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Effect of Gentiopicroside on sciatic nerve blood flow and nerve conduction velocity. (n=8 in each group). Panel A showed enhancement of Gentiopicroside on nerve blood flow. Panel B and C showed improvement of Gentiopicroside and oxcarbazepin on MNCV and SNCV respectively. *P<0.05 versus control group; #P<0.05 versus DPN model group; &P<0.05 versus oxcarbazepin model group by one-way ANOVO followed by Bonferroni tests.
Source publication
Background/aims:
Gentiopicroside is promising as an important secoiridoid compound against pain. The present study aimed to investigate the analgesic effect and the probable mechanism of Gentiopicroside on Diabetic Peripheral Neuropathy (DPN), and to figure out the association among Gentiopicroside, dyslipidemia and PPAR- γ/AMPK/ACC signaling path...
Contexts in source publication
Context 1
... shown in Fig. 3 panel A, sciatic nerve blood flow was significantly reduced in DPN rats (P<0.05). After Gentiopicroside intervention, sciatic nerve blood flow was significantly enhanced (P<0.05). There seemed a dose-dependent effect of Gentiopicroside on nerve blood flow. However, oxcarbazepin, a known drug for DPN, did not improve the nerve blood ...
Context 2
... was an obvious fall in Moter Nerve Conduction Velocity (MNCV) and Sensory Nerve Conduction Velocity (SNCV) in DPN rats according to Fig. 3 panel B and C (P<0.05). Gentiopicroside as well as oxcarbazepin showed improvement in raising MNCV and SNCV (P<0.05). There was no statistical difference between different drug group and different dose ...
Citations
... According to Lu and collaborators [52], GPS decreased hyperalgesia in Sprague Dawley rats stimulated with hot, cold, and mechanical allodynia. The application of GPS in the treatment of diabetic peripheral neuropathy was suggested by the authors, as the compound was capable of restoring nerve blood flow, improving motor nerve conduction velocity and sensory nerve conduction velocity parameters, and regulating dyslipidemia. ...
Citation: Antoniadi, L.; Bartnik, M.; Angelis, A.; Wawruszak, A.; Halabalaki, M.; Kukula-Koch, W.; Skaltsounis, L.A. Gentiopicroside-An Insight into Its Pharmacological Significance and Future Perspectives. Cells 2024, 13, 70. Abstract: Gentiopicroside (GPS) is a leading component of several plant species from the Gentianaceae botanical family. As a compound with plenty of biological activities and a component of herbal drugs, GPS has an important role in the regulation of physiological processes in humans. The results of recently published scientific studies underline a meaningful role of this molecule as an active factor in metabolic pathways and mechanisms, which may have an influence in the treatment of different diseases, including digestive tract disorders, malignant changes, neurological disorders, microbial infections, bone formation disorders, inflammatory conditions, and others. This review aims to collect previously published reports on the biological properties of GPS as a single compound that were confirmed by in vitro and in vivo studies, and to draw attention to the newly discovered role of this bitter-tasting secoiridoid. Thanks to these properties, the research on this substance could be revisited.
... According to Lu and collaborators [54] GPS decreased hyperalgesia of Sprague Dawley rats stimulated with hot and cold and mechanical allodynia. The application of GPS in the treatment of diabetic peripheral neuropathy was suggested by the authors as the compound was capable of restoring nerve blood flow, improve moter nerve conduction velocity and sensory nerve conduction velocity parameters and regulate dyslipidemia. ...
Gentiopicroside (GPS) is a leading component of several plant species from Gentianaceae botanical family. As a compound with plenty biological activities and a component that is often consumed in dietary supplements and herbal drugs, GPS has an important role in the regulation of physiological processes in humans. Recent studies on the type 2 receptors shed new light on GPS applications showing its agonistic properties that could be meaningful in the future therapeutic strategies of Parkinson’s disease, thyroid disorders or cancer states. This review aims to collect previously published reports on the biological properties of GPS as a single compound that were confirmed by in vitro and in vivo studies, and to draw attention at the newly discovered role of this bitter-tasting secoiridoid as a type 2 receptor agonist. Thanks to these properties, the research on this substance could be revisited.
... GPS has confirmed the protective effect on CNS (Oztürk et al. 2002), which is involved in the expression of major genes in the PPAR-γ/AMPK/ACC signaling pathway by inhibiting ACC expression through PPAR-γ regulated the activation of AMPK. Depending on regulating this characteristic signaling pathway, GPS exerted a nerveprotective effect by ameliorating hyperalgesia, enhancing nerve blood flow, and improving motor nerve conduction velocity (MNCV) as well as sensory nerve conduction velocity (SNCV) (Lu et al. 2018). Similarly, after longterm treatment, GPS caused antinociceptive effects on restoring the sciatic nerves (Liu et al. 2016) and exerted neuritogenic activity (Chiba et al. 2011). ...
Gentiopicroside (GPS), a single compound isolated from Gentiana lutea L. and the crucial representative of secoiridoid constituent, has been permitted for centuries in traditional Chinese medicine. GPS and its metabolites have been increasingly used in the search for clinical management with therapeutic properties and fewer side effects. The objective of this review was to provide a comprehensive overview of the involvement of molecular pathways in the therapeutic effects of GPS on human diseases and chronic conditions. This study presents a meticulously conducted comprehensive search of the PubMed and Google Scholar databases (from 1983 to 2023), aimed at identifying articles relating to regulatory mechanisms of GPS on human diseases and the pharmacokinetics of GPS. The inclusion criteria were meticulously and precisely defined to encompass original research papers that explicitly focused on elucidating the regulatory mechanisms of GPS in various human diseases through in vitro and animal studies. Notably, these studies were mandated to integrate specific genetic markers or pathways as essential components of their research inquiries. The evaluated pharmacokinetic parameters included maximum plasma concentration (Cmax), time to reach maximum plasma concentration (Tmax), area under the curve (AUC), clearance, and plasma half-life (t1/2). Subsequently, through a rigorous screening process of titles and abstracts, studies conducted in vitro or on animals, as well as those reporting pharmacokinetic data related to drugs other than GPS or language barriers, were systematically excluded. Drawing from the data and studies pertaining to this review, we conducted a thorough and informative analysis of the pharmacological characteristics and biological functions of GPS. These encompassed a wide range of effects, including hepatoprotective, anti-inflammatory, antifibrotic, antioxidant, analgesic, antitumor, and immunomodulatory properties. The analysis provided a comprehensive and insightful understanding of GPS’s pharmacological profile and its diverse activities. Enhancing theoretical and experimental methodologies could prove advantageous in expanding the clinical applications of GPS. This could involve optimizing the bioavailability and pharmacokinetics of GPS, uncovering additional biomarkers and potential biotransformation pathways, and investigating its combined effects with standard-of-care medications.
... In addition, GPS has been found to exert antiinflammatory, anti-oxidant, and cholagogic pharmacological activities in all kinds of disease models (Wu et al., 2017;Li et al., 2018;Jin et al., 2020). In regard to diabetes and its complications, GPS significantly improved peripheral neuropathy in STZ-induced diabetic rats, and its effects may be associated with the improvement of neural blood flow and the regulation of dyslipidemia (Lu et al., 2018). GPS significantly improved diabetic retinopathy and diabetic nephropathy by inhibiting the inflammatory response and oxidative stress Xu et al., 2022). ...
... The diabetic mice were divided into two groups, based on their blood glucose level and body weight: 1) the diabetic model group (Mod); and 2) the GPS intragastric administration treatment group (GPS, 50 mg/kg). The dosage selected was based on previously published articles (Lu et al., 2018;Xiao et al., 2020;Xiao et al., 2022;Xu et al., 2022;Zou et al., 2022). Mice that were administered a normal diet were used as the normal control group (Nor). ...
... GPS can improve liver diseases, such as alcoholic liver disease Yang et al., 2020), cholestatic liver disease (Tang et al., 2016), and drug-induced liver injury (Han et al., 2018). In addition, other studies have found that GPS can alleviate diabetes (Xiao et al., 2022), diabetic retinopathy , diabetic nephropathy (Xiao et al., 2020), and peripheral neuropathy (Lu et al., 2018). However, the metabolic pathway through which GPS improves T2DM and gluconeogenesis, and regulates gluconeogenesis remains has not been elucidated as yet. ...
Gluconeogenesis is closely related to the occurrence and development of type 2 diabetes mellitus (T2DM). Gentiopicroside (GPS) is the main active secoiridoid glycoside in Gentiana manshurica Kitagawa, which can improve chronic complications associated with diabetes and regulate glucose metabolism. However, the effects and potential mechanisms by which GPS affects T2DM understudied and poorly understood. In this study, we systematically explored the pharmacological effects of GPS on T2DM induced by a high-fat diet (HFD) and streptozotocin (STZ) as well as explored its related mechanisms. The results showed that GPS supplementation discernibly decreased blood glucose levels, food intake and water consumption, ameliorated glucose intolerance, abnormal pyruvate tolerance, insulin resistance and dyslipidemia. Furthermore, GPS discernibly ameliorated pathological morphological abnormalities of the liver and pancreas, reduced hepatic steatosis and maintain the balance between α-cells and β-cells in pancreas. Moreover, GPS significantly inhibited gluconeogenesis, as evidenced by the suppressed protein expression of phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase) in the liver. Additionally, the results of Western blot analysis revealed that GPS increased p-PI3K, p-AKT, and p-FOXO1 expression levels, and decreased FOXO1 expression at protein level in the liver. Furthermore, the results of the immunostaining and Western blot analysis demonstrated that GPS supplementation increased the expression of zonula occludens-1 (ZO-1) and occludin in the ileum. Collectively, these results indicate that GPS may inhibit hepatic gluconeogenesis by regulating the PI3K/AKT/FOXO1 signaling pathway and maintain intestinal barrier integrity, and ultimately improve T2DM. Together, these findings indicate that GPS is a potential candidate drug for the prevention and treatment of T2DM, and the results of our study will provide experimental basis for further exploration of the possibility of GPS as a therapeutic agent for T2DM.
... Meanwhile, 25, 50 or 100 mg/kg GPC (high-performance liquid chromatography (HPLC) ≥98%, 356.32, C 16 H 20 O 9 , B20763, Shanghai Yuanye, Shanghai, China) was administered by gavage to rats [18,19]. Ultimately, rats were killed with phenobarbital intraperitoneal injection (57-30-7, Sigma-Aldrich, Shanghai, China). ...
Background:
Cerebral ischemia-reperfusion (CI/R) injury is induction of blood flow restoration after an ischemic stroke. Gentiopicroside (GPC) is the principal active secoiridoid glycoside of Gentiana Manshurica Kitagawa. This research aimed to illuminate the function of GPC and its mechanism in CI/R injury.
Methods:
After CI/R injury models were constructed, GPC (25, 50 or 100 mg/kg) was then administered by gavage to rats. Rats were grouped into Sham, CI/R, CI/R+25 mg/kg GPC, CI/R+50 mg/kg GPC, and CI/R+100 mg/kg GPC. Neuronal cells were exposed to oxygen-glucose deprivation and reperfusion (OGD/R) injury to establish ischemic-like conditions in vitro, and cells were further treated with 25, 50, or 100 μM GPC. Cells were grouped into control, OGD/R, OGD/R+25 μM GPC, OGD/R+50 μM GPC, and OGD/R+100 μM GPC. GPC's function on rat cerebral injury, angiogenesis, oxidative stress, neuronal injury and immune dysfunction in vivo was estimated using hematoxylin-eosin staining, Western blot, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining, commercial kits and enzyme linked-immunosorbent assay. Meanwhile, GPC's mechanism in CI/R injury was examined via Western blot. GPC's function in vitro was estimated via Cell Counting Kit-8 assay, 5-ethynyl-2'-deoxyuridine (EdU) staining, flow cytometry.
Results:
GPC alleviated cerebral injury through decreasing cerebral infarction volume, cerebral indexes, brain water contents (p < 0.05). GPC reduced oxidative stress and boosted cerebral angiogenesis in CI/R rats (p < 0.05). Meanwhile, GPC weakened neuronal cell apoptosis, and decreased neuron-specific enolase and S100beta protein levels in CI/R rats. GPC reduced inflammatory cytokines contents in serum and brain tissues of CI/R rats (p < 0.05). Moreover, GPC increased the viability and proliferation in OGD/R-treated neuronal cells, but decreased cell apoptosis (p < 0.05). Mechanistically, GPC upregulated vascular endothelial growth factor (VEGF) and phosphorylated nuclear factor E2-related factor 2 (p-Nrf2) levels in CI/R rat brain tissues (p < 0.05).
Conclusions:
GPC reduced cerebrovascular angiogenesis, neuronal injury and immune disorder in CI/R injury through elevating VEGF and p-Nrf2.
... Patients with T2DM who were not controlled by lifestyle treatments have shown that chiglitazar is effective and safe (Ji et al., 2021). In the meantime, chiglitazarz is (Zheng et al., 2015) Hericerin Hericium erinaceus + Anti-cancer and anti-inflammatory activities (Zheng et al., 2020) Picrasidine N Picrasma quassioides + Anti-cancer activity (Zhao et al., 2016) Sanguinarine Fumaria parviflora and Argemone grandiflora + + Anti-cancer, anti-platelet, antihypertensive, anti-angiogenic and antiinvasive activities Trigonelline Coffea salvatrix and Crossandra nilotica + Anti-cancer and anti-hypoglycemic activities (Ibarra et al., 2008) Amino acid 4-Hydroxyisoleucine Trigonella foenumgraecum + Anti-dyslipidemic, anti-diabetic and antihyperglycemic activities (Ibarra et al., 2008) (Guo et al., 2015) Gentiopicroside Exacum affine and Coutoubea spicata + Choleretic, anti-hepatotoxic, adaptogenic and anti-inflammatory activities (Lu et al., 2018) Ginsenoside Re Panax ginseng + Anti-diabetic, neuroregulatory, antiinflammatory, pro-cardiac, anti-cancer, anti-viral, anti-fungal and anti-oxidant activities (Gao et al., 2013) Ginsenoside Rg3 ...
... Gypenoside XLIX suppress NF-κB activation and tumor necrosis factor (TNF)-α induced vascular cell adhesion molecule (VCAM)− 1 gene overexpression in human endothelial cells via activation of PPARα pathway (Huang et al., 2006(Huang et al., , 2007. Gentiopicroside was discovered to be able to regulate PPARγ-mediated AMPK activation in diabetic peripheral neuropathy rats, hence mediating the expression of ACC and reducing diabetic peripheral neuropath (Lu et al., 2018). According to in vivo results, glycyrrhizic acid administration treatment increased total PPARγ levels in mouse visceral, subcutaneous, and subcutaneous adipose tissues as well as the liver, kidney, abdomen, quadriceps, and femoris muscles. ...
Background:
Peroxisome proliferator-activated receptors (PPARs) are a class of ligand-activated nuclear transcription factors, members of the type nuclear receptor superfamily, with three subtypes, namely PPARα, PPARβ/δ, and PPARγ, which play a key role in the metabolic syndrome. In the past decades, a large number of studies have shown that natural products can act by regulating metabolic pathways mediated by PPARs.
Purpose:
This work summarizes the physiological importance and clinical significance of PPARs and reviews the experimental evidence that natural products mediate metabolic syndrome via PPARs.
Methods:
This study reviews relevant literature on clinical trials, epidemiology, animals, and cell cultures published in NCBI PubMed, Scopus, Web of Science, Google Scholar, and other databases from 2001 to October 2022. Search keywords were "natural product" OR "botanical" OR "phytochemical" AND "PPAR" as well as free text words.
Results:
The modulatory involvement of PPARs in the metabolic syndrome has been supported by prior research. It has been observed that many natural products can treat metabolic syndrome by altering PPARs. The majority of currently described natural compounds are mild PPAR-selective agonists with therapeutic effects that are equivalent to synthetic medicines but less harmful adverse effects.
Conclusion:
PPAR agonists can be combined with natural products to treat and prevent metabolic syndrome. Further human investigations are required because it is unknown how natural products cause harm and how they might have negative impacts.
... AMPK, an evolutionarily conserved energy sensor, plays a crucial role in various diseases, including inflammation [23], diabetes [24], and cancer [25]. The AMPK-dependent mechanism is also considered as a potential therapeutic target of sepsis. ...
Background
Heart failure is a common complication of sepsis with a high mortality rate. It has been reported that melatonin can attenuate septic injury due to various properties. On the basis of previous reports, this study will further explore the effects and mechanisms of melatonin pretreatment, posttreatment, and combination with antibiotics in the treatment of sepsis and septic myocardial injury.
Methods and results
Our results showed that melatonin pretreatment showed an obvious protective effect on sepsis and septic myocardial injury, which was related to the attenuation of inflammation and oxidative stress, the improvement of mitochondrial function, the regulation of endoplasmic reticulum stress (ERS), and the activation of the AMPK signaling pathway. In particular, AMPK serves as a key effector for melatonin-initiated myocardial benefits. In addition, melatonin posttreatment also had a certain degree of protection, while its effect was not as remarkable as that of pretreatment. The combination of melatonin and classical antibiotics had a slight but limited effect. RNA-seq detection clarified the cardioprotective mechanism of melatonin.
Conclusion
Altogether, this study provides a theoretical basis for the application strategy and combination of melatonin in septic myocardial injury.
... Peroxisome proliferator-activated receptor gamma (PPARG) is a regulator of adipocyte differentiation, which can express PPARγ and is known to be important for ameliorating DPN. Besides, multiple drugs or small molecules could improve DPN by modulating the PPAR pathway [29,46,47]. Fatty acid binding protein 4 (FABP4) mainly participates in fatty acid uptake, transport, and metabolism. ...
Dysregulation of adipogenesis is related to diabetic peripheral neuropathy (DPN) pathogenesis, which may be mediated by immune infiltration. Nevertheless, the expression patterns of multiple adipogenesis-related genes and the differences of immune infiltration in different lipid metabolism levels remain unknown. GSE95849, a gene expression matrix containing DPN patients and healthy participants, was downloaded from Gene Expression Omnibus (GEO) database. Differentially expressed adipogenesis-related genes (DEARGs) were screened by overlapping the adipogenesis-related genes with differentially expressed genes (DEGs). DPN patients from GSE24290 and GSE148059 were divided into two adipogenesis subgroups according to the expression of DEARGs. The single-sample gene set enrichment analysis (ssGSEA) was used to estimate the abundance of the immune cells between two subgroups. The analysis of immune infiltration suggested that a variety of immune cells and immune processes were elevated in the high expression group of DEARGs. The differentially expressed genes of the two subgroups were mainly enriched in biological processes and signaling pathways related to lipid metabolism. PPARG, FABP4, LIPE, FASN, SCD, DGAT2, PNPLA2, ADIPOQ, LEP, and CEBPA were identified as the hub genes of the two subgroups, whose related transcription factors (TFs) and miRNAs were predicted. An immunohistochemical assay was used to verify the expression of hub genes in DPN nerve tissues. Our comprehensive analysis of adipogenesis subgroups in DPN illustrated that different expression patterns of DEARGs may lead to different immune and inflammatory states. The identification of DEARGs may help to further distinguish the different characteristics of DPN patients and lay the foundation for targeted treatment. Our findings may bring a novel perspective to the diagnosis and treatment of DPN patients.
... Gentiopicroside (Supporting Information Fig. S1A) is the main active compound of Gentiana manshurica Kitagawa with extensive pharmacological activities including anti-inflammatory, antioxidative and choleretic 33e35 . Recently, it was found that gentiopicroside ameliorated peripheral neuropathy and retinopathy effectively in diabetic mice 36,37 . Moreover, our previous study found that GPS significantly improved blood glucose levels and effectively inhibited inflammation to alleviate renal microvascular lesion 38 . ...
... As the main active component of Gentiana manshurica Kitagawa, gentiopicroside has biological activity against a variety of liver diseases including ALD 34,49 , cholestatic liver disease 50 and drug-induced liver injury 51,52 . Recently, GPS was found to play a role in alleviating diabetes and diabetic complications including retinal microvasculopathy and peripheral neuropathy 36,37 . Additionally, our previous study determined the hypoglycemic and renal protective effects of GPS 38 . ...
The obstruction of post-insulin receptor signaling is the main mechanism of insulin-resistant diabetes. Progestin and adipoQ receptor 3 (PAQR3), a key regulator of inflammation and metabolism, can negatively regulate the PI3K/AKT signaling pathway. Here, we report that gentiopicroside (GPS), the main bioactive secoiridoid glycoside of Gentiana manshurica Kitagawa, decreased lipid synthesis and increased glucose utilization in palmitic acid (PA) treated HepG2 cells. Additionally, GPS improved glycolipid metabolism in streptozotocin (STZ) treated high-fat diet (HFD)-induced diabetic mice. Our findings revealed that GPS promoted the activation of the PI3K/AKT axis by facilitating DNA-binding protein 2 (DDB2)-mediated PAQR3 ubiquitinated degradation. Moreover, results of surface plasmon resonance (SPR), microscale thermophoresis (MST) and thermal shift assay (TSA) indicated that GPS directly binds to PAQR3. Results of molecular docking and cellular thermal shift assay (CETSA) revealed that GPS directly bound to the amino acids of the PAQR3 NH2-terminus including Leu40, Asp42, Glu69, Tyr125 and Ser129, and spatially inhibited the interaction between PAQR3 and the PI3K catalytic subunit (P110α) to restore the PI3K/AKT signaling pathway. In summary, our study identified GPS, which inhibits PAQR3 expression and directly targets PAQR3 to restore insulin signaling pathway, as a potential drug candidate for the treatment of diabetes.
... inflammatory response and lipotoxicity in hepatocytes. Besides, the link of PPARγ and AMPK/mTOR/autophagy pathway was explored in other disease models [42][43][44][45][46][47][48]. To make sure the mechanism, mice were treated with at least one of the si-PPARγ and Rosi. ...
Background:
Hepatic ischemia-reperfusion (IR) injury is one of the severe complications associated with liver surgery and leads to liver dysfunction. PPARγ is always linked with various physiologic pathways, and it can alleviate liver damage in IR injury.
Aim:
In this study, we explored the potential mechanism of PPARγ in the pathogenesis of hepatic IR injury by mice model.
Methods:
After treated with si-PPARγ or rosiglitazone, mice were subjected to hepatic ischemia-reperfusion. Liver tissue and blood samples were collected to evaluate liver injury and detected relative mRNA and protein expressions.
Results:
The expression of PPARγ was increased after reperfusion. And the alleviation of PPARγ aggravated the liver damage in IR; at the same time, upregulation of the expression of PPARγ released the liver damage. And these effects of PPARγ in IR were related to the AMPK/mTOR/autophagy signaling pathway.
Conclusion:
PPARγ plays an important role in hepatic IR injury at least partly via the AMPK/mTOR/autophagy pathway.
