-
BMC Complementary Medicine and Therapies Jun 2024Alzheimer's disease is a neurodegenerative age-related disease that primarily affects the elderly population leading to progressive memory impairments and neural...
BACKGROUND
Alzheimer's disease is a neurodegenerative age-related disease that primarily affects the elderly population leading to progressive memory impairments and neural deficits. It is counted as a major cause of geriatric dependency and disability. The pathogenesis of Alzheimer's disease incidence is complex and involves various hypotheses, including the cholinergic hypothesis, deposition of β-amyloid plaques, neuroinflammation, oxidative stress, and apoptosis. Conventional treatments such as donepezil aim to delay the symptoms but do not affect the progression of the disease and may cause serious side effects like hepatoxicity. The use of natural candidates for Alzheimer's disease treatment has drawn the attention of many researchers as it offers a multitargeted approach.
METHODS
This current study investigates the metabolic profiles of total defatted methanolic extract of Vitex pubescens bark and its polar fractions, viz. ethyl acetate and n-butanol, using ultra-performance liquid chromatography-electrospray ionization-quadrupole time-of-flight tandem mass spectrometry(UPLC-ESI-QTOF/MS/MS) technique as well as evaluate the antioxidant using free radical scavenging assays, viz. DPPH and ABTS assays and in-vitro acetylcholinesterase inhibitory activities using Ellman's microplate assay.
RESULTS
Metabolic profiling revealed a total of 71, 43, and 55 metabolites tentatively identified in the defatted methanolic extract, ethyl acetate, and n-butanol fractions, respectively. Phenolic acids were the most abundant class, viz. benzoic acids, and acyl quinic acid derivatives followed by flavonoids exemplified mainly by luteolin-C-glycosides and apigenin-C-glycosides. Quantification of the total phenolic and flavonoid contents in the total defatted methanolic extract confirmed its enrichment with phenolics and flavonoids equivalent to 138.61 ± 9.39 µg gallic acid/mg extract and 119.63 ± 4.62 µg rutin/mg extract, respectively. Moreover, the total defatted methanolic extract exhibited promising antioxidant activity confirmed through DPPH and ABTS assays with a 50% inhibitory concentration (IC) value equivalent to 52.79 ± 2.16 µg/mL and 10.02 ± µg/mL, respectively. The inhibitory activity of acetylcholine esterase (AchE) was assessed using in-vitro Ellman's colorimetric assay, the total defatted methanolic extract, ethyl acetate, and n-butanol fractions exhibited IC values of 52.9, 15.1 and 108.8 µg/mL that they proved the significant inhibition of AchE activity.
CONCLUSION
The results obtained herein unraveled the potential use of the total methanolic extract of Vitex pubescens bark and its polar fractions as natural candidates for controlling Alzheimer's disease progression.
Topics: Plant Extracts; Antioxidants; Cholinesterase Inhibitors; Plant Bark; Tandem Mass Spectrometry; Vitex; Chromatography, High Pressure Liquid; Spectrometry, Mass, Electrospray Ionization; Humans
PubMed: 38877470
DOI: 10.1186/s12906-024-04520-3 -
Biomedicine & Pharmacotherapy =... Jul 2024
PubMed: 38871545
DOI: 10.1016/j.biopha.2024.116916 -
Nature Communications Jun 2024Urate, the physiological form of uric acid and a potent antioxidant in serum, plays a pivotal role in scavenging reactive oxygen species. Yet excessive accumulation of...
Urate, the physiological form of uric acid and a potent antioxidant in serum, plays a pivotal role in scavenging reactive oxygen species. Yet excessive accumulation of urate, known as hyperuricemia, is the primary risk factor for the development of gout. The high-capacity urate transporter GLUT9 represents a promising target for gout treatment. Here, we present cryo-electron microscopy structures of human GLUT9 in complex with urate or its inhibitor apigenin at overall resolutions of 3.5 Å and 3.3 Å, respectively. In both structures, GLUT9 exhibits an inward open conformation, wherein the substrate binding pocket faces the intracellular side. These structures unveil the molecular basis for GLUT9's substrate preference of urate over glucose, and show that apigenin acts as a competitive inhibitor by occupying the substrate binding site. Our findings provide critical information for the development of specific inhibitors targeting GLUT9 as potential therapeutics for gout and hyperuricemia.
Topics: Humans; Glucose Transport Proteins, Facilitative; Uric Acid; Apigenin; Cryoelectron Microscopy; Binding Sites; Protein Binding; Hyperuricemia; Models, Molecular; Gout; HEK293 Cells
PubMed: 38866775
DOI: 10.1038/s41467-024-49420-9 -
Scientific Reports Jun 2024Previous studies have shown that scutellarin inhibits the excessive activation of microglia, reduces neuronal apoptosis, and exerts neuroprotective effects. However,...
Previous studies have shown that scutellarin inhibits the excessive activation of microglia, reduces neuronal apoptosis, and exerts neuroprotective effects. However, whether scutellarin regulates activated microglia-mediated neuronal apoptosis and its mechanisms remains unclear. This study aimed to investigate whether scutellarin can attenuate PC12 cell apoptosis induced by activated microglia via the JAK2/STAT3 signalling pathway. Microglia were cultured in oxygen-glucose deprivation (OGD) medium, which acted as a conditioning medium (CM) to activate PC12 cells, to investigate the expression of apoptosis and JAK2/STAT3 signalling-related proteins. We observed that PC12 cells apoptosis in CM was significantly increased, the expression and fluorescence intensity of the pro-apoptotic protein Bax and apoptosis-related protein cleaved caspase-3 were increased, and expression of the anti-apoptotic protein B-cell lymphoma-2 (Bcl-2) was decreased. Phosphorylation levels and fluorescence intensity of the JAK2/STAT3 signalling pathway-related proteins JAK2 and STAT3 decreased. After treatment with scutellarin, PC12 cells apoptosis as well as cleaved caspase-3 and Bax protein expression and fluorescence intensity decreased. The expression and fluorescence intensity of Bcl-2, phosphorylated JAK2, and STAT3 increased. AG490, a specific inhibitor of the JAK2/STAT3 signalling pathway, was used. Our findings suggest that AG490 attenuates the effects of scutellarin. Our study revealed that scutellarin inhibited OGD-activated microglia-mediated PC12 cells apoptosis which was regulated via the JAK2/STAT3 signalling pathway.
Topics: Animals; Apigenin; STAT3 Transcription Factor; Janus Kinase 2; Glucuronates; PC12 Cells; Apoptosis; Microglia; Signal Transduction; Rats; Mice; Caspase 3; Glucose; Neuroprotective Agents; Phosphorylation; bcl-2-Associated X Protein; Tyrphostins
PubMed: 38862696
DOI: 10.1038/s41598-024-64226-x -
BMC Plant Biology Jun 2024One of the most effective strategies to increase phytochemicals production in plant cultures is elicitation. In the present study, we studied the effect of abiotic and...
BACKGROUND
One of the most effective strategies to increase phytochemicals production in plant cultures is elicitation. In the present study, we studied the effect of abiotic and biotic elicitors on the growth, key biosynthetic genes expression, antioxidant capacity, and phenolic compounds content in Rhizobium (Agrobacterium) rhizogenes-induced hairy roots cultures of Ficus carica cv. Siah.
METHODS
The elicitors included methyl jasmonate (MeJA) as abiotic elicitor, culture filtrate and cell extract of fungus Piriformospora indica as biotic elicitors were prepared to use. The cultures of F. carica hairy roots were exposed to elicitores at different time points. After elicitation treatments, hairy roots were collected, and evaluated for growth index, total phenolic (TPC) and flavonoids (TFC) content, antioxidant activity (2,2-diphenyl-1-picrylhydrazyl, DPPH and ferric ion reducing antioxidant power, FRAP assays), expression level of key phenolic/flavonoid biosynthesis genes, and high-performance liquid chromatography (HPLC) analysis of some main phenolic compounds in comparison to control.
RESULTS
Elicitation positively or negatively affected the growth, content of phenolic/flavonoid compounds and DPPH and FRAP antioxidant activities of hairy roots cultures in depending of elicitor concentration and exposure time. The maximum expression level of chalcone synthase (CHS: 55.1), flavonoid 3'-hydroxylase (F3'H: 34.33) genes and transcription factors MYB3 (32.22), Basic helix-loop-helix (bHLH: 45.73) was induced by MeJA elicitation, whereas the maximum expression level of phenylalanine ammonia-lyase (PAL: 26.72) and UDP-glucose flavonoid 3-O-glucosyltransferase (UFGT: 27.57) genes was obtained after P. indica culture filtrate elicitation. The P. indica elicitation also caused greatest increase in the content of gallic acid (5848 µg/g), caffeic acid (508.2 µg/g), rutin (43.5 µg/g), quercetin (341 µg/g), and apigenin (1167 µg/g) phenolic compounds.
CONCLUSIONS
This study support that elicitation of F. carica cv. Siah hairy roots can be considered as an effective biotechnological method for improved phenolic/flavonoid compounds production, and of course this approach requires further research.
Topics: Oxylipins; Cyclopentanes; Acetates; Plant Roots; Phenols; Ficus; Flavonoids; Gene Expression Regulation, Plant; Antioxidants; Basidiomycota; Plant Growth Regulators; Agrobacterium
PubMed: 38853268
DOI: 10.1186/s12870-024-05178-2 -
Frontiers in Nutrition 2024L. (Lamiaceae), known in English as 'wild thyme', is primarily found in the Palearctic realm (Eurasia, North Africa) and has been utilized traditionally for culinary,...
L. (Lamiaceae), known in English as 'wild thyme', is primarily found in the Palearctic realm (Eurasia, North Africa) and has been utilized traditionally for culinary, nutritional, medicinal, and aromatic purposes. The essential oil extracted from wild thyme is particularly noteworthy, being used extensively in the food industry as a flavoring agent and preservative. The plant's aerial parts are commonly employed as an element of the diet (e.g., tea)/for culinary uses and in local/traditional medicine (primarily for managing respiratory and gastrointestinal conditions), similar to the use of common thyme. There is practically no information available on the species' nutritional benefits. Pharmacological studies, including and research, alongside a limited number of clinical trials, have investigated extracts of , although these extracts are often phytochemically poorly characterized in different experimental protocols and models. These studies have demonstrated a range of therapeutic effects, such as antimicrobial (notably the essential oil) and anti-inflammatory, as well as its preventative health benefits and nutritional value of wild thyme. Preclinical studies have corroborated the plant's anti-inflammatory potential, particularly in conditions like inflammatory bowel diseases (IBD) and irritable bowel syndromes (IBS). Additionally, evidence of hepatoprotective activities and benefits in managing metabolic syndrome and cardiovascular health issues, such as lipid metabolism regulation, cholesterol reduction, antidiabetic, antihypertensive, and immunomodulatory effects, have been observed predominantly in rodent models. Phytochemical analysis of wild thyme reveals an essential oil fraction below 1%, along with non-volatile compounds predominantly comprising phenolic acids (such as rosmarinic, salvianolic, and caffeic acids) and flavonoids (mainly glucosides of luteolin, apigenin, and their derivatives). These components are believed to contribute significantly to the plant's medicinal, nutritional, and preventive health properties. Despite promising findings, there is a need for more rigorously designed controlled clinical trials using phytochemically characterized wild thyme. The plant has an excellent safety and tolerability record. This review at the interface of nutritional/preventive health properties and as pharmacological activities highlights the current role of wild thyme in nutrition and general healthcare as well as its future potential, and also points to important gaps in the literature.
PubMed: 38846542
DOI: 10.3389/fnut.2024.1380962 -
Current Research in Pharmacology and... 2024Diabetes mellitus (DM) is a global health burden that is characterized by the loss or dysfunction of pancreatic β-cells. In pancreatic β-cells, endoplasmic reticulum... (Review)
Review
Diabetes mellitus (DM) is a global health burden that is characterized by the loss or dysfunction of pancreatic β-cells. In pancreatic β-cells, endoplasmic reticulum (ER) stress is a fact of life that contributes to β-cell loss or dysfunction. Despite recent advances in research, the existing treatment approaches such as lifestyle modification and use of conventional therapeutics could not prevent the loss or dysfunction of pancreatic β-cells to abrogate the disease progression. Therefore, targeting ER stress and the consequent unfolded protein response (UPR) in pancreatic β-cells may be a potential therapeutic strategy for diabetes treatment. Dietary phytochemicals have therapeutic applications in human health owing to their broad spectrum of biochemical and pharmacological activities. Flavonoids, which are commonly obtained from fruits and vegetables worldwide, have shown promising prospects in alleviating ER stress. Dietary flavonoids including quercetin, kaempferol, myricetin, isorhamnetin, fisetin, icariin, apigenin, apigetrin, vitexin, baicalein, baicalin, nobiletin hesperidin, naringenin, epigallocatechin 3-O-gallate hesperidin (EGCG), tectorigenin, liquiritigenin, and acacetin have shown inhibitory effects on ER stress in pancreatic β-cells. Dietary flavonoids modulate ER stress signaling components, chaperone proteins, transcription factors, oxidative stress, autophagy, apoptosis, and inflammatory responses to exert their pharmacological effects on pancreatic β-cells ER stress. This review focuses on the role of dietary flavonoids as potential therapeutic adjuvants in preserving pancreatic β-cells from ER stress. Highlights of the underlying mechanisms of action are also presented as well as possible strategies for clinical translation in the management of DM.
PubMed: 38846008
DOI: 10.1016/j.crphar.2024.100184 -
The EPMA Journal Jun 2024Despite their subordination in humans, to a great extent, mitochondria maintain their independent status but tightly cooperate with the "host" on protecting the joint...
Despite their subordination in humans, to a great extent, mitochondria maintain their independent status but tightly cooperate with the "host" on protecting the joint life quality and minimizing health risks. Under oxidative stress conditions, healthy mitochondria promptly increase mitophagy level to remove damaged "fellows" rejuvenating the mitochondrial population and sending fragments of mtDNA as SOS signals to all systems in the human body. As long as metabolic pathways are under systemic control and well-concerted together, adaptive mechanisms become triggered increasing systemic protection, activating antioxidant defense and repair machinery. Contextually, all attributes of mitochondrial patho-/physiology are instrumental for predictive medical approach and cost-effective treatments tailored to individualized patient profiles in primary (to protect vulnerable individuals again the health-to-disease transition) and secondary (to protect affected individuals again disease progression) care. Nutraceuticals are naturally occurring bioactive compounds demonstrating health-promoting, illness-preventing, and other health-related benefits. Keeping in mind health-promoting properties of nutraceuticals along with their great therapeutic potential and safety profile, there is a permanently growing demand on the application of mitochondria-relevant nutraceuticals. Application of nutraceuticals is beneficial only if meeting needs at individual level. Therefore, health risk assessment and creation of individualized patient profiles are of pivotal importance followed by adapted nutraceutical sets meeting individual needs. Based on the scientific evidence available for mitochondria-relevant nutraceuticals, this article presents examples of frequent medical conditions, which require protective measures targeted on mitochondria as a holistic approach following advanced concepts of predictive, preventive, and personalized medicine (PPPM/3PM) in primary and secondary care.
PubMed: 38841620
DOI: 10.1007/s13167-024-00358-4 -
Heliyon Jun 2024Constipation is one of the chronic gastrointestinal functional diseases that affects the quality of life. While Qi Lang Formula (QLF) has demonstrated effectiveness in...
BACKGROUND
Constipation is one of the chronic gastrointestinal functional diseases that affects the quality of life. While Qi Lang Formula (QLF) has demonstrated effectiveness in alleviating constipation symptoms, its precise mechanism remains elusive.
METHODS
QLF was analyzed using UPLC-MS/MS. Targets for QLF were collected from SwissADME, Herb, ITCM databases, and constipation-related targets from scRNA-seq and Genecards databases. Overlapping targets suggested potential QLF therapy targets for constipation. Enrichment analysis used the KOBAS database. A "drug-ingredient-target" network was constructed with Cytoscape, and AutoDock verified active ingredient binding. H&E staining assessed colonic mucosa changes, TEM examined ICC structural changes. ELISA measured neurotransmitter levels, and Western blot verified QLF's effect on target proteins. ICC proliferation was observed through immunofluorescence.
RESULTS
We identified 89 targets of QLF associated with ICC-related constipation, with c-Kit emerging as the pivotal target. Molecular docking studies revealed that Atractylenolide Ⅲ, Apigenin, Formononetin, Isorhamnetin, Naringenin, and Ononin exhibited strong binding affinities for the c-Kit structural domain. QLF significantly enhanced first stool passage time, fecal frequency, fecal moisture content, and intestinal propulsion rate. Further analysis unveiled that QLF not only restored neurotransmitter levels but also mitigated colon muscular fiber ruptures. ICC ultrastructure exhibited partial recovery, while Western blot confirmed upregulated c-Kit expression and downstream targets. Immunofluorescence results indicated ICC proliferation post QLF treatment in rat colon.
CONCLUSION
Our findings suggest that QLF may promote ICC proliferation by targeting SCF/c-Kit and its downstream signaling pathway, thereby regulating intestinal motility.
PubMed: 38841509
DOI: 10.1016/j.heliyon.2024.e31860 -
Frontiers in Pharmacology 2024(PC) is used in traditional Chinese medicine and food, as it exerts pharmacological effects, such as immune-modulatory, antibacterial, antioxidant, antitumor, and...
(PC) is used in traditional Chinese medicine and food, as it exerts pharmacological effects, such as immune-modulatory, antibacterial, antioxidant, antitumor, and antiviral. Currently, the pharmacokinetics (PK) studies of PC mainly focus on individual components. However, research on these individual components cannot reflect the actual PK characteristics of PC after administration. Therefore, the simultaneous determination of multiple components in rat plasma using UPLC-MS/MS was used for the pharmacokinetic study after oral administration of PC extract in this study, providing reference value for the clinical application of PC. In the present study, a reliable and sensitive ultra-high performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the simultaneous determination of 15 prototype components (vanillic acid, vitexin, verbascoside, isoacteoside, hyperoside, cosmosiin, apigenin, β-rhamnocitrin, acacetin, ombuin, pogostone, pachypodol, vicenin-2, retusin, and diosmetin-7-O-β-D-glucopyranoside) in rat plasma after oral administration of the PC extract. Plasma samples were prepared via protein precipitation using acetonitrile, and icariin was used as the internal standard (IS). The intra-day and inter-day accuracies ranged from -12.0 to 14.3%, and the precision of the analytes was less than 11.3%. The extraction recovery rate of the analytes ranged from 70.6-104.5%, and the matrix effects ranged from 67.4-104.8%. Stability studies proved that the analytes were stable under the tested conditions, with a relative standard deviation lower than 14.1%. The developed method can be applied to evaluate the PK of 15 prototype components in PC extracts of rats after oral administration using UPLC-MS/MS, providing valuable information for the development and clinical safe, effective, and rational use of PC.
PubMed: 38841366
DOI: 10.3389/fphar.2024.1293464