**4.1 Anti-inflammatory effects of Apigenin**

Among the flavonoids, Apigenin is one of the most widely found and most studied phenolics in the plant kingdom. Apigenin is commonly found in many fruits, vegetables, and plants, mainly in parsley, celery, artichoke, onion, spinach, chamomile, thyme, basil, wheat sprouts, and oranges [82, 83]. Apigenin has been found to have an anti-inflammatory effect by suppressing lipopolysaccharide (LPS)-induced *Cyclooxygenase*-*2* (COX-2) and nitric oxide synthetase-2 activities and expressions in mouse macrophages [84]. It has been reported that Apigenin regulates different anti-inflammatory pathways including PI3K/Akt and p38/Mitogen-activated protein kinase (MAPK), also prevents inhibitory kB (IKB) degradation and nuclear translocation of *nuclear factor kappa B* (NF-κB), and reduced COX-2 activity [85–87]. Inhibition of NF-κB activation occurs by preventing the inhibitory kB (IkB) degradation [88]. Nitric oxide (NO) is an important intra and intercellular signal molecule that plays a role in the regulation of physiological and pathophysiological mechanisms. It relaxes vascular smooth muscles, inhibits platelet aggregation, stimulates angiogenesis, lowers blood pressure, transmits neuronal signals, activates macrophages, and can act as a cytotoxic agent in inflammation [89, 90]. The anti-inflammatory properties of apigenin are formed by the dose-dependent suppression of the inflammatory mediator's prostaglandin and NO by inhibition of *inducible nitric oxide synthase* (iNOS), and COX-2 in BV-2 murine microglial cells [91]. It has been reported that Apigenin exerts most of its effects in both human and murine cell culture models through interactions with signaling molecules in the 3 major MAPK pathways (p38, JNK, and ERK) [92, 93]. Apigenin suppresses TNF-α-induced NF-κB transcriptional activation [94]. Apigenin suppresses LPS -induced NF-κB activity in lung tissue,

reduces the infiltration of inflammatory cells, and reduces the accumulation of chemotactic factors [95]. Apigenin inhibits the production of proinflammatory cytokines IL-1β, IL-8, and TNF-α by suppressing NF-κB activity in mouse macrophages stimulated by LPS, and that apigenin suppresses inflammation and modulates immune responses [96]. It has been determined that dietary apigenin administration to ovalbumin-sensitized BALB/c mice inhibits the release of interleukin-4 (IL-4) from Th2 cells [97]. Apigenin has been reported to have anti-inflammatory potential by suppressing T helper cell-1 and -2 (Th1-Th2) related chemokine production by human monocyte cells by modulating mitogen-activated protein kinase pathways [86]. Prophylactic administration of apigenin in mice with intratracheal acute lung injury caused increased levels of IL-6, IL-1β, and TNF-α, leukocyte count, and percentage of neutrophils in bronchoalveolar lavage fluid by suppressing COX-2 and NF-κB pathways. It has an anti-inflammatory effect by reducing it [98]. In a study investigating the effects and molecular mechanisms of apigenin on cisplatin-induced kidney damage in mice; It has been shown that apigenin improves the pathological changes induced by cisplatin in a dose-dependent manner and decreases the increases in TNF-α, IL-1β, and transforming growth factor-beta (TGF-β) mRNA expressions in a dose-dependent manner [99]. Apigenin also strongly suppressed CD40, TFN-α, and IL-6 production levels in murine microglia through inhibition of IFN- γ induced phosphorylation of signal transducer and activator of transcription 1 (STAT1) [100]. Apigenin has demonstrated neuroprotective properties against apoptosis induced by endoplasmic reticulum stress in HT22 murine hippocampal neuronal cells through reduction of ROS, mitochondrial damage, and endoplasmic reticulum-stress-related proteins [101].
