Celastrol Alleviates Gamma Irradiation-Induced Damage by Modulating Diverse Inflammatory Mediators

Abstract

The present study aimed to explore the possible radioprotective effects of celastrol and relevant molecular mechanisms in an in vitro cell and in vivo mouse models exposed to gamma radiation. Human keratinocytes (HaCaT) and foreskin fibroblast (BJ) cells were exposed to gamma radiation of 20 Gy, followed by treatment with celastrol for 24 h. Cell viability, reactive oxygen species (ROS), nitric oxide (NO) and glutathione (GSH) production, lipid peroxidation, DNA damage, inflammatory cytokine levels, and NF-κB pathway activation were examined. The survival rate, levels of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) in blood, and p65 and phospho-p65 expression were also evaluated in mice after exposure to gamma radiation and celastrol treatment. The gamma irradiation of HaCaT cells induced decreased cell viability, but treatment with celastrol significantly blocked this cytotoxicity. Gamma irradiation also increased free radical production (e.g., ROS and NO), decreased the level of GSH, and enhanced oxidative DNA damage and lipid peroxidation in cells, which were effectively reversed by celastrol treatment. Moreover, inflammatory responses induced by gamma irradiation, as demonstrated by increased levels of IL-6, TNF-α, and IL-1β, were also blocked by celastrol. The increased activity of NF-κB DNA binding following gamma radiation was significantly attenuated after celastrol treatment. In the irradiated mice, treatment with celastrol significantly improved overall survival rate, reduced the excessive inflammatory responses, and decreased NF-κB activity. As a NF-κB pathway blocker and antioxidant, celastrol may represent a promising pharmacological agent with protective effects against gamma irradiation-induced injury.

Nobiletin in Cancer Therapy: How This Plant Derived-Natural Compound Targets Various Oncogene and Onco-Suppressor Pathways

“…This suggestion is due to the presence of beneficial natural chemicals in plants and fruits and, also, their metabolites, which exert health-promoting effects after being absorbed in the body [3][4][5][6][7][8][9][10]. It has been demonstrated that the identification, isolation, and purification of these natural chemicals may be a milestone in the treatment of diseases, particularly in human malignancies [11][12][13][14][15][16][17][18][19][20]. A high number of studies have focused on cancer therapy using plant-derived natural compounds [6,[13][14][15][16][17][18][19][20].…”

Drug repurposing to face Covid-19: Celastrol, a potential leading drug capable of inhibiting SARS-CoV-2 replication and induced inflammation

“…This triterpene also dampens HIV-1 Tat-induced inflammatory responses, inhibits the production of proinflammatory chemokines, such as CXCL10, IL-8, and MCP-1 (YOUN et al, 2014), and suppresses replication of Dengue virus serotype 1-4 by promoting IFN-α expression and stimulating downstream antiviral responses 74 . Celastrol suppresses the production of cytokines during cytokine storm and of chemokines related to worse disease prognosis, such as IL-8, IL-6, CXCL1, and CCL20 [75][76][77] , lowers the levels of anti-inflammatory markers 78 , and stimulates type I interferon production and expression of interferon-stimulated genes against Dengue virus infection 74 .…”

“…A recent study using a mouse model of acute toxicity has demonstrated that celastrol is safe even when orally administered at a high dose (62.5 mg/kg body weight) 110 . Intraperitoneal administration of celastrol (0.25 mg/kg body weight) increases the gamma irradiated-mice survival rate by around 70 78 . To surpass celastrol toxicity, solubility, and pharmacokinetic issues, several pharmaceutical approaches have been proposed, such as nanoencapsulation, liposomes, and sugar-silica nanoparticles [111][112][113] .…”

A Role for Maternal Factors in Suppressing Cytoplasmic Incompatibility

“…The four compounds that suppress wRiinduced CI are known inducers of DNA damage, whereas the three compounds that suppress both wRi-and wMel-induced CI, reportedly support DNA integrity ( Figure 5) (Additional File S3). Though celastrol can exert detrimental impacts on DNA (Han et al, 2018;Wang et al, 2020), it has also been shown to suppress radiation-induced damage (Xu et al, 2013;Moreira et al, 2019). Cycloheximide treatments prevent formation of single-and double-strand DNA breaks (Yoshioka et al, 1987;Lorico et al, 1988).…”