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Phloretin ameliorates chemokines and ICAM-1 expression via blocking of the NF-κB pathway in the TNF-α-induced HaCaT human keratinocytes
Abstract
Previous studies found that phloretin had anti-oxidant, anti-inflammatory, and anti-tumor properties. In this study, we investigated whether phloretin could suppress the production of the intercellular adhesion molecule (ICAM)-1 and chemokines through downregulation of the nuclear transcription factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways in TNF-α-stimulated HaCaT human keratinocytes. HaCaT cells were treated with phloretin and then the cells were stimulated by TNF-α. Phloretin treatment decreased the production of IL-6, IL-8, CCL5, MDC, and TARC. Phloretin decreased ICAM-1 protein and mRNA expression, and also suppressed the adhesion of monocyte THP-1 cells to inflammatory HaCaT cells. Phloretin inhibited NF-κB translocation into the nucleus and also suppressed the phosphorylation of Akt and MAPK signal. In addition, phloretin increased heme oxygenase-1 production in a concentration-dependent manner. These results demonstrated that phloretin has anti-inflammatory effects to inhibit chemokines and ICAM-1 expressions through suppression of the NF-κB and MAPK pathways in human keratinocytes.
Copyright © 2015. Published by Elsevier B.V.
... Hence, these transcription factors act as both primary inducers and targets of the immune responses occurring in the keratinocytes. As NF-κB and MAPK are critical in skin immunopathology, the development of an effective strategy to block these pathways is a key step to controlling skin inflammation [10][11][12]. ...
... They decrease chemokine and cytokine production by inhibiting the activity of NF-κB or MAPK pathways [13][14][15][16]. However, steroids are immunosuppressive agents that inhibit immunocyte functions, and long-term dosage of non-steroidal anti-inflammatory drugs can cause side effects, such as allergic reactions or drug resistance [4,12]. Therefore, the development of novel, complementary, and alternative drugs that can alleviate inflammatory skin diseases is of particular interest. ...
... MCP-1 is a type of monocyte chemotactic activating factor, and it is a representative chemokine with regulated-upon-activation, normal T cell-expressed, and secreted (RANTES). MCP-1 is also known to be an important mediator of a variety of pathological conditions, including psoriasis and atopic dermatitis, and can be produced by fibroblasts, endothelial cells, mast cells, and keratinocytes [8,12,14]. Therefore, we studied the inflammation panel comprising the cytokine array, which indicated that DMC significantly inhibited the expression of chemokines and pro-inflammatory cytokines such as IL-8, IL-6, and MCP-1 in TNF-α-stimulated HaCaT cells in a dose-dependent manner (Figure 2). These findings suggest that DMC may be useful to treat inflammatory skin diseases such as psoriasis and other related allergic diseases, based on its regulatory effects on chemokines and pro-inflammatory cytokines. ...
7,8-dimethoxycoumarin (DMC, C11H10O4), a natural coumarin compound, is present in Citrus plants including Citrus decumana and grapefruit. It is known to have protective effects on the kidneys against Cisplatin and ischemia-reperfusion injury. However, the underlying mechanisms of its inhibitory effects on skin inflammation have not been investigated in vitro. Tumor necrosis factor (TNF)-α is known to be one of the main causative agents of skin inflammation. It induces pro-inflammatory cytokines and chemokines by activating nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling. In this study, we investigated the inhibitory effect of DMC on the expression of pro-inflammatory cytokines and chemokines in TNF-α-treated human keratinocyte HaCaT cells. Pretreatment with DMC inhibited TNF-α-treated cytokines (interleukin 6; IL-6) and chemokines (IL-8 and monocyte chemoattractant protein-1). In addition, DMC significantly inhibited TNF-α-treated NF-κB activation and phosphorylation of MAPKs, such as c-Jun N-terminal kinases (JNK) and extracellular-signal-regulated kinase (ERK). These results suggest that DMC may elicit an anti-inflammatory response by suppressing TNF-α-treated activation of NF-κB and MAPK pathways in keratinocytes. Hence, it might be a useful therapeutic drug against skin inflammatory diseases.
... TNF-α-stimulated HaCaT human keratinocytes 10, 30, or 100 µM Decreased the production of IL-6, IL-8, and CCL5; inhibited NF-κB nuclear translocation; suppressed phosphorylation of Akt and MAPK signal. [36] Human THP-1 monocytes 1, 10, or 30 µg/mL Reduced TNF-α, IL-6 and COX-2 expression [37] Rat basophilic leukemia RBL-2H3 cells 12 HepG2-xenografted tumor 10 mg/kg phloretin or +1 mg/kg paclitaxel Reduced tumor growth more than fivefold in the phloretin and paclitaxel-treated mice compared to the paclitaxel only treated mice [15] aberrant activation of various kinases and transcription factors involved in inflammatory signaling pathways. The following section will focus on detailing the molecular targets of phloretin as an anti-cancer agent ( Figure 1). ...
... Phloretin reduced the expression of COX-2 and intracellular adhesion molecule -1 (ICAM-1), and the production of IL-6 in human lung epithelial (A549) cells stimulated with IL-1β by blocking the activation of NF-κB via downregulation of Akt and MAP kinases phosphorylation [35]. Likewise, the secretion of various cytokines and chemokines, such as IL-6, IL-8, and monocyte chemoattractant protein-1(MCP1), and the reduced expression of ICAM-1 in TNF-α-stimulated HaCaT keratinocytes by phloretin, have been attributed to the inactivation of NF-κB and MAP kinases [36]. Huang et al. recently reported that treatment with phloretin attenuated the gene expression of a variety of inflammatory markers, such as COX-2, iNOS, CCL5, MCP1, and ICAM-1 in LPS-treated mouse lung tissue [22,34,36,52,53]. ...
... Likewise, the secretion of various cytokines and chemokines, such as IL-6, IL-8, and monocyte chemoattractant protein-1(MCP1), and the reduced expression of ICAM-1 in TNF-α-stimulated HaCaT keratinocytes by phloretin, have been attributed to the inactivation of NF-κB and MAP kinases [36]. Huang et al. recently reported that treatment with phloretin attenuated the gene expression of a variety of inflammatory markers, such as COX-2, iNOS, CCL5, MCP1, and ICAM-1 in LPS-treated mouse lung tissue [22,34,36,52,53]. ...
Apple is a rich source of bioactive phytochemicals that help improve health by preventing and/or curing many disease processes, including cancer. One of the apple polyphenols is phloretin [2′,4′,6′-Trihydroxy-3-(4-hydroxyphenyl)-propiophenone], which has been widely investigated for its antioxidant, anti-inflammatory and anti-cancer activities in a wide array of preclinical studies. The efficacy of phloretin in suppressing xenograft tumor growth in athymic nude mice implanted with a variety of human cancer cells, and the ability of the compound to interfere with cancer cells signaling, have made it a promising candidate for anti-cancer drug development. Mechanistically, phloretin has been reported to arrest the growth of tumor cells by blocking cyclins and cyclin-dependent kinases and induce apoptosis by activating mitochondria-mediated cell death. The blockade of the glycolytic pathway via downregulation of GLUT2 mRNA and proteins, and the inhibition of tumor cells migration, also corroborates the anti-cancer effects of phloretin. This review sheds light on the molecular targets of phloretin as a potential anti-cancer and anti-inflammatory natural agent.
... Different regions of the body can be affected including the neck, trunk, arms, legs, head, face, genitals, knees, and elbows, as well as the palmoplantar regions [3,4]. The quality of life of patients can be drastically decreased by the painful lesions, reduced self-confidence, social discomfort, anxiety, and depression linked with expressed and secreted (RANTES/ CCL5), macrophage-derived chemokine (CCL22/MDC), and thymus and activation-regulated chemokine TARC/ CCL17 [36]. In another study, the oral administration of phloretin in a mouse model of allergic contact dermatitis induced by 2,4-dinitrochlorobenzene (DNCB) allowed the reduction in pro-inflammatory cytokine levels including interleukin-4 (IL-4), IL-6, interleukin-17A (IL-17A), interferon gamma (IFN-γ), and thymic stromal lymphopoietin (TSLP) [37]. ...
... This study also showed that the interactions between IL-2-stimulated T cells and psoriatic keratinocytes require direct cellular contact [41]. macrophage-derived chemokine (CCL22/MDC), and thymus and activation-regulated chemokine TARC/ CCL17 [36]. In another study, the oral administration of phloretin in a mouse model of allergic contact dermatitis induced by 2,4-dinitrochlorobenzene (DNCB) allowed the reduction in pro-inflammatory cytokine levels including interleukin-4 (IL-4), IL-6, interleukin-17A (IL-17A), interferon gamma (IFN-γ), and thymic stromal lymphopoietin (TSLP) [37]. ...
Plaque psoriasis is a chronic inflammatory skin disease causing red inflamed lesions covered by scales. Leukocytes, including dendritic cells and T cells, participate in the inflammation of the skin by producing multiple cytokines, thus contributing to the hyperproliferation of keratinocytes. Lack of effectiveness and toxic side effects are the main concerns with conventional treatments, and research involving new antipsoriatic molecules is essential. In this study, the anti-inflammatory and antiproliferative effects of two natural polyphenols, phloretin and balsacone C, were investigated using the coculture of T cells and psoriatic keratinocytes. Phloretin exerted antiproliferative activity by regulating the expression of antigen Ki67 and proliferating cell nuclear antigen (PCNA). These effects were comparable to those of methotrexate, a reference treatment for moderate to severe psoriasis. With balsacone C, the expression of Ki67 was also reduced. Additionally, phloretin decreased the levels of multiple pro-inflammatory cytokines: monocyte chemoattractant protein-1 (MCP-1/CCL2), macrophage inflammatory protein-1α (MIP-1α), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-1 alpha (IL-1α), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), interleukin-17A (IL-17A), and tumor necrosis factor alpha (TNF-α). The increased interleukin-2 (IL-2) levels with phloretin and methotrexate also represented anti-inflammatory activity. Balsacone C and methotrexate decreased the levels of IL-1α and IL-1β, but methotrexate exerted a higher reduction. In summary, the anti-inflammatory effects of phloretin were more pronounced than those of methotrexate and balsacone C. In addition, the expression of lymphocyte common antigen (CD45) was more similar to that of the healthy condition after using phloretin or methotrexate. Finally, phloretin stood out from the other compounds and appears promising for psoriasis treatment.
... Plants are the major sources of natural antioxidant and anti-inflammatory phytomedicines [107,108]. Phloretin displays these activities and, hence, can be used for the management of oxidative stress and inflammatory degenerative disease [26,109,110]. Phloretin shows significant antioxidant action against 2,2-diphenyl-1-picrylhydrazyl (DPPH; IC50 = 10 mmol/L) and 2,2 -azino-bis-3-ethylbenzothiazoline-6sulfonic acid (ABTS; IC50 = 4.54 mmol/L) assays [29]. Also, phloretin decreases the matrix MMP-1, tyrosinase, and elastase activity. ...
... In fact, phloretin reduces the formation of pro-inflammatory cytokines, such as IL-10, IL-8, IL-6, and TNF-α. Additionally, it also inhibits the inducible nitric oxide synthetase (iNOS) and cyclooxygenase-2 (COX2) activity and thereby reduces the formation of nitric oxide and prostaglandins [110,112,113]. Phloretin activates Nrf2 signaling to decrease the release of IL-8 triggered by LPS and thereby produces an antiinflammatory effect in retinal pigment epithelium, and also inhibits the cellular glucose uptake [28]. ...
Phloretin is a flavonoid of the dihydrogen chalcone class, present abundantly in apples and strawberries. The beneficial effects of phloretin are mainly associated with its potent antioxidant properties. Phloretin modulates several signaling pathways and molecular mechanisms to exhibit therapeutic benefits against various diseases including cancers, diabetes, liver injury, kidney injury, encephalomyelitis, ulcerative colitis, asthma, arthritis, and cognitive impairment. It ameliorates the complications associated with diabetes such as cardiomyopathy, hypertension, depression, memory impairment, delayed wound healing, and peripheral neuropathy. It is effective against various microbial infections including Salmonella typhimurium, Listeria monocytogenes, Mycobacterium tuberculosis, Escherichia coli, Candida albicans and methicillin-resistant Staphylococcus aureus. Considering the therapeutic benefits, it generated interest for the pharmaceutical development. However, poor oral bioavailability is the major drawback. Therefore, efforts have been undertaken to enhance its bioavailability by modifying physicochemical properties and molecular structure, and developing nanoformulations. In the present review, we discussed the pharmacological actions, underlying mechanisms and molecular targets of phloretin. Moreover, the review provides insights into physicochemical and pharmacokinetic characteristics, and approaches to promote the pharmaceutical development of phloretin for its therapeutic applications in the future. Although convincing experimental data are reported, human studies are not available. In order to ascertain its safety, further preclinical studies are needed to encourage its pharmaceutical and clinical development.
... Phloretin (PT), a kind of flavonoid substance with the chemical composition of 3-(4hydroxyphenyl)-1-(2,4,6-trihydroxyphenyl)-1-propanone, is one of the most widely studied compounds among natural compounds [10]. It is mainly found in the peel and root bark of apples, pears and other fruits, and exhibits antioxidant, anticancer, anti-inflammatory, and antimicrobial properties [11][12][13][14]. Of particular note, PT has been reported to have strong antibacterial activity against Gram-negative bacteria by altering the activity of key enzymes responsible for energy metabolism and redox balance within the bacteria, reducing its ability to cope with oxidative stress [15]. ...
... Results from the present study demonstrated that PT inhibited the activation of NF-κB and TLR4, which is similar to a previous report of PT inhibiting the TLR4 signaling pathway, thereby alleviating inflammation in Nontypeable Haemophilus influenzae (NTHi)-infected mice [44]. Moreover, it has been reported that PT treatment significantly alleviated the DSSinduced increase in TLR4 expression and PT suppressed the NF-κB signaling, thereby the production of inflammatory cytokines and chemokines was inhibited [13,45]. Taking these findings together, these suggest that PT may inhibit the expression of the TLR4/NF-κB pathway to protect BRECs from inflammation. ...
Lipopolysaccharide (LPS) is an endotoxin that induces immune and inflammatory responses in the rumen epithelium of dairy cows. It is well-known that flavonoid phloretin (PT) exhibits anti-oxidative, anti-inflammatory and antibacterial activity. The aim of this research was to explore whether PT could decrease LPS-induced damage to bovine rumen epithelial cells (BRECs) and its molecular mechanisms of potential protective efficacy. BRECs were pretreated with PT for 2 h and then stimulated with LPS for the assessment of various response indicators. The results showed that 100 µM PT had no significant effect on the viability of 10 µg/mL LPS-induced BRECs, and this dose was used in follow-up studies. The results showed that PT pre-relieved the decline in LPS-induced antioxidant indicators (T-AOC and GSH-PX). PT pretreatment resulted in decreased interleukin-1β (IL-1β), IL-6, IL-8, tumor necrosis factor-α (TNF-α) and chemokines (CCL2, CCL5, CCL20) expression. The underlying mechanisms explored reveal that PT may contribute to inflammatory responses by regulating Toll-like receptor 4 (TLR4), nuclear transcription factor-κB p65 (NF-κB p65), and ERK1/2 (p42/44) signaling pathways. Moreover, further studies found that LPS-induced BRECs showed decreased expression of claudin-related genes (ZO-1, Occludin); these were attenuated by pretreatment with PT. These results suggest that PT enhances the antioxidant properties of BRECs during inflammation, reduces gene expression of pro-inflammatory cytokines and chemokines, and enhances barrier function. Overall, the results suggest that PT (at least in vitro) offers some protective effect against LPS-induced ruminal epithelial inflammation. Further in vivo studies should be conducted to identify strategies for the prevention and amelioration of short acute rumen acidosis (SARA) in dairy cows using PT.
... These factors lead to skin inflammation through an increase in immunocyte infiltration at the site of inflammation in the skin [9][10][11][12]. Previous studies have reported that transcription factors, such as the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), signal transducer, and activator of transcription-1 (STAT-1), as well as mitogen-activated protein kinase (MAPK), play important roles in the production of cytokines and chemokines in skin inflammation [13][14][15]. Therefore, inhibition of proinflammatory cytokines and chemokine production through the regulation of transcription factors, including NF-kB, STAT-1, and MAPKs in epidermal keratinocytes, can be an adequate strategy for inflammatory skin diseases. ...
... These factors lead to skin inflammation through an increase in immunocyte infiltration at the site of inflammation in the skin [9][10][11][12]. Previous studies have reported that transcription factors, such as the nuclear factor kappalight-chain-enhancer of activated B cells (NF-kB), signal transducer, and activator of transcription-1 (STAT-1), as well as mitogen-activated protein kinase (MAPK), play important roles in the production of cytokines and chemokines in skin inflammation [13][14][15]. Therefore, inhibition of pro-inflammatory cytokines and chemokine production through the regulation of transcription factors, including NF-kB, STAT-1, and MAPKs in epidermal keratinocytes, can be an adequate strategy for inflammatory skin diseases. ...
Artemisia anomala S. Moore is a perennial herbaceous plant classified as Asteraceae of the genus Artemisia. Many species of Artemisia have been used as medicinal materials. Artemisia anomala S. Moore has been widely used in China to treat inflammatory diseases. However, the mechanism of its action on the keratinocyte inflammatory response is poorly understood. Here, we investigated the anti-inflammatory reaction of Artemisia anomala S. Moore ethanol extract (EAA) using human keratinocyte (HaCaT) cells, which involved investigating the nuclear factor kappa B (NF-κB), signal transducer, and activator of transcription-1 (STAT-1), as well as mitogen-activated protein kinase (MAPK) signaling pathways and atopic dermatitis-like skin lesions in mice. We elucidated the anti-inflammatory effects of EAA on tumor necrosis factor-α/interferon-γ (TNF-α/IFN-γ)-treated human keratinocyte cells and 2,4-dinitrochlorobenzene (DNCB)-induced atopic dermatitis (AD)-like mice. The levels of chemokines and cytokines (IL-8, IL-6, TARC, and RANTES) were determined by an enzyme-linked immunosorbent assay. The NF-κB, STAT-1, and MAPK signaling pathways in HaCaT cells were analyzed by western blotting. Thickening of the mice dorsal and ear skin was measured and inflammatory cell infiltration was observed by hematoxylin and eosin staining. Results showed that EAA suppressed IL-8, IL-6, TARC, and RANTES production. EAA inhibited nuclear translocation of NFκB and STAT-1, as well as reduced the levels of phosphorylated ERK MAPKs. EAA improved AD-like skin lesions in DNCB-treated mice. These findings suggest that EAA possesses stronger anti-inflammatory properties and can be useful as a functional food or candidate agent for AD.
... Next, mice inhaled 2% OVA administered with an ultrasonic nebulizer for 30 min to induce asthma symptoms (DeVilbiss Pulmo-Aide 5650D, United States) on days 14, 17, 20, 23, and 27. Then, for 2 weeks (days [14][15][16][17][18][19][20][21][22][23][24][25][26][27], in addition to their regular diet, each mouse group received a daily dose of saline (N and OVA groups), sesamol (S10 and S30 groups), or prednisolone (P group). On day 28, we calculated the AHR in all mice; then, on day 29, we sacrificed mice to investigate the asthma pathology, immune regulation, inflammation, and oxidative stress. ...
... Human bronchial epithelial cells (BEAS-2B, American Type Culture Collection, Manassas, VA) were cultured in dulbecco's modified eagle medium (DMEM)/F12 medium, and seeded into 24-well plates. Cell viability was determined using the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT) solution (Sigma), as described previously [20]. BEAS-2B cells were treated with sesamol (0-100 µM) for 1 h, then cells were stimulated with or without 10 ng/mL TNF-α and 10 ng/mL IL-4 for 24 h. ...
Sesamol, isolated from sesame seeds (Sesamum indicum), was previously shown to have antioxidative, anti-inflammatory, and anti-tumor effects. Sesamol also inhibited lipopolysaccharide (LPS)-induced pulmonary inflammatory response in rats. However, it remains unclear how sesamol regulates airway inflammation and oxidative stress in asthmatic mice. This study aimed to investigate the efficacy of sesamol on oxidative stress and airway inflammation in asthmatic mice and tracheal epithelial cells. BALB/c mice were sensitized with ovalbumin, and received oral sesamol on days 14 to 27. Furthermore, BEAS-2B human bronchial epithelial cells were treated with sesamol to investigate inflammatory cytokine levels and oxidative responses in vitro. Our results demonstrated that oral sesamol administration significantly suppressed eosinophil infiltration in the lung, airway hyperresponsiveness, and T helper 2 cell-associated (Th2) cytokine expressions in bronchoalveolar lavage fluid and the lungs. Sesamol also significantly increased glutathione expression and reduced malondialdehyde levels in the lungs of asthmatic mice. We also found that sesamol significantly reduced proinflammatory cytokine levels and eotaxin in inflammatory BEAS-2B cells. Moreover, sesamol alleviated reactive oxygen species formation, and suppressed intercellular cell adhesion molecule-1 (ICAM-1) expression, which reduced monocyte cell adherence. We demonstrated that sesamol showed potential as a therapeutic agent for improving asthma.
... Oxidative stress regulates NF-ĸB activation, and the manifest of such stress has been demonstrated in sufferers from sepsis. Previously it was reported that phloretin possess anti-inflammatory properties due to inhibition of nucleus NF-κB translocation and suppression of mitogen-activated protein kinase (MAPK) signaling pathway proteins phosphorylation in human keratinocytes [37,39]. It is more likely that an increase in NF-ĸB and, therefore, up-regulation of cytokines, will happen in these patients [38]. ...
... Furthermore, the apple juice critically hinder the expression of NF-ĸB regulated pro-inflammatory genes (IL-1β, CXCL9, TNF-α), inflammatory-related enzymes (CYP3A4, COX-2), and transcription factors (STAT1, IRF1) in LPS/IFN-γ provoked MonoMac6 cells without significant influence on the expression of house-keeping genes [37]. Phloretin exhibited antiinflammatory effects through decreasing IL-6, IL-8, intercellular adhesion molecule (ICAM)-1 production and mRNA expression in TNF-α stimulated HaCaT human cells [39]. Furthermore, neuroprotective effects of phloretin has been demonstrated thorough Nrf2 pathway activation and oxidative stress suppression in rat [36]. ...
Background
Sepsis is a debilitating systemic disease and described as a severe and irregular systemic inflammatory reaction syndrome (SIRS) against infection. We employed CLP (Cecal Ligation and Puncture) model in rats to investigate anti-inflammatory and antioxidant effects of phloretin, as a natural antioxidant agent, and its protective effect on liver tissue damage caused by sepsis.
Methods
Male Wistar albino rats were randomly divided into three groups: sham group, CLP induced sepsis group and phloretin treated CLP group. Sepsis was induced by CLP method. 50 mmol/kg Phloretin was administered intraperitoneally in two equal doses immediately after surgery.
Results
It was observed that blood urea nitrogen (BUN) and tumor necrosis factor alpha (TNF-α) levels were dramatically increased in the CLP induced sepsis group (43.88 ± 1.905 mg/dl, 37.63 ± 1.92, respectively) when compared to the sham group. Moreover, tissue Glutathione (GSH) and liver nuclear factor ĸB (NF-ĸB p65) transcription factor values were higher in CLP induced sepsis group. This elevation was considerably reduced in the phloretin treated CLP group. No significant differences were observed in serum creatinine and creatinine phosphokinase levels.
Conclusions
The present study suggested that phloretin, as a natural protective agent, act against tissue damages introduced following the experimental sepsis induced model, likely caused by free oxygen radicals.
... Chen et al., 2024;Wei et al., 2020), anti-diabetes, and anti-cancer (Fan et al., 2022;Han et al., 2017;Kumar et al., 2023). PT has the potentials to reduce the production of melanin, inhibiting tyrosinase activity and preventing photoaging, melasma, and acne (Casarini et al., 2020;Huang et al., 2015). It is now widely used as a tanning and whitening cosmetic. ...
The purpose of this study was to prepare and evaluate the formulation of nanoemulsions (NEs) to encapsulate phloretin (PT) to improve its stability, antioxidant, and tyrosinase inhibitory competence. The aim of this study was to improve the stability, antioxidant, and tyrosinase inhibitory effects of PT via NEs. The formulations were prepared using low energy emulsification method for PT‐VE‐NEs, α‐tocopherol (Vitamin E) and medium chain triglycerides (MCT) were used as the oil phase, and Tween 60 was used as the emulsifier and PEG‐400 as the co‐emulsifier. The droplet size and zeta potential of oil‐in‐water NEs were evaluated using dynamic light scattering. The PT‐VE‐NEs were also characterized by transmission electron microscopy and Fourier transform infrared spectroscopy. The mean droplet diameter was 14.85 ± 0.14 nm, with a zeta potential of −2.47 ± 0.51 mV. Fourier transform infrared spectroscopy revealed the formation of molecular interactions in the NEs formulations. PT‐VE‐NEs size was maintained the same during the in vitro digestion study. The particle size of PT‐VE‐NE remained stable during in vitro digestion. The addition of VE significantly improved the antioxidant, tyrosinase inhibitory effects, as well as thelion and physical stability of PT‐VE‐NE. The results revealed that NEs is a promising strategy to improve the functionality and stability of PT and VE. PT‐VE‐NEs will be applied for the preservation of fruits.
... As well as killing P. acnes, PHL (1-50 μM) inhibited P. acnesinduced inflammatory signaling via Toll-like receptor 2 (TLR-2) in keratinocytes (Cheon et al. 2019). Furthermore, 10, 30, or 100 μM PHL was found to downregulate the production of proinflammatory cytokines and inhibit NF-κB nuclear translocation in TNF-α-stimulated human keratinocytes (HaCaT cells) (Huang et al. 2015). These studies suggest that PHL has the potential to be an effective treatment for inflammatory acne. ...
Honey has been reported to have a range of biological activities including antimicrobial, immunomodulatory, and wound healing effects. Indeed, medical‐grade honey is currently used in hospitals for the clinical management of wound infections. Honey is also of scientific interest for its therapeutic effects on other dermatological disorders such as atopic dermatitis, rosacea, and skin cancer. Recent studies have uncovered that honey contains a range of phytochemicals including flavonoids, dicarboxylic acids, coumarins, and phenolic acids. In this review, PubMed was used to search the scientific literature on the biological properties of honey phytochemicals in relation to dermatological disorders and to evaluate their potential as bioactive agents, drugs, or cosmeceuticals for the treatment of skin disease. The review revealed that phytochemicals found in honey have antimicrobial, anti‐inflammatory, antiaging, antioxidant, anticancer, depigmenting, photoprotective, wound healing, and skin barrier enhancing properties. Although further high‐quality studies are required to establish clinical efficacy, these findings suggest that honey phytochemicals may have the potential to be used as bioactive agents for the management of a range of dermatological disorders including wounds, psoriasis, atopic dermatitis, vitiligo, rosacea, and skin cancer.
... The researchers discovered that phloretin modulated the ASK-1-MAPK signal transduction pathway, resulting in the transcription of apoptotic genes. This mechanism effectively prevented osteoclast absorption induced by estrogen deficiency, thereby highlighting the potential of phloretin in mitigating bone loss (87). In conclusion, phloridzin metabolites play an important role in regulating bone dynamics and increasing bone mineral density and content. ...
Osteoporosis is a common metabolic disease in middle-aged and elderly people. It is characterized by a reduction in bone mass, compromised bone microstructure, heightened bone fragility, and an increased susceptibility to fractures. The dynamic imbalance between osteoblast and osteoclast populations is a decisive factor in the occurrence of osteoporosis. With the increase in the elderly population in society, the incidence of osteoporosis, disability, and mortality have gradually increased. Polyphenols are a fascinating class of compounds that are found in both food and medicine and exhibit a variety of biological activities with significant health benefits. As a component of food, polyphenols not only provide color, flavor, and aroma but also act as potent antioxidants, protecting our cells from oxidative stress and reducing the risk of chronic disease. Moreover, these natural compounds exhibit anti-inflammatory properties, which aid in immune response regulation and potentially alleviate symptoms of diverse ailments. The gut microbiota can degrade polyphenols into more absorbable metabolites, thereby increasing their bioavailability. Polyphenols can also shape the gut microbiota and increase its abundance. Therefore, studying the synergistic effect between gut microbiota and polyphenols may help in the treatment and prevention of osteoporosis. By delving into how gut microbiota can enhance the bioavailability of polyphenols and how polyphenols can shape the gut microbiota and increase its abundance, this review offers valuable information and references for the treatment and prevention of osteoporosis.
... Besides enhancing the nuclear translocation of Nrf2, the pretreatment of phloretin in a mouse model of LPS-induced lung injury has also been determined to significantly decrease pro-inflammatory cytokines by reducing p65 and the phosphorylation of the MAP kinases, p38, ERK 1/2, and JNK [54,60]. Furthermore, being associated with the blocking activity of phloretin on the nuclear translocation of NF-κB and the phosphorylation of Akt and MAP kinases, pretreatment of phloretin inhibits the secretion of inflammatory markers such as IL-6, PGE2, TNF-α, and NO and reduces the expression of COX-2, ICAM-1, CCL5, MCP1, and iNOS [57,59,60,[62][63][64] (Figure 7). Consequently, phloretin has incredible antioxidant activity due to the O-H bonds in its chemical structure and shows significant anti-inflammatory activity through multiple pathways. ...
Phloretin is a natural dihydrochalcone found in many fruits and vegetables, especially in apple tree leaves and the Manchurian apricots, exhibiting several therapeutic properties, such as antioxidant, antidiabetic, anti-inflammatory, and antitumor activities. In this review article, the diverse aspects of the anticancer potential of phloretin are addressed, presenting its antiproliferative, proapoptotic, antimetastatic, and antiangiogenic activities in many different preclinical cancer models. The fact that phloretin is a planar lipophilic polyphenol and, thus, a membrane-disrupting Pan-Assay Interference compound (PAIN) compromises the validity of the cell-based anticancer activities. Phloretin significantly reduces membrane dipole potential and, therefore, is expected to be able to activate a number of cellular signaling pathways in a non-specific way. In this way, the effects of this minor flavonoid on Bax and Bcl-2 proteins, caspases and MMPs, cytokines, and inflammatory enzymes are all analyzed in the current review. Moreover, besides the anticancer activities exerted by phloretin alone, its co-effects with conventional anticancer drugs are also under discussion. Therefore, this review presents a thorough overview of the preclinical anticancer potential of phloretin, allowing one to take the next steps in the development of novel drug candidates and move on to clinical trials.
... Phloretin is a recognized natural protective agent which acts against tissue damage caused by free oxygen radicals [194]. The most important pharmacological impacts of phloretin are anti-inflammatory effects [195][196][197][198], anti-apoptotic effects [199], antitumor activity [200], nootropic, neuroprotective, and neurotrophic activities [201][202][203], its effects against liver injury [204,205], its impacts against diabetic neuropathy [206,207], its effects against human cervical cancer cells [208,209], its positive effects against gastric cancer [210], breast cancer [211], hyperuricemia-related renal diseases [212], and as ZIKV antivirals [213]. ...
Natural products have a broad range of diversity of multidimensional chemical formation which play an important role, and indicate the crucial nature as a golden source for gaining herbal drug discovery. Thymoquinone performs various functions and has anticancer, anti-inflammatory, antioxidant, and anti-diabetic, impacts. It shows the significant influence on the treatment of different cancer types, such as bone cancer, bladder cancer, lung cancer, breast cancer, prostate cancer, and colon cancer. Sulforaphane has anticancer and antimicrobial properties, an anticarcinogenic constituents. Phloretin is a dihydrochalcone flavonoid which indicates a potent antioxidant activity in peroxynitrite scavenging and restraint of lipid peroxidation. The most important health benefits of phloretin are anti-inflammatory, and antioxidant activity, and impacts on cancer cells. Its antioxidant activity occurs through a reducer of lipid peroxidation, the scavenger of ROS, and its anti-inflammatory impacts happen through declined level of cytokines, adhesion molecules, chemokines, suppression of NF-κβ transcription, and decreased expression of COX-2 and iNOS. Phloretin impacts cancer cells through cytotoxic and apoptotic activity and activation of immune cells against tumor. Epigallocatechin-3-gallate is the most abundant tea polyphenol, followed by other polyphenols, namely, catechin, epicatechin, epigallocatechin, and epicatechin-3-gallate. In this review manuscript, some important medical health advantages and pharmaceutical effects of thymoquinone, sulforaphane, phloretin, and epigallocatechin have been mentioned.
... The exposure of cultured ARPE-19 cells to LPS increased IL-6 and IL-8 secretion by 20-and 74-fold, respectively, while phloretin pretreatment reduced IL-6 and IL-8 levels to 42% or 11.2%, respectively, of those seen in cells exposed to LPS alone. Similar results have been reported by Huang et al. in LPS-stimulated mouse macrophages, as well as in TNFαstimulated keratinocytes, and IL-1β-stimulated myofibroblasts [5,7,21]. ...
During age-related macular degeneration (AMD), chronic inflammatory processes, possibly fueled by high glucose levels, cause a breakdown of the retinal pigment epithelium (RPE), leading to vision loss. Phloretin, a natural dihydroxychalcone found in apples, targets several anti-inflammatory signaling pathways and effectively inhibits transporter-mediated glucose uptake. It could potentially prevent inflammation and cell death of RPE cells through either direct regulation of inflammatory signaling pathways or through amelioration of high glucose levels. To test this hypothesis, ARPE-19 cells were incubated with or without phloretin for 1 h before exposure to lipopolysaccharide (LPS). Cell viability and the release of pro-inflammatory cytokines interleukin 6 (IL-6), IL-8 and vascular endothelial growth factor (VEGF) were measured. Glucose uptake was studied using isotope uptake studies. The nuclear levels of nuclear factor erythroid 2-related factor 2 (Nrf2) were determined alongside the phosphorylation levels of mitogen-activated protein kinases. Phloretin pretreatment reduced the LPS-induced release of IL-6 and IL-8 as well as VEGF. Phloretin increased intracellular levels of reactive oxygen species and nuclear translocation of Nrf2. It also inhibited glucose uptake into ARPE-19 cells and the phosphorylation of Jun-activated kinase (JNK). Subsequent studies revealed that Nrf2, but not the inhibition of glucose uptake or JNK phosphorylation, was the main pathway of phloretin’s anti-inflammatory activities. Phloretin was robustly anti-inflammatory in RPE cells and reduced IL-8 secretion via activation of Nrf2 but the evaluation of its potential in the treatment or prevention of AMD requires further studies.
... When stimulated with inflammatory cytokines such as IFN-γ and TNF-α, human keratinocytes can express adhesion molecules such as ICAM-1 [31][32][33]. In some studies, the decrease in ICAM-1 expression by natural agents decreased the infiltration of immune cells into the skin, which could ameliorate inflammatory diseases of the skin [34]. Similarly, our study showed that the mRNA expression of ICAM-1 was reduced by PAB. ...
Polyopes affinis is a red algal species commonly found on the South coast and near Jeju Island, Korea. This study aimed to determine whether P. affinis extracts can inhibit the pathogenesis of T-helper-2 (Th2)-mediated inflammation in a human keratinocyte cell line of atopic dermatitis (AD). Cells were incubated with 10 ng/mL of interferon gamma (IFN-γ) and 10 ng/mL of tumor necrosis factor-alpha (TNF-α) at various concentrations of PAB (10, 30, and 60 µg/mL) and PAA (100, 500, and 1000 µg/mL) extracts. A gene-ontology (GO)-enrichment analysis revealed that PAB significantly enriched the genes associated with biological processes such as cell adhesion, immune response, inflammation, and chemokine-mediated pathways. PAB suppressed the expression of the secretory proteins and mRNAs that are associated with the thymus and the production of activation-regulated chemokines (TARC/CCL17) and macrophage-derived chemokines (MDC/CCL22). The effect of the extract on mitogen-activated protein kinases (MAPKs) was related to its inhibition of TARC/CCL17 and MDC/CCL22 production by blocking NF-κB and STAT1 activation. These results suggest that seaweed extract may improve AD by regulating pro-inflammatory chemokines. In conclusion, we first confirmed the existence of phloroglucinol, a polyphenol formed from a precursor called phlorotannin, which is present in PAB, and this result proved the possibility of PAB being used as a treatment for AD.
... The skin, which is divided into two major compartments known as the dermis and the epidermis, is the primary interface between the internal body and the external environment, serving as the first line of defense against exogenous stimuli, such as microbial, chemical, and thermal agents [1,2]. HaCaT keratinocytes which are mainly present in the skin's epidermis external layer are activated and produce inflammatory mediators that induce inflammation when exposed to inflammatory stimuli [3,4]. ...
Recent studies have revealed that marine brown seaweeds contain numerous bioactive compounds which exhibit various bioactivities. The present study investigated the effect of low molecular weight fucoidan (SCF) isolated from Sargassum confusum, a brown alga, on inflammatory responses and oxidative stress in HaCaT keratinocytes stimulated by tumor necrosis factor (TNF)-α/interferon (IFN)-γ. SCF significantly increased the cell viability while decreasing the intracellular reactive oxygen species (ROS) production in TNF-α/IFN-γ-stimulated HaCaT keratinocytes. In addition, SCF effectively reduced inflammatory cytokines (interleukin (IL)-1β, IL-6, IL-8, IL-13, TNF-α, and IFN-γ) and chemokines (Eotaxin, macrophage-derived chemokine (MDC), regulated on activation, normal T cell expressed and secreted (RANTES), and thymus and activation-regulated chemokine (TARC)) expression, by down-regulating the expression of epithelial and epidermal innate cytokines (IL-25, IL-33, and thymic stromal lymphopoietin (TSLP)). Furthermore, SCF suppressed the activation of TNF-α/IFN-γ-stimulated mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) signaling pathways, while activating the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway. The cytoprotective effect of SCF against TNF-α/IFN-γ stimulation was considerably reduced upon inhibition of HO-1 activity by ZnPP. Overall, these results suggest that SCF effectively suppressed inflammatory responses and oxidative stress in TNF-α/IFN-γ-stimulated HaCaT keratinocytes via activating the Nrf2/HO-1 signaling pathway.
... Phloretin (2′,4′,6′-Trihydroxy-3-(4-hydroxyphenyl)propiophenone), a natural polyphenolic compound, is found in apples, pears, and the Rosaceae family species (Lu & Foo, 1997;Mariadoss et al., 2019a). Phloretin has demonstrated various pharmacological effects, especially anti-oxidant, anti-inflammatory (Huang et al., 2015), and antitumor properties (Mariadoss et al., 2019b). Phloretin depicts anti-cancer activity in vitro in human esophageal cancer cells via mitochondria-dependent pathway by inducing downregulation of BCL-2 and upregulation of p53 protein thereby promoting apoptosis in cancer cells (Duan et al., 2017). ...
Recent advances demonstrate phytochemicals to be a potent anticancer therapeutic agent as various anti-cancer targets. This study depicts the anti-cancer potential against certain crucial common cancer targets leading to cancer cell proliferation and survival. The main objective of this study is to study the anti-cancer potential of phloretin against certain cancer targets. Ligand analysis was performed and Phloretin was chosen as the experimental ligand and Bcl-2, NF Kappa B, Carbonic anhydrase I (CA-1), Inducible Nitric Oxide Synthase (iNOS), Endothelial Nitric oxide synthase (eNOS), Caspase 3, and Caspase 9 proteins were chosen as targets. Induced fit molecular docking was performed by the use of Glide 6.5 software (Schrodinger - 2015). The docked poses were further evaluated based on binding energy, Conformational changes, and the amino acid residues involved in the protein-ligand interaction. The docking results depicted that phloretin showed notable binding affinity especially with carbonic anhydrase I, ENOS, and INOS. It also showcased significant potential against Caspase 3 and NF Kappa, thereby showing its potential as an effective anti-cancer therapeutics. During this study, the Inhibitory potential of Phloretin was studied as a result of this molecular docking study. This Insilico study revealed the binding efficiency of phloretin against the aforementioned targets. In vitro analysis is required for further validation of this data.
... In mouse lung, NTHi stimulated inflammation, particularly neutrophil influx as measured by CXCL1, which was suppressed by a phloretin diet. Previously, phloretin was found to inhibit IL8/CXCL1 in vitro in LPS/IFNg exposed human monocytic cells (Jung et al., 2009) and TNF-exposed human keratinocyte cells (Huang et al., 2015). However, the antibacterial effect of the phloretin diet may have reduced the initial inflammatory response to NTHi, therefore also contributing to the CXCL1 inhibition. ...
Bacterial infections contribute to accelerated progression and severity of chronic obstructive pulmonary disease (COPD). Apples have been associated with reduced symptoms of COPD and disease development due to their polyphenolic content. We examined if phloretin, an apple polyphenol, could inhibit bacterial growth and inflammation induced by the main pathogens associated with COPD. Phloretin displayed bacteriostatic and anti-biofilm activity against nontypeable Haemophilus influenzae (NTHi), Moraxella catarrhalis, Streptococcus pneumoniae, and to a lesser extent, Pseudomonas aeruginosa. In vitro, phloretin inhibited NTHi adherence to NCI-H292 cells, a respiratory epithelial cell line. Phloretin also exhibited anti-inflammatory activity in COPD pathogen-induced RAW 264.7 macrophages and human bronchial epithelial cells derived from normal and COPD diseased lungs. In mice, NTHi bacterial load and chemokine (C-X-C motif) ligand 1 (CXCL1), a neutrophil chemoattractant, was attenuated by a diet supplemented with phloretin. Our data suggests that phloretin is a promising antimicrobial and anti-inflammatory nutraceutical for reducing bacterial-induced injury in COPD.
... Atopic dermatitis (AD) is a chronic inflammatory disease characterized by severe itching and is caused by genetic and environmental factors, including microbial infection (1). Keratinocyte-derived cytokines and chemokines, such as interleukin-6 (IL-6), IL-8, thymus and activation-regulated chemokine (TARC), macrophage-derived chemokine (MDC), regulated upon activation, normal T cell expressed, and secreted (RANTES) and monocyte chemoattractant protein-1 (MCP-1), are closely related to the pathophysiology of AD (2)(3)(4). It is known that the combination of tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) induces the expression of inflammatory cytokines and chemokines in keratinocytes (5)(6)(7). ...
3,4,5‑Trihydroxycinnamic acid (THCA) exhibits anti‑inflammatory activity in acute or chronic inflammatory disorders, such as acute lung injury and asthma. The present study investigated the anti‑inflammatory activity of THCA in a tumor necrosis factor‑α/interferon‑γ (TI) mixture‑stimulated human keratinocyte cell line. The results of ELISA and reverse transcription‑quantitative PCR revealed that THCA reduced the secretion and mRNA expression levels of interleukin (IL)‑6; IL‑8; thymus and activation‑regulated chemokine; macrophage‑derived chemokine; regulated upon activation, normal T cell expressed and secreted; and monocyte chemoattractant protein‑1 in TI mixture‑stimulated HaCaT cells. In addition, the results of western blot analysis demonstrated that THCA exerted inhibitory activity on the activation of AKT, ERK and nuclear factor‑κB in TI mixture‑stimulated HaCaT cells. Furthermore, THCA upregulated the expression levels of heme oxygenase‑1 and NAD(P)H:quinone oxidoreductase 1, and the activation of nuclear factor erythroid 2‑related factor 2 in HaCaT cells. These results demonstrated that THCA may exhibit anti‑inflammatory activity in activated HaCaT cells.
... It is possible that the pre-treatment with the various tocopheryl derivatives in TNFα-stimulated HT29 cells prevents the oxidative stress, and then the activation of redox-sensitive regulatory transcription factors, such as NF-kB. In fact, TNFα administration to an animal model can up-regulate ICAM-1 and Cl-2 expression by NF-kB activation [69,70], as in various types of cells stimulated with TNFα [71][72][73]. Vitamin E reduces the phenobarbital-induced NF-kB activation in rats [74], and δ-Toc inhibits the phosphorylation of a kinase essential for TNFα-induced NF-kB activation in macrophages [75]. Moreover, δ-Toc prevents constitutive NF-kB activation in pancreatic cancer [76], and α-Toc succinate reduces NF-kB activity and ICAM-1 expression in prostate cancer cells [77]. ...
Vitamin E, a fat-soluble compound, possesses both antioxidant and non-antioxidant properties. In this study we evaluated, in intestinal HT29 cells, the role of natural tocopherols, α-Toc and δ-Toc, and two semi-synthetic derivatives, namely bis-δ-Toc sulfide (δ-Toc)2S and bis-δ-Toc disulfide (δ-Toc)2S2, on TNFα-induced oxidative stress, and intercellular adhesion molecule-1 (ICAM-1) and claudin-2 (Cl-2) expression. The role of tocopherols was compared to that of N-acetylcysteine (NAC), an antioxidant precursor of glutathione synthesis. The results show that all tocopherol containing derivatives used, prevented TNFα-induced oxidative stress and the increase of ICAM-1 and Cl-2 expression, and that (δ-Toc)2S and (δ-Toc)2S2 are more effective than δ-Toc and α-Toc. The beneficial effects demonstrated were due to tocopherol antioxidant properties, but suppression of TNFα-induced Cl-2 expression seems not only to be related with antioxidant ability. Indeed, while ICAM-1 expression is strongly related to the intracellular redox state, Cl-2 expression is TNFα-up-regulated by both redox and non-redox dependent mechanisms. Since ICAM-1 and Cl-2 increase intestinal bowel diseases, and cause excessive recruitment of immune cells and alteration of the intestinal barrier, natural and, above all, semi-synthetic tocopherols may have a potential role as a therapeutic support against intestinal chronic inflammation, in which TNFα represents an important proinflammatory mediator.
... Similarly, Huang et al. demonstrate that phloretin is more effective in inhibiting inflammatory response than phlorizin in cellular experiments ). In addition, phloretin exerts the anti-inflammatory effect through blocking the NF-jB and MAPK pathways in human lung epithelial cells, and it can also inhibit the expression of COX-2, intercellular adhesion molecule (ICAM)-1, and chemokines in keratinocytes (Huang et al. 2015a(Huang et al. , 2015b. Besides, phloretin downregulates the level of phosphorylated-JNK, which is involved in the inflammatory response caused by Propionibacterium acnes in keratinocytes (Cheon et al. 2019). ...
Sweet tea (Lithocarpus polystachyus Rehd.) has been consumed as herbal tea to prevent and manage diabetes for a long time. Recent studies indicate that sweet tea is rich in a variety of bioactive compounds, especially a class of nonclassical flavonoids, dihydrochalcones. In order to provide a better understanding of sweet tea and its main dihydrochalcones on human health, this review mainly summarizes related literature in the recent ten years, with the potential molecular mechanisms emphatically discussed. Phlorizin, phloretin, and trilobatin, three natural sweeteners, are the main dihydrochalcones in sweet tea. In addition, sweet tea and its dihydrochalcones exhibit plenty of health benefits, such as antioxidant, anti-inflammatory, antimicrobial, cardioprotective, hepatoprotective, antidiabetic, and anticancer effects, which are associated with the regulation of different molecular targets and signaling pathways. Therefore, sweet tea, as a rare natural source of dihydrochalcones, can be processed and developed into nutraceuticals or functional foods, with the potential application in the prevention and management of certain chronic diseases.
... Recently, various biological activities of phloretin have been reported, including anti-tumor (Wu et al., 2018;Choi, 2019), anti-inflammatory (Alsanea et al., 2017;, and anti-oxidation properties (Ren et al., 2016;Yang et al., 2018;Zhang et al., 2019). Phloretin has been reported to remove excess ROS from several types of cells through the redox signaling pathways, such as nuclear factor-κB/mitogen-activated protein kinase (Huang et al., 2015) and liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) pathways , to exert antioxidant activity. However, whether the antioxidant activity of phloretin is exerted in skeletal muscle cells, and can be further used for the treatment of muscle diseases, such as skeletal myopathies, are still unknown. ...
A new direction for the treatment of skeletal myopathies, which are mainly caused by abnormal mitochondrial metabolism, is the application of drugs and active substances to relieve oxidative stress in mitochondria. Phloretin, a dihydrochalcone active substance widely present in succulent fruits, has attracted attention for its strong antioxidant activity. This study aimed to investigate the potential antioxidant effects of phloretin and its potential mechanism of action in C2C12 mouse myoblasts. Under oxidative stress caused by 500 μmol/L H2O2, the addition of 10 μmol/L phloretin ameliorated the high level of reactive oxygen species, increased CuZn/Mn-dependent superoxide dismutase activities, and restored the loss of mitochondrial membrane potential. Additionally, apoptosis, necrocytosis, and the inhibition of cell proliferation caused by H2O2 stimulation were alleviated by phloretin. Moreover, phloretin significantly increased the expression of cyclin D1 and alleviated the stagnation trend of the G1 phase of cell proliferation caused by H2O2. Furthermore, the addition of phloretin simultaneously significantly increased the protein and mRNA expression of heme oxygenase-1 (HO-1) and alleviated the inhibitory phosphorylation of p-nuclear factor erythroid 2-related factor 2 (Nrf2), p-AMP-activated protein kinase (AMPK), and p-liver kinase B1 (LKB1) induced by H2O2. Moreover, the expression of nuclear Nrf2 was higher with phloretin treatment than without phloretin treatment. Overall, phloretin alleviated the proliferation inhibition and apoptosis induced by H2O2 and exerted antioxidant effects via the LKB1/AMPK/Nrf2/HO-1 pathway in C2C12 cells. These results provide insight for the application of phloretin to alleviate oxidative damage to muscle.
... It is found abundantly in apples and many plants including Pieris japonica, Hoveniae lignum, and Loise-leuria procumbens [8,9]. It has been studied comprehensively due to its multifunctional roles including antioxidant [10], anti-inflammatory [11], cardioprotective [12], anticancer [13], and antibacterial activities [14]. In our recent study, we observed that phloretin has an anti-bacterial activity against Propionibacterium acnes bacteria [15] and it protected the HEK293 cells from the P. acnesinduced inflammation by specifically targeting the dimerization of TLR2/1 suggesting its potential as an antibacterial as well as anti-inflammatory agent [16]. ...
... The final product of oxidative stress in the human body is MDA, which has cytotoxicity and hidden carcinogenic properties, and an abnormal level of MDA can lead to abnormal apoptosis in vivo [16]. MDA is formed by excessive free radical oxidative stress in extracellular membrane lipids, which can result in mitochondrial enzyme metabolic disorders and damage liver cell function [17]. ...
Objective:
To analyze the associations of severity of fatty liver with oxidative stress, serum amyloid protein A (SAA), C-reactive protein (CRP) and degree of cerebral arteriosclerosis (CAS) in CAS patients with the complication of fatty liver, and to explore the predictive values of risk factors for these patients.
Methods:
A total of 200 patients diagnosed with CAS in our hospital from October 2016 to November 2018 were selected, including 90 cases with fatty liver (observation group) and 110 cases without fatty liver (control group), and there were 123 males and 77 females. The general clinical data, liver function, oxidative stress status, inflammatory factor levels, and degree of CAS were compared between the two groups, and their correlations and influencing factors were explored.
Results:
1) There were no significant differences in the age, gender, and high-density lipoprotein (HDL) level between the observation group and control group (P>0.05). The body mass index (BMI), total cholesterol (TC), triglyceride (TG) and low-density lipoprotein (LDL) levels in the observation group were significantly higher than those in the control group. 2) The levels of liver function indexes, including alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transpeptidase (GGT), in the observation group were significantly higher than those in the control group, all (P<0.05). 3) In terms of the oxidative stress, the level of malondialdehyde (MDA) in the observation group was higher than that in the control group, while the levels of superoxide dismutase (SOD) and glutathione (GSH) in the observation group were obviously lower than in the control group, all (P<0.05). 4) The levels of inflammatory factors, including SAA, CRP and interleukin-6 (IL-6), in the observation group were much higher than those in the control group (P<0.05). 5) Observation group had higher whole blood low shear viscosity, whole blood high shear viscosity, and plasma viscosity than the control group (P<0.05). 6) ALT (r = 0.422, P = 0.000) and SAA (r = 0.828, P = 0.000) had positive correlations with the plasma viscosity, while GSH (r = -0.719, P<0.001) had a negative correlation with the plasma viscosity.
Conclusion:
The liver function index levels, oxidative stress status, and inflammatory factor levels in CAS patients may affect the severity of arteriosclerosis and fatty liver.
... NF-κB phosphorylation is abundantly detected in the lesional skin of psoriasis. TNF-α can activate ROS-dependent NF-κB phosphorylation in keratinocytes [41]. The p-NF-κB is also promoted in IMQ-induced keratinocyte inflammation via the MAPK pathway [19,42]. ...
[1-(4-chloro-3-nitrobenzenesulfonyl)-1H-indol-3-yl]-methanol (CIM) has been used as a bioactive agent for inhibiting tumor growth and angiogenesis via mitogen-activated protein kinase (MAPK) and NF-κB blocking. The present work was undertaken to investigate the potential of CIM against psoriasis using imiquimod (IMQ)-stimulated psoriasis-like mouse and in vitro HaCaT keratinocytes as the models. We demonstrated that topical CIM treatment reduced IMQ-activated scaling, erythema, and barrier dysfunction. This compound also restrained the recruitment of neutrophils. The cytokines, including TNF-α, IL-1β, IL-6, and IL-17 in psoriasiform skin, can be attenuated to normal baseline by CIM. Topically applied CIM can be easily delivered into skin based on the affinity with stratum corneum (SC) ceramides. IMQ intervention increased the permeability by 3-fold as compared to healthy skin. CIM ameliorated psoriatic lesion without incurring overt signs of irritation. Both TNF-α and IMQ were employed as the stimulators to activate HaCaT for reciprocal elucidation of the mechanism of action. CIM inhibited the overexpression of IL-1β, IL-6, and IL-24 in HaCaT. CIM exerted anti-inflammatory activity by suppressing the phosphorylation of NF-κB and activator protein-1 (AP-1) through MAPK pathways. Our results indicate that CIM has potential as the antipsoriatic molecule. The detailed signaling pathways still need further investigation.
... THP-1 cells were stained with calcein-AM solution (Sigma) for 30 min. BEAS-2B cells were co-cultured with THP-1 cells, and adherent THP-1 cells were observed by fluorescence microscopy (Olympus, Tokyo, Japan) as described previously [30]. ...
Licochalcone A was isolated from Glycyrrhiza uralensis and previously reported to have antitumor and anti-inflammatory effects. Licochalcone A has also been found to inhibit the levels of Th2-associated cytokines in the bronchoalveolar lavage fluid (BALF) of asthmatic mice. However, the molecular mechanism underlying airway inflammation and how licochalcone A regulates oxidative stress in asthmatic mice are elusive. In this study, we investigated whether licochalcone A could attenuate inflammatory and oxidative responses in tracheal epithelial cells, and whether it could ameliorate oxidative stress and airway inflammation in asthmatic mice. Inflammatory human tracheal epithelial (BEAS-2B) cells were treated with licochalcone A to evaluate oxidative responses and inflammatory cytokine levels. In addition, BALB/c mice were sensitized with ovalbumin (OVA) and injected intraperitoneally with licochalcone A (5 or 10 mg/kg). Licochalcone A significantly inhibited reactive oxygen species, eotaxin, and proinflammatory cytokines in BEAS-2B cells. Licochalcone A also decreased intercellular adhesion molecule 1 levels in inflammatory BEAS-2B cells, blocking monocyte cell adherence. We also found that licochalcone A significantly decreased oxidative responses, reduced malondialdehyde levels, and increased glutathione levels in the lungs of OVA-sensitized mice. Furthermore, licochalcone A decreased airway hyper-responsiveness, eosinophil infiltration, and Th2 cytokine production in the BALF. These findings suggest that licochalcone A alleviates oxidative stress, inflammation, and pathological changes by inhibiting Th2-associated cytokines in asthmatic mice and human tracheal epithelial cells. Thus, licochalcone A demonstrated therapeutic potential for improving asthma.
... However, Phlor did not affect the levels of IL-6, ICAM-1, and MCP-1 at the concentrations investigated. In contrast, Phlor has been shown effective to reduce the levels of IL-6 in LPS-treated macrophages [48], ICAM-1 in IL-1β-treated epithelial lung cells [49] and MCP-1 in colon and immune cells [35]. These results indicate that the effects of the apple polyphenols, including Phlor vary depending on numerous factors such as the cell line investigated, the specific pro-inflammatory cytokine tested, as well as the experimental conditions. ...
Plant-derived food consumption has gained attention as potential intervention for the improvement of intestinal inflammatory diseases. Apple consumption has been shown to be effective at ameliorating intestinal inflammation symptoms. These beneficial effects have been related to (poly)phenols, including phloretin (Phlor) and its glycoside named phloridzin (Phldz). To deepen the modulatory effects of these molecules we studied: i) their influence on the synthesis of proinflammatory molecules (PGE2, IL-8, IL-6, MCP-1, and ICAM-1) in IL-1β-treated myofibroblasts of the colon CCD-18Co cell line, and ii) the inhibitory potential of the formation of advanced glycation end products (AGEs). The results showed that Phlor (10–50 μM) decreased the synthesis of PGE2 and IL-8 and the formation of AGEs by different mechanisms. It is concluded that Phlor and Phldz, compounds found exclusively in apples, are positively associated with potential beneficial effects of apple consumption.
... Phloretin has the potential to block the pro-inflammatory gene expression in tumor necrosis factor-α (TNF-α) stimulated HaCaT cells, and at a concentration of 6.8 µM can effectively inhibit the proliferation of 50% of cells after 48 h of treatment. Also, phloretin was found to decrease the levels of interleukin (IL)-10, IL-8, interferon γinduced protein 10 kDa (IP-10), and NF-κB promoter signal transduction in a dose-dependent manner [18]. ...
Over the past two decades, many researchers have concluded that a diet rich in polyphenolic compounds plays an important therapeutic role in reducing the risk of cancer, cardiovascular disease, inflammation, diabetes, and other degenerative diseases. Polyphenolic compounds have been reported to be involved in neutralization of reactive oxygen species and charged radicals, and have anticarcinogenic effects, hepatoprotective effects, low-glycaemic response, and other benefits. The benefits of fruits and vegetables may be partly attributable to polyphenolic compounds, which have antioxidant and free radical scavenging properties. Fruits such as apples contain a variety of phytochemicals, including (+)-catechin and (-)-epicatechin, phlorizin, phloretin quercetin, cyanidin-3-Ogalactoside, chlorogenic acid, and p-coumaric acid, all of which are strong antioxidants. Phloretin, a natural phenolic compound, is a dihydrochalcone, which is present in the apple. It exhibits a wide variety of activities such as antioxidative, anti-inflammatory, anti-microbial, anti-allergic, anticarcinogenic, anti-thrombotic, and hepatoprotective, besides being involved in the activation of apoptotic associated gene expression and signal transduction in molecular pathways. Despite a multitude of clinical studies, new efforts are needed in clinical research to determine the complete therapeutic potential of phloretin.
... We speculated that this may be related to the immune imbalance of Th2/Th1 in mice with chronic eczema, and there was an immune imbalance of Th2/Th1 in chronic eczema mice, which was dominated by the activation of Th2 cells, thus leading to the increase of IL-4 expression level in mice (25,26). Huang et al (27) and Han et al (28) also reported that ICAM-1 level in chronic eczema patients were significantly higher than those in normal controls, similar to our results. ICAM-1 can be expressed in keratinocytes under the stimulation of sensitization, while scales, as one of the special diagnosis of chronic eczema, can further develop keratinocytes (29,30), which may also be the reason for the increase of ICAM-1 level in chronic eczema patients. ...
Effect of total glucosides of paeony on the changes of IL-4 and ICAM-1 levels in eczema mouse model serum was investigated. A total of 38 KM mice of SPF grade were divided into 3 groups: the control group (n=10), the model group (n=15) and the treatment group (n=13). The pathological model of chronic eczema in mouse right ear was induced using dinitrochlorobenzene acetone solution. Two ears of mice in the control group and the left ear of mice in the model and treatment groups were smeared with acetone as control. The mice in the treatment group were treated by administration with total glucoside of paeony. The changes of IL-4 and ICAM-1 levels were measured using caudal vein blood collection. The mouse ear weight was measured and the relationship among IL-4 and ICAM-1 levels, ear thickness and treatment time was analyzed. Mouse ear thickness in the model group was higher than that in the treatment and control groups (P<0.05). The weight of the mouse right ear in the model and treatment groups was significantly higher than that of the left ear (P<0.05). Furthermore, The IL-4 and ICAM-1 levels of mice in the model group were higher than that in the treatment and control groups (P<0.05). The IL-4 and ICAM-1 levels of mice in the model and treatment groups increased compared to that before modeling (P<0.05). The IL-4 and ICAM-1 levels of mice were positively correlated with ear thickness in the model group (r=0.865, P=0.002; r=0.833, P=0.009). In addition, the IL-4 level of mice was positively correlated with the ICAM-1 level in the model group (r=0.812, P=0.014). Finally, IL-4 and ICAM-1 may be involved in the pathologic process of chronic eczema. Therefore, the study showed that the total glucosides of paeony may play a role in the treatment of chronic eczema by regulating the IL-4 and ICAM-1 levels.
... Phloretin, a natural polyphenolic compound, is found in apples, pears and the Rosaceae family species [31]. Extensive research studies have reported that phloretin (2',4',6'-trihydroxy-3-(4-hydroxyphenyl)-propiophenone) has a wide range of pharmacological activities, such as anti-oxidant [32], anti-inflammatory [33], anti-tumor [34], and anti-microbial activity [35]. ...
Background: Mounting evidence over the past decade suggests that the number of phytochemicals were identified and designed on the basis of computer modeling (In slico method) to understand the interactions among the anti-cancer targeting proteins. Objectives: The aim of the present research was to find the anti-cancer targeting efficiency of phloretin by molecular docking. Methods: Based on the experimental evidence, a phytochemical of phloretin and epidermal growth factor receptor (EGFR), B cell lymphoma 2 (Bcl-2), nuclear factor-κB (NFkB), c-Kit receptor protein-tyrosine kinase, Farnesyl transferase, platelet-derived growth factors (PDGFs) and vascular endothelial growth factor receptor 2 (VEGFR2) proteins were utilized to perform induced fit docking by using Glide 6.5 (Schrodinger 2014-2). Multiple numbers of the poses were generated and evaluated for understanding the binding conformations and common interacting residues between ligands and proteins. Results: The docking results revealed that phloretin exhibited significant binding interaction pattern when compare to the known cancer target native inhibitor. Conclusion: Phloretin revealed good docking score and glide energy. Further studies are needed to explore its pharmacophoere properties and inhibitory potential in experimental models.
... Phloretin has anti-inflammatory effects, modulating the immune cell activity. The compound inhibits the expression and secretion of diverse pro-inflammatory agents including cytokines, such as IL-6, IL-8 and TNF-a, chemokines and adhesion molecules (Huang et al. 2015;Jung et al. 2009;Van Raemdonck et al. 2015). In addition, phloretin treatment decreases the expression of other pro-inflammatory proteins such as cyclooxigenase-2 (COX-2) and the inducible isoforms of the nitric oxide synthase (iNOS) (Chang et al. 2012). ...
Dihydrochalcones are a class of secondary metabolites, whose demand in biological and pharmacological applications is rapidly growing. Phloretin is one of the best known and abundant dihydrochalcone characterized by the presence of 2,6-dihydroxyacetophenone pharmacophore. It is a versatile molecule with anticancer, antiosteoclastogenic, antifungal, antiviral, anti-inflammatory, antibacterial and estrogenic activities and able to increase the fluidity of biological membranes and penetration of administered drugs. In this review we have performed a critical evaluation of available literature as far as phloretin beneficial effects and activation/block of intracellular signal cascade are of concern. In addition, we supply useful information on its chemical properties, sources and bioavailability.
... Phloretin (PT), a flavonoid of the chalcone class, is found in the fruit, leaves, and bark of apple trees (8). PT has many biological functions; it was shown to regulate glucose transporters, promote apoptosis in tumor cells, and enhance lipid metabolism to defend against obesity (9,10). PT was also found to have antioxidase activity, which reduced oxidative damage in a rat model of cerebral ischemia (11). ...
Phloretin (PT), isolated from the apple tree, was previously demonstrated to have antioxidative and anti-inflammatory effects in macrophages and anti-adiposity effects in adipocytes. Inflammatory immune cells generate high levels of reactive oxygen species (ROS) for stimulated severe airway hyperresponsiveness (AHR) and airway inflammation. In this study, we investigated whether PT could reduce oxidative stress, airway inflammation, and eosinophil infiltration in asthmatic mice, and ameliorate oxidative and inflammatory responses in tracheal epithelial cells. BALB/c mice were sensitized with ovalbumin (OVA) to induce asthma symptoms. Mice were randomly assigned to the five experimental groups: normal controls; OVA-induced asthmatic mice; and OVA-induced mice injected intraperitoneally with one of the three PT doses (5, 10, or 20 mg/kg). In addition, we treated inflammatory human tracheal epithelial cells (BEAS-2B cells) with PT to assess oxidative responses and the levels of proinflammatory cytokines and chemokines. We found that PT significantly reduced goblet cell hyperplasia and eosinophil infiltration, which decreased AHR, inflammation, and oxidative responses in the lungs of OVA-sensitized mice. PT also decreased malondialdehyde levels in the lung and reduced Th2 cytokine production in bronchoalveolar lavage fluids. Furthermore, PT reduced ROS, proinflammatory cytokines, and eotaxin production in BEAS-2B cells. PT also suppressed monocyte cell adherence to inflammatory BEAS-2B cells. These findings suggested that PT alleviated pathological changes, inflammation, and oxidative stress by inhibiting Th2 cytokine production in asthmatic mice. PT showed therapeutic potential for ameliorating asthma symptoms in the future.
Methotrexate is successfully used as the gold standard for managing moderate‐to‐severe psoriasis. However, the low bioavailability and short half‐life of the oral pills and the invasiveness of the parenteral injections make these suboptimal therapeutic options. Microneedles, bridging the advantages of the former forms, are successfully used to deliver methotrexate for different therapeutic purposes. However, the utilized dissolving microneedles demand frequent administration, potentially compromising patients’ compliance. Additionally, the high toxicity of methotrexate prompts a quest for safer alternatives. Phloretin, a natural compound with confirmed antipsoriatic potential, emerges as a promising candidate. Herein, microneedle patches with separable, slow‐degrading tips are developed for the sustained delivery of methotrexate and phloretin, as a comprehensive solution for long‐term psoriasis management. Both compounds are individually loaded at varying doses and display sustained‐release profiles. The developed microneedle patches demonstrate high mechanical strength, favorable drug delivery efficiency, and remarkable antipsoriatic potential both in vitro in keratinocytes and in vivo in a psoriasis mouse model. Comparative analysis with two subcutaneous injections reveals a similar antipsoriatic efficacy with a single patch of either compound, with prominent phloretin safety. Therefore, the developed patches present a superior alternative to methotrexate's current marketed forms and provide a viable alternative (phloretin) with comparable antipsoriatic efficacy and higher safety.
Tumor heterogeneity poses a significant challenge in osteosarcoma (OS) treatment. In this regard, the “omics” era has constantly expanded our understanding of biomarkers and altered signaling pathways (i.e., PI3K/AKT/mTOR, WNT/β-catenin, NOTCH, SHH/GLI, among others) involved in OS pathophysiology. Despite different players and complexities, many commonalities have been described, among which the nuclear factor kappa B (NF-κB) stands out. Its altered activation is pervasive in cancer, with pleiotropic action on many disease-relevant traits. Thus, in the scope of this article, we highlight the evidence of NF-κB dysregulation in OS and its integration with other cancer-related pathways while we summarize the repertoire of compounds that have been described to interfere with its action. In silico strategies were used to demonstrate that NF-κB is closely coordinated with other commonly dysregulated signaling pathways not only by functionally interacting with several of their members but also by actively participating in the regulation of their transcription. While existing inhibitors lack selectivity or act indirectly, the therapeutic potential of targeting NF-κB is indisputable, first for its multifunctionality on most cancer hallmarks, and secondly, because, as a common downstream effector of the many dysregulated pathways influencing OS aggressiveness, it turns complex regulatory networks into a simpler picture underneath molecular heterogeneity.
Phloretin (PHL), a flavonoid of the dihydrogen chalcone class, is reported to have low oral bioavailability due to its poor solubility and absorption. A common approach to enhance the solubility of such flavonoids is solubilization in a polymeric or lipidic matrix which would help in enhance dissolution rate and solubility. Accordingly, in the current study PHL was dissolved in Gelucire® 44/14 by melt-fusion technique and the viscous semisolid melt was adsorbed on a solid carrier to obtain free flowing granules. SeDeM-SLA (Solid-Liquid Adsorption) expert system was employed to select the most suitable carrier. This study achieved positive outcomes through the successful development of formulated oral PHL granules. The granules exhibited good stability, and favourable pharmacokinetic properties. In addition, the selected carrier effectively retained the antioxidant properties of phloretin.
D-mannose is a C-2 epimer of glucose, widely distributed in nature. Atopic dermatitis (AD) is a chronic inflammatory disease characterized by repetitious itching. The present study aimed to explore the protective effect and the underlying mechanism of D-mannose against the development of atopic dermatitis. We tested the effect of D-mannose by establishing DNCB (2,4-dinitrochlorobenzene)-induced AD mice models in vivo and culturing keratinocytes (HaCaT and NHEK) in vitro. The skin lesion severity was evaluated by histochemical staining. Cytokine expression levels were measured by real-time PCR and ELISA assay. The expression of the mammalian target of rapamycin (mTOR)/ nuclear transcription factor κB (NF-κB)-signaling-related molecules were determined by western blotting. Here, we found that topical supplementation of D-mannose remarkably attenuated skin lesions and recovered skin barrier function in AD mice model induced by DNCB. Furthermore, in vivo and in vitro experiments indicated that D-mannose inhibited tumor necrosis factor-α (TNF-α)-mediated increased expression of inflammatory cytokines. D-mannose also markedly downregulated TNF-α-stimulated activation of mTOR/NF-κB signaling pathway that was crucial for regulating the inflammatory condition. However, these effects were abolished by treatment with inhibitors of mTOR or NF-κB in HaCaT and NHEK. As far as we know, this is the first study uncovering the effective role of D-mannose via skin topical application. We found that D-mannose plays a regulatory role on inflammatory keratinocytes, suggesting its therapeutic utilization as a potential drug against atopic dermatitis.
Lithocarpus polystachyus (Wall.) Rehd. (L. polystachyus), a natural resource of herbal tea, has been historically consumed by several ethnic minorities. Modern investigations demonstrated L. polystachyus as a versatile pharmacological agent, with antioxidant, anti-inflammatory, anti-diabetes, anti-tumor, anti-hypertension, anti-obesity, hepatoprotection, and neuroprotection activities, meanwhile, no toxicity. Dihydrochalcones as its major, if not the most abundant, active ingredients, are known for numerous biological properties. Particularly, phloridzin, trilobatin, and phloretin, three prominent members of dihydrochalcones, have attracted attentions as either drug candidates or building blocks in modern drug development. In this review, we’ve brought together an up-to-date researches on the bioactive constituents, pharmacological effects and emerging mechanisms of L. polystachyus. We hope this review will provide a scientific rationale for understanding the health benefits, and if possible, preclinical assessment of novel applications of L. polystachyus.
Rheumatoid arthritis (RA) is a chronic autoimmune disease that primarily affects the synovial joints. RA has well-known clinical manifestations and can cause progressive disability and premature death along with socioeconomic burdens. Interleukin-6 (IL-6) has been implicated in the pathology of RA where it can stimulate pannus formation, osteoclastogenesis, and oxidative stress. Flavonoids are plant metabolites with beneficial pharmacological effects, including anti-inflammatory, antioxidant, antidiabetic, anticancer, and others. Flavonoids are polyphenolic compounds found in a variety of plants, vegetables, and fruits. Many flavonoids have demonstrated anti-arthritic activity mediated mainly through the suppression of pro-inflammatory cytokines. This review thoroughly discusses the accumulate data on the role of flavonoids on IL-6 in RA.
The beneficial health roles of dietary polyphenols in preventing oxidative stress related chronic diseases have been subjected to intense investigation over the last two decades. As our understanding of the role of gut microbiota advances our knowledge of the antioxidant and anti-inflammatory functions of polyphenols accumulates, there emerges a need to examine the prebiotic role of dietary polyphenols. This review focused on the role of different types and sources of dietary polyphenols on the modulation of the gut microbiota, their metabolites and how they impact on host health benefits. Inter-dependence between the gut microbiota and polyphenol metabolites and the vital balance between the two in maintaining the host gut homeostasis were discussed with reference to different types and sources of dietary polyphenols. Similarly, the mechanisms behind the health benefits by various polyphenolic metabolites bio-transformed by gut microbiota were also explained. However, further research should focus on the importance of human trials and profound links of polyphenols-gut microbiota-nerve-brain as they provide the key to unlock the mechanisms behind the observed benefits of dietary polyphenols found in vitro and in vivo studies.
Botanical molecules are known to have the ability to counteract ultraviolet radiation-induced skin damage. The interest in the development of natural compound-based products for the prevention of solar ultraviolet radiation-induced skin photoaging, melasma, and photocarcinogenesis has been increasing. Recently, the flavonoid phloretin has attracted the attention of researchers in the dermatological field for application in cosmetics and therapeutics. In addition to its antioxidant activity, phloretin has been shown to have properties such as anti-aging and depigmenting effects. In this study, we review the dermatological treatments with phloretin for conditions such as melasma, photoaging, acne, and melanoma. Phloretin has been shown to inhibit elastase and matrix metalloproteinase-1 activity, to reduce cellular tyrosinase activity and melanin content, and induce apoptosis in B16 mouse melanoma 4A5 cells. An in vivo study showed that phloretin, applied topically to the dorsal skin of mice, suppressed the 12-O-tetradecanoylphorbol 13-acetate-induced expression of COX-2, a critical molecular target of many chemopreventive, as well as anti-inflammatory agents. Phloretin can penetrate the skin; nevertheless, its penetration profile in different skin layers has not yet been evaluated. Despite its health benefits, phloretin application has been limited because of its photoinstability and poor aqueous solubility, among other limitations. Therefore, we reviewed the recent advances in pharmaceutical applications such as the use of nanotechnology, in order to improve the cutaneous availability of phloretin. In this review, we also focus on the oral application, product development challenges, and recent progress and future research directions on phloretin.
Atopic dermatitis (AD) is a chronic inflammatory disease of the skin that substantially affects a patient’s quality of life. While steroids are the most common therapy used to temporally alleviate the symptoms of AD, effective and nontoxic alternatives are urgently needed. In this study, we utilized a natural, plant-derived phenolic compound, phloretin, to treat allergic contact dermatitis (ACD) on the dorsal skin of mice. In addition, the effectiveness of phloretin was evaluated using a mouse model of ACD triggered by 2,4-dinitrochlorobenzene (DNCB). In our experimental setting, phloretin was orally administered to BALB/c mice for 21 consecutive days, and then, the lesions were examined histologically. Our data revealed that phloretin reduced the process of epidermal thickening and decreased the infiltration of mast cells into the lesion regions, subsequently reducing the levels of histamine and the pro-inflammatory cytokines interleukin (IL)-6, IL-4, thymic stromal lymphopoietin (TSLP), interferon-γ (IFN-γ) and IL-17A in the serum. These changes were associated with lower serum levels after phloretin treatment. In addition, we observed that the mitogen-activated protein kinase (MAPK) and NF-κB pathways in the dermal tissues of the phloretin-treated rodents were suppressed compared to those in the AD-like skin regions. Furthermore, phloretin appeared to limit the overproliferation of splenocytes in response to DNCB stimulation, reducing the number of IFN-γ-, IL-4-, and IL-17A-producing CD4 ⁺ T cells in the spleen back to their normal ranges. Taken together, we discovered a new therapeutic role of phloretin using a mouse model of DNCB-induced ACD, as shown by the alleviated AD-like symptoms and the reversed immunopathological effects. Therefore, we believe that phloretin has the potential to be utilized as an alternative therapeutic agent for treating AD.
Background
Thalidomide can be a TNF-α inhibitor for treating skin inflammation. This drug exhibits a strong toxicity that limits its application.
Objective
We synthesized a thalidomide analog containing the benzyl chloride group (2-[1-(3-chlorobenzyl)-2,6-dioxopiperidin-3-yl]isoindoline-1,3-dione, CDI) to examine anti-inflammatory activity against psoriasis.
Methods
The evaluation was conducted by the experimental platforms of in vitro TNF-α- or imiquimod (IMQ)-stimulated HaCaT cells and in vivo IMQ-induced psoriasiform plaque.
Results
Using the in vitro keratinocyte model, we demonstrated a greater inhibition of IL-1β, IL-6, and IL-24 by CDI than by thalidomide. No significant cytotoxicity was observed at 100 μM. CDI delivered facilely into the skin with a cutaneous targeting ability 228-fold greater than thalidomide. CDI caused a negligible irritation on healthy mouse skin. We showed that topically applied CDI reduced IMQ-induced red scaly lesions, hyperplasia, microabscesses, and cytokine expression in the mouse model. The skin-barrier function measured by transepidermal water loss (TEWL) could be partially recovered from 50.6 to 36.3 g/m²/h by CDI. The mechanistic study showed that CDI suppressed cytokine production by inhibiting the phosphorylation of NF-κB and AP-1 via MAPK pathways.
Conclusion
CDI would be beneficial for the development of a therapeutic agent against psoriasis.
Macrophages are the cells of the first-line defense system, which protect the body from foreign invaders such as bacteria. However, Gram-negative bacteria have always been the major challenge for macrophages due to the presence of lipopolysaccharides on their outer cell membrane. In the present study, we evaluated the effect of phloretin, a flavonoid commonly found in apple, on the protection of macrophages from Escherichia coli infection. RAW 264.7 cells infected with standard E. coli, or virulent E. coli K1 21 strain were treated with phloretin in a dose- dependent manner to examine its efficacy in protection of macrophages. Our results revealed that phloretin treatment reduced the production of nitric oxide (NO) and generation of reactive oxygen species along with reducing the secretion of proinflammatory cytokines induced by the E. coli and E. coli K1 21 strains in a concentration-dependent manner. Additionally, treatment of phloretin downregulated the expression of E. coli-induced major inflammatory markers i.e. cyclooxygenase-2 (COX-2) and hemeoxygenase-1 (HO-1), in a concentration dependent manner. Moreover, the TLR4-mediated NF-κB pathway was activated in E. coli-infected macrophages but was potentially downregulated by phloretin at the transcriptional and translational levels. Collectively, our data suggest that phloretin treatment protects macrophages from infection of virulent E. coli K1 strain by downregulating the TLR4-mediated signaling pathway and inhibiting NO and cytokine production, eventually protecting macrophages from E. coli-induced inflammation.
Diabetic neuropathy (DN) is one of most disabling disorder complicating diabetes mellites (DM), which affects more than 50% of the all diabetic patients during the disease course. Duloxetine (DX) is one of the first-line medication that approved by FDA for management of DN, nevertheless, it is too costly and has many adverse effects. Recently, phloretin (PH) exhibited powerful euglycemic, antihyperlipidemic, antioxidant, and anti-inflammatory activities. Therefore, we investigated the in vivo possible antineuropathic activity of phloretin, besides, its modulating effects on duloxetine potency, in a rat model of DN. Twelve-week-old male Wistar rats received a single intraperitoneal injection of 55 mg/kg STZ to induce DM. Either DX (30 or 15 mg/kg dissolved in distilled water), PH (50 0r 25 mg/kg dissolved in 0.5% DMSO) or a combination of 15 mg/kg DX and 25 mg/kg PH, used daily orally for 4 weeks to treat DN, starting from the end of the 4th week of DM development, when DN confirmed. Our finding showed that both DX and PH dose-dependently improved behavioral parameters (with the superiority of DX), sciatic nerve tissue antioxidant state, and suppressed tissue inflammatory cytokine, besides, they abrogated the tissue histopathological changes (with the superiority of PH). Moreover, DX augmented the DM metabolic disturbance and hepatic dysfunction, however, PH effectively amended these disorders. Furthermore, the low-dose combination of both, had the merits of both medications, with the alleviation of their disadvantages. Therefore, phloretin could be a promising agent in the management of DN either alone or in combination with duloxetine.
Quercetin (QC) is a dietary flavonoid abundant in many natural plants. A series of studies have shown that it has been shown to exhibit several biological properties, including anti-inflammatory, anti-oxidant, cardio-protective, vasodilatory, liver-protective and anti-cancer activities. However, so far the possible therapeutic effect of QC on psoriasis has not been reported. The present study was undertaken to evaluate the potential beneficial effect of QC in psoriasis using a generated imiquimod (IMQ)-induced psoriasis-like mouse model, and to further elucidate its underlying mechanisms of action. Effects of QC on PASI scores, back temperature, histopathological changes, oxidative/anti-oxidative indexes, pro-inflammatory cytokines and NF-κB pathway in IMQ-induced mice were investigated. Our results showed that QC could significantly reduce the PASI scores, decrease the temperature of the psoriasis-like lesions, and ameliorate the deteriorating histopathology in IMQ-induced mice. Moreover, QC effectively attenuated levels of TNF-α, IL-6 and IL-17 in serum, increased activities of GSH, CAT and SOD, and decreased the accumulation of MDA in skin tissue induced by IMQ in mice. The mechanism may be associated with the down-regulation of NF-κB, IKKα, NIK and RelB expression and up-regulation of TRAF3, which were critically involved in the non-canonical NF-κB pathway. In conclusion, our present study demonstrated that QC had appreciable anti-psoriasis effects in IMQ-induced mice, and the underlying mechanism may involve the improvement of antioxidant and anti-inflammatory status and inhibition on the activation of the NF-κB signaling. Hence, QC, a naturally occurring flavone with potent anti-psoriatic effects, has the potential for further development as a candidate for psoriasis treatment.
Phloretin, which can be isolated from apple trees, has demonstrable anti-inflammatory and anti-oxidant effects in macrophages. We previously reported that phloretin could inhibit the inflammatory response and reduce intercellular adhesion molecule 1 (ICAM-1) expression in interleukin (IL)-1β-activated human lung epithelial cells. In the present study we now evaluate whether phloretin exposure could ameliorate lipopolysaccharide (LPS)-induced acute lung injury in mice. Intra-peritoneal injections of phloretin were administered to mice for 7 consecutive days, prior to the induction of lung injury by intra-tracheal administration of LPS. Our subsequent analyses demonstrated that phloretin could significantly suppress LPS-induced neutrophil infiltration of lung tissue, and reduce the levels of IL-6 and tumor necrosis factor (TNF)-α in serum and bronchoalveolar lavage fluid. We also found that phloretin modulated myeloperoxidase activity and superoxide dismutase activity, with decreased gene expression levels for chemokines, proinflammatory cytokines, and ICAM-1 in inflamed lung tissue. Phloretin also significantly reduced the phosphorylation of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK), thus limiting the inflammatory response, while promoting expression of heme oxygenase (HO)-1 and nuclear factor erythroid 2-related factor 2, both of which are cytoprotective. Our findings suggest that, mechanistically, phloretin attenuates the inflammatory and oxidative stress pathways that accompany lung injury in mice via blockade of the NF-κB and MAPK pathways.
Phloretin (C15 H14 O5 ), a dihydrochalcone flavonoid, is mainly found in fruit, leaves, and roots of apple tree. Phloretin exerts antioxidant, anti-inflammatory, and anti-tumor activities in mammalian cells through mechanisms that have been partially elucidated throughout the years. Phloretin bioavailability is well known in humans, but still remains to be better studied in experimental animals, such as mouse and rat. The focus of the present review is to gather information regarding the mechanisms involved in the phloretin-elicited effects in different in vitro and in vivo experimental models. Several manuscripts were analyzed and data raised by authors were described and discussed here in a mechanistic manner. Comparisons between the effects elicited by phloretin and phloridzin were made whenever possible, as well as with other polyphenols, clarifying questions about the use of phloretin as a potential therapeutic agent. Toxicological aspects associated to phloretin exposure were also discussed here. Furthermore, a special section containing future directions was created as a suggestive guide towards the elucidation of phloretin-related actions in mammalian cells and tissues. © 2016 BioFactors, 2016.
Atopic dermatitis (AD) is a chronic allergic dermatosis characterized by epidermal thickening and dermal inflammatory infiltrates with a dominant Th2 profile during the acute phase, whereas a Th1 profile is characteristic of the chronic stage. Among chemokines and chemokine receptors associated with inflammation, increased levels of CX3CL1 (fractalkine) and its unique receptor, CX3CR1, have been observed in human AD. We have thus investigated their role and mechanism of action in experimental models of AD and psoriasis. AD pathology and immune responses, but not psoriasis, were profoundly decreased in CX3CR1-deficient mice and upon blocking CX3CL1-CX3CR1 interactions in wild-type mice. CX3CR1 deficiency affected neither antigen presentation nor T cell proliferation in vivo upon skin sensitization, but CX3CR1 expression by both Th2 and Th1 cells was required to induce AD. Surprisingly, unlike in allergic asthma, where CX3CL1 and CX3CR1 regulate the pathology by controlling effector CD4(+) T cell survival within inflamed tissues, adoptive transfer experiments established CX3CR1 as a key regulator of CD4(+) T cell retention in inflamed skin, indicating a new function for this chemokine receptor. Therefore, although CX3CR1 and CX3CL1 act through distinct mechanisms in different pathologies, our results further indicate their interest as promising therapeutic targets in allergic diseases.
Background
Acute liver damage is primarily induced by one of several causes, among them viral exposure, alcohol consumption, and drug and immune system issues. Agents with the ability to inhibit tyrosinase and protect against DNA damage caused by reactive oxygen species (ROS) may be therapeutically useful for the prevention or treatment of ROS-related diseases.
Methods
This investigation examined the hepatoprotective effects of phloretin and phloretin isonicotinyl hydrazone (PIH) on d-galactosamine (D-GalN)-induced acute liver damage in Kunming mice, as well as the possible mechanisms. The serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyl transferase (γ-GT), alkaline phosphatase (ALP), and total bilirubin (TB) as well as the histopathological changes in mouse liver sections were determined. The antioxidant effects of phloretin, quercetin, and PIH on lipid peroxidation in rat liver mitochondria in vitro, 1,1-diphenyl-2-picrylhydrazyl (DPPH) or 2,2-azino-bis-(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS) free radical scavenging activity in vitro, and supercoiled pBR322 plasmid DNA were confirmed. The experiment also examined the antityrosinase activity, inhibition type, and inhibition constant of phloretin and PIH.
Results
Phloretin, quercetin, or PIH significantly prevented the increase in serum ALT, AST, γ-GT, ALP, and TB in acute liver damage induced by D-GalN, and produced a marked reduction in the histopathological hepatic lesions. Phloretin, quercetin, or PIH also exhibited antioxidant effects on lipid peroxidation in rat liver mitochondria in vitro, DPPH or ABTS free radical scavenging activity in vitro, and supercoiled pBR322 plasmid DNA. Phloretin, quercetin, or PIH also exhibited good antityrosinase activity.
Conclusion
To the best of our knowledge, this was the first study of the hepatoprotective effects of phloretin and PIH on D-GalN-induced acute liver damage in Kunming mice as well as the possible mechanisms. This was also the first study of the lipid peroxidation inhibition activity of phloretin and PIH in liver mitochondria induced by the Fe2+/vitamin C (Vc) system in vitro, the protective effects on supercoiled pBR322 plasmid DNA, and the antityrosinase activity of phloretin and PIH.
Atopic dermatitis (AD) is a chronic inflammatory skin disease in which the skin barrier function is disrupted. In this inflammatory AD environment, cytokines are up-regulated, but the cytokine effect on the AD skin barrier is not fully understood. We aimed to investigate the influence of Th2 (IL-4, IL-13, IL-31) and pro-inflammatory (TNF-α) cytokines on epidermal morphogenesis, proliferation, differentiation and stratum corneum lipid properties. For this purpose, we used the Leiden epidermal model (LEM) in which the medium was supplemented with these cytokines. Our results show that IL-4, IL-13, IL-31 and TNF-α induce spongiosis, augment TSLP secretion by keratinocytes and alter early and terminal differentiation-protein expression in LEMs. TNF-α alone or in combination with Th2 cytokines decreases the level of long chain free fatty acids (FFAs) and ester linked ω-hydroxy (EO) ceramides, consequently affecting the lipid organization. IL-31 increases long chain FFAs in LEMs but decreases relative abundance of EO ceramides. These findings clearly show that supplementation with TNF-α and Th2 cytokines influence epidermal morphogenesis and barrier function. As a result, these LEMs show similar characteristics as found in AD skin and can be used as an excellent tool for screening formulations and drugs for the treatment of AD.Journal of Investigative Dermatology accepted article preview online, 11 February 2014; doi:10.1038/jid.2014.83.
Adhesion molecules such as ICAM-1 are important in the infiltration of leukocytes into the site of inflammation. In this study, we investigated the inhibitory effects of curcumin on ICAM-1 expression and monocyte adhesiveness as well as its underlying action mechanism in the TNF-α-stimulated keratinocytes. Curcumin induced expression of heme oxygenase-1 (HO-1) in the human keratinocyte cell line HaCaT. In addition, curcumin induced Nrf2 activation in dose- and time-dependent manners in the HaCaT cells. Curcumin suppressed TNF-α- induced ICAM-1 expression and subsequent monocyte adhesion, which were reversed by the addition of tin protoporphyrin IX (SnPP), a specific inhibitor of HO-1, or HO-1 knockdown using siRNA. Furthermore, Nrf2 knockdown using siRNA reversed the inhibitory effect of curcumin on the TNF-α-induced ICAM-1 expression and adhesion of monocytes to keratinocytes. These results suggest that curcumin may exert its anti-inflammatory activity by suppressing the TNF-α-induced ICAM-1 expression and subsequent monocyte adhesion via expression of HO-1 in the keratinocytes. [BMB Reports 2013; 46(8): 410-415].
BACKGROUND: Atopic dermatitis (AD) is a chronic, itching skin disease, and conventional therapies offer inadequate symptom management. Patients with AD are increasingly turning to Chinese medicine. OBJECTIVE: We systematically evaluated the clinical evidence of the efficacy and safety of oral Chinese herbal medicine for AD. METHODS: Searches were conducted on major electronic databases using the following key words: "randomized controlled trials," "atopic dermatitis," "traditional Chinese medicine," "traditional East Asian medicine," "herbal medicine," "Chinese herbal drugs," "medicinal plants," "phytotherapy," "Kampo medicine," and "Korean traditional medicine." The results were screened to include English/Chinese randomized controlled trials. A metaanalysis was conducted on suitable outcome measures. RESULTS: Seven randomized controlled trials were included (1 comparing Chinese herbal medicine and Western medicine with Western medicine alone; 6 comparing Chinese herbal medicine with placebo). Combined Chinese herbal medicine with Western medicine was superior to Western medicine alone. Three placebo controlled trials showed significant treatment efficacy and 2 showed significantly reduced concurrent therapy with Chinese herbal medicine. No abnormalities in safety profile or severe adverse events were reported. LIMITATIONS: A metaanalysis of all included studies could not be conducted because of study heterogeneity. CONCLUSIONS: Chinese herbal medicine significantly improved symptom severity of AD and was reported as well tolerated. However, the poor quality of studies did not allow for valid conclusions to support its tolerability and routine use. Additional studies addressing the methodologic issues are warranted to determine the therapeutic benefit of Chinese herbal medicine for AD.
Background:
Statins are extensively used for cardiovascular disease prevention. Statins reduce mortality rates more than other lipid-modulating drugs, although evidence from randomized controlled trials also suggests that statins unexpectedly increase the risk of diabetes and improve immune function. Physiologically, statins would be expected to lower androgens because statins inhibit production of the substrate for the local synthesis of androgens and statins' pleiotropic effects are somewhat similar to the physiological effects of lowering testosterone, so we hypothesized that statins lower testosterone.
Methods:
A meta-analysis of placebo-controlled randomized trials of statins to test the a priori hypothesis that statins lower testosterone. We searched the PubMed, Medline and ISI Web of Science databases until the end of 2011, using '(Testosterone OR androgen) AND (CS-514 OR statin OR simvastatin OR atorvastatin OR fluvastatin OR lovastatin OR rosuvastatin OR pravastatin)' restricted to randomized controlled trials in English, supplemented by a bibliographic search. We included studies with durations of 2+ weeks reporting changes in testosterone. Two reviewers independently searched, selected and assessed study quality. Two statisticians independently abstracted and analyzed data, using random or fixed effects models, as appropriate, with inverse variance weighting.
Results:
Of the 29 studies identified 11 were eligible. In 5 homogenous trials of 501 men, mainly middle aged with hypercholesterolemia, statins lowered testosterone by -0.66 nmol/l (95% confidence interval (CI) -0.14 to -1.18). In 6 heterogeneous trials of 368 young women with polycystic ovary syndrome, statins lowered testosterone by -0.40 nmol/l (95% CI -0.05 to -0.75). Overall statins lowered testosterone by -0.44 nmol/l (95% CI -0.75 to -0.13).
Conclusions:
Statins may partially operate by lowering testosterone. Whether this is a detrimental side effect or mode of action warrants investigation given the potential implications for drug development and prevention of non-communicable chronic diseases. See commentary article here http://www.biomedcentral.com/1741-7015/11/58.
Heme oxygenase-1 (HO-1) system catalyzes heme to biologically active products: carbon monoxide, biliverdin/bilirubin and free iron. It is involved in maintaining cellular homeostasis and many physiological and pathophysiological processes. A growing body of evidence indicates that HO-1 activation may play an important protective role in acute and chronic inflammation of gastrointestinal tract. This review focuses on the current understanding of the physiological significance of HO-1 induction and its possible roles in the gastrointestinal inflammation studied to date. The ability to upregulate HO-1 by pharmacological means or using gene therapy may offer therapeutic strategies for gastrointestinal inflammation in the future.
The mitogen-activated protein kinases (MAPKs) regulate diverse cellular programs by relaying extracellular signals to intracellular responses. In mammals, there are more than a dozen MAPK enzymes that coordinately regulate cell proliferation, differentiation, motility, and survival. The best known are the conventional MAPKs, which include the extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun amino-terminal kinases 1 to 3 (JNK1 to -3), p38 (α, β, γ, and δ), and ERK5 families. There are additional, atypical MAPK enzymes, including ERK3/4, ERK7/8, and Nemo-like kinase (NLK), which have distinct regulation and functions. Together, the MAPKs regulate a large number of substrates, including members of a family of protein Ser/Thr kinases termed MAPK-activated protein kinases (MAPKAPKs). The MAPKAPKs are related enzymes that respond to extracellular stimulation through direct MAPK-dependent activation loop phosphorylation and kinase activation. There are five MAPKAPK subfamilies: the p90 ribosomal S6 kinase (RSK), the mitogen- and stress-activated kinase (MSK), the MAPK-interacting kinase (MNK), the MAPK-activated protein kinase 2/3 (MK2/3), and MK5 (also known as p38-regulated/activated protein kinase [PRAK]). These enzymes have diverse biological functions, including regulation of nucleosome and gene expression, mRNA stability and translation, and cell proliferation and survival. Here we review the mechanisms of MAPKAPK activation by the different MAPKs and discuss their physiological roles based on established substrates and recent discoveries.
Mouse CCL8 is a CC chemokine of the monocyte chemoattractant protein (MCP) family whose biological activity and receptor usage have remained elusive. Here we show that CCL8 is highly expressed in the skin, where it serves as an agonist for the chemokine receptor CCR8 but not for CCR2. This distinguishes CCL8 from all other MCP chemokines. CCL8 responsiveness defined a population of highly differentiated, CCR8-expressing inflammatory T helper type 2 (T(H)2) cells enriched for interleukin (IL)-5. Ccr8- and Ccl8-deficient mice had markedly less eosinophilic inflammation than wild-type or Ccr4-deficient mice in a model of chronic atopic dermatitis. Adoptive transfer studies established CCR8 as a key regulator of T(H)2 cell recruitment into allergen-inflamed skin. In humans, CCR8 expression also defined an IL-5-enriched T(H)2 cell subset. The CCL8-CCR8 chemokine axis is therefore a crucial regulator of T(H)2 cell homing that drives IL-5-mediated chronic allergic inflammation.
The AMP-activated protein kinase (AMPK) is a sensor of energy status that, when activated by metabolic stress, maintains cellular energy homeostasis by switching on catabolic pathways and switching off ATP-consuming processes. Recent results suggest that activation of AMPK by the upstream kinase LKB1 in response to nutrient lack occurs at the surface of the lysosome. AMPK is also crucial in regulation of whole body energy balance, particularly by mediating effects of hormones acting on the hypothalamus. Recent crystal structures of complete AMPK heterotrimers have illuminated its complex mechanisms of activation, involving both allosteric activation and increased net phosphorylation mediated by effects on phosphorylation and dephosphorylation. Finally, AMPK is negatively regulated by phosphorylation of the ‘ST loop’ within the catalytic subunit.
Chemokines are low-molecular-weight, secreted proteins that act as leukocyte-specific chemoattractants. The chemokine family has more than 40 members. Based on the position of two conserved cysteines in the N-terminal domain, chemokines can be divided into the CXC, C, CC, and CX3C subfamilies. The interaction of chemokines with their receptors mediates signaling pathways that play critical roles in cell migration, differentiation, and proliferation. The receptors for chemokines are G protein-coupled receptors (GPCRs), and thus far, seven CXC receptors have been cloned and are designated CXCR1-7. Constitutively active GPCRs are present in several human immune-mediated diseases and in tumors, and they have provided valuable information in understanding the molecular mechanism of GPCR activation. Several constitutively active CXC chemokine receptors include the V6.40A and V6.40N mutants of CXCR1; the D3.49V variant of CXCR2; the N3.35A, N3.35S, and T2.56P mutants of CXCR3; the N3.35 mutation of CXCR4; and the naturally occurring KSHV-GPCR. Here, we review the regulation of CXC chemokine receptor signaling, with a particular focus on the constitutive activation of these receptors and the implications in physiological conditions and in pathogenesis. Understanding the mechanisms behind the constitutive activation of CXC chemokine receptors may aid in pharmaceutical design and the screening of inverse agonists and allosteric modulators for the treatment of autoimmune diseases and cancers.
There is lack of information and evidence-based studies on the treatment of pediatric pustular psoriasis. Previous reports have emphasized the limitations of the existing data and encouraged the exploration of therapy optimization through more structured research. The objective of the current study was to perform a systematic review of systemic interventions for pediatric pustular psoriasis with an emphasis on clinical response and treatment outcomes. A systematic literature search was conducted using the PubMed and Embase databases from 1982 to 2012. Of 632 references identified, 14 met our inclusion criteria and were included in the analysis. A cohort of eight patients from the Hospital for Sick Children, Toronto, Canada, was also included. Information was limited to systemic treatments in children. Only English- and Spanish-language articles were included. Information was gathered from 24 patients, 22 of whom (92%) presented with generalized pustular psoriasis and 2 (8%) with acral distribution. The mean age at presentation was 6.3 ± 4.9 years. More than one intervention was required in 12 (50%) cases. The most common therapies used for generalized pustular psoriasis were acitretin, cyclosporine, and methotrexate. We identified that there is lack of information regarding long-term response to systemic drugs because the data were focused on treatment initiation. Treatment of pustular psoriasis in pediatrics is challenging. Although acitretin, methotrexate, and cyclosporine seem to control generalized pustular psoriasis within 3 months of therapy initiation, information on long-term follow-up is lacking. Furthermore, physicians may encounter difficulties after discontinuing or tapering medications.
Occupational skin symptoms are prevalent among the workers of the seafood processing industry. In this study we investigate the role of salmon (Salmo salar) and king crab trypsin (Paralithodes camtschaticus) as inducers of inflammation in skin via secretion of inflammatory mediators. Human skin keratinocytes (HaCaT cells) were exposed to purified salmon and king crab trypsin. We observed that salmon trypsin enhanced the secretion of IL-8 and MMP-2 and crab trypsin enhanced the secretion of IL-8, MMP-2 and MMP-9 in a dose dependent manner. As protease activated receptors (PAR)-2 in skin are known to play an important role in physiology and pathology, we explored the involvement of in mediating the release of interleukin (IL)-8 and matrix metalloproteinase (MMP) -2 and -9 subsequent to exposure of skin keratinocytes to salmon and crab trypsin. In addition we observed that salmon and crab trypsin exhibit individual differences in stimulating the release of these inflammatory mediators. Finally, using specific small interfering RNA (siRNA) against PAR-2, we confirmed that the increase in secretion of IL-8, MMP-2 and MMP-9 in skin keratinocytes following exposure to salmon and crab trypsin was mediated via activation of PAR-2. These results suggest that exposure to proteases from the seafood may lead to inflammatory reactions in skin.
We have previously reported that P2Y11 receptor mediates IFN-γ-induced IL-6 production in human keratinocytes, suggesting the importance of purinergic signaling in skin inflammatory diseases. In this study, the involvement of various P2 receptors in IL-6 production induced by silica nanoparticle 30 (SNP30) was examined in a human keratinocyte cell line, HaCaT. Exposure to SNP30 increased IL-6 production in the cells. Ecto-nucleotidase (apyrase), a non-selective antagonist of P2Y receptors (suramin), and a selective P2Y11 receptor antagonist (NF157) all inhibited IL-6 production. Nucleotides such as ATP and UTP themselves also significantly increased IL-6 production in the cells. It was further confirmed that ATP was released from HaCaT cells exposed to SNP30. These results strongly support the possible role of ATP in SNP30-induced IL-6 production by HaCaT cells. In conclusion, these data demonstrate that P2Y11 receptor also mediates SNP30-induced IL-6 production in human keratinocytes, confirming that the ATP- P2Y11 purinergic signaling is a common pathway leading to induction of skin inflammatory diseases.
Background
Staphylococcus aureus (S. aureus) is found on the skin of approximately 90% of patients with atopic dermatitis and approximately 20% of apparently healthy subjects. S. aureus induces keratinocytes and immune cells to secrete immunoregulatory factors that cause epidermal barrier dysfunction in atopic skin. Objective: This study examined factors that cause epidermal permeability barrier dysfunction in skin colonized by S. aureus. Methods: We examined the effect of S. aureus on keratinocyte differentiation in the stratum corneum (SC) of in vivo skin, normal human keratinocytes (NHKs) and a reconstructed human epidermis (RHE) model. The fold change in expression of the terminal differentiation markers and the level of secreted cytokines were investigated. Results: The SC displayed decreased expression of keratin 10 (KRT 10). NHKs treated with S. aureus extracts increased expression of interleukin (IL)-6 and significantly reduced expression of the terminal differentiation markers KRT 1, KRT 10, Loricrin (LOR), and filaggrin (FLG); however, the expression of basal layer markers (KRT 5, KRT 14) remained unchanged. Treatment of NHKs with an anti-IL-6 antibody in combination with IL-6 or the S. aureus extracts inhibited the decrease in KRT 10 mRNA or protein expression. After the RHEs were exposed to the S. aureus extracts, KRT 1 and KRT 10 protein levels decreased. Conclusions: These findings suggest that S. aureus inhibits the terminal differentiation of keratinocytes by stimulating IL-6 secretion.
T-cell acute lymphoblastic leukemia (T-ALL) is characterized as a high-risk stratified disease associated with frequent relapse, chemotherapy resistance, and a poorer prognostic outlook than B-precursor ALL. Many of the challenges in treating T-ALL reflect the lack of prognostic cytogenetic or molecular abnormalities on which to base therapy, including targeted therapy. Notch1 activating mutations were identified in more than 50% of T-ALL cases and can be therapeutically targeted with γ-secretase inhibitors (GSIs). Mutant Notch1 can activate cMyc and PI3K-AKT-mTOR1 signaling in T-ALL. In T-ALLs with wild-type phosphatase and tensin homolog deleted on chromosome ten (PTEN), Notch1 transcriptionally represses PTEN, an effect reversible by GSIs. Notch1 also promotes growth factor receptor (IGF1R and IL7Rα) signaling to PI3K-AKT. Loss of PTEN is common in primary T-ALLs due to mutation or posttranslational inactivation and results in chronic activation of PI3K-AKT-mTOR1 signaling, GSI-resistance, and repression of p53-mediated apoptosis. Notch1 itself might regulate posttranslational inactivation of PTEN. PP2A is activated by Notch1 in PTEN-null T-ALL cells, and GSIs reduce PP2A activity and increase phosphorylation of AKT, AMPK, and p70S6K. This review focuses on the central role of the PI3K-AKT-mTOR1 signaling in T-ALL, including its regulation by Notch1 and potential therapeutic interventions, with emphasis on GSI-resistant T-ALL.
Atopic eczema (AE) is a challenge for modern medicine, because it is prevalent, severely affects quality of life of patients and their families, and causes high socioeconomic costs. The pathogenesis of AE is complex. While initial studies suggested a Th2 deviation as primary reason for the disease, numerous studies addressed a genetically predetermined impaired epidermal barrier as leading cause in a subgroup of patients. Recently, immune changes beyond the initial Th2 concept were defined in AE, with a role for specialized dendritic cells as well as newly identified T helper cell subsets such as Th17 and Th22 cells. Furthermore, trigger factors are expanded beyond classical Th2 allergens such as pollen or house dust mites to microbial products as well as self-antigens. This review pieces together our current understanding of immune as well as barrier abnormalities into the pathogenesis mosaic of AE.
Background Macrophage inflammatory protein (MIP)-1α binds to C–C chemokine receptor (CCR)-1 with high affinity. CCR-1 is expressed on neutrophils, eosinophils, monocytes, T lymphocytes and basophils; cells characteristic of atopic allergic inflammation. In vitro, MIP-1α is chemotactic for monocytes, T cells and basophils and is also a potent histamine-releasing factor for basophils and mast cells. Although increased levels of MIP-1α were shown in atopic allergic disorders, the kinetics of expression of these CC chemokines in vivo is largely unknown.
Objective To investigate the kinetics of expression of MIP-1α and receptor CCR-1 and the relationships between the expression and infiltration of inflammatory cells in allergen-induced cutaneous late-phase reactions in atopic subjects.
Methods Cryostat sections, obtained from skin biopsies from 10 human atopic subjects at 6, 24, 48, 72 h and 7 days after allergen challenge, were processed for immunohistochemistry and in situ hybridization using 35S-labelled riboprobes.
Results The peak expression of allergen-induced mRNA for MIP-1α and CCR-1 was 6 h. This was maintained at 24 h, and gradually returned to base line at 7 days. At 6 h, the number of cells expressing MIP-1α mRNA significantly correlated with elastase+ neutrophils and BB-1+ basophils. At 24 h, the MIP-1α mRNA+ cells significantly correlated with CD68+ macrophages. There were significant inverse correlations between the numbers of MIP-1α mRNA cells and the numbers of Tryptase+ mast cells at 6 and 24 h after allergen challenge.
Conclusion Allergen-induced cutaneous late-phase reactions in humans were associated with increased expression of MIP-1α and CCR-1. This may be relevant to the infiltration of neutrophils, eosinophils, basophils and macrophages.
Pruritus causes significant impairment in the quality of life of patients suffering from atopic dermatitis. Treatments for itch in atopic dermatitis range from simple avoidance of pruritus triggers to more complicated systemic therapy. Several treatments aim to target specific mediators of itch in atopic dermatitis, whereas others improve pruritus by reducing inflammation. Currentlythe most effective treatments for atopic dermatitis-associated itch are primarily topical or systemic anti-inflammatory agents. Better management of pruritus in atopic dermatitis is an important goal and necessitates the development of novel targeted treatments as well as efficient use of current therapies.
Many reports suggest that phloretin and phlorizin have antioxidant properties and can inhibit glucose transportation, the anti-inflammatory effects and mechanism of phloretin and phlorizin remain unclear. This study aims to evaluate the anti-inflammatory effects of phloretin and phlorizin in LPS-stimulated murine RAW264.7 macrophages. RAW264.7 cells were pretreated with various concentrations of phloretin or phlorizin (3-100μM) and cell inflammatory responses were induced with LPS. Pretreated with 10μM phloretin significantly inhibited the levels of NO, PGE(2), IL-6, TNF-α, iNOS and COX-2. Furthermore, it was demonstrated that phloretin suppressed the nuclear translocation of NF-κB subunit p65 proteins, and decreased phosphorylation in MAPK pathways. Surprisingly, phlorizin did not suppress the inflammatory response in LPS-stimulated RAW264.7 cells. These results suggest that phloretin has an anti-inflammatory effect that reduces levels of proinflammatory cytokines and mediators in RAW264.7 cells.
Illicium verum Hook. f. (star anise) has been used in traditional medicine for treatment of skin inflammation, rheumatism, asthma, and bronchitis. This study investigated the anti-inflammatory effects of Illicium verum extract (IVE) in the human keratinocyte HaCaT cell line.
We investigated the effectiveness of IVE in tumor necrosis factor-α (TNF-α)/interferon-γ (IFN-γ)-induced human keratinocytes. To measure the effects of IVE on chemokine and pro-inflammatory cytokine expression in HaCaT cells, we used the following methods: cell viability assay, reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, western blotting, and luciferase reporter assay.
IVE inhibited the expression of TNF-α/IFN-γ-induced mRNA and protein expression of thymus and activation-regulated chemokine (TARC/CCL17), macrophage-derived chemokine (MDC/CCL22), interleukin (IL)-6, and IL-1β. Furthermore, IVE decreased TNF-α/IFN-γ-induced mRNA expression of intercellular adhesion molecule-1 (ICAM-1). IVE inhibited nuclear factor (NF)-κB translocation into the nucleus, as well as phosphorylation and degradation of IκBα. IVE inhibited TNF-α/IFN-γ-induced NF-κB and signal transducer and activator of transcription (STAT)1 activation in a dose-dependent manner. In addition, IVE significantly inhibited activation of extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (MAPK), and Akt. Furthermore, IVE contained 2.14% trans-anethole and possessed significant anti-inflammatory activities.
IVE exerts anti-inflammatory effects by suppressing the expression of TNF-α/IFN-γ-induced chemokines, pro-inflammatory cytokines, and adhesion molecules via blockade of NF-κB, STAT1, MAPK, and Akt activation, suggesting that IVE may be a useful therapeutic candidate for inflammatory skin diseases, such as atopic dermatitis.
Atopic dermatitis, also known as atopic eczema, is a chronic pruritic skin condition affecting approximately 17.8 million persons in the United States. It can lead to significant morbidity. A simplified version of the U.K. Working Party's Diagnostic Criteria can help make the diagnosis. Asking about the presence and frequency of symptoms can allow physicians to grade the severity of the disease and response to treatment. Management consists of relieving symptoms and lengthening time between flare-ups. Regular, liberal use of emollients is recommended. The primary pharmacologic treatment is topical corticosteroids. Twice-daily or more frequent application has not been shown to be more effective than once-daily application. A maintenance regimen of topical corticosteroids may reduce relapse rates in patients who have recurrent moderate to severe atopic dermatitis. Pimecrolimus and tacrolimus are calcineurin inhibitors that are recommended as second-line treatment for persons with moderate to severe atopic dermatitis and who are at risk of atrophy from topical corticosteroids. Although the U.S. Food and Drug Administration has issued a boxed warning about a possible link between these medications and skin malignancies and lymphoma, studies have not demonstrated a clear link. Topical and oral antibiotics may be used to treat secondary bacterial infections, but are not effective in preventing atopic dermatitis flare-ups. The effectiveness of alternative therapies, such as Chinese herbal preparations, homeopathy, hypnotherapy/biofeedback, and massage therapy, has not been established.
Kawasaki disease is an acute febrile vasculitis of childhood that is associated with elevated production of inflammatory cytokines, causing damage to the coronary arteries. The production of proinflammatory cytokines and expression of adhesion molecules in human coronary arterial endothelial cells (HCAECs) is regulated by nuclear transcription factor-κB (NF-κB) activation. We have previously reported that the active form of vitamin D, 1α,25-dihydroxyvitamin D(3) (1α,25-(OH)(2)D(3)), inhibits tumor necrosis factor-α (TNF-α)-induced NF-κB activation. In this study, we examined the anti-inflammatory effects of 1α,25-(OH)(2)D(3) on TNF-α-induced adhesion molecule expression (vascular cellular adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1)) and cytokine production (interleukin-6 (IL-6) and IL-8) in HCAECs. Pretreatment with 1α,25-(OH)(2)D(3) significantly inhibited TNF-α-induced VCAM-1 expression and IL-8 production in HCAECs. Our results suggest that adjunctive 1α,25-(OH)(2)D(3) therapy may modulate the inflammatory response during Kawasaki disease vasculitis.
Mechanical ventilation is an indispensable supportive intervention for acute respiratory failure. However, mechanical ventilation can provoke ventilator-induced lung injury, which remains one of the major causes of morbidity and mortality in critically ill patients. Excessive inflammatory response characterized by infiltration of inflammatory cells and overproduction of inflammatory mediators contributes to the pathogenesis of ventilator-induced lung injury. At present, apart from the protective ventilation strategy, no other pharmacological intervention is available to attenuate ventilator-induced lung injury. Heme oxygenase-1 (HO-1) is the inducible isoform of the first and rate-limiting enzyme which degrades heme into carbon monoxide, ferritin and bilirubin. Accumulating evidence suggests that HO-1 system may function as a crucial negative regulator in the modulation of inflammatory process. This anti-inflammatory action of HO-1 is mediated essentially by the regulation of the key cells involved in inflammation and restoration of the balance between pro-inflammatory and anti-inflammatory mediators. Therefore, HO-1 system represents a promising therapeutic target for intervention of ventilator-induced lung injury.
The disturbed cytokine-chemokine network could play an important role in the onset of diseases with inflammatory processes such as chronic idiopathic urticaria (CIU). Our main objectives were to evaluate the relation between proinflammatory chemokine serum levels from CIU patients and their response to autologous skin test (ASST) and basophil histamine release (BHR). We also aimed to assess the chemokine secretion by peripheral blood mononuclear cells (PBMC) upon polyclonal stimulus and to evaluate chemokine C-C ligand 2/C-X-C chemokine 8 (CCL2/CXCL8) and Toll-like receptor-4 (TLR-4) expression in monocytes. We observed significantly higher serum levels of the CXCL8, CXCL9, CXCL10 and CCL2 in CIU patients compared to the healthy group, regardless of the BHR or ASST response. The basal secretion of CCL2 by PBMC or induced by Staphylococcus aureus enterotoxin A (SEA) was higher in CIU patients than in the control group, as well as for CXCL8 and CCL5 secretions upon phytohaemagglutinin stimulation. Also, up-regulation of CCL2 and CXCL8 mRNA expression was found in monocytes of patients upon SEA stimulation. The findings showed a high responsiveness of monocytes through CCL2/CXCL8 expression, contributing to the creation of a proinflammatory environment in CIU.
Atopic dermatis (AD) is a very common inflammatory skin disease in childhood. Various doctors such as paediatricians, general practitioners, allergologists and dermatologists are regularly consulted by these children and their parents, but there is no clear consensus on the diagnostic work-up that should be performed when evaluating a child with eczema. A careful history, clinical examination and adequate documentation of disease severity are essential in all children with eczema, irrespective of their disease severity. AD is a clinical diagnosis; diagnostic criteria, such as the UK diagnostic criteria, can be helpful for an accurate definition of the disease. A careful history, including alarm symptoms, respiratory symptoms and the impact of the disease on psychosocial functioning is important. Clinical scoring lists such as SCORAD and EASI are well validated for clinical studies; they are, however, not very suitable tools in clinical practice. More simple scoring systems, such as Three Item Severity Score (TIS) and Investigator Global Assessment (IGA), are more easy to use for clinical record keeping in daily practice. Allergen testing in children with AD without a history of acute non-eczematous reactions after allergen exposure is not necessary. In very young children with eczema, not yet exposed to foods, routine allergen testing is not necessary. If in individual cases, the decision is made to perform allergen tests, oral challenges should performed to confirm the diagnoses of food allergy.
Activation of NF-κB transcription factors by receptors of the innate or adaptive immune system is essential for host defense. However, after danger is eliminated, NF-κB signaling needs to be tightly downregulated for the maintenance of tissue homeostasis. This review highlights key negative regulatory principles that affect the amount, localization or conformational properties of NF-κB-activating proteins to attenuate the NF-κB response. These mechanisms are needed to prevent inflammation, autoimmune disease and oncogenesis.
Psoriasis is a common skin disease affecting about 1-3% of the world population. Many types of cells, including lymphocytes, dendritics APCs (antigen presenting cells), NKT (natural killer T) cells, neutrophils, keratinocytes and fibroblasts are involved in the pathogenesis of psoriasis.The aim of our study was to assess in psoriatic patients the production of IL-8, IL-10 and IL-12 cytokines by neutrophils, fibroblasts and fibroblasts - neutrophils interaction.
The production of IL-8, IL-10 and IL-12 cytokines was evaluated in supernatants after cells incubation for 21 h in culture medium alone and in medium in the presence of IL-8 or TNF-α. Concentrations of IL-8, IL-10, IL-12 were measured by enzyme-linked immunosorbent assay (ELISA) method using commercially available kits.
Our results demonstrate that fibroblasts are not able to produce IL-10 and IL-12 but they generate IL-8. The amount of IL-8 depends on the site of derivation of fibroblasts and on the stimuli. Neutrophils released IL-8, IL-12 (at a lower level in psoriatic patients) and IL-10 but only in the case of healthy donors and at a very low concentration. Moreover, we observed higher concentrations of IL-12 and IL-8 in supernatants as a result of fibroblasts-neutrophils interaction in psoriatic patients.
Our results suggest that fibroblasts take part in the inflammatory reaction in psoriasis via cytokines or direct interaction with neutrophils. Fibroblasts probably do not exert any anti-inflammatory effect.
Mutations in Ras play a critical role in the development of human cancers, including breast cancer. We investigated the possible antiproliferative effects of the naturally occurring dihydrochalcone phloretin [2',4',6'-trihydroxy-3-(4-hydroxyphenyl)-propiophenone] on H-Ras-transformed MCF10A human breast epithelial (H-Ras MCF10A) cells. Phloretin suppressed H-Ras MCF10A cell proliferation in a dose-dependent manner and induced nuclear condensation in the cells, indicating that phloretin-induced cell death occurs mainly via the induction of apoptosis. Prominent upregulation of p53 and Bax and cleavage of poly (ADP)-ribose polymerase were also detected in the phloretin-treated cells. Finally, phloretin markedly increased caspase-3 activity as well as JNK and p38 mitogen-activated protein kinase signaling. Our findings suggest that the phloretin-induced apoptosis of breast tumor cells contributes to the chemopreventive potential of phloretin against breast cancer.
Phloretin (Ph), which can be obtained from apples, apple juice, and cider, is a known inhibitor of the type II glucose transporter (GLUT2). In this study, real-time PCR analysis of laser-capture microdissected (LCM) human hepatoma cells showed elevated expression (>5-fold) of GLUT2 mRNA in comparison with nonmalignant hepatocytes. In vitro and in vivo studies were performed to assess Ph antitumor activity when combined with paclitaxel (PTX) for treatment of human liver cancer cells. Inhibition of GLUT2 by Ph potentiated the anticancer effects of PTX, resensitizing human liver cancer cells to drugs. These results demonstrate that 50-150 microM Ph significantly potentiates DNA laddering induced in Hep G2 cells by 10 nM PTX. Activity assays showed that caspases 3, 8, and 9 are involved in this apoptosis. The antitumor therapeutic efficacy of Ph (10 mg/kg body weight) was determined in cells of the SCID mouse model that were treated in parallel with PTX (1 mg/kg body weight). The Hep G2-xenografted tumor volume was reduced more than fivefold in the Ph + PTX-treated mice compared to the PTX-treated group. These results suggest that Ph may be useful for cancer chemotherapy and chemoprevention.
Atopic dermatitis (AD) and psoriasis are genetically determined inflammatory skin disorders characterized by abnormal cytokine production. From association studies there is evidence that functionally relevant cytokine gene polymorphisms contribute to the genetic basis of psoriasis. Association studies in AD have mostly been limited to polymorphisms of T-helper 2-type cytokines, which dominate in acute AD lesions. Unexpectedly, the results of recent genome scans indicate linkage of AD to psoriasis susceptibility loci. Therefore, AD may also be influenced by genes that modulate cutaneous inflammation independently from atopic mechanisms.
To investigate further the role of cytokine gene polymorphisms in AD.
Polymorphisms in the genes encoding tumour necrosis factor-alpha (TNFA-238 G/A, -308 G/A), interleukin (IL)-1beta (IL1B-511 T/C, +3953 T/C), IL-6 (IL6-174 C/G), IL-10 (IL10-1082 A/G) and the IL-1 receptor antagonist (IL1RN intron 2) were investigated in German patients with AD (n = 94) and in healthy nonatopic individuals (n = 214) by polymerase chain reaction-based methods and direct cycle sequencing.
No association was found between AD and any of the polymorphisms analysed. This is in contrast to the recently described association between psoriasis and the TNFA-238 and IL1B-511 polymorphisms.
Our data indicate that cytokine gene polymorphisms may act as specific markers of inflammatory skin diseases rather than contribute to a general disposition towards cutaneous inflammation.
In humans, lesions of contact eczema or atopic dermatitis can exhibit increases in epidermal nerves, but the mechanism resulting in such nerve elongation are not fully understood. We found that contact hypersensitivity reactions to oxazolone in mice were associated with significant increases in the length of nerves in the epidermis and dermis. Using genetically mast cell-deficient c-kit mutant mice selectively repaired of their dermal mast cell deficiency with either wild-type or tumor necrosis factor (TNF)-deficient mast cells, we found that mast cells, and mast cell-derived TNF, significantly contributed to the elongation of epidermal and dermal PGP 9.5+ nerves and dermal CGRP+ nerves, as well as to the inflammation observed at sites of contact hypersensitivity in response to oxazolone. Moreover, the percentage of mast cells in close proximity to dermal PGP 9.5+ nerve fibers was significantly higher in wild-type mice and in c-kit mutant mice repaired of their dermal mast cell deficiency by the adoptive transfer of wild-type mast cells than in TNF-deficient mice or in TNF-/- mast cell-engrafted c-kit mutant mice. These observations show that mast cells, and mast cell-derived TNF, can promote the elongation of cutaneous nerve fibers during contact hypersensitivity in the mouse.
Phloretin, which is present in apples and pears, has been found to inhibit the growth of several cancer cells and induce apoptosis of B16 melanoma and HL60 human leukemia cells. The present study examined whether and how phloretin induces apoptosis of HT-29 human colon cancer cells. Phloretin (0-100 micromol/L) substantially decreased viable cell number and induced apoptosis of HT-29 cells in a dose-dependent manner. Western blot analysis of total cell lysates revealed that phloretin increased the protein levels of Bax but had no effect on Bcl-2. In addition, phloretin induced cleavage of caspase-8, -9, -7, and -3 and poly(ADP-ribose) polymerase. Furthermore, phloretin increased the levels of cytochrome c and Smac/Diablo in the cytosol. The present results indicate that phloretin inhibits HT-29 cell growth by inducing apoptosis, which may be mediated through changes in mitochondrial membrane permeability and activation of the caspase pathways.
IKKbeta/IKBKB (IkappaB kinase beta), also designated as IKK2, was named after its function of phosphorylating IkappaB molecules, the inhibitors of NF-kappaB transcription factors. The kinase activity of IKKbeta targets two adjacent serine residues of IkappaB leading to ubiquitination and proteasomal degradation of the inhibitor, followed by release and activation of NF-kappaB. Many signaling pathways that activate NF-kappaB converge at the level of IKKbeta. Examples of stimuli leading to IKKbeta and subsequent NF-kappaB activation include inflammatory cytokines (IL-1, TNFalpha), endotoxins (lipopolysaccharide), viral infection and double strand RNA as well as physical signals such as UV-irradiation. Transcription factors of the NF-kappaB protein family have a great variety of functions in regulating the immune system, cellular differentiation, survival and proliferation. NF-kappaB is an essential factor in acute as well as chronic inflammation, a pathological state which is either cause or co-factor in a great variety of diseases. Moreover, recent data suggest that many variants of cancer are characterized by elevated constitutive activity of NF-kappaB, which can act as a survival factor for malignant cells by its predominantly anti-apoptotic function. Given the tight regulation of NF-kappaB by IkappaB molecules and the central role of IKKbeta in phosphorylation and degradation of the inhibitor, IKKbeta is a very promising target for pharmaceutical substances aiming at interfering with NF-kappaB activation.