The neurosurvival factor Humanin inhibits β-cell apoptosis via signal transducer and activator of transcription 3 activation and delays and ameliorates diabetes in nonobese diabetic mice

Hoang, Phuong Thi; Park, Patricia; Cobb, Laura J.; Paharkova-Vatchkova, Valdislava; Hakimi, Michael; Cohen, Pinchas; Lee, Kuk‐Wha

doi:10.1016/j.metabol.2009.08.001

Cited by 126 publications

(113 citation statements)

References 40 publications

(53 reference statements)

Supporting

Mentioning

106

Contrasting

Unclassified

Order By: Relevance

“…STAT3 activation in Treg cells, associated with type 1 diabetes resistance in NOD mice (61), controls the macrophage IL-10-mediated anti-inflammatory response (62) and is an important survival factor in β-cells (63,64). Our data show that GHmediated interference in type 1 diabetes development involves an increase in β-cell mass, protection of the periinsular laminin layer, and a direct effect on immune cells-mainly macrophages, Th17, and possibly Treg cells.…”

Section: Discussionmentioning

confidence: 68%

Growth hormone prevents the development of autoimmune diabetes

Villares

Kakabadse

Juarranz

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Evidence supports a relationship between the neuroendocrine and the immune systems. Data from mice that overexpress or are deficient in growth hormone (GH) indicate that GH stimulates T and B-cell proliferation and Ig synthesis, and enhances maturation of myeloid progenitor cells. The effect of GH on autoimmune pathologies has nonetheless been little studied. Using a murine model of type 1 diabetes, a T-cell-mediated autoimmune disease characterized by immune cell infiltration of pancreatic islets and destruction of insulin-producing β-cells, we observed that sustained GH expression reduced prodromal disease symptoms and eliminated progression to overt diabetes. The effect involves several GH-mediated mechanisms; GH altered the cytokine environment, triggered anti-inflammatory macrophage (M2) polarization, maintained activity of the suppressor T-cell population, and limited Th17 cell plasticity. In addition, GH reduced apoptosis and/or increased the proliferative rate of β-cells. These results support a role for GH in immune response regulation and identify a unique target for therapeutic intervention in type 1 diabetes.beta cells | Tregs G rowth hormone (GH) is a pleiotropic hormone that affects a broad spectrum of physiological functions, from carbohydrate and lipid metabolism to the immune response (1). Several studies have linked GH with autoimmune diseases, although its effects on the immune system are still debated. Whereas some reports using GH-deficient mice indicate that it does not affect immune competence (2), others suggest that GH is necessary for correct immune system development (1, 3). The GH receptor (GHR) is expressed by several lymphocyte subpopulations (4). GH stimulates in vitro T and B-cell proliferation (5) and Ig synthesis (6); enhances human myeloid progenitor cell maturation (7); and modulates in vivo Th1/Th2 (8) and humoral immune responses (1). In addition, therapeutic activation of the GH/STAT5B axis is postulated as a target for restoring mucosal tolerance in Crohn disease (9, 10). A single point mutation in STAT5B limits its DNA binding activity as well as maintenance of FOXP3 expression by Treg cells in nonobese diabetic (NOD) mice (11). These mice develop type 1 diabetes, which is characterized by autoimmune destruction of pancreatic β-cells due to the effect of environmental factors on genetically predisposed individuals (12,13). Although this murine model does not completely mimic the human disease, most steps in the pathogenesis, including prodromal and clinical symptoms, are closely comparable (14).Despite the interdependence of GH and insulin regulation and the known effects of GH and insulin-like growth factor 1 (IGF1) on pancreatic β-cell survival, proliferation and neogenesis (15, 16), hormone influences have not been described in type 1 diabetes; no specific studies have addressed the consequences of long-term GH replacement therapy in this disease. Here we show the effects of long-term GH supplementation as a tool to modulate autoimmune attack on pancreatic β-cells. NOD...

show abstract

Section: Discussionmentioning

confidence: 68%

Growth hormone prevents the development of autoimmune diabetes

Villares

Kakabadse

Juarranz

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…2-4 for review). Humanin also suppresses cell death in a variety of non-AD-related in vitro and in vivo cell death models; for example, serum deprivation-induced death of several cell types including PC12 neuronal cells (5), primary peripheral lymphocytes (6), K562 myeloblasts (7), and cultured islet ␤ cells (8), as well as death of Leydig cells during the first wave of spermatogenesis (9), ischemia-induced neuronal death in a mouse ischemic stroke model (10,11), gonadotropin-releasing hormone antagonist-induced death of testicular germ cells (12), ischemic death of myocardiocytes (13), and oxidized LDL-induced death of vascular endothelial cells (14). Humanin has other functions aside from inhibition of cell death.…”

Section: Humanin Is a Secreted Bioactive Peptide That Suppresses Cellmentioning

confidence: 99%

SH3-binding Protein 5 Mediates the Neuroprotective Effect of the Secreted Bioactive Peptide Humanin by Inhibiting c-Jun NH2-terminal Kinase

Takeshita

Hashimoto

Nawa

et al. 2013

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: Humanin, a secreted bioactive peptide, suppresses a variety of cell toxicities. Results: An intracellular protein SH3BP5, which directly inhibits JNK activity, is identified as an effector of Humanin. Conclusion: SH3BP5 is a physiological inhibitor of JNK and the firstly identified effector of Humanin. Significance: The discovery provides a novel mechanistic insight into the actions of JNK and Humanin.

show abstract

“…However, mitochondrial ATP production and the fast kinetics of signal transduction in necrotic cell death rule out the involvement of transcription factors (6,49). Moreover, BAX was shown to be a proapoptotic protein rather than mediating necrosis (50).…”

Section: Discussionmentioning

confidence: 99%

Humanin Derivatives Inhibit Necrotic Cell Death in Neurons

Cohen

Lerner-Yardeni

Meridor

et al. 2015

Mol Med

View full text Add to dashboard Cite

Humanin and its derivatives are peptides known for their protective antiapoptotic effects against Alzheimer's disease. Herein, we identify a novel function of the humanin-derivative AGA(C8R)-HNG17 (namely, protection against cellular necrosis). Necrosis is one of the main modes of cell death, which was until recently considered an unmoderated process. However, recent findings suggest the opposite. We have found that AGA(C8R)-HNG17 confers protection against necrosis in the neuronal cell lines PC-12 and NSC-34, where necrosis is induced in a glucose-free medium by either chemohypoxia or by a shift from apoptosis to necrosis. Our studies in traumatic brain injury models in mice, where necrosis is the main mode of neuronal cell death, have shown that AGA(C8R)-HNG17 has a protective effect. This result is demonstrated by a decrease in a neuronal severity score and by a reduction in brain edema, as measured by magnetic resonance imaging (MRI). An insight into the peptide's antinecrotic mechanism was attained through measurements of cellular ATP levels in PC-12 cells under necrotic conditions, showing that the peptide mitigates a necrosis-associated decrease in ATP levels. Further, we demonstrate the peptide's direct enhancement of the activity of ATP synthase activity, isolated from rat-liver mitochondria, suggesting that AGA(C8R)-HNG17 targets the mitochondria and regulates cellular ATP levels. Thus, AGA(C8R)-HNG17 has potential use for the development of drug therapies for necrosis-related diseases, for example, traumatic brain injury, stroke, myocardial infarction, and other conditions for which no efficient drug-based treatment is currently available. Finally, this study provides new insight into the mechanisms underlying the antinecrotic mode of action of AGA(C8R)-HNG17.

show abstract

The neurosurvival factor Humanin inhibits β-cell apoptosis via signal transducer and activator of transcription 3 activation and delays and ameliorates diabetes in nonobese diabetic mice

Cited by 126 publications

References 40 publications

Growth hormone prevents the development of autoimmune diabetes

Growth hormone prevents the development of autoimmune diabetes

SH3-binding Protein 5 Mediates the Neuroprotective Effect of the Secreted Bioactive Peptide Humanin by Inhibiting c-Jun NH2-terminal Kinase

Humanin Derivatives Inhibit Necrotic Cell Death in Neurons

Contact Info

Product

Resources

About