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A review of the ethnopharmacology, phytochemistry, pharmacology and toxicology of Fructus Gardeniae (Zhi-zi)
Abstract
Ethnopharmacological relevance
Fructus Gardeniae (FG) is the dried fruit of Gardenia jasminoides Ellis (GjE), which belongs to the family Rubiaceae. FG has a long history of use as a herb, and was originally recorded in Sheng Nong's herbal classic. FG has also been widely used as both medicine and food.
Aim of study
This review aimed to provide a systematic and comprehensive analysis of the current research progress of FG in terms of ethnopharmacology, phytochemistry, pharmacology and toxicity, to provide new insights and extensive field of view for subsequent studies.
Methods
Scientific databases, including CNKI, VIP (Chinese literature), PubMed, Science Direct, Elsevier and Google Scholar (English literatures) were searched to gather data about FG and its main active ingredients such as geniposide and genipin (only regarding toxicity).
Results
Many chemical constituents have been identified from the fruit of GjE, including iridoids, terpenoids, flavonoids, organic acids, volatile oils and others. The constituents of different parts of FG and processed FG are different from those of whole FG. FG extract and its main active constituents have been reported to have pharmacological properties such as hepatoprotective, choleretic, anti-inflammatory, antioxidant, neuroprotective, anti-diabetic, anti-apoptotic and antitumor activities. However, an increasing number of studies have shown that FG induces multiple organ injury, especially causing hepatotoxicity and nephrotoxicity, which could increase the risk during clinical use. The available literature shows that geniposide, a major active component of FG and a critical marker for its quality, is associated with the pharmacology and toxicity of FG.
Conclusion
Although a large number of studies examining FG have been published, issues remain. In the aspect of FG's pharmacology, the traditional efficacy and modern pharmacological effects of FG should be combined, which to broadens clinical application prospects. In addition, few studies have assessed the toxicity of FG. Toxicity assessment of FG should tackle various aspects, including compatibility, processing and the symptom-based prescription theory, in addition to over-dosage or long-term use, for a reasonable clinical use.
... Modern phytochemical analyses have revealed that GF contains four main types of chemical components in relatively high concentrations: iridoids, terpenoids, organic acids, and flavonoids [15]. The predominant iridoids in GF include geniposide, gardenoside, and geniposidic acid, and geniposide serves as a critical marker of the quality of GF [16]. Diterpenes in GF are mainly composed of crocin compounds, most of which are pigments. ...
... Diterpenes in GF are mainly composed of crocin compounds, most of which are pigments. Among the organic acids contained in gardenia, chlorogenic acid has the highest content [16]. Furthermore, a previous study revealed that GF is rich in various types of pectin, including water-soluble pectin, acid-soluble pectin, xylan/alkaline-soluble pectin, and cellulose [17]. ...
The present study aimed to explore the effect of GF powder on the growth performance, diarrhea rate, antioxidant and immune capacity, and intestinal health of weaned piglets. A total of 144 weaned piglets (8.29 ± 0.11 kg) at 21 d old were randomly assigned to four groups, with each treatment consisting of six replicate pens, with six piglets per pen, and each pen containing three barrows and three gilts. The piglets were fed a basal diet supplement with 0%, 0.4%, 0.6%, and 0.8% GF powder (n = 36). Our results indicated that compared with the basal diet, the F/G and diarrhea rate were remarkably decreased in the 0.8% GF group (p < 0.05). Serum biochemical parameters showed that supplementation with GF significantly increased the content of HDL-C (0.6 and 0.8% levels), IL-6 (0.8% level), IL-10 (0.4, 0.6, and 0.8% levels), Ig G (0.4% level), and Ig A (0.8% level) compared with the basal diet (p < 0.05). The index of antioxidant capacity showed that compared with a basal diet, supplementation with GF significantly decreased serum MDA content (0.4% and 0.8% levels) and jejunal and ileal MDA content (0.4%, 0.6%, and 0.8% levels) (p < 0.05). Additionally, compared with the basal diet, supplementation with GF significantly increased serum and ileal T-AOC content (0.4%, 0.6%, and 0.8% levels), serum T-SOD content (0.4% and 0.8% levels), ileal T-SOD content (0.4%, 0.6%, and 0.8% levels), CAT content (0.4%, 0.6%, and 0.8% levels), and jejunal GSH-Px content (0.8% level) (p < 0.05). The results of gene expression indicate that compared with the basal diet, supplementation with GF significantly increased Nrf 2 (0.4% level), NQO (0.4% level), SOD 1 (0.4% and 0.8% levels), and GCLC (0.4% level) and GCLM (0.8% level) abundance in jejunal mucosa; supplementation with GF significantly increased Nrf 2 (0.4%, 0.6%, and 0.8% levels), HO-1 (0.4% level), NQO (0.8% level), SOD 1 (0.4% and 0.8% levels), and GCLC (0.4% level) and GCLM (0.8% level) abundance in ileal mucosa (p < 0.05). Ulteriorly, the present results indicate that supplementation with GF at the 0.8% level significantly increased the villus height in the jejunum and ileum as well as the villus/crypt ratio in the ileum compared with the basal diet (p < 0.05). Compared with the basal diet, 0.4% GF significantly increased Occludin gene expression in ileal mucosa (p < 0.05), 0.6% GF significantly increased ZO-1, Claudin-1, and Occludin gene expression in jejunal mucosa (p < 0.05), and 0.8% GF significantly increased ZO-1 and Occludin gene expression in jejunal mucosa along with Occludin expression in ileal mucosa (p < 0.05). Furthermore, colonic microbiota composition showed that Shannon, observed species, and Chao 1 indices were significantly increased in the 0.8% GF group compared with the basal diet (p < 0.05). At the phylum level, in comparison with the basal diet, the relative abundance of Firmicutes significantly decreased in the 0.4%, 0.6%, and 0.8% GF groups, and Bacteroidetes increased in the 0.8% GF group (p < 0.05). At the genus level, compared with the basal diet, 0.6% and 0.8% GF significantly increased Prevotella abundance, and 0.6% GF significantly decreased Coprococcus abundance (p < 0.05). At the species level, compared with the basal diet, 0.8% GF significantly increased Prevotella copri abundance, and 0.4%, 0.6%, and 0.8% GF significantly decreased Blautia obeum abundance (p < 0.05). In summary, a dietary supplement with 0.8% Gardeniae Fructus powder significantly decreased the F/G and diarrhea rate and improved antioxidant capacity and intestinal barrier function, which may be associated with the improvement of the relative abundance of Prevotella copri. These findings indicate that Gardeniae Fructus powder may be used as a feed additive in swine weaning.
... Gardeniae Fructus, the dried ripe fruit of Gardenia jasminoides Ellis, is one of the most commonly used traditional Chinese medicine. Iridoids, which include geniposide and genipin, and crocins have been identified as the major bioactive constituents in Gardeniae Fructus ( Fig. 1a and Supplementary Fig. 1) [12]. Although both geniposide and genipin exert anti-proliferative activities, genipin was reported to work more efficiently in many types of cancer cells [13][14][15]. ...
... Genipin, the most active constituent of Gardeniae Fructus, has been reported to exert anti-cancer activities in various malignancies [12,14,15]. In this study, we first validated the inhibitory effects of genipin on cell viability and proliferation of GC cells. ...
Ferroptosis has been demonstrated to suppress cancer development and is targeted for cancer therapy. Genipin, an iridoid constituent in Gardeniae Fructus, has been reported to exert anti-cancer abilities. However, whether genipin could induce ferroptosis remains unclear. The purpose of this study is to explore the anti-gastric cancer (GC) effects of genipin by inducing ferroptosis and to identify the potential targets. CCK-8 and colony formation assays were performed to evaluate the anti-GC effects of genipin. Flowcytometry and western blot were used to indicate ferroptosis-inducing ability of genipin. The potential targets of genipin were analyzed by network pharmacology, screened using UALCAN and KM-plotter database and evaluated by molecular docking. The results showed that genipin inhibited cell viability and proliferation of GC cells. Genipin treatment decreased levels of GPX4 and SLC7A11, induced accumulation of lipid peroxidation intracellularly and led to ferroptosis in GC cells. Network pharmacology analysis identified that lipid- and ROS-related pathways involved in ferroptosis ranked high among genipin-GC common targets. Data from UALCAN and KM-plotter database demonstrated that expression levels of ferroptosis-related targets, including AURKA, BCAT2, DHODH, and GPI, increased in GC tissues and the higher levels of the above four targets were related to tumor stage, tumor grade, and poor prognosis. Among these four targets, AURKA, BCAT2, and DHODH were confirmed by molecular docking with binding energies less than − 5. Taken together, our study demonstrates that genipin could exert anti-GC ability by inducing ferroptosis and provides evidence for the potential application of genipin in GC treatment.
... However, high-dose consumption of GF can result in damage to multiple organs, such as the liver and kidneys [87,88]. The toxicity mechanism of IMP is as follows: (I) Geniposide is the main component of GF, metabolized to genipin by intestinal flora, amino acids, and sulfuric acids. ...
Idiopathic mesenteric phlebosclerosis (IMP) is a rare form of ischemic colitis that predominantly impacts Asian populations. Despite some recognizable signs, there is a significant lack of awareness about IMP. In this review, we explore the etiology, pathogenesis, imaging manifestations, endoscopic traits, and therapeutic modalities of IMP. In addition, we discuss the deficiencies in the current comprehension of IMP and the potential research orientations in future.
... Xiao et al. [13] focused on two major phytochemicals of GJEO, genipin and crocin, which possess potent medicinal properties. Numerous chemical components have been identified in the fruit, including iridoids, terpenoids, flavonoids, organic acids, and volatile oils [14,15]. Song et al. [16] identified two new molecules (3beta,23-dihydroxyurs-12-en-28-oic acid and 3beta,19alpha-dihydroxy-urs-12-en-28-oic acid) among 15 compounds from flowers of G. jasminoides using nuclear magnetic resonance spectroscopy (NMR) techniques and physicochemical properties. ...
Aromatic and medicinal plants have been integral to human civilization for thousands of years, serving not only as vital components in traditional and modern medicine but also as sources of captivating fragrances that enhance our sensory experiences. The main objective of this study was to explore the chemical composition, antioxidant and antimicrobial properties, and in silico molecular docking attributes of Gardenia jasminoides essential oil (GJEO). The chemical compositions were determined using gas chromatography–mass spectrometry (GC-MS) analysis. The antioxidant activity was determined by 2,2-Diphenyl-1-picrylhydrazyl (DPPH) and total antioxidant capacity (TAC) test. The antimicrobial activity was tested in vitro using three microbial strains (Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus), and two fungal strains (Candida albicans and Aspergillus niger). In silico analysis by molecular docking was used to determine the interaction types of topoisomerase II receptors and the most important antioxidant and antimicrobial compounds (Eugenol, Methyleugenol, and α-Terpineol ligands). The obtained results highlight the presence of 25 volatile compounds including 5 new detected compounds: Methyleugenol (15.41%), 1-Undecyne (3.4%), 2,6,10-Dodecatrien-1-ol, 3,7,11-trimethyl- (1.11%), 2,5-Cyclohexadiene-1,4-dione, 2,6-bis(1,1-dimethylethyl)- (0.4%), and 5,9-Tetradecadiyne (0.32%). The antioxidant capacity of GJEO is around 1.25 µg equivalent of ascorbic acid/mL for TAC assay and IC50 = 19.05 µL/mL for DPPH test. GJEO exhibited significant antimicrobial activity, particularly against Pseudomonas aeruginosa, with a minimum inhibitory concentration (MIC) of 16.67 µL/mL. In silico molecular docking analysis revealed strong interactions between ethyleugenol characterized by multiple bonding interactions, including Pi–Alkyl and carbon–hydrogen bonds, while α-Terpineol formed hydrogen and alkyl interactions. These results underline the potential of Gardenia jasminoides essential oil as a promising source of bioactive compounds with antioxidant and antimicrobial properties, highlighting its possible applications in pharmaceuticals and natural therapies.
... Building on these findings, our research led to the development of Xiongzhitongluo (XZTL) granules. XZTL granules comprise seven herbs (components detailed in Table 1), each with documented effects on inflammation, cerebrovascular diseases, and related conditions (18)(19)(20)(21)(22). ...
Introduction
Acute ischemic stroke (AIS) poses a significant risk to human health. Intravenous thrombolysis and mechanical thrombectomy are essential treatments for AIS, offering substantial benefits for neurological recovery and brain protection. However, their efficacy is often limited by stringent time constraints and contraindications, restricting accessibility for certain patient populations. Investigating novel therapeutic strategies is, therefore, crucial. Our team developed Xiongzhitongluo granules specifically for AIS and is conducting a randomized controlled trial (RCT) to validate their effectiveness.
Methods and analysis
This multi-center, randomized, double-blind, placebo-controlled clinical trial includes 120 participants randomly allocated to the intervention or placebo group. Participants will receive a 14-day treatment alongside routine medications and will be monitored at multiple time points: days 1, 3, 5, 7, 14, 30, 60, and 90. The primary outcome is the change in the National Institutes of Health Stroke Scale (NIHSS) score from baseline to day 14. Secondary outcomes include the Scandinavian Stroke Scale (SSS), Barthel Index (BI), modified Rankin Scale (mRS), Brief Mini-Mental State Examination (MMSE), and traditional Chinese medicine (TCM) symptom assessment. Safety evaluations will include vital signs and laboratory tests. Data will be recorded using Epidata V3.1 and analyzed with SPSS 26.0.
Ethics and dissemination
This study received approval from the Ethics Committee of Xiyuan Hospital, China Academy of Chinese Medical Sciences (2021XLA102-2). Written informed consent was obtained from all participants.
Clinical trial registration
https://clinicaltrials.gov/, identifier, ChiCTR2200061859.
... The antioxidant properties of Gardenia jasminoides Ellis (GF) have been extensively validated (Tian et al., 2022;Zhang X. et al., 2023), and its distribution and cultivation are extensive, with abundant resources (Jin et al., 2023). GF is a popular shrub from the Rubiaceae family, scientifically called Yellow Gardenia Jasminoides Ellis and Mountain Gardenia Jasminoides Ellis. ...
This study aimed to prepare Gardenia fructus carbon dots (GF-CDs) and examine their efficacy in mitigating oxidative stress and apoptosis in intestinal porcine epithelial cells from the jejunum (IPEC-J2 cells) induced by lipopolysaccharide (LPS). The GF-CDs were synthesized using a one-step hydrothermal method. The oxidative damage model of IPEC-J2 cells was induced through LPS treatment. The potential mechanism by which GF-CDs affect cellular oxidative damage was examined through the perspectives of apoptosis, reactive oxygen species level, antioxidant-related enzyme index, mRNA transcription of antioxidant-related genes, and the expression of antioxidant proteins. The results revealed that GF-CDs, characterized by particle sizes<7 nm, abundant functional groups, and good water solubility, were synthesized using a one-step hydrothermal method. The carbon spots of Gardenia fructus at concentrations of 50, 100, and 200 μg/mL exhibited protective effects, as evidenced by their ability to enhance viability (P<0.01) and restore cellular morphology after oxidative damage. The GF-CDs decreased oxidative damage and reduced the apoptosis rate of cells by upregulating AKT1 expression and downregulating the expression of Caspase 3, STAT3, TNF-α, and JNK. These results indicate that GF-CDs have the characteristic physicochemical properties of CDs, exhibit biological activities related to antioxidation and cellular damage mitigation, and may serve as a potential healthcare product in swine raising.
... In China, Fructus gardenia (FGE), the dried, ripe fruit of Gardenia jasminoides, is commonly used to treat inflammation, hepatitis, viral encephalitis, tonsillitis, tracheitis, and high fever (Tian et al. 2022). This evergreen flowering plant, part of the coffee family Rubiaceae, is native to Southeast Asia. ...
Gout is a prevalent metabolic disorder characterized by increased uric acid (UA) synthesis or decreased UA clearance from the bloodstream, leading to the formation of urate crystals in joints and surrounding tissues. Hyperuricemia (HUA), the underlying cause of gout, poses a growing challenge for healthcare systems in developed and developing countries. Currently, the most common therapeutic approaches for gouty HUA primarily involve the use of allopathic or modern medicine. However, these treatments are often accompanied by adverse effects and may not be universally effective for all patients. Therefore, this systematic review aims to provide a comprehensive outline of phytochemical compounds that have emerged as alternative treatments for HUA associated with gout and to examine their specific mechanisms of action. A systematic search was conducted to identify phytochemicals that have previously been evaluated for their effectiveness in reducing HUA. From a review of > 800 published articles, 100 studies reporting on 50 phytochemicals associated with the management of HUA and gout were selected for analysis. Experimental models were used to investigate the effects of these phytochemicals, many of which exhibited multiple mechanisms beneficial for managing HUA. This review offers valuable insights for identifying and developing novel compounds that are safer and more effective for treating HUA associated with gout.
... Consuming beverages, fruits, and vegetables that are rich in phenolic acids may decelerate the onset and progression of chronic ailments, including obesity, cardiovascular disease, diabetes, and cancer [5]. Research has shown that the phenolic acids in MEHHs may prevent and ameliorate disorders in glucose and lipid metabolism by modulating glucose and lipid metabolism, insulin signaling, reducing insulin resistance, curtailing inflammation and oxidative stress, and regulating gut flora [6][7][8][9][10][11]. ...
Glucose and lipid metabolism disorders are the core pathological mechanism of a variety of metabolic diseases, and the incidence of related diseases is increasing year by year, which seriously threatens human life and health. Traditional Chinese medicine with medicinal and edible properties refers to Chinese medicinal resources that have both medicinal and edible characteristics. Due to its safety and its health-promoting and medicinal functions, traditional Chinese medicine has received increasing attention in the development of functional health foods. Phenolic acids are important secondary metabolites that are ubiquitous in medicinal and edible homologous plants, and the regulation of glycolipid metabolism is an important activity and plays a key role in many diseases. In this paper, we focus on the alleviation of glycolipid disorders using MEHH phenolic acids, which regulate glucose metabolism and lipid metabolism, improve insulin resistance, inhibit inflammatory responses, alleviate oxidative stress, and regulate intestinal flora; additionally, we summarize the mechanism in order to provide a reference for MEHH phenolic acids in the treatment of glycolipid metabolism diseases.
... Future research should further explore the specific molecular mechanisms and clinical application potential of these bioactive constituents to provide more options for treating skin barrier dysfunction. Table 6 summarizes the pharmacological effects and applications Hepatoprotective, choleretic, anti-inflammatory, antioxidant, neuroprotective, anti-diabetic, anti-apoptotic, and anti-tumor [139] Psoriasis [140] 6 ...
The skin barrier is essential for maintaining the body’s internal homeostasis, protecting against harmful external substances, and regulating water and electrolyte balance. Traditional Chinese Medicine (TCM) offers notable advantages in restoring skin barrier function due to its diverse components, targets, and pathways. Recent studies have demonstrated that active ingredients in TCM can safely and effectively repair damaged skin barriers, reinstating their proper functions. This review article provides a comprehensive overview of the mechanisms underlying skin barrier damage and explores how the bioactive constituents of TCM contribute to skin barrier repair, thereby offering a theoretical framework to inform clinical practices.
... Recent research has shown that geniposide possesses pharmacological properties in combating inflammation, oxidative stress, apoptosis, and thrombosis [12]. It is extensively utilized as a natural medical remedy for various ailments, such as arthritis, diabetes, Alzheimer's disease, and cardiovascular disorders [13][14][15][16]. ...
In recent years, the prevalence and fatality rates of atherosclerotic cardiovascular disease have not only shown a consistent rise that cannot be ignored, but have also become a pressing social health problem that requires urgent attention. While interventional surgery and drug therapy offer significant therapeutic results, they often come with common side effects. Geniposide, an active component extracted from the Chinese medicine Gardenia jasminoides Ellis, shows promise in the management of cardiac conditions. This review comprehensively outlines the underlying pharmacological mechanisms by which geniposide exerts its effects on atherosclerosis. Geniposide exhibits a range of beneficial effects including alleviating inflammation, inhibiting the development of macrophage foam cells, improving lipid metabolism, and preventing platelet aggregation and thrombosis. It also demonstrates mitochondrial preservation, anti-apoptotic effects, and modulation of autophagy. Moreover, geniposide shows potential in improving oxidative stress and endoplasmic reticulum stress by maintaining the body’s antioxidant and oxidative balance. Additionally, this review comprehensively details the biological properties of geniposide, including methods of extraction and purification, as well as its pharmacokinetics and toxicological characteristics. It further discusses the clinical applications of related biopharmaceuticals, emphasizing the potential of geniposide in the prevention and treatment of atherosclerotic cardiovascular diseases. Furthermore, it highlights the limitations of current research, aiming to provide insights for future studies.
Graphical Abstract
... Clinical trials and research have been conducted to evaluate the effectiveness and safety of TCM, providing scientific evidence to support its rational clinical use and identify potential risks [1,2,5]. However, the complex nature of TCM, which typically consists of a combination of various natural herbal components, each with unique pharmacological effects and toxicities, complicates its evaluation and makes it challenging to determine its precise efficacy and associated risks [80][81][82]. Quality control is a critical concern in TCM due to its vulnerability to factors such as the quality of raw materials, processing techniques, and standardization levels. Ensuring consistency and high quality is indispensable in accurately assessing the effectiveness of TCM [83,84]. ...
Objective
The traditional Chinese patent medicine (TCPM), Simo decoction (Simo decoction oral solution), with its primary ingredient Arecae semen (Binglang, Areca catechu L.), known for its potential carcinogenic effects, is the subject of this study. The research aims to analyze the effectiveness and potential risks of Simo decoction, particularly as a carcinogen, and to suggest a framework for evaluating the risks and benefits of other herbal medicines.
Methods
The study is based on post-marketing research of Simo decoction and Arecae semen. It utilized a wide range of sources, including ancient and modern literature, focusing on the efficacy and safety of Simo decoction. The research includes retrospective data on the sources, varieties, and toxicological studies of Arecae semen from databases such as Pubmed, Clinical Trials, Chinese Clinical Trial Registry, China National Knowledge Infrastructure, WHO-UMC Vigibase, and China National Center for ADR Monitoring.
Results
Common adverse drug reactions (ADRs) associated with Simo decoction include skin rash, nausea, vomiting, abdominal pain, and diarrhea. However, no studies exist reporting the severe ADRs, such as carcinogenic effects. Arecae semen is distributed across approximately 60 varieties in tropical Asia and Australia. According to the WHO-UMC Vigibase and the National Adverse Drug Reaction Monitoring System databases, there are currently no reports of toxicity related to Arecae semen in the International System for Classification of ADRs (ISCR) or clinical studies.
Conclusion
Risk-benefit analysis in TCPM presents more challenges compared to conventional drugs. The development of a practical pharmacovigilance system and risk-benefit analysis framework is crucial for marketing authorization holders, researchers, and regulatory bodies. This approach is vital for scientific supervision and ensuring the safety and efficacy of drug applications, thus protecting public health.
... Pharmacological investigations have demonstrated that the HQFD has anti-inflammatory, antiviral, antibacterial, anticancer, antioxidant, and antiapoptotic properties. [9][10][11] The prescription is extensively used clinically to manage pulmonary inflammation, neurological disorders, and neuronal dysfunction, as well as various cardiovascular and cerebrovascular conditions. 12,13 However, the precise mechanisms underlying the synergistic effects of these 2 TCMs remain incompletely understood. ...
Objective: In this study, a network pharmacological approach, and in vivo validation experiments were used to screen the active components of the Huangqin Qingfei decoction (HQFD) for their therapeutic efficacy in pneumonia. Methods: The active ingredients and targets of the HQFD were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, while pneumonia-related targets were obtained from GeneCards, Online Mendelian Inheritance in Man, and the Therapeutic Target Database. A protein–protein interaction network was constructed to identify core targets, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses using Metascape. A lipopolysaccharide-induced pneumonia mouse model was established, and verification of the main targets predicted by network pharmacology and therapeutic efficacy assessment was conducted using pathological staining, Western blot, and polymerase chain reaction. Results: We identified 51 active components in the HQFD that primarily affected pneumonia-related targets AKT1, PTGS2, MAPK14, and MMP9. The outcomes of the pathway enrichment analyses conducted by the KEGG and the GO demonstrated that the HQFD regulates genes associated with pathways in cancer, the lipid and atherosclerosis, as well as the AGE-RAGE signaling pathway in diabetic complications. Experiments on animals demonstrated that the AKT1, PTGS2, MAPK14, and MMP9 mRNA expression and p-AKT, p-P38, PTGS2, and MMP9 protein expression in lung tissues were significantly upregulated in the model group when compared to the control group. AKT1, PTGS2, MAPK14, MMP9 mRNA expression, and p-AKT, p-P38, PTGS2, and MMP9 protein expression were all lower in the HQFD groups in contrast to the model group. Conclusions: The effects of HQFD on pneumonia can be attributed to its active ingredients, including beta-sitosterol, wogonin, and quercetin. The mechanism involves multiple targets and pathways, including the PI3K-AKT signaling pathway, MAPK signaling pathway, and NF-kappa B signaling pathway, and modulation of AKT, PTGS2, MAPK14, and MMP9 expression. The HQFD reduces inflammatory damage and pneumonia symptoms via these mechanisms.
... Gardeniae Fructus known as Zhizi in Chinese, serves as a common Chinese herbal medicine and finds applications in pharmaceuticals, food, cosmetics, and dye industries (Chen et al., 2020b;Tian et al., 2022;Jin et al., 2023). Its historical use dates back over 2000 years to the Han Dynasty, when it was documented as both a medicinal and dyeing agent. ...
Gardeniae Fructus (Zhizi) serves as both a medicinal and edible substance and finds widespread use in various industries. There are often two kinds of medicinal materials in the market: Zhizi and Shuizhizi. Typically, Zhizi with small, round fruit is used for medicinal purposes, while Shuizhizi, characterized by large, elongated fruit, is employed for dyeing. Market surveys have revealed a diverse range of Zhizi types, and modern research indicates that Shuizhizi contains rich chemical components and pharmacological activities. In this study, we collected 25 batches of Zhizi and Shuizhizi samples, categorizing them based on appearance into obovate and round fruits, with seven length grades (A–G). Using the ultra-high performance liquid chromatography coupled with triple quadrupole mass spectrometry (UHPLC-QQQ-MS/MS) method, we simultaneously quantified 13 main chemical components in fruits of Gardenia species. In addition, we compared the weight percentage of the pericarp, flesh, and seeds parts of samples with different traits, and quantified 13 chemical components in different parts. Results indicated that, aside from a few instances of overlapping fruit size ranges, Shuizhizi generally exhibits larger and longer dimensions than Zhizi. The weight proportion of the Shuizhizi pericarp is often higher than that of the Zhizi pericarp. Quantitative results highlighted significant differences in the chemical component content between Zhizi and Shuizhizi, with Shuizhizi generally containing higher levels of iridoids. The PCA and OPLS-DA analysis distinctly divided Shuizhizi and Zhizi, among which three iridoids, two organic acids, and one flavonoid made significant contributions to their classification. Cluster heatmap analysis also demonstrated complete separation between Zhizi and Shuizhizi, with clear distinctions among Zhizi samples from different origins. The distribution of the 13 chemical components in different Zhizi and Shuizhizi parts remained consistent, with iridoids and pigments concentrated in the seeds and flesh, and two organic acids and one flavonoid enriched in the pericarp. In summary, this study contributes valuable insights for classifying Zhizi and offers guidance on the rational use of Shuizhizi and the different parts of Zhizi.
... Margaritifera Concha has sedative, antiepileptic, antioxidant, and antidepressant properties [4][5][6], while Bubali Cornu displays sedative, anticonvulsant, antipyretic, and cardiotonic effects [7]. Gardeniae Fructus exhibits hepatoprotective and choleretic effects, anti-inflammatory, immunomodulatory, antiangiogenesis, and antioxidant activities [8]. Cholic acid provides antibacterial and choleretic effects [9,10]. ...
Qingkailing capsules are a classic traditional Chinese medicine prescription with remarkable clinical effects for the treatment of fevers. However, the chemical components of Qingkailing capsules are still unclear. To obtain and characterize the chemical profile of Qingkailing capsules, the present study applied a rapid, accurate, and sensitive method using ultra-high-performance liquid chromatography combined with Fourier transform ion cyclotron resonance mass spectrometry (UHPLC-FT-ICR-MS) to perform a comprehensive chemical characterization of Qingkailing capsules. Leveraging the high separation speed and good separation of UHPLC, the accurate mass data (within 5 ppm) and fragment ions, a total of 276 compounds, including 67 flavonoids and their glycosides, 52 organic acids, 75 terpenoids, 23 steroids, 22 phenylpropanoids, and 37 other compounds, were unambiguously or tentatively identified. This comprehensive analysis of the chemical components of Qingkailing capsules contributes to the quality evaluation and provides a scientific and reasonable basis for further study of prototype components and metabolites in vivo and pharmacological research, ultimately facilitating the advancement of Qingkailing capsules for further development and the therapeutic use of Qingkailing capsules in clinical applications.
... ES starch content reaches more than 70% and is rich in flavonoids and organic acids. Modern pharmacological studies have shown that organic acids and flavonoids have anti-inflammatory, antioxidant properties and therapeutic effects on the nervous, digestive, and reproductive systems (Tian et al., 2022). Moreover, organic acids and flavonoids can be used as quality indicators in ES-related quality control measures. ...
Introduction
Euryales Semen, a medicinal herb widely utilized in Asia, faces a critical constraint in its production, primarily attributed to fertilizer utilization. Understanding the impact of different fertilization schemes on Euryales Semen (ES) planting and exploring the supporting mechanism are crucial for achieving high yield and sustainable development of the ES planting industry.
Methods
In this study, a field plot experiment was conducted to evaluate the effects of four different fertilization treatments on the yield and quality of ES using morphological characteristics and metabolomic changes. These treatments included a control group and three groups with different organic fertilizer to chemical fertilizer ratios (3:7, 5:5, and 7:3). The results of this study revealed the mechanisms underlying the effect of the different treatments on the yield and quality of Euryales Semen. These insights were achieved through analyses of soil physicochemical properties, soil enzyme activity, and soil microbial structure.
Results
We found that the quality and yield of ES were the best at a ratio of organic fertilizer to chemical fertilizer of 7:3. The optimality of this treatment was reflected in the yield, soil available nitrogen, soil available phosphorus, and soil enzyme activity of ES. This ratio also increased soil microbial diversity, resulting in an increase and decrease in Proteobacteria and Firmicutes abundances, respectively. In addition, linear discriminant analysis showed that Chloroflexi, Gammaproteobacteria, and Hypocreales-incertae-sedis were significantly enriched in the ratio of organic fertilizer to chemical fertilizer of 7:3. Variance partitioning analysis showed that the soil properties, enzyme activities, and their interactions cumulatively can explain 90.80% of the differences in Euryales Semen yield and metabolome. In general, blending organic and chemical fertilizers at a 7:3 ratio can enhance soil fertility, boost Euryales Semen yield and quality, and bring forth conditions that are agriculturally beneficial to microbial (bacteria and fungi) dynamics.
Discussion
This study initially revealed the scientific connotation of the effects of different fertilization patterns on the planting of Euryales Semen and laid a theoretical foundation for the study of green planting patterns of Euryales Semen with high quality and yield.
... Gardenia, as a common traditional Chinese medicine and food, is used clinically to treat various diseases, including jaundice, diarrhea and liver disease [1], and is a common traditional Chinese medicine administered for liver protection and cholagogue [2,3]. Gardenia's main active component of hepatoprotective and choleretic effects is geniposide, which has a wide range of pharmacological effects and has great development and utilization value [4][5][6][7]. ...
Gardenia, as a medicinal and edible herb, has the pharmacological activity of protecting the liver and cholagogue, but the hepatotoxicity induced by the chemical component genipin (GP) limits its application. The aim of this study was to evaluate the acute and subacute hepatotoxicity of genipin in normal mice and mice with α-naphthalene isothiocyanate (ANIT)-induced liver injury. The results of the acute study showed that the LD50 of genipin was 510 mg/kg. Genipin exhibited hepatotoxicity in normal and jaundiced mice at doses of 125 mg/kg, 250 mg/kg, and 500 mg/kg, which increased with dose. In a 28-day subacute study, the 50 mg/kg and 100 mg/kg dose groups showed some pharmacodynamic effects at 7 days but exhibited hepatotoxicity that increased with time and improved after drug withdrawal. In addition, based on proteomics, the mechanism of liver injury induced by genipin may be related to the disruption of the UDP-glucuronosyltransferase system and cytochrome P450 enzyme activity. In conclusion, this study showed that genipin hepatotoxicity was time- and dose dependent, but it is worth mentioning that hepatotoxicity was reversible. It is hoped that this study will provide a scientific basis for circumventing the adverse effects of genipin.
... The recruited rats were separated into normal group, model group, geniposide subgroups (Gen-L: 200 mg/kg; Gen-M: 400 mg/kg; Gen-H: 500 mg/kg), considering that geniposide at a single dose of close to 600 mg/kg could induce hepatotoxicity in rats after oral administration [15]. All rats were divided into each group randomizedly according to body weight (n = 6). ...
Continuously hyperglycation-induced lesion and poor blood flow contributed to the wound incurable and susceptible to infection. About fifteen percent of people with diabetes would develop ulcers during their lifetime, especially on the feet, which could lead to severe tissue destruction and eventual amputation. Various strategies were limited to accelerate wound healing in diabetic patients for high cost and unsatisfied effects. Geniposide is well-known for its anti-inflammation and anti-apoptosis in several pathological tissues. This study is to explore the protective effect of geniposide on wound healing rate, inflammatory response, nutritional function and cellular apoptosis in diabetic rats. Diabetic rats was induced by streptozotocin and defined as plasma glucose >300 mg/dl. Western blot and immunostaining technologies were performed to mark and quantify the target proteins. The oral administration of geniposide (200 mg/kg and 500 mg/kg) could significantly promote wound healing by the increment of lesion retraction in diabetic rats compared to model group. In the apoptotic study of skin wound in diabetic rats, the TUNEL-positive cells were greatly decreased in geniposide subgroups (P < 0.05). The levels of TNF-α, IL-1β and IL-6 were significantly inhibited by geniposide with the IC50 value of 470 mg/kg, 464 mg/kg and 370 mg/kg body weight respectively, which might be related to the enhancement of the phosphorylation of PI3K and Akt proteins. Geniposide enhanced the repairment of skin wound in diabetic rats by inhibiting inflammatory response and apoptosis.
... Fructus Gardeniae (FG) is the dried fruit of Gardenia jasminoides Ellis (GjE), belonging to the family Rubiaceae [4]. Geniposide (C 17 H 24 O 10 ), a well-known iridoid glycoside compound, is one of the main bioactive components of FG [5]. ...
This study aims to identify the mechanism of geniposide regulating oxidative stress in colorectal cancer (CRC) through network pharmacology and bioinformatics analysis. Targets of geniposide, oxidative stress-related targets and targets related to CRC were applied from databases. The hub genes for geniposide regulating oxidative stress in CRC were identified with the protein–protein interaction (PPI) network. Furthermore, we applied Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment to analyze the hub genes from a macro perspective. We verified the hub genes by molecular docking, GEPIA, HPA and starBase database. We identified five hub genes: IL1B, GSK3B, NOS3, RELA and CDK4. GO analysis results suggested that the anti-colorectal cancer effect of geniposide by regulating oxidative stress is possibly related to the influence of multiple biological processes, including response to temperature stimulus, response to alkaloid, nitric oxide biosynthetic process, nitric oxide metabolic process, reactive nitrogen species metabolic process, cellular response to peptide, etc. KEGG enrichment analysis results indicated that the PI3K–Akt signaling pathway, IL-17 signaling pathway, p53 signaling pathway, NF-κB signaling pathway and NOD-like receptor signaling pathway are likely to be the significant pathways. Molecular docking results showed that the geniposide had a good binding activity with the hub genes. This study demonstrates that geniposide can regulate oxidative stress in CRC, and induction of oxidative stress is one of the possible mechanisms of anti-recurrence and metastasis effects of geniposide against CRC.
Background
Gardeniae fructus (Zhi-Zi) is the dry ripe fruit of the plant Gardenia jasminoides Ellis (Rubiaceae), which can be used as both food and medicine. Geniposide, a key constituent of Gardeniae fructus, serves as an indicator component for evaluating the quality of Gardeniae fructus. Traditionally, the quantification of geniposide in Gardeniae fructus is achieved through High-performance Liquid Chromatography (HPLC)-based methods.
Objective
The present study aimed to introduce a rapid approach to quantifying geniposide content in Gardeniae fructus along with validating its effectiveness.
Methods
The experiments involved finding a suitable deuterium solvent, Internal Standard (IS), specific peak, and Nuclear Magnetic Resonance (NMR) parameters for quantitation, and validating specificity, accuracy, precision, and stability.
Results
The results have indicated that methanol-d4 as a solvent has facilitated excellent signal separation in the proton Nuclear Magnetic Resonance (1H NMR) spectroscopy, with trimethyl 1,3,5- benzenetricarboxylate emerging as the ideal IS. The specific signal at δ 7.45, corresponding to H-3 in geniposide, has been identified as the optimal peak for integration. The application of distinctive signals from the 1H NMR spectroscopy has allowed for the precise quantification of geniposide in Gardeniae fructus.
Conclusion
This study has suggested using 1H NMR to quantify geniposide in Gardeniae fructus to be a viable alternative to HPLC-based methods, providing a suitable approach for quality control of Gardeniae fructus.
Objective
Patients with coronavirus disease 2019 (COVID-19) experience various symptoms such as fever, cough, fatigue, and headache. At present, only two traditional over-the-counter medications, acetaminophen, and ibuprofen, are recommended for treating COVID-19 symptoms. However, there is an urgent need to discover safer remedies, potentially found in daily food items, that can be used for long-term prevention of COVID-19 symptoms. This study aimed to explore safe natural products capable of alleviating COVID-19 symptoms.
Materials and Methods
We developed a Transcriptome-based Functional Gene Module Reference (TFGMR) approach, utilizing gene expression data from natural products and gene modules associated with COVID-19. Our hypothesis was that candidate natural products would significantly inhibit the expression of genes linked to COVID-19 symptoms without enhancing the expression of genes related to severe acute respiratory syndrome coronavirus 2 invasion.
Results
Using the TFGMR approach, we identified 109 natural products with the potential to alleviate COVID-19 symptoms, with 15 of them having experimental evidence supporting their efficacy. These natural products consist of three daily food items – olive oil, nuts, and a mixture of vegetables, fruits, and yogurt; 43 functional foods, such as Fructus Gardeniae and Flos Lonicerae; as well as 63 natural drugs such as Plantamajoside and Safflomin A. These findings suggest that incorporating these three daily food items into one’s diet may contribute to the prevention of COVID-19.
Conclusion
The study underscores the importance of recommending functional foods based on robust scientific evidence supporting their efficacy. The integration of diverse technological approaches holds promise in identifying safe remedies that could aid in the prevention and alleviation of COVID-19 symptoms, providing new opportunities for their everyday use.
Background/Objectives: Gardeniae Fructus (GF) has been widely used as both food and medicinal purposes for thousands of years, but their antioxidant properties and potential metabolite biomarkers remain unclear. Methods: The purposes of this study were to examine antioxidant activities of 21 GF varieties from different geographical origins in China and identify potential biomarkers of antioxidant properties using an untargeted LC–MS-based metabolomics approach. Results: The results demonstrate that metabolomics had the ability to trace the geographical origins of GF. We found that antioxidant activities varied with different varieties of GF, which was dependent on their chemical compositions. The key chemical categories were obtained as the primary contributors of the antioxidant activity, including prenol lipids, flavonoids, coumarins and derivatives, as well as steroids and steroid derivatives. In addition, adouetine Y, coagulin R 3-glucoside and epicatechin 3-glucoside were identified as potential biomarkers for the antioxidant activity of GF. Conclusions: Therefore, our study sheds light on the metabolic characteristics and biomarkers of the antioxidant properties of GF, contributing to the selection and cultivation of a high antioxidant variety.
Gardenia jasminoides J.Ellis, a well-known traditional Chinese medicine, has been widely used in Asian countries for centuries. This study presented the skin barrier repair efficacy and safety evaluation of an extract from G. jasminoides. The results showed that GarPepair was primarily composed of geniposide and genipin-1-β-D-gentiobioside with concentrations of 3.39 and 1.03 mg/mL, respectively. GarPepair (1.25%, w/w), geniposide (50 μg/mL), and genipin-1-β-D-gentiobioside (50 μg/mL) showed no cytotoxicity but could significantly up-regulate mRNA level (82.5%, 54.4%, and 99.4%, respectively) and protein expression (68.7%, 57.1%, and 92.6%, respectively) of ZO-1 in HaCat cells induced by lipopolysaccharide. Moreover, GarPepair showed low acute toxicity on zebrafish with an IC50 value of 5.91% (w/w), indicating that GarPepair had high safety. In summary, we can conclude that GarPepair and its active ingredients (geniposide and genipin-1-β-D-gentiobioside) had significant skin barrier repair efficacy with high safety, making it suitable for use as an active substance in cosmetics.
Introduction
Due to the high mortality rate and increasing severity of antibiotic resistance, there is a growing interest in new treatments for Klebsiella pneumoniae (KP)-induced pneumonia. Research has shown that the single herbs of SiHuangQingXinWan (SHQXW) are effective in treating pneumonia caused by KP. The PI3K/AKT signaling pathway has garnered attention for its potential role in the management of bacterial infections. This study aimed to evaluate the anti-pneumonia effect of SHQXW and to investigate its mechanism of action.
Materials and Methods
The potential plant metabolites and molecular targets of SHQXW in the context of pneumonia were determined through ultra-high performance liquid chromatography-tandem mass-spectrometry (UHPLC-MS/MS) and bioinformatics analysis. The therapeutic effect of SHQXW was evaluated in a KP-induced pneumonia murine model with imipenem/cilastatin as a positive control. Transcriptomics and non-targeted metabolomics were carried out to unveil potential mechanisms and targets for anti-pneumonia effects. Additionally, an in-depth exploration on the PI3K/AKT signaling pathway was conducted in this study.
Results
A total of 24 potential plant metabolites and 285 SHQXW-pneumonia-related targets selected by Homo sapiens were identified in this study. The tested doses of SHQXW significantly reduced mortality, improved body weight, decreased the lung index, reduced the bacterial load, and alleviated lung pathological damage in the KP-induced pneumonia murine model (p < 0.05). Notably, 1.3 g/kg/day of SHQXW provided the most effective protective outcome. Furthermore, SHQXW demonstrated the ability to suppress the production of inflammatory factors such as IL-1α, IL-1β, IL-3, IL-6, IL-12p70, G-CSF, GM-CSF, MCP-1, KC, and TNF-α. Analysis of transcriptomic and metabolomic data revealed that SHQXW could modulate inflammation-related signaling pathways (TNF, HIF-1, NF-κB, and PI3K/AKT) and metabolites to regulate pulmonary inflammation. Additional experiments using RT-qPCR and western blotting indicated that SHQXW may exert anti-inflammatory effects by activating the PI3K/AKT pathway.
Discussion
The findings indicate that SHQXW effectively reduces inflammation in mice with KP-induced pneumonia by modulating inflammatory signaling pathways and metabolites, rather than by directly inhibiting the growth of KP. This study introduces a novel treatment approach for KP-induced pneumonia and presents a new outlook on drug development.
Hepatic, biliary, and pancreatic cancer pose significant challenges in the field of digestive system diseases due to their highly malignant nature. Traditional Chinese medicine (TCM) has gained attention as a potential therapeutic approach with long-standing use in China and well-recognized clinical benefits. In this review, we systematically summarized the clinical applications of TCM that have shown promising results in clinical trials in treating hepatic, biliary, and pancreatic cancer. We highlighted several commonly used TCM therapeutics with validated efficacy through rigorous clinical trials, including Huaier Granule, Huachansu, and Icaritin. The active compounds and their potential targets have been thoroughly elucidated to offer valuable insights into the potential of TCM for anti-cancer drug discovery. We emphasized the importance of further research to bridge the gap between TCM and modern oncology, facilitating the development of evidence-based TCM treatment for these challenging malignancies.
Graphical Abstract
We employed a straightforward microwave-assisted extraction technique to investigate the presence of carbon dots (CDs) in Chinese herbal extracts derived from fructus gardeniae and gardenia charcoal, designated as CDs-1 and CDs-2, respectively. The found CDs exhibited unique photoluminescence with quantum yields of 0.95% for CDs-1 and 1.81% for CDs-2, indicating significant potential for bioimaging applications. Both CD types maintain approximately 80% of their fluorescence intensity after 120 min of continuous 365 nm UV exposure, underscoring their stability and suitability for prolonged biological studies. Moreover, antioxidant activity tests showed that CDs-2 have a higher scavenging capacity, with an SC-50 value of 21.7 μg/mL, compared to 35.9 μg/mL for CDs-1, attributed to their higher content of surface functional groups during the extraction procedure. Notably, the results indicated that the carbonization process of fructus gardeniae leads to the formation of CDs, suggesting a potential link between traditional herbal treatments and modern nanotechnology. This research demonstrates that active compounds in Chinese herbal medicine could possess therapeutic properties when adsorbed on the surface of CDs.
Gardenia fruit is a popular functional food and raw material for natural pigments. It comes from a wide range of sources, and different products sharing the same name are very common. Volatile organic compounds (VOCs) are important factors that affect the flavor and quality of gardenia fruit. This study used the Heracles NEO ultra-fast gas phase electronic nose with advanced odor analysis performance and high sensitivity to analyze six batches of gardenia fruit from different sources. This study analyzed the VOCs to find a way to quickly identify gardenia fruit. The results show that this method can accurately distinguish the odor characteristics of various gardenia fruit samples. The VOCs in gardenia fruit are mainly organic acid esters, ketones, and aldehyde compounds. By combining principal component analysis (PCA) and discriminant factor analysis (DFA), this study found that the hexanal content varied the most in different gardenia fruit samples. The VOCs allowed for the fruit samples to be grouped into two main categories. One fruit sample was quite different from the fruits of other origins. The results provide theoretical support for feasibility of rapid identification and quality control of gardenia fruit and related products in the future.
It is well-known that the hepatotoxicity of drugs can significantly influence their clinical use. Despite their effective therapeutic efficacy, many drugs are severely limited in clinical applications due to significant hepatotoxicity. In response, researchers have created several machine learning-based hepatotoxicity prediction models for use in drug discovery and development. Researchers aim to predict the potential hepatotoxicity of drugs to enhance their utility. However, current hepatotoxicity prediction models often suffer from being unverified, and they fail to capture the detailed toxicological structures of predicted hepatotoxic compounds. Using the 56 chemical constituents of Gardenia jasminoides as examples, we validated the trained hepatotoxicity prediction model through literature reviews, principal component analysis (PCA), and structural comparison methods. Ultimately, we successfully developed a model with strong predictive performance and conducted visual validation. Interestingly, we discovered that the predicted hepatotoxic chemical constituents of Gardenia possess both toxic and therapeutic effects, which are likely dose-dependent. This discovery greatly contributes to our understanding of the dual nature of drug-induced hepatotoxicity.
The detection of anions using carbon dots (CDs) has received less attention compared to cations. Therefore, the present study aimed to develop a fluorescence sensor based on carbon dots (CDs) capable of detecting S2- in real water samples. The CDs were successfully prepared from the residues of a traditional Chinese herb, Gardenia, which emitted green photoluminescence (PL) under ultraviolet light irradiation. The as-prepared CDs were quasi-spherical in shape and ranged in size from 10 to 30 nm. Different detailed analyses proved that the CDs had good morphology, various functional groups, high water solubility, great optical features, and excellent stability under diverse environmental conditions. The ion detection showed that only Ag+ had the strongest fluorescence quenching effect on the CDs, however, the addition of S2- could recover their fluorescence. Based on these results, an "off-on" fluorescence sensor was achieved to selectively detect the concentration of S2- in real water samples with a limit of detection (LOD) of 39 μM, which further expanded the application of residues from traditional Chinese herbal medicine.
Introduction
Fructus Gardeniae (ZZ), a traditional Chinese herb, has been used in treating patients with jaundice, inflammation, etc. When mixed with ginger juice and stir‐baked, ginger juice‐processed Fructus Gardeniae (JZZ) is produced, and the chemical compositions in ZZ would be changed by adding the ginger juice.
Objective
To illuminate the differential components between ZZ and JZZ.
Methods
HPLC, UHPLC‐Q‐TOF‐MS, and Heracles NEO ultra‐fast gas phase electronic nose were applied to identify the differential components between ZZ and JZZ.
Results
HPLC fingerprints of ZZ and JZZ were established, and 24 common peaks were found. The content determination results showed that the contents of shanzhiside, geniposidic acid, genipin‐1‐β‐D‐gentiobioside and geniposide increased, while the contents of crocin I and crocin II decreased in JZZ. By UHPLC‐Q‐TOF‐MS, twenty‐six possible common components were inferred, among which 11 components were different. In further investigation, eight components were identified as the possible distinctive non‐volatile compounds between ZZ and JZZ. By Heracles NEO ultra‐fast gas phase electronic nose, four substances were inferred as the possible distinctive volatile compounds in JZZ.
Conclusion
Shanzhiside, caffeic acid, genipin‐1‐β‐D‐gentiobioside, geniposide, rutin, crocin I, crocin II, and 4‐Sinapoyl‐5‐caffeoylquinic acid were identified as the possible differential non‐volatile components between ZZ and JZZ. Aniline, 3‐methyl‐3‐sulfanylbutanol‐1‐ol, E‐3‐octen‐2‐one, and decyl propaonate were inferred as the possible distinctive volatile compounds in JZZ. This experiment explored a simple approach with objective and stable results, which would provide new ideas for studying decoction pieces with similar morphological appearance, especially those with different odors.
Gardenia fruit (GF) is the mature fruit of Gardenia jasminoides Ellis, boasting a rich array of nutrients and phytochemicals. Over time, GF has been extensively utilized in both food and medicinal contexts. In recent years, numerous studies have delved into the chemical constituents of GF and their associated pharmacological activities, encompassing its phytochemical composition and health-promoting properties. This review aims to provide a critical and comprehensive summary of GF research, covering nutrient content, extraction technologies, and potential health benefits, offering new avenues for future investigations and highlighting its potential as an innovative food resource. Additionally, the review proposes novel industrial applications for GF, such as utilizing gardenia yellow/red/blue pigments in the food industry and incorporating it with other herbs in traditional Chinese medicine. By addressing current challenges in developing GF-related products, this work provides insights for potential applications in the cosmetics, food, and health products industries. Notably, there is a need for the development of more efficient extraction methods to harness the nutritional components of GF fully. Further research is needed to understand the specific molecular mechanisms underlying its bioactivities. Exploring advanced processing techniques to create innovative GF-derived products will show great promise for the future.
Fructus Gardeniae (FG) is medicine food widely used for the treatment and prevention of various diseases. However, in recent years, research has suggested that high doses of FG can cause hepatotoxicity and nephrotoxicity. To assess this potential toxicity in more depth, this study investigated the effects of decocted FG and two of its bioactive constituents (geniposide and genipin) on liver and kidney function in rats. Rats were intragastrically administered FG (330 mg/kg body weight), geniposide (50 mg/kg body weight), or genipin (50 mg/kg body weight) for 12 weeks. Changes in body weight, liver and kidney indices, biochemical indices, and inflammatory factors were monitored. In addition, pathological sections were assessed and the expression of caspase-3, NF-κBp65, COX-2, and iNOS was detected by immunohistochemistry and Western blot. It was found that the levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, creatinine, and urea nitrogen increased following administration of FG, geniposide, and genipin. Furthermore, the activities of superoxide dismutase and reduced glutathione decreased following treatment, while malondialdehyde levels increased. Pathological and immunohistochemical evaluations further confirmed that FG and its constituents may cause damage to the liver and kidneys. The mechanism study revealed that the protein level of inflammatory pathway increased and further promoted apoptosis, suggesting that it should not be taken orally for extended periods of time.
Practical applications
Chinese medicine and food safety have always been public health concerns. Fructus Gardeniae (FG) is a plant with a dual-purpose as it is used as both a medicine and food. Medicinally, it has the effects of heat-clearing and detoxification. However, its adverse effects and related mechanisms are not clear, and this has potential safety implications. In this study, rats were treated with FG for 12 weeks and found that the long-term administration of FG or high dosing can lead to damage to liver and kidney function. Therefore, close attention must be paid to the dosage of FG in order to achieve a therapeutic effect and avoid adverse reactions. Thus, this study lays a foundation for the safety evaluation and clinical application of FG.
Overactivation of the PI3-K/Akt/mTOR signaling pathway and inhibition of autophagy in the brain are involved in Alzheimer’s disease. The present paper’s goal was to explore the potential mechanisms of geniposide to protect against Alzheimer’s disease. We treated the human neuroblastoma SH-SY5Y cell line with Aβ1-42 as an Alzheimer’s disease in vitro model to explore the potential mechanisms of geniposide to protect against Alzheimer’s disease. Further, SH-SY5Y cells damaged by Aβ1-42 were treated with geniposide. Akt/mTOR-related proteins and autophagy-associated proteins were measured to reveal the molecular mechanisms by which geniposide protects against Aβ1-42-induced toxicity. Results showed that Akt and mTOR’s geniposide inhibited phosphorylation induced by Aβ1-42, enhanced expression of the LC3II/LC3I ratio, and Atg7 and Beclin1 expression and inhibited expression of p62 induced by Aβ1-42. Our results lead us to hypothesize that inhibition of the Akt/mTOR signaling pathway and autophagy enhancement are fundamental molecular mechanisms for geniposide to protect against Aβ toxicity.
Background:
Geniposide (GE) is the main component in gardenia fruit. This study aimed to investigate the protective effects and potential mechanisms of GE on dextran sulfate sodium (DSS)-induced colitis in mice and lipopolysaccharide (LPS)-induced RAW 264.7 cells.
Methods:
The in vivo acute colitis experimental model was established by administering drinking water containing 3% DSS to the mice for 7 days. GE was administered to the mice via oral gavage at 20 and 40 mg/kg for 7 days. Colon length, colon myeloperoxidase (MPO) level, serum and colon malondialdehyde (MDA) levels, and superoxide dismutase (SOD) activity were determined, and histological evaluation was performed. The levels of interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α (TNF-α) in the serum and colon were detected. The expression of proteins of the nuclear factor E2 related factor 2 (Nrf-2)/HO-1/ NF-κB pathway in the colon was detected. The in vitro model of LPS-induced RAW 264.7 cells to simulate enteritis model. Cell viability, IL-6, IL-1β, and TNF-α levels in the cell supernatant were measured. The MPO levels in RAW 264.7 cells and DSS-induced mice and MDA and SOD levels in the cell supernatant were measured. The expression of proteins of the Nrf-2/HO-1/NF-κB pathway in RAW 264.7 cells was determined.
Results:
GE treatment resulted in significant histological changes and reduced the expression of inflammatory mediators IL-6, IL-1β, and TNF-α the in serum, colon, and cell supernatant effectively. Parenteral nutrition reduced MPO content in the colon and RAW 264.7 cells. GE treatment increased SOD levels in the serum, colon, and cell supernatant. GE restored the protein expression of the Nrf-2/HO-1/ NF-κB pathway in RAW 264.7 cells and nude mice, and these changes were blocked significantly by Nrf-2 siRNA.
Conclusions:
These findings demonstrated that GE ameliorated inflammation and oxidative stress in experimental colitis via modulation of the Nrf-2/HO-1/NF-κB pathway. Thus, GE could serve as a potential therapeutic agent for the treatment of ulcerative colitis (UC).
Non‐alcohol fatty liver disease (NAFLD) is a common disease which causes serious liver damage. Geniposide (GEN), a kind of iridoid glycoside extracted from Gardenia jasminoides fruit, has many biological effects, such as resistance to cell damage and anti‐neurodegenerative disorder. Lipid accumulation was obvious in tyloxapol‐induced liver and oil acid (OA) with palmitic acid (PA)‐induced HepG2 cells compared with the control groups while GEN improved the increasing conditions. GEN significantly lessened the total cholesterol (TC), the triglyceride (TG), low‐density lipoprotein (LDL), very low‐density lipoprotein (VLDL), myeloperoxidase (MPO), reactive oxygen species (ROS) and increased high‐density lipoprotein (HDL), superoxide dismutase (SOD) to response the oxidative stress via activating nuclear factor erythroid‐2–related factor 2 (Nrf2), haeme oxygenase (HO)‐1 and peroxisome proliferator‐activated receptor (PPAR)α which may influence the phosphorylation of adenosine 5’‐monophosphate–activated protein kinase (AMPK) signalling pathway in mice and cells. Additionally, GEN evidently decreased the contents of sterol regulatory element‐binding proteins (SREBP)‐1c, phosphorylation (P)‐mechanistic target of rapamycin complex (mTORC), P‐S6K, P‐S6 and high mobility group protein (HMGB) 1 via inhibiting the expression of phosphoinositide 3‐kinase (PI3K), and these were totally abrogated in Nrf2−/− mice. Our study firstly proved the protective effect of GEN on lipid accumulation via enhancing the ability of antioxidative stress and anti‐inflammation which were mostly depend on up‐regulating the protein expression of Nrf2/HO‐1 and AMPK signalling pathways, thereby suppressed the phosphorylation of mTORC and its related protein.
Background and Purpose
As a typical hypervascular tumour, hepatocellular carcinoma (HCC) is predominantly grown through angiogenesis. Geniposide is a promising anti‐inflammatory compound found in Gardenia jasminoides, but its effects on the progression of HCC remain untested.
Experimental Approach
The anti‐HCC effects of geniposide was investigated in cellular models and orthotopic HCC mice. Transcriptional regulation of the VEGF promoter was measured by dual‐luciferase reporter assay. The anti‐angiogenic action of geniposide was measured by tube formation assay. Both surface plasmon resonance techniques and human phospho‐kinase array analysis were utilized to validate the relationship between targets of geniposide and hepatocarcinogenesis.
Key Results
Geniposide exhibited significant disruption of HCC proliferation, invasion, angiogenesis and lung metastasis in orthotopic HCC mice. Geniposide inhibited secretion of VEGF by HCC and suppressed the migration of endothelial cells and the formation of intra‐tumour blood vessels, without cytotoxicity and independently of the transcription factor HIF‐1α. Direct inhibition of TLR4 by geniposide led to the shutdown of the TLR4/MyD88 pathway and STAT3/Sp1‐dependent VEGF production. However, LPS, an agonist of TLR4, restored STAT3/Sp1‐related VEGF production in geniposide‐inhibited HCC angiogenesis.
Conclusion and Implications
The direct inhibitory effect of geniposide on TLR4/MyD88 activation contributes to the suppression of STAT3/Sp1‐dependent VEGF overexpression in HCC angiogenesis and pulmonary metastasis. This action of geniposide was not affected by stabilization of HIF‐1α. Our study offers a novel anti‐VEGF mechanism for the inhibition of HCC.
Epidemic and pandemic influenza A virus (IAV) poses a significant threat to human populations worldwide. Iridoid glycosides are principal bioactive components from the Gardenia jasminoides J. Ellis fruit that exhibit antiviral activity against several strains of IAV. In the present study, we evaluated the protective effect of Fructus Gardeniae iridoid glycoside extracts (IGEs) against IAV by cytopathogenic effect(CPE), MTT and a plaque formation assay in vitro and examined the reduction in the pulmonary index (PI), restoration of body weight, reduction in mortality and increases in survival time in vivo. As a host factor, PACT provides protection against the pathogenic influenza A virus by interacting with IAV polymerase and activating the IFN-I response. To verify the whether IGEs suppress IAV replication in a PACT-dependent manner, IAV RNA replication, expression of PACT and the phosphorylation of eIF2α in A549 cells were detected; the levels of IFNβ, PACT and PKR in mouse lung tissues were determined; and the activity of IAV polymerase was evaluated in PACT-compromised cells. The results indicated that IGEs sufficiently alleviated cell damage and suppressed IAV replication in vitro, protecting mice from IAV-induced injury and lethal IAV infection. These anti-IAV effects might be related to disrupted interplay between IVA polymerase and PACT and/or prevention of a PACT-dependent overactivated IFN-I antiviral response. Taken together, our findings reveal a new facet of the mechanisms by which IGEs fight the influenza A virus in a PACT-dependent manner.
Fructus Gardeniae (FG) is a common Chinese medicine and food. However, the toxicity of FG has drawn increasing concern, especially its hepatotoxicity. The purpose of this study was to screen the hepatotoxic components of FG and evaluate their effects on rat liver BRL-3A cells. The chemical composition of FG was determined by HPLC-ESI-MS. CCK-8 assay was used to evaluate the cytotoxicity of ten chemical components from FG, and then the toxic components with significant inhibitory activity were selected for further study. The results showed that geniposide, genipin, genipin-1-gentiobioside, gardenoside, and shanzhiside all suppress cells viability. Apoptosis assays further indicated that geniposide and its metabolite genipin are the main hepatotoxic components of FG. Pretreatment of cells with geniposide or genipin increased the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP). The activities of superoxide dismutase (SOD) and glutathione (GSH) were decreased, while the malondialdehyde (MDA) level was increased. The cell contents of tumor necrosis factor (TNF-α), interleukin-6 (IL-6), and nitric oxide (NO) were also increased. Molecular docking simulations were used to investigate the mechanism of FG-induced hepatotoxicity, revealing that geniposide and genipin bind strongly to the pro-inflammatory factor TNFR1 receptor of the NF-κB and MAPK signaling pathways. The obtained results strongly indicate that the hepatotoxicity of FG is caused by iridoids compounds. Genipin had the most significant hepatotoxic effect. These toxic substances destroy the cell antioxidant defense system, increasing inflammatory injury to the liver cells and leading to apoptosis and even necrosis. Thus, this study lays a foundation for toxicology research into FG and its rational application.
Geniposide is an active ingredient with anti-apoptotic and anti-inflammatory properties. This study was to examine the effects of geniposide on a cell model of spinal cord injury (SCI). PC12 cells were administrated with geniposide before subjected to LPS. The effects of geniposide were analyzed by utilizing CCK-8 assay, apoptosis assay, ELISA, RT-qPCR and Western blot. We found that PC12 cells viability was unchanged by treating with geniposide. However, geniposide with concentrations of 200 or 300 μg/mL significantly mitigated LPS-evoked viability loss. Meanwhile, apoptosis driven by LPS was mitigated by geniposide, which accompanied with p53, Bax and cleaved caspase-3 down-regulation, and Bcl-2 up-regulation. Besides this, the expression and release of IL-1β, IL-6, IL-8 and TNF-α evoked by LPS were mitigated by geniposide. miR-145-5p was a target of geniposide. miR-145-5p expression was up-regulated by geniposide, and geniposide did not protect PC12 cells against LPS injury when miR-145-5p was silenced. Moreover, geniposide inhibited NF-κB and JNK pathways via up-regulating miR-145-5p. In short, the present work described the neuroprotective effects of geniposide by targeting miR-145-5p. Further mechanisms involved in geniposide’s beneficial effects are correlated with the inhibited NF-κB and JNK pathways.
Highlights
Geniposide prevents LPS-induced injury in PC12 cells;
Geniposide up-regulates miR-145-5p;
Geniposide protects PC12 cells via up-regulation of miR-145-5p;
Geniposide inhibits NF-κB and JNK pathways via up-regulation of miR-145-5p.
The dried ripe fruit of Gardenia jasminoides Ellis was usually applied as an herb medicine in Traditional Chinese Medicine. It was suggested that the Gardenia jasminoides oil extract (oil from Fructus Gardeniae [OFG]) might serve as a potential treatment for depression, whereas its pathogenesis still remained not fully understood. The present research was conducted to evaluate the anti-depressive effect of OFG in mice and explore its potential mechanism. The OFG and ketamine (KET) were intragastrically and intraperitoneally treated, respectively. Thereafter, the animals were subjected to the behavior tests. The expressions of protein kinase A (PKA), brain derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB) in hippocampus were detected by Western blot. The selective PKA inhibitor H-89 was also applied to confirm the mechanism. As a result, OFG and KET treatment improved the behavior performance. Furthermore, the administrations of OFG effectively enhanced the expressions of PKA, p-CREB, and BDNF. With the application of selective PKA inhibitor H-89, the ameliorated effects caused by OFG were blocked, but not by KET. In conclusion, the presented work indicated that OFG-exerted protective effect on depression through PKA-CREB-BDNF signaling.
Atherosclerosis (AS) is the common pathological basis of chronic cardiovascular diseases and is associated with inflammation and lipid metabolism dysfunction. Geniposide, the main active ingredient of Gardenia jasminoides Ellis fruit, exhibits a variety of anti-inflammatory and anti-oxidative functions; however, its role in AS remains unclear. The aim of this study was to investigate the mechanisms of geniposide in alleviating inflammation and thereby attenuating the development of AS. ApoE−/− mice were fed a high fat diet to induce AS and were treated with geniposide (50 mg/kg) for 12 weeks. Blood glucose and lipid levels were measured by biochemical analysis. H&E, Masson and Oil red O staining were performed to observe morphological changes and lipid deposition in the aorta and liver. Serum inflammatory cytokines were detected by ELISA. Dual-luciferase reporter gene assay was used to verify the target relationship between microRNA-101 (miR-101) and mitogen-activated protein kinase phosphatase-1 (MKP-1). The levels of miR-101, p-p38, and MKP-1 in the aorta were detected by qPCR and western blotting. The anti-inflammatory effect of geniposide in vitro was investigated in the RAW264.7 macrophage cell line. A miR-101 mimic and an inhibitor were used to study the effect of miR-101 on regulating the expression of the target MKP-1 and the downstream inflammatory cytokines. Geniposide treatment reduced lipid levels and plaque size in the mouse model of AS. Geniposide downregulated miR-101 to upregulate MKP-1 and suppress the production of inflammatory factors in vitro and in vivo. Geniposide suppressed the levels of inflammatory factors in the presence of the miR-101 mimic, whereas no obvious effect was observed in the miR-101 inhibitor group. We concluded that geniposide reduced the plaque size and alleviated inflammatory injury in ApoE−/− mice and RAW264.7 cells. The specific anti-inflammatory mechanism was related to the miR-101/ MKP-1/p38 signaling pathway.
Gardeniae fructus (GF), an evergreen Rubiaceae shrub, is one of the most commonly used Chinese herbs in traditional Chinese medicine (TCM) and has been used for over a thousand years. It is usually prescribed for the treatment of brain aging, vascular aging, bone and joint aging, and other age-related diseases. It has been demonstrated that several effective compounds of GF, such as geniposide, genipin and crocin, have neuroprotective or related activities which are involved in senile disease treatment. These bioactivities include the mitochondrion dysfunction, antioxidative activity, apoptosis regulation and an anti-inflammatory activity, which related to multiple signaling pathways such as the nuclear factor-κB pathway, AMP-activated protein kinase signaling pathway, and the mitogen-activated protein kinase pathway. To lay the ground for fully elucidating the potential mechanisms of GF in treating age-related pathologies, we summarized the available research conducted in the last fifteen years about GF and its effective components, which have been studied in vivo and in vitro
Iridoid glycosides are natural products occurring widely in many herbal plants. Geniposide (C17H24O10) is a well-known one, present in nearly 40 species belonging to various families, especially the Rubiaceae. Along with this herbal component, dozens of its natural derivatives have also been isolated and characterized by researchers. Furthermore, a large body of pharmacological evidence has proved the various biological activities of geniposide, such as anti-inflammatory, anti-oxidative, anti-diabetic, neuroprotective, hepatoprotective, cholagogic effects and so on. However, there have been some research articles on its toxicity in recent years. Therefore, this review paper aims to provide the researchers with a comprehensive profile of geniposide on its phytochemistry, pharmacology, pharmacokinetics and toxicology in order to highlight some present issues and future perspectives as well as to help us develop and utilize this iridoid glycoside more efficiently and safely.
Fructus Gardenia (FG), containing the major active constituent Geniposide, is widely used in China for medicinal purposes. Currently, clinical reports of FG toxicity have not been published, however, animal studies have shown FG or Geniposide can cause hepatotoxicity in rats. We investigated Geniposide-induced hepatic injury in male Sprague-Dawley rats after 3-day intragastric administration of 100 mg/kg or 300 mg/kg Geniposide. Changes in hepatic histomorphology, serum liver enzyme, serum and hepatic bile acid profiles, and hepatic bile acid synthesis and transportation gene expression were measured. The 300 mg/kg Geniposide caused liver injury evidenced by pathological changes and increases in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and γ-glutamytransferase (γ-GT). While liver, but not sera, total bile acids (TBAs) were increased 75% by this dose, dominated by increases in taurine-conjugated bile acids (t-CBAs). The 300 mg/kg Geniposide also down-regulated expression of Farnesoid X receptor (FXR), small heterodimer partner (SHP) and bile salt export pump (BSEP). In conclusion, 300 mg/kg Geniposide can induce liver injury with associated changes in bile acid regulating genes, leading to an accumulation of taurine conjugates in the rat liver. Taurocholic acid (TCA), taurochenodeoxycholic acid (TCDCA) as well as tauro-α-muricholic acid (T-α-MCA) are potential markers for Geniposide-induced hepatic damage.
Background/aims:
Myocardial ischemia/reperfusion injury is a major cause of morbidity and mortality associated with coronary heart disease. Many studies have demonstrated that natural products are promising chemotherapeutic drugs counteracting the loss of cardiomyocytes. Thus, the purpose of the present study was to investigate the effects of geniposide, a traditional Chinese herb extract from Gardenia jasminoides J. Ellis, on cardiomyocyte apoptosis induced by hypoxia/reoxygenation (H/R) in H9c2 cells, and their underlying mechanisms.
Methods:
Cell viability and apoptosis ratio were assessed using the cell counting kit-8 assay and Annexin V/propidium iodide (PI) staining. The concentrations of lactate dehydrogenase (LDH), intracellular total superoxide dismutase (T-SOD), and malondialdehyde (MDA) were detected by microplate reader. The production of reactive oxygen species/reactive nitrogen species (ROS/RNS), the level of mitochondrial calcium, and mitochondrial membrane potential depolarization were measured by confocal laser scanning microscopy. Mitochondrial morphology was visualized using transmission electron microscopy. The expressions of Bcl-2 mRNA and Caspase-3 mRNA were measured by reverse transcription-polymerase chain reaction (RT-PCR). The protein levels of cleaved caspase-3, Bcl-2, Bax, AKT, p-AKTserine473, cytochrome-c were detected by western bloting.
Results:
Geniposide pretreatment increased cell viability, decreased LDH levels in the supernatant, and inhibited cardiomyocyte apoptosis caused by H/R. Furthermore, geniposide reversed mitochondrial dysfunction by decreasing oxidative stress products (ROS/RNS and MDA), increasing anti-oxidative enzyme (T-SOD) level, improving mitochondrial morphology, attenuating mitochondrial calcium overload and blunting depolarization of mitochondrial membrane. Moreover, geniposide pretreatment increased Bcl-2 level and decreased Bax level, thus enhancing the Bcl-2/Bax ratio. Consistent with the above result, Bcl-2 mRNA expression was upregulated and caspase-3 mRNA expression was downregulated by geniposide. In addition, geniposide decreased the protein expression of cleaved caspase-3 and cytochrome-c and increased the level p-AKTserine473. The protective effects of geniposide were partially reversed by glucagon-like pepitide-1 receptor antagonist exendin-(9-39) and the phosphatidylinositol 3 kinase (PI3K) inhibitor LY294002.
Conclusions:
Our results suggest that geniposide pretreatment inhibits H/R-induced myocardial apoptosis by reversing mitochondrial dysfunction, an effect in part due to activation of GLP-1R and PI3K/AKT signaling pathway.
The neuroinflammation induced by amyloid-β (Aβ) is one of the key events in Alzheimer's disease (AD) progress in which microglia are the main cells involved. Receptor for advanced glycation end products (RAGE) mediates and enhances Aβ-induced microglial activation and leads to induction of proinflammatory mediators, such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). Geniposide, a pharmacologically active component purified from gardenia fruit, exhibits a broad spectrum anti-inflammatory effect as well as neurotrophic and neuroprotective properties. However, the effects of geniposide on Aβ-mediated microglial pathways have not been fully discovered. Here, we demonstrate that geniposide treatment significantly blocks Aβ-induced RAGE-dependent signaling (activation of ERK and NF-κB) along with the production of TNF-α and IL-1β in cultured BV2 microglia cells. Notably, based on the data from coimmunoprecipitation assay, we infer that geniposide exerts protective effects on Aβ-induced inflammatroy response through blocking Aβ binding to RAGE and suppressing the RAGE-mediated signaling pathway. Taken together, these findings indicate that geniposide is a potent suppressor of neuroflammation through inhibiting RAGE-dependent signaling pathway. Thus, geniposide may be a potential therapeutic agent for the treatment of neuroinflammation that is involved in neurological diseases such as AD.
We have previously demonstrated that geniposide attenuates the production of Aβ1–42 both in vitro and in vivo via enhancing leptin receptor signaling. But the role played by geniposide in the phosphorylation of tau and its underlying
molecular mechanisms remain unclear. In this study, we investigated the effect of geniposide on the phosphorylation of tau
and the role of leptin signaling in this process. Our data suggested that, accompanied by the up-regulation of leptin receptor
expression, geniposide significantly decreased the phosphorylation of tau in rat primary cultured cortical neurons and in
APP/PS1 transgenic mice, and this geniposide-induced decrease of tau phosphorylation could be prevented by leptin antagonist
(LA). Furthermore, LA also prevented the phosphorylation of Akt at Ser-473 site and GSK-3β at Ser-9 site induced by geniposide.
All these results indicate that geniposide may regulate tau phosphorylation through leptin signaling, and geniposide may be
a promising therapeutic compound for the treatment of Alzheimer's disease in the future.
Objective: To study the main constituents from Gardenia jasminoides. Method In this study, the chemical constituents of enrichment fraction of iridoid glycosides were isolated by various chromatographic techniques and their structures were elucidated by spectroscopic analyses and comparison of NMR data with those reported in literatures. Results: The 60% ethanol extract of G. jasminoides was subjected to HP-20 macroporous adsorption resin CC to yield 30% ethanol fraction (GJ-2, UPLC-Q/TOF-MS method was used to identify the enrichment fraction of iridoid glycosides). Thirty-one compounds were obtained and characterized as 2'-O-trans-coumaroylgardoside (1), 6'-O-trans-sinapoylgardoside (2), 7-deoxygardoside (3), tarenninoside C (4), 2'-O-coumaroylmussaenosidic acid (5), 10-O-caffeoyl deacetyldaphylloside (6), 6'-O-trans-sinapoylgeniposide (7), genipin-1-O-β-D-gentiobioside (8), geniposide (9), 7-deoxy-8-epiloganicacid (10), secologanoside (11), gardenamide A (12), 6'-O-trans-sinapoyljasminoside B (13), epijasminoside A (14), jasminodiol (15), 6'-O-trans-sinapoyljasminoside L (16), 3-(β-D- glucopyranosyl-oxymethyl)-2,4,4-trimethyl-2-cyclohexen-1-one (17), jasminoside C (18), sinapinic acid (19), caffeic acid (20), methyl gallate (21), C-veratroylglucol (22), β-hydroxypropiosyringone (23), 3-hydroxy-1-(4-hydroxy-3-methoxyphenoyl) propan-1-one (24), threo-guaiacylglycerol-8'-vanillic acid ether (25), 1,2-bis-(4-hydroxy-3-methoxyphenyl)-1,3-propanediol (26), trans-2,3,5,4'-tetrahydroxystilbene-2-β-D-glucoside (27), 1-sinapoyl-β-D-glucopyranoside (28), 1,3,5-trimethoxybenzene (29), rutin (30), and glycyrrhisoflavone (31), respectively. Conclusion: Compounds 1-12are iridoid glycosides and 13-18are monoterpenoid glycosides. Compounds 6, 10, 22-29, and 31 were identified from Gardeniae Fructus for the first time. © 2020, Editorial Office of Chinese Traditional and Herbal Drugs. All right reserved.
Background
Herb-induced liver injury is a leading cause of drug-induced liver injury in China and its incidence is also increasing worldwide. Gardeniae Fructus (ZZ) has aroused wide concern for hepatotoxicity in recent decades. But when ZZ is administered in combination with Semen Sojae Praeparatum (DDC) to compose a herbal pair Zhizichi Decoction (ZZCD), lower hepatotoxicity is observed. The mechanism involved in the attenuated effect remains to be investigated.
Hypothesis/purpose
Our previous studies showed that DDC benefited host metabolism by regulating the gut microbiota and it reduced the exposure of major toxic components of ZZ. The present study was aimed to investigate how DDC attenuated hepatotoxicity of ZZ from the perspective of gut microbiota.
Methods
Rats received ZZ and ZZCD treatment of different dosages and antibiotic treatment was applied to explore the involvement of gut microbiota. Biochemical assays and histopathological analysis were conducted to evaluate liver injury. Gut microbiota in caecal contents was profiled by 16S rRNA sequencing. Short-chain fatty acids (SCFAs) in caecal contents were measured by gas chromatography mass spectrometry (GCMS). To verify the protective effect of butyrate, it was administered with genipin, the major hepatotoxic metabolite of ZZ, to rats and HepG2 cells. Plasma lipopolysaccharide (LPS) level and colon tissue section were used to evaluate gut permeability. Expression level of Nuclear factor erythroid-derived 2-like 2 (Nrf2) was detected by immunohistochemistry in vitro and by western blot in vivo.
Results
Our study showed that ZZCD displayed lower hepatotoxicity than ZZ at the same dosage. ZZ induced gut dysbiosis, significantly reducing Lactobacillus and Enterococcus levels and increasing the Parasutterella level. In combination with DDC, these alterations were reversed and beneficial genus including Akkermansia and Prevotella were significantly increased. Besides, butyrate production was diminished by ZZ but was restored when in combination with DDC. Butyrate showed detoxification on genipin-induced liver injury by promoting colon integrity and promoting Nrf2 activation. Besides, it protected genipin-induced hepatocyte damage by promoting Nrf2 activation.
Conclusion
DDC attenuates ZZ-induced liver injury by regulating the microbiota, promoting butyrate production and activating antioxidant response.
To study the time-toxicity relationship and mechanism of Gardeniae Fructus extract on the hepatoxicity in rats. Rats were randomly divided into C group(0 day), D5 group(5 days), D12 group(12 days), D19 group(19 days), and D26 group(7 days recovery after 19 days of administration). The rats in normal group received normal saline through intragastric administration, and the rats in other groups received 10 g·kg~(-1 )Gardeniae Fructus extract through intragastric administration. After the final administration, the livers were collected. Hematoxylin-eosin staining was used to observe the histopathological changes in the liver tissue. Total liver proteins were extracted for proteomic analysis, detected by the Nano-ESI liquid-mass spectrometry system and identified by Protein Disco-very software. SIEVE software was used for relative quantitative and qualitative analysis of proteins. The protein-protein interaction network was constructed based on STRING. Cytoscape software was used for cluster analysis of differential proteins. Kyoto encyclopedia of genes and genomes(KEGG) database was used to perform enrichment signal pathway analysis. Pearson correlation analysis was performed for the screened differential protein expression and liver pathology degree score. The results showed that the severity of liver injury in D5, D12 and D19 groups was significantly higher than that in group C. The degree of liver damage in D5 group was slightly higher than that in D12 and D19 groups, with no significant difference between group D26 and group C. Totally 147 key differential proteins have been screened out by proteomics and mainly formed 6 clusters, involving in drug metabolism pathways, retinol metabolism pathways, proteasomes, amino acid biosynthesis pathways, and glycolysis/gluconeogenesis pathways. The results of Pearson correlation analysis indicated that differential protein expressions had a certain temporal relationship with the change of liver pathological degree. The above results indicated that the severity of liver damage caused by Gardeniae Fructus extract did not increase with time and would recover after drug with drawal. The above pathways may be related to the mechanism of liver injury induced by Gardeniae Fructus extract.
Two new iridoid glycosides, genipin 1,10-di-O-α-l-rhamnoside (1) and genipin 1,10-di-O-β-d-xylopyranoside (2), along with thirteen known compounds (3–15) were isolated from Gardeniae Fructus. Their structures were elucidated by physical data analyses such as NMR, UV, IR, HR-ESI-MS, as well as chemical hydrolysis. All compounds were tested for their tyrosinase inhibitory and antioxidant activities. At a concentration of 25 μM, compound 13 showed obvious mushroom tyrosinase inhibition activity with % inhibition value of 36.52±1.98%, with kojic acid used as the positive control (46.09±1.29%). At a concentration of 1 mM, compounds 8 and 9 exhibited considerable DPPH radical scavenging activities, with radical scavenging rates of 48.54 ± 0.47%, 58.59 ± 0.39%, respectively, with l-ascorbic acid used as the positive control (59.02 ± 0.77%).
Geniposide (GE) can effectively inhibit diabetic nephropathy (DN), but its mechanism is unclear. The objective of this study was to explore the antidiabetic nephropathy effects of GE both in high fat diet/streptozotocin-induced DN mice and in high glucose-induced podocyte model. Renal function in DN mice was evaluated by levels of serum creatinine (Scr) and blood urea nitrogen (BUN). Renal inflammation was appraised by pro-inflammatory cytokines: Tumor necrosis factor α (TNF-α), Interleukin 6 (IL-6) and IL-1β via ELISA assay. Renal histopathology analysis was conducted via hematoxylin and eosin, Masson and periodic acid-silver metheramine staining. Cellular viability was measured by Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay. Moreover, the related proteins p–NF–κB, ASC, Cleave-IL-1β, NLRP3, Cleave-Caspase-1 and GSDMD-N in AMPK/SIRT1/NF-κB pathway were assayed by Western blotting. In order to further investigate the effects of GE on podocytes, we also assessed these protein levels in AMPK/SIRT1/NF-κB pathway after siRNA-AMPK intervention by Western blotting. GE alleviated renal dysfunction as evidenced by decreased levels of Scr, BUN, TNF-α, IL-6 and IL-1β. Histological examination revealed GE effectively attenuated kidney damage, including glomerular basement membrane thickening and inflammatory cells infiltration. AMPK, p-AMPK and SIRT1 levels were obviously decreased both in DN mice and in podocyte model, but GE reversed these changes. The protein expressions in APMK/SIRT1/NF-κB pathway were significantly decreased by GE treatment. These results suggested that GE could efficiently block oxidative stress and inflammatory responses accompanied with pyroptosis, thus inhibiting the development of DN, and its mechanism might be related to APMK/SIRT1/NF-κB pathway.
Gardeniae Fructus has the traditional effects of promoting intelligence and inducing resuscitation, but its mechanism is unclear. In this study, the relationship between Gardeniae Fructus's traditional effect of promoting intelligence and inducing resuscitation and anti-Alzheimer's disease effect was taken as the starting point to investigate the anti-Alzheimer's disease mechanism of the major absorbed components in Gardeniae Fructus by the network pharmacology method. The network pharmacology research model of "absorbed composition-target-pathway-disease" was adopted. In this study, the active components screening and target prediction technology were used to determine the active components and targets of Gardeniae Fructus in treatment of Alzheimer's disease. The enrichment pathway and biological process of Gardeniae Fructus were studied by using the bioinformatics annotation database(DAVID), and the results of molecular docking validation network analysis were used to elaborate the mechanism of Gardeniae Fructus in treatment of Alzheimer's disease. It was found that 35 absorbed components of Gardeniae Fructus not only regulated 48 targets such as cholines-terase(BCHE) and carbonic anhydrase 2(CA2), but also affected 11 biological processes(e.g. transcription factor activity, nuclear receptor activity, steroid hormone receptor activity, amide binding and peptide binding) and 7 metabolic pathways(MAPK signaling pathway, Alzheimer disease and estrogen signaling pathway, etc.). Molecular docking results showed that more than 60% of the active components could be well docked with key targets, and the relevant literature also showed that the active components could inhibit the MAPK1 expression of key targets, indicating a high reliability of results. These results indicated that Gardeniae Fructus may play its anti-Alzheimer's disease action via a "multi-ingredients-multi-targets and multi-pathways" mode, providing a scientific basis for further drug research and development.
Two new iridoid glycosides, 2′-O-cis-coumaroylgardoside (1), and 6′-O-caffeoylioxide (2), were isolated from the fruit of Gardenia jasminoides. The structures of these compounds were elucidated based on spectroscopic analysis (HR-ESI-MS, NMR) and chemical methods. The anti-inflammatory activities of the isolates were evaluated by measuring their inhibitory effects on PGE2 production in LPS stimulated RAW 264.7 macrophages, compounds 1 and 2 could reduce PGE2 levels in LPS-activated RAW 264.7 macrophages with IC50 values of 121.4 and 83.38 μM, respectively.
Hypercholesterolemia is the main risk factor to threaten human health and geniposide has been found to have hypolipidemic functions. However, its underlying mechanism is not clear. In this study, we firstly confirmed the hypolipidemic functions of geniposide in C57BL/6 and ApoE-/- mice (i.p, 50 mg/kg/d). Then hepatic or arterial lipid accumulation was analyzed through histomorphology. Moreover, the effects of geniposide on the bile acid metabolism were analyzed by the hepatic RNA-seq and biological molecular analysis. Mechanistically, GW4064, an FXR agonist, was carried out to verify the mechanisms of geniposide in human HepG2 and Caco2 cells. As expected, geniposide decreased the lipid accumulations both in plasma and liver. Morever, the atherosclerotic plaque shrank in HCD-fed ApoE-/- mice with geniposide treatment. The molecular analysis revealed that geniposide accelerated the hepatic synthesis of bile acids through inactivating the negative feedback regulation of bile acids mediated by FXR, led to the enhancive reverse cholesterol transport and cholesterol catabolism. What's more, geniposide reduced ileal FXR-mediated reabsorption of bile acids, resulting in the increasing excretion of bile acids. Our study pointed out the regulatory functions of geniposide on FXR-mediated liver-gut crosstalk of bile acids and geniposide might be a novel strategy for maintaining cholesterol homeostasis.
The aim of this paper was to screen out relevant genes of geniposide-induced hepatotoxicity based on genomics,in order to provide a scientific basis for the non-clinical evaluation of drugs containing Gardeniae Fructus and geniposide. Fifty-five SD rats were randomly divided into normal control group,24 h group and 72 h group. The changes of appearance,behavior and weight of rats were observed after administration by gavage for 3 days. The activities of ALT and AST were detected. Molecular mechanism of geniposideinduced hepatotoxicity was investigated by Affymetrix miRNA 4. 0 and Affymetrix Rat Gene 2. 0 to examine the gene expression levels in Sprague-Dawley rat livers at 24 h and 72 h after administration of overdose-geniposide( 300 mg·kg-1 daily),and then verified by Realtime quantitative PCR. Compared with the normal control group,the activities of ALT and AST were markedly increased. In addition,experimental results indicated that 324 genes were differentially expressed,among which 259 were up-regulated and 65 down-regulated.Nine candidate genes were verified by qRT-PCR,including Bcl2,Il1 b,Tpm3,MMP2,Col1α1,Ifit1,Aldob,Nr0 b2,Cyp2 c23. And Bcl2,Col1α1,Aldob,Nr0 b2 and Cyp2 c23 were found to be correlated with geniposide-induced hepatotoxicity. This study provides an important clue for mechanism of geniposide-induced hepatotoxicity.
Objective
To study the antidepressant-like effect and action mechanism of geniposide and eleutheroside B combination treatment on the lipopolysaccharide (LPS)-induced depression mice model.
Methods
Depression mice model was established by lipopolysaccharide (LPS) injection. Totally 48 mice were randomly divided into 6 groups (8 rats per group) according to a random number table, including normal, model, fluoxetine (20 mg/kg), geniposide (100 mg/kg) + eleutheroside B (100 mg/kg), geniposide + eleutheroside B + WAY 100635 (0.03 mg/kg), geniposide + eleutheroside B+ N-methyl-D-aspartic acid receptor (NMDA, 75 mg/kg) groups, respectively. After continuous administration for 10 days, autonomic activity tests after 30 min of administration were performed on the 10th day. On the 11th day, except for the normal group, the mice in the other groups were intraperitoneally injected with LPS (1 mg/kg), and the behavioral tests were performed 4 h later. Enzyme linked immunosorbent assay was used to detect tumor necrosis factor alpha (TNF- α) and interleukin-1 β (IL-1 β) levels in mice serum. The mRNA expression of indoleamine 2,3-dioxygenase (IDO) and nuclear transcription factor (NF- κB) were detected by real-time quantitative polymerase chain reaction. Western-blot analysis was used to detect IDO and NF- κB protein expressions in hippocampus tissue.
Results
Compared with the normal group, a single administration of LPS increased the immobility time in the forced swimming test (FST) and tail suspension test (TST, P<0.01), without affecting autonomous activity. Compared with the model group, fluoxetine and geniposide + eleutheroside B administration significantly improved the immobility time of depressed mice in the FST and TST, decreased serum IL-1 β content, inhibited the expression levels of NF- κ B gene and protein in hippocampus tissues (P<0.05 or P<0.01). Compared with the model group, geniposide + eleutheroside B treatment significantly reduced serum TNF-α content and inhibited IDO mRNA and protein expressions in hippocampus (P<0.05 or P<0.01). In addition, NMDA partly prevented the inhibition of IDO mRNA expression by geniposide + eleutheroside B; NMDA and WAY-100635 also partly prevented the reduction of IL-1 ß content induced by geniposide + eleutheroside B treatment (P<0.05 or P<0.01).
Conclusions
The combination of geniposide and eleutheroside B showed a certain antidepression-like effect. Its main mechanism of action may be contributed to inhibiting the activation of NF- κB, decreasing the proinflammatory cytokines such as TNF-α, IL-1 β, and inhibiting in the neuroinflammatory reaction. Additionally, it also affects tryptophan metabolism, reduces the expression of a key enzyme of tryptophan metabolism, IDO. And this antidepressant-like effect may be mediated by 5-hydroxytryptamine and glutamate systems.
Alcoholic steatosis is one of the most prevalent forms of liver disease, and appropriate insight and application of anti-steatosis drugs must be considered. Geniposide, the major active constituent of the Gardenia jasminoides (Ellis) fruit, has been commonly used as a traditional herbal medicine for the treatment of liver diseases. However, its hepatoprotective effect on alcoholic steatosis has not been reported. Moreover, geniposide overdose-induced hepatotoxicity had been demonstrated. Hence, its therapeutic effects and overdose-induced hepatotoxicity in rat models along with corresponding targets, especially the targets of transcription factors (TFs), were systematically investigated in this study by using a concatenated tandem array of consensus TF response elements. The results indicate that geniposide can attenuate alcoholic steatosis and liver injury by enhancing the transcriptional activities of peroxisome proliferator-activated receptor-ɑ and hepatocyte nuclear factors 1ɑ and 4ɑ, while geniposide overdose perturbs other TFs. In addition, therapeutic doses and overdoses of geniposide have differentiated target TFs. This study is the first to provide a systematic insight into the difference of critical transcription factors between the actions of therapeutic doses and overdoses of geniposide, as well as much-needed attention to the important topic of alcoholic liver disease therapy.
Hyperuricemia is a key risk factor for kidney disease. Geniposide possesses various pharmacological activities, however, to our knowledge, no previous work investigated the therapeutic effect of geniposide on urate nephropathy. The present study established a chronic hyperuricemia model using a combination of adenine and ethambutol administration. The potential beneficial effects and mechanisms of geniposide on hyperuricemia and nephropathy were also investigated. The results demonstrated that geniposide significantly decreased SUA levels via inhibition of the XOD activity and increasing the excretion of urinary uric acid. Geniposide also markedly improved kidney damage related to hyperuricemia. Further investigation indicated that geniposide improved the symptoms of nephropathy via decreasing the production of proinflammatory cytokines, including IL-1β, PG-E2, and TNF-α, and inhibiting the expression of TGF-β1. The molecular mechanism of action may be associated with suppression of TLR4/MyD88 signaling and NLRP3 inflammasome activation to reduce IL-1β and TNF-α production respectively in hyperuricemic mice.
To screen the active ingredients of Gardenia jasminoides and potential targets,and investigate the mechanisms against cholestasis based on network pharmacology technology. Twenty-one active components of G. jasminoides were retrieved and the target sites were screened by using Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform( TCMSP). Cytoscape3. 2. 1 was used to construct the component-target network. Two hundred and eight targets related to cholestasis were searched and screened through Dis Ge NET,KEGG and OMIM databases. The key targets of G. jasminoides components and cholestasis were integrated and screened,and the component-target-disease network was constructed with Cytoscape 3. 2. 1 software to screen out the core network whose freedom degree was greater than the average value. The Clue GO plug-in of Cytoscape 3. 2. 1 software was used to analyze the biological processes and pathway enrichment of G. jasminoides in regulation of cholestasis. GO biological process analysis revealed 17 biological processes,involving 3 signaling biological processes related to cholestasis,i.e. acute inflammatory response,positive regulation of reactive oxygen species metabolic process,and nitric oxide biosynthetic process. KEGG-KEEG-305 terms and REACTOME pathways analysis revealed 17 regulatory pathways,involving 4 signaling pathways related to cholestasis,i.e. metabolism of xenobiotics by cytochrome P450,nuclear receptor transcription pathway,GPVI-mediated activation cascade and platelet activation. It was found that aqueous extract of G. jasminoides could improve serum biochemical abnormalities in ANIT-induced cholestasis rats. Aqueous extract of G. jasminoides could decrease the protein and mRNA expression levels of ESR1 in liver tissues,and increase the protein and mRNA expression levels of PPARG,NOS2,F2 R,NOS3,and NR3 C1. To sum up,the possible mechanisms of G. jasminoides against cholestasis may be related with the above three processes and four pathways.
Geniposide is a natural hepatotoxic iridoid glycoside. Its hydrolysate of intestinal microbiota, genipin, is thought to be responsible for the hepatotoxicity. However, the underlying mechanism that genipin contributes to the hepatotoxicity of geniposide is not well understood. In this study, we found that genipin spontaneously converted into a reactive dialdehyde intermediate and covalently bond to the primary amine group of free amino acids in both of the phosphate buffers and geniposide-treated rats. Furthermore, genipin dialdehyde can form the covalent linkage to the primary amino group (ε) of lysine side chains of the hepatic proteins in geniposide-treated rats. Pretreatment with β-glucosidase or antibiotics significantly modulated the genipin dialdehyde formation and protein modification, revealing the essential role of microbial glycosidases. The levels of protein adduct were that mapped onto the hepatotoxicity of geniposide. In summary, this study demonstrates that the intestinal microbiota mediated covalent modification of the hepatic protein by genipin dialdehyde may play a crucial role in the liver injury of geniposide. The study is also helpful for understanding the contribution of intestinal microbiota to the metabolic activation of xenobiotics.
Ethnopharmacological relevance
Fructus Gardenia (FG) is a widely used bitter and cold herb for clearing heat and detoxicating. Currently, toxicity of FG and its relative formula has been reported in many clinical and animal studies. However, no systematic research has been carried out on FG-related gastrointestinal (GI) injury which has been emphasized in China since the Ming Dynasty.
Aim of the study
The purpose of this article is to investigate whether FG could damage GI and explore the mechanisms involved.
Material and methods
FG was given to male mice by 7-day intragastric administration at average doses of 0.90 g (L group), 1.50 g (M group), and 3.00 g (H group) crude drug/kg FG. Comprehensive understanding of changes in weight, diarrhea degree, stool routine, histomorphology and inflammatory factors of stomach, small intestine, and colon for evaluating the effect of different doses of FG on GI injury. Moreover, metabolomics-based mechanisms exploration of FG on GI injury was carried out via HPLC-Q-TOF/MS analysis on mice urine.
Results
High dose FG caused GI injury with serious diarrhea, decreased weight, abnormal stool routine, sever alteration in histomorphology of small intestine and colon (mild change in stomach), and significant change in inflammatory factors. The results of metabolomics suggested that 55 endogenous metabolites dispersed in 21 significantly altered metabolic pathways in 3.00 g/kg crude FG treated mice. The hub metabolites of GI injury were mainly related with vitamin B6 metabolism, phenylalanine metabolism, arachidonic acid metabolism, and taurine and hypotaurine metabolism via correlated network analysis.
Conclusion
FG affected the normal functions of GI via the regulating a variety of metabolic pathways to an abnormal state, and our results provided a research paradigm for the GI-injury of the relative bitter and cold traditional Chinese medicines.
A new cycloartane triterpenoid, named gardenolic acid C (1), a new ursane triterpenoid, named 3β,16β,21β,23,24-pentahydroxy urs-12,18,20-trien-28-oic acid γ-lactone (2), together with three know triterpenoids, gardenolic acid A (3), gardenolic acid B (4), and 3α,16β,23,24-tetrahydroxy-28-nor-ursane-12,17,19,21-tetraen (5) were isolated from the fruits of Gardenia jasminoides Ellis. The structures of these compounds were elucidated by analyses of spectroscopic data. All isolates were evaluated for their neuroprotective effects in vitro.
There are three species of medicinal plants of Euscaphis, and two of them are species in China, including Euscaphis japonica and E. konishii, which are valuable traditional Chinese medicine, and are widely used in the folk. Until now, triterpenes, phenoic acids, flavonoids, sesquiterpenes and others components have been found in Euscaphis. Accumulating studies showed that Euscaphis possess the pharmacological activity of anti-inflammatory, anticancer, antiliver fibrosis and antibacteria. This article summarized the chemical and pharmacological research of Euscaphis, which would provide reference to its plant resources utilization and medicinal material basic research. © 2018, Editorial Office of Chinese Traditional and Herbal Drugs. All right reserved.
Gardeniae Fructus, which is widely used in health foods and clinical medicines, is a type of edible food and medicine. Dictionary of traditional Chinese medicine prescriptions provides good materials for prescription analysis and the R&D of traditional Chinese medicines. The composition regularity of formulae containing Gardeniae Fructus in dictionary of traditional Chinese medicine prescriptions was analyzed on the basis of the traditional Chinese medicine inheritance support system(TCMISS), in order to provide reference for clinical application and the R&D of new drugs. TCMISS was applied to establish a database of prescriptions containing Gardeniae Fructus. The software's frequency statistics and association rules and other date mining technologies were adopted to analyze commonly used drugs, combination rules and core combined formulae containing Gardeniae Fructus. Totally 3 523 prescriptions were included in this study and involved 1 725 Chinese herbs. With a support degree of 352(10%) and confidence coefficient of 90%, 57 most commonly used drug combinations were screened. Drugs adopted in core combinations were relatively concentrated and selected according to definite composition methods. They were used to mainly treat 18 diseases. Gardeniae Fructus have often been combined with herbs for heat-clearing and detoxification, expelling pathogenic wind, relieving exterior syndrome, invigorating the circulation of blood and gas and promoting blood circulation for removing blood stasis to mainly treat jaundice, typhoid, headache and other syndromes.
Ethnopharmacological relevance:
Geniposide, the major active constituent of Fructus Gardeniae (FG), has been widely used to treat the various diseases in China.
Aim of the study:
The chronic toxicity study was conducted to investigate the safety of Geniposide.
Materials and methods:
Sprague-Dawley (SD) rats of both sexes were administered orally Geniposide 25, 50, 100mg/kg by gavage once daily at volume of 10mL/kg for 26 weeks repeated. Endpoints evaluated included clinical observations, food consumption, body weights, blood biochemistry, hematology, and histomorphological observation.
Results:
The administration of Geniposide did not influence the animal mortality, general conditions of animals, body weights and food consumption. After 4 weeks administration, there was no significant toxicity. However, in the 13 weeks toxicity study, a few hematological parameters and some relative organ weights of male rats in Geniposide 50 and 100mg/kg group showed significant increase. Reticulocyte (%) (Retic) of male and female rats administered with 100mg/kg Geniposide were increased significantly. In addition, two female rats in group of 100mg/kg Geniposide showed slight pathological changes in hepatic and renal tissue. Furthermore, in a chronic (26 weeks) toxicity study, alanine aminotransferase (ALT), aspartate aminotransferase (AST), sodium (Na(+)), potassium (K(+)), white blood cell (WBC), red blood cell (RBC), hemoglobin (HGB) and liver, spleen relative organ weight of male rats, and Retic, liver, thymus, kidneys relative organ weight of female rats administered 100mg/kg Geniposide showed differences significantly. Urinalysis results of male and female rats in 100mg/kg Geniposide group revealed changes obviously. Histopathological structure of hepatic and renal tissues in Geniposide high dose group exhibited seriously abnormalities and pigment deposition.
Conclusion:
The results indicated Geniposide has affected serum biochemistry, urinalysis and hematology parameters, and relative organ weights, especially caused obviously pathological abnormalities of liver and kidney tissues. Therefore, Geniposide at high dose level (100mg/kg) administered for 26 weeks could induce obvious damage on liver and kidney.
Our previous work revealed that in the pancreatic ? cell line, geniposide modulated ATP production and glucose-stimulated insulin secretion (GSIS) induced by the acute stimulation of high glucose concentration. However, the effects of geniposide on functional impairment and the mass of ?-cells exposed to elevated levels of glucose remains unknown. In the present study, impaired GSIS and restrained proliferation were observed in the prolonged culture of insulinoma INS-1 cells with 33mM of glucose (high glucose). Our results indicate that the glucose-induced impairment of insulin release was significantly reverted by the inclusion of 1 or 10?M of geniposide. Moreover, induction of the phosphorylation of AMP-activated protein kinase (AMPK) was observed, which promoted the utilization of nutrient stores for energy production. AMPK phosphorylation was enhanced by an increased number of INS-1 cells, and the increased expression of AMPK downstream target heme oxygenase 1 (HO-1), under high glucose concentration. Furthermore, geniposide protected rat insulinoma cells from apoptosis in high-glucose concentrations. We have shown that these effects were associated with an increased apoptosis-related Bcl-2/BAX protein ratio. In conclusion, geniposide dose dependently improves ?-cell function and increases the proliferation of ?-cells exposed to prolonged hyperglycemia.
Four new iridoids, 2'-O-trans-coumaroylshanzhiside (1), 6'-O-trans-coumaroyl- shanzhiside (2), 8α-butylgardenoside B (3), 6α-methoxygenipin (4), and one new phenylpropanoid glucoside, 4-methoxy-benzenepropanol-3-O-β-D-glucopyranoside (5), together with sixteen known compounds, were isolated from the edible flowers of wild Gardenia jasminoides Ellis. Their chemical structures were characterized by extensive spectroscopic techniques, including 1D/2D NMR, HRESIMS, and CD experiments. The absolute configurations of the new isolates' sugar moiety were assigned by HPLC analysis of the acid hydrolysates. Furthermore, the antioxidant activities of those isolates were preliminarily evaluated by DPPH scavenging experiment. And comparison of (1) H NMR spectra for the ethanol extract of G. jasminoides Ellis, gardenoside B and geniposide revealed that the flowers of this plant have a considerable content of gardenoside B instead of geniposide in the fruits, indicating different activities and applications in people's daily life. This article is protected by copyright. All rights reserved.
Ethnopharmacological relevance:
Geniposide (GE) is one of the major iridoid glycosides isolated from the fruit of Gardenia jasminoides Ellis that has been used to treat hepatic disorders including cholestasis. However, the underlying mechanisms for GE ameliorating the reduction in bile acids accumulation by α-naphthylisothiocyanate (ANIT) remain unclear.
Aim of the study:
The purpose of this study is to characterize the efficacy of GE in regulation of bile acids uptake, synthesis, metabolism, and transport in ANIT-induced rats.
Materials and methods:
Sprague-Dawley rats were orally administrated with vehicle, GE (25, 50, and 100mg/kg), and ursodeoxycholic acid (UDCA) (60mg/kg) once daily for seven days. On the fifth day, a single dose of ANIT (75mg/kg) was administrated via oral gavage. Blood biochemical determination, bile flow rate and liver histopathology were measured to evaluate the protective effect of GE. The mRNA expressions and protein levels of transporters and enzymes involved in bile acids homeostasis were determined by quantitative real-time polymerase chain reaction (PCR) and western blot to study the underlying mechanism of GE against ANIT-induced rats.
Results:
GE (25, 50, and 100mg/kg, po) dose-dependently prevented ANIT-induced changes in serum markers for liver injury. GE treatment reduced basolateral bile acids uptake via repression of OATP2 (P<0.05). Bile acids biosynthesis was decreased through down-regulation of CYP7A1, CYP8B1, and CYP27A1 (P<0.05). GE significantly increased canalicular bile acids secretion via BSEP (P<0.05), subsequently stimulating bile flow during cholestasis. GE also markedly enhanced mRNA level of basolateral transporter OSTβ (P<0.01). Bile acids transported to the plasma were cleared into the urine, resulting in down-regulation of plasma bile acids. However, GE did not alter the mRNA levels of CYP3A2, UGT1A1 and SULT2A1. Furthermore, the gene and protein expression analysis demonstrated activation of FXR, PXR, and SHP after GE administration.
Conclusion:
GE attenuates ANIT-induced hepatotoxicity and cholestasis in rats, due to regulation enzymes and transporters responsible for bile acids homeostasis.
Ethnopharmacological relevance:
Gardenia jasminoides Ellis is a traditional Chinese medicine (TCM) that containing a variety of effective active ingredients and exhibits diverse pharmacological functions, such as anti-inflammatory, antioxidant and nerve protection.
Aim of the study:
This study investigated the effect of Gardenia jasminoides extract (GJE) and Geniposide on learning and memory improvement and neuroprotection in a rat model with chronic cerebral ischemia, as well as explore the underlying mechanisms.
Materials and methods:
The crude GJE was prepared using the methods of water extraction and alcohol precipitation, and refined by macroporous adsorption resin. The chronic cerebral ischemia model was simulated by permanent occlusion of bilateral common carotid arteries in rats. GJE was taken at three doses groups (150mg/kg, 100mg/kg, 50mg/kg), Geniposide group (50mg/kg), and oral administration for 30 days. Memory function was assessed using Morris water maze test. The morphological changes of hippocampus and related parts of brain in rats by Hematoxylin and Eosin (HE) staining were observed. Moreover, the levels of Acetylcholin Esterase (AchE), Nitric Oxide Synthase (NOS), Malondialdehyde (MDA), Superoxide Dismutase (SOD) in the brain tissue were quantified.
Results:
GJE contained 27% gardenoside and 72% total iridoid glycoside. The chronic cerebral ischemia rat model has been proved successfully. The memory function of the rats assessed using Morris water maze test showed that GJE significantly shortened the escape latency of rats, but had no significant improvement on the number of times crossing the platform and the percentage of time spent in the target quadrant. HE staining showed that the apoptosis and necrosis of the cortex and hippocampus in the GJE group were significantly reduced. In addition, it was found that GJE could significantly improved the content of SOD, inhibited NOS and AchE activity in brain tissue, but did not show a significant reduction in the content of MDA. The effect of medium dosage of GJE was the best among these three dose groups and also better than Geniposide according to the results of all the detection index.
Conclusions:
GJE had the functions of learning and memory improvement and the neuroprotection on chronic cerebral ischemia model rats. The mechanisms were found to be strongly correlated with antioxygen free radical, reduction of NO toxicity and AChE activity, and brain neuron protective effect. GJE could be able to play a better effect on improving chronic cerebral ischemia than Geniposide.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory deficits and cognitive decline. Amyloid-β (Aβ) deposition and cholinergic defect are widely thought to be the underlying mechanism of learning and memory impairment. Geniposide, which is the main active component of the traditional Chinese herbal Gardenia jasminoides Ellis, elicits neuroprotective effects by alleviating inflammation responses and oxidative damages. In this study, we investigated the protective effect of geniposide on levels of cholinergic markers, RAGE, RAGE-dependent signalling pathways and amyloid accumulation in the APPswe/PS1dE9 AD model mouse. Geniposide suppressed MAPK signaling over-activation mediated by Aβ-RAGE interaction, resulting in reduced Aβ accumulation and amelioration of cholinergic deficits in the cerebral hippocampus. Furthermore, geniposide inhibited the toxic effect of oligomeric Aβ1-42 induced cholinergic deficit by increasing ChAT levels and activity but decreasing AChE activity in cultured primary hippocampal neurons. These results indicated that geniposide enhanced cholinergic neurotransmission, which likely contributes to its memory enhancing effect.
OBJECTIVE: To investigate the mechanism of Musk and Borneol on cerebral ischemia and reperfusion injury at different time points of acute phase in rats.
The aim of this study was to explore the protective effects of geniposide against Influenza A (H1N1) pdm09 virus in vitro and in vivo. In vitro, geniposide was administered as a precaution drug, a direct deactivation drug or a treatment drug at different doses. Peramivir was applied as a positive control. The quantitative colorimetric MTT assay was applied to test both the cytotoxicity of geniposide on Madin-Darby Canine Kidney (MDCK) cells and the cytopathogenic effect (CPE) of geniposide on MDCK cells infected by influenza A (H1N1) virus. The viral inhibitory rate of geniposide on NT0901 was also calculated. In vivo, we presented a mouse model of influenza A (H1N1) pdm09 virus infection. Geniposide (5, 10, or 20 mg/kg) or peramivir (30mg/kg) were used as treatment procedures. Lung index and the survival rate were calculated to evaluate the therapeutic effects of geniposide or peramivir on NT0901-infected mice. Haematoxylin and eosin (H&E) stain was used to access the pathological alterations of lung tissues. The study in vitro demonstrated that the TD50(median toxic dose) of geniposide was higher than 1 040 μmoI/L. Besides, the EC50(concentration for 50% of maximal effect) of geniposide administered for precaution, direct deactivation and therapy were 91.90, 96.25, 87.68 μmol/L, respectively. These results suggested that geniposide could block the damage of NT0901 on MDCK cells in a dose-dependent manner. The results in vivo showed that geniposide could significantly alleviate the lung index elevation and inflammatory responses in lung tissues induced by NT0901, reduce the mortality of infected mice and extend their survival time. In conclusion, our investigation indicates that geniposide is highly effective in inhibiting cytopathogenic effect and acute lung injury caused by influenza A(H1N1) pdm09 virus. Geniposide may be a potential therapeutic agent for the suppression of influenza virus.
OBJECTIVE: To investigate the phenylpropanoids constituents of Gardenia jasminoides.
OBJECTIVE: To develop an UPLC method for simultaneous determination of seven components in Gardenia jasminoides, ie, gardoside, shanzhiside, deacetyl asperulosidic acid methyl ester, gardenoside (RG), genipin-1-β-D-gentiobioside, chlorogenic acid, and gardenoside to evaluate the quality of Gardenia jasminoides. METHODS: ACQUITY UPLC HSS T3 column was used for the UPLC analysis. The mobile phase was acetonitrile-0.05% phosphoric acid solution. Gradient elution was conducted at a flow rate of 0.2 mL·min-1. The column temperature was maitained at 30℃ and detection wavelength was set at 238 nm. A linear model was obtained through principal component analysis (PCA), and the scores of the principal components were used to evaluate the quality of Gardenia jasminoides Alba decoction pieces comprehensively. RESULTS: The seven components could be well separated from each other with good specificity, precision, repeatability, linearity, recovery rate and stability. The 25 Gardenia jasminoides Ellis samples and two Gardenia jasminoides Ellis var.grandiflora Nakai samples conformed to the quality requirements in the chapter of gardoside, shanzhiside, deacetyl asperulosidic acid methyl ester, gardenoside(RG), genipin-1-β-D-gentiobioside, chlorogenic acid, gardenoside. As the comprehensive evaluation shown, the quality of wild Gardenia jasminoides samples from Jiangxi province was better; Gardenia jasminoides from inland provinces excelled those from coastal provinces; and Gardenia jasminoides across Jiangxi province were of stable and higher quality. CONCLUSION: The method established in this study can effectively assay geniposide, gardoside, shanzhiside, deacetyl asperulosidic acid methyl ester, gardenoside and genipin gentiobioside in Gardenia jasminoides, thus it can be used for the quality control of Gardenia jasminoides.
Ethnopharmacological relevance:
Fructus gardenia is widely used for treatment of stroke and infectious diseases in Chinese medicine. Geniposide is the key bioactive compound related to the pharmacodynamic actions of gardenia on ischemic stroke. The molecular mechanism by which geniposide improves the ischemic brain injury was observed in the study.
Aim of the study:
Recent studies showed that geniposide had protective activities against the inflammatory response in ischemic stroke. However, the molecular mechanism of geniposide anti-inflammatory role has not yet been fully elucidated. In this study, we investigated the effect of geniposide on the expression of P2Y14 receptor and downstream signaling pathway in brain microvascular endothelial cells (BMECs).
Materials and methods:
An in vitro model of cerebral ischemia in BMECs was established by oxygen-glucose-deprivation (OGD). To further confirm the specific effect of geniposide on P2Y14 receptor and downstream signaling pathways, we set up a UDP-glucose (an agonist of the P2Y14 receptor) stimulated model. After administration of geniposide, the expression of P2Y14 receptor, phosphorylation of RAF-1, mitogen activated protein kinase kinase1/2 (MEK1/2), extracellular signal-regulated kinase 1/2 (ERK1/2), level of interleukin-8 (IL-8), interleukin-1β (IL-1β), monocyte chemotactic protein 1 (MCP-1) in BMECs were determined.
Results:
The mRNA and protein expression of P2Y14 in the rat BMECs were up-regulated in OGD-induced injury. After administration of Geniposide, the expression of P2Y14 receptor was significantly down-regulated, the phosphorylation of RAF-1, MEK1/2, ERK1/2 were suppressed. Similar data were obtained in UDP-glc stimulated model. We also observed that geniposide markedly declined the production of IL-8, IL-1β and MCP-1 in OGD-induced BMECs.
Conclusion:
Geniposide exerted anti-inflammatory effects by interfering with the expression of P2Y14 receptor, which subsequently inhibits the downstream ERK1/2 signaling pathways and the release of the pro-inflammatory cytokines IL-8, MCP-1, IL-1β. Therefore, this study provides the evidence for gardenia's clinical application in cerebral ischemia.
Objective: To investigate the chemical constituents of monoterpenes in the fruits of Gardenia jasminoides. Methods: Various column chromatographies were used in the isolation and purification, and the physicochemical constant determination and spectral analysis were adopted to identify the chemical structures of monoterpenes. Results: Twelve monoterpenes were isolated from G. jasminoides, such as jasminoside B (1), jasminoside G (2), jasminodiol (3), crocusatin-C (4), (7S)-6-(hydroxymethyl)-1, 1, 5-trimethylcyclohex-3-enone (5), bornyl-6-O-β-D-xylopyranosyl-β-D-glucopyranoside (6), (10R, 11R)-gardendiol (7), (10S, 11S)-gardendiol (8), (5S, 9S)-gardenate A (9), (5R, 9R)-gardenate A (10), jasminoside E (11), and 5, 6-dihydroxymethyl-1, 1-dimethylcyclohex-4-enone (12). Conclusion: Compounds 5, 6, 8, 10, and 12 are first isolated from this plant.
Objective: To compare the changes of seven kinds of compounds in the fruits, seeds, and peels of Gardeniae Fructus. Methods: Quantitative analysis of geniposidic acid, deacetyl asperulosidic acid methyl ester, genipin-1-gentiobioside, geniposide, chlorogenic acid, crocin I, and crocin II in the fruits, seeds, and peels of Gardeniae Fructus with rocessed and no processed, were firstly carried out by HPLC/DAD. Results: The conents of deacetyl asperulosidic acid methyl ester and chlorogenic acid were higher in the peels of Gardeniae Fructus. The conents of genipin-1-gentiobioside, geniposide, crocin I, and crocin II were higher in the seeds of Gardeniae Fructus. Geniposidic acid content was increased in turn, the content of deacetyl asperulosidic acid methyl ester, geniposide, chlorogenic acid, crocin I, and crocin II were reduced in turn and genipin-1-gentiobioside contents were not changed from crude, stir-fired, and stir-baked products. Conclusion: The contents of eacetyl asperulosidic acid methyl ester, genipin-1-gentiobioside, geniposide, chlorogenic acid, crocin I, and crocin II between the seeds and peels of Gardeniae Fructus exist differences. The main ingredients of Gardeniae Fructus are decreased after processing except the increasing of geniposidic acid. ©, 2015, Editorial Office of Chinese Traditional and Herbal Drugs. All right reserved.
Objective: To investigate the neuroprotective effect of geniposide on 1-methyl-4-phenyl- 1, 2, 3, 6-tetrahydropyridine (MPTP) induced Parkinson's disease (PD) model mice and possible mechanism. Methods: A total of 48 male C57BL/6 mice were randomly divided into control, model, geniposide and MPTP + geniposide groups. The behaviors of C57BL/6 mice were assessed by using open field test, the tyrosine hydroxylase (TH) and Bcl-2 positive neurons in the midbrain substantia nigra of mice were detected by immunohistochemistry and the number of apoptosis neurons were observed with TdT-mediated dUTP- biotin nick end labeling (TUNEL). Results: The number of mobile grid [(76.33 ± 8.59) times/5 min], standing [(19.58 ± 3.97) times/5 min], TH-positive neurons [(12.83 ± 2.32)/HPF] and Bcl-2-positive neurons [(10.83 ± 2.23)/HPF] in model group were significantly lower than those in the control group [(142.50 ± 11.65) times/5 min, (39.17 ± 4.75) times/5 min, (35.67 ± 1.75)/HPF, (20.67 ± 1.75)/HPF; P = 0.000, for all]. The apoptosis neurons in model group [(20.33 ± 2.58)/HPF] were significantly higher than that in control group [(3.83 ± 1.67) /HPF, P = 0.000). The number of mobile grid [(97.67 ± 13.15) times/5 min, P = 0.000], standing [(29.33 ± 2.90) times/5 min, P = 0.000], TH-positive neurons [(17.50 ± 2.07)/HPF, P = 0.002] and Bcl-2-positive neurons [(15.17 ± 2.79) /HPF, P = 0.003] in MPTP + geniposide group were significantly higher than those in model group. The number of apoptosis neurons [(14.67 ± 3.08) /HPF] in MPTP + geniposide group was significantly lower than that in model group (P = 0.001). Conclusions: Geniposide can protect dopaminergic neurons in MPTP-induced neurodegeneration and the mechanism may be associated with the inhibition of neuronal apoptosis.
Parkinson's disease (PD) is a chronic neurodegenerative disease, and there is no cure for it at present. We tested the drug Geniposide, an active component of Gardenia jasminoides Ellis which is used in traditional Chinese medicine. Geniposide has shown neuroprotective and growth-factor like effects in several in vivo and in vitro studies. In the present study, Geniposide had been tested in an acute PD mouse model induced by four 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intraperitoneal injections. Geniposide treatment (100mg/kg ip.) for 8 days after MPTP treatment (30mg/kg ip.) improved the locomotor and exploratory activity of mice (open field), and improved bradykinesia and movement balance of mice (rotarod, swim test). Geniposide treatment also restored tyrosine hydroxylase (TH) positive dopaminergic neuron numbers in the substantia nigra pars compacta. Drug treatment also increased levels of growth factor signaling molecule Bax and reduced the apoptosis signaling molecule Bcl-2. Caspase 3 activation was also reduced in the substantia nigra. We conclude that Geniposide exerted its neuroprotective effect by enhancing growth factor signaling and the reduction of apoptosis. Geniposide is an ingredient in Chinese traditional medicine with few known side effects and shows potential as a drug treatment for Parkinson's disease.