Thymoquinone Rescues T Lymphocytes from Gamma Irradiation-Induced Apoptosis and Exhaustion by Modulating Pro-Inflammatory Cytokine Levels and PD-1, Bax, and Bcl-2 Signaling

Abstract

Background/Aims: Recent studies have shown that thymoquinone (TQ) exerts protective effects against ionizing radiation-induced cataracts in lens after total cranium irradiation of rats. Nevertheless, there is no published work investigated the effects of TQ on T cell development and biology in animal models exposed to gamma radiation. Therefore, in the present study we focused on determining the effects of TQ on radiation damage in the thymus, radiation-induced T cell imbalance, and on immune dysfunction induced by gamma-rays. Methods: Three groups of rats were used: a control group, a gamma-irradiated group, and a gamma-irradiated group that was orally supplemented with TQ. Serum lipid profiles, malondialdehyde (MDA) levels, and pro-inflammatory cytokine levels were measured to assess gamma irradiation-induced oxidative stress and inflammatory capacity. T cell apoptosis was evaluated by annexin V/propidium iodide staining followed by flow cytometry analysis. The expression of pro-apoptotic proteins such as Bax and caspase-3, the anti-apoptotic protein Bcl-2, and an exhaustion marker of T cells (PD-1) in CD4⁺ and CD8⁺ T cell populations was evaluated using flow cytometry analysis. The T cell architecture of the thymus gland was evaluated by histological analysis. Results: Exposure to gamma radiation increased triglyceride, cholesterol, LDL-C, MDA, TNF-α and IL-6 levels and decreased HDL-C levels. The altered lipid profile and MDA and pro-inflammatory cytokine (TNF-α and IL-6) levels induced by exposure to gamma radiation were significantly restored in TQ-treated gamma-irradiated rats. Rats exposed to gamma radiation exhibited increased exhaustion of T lymphocytes via down-regulation of Bcl-2 expression and upregulation of PD-1, Bax, and caspase-3 expression, which sensitized these cells to apoptosis. Interestingly, treatment of gamma-irradiated rats with TQ decreased T cell exhaustion and apoptosis by modulating the expression of Bcl-2, PD-1, Bax, and caspase-3. Conclusions: Our results provide evidence for the beneficial effects of TQ as an effective radioprotective candidate that enhances cellular immunity.

The effect of 131I-induced hypothyroidism on the levels of nitric oxide (NO), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), total nitric oxide synthase (NOS) activity, and expression of NOS isoforms in rats

“…As shown in Figures 1 and 2, compared to control group, the levels of IL-6 and TNF-α increased with longer duration of the 131 I treatment. Although an increase of TNF-α and IL-6 was also induced by the exposure of rats to gamma radiation [27], we showed that at the end of month 2 and 4, when the CPM was similar to the natural background value, the levels of TNF-α and IL-6 were still continually increasing, indicating that the elevated levels of the pro-inflammatory cytokines are probably associated with hypothyroidism. In addition, increased levels of TNF-α and IL-6 have been suggested as a risk factor for adverse cardiovascular events [14,28].…”

Pharmacotherapy with Thymoquinone Improved Pancreatic β-Cell Integrity and Functional Activity, Enhanced Islets Revascularization, and Alleviated Metabolic and Hepato-Renal Disturbances in Streptozotocin-Induced Diabetes in Rats

“…Interestingly, data of the present study are in harmony whereas therapy with TQ exhibited profound restoration of survivin expression with concomitant downregulation of caspase-3 levels in the pancreatic tissues of STZ-diabetic rats; proposing the anti-apoptotic role mediated by TQ against the peculiar β-cell cytotoxic-, apoptotic-, and destructive effects induced by STZ in this model [22,23,24]. Although it has been shown [27,35] that TQ is a potent antineoplastic agent that induces apoptosis in cancer cells, its distinguished anti-apoptotic properties, via decreasing apoptotic drivers and increasing anti-apoptotic proteins, have also been observed in several non-cancerous modalities, suggesting its paradoxical anti-apoptotic and apoptotic dual roles in non-cancerous and cancerous cell injuries, respectively [19,36,37,38,39]. …”

Thymoquinone as a Potential Adjuvant Therapy for Cancer Treatment: Evidence from Preclinical Studies

“…Results from those studies showed that animal treated with macerated extracts of Nigella sativa L. seeds (contains TQ along with other components) experienced less damage in their liver, spleen, brain, and intestines upon exposure to radiation. Another recently published work demonstrated the rescue of T-lymphocytes by TQ from gamma irradiation-induced apoptosis (Guida et al, 2016). From mechanistic point of view, these radioprotective effect of TQ is mainly mediated through its free radical scavenging ability and anti-oxidant properties (Velho-Pereira et al, 2012).…”