PMID:  Am J Transl Res. 2022 ;14(12):8588-8598. Epub 2022 Dec 15. PMID: 36628216 Abstract Title:  Hydroxysafflor yellow A mitigates myocardial fibrosis induced by isoproterenol and angiotensin II. Abstract:  AIMS: To investigate the potential inhibitory effect of Hydroxysafflor yellow A (HSYA) on myocardial fibrosis induced by isoproterenol (ISO) and angiotensin II (Ang II) and the possible underlying mechanism.METHODS: Mice were injected subcutaneously with ISO and given HSYA by gavage in vivo. Masson's trichrome staining, immunohistochemical staining and immunofluorescence assays were conducted to evaluate the expression and localization of collagen and inflammatory cytokines, respectively. In vitro, cardiac fibroblasts (CFs) were treated with various doses of HSYA and induced with Ang II. Cell proliferation and migration were assessed using wound healing assay. Cell counting kit-8 was used to measure the cell viability. Collagen I, collagen III, phosphorylation of Smad2/3, Smad2/3, TGF1, interleukin (IL)-1, IL-18, NLRP3 inflammasome-associated proteins were detected by Western blotting. Levels of reactive oxygen species (ROS) were evaluated using 2',7'-dichlorofluorescein diacetate assay.RESULTS: HSYA significantly inhibited ISO-induced myocardial fibrosis, NLRP3 inflammasome activation as well as IL-18 and IL-1expressions in mice. HSYA significantly reduced the proliferation and migration of CFs, and suppressed the accumulation of collagen I and collagen III. TGF1 and P-Smad2/3 induced by Ang II was repressed by HSYA. HSYA downregulated IL-1and IL-18, blocked NLRP3 activation, and reduced ROS in CFs.CONCLUSION: HSYA may inhibit myocardial fibrosis by blocking NLRP3 pathway in CFs.

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PMID:  Front Pharmacol. 2022 ;13:1063035. Epub 2022 Dec 15. PMID: 36588739 Abstract Title:  Protective potential of hydroxysafflor yellow A in cerebral ischemia and reperfusion injury: An overview of evidence from experimental studies. Abstract:  Ischemic stroke, mostly caused by thromboembolic or thrombotic arterial occlusions, is a primary leading cause of death worldwide with high morbidity and disability. Unfortunately, no specific medicine is available for the treatment of cerebral I/R injury due to its limitation of therapeutic window. Hydroxysafflor yellow A, a natural product extracted from, has been extensively investigated on its pharmacological properties in cerebrovascular diseases. However, review focusing on the beneficial role of HSYA against cerebral I/R injury is still lacking. In this paper, we reviewed the neuroprotective effect of HSYA in preclinical studies and the underlying mechanisms involved, as well as clinical data that support the pharmacological activities. Additionally, the sources, physicochemical properties, biosynthesis, safety and limitations of HSYA were also reviewed. As a result, HSYA possesses a wide range of beneficial effects against cerebral I/R injury, and its action mechanisms include anti-excitotoxicity, anti-oxidant stress, anti-apoptosis, anti-inflammation, attenuating BBB leakage and regulating autophagy. Collectively, HSYA might be applied as one of the promising alternatives in ischemic stroke treatment.

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PMID:  J Pharm Pharmacol. 2023 Apr 17 ;75(5):666-676. PMID: 36952592 Abstract Title:  The combination of astragaloside IV and Panax notoginseng saponins attenuates cerebral ischaemia-reperfusion injury in rats through ferroptosis and inflammation inhibition via activating Nrf2. Abstract:  OBJECTIVES: This study aimed to observe the effect of the combination of astragaloside IV (AST IV) and Panax notoginseng saponins (PNS) on cerebral ischaemia-reperfusion injury (CIRI) and explore the specific mechanism of the nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated combination of AST IV and PNS against CIRI based on ferroptosis and inflammatory response.METHODS: The therapeutic effect and mechanism of AST IV and PNS were evaluated by constructing a Sprague-Dawley rat middle cerebral artery ischaemia-occlusion-reperfusion model. The specific mechanism of the combination of AST IV and PNS against CIRI was revealed through the combined intervention of the Nrf2-specific inhibitor brusatol.KEY FINDINGS: After AST IV and PNS treatment, the cerebral infarction area of the rats was reduced; behavioural performance was improved; Fe2+, malondialdehyde, lipid peroxidation, interleukin-6, interleukin-1, tumour necrosis factor-and myeloperoxidase levels were reduced; and glutathione and glutathione peroxidase 4 levels were increased. In addition, the expression of Nrf2 was significantly increased, the combined treatment was more effective than the single treatment, and the Nrf2 inhibitor brusatol could reverse the effects of the combined intervention of AST IV and PNS.CONCLUSIONS: The findings of this study suggest that combining AST IV and PNS attenuates CIRI by activating Nrf2 to inhibit ferroptosis and inflammatory responses.

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PMID:  Biomed Pharmacother. 2022 Oct ;154:113603. Epub 2022 Sep 7. PMID: 36942596 Abstract Title:  Astragaloside trigger autophagy: Implication a potential therapeutic strategy for pulmonary fibrosis. Abstract:  Pulmonary fibrosis is an abnormal wound-healing response to repeated alveolar injury, characterized by continuous inflammation and abnormal collagen deposition. Its treatment is problematic. Astragaloside (AST) is an active component of Astragalus membranaceus with anti-inflammatory and anti-tumor properties. Although the underlying mechanisms are unknown, AST is also used to treat fibrotic diseases. This study aimed to investigate the mechanisms of action of AST in pulmonary fibrosis treatment. We found that AST significantly improved restrictive ventilatory impairment, compliance, total lung capacity, and functional residual capacity. In mice with pulmonary fibrosis, extracellular matrix deposition in the pulmonary parenchyma and intemperate inflammation were reversed. This therapeutic effect can be attributed to autophagy, activating the genes for autophagy flux and autophagic vacuoles. Impaired autophagy increased susceptibility to pulmonary fibrosis by exacerbating collagen deposition in vitro and in vivo. Using a combination of molecular docking and network pharmacology, the Ras/Raf/MEK/ERK signaling pathway was identified as a possible candidate for the pharmacologic target of AST. Functional dephosphorylation of MEK and ERK inhibited the Ras/Raf/MEK/ERK signaling pathway, which converges at the rapamycin switch to initiate autophagy. Inhibitors of Ras and MEK regulated autophagy. These findings suggest that AST might treat pulmonary fibrosis by modulating the Ras/Raf/MEK/ERK signaling pathway mediated by depression.

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PMID:  Drug Des Devel Ther. 2023 ;17:771-790. Epub 2023 Mar 10. PMID: 36925998 Abstract Title:  The Molecular Basis of the Anti-Inflammatory Property of Astragaloside IV for the Treatment of Diabetes and Its Complications. Abstract:  Astragali Radix is a significant traditional Chinese medication, and has a long history of clinical application in the treatment of diabetes mellitus (DM) and its complications. AS-IV is an active saponin isolated from it. Modern pharmacological study shows that AS-IV has anti-inflammatory, anti-oxidant and immunomodulatory activities. The popular inflammatory etiology of diabetes suggests that DM is a natural immune and low-grade inflammatory disease. Pharmacological intervention of the inflammatory response may provide promising and alternative approaches for the prevention and treatment of DM and its complications. Therefore, this article focuses on the potential of AS-IV in the treatment of DM from the perspective of an anti-inflammatory molecular basis. AS-IV plays a role by regulating a variety of anti-inflammatory pathways in multiple organs, tissues and target cells throughout the body. The blockade of the NF-B inflammatory signaling pathway may be the central link of AS-IV's anti-inflammatory effect, resulting in a reduction in the tissue structure and function damage stimulated by inflammatory factors. In addition, AS-IV can delay the onset of DM and its complications by inhibiting inflammation-related oxidative stress, fibrosis and apoptosis signals. In conclusion, AS-IV has therapeutic prospects from the perspective of reducing the inflammation of DM and its complications. An in-depth study on the anti-inflammatory mechanism of AS-IV is of great significance for the effective use of Chinese herbal medicine and the promotion of its status and influence on the world.

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PMID:  Molecules. 2023 Feb 26 ;28(5). Epub 2023 Feb 26. PMID: 36903422 Abstract Title:  Antioxidant Activity of Polysaccharides from the Edible Mushroom. Abstract:  In this study the antioxidant and neuroprotective activity of an enriched polysaccharide fraction (EPF) obtained from the fruiting body of cultivatedwas evaluated. Proximate composition (moisture, proteins, fat, carbohydrates and ash) was determined using the AOAC procedures. The EPF was extracted by using, in sequence, hot water and alkaline extractions followed by deproteinization and precipitation with cold ethanol. Total- and-glucans were quantified using the Megazyme International Kit. The results showed that this procedure allows a high yield of polysaccharides with a higher content of (1-3; 1-6)--D-glucans. The antioxidant activity of EPF was detected from the total reducing power, DPPH, superoxide, hydroxyl and nitric oxide radical scavenging activities. The EPF was found to scavenge DPPH, superoxide, hydroxyl and nitric oxide radicals with a IC50 values of 0.520.02, 1.150.09, 0.890.04 and 2.830.16 mg/mL, respectively. As assessed by the MTT assay, the EPF was biocompatible for DI-TNC1 cells in the range of 0.006-1 mg/mL and, at concentrations ranging from 0.05 to 0.2 mg/mL, significantly counteracted HO-induced reactive oxygen species production. This study demonstrated that polysaccharides extracted frommight be used as functional food to potentiate the antioxidant defenses and to reduce oxidative stress.

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PMID:  Front Nutr. 2023 ;10:1118923. Epub 2023 Jan 25. PMID: 36761225 Abstract Title:  Hypolipidemic mechanism ofpolysaccharides in high-fat diet-induced obese mice based on metabolomics. Abstract:  OBJECTIVE: In this study, the structure ofpolysaccharides (PEPs) was characterized, and the mechanism of PEP on obesity and hyperlipidemia induced by high-fat diet was evaluated by metabonomic analysis.METHODS: The structure of PEPs were characterized by monosaccharide composition, Fourier transform infrared spectroscopy and thermogravimetry. In animal experiments, H&E staining was used to observe the morphological difference of epididymal adipose tissue of mice in each group. Ultrahigh performance liquid chromatography (UHPLC)-(QE) HFX -mass spectrometry (MS) was used to analyze the difference of metabolites in serum of mice in each group and the related metabolic pathways.RESULTS: The PEPs contained nine monosaccharides: 1.05% fucose, 0.30% arabinose, 17.94% galactose, 53.49% glucose, 1.24% xylose, 23.32% mannose, 1.30% ribose, 0.21%galacturonic acid, and 1.17% glucuronic acid. The PEPs began to degrade at 251C (T0), while the maximum thermal degradation rate temperature (Tm) appeared at 300C. The results histopathological observation demonstrated that the PEPs had signifificant hypolipidemic activities. After PEPs intervention, the metabolic profile of mice changed significantly. A total of 29 different metabolites were selected as adjunctive therapy to PEPs, for treatment of obesity and hyperlipidemia-related complications caused by a high-fat diet. These metabolites include amino acids, unsaturated fatty acids, choline, glycerol phospholipids, and other endogenous compounds, which can prevent and treat obesity and hyperlipidemia caused by a high-fat diet by regulating amino acid metabolism, fatty acid metabolism, and changes in metabolic pathways such as that involved in the citric cycle (TCA cycle).CONCLUSIONS: The presented results indicate that PEPs treatment can alleviate the obesity and hyperlipidemia caused by a high-fat diet and, thus, may be used as a functional food adjuvant, providing a theoretical basis and technical guidance for the prevention and treatment of high-fat diet-induced obesity and hyperlipidemia.

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PMID:  Int J Med Mushrooms. 2023 ;25(1):1-12. PMID: 36734915 Abstract Title:  King Oyster Mushroom, Pleurotus eryngii (Agaricomycetes), Extract Can Attenuate Doxorubicin-Induced Lung Damage by Inhibiting Oxidative Stress in Rats. Abstract:  Doxorubicin (DOX), a broad spectrum chemotherapeutic, has toxic effects on healthy tissues. Mitochondrial processes and oxidative stress act in the DOX-induced toxicity, therefore antioxidant therapies are widely used. The study was aimed to evaluate the therapeutic potential of Pleurotus eryngii extract (PEE), an extract of a fungus with antioxidant properties, against DOX-induced lung damage. Rats were divided into Control, DOX, DOX + PEE, and PEE groups (n = 6). DOX was administered intraperitoneally in a single dose (10 mg/kg BW) and PE (200 mg/kg BW) was administered by oral gavage every other day for 21 days. Histopathological evaluations, immunohistochemical analyses, total oxidant status (TOS)/total antioxidant status (TAS) method, and quantitative real-time polymerase chain reaction (qRT-PCR) analysis were performed. DOX led to severe histopathological disruptions in rat lungs. Also, DOX remarkably increased the expression of dynamin 1 like (DRP1) and decreased the expression of mitofusin 1 (MFN1) and mitofusin 2 (MFN2) genes, which are related to mitochondrial dynamics. Moreover, DOX caused an increase in TOS/ TAS and 8-hydroxy-2-deoxyguanosine (8-OHdG) levels. On the other hand, PEE treatment remarkably normalized the histopathological findings, mitochondrial dynamics-related gene expressions, markers of oxidative stress, and DNA damage. The present study signs out that PEE can ameliorate the DOX-mediated lung toxicity and the antioxidant mechanism associated with mitochondrial dynamics can have a role in this potent therapeutic effect.

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This fall, in a series of ground-breaking water memory experiments to be conducted legendary CymaScope instrument is set to reveal insights into the mechanisms of homeopathy, as well shedding light on what the real purpose of the King's Chamber may be. 

To learn how you can contribute to this important research mission, join the upcoming AUREA event on June 9-11th, and please read on...

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PMID:  Cells. 2023 Feb 22 ;12(5). Epub 2023 Feb 22. PMID: 36899824 Abstract Title:  Role of SARS-CoV-2 Spike-Protein-Induced Activation of Microglia and Mast Cells in the Pathogenesis of Neuro-COVID. Abstract:  Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). About 45% of COVID-19 patients experience several symptoms a few months after the initial infection and develop post-acute sequelae of SARS-CoV-2 (PASC), referred to as "Long-COVID," characterized by persistent physical and mental fatigue. However, the exact pathogenetic mechanisms affecting the brain are still not well-understood. There is increasing evidence of neurovascular inflammation in the brain. However, the precise role of the neuroinflammatory response that contributes to the disease severity of COVID-19 and long COVID pathogenesis is not clearly understood. Here, we review the reports that the SARS-CoV-2 spike protein can cause blood-brain barrier (BBB) dysfunction and damage neurons either directly, or via activation of brain mast cells and microglia and the release of various neuroinflammatory molecules. Moreover, we provide recent evidence that the novel flavanol eriodictyol is particularly suited for development as an effective treatment alone or together with oleuropein and sulforaphane (ViralProtek), all of which have potent anti-viral and anti-inflammatory actions.

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PMID:  Ann Med Surg (Lond). 2023 Mar ;85(3):365-372. Epub 2023 Mar 9. PMID: 36923747 Abstract Title:  Effect of the olive leaf extract in chronic spinal cord injury model: an experimental research. Abstract:  UNLABELLED: Posttraumatic myelopathy is defined as a spinal cord injury (SCI) that results in varying degrees of motor and sensory deficits. The degree of 'secondary damage,' which is caused by a variety of cellular, molecular, and biochemical cascades is linked to the outcome of SCI. According to research, the beneficial effects of oleuropein and its derivatives have been linked to radical scavenging/antioxidant actions and anti-inflammatory effects.MATERIALS AND METHODS: This study was divided into six groups: control negative (sham-operated) group, control positive 1 and 2 (early chronic and chronic), treatment groups 1, 2, and 3 (prophylactic, concomitant, and late). Olive leaf extract (OLE) given dose was 350 mg/kg body weight. Blood was taken from the left corotic artery before the animals were terminated, seromarker assessment, enzyme-linked immunosorbent assay of IL-6, TNF-, brain-derived neurotrophic factor (BDNF), and assessment of functional motoric outcome before the animal was terminated.RESULTS: Chronic spinal cord compression increased serum levels of IL-6, TNF-, and decreased serum level of BDNF. OLE 350 mg/kg body weight decreased serum levels of IL-6, TNF-and increased functional motoric outcome, especially in prophylactic and concomitant therapy.DISCUSSION: These findings indicate that OLE may be effective in protecting chronic SCI model.CONCLUSION: Oleuropein has a potential effect to reduce the IL-6 and TNF-in rabbit model of SCI, and the BDNF value risen after the administration of Oleuropein.

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PMID:  Int J Mol Sci. 2023 Feb 22 ;24(5). Epub 2023 Feb 22. PMID: 36901783 Abstract Title:  Molecular Mechanisms of the Protective Effects of Olive Leaf Polyphenols against Alzheimer's Disease. Abstract:  Alzheimer's Disease (AD) is the cause of around 60-70% of global cases of dementia and approximately 50 million people have been reported to suffer this disease worldwide. The leaves of olive trees () are the most abundant by-products of the olive grove industry. These by-products have been highlighted due to the wide variety of bioactive compounds such as oleuropein (OLE) and hydroxytyrosol (HT) with demonstrated medicinal properties to fight AD. In particular, the olive leaf (OL), OLE, and HT reduced not only amyloid-formation but also neurofibrillary tangles formation through amyloid protein precursor processing modulation. Although the isolated olive phytochemicals exerted lower cholinesterase inhibitory activity, OL demonstrated high inhibitory activity in the cholinergic tests evaluated. The mechanisms underlying these protective effects may be associated with decreased neuroinflammation and oxidative stress via NF-B and Nrf2 modulation, respectively. Despite the limited research, evidence indicates that OL consumption promotes autophagy and restores loss of proteostasis, which was reflected in lower toxic protein aggregation in AD models. Therefore, olive phytochemicals may be a promising tool as an adjuvant in the treatment of AD.

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PMID:  Life (Basel). 2023 Feb 8 ;13(2). Epub 2023 Feb 8. PMID: 36836827 Abstract Title:  Leaf Phenolics Oleuropein, Hydroxytyrosol, Tyrosol, and Rutin Induce Apoptosis and Additionally Affect Temozolomide against Glioblastoma: In Particular, Oleuropein Inhibits Spheroid Growth by Attenuating Stem-like Cell Phenotype. Abstract:  The effects ofleaf extract (OLE) phenolics, including oleuropein (OL), hydroxytyrosol (HT), tyrosol (TYR), and rutin against glioblastoma (GB), independently and in combination with temozolomide (TMZ), were investigated in T98G and A172 cells. Cell growth was assessed by WST-1, real-time cell analysis, colony formation, and cell cycle distribution assays. A dual acridine orange propidium iodide (AO/PI) staining and annexin V assay determined cell viability. A sphere-forming assay, an intracellular oxidative stress assay, and the RNA expression of CD133 and OCT4 investigated the GB stem-like cell (GSC) phenotype. A scratch wound-healing assay evaluated migration capacity. OL was as effective as OLE in terms of apoptosis promotion (

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PMID:  Redox Rep. 2023 Dec ;28(1):2187564. PMID: 36932927 Abstract Title:  Hydroxytyrosol attenuates ethanol-induced liver injury by ameliorating steatosis, oxidative stress and hepatic inflammation by interfering STAT3/iNOS pathway. Abstract:  Hydroxytyrosol (HT) is a polyphenol with a wide range of biological activities. Excessive drinking can lead to oxidative stress and inflammation in the liver, which usually develop into alcohol liver disease (ALD). At present, there is no specific drug to treat ALD. In this paper, the protection effect of HT on ALD and the underline mechanism were studied.HepG2 cells were exposed to ethanoland C57BL/6J mice were fed with a Lieber-DeCarli ethanol liquid diet.triglyceride (TG) level in serum and the expression of fatty acid synthase (FASN) were reduced significantly by the treatment with HT The acetaldehyde dehydrogenase (ALDH) activity was increased, the serum level of malondialdehyde (MDA) was decreased, catalase (CAT) and glutathione (GSH) were increased, suggesting that HT may reduce its oxidative damage to the body by promoting alcohol metabolism. Furthermore, according to the mRNA levels of tnf-, il-6 and il-1, HT inhibited ethanol-induced inflammation significantly. The anti-inflammatory mechanism of HT may be related to suppress the STAT3/iNOS pathway.Our study showed that HT could ameliorate ethanol-induced hepatic steatosis, oxidative stress and inflammation and provide a new candidate for the prevention and treatment of ALD.

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PMID:  Eur J Clin Invest. 2023 Jul ;53(7):e13983. Epub 2023 Mar 24. PMID: 36912212 Abstract Title:  Association of hydroxytyrosol enriched olive oil with vascular function in chronic coronary disease. Abstract:  BACKGROUND: Hydroxytyrosol reduces low-density lipoprotein oxidation, contributing to prevention of atherosclerosis progression.METHODS: In a prospective, crossover, double-blind, placebo-controlled trial, 30 chronic coronary artery syndrome (CCAS) patients were randomized to 4 capsules/day, containing 412.5 mg olive oil with 2.5 mg hydroxytyrosol (OOHT) each one or placebo for 1month and then were crossed over to the alternate treatment (placebo or OOHT). We measured (a) perfused boundary region (PBR) of the sublingual arterial microvessels (increased PBR indicates reduced glycocalyx thickness), (b) flow-mediated dilation (FMD), (c) Coronary Flow Reserve (CFR) and markers of LV diastolic function by Doppler echocardiography, (d) pulse wave velocity (PWV), and (e) oxidative stress, inflammatory biomarkers and blood lipids at baseline and after treatment.RESULTS: Treatment with OOHT improved PBR, FMD, CFR and PWV compared to baseline (1.8 .3 vs. 1.7  .4 m, p =.040, 3.7 2.1 vs. 6.5%2.3%, p 

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PMID:  Molecules. 2023 Feb 16 ;28(4). Epub 2023 Feb 16. PMID: 36838850 Abstract Title:  Effects of Hydroxytyrosol in Endothelial Functioning: A Comprehensive Review. Abstract:  Pharmacologists have been emphasizing and applying plant and herbal-based treatments in vascular diseases for decades now. Olives, for example, are a traditional symbol of the Mediterranean diet. Hydroxytyrosol is an olive-derived compound known for its antioxidant and cardioprotective effects. Acknowledging the merit of antioxidants in maintaining endothelial function warrants the application of hydroxytyrosol in endothelial dysfunction salvage and recovery. Endothelial dysfunction (ED) is an impairment of endothelial cells that adversely affects vascular homeostasis. Disturbance in endothelial functioning is a known precursor for atherosclerosis and, subsequently, coronary and peripheral artery disease. However, the effects of hydroxytyrosol on endothelial functioning were not extensively studied, limiting its value either as a nutraceutical supplement or in clinical trials. The action of hydroxytyrosol in endothelial functioning at a cellular and molecular level is gathered and summarized in this review. The favorable effects of hydroxytyrosol in the improvement of endothelial functioning from in vitro and in vivo studies were scrutinized. We conclude that hydroxytyrosol is capable to counteract oxidative stress, inflammation, vascular aging, and arterial stiffness; thus, it is beneficial to preserve endothelial function both in vitro and in vivo. Although not specifically for endothelial dysfunction, hydroxytyrosol safety and efficacy had been demonstrated via in vivo and clinical trials for cardiovascular-related studies.

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PMID:  Int J Mol Sci. 2023 Feb 4 ;24(4). Epub 2023 Feb 4. PMID: 36834520 Abstract Title:  Hydroxytyrosol and Its Potential Uses on Intestinal and Gastrointestinal Disease. Abstract:  In recent years, the phytoconstituents of foods in the Mediterranean diet (MD) have been the subject of several studies for their beneficial effects on human health. The traditional MD is described as a diet heavy in vegetable oils, fruits, nuts, and fish. The most studied element of MD is undoubtedly olive oil due precisely to its beneficial properties that make it an object of interest. Several studies have attributed these protective effects to hydroxytyrosol (HT), the main polyphenol contained in olive oil and leaves. HT has been shown to be able to modulate the oxidative and inflammatory process in numerous chronic disorders, including intestinal and gastrointestinal pathologies. To date, there is no paper that summarizes the role of HT in these disorders. This review provides an overview of the anti-inflammatory and antioxidant proprieties of HT against intestinal and gastrointestinal diseases.

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PMID:  Int J Mol Sci. 2023 Jan 20 ;24(3). Epub 2023 Jan 20. PMID: 36768382 Abstract Title:  Hydroxytyrosol Reduces Foam Cell Formation and Endothelial Inflammation Regulating the PPAR/LXR/ABCA1 Pathway. Abstract:  Cholesterol accumulation in macrophages leads to the formation of foam cells and increases the risk of developing atherosclerosis. We have verified whether hydroxytyrosol (HT), a phenolic compound with anti-inflammatory and antioxidant properties, can reduce the cholesterol build up in THP-1 macrophage-derived foam cells. We have also investigated the potential mechanisms. Oil Red O staining and high-performance liquid chromatography (HPLC) assays were utilized to detect cellular lipid accumulation and cholesterol content, respectively, in THP-1 macrophages foam cells treated with HT. The impact of HT on cholesterol metabolism-related molecules (SR-A1, CD36, LOX-1, ABCA1, ABCG1, PPARand LRX-) in foam cells was assessed using real-time PCR (RT-qPCR) and Western blot analyses. Finally, the effect of HT on the adhesion of THP-1 monocytes to human vascular endothelial cells (HUVEC) was analyzed to study endothelial activation. We found that HT activates the PPAR/LXRpathway to upregulate ABCA1 expression, reducing cholesterol accumulation in foam cells. Moreover, HT significantly inhibited monocyte adhesion and reduced the levels of adhesion factors (ICAM-1 and VCAM-1) and pro-inflammatory factors (IL-6 and TNF-) in LPS-induced endothelial cells. Taken together, our findings suggest that HT, with its ability to interfere with the import and export of cholesterol, could represent a new therapeutic strategy for the treatment of atherosclerotic disease.

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PMID:  Heliyon. 2023 Jan ;9(1):e12963. Epub 2023 Jan 13. PMID: 36704293 Abstract Title:  Hydroxytyrosol: Its role in the prevention of cardiovascular diseases. Abstract:  In recent years, non-pharmacology treatments and their effectiveness have gained popularity due to their beneficial properties in the prevention of cardiovascular diseases. Phenolic compounds intake provides a natural means of improvingantioxidant status. Thus, the purpose of this review is to discuss the potential benefits of hydroxytyrosol (HT), a phenolic compound with powerful antioxidant and anti-inflammatory properties, in preventing and reducing cardiovascular risk factors, concretely atherosclerosis. Closer inspection of the studies showed a significant improvement of lipid profile, antioxidant capacity and inflammatory state. A note of caution is due instudies because the lack of validated approaches difficult the goodness of fit with theand clinical research. However, animal and clinical studies were very encouraging, determining HT supplementation useful on inflammation, oxidative stress, endothelial function and cardiovascular diseases in general.

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PMID:  Int J Mol Sci. 2022 Dec 26 ;24(1). Epub 2022 Dec 26. PMID: 36613822 Abstract Title:  Effects of Oleuropein and Hydroxytyrosol on Inflammatory Mediators: Consequences on Inflammaging. Abstract:  Aging is associated with a low-grade, systemic inflammatory state defined as "inflammaging", ruled by the loss of proper regulation of the immune system leading to the accumulation of pro-inflammatory mediators. Such a condition is closely connected to an increased risk of developing chronic diseases. A number of studies demonstrate that olive oil phenolic compound oleuropein and its derivative hydroxytyrosol contribute to modulating tissue inflammation and oxidative stress, thus becoming attractive potential candidates to be used in the context of nutraceutical interventions, in order to ameliorate systemic inflammation in aging subjects. In this review, we aim to summarize the available data about the anti-inflammatory properties of oleuropein and hydroxytyrosol, discussing them in the light of molecular pathways involved in the synthesis and release of inflammatory mediators in inflammaging.

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PMID:  Sci Rep. 2023 Feb 11 ;13(1):2452. Epub 2023 Feb 11. PMID: 36774383 Abstract Title:  Oleuropein confers neuroprotection against rotenone-induced model of Parkinson's disease via BDNF/CREB/Akt pathway. Abstract:  Major pathological features of Parkinson's disease (PD) include increase in oxidative stress leading to the aggregation of-synuclein, mitochondrial dysfunction and apoptosis of dopaminergic neurons. In addition, downregulation of the expression of neurotrophic factors like-Brain Derived Neurotrophic Factor (BDNF) is also involved in PD progression. There has been a lot of interest in trophic factor-based neuroprotective medicines over the past few decades to treat PD symptoms. Rotenone, an insecticide, inhibits the mitochondrial complex I causing overproduction of ROS, oxidative stress, and aggregation of-synuclein. It has been shown that BDNF and Tropomyosin receptor kinase B (TrkB) interaction initiates the regulation of neuronal cell development and differentiation by the serine/threonine protein kinases like Akt and GSK-3. Additionally, Transcription factor CREB (cAMP Response Element-binding protein) also determines the gene expression of BDNF. The homeostasis of these signalling cascades is compromised with the progression of PD. Therefore, maintaining the equilibrium of these signalling cascades will delay the onset of PD. Oleuropein (OLE), a polyphenolic compound present in olive leaves has been documented to cross blood brain barrier and shows potent antioxidative property. In the present study, the dose of 8, 16 and 32 mg/kg body weight (bwt) OLE was taken for dose standardisation. The optimised doses of 16 and 32 mg/kg bwt was found to be neuroprotective in Rotenone induced PD mouse model. OLE improves motor impairment and upregulate CREB regulation along with phosphorylation of Akt and GSK-3in PD mouse. In addition, OLE also reduces the mitochondrial dysfunction by activation of enzyme complexes and downregulates the proapoptotic markers in Rotenone intoxicated mouse model. Overall, our study suggests that OLE may be used as a therapeutic agent for treatment of PD by regulating BDNF/CREB/Akt signalling pathway.

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PMID:  Pharmaceuticals (Basel). 2022 Nov 27 ;15(12). Epub 2022 Nov 27. PMID: 36558929 Abstract Title:  Eriodictyol Suppresses Gastric Cancer Cells via Inhibition of PI3K/AKT Pathway. Abstract:  Gastric cancer (GC) is among the five most common malignancies worldwide. Traditional chemotherapy cannot efficiently treat the disease and faces the problems of side effects and chemoresistance.Fructus (POF), with flavonoids as the main bioactive compounds, exerts anti-cancer potential. In this study, we compared the anti-GC effects of the main flavonoids from POF and investigated the anti-cancer effects of eriodictyol towards GC both in vitro and in vivo. CCK-8 assays were performed to examine the inhibitory effects of common flavonoids from POF on GC cell viability. Colony formation assays were used to determine cell proliferation after eriodictyol treatment. Cell cycle distribution was analyzed using flow cytometry. Induction of apoptosis was assessed with Annexin V/PI staining and measurement of related proteins. Anti-cancer effects in vivo were investigated using a xenograft mouse model. Potential targets of eriodictyol were clarified by network pharmacological analysis, evaluated by molecular docking, and validated with Western blotting. We found that eriodictyol exhibited the most effective inhibitory effect on cell viability of GC cells among the common flavonoids from POF including quercetin, taxifolin, and kaempferol. Eriodictyol suppressed colony formation of GC cells and induced cell apoptosis. The inhibitory effects of eriodictyol on tumor growth were also validated using a xenograft mouse model. Moreover, no obvious toxicity was identified with eriodictyol treatment. Network pharmacology analysis revealed that PI3K/AKT signaling ranked first among the anti-GC targets. The molecular docking model of eriodictyol and PI3K was constructed, and the binding energy was evaluated. Furthermore, efficient inhibition of phosphorylation and activation of PI3K/AKT by eriodictyol was validated in GC cells. Taken together, our results identify eriodictyol as the most effective anti-GC flavonoids from POF and the potential targets of eriodictyol in GC. These findings suggest that eriodictyol has the potential to be a natural source of anti-GC agents.

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PMID:  Anticancer Res. 2022 Aug ;42(8):3789-3798. PMID: 35896263 Abstract Title:  Eriodictyol Attenuates Cholangiocarcinoma Malignancy by Regulating HMOX1 Expression: AnStudy. Abstract:  BACKGROUND/AIM: Cholangiocarcinoma remains one of the most dangerous types of cancer. Eriodictyol is a well-known flavonoid having effective bioactivity against various malignant tumor types. However, the anticancer effect of eriodictyol against cholangiocarcinoma remains ambiguous. Thus, the aim of the present study was to investigate the effects of eriodictyol on human cholangiocarcinoma.MATERIALS AND METHODS: The biological effects of eriodictyol were validated by viability assay, colony formation and western blot analysis. The significance of heme oxygenase 1 (HMOX1) expression in cholangio-carcinoma was demonstrated using bioinformatics analysis and knockdown of HMOX1 by transfection with short interfering (si)-RNA.RESULTS: Eriodictyol highly reduced the in vitro viability of SNU-308, SNU-478, SNU-1079, and SNU-1196 cholangiocarcinoma cells compared with that of 293T cells, in a dose-dependent manner. The anticancer effect of eriodictyol was achieved by caspase-3-mediated apoptosis. In particular, eriodictyol increased HMOX1 expression, which resulted in attenuation of cholangiocarcinoma cell proliferation. In contrast, ablating HMOX1 expression by si-RNA transfection against HMOX1 made cholangiocarcinoma cells insensitive to the antiproliferative effect of eriodictyol treatment.CONCLUSION: These results collectively indicate that eriodictyol acts as an anticancer agent via regulation of HMOX1 expression against human cholangiocarcinoma.

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PMID:  Naunyn Schmiedebergs Arch Pharmacol. 2022 Sep ;395(9):1109-1123. Epub 2022 Jul 20. PMID: 35857038 Abstract Title:  Potential cancer treatment effects of brusatol or eriodictyol combined with 5-fluorouracil (5-FU) in colorectal cancer cell. Abstract:  Colorectal cancer is among the most frequently diagnosed cancers in patients today. In the treatment of this disease, combination or multicomponent therapy has been identified as a potential method to improve patient response and delay side effects. The aim of this study was to determine the effects on cell viability of commercial Bru and Erio used together with the anticancer drug 5-FU in the human colorectal cancer (CRC) cell line (HT-29 cell line) for the first time, as far as can be determined from available literature at this time. Additionally, the research seeks to study any potential effects on apoptosis. For this purpose, the effects of independent and combined treatments of the aforementioned agents on cell viability were investigated through the MTT experiment. Apoptotic effects were determined by Annexin V/PI and real-time PCR methods. In addition, a cell cycle analysis was used to determine the distribution of cells in the cycle. Data from experiments for 48 h showed that Bru, alone or in combination with 5-FU, is capable of causing an increase in the percentage of apoptotic cells in HT-29 cells compared to those of Erio alone or in combination with 5-FU. A significant increase in the level of bax and caspase-3 apoptotic genes was also detected in combinations of ICconcentrations of Bru and 5-FU. These findings suggest that unlike Erio, Bru alone or in combination with 5-FU may be useful for increasing the effects of 5-FU used in the treatment of CRC and to provide data on alternative treatment approaches.

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PMID:  Nutrients. 2022 Jun 20 ;14(12). Epub 2022 Jun 20. PMID: 35745283 Abstract Title:  Eriodictyol Attenuates HO-Induced Oxidative Damage in Human Dermal Fibroblasts through Enhanced Capacity of Antioxidant Machinery. Abstract:  Oxidative stress in dermal fibroblasts is strongly correlated with the aging process of the skin. The application of natural compounds that can increase the ability of dermal fibroblasts to counteract oxidative stress is a promising approach to promote skin health and beauty. Eriodictyol is a flavonoid that exerts several pharmacological actions through its antioxidant properties. However, its protective effects on dermal fibroblasts have not yet been investigated. In this study, we investigated whether eriodictyol protects human dermal fibroblasts (BJ fibroblasts) from the harmful effects of hydrogen peroxide (HO). Eriodictyol pretreatment significantly prevented necrotic cell death caused by HOexposure. In addition, the level of 2',7'-dichloro-dihydro-fluorescein oxidation was decreased, and that of glutathione was maintained, indicating that the beneficial effects of eriodictyol against HOwere closely associated with oxidative-stress attenuation. Eriodictyol mediates its antioxidant effects on dermal fibroblasts against HOthrough (i) the direct neutralization of reactive oxygen species; (ii) the enhancement of the activities of HO-detoxifying enzymes, including catalase and glutathione peroxidase; and (iii) the induction of the expressions of catalase and glutathione peroxidase 1 via the activation of the Nrf2 signaling system. These results support the potential application of eriodictyol as an ingredient in skincare products for cosmeceutical and pharmaceutical purposes.

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n/a PMID:  Phytomedicine. 2022 Jul 20 ;102:154159. Epub 2022 May 7. PMID: 35580441 Abstract Title:  Eriodictyol inhibits breast carcinogenesis by targeting circ_0007503 and repressing PI3K/Akt pathway. Abstract:  BACKGROUND: Eriodictyol in citrus fruits, Eriodictyon californicum and several Chinese herbal medicines shows great promise for chronic disease prevention, including cancers. However, its role in chemopreventive activities against breast carcinogenesis is unknown. PURPOSE: In the present study, we investigated the chemopreventive effect and the underlying mechanism of eriodictyol on carcinogens-induced breast carcinogenesis in vivo and in vitro. METHODS: The carcinogenic transformation in MCF10A cells was induced by the environmental carcinogens in vitro. The chemopreventive effect in vivo was evaluated by using the experimental model of 1-methyl-1-nitrosourea (MNU)-induced mammary tumorigenesis in rats. The activation of the PI3K/Akt pathway was detected by western blot assay; the levels of circular RNAs (circRNAs) were measured by qRT-PCR. RESULTS: First, eriodictyol significantly reduces cells viability and induces apoptosis in breast cancer cells in a dose-dependent manner in vitro (P < 0.05). Next, eriodictyol could effectively suppress environmental carcinogens-induced acquisition of carcinogenic properties in human breast epithelial cell MCF10A (P < 0.05). In vivo, eriodictyol administration reduces the incidence of mammary tumor by 50% in carcinogen-treated female rats (P < 0.05). Further study revealed that eriodictyol represses the PI3K/Akt signaling pathway and down-regulates the level of circ_0007503 in breast cancer cells and in breast carcinogenesis (P < 0.01). When the effect of eriodictyol on circ_0007503 was blocked by transfection of a circ_0007503 over-expression plasmid, the cytotoxic effects and the suppression of the PI3K/Akt pathway of eriodictyol in breast cancer cells were significantly reduced (P < 0.05). CONCLUSION: Our data indicated that eriodictyol could effectively suppress breast carcinogenesis in vitro and in vivoThe mechanism may be attributed to targeting circ_0007503 and inhibiting PI3K/Akt pathway.

PMID:  Molecules. 2022 Apr 12 ;27(8). Epub 2022 Apr 12. PMID: 35458684 Abstract Title:  Eriodictyol and Homoeriodictyol Improve Memory Impairment in A-Induced Mice by Inhibiting the NLRP3 Inflammasome. Abstract:  (1) Alzheimer's disease (AD) is a neurodegenerative disorder, and it is now widely accepted that neuroinflammation plays a key role in its pathogenesis. Eriodictyol (Eri) and homoeriodictyol (Hom), dihydroflavonoids extracted from a variety of plants, have been confirmed to display a relationship with neuroprotection. (2) Methods: An AD mouse model was constructed by intracerebroventricular (ICV) injection of the Apeptide, and Eri and Hom were administered orally for 4 weeks. UPLC-MS/MS was used to determine whether Eri and Hom cross the blood-brain barrier to exert their therapeutic effects. Histological changes in the brain and levels of Awere evaluated, and Y-maze and new object recognition experiments were conducted to assess the effects of Eri and Hom on A-induced memory impairment in mice. The levels of oxidative stress and apoptosis in peripheral immune cells and progenitor cells in the hippocampal region were analyzed by flow cytometry and in vitro assays. Western blotting and enzyme-linked immunosorbent assays (ELISA) were used to measure the expression levels of NLRP3 inflammasome-related proteins and inflammatory factors in the brain. The effect of nigericin (an agonist of the NLRP3 inflammasome) on Eri and Hom intervention in LPS-induced N9 microglia was examined using a High Content Screening System. (3) Results: Eri and Hom reduced neuronal damage in mouse brain tissue, decreased Alevels in the brain, downregulated oxidative stress and apoptosis levels, and improved learning and memory capacity by crossing the blood-brain barrier to exert its effects. Moreover, Eri and Hom inhibited NLRP3 inflammasome activation and ameliorated immune cell disorder. Furthermore, the effect of Eri and Hom on LPS-induced N9 microglia disappeared after the addition of nigericin to agonize NLRP3 receptors. (4) Conclusions: Eri and Hom improved A-induced memory impairment in mice by inhibiting the NLRP3 inflammasome.

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PMID:  Front Nutr. 2022 ;9:839364. Epub 2022 Mar 3. PMID: 35308267 Abstract Title:  Proteomic Analysis of the Protective Effect of Eriodictyol on Benzo(a)pyrene-Induced Caco-2 Cytotoxicity. Abstract:  We evaluated the possible protective effects of six polyphenols on benzo(a)pyrene (BaP)-induced cytotoxicity in Caco-2 cells. We show that treatment with quinic acid, ferulic acid, homovanillic acid, trolox and BaP decreased cell viability, whereas naringenin and eriodictyol affected viability in a bi-phasic manner with low concentrations decreasing viability whereas higher concentrations increase viability. Co-treatment with 20M eriodictyol or naringenin reduced BaP-induced cytotoxicity, including cell apoptosis, cell cycle progression, and oxidative stress. Our results show that the protective effect of eriodictyol was superior to that of naringenin. The potential protective mechanisms of eriodictyol on BaP-induced toxicity were investigated by proteomics. We identified 80 differentially expressed proteins (DEPs) with proteins associated with genetic information processing pathway representing the highest proportion and number of proteins responding to eriodictyol treatment, including key proteins such as RPA2, SNRPA, RAD23B, NUP155 and AARS. Our results provide new knowledge on how polyphenols may prevent BaP-induced carcinogenesis.

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PMID:  Immunopharmacol Immunotoxicol. 2022 Feb ;44(1):67-75. Epub 2021 Nov 25. PMID: 34821534 Abstract Title:  Macluraxanthone B inhibits LPS-induced inflammatory responses in RAW264.7 and BV2 cells by regulating the NF-B and MAPK signaling pathways. Abstract:  OBJECTIVE: The prenylated xanthones compounds, macluraxanthone B (MCXB) was isolated from the MeOH extracts of. In this study, we investigated the effect of MCXB on inflammatory response.MATERIALS AND METHODS: Anti-inflammatory effects of MCXB were examined in lipopolysaccharide (LPS)-stimulated RAW264.7 and BV2 cells. We observed their anti-inflammatory effects by ELISA, western blot analysis, and immunofluorescence.RESULTS: MCXB significantly inhibited the LPS-stimulated production of nitric oxide (NO), prostaglandin E2 (PGE), interleukin-6 (IL-6), and tumor necrosis factor (TNF)-in RAW264.7 and BV2 cells. MCXB also reduced the LPS-induced expression of inducible NO synthase (iNOS) and cyclooxygenase (COX)-2 proteins. Incubating cells with MCXB prevented subsequent activation of the nuclear factor kappa B (NF-B) signaling pathway by inhibiting the nuclear localization and DNA-binding activity of the p65 subunit induced by LPS. MCXB inhibited the phosphorylation of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and p38 mitogen-activated protein kinases (MAPKs) in RAW264.7 and BV2 cells. MCXB induced the expression of heme oxygenase (HO)-1 protein, and the inhibitory effect of MCXB on nitric oxide production was partially reversed by a selective HO-1 inhibitor.DISCUSSION AND CONCLUSIONS: Our results suggested that the anti-inflammatory effect of MCXB is partly regulated by HO-1 induction. In conclusion, MCXB could be a useful candidate for the development of therapeutic and preventive agents to treat inflammatory diseases.

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PMID:  Nat Prod Res. 2021 Dec ;35(23):5409-5414. Epub 2020 Jun 8. PMID: 32508145 Abstract Title:  Immuno-modulatory effects of macluraxanthone on macrophage phenotype and function. Abstract:  Macluraxanthone was previously reported to have many biological activities, including anti-cholinesterase, anti-oxidant, anti-cancer, anti-malarial and anti-inflammatory effects. The aim of the current study was to further characterise the effect of macluraxanthone on human macrophage, a type of immune cell that has been implicated in the development of various inflammatory diseases. The expression of surface markers and cytokine production by THP-1 human macrophages following treatment with macluraxanthone were investigated. Macluraxanthone was shown to promote polarisation of M1-like pro-inflammatory macrophages by increasing the percentage of macrophages expressing CD86, while decreasing their CD14, CD11b and CD80 expression. However, in the presence of the pro-inflammatory stimulus lipopolysaccharide, macluraxanthone significantly decreased TNF-and IL-10 cytokine production.

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PMID:  Front Pharmacol. 2020 ;11:452. Epub 2020 Apr 15. PMID: 32351391 Abstract Title:  Gerontoxanthone I and Macluraxanthone Induce Mitophagy and Attenuate Ischemia/Reperfusion Injury. Abstract:  Mitophagy is a crucial process in controlling mitochondrial biogenesis. Balancing mitophagy and mitochondrial functions is required for maintaining cellular homeostasis. In this study, we found that Gerontoxanthone I (GeX1) and Macluraxanthone (McX), xanthone derivatives isolated fromC. Y. Wu ex Y. H. Li, induced Parkin puncta accumulation and promoted mitophagy. GeX1 and McX treatment induced the degradation of mitophagy-related proteins such as Tom20 and Tim23. GeX1 and McX directly stabilized PTEN-induced putative kinase 1 (PINK1) on the outer membrane of the mitochondria, and then recruited Parkin to mitochondria. This significantly induced phosphorylation and ubiquitination of Parkin, suggesting that GeX1 and McX mediate mitophagy through the PINK1-Parkin pathway. Transfecting ParkinS65A or pretreated MG132 abolished the induction effects of GeX1 and McX on mitophagy. Furthermore, GeX1 and McX treatment decreased cell death and the level of ROS in an ischemia/reperfusion (IR) injury model in H9c2 cells compared to a control group. Taken together, our data suggested that GeX1 and McX induce PINK1-Parkin-mediated mitophagy and attenuate myocardial IR injury.

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PMID:  Toxicol Rep. 2022 ;9:1655-1665. Epub 2022 Aug 17. PMID: 36518482 Abstract Title:  Bellidifolin from(Michx.) Hulten protects H9c2 cells from hydrogen peroxide-induced injury via the PI3K-Akt signal pathway. Abstract:  Cardiovascular disease is the most common disease in the world and the first among the causes of human death. Its morbidity and mortality increase annually, but no effective treatment is available. Therefore, new drugs should be developed to treat cardiovascular disease.(Michx.) Hulten () is an important Mongolian medicine in China and elicits protective effects on cardiovascular health. In this study, liquid chromatography-mass spectrometry (LC-MS) combined with network pharmacology was used to screen the main active ingredients and confirm that bellidifolin was one of the main components for the treatment of ischemic heart disease. Then, rat myocardial (H9c2) cells injury model induced by hydrogen peroxide (HO)was established to verify the effect of bellidifolin on oxidative stress stimulation, including determination of antioxidant enzyme activity and apoptosis. Transcriptome sequencing, qRT-PCR, and western blot were performed to further verify the antioxidant stress mechanism of bellidifolin. Results showed that bellidifolin pretreatment decreased the rate of apoptosis and the levels of lactate dehydrogenase (LDH), creatine kinase (CK), and alanine aminotransferase (ALT). Conversely, it increased the contents of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in a dose-dependent manner, indicating that bellidifolin caused a protective effect on cardiomyocyte injury. Bellidifolin minimized the HO-induced cell injury by activating the PI3K-Akt signal pathway and downregulating glycogen synthase kinase-3(GSK-3) and p-Akt1/Akt1. Therefore, this work revealed thathas a good development prospect as an edible medicinal plant in cardiovascular disease. Its bellidifolin component is a potential therapeutic agent for cardiovascular disease induced by oxidative stress damage.

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PMID:  Evid Based Complement Alternat Med. 2022 ;2022:6841276. Epub 2022 May 9. PMID: 35586685 Abstract Title:  Bellidifolin Inhibits SRY-Related High Mobility Group-Box Gene 9 to Block TGF-Signalling Activation to Ameliorate Myocardial Fibrosis. Abstract:  Myocardial fibrosis is the main morphological change of ventricular remodelling caused by cardiovascular diseases, mainly manifested due to the excessive production of collagen proteins. SRY-related high mobility group-box gene 9 (SOX9) is a new target regulating myocardial fibrosis. Bellidifolin (BEL), the active component of, can prevent heart damage. However, it is unclear whether BEL can regulate SOX9 to alleviate myocardial fibrosis. The mice were subjected to isoproterenol (ISO) to establish myocardial fibrosis, and human myocardial fibroblasts (HCFs) were activated by TGF-1 in the present study. The pathological changes of cardiac tissue were observed by HE staining. Masson staining was applied to reveal the collagen deposition in the heart. The measurement for expression of fibrosis-related proteins, SOX9, and TGF-1 signalling molecules adopted Western blot and immunohistochemistry. The effects of BEL on HCFs, activity were detected by CCK-8. The result showed that BEL did not affect cell viability. And, the data indicated that BEL inhibited the elevations in-SMA, Collagen I, and Collagen III by decreasing SOX9 expression. Additionally, SOX9 suppression by siRNA downregulated the TGF-1 expression and prevented Smad3 phosphorylation, as supported by reducing the expression of-SMA, Collagen I, and Collagen III. In vivo study verified that BEL ameliorated myocardial fibrosis by inhibiting SOX9. Therefore, BEL inhibited SOX9 to block TGF-1 signalling activation to ameliorate myocardial fibrosis.

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PMID:  Sci Rep. 2023 Mar 13 ;13(1):4172. Epub 2023 Mar 13. PMID: 36914687 Abstract Title:  Mangiferin relieves CCl4-induced liver fibrosis in mice. Abstract:  Hepatic fibrosis is a late stage process of many chronic liver diseases. Blocking the fibrosis process will be beneficial to the treatment and recovery of the diseases. Mangiferin has many pharmacological activities. Recently, it has been reported that mangiferin may relieve tissue fibrosis, including renal, myocardial, pulmonary fibrosis via anti-inflammatory and anti-oxidative effects in animal models. Here, we investigate the effects of mangiferin on CCl4-induced liver fibrosis and the underlying mechanism in mice. Thirty-two male C57BL/6 mice were randomly divided into 4 groups (n=8 in each group), injected with carbon tetrachloride (10% CCl4) for 8 weeks, and oral administrated with mangiferin (50 mg/kg or 100 mg/kg) from the fifth week. The serum levels of ALT, AST were analyzed to evaluate liver function. H&E, Masson's trichrome and Sirius red staining were used to assess liver morphology and the degree of liver fibrosis. Quantitative RT-PCR and Western blot were used to assay the gene expression and protein levels. The results showed that mangiferin alleviated the serum levels of AST, ALT, ALP, TBA and TBIL, reduced liver lesions, prevented hepatic parenchymal necrosis, and ameliorated collagen accumulation in the liver of CCl4-treated mice. Meanwhile, mangiferin inhibited the expression of inflammatory genes IL-6 and IL-1, fibrogenic genes-SMA, TGF-and MMP-2 and bile acid metabolism genes ABCB4, ABCB11, SULT2A1 in the liver of CCl4-treated mice. Furthermore, mangiferin reduced collagen accumulation and HSCs activation, inhibited the p-IB and p-p65 protein levels. Our results suggest that mangiferin could alleviate liver fibrosis in CCl4-treated mice through inhibiting NF-B signaling, and mango consuming may have beneficial effects to hepatic fibrosis.

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PMID:  Heliyon. 2023 Mar ;9(3):e13753. Epub 2023 Feb 15. PMID: 36873506 Abstract Title:  Mangiferin inhibits chronic stress-induced tumor growth in colorectal liver metastases via WAVE2 signaling pathway. Abstract:  BACKGROUND: Evidence indicates that chronic stress promotes progression of colorectal liver metastases (CLM). Mangiferin is the active chemical constituent of the rhizomes of. Mangiferin (MGF) exerts anti-inflammatory, anti-proliferative, anti-angiogenic, anti-fibrotic and antioxidant effects in a variety of cancers. Its mechanism in chronic stress and tumor growth is still poorly understood.METHODS: To investigate the effects of MGF on the CLM and tumor-associated depression, activated hepatic stellate cells (a-HSCs), HT-29 CRC cells, were used in chronic unpredictable mild stress (CUMS) of tumor-bearing models. Potential antidepressant activity was determined by FST, TST, SIT and serum cytokine (IL-6, IL-18 and TNF-) examination. Downstream signaling molecules were detected by Western blot, immunohistochemistry and fluorescence microscopy.RESULTS: CUMS induced depression behavior and depression-related cytokines and promoted tumor growth in CLM. MGF-treated mice significantly improved chronic stress behaviors by reducing depression-related cytokines. In addition, MGF treatment inhibits WAVE2 signaling pathway, leading to TGF-1 induced HSC inhibition, thereby reducing depressive behavior and tumor growth in CLM.CONCLUSION: MGF can alleviate CUMS induced tumor growth and the treatment of CLM patients with MGF may be beneficial.

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PMID:  Int J Environ Res Public Health. 2023 Feb 25 ;20(5). Epub 2023 Feb 25. PMID: 36901174 Abstract Title:  Induction of Apoptosis and Decrease of Autophagy in Colon Cancer Cells by an Extract of Lyophilized Mango Pulp. Abstract:  Previous studies have indicated that mango fruit has a chemopreventive capacity against colorectal cancer cells. The objective of this research was to evaluate the effect of an aqueous extract of lyophilized mango pulp (LMPE) on colon adenocarcinoma cells (SW480) and their metastatic derivatives (SW620) death and cellular invasion. DNA fragmentation was assessed by TUNEL assay; autophagy and expression of DR4 and Bcl-2 by flow cytometry; the expression of 35 apoptosis-related proteins and of matrix metalloproteinases 7 and 9 by immunodetection; and the invasive capacity of the cells by Boyden chamber. The results showed that LMPE at 30 mg/mL and 48 h of exposure results in DNA fragmentation and apoptosis in SW480 (

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PMID:  Nutr Res. 2023 Mar ;111:73-89. Epub 2023 Jan 28. PMID: 36841190 Abstract Title:  Antidiabetic properties of mango in animal models and humans: A systematic review. Abstract:  Mango has long been an attractive source of nutrition and pharmacological therapeutics. The mango plant (Mangifera indica L.) contains bioactive compounds that may have antidiabetic properties. This systematic review investigated the evidence for antidiabetic properties of the different parts of the mango plant in managing type 2 diabetes mellitus in animal models and humans. The electronic databases PubMed, FSTA, Web of Science, CINAHL, MEDLINE, and Cochrane Library were systematically searched to identify articles with clear objectives and methodologies available in the English language with publication date limits up to December 2020. Twenty-eight of 1001 animal and human studies met the inclusion criteria that investigated antidiabetic properties of mango from leaf (31%), flesh (38%), seed-kernel (7%), peel (14%), stem-bark (7%), and by-product (3%). Results support the glucose-lowering properties of mango in both animals and human. Proposed antidiabetic mechanisms of action include inhibition of-amylase and-glucosidase, improved antioxidant status, improved insulin sensitivity, facilitated glucose uptake, and gene regulation of glucose transporter type 4, insulin receptor substrate 1, and phosphoinositide 3-kinase. The animal and randomized control trial findings suggest that mango may be beneficial as an antidiabetic agent. Although these studies hold promise, additional observational studies and randomized control trials are required because human studies are significantly fewer in number, use mango flesh almost exclusively, and had modest blood glucose effects. Additional research gaps include identifying the mechanisms of action for the different components of the mango plant.

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PMID:  Prev Nutr Food Sci. 2022 Dec 31 ;27(4):436-447. PMID: 36721744 Abstract Title:  Inhibition of Cell Proliferation and Induction of Cell Cycle Arrest in Colon Cancer Cells by Lyophilized Mango (L.) Pulp Extract. Abstract:  The present study evaluated the antiproliferative capacity and possible cell death mechanisms of lyophilized mango pulp extract (LMPE), applied to human colon cancer cells (SW480) and their metastasis-derived counterparts (SW620). The total phenolic content of LMPE was estimated by the Folin-Ciocalteu method. Three assays were employed to determine its antioxidant capacity: ferric-reducing antioxidant power, oxygen radical absorbance capacity, and 2,2-diphenyl-1-picrylhydrazyl. Furthermore, the antiproliferative activity of LMPE was assessed by sulforhodamine B, clonogenic, and Ki-67 assays. Flow cytometry was employed to examine the cell cycle, production of intracellular reactive oxygen species (ROS), cell-surface phosphatidylserine, and change in mitochondrial membrane potential. LMPE exhibited a high level of total phenolic content and antioxidant activity. The mean maximal inhibitory concentration values of LMPE at 48 h of exposure were 43 and 29 mg/mL for SW480 and SW620, respectively. In the SW480 and SW620 cell lines, LMPE at 50 mg/mL and 48 h of exposure induced an increase in intracellular ROS, cell cycle arrest in the G2/M phase, and probably, apoptotic processes without mitochondrial depolarization. LMPE had an antiproliferative capacity against the human colorectal cancer cell lines SW480 and SW620. These results highlight the chemopreventive potential of LMPE in colorectal cancer treatments.

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PMID:  Drug Des Devel Ther. 2023 ;17:563-577. Epub 2023 Feb 23. PMID: 36860800 Abstract Title:  -Mangostin Inhibited M1 Polarization of Macrophages/Monocytes in Antigen-Induced Arthritis Mice by Up-Regulating Silent Information Regulator 1 and Peroxisome Proliferators-Activated ReceptorSimultaneously. Abstract:  BACKGROUND: -Mangostin (MG) showed the potentials in alleviating experimental arthritis, inhibiting inflammatory polarization of macrophages/monocytes, and regulating peroxisome proliferators-activated receptor(PPAR-) and silent information regulator 1 (SIRT1) signals. The aim of this study was to analyze the correlations among the above-mentioned properties.METHODS: Antigen-induced arthritis (AIA) was established in mouse, which was treated with MG in combination with SIRT1/PPAR-inhibitors to clarify the role of the two signals in the anti-arthritic actions. Pathological changes were systematically investigated. Phenotypes of cells were investigated by flow cytometry. Expression and co-localization of SIRT1 and PPAR-proteins in joint tissues were observed by the immunofluorescence method. Finally, clinical implications from the synchronous up-regulation of SIRT1 and PPAR-were validated by experiments in vitro.RESULTS: SIRT1 and PPAR-inhibitors (nicotinamide and T0070097) reduced the therapeutic effects of MG on AIA mice, and abrogated MG-induced up-regulation of SIRT1/PPAR-and inhibition of M1 polarization in macrophages/monocytes. MG has a good binding affinity to PPAR-, and MG promoted the co-expression of SIRT1 and PPAR-in joints. Synchronously activating SIRT1 and PPAR-was revealed to be necessary by MG to repress inflammatory responses in THP-1 monocytes.CONCLUSION: MG binds PPAR-and excites this signaling to initiate ligand-dependent anti-inflammatory activity. Due to certain unspecified signal transduction crosstalk mechanism, it then promoted SIRT1 expression and further limited inflammatory polarization of macrophages/monocytes in AIA mice.

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PMID:  Int J Immunopathol Pharmacol. 2023 ;37:3946320231161174. PMID: 36848930 Abstract Title:  Immunopotentiation effects of apigenin on NK cell proliferation and killing pancreatic cancer cells. Abstract:  Apigenin is a kind of flavonoid with many beneficial biological effects. It not only has direct cytotoxicity to tumor cells, but also can boost the antitumor effect of immune cells by modulating immune system. The purpose of this study was to investigate the proliferation of NK cells treated with apigenin and its cytotoxicity to pancreatic cancer cells in vitro, and explore its potential molecular mechanism. In this study, the effect of apigenin on NK cell proliferation and killing pancreatic cancer cells were measured by CCK-8 assay. Perforin, granzyme B (Gran B), CD107a, and NKG2D expressions of NK cells induced with apigenin were detected by flow cytometry (FCM). The mRNA expression of Bcl-2, Bax and protein expression of Bcl-2, Bax, p-ERK, and p-JNK in NK cells were evaluated by qRT-PCR and western blotting analysis, respectively. The results showed that appropriate concentration of apigenin could significantly promote the proliferation of NK cells in vitro and enhance the killing activity of NK cells against pancreatic cancer cells. The expressions of surface antigen NKG2D and intracellular antigen perforin and Gran B of NK cells were upregulated after treating with apigenin. Bcl-2 mRNA expression was increased, while Bax mRNA expression was decreased. Similarly, the expression of Bcl-2, p-JNK, and p-ERK protein was upregulated, and the expression of Bax protein was downregulated. The molecular mechanism of the immunopotentiation effects of apigenin may be that it up-regulates Bcl-2 and down-regulates Bax expression at the gene and protein levels to facilitate NK cell proliferation, and up-regulates the expression of perforin, Gran B, and NKG2D through the activation of JNK and ERK pathways to enhance NK cell cytotoxicity.

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PMID:  J Ethnopharmacol. 2023 Jun 12 ;309:116353. Epub 2023 Mar 10. PMID: 36907476 Abstract Title:  The aqueous extracts of Ageratum conyzoides inhibit inflammation by suppressing NLRP3 inflammasome activation. Abstract:  ETHNOPHARMACOLOGICAL RELEVANCE: Ageratum conyzoides L. (Asteraceae), a well-known and widely distributed traditional tropical medicinal herb, has been used to treat diverse diseases. Our preliminary research has shown that aqueous extracts of A. conyzoides leaf (EAC) have anti-inflammatory activity. However, the detailed underlying anti-inflammatory mechanism of EAC is still unclear.AIM OF THE STUDY: To determine the anti-inflammatory mechanism of action of EAC.MATERIALS AND METHODS: The major constituents of EAC were identified by ultra-performance liquid chromatography (UPLC) combined with quadrupole-time-of-flight mass/mass spectrometry (UPLC-Q-TOF-MS/MS). LPS and ATP were used to activate the NLRP3 inflammasome in two types of macrophages (RAW 264.7 and THP-1 cells). The cytotoxicity of EAC was measured by the CCK8 assay. The levels of inflammatory cytokines and NLRP3 inflammasome-related proteins were detected by ELISA and western blotting (WB), respectively. The oligomerization of NLRP3 and ASC and the resulting inflammasome complex formation were observed by immunofluorescence. The intracellular reactive oxygen species (ROS) level was measured by flow cytometry. Finally, an MSU-induced peritonitis model was established to evaluate the anti-inflammatory effects of EAC in vivo.RESULTS: Twenty constituents were identified in the EAC. Kaempferol 3,7-diglucoside, 1,3,5-tricaffeoylquinic acid, and kaempferol 3,7,4'-triglucoside were found to be the most potent ingredients. EAC significantly reduced the levels of IL-1, IL-18, TNF-, and caspase-1 in the two types of activated macrophages, implying that EAC can inhibit the activation of the NLRP3 inflammasome. A mechanistic study revealed that EAC inhibited NLRP3 inflammasome activation by blocking NF-B signalling pathway activation and scavenging the level of intracellular ROS to prevent NLRP3 inflammasome assembly in macrophages. Furthermore, EAC attenuated the in vivo expression of inflammatory cytokines by suppressing NLRP3 inflammasome activation in a peritonitis mouse model.CONCLUSION: Our results demonstrated that EAC inhibited inflammation by suppressing NLRP3 inflammasome activation, highlighting that this traditional herbal medicine might be used to treat NLRP3 inflammasome-driven inflammatory diseases.

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PMID:  Front Nutr. 2022 ;9:1061552. Epub 2022 Dec 9. PMID: 36570129 Abstract Title:  Computational screening for new neuroprotective ingredients against Alzheimer's disease from bilberry by cheminformatics approaches. Abstract:  Bioactive ingredients from natural products have always been an important resource for the discovery of drugs for Alzheimer's disease (AD). Senile plaques, which are formed with amyloid-beta (A) peptides and excess metal ions, are found in AD brains and have been suggested to play an important role in AD pathogenesis. Here, we attempted to design an effective and smart screening method based on cheminformatics approaches to find new ingredients against AD from(bilberry) and verified the bioactivity of expected ingredients through experiments. This method integrated advanced artificial intelligence models and target prediction methods to realize the stepwise analysis and filtering of all ingredients. Finally, we obtained the expected new compound malvidin-3-O-galactoside (Ma-3-gal-Cl). Theexperiments showed that Ma-3-gal-Cl could reduce the OHgeneration and intracellular ROS from the A/Cu/AA mixture and maintain the mitochondrial membrane potential of SH-SY5Y cells. Molecular docking and Western blot results indicated that Ma-3-gal-Cl could reduce the amount of activated caspase-3binding with unactivated caspase-3 and reduce the expression of phosphorylated p38binding with mitogen-activated protein kinase kinases-6 (MKK6). Moreover, Ma-3-gal-Cl could inhibit the Aaggregationbinding with Amonomer and fibers. Thus, Ma-3-gal-Cl showed significant effects on protecting SH-SY5Y cells from A/Cu/AA induced damageantioxidation effect and inhibition effect to the Aaggregation.

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PMID:  Life (Basel). 2022 Dec 11 ;12(12). Epub 2022 Dec 11. PMID: 36556444 Abstract Title:  Caucasian Blueberry: Comparative Study of Phenolic Compounds and Neuroprotective and Antioxidant Potential of Vaccinium myrtillus and Vaccinium arctostaphylos Leaves. Abstract:  (1) Background: Two Caucasian blueberriesL. andL. are famous berry bushes growing in the Caucasus region and used to treat neurological diseases, but the chemistry and bioactivity of leaf extracts are still poorly studied. (2) Methods: Phenolic compounds ofandleaf extracts were profiled and quantified by HPLC-PDA-ESI-tQ-MS. The neurotropic potential ofextracts was studied using the model of middle cerebral artery permanent occlusion to determine cerebral blood flow, the area of the brain tissue necrosis, and antioxidant enzyme activity (including superoxide dismutase, succinate dehydrogenase, and cytochrome C oxidase), as well as the concentration of TBARS. (3) Results: Hydroxycinnamates and flavonoids were identified in the leaves ofand, and the dominant metabolite of both extracts was 5--caffeoylquinic acid in the amount of 105-226 mg/g. The studied extracts enhanced the cerebral hemodynamics and decreased the frequency of necrotic and lipooxidative processes in the brain tissue, accompanied by an increase in the activity of antioxidant enzymes. The positive effect ofwas stronger and exceeded the effectiveness ofstandardized extract. (4) Conclusion: The leaf extracts of Caucasian blueberriesandas a new source of hydroxycinnamates demonstrated a protective effect of the brain ischemia pathology and can be used as therapeutic agents to treat neurological diseases.

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PMID:  J Chem Neuroanat. 2023 Jan ;127:102193. Epub 2022 Nov 19. PMID: 36414183 Abstract Title:  Neuroprotective effects of Vaccinium myrtillus on damage-related brain injury. Abstract:  Traumatic brain injury may trigger the secondary brain injury, which has the potential to be reversible and thus preventable. Anthocyanins are phylotherapeutic plants, which are reported to exhibit anti-inflammatory properties. This study aimed to evaluate the therapeutic efficiency of an anthocyanin, namely Vaccinium myrtillus, to alleviate secondary brain injury and identify possible mechanism of actions. It is hypothesized that lipid peroxidation and Na+ -K+ -ATPase activity may be involved in neuronal ischemia. Thus, brain tissue Malondialdehyde content, Na+ -K+ -ATPase content, and cleaved caspase-3 content was investigated following moderate head trauma in a rat model. Twenty-four Sprague-Dawley male rats were allocated into four groups: Control, Trauma, Solvent-Control, and Treatment. Trauma and Solvent-Control groups showed more prominent brain edema, neuronal ischemia, vascular congestion, increase in brain tissue Malondialdehyde and cleaved caspase-3 levels, and decreased Na+-K+-ATPase activity compared to the Control group. Although the Treatment group had comparable histological signs to the Trauma and Solvent-Control groups, Malondialdehyde level and Na+-K+-ATPase activity was similar to Control group, and cleaved caspase-3 levels were lower compared to Trauma and Solvent-Control groups. We conclude that anthocyanin extracts may alleviate secondary brain injury via anti-oxidative and anti-apoptotic mechanisms.

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PMID:  Curr Issues Mol Biol. 2022 Sep 30 ;44(10):4570-4583. Epub 2022 Sep 30. PMID: 36286028 Abstract Title:  Anti-Inflammatory Activity of Bilberry (L.). Abstract:  Inflammation is important in the pathogenesis of several chronic diseases. The anti-inflammatory properties of berries have been investigated but the anti-inflammatory activity of bilberry has received little attention and a detailed review is yet to be published. Therefore, we compiled information on the phytochemicals of bilberry and preclinical and clinical studies of its anti-inflammatory properties. The review was based on studies from 2007 to date. Phytoconstituents of bilberries were phenolic acids, organic acids, anthocyanins, coumarins, flavonols, flavanols, tannins, terpenoids, and volatile chemicals. Data from cell and animal model studies show that bilberry has an anti-inflammatory effect by lowering tumor necrosis factor-, interleukin (IL)-6, and IL-1expression, inducing nitric oxide synthases and cyclooxygenases, and altering the nuclear factor kappa B and Janus kinase-signal transducer and activator of transcription signaling pathways. Bilberry supplementation as fruits (frozen, processed, and whole), juices, and anthocyanins reduced levels of inflammatory markers in most clinical studies of metabolic disorders. Therefore, bilberry may be useful for the prevention and treatment of chronic inflammatory disorders.

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PMID:  Int J Mol Sci. 2022 Sep 20 ;23(19). Epub 2022 Sep 20. PMID: 36232316 Abstract Title:  Dried Bilberry (L.) Alleviates the Inflammation and Adverse Metabolic Effects Caused by a High-Fat Diet in a Mouse Model of Obesity. Abstract:  Obesity is an increasing problem worldwide. It is often associated with co-morbidities such as type II diabetes, atherosclerotic diseases, and non-alcoholic fatty liver disease. The risk of these diseases can be lowered by relieving the systemic low-grade inflammation associated with obesity, even without noticeable weight loss. Bilberry is an anthocyanin-rich wild berry with known antioxidant and anti-inflammatory properties. In the present study, a high-fat-diet-induced mouse model of obesity was used to investigate the effects of air-dried bilberry powder on weight gain, systemic inflammation, lipid and glucose metabolism, and changes in the gene expression in adipose and hepatic tissues. The bilberry supplementation was unable to modify the weight gain, but it prevented the increase in the hepatic injury marker ALT and many inflammatory factors like SAA, MCP1, and CXCL14 induced by the high-fat diet. The bilberry supplementation also partially prevented the increase in serum cholesterol, glucose, and insulin levels. In conclusion, the bilberry supplementation alleviated the systemic and hepatic inflammation and retarded the development of unwanted changes in the lipid and glucose metabolism induced by the high-fat diet. Thus, the bilberry supplementation seemed to support to retain a healthier metabolic phenotype during developing obesity, and that effect might have been contributed to by bilberry anthocyanins.

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PMID:  Clin Med Insights Case Rep. 2023 ;16:11795476231161170. Epub 2023 Mar 16. PMID: 36950702 Abstract Title:  Experience With a Non-Hormonal Centella Asiatica, Hyaluronic Acid and Prebiotic-Based Vaginal Gel in Women With Recurrent Vulvovaginal Candidiasis: Case Studies. Abstract:  Recurrent vulvovaginal candidiasis (RVVC) affects millions of women worldwide, severely impairing their quality of life. Despite the existence of multiple induction and maintenance therapeutic strategies, mainly based on antifungals, relapse rates are still high. Palomacareis a vaginal gel containing, among others, hyaluronic acid and, with repairing and moisturizing properties. A series of 5 clinical cases showed that symptoms improved and even disappeared in women with RVVC receiving Palomacare. None of the patients experienced recurrence after the treatment, having their vaginal health restored, suggesting that the non-hormonal, hyaluronic acid and prebiotic-based gel is effective for preventing RVVC relapse in women of reproductive age.

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PMID:  BMC Complement Med Ther. 2022 Jul 8 ;22(1):181. Epub 2022 Jul 8. PMID: 35804339 Abstract Title:  A defined anthocyanin mixture sourced from bilberry and black currant inhibits Measles virus and various herpesviruses. Abstract:  BACKGROUND: Anthocyanin-containing plant extracts and carotenoids, such as astaxanthin, have been well-known for their antiviral and anti-inflammatory activity, respectively. We hypothesised that a mixture of Ribes nigrum L. (Grossulariaceae) (common name black currant (BC)) and Vaccinium myrtillus L. (Ericaceae) (common name bilberry (BL)) extracts (BC/BL) with standardised anthocyanin content as well as single plant extracts interfered with the replication of Measles virus and Herpesviruses in vitro.METHODS: We treated cell cultures with BC/BL or defined single plant extracts, purified anthocyanins and astaxanthin in different concentrations and subsequently infected the cultures with the Measles virus (wild-type or vaccine strain Edmonston), Herpesvirus 1 or 8, or murine Cytomegalovirus. Then, we analysed the number of infected cells and viral infectivity and compared the data to non-treated controls.RESULTS: The BC/BL extract inhibited wild-type Measles virus replication, syncytia formation and cell-to-cell spread. This suppression was dependent on the wild-type virus-receptor-interaction since the Measles vaccine strain was unaffected by BC/BL treatment. Furthermore, the evidence was provided that the delphinidin-3-rutinoside chloride, a component of BC/BL, and purified astaxanthin, were effective anti-Measles virus compounds. Human Herpesvirus 1 and murine Cytomegalovirus replication was inhibited by BC/BL, single bilberry or black currant extracts, and the BC/BL component delphinidin-3-glucoside chloride. Additionally, we observed that BC/BL seemed to act synergistically with aciclovir. Moreover, BC/BL, the single bilberry and black currant extracts, and the BC/BL components delphinidin-3-glucoside chloride, cyanidin-3-glucoside, delphinidin-3-rutinoside chloride, and petunidin-3-galactoside inhibited human Herpesvirus 8 replication.CONCLUSIONS: Our data indicate that Measles viruses and Herpesviruses are differentially susceptible to a specific BC/BL mixture, single plant extracts, purified anthocyanins and astaxanthin. These compounds might be used in the prevention of viral diseases and in addition to direct-acting antivirals, such as aciclovir.

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PMID:  Psychopharmacology (Berl). 2023 May ;240(5):1169-1178. Epub 2023 Mar 20. PMID: 36939856 Abstract Title:  Xanthohumol improves cognitive impairment by regulating miRNA-532-3p/Mpped1 in ovariectomized mice. Abstract:  RATIONALE: Studies have shown the potential neuroprotective effect of xanthohumol, while whether xanthohumol has the ability of repairing cognitive impairment and its underlying mechanism still remains obscure.OBJECTIVES: To unravel the mechanism of xanthohumol repairing cognitive impairment caused by estrogen deprivation.METHODS: C57BL/6 J female mice that underwent bilateral ovariectomy to establish cognitive decline model were randomly divided into three xanthohumol-treated groups and a saline-treated model group. For identifying the neuroprotective function of xanthohumol, Morris water maze (MWM) test and open field test (OFT) were conducted. After extracting total RNA of mouse hippocampus of different groups, mRNA-seq and microRNA (miRNA)-seq analysis were performed, and the differentially expressed miRNAs (DEMIs) and their target genes were further validated by qPCR. MiR-532-3p and its downstream gene Mpped1 were screened as targets of xanthohumol. Influence of miR-532-3p/Mpped1 to cognitive ability was examined via MWM test and OFT after stereotactic brain injection of Mpped1 overexpressed adeno-associated virus. The regulation of miR-532-3p on Mpped1 was confirmed in hippocampal neuronal cell line HT22 by luciferase reporter gene assay.RESULTS: Xanthohumol treatment reversed the cognitive decline of OVX mice according to behavioral tests. By comparing miRNA levels of xanthohumol-treated groups with saline-treated group, we found that the main changed miRNAs were miR-122-5p, miR-532-3p, and miR-539-3p. Increased miR-532-3p in OVX mice was suppressed by xanthohumol treatment. Furthermore, the downstream gene of miR-532-3p, Mpped1, was also increased by xanthohumol and showed the capability of relieving cognitive impairment of OVX mice after overexpressed in hippocampus. The 3' untranslated region of Mpped1 was identified as the target region of miR-532-3p, and agomiR-532-3p remarkably reduced the expression of Mpped1 mRNA.CONCLUSIONS: Xanthohumol has the ability of repairing cognitive impairment through removing the inhibition of miR-532-3p on Mpped1 in mouse hippocampus. This finding not only advances the understanding of neuroprotective mechanism of xanthohumol, but also provides novel treatment targets for dementia of postmenopausal women.

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PMID:  Phytother Res. 2023 Mar 7. Epub 2023 Mar 7. PMID: 36882184 Abstract Title:  Xanthohumol inhibits non-small cell lung cancer via directly targeting T-lymphokine-activated killer cell-originated protein kinase. Abstract:  Xanthohumol is a principal prenylated chalcone isolated from hops. Previous studies have shown that xanthohumol was effective against various types of cancer, but the mechanisms, especially the direct targets for xanthohumol to exert an anticancer effect, remain elusive. Overexpression of T-lymphokine-activated killer cell-originated protein kinase (TOPK) promotes tumorigenesis, invasion and metastasis, implying the likely potential for targeting TOPK in cancer prevention and treatment. In the present study, we found that xanthohumol significantly inhibited the cell proliferation, migration and invasion of non-small cell lung cancer (NSCLC) in vitro and suppressed tumor growth in vivo, which is well correlated with inactivating TOPK, evidenced by reduced phosphorylation of TOPK and its downstream signaling histone H3 and Akt, and decreased its kinase activity. Moreover, molecular docking and biomolecular interaction analysis showed that xanthohumol was able to directly bind to the TOPK protein, suggesting that TOPK inactivation by xanthohumol is attributed to its ability to directly interact with TOPK. The findings of the present study identified TOPK as a direct target for xanthohumol to exert its anticancer activity, revealing novel insight into the mechanisms underlying the anticancer activity of xanthohumol.

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PMID:  Front Pharmacol. 2023 ;14:1105726. Epub 2023 Jan 18. PMID: 36744265 Abstract Title:  Xanthohumol alleviates oxidative stress and impaired autophagy in experimental severe acute pancreatitis through inhibition of AKT/mTOR. Abstract:  Severe acute pancreatitis (SAP) is a lethal gastrointestinal disorder, yet no specific and effective treatment is available. Its pathogenesis involves inflammatory cascade, oxidative stress, and autophagy dysfunction. Xanthohumol (Xn) displays various medicinal properties, including anti-inflammation, antioxidative, and enhancing autophagic flux. However, it is unclear whether Xn inhibits SAP. This study investigated the efficacy of Xn on sodium taurocholate (NaT)-induced SAP (NaT-SAP)and. First, Xn attenuated biochemical and histopathological responses in NaT-SAP mice. And Xn reduced NaT-induced necrosis, inflammation, oxidative stress, and autophagy impairment. The mTOR activator MHY1485 and the AKT activator SC79 partly reversed the treatment effect of Xn. Overall, this is an innovative study to identify that Xn improved pancreatic injury by enhancing autophagic fluxinhibition of AKT/mTOR. Xn is expected to become a novel SAP therapeutic agent.

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PMID:  Front Cardiovasc Med. 2022 ;9:944902. Epub 2022 Sep 23. PMID: 36211585 Abstract Title:  Effect of metformin on adverse outcomes in T2DM patients: Systemic review and meta-analysis of observational studies. Abstract:  BACKGROUND: The cardiovascular protection effect of metformin on patients with type 2 diabetes mellitus (T2DM) remains inconclusive. This systemic review and meta-analysis were to estimate the effect of metformin on mortality and cardiovascular events among patients with T2DM.METHODS: A search of the Pubmed and EMBASE databases up to December 2021 was performed. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were pooled by a random-effects model with an inverse variance method.RESULTS: A total of 39 studies involving 2473009 T2DM patients were adopted. Compared to non-metformin therapy, the use of metformin was not significantly associated with a reduced risk of major adverse cardiovascular event (MACE) (HR = 1.06, 95%CI 0.91-1.22;= 82%), hospitalization (HR = 0.85, 95%CI 0.64-1.13;= 98%), heart failure (HR = 0.86, 95%CI 0.60-1.25;= 99%), stroke (HR = 1.16, 95%CI 0.88-1.53;= 84%), and risk of AMI (HR = 0.88, 95%CI 0.69-1.14;= 88%) in T2DM patients. Metformin was also not associated with significantly lowered risk of MACE compared to dipeptidyl peptidase-4 inhibitor (DPP-4i) in T2DM patients (HR = 0.95, 95%CI 0.73-1.23;= 84%).CONCLUSIONS: The effect of metformin on some cardiovascular outcomes was not significantly better than the non-metformin therapy or DPP-4i in T2DM patients based on observational studies.

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