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The stimulator of interferon genes (STING) signaling pathway is crucial for the pathogenesis of autoimmune and inflammatory disorders, including acute lung injury (ALI). Apigenin (4 ′ ,5,7-trihydroxyflavone) is a natural flavonoid widely found in fruits, vegetables, and Chinese medicinal herbs that exhibits a range of pharmacological effects, such as antibacterial and anti-inflammatory activities. However, the efficacy of apigenin in STING pathway-mediated diseases remains unclear. Accordingly, this study screened Chinese medicines to identify potent agents that reduced the synthesis of type I interferons (IFNs). The results revealed apigenin as a potent compound with low cytotoxicity that markedly reduced the synthesis of type I IFNs in response to STING pathway agonists. Besides, apigenin markedly suppressed innate immune responses triggered by the STING agonist SR-717. Mechanistically, apigenin downregulated IFN beta 1 (IFNB1) expression mediated by the STING pathway via dose-dependent inhibition of STING expression, reduction of dimerization, nuclear translocation of phosphorylated IRF3, and disruption of the association between STING and IRF3. Moreover, apigenin effectively mitigated pathological pulmonary inflammation and lung edema in lipopolysaccharide (LPS)-induced ALI in mice. Apigenin further strongly attenuated the hallmarks of immoderate inflammation (interleukin (IL)-6, IL-1 β , and tumor necrosis factor α) and innate immune responses (IFNB1, C-X-C motif chemokine ligand 10, and IFN-stimulated gene 15) by preventing the activation of the STING/IRF3 pathway both in vitro and in vivo. Importantly, SR-717 significantly reversed the inhibitory effects of apigenin in LPS-induced THP1-BlueTM ISG macrophages. Collectively, apigenin effectively alleviated innate immune responses and mitigated inflammation in LPS-induced ALI via inhibition of the STING/IRF3 pathway. These findings suggest the potential of apigenin as a prophylactic and therapeutic candidate for managing STING-mediated diseases. [ABSTRACT FROM AUTHOR]

Background: Apigenin has been reported to exhibit anti-inflammatory and anti-oxidative activities. This study aimed to investigate the protective role of Apigenin on chemotherapy-induced peripheral neuropathy (CIPN). Methods: CIPN mouse model was established using Paclitaxel treatment. Hot plate and tail prick latency tests were performed to examine the allodynia and hyperalgesia behaviors. Antiinflammatory and anti-oxidative effects of Apigenin on CIPN were determined by enzyme-linked immunosorbent (ELISA) assay, Western blot, and qRT-PCR. Nuclear recruitment of nuclear factor erythroid 2-related factor 2 (NRF2) was analyzed to evaluate the underlying mechanisms of the protective effects of Apigenin. Results: Apigenin significantly alleviated CIPN-induced nociceptive behaviors of CIPN mice. It also decreased the TNF-α and IL-1β levels, suppressed oxidative stress and inflammation in the surgical spinal cord tissues. Mechanistically, Apigenin altered the pro-inflammatory and anti-inflammatory phenotypes ratio of microglia through promoting the nuclear recruitment of NRF2 and activating the NRF2/Antioxidant Response Element (ARE) signaling pathway. Conclusions: In summary, Apigenin relieves CIPN by regulating microglia activation and polarization, which provides a potential therapeutic strategy for CIPN treatment. [ABSTRACT FROM AUTHOR]

Apigenin is a plant flavone proven with biological properties such as anti-inflammatory, antioxidant, and antimicrobial effects. This study, it was aimed to examine the possible anti-inflammatory, antioxidant, and neuroprotective effects of apigenin in the setting of the mild traumatic brain injury (TBI) model. Wistar albino male rats were randomly assigned to groups: control (n = 9), TBI (n = 9), TBI + vehicle (n = 8), and TBI + apigenin (20 and 40 mg/kg, immediately after trauma; n = 6 and n = 7). TBI was performed by dropping a 300 g weight from a height of 1 m onto the skull under anesthesia. Neurological examination and tail suspension tests were applied before and 24 h after trauma, as well as Y-maze and object recognition tests, after that rats were decapitated. In brain tissue, luminol- and lucigenin-enhanced chemiluminescence levels and cytokine ELISA levels were measured. Histological damage was scored. Data were analyzed with one-way ANOVA. After TBI, luminol (p <.001) and lucigenin (p <.001) levels increased, and luminol and lucigenin levels decreased with apigenin treatments (p <.01–.001). The tail suspension test score increased with trauma (p <.01). According to the pre-traumatic values, the number of entrances to the arms (p <.01) in the Y-maze decreased after trauma (p <.01). In the object recognition test, discrimination (p <.05) and recognition indexes (p <.05) decreased with trauma. There was no significant difference among trauma apigenin groups in behavioral tests. Interleukin (IL)-10 levels, one of the anti-inflammatory cytokines, decreased with trauma (p <.05), and increased with 20 and 40 mg apigenin treatment (p <.001 and p <.01, respectively). The histological damage score in the cortex was decreased in the apigenin 20 mg treatment group significantly (p <.05), but the decrease observed in the apigenin 40 mg group was not significant. The results of this study revealed that apigenin 20 and 40 mg treatment may have neuroprotective effects in mild TBI via decreasing the level of luminol and lucigenin and increasing the IL-10 levels. Additionally, apigenin 20 mg treatment ameliorated the trauma-induced cortical tissue damage. [ABSTRACT FROM AUTHOR]

Apigenin is one of the flavonoids found in abundance in various natural sources, including fruits and vegetables, with important functions in the prevention and treatment of various health problems. It is known that apigenin, which has a very high pharmacological activity, has mainly antioxidant, anti-inflammatory and anti-neoplastic effects, and exhibits these effects by up-or down-regulating proteins in specific pathways. This study focused on the effects of apigenin on inflammation, oxidant-antioxidant balance, cancer, apoptosis and cell cycle, and these properties were supported by in vivo and in vitro studies. As a result of the researches, it was concluded that apigenin exhibits anti-inflammatory, antioxidant and anti-carcinogenic properties. Moreover, it has been observed that apigenin leads damaged, worn or cancerous cells to apoptosis, inhibits the proliferation of such cells by stopping the cell cycle at various checkpoints, and thus exhibits an antiproliferative effect. [ABSTRACT FROM AUTHOR]

Apigenin (4,'5,7-trihydroxyflavone) is one of the most studied flavonoids with low toxicity and abundantly present phenolic compound in the plant kingdom. The main sources of apigenin are fruits, vegetables, nuts, herbs, honey, and plant-based drinks like tea. Numerous plants produce apigenin as a secondary metabolite and its intake is strongly related to its anti-inflammatory propensities. The purpose of present review was to wade through the literature on the anti-inflammatory mechanisms of this metabolite in various diseases and summarize the key objectives as they appear. Existing literature reported that apigenin is a promising candidate in managing a panoply of inflammatory-related diseases including cancer, diabetes, obesity, depression, insomnia, infection, and respiratory, cardiovascular, hepatoprotective, neurodegenerative, and skin diseases. Studies showed that apigenin significantly decreases the secretion of various proinflammatory cytokines specifically tumor necrosis factor (TNF)-α, IL-1β, IL-6, and IL-10. Moreover, apigenin effectively blocks the nitric oxide-mediated cyclooxygenase-2 expression and monocyte attachment and Prostaglandin by lowering iNOS and COX-2 in both microglial and macrophage mouse cells. Apigenin can slow the course of nonalcoholic fatty liver disease (NAFLD) in vivo by reducing high fat diet (HFD)-induced deposition of lipids and oxidative stress. It also controlled redox imbalances, suppress neuronal death and showed memory enhancement/learning skills and a reduction of fibrillar amyloid deposits with lowered insoluble Aβ concentrations in vivo. Taken together, it can be argued that apigenin can wane inflammation and thus offers a promising future in slowing down the development of chronic diseases and associated complications. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a progressive hypokinetic movement disorder caused by selective degeneration of dopaminergic neurons in striatum and dopamine deficiency in a region of the midbrain. LPS is an endotoxin, used as animal model to induce microglial activation, neuroinflammation, oxidative stress, and neurotransmitter alteration with PD-like symptoms. Therefore, to prevent neuroinflammation and neurotransmitter changes and to restore normal brain physiology, we tried apigenin (AGN) alone and in combination with piperine (bioenhancer), in LPS experimental model of rats. In this study, rats were treated with single unilateral intranigral injection of LPS at a dose of 5 μg/5 μl on day 0. The oral administration of AGN (25 and 50 mg/kg; p.o.) alone, AGN (25 mg/kg; p.o.) in combination with piperine (2.5 mg/kg; p.o.), and bromocriptine (10mg/kg; p.o.) started from day 7th once in a day. Intranigral injection of LPS significantly altered body weight and behavioral parameters assessed on weekly basis. Furthermore, the biochemical and neuroinflammatory analysis confirmed (on day 22nd) increased level of nitrite, MDA, SOD, TNF-α, IL-1β, IL-6, and caspase-1, and decreased level of CAT, GSH, and complex-I. Furthermore, altered level of neurotransmitters (DA, GABA, and glutamate) and cellular changes were observed from histopathological and immunohistochemistry (NF-kB and Nrf-2) analysis. Treatment with AGN (25 and 50 mg/kg; p.o.) alone and AGN (25 mg/kg; p.o.) in combination with piperine (2.5 mg/kg; p.o.) significantly attenuated the alteration in body weight, motor impairments, oxidative stress, neuroinflammation, and neurotransmitters in rat brain. The neuroprotective effect of AGN against LPS-induced cell death is attributed by modulating NF-kB and Nrf2 signaling pathway in the striatum. [ABSTRACT FROM AUTHOR]

Background/objective: Apigenin is a member of the flavonoid family that can regulate various biological processes, which is characterized as a treatment of different inflammatory disorders and pathological problems associated with oxidative stress (OS). Recent research has focused on apigenin immunomodulatory properties as a potential treatment for different types of lung injuries. This meta-analysis was designed to determine the impact of apigenin treatment on inflammatory markers and OS parameters in animal models of lung injuries. Methods: The comprehensive literature search was conducted using electronic databases such as Google Scholar, PubMed, Web of Science, Scopus, and Embase up to August 2021. To assess apigenin's effect on inflammatory mediators and OS biomarkers in lung injury animal models, we used the I2 statistic to determine the heterogeneity. We then pooled data as standardized mean difference (SMD) with a 95% confidence interval (CI). Results: Our meta-analysis of the pooled data for inflammatory biomarkers demonstrated that the apigenin administration significantly decreased the NF-κB expression (SMD − 1.60, 95% CI [− 2.93 to − 0.26]; I2 = 89.0%, p < 0.001), IL-1β (SMD − 4.30, 95% CI [− 6.24 to − 2.37]; I2 = 67.3%, p = 0.047), IL-6 (SMD − 4.10, 95% CI [− 5.04 to − 3.16]; I2 = 72.6%, p < 0.001), TNF-α (SMD − 3.74, 95% CI [− 4.67 to − 2.82]; I2 = 84.1%, p < 0.001), and TNF-α gene expression (SMD − 3.44, 95% CI [− 4.44 to − 2.43]; I2 = 0.0%, p = 0.622). This study also indicated the efficacy of apigenin in increasing the level of CAT (SMD 4.56, 95% CI [3.57 to 5.55]; I2 = 15.3%, p = 3.15), GSH (SMD 5.12, 95% CI [3.53 to 6.70]; I2 = 77.6%, p < 0.001), and SOD (SMD 3.45, 95% CI [2.50 to 4.40]; I2 = 79.2%, p < 0.001), and decreasing the level of MDA (SMD − 3.87, 95% CI [− 5.25 to − 2.49]; I2 = 80.3%, p < 0.001) and MPO (SMD − 4.02, 95% CI [− 5.64 to − 2.40]; I2 = 88.9%, p < 0.001), TGF− β (SMD − 3.81, 95% CI [− 4.91 to − 2.70]; I2 = 73.4%, p = 0.001) and W/D level (SMD − 3.22, 95% CI [− 4.47 to − 1.97]; I2 = 82.1%, p < 0.001) than control groups. Conclusion: Overall, our findings showed the immunomodulatory potential of apigenin as an alternative treatment for the suppression of inflammatory responses and OS in different types of lung injury diseases. Nevertheless, due to the paucity of clinical studies, reliable preclinical models, and clinical settings, evaluating the influence of apigenin on lung injury is required in the future. Before conducting large-scale clinical trials, detailed human pharmacokinetic studies are also needed to establish dosage ranges and determine the initial safety and tolerability of apigenin. [ABSTRACT FROM AUTHOR]

• Apigenin might regulate the differentially altered protein (DEPs) while reducing inflammation in RA. • TNF-α activates the differential expression of pro-inflammatory cytokines, TTR, and RAGE via NF-kB pathway activation. • Anti-inflammatory effect of apigenin impedes TNF-α mediated dysregulation or expression associated with RA pathogenesis. Rheumatoid arthritis (RA) is a chronic inflammatory disease induced by TNF-α, which increases fibroblast-like synoviocytes inflammation, resulting in cartilage destruction. The current work sought to comprehend the pathophysiological importance of TNF-α stimulation on differential protein expression and their regulation by apigenin using in-vitro and in-vivo models of RA. The human RA synovial fibroblast cells were stimulated with or without TNF-α (10 ng/ml) and treated with 40 μM apigenin. In-silico, in-vitro and in-vivo studies were performed to confirm the pathophysiological significance of apigenin on pro-inflammatory cytokines and on differential expression of TTR and RAGE proteins. TNF-α induced inflammatory response in synoviocytes revealed higher levels of IL-6, IL-1β, and TNF-α cytokines and upregulated differential expression of TTR and RAGE. In-silico results demonstrated that apigenin has a binding affinity towards TNF-α, indicating its potential effect in the inflammatory process. Both in-vitro and in-vivo results obtained by Western Blot analysis suggested that apigenin reduced the level of p65 (p = 0.005), TTR (p = 0.002), and RAGE (p = 0.020). The findings of this study suggested that TNF-α promotes the differential expression of pro-inflammatory cytokines, TTR, and RAGE via NF-kB pathways activation. Anti-inflammatory effect of apigenin impedes TNF-α mediated dysregulation or expression associated with RA pathogenesis. [ABSTRACT FROM AUTHOR]

[Display omitted] • OL extracts presented anti-inflammatory, anti-cholinergic, and antioxidant activities. • Anti-cholinesterase activity of OL extracts was affected by flavonoids content. • COX-2 inhibitory activity was affected by secoiridoids. • Secoiridoid compounds and flavonoids equally affected to the antioxidant effects. In this study, the phytochemical profile of fifty olive leaves (OL) extracts from Spain, Italy, Greece, Portugal, and Morocco was characterized and their anti-cholinergic, anti-inflammatory, and antioxidant activities were evaluated. Luteolin-7 -O- glucoside, isoharmnentin, and apigenin were involved in the acetylcholinesterase (AChE) inhibitory activity, while oleuropein and hydroxytyrosol showed noteworthy potential. Secoiridoids contributed to the cyclooxygenase-2 inhibitory activity and antioxidant capacity. Compounds such as oleuropein, ligstroside and luteolin-7 -O- glucoside, may exert an important role in the ferric reducing antioxidant capacity. It should be also highlighted the role of hydroxytyrosol, hydroxycoumarins, and verbascoside concerning the antioxidant activity. This research provides valuable insights and confirms that specific compounds within OL extracts contribute to distinct anti-cholinergic, anti-inflammatory, and anti-oxidative effects. [ABSTRACT FROM AUTHOR]

Background: Osteoarthritis (OA) is a degenerative joint disease that causes a variety of adverse health effects. Considering the need to identify additional effective therapeutic options for OA therapy, we investigated the effect of co-injection of apigenin and synovial membrane-derived mesenchymal stem cells (SMMSCs) on OA in male rats' knee joints. Methods: The study was performed in 2019 at the Department of Pharmacology, Shiraz University of Medical Sciences, Shiraz, Iran. Anterior cruciate ligament transection (ACLT) was used to induce OA. For three weeks, male Sprague-Dawley rats (eight groups, n=6 each) were treated once-weekly with intra-articular injections of apigenin alone or in combination with SMMSC (three million cells), phosphate-buffered saline, or hyaluronic acid. After three months, the interleukin 1 beta (IL-1β), tumor necrosis factor-alpha (TNF- α), superoxide dismutase (SOD), and malondialdehyde (MDA) levels were measured in the cartilage homogenate. The expression of extracellular matrix (ECM) components including collagen 2a1, aggrecan, IL-1β, TNF-α, inducible nitric oxide synthase (iNOS), transcription factor SOX-9, and matrix metalloproteinases 3 and 13 were assessed using real-time polymerase chain reaction (RT-PCR) analysis. Radiological evaluation and histopathological assessment were used to evaluate the knees. Results: Levels of TNF-α (P=0.009), MDA (P0.001>), and IL-1β (P<0.001) decreased and the level of SOD increased (P=0.004) in the apigenin 0.3 µM with SMMSCs group. RT-PCR analysis indicated that IL-1β in the apigenin 0.3 µM with SMMSCs group reduced significantly (P>0.001). This group also exhibited increased expression levels of SOX-9, collagen 2a1, and aggrecan (P>0.001). Conclusion: Apigenin may have supplementary beneficial effects on cell therapy in a rat model of OA due to its possible effect on the reduction of oxidative stress, suppression of inflammation, and promotion of production of ECM components. [ABSTRACT FROM AUTHOR]

Lagotis brachystachya Maxim is a herb widely used in traditional Tibetan medicine. Our previous study indicated that total extracts from Lagotis brachystachya could lower uric acid levels. This study aimed to further elucidate the active components (luteolin, luteoloside and apigenin) isolated from Lagotis brachystachya and the underlying mechanism in vitro and in vivo. The results showed that treatment with luteolin and luteoloside reversed the reduction of organic anion transporter 1 (OAT1) levels, while apigenin attenuated the elevation of urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) levels in uric acid-treated HK-2 cells, which was consistent with the finding in the kidneys of potassium oxonate (PO)-induced mice. On the other hand, hepatic xanthine oxidase activity was inhibited by the components. In addition, all of these active components improved the morphology of the kidney in hyperuricemic mice. Moreover, molecular docking showed that luteolin, luteoloside and apigenin could bind Toll-like receptor 4 (TLR4) and NLR family pyrin domain containing 3 (NLRP3). Congruently, western blot analysis showed that the components inhibited TLR4/myeloid differentiation primary response 88 (MyD88)/NLRP3 signaling. In conclusion, these results indicated that luteolin, luteoloside and apigenin could attenuate hyperuricemia by decreasing the production and increasing the excretion of uric acid, which were mediated by inhibiting inflammatory signaling pathways. [ABSTRACT FROM AUTHOR]

Neuroinflammation is initiated by activation of the brain's innate immune system in response to an inflammatory challenge. Insufficient control of neuroinflammation leads to enhanced or prolonged pathology in various neurological conditions including multiple sclerosis and Alzheimer's disease. Nicotinamide adenine dinucleotide (NAD+) plays critical roles in cellular energy metabolism and calcium homeostasis. Our previous study demonstrated that deletion of CD38, which consumes NAD+, suppressed cuprizone-induced demyelination, neuroinflammation, and glial activation. However, it is still unknown whether CD38 directly affects neuroinflammation through regulating brain NAD+ level. In this study, we investigated the effect of CD38 deletion and inhibition and supplementation of NAD+ on lipopolysaccharide (LPS)-induced neuroinflammation in mice. Intracerebroventricular injection of LPS significantly increased CD38 expression especially in the hippocampus. Deletion of CD38 decreased LPS-induced inflammatory responses and glial activation. Pre-administration of apigenin, a flavonoid with CD38 inhibitory activity, or nicotinamide riboside (NR), an NAD+ precursor, increased NAD+ level, and significantly suppressed induction of cytokines and chemokines, glial activation and subsequent neurodegeneration after LPS administration. In cell culture, LPS-induced inflammatory responses were suppressed by treatment of primary astrocytes or microglia with apigenin, NAD+, NR or 78c, the latter a specific CD38 inhibitor. Finally, all these compounds suppressed NF-κB signaling pathway in microglia. These results suggest that CD38-mediated neuroinflammation is linked to NAD+ consumption and that boosting NAD+ by CD38 inhibition and NR supplementation directly suppress neuroinflammation in the brain. [ABSTRACT FROM AUTHOR]

Neuroinflammation is initiated by activation of the brain's innate immune system in response to an inflammatory challenge. Insufficient control of neuroinflammation leads to enhanced or prolonged pathology in various neurological conditions including multiple sclerosis and Alzheimer's disease. Nicotinamide adenine dinucleotide (NAD+) plays critical roles in cellular energy metabolism and calcium homeostasis. Our previous study demonstrated that deletion of CD38, which consumes NAD+, suppressed cuprizone‐induced demyelination, neuroinflammation, and glial activation. However, it is still unknown whether CD38 directly affects neuroinflammation through regulating brain NAD+ level. In this study, we investigated the effect of CD38 deletion and inhibition and supplementation of NAD+ on lipopolysaccharide (LPS)‐induced neuroinflammation in mice. Intracerebroventricular injection of LPS significantly increased CD38 expression especially in the hippocampus. Deletion of CD38 decreased LPS‐induced inflammatory responses and glial activation. Pre‐administration of apigenin, a flavonoid with CD38 inhibitory activity, or nicotinamide riboside (NR), an NAD+ precursor, increased NAD+ level, and significantly suppressed induction of cytokines and chemokines, glial activation and subsequent neurodegeneration after LPS administration. In cell culture, LPS‐induced inflammatory responses were suppressed by treatment of primary astrocytes or microglia with apigenin, NAD+, NR or 78c, the latter a specific CD38 inhibitor. Finally, all these compounds suppressed NF‐κB signaling pathway in microglia. These results suggest that CD38‐mediated neuroinflammation is linked to NAD+ consumption and that boosting NAD+ by CD38 inhibition and NR supplementation directly suppress neuroinflammation in the brain. [ABSTRACT FROM AUTHOR]

Apigenin displays antioxidant and anti-inflammatory effects. However, effects of apigenin magnesium (AM) complex on these aspects remain unknown. This study investigated the effects of AM complex on oxidative stress and inflammatory responses in hydrogen peroxide (H2O2)-induced rat hepatic stellate cells (HSCs). The antioxidant and anti-inflammatory effects of AM complex at concentrations of 0.625, 1.25, and 2.5 mg/mL were evaluated, comparing to HSCs treated by H2O2 alone. Cell viability, reactive oxygen species (ROS), the activity of superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA), nitric oxide (NO), interleukin 6 (IL-6), and nuclear factor-kappa B (NF-κB) levels were measured. Moreover, cell apoptosis, mRNA expression levels of transforming growth factor-β (TGF-β), NF-κB, and inducible nitric oxide synthase (iNOS) were assessed. AM complex significantly inhibited oxidative stress and inflammatory response at concentrations of 0.625, 1.25, and 2.5 mg/mL (IC50 = 1.679 mg/mL). AM complex elevated the survival rate of H2O2-treated HSCs and had no toxic effects on HSCs. AM complex also promoted SOD activity and GSH levels but suppressed ROS, MDA, and NO levels. Additionally, AM complex decreased IL-6 and NF-κB levels, gene expression of TGF-β, NF-κB, and iNOS, as well as induced apoptosis of HSCs. Data indicated that AM complex mitigated oxidative stress and inflammatory responses on H2O2-treated HSCs, suggesting that AM complex is a possible candidate for anti-hepatic diseases. Additional efforts, both in vivo and in humans, are required to assess of AM complex as a potential therapeutic drug in liver diseases. [ABSTRACT FROM AUTHOR]

Human fetuses with trisomy 21 (T21) have atypical brain development that is apparent sonographically in the second trimester. We hypothesize that by analyzing and integrating dysregulated gene expression and pathways common to humans with Down syndrome (DS) and mouse models we can discover novel targets for prenatal therapy. Here, we tested the safety and efficacy of apigenin, identified with this approach, in both human amniocytes from fetuses with T21 and in the Ts1Cje mouse model. In vitro , T21 cells cultured with apigenin had significantly reduced oxidative stress and improved antioxidant defense response. In vivo , apigenin treatment mixed with chow was administered prenatally to the dams and fed to the pups over their lifetimes. There was no significant increase in birth defects or pup deaths resulting from prenatal apigenin treatment. Apigenin significantly improved several developmental milestones and spatial olfactory memory in Ts1Cje neonates. In addition, we noted sex-specific effects on exploratory behavior and long-term hippocampal memory in adult mice, and males showed significantly more improvement than females. We demonstrated that the therapeutic effects of apigenin are pleiotropic, resulting in decreased oxidative stress, activation of pro-proliferative and pro-neurogenic genes (KI67, Nestin, Sox2 , and PAX6), reduction of the pro-inflammatory cytokines INFG, IL1A, and IL12P70 through the inhibition of NFκB signaling, increase of the anti-inflammatory cytokines IL10 and IL12P40, and increased expression of the angiogenic and neurotrophic factors VEGFA and IL7. These studies provide proof of principle that apigenin has multiple therapeutic targets in preclinical models of DS. [ABSTRACT FROM AUTHOR]

Apigenin, a flavonoid found in many plants, has various biological properties. We aimed to investigate the anti-inflammatory and anti-oxidative activity of apigenin against carbon tetrachloride (CCl4)-induced acute liver injury in mice and hydrogen peroxide (H2O2)-induced oxidative stress in HepG2 cells and possible mechanism. In vivo, apigenin significantly reduced alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity in serum of mice challenged by CCl4 and markedly alleviated the lipid peroxidation as indicated by the increased level of superoxide dismutase (SOD), reduced glutathione (GSH), glutathione peroxidases (GSH-Px) and catalase (CAT), and the decreased malondialdehyde (MDA) in liver tissue. Apigenin also ameliorated inflammation by downregulating tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and upregulating IL-10. Consistently, the elevated ALT and AST level; the impaired balance between SOD, GSH activity, and excessive ROS; and the increased gene expression of TNF-α and IL-6 resulting from H2O2-induced oxidative stress were restored by apigenin. Moreover, the results from Western blot, real-time qPCR, and immunofluorescence assay indicated that apigenin enhanced the activity of TNF receptor-associated factor (TRAF) 2/3 and cellular inhibitor of apoptosis protein (c-IAP) 1, ameliorated NF-κB-inducing kinase (NIK), and mediated the nuclear translocation of NF-κB2, therefore had an inhibitory effect on the non-canonical NF-κB pathway which was activated in both models. siNIK canceled the protective effect of apigenin on H2O2-induced HepG2 cells. Altogether, our results demonstrated that apigenin mitigated liver injury by ameliorating inflammation and oxidative stress through suppression of the non-canonical NF-κB pathway, indicating the potential of apigenin for treatment of the liver injury. [ABSTRACT FROM AUTHOR]

Objective: Apigenin is a natural flavonoid compound extracted from Matricaria chamomilla. We evaluated the anti-inflammatory effects of apigenin in this study using the Lipopolysaccharide (LPS)-stimulated BV2 microglia. Methods: BV2 cells were treated with apigenin for 1 h and then treated with LPS. The inflammatory cytokine productions were tested by qRT-PCR and ELISA. The expression of GSK3β, Nrf2, and NF-κB signaling pathways were measured by western blot analysis. Results: Apigenin significantly attenuated LPS-induced TNF-α, IL-1β, and IL-6 production. Apigenin suppressed LPS-induced NF-κB activation. Furthermore, GSK3β, Nrf2, and HO-1 were concentration-dependently increased by apigenin. The suppression of apigenin on LPS-induced inflammatory response and NF-κB activation were prevented when Nrf2 was knocked out or by GSK3β inhibitor. Conclusions: Collectively, apigenin suppressed LPS-induced microglia activation via activating GSK3β/Nrf2 signaling pathway. [ABSTRACT FROM AUTHOR]

Psoriasis is an immune-mediated skin disease characterized by keratinocytes hyperproliferation, abnormal differentiation and inflammation. Therefore, this study aimed to investigate in-vitro and in-vivo anti-inflammatory and anti-proliferative activity to evaluate anti-psoriatic potential of apigenin. For in-vivo study, 5 % imiquimod cream was used to induce psoriasis-like skin inflammation in BALB/c mice to mimic human psoriatic conditions. PASI score, CosCam score, histopathology, immunohistochemistry, qRT-PCR, and ELISA were done to evaluate the anti-psoriatic potential of topically applied apigenin. For in-vitro studies, LPS-induced inflammation in RAW 264.7 was done, and qRT-PCR, ELISA, and immunofluorescence were conducted to evaluate the anti-inflammatory activity of apigenin. Migration and cell doubling assay in HaCaT cells were performed to assess the anti-proliferative effect of apigenin. Acute dermal toxicity profile of apigenin has also been done as per OECD guidelines. Results showed that apigenin significantly reduce the PASI and CosCam scores, ameliorate the deteriorating histopathology, and effectively downregulated the expression of CCR6, IL-17A, and NF-κB. Apigenin effectively downregulated the expression and secretion of pro-inflammatory cytokines through IL-23/IL-17/IL-22 axis. Apigenin suppressed nuclear translocation of NF-κB in LPS-induced RAW 264.7 cells. Cell migration and cell doubling assay in HaCaT cells showing the anti-proliferative potential of apigenin and it was found safe in acute dermal toxicity study. Apigenin was found effective against psoriasis in both in-vitro and in-vivo models suggesting apigenin as a potential candidate for the development of anti-psoriatic agent. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract Paraquat (PQ) induces acute lung injury (ALI) and immunotoxicity. Apigenin exerts anti-oxidant and anti-inflammatory properties. The purpose of this study was to investigate the possible protective effects of apigenin on PQ-induced ALI and immunotoxicity in mice. Female C57BL/6 mice received a single injection of PQ (50 mg/kg). Apigenin was given for 7 consecutive days starting 5 days before PQ exposure. The toxicity markers were evaluated in terms of weight loss, lung histopathology, oxidative stress, inflammation, and T cell functions after PQ exposure. Poisoned mice exhibited severe lung tissue lesions, inflammatory cell infiltration and the release of pro-inflammatory cytokines IL-6 and TNF-α. PQ administration increased the lung wet/dry ratios and lipid peroxidation by the increase of MDA levels and decreased anti-oxidase activity including SOD, GSH-PX, and CAT. While such effect on lung was reversed by apigenin. Importantly, PQ-induced immunotoxicity was also observed in a decrease of spleen weight, inhibition of T cell proliferation and T-cell secreting IL-2 from splenocytes. Further mechanism analysis found that PQ administration could decrease total splenocytes, CD4+ and CD8+ T cells, SOD, GSH-PX, and CAT activity, and increased the levels of MDA and the concentrations of pro-inflammatory cytokines IL-6 and TNF-α compared to control mice. However, apigenin treatment reversed PQ-induced immunotoxicity. In summary, all results suggest that apigenin has beneficial effects on PQ-induced ALI and immunotoxicity possibly, and it could be related, at least in part, to its ability in modulating inflammation and oxidative stress, although in-depth studies might be needed to fully understand the mechanism of action. Highlights • Apigenin attenuated paraquate-induced acute lung injury. • Apigenin reversed the paraquat-induced immunotoxicity including spleen weight loss and T cell functions. • The apigenin's protective effects were related to its ability to modulate inflammation and oxidative stress. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Naringenin, a citrus flavonoid that possesses various biological activities, has emerged as a potential therapeutic agent for the management of a variety of diseases. Studies using cell culture system have shown that naringenin can inhibit inflammatory response in diverse cell types. Moreover, research using various animal models has further demonstrated therapeutic potentials of naringenin in the treatment of several inflammation-related disorders, such as sepsis, fulminant hepatitis, fibrosis and cancer. The mechanism of action of naringenin is not completely understood but recent mechanistic studies revealed that naringenin suppresses inflammatory cytokine production through both transcriptional and post-transcriptional mechanisms. Surprisingly, naringenin not only inhibits cytokine mRNA expression but also promotes lysosome-dependent cytokine protein degradation. This unique property of naringenin stands in sharp contrast with some widely-studied natural products such as apigenin and curcumin, which regulate cytokine production essentially at the transcriptional level. Therefore, naringenin may provide modality for the development of novel anti-inflammatory agent. This review article summarizes our recent studies in understanding how naringenin acts in cells and animal models. Particularly, we will discuss the anti-inflammatory activities of naringenin in various disease context and its potential use, as an immunomodulator, in the treatment of inflammatory related disease. [ABSTRACT FROM AUTHOR]

We have previously demonstrated that apigenin promotes the expression of antiangiogenic protein thrombospondin-1 (TSP1) via a mechanism driven by mRNA-binding protein HuR. Here, we generated a novel mouse model with whole-body THBS-1 gene knockout on SKH-1 genetic background, which allows studies of UVB-induced acute skin damage and carcinogenesis and tests TSP1 involvement in apigenin's anticancer effects. Apigenin significantly inhibited UVB-induced carcinogenesis in the wild-type (WT) animals but not in TSP1 KO (TKO) mice, suggesting that TSP1 is a critical component of apigenin's chemopreventive function in UVB-induced skin cancer. Importantly, TKO mice presented with the elevated cutaneous inflammation at baseline, which was manifested by increased inflammatory infiltrates (neutrophils and macrophages) and elevated levels of the two key inflammatory cytokines, IL-6 and IL-12. In agreement, maintaining normal TSP1 expression in the UVB-irradiated skin of WT mice using topical apigenin application caused a marked decrease of circulating inflammatory cytokines. Finally, TKO mice showed an altered population dynamics of the bone marrow myeloid progenitor cells (CD11b+), with dramatic expansion of the population of neutrophil progenitors (Ly6ClowLy6Ghigh) compared to the WT control. Our results indicate that the cutaneous tumor suppressor TSP1 is a critical mediator of the in vivo anticancer effect of apigenin in skin, specifically of its anti-inflammatory action. [ABSTRACT FROM AUTHOR]

Apigenin (AP) as a plant flavonoid is found to attenuate acrylonitrile (ACN) toxicity by reducing ROS production and inhibiting apoptosis. Therefore, the present study aimed to evaluate the role of AP on ACN-induced inflammation and apoptosis in germ cells and whether it is through the NF-κB signaling pathway. AP increased the concentrations of lactate dehydrogenase isozyme (LDH) and sorbitol dehydrogenase (SDH), while the concentrations of interleukin β (IL-1β), tumor-necrosis factor-α (TNF-α), and interleukin-6 (IL-6) were significantly reduced. AP could downregulate the expression of the nuclear factor of kappa B (NF-κB) and inhibit phosphorylation of the inhibitory κBα (IκBα). Cleaved caspase-3 was also upregulated by AP, and the apoptotic were less than those in the ACN group. These results suggest that AP might improve maturation and energy metabolism of testes, inhibit NF-κB activation. Then AP could further downregulate NF-κB signal and inhibit the germ cell apoptosis and reduce inflammatory caused by ACN. [ABSTRACT FROM AUTHOR]

Abstract: Aim: This study evaluated the anti‐inflammatory properties of a species of Sorghum bicolor leaf (SBL) grown in West Africa. Method: Cyclo‐oxygenase (COX)‐2:COX‐1 selectivity assay was carried out by plating isolated peripheral blood mononuclear cells in culture medium with specific SBL fractions: crude extract (J), ethyl‐acetate (JE) and aqueous (JA); secondary compounds from JE (JE5, JE6, JE7 and JE8); purified (P9) and semi‐purified (P8) compounds from JE5 at 5‐200 μg/mL for 1 hour. Test compounds and controls ibuprofen (50 μmol/L) and CAY10404 (1 μmol/L; 10 μmol/L) were added to two sets of plates, one without lipopolyshaccharide (LPS) and the other with LPS (1 μg/mL) for 24 hour. COX‐2IC50:COX‐1IC50 ratio represented 50% inhibition of the activity of COX‐2 to that of COX‐1 using ibuprofen as control. In separate experiments the supernatant of P8 and P9‐treated fractions of SBL and controls were plated with RAW 264.7 macrophage cells to measure prostaglandin (PG)‐E2 production and cell proliferation activity. Results: JA fraction of SBL had the highest ratio of COX‐2IC50:COX‐1IC5041.214 whereas JE had the lowest ratio COX‐2IC50:COX‐1IC501.161. Interestingly, JE5 derived from JE showed a ratio of COX‐2IC50:COX‐1IC500.495 while P8 derived from JE5 showed a dose‐dependent reduction in COX‐2IC50:COX‐1IC50 ratio and in PG‐E2 production, which was more effective compared to ibuprofen. A dose‐dependent reduction in RAW 264.7 macrophage cell proliferation was also observed in P8‐treated cells. The phenolic compounds identified in P8 include apigenin and apigeninidin adducts which may explain the exceptional anti‐inflammatory activity and efficacy in COX‐2 targeting. [ABSTRACT FROM AUTHOR]

Introduction: Apigenin (AP) has been reported to elicit anti-inflammatory effects. In this study, we investigated the effect of AP on sciatic nerve denervation-induced muscle atrophy.Methods: Sciatic nerve-denervated mice were fed a 0.1% AP-containing diet for 2 weeks. Muscle weight and cross-sectional area (CSA), and the expression of atrophic genes and inflammatory cytokines in the gastrocnemius were analyzed.Results: Denervation significantly induced muscle atrophy. However, values for muscle weight and CSA were greater in the denervated muscle of the AP mice than the controls. AP suppressed the expression of MuRF1, but upregulated both myosin heavy chain (MHC) and MHC type IIb. AP also significantly suppressed expression of tumor necrosis-alpha in the gastrocnemius and soleus muscles, and interleukin-6 expression in the soleus muscle.Discussion: AP appears to inhibit denervation-induced muscle atrophy, which may be due in part to its inhibitory effect on inflammatory processes within muscle. Muscle Nerve 58: 314-318, 2018. [ABSTRACT FROM AUTHOR]

Inflammatory responses during chronic diseases such as atherosclerosis, cancer etc., are harmful to host organisms. Generally NSAIDs are used to treat against these severe conditions but due to its adverse effects studies are going on with medicinal plants, since they are rich in bioactive compounds. Justicia gendarussa is one such plant which has been used as a remedial measure for treating inflammatory diseases since ancient time. Thus the present study involved in the isolation, characterization and identification of apigenin (flavonoid) from this plant and to elucidate its molecular mechanism against inflammation via TLR-NF-κB signaling pathway using ox-LDL induced hPBMCs in in vitro model. Methanolic extract was used for the isolation process and results showed that the F6 fraction collected from ethyl acetate through column chromatography showed 89% paw edema inhibition at a dose of 10 mg/kg in carrageenan induced rats. Purification of F6 by TLC with toluene: chloroform: acetone (8:5:7) and further characterization by 1 HNMR indicated the presence of bioactive compound, apigenin. In vitro studies revealed that pretreatment of ox-LDL induced hPBMCs with apigenin (25 μM) significantly ( P  < 0.05) reduced the levels of TLR4, MyD88, TRIF, TRAF6, NF-κB, COX-2, PGE2, IL-1β and TNF-α responsible for generating inflammation and elevated the level of anti-inflammatory cytokine, IL-10. These results indicate the therapeutic efficacy of bioflavonoid apigenin which was isolated from Justicia gendarussa against ox-LDL induced inflammation. Therefore apigenin can be treated as a suitable therapeutic agent against inflammatory diseases. [ABSTRACT FROM AUTHOR]

Background: A major feature of acute lung injury (ALI) is excessive inflammation in the lung. Vitexin is an active component from medicinal plants which has antioxidant and anti-inflammatory activities. Oxidative stress and inflammation play important roles in the pathophysiological processes in ALI. In the current study, we investigate the effect and potential mechanisms of Vitexin on lipopolysaccharide (LPS)-induced ALI. Methods: ALI was induced by LPS intratracheal instillation in C57BL/6 wild-type mice and Nrf2 gene knocked down (Nrf2-/-) mice. One hour before LPS challenge, Vitexin or vehicle intraperitoneal injection was performed. Bronchoalveolar lavage fluid and lung tissues were examined for lung inflammation and injury at 24 h after LPS challenge. Results: Our animal study’s results showed that LPS-induced recruitment of neutrophils and elevation of proinflammatory cytokine levels were attenuated by Vitexin treatment. Vitexin decreased lung edema and alveolar protein content. Moreover, Vitexin activated nuclear factor erythroid-2-related factor 2 (Nrf2), and increased the activity of its target gene heme oxygenase (HO)-1. The LPS-induced reactive oxygen species were inhibited by Vitexin. In addition, the activation of the nucleotide-binding domain and leucine-rich repeat PYD-containing protein 3 (NLRP3) inflammasome was suppressed by Vitexin. However, these effects of Vitexin were abolished in the Nrf2-/- mice. Our cell studies showed that Vitexin enhanced the expression of Nrf2 and HO-1 activity. Moreover, reactive oxygen species (ROS) and IL-1β productions were reduced in Vitexin-treated cells. However, knockdown of Nrf2 by siRNA in RAW cells reversed the benefit of Vitexin. Conclusions: Vitexin suppresses LPS-induced ALI by controlling Nrf2 pathway. [ABSTRACT FROM AUTHOR]

Background and purpose: Apigenin can exert beneficial actions in the prevention of obesity. However, its putative action on obesity-associated bowel motor dysfunctions is unknown. This study examined the effects of apigenin on colonic inflammatory and motor abnormalities in a mouse model of diet-induced obesity. Experimental approach: Male C57BL/6J mice were fed with standard diet (SD) or high-fat diet (HFD). SD or HFD mice were treated with apigenin (10 mg/Kg/day). After 8 weeks, body and epididymal fat weight, as well as cholesterol, triglycerides and glucose levels were evaluated. Malondialdehyde (MDA), IL-1β and IL-6 levels, and let-7f expression were also examined. Colonic infiltration by eosinophils, as well as substance P (SP) and inducible nitric oxide synthase (iNOS) expressions were evaluated. Motor responses elicited under blockade of NOS and tachykininergic contractions were recorded in vitro from colonic longitudinal muscle preparations. Key results: When compared to SD mice, HFD animals displayed increased body weight, epididymal fat weight and metabolic indexes. HFD mice showed increments in colonic MDA, IL-1β and IL-6 levels, as well as a decrease in let-7f expression in both colonic and epididymal tissues. HFD mice displayed an increase in colonic eosinophil infiltration. Immunohistochemistry revealed an increase in SP and iNOS expression in myenteric ganglia of HFD mice. In preparations from HFD mice, electrically evoked contractions upon NOS blockade or mediated by tachykininergic stimulation were enhanced. In HFD mice, Apigenin counteracted the increase in body and epididymal fat weight, as well as the alterations of metabolic indexes. Apigenin reduced also MDA, IL-1β and IL-6 colonic levels as well as eosinophil infiltration, SP and iNOS expression, along with a normalization of electrically evoked tachykininergic and nitrergic contractions. In addition, apigenin normalized let-7f expression in epididymal fat tissues, but not in colonic specimens. Conclusions and implications: Apigenin prevents systemic metabolic alterations, counteracts enteric inflammation and normalizes colonic dysmotility associated with obesity. [ABSTRACT FROM AUTHOR]

Context:Currently, the outcomes of the use of cisplatin in cancer therapy is limited by nephrotoxicity. Objective:This study aims to investigate the nephroprotective role of apigenin and myricetin against cisplatin-induced nephrotoxicity in mice. Materials and methods:Adult female Wistar Albino mice were divided into eight groups (n = 8). Group I served as normal control. Groups II, III and IV received apigenin (3 mg/kg, i.p.), myricetin (3 mg/kg, i.p.) or their combination respectively, for seven days. Group V served as positive control group, received vehicles for seven days and cisplatin (7.5 mg/kg, i.p.) for three days starting at day five. Groups VI, VII and VIII received apigenin, myricetin or their combination, respectively for seven days as well as cisplatin injection for three days starting at day five. by the end of the experimental period, a biochemical study involving, nephrotoxicity markers [serum creatinine (Cr) and blood urea nitrogen (BUN)], apoptotic marker [caspase 3], inflammatory mediators [tumour necrosis factor alpha (TNF-α), interleukin 6 (IL-6), cyclooxygenase I and II (COXI, COXII)] and oxidative stress biomarkers [malondialdehyde (MDA), reduced glutathione (GSH) and catalase] was conducted. In addition, renal histopathological alterations were evaluated. Results:Apigenin, myricetin and their combination significantly reduced blood BUN, serum Cr, caspase-3TNF-α, IL-6, COXI and COXII, MDA levels and significantly increased GSH level and catalase activity parallel to, histopathological improvement in kidney tissues. Discussion and conclusion:Apigenin and myricetin exhibited a protective and promising preventive strategy against cisplatin-induced nephrotoxicity due to their antioxidant and anti-inflammatory effects. [ABSTRACT FROM PUBLISHER]

Polyphenols such as apigenin, kaempferol or resveratrol are typically found in plants, including fruits, vegetables, herbs and spices, which have a wide range of biological functions such as antioxidative, anti-inflammatory, vasodilative, anticoagulative and proapoptotic. Discovering such multifunctional compounds in widely consumed plant-based products – ones that both inhibit the release of TNF-α from tissue macrophages and at the same time enhance the secretion of IL-10 – would be an important signpost in the quest for effective pharmacological treatment of numerous diseases that have an inflammatory etiology. The aim of the study is to investigate the impact of biologically active polyphenols such as apigenin, resveratrol and kaempferol on gene expression and protein secretion of IL-10 and TNF-α in line RAW-264.7. Cells were cultured under standard conditions. IL-10 and TNF-α genes expression were examined using QRT-PCR and to assess cytokines concentration ELISA have been used. Apigenin, kaempferol and resveratrol at a dose 30 μM significantly decrease the TNF-α expression and secretion. Apigenin decrease the IL-10 expression and secretion. Furthermore, increase in IL-10 secretion after administration of kaempferol and resveratrol were observed. In the process of administration of tested compounds before LPS, which activate macrophages, decrease of TNF-α secretion after apigenin and kaempferol and increase of IL-10 secretion after resveratrol were observed. The results of present work indicate that 1) apigenin, resveratrol and kaempferol may reduce the intensity of inflammatory processes by inhibiting the secretion of proinflammatory cytokine TNF-α, and resveratrol and kaempferol additionally by increasing the secretion of anti-inflammatory cytokine IL-10 2) the studies indicate the potentially beneficial – anti-inflammatory – impact of diet rich in products including apigenin, resveratrol and kaempferol. [ABSTRACT FROM AUTHOR]

Vitex spp. have been reported as constituents of herbal preparations, namely Vitex peduncularis , commonly used in Asian countries. Unlike other species extensively investigated, reports on the biological activities and chemical profile of V. peduncularis are still scarce. In this work, the polyphenolic profile of V. peduncularis stem bark was unveiled, revealing a high content of apigenin and luteolin derivatives. More than 20 polyphenols were identified and quantitated for the first time, including C -rhamnosyl flavones infrequently reported. Regarding potential anti-inflammatory properties, the methanolic extract of the stem bark significantly reduced the levels of NO in macrophages, which may be a consequence of scavenging effect upon • NO. Significant inhibition of phospholipase A 2 activity was also noted. Consequently, the therapeutic applicability of this edible plant is also broadened due to the anti-inflammatory properties found. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN), a microvascular complication of diabetes, has emerged as an important health problem worldwide. There is strong evidence to suggest that oxidative stress, inflammation, and fibrosis play a pivotal role in the progression of DN. Apigenin has been shown to possess antioxidant, anti-inflammatory, antiapoptotic, antifibrotic, as well as antidiabetic properties. Hence, we evaluated whether apigenin halts the development and progression of DN in streptozotocin (STZ)-induced diabetic rats. Male albino Wistar rats were divided into control, diabetic control, and apigenin treatment groups (5-20 mg/kg po, respectively), apigenin per se (20 mg/kg po), and ramipril treatment group (2 mg/kg po). A single injection of STZ (55 mg/kg ip) was administered to all of the groups except control and per se groups to induce type 1 diabetes mellitus. Rats with fasting blood glucose >250 mg/dl were included in the study and randomized to different groups. Thereafter, the protocol was continued for 8 mo in all of the groups. Apigenin (20 mg/kg) treatment attenuated renal dysfunction, oxidative stress, and fibrosis (decreased transforming growth factor-β1, fibronectin, and type IV collagen) in the diabetic rats. It also significantly prevented MAPK activation, which inhibited inflammation (reduced TNF-α, IL-6, and NF-κB expression) and apoptosis (increased expression of Bcl-2 and decreased Bax and caspase-3). Furthermore, histopathological examination demonstrated reduced inflammation, collagen deposition, and glomerulosclerosis in the renal tissue. In addition, all of these changes were comparable with those produced by ramipril. Hence, apigenin ameliorated renal damage due to DN by suppressing oxidative stress and fibrosis and by inhibiting MAPK pathway. [ABSTRACT FROM AUTHOR]

Apigenin is being used by humans in the form of plant extract for the treatment of a number of disorders and inflammatory conditions, until its discovery as a core compound. Apigenin, chemically known as 4′, 5, 7,-trihydroxyflavone is a yellow crystalline powder belonging to the flavone class, that is the aglycone of several naturally occurring glycosides. It is insoluble in water but soluble in organic solvents. Numerous pharmacological activities, including anti-inflammatory, anti-toxicant, anti-cancer, etc., are attributed to apigenin. Research has shown that apigenin has numerous molecular targets involved in inflammation. Based on thein vivo, in vitro, and clinical trial studies suggested that apigenin is a potent therapeutic agent to overcome diseases such as rheumatoid arthritis, autoimmune disorders, Parkinson’s disease, Alzheimer’s disease, and various type of cancers. Delayed plasma clearance and slow decomposition in liver increases its systemic bioavailability, and makes it a strong therapeutic agent in pharmaceutical studies. In the present review, detailed accounts of the properties of apigenin have been discussed. [ABSTRACT FROM PUBLISHER]

High calorie diet promotes oxidative stress and chronic low grade inflammation that predispose to brain dysfunction and neurodegeneration. Hippocampus region of the brain has been shown to be particularly sensitive to high calorie diet. We hypothesize that apigenin (API), a flavonoid could attenuate hippocampal derangements induced by high fat-high fructose diet (HFFD). In this study, we investigated the effects of API on oxidative stress and inflammation in the hippocampus, and compared with those of sitagliptin (STG), a standard drug with neuroprotective properties. The markers of oxidative stress and inflammation were examined using biochemical assays, western blotting and immunohistochemistry techniques. HFFD-fed rats showed severe pathological alterations and API treatment rescued the hippocampus from the derangements. API significantly improved the antioxidant machinery, reduced ROS levels and prevented the activation of the stress kinases, inhibitor of kappa B kinase beta (IKKβ) and c-Jun NH2 terminal kinase (JNK), and the nuclear translocation and activation of nuclear factor kappa B (NF-κB). The plasma levels of inflammatory cytokines were also reduced. Our findings suggest that hippocampal derangements triggered by HFFD feeding were effectively curtailed by API. Suppression of oxidative stress, NF-κB activation and JNK phosphorylation in the hippocampus are the mechanisms by which API offers neuroprotection in this model. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the effects and molecular mechanisms of the effects of apigenin on cisplatin (CP)-induced kidney injury in mice. Apigenin was intraperitoneally administered for 3 consecutive days before CP treatment. We found that apigenin pretreatment significantly attenuated the damage to the kidneys and decreased the levels of serum creatinine, blood urea nitrogen (BUN), glutathione peroxidase (GSH-PX) and superoxide dismutase (SOD), which were increased by CP. Apigenin significantly decreased the levels of TNF-α, IL-1β and TGFβ in the kidneys. Additionally, apigenin inhibited the activations of CYP2E1, phospho-NF-κB p65 and phospho-P38 MAPK in CP-induced renal injury. These results suggest that the renoprotective effects of apigenin may be related to the suppressions of oxidative stress and inflammation in CP-induced renal injury in mice. [ABSTRACT FROM AUTHOR]

Apigenin is one of the abundant flavonoids in fruits and vegetables of human diet with several demonstrated health benefits. The aim of the present study is to provide an overview of the current evidence regarding the effect of apigenin on different dermatological complications. Electronic databases including PubMed, Scopus, and Web of Science were searched to retrieve all papers assessing the dermatological effects of apigenin. Preclinical studies support beneficial effects of apigenin on UV-induced skin damage, vitiligo, dermatitis, wounds, skin aging, and some types of skin cancer. The compound mostly acts via inhibition of inflammation through suppression of pro-inflammatory cytokines and intracellular inflammatory mediators, as well as antioxidant properties such as improvement of endogenous antioxidant defense mechanisms. There are also some studies for the design and development of novel drug delivery systems for apigenin to improve its oral and topical bioavailability. Nevertheless, no clinical study has evaluated apigenin as a natural supplement for skin conditions. Considering the benefits of apigenin in preclinical models of dermatological disorders, as well as the acceptable safety of this compound, apigenin may be a future candidate to be used in dermatological disorders. Future clinical studies are needed to further confirm the safety and efficacy of apigenin in skin care products. [Display omitted] • Apigenin is an abundant flavonoid in human diet. • Preclinical studies show the benefits of apigenin in dermatological disorders. • Dermatological benefits of apigenin appear in both oral and topical administration. • Apigenin can be considered as a future cosmeceutical in skin care products. • Dietary apigenin-rich products can also be used to have a healthy skin. [ABSTRACT FROM AUTHOR]

Exposure to acrolein, one environmental and dietary pollutant, has been shown to cause inflammation. Here, we reported for the first time that acrolein aggravated lipopolysaccharide (LPS)-induced inflammation in Human umbilical vein endothelial cells (HUVEC) as evidenced by the further increased mRNA expression of three pro-inflammatory cytokines, including interleukin 1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor-alpha (TNF-α). Acrolein also further increased the generation of reactive oxygen species (ROS) and decreased the activity of glutathione peroxidase (GSH-Px) in LPS-pretreated HUVEC. Moreover, acrolein treatment further increased the nucleotide oligomerization domain-like receptor protein 3 (NLRP3) and apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) expression, caspase-1 cleavage, and downstream matures interleukin 18 (IL-18) and IL-1β level in LPS-pretreated HUVEC. Acrolein treatment also further increased the expressions of high-mobility group box 1 (HMGB1), toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and phospho–NF–κB P65 (P–P65) in the LPS pre-treated HUVEC. Thus, acrolein aggravated LPS-induced HUVEC inflammation through induction of oxidative stress, and activation of NLRP3 inflammasome and HMGB1/MYD88/NF-κB signaling pathway. In addition, apigenin and apigenin-7, 4′-O-dioctanoate attenuated acrolein-aggravated inflammation by targeting the above signaling pathways. Our findings could help to develop potential therapeutic strategies against acrolein-enhanced inflammation. [Display omitted] • Acrolein aggravated LPS-induced inflammation in HUVEC. • Acrolein increased ROS generation and decreased the GSH-Px activity. • Acrolein caused further activation of NLRP3 inflammasome. • Acrolein activated the HMGB1/TLR4/MyD88/NF-κB signaling pathway. • Apigenin-7, 4′-O-dioctanoate attenuated the acrolein-aggravated inflammation. [ABSTRACT FROM AUTHOR]

This study aims to investigate the protective effect of apigenin on the development of experimental autoimmune myocarditis (EAM) and the underlying mechanisms. An EAM model was induced in BALB/c mice by the injection of porcine cardiac myosin. Apigenin was orally administered from day 1 to 21. The severity of myocarditis was assessed by determination of heart weight/body weight ratio (HW/BW) and histopathological evaluation. Echocardiography was conducted to evaluate the cardiac function and heart structure. Antigen-specific T cell proliferation responses to cardiac myosin were evaluated by the lymphocyte proliferation assay. ELISA was used to determine serum levels of type 1 helper (Th1) and Th2 cytokines. Apigenin treatment significantly decreased HW/BW. Histopathologic analysis showed that the infiltration of inflammatory cells was reduced significantly by apigenin treatment. Meanwhile, apigenin administration effectively ameliorated autoimmune myocarditis-induced cardiac hypertrophy and cardiac dysfunction as well as inhibited lymphocyte proliferation in mice immunized with myosin. Furthermore, Th1 cytokines tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), and interleukin-2 (IL-2) were significantly downregulated, while Th2 cytokines IL-4 and IL-10 were markedly upregulated. The results indicated that apigenin can alleviate EAM due to its immunomodulatory reactions in modification of helper T cell balance. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the protective effects of apigenin against paraquat (PQ)-induced acute lung injury (ALI) in mice. Male Kunming mice were randomly divided into five groups: group 1 (control), group 2 (PQ), group 3 (PQ + apigenin 25 mg/kg), group 4 (PQ + apigenin 50 mg/kg), and group 5 (PQ + apigenin 100 mg/kg). The PQ + apigenin group received apigenin by gavage daily for consecutive 7 days, respectively, while the mice in control and PQ groups were given an equivalent volume of saline. We detected the lung wet/dry weight ratios and the histopathology of the lung. The levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), malondialdehyde (MDA), myeloperoxidase (MPO), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) were determined using enzyme-linked immunosorbent assay (ELISA) kits. The activity of nuclear factor (NF)-κB was also determined. The results indicated that apigenin administration decreased biochemical parameters of inflammation and oxidative stress, and improved oxygenation and lung edema in a dose-dependent manner. These protective effects of apigenin were associated with inhibition of NF-κB. In conclusion, apigenin reduces PQ-induced ALI by inhibition of inflammation and oxidative stress. [ABSTRACT FROM AUTHOR]

The increasing prevalence of inflammatory diseases and the adverse effects associated with the long-term use of current anti-inflammatory therapies prompt the identification of alternative approaches to reestablish immune balance. Apigenin, an abundant dietary flavonoid, is emerging as a potential regulator of inflammation. Here, we show that apigenin has immune-regulatory activity in vivo. Apigenin conferred survival to mice treated with a lethal dose of Lipopolysaccharide (LPS) restoring normal cardiac function and heart mitochondrial Complex I activity. Despite the adverse effects associated with high levels of splenocyte apoptosis in septic models, apigenin had no effect on reducing cell death. However, we found that apigenin decreased LPS-induced apoptosis in lungs, infiltration of inflammatory cells and chemotactic factors' accumulation, re-establishing normal lung architecture. Using NF-κB luciferase transgenic mice, we found that apigenin effectively modulated NF-κB activity in the lungs, suggesting the ability of dietary compounds to exert immune-regulatory activity in an organ-specific manner. Collectively, these findings provide novel insights into the underlying immune-regulatory mechanisms of dietary nutraceuticals in vivo. [ABSTRACT FROM AUTHOR]

Apigenin is one of the plant flavonoids present in fruits and vegetables, acting as an important nutraceutical component. It is recognized as a potential antioxidant, antimicrobial, and anti-inflammatory molecule. In the present study, the mechanism of anti-inflammatory action of apigenin on lipopolysaccharide (LPS)-induced pro-inflammatory cytokines and activator protein-1 (AP-1) factors in human lung A549 cells was investigated. The anti-inflammatory activity of apigenin on LPS-induced inflammation was determined by analyzing the expression of pro-inflammatory cytokines, nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and different AP-1 factors. Apigenin significantly inhibited the LPS-induced expression of iNOS, COX-2, expression of pro-inflammatory cytokines (IL-1β, IL-2, IL-6, IL-8, and TNF-α), and AP-1 proteins (c-Jun, c-Fos, and JunB) including nitric oxide production. Study confirms the anti-inflammatory effect of apigenin by inhibiting the expression of inflammatory mediators and AP-1 factors involved in the inflammation and its importance in the treatment of lung inflammatory diseases. [ABSTRACT FROM AUTHOR]

Early brain injury (EBI) following subarachnoid hemorrhage (SAH) is associated with high morbidity and mortality. Inflammation has been considered as the major contributor to brain damage after SAH. SAH induces a systemic increase in pro-inflammatory cytokines and chemokines. Disruption of blood–brain barrier (BBB) facilitates the influx of inflammatory cells. It has been reported that the activation of toll-like receptor 4 (TLR4)/NF-κB signaling pathway plays a vital role in the central nervous system diseases. Apigenin, a common plant flavonoid, possesses anti-inflammation effect. In this study, we focused on the effects of apigenin on EBI following SAH and its anti-inflammation mechanism. Our results showed that apigenin (20 mg/kg) administration significantly attenuated EBI (including brain edema, BBB disruption, neurological deficient, severity of SAH, and cell apoptosis) after SAH in rats by suppressing the expression of TLR4, NF-κB and their downstream pro-inflammatory cytokines in the cortex and by up-regulating the expression of tight junction proteins of BBB. Double immunofluorescence staining demonstrated that TLR4 was activated following SAH in neurons, microglia cells, and endothelial cells but not in astrocytes. Apigenin could suppress the activation of TLR4 induced by SAH and inhibit apoptosis of cells in the cortex. These results suggested that apigenin could attenuate EBI after SAH in rats by suppressing TLR4-mediated inflammation and protecting against BBB disruption. [ABSTRACT FROM AUTHOR]

To evaluate the effect of apigenin (AP) on arthritis in rats stimulated by Freund’s complete adjuvant (FCA) was the main purpose of the investigation. Arthritis model was established by the administration of 0.1 ml FCA in the palmar surface. AP and diclofenac sodium (DS) were administered to explore and evidence the protective effects against adjuvant-induced arthritis (AA). Cytokines tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β) and interleukin-6 (IL-6) were detected to assess the anti-inflammatory effect of AP. Besides, pathological conditions were examined in rat paws. Related-proteins of nuclear factor kappa B (NF-κB) signal pathway activated by P2X7 were investigated to determine the molecular mechanism of AP and their expressions were measured by western blot. The data showed that AP significantly suppressed the expressions of P2X7/NF-κB signal-related proteins and alleviated inflammatory reactions. Therefore, it was assumed that AP might be a potential therapeutic candidate to treat arthritis. [ABSTRACT FROM AUTHOR]

Increasing evidence shows that inflammation may contribute to the pathophysiology of depression. Apigenin, one type of natural flavone, has a number of biological actions including anti-inflammatory effects. Although it has potential antidepressant activity in a chronic mild stress model, the mechanisms of antidepressant effect for apigenin remain unclear. Here, we examined the effects of apigenin on lipopolysaccharide (LPS)-induced depressive-like behavior in male mice. A single administration of LPS (0.5 mg/kg, i.p.) increased the immobility time in the tail suspension test (TST) and reduced sucrose preference without changing spontaneous locomotor activity in open field test (OFT). Pre-treatment with apigenin (25, 50 mg/kg, i.p.) or fluoxetine (positive control drug, 20 mg/kg, i.p.) once daily for 7 consecutive days prevented the abnormal behavior induced by LPS. Apigenin or fluoxetine also effectively attenuated LPS-induced production of pro-inflammatory cytokines IL-1β (interleukin-1β) and TNF-α (tumor necrosis factor-α). Moreover, apigenin or fluoxetine significantly suppressed the inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression at both the mRNA and protein level via the modulation of nuclear factor-κB (NF-κB) activation in the prefrontal cortex. Additionally, apigenin (50 mg/kg, i.p.) or fluoxetine (20 mg/kg, i.p.) effectively reversed the depressive-like behavior induced by TNF-α (0.1 fg/site, i.c.v.) without altering the locomotor activity. These results demonstrate that apigenin exhibits antidepressant-like effects in LPS treated mice, partially due to its anti-inflammatory properties. [ABSTRACT FROM AUTHOR]

This study aims to evaluate the possible mechanisms responsible for the anti-inflammatory effects of apigenin lipopolysaccharide (LPS)-induced inflammatory in acute lung injury. In this study, the anti-inflammatory effects of apigenin on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice and the possible mechanisms involved in this protection were investigated. Pretreatment with apigenin prior to the administration of intratracheal LPS significantly induced a decrease in lung wet weight/dry weight ratio in total leukocyte number and neutrophil percent in the bronchoalveolar lavage fluid (BALF) and in IL-6 and IL-1β, the tumor neurosis factor-α (TNF-α) in the BALF. These results showed that anti-inflammatory effects of apigenin against the LPS-induced ALI may be due to its ability of primary inhibition of cyclooxygenase-2 (COX-2) gene expression and nuclear factor kB (NF-kB) gene expression of lung. The results presented here suggest that the protective mechanism of apigenin may be attributed partly to decreased production of proinflammatory cytokines through the inhibition of COX-2 and NF-kB activation. The results support that use of apigenin is beneficial in the treatment of ALI. [ABSTRACT FROM AUTHOR]

Background: Apigenin is a non-toxic natural flavonoid that is abundantly present in common fruits and vegetables. It has been reported that apigenin has various beneficial health effects such as anti-inflammation and chemoprevention. Multiple studies have shown that inflammation is an important risk factor for atherosclerosis, diabetes, sepsis, various liver diseases, and other metabolic diseases. Although it has been long realized that apigenin has anti-inflammatory activities, the underlying functional mechanisms are still not fully understood. Methodology and Principal Findings: In the present study, we examined the effect of apigenin on LPS-induced inflammatory response and further elucidated the potential underlying mechanisms in human THP-1-induced macrophages and mouse J774A.1 macrophages. By using the PrimePCR array, we were able to identify the major target genes regulated by apigenin in LPS-mediated immune response. The results indicated that apigenin significantly inhibited LPS-induced production of pro-inflammatory cytokines, such as IL-6, IL-1β, and TNF-α through modulating multiple intracellular signaling pathways in macrophages. Apigenin inhibited LPS-induced IL-1β production by inhibiting caspase-1 activation through the disruption of the NLRP3 inflammasome assembly. Apigenin also prevented LPS-induced IL-6 and IL-1β production by reducing the mRNA stability via inhibiting ERK1/2 activation. In addition, apigenin significantly inhibited TNF-α and IL-1β-induced activation of NF-κB. Conclusion and Significance: Apigenin Inhibits LPS-induced Inflammatory Response through multiple mechanisms in macrophages. These results provided important scientific evidences for the potential application of apigenin as a therapeutic agent for inflammatory diseases. [ABSTRACT FROM AUTHOR]

Highlights: [•] Vitexin and isovitexin are C-glycosylated derivatives of apigenin. [•] Isovitexin was found as the most potent inhibitor against AR, AGE, and ChEs. [•] Vitexin showed the most potent PTP1B inhibitory activity. [•] Apigenin rather than vitexin and isovitexin showed anti-inflammatory activity. [•] C-glycosylation of apigenin might relate to intensity of respective bioactivities. [Copyright &y& Elsevier]

Abstract: The aim of this study was to develop and evaluate a novel topical delivery system for apigenin by using ethosomes. An optimal apigenin-loaded ethosome formulation was identified by means of uniform design experiments. Skin deposition and transdermal flux of apigenin loaded in ethosomes, liposomes, and deformable liposomes were compared in vitro and in vivo. The efficiency of apigenin encapsulation increased with an increase in the amount of phospholipids in ethosome formulations. Moreover, skin deposition and transdermal flux of apigenin improved with an increase in the levels of phospholipids (Lipoid S 75) and short-chain alcohols (propylene glycol and ethanol), but decreased with an increase in the ratio of propylene glycol to ethanol. Profiles of skin deposition versus time for ethosomes varied markedly between in vivo and in vitro studies compared with those of liposomes or deformable liposomes. Optimized ethosomes showed superior skin targeting both in vitro and in vivo. Moreover, they had the strongest effect on reduction of cyclooxygenase-2 levels in mouse skin inflammation induced by ultraviolet B (UVB) light. Therefore, apigenin-loaded ethosomes represent a promising therapeutic approach for the treatment of UVB-induced skin inflammation. [Copyright &y& Elsevier]

Acute and chronic inflammation is characterized by increased reactive oxygen species (ROS) production, dysregulation of mitochondrial metabolism and abnormal immune function contributing to cardiovascular diseases and sepsis. Clinical and epidemiological studies suggest potential beneficial effects of dietary interventions in inflammatory diseases but understanding of how nutrients work remains insufficient. In the present study, we evaluated the effects of apigenin, an anti-inflammatory flavonoid abundantly found in our diet, in endothelial cells during inflammation. Here, we show that apigenin reduced lipopolysaccharide (LPS)-induced apoptosis by decreasing ROS production and the activity of caspase-3 in endothelial cells. Apigenin conferred protection against LPS-induced mitochondrial dysfunction and reestablished normal mitochondrial complex I activity, a major site of electron leakage and superoxide production, suggesting its ability to modulate endothelial cell metabolic function during inflammation. Collectively, these findings indicate that the dietary compound apigenin stabilizes mitochondrial function during inflammation preventing endothelial cell damage and thus provide new translational opportunities for the use of dietary components in the prevention and treatment of inflammatory diseases. [ABSTRACT FROM AUTHOR]

Abstract: Infection with Helicobacter pylori causes extensive gastric epithelial cell inflammation which may progress to atrophic gastritis, intestinal metaplasia, and even gastric adenocarcinoma. Apigenin (4′,5,7-Trihydroxyflavone) is widely distributed in fruits and vegetables, and is a well-known antiinflammatory supplement with low cytotoxicity. In this study, we investigated the anti-inflammatory effects of apigenin in H. pylori-infected MKN45 cells, for which IκBα, cyclooxygenase-2 (COX-2), intercellular adhesion molecule-1 (ICAM-1), reactive oxygen species (ROS), interleukin-8 (IL-8), IL-6, IL-1β, and mucin-2 (MUC-2) expressions were examined. Apigenin treatments (9.3–74μM) significantly increased the IκBα expression, and thus inhibited nuclear factor kappa B (NF-κB) activation, and the inflammatory factor (COX-2, ICAM-1, ROS, IL-6, and IL-8) expressions decreased. The ROS levels decreased partially based on the intrinsic scavenging property of apigenin. In summary, apigenin treatments effectively inhibited NF-κB activation and the related inflammatory factor expressions, as well as increased MUC-2 expression in the H. pylori-infected MKN45 cells. The compound shows great potential as a candidate agent for the inhibition of H. pylori-induced extensive gastric epithelial cell inflammation. [Copyright &y& Elsevier]