Geniposidic acid(GA), a natural iridoid, exists in the roots, stems, leaves, flowers, bark, fruits, and seeds of medicinal plants of Rubiaceae, Eucommiaceae, and Plantaginaceae. Modern pharmacological studies have revealed that GA has multiple pharmacological activities, including organ-protective, anti-inflammatory, antioxidative, anti-osteoporosis, anti-neurodegenerative, and anti-cardiovascular effects. GA can enhance cell/organism defenses by upregulating key anti-inflammatory and antioxidant cytokines, while downregulating key node proteins in pro-inflammatory signaling pathways such as AhR and TLR4/MyD88, thereby exerting pharmacological effects such as organ protection. Pharmacokinetic investigations have suggested that after oral administration, GA can be distributed in multiple organs(kidney, liver, heart, spleen, lung, etc.). In addition, the pharmacokinetic behavior of GA could be significantly altered under disease conditions, as demonstrated by a marked increase in systematic exposure. This article comprehensively summarizes the reported pharmacological activities and mechanisms and systematically analyzes the pharmacokinetic characteristics and key parameters of GA, with the aim of providing a theoretical basis and scientific reference for the precise clinical application of GA-related Chinese patent medicines, as well as for the investigation and development of innovative drugs based on GA.
Humans ; Drugs, Chinese Herbal/chemistry* ; Animals ; Iridoid Glucosides/chemistry* ; Plants, Medicinal/chemistry* ; Anti-Inflammatory Agents/pharmacology*

This study aimed to explore the mechanisms and molecular targets of total flavones of Abelmoschus manihot(TFA) plus empagliflozin(EM) in attenuating diabetic tubulopathy(DT) by targeting mitochondrial homeostasis and pyroptosis-apoptosis-necroptosis(PANoptosis). In the in vivo study, the authors established the DT rat models through a combination of uninephrectomy, administration of streptozotocin via intraperitoneal injections, and exposure to a high-fat diet. Following modeling successfully, the DT rat models received either TFA, EM, TFA+EM, or saline(as a vehicle) by gavage for eight weeks, respectively. In the in vitro study, the authors subjected the NRK52E cells with or without knock-down Z-DNA binding protein 1(ZBP1) to a high-glucose(HG) environment and various treatments including TFA, EM, and TFA+EM. In the in vivo and in vitro studies, The authors investigated the relative characteristics of renal tubular injury and renal tubular epithelial cells damage induced by reactive oxygen species(ROS), analyzed the relative characteristics of renal tubular PANoptosis and ZBP1-mediatted PANoptosis in renal tubular epithelial cells, and compared the relative characteristics of the protein expression levels of marked molecules of mitochondrial fission in the kidneys and mitochondrial homeostasis in renal tubular epithelial cells, respectively. Furthermore, in the network pharmacology study, the authors predicted and screened targets of TFA and EM using HERB and SwissTargetPrediction databases; The screened chemical constituents and targets of TFA and EM were constructed the relative network using Cytoscape 3.7.2 network graphics software; The relative targets of DT were integrated using OMIM and GeneCards databases; The intersecting targets of TFA, EM, and DT were enriched and analyzed signaling pathways by Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG) software using DAVID database. In vivo study results showed that TFA+EM could improve renal tubular injury, the protein expression levels and characteristics of key signaling molecules in PANoptosis pathway in the kidneys, and the protein expression levels of marked molecules of mitochondrial fission in the kidneys. And that, the ameliorative effects in vivo of TFA+EM were both superior to TFA or EM. Network pharmacology study results showed that TFA+EM treated DT by regulating the PANoptosis signaling pathway. In vitro study results showed that TFA+EM could improve ROS-induced cell injury, ZBP1-mediatted PANoptosis, and mitochondrial homeostasis in renal tubular epithelial cells under a state of HG, including the protein expression levels of marked molecules of mitochondrial fission, mitochondrial ultrastructure, and membrane potential level. And that, the ameliorative effects in vitro of TFA+EM were both superior to TFA or EM. More importantly, using the NRK52E cells with knock-down ZBP1, the authors found that, indeed, ZBP1 was mediated PANoptosis in renal tubular epithelial cells as an upstream factor. In addition, TFA+EM could regulate the protein expression levels of marked signaling molecules of PANoptosis by targeting ZBP1. In summary, this study clarified that TFA+EM, different from TFA or EM, could attenuate DT with multiple targets by ameliorating mitochondrial homeostasis and inhibiting ZBP1-mediated PANoptosis. These findings provide the clear pharmacological evidence for the clinical treatment of DT with a novel strategy of TFA+EM, which is named "coordinated traditional Chinese and western medicine".
Animals ; Rats ; Mitochondria/metabolism* ; Benzhydryl Compounds/administration & dosage* ; Glucosides/administration & dosage* ; Abelmoschus/chemistry* ; Male ; Homeostasis/drug effects* ; Flavones/administration & dosage* ; Rats, Sprague-Dawley ; Diabetic Nephropathies/physiopathology* ; Drugs, Chinese Herbal/administration & dosage* ; DNA-Binding Proteins/genetics* ; Humans ; Apoptosis/drug effects*

The molecular mechanism of verbascoside(OC1) in promoting acetylcholine(ACh) release in the pathogenesis of Alzheimer's disease(AD) was studied. Adrenal pheochromocytoma cells(PC12) of rats induced by β-amyloid protein(1-42)(Aβ_(1-42)) were used as AD models in vitro and were divided into control group, model group(Aβ_(1-42) 10 μmol·L~(-1)), OC1 treatment group(2 and 10 μg·mL~(-1)). The effect of OC1 on phosphorylated proteins in AD models was analyzed by whole protein phosphorylation quantitative omics, and the selectivity of OC1 for calcium channel subtypes was virtually screened in combination with computer-aided drug design. The fluorescence probe Fluo-3/AM was used to detect Ca~(2+) concentration in cells. Western blot analysis was performed to detect the effects of OC1 on the expression of phosphorylated calmodulin-dependent protein kinase Ⅱ(p-CaMKⅡ, Thr286) and synaptic vesicle-related proteins, and UPLC/Q Exactive MS was used to detect the effects of OC1 on ACh release in AD models. The effects of OC1 on acetylcholine esterase(AChE) activity in AD models were detected. The results showed that the differentially modified proteins in the model group and the OC1 treatment group were related to calcium channel activation at three levels: GO classification, KEGG pathway, and protein domain. The results of molecular docking revealed the dominant role of L-type calcium channels. Fluo-3/AM fluorescence intensity decreased under the presence of Ca~(2+) chelating agent ethylene glycol tetraacetic acid(EGTA), L-type calcium channel blocker verapamil, and N-type calcium channel blocker conotoxin, and the effect of verapamil was stronger than that of conotoxin. This confirmed that OC1 promoted extracellular Ca~(2+) influx mainly through its interaction with L-type calcium channel protein. In addition, proteomic analysis and Western blot results showed that the expression of p-CaMKⅡ and downstream vesicle-related proteins was up-regulated after OC1 treatment, indicating that OC1 acted on vesicle-related proteins by activating CaMKⅡ and participated in synaptic remodeling and transmitter release, thus affecting learning and memory. OC1 also decreased the activity of AChE and prolonged the action time of ACh in synaptic gaps.
Animals ; Rats ; Glucosides/administration & dosage* ; Acetylcholine/metabolism* ; Alzheimer Disease/genetics* ; PC12 Cells ; Phenols/chemistry* ; Neurotransmitter Agents/metabolism* ; Drugs, Chinese Herbal ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/genetics* ; Humans ; Phosphorylation/drug effects* ; Calcium/metabolism* ; Polyphenols

This study investigated the regulatory potential of salidroside (SAL), a primary active compound in Rhodiola rosea L., on osteoclast differentiation by modulating the hypoxia-inducible factor 1-alpha (HIF-1a) pathway in osteoblasts. Luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay were employed to validate whether the receptor activator of nuclear factor-?B ligand (RANKL) is the downstream target gene of HIF-1a in osteoblasts. The study also utilized lipopolysaccharide (LPS)-induced mouse osteolysis to examine the impact of SAL on osteolysis in vivo. Furthermore, conditioned medium (CM) from SAL-pretreated osteoblasts was used to investigate the paracrine effects on osteoclastogenesis through the HIF-1a pathway. Hypoxic condition-induced overexpression of HIF-1a upregulated RANKL levels by binding to the RANKL promoter and enhancing transcription in osteoblastic cells. In vivo, SAL significantly alleviated bone tissue hypoxia and decreased the expression of HIF-1a by downregulating the expression of RANKL, vascular endothelial growth factor (VEGF), interleukin 6 (IL-6), and angiopoietin-like 4 (ANGPTL4). In the paracrine experiment, conditioned media from SAL-pretreated osteoblasts inhibited differentiation through the HIF-1a/RANKL, VEGF, IL-6, and ANGPTL4 pathways. RANKL emerges as the downstream target gene regulated by HIF-1a in osteoblasts. SAL significantly alleviates bone tissue hypoxia and bone loss in LPS-induced osteolysis through the HIF-1a/RANKL, VEGF, IL-6, and ANGPTL4 pathways. SAL inhibits osteoclast differentiation by regulating osteoblast paracrine secretion.
Animals ; Osteoblasts/cytology* ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics* ; Glucosides/administration & dosage* ; Cell Differentiation/drug effects* ; Phenols/administration & dosage* ; Mice ; Osteoclasts/metabolism* ; RANK Ligand/genetics* ; Rhodiola/chemistry* ; Osteogenesis/drug effects* ; Signal Transduction/drug effects* ; Interleukin-6/genetics* ; Male ; RAW 264.7 Cells ; Osteolysis/genetics* ; Humans ; Mice, Inbred C57BL

Traditional Chinese medicine of Polygonum cuspidatum has been utilized in China for thousands of years. Its primary active compound, polydatin, exhibits a variety of pharmacological effects including the regulation of glucose and lipid metabolism, suppression of cough and asthma, as well as antibacterial and anti-inflammatory properties. However, conventional methods for polydatin production are inadequate to satisfy the market demand. This study aims to explore the green and efficient preparation of polydatin. With resveratrol as the substrate, we efficiently synthesized polydatin by using the triple mutant IGW (Y14I/I62G/M315W) of the glycosyltransferase UGT_BS based on a strategy of two-enzyme coupled with one-pot and realized the recycling of uridine diphosphate-glucose (UDPG). The conditions of the two-enzyme reaction were optimized. Under the conditions of 35 ℃, pH 8.0, IGW: AtSuSy1 activity ratio of 3:4, dimethyl sulfoxide (DMSO) volume fraction of 5%, uridine diphosphate (UDP) concentration of 0.10 mmol/L, and sucrose concentration of 0.6 mol/L, the conversion of 2 mmol/L resveratrol reached 80.6% within 1 h, and the proportion of polydatin was over 90%. This study achieved the recycling of UDPG via a two-enzyme coupling system and shortened the reaction time. At the same time, the fed-batch strategy was adopted, and the yield of polydatin reached 6.28 g/L after 24 h in the one-pot coupling reaction, which provided a new strategy for green and efficient preparation of polydatin.
Stilbenes/chemistry* ; Glucosides/biosynthesis* ; Resveratrol ; Fallopia japonica/chemistry* ; Glycosyltransferases/genetics*

Chromatographic techniques were employed to separate and purify the active components with antioxidant activity from the aboveground part of Lythrum salicaria. The data of 1D/2D NMR, optical rotation, and high-resolution mass spectrometry were used to identify the purified compounds. Six phenolic glucosides were identified, including 6'-(p-methoxyphenyl)gallate-7-O-β-D-glucopyranoside(1), 6'-ethyl-p-hydroxyphenylethanol-β-D-glucopyranoside(2), 3,4,5-trimethoxyphenol-β-D-glucopyranoside(3), 3,4,5-trimethoxyphenyl 1-O-β-apiofuranosyl(1″→6')-β-glucopyranoside(4), benzylalcohol O-α-L-arabinopyranosyl(1→6)-β-D-glucopyranoside(5), and 6'-acetylethanol-β-D-glucopyranoside(6). Compounds 1 and 2 were novel phenolic glucosides, and compounds 3-6 were isolated from Lythrum for the first time. Furthermore, the antioxidant activities of compounds 1-6 were evaluated. Compound 1 showed potent antioxidant activity, with the half maximal inhibitory concentration(IC_(50)) of 0.16 mmol·L~(-1), which was stronger than that of the positive control trolox with the IC_(50) of 0.24 mmol·L~(-1).
Antioxidants/isolation & purification* ; Glucosides/pharmacology* ; Phenols/isolation & purification* ; Lythrum/chemistry* ; Molecular Structure ; Drugs, Chinese Herbal/pharmacology* ; Magnetic Resonance Spectroscopy

Ten lignans were isolated from the ethanol extract of stems and branches of Rhododendron ovatum through column chromatography over silica gel, ODS, Sephadex LH-20, and MCI-gel resin and semi-preparative RP-HPLC. The structures of all compounds were elucidated by extensive spectroscopic data analysis(UV, IR, HR-ESI-MS, ECD and NMR) as(-)-4-epi-lyoniresinol-9'-O-α-L-rhamnopyranoside(1),(+)-lyoniresinol-3α-O-α-L-rhamnopyranoside(2),(+)-5'-methoxyisolariciresinol-9'-O-α-L-rhamnopyranoside(3),(-)-lyoniresinol-3α-O-β-D-glucopyranoside(4),(+)-lyoniresinol-3α-O-β-D-glucopyranoside(5),(-)-4-epi-lyoniresinol-9'-O-β-D-glucopyransoide(6), racemiside(7), neociwujiaphenol(8),(+)-syringaresinol(9), and homohesperitin(10). Among them, compound 1 was a new aryltetralin-type lignan. All the isolated lignans were tested for antioxidant activities in Fe~(2+)-cysteine induced rat liver microsomal lipid peroxidation in vitro, and compounds 8 and 9 showed antioxidant activities on the formation of malondiadehyde(MDA) in rat liver microsomes at 1×10~(-5) mol·L~(-1), with significant inhibitory rates of 75.20% and 91.12%, respectively.
Animals ; Rats ; Glucosides/chemistry* ; Rhododendron ; Antioxidants/pharmacology* ; Lignans/chemistry* ; Plant Stems

Chemical fractionation of the n-BuOH partition, which was generated from the EtOH extract of the flower buds of Tussilago farfara, afforded a series of polar constituents including four new sesquiterpenoids (1-4), one new sesquiterpenoid glucoside (5) and one known analogue (6) of the eudesmane type, as well as five known quinic acid derivatives (7-11). Structures of the new compounds were unambiguously characterized by detailed spectroscopic analyses, with their absolute configurations being established by X-ray crystallography, electronic circular dichroism (ECD) calculation and induced ECD experiments. The inhibitory effect of all the isolates against LPS-induced NO production in murine RAW264.7 macrophages was evaluated, with isochlorogenic acid A (7) showing significant inhibitory activity.
Animals ; Flowers/chemistry* ; Glucosides/pharmacology* ; Mice ; Sesquiterpenes/pharmacology* ; Sesquiterpenes, Eudesmane/pharmacology* ; Tussilago/chemistry*

A series of 26 novel derivatives have been synthesized through structural modification of gentiopicroside, a lead COX-2 inhibitor. And their in vivo and in vitro anti-inflammatory activities have been investigated. The in vitro anti-inflammatory activities were evaluated against NO, PGE₂, and IL-6 production in the mouse macrophage cell line RAW264.7 stimulated by LPS. Results showed that most compounds had good inhibitory activity. The in vivo inhibitory activities were further tested against xylene-induced mouse ear swelling. Results demonstrated that several compounds were more active than the parent compound gentiopicroside. The inhibition rate of the most active compound P23 (57.26%) was higher than positive control drug celecoxib (46.05%) at dose 0.28 mmol·kg^-1. Molecular docking suggested that these compounds might bind to COX-2 and iNOS. Some of them, e.g P7, P14, P16, P21, P23, and P24, had high docking scores in accordance with their potency of the anti-inflammatory activitiy, that downregulation of the inflammatory factors, NO, PGE₂, and IL-6, was possibly associated with the suppression of iNOS and COX-2. Therefore, these gentiopicroside derivatives may represent a novel class of COX-2 and iNOS inhibitors.
Animals ; Anti-Inflammatory Agents/pharmacology* ; Cyclooxygenase 2/chemistry* ; Dinoprostone ; Interleukin-6/metabolism* ; Iridoid Glucosides ; Mice ; Molecular Docking Simulation ; Pyridinolcarbamate

This study aims to explore the key factors influencing the processing of braised Rehmanniae Radix, optimize the processing, and determine the correlation between the components in different processed products and chroma values, which is expected to add quantitative indexes for the processing of braised Rehmanniae Radix and better control the processing. The weights of the indexes catalpol, rehmannioside D, verbascoside, isoacteoside, 5-hydroxymethylfurfural, reducing sugar, and appearance were calculated based on analytic hierarchy process(AHP) in combination with coefficient of variation, and the overall desirability(OD) was obtained. Box-Behnken design was used to explore the optimal amount of water added, time for soaking with rice wine, and steaming time in the processing of braised Rehmanniae Radix. Colorimeter was employed to determine the chroma of 17 samples and raw samples, and SPSS, Prism, and other software to investigate the correlation between the components in braised Rehmanniae Radix and the chroma values. The results showed that each factor influenced the processing, and the influence followed the order of steaming time>amount of water added>time for soaking with rice wine. The optimal processing process is as below: A total of 100 g medicinal material was added with 7 times of water, followed by soaking with rice wine for 5 h and steaming in a pot for 6 h. The correlation analysis suggested the extremely significantly positive correlation between L~* and content of catalpol, between a~* and 5-hydroxymethylfurfural content, and between b~* and catalpol content, and the extremely significantly negative correlation between L~* and the content of 5-hydroxymethylfurfural and reducing sugar, and between b~* and the content of 5-hydroxymethylfural and reducing sugar. In this experiment, response surface methodology was used to optimize the processing technology of braised Rehmanniae Radix and the optimized process was rational and feasible. The content of chemical components in braised Rehmanniae Radix was significantly correlated with the chroma. This study provided a new method for the quality evaluation of braised Rehmanniae Radix.
Drugs, Chinese Herbal/chemistry* ; Excipients ; Furaldehyde/analogs & derivatives* ; Iridoid Glucosides ; Plant Extracts ; Rehmannia/chemistry* ; Sugars ; Technology ; Water