Paraquat (N, N′- dimethyl-4,4 ′ - bipyridinium dichloride) is a quaternary nitrogen-containing compound and is a broad-spectrum herbicide that has increased agricultural production due to the variety of crops in which it is used. Other popular trade names for paraquat include methyl viologen, and paraquat dichloride (Dinis-Oliveira et al., 2008, Tsai, 2013). In more than 120 countries around the world, over 100 crops are treated with paraquat, the third most popular herbicide due to its low cost.(Dinis-Oliveira et al., 2008)
Paraquat toxicity has resulted in many cases of human poisoning and deaths due to multiple organ failure, including the nervous system, the heart, liver, and the kidneys (Wright et al., 1997). Remarkably, paraquat accumulates mainly in lung tissue; as a result, PQ ingestion, whether accidental or intentional, may result in death due to progressive lung fibrosis and respiratory failure(Yan et al., 2017, Zeinvand-Lorestani et al., 2018).
Although the guidelines for the treatment of PQ poisoning patients have not yet been thoroughly established, current therapies include supportive care alone as well as combinations of hemodialysis, immunological modulation, antioxidant therapy, and hemoperfusion (Qian et al., 2014). Despite these treatments, the current mortality rate of PQ poisoning is still over 50%(Xu et al., 2015). Oxidative stress is a crucial molecular mechanism of paraquat induced lung fibrosis, it often occurs in the lung after exposure to paraquat and alters the usual balance between oxides and peroxides while increasing the quantities of reactive oxygen species (ROS)(Kinnula and Crapo, 2003, Faner et al., 2012) ,such as superoxide anion (O2−), singlet oxygen (O) as well as hydroxyl and peroxyl radicals (Suntres, 2002) ROS cause lung fibrosis by promoting lung cell death and reducing autophagy levels in alveolar epithelial cells.(Jones, 2006)
The most traditional and commonly used medicinal herb is Milk Thistle (Silybum marianum), which is used for its antioxidant properties. (Negi et al., 2008)Silymarin is derived from the plant's seeds and fruits and it was found to be a potent antioxidant.(Comar and Kirby, 2005)
Silibinin has also been shown to have powerful anti-proliferative effects against a variety of cancer cell lines(Gazak et al., 2007). Furthermore, a study of the cancer chemo-preventive and anticarcinogenic properties of silymarin and Silibinin found that the effects of silymarin are related to its majot component Silibinin.(Hogan et al., 2007). Some studies have also proved that Silibinin has hepatoprotective effect against oxidative stress and ROS.(Haddad et al., 2011)
Cinnamon is a plant with many uses as a herbal remedy. Its constituents include, tannin, mucilage, resin, sugar, and essential oil, the most important of which is CD, which has anti-inflammatory, antibacterial, and antioxidant qualities.(Barceloux, 2009) Furthermore, Cinnamic acid, a primary active phenolic component in cinnamon, has a diversity of pharmacological activities, including antioxidant and antibacterial activity (Chen et al., 2011). CA has strong antioxidant activity due to the existence of vinyl fragments in its structure. This property has sparked our interest in studying this natural compound as a potential target for the treatment of pathological diseases caused by oxidative stress(Babaeenezhad et al., 2021).
The AKT/mTOR signalling pathway is a key regulator of cell growth, proliferation and survival. It is triggered by a variety of extracellular signals such as growth factors, cytokines, and hormones. The pathway consists of two main components: phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) .(Shiau et al., 2022)
The PI3K/Akt/mTOR signalling pathway is involved in the regulation of oxidative stress, which occurs when there is an imbalance between the cell's ability to scavenge reactive oxygen species (ROS) and their production. Oxidative stress can be regulated via the PI3K/Akt/mTOR pathway, which modulates the expression of catalase and superoxide dismutase (SOD), two antioxidant enzymes. Additionally, mTOR can regulate oxidative stress by modulating mitochondrial function and autophagy(Shiau et al., 2022).
The vital functions of microRNAs (miRNAs), an emerging class of gene expression regulators, in numerous biological processes, including cell proliferation, apoptosis, cell cycle progression and organ development, are well established (Muluhngwi and Klinge, 2015). Also, miR193a was found to be methylated in patients with non- small cell lung cancer. An additional investigation revealed that miR193a-3p promoted apoptosis in lung cancer cells by adversely affecting ERBB4, a protein that is frequently aberrated in human lung cancer, thereby inhibiting cell invasion and proliferation.(Liang et al., 2015)
The purpose of this research is to determine whether cinnamic acid and silibinin can protect against paraquat-induced pulmonary toxicity via the PI3K/Akt/mTOR pathway and miRNA 193-a signalling pathway.