ABSTRACT
OBJECTIVES: This study aims to evaluate the neuroprotective effect of caffeic acid (CAF) against cadmium chloride (CdCl2) in rats via its effect on memory index as well as on altered enzymatic activity in the brain of CdCl2-induced neurotoxicity. METHODS: The experimental rats were divided into seven groups (n=6 rats per group) of healthy rats (group 1), CdCl2 -induced (CD) (3â¯mg/kg BW) rats (group 2), CD rats + Vitamin C (group 3), CD rats + CAF (10 and 20â¯mg/kg BW respectively) (group 4 & 5), and healthy rat + CAF (10 and 20â¯mg/kg BW respectively) (group 6 & 7). Thereafter, CdCl2 and CAF were administered orally to the experimental rats in group 2 to group 5 on daily basis for 14 days. Then, the Y-maze test was performed on the experimental rats to ascertain their memory index. RESULTS: CdCl2 administration significantly altered cognitive function, the activity of cholinesterase, monoamine oxidase, arginase, purinergic enzymes, nitric oxide (NOx), and antioxidant status of Cd rats (untreated) when compared with healthy rats. Thereafter, CD rats treated with vitamin C and CAF (10 and 20â¯mg/kg BW) respectively exhibited an improved cognitive function, and the observed altered activity of cholinesterase, monoamine oxidase, arginase, purinergic were restored when compared with untreated CD rats. Also, the level of brain NOx and antioxidant status were significantly (p<0.05) enhanced when compared with untreated CD rats. In the same vein, CAF administration offers neuro-protective effect in healthy rats vis-à-vis improved cognitive function, reduction in the activity of some enzymes linked to the progression of cognitive dysfunction, and improved antioxidant status when compared to healthy rats devoid of CAF. CONCLUSIONS: This study demonstrated the neuroprotective effect of CAF against CdCl2 exposure and in healthy rats.
Subject(s)
Brain , Cadmium Chloride , Caffeic Acids , Memory Disorders , Neuroprotective Agents , Rats, Wistar , Animals , Rats , Memory Disorders/chemically induced , Memory Disorders/drug therapy , Memory Disorders/metabolism , Brain/drug effects , Brain/metabolism , Caffeic Acids/pharmacology , Male , Neuroprotective Agents/pharmacology , Maze Learning/drug effects , Antioxidants/pharmacology , Antioxidants/metabolism , Monoamine Oxidase/metabolism , Memory/drug effects , Cholinesterases/metabolism , Nitric Oxide/metabolism , Arginase/metabolismABSTRACT
BACKGROUND: Chichoric acid (CA) is a major active ingredient found in chicory and Echinacea. As a derivative of caffeic acid, it has various pharmacological effects. PURPOSE: Due to the unclear etiology and disease mechanisms, effective treatment methods for ulcerative colitis (UC) are currently lacking. The study investigated the therapeutic effects of the folate-chicory acid liposome on both LPS-induced macrophage inflammation models and dextran sulfate sodium (DSS)-induced mouse UC models. METHODS: Folate-chicory acid liposome was prepared using the double emulsion ultrasonic method with the aim of targeting folate receptors specifically expressed on macrophages. The study investigated the therapeutic effects of the folate-chicory acid liposome on both LPS-induced macrophage inflammation models and DSS -induced mouse UC models. Furthermore, the effects of the liposomes on macrophage polarization and their underlying mechanisms in UC were explored. RESULTS: The average particle size of folate-chicory acid liposome was 120.4 ± 0.46 nm, with an encapsulation efficiency of 77.32 ± 3.19 %. The folate-chicory acid liposome could alleviate macrophage apoptosis induced by LPS, decrease the expression of inflammatory factors in macrophages, enhance the expression of anti-inflammatory factors, inhibit macrophage polarization towards the M1 phenotype, and mitigate cellular inflammation in vetro. In vivo test, folate-chicory acid liposome could attenuate clinical symptoms, increased colon length, reduced DAI scores, CMDI scores, and alleviated the severity of colonic histopathological damage in UC mice. Furthermore, it inhibited the polarization of macrophages towards the M1 phenotype in the colon and downregulated the TLR4/NF-κB signaling pathway, thereby ameliorating UC in mice. CONCLUSION: Folate-chicory acid liposome exhibited a uniform particle size distribution and high encapsulation efficiency. It effectively treated UC mice by inhibiting the polarization of macrophages towards the M1 phenotype in the colon and downregulating the TLR4/NF-κB signaling pathway.
Subject(s)
Caffeic Acids , Colitis, Ulcerative , Folic Acid , Lipopolysaccharides , Liposomes , Macrophages , NF-kappa B , Signal Transduction , Toll-Like Receptor 4 , Animals , Colitis, Ulcerative/drug therapy , Colitis, Ulcerative/chemically induced , Folic Acid/pharmacology , Folic Acid/chemistry , Folic Acid/analogs & derivatives , Toll-Like Receptor 4/metabolism , Mice , NF-kappa B/metabolism , Signal Transduction/drug effects , Macrophages/drug effects , Caffeic Acids/pharmacology , Caffeic Acids/chemistry , Male , RAW 264.7 Cells , Disease Models, Animal , Dextran Sulfate , Succinates/pharmacology , Succinates/chemistry , Mice, Inbred C57BL , Apoptosis/drug effects , Anti-Inflammatory Agents/pharmacologyABSTRACT
Traditional folk treatments for the prevention and management of urinary tract infections (UTIs) and other infectious diseases often include plants and plant extracts that are rich in phenolic compounds. These have been ascribed a variety of activities, including inhibition of bacterial interactions with host cells. Here, we tested a panel of four well-studied phenolic compounds-caffeic acid phenethyl ester (CAPE), resveratrol, catechin, and epigallocatechin gallate-for the effects on host cell adherence and invasion by uropathogenic Escherichia coli (UPEC). These bacteria, which are the leading cause of UTIs, can bind and subsequently invade bladder epithelial cells via an actin-dependent process. Intracellular UPEC reservoirs within the bladder are often protected from antibiotics and host defenses and likely contribute to the development of chronic and recurrent infections. In cell culture-based assays, only resveratrol had a notable negative effect on UPEC adherence to bladder cells. However, both CAPE and resveratrol significantly inhibited UPEC entry into the host cells, coordinate with attenuated phosphorylation of the host actin regulator Focal Adhesion Kinase (FAK or PTK2) and marked increases in the numbers of focal adhesion structures. We further show that the intravesical delivery of resveratrol inhibits UPEC infiltration of the bladder mucosa in a murine UTI model and that resveratrol and CAPE can disrupt the ability of other invasive pathogens to enter host cells. Together, these results highlight the therapeutic potential of molecules like CAPE and resveratrol, which could be used to augment antibiotic treatments by restricting pathogen access to protective intracellular niches.IMPORTANCEUrinary tract infections (UTIs) are exceptionally common and increasingly difficult to treat due to the ongoing rise and spread of antibiotic-resistant pathogens. Furthermore, the primary cause of UTIs, uropathogenic Escherichia coli (UPEC), can avoid antibiotic exposure and many host defenses by invading the epithelial cells that line the bladder surface. Here, we identified two plant-derived phenolic compounds that disrupt activation of the host machinery needed for UPEC entry into bladder cells. One of these compounds, resveratrol, effectively inhibited UPEC invasion of the bladder mucosa in a mouse UTI model, and both phenolic compounds significantly reduced host cell entry by other invasive pathogens. These findings suggest that select phenolic compounds could be used to supplement existing antibacterial therapeutics by denying uropathogens shelter within host cells and tissues and help explain some of the benefits attributed to traditional plant-based medicines.
Subject(s)
Escherichia coli Infections , Focal Adhesion Kinase 1 , Phenols , Plant Extracts , Urinary Tract Infections , Uropathogenic Escherichia coli , Animals , Female , Humans , Mice , Bacterial Adhesion/drug effects , Caffeic Acids/pharmacology , Catechin/pharmacology , Catechin/analogs & derivatives , Cell Line , Epithelial Cells/microbiology , Epithelial Cells/drug effects , Escherichia coli Infections/drug therapy , Escherichia coli Infections/microbiology , Focal Adhesion Kinase 1/metabolism , Focal Adhesion Kinase 1/antagonists & inhibitors , Phenols/pharmacology , Phenylethyl Alcohol/analogs & derivatives , Plant Extracts/pharmacology , Resveratrol/pharmacology , Urinary Bladder/microbiology , Urinary Bladder/drug effects , Urinary Bladder/pathology , Urinary Tract Infections/microbiology , Urinary Tract Infections/drug therapy , Uropathogenic Escherichia coli/drug effectsABSTRACT
Acute myocardial infarction (MI) is one of the leading causes of mortality around the world. Prunella vulgaris (Xia-Ku-Cao in Chinese) is used in traditional Chinese medicine practice for the treatment of cardiovascular diseases. However, its active ingredients and mechanisms of action on cardiac remodeling following MI remain unknown. In this study, we investigated the cardioprotective effect of P. vulgaris on MI rat models. MI rats were treated with aqueous extract of P. vulgaris or phenolic acids from P. vulgaris, including caffeic acid, ursolic acid or rosmarinic acid, 1 day after surgery and continued for the following 28 days. Then the cardioprotective effect, such as cardiac function, inflammatory status, and fibrosis areas were evaluated. RNA-sequencing (RNA-seq) analysis, real-time polymerase chain reaction (PCR), western blotting, and ELISA were used to explore the underlying mechanism. In addition, ultra-high performance liquid chromatography/mass spectrometer analysis was used to identify the chemicals from P. vulgaris. THP-1NLRP3-GFP cells were used to confirm the inhibitory effect of P. vulgaris and phenolic acids on the expression and activity of NLRP3. We found that P. vulgaris significantly improved cardiac function and reduced infarct size. Meanwhile, P. vulgaris protected cardiomyocyte against apoptosis, evidenced by increasing the expression of anti-apoptosis protein Bcl-2 in the heart and decreasing lactate dehydrogenase (LDH) levels in serum. Results from RNA-seq revealed that the therapeutic effect of P. vulgaris might relate to NLRP3-mediated inflammatory response. Results from real-time PCR and western blotting confirmed that P. vulgaris suppressed NLRP3 expression in MI heart. We also found that P. vulgaris suppressed NLRP3 expression and the secretion of HMGB1, IL-1ß, and IL-18 in THP-1NLRP3-GFP cells. Further studies indicated that the active components of P. vulgaris were three phenolic acids, those were caffeic acid, ursolic acid, and rosmarinic acid. These phenolic acids inhibited LPS-induced NLRP3 expression and activity in THP-1 cells, and improved cardiac function, suppressed inflammatory aggregation and fibrosis in MI rat models. In conclusion, our study demonstrated that P. vulgaris and phenolic acids from P. vulgaris, including caffeic acid, ursolic acid, and rosmarinic acid, could improve cardiac function and protect cardiomyocytes from ischemia injury during MI. The mechanism was partially related to inhibiting NLRP3 activation.
Subject(s)
Myocardial Infarction , Prunella , Rats , Animals , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Prunella/metabolism , Ventricular Remodeling , Myocardial Infarction/drug therapy , Myocytes, Cardiac , Fibrosis , Caffeic Acids/pharmacologyABSTRACT
OBJECTIVES: Mitogen-activated protein kinase-3 (MAPK3) is the upstream regulator in the MAPK cascade and is involved in many critical signaling pathways and biological processes, such as cell proliferation, survival, and apoptosis. MAPK3 overexpression is linked to onset, development, metastasis, and drug resistance in several human cancers. Thus, identifying novel and effective MAPK3 inhibitors is highly demanded. Herein, we aimed to discover organic compounds from cinnamic acid derivatives as potential MAPK3 inhibitors. METHODS: The binding affinity of 20 cinnamic acids to the MAPK3 active site was tested using the AutoDock 4.0 software. Top-ranked cinnamic acids were ranked based on the ΔG binding values between the ligands and the receptor's active site. Interaction modes between top-ranked cinnamic acids and MAPK3 catalytic site were indicated using the Discovery Studio Visualizer tool. Molecular dynamics (MD) simulation was carried out to study the stability of the docked pose for the most potent MAPK3 inhibitor in this study. RESULTS: Cynarin, chlorogenic acid, rosmarinic acid, caffeic acid 3-glucoside, and cinnamyl caffeate exhibited a salient binding affinity to the MAPK3 active site with the criteria of ΔG binding <-10 kâ¯cal/mol. Further, the inhibition constant value for cynarin was calculated at the picomolar concentration. The docked pose of cynarin within the MAPK3 catalytic domain was stable in 100â¯ns simulation. CONCLUSIONS: Cynarin, chlorogenic acid, rosmarinic acid, caffeic acid 3-glucoside, and cinnamyl caffeate might be helpful in cancer therapy by inhibiting MAPK3.
Subject(s)
Chlorogenic Acid , Neoplasms , Humans , Caffeic Acids/pharmacology , Glucosides , Neoplasms/drug therapy , Rosmarinic AcidABSTRACT
BACKGROUND: Epidermal growth factor receptor (EGFR) is upregulated in prostate cancer (PCa). However, suppression of EGFR did not improve the patient outcome, possibly due to the activation of PI3K/Akt signaling in PCa. Compounds able to suppress both PI3K/Akt and EGFR signaling may be effective for treating advanced PCa. PURPOSE: We examined if caffeic acid phenethyl ester (CAPE) simultaneously suppresses the EGFR and Akt signaling, migration and tumor growth in PCa cells. METHODS: Wound healing assay, transwell migration assay and xenograft mice model were used to determine the effects of CAPE on migration and proliferation of PCa cells. Western blot, immunoprecipitation, and immunohistochemistry staining were performed to determine the effects of CAPE on EGFR and Akt signaling. RESULTS: CAPE treatment decreased the gene expression of HRAS, RAF1, AKT2, GSK3A, and EGF and the protein expression of phospho-EGFR (Y845, Y1069, Y1148, Y1173), phospho-FAK, Akt, and ERK1/2 in PCa cells. CAPE treatment inhibited the EGF-induced migration of PCa cells. Combined treatment of CAPE with EGFR inhibitor gefitinib showed additive inhibition on migration and proliferation of PCa cells. Injection of CAPE (15 mg/kg/3 days) for 14 days suppressed the tumor growth of prostate xenografts in nude mice as well as suppressed the levels of Ki67, phospho-EGFR Y845, MMP-9, phospho-Akt S473, phospho-Akt T308, Ras, and Raf-1 in prostate xenografts. CONCLUSIONS: Our study suggested that CAPE can simultaneously suppress the EGFR and Akt signaling in PCa cells and is a potential therapeutic agent for advanced PCa.
Subject(s)
Phenylethyl Alcohol , Prostatic Neoplasms , Male , Humans , Animals , Mice , Proto-Oncogene Proteins c-akt/metabolism , Prostate/pathology , Phosphatidylinositol 3-Kinases/metabolism , Mice, Nude , Epidermal Growth Factor , Prostatic Neoplasms/pathology , Caffeic Acids/pharmacology , Caffeic Acids/therapeutic use , ErbB Receptors , Phenylethyl Alcohol/pharmacology , Cell Line, Tumor , Cell ProliferationABSTRACT
Coffee presents beneficial health properties, including antiobesity effects. However, its effects on inflammation are controversial. Hydroxycinnamic acids are the main coffee phenolic bioactive compounds. In human bioavailability studies carried out with coffee, among the most abundant compounds found in urine and plasma were the colonic metabolites, dihydrocaffeic (DHCA), dihydroferulic (DHFA), and hydroxyhippuric (HHA) acids. To understand the hepato-protective potential of these three compounds, we tested whether treatment with realistic concentrations (0.5-10 µM) were effective to counteract inflammatory process and oxidative status induced by tumor necrosis factor α (TNF-α). First, we established a novel model of inflammation/oxidation using TNF-α and HepG2 cells. Afterwards, we evaluated the activity of DHCA, DHFA, and HHA against the inflammatory/oxidative challenge through the determination of the inflammatory mediators, interleukins (IL)-6, and IL-8 and chemokines, monocyte chemoattractant protein-1, and macrophage inflammatory protein-1, as well as the levels of biomarkers of oxidative stress, such as reactive oxygen species, reduced glutathione, and the antioxidant enzymes glutathione peroxidase and reductase. Results showed that all three compounds have a potential hepato-protective effect against the induced inflammatory/oxidative insult.
Subject(s)
Coffee , Phenols , Humans , Phenols/pharmacology , Phenols/metabolism , Tumor Necrosis Factor-alpha/metabolism , Caffeic Acids/pharmacology , Caffeic Acids/metabolism , Oxidative Stress , Antioxidants/pharmacology , Antioxidants/metabolism , Hepatocytes/metabolism , Glutathione Peroxidase/metabolism , Interleukin-6/metabolism , InflammationABSTRACT
Salvianolic acid A (SAA) is one of bioactive polyphenol extracted from a Salvia miltiorrhiza (Danshen), which was widely used to treat cardiovascular disease in traditional Chinese medicine. SAA has been reported to be protective in cardiovascular disease and ischemia injury, with anti-inflammatory and antioxidative effect, but its role in acute lung injury (ALI) is still unknown. In this study, we sought to investigate the therapeutic effects of SAA in a murine model of lipopolysaccharide- (LPS-) induced ALI. The optimal dose of SAA was determined by comparing the attenuation of lung injury score after administration of SAA at three different doses (low, 5 mg/kg; medium, 10 mg/kg; and, high 15 mg/kg). Dexamethasone (DEX) was used as a positive control for SAA. Here, we showed that the therapeutic effect of SAA (10 mg/kg) against LPS-induced pathologic injury in the lungs was comparable to DEX. SAA and DEX attenuated the increased W/D ratio and the protein level, counts of total cells and neutrophils, and cytokine levels in the BALF of ALI mice similarly. The oxidative stress was also relieved by SAA and DEX according to the superoxide dismutase and malondialdehyde. NET level in the lungs was elevated in the injured lung while SAA and DEX reduced it significantly. LPS induced phosphorylation of Src, Raf, MEK, and ERK in the lungs, which was inhibited by SAA and DEX. NET level and phosphorylation level of Src/Raf/MEK/ERK pathway in the neutrophils from acute respiratory distress syndrome (ARDS) patients were also inhibited by SAA and DEX in vitro, but the YEEI peptide reversed the protective effect of SAA completely. The inhibition of NET release by SAA was also reversed by YEEI peptide in LPS-challenged neutrophils from healthy volunteers. Our data demonstrated that SAA ameliorated ALI via attenuating inflammation, oxidative stress, and neutrophil NETosis. The mechanism of such protective effect might involve the inhibition of Src activation.
Subject(s)
Acute Lung Injury , Caffeic Acids , Extracellular Traps , Lactates , Acute Lung Injury/chemically induced , Acute Lung Injury/drug therapy , Acute Lung Injury/metabolism , Animals , Caffeic Acids/pharmacology , Cardiovascular Diseases/pathology , Extracellular Traps/drug effects , Extracellular Traps/metabolism , Humans , Lactates/pharmacology , Lipopolysaccharides/toxicity , Lung/pathology , Mice , Mitogen-Activated Protein Kinase Kinases , Neutrophils/metabolismABSTRACT
OBJECTIVES: The antidiabetic potential of caffeic acid in fructose/streptozotocin-induced type 2 diabetic rats was examined in this study. METHODS: Male Sprague-Dawley rats were supplied with 10% fructose solution for 14 days followed by an intraperitoneal injection of 40 mg/kg bw streptozotocin to induce type 2 diabetes (T2D). Rats were treated with both low (150 mg/kg bw) and high (300 mg/kg bw) doses of caffeic acid for 5 weeks, while the positive control group was treated with metformin (200 mg/kg bw). KEY FINDINGS: Treatment with caffeic acid significantly decreased blood glucose levels and elevated serum insulin levels while improving glucose tolerance, pancreatic ß-cell function and morphology. It also led to a significant reduction of serum cholesterol, triglyceride, LDL-cholesterol, ALT, AST, creatinine, urea and uric acid levels, while increasing HDL cholesterol levels. Caffeic acid significantly (P < 0.05) elevated hepatic glycogen level, serum and pancreatic glutathione level, superoxide dismutase and catalase activities with a concomitant decrease in malondialdehyde level, α-amylase, lipase, adenosine triphosphatase (ATPase), ectonucleoside triphosphate diphosphohydrolase (ENTPDase), 5'-nucleotidase (5'-NTD) and acetylcholinesterase activities. CONCLUSION: The results suggest caffeic acid as a potent natural product with therapeutic effects against T2D. Further molecular and clinical studies are, however, required to ascertain these findings.
Subject(s)
Caffeic Acids , Diabetes Mellitus, Experimental , Diabetes Mellitus, Type 2 , Dyslipidemias , Acetylcholinesterase , Animals , Blood Glucose , Caffeic Acids/pharmacology , Cholesterol , Cholinergic Agents , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Type 2/chemically induced , Diabetes Mellitus, Type 2/drug therapy , Dyslipidemias/chemically induced , Dyslipidemias/drug therapy , Fructose/adverse effects , Homeostasis , Hypoglycemic Agents/therapeutic use , Male , Oxidative Stress , Plant Extracts/pharmacology , Rats , Rats, Sprague-Dawley , Streptozocin/pharmacologyABSTRACT
Caffeic acid phenethyl ester (CAPE) is a natural component isolated from propolis and used in traditional medicine. We aimed to investigate the antimicrobial properties and action mechanism of CAPE and caffeamide derivatives (26G and 36M) against oral disease microbes. We resolved the minimum inhibitory and bactericidal concentrations of 26G and 36M and their stability at different temperatures and pH. We also evaluated their effect on biofilm formation and antibiotic resistance gene expression in methicillin-resistant Staphylococcus aureus (MRSA). Our results revealed that 26G and 36M showed the best anticancer and antimicrobial activities, respectively, compared with the other four caffeamide derivatives. Both 26G and 36M showed heat-dependent decreases in antimicrobial activity. The 36M derivative was stable irrespective of pH, whereas 26G was not stable under high pH conditions. Biofilm formation and antibiotic resistance-related gene expression were consistent with their respective phenotypes. This study provides evidence for the potential application of CAPE and caffeamide derivatives in dental medicine to cure or prevent oral diseases.
Subject(s)
Anti-Infective Agents , Methicillin-Resistant Staphylococcus aureus , Phenylethyl Alcohol , Anti-Bacterial Agents/pharmacology , Anti-Infective Agents/pharmacology , Caffeic Acids/chemistry , Caffeic Acids/pharmacology , Phenylethyl Alcohol/analogs & derivativesABSTRACT
Chicoric acid (CA), a polyphenolic acid obtained from chicory and purple coneflower (Echinacea purpurea), has been regarded as a nutraceutical to combat inflammation, viruses and obesity. Parkinson's disease (PD) is a common neurodegenerative disorder, and the microbiota-gut-brain axis might be the potential mechanism in the pathogenesis and development of PD. The results obtained in this study demonstrated that oral pretreatments of CA significantly prevented the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced motor dysfunctions and death of nigrostriatal dopaminergic neurons along with the inhibition of glial hyperactivation and the increment in striatal neurotrophins. 16S rRNA sequence results showed that CA significantly reduced MPTP-induced microbial dysbiosis and partially restored the composition of the gut microbiota to normal, including decreased phylum Bacteroidetes and genera Parabacteroide, as well as increased phylum Firmicutes, genera Lactobacillus and Ruminiclostridium. Besides, CA promoted colonic epithelial integrity and restored normal SCFA production. We also observed that proinflammatory cytokines such as TNF-α and IL-1ß in the serum, striatum and colon were reduced by CA, indicating that CA prevented neuroinflammation and gut inflammation, in which the suppression of the TLR4/MyD88/NF-κB signaling pathway might be the underlying molecular mechanism. These findings demonstrated that CA had neuroprotective effects on MPTP-induced PD mice possibly via modulating the gut microbiota and inhibiting inflammation throughout the brain-gut axis.
Subject(s)
Caffeic Acids/therapeutic use , Echinacea , Neuroprotective Agents/therapeutic use , Parkinson Disease/drug therapy , Succinates/therapeutic use , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine , Animals , Caffeic Acids/pharmacology , Dietary Supplements , Disease Models, Animal , Gastrointestinal Microbiome/drug effects , Male , Mice , Mice, Inbred C57BL , Neuroprotective Agents/pharmacology , Parkinson Disease/metabolism , Parkinson Disease/microbiology , Phytotherapy , Random Allocation , Signal Transduction/drug effects , Succinates/pharmacology , Toll-Like Receptor 4/metabolismABSTRACT
Chicoric acid (CA), a polyphenolic acid compound extracted from chicory and echinacea, possesses antiviral, antioxidative and anti-inflammatory activities. Growing evidence supports the pivotal roles of brain-spleen and brain-gut axes in neurodegenerative diseases, including Parkinson's disease (PD), and the immune response of the spleen and colon is always the active participant in the pathogenesis and development of PD. In this study, we observe that CA prevented dopaminergic neuronal lesions, motor deficits and glial activation in PD mice, along with the increment in striatal brain-derived neurotrophic factor (BDNF), dopamine (DA) and 5-hydroxyindoleacetic acid (5-HT). Furthermore, CA reversed the level of interleukin-17(IL-17), interferon-gamma (IFN-γ) and transforming growth factor-beta (TGF-ß) of PD mice, implicating its regulatory effect on the immunological response of spleen and colon. Transcriptome analysis revealed that 22 genes in the spleen (21 upregulated and 1 downregulated) and 306 genes (190 upregulated and 116 downregulated) in the colon were significantly differentially expressed in CA-pretreated mice. These genes were functionally annotated with GSEA, GO and KEGG pathway enrichment, providing the potential target genes and molecular biological mechanisms for the modulation of CA on the spleen and gut in PD. Remarkably, CA restored some gene expressions to normal level. Our results highlighted that the neuroprotection of CA might be associated with the manipulation of CA on brain-spleen and brain-gut axes in PD.
Subject(s)
Anti-Inflammatory Agents/therapeutic use , Caffeic Acids/therapeutic use , MPTP Poisoning/metabolism , Neuroprotective Agents/therapeutic use , Succinates/therapeutic use , Transcriptome , Animals , Anti-Inflammatory Agents/pharmacology , Caffeic Acids/pharmacology , Colon/drug effects , Colon/metabolism , Cytokines/genetics , Cytokines/metabolism , MPTP Poisoning/drug therapy , MPTP Poisoning/prevention & control , Male , Mice , Mice, Inbred C57BL , Neuroprotective Agents/pharmacology , Spleen/drug effects , Spleen/metabolism , Succinates/pharmacologyABSTRACT
In the present study, we evaluated the radiomodulatory potential of caffeic acid phenethyl ester (CAPE), an active component of traditional herbal medicine propolis. CAPE has been identified as a potent anticancer agent in multiple cancer types and is reported to have the dual role of radioprotection and radiosensitization. However, the radiomodulatory potential of CAPE in prostate cancer (PCa), which eventually becomes radioresistant is not known. Therefore, we studied the effect of co-treatment of CAPE and gamma radiation on androgen-independent DU145 and PC3 cells. The combination treatment sensitized PCa cells to radiation in a dose-dependent manner. The radiosensitizing effect of CAPE was observed in both cell lines. CAPE enhanced the level of ionizing radiation (IR)-induced gamma H2AX foci and cell death by apoptosis. The combination treatment also decreased the migration potential of PCa cells. This was confirmed by increased expression of E-cadherin and decrease in vimentin expression. CAPE sensitized PCa cells to radiation in vitro and induced apoptosis, augmented phosphorylation of Akt/mTOR, and hampered cell migration. At the mechanistic level, co-treatment of CAPE and IR inhibited cell growth by decreasing RAD50 and RAD51 proteins involved in DNA repair. This resulted in enhanced DNA damage and cell death. CAPE might represent a promising new adjuvant for the treatment of hormone-refractory radioresistant PCa.
Subject(s)
Phenylethyl Alcohol , Prostatic Neoplasms , Androgens/pharmacology , Apoptosis , Caffeic Acids/pharmacology , Cell Line, Tumor , DNA Damage , DNA Repair , Humans , Male , Phenylethyl Alcohol/analogs & derivatives , Phenylethyl Alcohol/pharmacology , Prostatic Neoplasms/metabolismABSTRACT
Chemical investigation of the ethanol extract of the leaves of Newbouldia laevis (P. Beauv) led to the isolation of two new caffeic acid glycosides, Newboulasides A (1) and B (2). The structures of these compounds were determined on the basis of extensive spectroscopic methods, including 1D-, 2D-NMR and MS data. The extracts and fractions and the isolated compounds were evaluated for their inhibition of α-amylase enzyme activity. The extract showed inhibition of α-amylase activity with IC50 value of 102.91 µg/mL, while the isolated compounds (1 and 2) exhibited pronounced inhibition with IC50 values of 4.95 and 4.44 µg/mL respectively, comparable to the standard - Acarbose with IC50 value of 4.05 µg/mL. Our findings demonstrated that the inhibition of α-amylase activity may be part of the mechanisms through which N. leavis exhibits antidiabetic effect.
Subject(s)
Bignoniaceae/chemistry , Caffeic Acids , Glycoside Hydrolase Inhibitors , Glycosides , alpha-Amylases/antagonists & inhibitors , Caffeic Acids/pharmacology , Glycoside Hydrolase Inhibitors/pharmacology , Glycosides/pharmacology , Phytochemicals/pharmacology , Plant Extracts/pharmacologyABSTRACT
Chronic cerebral ischemia (CCI) refers to long-term hypoperfusion of cerebral blood flow with the main clinical manifestations of progressive cognitive impairment. The pathological mechanism of CCI is complex, and there is a lack of effective treatments. Salvianolic acid A (SalA) is a neuroprotective extract of Salvia miltiorrhiza with the effects of anti-inflammation and anti-apoptosis. In this study, the effect of SalA on cognitive function and Drd2/Cryab/NF-κB signaling pathway in rats with CCI was investigated. Morris water maze and open field test were used to observe the effects of SalA on the cognitive function of CCI rats. The pathological changes in the brain were observed by HE, Nissl, and LFB staining. TUNEL staining, enzyme-linked immunosorbent assay, and western blot analysis were used to detect the inflammatory and apoptosis in the cortex and hippocampus. The expression of Drd2/Cryab/NF-κB pathway-related molecules and Drd2 localization were detected by western blotting and dual immunofluorescence, respectively. SH-SY5Y cells were exposed to chronic hypoglycemic and hypoxic injury in vitro, and Drd2 inhibitor haloperidol was used to verify the involved pathway. The results showed that SalA could improve the cognitive function of CCI rats, reduce pathological damage of cortex and hippocampus, inhibit neuroinflammation and apoptosis, and suppress the activation of NF-κB by regulating Drd2/Cryab pathway. And SalA inhibited NF-κB activation and nuclear translocation in SH-SY5Y cells by upregulating Drd2/Cryab pathway, which was reversed by haloperidol interference. In conclusion, SalA could relieve CCI-induced cognitive impairment in rats, at least partly through the Drd2/Cryab/NF-κB pathway.
Subject(s)
Brain Ischemia/drug therapy , Caffeic Acids/therapeutic use , Cognitive Dysfunction/drug therapy , Lactates/therapeutic use , Neuroinflammatory Diseases/drug therapy , Neuroprotective Agents/therapeutic use , Animals , Brain/drug effects , Brain/metabolism , Brain/pathology , Brain Ischemia/metabolism , Brain Ischemia/pathology , Caffeic Acids/pharmacology , Cell Hypoxia/drug effects , Cell Line, Tumor , Chronic Disease , Cognitive Dysfunction/metabolism , Cognitive Dysfunction/pathology , Crystallins/metabolism , Glucose/metabolism , Humans , Lactates/pharmacology , Male , Microtubule-Associated Proteins/metabolism , NF-kappa B/metabolism , Neuroinflammatory Diseases/metabolism , Neuroinflammatory Diseases/pathology , Neuroprotective Agents/pharmacology , Rats, Wistar , Receptors, Dopamine D2/metabolismABSTRACT
Propolis is produced by honeybees from materials collected from plants they visit. It is a resinous material having mixtures of wax and bee enzymes. Propolis is also known as bee glue and used by bees as a building material in their hives, for blocking holes and cracks, repairing the combs and strengthening their thin borders. It has been extensively used since ancient times for different purposes in traditional human healthcare practices. The quality and composition of propolis depend on its geographic location, climatic zone and local flora. The New Zealand and Brazilian green propolis are the two main kinds that have been extensively studied in recent years. Their bioactive components have been found to possess a variety of therapeutic potentials. It was found that Brazilian green propolis improves the cognitive functions of mild cognitive impairments in patients living at high altitude and protects them from neurodegenerative damage through its antioxidant properties. It possesses artepillin C (ARC) as the key component, also known to possess anticancer potential. The New Zealand propolis contains caffeic acid phenethyl ester (CAPE) as the main bioactive with multiple therapeutic potentials. Our lab performed in vitro and in vivo assays on the extracts prepared from New Zealand and Brazilian propolis and their active ingredients. We provided experimental evidence that these extracts possess anticancer, antistress and hypoxia-modulating activities. Furthermore, their conjugation with γCD proved to be more effective. In the present review, we portray the experimental evidence showing that propolis has the potential to be a candidate drug for different ailments and improve the quality of life.
Subject(s)
Anti-Anxiety Agents/pharmacology , Antineoplastic Agents/pharmacology , Antioxidants/pharmacology , Propolis/pharmacology , Animals , Brazil , Caffeic Acids/pharmacology , Humans , New Zealand , Phenylethyl Alcohol/analogs & derivatives , Phenylethyl Alcohol/pharmacology , Phenylpropionates/pharmacologyABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Danshen water extract (DWE), obtained from the Salvia miltiorrhiza Bunge (Family Lamiaceae) root, is usually employed in Chinese traditional medicine as treatment to cardiovascular ailments and cerebrovascular diseases. Intriguingly, the extract was also found to contain vast beneficial properties in Alzheimer's disease (AD) treatment. AIM OF THE STUDY: Alzheimer's disease is the most significant type of neurodegenerative disorder plaguing societies globally. Its pathogenesis encompasses the hallmark aggregation of amyloid-beta (Aß). Of all the Aß oligomers formed in the brain, Aß42 is the most toxic and aggressive. Despite this, the mechanism behind this disease remains elusive. In this study, DWE, and its major components, Salvianolic acid A (SalA) and Salvianolic acid B (SalB) were tested for their abilities to attenuate Aß42's toxic effects. METHODS: The composition of DWE was determined via Ultra-Performance Liquid Chromatography (UPLC). DWE, SalA and SalB were first verified for their capability to diminish Aß42 fibrillation using an in vitro activity assay. Since Aß42 aggregation results in neuronal degeneration, the potential Aß42 inhibitors were next evaluated on Aß42-exposed PC12 neuronal cells. The Drosophila melanogaster AD model was then employed to determine the effects of DWE, SalA and SalB. RESULTS: DWE, SalA and SalB were shown to be able to reduce fibrillation of Aß42. When tested on PC12 neuronal cells, DWE, SalA and SalB ameliorated cells from cell death associated with Aß42 exposure. Next, DWE and its components were tested on the Drosophila melanogaster AD model and their rescue effects were further characterized. The UPLC analysis showed that SalA and SalB were present in the brains and bodies of Drosophila after DWE feeding. When human Aß42 was expressed, the AD Drosophila exhibited degenerated eye structures known as the rough eye phenotype (REP), reduced lifespan and deteriorated locomotor ability. Administration of DWE, SalA and SalB partially reverted the REP, increased the age of AD Drosophila and improved most of the mobility of AD Drosophila. CONCLUSION: Collectively, DWE and its components may have therapeutic potential for AD patients and possibly other forms of brain diseases.
Subject(s)
Alzheimer Disease/drug therapy , Benzofurans/pharmacology , Caffeic Acids/pharmacology , Lactates/pharmacology , Neurons/drug effects , Phytotherapy , Salvia miltiorrhiza/chemistry , Amyloid beta-Peptides/metabolism , Animals , Cell Survival/drug effects , Drosophila melanogaster , Female , PC12 Cells , Peptide Fragments/metabolism , Plant Extracts/chemistry , Plant Extracts/therapeutic use , RatsABSTRACT
In this study, untargeted lipidomics based on UPLC-Q/TOF-MS, network pharmacology and atomic force microscopy were used to explore the common biomarkers of hyperlipidemia and coronary heart disease, the therapeutic mechanism of the main components of Salvia miltiorrhiza as well as the action mechanism of key lipids. Firstly, the serum samples of 30 healthy people, 30 patients with coronary heart disease and 30 patients with hyperlipidemia were analyzed by using lipidomics technology to obtain biomarkers which can be used to link hyperlipidemia and coronary heart disease and to find potential targets; then, the key components and core targets of Salvia miltiorrhiza intervention in hyperlipidemia and coronary heart disease were analyzed by network pharmacology, the results were verified by atomic force microscopy. It showed that SMS2 might be the key target. And through network pharmacology and atomic force microscope analysis, it can be inferred that salvianolic acid A can combine with SMS2 to play a therapeutic role.
Subject(s)
Coronary Disease/prevention & control , Hyperlipidemias/prevention & control , Lipidomics , Metabolic Networks and Pathways/drug effects , Network Pharmacology , Salvia miltiorrhiza/chemistry , Caffeic Acids/pharmacology , Chromatography, High Pressure Liquid , Female , Healthy Volunteers , Humans , Lactates/pharmacology , Male , Membrane Proteins/drug effects , Microscopy, Atomic Force , Middle Aged , Nerve Tissue Proteins/drug effects , Transferases (Other Substituted Phosphate Groups)/drug effectsABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Salvianolic acid A (SAA) is extracted from traditional Chinese medicine Salvia miltiorrhiza and is the main water-soluble and the biologically active ingredient. SAA possesses a variety of pharmacological activities and has an excellent protective effect on kidney disease, especially steroid resistant nephrotic syndrome (SRNS), and has advantages in improving the efficacy of glucocorticoids, but its mechanism needs to be further explored. PURPOSE: The study was designed to explore the effect of suPAR and uPAR in SRNS patients and evaluate the potential effect of SAA in improving podocyte steroid resistance and explore its mechanism. METHODS AND MATERIALS: The ELISA kits were used to detect the levels of suPAR in the blood and urine of subjects. The levels of uPAR, GRα, and GRß expression in renal tissues of SRNS patients was detected by immunohistochemistry and analyzed using the Pearson method. In vitro studies, steroid resistance model was induced by the TNF-α and IFN-γ. The protein and mRNA expression of Nephrin, GR, GRα and GRß were analyzed using western blot and qRT-PCR. The activity of GR-DNA binding was detected by using TransAM™ GR kits. Adriamycin further induced steroid resistance podocyte. Flow cytometry was used to detect the effect of SAA on podocyte apoptosis. ELISA assay was used to detect the suPAR expression in the podocyte supernatant. Western blot and qRT-PCR were used to detect the protein and mRNA expression of uPAR and Nephrin in podocytes. RESULTS: The serum and urine levels of suPAR were conspicuously higher in SRNS patients than healthy volunteers and SSNS patients, and the expression of uPAR in renal tissue of SRNS patients is negatively correlated with GRα, but positively correlated with GRß. The combination of TNF-α and IFN-γ could conspicuously increase the GRß expression and reduce GRα/GRß, and induce steroid resistance in podocytes. Moreover, we found that SAA could reduce the apoptosis of podocytes and suppress the expression of suPAR/uPAR, and increase the expression of Nephrin. CONCLUSION: The level of suPAR and uPAR expression may have important value in predicting glucocorticoids resistance in patients with idiopathic nephrotic syndrome (INS). The combination of TNF-α and IFN-γ induce podocytes can establish steroid resistance model in vitro. SAA could improve glucocorticoids resistance of podocyte which can be attributed in part to regulate the suPAR/uPAR-αvß3 signaling pathway.
Subject(s)
Caffeic Acids/pharmacology , Glucocorticoids/pharmacology , Lactates/pharmacology , Nephrotic Syndrome/drug therapy , Receptors, Urokinase Plasminogen Activator/genetics , Adult , Caffeic Acids/isolation & purification , Case-Control Studies , Female , Humans , Lactates/isolation & purification , Male , Membrane Proteins/genetics , Middle Aged , Nephrotic Syndrome/genetics , Nephrotic Syndrome/physiopathology , Podocytes/drug effects , Podocytes/metabolism , Receptors, Glucocorticoid/genetics , Salvia miltiorrhiza/chemistry , Signal Transduction/drug effects , Young AdultABSTRACT
Cats infected with feline calicivirus (FCV) often display oral ulcers and inflammation of the upper respiratory tract, which can lead to death in severe cases. Antiviral therapy is one of the most effective ways to control FCV infection. Natural compounds in Chinese herbal medicines and medicinal plants provide abundant resources for research on antiviral drugs. In this study, we found that icariin (ICA), formononetin (FMN) and caffeic acid phenethyl ester (CPAE) show low cytotoxicity towards F81 cells, that the three natural compounds have apparent antiviral effects on FCV in vitro, and that they can inhibit different FCV strains. Then, we found that ICA and FMN mainly function in the early stage of FCV infection, while CAPE can function in both the early and late stages of FCV infection. Finally, we found that ICA has an antagonistic effect on FMN and CAPE in FCV infection, and FMN has a synergistic effect with CAPE against FCV infection. Our results showed that ICA, FMN and CAPE may be potential drug candidates for FCV-induced diseases.