“Inflammaging” as a Druggable Target: A Senescence‐Associated Secretory Phenotype—Centered View of Type 2 Diabetes

Prattichizzo, Francesco; Nigris, Valeria De; Sala, Lucia La; Procopio, Antonio Domenico; Olivieri, Fabiola; Ceriello, Antonio

doi:10.1155/2016/1810327

Cited by 98 publications

(101 citation statements)

References 127 publications

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“…The link between T2DM and inflammation is well established. T2DM is considered to be, in part, a consequence of subclinical chronic low-grade inflammation (1)(2)(3). Several studies have reported that circulating inflammatory cytokines, such as c-reactive protein, TNF-α, IL-1β, IL-6 and IL-18, are significantly elevated in T2DM patients (33)(34)(35)(36)(37)(38).…”

Section: Discussionmentioning

confidence: 99%

“…Type 2 diabetes mellitus (T2DM) presents a major and growing health problem throughout the world. Microvascular and macrovascular complications often occur in T2DM, and chronic low-grade inflammation plays a central role in this process (1)(2)(3). The inflammatory response is associated with both insulin resistance and the development of vascular complications in T2DM patients (4,5).…”

Section: Introductionmentioning

confidence: 99%

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Hydrogen sulfide modulates high glucose‑induced NLRP3 inflammasome activation in 3T3‑L1 adipocytes

Zhang²,

Ruan

et al. 2019

Exp Ther Med

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Activation of the NACHT leucine rich repeat and pyd domains-containing 3 (NLRP3) inflammasome plays an important role in the initiation of inflammation in adipose tissue in diabetic patients. However, the mechanisms underlying this are not fully understood. Hydrogen sulfide (H 2 S) has been shown to have anti-inflammatory properties in various cell types. The present study aimed to investigate the effect of H 2 S on high glucose (HG)-induced NLRP3 inflammasome activation in adipocytes. Adipocytes were differentiated from 3T3-L1 cells and treated with low glucose (LG), HG, H 2 S donor sodium hydrosulfide (NaHS) or N-acetyl-tyrosyl-valyl-alanyl-aspartyl chloromethyl ketone, an inhibitor of the cysteine protease caspase-1. The expression levels of NLRP3, apoptosis-associated speck-like protein containing A CARD (ASC) and caspase-1, and the release of interleukin (IL)-1β and IL-18 were measured. The results of the present study indicated that HG increased the expression levels of NLRP3, ASC and cleaved caspase-1, and the release of IL-1β and IL-18 in adipocytes. Caspase-1 inhibition abolished HG-induced production of IL-1β and IL-18 in adipocytes. Furthermore, NaHS inhibited the expression of NLRP3, ASC and cleaved caspase-1, and the production of IL-1β and IL-18 in adipocytes treated with HG. In conclusion, HG may increase and exogenous H 2 S may inhibit HG-induced NLRP3 inflammasome activation in adipocytes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hydrogen sulfide modulates high glucose‑induced NLRP3 inflammasome activation in 3T3‑L1 adipocytes

Zhang²,

Ruan

et al. 2019

Exp Ther Med

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“…The definite pathogenic relevance of senescence for the onset of type-2 diabetes and the progression of its multiorgan complications, or whether senescence precedes or follows the onset of perpetual inflammation and insulin resistance are topics of intense debate [7]. Anyhow, diabetic patients experience an obvious accelerated aging process that increases their predisposition to morbidity and earlier death.…”

Section: Diabetes Cellular Senesce and Chronic Woundsmentioning

confidence: 99%

“…As derived from a diabetic donor, this population of senescent, arrested cells may be impinged by a variety of hyperglycemia-associated stressor factors including reactive oxygen species. Different pathogenic loops linked to diabetes progression and complications development, appear to be mechanistically related to the orchestration of a senescencent phenotype [7].…”

Section: Introductionmentioning

confidence: 99%

Epidermal Growth Factor Therapy Impact on Scar Tissue Resilience of Diabetic Lower Limbs Ulcers-An Enlightening Hypothesis

Berlanga‐Acosta¹,

Mendoza‐Marí²,

García‐Ojalvo³

et al. 2018

J Diabetes Metab

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Diabetes patients experience an accelerated aging process that increases their predisposition to multiorgan complications and earlier death. Lower extremity ulceration and wound chronification are among the devastating complications of diabetes. Likewise, ulcer recurrence is a frequent and challenging event whose cellular and molecular driving forces have remained elusive. Thus far educative prevention and interventions on predisposing factors are the only tools to prolong ulcer remission. Cellular senescence plays a critical role in diabetics healing impairment. Hyperglycemia-associated glucooxidative stress and other biochemical derangements can foster this premature senescence. Since diabetic microenvironment is permissive to senescence, we have hypothesized that the increasing thresholds of scar's senescent fibroblasts may contribute to wound recurrence. Diabetic wounds healing therapies have not accounted for a consistent reduction in recurrences rates. Reviewing 18 clinical trials of representative therapeutic alternatives for the healing of diabetic lower extremity wounds; indicated that epidermal growth factor therapy-either topical or by infiltrative delivery, proved to be the only intervention associated to the lowest recurrences rates. According to literature evidences, we propose that epidermal growth factor exerts a local rejuvenating effect by replacing senescent cells, or by dismounting/reversing the fibroblasts' epigenetic senescence program. This growth factor may potentially act as a senolytic agent for diabetic wounds, promoting the neodermal resilience and tolerance to physical and mechanical stress.

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“…Closely tied to the progression of clinical disease with advanced age are metabolic disorders (1, 10, 11, 41, 42) that includes DM (8, 43). In particular, DM is increasing in incidence throughout the world (28, 41) and it is predicted that greater than 350 million individuals currently have DM (44–48).…”

Section: Increased Lifespan Degenerative Disorders and Cell Injurymentioning

confidence: 99%

Erythropoietin and mTOR: A “One-Two Punch” for Aging-Related Disorders Accompanied by Enhanced Life Expectancy

Maiese¹

2016

CNR

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Life expectancy continues to increase throughout the world, but is accompanied by a rise in the incidence of non-communicable diseases. As a result, the benefits of an increased lifespan can be limited by aging-related disorders that necessitate new directives for the development of effective and safe treatment modalities. With this objective, the mechanistic target of rapamycin (mTOR), a 289-kDa serine/threonine protein, and its related pathways of mTOR Complex 1 (mTORC1), mTOR Complex 2 (mTORC2), proline rich Akt substrate 40 kDa (PRAS40), AMP activated protein kinase (AMPK), Wnt signaling, and silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), have generated significant excitement for furthering novel therapies applicable to multiple systems of the body. Yet, the biological and clinical outcome of these pathways can be complex especially with oversight of cell death mechanisms that involve apoptosis and autophagy. Growth factors, and in particular erythropoietin (EPO), are one avenue under consideration to implement control over cell death pathways since EPO can offer potential treatment for multiple disease entities and is intimately dependent upon mTOR signaling. In experimental and clinical studies, EPO appears to have significant efficacy in treating several disorders including those involving the developing brain. However, in mature populations that are affected by aging-related disorders, the direction for the use of EPO to treat clinical disease is less clear that may be dependent upon a number of factors including the understanding of mTOR signaling. Continued focus upon the regulatory elements that control EPO and mTOR signaling could generate critical insights for targeting a broad range of clinical maladies.

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“Inflammaging” as a Druggable Target: A Senescence‐Associated Secretory Phenotype—Centered View of Type 2 Diabetes

Cited by 98 publications

References 127 publications

Hydrogen sulfide modulates high glucose‑induced NLRP3 inflammasome activation in 3T3‑L1 adipocytes

Hydrogen sulfide modulates high glucose‑induced NLRP3 inflammasome activation in 3T3‑L1 adipocytes

Epidermal Growth Factor Therapy Impact on Scar Tissue Resilience of Diabetic Lower Limbs Ulcers-An Enlightening Hypothesis

Erythropoietin and mTOR: A “One-Two Punch” for Aging-Related Disorders Accompanied by Enhanced Life Expectancy

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