Flavonoids as Potential Anti-Inflammatory Molecules

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1		Jameel Al-Khayri	--	3570	2022-05-23 14:49:48	\|
2	format	Jason Zhu	Meta information modification	3570	2022-05-24 03:08:48	\|

This entry is adapted from the peer-reviewed paper 10.3390/molecules27092901

Hydroxylated polyphenols, also called flavonoids, are richly present in vegetables, fruits, cereals, nuts, herbs, seeds, stems, and flowers of numerous plants. They possess numerous medicinal properties such as antioxidant, anti-cancer, anti-microbial, neuroprotective, and anti-inflammation. Studies show that flavonoids activate antioxidant pathways that render an anti-inflammatory effect. They inhibit the secretions of enzymes such as lysozymes and β-glucuronidase and inhibit the secretion of arachidonic acid, which reduces inflammatory reactions. Flavonoids such as quercetin, genistein, apigenin, kaempferol, and epigallocatechin 3-gallate modulate the expression and activation of a cytokine such as interleukin-1beta (IL-1β), Tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-8 (IL-8); regulate the gene expression of many pro-inflammatory molecules such s nuclear factor kappa-light chain enhancer of activated B cells (NF-κB), activator protein-1 (AP-1), intercellular adhesion molecule-1 (ICAM), vascular cell adhesion molecule-1 (VCAM), and E-selectins; and also inhibits inducible nitric oxide (NO) synthase, cyclooxygenase-2, and lipoxygenase, which are pro-inflammatory enzymes.

anti-inflammation flavonoids Mechanism

1. Mechanism of Action of Flavonoids

Although the exact mechanism of flavonoids has yet to be studied, it is known that it exhibits anti-inflammatory properties by targeting many pathways. Different flavonoids have their unique way of reducing inflammation; many studies have concentrated on different types of flavonoids and their mode of action.

Quercetin showed its anti-inflammatory activity by inhibiting the c-Jun N terminal kinase and extracellular signal-regulated kinase, thereby inhibiting MAPK and AP-1 and NF-κB activity. Catechins also inhibited MAPK, AP-1, and NF-κB by inhibiting c-Jun N terminal kinase and p38 kinase. This implies that flavonoid targets the MAPK pathway and AP-1 transcription factor for decreasing inflammatory reactions ^[1]. It is also reported to decrease neutrophil recruitment and modulate actin polymerization in neutrophils ^[2]. Quercetin also could activate cyclic guanosine monophosphate (cGMP)/Protein kinase G (PKG)/adenosine triphosphate (ATP)-sensitive potassium channels pathway, leading to the hyperpolarization of nociceptive neurons, similarly to morphine and dipyrone, which is required in pain reduction ^[3]^[4]. This also reduced protein kinase C epsilon type (PKCε) and transient receptor potential cation channel subfamily V member 1 (TRPV1) in the spinal cord and DRG of paclitaxel-induced peripheral neuropathy rats and mice ^[5]. In quercetin and myricetin, the 3′-OH of the B ring interacts with PI3K and thereby attenuates the PI3K/Akt pathway^[2].

Apigenin reduced the levels of microRNA (miR33) and Toll-like receptor (TLR-4), NF-κB p65 pathway, leading to an increase in the ATP binding cassette A1 (ABCA1), which reduced lipid accumulation and also lessened muscle cells and macrophages in the atherosclerosis region of LPS-challenged apo-/- mice ^[6]. In TNF-α-treated human umbilical vein endothelial cells (HUVECS), isoliquiritigenin reduced the expression of NF-k-B inhibitor alpha (IkB-α), E-selectin, THP-1 monocyte adhesion, VCAM-1, and platelet endothelial cell adhesion molecule-1 (PECAM-1) by inhibiting NF-κB. It was also observed in the angiotensin II-induced hypertensive model; isoliquiritigenin reduced TNF-α and IL-1β; hence, extracellular deposition was reduced. In addition, the apoptosis induced by oxidative stress via nuclear factor E2-related factor (Nrf2) and NF-κB pathway was attenuated^[6].

Rutin decreased the levels of IL-6 and TNF-α by down-regulating NF-κB and ERK1/2 pathways; this also decreased VCAM-1 and ICAM-1 expressions in the high mobility group box 1 (HMGB) in induced HUVECS ^[6]. This also activated cGMP/PKG/ATP-sensitive potassium channels pathway and Nrf2/hemeoxygenase (HO) pathway and inhibited the NF-κB pathway to reduce pain and pro-inflammatory cytokines TNF-α and IL-1β^[2]^[7].

Silymarin reduced hypoxia-inducible factor-1α (HIF-1α) and inducible nitric oxide synthase (iNOS) by inhibiting NF-κB. The major component of silymarin, silibinin, is known to decrease epidermal growth factor receptor (EGFR), thereby reducing hypertrophy. In a study conducted by Iio et al., they showed that quercetin and baicalein inhibited the glyoxalase-I enzyme, which is known to have inflammatory properties by releasing histamine ^[8]. Luteolin, quercetin, kaempferol, and apigenin are shown to reduce the secretion of glucuronidase-1 and lysozyme enzymes from neutrophils ^[9].

Genistein is shown to affect the tyrosine kinase pathway and exhibit anti-inflammatory properties. They inhibited the activity of p56 lck, a T-cell protein kinase involved in IL-2 and IL-2R expression, hence reducing the cytokines in T-cells stimulated by phytohaemagglutinin (PHA)/phorbolmyristate acetate (PMA) ^[9]. Luteolin reduces inflammatory responses in alveolar macrophages by attenuating NF-κB and AP-1 pathways. Genistein, kaempferol, quercetin, and daidzein not only inhibited NF-κB also inhibited the Signal transducer and activator of transcription 1 (STAT-1) activation, thereby having higher potency to decrease NO synthesis ^[9].

Apigenin was observed to alleviate interferon-gamma (IF-γ) in vivo. It was also shown that flavonoids reprogram a pro-inflammatory response to anti-inflammatory in LPS- or IF-γ induced cells ^[10]. Flavonoids also enhance natural killer (NK) cells and cytotoxic T cells activity. A study conducted by Ruiz-Iglesias et al. (2020) shows that hesperidin modulated systemic immunity in rats that underwent high training and exercise ^[11]. Fisetin inhibits the phosphorylation of MAPK and translocation of NF-κB to reduce cytokine secretion in phorbol-12-myristate-13-acetate plus calcium ionophore (PMACI) induced rats. Luteolin-8-C-fucopyranoside (LU8C-FP) also targets NF-κB and MAPKs pathways to reduce IL-6 ^[12]. In a study by Kang et al. (2010), luteolin from Lonicera japonica Thunb. inhibited ERK1/2, c-Jun N-terminal kinases (JNK)1/2, and NF-κB pathway and also inhibited IL-6, TNF-α, and COX2 expression^[13]. Andrographolide, a flavonoid isolated from Andrographis paniculata (Burm. f.) Nees, inhibited NF-κB via the STAT3 pathway in LPS-induced RAW264.7 cells ^[14]. Kaempferol present in Folium eriobotryae decreased iNOS expression and NF-κB activation ^[15]. Daidzein, genistein, isorhamnetin, kaempferol, quercetin, naringenin, and pelargonidin reduced iNOS expression and attenuated NF-κB activity. Daidzein, genistein, kaempferol, and quercetin also inhibited the STAT-1 pathway ^[16].

Vitexin could attenuate the receptor activator of nuclear factor kappa-Β ligand (RANKL)-induced activation of MAPK and NF-κB pathway and also the activation of the Nrf2/HO-1 pathway ^[17]. It further inactivated transient receptor potential cation channel subfamily V member 1 (TRPV1) expression and thereby could reduce pain in capsaicin-induced pain in in vivo studies ^[18]. Oroxylin A attenuates calcium STAT pathway, thereby reducing NO and cytokines in LPS induced mouse model ^[19].

In addition, flavonoids are also potent antioxidant molecules that impart anti-inflammatory activity. They induce transcription factors such as Nrf2, a antioxidant responsive element (ARE), which mediates the expression of antioxidant proteins. Nrf2 suppressed the expression of MCP-1 and VCAM-1 and thereby decreased monocyte adhesion and transmigration to endothelial cells, which reduced MAPK and p38 expression and inhibited the formation of atherosclerotic lesions in mice and rabbits ^[20]. Oroxylin A activates the Nrf2/ARE pathway and inhibits NF-κB ^[19]. Flavonoids also induce enzymes such as hemeoxygenases, superoxide dismutase, γ-glutamylcysteine synthetase, glutathione peroxidase, and glutathione reductase, which are antioxidants ^[1]. Many diseases such as Alzheimer’s disease, rheumatoid arthritis, type II diabetes, and some types of cancer are induced by hyper-inflammatory responses. Cytokines such as IL-1β, IL-6, and TNF-α are observed to be in high levels in these conditions ^[12]. Hence the anti-inflammatory activity of flavonoids helps in preventing many health disorders.

2. Effects of Flavonoids in Cardiovascular Disease

Cardiovascular diseases (CVDs) include hypertension, myocardial infarction, and atherosclerosis and are the major causes of death in most the developed countries ^[9]^[12]. Chronic inflammation plays a vital role in the beginning and progression of CVDs ^[6]. The activity of flavonoids against inflammation thereby shows beneficial effects in reducing CVDs. Quercetin, a flavonoid, inhibits the NF-κB and Akt pathways induced by LPS, resulting in a reduced level of IL-6, TNF-α, and IL-1β in neonatal rat cardiac fibroblast. Luteolin and rutin enhanced NO in vivo sodium fluoride-induced hypertensive model, thereby reducing kidney injury marker-1, NF-κB, and cardiac troponin-1 (cTn) and also reduced blood pressure. In neonatal rat cardiac myocytes, luteolin reduced the degradation of IκB-β, NF-κB translocation, and DNA binding; hence, TNF-α levels were maintained low ^[6].

Fisetin downregulates NF-κB and receptors for advanced glycation end products and, hence, reduces myocardial injury markers, TNF-α, IL-6, lactate dehydrogenase (LDH), creatine kinase-muscle/brain (CK-MB) in blood, and normalised the ultrastructure and histology of the heart. It also balanced anti- and pro-apoptotic genes and anti- and pro-oxidants in the myocardium. As NF-κB expression decreased, IL-6, TNF-α, and IL-1β levels are low; hence, the occurrence of diabetic cardiomyopathy decreases and maintains normal heart morphology and low-level cardiac function markers such as CK-MB, LDH, cTn ^[6]. In carfilzomib-induced cardiotoxicity rat, rutin up-regulated IF-κB-α and, hence, down-regulated NF-κB, which attenuated the heavy chain of β-myosin, reducing B type natriuretic peptide mRNA expression and, hence, providing protection from myocardial hypertrophy ^[21].

Chrysin, one of the flavones, is known to suppress vascular endothelial growth factors (VEGF), Akt, and NF-κB and MAPK pathway, which prevented rats from doxorubicin-induced cardiomyopathy ^[6]. In another study, chrysin reduced the right ventricular systolic pressure and mean pulmonary artery pressure and also decreased the expression of collagen I, collagen III, and NF-κB in a monocrotaline-induced pulmonary arterial hypertension ^[22]. Chrysin also reduced hemodynamic and ventricular dysfunction and myocardial ultrastructure damage in isoprenaline-induced myocardial injury in a rat model. It has been observed that chrysin increases peroxisome proliferator-activated receptor gamma (PPAR-γ), whereas it inhibits TNF-α and NF-κB. Studies have shown that chrysin could decrease fibrosis in interstitial and perivascular regions and collagen expression in myocardial infarction in rat models ^[6]^[23]. Genistein reversed the atherosclerotic damage caused by angiotensin-induced NF-κB, CRP, MMP-9, the phosphorylation of p38, and ERK1/2, and it also increased PPAR-γ ^[6].

3. Effect of Flavonoids in Type 2 Diabetes

Diabetes mellitus is one of the extremely common metabolic disorders in the growing world ^[24]. The disease is characterised by increased blood glucose levels leading to health complications, including nephropathy, CVDs, retinopathy, etc. ^[24]. The cause of the disease is either lower insulin production due to genetic mutation or hereditary, modification in habitual eating patterns, or insulin resistance caused by over secretion of insulin or chronic inflammations leading to autoimmune disorders ^[24]. Flavonoids not only act on the inflammatory pathway but also maintain blood glucose levels and reduce the risk of diabetes-related disease ^[24]. Quercetin showed an anti-inflammatory response in hypertriglyceridemia-related acute pancreatitis in rats by reducing TNF-α, IL-1β, NF-κB, and IL-6, hence reducing histopathological damage ^[12]. It is also shown to enhance the 5’ adenosine monophosphate-activated protein kinase (AMPK) pathway, thereby stimulating GLUT4 expression ^[24]. Animal studies have shown that a reduction in blood glucose levels was observed when animals were treated with 10, 25, and 50 mg/kg of body weight quercetin ^[25]. In a study, Chinese-consuming quercetin had lower chances of obtaining type 2 diabetes. It was also observed to reduce lipid peroxidation, glucose absorption by GLUT2, and a reduction in insulin-dependent PI3K activation was also observed. The regulatory effect on NF-κB also stimulated glucose-induced insulin secretion. They also inhibited tyrosine kinase inhibitors, which prevented diabetes ^[24].

Quercetin reduced glucokinase GLUT4 activity and also decreased hepatic gluconeogenesis and glycogenolysis and enhanced cell survival-related genes and the proliferation of liver in streptozotocin (STZ)-induced diabetic rats. Quercetin with sitagliptin improved β-cell function, glycemic control, metabolic profile, oxidative, and inflammatory activities in STZ-induced diabetic rats ^[24]. Rutin is one of the most effective flavonoids against diabetes. It is shown to reduce fasting blood glucose, improve glucose tolerance, and also reduce serum lipids more effectively. It is also observed to activate hepatic enzymes hexokinase, reduce gluconeogenesis, and improve lipid metabolism. Rutin treatment reduces glycosylated haemoglobin and fasting blood glucose levels in STZ-induced diabetic rats. Rutin was also observed to reduce caspase-3 activity by enhancing BCL-2 activity in the diabetic retina ^[24]^[26]. Kaempferol enhances adenosine monophosphate (AMP)-induced protein expression; suppresses apoptosis, thereby improving cellular viability and function. In a study, kaempferol decreased the RhoA/Rho kinase-induced pro-inflammatory pathway in normal rat kidney-52E cells (NRK-52E) and renal proximal tubule epithelial cells (RPTEC) ^[24]. Eriodictyol decreased the glucose-stimulated oxidative stress, inflammation, and cell viability by regulating the Nrf-2/HO-1 pathway. Hesperidin improved the Klotho/fibroblast growth factor-23 (FGF-23) pathway, thereby reducing insulin toxicity in liver cells. Apigenin regulated MAPK-NF-κB-TNF-α and transforming growth factor-beta-1 (TGF-β1)-MAPK-fibronectin signalling in STZ-induced diabetic nephropathy. Chrysin’s anti-inflammatory activity prevented STZ-induced diabetic mice from diabetic neuropathy. Baicalein activates the AMPK pathway and reduces insulin resistance and also modulates the PI3K/Akt pathway to reduce oxidative stress and inflammation in diabetic cardiomyopathy. They also regulate HMGB1/TLR4/NF-κB signalling, decreasing hepatic inflammation in diabetic mice ^[24]. Hence, the anti-inflammatory effect of flavonoids shows a protective effect against diabetic-induced disorders.

4. Effects of Flavonoids in Rheumatoid Arthritis (RA)

Rheumatoid arthritis, an autoimmune disease caused by the infiltration of immune cells such as T-cells, macrophages, fibroblasts, and B cells in the synovial membrane, leading to the destruction of joints and, hence, a loss of its function. The anti-inflammatory activity of flavonoids is known to have a role in reducing pain and inflammation in joints. Oroxylin A at 10 mg/kg body weight in type II collagen-induced arthritis (CIA) mice model reduced Th17 and enhanced T_reg cells and also inhibited TNF-α, IL-6, IL-17, and IL-1β; it also suppressed ERK1/2, MAPK, and NF-κB pathways ^[27]^[28]. Baicalin enhances Foxp3+ and T_reg, inhibits Th17 differentiation in vitro and in vivo ^[29]. In another study, baicalin reduced splenic Th17 cells in murine adjuvant-induced arthritis. Baicalin also reduced CIA in rat synovium via the reduction of IL-1β and TNF-α ^[30]. Baicalin containing UP446 could reduce RA by reducing TNF-α, IL-6, IL-17, and IL-1β. The combinations of flavonoids derived from Scutellaria roots are able to reduce PGE2 ^[31]. Icariin, a prenylated flavonoid, blocks the STAT3 pathway, hence reducing IL-17 and Th17, which reduces the cartilage and bone degradation in CIA mice ^[32]. Apple is rich in flavonoids such as procyanidin and condensed tannins. It was shown that the supplementation of condensed tannins from apples showed delayed arthritis symptoms in DBA1/J mice with CIA ^[33]. It was also observed in a study that procyanidin in apples could reduce IFN-γ and IL-17 ^[31]. Grape seed extract containing proanthocyanidin reduced TNF-α, thereby reducing CIA. It was also observed to reduce osteoclastogenesis in vitro ^[34].

5. Effects of Flavonoids in Neurodegenerative Diseases

Flavonoids are also known to have neuroprotective properties. Flavonoids interact with glial signalling and other cellular pathways, hence enhancing neuronal function and also impacting neuronal regeneration ^[35]. Flavonoids in blueberry activate the ERK pathway, which enhances cAMP response element-binding protein (CREB); hence, the brain-derived neurotrophic factor (BDNF) is up-regulated in the hippocampus of a rat. CREB activation by flavonoids is impactful in the regulation of memory and synaptic plasticity. Catechins are used in the green tea-modulated protein kinase A/CREB pathway to reduce amyloid beta 42 (Aβ₄₂) oligomers. Flavonoids also stabilise Nrf-2, hypoxia-inducible factor-1, to regulate PPAR-γ and the activation of PPAR-γ coactivator 1-alpha (PGC-1α), to reduce oxidative stress, and improve mitochondrial dysfunction; thereby, Alzheimer’s progression is attenuated. Quercetin binds to the ATP-binding pocket of PI3K and inhibits its activity, thereby activating pro-survival pathways. Hesperetin is observed to activate the Akt/protein kinase B pathway to up-regulate pro-survival signals in cortical neurons. ECG elevates the phosphorylation of CREB via ERK and PI3K pathway, which enhances glutamate receptor-2; hence, neurotransmission, synaptogenesis, and plasticity are modulated. Wogonin reduces Aβ accumulation in SH-SY5Y cells via the mammalian target of rapamycin (mTOR) pathway ^[35].

Apigenin decreased mRNA expression levels of TNF-α, IL-1β, and IL-6 in subarachnoid haemorrhage rats ^[12]. Baicalin reduced Th17 and Th1 cell differentiation via STAT/NF-κB signalling, thereby alleviating the severity of autoimmune encephalomyelitis (EAE) ^[36].

6. Effects of Flavonoids in Retinal Degeneration

Retinal degeneration due to mutations, excessive light exposure, and also inheritance is the major cause of blindness. Rhodopsin and cone opsins are major photoreceptors that are required for sight. Excessive light results in the degeneration of photoreceptors by enhancing ROS and pro-inflammatory cytokines and induces apoptosis. Therapeutics aims to reduce inflammation, oxidative stress management, and anti-apoptotic pathways acceleration. Many flavonoids are shown to have all these properties. It was observed that the intraperitoneal injection of quercetin or myricetin at 20 mg/kg for ATP-binding cassette subfamily member 4 (Abca4^−/−) retinol dehydrogenase 8 (Rdh8^−/−) mice 30 min before exposure to 10,000 Lux light for 45 min showed a protective effect against light-induced retinal degeneration by maintaining retinal morphology and function ^[37]. The treatment of quercetin or myricetin at 20 mg/kg to BALB/c mice also showed a positive effect on retinal protection. It was observed that dimethyl sulfoxide (DMSO)-treated mice activated microglia formation and inflammatory reactions after exposure to light; in contrast, in quercetin or myricetin-treated mice, the attenuation of these pathways was observed. The functions of DMSO-treated and light-exposed mice were recovered by flavonoid treatment. Myricetin could reduce ROS in light-induced Abca4^−/−Rdh8^−/− mice but could not eliminate it completely. However, inflammatory cytokines such as the CC motif chemokine ligand-2 (CCL2), IL-6, and TNF-α were completely decreased by the treatment of either quercetin or myricetin in light-induced Abca4^−/−Rdh8^−/−mice. It was also observed that flavonoids could halt the expression of BAX via balancing BAX/BCL-2 in Abca4^−/−Rdh8^−/− mice ^[37].

Fisetin is also known to enhance myocyte enhancer factor 2c (Mef2c) ^[38], which induces the gene expression of photoreceptors. It was also shown in a study that the flavonoid-treated cells increased the gene expression of rhodopsin, M, and S opsin by 2–3, 4–5, and 3.5–4.5-fold three days after illumination and further increased on the seventh day ^[37].

7. Effects of Flavonoids in Inflammatory Bowel Disease (IBD)

Inflammatory bowel disease (IBD) represents a group of intestinal disorders that cause the prolonged inflammation of the digestive tract. This disease is characterised by abdominal bleeding, pain, diarrhoea, and loss of appetite ^[39]. Flavonoids show a beneficial effect in reducing inflammation. Rutin was able to reduce cytokines such as IL-1β and reduce inflammation in the colon in trinitrobenzene sulfonic acid (TNBS) induced colitis. It has been found that 0.1% of rutin in the diet for two weeks reduced the dextran–sulphate sodium (DSS)-induced colitis ^[39]. Quercetin reduced iNOS expression via the NF-κB pathway in DSS-induced colitis. Quercetin of 50–100 mg/kg maintained the GSH levels in acetic acid-induced colitis. Morin also reduced intestinal inflammation by acting on colonic leukotriene B4 (LTB4), IL-1β, and NO. Kaempferol inhibits the NF-κB pathway to reduce IL-6, IL-1β, COX2, NOS, TNF-α, and reduces DSS-induced colitis ^[40]. Isoflavones act as oestrogen receptors and use signalling to reduce TNBS-induced colitis. Fermented soy gram, consisting of isoflavones, down-regulated IL-1β and up-regulated IL-10; hence, the permeability of intestinal cells decreased in TNBS-induced colitis. Isoflavones also reduced IL-8 via TNF-α inhibition in Caco-2 cell lines. Genistein is also known to mimic oestrogen and reduce IBD symptoms. Moreover, genistein inhibited MPO and COX2 activity via the NF-κB pathway. Daidzein is one of the isoflavones that reduces IL6-, IL-8, IL-12, INF-γ, and up-regulates IL-10 in mesenteric lymph node cells in DSS-induced colitis ^[40].

Naringin decreased xanthine oxidase, alkaline phosphatase, MPO, malondialdehyde (MDA), and NO. They also downregulated iNOS, ICAM-1, MCP-1, IL-6, MIP-2, PGE₂, INF-γ, and IL-17A. This reduced DSS-induced colitis. Hesperidin also reduced colitis by attenuating MDA, MPO, and IL-6. Anthocyanins also show anti-inflammatory properties and reduce pro-inflammatory cytokines. Anthocyanins reduce IBD by minimising the expression of IL-6, IL-9, INF-γ, MPO, TNF-α, IL-1β, IL-17A, iNOS, and COX2. Apigenin and luteolin decreased IBD by regulating TNF-α, IL-1β, iNOS, and COX2 expression. Luteolin was also observed to reduce CD4⁺ T cell infiltration. Diosmin acted on LTB4 MPO to increase GSH levels. Wogonin and tangeretin increased claudin-1 zonula occluden-1 in the tight junctions. They also reduced IL-6, IL-1β, IL-8, iNOS, and COX2; and TLR4, MyD88, TGF-β-activated kinase 1 (TAK1), IL-23, and TNF-α expression. Tangeritin also decreased T helper cells in Th1 and Th17 differentiation ^[40].

8. Effect of Flavonoids in Cancer Treatment

Inflammation is responsible for controlling many cellular pathways, for which its unregulated expression leads to cancer. Hence, inflammation is a hallmark of cancer initiation and progression. The anti-inflammatory property of flavonoids also reduces cancer progression; hence, flavonoids show anti-cancer activities as well. Hesperidin was seen to decrease cell viability in the C6 glioma cell line ^[41]. Flavonoids are known to inhibit TNF-α, which otherwise would induce MCP-1/CCL2 release; this further enhances the infiltration of tumour-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), T_regs, metastasis-associated macrophages (MAMs), tumour-associated neutrophils (TANs), and Th17 cells, which are required for maintaining tumour microenvironments. Flavonoids also inhibit fibroblast differentiation into cancer-associated fibroblast by targeting TGF-β2 ^[42]. In a study by Hou et al. (2019), flavonoids target TNF-α, and IL-1β to reduce inflammation and, hence, inhibit recurrent colitis and colorectal cancer ^[43]. The flavonoids are also known to attenuate many signalling pathways relating to inflammation and cell proliferation, which include MAPK, NF-κB, ERK1/2, mTOR, PI3K, and Akt pathways. Flavonoids are studied to decrease C-X-C motif chemokine receptor 4 (CXCR4) expression, which reduces metastasis. It also modulates the Integrin-linked protein kinase (ILK)/Yes1-associated transcriptional regulator (YAP) pathway to reduce Epithelial-mesenchymal transition (EMT) and metastasis ^[42]. Ageratum conyzoides L. showed a cytotoxic effect against mouse leukaemia cells and human non-small lung cancer cells ^[44]. It also inhibited the growth of glioblastoma cell lines and prostate cancer cell lines ^[45]^[46]. Flavonoids in A. conyzoides inhibit the proliferation of HeLa cells by inducing S phase arrest in the cell cycle. They also induced apoptosis in HeLa cells ^[45]. Many flavonoids reportedly arrested the cell cycle at G0/G1 phase or G2/M phase transitions ^[47]. Flavonoids from Chinese bayberry induced G1 phase arrest in ovarian cancer cells ^[48]. The flavonoids of Citrus platymamma Hort.et Tanaka showed the growth inhibition of A549 human lung cancer cells by arresting the cell cycle at G2/M phase ^[49]. Licochalcone 2′,4′-Dihydroxy-6′-methoxy-3′,5′dimethylchalcone is the flavonoid that enhanced intracellular ROS levels to activate apoptotic pathway in bladder and hepatocellular cancer cells ^[50]^[51]. Further reports suggest that luteolin and quercetin could attenuate EMT, thereby reducing the progression of cancer in squamous carcinoma cells ^[52]. Isoliquiritigenin, a flavonoid from licorice, inhibited EMT in ovarian cancer cells ^[53]. In a study, cells treated with flavonoid from A. Conyzoides showed enhanced E-cadherins and reduced N-cadherins and vimentin in xenograft tumours, thereby inhibiting invasion and migration of HeLa cells ^[45].

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Subjects: Agriculture, Dairy & Animal Science; Biotechnology & Applied Microbiology; Food Science & Technology

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Sahana G R

FATIMA MOHAMMED ALESSA

Muneera Al-Mssallem

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