{"id":92234,"date":"2016-07-09T02:34:17","date_gmt":"2016-07-09T02:34:17","guid":{"rendered":"http:\/\/healthmedicinet.com\/i\/redox-modulation-of-cellular-stress-response-and-lipoxin-a4-expression-by-hericium-erinaceus-in-rat-brain-relevance-to-alzheimers-disease-pathogenesis\/"},"modified":"2016-07-09T02:34:17","modified_gmt":"2016-07-09T02:34:17","slug":"redox-modulation-of-cellular-stress-response-and-lipoxin-a4-expression-by-hericium-erinaceus-in-rat-brain-relevance-to-alzheimers-disease-pathogenesis","status":"publish","type":"post","link":"https:\/\/healthmedicinet.com\/i\/redox-modulation-of-cellular-stress-response-and-lipoxin-a4-expression-by-hericium-erinaceus-in-rat-brain-relevance-to-alzheimers-disease-pathogenesis\/","title":{"rendered":"Redox modulation of cellular stress response and lipoxin A4 expression by Hericium Erinaceus in rat brain: relevance to Alzheimer\u2019s disease pathogenesis"},"content":{"rendered":"

AD has gained widespread attention because of its high economic costs, which have
\n reached $400 billion per year in the USA alone, as well as the social costs, which
\n are more difficult to quantify 26<\/a>]. AD-related pathological markers include a progressive death of neurons in specific
\n areas with an accumulation of intracellular neurofibrillary tangles (NFTs) and extracellular
\n depositions of amyloid plaques (APs). NFTs are composed of the misfolded hyperphosphorylated
\n microtubule-associated protein Tau (MAPT or Tau), whereas APs are extracellular deposits
\n of misfolded and aggregated amyloid-beta peptides (A?) 27<\/a>], 28<\/a>]. Because both NFTs and APs are persistently found in areas with severe neuronal death,
\n these proteins were considered to be the main cause of neuronal loss and the emergence
\n of dementia, which is a crucial symptom of AD; however, numerous drug trials based
\n on these proteins have failed to provide a useful AD therapy 28<\/a>]. A post-mortem study demonstrated that the misfolded protein accumulation is a shared
\n pattern in many neurodegenerative diseases, including AD 25<\/a>], concurring to the conclusion that accumulation of misfolded proteins is a prominent
\n potential cause of neurodegeneration in AD 29<\/a>]. Recently, the involvement of neuroinflammation and microglial activation in the
\n pathogenesis of AD has been emphasized by compelling evidence from basic and clinical
\n research studies indicating that inflammation induced by A? is intimately associated
\n with the development of AD neuropathology 19<\/a>]. Relevant to the central role of neuroinflammation in AD pathgenesis, are recent
\n advances in knowledge of the mechanisms of inflammatory resolution, identifying lipoxins
\n as attractive therapeutic tools to treat diseases in which inflammation is involved
\n 22<\/a>]. LXA4 is generated via the lipoxygenase pathway during cell-cell interactions in
\n inflammatory conditions, whereas aspirin-triggered LXA4 (ATL), a molecule that displays
\n the same anti-inflammatory activities as the native lipoxins, is generated after the
\n acetylation of cyclooxygenase-2 and is more resistant to metabolic inactivation 23<\/a>]. Lipoxins potentiate inflammatory resolution by means of potent agonistic actions
\n at the G-protein coupled receptor, termed LXA4 receptor (ALX\/FPR2). Activation of
\n ALX by LXA4 reduces many endogenous processes, such as neutrophil and eosinophil recruitment
\n and activation, leukocyte migration, NF-kB translocation, and chemokine and cytokine
\n production 22<\/a>]. Likewise, evidence shows that LXA4 signaling primes macrophages for chemotaxis and
\n enhances phagocytosis of microorganisms and apoptotic cells. In the nervous system,
\n LXA4 protects neurons against experimental stroke and A?
\n 42<\/sub>
\n toxicity by modulating inflammation. In addition, lipoxins inhibit inflammatory pain
\n processing through their actions on astrocytic activation in the spinal cord 30<\/a>], 31<\/a>]. However, the ability of LXA4 signaling to modulate neuroinflammation and AD pathology
\n in vivo has not been yet completely elucidated.\n <\/p>\n

Mushrooms provide a great potential as a polypharmaceutic drug because of the complexity
\n of their chemical contents and different varieties of bioactivities. If available
\n evidence suggests anti-oxidants, anti-tumor, antivirus, anti-cancer, anti-inflammatory,
\n immune modulating, anti-microbial, and anti-diabetic activities from mushrooms 32<\/a>], however, contrarily to plant herbal medicines, which are widely explored and relatively
\n more advanced, the brain and cognition health effects of mushrooms are in the early
\n stages of research. Here, by extending previous finding on nutritional approaches
\n to neuroinflammation, we provide experimental evidence that administration of H. erinaceus<\/em> for 3\u00a0month to rats results in up regulation of vitagenes, in particular Hsp70, HO-1
\n and Trx, an effect associated with increased synthesis of LXA4 in different brain
\n regions of rat. This latter, an endogenous eicosanoid, is emerging as an important
\n resolvin, a class of compounds endowed with the capability to promote resolution of
\n inflammation, therefore suggesting that nutritional modulation with H. erinaceus<\/em>, through redox-dependent vitagene network might activate endogenous \u201cbraking signal\u201d
\n processes impacting the inflammatory process. We also provide evidence of neuroprotective
\n action of H. erinaceus<\/em> when administered orally to rat. Expression of LXA4, measured in different brain
\n regions after oral administration of a biomass H. erinaceus<\/em> preparation for 3 month increased significantly in all brain regions examined, as
\n compared to control group of animals, particularly in cortex and cerebellum, followed
\n by substantia Nigra, striatum and cerebellum. LXA4 up-regulation was associated with
\n an increased content of redox sensitive proteins involved in cellular stress response,
\n such as Hsp72, HO-1 and Trx. We show that SN exhibited lower LXA4 content respect
\n to other brain regions examined, both in control and mushroom stimulated animals.
\n This finding is relevant to AD and PD pathogenesis, particularly to theories connecting
\n aging and neuronal degeneration with oxidative damage. SN neurons are depleted during
\n physiological aging and even more so in all neurodegenerative processes associated
\n with Parkinsonian symptoms. 33<\/a>]\u201337<\/a>]. In addition, we demonstrate that H. erinaceus<\/em> treatment resulted in a significant increase of LXA4 in most of the brain regions
\n examined and modulated expression of cytoprotective proteins, such as HO-1, Hsp70
\n and Trx. Our results are consistent with recent evidence obtained in mice, showing
\n neuroprotection by H. erinaceus<\/em> on Ab25\u201335 peptide-induced cognitive dysfunction 38<\/a>], 39<\/a>]. In this study the powder of H.\u00a0erinaceus<\/em> was mixed with a normal powdered diet and the Ab25\u201335 peptide was administered by
\n intracerebroventricular injection. The results revealed that H. erinaceus prevented
\n impairments of spatial short-term and visual recognition memory induced by Ab25\u201335
\n in mice. Furthermore, human trials with H. erinaceum<\/em> derivatives also have showed promising results in patients with dementia based on
\n Revised Hasegawa Dementia Scale (HDS-R) 40<\/a>].\n <\/p>\n

Our results indicating that nutritional modulation of critical proteins involved in
\n brain stress tolerance can be achieved via supplementation with a well characterized
\n strain of H. erinaceus<\/em> are relevant to those theories connecting proteome control quality failure with age-associated
\n neurodegenerative diseases. Consistent to this notion, in AD pathology, the accumulation
\n of APs composed of A? aggregates and neurofibrillary tangles NFTs composed of misfolded
\n Tau proteins, accumulation of these proteins as consequence of faulty protein quality
\n control mechanisms, is associated with a deficit in those mechanisms participating
\n to induction of cytoprotective proteins (Hsps) or, more in general, involved in the
\n cellular pathways of stress tolerance. It is conceivable that in these conditions
\n administration of H. erinaceus<\/em> mushroom, which increases the redox potential associated with induction of vitagenes,
\n may help vulnerable neurons to resist to proteotoxic insults and hence to apoptotic
\n neurodegeneration. This is furtherly corroborated by the finding indicating that restoration
\n of normal proteostasis is crucial for neuronal survival 41<\/a>].\n <\/p>\n

The molecular chaperone Hsp70 protects cells from injury by binding damaged proteins
\n under stressful situations. Members of the 70\u00a0kDa-heat shock protein family (Hsp70s)
\n are, in their function as molecular chaperones, involved in folding of newly synthesized
\n proteins and refolding of damaged or misfolded proteins, as well as in assembly and
\n disassembly of protein complexes. All human Hsp70s have highly conserved domain structures
\n 42<\/a>]. They consist of an N-terminal ATPase domain, a middle region and an N-terminal peptide
\n binding domain. However, they differ in expression patterns, cellular localization
\n and function. There are Hsp70\u2019s specifically located in the endoplasmatic reticulum
\n (Grp78, also known as BiP) and in the mitochondria (Grp75, also known as mortalin).
\n However, the members which are mainly located in the cytosol and nucleus are the heat
\n shock cognate protein 70 (Hsc70) and the heat shock protein 70 (Hsp70). Cellular stress
\n often leads to protein unfolding and, therefore, to increased protein hydrophobicity,
\n which may result in the formation of toxic protein aggregates 42<\/a>]. As recently demonstrated, Hsp70 expression is induced under the mild oxidative stress
\n conditions, when oxidative damage to proteins leads to their unfolding 43<\/a>], and the heat shock response is activated driving increases in the expression of
\n molecular chaperones, which reaches about two-fold the baseline levels 43<\/a>]. Although HSP\u2019s can refold mildly disordered proteins, it is clear that HSP\u2019s are
\n not able to repair covalently-modified oxidized proteins or to reverse oxidative protein
\n modifications, which results in increased protein hydrophobicity, as triggering signal
\n for the activation of a highly regulated and rapid series of events, called the \u2018heat
\n shock response\u2019 (HSR). Heat shock transcription factor 1 (HSF1) is bound to a complex
\n of heat shock proteins (Hsps), such as Hsp70 and Hsp90, during non-stressed conditions
\n and, therefore, kept in an inactive state. When Hsps recognize hydrophobic patches
\n of damaged and unfolded proteins, the Hsps dissolve from the complex with HSF1 in
\n response to cellular stress. This event is followed by HSF1 trimer formation, which
\n further leads to the activation and translocation of the transcription factor into
\n the nucleus, where the trimer binds to the heat shock gene promoters, the so called
\n heat shock elements (HSEs). This leads to the fast expression of Hsps 44<\/a>]. Moreover, the heat shock genes do not contain introns, which further accelerates
\n their expression. An unfolded protein that binds to Hsp70 may be either refolded into
\n its native non-toxic conformation and then released, or may stay bound by Hsp70 to
\n protect non-damaged molecules. Since most oxidative protein modifications are not
\n repairable due to their covalent nature, the majority of oxidized proteins are degraded
\n by the proteasomal system.\n <\/p>\n","protected":false},"excerpt":{"rendered":"

AD has gained widespread attention because of its high economic costs, which have reached $400 billion per year in the USA alone, as well as the social costs, which are more difficult to quantify 26]. AD-related pathological markers include a progressive death of neurons in specific areas with an accumulation of intracellular neurofibrillary tangles (NFTs) Read More<\/a><\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[],"tags":[],"class_list":["post-92234","post","type-post","status-publish","format-standard","hentry"],"_links":{"self":[{"href":"https:\/\/healthmedicinet.com\/i\/wp-json\/wp\/v2\/posts\/92234","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/healthmedicinet.com\/i\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/healthmedicinet.com\/i\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/healthmedicinet.com\/i\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/healthmedicinet.com\/i\/wp-json\/wp\/v2\/comments?post=92234"}],"version-history":[{"count":0,"href":"https:\/\/healthmedicinet.com\/i\/wp-json\/wp\/v2\/posts\/92234\/revisions"}],"wp:attachment":[{"href":"https:\/\/healthmedicinet.com\/i\/wp-json\/wp\/v2\/media?parent=92234"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/healthmedicinet.com\/i\/wp-json\/wp\/v2\/categories?post=92234"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/healthmedicinet.com\/i\/wp-json\/wp\/v2\/tags?post=92234"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}