PMID: 

Anat Sci Int. 2019 Apr 4. Epub 2019 Apr 4. PMID: 30949912

Abstract Title: 

The natural plant flavonoid apigenin is a strong antioxidant that effectively delays peripheral neurodegenerative processes.

Abstract: 

Oxidative stress contributes to the progression of neurodegenerative diseases of the central and peripheral nervous systems, including Alzheimer's disease, Parkinson's disease, stroke, and diabetic neuropathy. Despite the greater capability of peripheral nerves to regenerate compared with those in the brain or spinal cord, chronic oxidative stress leads to irreversible neurodegeneration in peripheral nerves. Thus, many efforts have been made to defend against irreversible peripheral nerve degeneration and oxidative stress. Numerous phytochemicals have been revealed as antioxidants which neutralize free radicals and reduce peripheral neurocellular damage. Among them, polyphenols alleviate neurodegeneration by interacting with reactive oxygen species. Apigenin is a polyphenol found in plant-derived foods, including parsley, thyme, celery, and chamomile tea. Apigenin has been reported to exert antioxidative effects by scavenging free radicals. In particular, apigenin has a neuroprotective effect against oxidative stress in neurological disorders, such as cerebral ischemia. However, to date, no studies have shown an association of the inhibitory effect of apigenin with peripheral nerve degeneration. In this work, we showed that apigenin has a neuroprotective effect against peripheral nerve degeneration according to four key phenotypes: axonal degradation, myelin fragmentation, trans-dedifferentiation, and proliferation of Schwann cells via Krox20- and extracellular signal-regulated kinase-independent processes. Thus, apigenin could be a good candidate to treat peripheral neurodegenerative diseases.

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PMID: 

Pancreas. 2019 May/Jun;48(5):711-718. PMID: 31091220

Abstract Title: 

Apigenin Decreases Acinar Cell Damage in Pancreatitis.

Abstract: 

OBJECTIVE: Chronic pancreatitis is the consequence of multiple episodes of recurrent acute pancreatitis (RAP). We hypothesized that apigenin can minimize the sequelae of RAP by limiting acinar cells' proinflammatory signaling pathways.METHODS: AR42J acinar cells were treated in vitro with transforming growth factorβ (TGF-β), apigenin, and other inhibitors. Dual luciferase reporter assay measured parathyroid hormone-related protein (PTHrP) promoter activity. MAPK/ERK pathway activity was assessed by immunoblotting and in vivo by immunohistochemistry with a cerulein-induced RAP mouse model. Nuclear factor κB nuclear localization was analyzed in vitro in cells stimulated with tumor necrosis factor α. Primary acini were isolated and treated with cerulein; interleukin 6 messenger RNA was measured comparing PTHrP wild-type and knockout mice.RESULTS: Apigenin and PD98059 each downregulated TGF-β stimulation of PTHrP P3 promoter activity. In a RAP mouse model, apigenin reduced pERK nuclear localization in acinar cells and preserved acinar cell architecture. Apigenin suppressed tumor necrosis factor α-mediated signaling by decreasing nuclear factor κ B nuclear localization and decreasedinterleukin 6 messenger RNA levels via a PTHrP-dependent mechanism.CONCLUSIONS: Apigenin reduced inflammatory responses in experimental models of RAP. The mechanisms mediating the actions of apigenin, in part, are owing to attenuation of PTHrP and TGF-β proinflammatory signaling.

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PMID: 

J BUON. 2019 Mar-Apr;24(2):488-493. PMID: 31127995

Abstract Title: 

Apigenin inhibits in vitro and in vivo tumorigenesis in cisplatin-resistant colon cancer cells by inducing autophagy, programmed cell death and targeting m-TOR/PI3K/Akt signalling pathway.

Abstract: 

PURPOSE: Colon cancer is one of the deadly malignancies and the second most frequent cancer in the world. The development of drug resistance and dearth of the viable drug options forms an obstacle in the treatment of colon cancer. Herein, the anticancer potential of Apigenin was examined against cisplatin-resistant colon cancer cells.METHODS: The proliferation rate of the cisplatin-resistant colon cancer cell line HT-29 was assessed by WST-1 assay. Autophagy was detected by electron microscopy. Apoptotic cell death was analysed by propidium iodide (PI) staining. Cell cycle analysis was performed by flow cytometry. Protein expression was determined by immuno blotting. Xenografted mice models were used for in vivo evaluation of Apigenin.RESULTS: The results showed that Apigenin could considerably inhibit the proliferation of colon cancer cells. The anticancer activity of Apigenin against the HT-29 colon cancer cells was found to be due to induction of autophagy and apoptosis. The Apigenin-triggered apoptosis and autophagy were also linked with alteration in the apoptosis and autophagy-related protein expression. Furthermore, it was found that Apigenin could inhibit the m-TOR/PI3K/AKT signalling pathway in the cisplatin-resistant colon cancer cells. The effects of Apigenin were also examined in vivo in xenografted mice models and it was revealed that Apigenin inhibited the growth of xenografted tumors.CONCLUSIONS: Taken together, these results indicate that Apigenin could inhibit the growth of cisplatin-resistant colon cancer cells in vitro and in vivo and may be used for the improvement of therapy of colon cancer.

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PMID: 

Aging (Albany NY). 2019 Jun 5 ;11(11):3668-3678. PMID: 31170089

Abstract Title: 

Apigenin inhibits growth and migration of fibroblasts by suppressing FAK signaling.

Abstract: 

The naturally occurring compound apigenin has many biological effects, including anti-inflammatory, antioxidative and anticancer effects. Although hypertrophic scar formation is a common surgical complication, there is still no good treatment for it. In the present study, we examined the effect of apigenin on hypertrophic scar. After isolating fibroblasts from human hypertrophic scars, we assess the effects of apigenin on fibroblast cell survival, apoptosis and migration. The results showed that apigenin dose-dependently inhibited the growth and migration of hypertrophic scar fibroblasts. By inhibiting FAK kinase activity and FAK phosphorylation, apigenin also inhibited activation of the FAK signaling pathway. Apigenin thus appears to inhibit the growth and migration of hypertrophic scar fibroblasts by inhibiting FAK signaling. This suggests apigenin could potentially provide a new option for the treatment of hypertrophic scars.

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PMID: 

J Exp Clin Cancer Res. 2019 Jun 10 ;38(1):246. Epub 2019 Jun 10. PMID: 31182131

Abstract Title: 

Targeting the SPOCK1-snail/slug axis-mediated epithelial-to-mesenchymal transition by apigenin contributes to repression of prostate cancer metastasis.

Abstract: 

BACKGROUND: Prostate cancer (PCa) is considered one of the most prevalent malignancy globally, and metastasis is a major cause of death. Apigenin (API) is a dietary flavonoid which exerts an antimetastatic effect in various cancer types. Sparc/osteonectin, cwcv, and kazal-like domains proteoglycan 1 (SPOCK1) is a crucial modulator of tumor growth and metastasis in cancers. However, the role and underlying regulatory mechanisms of SPOCK1 in the API-mediated antimetastatic effects of PCa remain unclear.METHODS: MTS, colony formation, wound-healing, and transwell assays were conducted to evaluate the effects of API on PCa cell proliferative, migratory, and invasive potentials. In vivo orthotopic bioluminescent xenograft model were employed to determine antitumor activity of API. PCa cells were transfected with either Snail-, Slug-, SPOCK1-overexpressing vector, or small hairpin (sh)SPOCK1 to determine the invasive abilities and expression levels of SPOCK1 and epithelial-to-mesenchymal transition (EMT) biomarkers in response to API treatment. Immunohistochemical (IHC) assays were carried out to evaluate the expression level of SPOCK1 in PCa xenografts and a PCa tissue array. Associations of SPOCK1 expression with clinicopathological features and prognoses of patients with PCa were analyzed by GEO or TCGA RNA-sequencing data.RESULTS: API significantly suppressed in vitro PCa cell proliferation, migration, and invasion and inhibited in vivo PCa tumor growth and metastasis. Moreover, survival times of animals were also prolonged after API treatment. Mechanistic studies revealed that API treatment resulted in downregulation of SPOCK1, which was accompanied by reduced expressions of mesenchymal markers and subsequent attenuation of invasive abilities of PCa cells. Overexpression of SPOCK1 in PCa xenografts resulted in significant promotion of tumor progression and relieved the anticancer activities induced by API, whereas knockdown of SPOCK1 had opposite effects. In clinical, SPOCK1 levels were higher in tumor tissues compared to non-tumor tissues, which was also significantly correlated with shorter disease-free survival in PCa patients.CONCLUSIONS: Levels of SPOCK1 increase with the progression of human PCa which suggests that SPOCK1 may act as a prognostic marker or therapeutic target for patients with PCa. Suppression of SPOCK1-mediated EMT signaling contributes to the antiproliferative and antimetastatic activities of API in vitro and in vivo.

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PMID: 

Int J Mol Sci. 2019 Jun 27 ;20(13). Epub 2019 Jun 27. PMID: 31252615

Abstract Title: 

Antitumor and Anti-Invasive Effect of Apigenin on Human Breast Carcinoma through Suppression of IL-6 Expression.

Abstract: 

Interleukin (IL)-6 plays a crucial role in the progression, invasion, and metastasis of breast cancer. Triple-negative breast cancer (TNBC) cell line MDA-MB-231 is known for its aggressive metastasis. Epithelial to mesenchymal transition (EMT) is a critical process in cancer metastasis. The positive correlation between IL-6 and EMT in tumor microenvironment is reported. We found significantly upregulated IL-6 expression in MDA-MB-231 cells. A blockade of IL-6 expression decreased levels of phosphorylated signal transducer and activator of transcription 3 (pSTAT3), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), phosphorylated protein kinase B (pAkt), and cell cycle-related molecules, including cyclin-dependent kinases (CDKs) and cyclins in MDA-MB-231 cells. A short-hairpin RNA (shRNA)-mediated blockade of IL-6 expression inhibited migration and N-cadherin expression and induced E-cadherin expression in MDA-MB-231 cells. Growth rate was slower for the tumors derived from IL-6 shRNA-treated MDA-MB-231 cells than for those derived from control shRNA-treated MDA-MB-231 cells. The expression of pSTAT3, phosphorylated extracellular signal-regulated kinase (pERK), PI3K, pAkt, snail, vimentin, and N-cadherin was significantly lower in tumors from IL-6 shRNA-treated MDA-MB cells. In addition, apigenin treatment significantly inhibited the growth of MDA-MB-231-derived xenograft tumors along with the protein expressions of pSTAT3, pERK, IL-6, PI3K, pAkt, and N-cadherin. Our results demonstrate that the anti-invasive effect of apigenin in MDA-MB-231-derived xenograft tumors is mediated by the inhibition of IL-6-linked downstream signaling pathway.

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PMID: 

Anticancer Agents Med Chem. 2019 07 3. Epub 2019 Jul 3. PMID: 31272364

Abstract Title: 

Apigenin-mediated Alterations in Viability and Senescence of SW480 Colorectal Cancer Cells Persist in The Presence of L-thyroxine.

Abstract: 

INTRODUCTION: Deregulation of Thyroid Hormones (THs) system in Colorectal Cancer (CRC) suggests that these hormones may play roles in CRC pathogenesis. Flavonoids are polyphenolic compounds, which possess potent antitumor activities and interfere, albeit some of them, with all aspects of THs physiology. Whether the antitumor actions of flavonoids are affected by THs is unknown. Therefore, we investigated the effects of Apigenin (Api), a well-known flavone, on some tumorigenic properties of SW480 CRC cells in the presence and absence of L-thyroxine (T4).METHODS: Cell viability was assessed by MTT assay. Flow cytometry and DNA electrophoresis were used to evaluate cell death. Cell senescence was examined by in situ detection ofβ-galactosidase activity. Protein expression was assessed by antibody array technique.RESULTS: While T4 had minimal effects, Api reduced cell growth and senescence by induction of apoptosis. Expression of anti-apoptotic and pro-apoptotic proteins were differentially affected by Api and T4. Survivin, HSP60 and HTRA were the most expressed proteins by the cells. Almost all Api-induced effects persisted in the presence of T4.CONCLUSION: These data suggest that Api may inhibit CRC cell growth and progression through induction of apoptosis rather than cell necrosis or senescence. In addition, they suggest that T4 has minimal effects on CRC cell growth, and is not able to antagonize the anti-growth effects of Api. Regardless of the treatments, cells expressed high levels of survivin, HSP60 and HTRA, indicating that these proteins may play central roles in SW480 CRC cell immortality.

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PMID: 

Life Sci. 2019 Jul 4:116623. Epub 2019 Jul 4. PMID: 31279781

Abstract Title: 

Apigenin attenuates doxorubicin induced cardiotoxicity via reducing oxidative stress and apoptosis in male rats.

Abstract: 

AIMS: Doxorubicin, an antibiotic belonging to anthracycline family, has been used for treatment of malignancies. Cardiotoxicity is the main adverse effect of doxorubicin. Apigenin, as a flavonoid, has antioxidant, anti-inflammatory and anti-tumoral properties. The aim of this study was the assessment of any protective effect of apigenin on cardiotoxicity induced by doxorubicin.MAIN METHODS: 40 male Wistar rats were randomly divided into 4 groups: control, cardiotoxicity (DOX), apigenin treated group (DOX + Api 25) and apigenin group (Api 25). At the end of the experiment, the markers of cardiac function (%EF, %FS, LVIDs, LVIDd), cardiac and liver injury (LDH, CK-MB, cTn-I, ALT, and AST), cardiac apoptosis (Bax, Bcl-2 and Caspase3), cardiac oxidative stress (SOD, GSH, MDA) and cardiac fibrosis were measured.KEY FINDINGS: Apigenin improved cardiac functional parameters. The levels of cardiac and liver injury markers were significantly decreased in DOX + Api 25 compared to DOX. Treatment with apigenin caused significant decrease in percentage of cardiac fibrosis in comparison with DOX. Apigenin in DOX + Api 25 group led to significant decrease in apoptotic proteins (Casp3, Bax) and a significant increase in anti-apoptotic proteins (Bcl2).In apigenin treatment groups, SOD levels significantly increased while a significant decrease was observed in MDA. The amount of GSH in DOX + Api 25 had no significant change in comparison to control and Api 25 groups.SIGNIFICANCE: Apigenin reduced cardiac injuries induced by DOX through anti-fibrotic, antioxidant and anti-apoptotic properties. It seems that apigenin prevents cardiac injuries and improves cardiac function.

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PMID: 

In Vivo. 2019 Jul-Aug;33(4):1133-1141. PMID: 31280202

Abstract Title: 

Apigenin Exerts Anti-inflammatory Effects in an Experimental Model of Acute Pancreatitis by Down-regulating TNF-α.

Abstract: 

BACKGROUND/AIM: This study investigated the anti-inflammatory effect of apigenin in an experimental model of acute pancreatitis. Inflammatory response was reflected by tissue expression of the cytokine TNF-α coupled with histological examination.MATERIALS AND METHODS: Wistar rats were divided into three groups: Sham-group animals underwent laparotomy only, without any other interventions. Control-group animals underwent laparotomy and bilio-pancreatic duct ligation to induce pancreatitis without apigenin administration. Apigenin group animals were further treated with apigenin. Euthanasia was performed at 6, 12, 24, 48 and 72 h post-operatively.RESULTS: Over-expression of TNF-α in relation to postoperative time was observed in the control group (p

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PMID: 

Med Sci Monit. 2019 Jul 16 ;25:5280-5288. Epub 2019 Jul 16. PMID: 31309931

Abstract Title: 

Apigenin Protects Against Renal Tubular Epithelial Cell Injury and Oxidative Stress by High Glucose via Regulation of NF-E2-Related Factor 2 (Nrf2) Pathway.

Abstract: 

BACKGROUND Diabetic nephropathy (DN) is a disease characterized by oxidative stress and apoptosis of renal tubular epithelial cells driven by hyperglycemia. Apigenin is a flavonoid compound that possesses potent anti‑apoptotic properties. The present study aimed to explore the protective effects and underlying mechanisms of apigenin on renal tubular epithelial cells exposed to hyperglycemia. MATERIAL AND METHODS Human renal epithelial cell HK-2 were incubated to D-glucose to establish in vitro DN model. The cell viability, lactate dehydrogenase (LDH) release, apoptosis and oxidative stress were evaluated. qRT-PCR was performed to determine the mRNA levels of NF-E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Western blot analysis was performed to measure the protein expressions of Nrf2. RESULTSIn HK-2 cells, high glucose reduced cell viability in a concentration- and time-dependent manner. Apigenin suppressed the decrease in cell viability and increase in supernatant LDH release at 100 and 200 μM after 48-h treatment. Apigenin reduced apoptotic rate and pro-inflammatory cytokines production. Apigenin suppressed oxidative stress and increased mRNA expressions of Nrf2 and HO-1. Inhibition of Nrf2 using small interfering RNA (siRNA), or cotreatment with LY294002, an inhibitor of PI3K/Akt, abolished the protective effect on high glucose-induced injury, oxidative stress, and pro-inflammatory cytokines production by apigenin. LY294002 also attenuated the increase in Nrf2 protein by apigenin in high glucose-treated HK-2 cells. CONCLUSIONS Apigenin protects renal tubular epithelial cells against high glucose-induced injury through suppression of oxidative stress and inflammation viaactivation of the Nrf2 pathway.

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