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International Journal of Molecular... Jun 2020Apigenin (4',5,7-trihydroxyflavone, flavonoid) is a phenolic compound that is known to reduce the risk of chronic disease owing to its low toxicity. The first study on...
Apigenin (4',5,7-trihydroxyflavone, flavonoid) is a phenolic compound that is known to reduce the risk of chronic disease owing to its low toxicity. The first study on apigenin analyzed its effect on histamine release in the 1950s. Since then, anti-mutation and antitumor properties of apigenin have been widely reported. In the present study, we evaluated the apigenin-mediated amelioration of skin disease and investigated its applicability as a functional ingredient, especially in cosmetics. The effect of apigenin on RAW264.7 (murine macrophage), RBL-2H3 (rat basophilic leukemia), and HaCaT (human immortalized keratinocyte) cells were analyzed. Apigenin (100 μM) significantly inhibited nitric oxide (NO) production, cytokine expression (interleukin (IL)-1β, IL6, cyclooxygenase (COX)-2, and inducible nitric oxide synthase [iNOS]), and phosphorylation of mitogen-activated protein kinase (MAPK) signal molecules, including extracellular signal-regulated kinase (ERK) and c-Jun N-terminal protein kinase (JNK) in RAW264.7 cells. Apigenin (30 M) also inhibited the phosphorylation of signaling molecules (Lyn, Syk, phospholipase Cγ1, ERK, and JNK) and the expression of high-affinity IgE receptor FcεRIα and cytokines (tumor necrosis factor (TNF)-α, IL-4, IL-5, IL-6, IL-13, and COX-2) that are known to induce inflammation and allergic responses in RBL-2H3 cells. Further, apigenin (20 μM) significantly induced the expression of filaggrin, loricrin, aquaporin-3, hyaluronic acid, hyaluronic acid synthase (HAS)-1, HAS-2, and HAS-3 in HaCaT cells that are the main components of the physical barrier of the skin. Moreover, it promoted the expression of human β-defensin (HBD)-1, HBD-2, HBD-3, and cathelicidin (LL-37) in HaCaT cells. These antimicrobial peptides are known to play an important role in the skin as chemical barriers. Apigenin significantly suppressed the inflammatory and allergic responses of RAW264.7 and RBL cells, respectively, and would, therefore, serve as a potential prophylactic and therapeutic agent for immune-related diseases. Apigenin could also be used to improve the functions of the physical and chemical skin barriers and to alleviate psoriasis, acne, and atopic dermatitis.
Topics: Animals; Anti-Allergic Agents; Anti-Inflammatory Agents; Apigenin; Cell Line; Cytokines; Extracellular Signal-Regulated MAP Kinases; Filaggrin Proteins; HaCaT Cells; Humans; Immunoglobulin E; Interleukin-1beta; JNK Mitogen-Activated Protein Kinases; Mast Cells; Mice; Nitric Oxide; Nitric Oxide Synthase Type II; Phosphorylation; RAW 264.7 Cells; Rats; Receptors, IgE; Signal Transduction; Skin; Skin Diseases; Skin Physiological Phenomena; Tumor Necrosis Factor-alpha
PubMed: 32610574
DOI: 10.3390/ijms21134620 -
Cell Death & Disease Nov 2020Idiopathic pulmonary fibrosis (IPF) is featured with inflammation and extensive lung remodeling caused by overloaded deposition of extracellular matrix. Scutellarin is...
Idiopathic pulmonary fibrosis (IPF) is featured with inflammation and extensive lung remodeling caused by overloaded deposition of extracellular matrix. Scutellarin is the major effective ingredient of breviscapine and its anti-inflammation efficacy has been reported before. Nevertheless, the impact of scutellarin on IPF and the downstream molecular mechanism remain unclear. In this study, scutellarin suppressed BLM-induced inflammation via NF-κB/NLRP3 pathway both in vivo and in vitro. BLM significantly elevated p-p65/p65 ratio, IκBα degradation, and levels of NLRP3, caspase-1, caspase-11, ASC, GSDMD, IL-1β, and IL-18, while scutellarin reversed the above alterations except for that of caspase-11. Scutellarin inhibited BLM-induced epithelial-mesenchymal transition (EMT) process in vivo and in vitro. The expression levels of EMT-related markers, including fibronectin, vimentin, N-cadherin, matrix metalloproteinase 2 (MMP-2) and MMP-9, were increased in BLM group, and suppressed by scutellarin. The expression level of E-cadherin showed the opposite changes. However, overexpression of NLRP3 eliminated the anti-inflammation and anti-EMT functions of scutellarin in vitro. In conclusion, scutellarin suppressed inflammation and EMT in BLM-induced pulmonary fibrosis through NF-κB/NLRP3 signaling.
Topics: Animals; Apigenin; Epithelial-Mesenchymal Transition; Glucuronates; Inflammation; Male; Mice; NF-kappa B; Pulmonary Fibrosis; Transfection
PubMed: 33188176
DOI: 10.1038/s41419-020-03178-2 -
Oxidative Medicine and Cellular... 2022Plant preparations have been used to treat various diseases and discussed for centuries. Research has advanced to discover and identify the plant components with... (Review)
Review
Plant preparations have been used to treat various diseases and discussed for centuries. Research has advanced to discover and identify the plant components with beneficial effects and reveal their underlying mechanisms. Flavonoids are phytoconstituents with anti-inflammatory, antimutagenic, anticarcinogenic, and antimicrobial properties. Herein, we listed and contextualized various aspects of the protective effects of the flavonols quercetin, isoquercetin, kaempferol, and myricetin and the flavones luteolin, apigenin, 3',4'-dihydroxyflavone, baicalein, scutellarein, lucenin-2, vicenin-2, diosmetin, nobiletin, tangeretin, and 5-O-methyl-scutellarein. We presented their structural characteristics and subclasses, importance, occurrence, and food sources. The bioactive compounds present in our diet, such as fruits and vegetables, may affect the health and disease state. Therefore, we discussed the role of these compounds in inflammation, oxidative mechanisms, and bacterial metabolism; moreover, we discussed their synergism with antibiotics for better disease outcomes. Indiscriminate use of antibiotics allows the emergence of multidrug-resistant bacterial strains; thus, bioactive compounds may be used for adjuvant treatment of infectious diseases caused by resistant and opportunistic bacteria direct and indirect mechanisms. We also focused on the reported mechanisms and intracellular targets of flavonols and flavones, which support their therapeutic role in inflammatory and infectious diseases.
Topics: Anti-Bacterial Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antioxidants; Apigenin; Flavones; Flavonoids; Flavonols; Kaempferols; Luteolin; Plant Preparations; Quercetin
PubMed: 36111166
DOI: 10.1155/2022/9966750 -
Molecules (Basel, Switzerland) Sep 2022With technological advancements in the medicinal and pharmaceutical industries, numerous research studies have focused on the propolis produced by stingless bees (... (Review)
Review
With technological advancements in the medicinal and pharmaceutical industries, numerous research studies have focused on the propolis produced by stingless bees ( tribe) and honeybees as alternative complementary medicines for the potential treatment of various acute and chronic diseases. Propolis can be found in tropical and subtropical forests throughout the world. The composition of phytochemical constituents in propolis varies depending on the bee species, geographical location, botanical source, and environmental conditions. Typically, propolis contains lipid, beeswax, essential oils, pollen, and organic components. The latter include flavonoids, phenolic compounds, polyphenols, terpenes, terpenoids, coumarins, steroids, amino acids, and aromatic acids. The biologically active constituents of propolis, which include countless organic compounds such as artepillin C, caffeic acid, caffeic acid phenethyl ester, apigenin, chrysin, galangin, kaempferol, luteolin, genistein, naringin, pinocembrin, coumaric acid, and quercetin, have a broad spectrum of biological and therapeutic properties such as antidiabetic, anti-inflammatory, antioxidant, anticancer, rheumatoid arthritis, chronic obstruct pulmonary disorders, cardiovascular diseases, respiratory tract-related diseases, gastrointestinal disorders, as well as neuroprotective, immunomodulatory, and immuno-inflammatory agents. Therefore, this review aims to provide a summary of recent studies on the role of propolis, its constituents, its biologically active compounds, and their efficacy in the medicinal and pharmaceutical treatment of chronic diseases.
Topics: Amino Acids; Animals; Antioxidants; Apigenin; Caffeic Acids; Coumaric Acids; Coumarins; Flavonoids; Genistein; Humans; Hypoglycemic Agents; Kaempferols; Lipids; Luteolin; Oils, Volatile; Pharmaceutical Preparations; Propolis; Quercetin; Terpenes
PubMed: 36144852
DOI: 10.3390/molecules27186120 -
CNS Neuroscience & Therapeutics Nov 2022To investigate the effect of apigenin on fibrous scar formation after mouse spinal cord injury (SCI).
AIM
To investigate the effect of apigenin on fibrous scar formation after mouse spinal cord injury (SCI).
METHODS
The pneumatic impactor strike method was used to establish an SCI model. Mice were intraperitoneally injected with 5 mg/kg or 20 mg/kg apigenin daily for 28 days after SCI. The Basso Mouse Scale (BMS) score, hematoxylin-eosin staining, and immunohistochemical staining were used to assess the effect of apigenin on scar formation and motor function recovery. Western blotting and qRT-PCR were used to detect the expression of fibrosis-related parameters in spinal cord tissue homogenates. NIH-3 T3 cells and mouse primary spinal cord fibroblasts, α-Smooth muscle actin (α-SMA), collagen 1, and fibronectin were used to evaluate apigenin's effect in vitro. Western blotting and immunofluorescence techniques were used to study the effect of apigenin on TGFβ/SMADs signaling.
RESULTS
Apigenin inhibited fibrous scar formation in the mouse spinal cord and promoted the recovery of motor function. It reduced the expression of fibroblast-related parameters and increased the content of nerve growth factor in vivo, decreasing myofibroblast activation and collagen fiber formation by inhibiting TGFβ-induced SMAD2/3 phosphorylation and nuclear translocation in vitro.
CONCLUSION
Apigenin inhibits fibrous scar formation after SCI by decreasing fibrosis-related factor expression through TGFβ/SMADs signaling.
Topics: Actins; Animals; Apigenin; Cicatrix; Collagen; Eosine Yellowish-(YS); Fibronectins; Hematoxylin; Mice; Nerve Growth Factors; Recovery of Function; Signal Transduction; Spinal Cord; Spinal Cord Injuries; Transforming Growth Factor beta
PubMed: 35906830
DOI: 10.1111/cns.13929 -
Biomedicine & Pharmacotherapy =... May 2021Doxorubicin (DOX) is an anthracycline antitumor antibiotic widely utilized in treating various tumors. Nevertheless, the toxicity of DOX toward normal cells limits its...
BACKGROUND AND OBJECTIVE
Doxorubicin (DOX) is an anthracycline antitumor antibiotic widely utilized in treating various tumors. Nevertheless, the toxicity of DOX toward normal cells limits its applicability, with nephrotoxicity considered a major dose-limiting adverse effect. Apigenin (APG), a flavonoid widely distributed in natural plants, has been reported to have antioxidant, anti-inflammatory, and mild tumor-suppressive properties. In this study, we investigated the role of APG in DOX-induced nephrotoxicity and chemotherapeutic efficacy.
METHODS
Male BALB/c mice were administered DOX (11.5 mg/kg) via the tail vein to establish the DOX nephropathy model. After treatment with or without APG (125, 250, and 500 mg/kg) for two weeks, urine, serum, and tissue samples were collected to evaluate proteinuria, serum albumin, serum creatinine (Scr), blood urea nitrogen (BUN), superoxide dismutase (SOD) activity, malondialdehyde (MDA), glutathione (GSH), and pathological changes. Rat renal tubular epithelial cells (NRK52E), murine podocyte cells (MPC5), and murine breast cancer cells (4T1) were utilized to verify the effect of APG on DOX-induced cell injury. An MTT assay was employed to analyze cell viability. Apoptosis was evaluated using a colorimetric TUNEL staining and cleaved caspase-3 protein analysis by western blotting. A reactive oxygen species (ROS)/superoxide (O-) fluorescence probe was employed to determine oxidative injury. Western blotting was used to analyze nephrin, α-smooth muscle actin (α-SMA), collagen I (Col1), fibronectin (FN), and SOD2 expression. The mRNA levels of tumor necrosis factor-α (TNF-α), interleukin-18 (IL-18), IL-6, NACHT, LRR, PYD domain-containing protein 3 (NLRP3), caspase-1, and IL-1β were tested by reverse transcription-polymerase chain reaction (RT-PCR).
RESULTS
APG ameliorated DOX-elicited renal injuries in both the glomeruli and tubules. The DOX + APG groups had much lower tissue MDA, IL-6, TNF-α, NLRP3, caspase-1, and IL-1β levels and generation of intracellular ROS, but significantly higher SOD activity and GSH levels compared to those of the DOX group. Additionally, APG attenuated DOX-induced morphological changes, loss of cellular viability, and apoptosis in NRK-52E and MPC-5 cells, but not in 4T1 cells.
CONCLUSION
APG has a protective role against DOX-induced nephrotoxicity, without weakening DOX cytotoxicity in malignant tumors. Thus, APG may serve as a potential protective agent against renal injury and inflammatory diseases and may be a promising candidate to attenuate renal toxicity in cancer patients treated with DOX.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antibiotics, Antineoplastic; Antioxidants; Apigenin; Apoptosis; Cell Line, Tumor; Doxorubicin; Kidney Diseases; Kidney Function Tests; Kidney Glomerulus; Kidney Tubules; Male; Mice; Mice, Inbred BALB C; Oxidative Stress; Rats; Reactive Oxygen Species
PubMed: 33556877
DOI: 10.1016/j.biopha.2021.111308 -
Redox Biology Nov 2021Although effective drugs have been developed, including 5-fluorouracil (5-FU), advanced colorectal cancer (CRC) shows low therapeutic sensitivity resulting from the...
Although effective drugs have been developed, including 5-fluorouracil (5-FU), advanced colorectal cancer (CRC) shows low therapeutic sensitivity resulting from the development of 5-FU resistance. Thymidylate synthase (TS) is a target protein of 5-FU, and elevated TS lowers the 5-FU sensitivity of CRC cells. Here, we tested the efficacy of several candidate phytochemicals against human CRC-derived HCT116 cells expressing wild-type tumor suppressor protein P53 and HT29 cells expressing mutant P53. Among them, we found that apigenin enhanced the inhibitory effect of 5-FU on cell viability. In addition, apigenin inhibited the upregulation of TS induced by 5-FU. Apigenin also potentiated 5-FU-induced apoptosis of HCT116 cells and enhanced cell cycle disruption. Furthermore, apigenin increased reactive oxygen species production, intracellular and intramitochondrial Ca concentrations, and mitochondrial membrane potential upon cotreatment with 5-FU. Knockdown of forkhead box protein M, a transcription factor modulating 5-FU sensitivity, enhanced the potentiation of apoptosis by apigenin in HCT116 cells. Moreover, apigenin suppressed TS expression and inhibited the viability of 5-FU-resistant HCT116 cells. Therefore, apigenin may improve the therapeutic efficacy of 5-FU against CRC by suppressing TS, but apoptosis induction is mainly dependent on functional P53.
Topics: Antineoplastic Combined Chemotherapy Protocols; Apigenin; Apoptosis; Colorectal Neoplasms; Drug Resistance, Neoplasm; Drug Synergism; Fluorouracil; Humans; Thymidylate Synthase
PubMed: 34562873
DOI: 10.1016/j.redox.2021.102144 -
British Journal of Pharmacology Oct 2022Atopic dermatitis (AD) is one of the most common chronic inflammatory cutaneous diseases with unmet clinical needs. As a common ingredient found in several medicinal...
BACKGROUND AND PURPOSE
Atopic dermatitis (AD) is one of the most common chronic inflammatory cutaneous diseases with unmet clinical needs. As a common ingredient found in several medicinal herbs with efficacy on cutaneous inflammatory diseases, Scutellarein (Scu) has been shown to possess anti-inflammatory and anti-proliferative activities. We aimed to evaluate the therapeutic efficacy of Scu against AD and its underlying molecular mechanism.
EXPERIMENTAL APPROACH
Efficacy of Scu on AD was evaluated in 2,4-dinitrofluorobenzene (DNFB) and carvacrol-induced dermatitis mouse models. Cytokine mRNA and serum IgE levels were examined using qPCR and ELISA, respectively. Voltage clamp recordings were used to measure currents mediated by transient receptor potential (TRP) channels. In silico docking, site-direct mutagenesis, and covalent modification were used to explore the binding pocket of Scu on TRPV3.
KEY RESULTS
Subcutaneous administration of Scu efficaciously suppresses DNFB and carvacrol-induced pruritus, epidermal hyperplasia and skin inflammation in wild type mice but has no additional benefit in Trpv3 knockout mice in the carvacrol model. Scu is a potent and selective TRPV3 channel allosteric negative modulator with an apparent affinity of 1.18 μM. Molecular docking coupled with site-direct mutagenesis and covalent modification of incorporated cysteine residues demonstrate that Scu targets the cavity formed between the pore helix and transmembrane helix S6. Moreover, Scu attenuates endogenous TRPV3 activity in human keratinocytes and inhibits carvacrol-induced proliferative and proinflammatory responses.
CONCLUSION AND IMPLICATIONS
Collectively, these data demonstrate that Scu ameliorates carvacrol-induced skin inflammation by directly inhibiting TRPV3, and TRPV3 represents a viable therapeutic target for AD treatment.
Topics: Animals; Anti-Inflammatory Agents; Apigenin; Cymenes; Cysteine; Cytokines; Dermatitis, Atopic; Dinitrofluorobenzene; Humans; Immunoglobulin E; Inflammation; Mice; Mice, Knockout; Molecular Docking Simulation; RNA, Messenger; TRPV Cation Channels; Transient Receptor Potential Channels
PubMed: 35771623
DOI: 10.1111/bph.15913 -
Molecules (Basel, Switzerland) Jun 2022Inflammation is a severe topic in the immune system and play a role as pro-inflammatory mediators. In response to such inflammatory substances, immune cells release...
Inflammation is a severe topic in the immune system and play a role as pro-inflammatory mediators. In response to such inflammatory substances, immune cells release cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). Lipopolysaccharide (LPS) is known as an endotoxin in the outer membrane of Gram-negative bacteria, and it catalyzes inflammation by stimulating the secretion of inflammatory-mediated cytokines such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) by stimulated immune cells. Among the pathways involved in inflammation, nuclear factor kappa (NF-кB) and mitogen-activated protein kinases (MAPKs) are important. NF-kB is a diploid composed of p65 and IkBα and stimulates the pro- gene. MAPKs is a family consisting of the extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK), and p38, JNK and p38 play a role as proinflammatory mediators. Thus, we aim to determine the scutellarein (SCU) effect on LPS stimulated RAW264.7 cells. Furthermore, since scutellarein has been shown to inhibit the SARS coronavirus helicase and has been used in Chinese medicine to treat inflammatory disorders like COVID-19, it would be required to examine scutellarein's anti-inflammatory mechanism. We identified inflammation-inducing substances using western blot with RAW264.7 cells and SCU. And we discovered that was reduced by treatment with SCU in p-p65 and p-IκBα. Also, we found that p-JNK and p-ERK were also decreased but there was no effect in p-p38. In addition, we have confirmed that the iNOS was also decreased after treatment but there is no change in the expression of COX-2. Therefore, this study shows that SCU can be used as a compound to treat inflammation.
Topics: Animals; Apigenin; COVID-19; Cyclooxygenase 2; Cytokines; Extracellular Signal-Regulated MAP Kinases; Inflammation; Lipopolysaccharides; Mice; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; RAW 264.7 Cells; Signal Transduction
PubMed: 35744907
DOI: 10.3390/molecules27123782 -
Journal of Neurochemistry Jul 2021Neuroinflammation is initiated by activation of the brain's innate immune system in response to an inflammatory challenge. Insufficient control of neuroinflammation...
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.
Topics: ADP-ribosyl Cyclase 1; Animals; Apigenin; Astrocytes; Chemokines; Cytokines; Gene Deletion; Hippocampus; Inflammation; Injections, Intraventricular; Lipopolysaccharides; Macrophage Activation; Male; Membrane Glycoproteins; Mice; Mice, Inbred ICR; Mice, Knockout; Microglia; NAD; NF-kappa B; Nerve Degeneration; Niacinamide; Pyridinium Compounds
PubMed: 33871064
DOI: 10.1111/jnc.15367