**4.4 Anti-inflammatory**

Inflammation is a complicated process characterized primarily by inflammatory cytokines, such as interleukin-6, tumor necrosis factor-alpha (TNF-α), interleukin-1β, and also a chain of molecular messengers, such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). These inflammatory cytokines have also been linked to the development of several inflammatory disorders, particularly colorectal cancer, Alzheimer's disease, multiple sclerosis, and Parkinson's disease [35]. Orange (*Citrus aurantium L.)* isolate has been shown to inhibit UVBinduced COX-2 expression and prostaglandin (PG) E2 generation in HaCaT cells while also acting as a PPAR-c agonist [58]. *Citrus* fruit contains volatile oil coumarin and flavonoids, which have anti-inflammatory properties and can be utilized as a remedy to prevent or treat chronic inflammatory illnesses.

A meal incorporating 0.1% rutin, in particular, alleviated dextran sulfate sodium (DSS)-induced colon inflammation in mice, increasing histological ratings and mitigating weight loss, presumably via lowering pro-inflammatory cytokine production [59]. Furthermore, studies suggest that quercetin (50 and 100 mg/kg) treatment lowered structural, clinical, and behavioral outcomes in rats' colons [60]. Isoquercitrin, a flavonoid with anti-inflammatory properties and antioxidants, is a glycoside that is chemically related to quercetin. This flavonoid reduces the levels of cyclo-oxygenase-2 (COX-2) and iNOS in rats, which helps them recover from acute colitis [61]. Kumar et al. observed that administering naringin at various dosages decreased acetic acidinduced colitis in animal models by decreasing DNA damage and inflammatory responses [62]. Naringenin is abundant in *Citrus* and has been extensively researched for its potential efficacy in several animal models of inflammatory illness. Apigenin is a flavone that may be found in a variety of fruits and vegetables, with grapefruit having the highest concentration. Its potential to relieve symptoms of inflammatory diseases is considered to be due to both anti-inflammatory and antioxidant properties. This was achieved by activating the aryl hydrocarbon (Ah)-receptor, which in turn produced good protective enzymes and cytokines, resulting in an improvement in the antiinflammatory system [63]. Diosmin, a *Citrus* flavone recognized for its anti-inflammatory, antioxidant, and vasotonic effects, has also been researched for its potential to attenuate experimentally-induced colitis in animal models [64]. Among flavones, luteolin has proven tremendous anti-inflammatory efficacy in lots of experimental models. Luteolin inhibited intracellular inflammatory send signal in HT-29 colon epithelial by downregulating the Janus kinase (JAK)/sign transducer and activator of transcription (STAT) pathway [65]. Nobiletin and tangeretin are polymethoxylated flavones determined in *Citrus,* which have been established to assist in inflammation in many studies. In each *in vitro* and *in vivo* experiments, nobiletin suppressed inflammatory processes, along with the suppression of iNOS and COX-2 expression, and repaired the impaired intestinal barrier characteristic in trinitrobenzene sulfonic acid

(TNBS)-induced colitis in rats and Caco-2 monolayer inhibiting the protein kinase b (Akt)-NF-jB-myosin light-chain kinase (MLCK) pathway affects the latter [66].

#### **4.5 Anti-cancer**

Secondary metabolites in *Citrus* fruits, such as coumarins, limonoids, and flavonoids, have been linked to a lower risk of cancer, including lung tumorigenesis, colonic tumorigenesis, breast cancer, hematological malignancies, gastric cancer, and hepatocarcinogenesis, among others [66–70]. Chang and Jia observed that the flavedo fraction of organ (*Citrus reticulata cv. Suavissima*) inhibited tumor growth by blocking epithelial-to-mesenchymal transformation and interfering with the (transforming growth factor-β1) TGF-β1–SMAD (Suppressor of Mothers against Decapentaplegic) Snail/Slug axis [71]. *Citrus* may lower cancer by inhibiting oxidative stress and damage, as well as interfering with cancer initiation, development, and progression [72]. *Citrus bergamia* (bergamot) juice has subsequently been revealed to exhibit anti-cancer potential in several *in vitro* and *in vivo* studies, with the flavonoid content attributed to this effect [73]. Vitamin C has been suggested to combat inflammation and consequent oxidative damage to DNA, both of which have a role in the beginning and progression of cancer. Furthermore, because of its pro-oxidant activity, vitamin C can destroy cancer cells [36].

#### **4.6 Cardiovascular protection properties**

Several recent epidemiologic studies commonly correlate greater flavonoid-rich food consumption to lower cardiovascular morbidity and mortality [74]. Several studies have demonstrated that *Citrus*-derived flavonoids may reduce triglyceride levels (TG) and blood cholesterol (CH). Using HepG2 cells, the optimum structure was found to be complete methoxylation of the A-ring of *Citrus* flavonoids for expressing a profound impact on regulating hepatic metabolic activity by decreasing apoB-containing lipoprotein production [75]. Nobiletin and tangeretin, which have the ideal chemical composition, may reduce blood triglycerides, but several *Citrus* flavonoids, such as naringin and hesperidin, that lack a methoxylated A-ring might have little or no lipid-lowering activity *in vivo* [76].

#### **4.7 Impact on hyperglycemia**

*Citrus* flavonoids (naringin, nobiletin hesperidin, and neohesperidin) reduced amylase-catalyzed starch digestion considerably. Furthermore, neohesperidin and naringin hindered only amylose digestion, but nobiletin and hesperidin inhibited both amylopectin and amylose metabolism. This research shows that *Citrus* flavonoids had an essential part in avoiding hyperglycemia development, in part by interacting with starch, improving hepatic metabolism and glycogen content while inhibiting hepatic gluconeogenesis [77]. Naringin, hesperidin, and nobiletin were also shown to have antidiabetic properties, perhaps through increasing insulin sensitivity or increasing hepatic gluconeogenesis in hyperglycemic mice [78]. According to one research, streptozotocin nicotinamide-induced experimental in diabetic rats, naringenin protects against diabetes by exerting antihyperglycemic and antioxidant properties [79]. Chronic naringenin therapy in diabetic animals might avoid functional alterations in vascular reactivity via a prostaglandin-independent and NO-dependent mechanism [80].
