Humanin Research & Studies

Amyloid beta (Aβ), a key component of drusen in age-related macular degeneration (AMD), induces oxidative stress, mitochondrial dysfunction, and degeneration in the retinal pigment epithelium (RPE), contributing to progressive vision loss in the elderly. We investigated the protective role of Humanin (HN), a mitochondria-derived peptide with known neuroprotective effects in Aβ-related neurodegenerative diseases, in retinal pathology induced by subretinal injection of FITC-labeled Aβ. HN enhanced the clearance of Aβ-accumulated mitochondria in the RPE while preserving retinal function and RPE barrier integrity. In ARPE-19 cells, HN activated AMP-activated protein kinase (AMPK), leading to phosphorylation of ULK1 and Beclin1, which promoted the interaction between Beclin1 and Parkin and their translocation to mitochondria. This process facilitated the removal of Aβ-accumulated mitochondria in the RPE. Our results demonstrate that targeting mitophagy in the RPE with HN may offer a promising therapeutic strategy for AMD.

Humanin (HN) is an endogenous micropeptide also known as a mitochondria-derived peptide. It has a neuroprotective effect against Alzheimer's disease (AD) and other neurodegenerative diseases by improving hippocampal acetylcholine and attenuating the development of oxidative stress and associated neurotoxicity. HN protects the neuron from the toxic effects of amyloid beta (Aβ). HN is regarded as a biomarker of mitochondrial stress. Interestingly, aging reduces brain expression of HN, leading to cognitive impairment and elevating the risk of neurodegeneration, including AD. However, in old subjects and AD patients, circulating HN levels increase as a compensatory mechanism to reduce neurodegeneration and mitochondrial dysfunction in AD. Conversely, other studies demonstrated a reduction in circulating HN levels in AD. These findings indicated controversial points regarding the precise mechanistic role of HN in AD. Therefore, the aim of this review was to discuss the exact role of HN in AD neuropathology and also to discuss the molecular mechanisms of HN in AD.

The role of mitochondria peptides in the spreading of glioblastoma remains poorly understood. In this study, we investigated the mechanism underlying intracranial glioblastoma progression. Our findings demonstrate that the mitochondria-derived peptide, humanin, plays a significant role in enhancing glioblastoma progression through the intratumoral activation of the integrin alpha V (ITGAV)-TGF beta (TGFβ) signaling axis. In glioblastoma tissues, humanin showed a significant upregulation in the tumor area compared to the corresponding normal region. Utilizing multiple in vitro pharmacological and genetic approaches, we observed that humanin activates the ITGAV pathway, leading to cellular attachment and filopodia formation. This process aids the subsequent migration and invasion of attached glioblastoma cells through intracellular TGFβR signaling activation. In addition, our in vivo orthotopic glioblastoma model provides further support for the pro-tumoral function of humanin. We observed a correlation between poor survival and aggressive invasiveness in the humanin-treated group, with noticeable tumor protrusions and induced angiogenesis compared to the control. Intriguingly, the in vivo effect of humanin on glioblastoma was significantly reduced by the treatment of TGFBR1 inhibitor. To strengthen these findings, public database analysis revealed a significant association between genes in the ITGAV-TGFβR axis and poor prognosis in glioblastoma patients. These results collectively highlight humanin as a pro-tumoral factor, making it a promising biological target for treating glioblastoma.

Humanin is a 24-mer peptide first reported in the early 2000s as a new neuroprotective/cytoprotective factor rescuing neuronal cells from death induced by various Alzheimer's disease-associated insults. Nowadays it is known that humanin belongs to the novel class of the so-called mitochondrial-derived peptides (which are encoded by mitochondrial DNA) and has been shown to exert beneficial cytoprotective effects in a series of in vitro and/or in vivo experimental models of human diseases, including not only neurodegenerative disorders but other human diseases as well (e.g., age-related macular degeneration, cardiovascular diseases, or diabetes mellitus). This review article is focused on the presentation of recent in vitro and in vivo research results associated with the neuroprotective action of humanin as well as of various, mainly synthetic, analogues of the peptide; moreover, the main mode(s)/mechanism(s) through which humanin and humanin analogues may exert in vitro and in vivo regarding neuroprotection have been reported. The prospects of humanin and humanin analogues to be further investigated in the frame of future research endeavors against neurodegenerative/neural diseases have also been briefly discussed.

Senescence is a cellular aging process in all multicellular organisms. It is characterized by a decline in cellular functions and proliferation, resulting in increased cellular damage and death. These conditions play an essential role in aging and significantly contribute to the development of age-related complications. Humanin is a mitochondrial-derived peptide (MDP), encoded by mitochondrial DNA, playing a cytoprotective role to preserve mitochondrial function and cell viability under stressful and senescence conditions. For these reasons, humanin can be exploited in strategies aiming to counteract several processes involved in aging, including cardiovascular disease, neurodegeneration, and cancer. Relevance of these conditions to aging and disease: Senescence appears to be involved in the decay in organ and tissue function, it has also been related to the development of age-related diseases, such as cardiovascular conditions, cancer, and diabetes. In particular, senescent cells produce inflammatory cytokines and other pro-inflammatory molecules that can participate to the development of such diseases. Humanin, on the other hand, seems to contrast the development of such conditions, and it is also known to play a role in these diseases by promoting the death of damaged or malfunctioning cells and contributing to the inflammation often associated with them. Both senescence and humanin-related mechanisms are complex processes that have not been fully clarified yet. Further research is needed to thoroughly understand the role of such processes in aging and disease and identify potential interventions to target them in order to prevent or treat age-related conditions.

Humanin (HN) is an endogenous peptide factor and known as a member of mitochondrial-derived peptides. We first found the gene encoding this novel 24-residue peptide in a brain of an Alzheimer's disease (AD) patient as an antagonizing factor against neuronal cell death induced by AD-associated insults.

The discovery of humanin (HN/MTRNR2) 20 years ago blazed a trail to identifying mitochondrial derived peptides with biological function.

Humanin, a mitochondria-derived peptide, has been found to exert variously protective function in many tissues, especially in the nervous tissues. However, relatively limited studies have focused on the role of humanin in the regulation of reproduction. Current observations indicate that humanin plays an important role in regulating the response of the cell to oxidative stress and apoptosis in ovaries and testes via the modulation of several signaling pathways, especially when the body is in an abnormal state. Even so, the detailed mechanism of humanin function needs to be explored urgently. In this passage, we demonstrate how humanin exerts its protective role in female and male reproduction and raise several questions that need further investigations. Given humanin's new frontier for the design of novel therapeutic approaches for male infertility, male contraception, female infertility, and glucose metabolism in polycystic ovary syndrome, it is worthy of further study on its protective effects and clinical applications in reproductive function.

Humanin (HN) is an endogenous 24-residue peptide that was first identified as a protective factor against neuronal death in Alzheimer's disease (AD). We previously demonstrated that the highly potent HN derivative HNG (HN with substitution of Gly for Ser14) ameliorated cognitive impairment in AD mouse models. Despite the accumulating evidence on the antagonizing effects of HN against cognitive deficits, the mechanisms behind these effects remain to be elucidated.

Mitochondria-derived peptides (MDPs) are bioactive peptides encoded by and secreted from the mitochondria. To date, a few MDPs including humanin, MOTS-c and SHLP1-6, and their diverse biological functions have been identified. The first and most studied MDP is humanin, a 24-amino-acid poly peptide. It was first identified in 2001 in the surviving neurons of patient with Alzheimer's disease, and since then has been well characterized for its neuro-protective effect through inhibition of apoptosis. Over the past two decades, humanin has been reported to play critical roles in aging as well as multiple diseases including metabolic disorders, cardiovascular diseases, and autoimmune disease. Humanin has been shown to modulate multiple biological processes including autophagy, ER stress, cellular metabolism, oxidative stress, and inflammation. A role for humanin has been shown in a wide range of cardiovascular diseases, such as coronary heart disease, atherosclerosis, and myocardial fibrosis. In this minireview, we will summarize the literature demonstrating a role for humanin in cardio-protection following myocardial ischemia-reperfusion induced injury and the potential mechanisms that mediate it.

The mitochondria produce specific peptides-mitochondrial-derived peptides-that mediate the transcriptional stress response by their translocation into the nucleus and interaction with deoxyribonucleic acid. Mitochondrial-derived peptides are regulators of metabolism. This class of peptides comprises humanin, mitochondrial open reading frame of the 12S ribosomal ribonucleic acid type c (MOTS-c) and small humanin-like peptides (SHLPs). Humanin inhibits mitochondrial complex 1 activity and limits the level of oxidative stress in the cell. Data show that mitochondrial-derived peptides have a role in improving metabolic diseases, such as type 2 diabetes. Perhaps humanin can be used as a marker for mitochondrial function in cardiovascular disease or as a pharmacological strategy in patients with endothelial dysfunction. The goal of this review is to discuss the newly emerging functions of humanin, and its biological role in cardiovascular disorders.

The process of programmed cell death, or apoptosis, is known as a key player in the development and progression of cardiovascular disease. The proposed mechanism for apoptosis is the activation of two main apoptotic signaling pathways (the extrinsic and intrinsic pathways), which lead to cell death. As the rate and amount of cardiomyocyte loss is the most important determinant of patient morbidity and mortality, novel treatment strategies targeting apoptosis are crucial. Recently, Humanin has been shown to exert protective effects against cellular apoptosis in both experimental and clinical studies. The potential cardioprotective mechanisms of Humanin have been shown to involve both the extracellular and intracellular signaling pathways. In this review, the current knowledge and the mechanisms inhibiting cellular apoptosis by Humanin during cardiac injury are comprehensively summarized. In addition, both research and clinical findings regarding the effects of Humanin on the heart and vasculature are also presented and discussed. Currently available information suggests that Humanin may exert cardioprotective benefits and could potentially be used as a novel pharmacological intervention against cellular apoptosis during myocardial injury.

Humanin is the first newly discovered peptide encoded in the mitochondrial genome in over three decades. It is the first member of a novel class of mitochondrial derived peptides. This small, 24 amino acid peptide was initially discovered to have neuroprotective effects and subsequent experiments have shown that it is beneficial in a diverse number of disease models including stroke, cardiovascular disease, and cancer. Over a decade ago, our lab found that humanin bound IGFBP-3 and more recent studies have found it to decrease circulating IGF-I levels. In turn, IGF-I also seems to regulate humanin levels and in this review, we cover the known interaction between humanin and IGF-I. Although the exact mechanism for how humanin and IGF-I regulate each other still needs to be elucidated, it is clear that humanin is a new player in IGF-I signaling.

Despite a bulk of evidence supporting the idea that increased neurotoxic insults lead to Alzheimer's disease (AD), the possibility still remains that insufficiency of an endogenous defense system contributes to the disease progression. Humanin is a bioactive peptide that is likely to inhibit both neuronal death and dysfunction only related to AD by binding to a Humanin receptor on the cell-surface and by activating a STAT3-mediated signal, preventing the onset of dementia. A couple of recent studies presented evidence suggesting that the Humanin signal is decreased in neurons of AD patients. If this is the case, the restoration or activation of the Humanin signal in neurons may change the course of AD.

Alzheimer's disease (AD) is a prevalent dementia-causing neurodegenerative disease. Neuronal death is closely linked to the progression of AD-associated dementia. Accumulating evidence has established that a 24-amino-acid bioactive peptide, Humanin, protects neurons from AD-related neuronal death. A series of studies using various murine AD models including familial AD gene-expressing transgenic mice have shown that Humanin is effective against AD-related neuronal dysfunction in vivo. Most recently, it has been shown that Humanin inhibits neuronal cell death and dysfunction by binding to a novel IL-6-receptor-related receptor(s) on the cell surface involving CNTFRalpha, WSX-1, and gp130. These findings suggest that endogenous Humanin [or a Humanin-like substance(s)] may suppress the onset of AD-related dementia by inhibiting both AD-related neuronal cell death and dysfunction.

Alzheimer's disease (AD) is the most prevalent neurological disease with dementia. AD-related dementia is caused by death and dysfunction of neurons involved in cognitive function. It has been generally believed that increased levels of toxic amyloid-betas (Abetas) are linked to the occurrence of neuronal death as well as dysfunction (Abeta cascade theory). Consequently, lowering levels of toxic Abetas in the brain is considered to be central for therapy of AD. Multiple drug candidates based on this therapeutic strategy have been developed and are being vigorously developed. Some clinical studies have indicated that this strategy is effective. In addition to this theory, Abeta-independent pathomechanisms have been shown to contribute to the progression of AD-related dementia, justifying alternative strategies for AD treatment that are effective against Abeta-independent pathomechanisms. A possible therapeutic strategy belonging to them is to directly suppress AD-related neuronal death and dysfunction. A series of studies indicated that a 24-amino-acid bioactive peptide named Humanin was shown to inhibit neuronal cell death induced by enforced expression of familial AD-related genes. Humanin also protected neurons from being killed by toxic Abetas in vitro. In addition, neuronal dysfunction-associated dementia of mice caused by muscarinic receptor antagonists and intracranially injected toxic Abetas was ameliorated by Humanin therapy. Multiple studies have indicated the existence of a putative specific Humanin receptor on the cell membrane. These results together suggest that an endogenous AD-related humoral factor(s) may inhibit the progression of AD-related dementia by inhibiting both neuronal cell death and dysfunction in vivo. Malfunction of this self-defense mechanism is also hypothesized to be another etiology or an aggravator of AD. Moreover, from a standpoint of AD therapy, stimulation of the AD defense mechanism by a potent Humanin derivative is a promising alternative strategy for AD treatment. The present patents cover Humanin and the methods of its clinical usage.

Humanin (HN) is a novel neuroprotective factor that consists of 24 amino acid residues. HN suppresses neuronal cell death caused by Alzheimer's disease (AD)-specific insults, including both amyloid-beta (betaAbeta) peptides and familial AD-causative genes. Cerebrovascular smooth muscle cells are also protected from Abeta toxicity by HN, suggesting that HN affects both neuronal and non-neuronal cells when they are exposed to AD-related cytotoxicity. HN peptide exerts a neuroprotective effect through the cell surface via putative receptor(s). HN activates a cellular signaling cascade that intervenes (at least) in activation of c-Jun N-terminal kinase. The highly selective effect of HN on AD-relevant cell death indicates that HN is promising for AD therapy. Additionally, a recent study showed that intracellularly overexpressed HN suppressed mitochondria-mediated apoptosis by inhibiting Bax activity.

Humanin (HN), a recently identified neuroprotective factor against Alzheimer's disease-related insults, has been reported to function as an anti cell-death factor through multiple mechanisms. One mechanism, revealed in a glioblastoma cell line, involves the apoptosis-inducing protein Bax. This, in addition to the fact that HN is produced in certain normal tissues, such as testis, implies a potential role of HN in oncogenesis. A second mechanism, in neuronal cells, is via a putative cell-surface receptor. It is through this mechanism that HN exhibits its neuroprotective activity.