Efficacy and safety of caffeic acid tablets in the treatment of thrombocytopenia: A systematic review and meta-analysis.

BACKGROUND: Caffeic acid tablets (CFA) are a proprietary Chinese medicine in treating thrombocytopenia. The efficacy and safety of CFA compared with other platelet-raising drugs for the treatment of thrombocytopenia have been widely reported in the literature, but there is no systematic evaluation. Therefore, we designed this meta-analysis to further establish the efficacy and safety of CFA in treating thrombocytopenia. METHODS: A computerized search was conducted in the Chinese biomedical database (CBM), Chinese National Knowledge Infrastructure (CNKI), Wanfang database, Chinese Scientific Journal Database (VIP), PubMed, and Web of Science databases using the keywords "caffeic acid tablets" and "thrombocytopenia." All randomized controlled trials were selected for the timeframe of build to 02/2023 and then screened and analyzed using RevMan 5.4 and stata17.0 software. RESULTS: A total of 35 publications with an overall 2533 patients were included in the study. The results of the meta-analysis showed that CFA were effective in the treatment of thrombocytopenia with a statistically significant difference [relative risk ratio (RR) = 1.24, 95% CI (1.17, 1.31), P < .00001] and in increasing platelet counts [standardized mean difference (SMD) = 1.50, 95% CI (1.09, 1.91), P < .00001], white blood cell count [SMD = 1.08, 95% CI (0.77, 1.39), P < .00001], and neutrophil count [SMD = 0.73, 95% CI (0.19, 1.28), P = .009], and CFA reduced myelosuppression [RR = 0.19, 95% CI (0.1, 0.37), P < .00001] and adverse effects [RR = 0.75, 95% CI (0.58, 0.96), P = .02]. CONCLUSION: CFA can effectively improve the clinical outcome of patients with thrombocytopenia with a good safety profile and are worth promoting. However, due to the low quality and small sample size of the included literature, a larger sample size and more standardized, high-quality studies are needed to validate these results.

Induction of glial cell line-derived neurotrophic factor by the squamosamide derivative FLZ in astroglia has neuroprotective effects on dopaminergic neurons.

Glial cell line-derived neurotrophic factor (GDNF) has neurotrophic activity for the survival of dopaminergic neurons, which is under active investigation for Parkinson's disease (PD) therapy. FLZ is a potential new drug for PD treatment. However, it is unclear whether neurotrophic activity contributes to the neuroprotective effects of FLZ. Here we found that FLZ markedly improved the function of dopaminergic neurons in primary mesencephalic neuron/glia cultures. Further investigation demonstrated that astroglia were required for FLZ to function as a neurotrophic regulator, as FLZ failed to show neurotrophic effects in the absence of astroglia. We clarified that GDNF was responsible for the neurotrophic effects of FLZ since FLZ selectively stimulated GDNF production, which was confirmed by the finding that the neurotrophic effect of FLZ was attenuated by GDNF-neutralizing antibody. Mechanistic study demonstrated that GDNF induction by FLZ was CREB-dependent and that PI3K/Akt was the main pathway regulating CREB activity, which was confirmed by in vivo studies. We also validated that the induction of GDNF by FLZ contributed to PD treatment in vivo. In conclusion, the present data provided evidence that FLZ had robust neurotrophic effects on dopaminergic neurons through sustained induction of GDNF in astroglia by activating the PI3K/Akt/CREB pathway.

Caffeic Acid Genotoxicity: Correlation of the Pig-a Assay with Regulatory Genetic Toxicology In Vivo Endpoints.

Caffeic acid is found in variety of fruits and vegetables. It is considered as possible human carcinogen (Group 2B). It is negative in Ames and mouse micronucleus (MN), but positive in mouse lymphoma and chromosomal aberration assays. The objective of this study was to evaluate the in vivo genotoxicity of caffeic acid using three different endpoints: in vivo MN, Pig-a, and comet assay. Two sets of six rats per group were administered vehicle (0.5% hydroxypropyl methylcellulose), 500, 1,000, or 2,000 mg/kg/day of caffeic acid for three consecutive days via oral gavage. One set of animals was used for the Pig-a and MN assay and the other set was used for the comet assay. N-Ethyl N-Nitrosourea was used as positive control for the Pig-a and MN assay, and ethyl methanesulfonate for the comet assay. From one set of animals, peripheral blood was collected on Days -1, 14, and 30 for the Pig-a assay and on Day 4 for the MN assay. The other set of animals was euthanized 3 hr after the last dose; liver and blood were collected for the comet assay. A statistically significant increase in the MN frequency was observed at 2,000 mg/kg/day. No increase in the red blood cells (RBCCD59- ) or reticulocytes (RETCD59- ) Pig-a mutant frequencies was observed on Days 14 or 30. No increase in DNA strand breaks was observed in the peripheral blood or liver in the comet assay. Environ. Mol. Mutagen. 2019. © 2019 Wiley Periodicals, Inc.

Efficacy and safety of a standardized extract from Achillea wilhelmsii C. Koch in patients with ulcerative colitis: A randomized double blind placebo-controlled clinical trial.

BACKGROUND: Using Achillea wilhelmsii as a dietary supplement for gastrointestinal disorders is common in Persian traditional medicine. Its anti-inflammatory, anti-spasmodic and antibacterial properties have been proven by different in vitro and in vivo studies, yet it has not been evaluated in a controlled clinical trial. AIM: This study intended to evaluate the efficacy and safety of A. wilhelmsii in patients with mild to moderate active ulcerative colitis in a randomized, double-blinded, placebo-controlled clinical trial. The hydroalcoholic extract of A. wilhelmsii was standardized based on caffeic acid. METHODS: Forty-nine patients were randomly received A. wilhelmsii capsules or placebo, twice daily for 4 weeks in a 1:1 ratio. The disease activity index (DAI) (Partial Mayo Score), haemoglobin, platelet count, erythrocyte sedimentation rate (ESR) and serum level of C-reactive protein (CRP) were measured at the entry and the end of the treatment. To standardize the extract, caffeic acid was detected and measured in the plant extract using high performance liquid chromatography (HPLC). RESULTS: Of 49 patients who entered the trial, 40 patients completed the study. In both treatment and placebo groups, significant reductions were observed in stool frequency, rectal bleeding, physician global assessment and partial mayo score. There was no significant difference in stool frequency (P = 0.176), rectal bleeding (P = 0.523), physician global assessment (P = 0.341) and partial mayo score (P = 1) in the treatment versus the placebo groups. Laboratory variables including hemoglobin, platelet count, ESR and CRP showed no significant difference between the treatment and the placebo group. Of all participants, only one patient in the treatment group complained about skin rash (grade 1 based on the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0). CONCLUSION: Oral administration of A. wilhelmsii powder for 4 weeks did not create a clinical response more than placebo. It seemed to be safe in UC patients. Further studies are obligatory to evaluate the therapeutic potential of A. wilhelmsii in the form of extract in UC patients.

Simultaneous identification of three pseudoallergic components in Danshen injection by using high-expression Mas-related G protein coupled receptor X2 cell membrane chromatography coupled online to HPLC-ESI-MS/MS.

Adverse drug reactions of Danshen injection mainly manifested as pseudoallergic reactions. In the present study, salvianolic acid A and a pair of geometric isomers (isosalvianolic acid C and salvianolic acid C) were identified as pseudoallergic components in Danshen injection by a high-expression Mas-related G protein coupled receptor X2 cell membrane chromatography coupled online with high-performance liquid chromatography with electrospray ionization tandem mass spectrometry. Their pseudoallergic activities were evaluated by in vitro assay, which were consistent with the retention times on the cell membrane chromatography column. Salvianolic acid C, the most outstanding compound, was further found to induce pseudoallergic reaction through Mas-related G protein coupled receptor X2. All the results above indicated that the system developed in this study is an effective method for simultaneously analyzing pseudoallergic components, even those with similar structures and the microcomponents in complex samples (salvianolic acid C in Danshen injection).

Immunomodulatory and cellular anti-oxidant activities of caffeic, ferulic, and p-coumaric phenolic acids: a structure-activity relationship study.

Many studies have been performed to assess the potential utility of natural products as immunomodulatory agents to enhance host responses and to reduce damage to the human body. To determine whether phenolic compounds (caffeic, ferulic, and p-coumaric acids) have immunomodulatory effects and clarify which types of immune effector cells are stimulated in vitro, we evaluated their effect on splenocyte proliferation and lysosomal enzyme activity. We also investigated the activity of natural killer (NK) cells and cytotoxic T lymphocytes (CTL). In addition, induction of the cellular antioxidant activity in splenocytes, macrophages, and red blood cells was determined by measuring the fluorescence of the DCF product. The study first results indicated that caffeic, ferulic, and p-coumaric acids significantly promote LPS-stimulated splenocyte proliferation, suggesting a potential activation of B cells, and enhanced humoral immune response in hosts treated by the tested natural products. Phenolic acids significantly enhanced the killing activity of isolated NK and CTL cells but had negligible effects on mitogen-induced proliferation of splenic T cells. We showed that caffeic acid enhances lysosomal enzyme activity in murine peritoneal macrophages, suggesting a potential role in activating such cells. Immunomodulatory activity was concomitant with the cellular antioxidant effect in macrophages and splenocytes of caffeic and ferulic acids. We conclude from this study that caffeic, ferulic, and p-coumaric acids exhibited an immunomodulatory effect which could be ascribed, in part, to their cytoprotective effect via their antioxidant capacity. Furthermore, these results suggest that these natural products could be potentially used to modulate immune cell functions in physiological and pathological conditions.

Effects of novel hybrids of caffeic acid phenethyl ester and NSAIDs on experimental ocular inflammation.

In this study, we report the design and synthesis of novel hybrids of caffeic acid phenetyl ester (CAPE) and non-steroidal anti-inflammatory drugs (NSAIDs). We assessed their effects on an experimental ocular inflammation in New Zealand rabbits. The formulations of CAPE-aspirin and CAPE-indomethacin hybrids were topical instilled in the rabbit׳s eye. Afterwards, the anti-inflammatory activity was evaluated by grading the clinical signs and by assessing the inflammatory cell count, protein, PGE2 and TNFα levels in the aqueous humor. Furthermore, ocular tolerability of hybrids formulations was evaluated in a separate set of animals by using a modified Draize test. The ocular inflammation in the control group was significantly higher than in both the hybrid-treated groups, as indicated by clinical grading and biomarkers assessment. However, only the CAPE-aspirin hybrid reduced, in a significant dose-dependent manner, the ocular inflammation elicited by paracentesis. CAPE-indomethacin hybrid was able to significantly attenuate the clinical grading and the PGE2 aqueous levels only at the highest dose (0.1%). CAPE-aspirin significantly reduced PGE2 and TNFα levels in the aqueous humor as well as proteins and PMNs. Finally, all formulations showed no ocular irritation compared with vehicle-treated group. In conclusion, CAPE-aspirin shows full anti-inflammatory efficacy in experimental model of ocular inflammation demonstrating an optimal pharmacological and safety profile. Taken together these data indicate that CAPE-aspirin hybrid represents a valid and safe new chemical entity potentially useful for the treatment of ocular inflammation.

Preparation of caffeic acid phenethyl ester-incorporated nanoparticles and their biological activity.

The aim of this study is to fabricate caffeic acid phenethyl ester (CAPE)-incorporated nanoparticles using methoxy poly(ethylene glycol)-b-poly(ε-caprolactone) (CE) copolymer and to study their antitumor activity against pulmonary metastasis model of CT26 colon carcinoma cells. CAPE-incorporated nanoparticles showed spherical shapes having small diameters less than 300 nm and CAPE was continuously released from CE nanoparticles over 4 days. CAPE-incorporated polymeric micelles properly inhibited proliferation and induced apoptosis of CT26 cells as well as CAPE itself. Furthermore, they showed similar anti-invasive and antimigrative effect against CT26 cells at in vitro compared with CAPE itself, indicating that CAPE-incorporated nanoparticles have at least equivalent anticarcinogenic activity against CT26 cells compared with CAPE itself. At pulmonary metastasis model of CT26 cells using nude mouse, CAPE-incorporated nanoparticles have superior antimetastatic efficacy against, that is, control treatment with pulmonary metastasis model showed significant increase of lung weight because of the metastasis of tumor cells, whereas CAPE or CAPE-incorporated nanoparticles properly inhibited metastasis of tumor cells. We suggest CAPE-incorporated nanoparticles as a promising candidate for antimetastatic chemotherapeutic agent. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:144-154, 2015.

Caffeic acid phenethyl ester: its protective role against certain major eye diseases.

As an effective compound found mainly in the honeybee product propolis, caffeic acid phenethyl ester (CAPE) has been commonly utilized as a medicine and remedial agent, in a number of countries. Specifically, it might inhibit nuclear factor kappa B at micromolar concentrations and demonstrate antioxidant, antineoplastic, antiproliferative, cytostatic, antiviral, antibacterial, antifungal, and anti-inflammatory features. This review article summarizes the recent progress regarding the favorable effects of CAPE on a number of eye disease models, including cataract and posterior capsule opacification, corneal diseases, retina and optic nerve-related diseases, ischemia/reperfusion injury of retina, inflammation and infection-related diseases. CAPE has been found to exhibit promising efficacy, with minimal adverse effects, in animal and cell culture studies of several eye diseases.

Antihypertensive effect of caffeic acid and its analogs through dual renin-angiotensin-aldosterone system inhibition.

Hypertension is a crucial risk factor for cardiovascular diseases and contributes to one third of global mortality. In addition to conventional antihypertensive drugs such as captopril, naturally occurring phytochemicals and their analogs are used for reducing the risk and occurrence of hypertension. Herein, we demonstrate the possible use of caffeic acid and its derivatives in the treatment of hypertension through multi-target modulation of renin-angiotensin-aldosterone system (RAAS). Caffeic acid along with its nineteen novel derivatives, chlorogenic acid, quercetin and captopril were all investigated for the inhibition of renin and angiotensin converting enzyme (ACE) activities and production of aldosterone. Compound 22 with CH2CH(Ph)2 moiety exhibited the strongest renin inhibition (IC50=229µM) among all compounds tested (P≤0.05). Caffeic acid was the weakest renin inhibitor (IC50=5704µM) among all the compounds assayed. Similar to renin inhibition, compound 22 (IC50=9.1µM) also exhibited about 47 times stronger ACE inhibition compared to the parent compound. Analysis of aldosterone revealed that compound 8 with n-Pr moiety was the strongest modulator of aldosterone production among all the derivatives (P≤0.05). Toxicity analysis using human fibroblasts (WI-38 cells) confirmed the non-toxic manifestations of caffeic acid and its derivatives in comparison to clinically used drug captopril.

Laccase-catalysed oxidation of ferulic acid and ethyl ferulate in aqueous medium: a green procedure for the synthesis of new compounds.

The enzymatic oxidation of ferulic acid (FA) and ethyl ferulate (EF) with Myceliophthora thermophila laccase, as biocatalyst, was performed in aqueous medium using an eco-friendly procedure to synthesize new active molecules. First, the commercial laccase was ultrafiltrated allowing for the elimination of phenolic contaminants and increasing the specific activity by a factor of 2. Then, kinetic parameters of this laccase were determined for both substrates (FA, EF), indicating a higher substrate affinity for ethyl ferulate. Additionally, enzymatic oxidation led to the synthesis of a FA-major product, exhibiting a molecular mass of 386 g/mol and a EF-major product with a molecular mass of 442 g/mol. Structural analyses by mass spectrometry allowed the identification of dimeric derivatives. The optical properties of the oxidation products showed the increase of red and yellow colours, with FA-products compared to EF-products. Additionally, enzymatic oxidation led to a decrease of antioxidant and cytotoxic activities compared to initial substrates. Consequently, this enzymatic procedure in aqueous medium could provide new compounds presenting optical, antioxidant and cytotoxic interest.

Efficacy of caffeic acid phenethyl ester (CAPE) in skin B16-F0 melanoma tumor bearing C57BL/6 mice.

In current work, we investigated the in-vitro efficacy of Caffeic acid Phenethyl Ester (CAPE) as an anti-melanoma agent in five melanoma cell lines B16-F0, B16F10, SK-MEL-28, SK-MEL-5, and MeWo and in-vivo efficacy study in skin B16-F0 melanoma tumor model in C57BL/6 mice. The IC(50) (48 h) of CAPE in above five melanoma cell lines was 15 µM. CAPE (20-200 µM) led to intracellular GSH depletion of 16-54%, and 10-25 fold increase in Reactive Oxygen Species (ROS) formation in B16-F0 cells. CAPE (15-30 µM) caused 5-7 fold increase in apoptosis in B16-F0 cells. CAPE (10, 20 and 30 mg/Kg/day) led to tumor size growth inhibition by 39 ± 33%, 54 ± 36%, and 57 ± 18%, respectively. The respective therapies led to plasma Alanine Amino Transferase (ALT) levels corresponding to 85 ± 18, 107 ± 26, 154 ± 35 IU/L in comparison to controls 66 ± 14 IU/L. At corresponding doses, the lipid peroxidation levels as measured by malondialdehyde (MDA) formation in liver homogenates were 255 ± 8 µM, 304 ± 21 µM, and 342 ± 14 µM in comparison to 208 ± 6 µM in controls. The level of MDA in kidney homogenates was 263 ± 21 µM, 282 ± 18 µM, and 350 ± 28 µM, respectively, in comparison to 212 ± 8 µM in controls. Administration of CAPE (10, 20, 30 mg/Kg/day) diminished free thiol contents in liver for 21 ± 15%, 40 ± 17%, and 44 ± 19% and in kidney homogenates for 25 ± 15%, 37 ± 18%, and 40 ± 22%, respectively, as compared to controls. Our study suggests that CAPE at 10 mg/Kg/day has significant anti-melanoma efficacy with minimal toxicity.

Biological evaluation of 2-(4-amino-phenyl)-3-(3,5-dihydroxylphenyl) propenoic acid.

2-(4-Aminophenyl)-3-(3,5-dihydroxylphenyl) propenoic acid (CSN-07001) is a new compound based on the combination of resveratrol and propenoic acid derivatives. In vitro cyclooxygenase (COX)/5-lipoxygenase (5-LOX) inhibition assays showed that the test compound exhibited a dual inhibitory activity against the COX (COX-1 IC(50) = 2.20 microM, COX-2 IC(50) = 1.76 microM) and 5-LOX (IC(50) = 0.28 microM) enzymes. Further, the enhanced COX-1/COX-2/5-LOX expression in lipopolysaccaride-induced lung inflammation in mice was also suppressed by CSN-07001 in a concentration-dependent manner. In vivo studies showed that CSN-07001 exhibited potent anti-inflammatory and antinociceptive effects in different experimental models. We further examined the risk of gastric damage induced by CSN-07001. The test compound was gastric-sparing in that it elicited markedly fewer stomach lesions than indomethacin in rats. Taken together, our data indicate that CSN-07001 exhibits a novel class of dual inhibitors of COX and 5-LOX having therapeutic potential as non-steroidal anti-inflammatory agents with an enhanced gastric safety profile.

Effects of caffeic acid phenethyl ester on glycerol-induced acute renal failure in rats.

1. Free radicals and nitric oxide (NO) play a crucial role in the pathogenesis of myoglobinuric acute renal failure (ARF). The aim of the present study was to investigate the effects of caffeic acid phenethyl ester (CAPE), an anti-oxidant, on the myoglobinuric ARF induced by intramuscular hypertonic glycerol injection. 2. Thirty rats were divided equally into three groups. Rats in group 1 were given saline and those in groups 2 and 3 were injected with glycerol (10 mL/kg, i.m.). Concomitant and 24 h after glycerol injection, CAPE (10 micromol/kg, i.p.) was administered to group 3 rats. Forty-eight hours after glycerol injection, blood samples and kidney tissues of rats were taken under anaesthesia. 3. Plasma concentrations of urea, creatinine, malondialdehyde (MDA) and NO were determined, as were superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activities and MDA levels in kidney tissues. Kidney morphology was also investigated. 4. In the group receiving CAPE, although SOD enzyme activity was found to be increased, we failed to find any protective effect of CAPE on other parameters investigated. Moreover, although CAPE significantly decreased NO levels, it increased plasma concentrations of urea and MDA. 5. We suggest that the effect of CAPE in decreasing NO concentrations may further increase the renal ischaemia in this model. Thus, CAPE may have a worsening rather than beneficial effect under these conditions in this model of ARF.

Propolis allergy. (II). The sensitizing properties of 1,1-dimethylallyl caffeic acid ester.

As shown in the preceding paper, propolis or bee-glue is the cause of an increasing number of allergic reactions in persons using it in external preparations and cosmetics. Propolis and its main contact allergen, 1,1-dimethylallyl caffeic acid ester, designated LB-1, show strong sensitizing properties in patients as well as in guinea pig experiments. 9 patients have been patch tested with this compound, 8 of whom reacted strongly. Chemical separation of different propolis samples and poplar bud extracts reveal that LB-1 is always present. Poplar bud secretion is the bee's major source for propolis and hence the origin of LB-1. A warning is indicated, in agreement with several other authors, that propolis should not be used in topical products because of its strong sensitizing properties.