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Journal of Neuroinflammation Jul 2019Alzheimer's disease (AD) is a neuropathology strongly associated with the activation of inflammatory pathways. Accordingly, inflammation resulting from obesity...
Malva parviflora extract ameliorates the deleterious effects of a high fat diet on the cognitive deficit in a mouse model of Alzheimer's disease by restoring microglial function via a PPAR-γ-dependent mechanism.
BACKGROUND
Alzheimer's disease (AD) is a neuropathology strongly associated with the activation of inflammatory pathways. Accordingly, inflammation resulting from obesity exacerbates learning and memory deficits in humans and in animal models of AD. Consequently, the long-term use of non-steroidal anti-inflammatory agents diminishes the risk for developing AD, but the side effects produced by these drugs limit their prophylactic use. Thus, plants natural products have become an excellent option for modern therapeutics. Malva parviflora is a plant well known for its anti-inflammatory properties.
METHODS
The present study was aimed to determine the anti-inflammatory potential of M. parviflora leaf hydroalcoholic extract (MpHE) on AD pathology in lean and obese transgenic 5XFAD mice, a model of familial AD. The inflammatory response and Amyloid β (Aβ) plaque load in lean and obese 5XFAD mice untreated or treated with MpHE was evaluated by immunolocalization (Iba-1 and GFAP) and RT-qPCR (TNF) assays and thioflavin-S staining, respectively. Spatial learning memory was assessed by the Morris Water Maze behavioral test. Microglia phagocytosis capacity was analyzed in vivo and by ex vivo and in vitro assays, and its activation by morphological changes (phalloidin staining) and expression of CD86, Mgl1, and TREM-2 by RT-qPCR. The mechanism triggered by the MpHE was characterized in microglia primary cultures and ex vivo assays by immunoblot (PPAR-γ) and RT-qPCR (CD36) and in vivo by flow cytometry, using GW9662 (PPAR-γ inhibitor) and pioglitazone (PPAR-γ agonist). The presence of bioactive compounds in the MpHE was determined by HPLC.
RESULTS
MpHE efficiently reduced astrogliosis, the presence of insoluble Aβ peptides in the hippocampus and spatial learning impairments, of both, lean, and obese 5XFAD mice. This was accompanied by microglial cells accumulation around Aβ plaques in the cortex and the hippocampus and decreased expression of M1 inflammatory markers. Consistent with the fact that the MpHE rescued microglia phagocytic capacity via a PPAR-γ/CD36-dependent mechanism, the MpHE possess oleanolic acid and scopoletin as active phytochemicals.
CONCLUSIONS
M. parviflora suppresses neuroinflammation by inhibiting microglia pro-inflammatory M1 phenotype and promoting microglia phagocytosis. Therefore, M. parviflora phytochemicals represent an alternative to prevent cognitive impairment associated with a metabolic disorder as well as an effective prophylactic candidate for AD progression.
Topics: Alzheimer Disease; Animals; Anti-Inflammatory Agents; Brain; Cognitive Dysfunction; Diet, High-Fat; Disease Models, Animal; Malva; Maze Learning; Mice; Mice, Transgenic; Microglia; PPAR gamma; Phagocytosis; Plant Extracts; Plant Leaves
PubMed: 31291963
DOI: 10.1186/s12974-019-1515-3 -
Microbial Cell Factories Aug 2022Scopoletin is a typical example of coumarins, which can be produced in plants. Scopoletin acts as a precursor for pharmaceutical and health care products, and also... (Review)
Review
Scopoletin is a typical example of coumarins, which can be produced in plants. Scopoletin acts as a precursor for pharmaceutical and health care products, and also possesses promising biological properties, including antibacterial, anti-tubercular, anti-hypertensive, anti-inflammatory, anti-diabetic, and anti-hyperuricemic activity. Despite the potential benefits, the production of scopoletin using traditional extraction processes from plants is unsatisfactory. In recent years, synthetic biology has developed rapidly and enabled the effective construction of microbial cell factories for production of high value-added chemicals. Herein, this review summarizes the progress of scopoletin biosynthesis in artificial microbial cell factories. The two main pathways of scopoletin biosynthesis are summarized firstly. Then, synthetic microbial cell factories are reviewed as an attractive improvement strategy for biosynthesis. Emerging techniques in synthetic biology and metabolic engineering are introduced as innovative tools for the efficient synthesis of scopoletin. This review showcases the potential of biosynthesis of scopoletin in artificial microbial cell factories.
Topics: Metabolic Engineering; Plants; Scopoletin; Synthetic Biology
PubMed: 35918699
DOI: 10.1186/s12934-022-01865-7 -
RSC Advances Apr 2020Neuronal cell death is a key feature of neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. Plant polyphenols, namely butein, isoliquiritigenin,...
Neuronal cell death is a key feature of neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. Plant polyphenols, namely butein, isoliquiritigenin, and scopoletin, have been shown to exhibit various biological activities including anti-inflammatory, antimicrobial, and antioxidant activities. Herein, butein, isoliquiritigenin, and scopoletin were explored for their neuroprotective properties against oxidative stress-induced human dopaminergic SH-SY5Y cell death. The cells exposed to hydrogen peroxide (HO) revealed a reduction in cell viability and increases in apoptosis and levels of reactive oxygen species (ROS). Interestingly, pretreatment of SH-SY5Y cells with 5 μM of butein, isoliquiritigenin, or scopoletin protected against the cell death induced by HO, and decreased the levels of apoptotic cells and ROS. In addition, the levels of SIRT1, FoxO3a, ADAM10, BCL-2, and antioxidant enzymes (catalase and SOD2) were maintained in the cells pretreated with butein, isoliquiritigenin, or scopoletin before HO treatment compared to cells without pretreatment and the reference (resveratrol). Molecular docking analysis revealed that the interactions between the activator-binding sites of SIRT1 and the phenolic compounds were similar to those of resveratrol. Taken together, the data suggest that these polyphenolic compounds could be potential candidates for prevention and/or treatment of neurodegeneration.
PubMed: 35498835
DOI: 10.1039/c9ra06056a -
Journal of Food Protection Nov 1996Hydrogen peroxide is responsible for certain bactericidal effects observed in biological systems, such as growth inhibition of one bacterial species by another and...
Hydrogen peroxide is responsible for certain bactericidal effects observed in biological systems, such as growth inhibition of one bacterial species by another and killing of invading microorganisms by activated phagocytic cells. HO might be generated in bacteriological media by their exposure to light and/or oxygen and become an important mediator of toxic effects. HO cytotoxicity is apparently due to its capacity-generally mediated by transition metal ions-to generate more reactive and cytotoxic oxygen species such as the hydroxyl radical, which is a powerful oxidant, and which can initiate oxidation of biomolecules. The conversion of HO into more cytotoxic compounds may be potentiated by reducing agents and by peroxidases. Cells may protect themselves against HO toxicity either by the action of catalases or, in the case of DNA damage, by repairing the damage after it has taken place. Assays for the detection and quantitation of HO in cell cultures include those based on (i) catalase-dependent oxidation of formate to CO, (ii) generation of fluorescent products due to a HO- mediated oxidative reaction, (iii) the loss of fluorescence upon the oxidation of scopoletin, (iv) change in absorbance upon oxidation of phenol red, or (v) formation of complexes with peroxidases. Some possible antimicrobial uses of HO in the food industry are presented.
PubMed: 31195444
DOI: 10.4315/0362-028X-59.11.1233 -
Zeitschrift Fur Naturforschung. C,... Jul 2022Scopoletin, also known as 6-methoxy-7 hydroxycoumarin, is one of the naturally occurring coumarin commonly found in many edible plants and plays an important role in... (Review)
Review
Scopoletin, also known as 6-methoxy-7 hydroxycoumarin, is one of the naturally occurring coumarin commonly found in many edible plants and plays an important role in human health. Despite the various potential pharmacological properties, the biosynthesis process, method of extraction, and mechanism of action on this compound have not been documented well. In this current review, the biosynthesis pathway, distribution of scopoletin in the plant kingdom, and extraction techniques are elaborated. The , , and pharmacological studies are also discussed on antioxidant, antimicrobial, anticancer, anti-inflammation, and neuroprotective aspects of scopoletin. This study may help to understand the benefit of scopoletin containing plants and would be beneficial for the prevention and treatment of diseases.
Topics: Humans; Scopoletin
PubMed: 35218175
DOI: 10.1515/znc-2021-0193 -
Frontiers in Pharmacology 2024Scopoletin is a coumarin synthesized by diverse medicinal and edible plants, which plays a vital role as a therapeutic and chemopreventive agent in the treatment of a... (Review)
Review
Scopoletin is a coumarin synthesized by diverse medicinal and edible plants, which plays a vital role as a therapeutic and chemopreventive agent in the treatment of a variety of diseases. In this review, an overview of the pharmacology, pharmacokinetics, and toxicity of scopoletin is provided. In addition, the prospects and outlook for future studies are appraised. Scopoletin is indicated to have antimicrobial, anticancer, anti-inflammation, anti-angiogenesis, anti-oxidation, antidiabetic, antihypertensive, hepatoprotective, and neuroprotective properties and immunomodulatory effects in both and experimental trials. In addition, it is an inhibitor of various enzymes, including choline acetyltransferase, acetylcholinesterase, and monoamine oxidase. Pharmacokinetic studies have demonstrated the low bioavailability, rapid absorption, and extensive metabolism of scopoletin. These properties may be associated with its poor solubility in aqueous media. In addition, toxicity research indicates the non-toxicity of scopoletin to most cell types tested to date, suggesting that scopoletin will neither induce treatment-associated mortality nor abnormal performance with the test dose. Considering its favorable pharmacological activities, scopoletin has the potential to act as a drug candidate in the treatment of cancer, liver disease, diabetes, neurodegenerative disease, and mental disorders. In view of its merits and limitations, scopoletin is a suitable lead compound for the development of new, efficient, and low-toxicity derivatives. Additional studies are needed to explore its molecular mechanisms and targets, verify its toxicity, and promote its oral bioavailability.
PubMed: 38464713
DOI: 10.3389/fphar.2024.1268464 -
Toxicology and Applied Pharmacology Feb 2022The number of patients with non-alcoholic fatty liver disease (NAFLD) is rapidly increasing due to the growing epidemic of obesity. Non-alcoholic steatohepatitis (NASH),...
BACKGROUND
The number of patients with non-alcoholic fatty liver disease (NAFLD) is rapidly increasing due to the growing epidemic of obesity. Non-alcoholic steatohepatitis (NASH), the inflammatory stage of NAFLD, is characterized by lipid accumulation in hepatocytes, chronic inflammation and hepatocyte cell death. Scopoletin and umbelliferone are coumarin-like molecules and have antioxidant, anti-cancer and anti-inflammatory effects. Cytoprotective effects of these compounds have not been described in hepatocytes and the mechanisms of the beneficial effects of scopoletin and umbelliferone are unknown.
AIM
To investigate whether scopoletin and/or umbelliferone protect hepatocytes against palmitate-induced cell death. For comparison, we also tested the cytoprotective effect of scopoletin and umbelliferone against bile acid-induced cell death.
METHODS
Primary rat hepatocytes were exposed to palmitate (1 mmol/L) or the hydrophobic bile acid glycochenodeoxycholic acid (GCDCA; 50 μmol/L). Apoptosis was assessed by caspase-3 activity assay, necrosis by Sytox green assay, mRNA levels by qPCR, protein levels by Western blot and production of reactive oxygen species (ROS) by fluorescence assay.
RESULTS
Both scopoletin and umbelliferone protected against palmitate and GCDCA-induced cell death. Both palmitate and GCDCA induced the expression of ER stress markers. Scopoletin and umbelliferone decreased palmitate- and GCDCA-induced expression of ER stress markers, phosphorylation of the cell death signaling intermediate JNK as well as ROS production.
CONCLUSION
Scopoletin and umbelliferone protect against palmitate and bile acid-induced cell death of hepatocytes by inhibition of ER stress and ROS generation and decreasing phosphorylation of JNK. Scopoletin and umbelliferone may hold promise as a therapeutic modality for the treatment of NAFLD.
Topics: Animals; Antioxidants; Apoptosis; Bile Acids and Salts; Cell Death; Cell Line, Tumor; Endoplasmic Reticulum Stress; Glycochenodeoxycholic Acid; Hep G2 Cells; Hepatocytes; Humans; Male; Necrosis; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Palmitates; Rats; Rats, Wistar; Reactive Oxygen Species; Scopoletin; Signal Transduction; Umbelliferones
PubMed: 34979142
DOI: 10.1016/j.taap.2021.115858 -
Plant & Cell Physiology Jul 2019Coumarins are a family of plant-derived secondary metabolites that are produced via the phenylpropanoid pathway. In the past decade, coumarins have emerged as... (Review)
Review
Coumarins are a family of plant-derived secondary metabolites that are produced via the phenylpropanoid pathway. In the past decade, coumarins have emerged as iron-mobilizing compounds that are secreted by plant roots and aid in iron uptake from iron-deprived soils. Members of the coumarin family are found in many plant species. Besides their role in iron uptake, coumarins have been extensively studied for their potential to fight infections in both plants and animals. Coumarin activities range from antimicrobial and antiviral to anticoagulant and anticancer. In recent years, studies in the model plant species tobacco and Arabidopsis have significantly increased our understanding of coumarin biosynthesis, accumulation, secretion, chemical modification and their modes of action against plant pathogens. Here, we review current knowledge on coumarins in different plant species. We focus on simple coumarins and provide an overview on their biosynthesis and role in environmental stress responses, with special attention for the recently discovered semiochemical role of coumarins in aboveground and belowground plant-microbe interactions and the assembly of the root microbiome.
Topics: Coumarins; Host-Pathogen Interactions; Plant Diseases; Plant Physiological Phenomena; Plants
PubMed: 31076771
DOI: 10.1093/pcp/pcz076 -
Biological & Pharmaceutical Bulletin 2019Hypertension is a disease of high prevalence and morbidity where vascular inflammation and associated oxidative stress (endothelial dysfunction) is the underlying cause...
Hypertension is a disease of high prevalence and morbidity where vascular inflammation and associated oxidative stress (endothelial dysfunction) is the underlying cause of this pathology. We are reporting the antihypertensive activity of extracts and fractions of Malva parviflora in mice with chronic and acute hypertension. Also, the treatments of this plant were able to counteract the kidney inflammation and associated oxidative stress. The chronic hypertension model consisted of administration of angiotensin II (AGII) during 12 weeks, causing a sustained increase in systolic (SBP) or diastolic (DBP) pressure, with values of pharmacological constants of: ED = 0.038 mg/kg y E = 135 mmHg for SBP and ED = 0.046 mg/kg y E = 98 mmHg for DBP. The chronic hypertension caused the inflammation and lipid peroxidation in kidneys, measured by of tissue level of cytokines such as interleukin-1β (IL-1β), IL-6, Tumor Necrosis Factor-α (TNF-α), IL-10 and malondialdehyde, and treatments for M. parviflora were able to modulate these parameters. The chemical fractionation allowed to identify three compounds: oleanolic acid, tiliroside and scopoletin, which were tested in a model of acute hypertension. The pharmacodynamic parameters for SBP were ED = 0.01 and 0.12 mg/kg while E = 33.22 and 37.74 mmHg for scopoletin and tiliroside, respectively; whereas that for DBP data were ED = 0.01 and 0.02 mg/kg; with an E = 7.00 and 6.24 mmHg, in the same order. M. parviflora, is able to counteract the effect of chronic and acute administration of AGII, on hypertension, but also the inflammatory and oxidative damage in the kidney. The oleanolic acid, scopoletin and tiliroside are the compounds responsible for such activities.
Topics: Angiotensin II; Animals; Antihypertensive Agents; Blood Pressure; Dose-Response Relationship, Drug; Flavonoids; Hypertension; Male; Malva; Mice; Mice, Inbred ICR; Plant Extracts; Scopoletin
PubMed: 30606987
DOI: 10.1248/bpb.b18-00355 -
Molecules (Basel, Switzerland) Jan 2023(1) Background: Scopoletin and scoparone, two naturally occurring coumarins, have garnered considerable attention and have been introduced to the market in China due to...
(1) Background: Scopoletin and scoparone, two naturally occurring coumarins, have garnered considerable attention and have been introduced to the market in China due to their high insecticidal efficacy and low toxicity. To investigate the structure-activity relationship of these coumarins, a series of scopoletin derivatives with aryl sulfate at C7 and different substitutes at C3 were designed and synthesized, and their insecticidal activity was studied. (2) Methods: A total of 28 new scopoletin derivatives were designed and synthesized. Most target compounds exhibited moderate insecticidal activity against the phytophagous mite and the brine shrimp . (3) Results: Among these compounds, compounds and possessed the best insecticidal activities against with LC values of 57.0 and 20.0 μg/mL, respectively, whereas that of the control drug was 15.0 μg/mL. Compound exhibited selective insecticidal activities against , with an LC value of 9.36 μg/mL, whereas its LC value against was 93.0 μg/mL. The enzymatic inhibitory activity on acetylcholinesterase (AChE) showed a consistent tendency with the insecticidal activity. Further molecular docking analyses predicted the binding conformations of these compounds, which showed a good correlation between the insecticidal activity and the binding scores. (4) Conclusions: In general, a decreased electron cloud density of the Δ olefinic bond is beneficial for improving the insecticidal activity against both and . In addition, naphthyl or benzene groups with a sulfate ester at the C7 position could further improve the insecticidal activity against . AChE was implied to be a site of action for potential insecticidal activity. The results provide insight into the rational design of a new generation of effective coumarin insecticides.
Topics: Animals; Insecticides; Acaricides; Scopoletin; Molecular Docking Simulation; Acetylcholinesterase; Structure-Activity Relationship; Molecular Structure
PubMed: 36677589
DOI: 10.3390/molecules28020530