Caffeic acid phenethyl ester inhibits neuro-inflammation and oxidative stress following spinal cord injury by mitigating mitochondrial dysfunction via the SIRT1/PGC1α/DRP1 signaling pathway.

BACKGROUND: The treatment of spinal cord injury (SCI) has always been a significant research focus of clinical neuroscience, with inhibition of microglia-mediated neuro-inflammation as well as oxidative stress key to successful SCI patient treatment. Caffeic acid phenethyl ester (CAPE), a compound extracted from propolis, has both anti-inflammatory and anti-oxidative effects, but its SCI therapeutic effects have rarely been reported. METHODS: We constructed a mouse spinal cord contusion model and administered CAPE intraperitoneally for 7 consecutive days after injury, and methylprednisolone (MP) was used as a positive control. Hematoxylin-eosin, Nissl, and Luxol Fast Blue staining were used to assess the effect of CAPE on the structures of nervous tissue after SCI. Basso Mouse Scale scores and footprint analysis were used to explore the effect of CAPE on the recovery of motor function by SCI mice. Western blot analysis and immunofluorescence staining assessed levels of inflammatory mediators and oxidative stress-related proteins both in vivo and in vitro after CAPE treatment. Further, reactive oxygen species (ROS) within the cytoplasm were detected using an ROS kit. Changes in mitochondrial membrane potential after CAPE treatment were detected with 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethyl-imidacarbocyanine iodide. Mechanistically, western blot analysis and immunofluorescence staining were used to examine the effect of CAPE on the SIRT1/PGC1α/DRP1 signaling pathway. RESULTS: CAPE-treated SCI mice showed less neuronal tissue loss, more neuronal survival, and reduced demyelination. Interestingly, SCI mice treated with CAPE showed better recovery of motor function. CAPE treatment reduced the expression of inflammatory and oxidative mediators, including iNOS, COX-2, TNF-α, IL-1ß, 1L-6, NOX-2, and NOX-4, as well as the positive control MP both in vitro and in vivo. In addition, molecular docking experiments showed that CAPE had a high affinity for SIRT1, and that CAPE treatment significantly activated SIRT1 and PGC1α, with down-regulation of DRP1. Further, CAPE treatment significantly reduced the level of ROS in cellular cytoplasm and increased the mitochondrial membrane potential, which improved normal mitochondrial function. After administering the SIRT1 inhibitor nicotinamide, the effect of CAPE on neuro-inflammation and oxidative stress was reversed.On the contrary, SIRT1 agonist SRT2183 further enhanced the anti-inflammatory and antioxidant effects of CAPE, indicating that the anti-inflammatory and anti-oxidative stress effects of CAPE after SCI were dependent on SIRT1. CONCLUSION: CAPE inhibits microglia-mediated neuro-inflammation and oxidative stress and supports mitochondrial function by regulating the SIRT1/PGC1α/DRP1 signaling pathway after SCI. These effects demonstrate that CAPE reduces nerve tissue damage. Therefore, CAPE is a potential drug for the treatment of SCI through production of anti-inflammatory and anti-oxidative stress effects.

Caffeic acid phenethyl ester attenuates indomethacin-induced gastric ulcer in rats.

Gastric ulcer is one of the most frequent gastrointestinal ailments worldwide. Indomethacin, one of the most potent NSAIDs, suffers undesirable ulcerogenic activity. Caffeic acid phenethyl ester (CAPE) has known health benefits. The current study examined the potential of CAPE to combat indomethacin-induced gastric ulcers in rats. Animals were randomized into 5 groups: control, Indomethacin (50 mg/kg) mg/kg), Indomethacin + CAPE (5 mg/kg/day), Indomethacin + CAPE (10 mg/kg), and Indomethacin + Omeprazole (30 mg/kg). CAPE prevented the rise in ulcer index, attenuated histopathological changes and preserved gastric mucin concentration. CAPE efficiently significantly prevented accumulation of malondialdehude (MDA) and prevented exhaustion of the enzymatic activities of catalase (CAT) and superoxide dismutase (SOD). Further, CAPE prevented the rise in the expression of tumor necrosis factor-α (TNF-α), cyclo-oxygenase-2 (COX-2) and nuclear factor kapp-B (NFκB). This was associated with down-regulation of Bax and up-regulation of Bcl-2 mRNA. Finally, CAPE prevented induced indomethacin-induced decrease in heat shock protein 70 (HSP70) in gastric tissues. In conclusion, CAPE possesses the ability to prevent indomethacin-induced gastric ulcer in rats. This involves, at least partially, antioxidation, anti-inflammation, anti-apoptosis and enhancement of HSP70 expression.

The anticancer impacts of free and liposomal caffeic acid phenethyl ester (CAPE) on melanoma cell line (A375).

The deadliest type of skin cancer, malignant melanoma, is also the reason for the majority of skin cancer-related deaths. The objective of this article was to investigate the efficiency of free caffeic acid phenethyl ester (CAPE) and liposomal CAPE in inducing apoptosis in melanoma cells (A375) in in vitro. CAPE was loaded into liposomes made up of hydrogenated soybean phosphatidylcholine, cholesterol, and 1,2-distearoyl-sn-glycero-3 phosphoethanolamine-N-[methoxy (polyethylene glycol)-2000], and their physicochemical properties were assessed. (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) test was performed for comparing the cytotoxicity of free CAPE and liposomal CAPE at dosages of 10, 15, 25, 50, 75 and the highest dose of 100 µg/mL for period of 24 and 48 h on A375 cell line to calculate IC50. Apoptosis and necrosis were evaluated in A375 melanoma cancer cells using flow cytometry. Atomic force microscopy was utilized to determine the nanomechanical attributes of the membrane structure of A375 cells. To determine whether there were any effects on apoptosis, the expression of PI3K/AKT1 and BAX/BCL2 genes was analyzed using the real-time polymerase chain reaction technique. According to our results, the maximum amount of drug release from nanoliposomes was determined to be 91% and the encapsulation efficiency of CAPE in liposomes was 85.24%. Also, the release of free CAPE was assessed to be 97%. Compared with liposomal CAPE, free CAPE showed a greater effect on reducing the cancer cell survival after 24 and 48 h. Therefore, IC50 values of A375 cells treated with free and liposomal CAPE were calculated as 47.34 and 63.39 µg/mL for 24 h. After 48 h of incubation of A375 cells with free and liposomal CAPE, IC50 values were determined as 30.55 and 44.83 µg/mL, respectively. The flow cytometry analysis revealed that the apoptosis induced in A375 cancer cells was greater when treated with free CAPE than when treated with liposomal CAPE. The highest nanomechanical changes in the amount of cell adhesion forces, and elastic modulus value were seen in free CAPE. Subsequently, the greatest decrease in PI3K/AKT1 gene expression ratio occurred in free CAPE.

Caffeic acid phenethyl ester: Unveiling its potential as a potent apoptosis inducer for combating hypopharyngeal squamous cell carcinoma.

Hypopharyngeal squamous cell carcinoma (HSCC) is a relatively rare form of head and neck cancer that is notorious for its poor prognosis and low overall survival rate. This highlights the need for new therapeutic options for this malignancy. The objective of the present study was to examine the ability of caffeic acid phenethyl ester (CAPE), which is an active compound found in propolis, to combat HSCC tumor growth. CAPE exerted its tumor­suppressive activity in HSCC cell lines through the induction of apoptosis. Mechanistically, the CAPE­mediated apoptotic process was attributed to the perturbation of the mitochondrial membrane potential and the activation of caspase­9. CAPE also modulated survivin and X­linked inhibitor of apoptosis, which are potent members of the inhibitors of apoptosis protein family, either through transcriptional or post­translational regulation, leading to HSCC cell line death. Therefore, the findings of the present study suggested that CAPE is an effective treatment alternative for HSCC via the stimulation of mitochondria­dependent apoptosis.

Caffeic Acid Phenethyl Ester Reduces the Adverse Effects of Nicotine on the Endometrium.

Background: Tobacco smoke contains various toxins that negatively affect the human reproductive system. Caffeic acid phenethyl ester (CAPE), a potent antioxidant, has protective effects on the reproductive system against oxygen-free radicals, methotrexate, and pesticides. Herein, the effect of CAPE on some key markers of endometrial receptivity has been evaluated. Methods: A cross-sectional study was conducted during 2018-2019 in the Department of Clinical Biochemistry, School of Medicine, Fasa University of Medical Sciences (Fasa, Iran). Primary endometrial cells were divided into five groups, namely control, nicotine, CAPE, vehicle, and nicotine+CAPE. Real-time polymerase chain reaction (PCR) and methylation-specific PCR were performed to evaluate gene expressions and methylation, respectively. Appropriate doses of CAPE and nicotine were determined using the MTT assay. Data were analyzed using SPSS software (version 16.0) with a one-way analysis of variance. P<0.01 was considered statistically significant. The fold change was calculated using the 2-∆ΔCT method. Results: Treatment of cells with nicotine significantly reduced the expression of C-X-C motif chemokine ligand 12 (CXCL12), fibroblast growth factor 2 (FGF2), and vascular endothelial growth factor A (VEGF-A) genes (P<0.0001). However, the expression levels increased significantly when treated with nicotine+CAPE (P<0.0001). Despite the reduced CXCL12 gene expression in cells treated with nicotine, CXCL12 was unmethylated in all study groups, indicating that the methylation status of the CXCL12 gene was not affected by nicotine or CAPE. Conclusion: CAPE can be a suitable agent to protect female smokers from the harmful effects of nicotine. This manuscript is available as a preprint on the Research Gate website.

The effect of caffeic acid on tendon healing in rats with an Achilles tendon injury model.

OBJECTIVES: This study aims to examine the effect of caffeic acid on tendon healing histopathologically and biomechanically in rats with an Achilles tendon injury model. MATERIALS AND METHODS: Twenty male Wistar-albino rats were used in this study. The rats were divided into two groups as the experimental group and control group. All rats underwent a bilateral achillotomy injury model and then surgical repair. Postoperatively, for four weeks, the experimental group was given intraperitoneal caffeic acid (100 mg/kg/day suspended in saline), while the control group was given only intraperitoneal saline. At the end of four weeks, after sacrificing each rat, right Achilles tendons were subjected to biomechanical analysis and the Achilles tendons were subjected to histopathological analysis. Bonar and Movin scores were used for histopathological analysis. In biomechanical analysis, tensile test was applied to Achilles tendons until rupture. For each tendon, failure load, displacement, cross-sectional area, maximum energy, total energy, length, stiffness, ultimate stress and strain parameters were recorded. RESULTS: According to Bonar and Movin scoring, the experimental group had lower scoring values than the control group (p=0.002 and p=0.002, respectively). Bonar scoring parameters were analyzed separately. Vascularity, collagen, and ground substance scores were lower in the experimental group compared to the control group (p=0.001, p=0.003, and p=0.047, respectively). No significant difference was found for tenocyte (p=0.064). In biomechanical analysis, failure load, displacement, ultimate stress, strain, and stiffness values were found to be higher in the experimental group compared to the control group (p=0.049, p=0.005, p=0.028, p=0.021, and p=0.049, respectively). CONCLUSION: The caffeic acid contributed positively to tendon healing histopathologically and biomechanically in rats with an Achilles tendon injury model.

Intralipid and caffeic acid phenethyl ester reverse the neurotoxic effects of organophosphate poisoning in rats.

Background: Organophosphate (Op)-containing herbicides continue to be widely used in the world. Although its usage and intoxication are widespread, the studies on organophosphate-induced neurotoxicity and treatment protocols are very few in the literature. Aims: This study aimed to investigate any potential effects of caffeic acid phenyl ester with/without intralipid on neurotoxicity produced by acute intoxication of glyphosate isopropylamine in an experimental rat model. Materials And Methods: Forty-nine wistar albino rats were randomly allotted into seven experimental groups: I, control; II, intralipid (IL); III, caffeic acid phenyl esther (CAPE); IV, glyphosate isopropylamine (GI); V, GI + IL; VI, GI + CAPE; and VII, GI + IL + CAPE. Total antioxidant and oxidant status levels were gauged, and the oxidative stress index was calculated in the serum samples. On the other hand, the tissues were analyzed with hematoxylin-eosin (HE) staining protocol and counted up by immunohistochemical method. Statistical evaluations were conducted using SPSS 11.5 for Windows (SPSS, Chicago, IL, USA). Results: Compared to the control, IL, and GI + IL + CAPE groups, the GI group significantly decreased the total antioxidant levels in brain tissues. In a supportive nature, a significant increase in the oxidative site index (OSI) in the GI group compared to other groups. Especially standing out point of these findings is the significant difference between the GI + IL + CAPE and the GI group. Parallelly, histopathological analysis extended severe neurotoxicity in the GI group. Neurotoxic status was reduced significantly in the GI + CAPE + IL group. The histopathologic examinations confirmed biochemical results. The results also revealed that CAPE and IL, probably their antioxidant effects, have a rehabilitative effect on neurotoxicity caused by GI. Conclusion: Therefore, CAPE and IL may function as potential cleansing and scavenger agents for supportive therapy regarding tissue damage or facilitate the therapeutic effects of the routine treatment of the patient with GI poisoning.

Caffeic acid phenethyl ester suppresses EGFR/FAK/Akt signaling, migration, and tumor growth of prostate cancer cells.

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.

Safety, tolerability, pharmacokinetics, and efficacy of kukoamine B in patients with sepsis: A randomized phase IIa trial.

PURPOSE: To evaluate the safety, tolerability, pharmacokinetics, and efficacy of kukoamine B (KB), an alkaloid compound with high affinity for both lipopolysaccharide (LPS) and oligodeoxynucle-otides containing CpG motifs (CpG DNA), in patients with sepsis-induced organ failure. MATERIALS AND METHODS: This was a multicenter, randomized, double-blind, placebo-controlled phase IIa trial. Patients with sepsis-induced organ failure were randomized to receive either KB (0.06, 0.12, or 0.24 mg/kg) or placebo, every 8 h for 7 days. Primary endpoint was safety, and secondary endpoints included pharmacokinetic (PK) parameters, changes in inflammatory mediators' level, and prognostic parameters. RESULTS: Of 44 patients enrolled, adverse events occurred in 28 patients [n = 20, 66.7% (KB pooled); n = 8, 57.1% (placebo)], while treatment emergent adverse events were reported in 14 patients [n = 10, 33.3% (KB pooled); n = 4, 28.6% (placebo)]. Seven patients died at 28-day follow-up [n = 4, 13.3% (KB pooled); n = 3, 21.4% (placebo)], none was related to study drug. PK parameters suggested dose-dependent drug exposure and no drug accumulation. KB did not affect clinical outcomes such as ΔSOFA score, vasopressor-free days or ventilator-free days. CONCLUSIONS: In patients with sepsis-induced organ failure, KB was safe and well tolerated. Further investigation is warranted. TRIAL REGISTRATION: http://ClinicalTrials.gov, NCT03237728.

Therapeutic efficacy of caffeic acid phenethyl ester in cancer therapy: An updated review.

Nowadays, there is a lot of public and scientific interest in using phytochemicals to treat human ailments. Existing cancer medicines still run across obstacles, despite significant advancements in the field. For instance, chemotherapy may result in severe adverse effects, increased drug resistance, and treatment failure. Natural substances that are phytochemically derived provide innovative approaches as potent therapeutic molecules for the treatment of cancer. Bioactive natural compounds may enhance chemotherapy for cancer by increasing the sensitivity of cancer cells to medicines. Propolis has been found to interfere with the viability of cancer cells, among other phytochemicals. Of all the components that make up propolis, caffeic acid phenethyl ester (CAPE) (a flavonoid) has been the subject of the most research. It demonstrates a broad spectrum of therapeutic uses, including antitumor, antimicrobial, antiviral, anti-inflammatory, immunomodulatory, hepatoprotective, neuroprotective, and cardioprotective effects. Studies conducted in vitro and in vivo have demonstrated that CAPE specifically targets genes involved in cell death, cell cycle regulation, angiogenesis, and metastasis. By altering specific signaling cascades, such as the NF-κB signaling pathway, CAPE can limit the proliferation of human cancer cells. This review highlights the research findings demonstrating the anticancer potential of CAPE with a focus on multitargeted molecular and biological implications in various cancer models.

A Central Contribution of TG2 Activity to the Antiproliferative and Pro-Apoptotic Effects of Caffeic Acid in K562 Cells of Human Chronic Myeloid Leukemia.

Caffeic acid (CA) has shown antitumor activity in numerous solid and blood cancers. We have recently reported that CA is active in reducing proliferation and triggering apoptosis in both Imatinib-sensitive and resistant Chronic Myeloid Leukemia (CML) cells. Tissue transglutaminase type 2 (TG2) enzyme is involved in cell proliferation and apoptosis of numerous types of cancer. However, its activity has different effects depending on the type of tumor. This work investigated the possible involvement of TG2 activation in the triggering of CA-dependent anticancer effects on the K562 cell line, which was studied as a model of CML. CA-dependent changes in TG2 activity were compared with the effects on cell proliferation and apoptosis. The use of N-acetylcysteine (NAC), an antioxidant molecule, suggested that the antiproliferative effect of CA was due to the increase in reactive oxygen species (ROS). The use of a TG2 inhibitor showed that TG2 activity was responsible for the increase in ROS generated by CA and reduced both caspase activation and triggering of CA-dependent apoptosis. The knocking-down of TGM2 transcripts confirmed the crucial involvement of TG2 activation in CML cell death. In conclusion, the data reported, in addition to ascertaining the important role of TG2 activation in the antiproliferative and pro-apoptotic mechanism of CA allowed us to hypothesize a possible therapeutic utility of the molecules capable of triggering the activation pathways of TG2 in the treatment of CML.

Caffeic acid phenethyl ester ameliorates imidacloprid-induced acute toxicity in the rat cerebral cortex.

This study aimed to investigate the role of caffeic acid phenethyl ester (CAPE), a compound found in propolis, on imidacloprid (IMI), a nicotinic acetylcholine receptor agonist that causes cerebral toxicity. 60 adult rats were randomly divided into five groups: control, IMI (100 mg/kg), and IMI+CAPE (1, 5, 10 mg/kg). Cerebral cortex tissue was examined histopathologically, biochemically, spectrophotometrically and immunohistochemically. The results showed that IMI caused toxicity in the cerebral cortex. However, CAPE (5 and 10 mg/kg) attenuated the deteriorated histopathological score and normalized the apoptotic markers (Bax and Caspase-3). Additionally, CAPE dose-dependently normalized the levels of TNF-α, dopamin, GFAP and NGF, and at the highest dose (10 mg/kg) also normalized the balance of oxidative parameters (MDA, SOD, CAT, and GSH). In conclusion, the antioxidant, anti-inflammatory, and anti-apoptotic effects of CAPE may be a promising treatment for acute IMI-induced cerebral cortex toxicity.

Forsythoside B attenuates neuro-inflammation and neuronal apoptosis by inhibition of NF-κB and p38-MAPK signaling pathways through activating Nrf2 post spinal cord injury.

BACKGROUND: Spinal cord injury (SCI) is a ruinous neurological pathology that results in locomotor and sensory impairment. Neuro-inflammation and secondary neuronal apoptosis contribute to SCI, with anti-inflammatory therapies the focus of many SCI studies. Forsythoside B (FTS•B), a phenylethanoid glycoside extracted from the leaves of Lamiophlomis rotata Kudo, has been shown previously to have anti-inflammatory properties. Nevertheless, the therapeutic effect of FTS•B on neuro-inflammation after SCI is unknown. METHODS: Neuro-inflammation was assessed by western blotting (WB), immunofluorescence (IF) staining, and enzyme-linked immunosorbent assay (ELISA) both in vitro and in vivo. Secondary neuronal apoptosis was simulated in a microglia-neuron co-culture model with the degree of apoptosis measured by WB, IF, and TUNEL staining. In vivo, FTS•B (10 mg/kg, 40 mg/kg) were intraperitoneally injected into SCI mice. Morphological changes following SCI were evaluated by Nissl, Hematoxylin-eosin, and Luxol Fast Blue staining. Basso Mouse Scale scores were used to evaluate locomotor function recovery. RESULTS: FTS•B markedly decreased the levels of iNOS, COX-2 and signature mediators of inflammation. Phosphorylated p38 and nuclear factor-kappa B (NF-κB) were markedly decreased by FTS•B. Additionally, FTS•B-induced inhibition of NF-κB and p38-MAPK signaling pathways was reversed by Nrf2 downregulation. Administration of FTS•B also significantly reduced apoptosis-related protein levels indicating that FTS•B ameliorated secondary neuronal apoptosis. FTS•B administration inhibited glial scar formation, decreased neuronal death, tissue deficiency, alleviated demyelination, and promoted locomotor recovery. CONCLUSION: FTS•B effectively attenuates neuro-inflammation and secondary neuronal apoptosis by inhibition of NF-κB and p38-MAPK signaling pathways through activating Nrf2 after SCI. This study demonstrates FTS•B to be a potential therapeutic for SCI.

Neuroprotection of chicoric acid in a mouse model of Parkinson's disease involves gut microbiota and TLR4 signaling pathway.

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.

Chicoric Acid Prevents Neuroinflammation and Neurodegeneration in a Mouse Parkinson's Disease Model: Immune Response and Transcriptome Profile of the Spleen and Colon.

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.

Natural products can be used in therapeutic management of COVID-19: Probable mechanistic insights.

The unexpected emergence of the new Coronavirus disease (COVID-19) has affected more than three hundred million individuals and resulted in more than five million deaths worldwide. The ongoing pandemic has underscored the urgent need for effective preventive and therapeutic measures to develop anti-viral therapy. The natural compounds possess various pharmaceutical properties and are reported as effective anti-virals. The interest to develop an anti-viral drug against the novel severe acute respiratory syndrome Coronavirus (SARS-CoV-2) from natural compounds has increased globally. Here, we investigated the anti-viral potential of selected promising natural products. Sources of data for this paper are current literature published in the context of therapeutic uses of phytoconstituents and their mechanism of action published in various reputed peer-reviewed journals. An extensive literature survey was done and data were critically analyzed to get deeper insights into the mechanism of action of a few important phytoconstituents. The consumption of natural products such as thymoquinone, quercetin, caffeic acid, ursolic acid, ellagic acid, vanillin, thymol, and rosmarinic acid could improve our immune response and thus possesses excellent therapeutic potential. This review focuses on the anti-viral functions of various phytoconstituent and alkaloids and their potential therapeutic implications against SARS-CoV-2. Our comprehensive analysis provides mechanistic insights into phytoconstituents to restrain viral infection and provide a better solution through natural, therapeutically active agents.

Salvianolic acid A relieves cognitive disorder after chronic cerebral ischemia: Involvement of Drd2/Cryab/NF-κB pathway.

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.

Role of inflammation and oxidative stress in tissue damage associated with cystic fibrosis: CAPE as a future therapeutic strategy.

Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, responsible for the synthesis of the CFTR protein, a chloride channel. The gene has approximately 2000 known mutations and all of them affect in some degree the protein function, which makes the pathophysiological manifestations to be multisystemic, mainly affecting the respiratory, gastrointestinal, endocrine, and reproductive tracts. Currently, the treatment of the disease is restricted to controlling symptoms and, more recently, a group of drugs that act directly on the defective protein, known as CFTR modulators, was developed. However, their high cost and difficult access mean that their use is still very restricted. It is important to search for safe and low-cost alternative therapies for CF and, in this context, natural compounds and, mainly, caffeic acid phenethyl ester (CAPE) appear as promising strategies to assist in the treatment of the disease. CAPE is a compound derived from propolis extracts that has antioxidant and anti-inflammatory activities, covering important aspects of the pathophysiology of CF, which points to the possible benefit of its use in the disease treatment. To date, no studies have effectively tested CAPE for CF and, therefore, we intend with this review to elucidate the role of inflammation and oxidative stress for tissue damage seen in CF, associating them with CAPE actions and its pharmacologically active derivatives. In this way, we offer a theoretical basis for conducting preclinical and clinical studies relating the use of this molecule to CF.

CAPE-pNO2 ameliorates diabetic brain injury through modulating Alzheimer's disease key proteins, oxidation, inflammation and autophagy via a Nrf2-dependent pathway.

AIMS: CAPE-pNO2, an active derivative of caffeic acid phenethyl ester, has been verified to exert protection of diabetic cardiomyopathy and diabetic nephropathy. The present study aims to explore the brain protection effects and potential mechanisms of CAPE-pNO2 on streptozotocin-induced diabetic brain injury in vivo and in vitro. MAIN METHODS: Biochemical indexes including triglyceride, total cholesterol, superoxide dismutase and malondialdehyde contents were detected. The histopathological structure of hippocampus and cerebral cortex were determined. Immunofluorescence and immunoblot methods were used to assess expression of oxidative stress, inflammation and autophagy pathway-related proteins of diabetic brain in vivo. Alzheimer's disease (AD)-associated key proteins were also checked in vivo. DCFH-DA assay, immunofluorescence and immunoblot methods were applied to verify the master role of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in vitro. KEY FINDINGS: First, CAPE-pNO2 could rescue the diabetic brain atrophy and diminish CA1 and CA3 cells of hippocampus and cerebral cortex. Second, CAPE-pNO2 could decrease Aß and p-tau (S396) expression through anti-oxidation, anti-inflammation and autophagy induction in vivo. Last, CAPE-pNO2 could down-regulate p-tau (S396) expression through Nrf2-related anti-oxidation mechanisms in vitro. SIGNIFICANCE: CAPE-pNO2 may exert brain protection via Nrf2-dependent way in diabetes. Additionally, Nrf2 was capable of regulating p-tau (S396) expression that is critical to AD.

MiR-182-5p/TLR4/NF-κB axis contributes to the protective effect of caffeic acid phenethyl ester against cadmium-induced spleen toxicity and associated damage in mice.

Cadmium (Cd) is a toxic heavy metal pollutant that can be accumulated in organs including the spleen, thereby threatening human health. In this study, the effect of caffeic acid phenethyl ester (CAPE, a bioactive component of honeybee propolis) on CdCl2-induced spleen toxicity and underlying mechanisms were examined in mice. Histological examinations revealed that CAPE (10 µmol/kg/day b.w.) could mitigate spleen damage induced by CdCl2 (1.5 mg/kg/day b.w.) in mice. Compared to the mice treated only by CdCl2, CAPE administration increased the body weight while decreasing the spleen weight, spleen Cd content and spleen to body ratio of the CdCl2-treated mice. Western blot and ELISA tests revealed that CAPE suppressed CdCl2-induced inflammation (indicated by the decreases in the levels of inflammatory indictors). TUNEL and Western blot results showed that CAPE suppressed CdCl2-induced apoptosis through reducing the percentage of TUNEL-positive cells and regulating apoptosis factors. The antagonistic effect of CAPE against CdCl2-induced spleen toxicity was realized by increasing miR-182-5p expression to regulate the TLR4/NF-κB pathway. Therefore, CAPE could be a food-derived spleen protector to counteract Cd-induced spleen toxicity through alleviating apoptosis and inflammation via the miR-182-5p/TLR4/NF-κB axis.