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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 -
In Silico Pharmacology 2024Alzheimer's disease (AD) is the most occurring neurodegenerative disorder that destroys learning, memory, and thinking skills. Although the pathophysiology of the...
Alzheimer's disease (AD) is the most occurring neurodegenerative disorder that destroys learning, memory, and thinking skills. Although the pathophysiology of the disease is least understood, the post-mortem brain of AD patients as well as animal models revealed the part of down regulated Wnt signalling in progression of the disease. The deficit in the Wnt signalling leads to the accumulation of amyloid beta peptides, phosphorylation of tau proteins, and synaptic dysfunctions, which are regarded as the major pathological features of AD. As the available drugs for AD are only able to mitigate the symptoms and are also associated with several side effects, the therapeutic potential of the bioactive compounds is being explored for their efficacies in managing the major pathologies. Consequently, a few bioactive compounds fundamentally isolated from species are established as promising neuroprotective agents in AD, however; their potential to regulate the Wnt signalling pathway is yet to be discovered. Considering the neuroprotective properties, in the present study efficiency of six small bioactive compounds viz., amentoflavone, isovitexin, orientin, apigenin, kaempferol, and garcinol have been investigated in modulating the receptor proteins (LRP6, DKK1, WIF1 and GSK3β) of the Wnt signalling pathway by molecular docking technique. While all the bioactive compounds could efficiently interact with the target proteins, amentoflavone, orientin, and isovitexin interact with all the target proteins viz., LRP6, DKK1, WIF1, and GSK3β with higher free energy of binding, more number of interactions, and similar mode of binding in comparison to their known or reported modulators. Thus, the present study set forth the investigated small bioactive molecules as potential drug candidates in AD therapeutics.
PubMed: 38840665
DOI: 10.1007/s40203-024-00226-z -
Frontiers in Chemistry 2024The integumentary system, a vital organ, constitutes a multifaceted barrier against pathogens and environmental factors, crucial for maintaining homeostasis. Intrinsic...
The integumentary system, a vital organ, constitutes a multifaceted barrier against pathogens and environmental factors, crucial for maintaining homeostasis. Intrinsic and extrinsic factors can accelerate skin aging and compromise its homeostatic functions and solar rays, particularly ultraviolet (UV) radiation, pose a significant risk for skin cancer. Polyphenols are molecules that donate hydrogen or electrons, preventing the oxidation of substances, such as lipids, or the formation of inflammatory mediators by cyclooxygenase enzymes. This study explored the safety, by HET-CAM (hen's egg test on chorioallantoic membrane), and protective effects of polyphenols (chlorogenic acid, apigenin, kaempferol, and naringenin) against stratum corneum UV-induced lipid peroxidation using an innovative method, the HPLC-TBARS-EVSC (high-performance liquid chromatography-thiobarbituric acid reactive substances- stratum corneum), and a stress test using methyl nicotinate and laser Doppler flowmetry to establish the samples' topical anti-inflammatory ability. An aqueous gel containing 0.1% / of each polyphenol was formulated using ammonium acryloyldimethyltaurate/VP copolymer. Through the utilization of the HET-CAM assay for safety assessment, chlorogenic acid, apigenin, kaempferol, and naringenin were classified as non-irritating active ingredients. This classification was based on their lack of adverse reactions within the vascularization of the chorioallantoic membrane. To assess the protective capabilities of four polyphenols against lipid peroxidation in the stratum corneum, the HPLC-TBARS-EVSC protocol was conducted. It was observed that only naringenin exhibited a significant reduction in epidermal lipoperoxidation, indicating superior anti-radical potential. Conversely, chlorogenic acid, apigenin, and kaempferol displayed a pro-oxidant profile under the specified test conditions. The laser Doppler flowmetry suggested the anti-inflammatory potential of naringenin, kaempferol, and chlorogenic acid, with naringenin showing superior efficacy involving all parameters quantified. Naringenin emerged as the only polyphenol capable of reducing the intensity of the inflammatory response induced by methyl nicotinate solution in the participants, compared to the blank gel and the untreated area. This comprehensive investigation underscores the diverse protective roles of polyphenols in skin health, emphasizing naringenin's notable anti-radical and anti-inflammatory properties.
PubMed: 38831914
DOI: 10.3389/fchem.2024.1400881 -
Journal of Agricultural and Food... Jun 20242-(2-Phenylethyl)chromones (PECs) are the primary constituents responsible for the promising pharmacological activities and unique fragrance of agarwood. However, the...
2-(2-Phenylethyl)chromones (PECs) are the primary constituents responsible for the promising pharmacological activities and unique fragrance of agarwood. However, the -methyltransferases (OMTs) involved in the formation of diverse methylated PECs have not been reported. In this study, we identified one Mg-dependent caffeoyl-CoA-OMT subfamily enzyme (AsOMT1) and three caffeic acid-OMT subfamily enzymes (AsOMT2-4) from NaCl-treated calli. AsOMT1 not only converts caffeoyl-CoA to feruloyl-CoA but also performs nonregioselective methylation at either the 6-OH or 7-OH position of 6,7-dihydroxy-PEC. On the other hand, AsOMT2-4 preferentially utilizes PECs as substrates to produce structurally diverse methylated PECs. Additionally, AsOMT2-4 also accepts nonPEC-type substrates such as caffeic acid and apigenin to generate methylated products. Protein structure prediction and site-directed mutagenesis revealed that residues of L313 and I318 in AsOMT3, as well as S292 and F313 in AsOMT4 determine the distinct regioselectivity of these two OMTs toward apigenin. These findings provide important biochemical evidence of the remarkable structural diversity of PECs in agarwood.
Topics: Methyltransferases; Thymelaeaceae; Plant Proteins; Wood; Substrate Specificity; Caffeic Acids; Methylation; Flavonoids
PubMed: 38830127
DOI: 10.1021/acs.jafc.4c02440 -
International Journal of Environmental... Jun 2024In our study, the protective role of synthetic aromatase inhibitors anastrozole (ANS), letrozole (LTZ) and exemestane (EXM) and natural aromatase inhibitors resveratrol...
In our study, the protective role of synthetic aromatase inhibitors anastrozole (ANS), letrozole (LTZ) and exemestane (EXM) and natural aromatase inhibitors resveratrol (RSV) and apigenin (APG) against testicular failure caused by exposure to Bisphenol A (BPA) was investigated. The epididymal sperm concentration, sperm motility and sperm morphology were determined. Oxidative stress and inflammatory response parameters were examined and histological examinations were performed in testicular tissues. Our results revealed that BPA exposure decreased serum testosterone and estrogen levels, increased FSH and LH levels ( < 0.05). BPA has been found to increase oxidative stress and inflammatory response and disrupt the histological structure. Also, BPA exposure decreased testicular weight, epididymal sperm concentration and motility, and increased abnormal sperm rate ( < 0.05). These results show that ANS, LTZ and RSV treatments reduce the BPA-induced testicular damage.
PubMed: 38825800
DOI: 10.1080/09603123.2024.2362810 -
Cancer Letters Aug 2024Extracellular vesicles are essential for intercellular communication and are involved in tumor progression. Inhibiting the direct release of extracellular vesicles seems...
Extracellular vesicles are essential for intercellular communication and are involved in tumor progression. Inhibiting the direct release of extracellular vesicles seems to be an effective strategy in inhibiting tumor progression, but lacks of investigation. Here, we report a natural flavonoid compound, apigenin, could significantly inhibit the growth of hepatocellular carcinoma by preventing microvesicle secretion. Mechanistically, apigenin primarily targets the guanine nucleotide exchange factor ARHGEF1, inhibiting the activity of small G protein Cdc42, which is essential in regulating the release of microvesicles from tumor cells. In turn, this inhibits tumor angiogenesis related to VEGF transported on microvesicles, ultimately impeding tumor progression. Collectively, these findings highlight the therapeutic potential of apigenin and shed light on its anticancer mechanisms through inhibiting microvesicle biogenesis, providing a solid foundation for the refinement and practical application of apigenin.
Topics: Humans; Neovascularization, Pathologic; Animals; Apigenin; Liver Neoplasms; Rho Guanine Nucleotide Exchange Factors; Cell-Derived Microparticles; Carcinoma, Hepatocellular; Mice; Cell Line, Tumor; cdc42 GTP-Binding Protein; Cell Proliferation; Xenograft Model Antitumor Assays; Human Umbilical Vein Endothelial Cells; Hep G2 Cells; Mice, Nude; Angiogenesis
PubMed: 38823764
DOI: 10.1016/j.canlet.2024.216961 -
Journal of Pharmaceutical and... Sep 2024The proprietary Chinese medicine Jinkui Shenqi Pill (PCM-JKSQP) is a classic compound used for the effective clinical treatment of kidney yang deficiency syndrome...
Integrated serum pharmacochemistry, network pharmacology, and pharmacokinetics to clarify the effective components and pharmacological mechanisms of the proprietary Chinese medicine Jinkui Shenqi Pill in treating kidney yang deficiency syndrome.
The proprietary Chinese medicine Jinkui Shenqi Pill (PCM-JKSQP) is a classic compound used for the effective clinical treatment of kidney yang deficiency syndrome (KYDS), a metabolic disease accompanied by kidney injury. However, its active ingredients and therapeutic mechanisms are not clear. This study employed serum pharmacochemistry, network pharmacology, and pharmacokinetics (PK) to identify the bioactive components of PCM-JKSQP and preliminarily clarify its mechanism in treating KYDS. One hundred and forty chemical components of PCM-JKSQP, 47 (20 parent compouds and 27 metabolites) of which were absorbed into the blood, were identified by ultra-high-performance liquid chromatography-quadrupole-orbitrap high-resolution mass spectrometry (UHPLC-Q-Orbitrap HRMS). The topological parameters of network pharmacology and high concentrations in blood found six parent components as PK markers (cinnamic acid, paeonol, loganin, morroniside, apigenin, and poricoic acid A). PK analysis further identified these six compounds as active ingredients. Protein-protein interaction (PPI) analysis and molecular docking simulation predicted and verified eight core targets (TP53, ESR1, CTNNB1, EP300, EGFR, AKT1, ERBB2, and TNF). Most were concentrated in the MAPK, HIF-1, and PI3K-AKT signaling pathways, indicating that these six active ingredients may mainly exert therapeutic effects through these three pathways via their core targets. The PK results also showed these six components were absorbed quickly, although cinnamic acid and paeonol were rapidly metabolized, with a short half-life and retention time. Loganin and morroniside did not have high peak concentrations, and apigenin and poricoic acid A had long retention times. This study provides a new overall perspective for exploring the bioactive components and mechanisms underlying the effects of PCM-JKSQP in treating KYDS.
Topics: Drugs, Chinese Herbal; Yang Deficiency; Network Pharmacology; Animals; Chromatography, High Pressure Liquid; Molecular Docking Simulation; Male; Medicine, Chinese Traditional; Kidney; Rats; Protein Interaction Maps; Kidney Diseases; Rats, Sprague-Dawley; Humans
PubMed: 38820836
DOI: 10.1016/j.jpba.2024.116251 -
Toxicology in Vitro : An International... May 2024Epigenetic methods to prevent the reproductive toxicity of oil-related environmental contaminants are currently unavailable. The present study aimed to examine the...
Epigenetic methods to prevent the reproductive toxicity of oil-related environmental contaminants are currently unavailable. The present study aimed to examine the ability of the microRNA miR-152 to mitigate the effects of benzene on ovarian cells. Porcine ovarian granulosa cells transfected or not transfected with miR-152 mimics were cultured with or without benzene (0, 10 and 100 ng/ml). The expression of miR-152; viability; proliferation (cell proliferation and expression of mRNAs and accumulation of PCNA and cyclin B1); apoptosis (expression of mRNAs and accumulation of bax and caspase 3; and the proportion of cells with fragmented DNA); and release of progesterone, estradiol and IGF-I were analyzed via RT-qPCR; the Trypan blue exclusion test; quantitative immunocytochemistry; BrdU; XTT; TUNEL assays; and ELISA. Administration of benzene promoted the expression of apoptosis markers and reduced cell viability, all measured markers of proliferation, the release of steroid hormones and IGF-I. Overexpression of miR-152 was associated with increased cell viability, proliferation, progesterone and IGF-I release and reduced apoptosis and estradiol output. Moreover, miR-152 mitigated or prevented the effects of benzene on all the measured parameters in addition to estradiol release. The present observations suggest the toxic effect of benzene and the stimulatory influence of miR-152 on ovarian cell functions. Moreover, this is the first demonstration of the ability of miRNAs to mitigate and prevent the reproductive toxicity of benzene.
PubMed: 38815736
DOI: 10.1016/j.tiv.2024.105855 -
Drug Development Research Jun 2024Apigenin, a natural flavonoid compound found in chamomile (Matricaia chamomilla L.) from the Asteraceae family, has been shown in our previous study to possess...
Apigenin, a natural flavonoid compound found in chamomile (Matricaia chamomilla L.) from the Asteraceae family, has been shown in our previous study to possess antimyocardial hypertrophy and anti-cardiac fibrosis effects. However, its effects and mechanisms on the pyroptosis of cardiomyocytes induced by doxorubicin (DOX) are poorly understood. The objective of this study was to investigate the role of GSK-3β and the effects of apigenin in DOX-induced cardiotoxicity. H9c2 cells stimulated with DOX were treated with SB216763 and apigenin. Additionally, a mouse model of DOX-induced cardiotoxicity was prepared and further treated with apigenin and SB216763 for 30 days. The findings revealed that treatment with SB216763 or apigenin resulted in a significant reduction in the levels of pyroptosis-related factors. Furthermore, the phosphorylation of GSK-3β was enhanced while the phosphorylation of nuclear factor-kB (NF-κB) p65 was reduced following treatment with either SB216763 or apigenin. Conversely, the effects of apigenin treatment were nullified in siRNA-GSK-3β-transfected cells. Results from computer simulation and molecular docking analysis supported that apigenin could directly target the regulation of GSK-3β. Therefore, our study confirmed that the inhibition of GSK-3β and treatment with apigenin effectively suppressed the pyroptosis of cardiomyocytes in both DOX-stimulated H9c2 cells and mice. These benefits may be attributed in part to the decrease in GSK-3β expression and subsequent reduction in NF-κB p65 activation. Overall, our findings revealed that the pharmacological targeting of GSK-3β may offer a promising therapeutic approach for alleviating DOX-induced cardiotoxicity.
Topics: Apigenin; Animals; Doxorubicin; Glycogen Synthase Kinase 3 beta; Pyroptosis; Myocytes, Cardiac; Mice; Cell Line; Male; Rats; Cardiotoxicity; Mice, Inbred C57BL; Molecular Docking Simulation; Indoles; Maleimides
PubMed: 38812449
DOI: 10.1002/ddr.22196