Mechanism Of Chlorogenic Acid Research Articles

Chlorogenic acid alleviates renal fibrosis by reducing lipid accumulation in diabetic kidney disease through suppressing the Notch1 and Stat3 signaling pathway

Aims Abnormal renal lipid metabolism causes renal lipid deposition, which leads to the development of renal fibrosis in diabetic kidney disease (DKD). The aim of this study was to investigate the effect and mechanism of chlorogenic acid (CA) on reducing renal lipid accumulation and improving DKD renal fibrosis. Methods This study evaluated the effects of CA on renal fibrosis, lipid deposition and lipid metabolism by constructing in vitro and in vivo models of DKD, and detected the improvement of Notch1 and Stat3 signaling pathways. Molecular docking was used to predict the binding between CA and the extracellular domain NRR1 of Notch1 protein. Results In vitro studies have shown that CA decreased the expression of Fibronectin, α-smooth muscle actin (α-SMA), p-smad3/smad3, alleviated lipid deposition, promoted the expression of carnitine palmitoyl transferase 1 A (CPT1A), and inhibited the expression of cholesterol regulatory element binding protein 1c (SREBP1c). The expression of Notch1, Cleaved Notch1, Hes1, and p-stat3/stat3 were inhibited. These results suggested that CA might reduce intercellular lipid deposition in human kidney cells (HK2) by inhibiting Notch1 and stat3 signaling pathways, thereby improving fibrosis. Further, in vivo studies demonstrated that CA improved renal fibrosis and renal lipid deposition in DKD mice by inhibiting Notch1 and stat3 signaling pathways. Finally, molecular docking experiments showed that the binding energy of CA and NRR1 was −6.6 kcal/mol, which preliminarily predicted the possible action of CA on Notch1 extracellular domain NRR1. Conclusion CA reduces renal lipid accumulation and improves DKD renal fibrosis by inhibiting Notch1 and stat3 signaling pathways.

Research progress on the pharmacological activity and mechanism of chlorogenic acid in alleviating acute kidney injury in sepsis patients

Sepsis-induced acute kidney injury (SAKI) is a serious perioperative complication and a common clinical syndrome characterized by a rapid deterioration in renal function with a high incidence of 70%. The causes of SAKI include impaired mitochondrial function of renal tubular epithelial cells, oxidative stress, inflammatory reaction and renal microcirculation disorder. Chlorogenic acid, as a natural product of plant origin, has various biological activities, such as antibacterial, antiviral, and anti-tumor, and plays a significant role in the treatment of SAKI. This article reviews the pharmacological activities of chlorogenic acid and the signaling pathways involved in relieving SAKI, in order to provide a theoretical basis for in-depth study of the mechanisms underlying the alleviation of SAKI and the confirmation of potential therapeutic targets.

Chlorogenic Acid Alleviated AFB1-Induced Hepatotoxicity by Regulating Mitochondrial Function, Activating Nrf2/HO-1, and Inhibiting Noncanonical NF-κB Signaling Pathway.

Aflatoxin B1 (AFB1), a kind of mycotoxin, imposes acute or chronic toxicity on humans and causes great public health concerns. Chlorogenic acid (CGA), a natural phenolic substance, shows a powerful antioxidant and anti-inflammatory effect. This study was conducted to investigate the effect and mechanism of CGA on alleviating cytotoxicity induced by AFB1 in L-02 cells. The results showed that CGA (160 μM) significantly recovered cell viability and cell membrane integrity in AFB1-treated (8 μM) cells. Furthermore, it was found that CGA reduced AFB1-induced oxidative injury by neutralizing reactive oxygen species (ROS) and activating the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway. In addition, CGA showed anti-inflammatory effects as it suppressed the expression of inflammation-related genes (IL-6, IL-8, and TNF-α) and AFB1-induced noncanonical nuclear factor kappa-B (NF-κB) activation. Moreover, CGA mitigated AFB1-induced apoptosis by maintaining the mitochondrial membrane potential (MMP) and inhibiting mRNA expressions of Caspase-3, Caspase-8, Bax, and Bax/Bcl-2. These findings revealed a possible mechanism: CGA prevents AFB1-induced cytotoxicity by maintaining mitochondrial membrane potential, activating Nrf2/HO-1, and inhibiting the noncanonical NF-κB signaling pathway, which may provide a new direction for the application of CGA.

Chlorogenic acid improves the cognitive deficits of sleep-deprived mice via regulation of immunity function and intestinal flora

BackgroundSleep deprivation (SD) has become a global health concern with serious consequences containing memory deficits and gastrointestinal dysfunctions. The gut-brain axis serves as a crucial link between the brain and gut, and the utilization of chlorogenic acid (CGA) presents a compelling strategy for mitigating or potentially resolving various neuroinflammation-associated disorders. However, it is still unknown how CGA may interact with the gut, microbiota and the brain during SD. PurposeThis study aims to explore the therapeutic effect and underlying mechanism of microbiota-gut-brain axis by which CGA prevents SD-induced cognitive deficits. Study design and methodsCGA (30, 60 mg/kg.bw.) was gavaged to C57BL/6 mice, and then they were submitted to 48-h SD. The cognitive and spatial learning abilities were investigated through behavioral tests. Furthermore, we explored the action mechanism of this compound with haematological analysis, histopathological examination, Western blot, ELISA and 16S rRNA gene pyrosequencing from colonic contents. ResultsThe cognitive deficits induced by SD were significantly relieved by administration of CGA in a dose-dependent manner. The hematoxylin and eosin staining of hippocampus and colon tissues indicated that pretreatment of CGA not only protected brain tissue from SD, but also maintained intestinal integrity. In the hippocampus, the increased pro-inflammatory neurometabolites were significantly prevented by CGA, and an immune profile capable of hippocampal-dependent spatial memory was improved via Nrf2/PPAR signaling pathways. The observed immunomodulatory effect was concomitant with augmentation of the intestinal barrier, as evidenced by the heightened expressions of tight junction proteins. 16S rRNA analysis of colonic contents revealed that levels of Clostridia_UCG-014 and lipopolysaccharide were significantly inhibited, and those of Lactobacillus and intestinal tight junction proteins were upregulated in the CGA group. Pathways of ko05322 (immune disease) and ko04610 (immune system) were significantly regulated by CGA. Based on PICRUSt2 algorithm, CGA probably influenced gut microbial functions via several metabolism pathways, such as arginine biosynthesis, pyrimidine metabolism and purine metabolism. ConclusionThe present study first proved the efficacy and mechanism of CGA in alleviating SD-induced cognitive impairment and neuroinflammation via creating a systemic protection, a bidirectional communication system connecting the gut with the brain. The intestinal barrier improvement and the reshaped “SD microbiota” profiles restored immunity functions, which were probably the main contributors to Nrf2/PPAR activation and the neuroprotective effect of CGA. Overall, this work provided novel insights of CGA, which might guide the more reasonable clinical use of CGA in the pathogenesis of sleep-related disorders.

Elucidating the Molecular Targets and Mechanisms of Chlorogenic Acid Against Alzheimer’s Disease via Network Pharmacology and Molecular Docking

Background: Chlorogenic acid (CGA), a polyphenolic substance extracted from many traditional Chinese medicines, exerts a mitigative effect in dementia, including Alzheimer’s disease (AD). However, the pathological mechanisms of CGA against AD remain obscure. Objective: To elucidate the core targets, functional characteristics, and underlying mechanisms of CGA against AD using network pharmacology approaches and molecular docking technologies. Methods: GEO database was used to identify the differentially expressed genes (DEGs) in AD. PharmMpper, TargetNet, and SwissTargetPrediction predicted the CGA-related targets. STRING and Cytoscape were employed to construct and analyze the PPI network. Moreover, the Metascape platform was used to perform the GO biological processes and KEGG pathways enrichment. Molecular docking was performed using Autodock Vina software. Results: A total of 5437 targets related to AD were identified with |log2Fold Change (FC)| ≥ 1 and P < 0.05. Based on public databases, 193 putative target genes of CGA were screened. Using the Venn diagram, we found 137 co-targets between CGA and AD. According to the PPI network, 23 core targets for CGA to treat AD were obtained. KEGG enrichment displayed that the PI3K-Akt signaling pathway, MAPK signaling pathway, apoptosis, and NOD-like receptor signaling pathway were several important signaling pathways involved in CGA against AD. SRC, EGFR, HSP90AA1, MAPK1, RHOA, and PIK3R1 were hub targets associated with the activities of CGA against AD. Molecular docking analysis revealed a good binding affinity between CGA and these targets through hydrogen bonds. Conclusion: CGA might exert therapeutic effects in AD by regulating multiple targets and signaling pathways. However, further in vitro and in vivo experiments are required to thoroughly confirm the detailed targets and mechanisms of CGA against AD.

Chlorogenic Acid Inhibits Ceramide Accumulation to Restrain Hepatic Glucagon Response.

Chlorogenic acid (CGA), a dietary natural phenolic acid, has been widely reported to regulate glucose and lipid metabolism. However, the protective effects and the underlying mechanisms of CGA on glucagon-induced hepatic glucose production remain largely uncharacterized. Herein, we investigated the efficacy of CGA on hepatic gluconeogenesis both in vivo and in vitro. The elevated levels of endogenous glucose production induced by infusion of glucagon or pyruvate were lowered in mice administered with CGA. Furthermore, chronic CGA treatment ameliorated the accumulation of glucose and ceramide in high-fat diet (HFD)-fed mice. CGA also attenuated HFD-fed-induced inflammation response. The protective effect of CGA on glucose production was further confirmed in primary mouse hepatocytes by inhibiting accumulation of ceramide and expression of p38 MAPK. Moreover, CGA administration in HFD-fed mice preserved the decreased phosphorylation of Akt in the liver, resulting in the inhibition of FoxO1 activation and, ultimately, hepatic gluconeogenesis. However, these protective effects were significantly attenuated by the addition of C2 ceramide. These results suggest that CGA inhibits ceramide accumulation to restrain hepatic glucagon response.

Chlorogenic acid ameliorates chronic stress-induced prefrontal cortex injury through activating the 5-HT/BDNF signaling pathway in rats

The chlorogenic acid (CGA) has a strong neuroprotective ability and cognitive improvement. The purpose of this study was to investigate the effect and mechanism of CGA on chronic restraint stress (CRS)-induced prefrontal cortex (PFC) injury and depression-like behavior. Rats were restrained for 6 h each day to create a CRS paradigm that lasted for 21 days. One hour prior to constraint, CGA (50 mg/kg, 100 mg/kg and 150 mg/kg) was intragastrically delivered. The results showed that CGA could reduce serum corticosterone (CORT) levels in rats and 100 mg/kg CGA could prevent CRS-induced depression-like behaviors. Histopathological revealed that 100 mg/kg CGA ameliorated CRS-induced PFC microstructural. Furthermore, 5-HT content was also increased. Therefore, 100 mg/kg of CGA will be used to further probe the molecular mechanism of regulating 5-HT. Observations using transmission electron microscopy demonstrated that CGA reduced CRS-induced PFC synaptic damage. CGA promotes cAMP-CREB-BDNF signaling pathway and inhibits indoleamine 2,3-dioxygenase (IDO) and serotonin transporter (SRET). Cellular thermal shift assays (CETSA) and molecular docking studies have shown that IDO, SERT and CGA docking have priority potential targets. Together, a protective effect of CGA is seen in rats with CRS-induced PFC by regulating the expression of IDO and SERT and then affecting the effect of 5-HT on the cAMP-CREB-BDNF signaling pathway.

Protective effects of chlorogenic acid on inflammatory responses induced by Staphylococcus aureus and milk protein synthesis in bovine mammary epithelial cells

Staphylococcus aureus (S. aureus) is a major mastitis-causing pathogen in dairy cows. Dairy cows with mastitis suffer from a decrease in milk yield and protein content. Chlorogenic acid (CGA) is a natural product with anti-inflammatory effects. In this study, we examined the function and mechanism of CGA with regard to its anti-inflammatory effects and evaluated its protective function in milk protein synthesis in bovine mammary epithelial cells (BMECs). BMECs were cultured with and without infection by S. aureus and CGA, and extracellular inflammatory cytokines and amino acids in the medium and milk proteins were determined by ELISA. The function of IL-10RA in anti-inflammatory processes and of SF-1 in milk protein synthesis was assessed by gene silencing. The activity of mTORC1, NF-κB, and STAT5 was examined by western blot. S. aureus caused intracellular infection and upregulated TNF-α, IL-1β, IL-6, and IL-8, whereas uptake of amino acids and milk protein synthesis were suppressed. CGA mitigated the S. aureus-induced inflammatory response and milk protein synthesis in vitro and in vivo. CGA alleviated S. aureus-induced inhibition of mTORC1 and STAT5 and upregulated IL-10 and IL-10RA. In addition, SF-1 was predicted to be a transcription factor of the milk protein-encoding genes α-LA, β-LG, and CSN2. S. aureus downregulated SF-1 and CGA reversed the decline in milk protein synthesis due to SF-1 knockdown. Thus, CGA mitigates the inflammatory response that is induced by S. aureus and protects the uptake of amino acids and milk protein synthesis in BMECs.

Chlorogenic Acid Prevents UVA-Induced Skin Photoaging through Regulating Collagen Metabolism and Apoptosis in Human Dermal Fibroblasts.

Skin aging is categorized as chronological aging and photo-aging that affected by intrinsic and extrinsic factors. The present study aimed to investigate the anti-aging ability and its underlying mechanism of chlorogenic acid (CGA) on human dermal fibroblasts (HDFs). In this study, CGA specifically up-regulated collagen I (Col1) mRNA and protein expressions and increased the collagen secretion in the supernatant of HDFs without affecting the cell viability, the latter was also demonstrated in BioMAP HDF3CGF system. Under ultraviolet A (UVA)-induced photoaging, CGA regulated collagen metabolism by increasing Col1 expression and decreasing matrix metalloproteinase 1 (MMP1) and MMP3 levels in UVA-irradiated HDFs. The activation of transforming growth factor-β (TGF-β)-mediated Smad2/3 molecules, which is crucial in Col1 synthesis, was suppressed by UVA irradiation and but enhanced at the presence of CGA. In addition, CGA reduced the accumulation of UVA-induced reactive oxygen species (ROS), attenuated the DNA damage and promoted cell repair, resulting in reducing the apoptosis of UVA-irradiated HDFs. In conclusion, our study, for the first time, demonstrate that CGA has protective effects during skin photoaging, especially triggered by UVA-irradiation, and provide rationales for further investigation of CGA being used to prevent or treat skin aging.

Chlorogenic acid exerts neuroprotective effect against hypoxia-ischemia brain injury in neonatal rats by activating Sirt1 to regulate the Nrf2-NF-κB signaling pathway

BackgroundNeonatal hypoxic-ischemic brain injury (HIE) is caused by perinatal asphyxia, which is associated with various confounding factors. Although studies on the pathogenesis and treatment of HIE have matured, sub-hypothermia is the only clinical treatment available for HIE. Previous evidence indicates that chlorogenic acid (CGA) exerts a potential neuroprotective effect on brain injury. However, the role of CGA on neonatal HI brain damage and the exact mechanism remains elusive.Here, we investigate the effects of CGA on HI models in vivo and in vitro and explore the underlying mechanism.MethodsIn the in vivo experiment, we ligated the left common carotid artery of 7-day-old rats and placed the rats in a hypoxic box for 2 h. We did not ligate the common carotid artery of the pups in the sham group since they did not have hypoxia. Brain atrophy and infarct size were evaluated by Nissl staining, HE staining and 2,3,5-triphenyltetrazolium chloride monohydrate (TTC) staining. Morris Water Maze test (MWM) was used to evaluate neurobehavioral disorders. Western-blotting and immunofluorescence were used to detect the cell signaling pathway. Malondialdehyde (MDA) content test, catalase (CAT) activity detection and Elisa Assay was used to detect levels of inflammation and oxidative stress. in vitro experiments were performed on isolated primary neurons.ResultIn our study, pretreatment with CGA significantly decreased the infarct volume of neonatal rats after HI, alleviated brain edema, and improved tissue structure in vivo. Moreover, we used the Morris water maze to verify CGA’s effects on enhancing the learning and cognitive ability and helping to maintain the long-term spatial memory after HI injury. However, Sirt1 inhibitor EX-527 partially reversed these therapeutic effects. CGA pretreatment inhibited neuronal apoptosis induced by HI by reducing inflammation and oxidative stress. The findings suggest that CGA potentially activates Sirt1 to regulate the Nrf2-NF-κB signaling pathway by forming complexes thereby protecting primary neurons from oxygen-glucose deprivation (OGD) damage. Also, CGA treatment significantly suppresses HI-induced proliferation of glial.ConclusionCollectively, this study uncovered the underlying mechanism of CGA on neonatal HI brain damage. CGA holds promise as an effective neuroprotective agent to promote neonatal brain recovery from HI-induced injury.Graphical 8NePktn-RrRjrUAHAHCXyYVideo

Chlorogenic Acid Alleviates the Inflammatory Stress of LPS-Induced BV2 Cell via Interacting with TLR4-Mediated Downstream Pathway.

Background Neuroinflammation is related with the inflammatory stress of brain tissue induced by the activation of microglial in the central nervous system (CNS), which is still an intractable disease for modern clinical system. Chlorogenic acid has multiple biological activities such as antivirus and anti-inflammation, while few researches have revealed its therapeutic functions in neuroinflammation. Methods BV2 cells were treated with lipopolysaccharide (LPS) to establish neuroinflammation cell models, and the effects and mechanism of chlorogenic acid in improving the inflammatory progression were investigated. In brief, the toxicity of chlorogenic acid on BV2 cells was detected with MTT assay. The levels of the inflammatory factors including TNF-α, IL-6, IL-1β, and IFN-α were measured with ELISA, and the abundances of TLR4, MyD88, TRIF, and NF-κB were observed by qRT-PCR and western blot. Results Chlorogenic acid did not exhibit obvious toxic and side effects on BV2 cells. The levels of TNF-α, IL-6, IL-1β, and IFN-α were observably upregulated in BV2 cells after treating with LPS. Chlorogenic acid significantly reduced the levels of TNF-α, IL-6, IL-1β, and IFN-α. Moreover, the abundances of TLR4, MyD88, TRIF, and NF-κB were increased in LPS-induced BV2 cells, while chlorogenic acid could obviously reduce their expressions. Conclusion This study suggests that chlorogenic acid can improve the inflammatory stress of LPS-induced BV2 cell via interacting with the TLR4-mediated downstream pathway, which is a potential drug for neuroinflammation treatment.

Effects of Chlorogenic Acid on Performance, Anticoccidial Indicators, Immunity, Antioxidant Status, and Intestinal Barrier Function in Coccidia-Infected Broilers.

Simple SummaryCoccidiosis impairs the growth performance, intestinal health, and immunity of broilers, resulting in significant economic losses to the poultry industry. The use of anticoccidial drugs can lead to the emergence of resistant strains and drug resistance, and the control effect of vaccines is limited. Thus, there is an urgent need to develop substitutes for anticoccidial drugs. Chlorogenic acid (CGA) was reported to have positive effects on the performance and intestinal health of broilers. However, little is known about the application and mechanism of CGA in coccidia-infected broilers. The results of this study showed that dietary supplementation with CGA exhibited anticoccidial activities, and improved growth performance, immunity, antioxidant status, and intestinal barrier function in coccidia-infected broilers.The effects of chlorogenic acid (CGA) on growth performance, anticoccidial indicators (oocysts per gram of excreta, cecal lesion score, and bloody diarrhea score), immunity, antioxidant status, and intestinal barrier function in coccidia-infected broilers were investigated. A total of 240 one-day-old Arbor Acres broilers were randomly divided into four groups with six replicates of ten broilers each for 42 days. Four treatments included control diet (non-infected control, NC), control diet +Eimeria infection (infected control, IC), control diet +0.5 g/kg CGA + Eimeria infection (CGA0.5), and control diet +1 g/kg CGA + Eimeria infection (CGA1). At day 14, each broiler in IC, CGA0.5, and CGA1 groups was orally inoculated with 1 mL saline containing 4 × 105 sporulated oocysts. The results showed that the CGA1 group increased the average daily gain by 12.57% (p < 0.001) and decreased the feed/gain ratio (p = 0.010) and mortality (p = 0.030) by 13.00% and 77.76%, respectively, of broilers from 14 to 42 days compared with the IC group. The CGA1 group decreased the oocysts per gram of excreta (p < 0.001) and bloody diarrhea score (p = 0.001) compared with the IC group. The CGA0.5 and CGA1 groups increased total antioxidant capacity (p < 0.001) at day 21 and villus height (p < 0.001) in the duodenum and jejunum at day 42, and decreased the levels of interleukin 6 (IL-6) (p = 0.002), malondialdehyde (MDA) (p < 0.001), D-lactic acid (p < 0.001), and diamine oxidase (DAO) (p < 0.001) at day 21 and the levels of MDA (p < 0.001) and D-lactic acid (p = 0.003) at day 42 compared with the IC group. In the CGA1 group, villus height in the duodenum (p < 0.001) and jejunum (p = 0.017) increased at day 21 and in the ileum (p < 0.001) at day 42, and the level of DAO (p < 0.001) decreased at day 42 compared with the IC group. Broilers in the IC group had a higher IL-6 level (p = 0.048) at day 42 and lower IL-10 (p = 0.027) and immunoglobulin A (p = 0.042) levels at day 21, and IL-10 level (p = 0.017) at day 42 than those in the NC group, while no significant differences were observed among the NC, CGA0.5, and CGA1 groups. In conclusion, dietary supplementation with 1 g/kg CGA improved growth performance, immunity, antioxidant status, and intestinal barrier function in coccidia-infected broilers.

Mechanism of chlorogenic acid in alveolar macrophage polarization in Klebsiella pneumoniae-induced pneumonia.

Chlorogenic acid (CA) has been discovered to regulate macrophage polarization in pneumonia. This study aims to analyze the functional mechanism of CA in alveolar macrophage (AM) polarization and provide a theoretical basis for treatment of Klebsiella pneumoniae (Kp)-induced pneumonia. Mice were infected with Kp, and treated with CA and silent information regulator 1 (SIRT1) inhibitor (Selisistat). Mouse survival rate was recorded and bacterial burden was detected. AM polarization and pathologic change of lung tissues were evaluated. Expressions of SIRT1 and HMGB1 and cytokine levels were detected. MH-S cells were infected with Kp to establish the pneumonia cell model, followed by transfection of si-SIRT1 and HMGB1 overexpression vector. The HMGB1 expression in the nucleus and cytoplasm was detected. HMGB1 subcellular localization and HMGB1 acetylation level were detected. Kp led to high death rates, SIRT down-regulation and increases in inflammatory factor level and bacterial burden, and promoted M1 polarization. CA treatment improved mouse survival rate and promoted M2 polarization and SIRT1 expression. SIRT1 decreased HMGB1 acetylation level to inhibit nuclear to the cytoplasm translocation. Silencing SIRT1 or HMGB1 overexpression reversed the effect of CA on Kp-induced pneumonia. Overall, CA activated SIRT1 to inhibit HMGB1 acetylation level and nuclear translocation, thereby promoting M2 polarization in AMs and alleviating Kp-induced pneumonia.

Chlorogenic Acid Alleviates Hyperglycemia-Induced Cardiac Fibrosis through Activation of the NO/cGMP/PKG Pathway in Cardiac Fibroblasts.

Hyperglycemia-induced cardiac fibrosis is one of the main causes of diabetic cardiomyopathy (DM). Chlorogenic acid (CGA) found in many foods has excellent hypoglycemic effectiveness, but it is not known whether CGA can improve DM by inhibiting cardiac fibrosis caused by hyperglycemia. Type I diabetic mice are induced by streptozotocin, and after treatment with CGA for 12 weeks, cardiac functions and fibrosis are determined. CGA significantly attenuates hyperglycemia-induced cardiac fibrosis and improves cardiac functions. The mechanism of CGA on fibrotic inhibition is further studied by immunofluorescence, western blot and RNA interference technology in vivo and in vitro. The results show CGA exerted its anti-fibrotic effects through activating the cyclic GMP/protein kinase G pathway (cGMP/PKG) to block hyperglycemia-induced nuclear translocation of p-Smad2/3, and then inhibiting pro-fibrotic gene expression in cardiac fibroblasts without depending on its hypoglycemic function. Moreover, the data also revealed that CGA increased cGMP level and activated PKG in cardiac fibroblasts by enhancing endothelial nitric oxide synthase (eNOS) activity and NO production. Besides lowering blood glucose, CGA also has an independent ability to inhibit cardiac fibrosis. Therefore, long-term consumption of foods rich in CGA for diabetic patients will have great benefits to improve diabetic cardiomyopathy.

Effects and Mechanism of Chlorogenic Acid on Weight Loss.

Chlorogenic Acid (CA) has diverse, recognized health effects. This study aimed to explore the effects of CA on fat reduction and the underlying mechanism of these effects. First, we established a Monosodium Glutamate (MSG)-induced obesity mouse model and subjected the mice to 4 weeks of CA gavage. Then, we established an oleic acidinduced model of human fatty liver in HepG2 cells, and administered a CA intervention to the cells for 48 h. Finally, we used Oil red O staining, biochemical detection kits, RT-PCR and Western blot analysis to evaluate the effects of CA on fat reduction and on related pathways. The CA treatment could reduce fat accumulation in the liver and reduce blood lipid levels. In addition, CA decreased the mRNA and protein levels of peroxisome proliferator-activated receptor gamma, coactivator 1 α (PGC-1α) and Uncoupling Protein 1 (UCP1) in the MSG-induced obesity mouse model and the oleic acid-induced HepG2 cells. Based on the above results, we deduced that CA could reduce body weight and fat deposition in vitro and in vivo and that the mechanism may be related to the PGC-1α/UCP-1 pathway. CA can be developed as a drug to lower blood lipids and to treat obesity.

In-silico Approach for The Prediction of Chlorogenic Acid as PPAR-γ Activator

Coffee is one of the essential crops commonly cultivated in Indonesia. Coffee contains diverse bioactive compounds, which are associated with human health benefits. One of the compounds is Chlorogenic acid, which able to decrease the risk of type 2 diabetes mellitus (T2DM). However, the mechanism of chlorogenic acid toward anti-diabetes still unclear. This study aimed to analyze and investigate the potential role of chlorogenic acid as anti-diabetes through their interaction with Peroxisome proliferator-activated receptor gamma (PPAR-γ) as an enzyme to phosphorylate and regulate the mechanism of T2DM. The physicochemical properties of chlorogenic acid also performed in this study. The PPAR-γ was downloaded from the PDB database, and the chlorogenic acid was retrieved from the PubChem database. The protein and ligand were prepared using the PyRx program and were docked using Hex 8.0.0 software. Discovery Studio client 4.1 software was used to analyze the interaction between chlorogenic acid and PPAR-γ protein. Based on the physicochemical properties, chlorogenic acid is highly permeable to the cell and easily absorbed. Thirteen amino acid residues of PPAR-γ (GLN410, SER394, ASP396, GLY395, GLU407, LEUA401, LEU400, VAL403, LYS373, LYS438, LEU377, LYS434, and GLY437) were identified on the chlorogenic acid-PPAR-γ interaction. Interestingly, the kind of interactions, including hydrophobic interaction, hydrogen bond, and van der Waals, which are supported by the tight interaction. Our study indicated that chlorogenic acid might have anti-diabetes activity through PPAR-γ interaction.&#x0D;

Effects of Chlorogenic Acid on Glucose Tolerance and Its Curve Characteristics in High-Fat Diet-Induced Obese Rats

Abstract Objectives To observe the improvement effect and its mechanism of chlorogenic acid (CGA) on the glucose tolerance and its curve characteristics in high fat diet-induced obesity (DIO) rats. Methods Eight of 56 male SD rats were randomly selected as the normal diet group (CON), and the rest were fed with high-fat diet. After 4 weeks, 24 DIO rats were screened and then randomly divided into high fat diet group (HFD group), 50% CGA group and 98% CGA group. The CGA groups received intragastric administrations of 50% CGA and 98% CGA (80 mg/kg/d) once a day for 8 weeks, respectively, while the CON and HFD groups received a carrier solution PBS. Body weight was measured weekly and OGTT was performed every 4 weeks. Fasting insulin and insulin release were measured, HOMA-IR was calculated. Histopathological examination by hematoxylin and eosin staining method were evaluated in the pancreatic tissues. Non-targeted metabolomics analysis of rat serum was performed using UHPLC-Q-Orbitrap MS. Results Before the intervention of CGA, blood glucose levels at 120 min after glucose loading (P &amp;lt; 0.05) and AUC-G (P &amp;lt; 0.05) were higher in HFD group than in CON group, and time to glucose peak was delayed (P &amp;lt; 0.05). At the end of 8 weeks intervention, the HOMA-IR index, insulin levels at 0,30,60 and 120 min after glucose loading and AUC-I increased (P &amp;lt; 0.05), pancreatic islets obviously showed hypertrophy and hyperplasia (P &amp;lt; 0.05) in HFD group. Compared with the HFD group, OGTT-60 min, 120 min blood glucose and AUC-G (P &amp;lt; 0.05) were lower in 50% CGA and 98% CGA groups, HOMA-IR index and OGTT-0, 30, 120 min serum insulin level decreased (P &amp;lt; 0.05), time to glucose peak shifted to an earlier time point (P &amp;lt; 0.05), abnormal islet hyperplasia attenuated (P &amp;lt; 0.05). AUC-I decreased only in 98% CGA group (P &amp;lt; 0.05). Serum GM3 in HFD group increased, while Cer (AP t14:0/29:1) and LysoPC (18:2) decreased significantly. Compared with HFD group, serum Cer (AP t14:0/29:1) increased significantly in both CGA groups. Serum LysoPC (18:2) increased in 50% CGA group and GM3 decreased significantly in 98% CGA group. Conclusions Both of 50% and 98% CGA could improve the glucose tolerance and delay in glucose peak time through ADPNR1/2-mediated ceramidase activity pathway and improve insulin signaling pathway. Funding Sources The research was supported by the National Key Research and Development Program (NO. 2016YFD0400603).

Chlorogenic Acid Stimulates the Thermogenesis of Brown Adipocytes by Promoting the Uptake of Glucose and the Function of Mitochondria.

Brown adipose tissue (BAT) prevents obesity and related diseases by uncoupling oxidative phosphorylation with adenosine triphosphate. Previous studies have demonstrated that polyphenols can promote the thermogenesis of BAT in mice. Chlorogenic acid (CGA) is a common phenolic acid found in fruits and vegetables, as well as traditional Chinese medicine, which is responsible for a variety of physiological activities. However, it is still unclear whether CGA has positive effects on the thermogenesis of BAT. In this study, CGA enhances the thermogenesis and proton leak of brown adipocytes, however, no changes are evident regarding the differentiation of C3 H10 T1/2 into brown adipocytes. Surprisingly, CGA promotes the uptake of glucose by upregulating the glucose transporter 2 and phosphofructokinase. Moreover, CGA increases the number and the function of mitochondrial. Taken together, CGA stimulates thermogenesis of brown adipocytes by promoting the uptake of glucose and the function of mitochondria. PRACTICAL APPLICATION: Chlorogenic acid (CGA) is widely found in fruits, vegetables, and traditional Chinese medicines, which has been considered to have antibacterial and anti-inflammatory function. However, whether it has the function of resisting obesity and promoting thermogenesis is still unclear. In this study, brown adipocyte was used to explore the function and mechanism of CGA on thermogenesis. It provides new ideas for the utilization of foods rich in CGA and traditional Chinese medicine.

Chlorogenic Acid Ameliorates Lead-Induced Renal Damage in Mice.

Lead (Pb) exposure is a global environmental problem and its exposure can lead to serious renal damage by disturbing the pro-oxidant/antioxidant balance and facilitating inflammation. Chlorogenic acid (CGA) is one of the most abundant polyphenols in the diet and has been reported to have many biological properties such as antioxidant and anti-inflammatory. In this study, we aimed to investigate the protective efficacy and mechanism of CGA against Pb-induced nephrotoxicity in mice. The results showed that CGA inhibited Pb-induced bodyweight loss, reduced kidney coefficients, and alleviated renal function and structure. Exploration on the potential mechanism demonstrated that CGA suppressed Pb-induced inflammation in the kidney by regulating NF-κB pathway activation. Furthermore, CGA significantly increased Pb-induced reduction in the activity of SOD and GSH-Px, and reduced Pb-induced increase in the content of MDA. The expression of Bax and Bcl-2 associated with apoptosis was also significantly regulated by CGA. These data indicated that CGA may play a potential treatment strategy for Pb toxicity.

Mechanism of chlorogenic acid in apoptotic regulation through AKT/GSK-3β pathway in colon cancer cell

Objective To investigate the regulation mechanism of chlorogenic acid (CGA) on proliferation and apoptosis of colon cancer cell. Methods The effect of CGA with different concentrations on the apoptosis of human colon cancer cell line HT-29 was detected by flow cytometry, the cell proliferation was detected by MTT assay, and the cell migration was detected by Transwell method. The nude mice tumor model of HT-29 cells was established by injecting 100 μl CGA (100 μg/ml) into the tumor area, and 100 μl saline was injected into the same area of control group. The tumor volume and quality were measured periodically. The expression level of AKT/GSK-3β signaling pathway was detected by Western Blot. Results CGA can significantly promote the apoptosis of HT-29 cells (P 0.05). The phosphorylated proteins (p-AKT and p-GSK-3) and β-catenin in the experimental group were significantly lower than those in the control group (all P<0.01). Conclusion CGA can inhibit the proliferation and metastasis of colon cancer cells, and promote apoptosis. This mechanism might involve AKT/GSK-3β pathways. Key words: Colon cancer; Chlorogenic acid; AKT/GSK-3β pathways; Proliferation; Apoptosis