Chemotherapeutic medications are regularly used to treat different types of cancer, but they also frequently disturb physiological homeostasis in a number of organs and can have physiological side effects in non-tumor cells. This is mostly because free radical production and the damaging effects of oxidative stress are common side effects of chemotherapy (Ali et al. 2017). Common chemotherapeutic medication doxorubicin (DOX) has been linked to a number of severe side effects, including kidney damage (Su et al. 2015). Among its most common side effects is nephrotoxicity, described as renal dysfunction with reduced filtration, reabsorption, and excretion, which is associated with significant risk of morbidity and mortality. Around 60% of cancer patients who receive chemotherapy develop nephrotoxicity, restricting the therapeutic effectiveness of Dox (Fukasawa et al. 2014; Ibrahim Fouad & Ahmed 2021)
A significant issue in the treatment of cancer is kidney impairment caused by doxorubicin (AlAsmari et al. 2022). DOX-impelled renal toxicity is one example of a multi-organ damage that is largely enabled by the production of free radicals and ultimately leads to the membrane lipid peroxidation (Ghibu et al. 2012). Reliable indications of kidney impairment include blood urea nitrogen (BUN), albumin, and Creatinine (Ali et al. 2021).This work aimed to assess the anti-inflammatory and tubules hydropic degeneration improvement effects of Cannabidiol oil to that of the medication of Trimetazidine in a rat model of Doxorubicin (DOX) - induced renal toxicity.
Creatinine, urea, Alb, T.P ALT, AST, interleukin 6 (IL-6) levels, and tumour necrosis factor-alpha (TNF-) levels gradually improved in the cannabidiol oil and Trimetazidine group compared to DOX-control positive group rats. Cannabidiol oil had a generous effect on the treatment of renal disorders with aggregates of inflammatory cells and areas of haemorrhage. In the group receiving CBD oil and trimetazine, the levels of Creatinine, urea, ALT, AST, Alb, T.P., and these substances had been restored to levels that were extremely close to control values. The reduction of interleukin-6 and tumor necrosis factor-alpha levels as results .Our investigation showed that cannabidiol oil had positive impacts on kidney function and histopathology. A single intraperitoneal dosage of doxorubicin that caused kidney damage was the actual cause of the enzyme imbalance in accordance with. (Chen et al. 2016).
Apoptosis stimulation and nitric oxide (NO) inflection are two other potential causes of the lethal adverse effects of DOX therapy. The subsequent direct or indirect stimulation of NO synthesis regulates the putative role of DOX in NOS metabolism. Chemotherapy-induced severe renal tubular abnormalities lead to acute renal failure. (Ruggiero et al. 2017). The majority of the mechanisms that regulate DOX-induced nephrotoxicity have proximal tubule cell-specific targets (Soltani Hekmat et al. 2021; Grant et al. 2019).
Natural chemicals and their structural counterparts have historically been very useful in pharmacotherapy, especially for cancer and infectious diseases (Atanasov et al., 2022). The present pharmaceutical commercial can obtain a wide range of essential medications from conventional medicinal plants and dietary supplements. Many medicinal plants have been employed since ancient times due to their usefulness as anti-inflammatory and anti-cytolytic medicine (Chavan and Aniket 2019; Mohammed et al. 2021).
Cannabidiol protected the DOX-induced renal injury in rats as shown by the significantly decreased serum Creatinine activity in DOX-injected animals. The anti-inflammatory and antioxidant properties of cannabidiol may help to reduce incursion. Rats exposed to DOX experienced a decrease in glomerular filtration rate, which is associated with higher blood levels of urea, Creatinine, and BUN. After DOX injection, it was shown that the kidney's ability to scavenge harmful H2O2 and lipid peroxides had been diminished due to a fall in SOD activities and a decrease in GSH levels; other researchers were also responsive of these results (Afsar et al. 2020).
A number of cells, including B lymphocytes, T lymphocytes, myeloid cells, epithelial cells, fibroblasts, endothelial cells, muscle cells, and adipocytes interact during the complex process of inflammation. These interactions are mediated by membrane-associated molecules, matrix metalloproteases (MMPs), and soluble factors like cytokines, chemokines, and growth factors. Tumour necrosis factor-alpha (TNF-alpha), IL-1, and IL-6 are pro-inflammatory cytokines that are important in inflammation. Among them, IL-6 is a key performer in the development of cancer, cytokine storms, autoimmune illnesses, and chronic inflammatory diseases. (Johnson et al. 2018)
Numerous trials have found that Dox increases the production of pro-inflammatory cytokines such interleukin-6 (IL-6), interleukin-1 beta (IL-1 beta), and tumour necrosis factor alpha (TNF-alpha), as well as causes inflammation. Additionally, it has been demonstrated that enhanced ROS generation following dox-induced kidney injury is crucial in triggering the intrinsic apoptotic pathway through mitochondrial instability. The mitochondrial-associated proteins Bax and Bcl-2 are important regulators of this pathway; a balanced ratio of Bcl-2 to Bax inhibits apoptosis, whereas an imbalance results in increased membrane permeability and cytochrome c leakage into the cytosol, which activates caspase-9 (Casp-9) and caspase-3 (Casp-3). DNA fragmentation and cell death are typically the results of such activation. Kidney damage was brought on by a single doxorubicin injection, as seen by the changed levels of serum Creatinine, blood urea nitrogen, and albumin (Wu et al. 2021; AlAsmari et al. 2021).
An antioxidant, an anti-inflammatory, and cytoprotective transcriptional factors known as nuclear factor (erythroid-derived 2)-like 2 (Nrf2) supports cellular defence mechanisms. The antioxidant defence genes heme oxygenase-1 (Ho-1), glutathione peroxidase (GPX), catalase (CAT), and superoxide dismutase (SOD) are activated when Nrf2 releases its cytoplasmic inhibitor protein in response to oxidative stress.( RojoVega et al. 2018, El-Emam et al. 2020).
Albumin, Creatinine, and blood urea nitrogen (BUN) are reliable indicators for kidney damage. Normal renal tissue does not permit albumin to flow out from the bloodstream to the urine, while also filtering creatinine and BUN from the bloodstream into the urine. However, in the event of renal dysfunction, these processes are disturbed: albumin is excreted in the urine, resulting in reduced serum concentrations, and creatinine and BUN are not filtered correctly, resulting in elevated serum values (Ali et al. 2021). In our current work, Dox treatment caused increases in serum creatinine and BUN alongside a significant decrease in albumin. The results are in fair agreement with the published reports. We also found prophylactic supplementation with CBD to attenuate these changes, suggesting that CBD may prevent renal damage caused by Dox.
. A pleiotropic cytokine called interleukin-6 (IL-6) modulates immunological and inflammatory responses as well as hematopoiesis, metabolism, and organ development. The signalling cascades known as classic and trans-signaling are likely used to distinguish between several physiopathological processes that IL-6 might simultaneously provoke. Dysregulated IL-6 has been shown to be the root cause of a number of autoimmune and inflammatory disorders, metabolic abnormalities, and malignancies in addition to having other significant physiological roles. Function of IL-6 in a number of renal disorders, including chronic kidney disease, IgA nephropathy, lupus nephritis, diabetic nephropathy, and acute kidney damage. (Su et al. 2017).
Inflammation, hematopoiesis, bone metabolism, and embryonic development are all impacted by IL-6, as are immunological reactions. Chronic inflammation, which is intimately associated to autoimmune disorders, cancer, and other chronic inflammatory diseases, is caused by IL-6. Chronic inflammation and the cytokine storm are uncontrolled inflammatory reactions, in contrast to acute inflammation that occurs during an immune response and wound healing. The transcription factors nuclear factor-kappa B (NF-B) and signal transducer and activator of transcription 3 (STAT3), as well as immune and non-immune cells, cytokines like IL-1, IL-6, and tumour necrosis factor alpha (TNF), play crucial roles in inflammation. The hyper activation of NF-B and subsequent production of several inflammatory cytokines are caused by synergistic interactions between NF-B and STAT3. The simultaneous activation of STAT3 and NF-B because IL-6 is an NF-B target (Toshio 2021).
Renal IL-6 mRNA expression rose in mice with either AKI or CKD, indicating the kidney is the source of the elevated serum IL-6 levels in the uremic state in accordance with our results (Fig. 3,4) of rising to IL6 levels in DNA frequency concentration. Circulating sIL-6R levels were increased in both CKD and AKI mice (Durlacher-Betzer et al. 2018).