits in high-functioning individuals with autism, particularly as tasks required heavier demands on working memory.	Denis-Donini et al. [70] highlighted the function of NF-kappaB in hippocampal neurogenesis and in short-term spatial memory.
Jyonouchi et al. [71] revealed intrinsic defects of innate immune responses in children with autism spectrum disorders and gastrointestinal symptoms.	Thomas et al. [39] confirmed that NF-kappaB has a crucial and multifaceted role in innate immune responses.
Grigorenko et al. [72] identified macrophage migration inhibitor factor, which is an upstream regulator of innate immunity, as a possible susceptibility gene for autism spectrum disorders.	Gore et al. [73] showed that macrophage migration inhibitor factor regulates subsequent adaptive immune responses by initiating a signalling cascade that activates NF-kappaB.
Johnson and Malow [74] highlighted frequent sleep problems among children with autism, such as obstructive sleep apnoea.	Yamauchi et al. [75] identified significantly greater activation of NF-kappaB, which occurred in obstructive sleep apnoea.