Deferoxamine-Loaded Injectable Chitosan-Grafted Chlorogenic Acid/Oxidized Hyaluronic Acid Hybrid Hydrogel with Antibacterial, Anti-inflammatory, and Angiogenesis-Promoting Properties for Diabetic Wound Repair.

Diabetic chronic wounds are notoriously difficult to heal as a result of their susceptibility to infection. To address this issue, we constructed an innovated and adaptable solution in the form of injectable chitosan (CS) hydrogel, denoted as CCOD, with enhanced antibacterial and anti-inflammatory properties. This hydrogel is created through a Schiff base reaction that combines chitosan-grafted chlorogenic acid (CS-CGA) and oxidized hyaluronic acid (OHA) with deferoxamine (DFO) as a model drug. The combination of CS and CGA has demonstrated excellent antibacterial and anti-inflammatory properties, while grafting played a pivotal role in making these positive effects stable. These unique features make it possible to customize injectable hydrogel and fit any wound shape, allowing for more effective and personalized treatment of complex bacterial infections. Furthermore, the hydrogel system is not only effective against inflammation and bacterial infections but also possesses antioxidant and angiogenic abilities, making it an ideal solution for the repair of chronic wounds that have been previously thought of as unmanageable.

Modulating macrophage phenotype for accelerated wound healing with chlorogenic acid-loaded nanocomposite hydrogel.

Wound healing involves distinct phases, including hemostasis, inflammation, proliferation, and remodeling, which is a complex and dynamic process. Conventional preparations often fail to meet multiple demands and provide prompt information about wound status. Here, a pH/ROS dual-responsive hydrogel (OHA-PP@Z-CA@EGF) was constructed based on oxidized hyaluronic acid (OHA), phenylboronic acid-grafted ε-polylysine (PP), chlorogenic acid (CA)-loaded ZIF-8 (Z-CA), and epidermal growth factor (EGF), which possesses intrinsic antibacterial, antioxidant, and angiogenic capacities. Due to the Schiff base and Phenylboronate ester bonds, the hydrogel exhibited excellent mechanical properties, strong adhesion, good biodegradability, high biocompatibility, stable rheological properties, and self-healing ability. Moreover, introducing Z-CA as an initiator and nanofiller led to the additional cross-linking of hydrogel through coordination bonds, which further improved the mechanical properties and antioxidant capabilities. Bleeding models of liver and tail amputations demonstrated rapid hemostatic properties of the hydrogel. Besides, the hydrogel regulated macrophage phenotypes via the NF-κB/JAK-STAT pathways, relieved oxidative stress, promoted cell migration and angiogenesis, and accelerated diabetic wound healing. The hydrogel also enabled real-time monitoring of the wound healing stages by colorimetric detection. This multifunctional hydrogel opens new avenues for the treatment and management of full-thickness diabetic wounds.

Recent Updates on the Therapeutics Benefits, Clinical Trials, and Novel Delivery Systems of Chlorogenic Acid for the Management of Diseases with a Special Emphasis on Ulcerative Colitis.

Ulcerative colitis (UC) is a multifactorial disorder of the large intestine, especially the colon, and has become a challenge globally. Allopathic medicines are primarily available for the treatment and prevention of UC. However, their uses are limited due to several side effects. Hence, an alternative therapy is of utmost importance in this regard. Herbal medicines are considered safe and effective for managing human health problems. Chlorogenic acid (CGA), the herbal-derived bioactive, has been reported for pharmacological effects like antiinflammatory, immunomodulatory, antimicrobial, hepatoprotective, antioxidant, anticancer, etc. This review aims to understand the antiinflammatory and chemopreventive potential of CGA against UC. Apart from its excellent therapeutic potential, it has been associated with low absorption and poor oral bioavailability. In this context, colon-specific novel drug delivery systems (NDDS)are pioneering to overcome these problems. The pertinent literature was compiled from a thorough search on various databases such as ScienceDirect, PubMed, Google Scholar, etc., utilizing numerous keywords, including ulcerative colitis, herbal drugs, CGA, pharmacological activities, mechanism of actions, nanoformulations, clinical updates, and many others. Relevant publications accessed till now were chosen, whereas non-relevant papers, unpublished data, and non-original articles were excluded. The present review comprises recent studies on pharmacological activities and novel drug delivery systems of CGA for managing UC. In addition, the clinical trials of CGA against UC have been discussed.

Chlorogenic Acid-Loaded Mesoporous Silica Nanoparticles Modified with Hexa-Histidine Peptides Reduce Skin Allergies by Capturing Nickel.

Nickel-induced contact dermatitis is a severe allergic reaction to objects or environments that contain nickel. Many nanomaterials have been developed to reduce skin allergies by capturing nickel, but few agents are effective and safe. In this work, mesoporous silica nanoparticles (MSN) were synthesized and decorated with hexa-histidine peptides (denoted as MSN-His6), making it a strong nickel chelator. Subsequently, a dietary polyphenol, chlorogenic acid, was loaded into the mesopores of MSN (denoted as MSN-His6@CGA), realizing the potential of its anti-inflammatory properties. In vitro and in vivo experiments revealed that the synthesized MSN-His6@CGA nanoparticles exhibited more stable and stronger chelation, better biocompatibility, and ideal allergy-relieving ability, whether for environmental metal contamination or for allergic contact dermatitis caused by prolonged nickel exposure. Thus, the application of mesoporous silica-based nanoparticles may represent an ideal approach to alleviate skin allergies by capturing nickel, which would benefit people who suffer from metal-induced contact dermatitis.

Protective effects of chlorogenic acid on the meat quality of oxidatively stressed broilers revealed by integrated metabolomics and antioxidant analysis.

Oxidation is a major cause of meat quality deterioration during broiler production, which leads to undesirable meat color and impaired water holding capacity (WHC), thereby impacting consumer appeal and satisfaction. Chlorogenic acid (CGA), a natural phenolic acid, is regarded as a potential, safer and healthier antioxidant to improve meat quality. To investigate the protective effects of CGA on the meat quality of oxidatively stressed broilers, 240 one-day-old male Cobb broiler chickens were allocated to four treatments: basal diet (control group), basal diet + dexamethasone (DEX) injection (DEX group), basal diet containing 500 mg kg-1 CGA (CGA group), and basal diet containing 500 mg kg-1 CGA + DEX injection (DEX_CGA group). Meat quality, antioxidant capacity, the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, and metabolomic profile were detected in the breast muscle of broilers. Then, correlation analysis between meat quality and antioxidant capacity, antioxidant-related genes, and metabolites was performed. The results indicated that CGA supplementation improved the growth performance and meat quality traits (pH, WHC, and meat color) and enhanced the antioxidant enzyme activity by activating the Nrf2 pathway in the breast muscle of oxidatively stressed broilers. A total of 619 metabolites were identified, among which 93 differential metabolites were found between control and DEX groups, and 65 differential metabolites were observed between DEX and DEX_CGA groups. Breast metabolic profiles were changed by DEX treatment, while CGA supplementation could normalize the metabolic changes in DEX-challenged broilers. Metabolic pathway analysis revealed that most of the differential metabolites between DEX and DEX_CGA groups were involved in pyrimidine/purine, propanoate and phenylalanine metabolism, primary bile acid biosynthesis, and lysine metabolism, which may contribute to explain the protective effects of CGA on meat quality. Moreover, according to the correlation analysis, four metabolites were identified as potential biomarkers to predict the meat quality. In conclusion, our findings demonstrate that CGA is an effective, natural and safe antioxidant to enhance the quality of meat from intensive industrial poultry production.

Anti-Inflammatory Properties, Bioaccessibility and Intestinal Absorption of Sea Fennel (Crithmum maritimum) Extract Encapsulated in Soy Phosphatidylcholine Liposomes.

A sea fennel (Crithmum maritimum) aqueous extract was prepared and loaded into soybean phosphatidylcholine liposomes. Both the free extract (FE), and the empty (L) and loaded (L-FE) liposomes were shown to be non-cytotoxic to THP-1 and Caco-2 cells. The anti-inflammatory effect was tested on THP-1 cells differentiated into macrophages. FE showed anti-inflammatory activity, revealed by the induced secretion of IL-10 cytokines in macrophages that were subsequently stimulated with LPS. Also, a decrease in TNF-α production by L was observed, evidencing that liposomes reduced the pro-inflammatory mediators' secretion. The liposomes (L) showed protective anti-inflammatory activity and also were able to downregulate the inflammation. Furthermore, L-FE were also found to downregulate the inflammation response, as they were able to decrease TNF-α secretion in macrophages previously exposed to LPS. The simulated in vitro gastrointestinal digestion (GID) of FE diminished the chlorogenic acid content (the main polyphenolic compound of the extract) by 40%, while in L-FE, the amount of this phenolic compound increased with respect to the undigested liposomes. The amount of bioaccessible chlorogenic, however, was similar for FE and L-FE. The percentage of chlorogenic acid absorbed through a Caco-2 cell monolayer after 3 h of incubation, was significantly similar for the extract and the liposomes (~1.5%), without finding significant differences once the extract and liposomes were digested.

Protective effects of chlorogenic acid on trimethyltin chloride-induced neurobehavioral dysfunctions in mice relying on the gut microbiota.

Trimethyltin chloride (TMT) is acknowledged to have potent neurotoxicity. Chlorogenic acid (CGA), the most abundant polyphenol in the human diet, is well-known for its neuroprotective activity. This investigation was performed to determine the effects and mechanisms of CGA on TMT-induced neurobehavioral dysfunctions. Mice received oral administrations of CGA (30 mg kg-1) for 11 days, in which they were intraperitoneally injected with TMT (2.7 mg kg-1) once on the 8th day. The daily intake of CGA significantly alleviated TMT-induced epilepsy-like seizure and cognition impairment, ameliorating hippocampal neuronal degeneration and neuroinflammation. Oral gavage of CGA potentially exerted neuroprotective effects through JNK/c-Jun and TLR4/NFκB pathways. Microbiome analysis revealed that daily consumption of CGA raised the relative abundance of Lactobacillus in TMT-treated mice. SCFAs, the gut microbial metabolites associated with neuroprotection, were increased in the mouse hippocampus following CGA treatment. TMT-induced neurotransmitter disorders were regulated by oral gavage of CGA, especially DL-kynurenine and acetylcholine chloride. Additionally, neurotransmitters in the mouse hippocampus were found to be highly associated with the gut microbiota. Our findings provided research evidence for the neuroprotective effect of CGA on TMT-induced neurobehavioral dysfunctions.

Protective mechanism of Erigeron breviscapus injection on blood-brain barrier injury induced by cerebral ischemia in rats.

This study investigates the protective effect of Erigeron breviscapus injection, a classic traditional Chinese medicine most typically used by Chinese minority to treat stroke, on cerebral ischemia-reperfusion injury and the related signaling pathways. Use network pharmacology methods to study the relationship between E. breviscapus (Vant.) Hand-Mazz. and ischemic stroke, predict the mechanism and active ingredients of E. breviscapus (Vant.) Hand-Mazz. in improving ischemic stroke disease. We study the protective effect of E. breviscapus injection on blood-brain barrier (BBB) injuries induced by cerebral ischemia in rats by regulating the ROS/RNS-MMPs-TJs signaling pathway. The rat model of focal cerebral ischemia-reperfusion injury has been prepared using the wire-suppository method. Firstly, the efficacy of E. breviscapus injection, Scutellarin and 3,5-dicaffeoylquinic acid in protecting BBB injury caused by cerebral ischemia has been evaluated. Secondly, the following two methods have been used to study the mechanism of E. breviscapus injection in regulating the ROS/RNS-MMPS-TJS signaling pathway: real-time PCR and western blot for the determination of iNOS, MMP-9, claudin-5, occludin, ZO-1 mRNA and protein expression in brain tissue. We find that PI3K-Akt signaling pathway predicted by network pharmaology affects the blood-brain barrier function, so we chose the blood-brain barrier-related MMP-9, claudin-5, iNOS, occludin and ZO-1 proteins are used for research. The results of our research show that 3 drugs can reduce the rate of cerebral infarction in rats, relieve the abnormal neuroethology of rats, reduce the degree of brain tissue lesion, increase the number of the Nissl corpuscle cells and repair the neuron ultrastructure in injured rats. At the same time, it can obviously reduce the ultrastructure damage of the BBB in rats. All three drugs significantly reduced the content of Evans blue in the ischemic brain tissue caused by cerebral ischemia in rats with BBB injury. In addition, E. breviscapus injection, Scutellarin and 3,5-dicaffeoylquinic acid can decrease the protein expression of iNOS and MMP-9 in rat ischemic brain tissue. In addition, 3,5-dicaffeoylquinic acid can increase the protein expression of claudin-5. We conclude that E. breviscapus injection, Scutellarin and 3,5-dicaffeoylquinic acid have obvious therapeutic effects on BBB and neuron injury induced by cerebral ischemia in rats. Our results from studying the mechanism of action show that E. breviscapus injection and Scutellarin inhibited the activation of MMP-9 by inhibiting the synthesis of iNOS, 3,5-dicaffeoylquinic acid inhibits the expression and activation of MMP-9 by inhibiting the activation of iNOS and reducing the generation of free radicals, thus reducing the degradation of important cytoskeleton connexin claudin-5 in the tight junction (TJ) structure by inhibiting the expression and activation of MMP-9. Finally BBB structure integrity was protected.

Combination immunotherapy of chlorogenic acid liposomes modified with sialic acid and PD-1 blockers effectively enhances the anti-tumor immune response and therapeutic effects.

Melanoma is one of the most common malignant tumors. The anti-PD-1 antibody is used for the treatment of metastatic melanoma. Treatment success is only 35-40% and a range of immune-related adverse reactions can occur. Combination of anti-PD1 antibody therapy with other oncology therapies has been attempted. Herein, we assessed whether chlorogenic acid liposomes modified with sialic acid (CA-SAL) combined with anti-PD1 antibody treatment was efficacious as immunotherapy for melanoma. CA-SAL liposomes were prepared and characterized. In a mouse model of B16F10 tumor, mice were treated with an anti-PD1 antibody, CA-SAL, or combination of CA-SAL + anti-PD1 antibody, and compared with no treatment controls. The tumor inhibition rate, tumor-associated macrophages (TAMs) phenotype, T-cell activity, and safety were investigated. We observed a significant decrease in the proportion of M2-TAMs and CD4+Fop3+ T cells, while there was a significant increase in the proportion of M1-TAMs and CD8+ T cells, and in the activity of T cells, and thus in the tumor inhibition rate. No significant toxicity was observed in major organs. CA-SAL and anti-PD1 Ab combination therapy presented synergistic anti-tumor activity, which enhanced the efficacy of the PD-1 checkpoint blocker in a mouse model of melanoma. In summary, combination immunotherapy of CA-SAL and anti-PD1 Ab has broad prospects in improving the therapeutic effect of melanoma, and may provide a new strategy for clinical treatment.

Effect of chlorogenic acid on intestinal inflammation, antioxidant status, and microbial community of young hens challenged with acute heat stress.

Heat stress in poultry is deleterious to productive performance. Chlorogenic acid (CGA) exerts antibacterial, anti-inflammatory, and antioxidant properties. This study was conducted to evaluate the effects of dietary supplemental CGA on the intestinal health and cecal microbiota composition of young hens challenged with acute heat stress. 100-day-old Hy-line brown pullets were randomly divided into four groups. The control group (C) and heat stress group (HS) received a basal diet. HS + CGA300 group and HS + CGA600 group received a basal diet supplemented with 300- and 600-mg/kg CGA, respectively, for 2 weeks before heat stress exposure. Pullets of HS, HS + CGA300 , and HS + CGA600 group were exposed to 38°C for 4 h while the control group was maintained at 25°C. In this study, dietary CGA supplementation had effect on mitigate the decreased T-AOC and T-SOD activities and the increasing of IL-1ß and TNFα induced by acute heat stress. Dietary supplementation with 600 mg/kg CGA had better effect on increasing the relative abundance of beneficial bacterial genera, such as Rikenellaceae RC9_gut_group, Ruminococcaceae UCG-005, and Christensenellaceae R-7_group, and deceasing bacteria genera involved in inflammation, such as Sutterella species. Therefore, CGA can ameliorate acute heat stress damage through suppressing inflammation and improved antioxidant capacity and cecal microbiota composition.

Chlorogenic Acid Enhances Doxorubicin-Mediated Cytotoxic Effect in Osteosarcoma Cells.

Despite the recurring outbreak of resistance mechanisms and adverse reactions, doxorubicin (Doxo) still remains the standard-of-care for several cancers, including osteosarcoma (OS). As an appealing source of phytochemical compounds, naturally occurring molecules have extensively been reported to overcome Doxo limitations in preclinical models. Unlike other dietary polyphenols, only few studies recognize chlorogenic acid (CGA) as a potential partner in combination therapy, while, conversely, its anticancer evidence is steadily growing, ultimately in OS. On this basis, herein we examine the cooperating effects between CGA and Doxo in U2OS and MG-63 human OS cells. With respect to Doxo alone, the concomitant administration of CGA further decreased cell viability and growth, promoting cell death potentially via apoptosis induction. Furthermore, a longer-lasting reduction in clonogenic potential deeply supported the CGA ability to improve Doxo efficacy in those cells. Remarkably, CGA treatment ameliorated Doxo-induced cytotoxicity in H9c2 rat cardiomyocyte cells instead. Although inactivation of p44/42 MAPK was detected in response to CGA plus Doxo, PD98059-mediated p44/42 MAPK impairment enhanced the combination outcome in OS cells. These findings firstly propose CGA as a promising chemosensitizer and cardioprotective agent in OS therapy, suggesting the p44/42 MAPK pathway as relevantly involved in CGA-mediated Doxo susceptibility.

Graphene Oxide Loaded with Protocatechuic Acid and Chlorogenic Acid Dual Drug Nanodelivery System for Human Hepatocellular Carcinoma Therapeutic Application.

Hepatocellular carcinoma or hepatoma is a primary malignant neoplasm that responsible for 75-90% of all liver cancer in humans. Nanotechnology introduced the dual drug nanodelivery method as one of the initiatives in nanomedicine for cancer therapy. Graphene oxide (GO) loaded with protocatechuic acid (PCA) and chlorogenic acid (CA) have shown some anticancer activities in both passive and active targeting. The physicochemical characterizations for nanocomposites were conducted. Cell cytotoxicity assay and lactate dehydrogenase were conducted to estimate cell cytotoxicity and the severity of cell damage. Next, nanocomposite intracellular drug uptake was analyzed using a transmission electron microscope. The accumulation and localization of fluorescent-labelled nanocomposite in the human hepatocellular carcinoma (HepG2) cells were analyzed using a fluorescent microscope. Subsequently, Annexin V- fluorescein isothiocyanate (FITC)/propidium iodide analysis showed that nanocomposites induced late apoptosis in HepG2 cells. Cell cycle arrest was ascertained at the G2/M phase. There was the depolarization of mitochondrial membrane potential and an upregulation of reactive oxygen species when HepG2 cells were induced by nanocomposites. In conclusion, HepG2 cells treated with a graphene oxide-polyethylene glycol (GOP)-PCA/CA-FA dual drug nanocomposite exhibited significant anticancer activities with less toxicity compared to pristine protocatechuic acid, chlorogenic acid and GOP-PCA/CA nanocomposite, may be due to the utilization of a folic acid-targeting nanodrug delivery system.

Protection Mechanisms Underlying Oral Administration of Chlorogenic Acid against Cadmium-Induced Hepatorenal Injury Related to Regulating Intestinal Flora Balance.

Cadmium (Cd) is a heavy metal, which is widely used in the industry and daily life. It has a long half-life, so large amounts of Cd can accumulate in humans and become toxic. Chlorogenic acid (CGA) can eliminate free radicals and inhibit lipid peroxidation and is mainly used to prevent metal toxicity. In the present study, mice are given CGA by intraperitoneal injection or gavage, respectively, to explore the mechanism of preventing Cd toxicity. In acute Cd-exposed mice, CGA treatment (ip) alleviated Cd-induced oxidative damage and reduced the production of NO and MPO in the liver and kidney tissues, while TLR4 expression levels did not change significantly. After 8 weeks of Cd exposure, CGA administration (gavage) significantly alleviated gut dysbiosis by decreasing the Firmicutes to Bacteroidetes ratio, enhancing the relative abundances of bacteria, including Ruminiclostridium_9, Alloprevotella, and Rikenella, and inhibiting the activation of the TLR4/MyD88/NF-κB signaling pathway. These findings suggested that protection mechanisms underlying the oral administration of CGA against the Cd-induced hepatorenal injury was related to the regulation of the intestinal flora balance. CGA can be used as an effective component in daily diet to prevent Cd toxicity.

Acute dose-response effect of coffee-derived chlorogenic acids on the human vasculature in healthy volunteers: a randomized controlled trial.

BACKGROUND: Epidemiological studies have reported lower risk of cardiovascular disease with moderate coffee consumption. In addition, emerging evidence indicates that consumption of coffee beverages enriched in chlorogenic acids (CGAs) may influence blood pressure and endothelial function, suggesting that the beneficial cardiovascular effect of coffee may relate to its CGA content. OBJECTIVES: We conducted a double-blind randomized crossover trial to test the effect of acute consumption of a decaffeinated green coffee extract (DGCE), rich in CGAs, on endothelial function in healthy subjects. METHODS: We compared 3 different doses of DGCE (302, 604, and 906 mg, respectively) with a placebo. Endothelial function was defined as the percentage change in the internal diameter of the brachial artery in response to flow-mediated dilation (%FMD). In addition, we followed the plasma concentration-time profiles of 25 systemic CGA metabolites over 24 h after DGCE consumption and we explored the relation between systemic concentrations of CGAs and the effect on %FMD. RESULTS: The DGCE formulations containing different amounts of CGAs resulted in dose-proportional increases in overall total polyphenol concentrations. The systemic appearance of total CGAs was biphasic, in agreement with previous results suggesting 2 sites of absorption in the gastrointestinal tract. Compared with the placebo group, a significant FMD increase (>1%) was observed 8.5, 10, and 24 h after consumption of 302 mg DGCE (∼156.4 mg CGAs). The differences with placebo observed in the other 2 groups were not statistically significant. Evaluation of the relation between phenolic exposure and %FMD showed a positive tendency toward a larger effect at higher concentrations and different behavior of CGA metabolites depending on the conjugated chemical position. CONCLUSIONS: We demonstrated an acute improvement in %FMD over time after ingestion of a DGCE, explained at least partly by the presence in the blood circulation of CGAs and their metabolites. This trial was registered at clinicaltrials.gov as NCT03520452.

Chlorogenic acid inhibits the proliferation of human lung cancer A549 cell lines by targeting annexin A2 in vitro and in vivo.

Chlorogenic acid, an important active component of coffee with anti-tumor activities, has been found for a hundred years. However, the lack of understanding about its target proteins greatly limits the exploration of its anti-tumor molecular mechanisms and clinical applications. Here, in vitro and animal experiments showed that chlorogenic acid had a significant inhibitory effect on the proliferation of A549 cells. The ability of chlorogenic acid to naturally emit fluorescence was exploited to screen its target proteins while avoiding false positives brought about by chemical modifications when using fluorescent tags. Consequently, we identified and verified annexin A2 as a covalent binding target of chlorogenic acid in A549 cells. We also discovered that chlorogenic acid inhibits the binding of annexin A2 to p50 subunit thereby inhibiting the expression of downstream anti-apoptotic genes cIAP1 and cIAP2 of the NF-κB signaling pathway in A549 cells in vitro and in vivo. Moreover, we found that chlorogenic acid hindered the binding of annexin A2 to actin possibly causing inhibition of tumor cell cycle and migration. Thus, this work demonstrates that chlorogenic acid binds annexin A2, causing a decrease in the expression of NF-κB downstream anti-apoptotic genes, and inhibiting the proliferation of A549 cells in vivo and in vitro.

Nephroprotective effects of chlorogenic acid against sodium arsenite-induced oxidative stress, inflammation, and apoptosis.

BACKGROUND: Chronic exposure to arsenic (As) leads to serious renal disorders. Chlorogenic acid (CGA), a phenolic compound, has several well known physiological benefits, including antioxidant and anti-inflammatory activities. The present study investigated the potential renoprotective effects of CGA on sodium arsenite (NaAsO2 )-induced kidney damage in mice. The mice were randomly allocated into five groups to receive daily treatment with CGA (200 mg kg-1 ), NaAsO2 (5 mg kg-1 ), NaAsO2 + CGA (100 mg kg-1 ), NaAsO2 + CGA (200 mg kg-1 ), or a control for 28 days. RESULTS: In the NaAsO2 -treated group, NaAsO2 induced significant renal dysfunction, oxidative damage, inflammation, and apoptosis, as demonstrated by marked increases in urea and creatinine levels accompanied by a decrease in the kidney index. Considerable increases in malondialdehyde and nitric oxide levels and parallel decreases in various antioxidant markers (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glutathione) levels were also detected in the renal tissues of NaAsO2 -treated mice. NaAsO2 exposure was associated with marked increases in renal inflammatory markers (interleukin-1ß and tumor necrosis factor-α) and apoptosis indicators including Bax and caspase-3 levels contaminant, with a marked decrease in Bcl-2, an anti-apoptotic protein, in the NaAsO2 -treated group compared with the control group. However, pretreatment with CGA substantially mitigated the renal injury and dysfunction associated with NaAsO2 exposure by reducing tissue inflammation and apoptosis and improving the antioxidant status. The CGA pretreatment also alleviated the NaAsO2 -induced histological alterations in renal tissues. CONCLUSION: Taken together, our results suggest the efficacy of CGA in alleviating As-mediated renal tissue damage. © 2020 Society of Chemical Industry.

Chlorogenic Acid Alleviates Aß25-35-Induced Autophagy and Cognitive Impairment via the mTOR/TFEB Signaling Pathway.

PURPOSE: Chlorogenic acid (CGA), a phenolic acid isolated from fruits and vegetables, has been established to have neuroprotective properties in relation to Alzheimer's disease (AD). However, the precise mechanism by which CGA prevents cognitive deficits in AD has not been well studied. This study aimed to explore the potential molecular mechanism of CGA action using an Aß25-35-induced SH-SY5Y neuron injury and cogxnitive deficits model in APP/PS1 mice. METHODS: Three-month-old male APP/PS1 double transgenic mice and a human neuroblastoma cell line (SH-SY5Y) were used to assess the effects of CGA on AD in vivo and in vitro, respectively. Cognitive function in mice was measured using a Morris water maze (MWM) test. Hematoxylin and eosin, monodansylcadaverine fluorescence, LysoTracker Red (LTR), and immunofluorescence staining were used to evaluate the morphological changes in vivo and in vitro. The protein expressions of autophagy markers (LC3B-II/LC3B-I, p62/SQSTM, beclin1 and Atg5) and lysosomal-function-related markers (cathepsin D, mTOR, p-mTOR P70S6K, p-p70s6k and TFEB) were analyzed with Western blot analyses. RESULTS: CGA treatment significantly improved spatial memory, relieved neuron damage, and inhibited autophagy in APP/PS1 mice (P<0.05). Moreover, CGA notably suppressed autophagosome production and enhanced autophagy flux in SH-SY5Y cells induced by Aß25-35 (P<0.05). Further analysis showed that CGA markedly promoted lysosomal activity, and this was accompanied by upregulated cathepsin D protein expression, which was induced by the mTOR/TFEB signaling pathway in APP/PS1 mice and Aß25-35-exposed SH-SY5Y cells (P<0.05). CONCLUSION: CGA treatment restored autophagic flux in the brain and alleviated cognitive impairments in APP/PS1 mice via enhanced activation of the mTOR/TFEB signaling pathway.

Administration of Apple Polyphenol Supplements for Skin Conditions in Healthy Women: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

This clinical study was performed to evaluate the effects of continuous apple polyphenol (AP) administration on facial skin conditions and pigmentation induced by ultraviolet (UV) irradiation in healthy women participants. Participants (n = 65, age 20-39 years) were randomized to receive tablets containing AP (300 or 600 mg/day) or placebo in a double-blinded, placebo-controlled clinical trial. Continuous administration of AP for 12 weeks significantly prevented UV irradiation induced skin pigmentation (erythema value, melanin value, L value), although a dose-dependent relationship was not clearly observed. In contrast, no significant differences were detected between the groups with regard to water content and trans-epidermal water loss. Our study demonstrated that APs and their major active compounds, procyanidins, have several health benefits. Here, we report that continuous administration of AP for 12 weeks alleviated UV irradiation induced skin pigmentation, when compared with placebo, in healthy women.

Protective Effects of Chlorogenic Acid on Cerebral Ischemia/Reperfusion Injury Rats by Regulating Oxidative Stress-Related Nrf2 Pathway.

INTRODUCTION: Cerebral ischemia-reperfusion (CI/R) injury is caused by blood flow recovery after ischemic stroke. Chlorogenic acid (CGA, 5-O-caffeoylquinic acid) is a major polyphenol component of Coffea canephora, Coffea arabica L. and Mate (Ilex paraguariensis A. StHil.). Previous studies have shown that CGA has a significant neuroprotective effect and can improve global CI/R injury. However, the underlying molecular mechanism of CGA in CI/R injury has not been fully revealed. MATERIALS: In this study, CI/R rat model was constructed. The rats were randomly divided into nine groups with ten in each group: Control, CGA (500 mg·kg-1), CI/R, CI/R + CGA (20 mg·kg-1), CI/R + CGA (100 mg·kg-1), CI/R + CGA (500 mg·kg-1), ML385 (30 mg·kg-1), CI/R + ML385 (30 mg·kg-1), CI/R + CGA + ML385. Cerebral infarction volume was detected by TTC staining. Brain pathological damage was detected by H&E staining. Apoptosis of cortical cells was detected by TUNEL staining. The expression of related proteins was detected by RT-qPCR and Western blotting. RESULTS: Step-down test and Y maze test showed that CGA dose-dependently mitigated CI/R-induced brain damage and enhanced learning and spatial memory. Besides, CGA promoted the expression of BDNF and NGF in a dose-dependent manner and alleviated CI/R-induced nerve injury. Moreover, CGA increased the activity of SOD and the level of GSH, as well as decreased production of ROS and LDH and the accumulation of MDA. Notably, CGA attenuated oxidative stress-induced brain injury and apoptosis and inhibited the expression of apoptosis-related proteins (cleaved caspase 3 and caspase 9). Additionally, CGA reversed CI/R induced inactivation of Nrf2 pathway and promoted Nrf2, NQO-1 and HO-1 expression. Nrf2 pathway inhibitor ML385 destroyed this promotion. DISCUSSION: All the data indicated that CGA had a neuroprotective effect on the CI/R rats by regulating oxidative stress-related Nrf2 pathway.

Phenolic Acid Subclasses, Individual Compounds, and Breast Cancer Risk in a Mediterranean Cohort: The SUN Project.

BACKGROUND: Biological and epidemiological evidence supports an inverse association of phenolic acids with obesity-related chronic diseases. However, no previous study has prospectively evaluated the relationship between subclasses and individual compounds of phenolic acids and the risk of postmenopausal breast cancer, one of the most important and prevalent obesity-related cancer sites. OBJECTIVE: This study examined associations between subclasses of phenolic acids, including hydroxycinnamic and hydroxybenzoic acids intake, and risk of breast cancer. DESIGN: The Seguimiento Universidad de Navarra (SUN) Project is a dynamic, permanently open prospective cohort which started in 1999. PARTICIPANTS/SETTING: Participants were 10,812 middle-aged women. All of them were university graduates. MAIN OUTCOME MEASURES: Usual diet was assessed at baseline and after 10 years of follow-up with a 136-item food frequency questionnaire. Phenolic acid intake was calculated by matching food consumption with the Phenol-Explorer database on phenolic acids content of each reported food item. STATISTICAL ANALYSIS PERFORMED: Participants were classified according to tertiles of subclasses or individual compounds of phenolic acids. Cox regression models were fitted to estimate multivariable-adjusted hazard ratios and 95% CIs for breast cancer incidence. RESULTS: Over an average of 11.8 years of follow-up, 101 incident cases of breast cancer were confirmed. After multivariable adjustment, an inverse association between hydroxycinnamic acids intake and breast cancer was observed (hazard ratio third tertile vs first tertile 0.37, 95% CI 0.16 to 0.85; P for trend=0.029) among postmenopausal women. Specifically, chlorogenic acids (3-, 4-, and 5- caffeoylquinic acids) showed the strongest inverse association (hazard ratio third tertile vs first tertile 0.33, 95% CI 0.14 to 0.78; P for trend=0.012). CONCLUSIONS: A higher intake of hydroxycinnamic acids, especially from chlorogenic acids-present in coffee, fruits, and vegetables-was associated with a lower incidence of breast cancer among postmenopausal women. Future observational studies are needed to corroborate these results.