Chlorogenic acid improves food allergy through the AMPK/ACC/CPT‐1 pathway

Meghnem D., Leong E., Pinelli M., Marshall J.S., Di Cara F.

Mast cells are specialized, tissue resident, immune effector cells able to respond to a wide range of stimuli. MCs are involved in the regulation of a variety of physiological functions, including vasodilation, angiogenesis and pathogen elimination. In addition, MCs recruit and regulate the functions of many immune cells such as dendritic cells, macrophages, T cells, B cells and eosinophils through their selective production of multiple cytokines and chemokines. MCs generate and release multi-potent molecules, such as histamine, proteases, prostanoids, leukotrienes, heparin, and many cytokines, chemokines, and growth factors through both degranulation dependent and independent pathways. Recent studies suggested that metabolic shifts dictate the activation and granule content secretion by MCs, however the metabolic signaling promoting these events is at its infancy. Lipid metabolism is recognized as a pivotal immunometabolic regulator during immune cell activation. Peroxisomes are organelles found across all eukaryotes, with a pivotal role in lipid metabolism and the detoxification of reactive oxygen species. Peroxisomes are one of the emerging axes in immunometabolism. Here we identified the peroxisome as an essential player in MCs activation. We determined that lack of functional peroxisomes in murine MCs causes a significant reduction of interleukin-6, Tumor necrosis factor and InterleukinL-13 following immunoglobulin IgE-mediated and Toll like receptor 2 and 4 activation compared to the Wild type (WT) BMMCs. We linked these defects in cytokine release to defects in free fatty acids homeostasis. In conclusion, our study identified the importance of peroxisomal fatty acids homeostasis in regulating mast cell-mediated immune functions.

Yu L., Mao L., Wu C., Ye W., Wang X.

• We studied the role of chlorogenic acid (CGA) in intestinal barrier function. • CGA downregulated CD14 to block the NF/κB signaling pathway. • CGA inhibited proinflammatory cytokine secretion via its effect on NF/κB signaling. • CGA was highly effective at preserving cell membrane integrity. Chlorogenic acid (CGA) is a polyphenol compound present in plant foods. CGA is a differentially excreted gut microbial metabolite in fecal samples of irritable bowel syndrome model mice and normal control mice. Here, we aimed to clarify the protective effect of CGA on intestinal barrier function. We used Caco-2 cells to create an intestinal epithelial cell barrier model, and evaluated tight-junctional permeability with fluorescein isothiocyanate–dextran. We treated Caco-2 cells with lipopolysaccharide and CGA, and measured tight-junction protein expression, TLR4/NF-κB pathway activation, and proinflammatory cytokine levels. CGA blocked the NF-κB pathway by downregulating CD14 and p65, and preventing phospho-p65 from entering cell nuclei. CGA showed anti-inflammatory effects by suppressing tumor necrosis factor-α, interleukin (IL)-1β, and IL-6 production, and thereby restored intestinal epithelial tight-junction integrity. In conclusion, CGA was highly effective at preserving cell membrane integrity, and inhibited proinflammatory cytokine secretion by downregulating CD14 to block the NF-kB pathway.

Trefts E., Shaw R.J.

The evolution of AMPK and its homologs enabled exquisite responsivity and control of cellular energetic homeostasis. Recent work has been critical in establishing the mechanisms that determine AMPK activity, novel targets of AMPK action, and the distribution of AMPK-mediated control networks across the cellular landscape. The role of AMPK as a hub of metabolic control has led to intense interest in pharmacologic activation as a therapeutic avenue for a number of disease states, including obesity, diabetes, and cancer. As such, critical work on the compartmentalization of AMPK, its downstream targets, and the systems it influences has progressed in recent years. The variegated distribution of AMPK-mediated control of metabolic homeostasis has revealed key insights into AMPK in normal biology and future directions for AMPK-based therapeutic strategies.

Zhang M., Deng H., Yi X., Xie S., Zhan Q.

This paper explored Chlorogenic acid regulating the biological behavior of RA FLSs and studied the functional role of microRNAs in it. In vivo experiment: Female DBA/1 J mice were used for model establishment and grouping. HE staining was employed. The damage of ankle cartilage was analyzed in each group of mice. The levels of serum cytokines TNF-α and IL-β were measured by ELISA. In vitro experiment: The cells were counterstained with Hoechst 33342, Transwell was used to detect cell invasion. Western blotting was used to detect the expression of Akt protein. The Akt expression plasmid and miR-23b mimic were co-transfected into RA FLSs, and the luciferase activity was measured using a dual-luciferase detection system. In vivo experiments found that Chlorogenic acid can significantly reduce arthritis index and inhibit TNF-α and IL-β levels. In vitro experiments found that TNF-α-induced proliferation of RA FLSs was significantly inhibited by Chlorogenic acid. Transwell invasion test showed that TNF-α-induced cell invasion was attenuated at the presence of Chlorogenic acid, which significantly inhibited Akt protein expression and phosphorylation. The expression of miR-23b in Chlorogenic acid-treated RA-FLSs increased, and silencing miR-23b enhanced the inhibitory effect of RA FLSs on Chlorogenic acid induction. Chlorogenic acid has potential anti-rheumatoid arthritis activity. Its inhibition of RA FLSs proliferation and invasion is related to the induction of miR-23b and the down-regulation of Akt expression.

Sun S., Gu Y., Wang J., Chen C., Han S., Che H.

Type 1 allergies, involve a complex interaction between dendritic cells and other immune cells, are pathological type 2 inflammatory immune responses against harmless allergens. Activated dendritic cells undergo extensive phenotypic and functional changes to exert their functions. The activation, differentiation, proliferation, migration, and mounting of effector reactions require metabolic reprogramming. Dendritic cells are important upstream mediators of allergic responses and are therefore an important effector of allergies. Hence, a better understanding of the underlying metabolic mechanisms of functional changes that promote allergic responses of dendritic cells could improve the prevention and treatment of allergies. Metabolic changes related to dendritic cell activation have been extensively studied. This review briefly outlines the basis of fatty acid oxidation and its association with dendritic cell immune responses. The relationship between immune metabolism and effector function of dendritic cells related to allergic diseases can better explain the induction and maintenance of allergic responses. Further investigations are warranted to improve our understanding of disease pathology and enable new treatment strategies.

Rodriguez-Coira J., Villaseñor A., Izquierdo E., Huang M., Barker-Tejeda T.C., Radzikowska U., Sokolowska M., Barber D.

There is increasing evidence that the metabolic status of T cells and macrophages is associated with severe phenotypes of chronic inflammation, including allergic inflammation. Metabolic changes in immune cells have a crucial role in their inflammatory or regulatory responses. This notion is reinforced by metabolic diseases influencing global energy metabolism, such as diabetes or obesity, which are known risk factors of severity in inflammatory conditions, due to the metabolic-associated inflammation present in these patients. Since several metabolic pathways are closely tied to T cell and macrophage differentiation, a better understanding of metabolic alterations in immune disorders could help to restore and modulate immune cell functions. This link between energy metabolism and inflammation can be studied employing animal, human or cellular models. Analytical approaches rank from classic immunological studies to integrated analysis of metabolomics, transcriptomics, and proteomics. This review summarizes the main metabolic pathways of the cells involved in the allergic reaction with a focus on T cells and macrophages and describes different models and platforms of analysis used to study the immune system and its relationship with metabolism.

Lv L., Qu X., Yang N., Liu Z., Wu X.

• Polyphenols can induce structural changes of tropomyosin (TM) by conjugate. • TM-polyphenol complexes can decrease the IgG/IgE binding capacity of TM. • TM-polyphenol complexes reduced ability of mediator release in RBL-2H3 cells. • TM-polyphenol complexes could significantly decrease allergenicity of TM in mice model. Here, the potential allergenicity of shrimp tropomyosin (TM) after conjugation with chlorogenic acid (CA) and (−)-epigallo-catechin 3-gallate (EGCG) was assessed. Conformational structures of TM-polyphenol complexes were detected using SDS-PAGE, circular dichroism (CD), and fluorescence. Potential allergenicity was assessed by immunological methods, a rat basophil leukemia cell model (RBL-2H3), and in vivo assays. Indirect ELISA showed that TM-polyphenol complexes caused a conformational change to TM structure, with decreased IgG/IgE binding capacity significantly fewer inflammatory mediators were released with EGCG-TM and CA-TM in a mediator-releasing RBL-2H3 cell line. Mice model showed low allergenicity to serum levels of TM-specific antibody and T-cell cytokine production. EGCG-TM and CA-TM might reduce the potential allergenicity of shrimp TM, which could be used to produce hypoallergenic food in the food industry.

Luo J., He W., Li X., Ji X., Liu J.

Chlorogenic acid (CGA) exhibits substantial biological function in antioxidant, antibacterial, anti-lipogenesis and anti-inflammatory activities. Increased sebum production and inflammation are considered important for the development of acne. However, the therapeutic effects of CGA on acne vulgaris remain unexplored. In this study, to assess the effects and underlying mechanisms of CGA on acne, a model of skin inflammation in ears of ICR mouse induced by living Propionibacterium acnes was used. 24 hours after 1.0 × 107 CFU, P. acnes were intradermally injected into the ears of the ICR mouse. 1, 5 and 10 mg of CGA mixed with vaseline were applied to the surface of the skin every 12 hours for 3 days. Then, skin inflammation in the ears was assessed and the change of SREBP1 and TNF-α expression was analysed after CGA treatment. The mechanisms of CGA in anti-inflammatory activity and lipogenesis were also studied in primary sebocytes and HaCaT cells. We found that CGA treatment effectively rescued ear swelling, redness and erythema skin in ears of ICR mouse induced by P. acnes and significantly downregulated the expression of inflammatory cytokines by reducing the activity of the NF-κB signalling pathway. Furthermore, CGA could inhibit lipogenesis at the protein secretion and transcription level by decreasing the AKT/mTOR/SREBP signalling pathway. Our findings suggest that CGA could become a potential alternative drug for the treatment of acne vulgaris.

Shi Z., Jiang W., Chen X., Xu M., Wang J., Lai Y., Zha D.

Abstract Allergic rhinitis (AR) is a non-infectious chronic inflammatory disease of nasal mucosa provoking T helper cell (Th) 17 response. Chlorogenic acid (CGA), one of the most abundant polyphenol compounds in various agricultural products, possesses antiviral, anti-inflammatory, and antibacterial properties. However, the effect of CGA on AR is unclear. Thus, our study explored the effect of CGA in modulating AR-related symptoms and immunoreaction, especially Th17 response. AR mice were induced by ovalbumin (OVA) administration and further treated with CGA or dexamethasone (Dex). The frequencies of rubbing and sneezing of AR mice were recorded. Histopathological analysis of nasal mucosa was conducted by Hematoxylin–Eosin and Periodic acid–Schiff stainings. The serum and nasal mucosa levels of OVA-immunoglobulin (Ig)E, interferon (IFN)-γ, retinoic acid-associated nuclear orphan receptor (ROR)-γt, and interleukin (IL)-17A were measured by enzyme-linked immunosorbent assay, quantitative reverse-transcription polymerase chain reaction (qRT-PCR), or Western blot. The ratio of CD4+IL-17+Th17 cells to CD4+ T cells in peripheral blood of AR mice was assessed by flow cytometer. CGA diminished the frequencies of rubbing and sneezing of AR mice in a concentration-dependent manner. CGA attenuated histopathological abnormalities and decreased goblet cell number in nasal mucosa of AR mice. CGA decreased the serum levels of OVA-IgE, ROR-γt, and IL-17A, while increasing the serum level of IFN-γ in AR mice. Meanwhile, CGA decreased the ratio of CD4+IL-17+Th17 cells to CD4+T cells in peripheral blood and the mRNA and protein levels of IL-17A and ROR-γt in AR mice. CGA ameliorated AR-related symptoms in mice by regulating Th17 cells, which could be a candidate for the treatment of AR.

Hu F., Guo Q., Wei M., Huang Z., Shi L., Sheng Y., Ji L.

Acetaminophen (APAP)-induced acute liver failure is a serious clinic issue. Our previous study showed that chlorogenic acid (CGA) alleviated APAP-induced liver inflammatory injury, but its concrete mechanism is still not clear. This study aims to elucidate the engaged mechanism involved in the CGA-provided alleviation on APAP-induced liver inflammation. CGA reduced the increased hepatic infiltration of immune cells and the elevated serum contents of high mobility group box 1 (HMGB1) and heat shock protein 60 (HSP60) in mice treated with APAP. CGA decreased the enhanced hepatic mRNA expression of some pro-inflammatory molecules in mice treated with APAP and in RAW264.7 cells stimulated with HMGB1 or HSP60. CGA attenuated liver mitochondrial injury, rescued the decreased lon protease homolog (Lon) protein expression, and reduced mitochondrial HSP60 release in mice treated with APAP. Moreover, the CGA-provided alleviation on APAP-induced liver inflammatory injury was diminished in mice treated with anti-HSP60 antibody. Further results showed that the CGA-provided alleviation on APAP-induced liver inflammation was also diminished in nuclear factor erythroid 2-related factor 2 (Nrf2) knock-out mice. Meanwhile, the CGA-provided reduce on serum HSP60 content and restore of mitochondrial Lon protein expression were all diminished in Nrf2 knock-out mice treated with APAP. In conclusion, our study revealed that CGA alleviated APAP-induced liver inflammatory injury initiated by HSP60 or HMGB1, and Nrf2 was critical for regulating the mitochondrial HSP60 release via rescuing the reduced mitochondrial Lon protein expression.

Dong F., Tan J., Zheng Y.

Luu M., Monning H., Visekruna A.

A body of evidence suggests that food allergy (FA) has increased in prevalence over the past few decades. Novel findings support the hypothesis that some commensal bacteria and particularly microbial metabolites might contribute to development of oral tolerance and prevention from FA. Recently, beneficial effects of short-chain fatty acids (SCFAs), the main class of gut microbiota-derived metabolites, on FA have been proposed. The intestinal SCFAs are major end products during bacterial fermentation of complex and non-digestible carbohydrates such as dietary fiber. The multifaceted mechanisms underlying beneficial effects of SCFAs on the mucosal immune system comprise the regulation of diverse cellular pathways in epithelial, dendritic and T cells, as well as the impact on the immunometabolism and epigenetic status of regulatory lymphocytes. Of note, SCFAs are effective inhibitors of histone deacetylases (HDACs). As a consequence, SCFAs appear to be implicated in attenuation of intestinal inflammation and autoimmune diseases. In this review, we will discuss the recent development in this research area by highlighting the role of the individual SCFAs acetate, propionate, butyrate and pentanoate in promoting the differentiation of regulatory T and B cells and their potential beneficial effects on the prevention of FA. In this context, targeted alterations in the gut microbiota in favor of SCFA producers or supplementation of medicinal food enriched in SCFAs could be a novel therapeutic concept for FA.

Elesela S., Morris S.B., Narayanan S., Kumar S., Lombard D.B., Lukacs N.W.

Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infection in children worldwide. Sirtuin 1 (SIRT1), a NAD+ dependent deacetylase, has been associated with induction of autophagy, reprogramming cellular metabolism, and regulating immune mediators. In this study, we investigated the role of SIRT1 in bone marrow dendritic cell (BMDC) function during RSV infection. SIRT1 deficient (SIRT1 -/-) BMDC showed a defect in mitochondrial membrane potential (Δ⍦m) that worsens during RSV infection. This defect in Δ⍦m caused the generation of elevated levels of reactive oxygen species (ROS). Furthermore, the oxygen consumption rate (OCR) was reduced as assessed in Seahorse assays, coupled with lower levels of ATP in SIRT1-/- DC. These altered responses corresponded to altered innate cytokine responses in the SIRT1-/- DC in response to RSV infection. Reverse Phase Protein Array (RPPA) functional proteomics analyses of SIRT1-/- and WT BMDC during RSV infection identified a range of differentially regulated proteins involved in pathways that play a critical role in mitochondrial metabolism, autophagy, oxidative and ER stress, and DNA damage. We identified an essential enzyme, acetyl CoA carboxylase (ACC1), which plays a central role in fatty acid synthesis and had significantly increased expression in SIRT1-/- DC. Blockade of ACC1 resulted in metabolic reprogramming of BMDC that ameliorated mitochondrial dysfunction and reduced pathologic innate immune cytokines in DC. The altered DC responses attenuated Th2 and Th17 immunity allowing the appropriate generation of anti-viral Th1 responses both in vitro and in vivo during RSV infection thus reducing the enhanced pathogenic responses. Together, these studies identify pathways critical for appropriate DC function and innate immunity that depend on SIRT1-mediated regulation of metabolic processes.

Peng L., Cao Y., Zhao S., Huang Y., Yang K., Huang W.

Memory T cells play a key role in the development of atherosclerosis (AS). This study aimed to investigate the role of AMPK signaling pathway of spleen memory T cells in the pathogenesis of AS in high-fat diet (HFD) fed mice.Mice were divided into 5 groups: normal group, AS group, AS + solvent group, AS + Compound C (AMPK inhibitor) group and AS + A-769662 (AMPK agonist) group. HFD animals were intraperitoneally treated with Compound C at 20 mg/kg thrice weekly or A-769662 at 30 mg/kg once daily for 15 weeks. Then, the degree of AS was assessed, and the proportion of memory T cell was determined by flow cytometry.AS was evident in the aorta of HFD mice. The areas of plaque formation in both AS + Compound C group and AS + A-769662 group reduced as compared to the AS group and AS + solvent group. After intervention of AMPK activity, the proportion of memory T cells in the spleen reduced as compared to the AS group and AS + solvent group; the pro proportion of memory T cells in HFD groups was markedly higher than in the normal group and this increase was more evident in the AS + Compound C than in the AS + A-769662 group.The decreased memory T cells can improve AS, which may be related to the AMPK signaling pathway. Thus, AMPK in the memory T cells may serve as a target in the prevention and treatment of AS.

Kumar R., Sharma A., Iqbal M.S., Srivastava J.K.

Background:: Chlorogenic acid (CGA) is a quinic acid conjugate of caffeic acid. It is an ester formed between caffeic acid and the 3-hydroxyl of L-quinic acid. This polyphenol is naturally present in substantial amount in the green coffee beans. Minor quantities of CGA are also reported in apples, eggplant, blueberries, tomatoes, strawberries and potatoes. CGA is reported to be beneficial in hypertension, hyperglycemia, antimicrobial, antitumor, memory enhancer, weight management etc. Further, it is also reported to have anticancer, antioxidant and anti-inflammatory activities. Since the last decade, CGA drew public attention for its widely recommended use as a medicine or natural food additive supplement for the management of obesity. Objective: The current review explores the medicinal promises of CGA and emphasizes on its antiobese property as reported by various scientific reports and publication. Conclusion: CGA shows promises as an antioxidant, glycemic control agent, anti-hypertensive, antiinflammatory, antimicrobial, neuro-protective and anti-obesity agent. It primarily activates the AMPactivated protein kinase, inhibits 3-hydroxy 3-methylglutaryl coenzyme-A reductase and strengthens the activity of carnitine palmitoyltransferase to control the obesity.

Xie J., Xiong S., Yu J., Ma X., Xiang F., Chen Y., Xia B., Li Y., Zhang Z., Liao D., Lin L.

Lin C., Jiang W., Itokazu N., Huang G.

Liu L., Dai J., Yang Q., Lv L.

Lopes C.R., Cunha R.A.

Hwangbo H., Choi Y.H.

Washiyama M.

Karagöz M.F., Koçyiğit E., Koçak T., Özturan Şirin A., Icer M.A., Ağagündüz D., Coreta‐Gomes F.

AbstractCoffee is one of the most consumed beverages worldwide, recognized for its unique taste and aroma and for its social and health impacts. Coffee contains a plethora of nutritional and bioactive components, whose content can vary depending on their origin, processing, and extraction methods. Gathered evidence in literature shows that the regular coffee consumption containing functional compounds (e.g., polysaccharides, phenolic compounds, and melanoidins) can have potential beneficial effects on cardiometabolic risk factors such as abdominal adiposity, hyperglycemia, and lipogenesis. On the other hand, coffee compounds, such as caffeine, diterpenes, and advanced glycation end products, may be considered a risk for cardiometabolic health. The present comprehensive review provides up‐to‐date knowledge on the structure–function relationships between different chemical compounds present in coffee, one of the most prevalent beverages present in human diet, and cardiometabolic health.

Farhan M., Rizvi A., Aatif M., Muteeb G., Khan K., Siddiqui F.A.

Given the ongoing rise in the occurrence of allergic disorders, alterations in dietary patterns have been proposed as a possible factor contributing to the emergence and progression of these conditions. Currently, there is a significant focus on the development of dietary therapies that utilize natural compounds possessing anti-allergy properties. Dietary polyphenols and plant metabolites have been intensively researched due to their well-documented anti-inflammatory, antioxidant, and immunomodulatory characteristics, making them one of the most prominent natural bioactive chemicals. This study seeks to discuss the in-depth mechanisms by which these molecules may exert anti-allergic effects, namely through their capacity to diminish the allergenicity of proteins, modulate immune responses, and modify the composition of the gut microbiota. However, further investigation is required to fully understand these effects. This paper examines the existing evidence from experimental and clinical studies that supports the idea that different polyphenols, such as catechins, resveratrol, curcumin, quercetin, and others, can reduce allergic inflammation, relieve symptoms of food allergy, asthma, atopic dermatitis, and allergic rhinitis, and prevent the progression of the allergic immune response. In summary, dietary polyphenols and plant metabolites possess significant anti-allergic properties and can be utilized for developing both preventative and therapeutic strategies for targeting allergic conditions. The paper also discusses the constraints in investigating and broad usage of polyphenols, as well as potential avenues for future research.

Yun Z., Li J., Zhu W., Yuan X., Zhao J., Liao M., Ma L., Chen F., Hu X., Ji J.

Nguyen V., Taine E.G., Meng D., Cui T., Tan W.

Chlorogenic acid (CGA) is a type of polyphenol compound found in rich concentrations in many plants such as green coffee beans. As an active natural substance, CGA exerts diverse therapeutic effects in response to a variety of pathological challenges, particularly conditions associated with chronic metabolic diseases and age-related disorders. It shows multidimensional functions, including neuroprotection for neurodegenerative disorders and diabetic peripheral neuropathy, anti-inflammation, anti-oxidation, anti-pathogens, mitigation of cardiovascular disorders, skin diseases, diabetes mellitus, liver and kidney injuries, and anti-tumor activities. Mechanistically, its integrative functions act through the modulation of anti-inflammation/oxidation and metabolic homeostasis. It can thwart inflammatory constituents at multiple levels such as curtailing NF-kB pathways to neutralize primitive inflammatory factors, hindering inflammatory propagation, and alleviating inflammation-related tissue injury. It concurrently raises pivotal antioxidants by activating the Nrf2 pathway, thus scavenging excessive cellular free radicals. It elevates AMPK pathways for the maintenance and restoration of metabolic homeostasis of glucose and lipids. Additionally, CGA shows functions of neuromodulation by targeting neuroreceptors and ion channels. In this review, we systematically recapitulate CGA’s pharmacological activities, medicinal properties, and mechanistic actions as a potential therapeutic agent. Further studies for defining its specific targeting molecules, improving its bioavailability, and validating its clinical efficacy are required to corroborate the therapeutic effects of CGA.

Pokhrel R.H., Acharya S., Mishra S., Gu Y., Manzoor U., Kim J., Park Y., Chang J.

Dębińska A., Sozańska B.

In light of the constantly increasing prevalence of allergic diseases, changes in dietary patterns have been suggested as a plausible environmental explanation for the development and progression of these diseases. Nowadays, much attention has been paid to the development of dietary interventions using natural substances with anti-allergy activities. In this respect, dietary polyphenols have been studied extensively as one of the most prominent natural bioactive compounds with well-documented anti-inflammatory, antioxidant, and immunomodulatory properties. This review aims to discuss the mechanisms underlying the potential anti-allergic actions of polyphenols related to their ability to reduce protein allergenicity, regulate immune response, and gut microbiome modification; however, these issues need to be elucidated in detail. This paper reviews the current evidence from experimental and clinical studies confirming that various polyphenols such as quercetin, curcumin, resveratrol, catechins, and many others could attenuate allergic inflammation, alleviate the symptoms of food allergy, asthma, and allergic rhinitis, and prevent the development of allergic immune response. Conclusively, dietary polyphenols are endowed with great anti-allergic potential and therefore could be used either for preventive approaches or therapeutic interventions in relation to allergic diseases. Limitations in studying and widespread use of polyphenols as well as future research directions are also discussed.

Zhong H., Li J., Cheng J.