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Parkinson's disease (PD) is a neurodegenerative disorder marked by the loss of dopaminergic neurons and the formation of α-synuclein aggregates. Mitochondrial dysfunction and oxidative stress are pivotal in PD pathogenesis, with impaired mitophagy contributing to the accumulation of mitochondrial damage. Hederagenin (Hed), a natural triterpenoid, has shown potential neuroprotective effects; however, its mechanisms of action in PD models are not fully understood. We investigated the effects of Hed on 6-hydroxydopamine (6-OHDA)-induced cytotoxicity in SH-SY5Y cells by assessing cell viability, mitochondrial function, and oxidative stress markers. Mitophagy induction was evaluated using autophagy and mitophagy inhibitors and fluorescent staining techniques. Additionally, transgenic Caenorhabditis elegans (C. elegans) models of PD were used to validate the neuroprotective effects of Hed in vivo by focusing on α-synuclein aggregation, mobility, and dopaminergic neuron integrity. Hed significantly enhanced cell viability in 6-OHDA-treated SH-SY5Y cells by inhibiting cell death and reducing oxidative stress. It ameliorated mitochondrial damage, evidenced by decreased mitochondrial superoxide production, restored membrane potential, and improved mitochondrial morphology. Hed also induced mitophagy, as shown by increased autophagosome formation and reduced oxidative stress; these effects were diminished by autophagy and mitophagy inhibitors. In C. elegans models, Hed activated mitophagy and reduced α-synuclein aggregation, improved mobility, and mitigated the loss of dopaminergic neurons. RNA interference targeting the mitophagy-related genes pdr-1 and pink-1 partially reversed these benefits, underscoring the role of mitophagy in Hed's neuroprotective actions. Hed exhibits significant neuroprotective effects in both in vitro and in vivo PD models by enhancing mitophagy, reducing oxidative stress, and mitigating mitochondrial dysfunction. These findings suggest that Hed holds promise as a therapeutic agent for PD, offering new avenues for future research and potential drug development. [Display omitted] • Hederagenin (Hed) enhances mitophagy in SH-SY5Y cells and C. elegans. • Hed protects mitochondria and decreases oxidative stress via mitophagy induction. • Hed reduces α-synuclein aggregation and improves mobility in NL5901 worms. • Hed reduces the loss of neurons and improves mobility in 6-OHDA-induced BZ555 worms. • Hed exhibits neuroprotection via activating mitophagy through Pdr-1 and pink-1 genes. [ABSTRACT FROM AUTHOR]

The prevalence of obesity is increasing globally, with approximately 700 million obese people worldwide. Currently, regulating energy homeostasis by increasing energy expenditure is attracting attention as a strategy for treating obesity. White adipose tissue is known to play a role in accumulating energy by storing excess energy, while brown adipose tissue expends energy and maintains body temperature. Thus, the browning of white adipose tissue has been shown to be effective in controlling obesity. Hedera helix (H. helix) has been widely used as a traditional medicine for various diseases. In several previous studies, hederagenin (HDG) from H. helix has demonstrated many biological activities. In this study, we investigated the antiobesity effect of HDG on fat browning in 3T3-L1 adipocytes. Consequent to HDG treatment, a reduction in lipid accumulation was measured through oil red O staining. In addition, this study investigated that HDG increases energy expenditure by upregulating the expression of several targets related to thermogenesis, including uncoupling protein 1 (UCP1). This process involves inhibiting lipogenesis via the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway and promoting lipolysis through the protein kinase A (PKA) pathway. HDG is expected to be effective in promoting fat browning, indicating its potential as a natural antiobesity candidate. [ABSTRACT FROM AUTHOR]

Hederagenin (HG) is a natural pentacyclic triterpenoid that can be isolated from various medicinal herbs. By modifying the structure of HG, multiple derivatives with superior biological activities and safety profiles have been designed and synthesized. Accumulating evidence has demonstrated that HG and its derivatives display multiple pharmacological activities against cancers, inflammatory diseases, infectious diseases, metabolic diseases, fibrotic diseases, cerebrovascular and neurodegenerative diseases, and depression. Previous studies have confirmed that HG and its derivatives combat cancer by exerting cytotoxicity, inhibiting proliferation, inducing apoptosis, modulating autophagy, and reversing chemotherapy resistance in cancer cells, and the action targets involved mainly include STAT3, Aurora B, KIF7, PI3K/AKT, NF-κB, Nrf2/ARE, Drp1, and P-gp. In addition, HG and its derivatives antagonize inflammation through inhibiting the production and release of proinflammatory cytokines and inflammatory mediators by regulating inflammation-related pathways and targets, such as NF-κB, MAPK, JAK2/STAT3, Keap1-Nrf2/HO-1, and LncRNA A33/Axin2/ß-catenin. Moreover, antipathogen, anti-metabolic disorder, anti-fibrosis, neuroprotection, and antidepression mechanisms of HG and its derivatives have been partially elucidated. The diverse pharmacological properties of HG and its derivatives hold significant implications for future research and development of new drugs derived from HG, which can lead to improved effectiveness and safety profiles. [ABSTRACT FROM AUTHOR]

Euphorbia serpens has been used in central-west region of Argentina in traditional medicine as diuretic plant. The aim of this present study was to evaluate the diuretic activity of E. serpens in-vivo. We used dried aerial parts, and infusions from these were orally administered to Wistar rats. Its effect was evaluated using furosemide as a positive drug and isotonic salt solution as negative control. Their urine output was quantified at several time intervals. The volume of urine excreted and Na+ increased significantly, being similar to furosemide. Mannitol, was the main component in aqueous extracts of E. serpens, and the acetone extract showed the presence of Δ12- oleanane-type triterpenoids compounds, mainly hederagenin. No toxic effects were observed. [ABSTRACT FROM AUTHOR]

Hederagenin (HDG), a medical herb, is known for its beneficial activities against diverse diseases. The cardioprotective effect of HDG has been preliminarily disclosed, but the efficacy and underlying mechanism by which HDG protects against myocardial ischemia–reperfusion (MI/R) injury have not been elucidated yet. To simulate MI/R injury, the left anterior descending artery was occluded for 30 min and then reperfusion for 120 min in a rat model, and the cellular model of hypoxia–reoxygenation (H/R) injury was constructed in H9c2 cardiomyocytes. Hematoxylin–eosin, Prussian blue, and 2,3,5-triphenyl-2H-tetrazolium chloride (TTC) staining were conducted to assess the histological injury, iron deposition, and myocardial infarction. Myocardial enzymes and oxidative stress-related factors were detected using their commercial kits. Lipid peroxidation was measured using BODIPY581/591 probe, and iron content was detected. Cell counting kit (CCK)-8, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), and flow cytometry assays were performed to assess cell viability and apoptosis. Protein levels were investigated by western blot. The interaction between HDG and 5-lipoxygenase (ALOX5) was verified using molecular docking. Our findings indicated that HDG significantly attenuated myocardial dysfunction by reducing infarction and myocardial injury. HDG significantly attenuated myocardial apoptosis in vitro and in vivo, as well as alleviating oxidative stress via reducing reactive oxygen species (ROS) and maintaining the balance between antioxidant and oxidant enzymes. Meanwhile, HDG inhibited I/R-induced ferroptosis in myocardium and cardiomyocytes, including reducing lipid peroxidation and iron level. Moreover, the binding relationship between HDG and ALOX5 was verified, and HDG could concentration dependently downregulate ALOX5. Furthermore, ALOX5 overexpression eliminated the inhibition of HDG on H/R-induced apoptosis, oxidative stress, and ferroptosis in H9c2 cardiomyocytes. HDG ameliorated myocardial dysfunction and cardiomyocyte injury by reducing apoptosis, oxidative stress, and ferroptosis through inhibiting ALOX5, providing a new perspective on the prevention and treatment of MI/R injury. [ABSTRACT FROM AUTHOR]

Many plant species, particularly legumes, protect themselves with saponins. Previously, a correlation was observed between levels of oleanolic acid-derived saponins, such as hederagenin-derived compounds, in the legume Medicago truncatula and caterpillar deterrence. Using concentrations that reflect the foliar levels of hederagenin-type saponins, the sapogenin hederagenin was not toxic to 4th instar caterpillars of the cabbage looper Trichoplusia ni nor did it act as a feeding deterrent. Female caterpillars consumed more diet than males, presumably to obtain the additional nutrients required for oogenesis, and are, thus, exposed to higher hederagenin levels. When fed the hederagenin diet, male caterpillars expressed genes encoding trypsin-like proteins (LOC113500509, LOC113501951, LOC113501953, LOC113501966, LOC113501965, LOC113499659, LOC113501950, LOC113501948, LOC113501957, LOC113501962, LOC113497819, LOC113501946, LOC113503910) as well as stress-responsive (LOC113503484, LOC113505107) proteins and cytochrome P450 6B2-like (LOC113493761) at higher levels than females. In comparison, female caterpillars expressed higher levels of cytochrome P450 6B7-like (LOC113492289). Bioinformatic tools predict that cytochrome P450s could catalyze the oxygenation of hederagenin which would increase the hydrophilicity of the compound. Expression of a Major Facilitator Subfamily (MFS) transporter (LOC113492899) showed a hederagenin dose-dependent increase in gene expression suggesting that this transporter may be involved in sapogenin efflux. These sex-related differences in feeding and detoxification should be taken into consideration in insecticide evaluations to minimize pesticide resistance. [ABSTRACT FROM AUTHOR]

The prevalence of obesity is increasing globally, with approximately 700 million obese people worldwide. Currently, regulating energy homeostasis by increasing energy expenditure is attracting attention as a strategy for treating obesity. White adipose tissue is known to play a role in accumulating energy by storing excess energy, while brown adipose tissue expends energy and maintains body temperature. Thus, the browning of white adipose tissue has been shown to be effective in controlling obesity. Hedera helix (H. helix) has been widely used as a traditional medicine for various diseases. In several previous studies, hederagenin (HDG) from H. helix has demonstrated many biological activities. In this study, we investigated the antiobesity effect of HDG on fat browning in 3T3-L1 adipocytes. Consequent to HDG treatment, a reduction in lipid accumulation was measured through oil red O staining. In addition, this study investigated that HDG increases energy expenditure by upregulating the expression of several targets related to thermogenesis, including uncoupling protein 1 (UCP1). This process involves inhibiting lipogenesis via the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway and promoting lipolysis through the protein kinase A (PKA) pathway. HDG is expected to be effective in promoting fat browning, indicating its potential as a natural antiobesity candidate.

Diabetic nephropathy is a major complication of diabetes mellitus and is related to dysfunction of renal cells. Hederagenin is a triterpenoid saponin from some Chinese herbs with anti‐inflammatory and anti‐diabetic activities. However, its role in diabetic nephropathy progression is still obscure. This study aimed to explore the effects of hederagenin on renal cell dysfunction in vitro. Human renal mesangial cells (HRMCs) and human renal proximal tubular epithelial cells (HRPTEpiCs) were cultured under high glucose (HG) conditions to mimic diabetic nephropathy‐like injury. Cell proliferation was evaluated by CCK‐8. mRNA and protein levels were determined by qRT‐PCR and western blotting, respectively. The secretion levels of fibrosis‐related biomarkers were analyzed by ELISA. Results showed that hederagenin reduced HG‐induced proliferation increase in HRMCs and HRPTEpiCs. Hederagenin attenuated HG‐induced increase in mRNA and protein expression of NLRP3, ASC, and IL‐1β. Hederagenin also suppressed HG‐induced increase in mRNA and secretion levels of FN, Col. IV, PAI‐1, and TGF‐β1. NLRP3 inhibitor MCC950 attenuated HG‐induced fibrosis of renal cells, and its activator nigericin reversed the suppressive effect of hederagenin on HG‐induced fibrosis. Bioinformatics analysis predicted cathepsin B (CTSB) as a target of hederagenin to modulate NOD‐like receptor (NLR) pathway. Hederagenin decreased CTSB level, and CTSB overexpression reversed the suppressive effect of hederagenin on HG‐induced NLRP3 inflammasome activation and fibrosis in HRMCs and HRPTEpiCs. In conclusion, hederagenin attenuates HG‐induced fibrosis of renal cells by inhibiting NLRP3 inflammasome activation via reducing CTSB expression, indicating a therapeutic potential of hederagenin in diabetic nephropathy. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a prevalently neurodegenerative disease characterized by neuronal damage which is associated with amyloid-β (Aβ) accumulation. Hederagenin is a triterpenoid saponin, exerting anti-apoptotic, anti-oxidative, anti-inflammatory, anti-tumoral, and neuroprotective activities. However, its role in AD progression is still obscure. The aim of this study was to explore the influences of hederagenin on Aβ-caused neuronal injury in vitro. Neuronal cells were treated with Aβ25–35 (Aβ) to establish a cellular model of AD. Cell viability was assessed using cell counting kit-8 (CCK-8). Oxidative stress was evaluated by detecting reactive oxygen species (ROS) generation and superoxide dismutase (SOD) activity. Apoptosis was investigated using TUNEL staining and caspase-3 activity assays. Protein tyrosine phosphatase nonreceptor type 1 (PTPN1) was screened by bioinformatics analysis. Protein levels of PTPN1 and protein kinase B (Akt) were measured by western blotting. Hederagenin (2.5, 5, and 10 μM) alone did not affect viability of neuronal cells, but relieved Aβ-induced viability reduction. Hederagenin mitigated Aβ-induced increase in ROS accumulation and decrease in SOD activity. Hederagenin attenuated Aβ-induced increase in apoptotic rate and caspase-3 activity. PTPN1 was screened as a target of hederagenin against AD by bioinformatics analysis. Hederagenin treatment resisted Aβ-induced decrease in PTPN1 mRNA and protein levels in neuronal cells. PTPN1 silencing attenuated the suppressive functions of hederagenin in Aβ-stimulated oxidative stress and apoptosis. Hederagenin mitigated Aβ-induced Akt signaling inactivation by upregulating PTPN1 expression. In conclusion, hederagenin attenuates oxidative stress and apoptosis in neuronal cells stimulated with Aβ by promoting PTPN1/Akt signaling activation. [ABSTRACT FROM AUTHOR]

To investigate the anti-cancer effect and mechanism of hederagenin on laryngeal squamous cell carcinoma cells. Laryngeal squamous cell carcinoma cells TU177 were divided into control group, hederagenin group (5, 10, 20 μM hederagenin), anti-microRNA-negative control group (transfected with anti-microRNA-negative control), anti-microRNA-1269 group (transfected with anti-microRNA-1269), hederagenin+microRNA-negative control group (transfected with microRNA-negative control, 20 μM hederagenin), hederagenin+microRNA-1269 group (transfected with microRNA-1269 mimics, 20 μM hederagenin). We used cell counting kit-8 and a plate replicating experiment to determine TU177 cell proliferation; the wound recuperation test to examine TU177 cell migration; the Transwell assay to identify TU177 cell assault; the Western blotting method to examine N and E-cadherin protein communication; and reverse transcription-quantitative polymerase chain reaction to evaluate microRNA-1269 expressing themselves. Compared with the control group, the inhibition rate (14.81±1.26) %, (32.94±3.22) %, (57.74±4.29) % vs. (0.00±0.00) % and E-cadherin protein expression of TU177 cells in the hederagenin (5, 10, 20 μM) group were notably increased (p<0.05), the number of clone formation, the invasion number (85.88±7.36) individuals, (70.67±5.37) individuals, (52.23±5.05) individuals vs. (119.34±12.89) individuals and the scratch healing rate [(56.91±4.85) %, (38.93±3.31) %, (24.22±2.19) % vs. (72.16±5.66) %], N-cadherin protein expression and microRNA-1269 expression [(0.77±0.06), (0.58±0.05), (0.38±0.04) vs. (1.00±0.00)] were notably reduced (p<0.05). Inhibition of cells was much higher in the anti-microRNA-negative control group [(48.98±4.62) % vs. (5.89±0.48) %], E-cadherin protein expression of TU177 in anti-microRNA-1269 group were notably increased (p<0.05), the number of clone formation, the invasion number [(61.36±5.13) individual vs. (118.02±11.84) individual], and the scratch healing rate (33.28±3.02) % vs. (73.11±6.39) %, N-cadherin protein expression were notably reduced (p<0.05). The rate of inhibition was much lower in the hederagenin+microRNA-negative control group (19.62±1.16) % vs. (58.35±4.72) % and E-cadherin protein expression of TU177 in the hederagenin+microRNA-1269 group were notably reduced (p<0.05), the number of clone formation, the invasion number [(91.94±7.83) individuals vs. (50.74±5.01) individuals], and the scratch healing rate (58.02±4.36) % vs. (23.07±3.02) %, N-cadherin protein expression were notably increased (p<0.05). Hederagenin has anti-proliferation, anti-migration and anti-invasion impacts on TU177 laryngeal squamous cell carcinoma cells by repressing microRNA-1269 expression. [ABSTRACT FROM AUTHOR]

Purpose: To determine the effect of Hederagenin (Hed) on rheumatoid arthritis (RA) in a cell model, and to elucidate the mechanism of action of Hed. Methods: MTT, EDU, and Immunoblot assays were used to determine the effects of Hed on the viability of fibroblast-like synovial cells, while the effects of Hed on inflammation were examined by enzymelinked immunosorbent assay (ELISA) and immunoblot assay. The influence of Hed on cell motility angiogenesis was evaluated by Transwell and tube formation assays, while immunoblot analysis was used to determine the mechanism of action of Hed. Results: Hed inhibited the viability of RA-FLS cells and suppressed the inflammation of RA-FLS cells (p < 0.05). Furthermore, Hed suppressed the migration and angiogenesis of RA-FLSl cells, as well as regulated MAPK pathway (p < 0.05). Conclusion: Hed inhibits the proliferation, angiogenesis and inflammation of fibroblast-like synovial cells in RA by regulating MAPK pathway. Therefore, Hed is a drug for the treatment of RA, However, in vivo studies to validate these findings are recommended. [ABSTRACT FROM AUTHOR]

Abstract Objective We investigated differentially expressed proteins (DEPs) in human glioblastoma U87 cells after treatment with hederagenin as a therapeutic screening mechanism and provided a theoretical basis for hederagenin in treating glioblastoma. Methods The Cell Counting Kit 8 assay was used to analyze the inhibitory effect of hederagenin on the proliferation of U87 cells. Protein was identified by tandem mass tags and LC-MS/MS analysis techniques. Annotation of DEPs, Gene Ontology enrichment and function, and Kyoto Encyclopedia of Genes and Genomes pathways and domains were all examined by bioinformatics. According to the TMT results, hub protein was selected from DEPs for WB verification. Results Protein quantitative analysis found 6522 proteins in total. Compared with the control group, 43 DEPs (P

Background: Sarcocephalus pobeguinii (Hua ex Pobég) is used in folk medicine to treat oxidative-stress related diseases, thereby warranting the investigation of its anticancer and anti-inflammatory properties. In our previous study, the leaf extract of S. pobeguinii induced significant cytotoxic effect against several cancerous cells with high selectivity indexes towards non-cancerous cells. Aim: The current study aims to isolate natural compounds from S. pobeguinii, and to evaluate their cytotoxicity, selectivity and anti-inflammatory effects as well as searching for potential target proteins of bioactive compounds. Methods: Natural compounds were isolated from leaf, fruit and bark extracts of S. pobeguinii and their chemical structures were elucidated using appropriate spectroscopic methods. The antiproliferative effect of isolated compounds was determined on four human cancerous cells (MCF-7, HepG2, Caco-2 and A549 cells) and non-cancerous Vero cells. Additionally, the anti-inflammatory activity of these compounds was determined by evaluating the nitric oxide (NO) production inhibitory potential and the 15-lipoxygenase (15-LOX) inhibitory activity. Furthermore, molecular docking studies were carried out on six putative target proteins found in common signaling pathways of inflammation and cancer. Results: Hederagenin (2), quinovic acid 3-O-[α-D-quinovopyranoside] (6) and quinovic acid 3-O-[β-D-quinovopyranoside] (9) exhibited significant cytotoxic effect against all cancerous cells, and they induced apoptosis in MCF-7 cells by increasing caspase-3/-7 activity. (6) showed the highest efficacy against all cancerous cells with poor selectivity (except for A549 cells) towards noncancerous Vero cells; while (2) showed the highest selectivity warranting its potential safety as a chemotherapeutic agent. Moreover, (6) and (9) significantly inhibited NO production in LPS-stimulated RAW 264.7 cells which could mainly be attributed to their high cytotoxic effect. Besides, the mixture nauclealatifoline G and naucleofficine D (1), hederagenin (2) and chletric acid (3) were active against 15-LOX as compared to quercetin. Docking results showed that JAK2 and COX-2, with the highest binding scores, are the potential molecular targets involved in the antiproliferative and anti-inflammatory effects of bioactive compounds. Conclusion: Overall, hederagenin (2), which selectively killed cancer cells with additional anti-inflammatory effect, is the most prominent lead compound which may be further investigated as a drug candidate to tackle cancer progression. [ABSTRACT FROM AUTHOR]

Background:Sarcocephalus pobeguinii (Hua ex Pobég) is used in folk medicine to treat oxidative-stress related diseases, thereby warranting the investigation of its anticancer and anti-inflammatory properties. In our previous study, the leaf extract of S. pobeguinii induced significant cytotoxic effect against several cancerous cells with high selectivity indexes towards non-cancerous cells.Aim: The current study aims to isolate natural compounds from S. pobeguinii, and to evaluate their cytotoxicity, selectivity and anti-inflammatory effects as well as searching for potential target proteins of bioactive compounds.Methods: Natural compounds were isolated from leaf, fruit and bark extracts of S. pobeguinii and their chemical structures were elucidated using appropriate spectroscopic methods. The antiproliferative effect of isolated compounds was determined on four human cancerous cells (MCF-7, HepG2, Caco-2 and A549 cells) and non-cancerous Vero cells. Additionally, the anti-inflammatory activity of these compounds was determined by evaluating the nitric oxide (NO) production inhibitory potential and the 15-lipoxygenase (15-LOX) inhibitory activity. Furthermore, molecular docking studies were carried out on six putative target proteins found in common signaling pathways of inflammation and cancer.Results: Hederagenin (2), quinovic acid 3-O-[α-D-quinovopyranoside] (6) and quinovic acid 3-O-[β-D-quinovopyranoside] (9) exhibited significant cytotoxic effect against all cancerous cells, and they induced apoptosis in MCF-7 cells by increasing caspase-3/-7 activity. (6) showed the highest efficacy against all cancerous cells with poor selectivity (except for A549 cells) towards non-cancerous Vero cells; while (2) showed the highest selectivity warranting its potential safety as a chemotherapeutic agent. Moreover, (6) and (9) significantly inhibited NO production in LPS-stimulated RAW 264.7 cells which could mainly be attributed to their high cytotoxic effect. Besides, the mixture nauclealatifoline G and naucleofficine D (1), hederagenin (2) and chletric acid (3) were active against 15-LOX as compared to quercetin. Docking results showed that JAK2 and COX-2, with the highest binding scores, are the potential molecular targets involved in the antiproliferative and anti-inflammatory effects of bioactive compounds.Conclusion: Overall, hederagenin (2), which selectively killed cancer cells with additional anti-inflammatory effect, is the most prominent lead compound which may be further investigated as a drug candidate to tackle cancer progression.

Objective: We investigated differentially expressed proteins (DEPs) in human glioblastoma U87 cells after treatment with hederagenin as a therapeutic screening mechanism and provided a theoretical basis for hederagenin in treating glioblastoma. Methods: The Cell Counting Kit 8 assay was used to analyze the inhibitory effect of hederagenin on the proliferation of U87 cells. Protein was identified by tandem mass tags and LC-MS/MS analysis techniques. Annotation of DEPs, Gene Ontology enrichment and function, and Kyoto Encyclopedia of Genes and Genomes pathways and domains were all examined by bioinformatics. According to the TMT results, hub protein was selected from DEPs for WB verification. Results: Protein quantitative analysis found 6522 proteins in total. Compared with the control group, 43 DEPs (P < 0.05) were involved in the highly enriched signaling pathway in the hederagenin group, among which 20 proteins were upregulated, and 23 proteins were downregulated. These different proteins are mainly involved in the longness regulating pathway–WORM, the hedgehog signaling pathway, Staphylococcus aureus infection, complement, coagulation cascades, and mineral absorption. KIF7 and ATAD2B expression were significantly down-regulated and PHEX and TIMM9 expression were significantly upregulated, according to WB analysis, supporting the TMT findings. Conclusion: Hederagenin inhibition of GBM U87 cells may be related to KIF7, which is mainly involved in the hedgehog signaling pathway. Our findings lay a foundation for additional study of the therapeutic mechanism of hederagenin. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA), a common degenerative joint disease, is characterized by the progressive degradation of articular cartilage and inflammation. Hederagenin (HE) is a pentacyclic triterpenoid saponin extracted from many herb plants. It has anti-inflammatory, anti-lipid peroxidative, anti-cancer, and neuroprotective activities. However, its effect on OA has not been investigated. Our study found that HE may be a potential anti-OA drug. In vitro, HE could suppress extracellular matrix (ECM) degradation via up-regulating aggrecan and Collagen II levels as well as downregulating MMPs and ADAMTS5 levels. It could also reduce proinflammatory and inflammatory cytokines or enzymes production, including TNF-α, IL-6, iNOS, COX-2, NO, and PGE2. Besides, HE markedly reduced IL-1β-induced C28/I2 cell apoptosis and ROS accumulation. Mechanistically, HE exerted chondroprotective and anti-inflammatory effects by partly inhibiting JAK2/STAT3/MAPK signalling pathway and the crosstalk of the two pathways. Also, HE exhibited anti-apoptotic and anti-oxidative effect via targeting Keap1-Nrf2/HO-1/ROS/Bax/Bcl-2 axis. In vivo, HE significantly reduced monosodium iodoacetate (MIA) induced cartilage destruction of rats with a lower OARSI score and inflammatory cytokine levels, further demonstrating its protective effects in OA progression. These results suggest that HE is a potential compound for the development of drugs to treat OA. [ABSTRACT FROM AUTHOR]

Abstract Hederagenin, a natural compound distributed in many medicinal plants, has a variety of pharmacological properties including anti-bacteria, anti-inflammation, anti-oxidation, and anti- apoptosis.. The aim of this study was to evaluate the effects of hederagenin on decreasing blood lipid and anti-oxidative stress in oleic acid-induced HepG2 cells and hyperlipidemic rats, and explore underlying mechanisms. In vitro, TG was used as the index to verify the lipid-lowering effect of hederagenin in oleic acid-induced HepG2 cells. In vivo, TC, TG, LDL-C, and HDL-C were used as direct indicators to study the antilipemic effect of hederagenin in hyperlipidemic rats. MDA, SOD, and GSH-PX were measured to analyze the anti-oxidative effect of hederagenin. The signaling pathways of anti-oxidation were evaluated using Western blot. Our results showed that hederagenin (250μmol/L) increased significantly TG clearance rate. In addition, treatment with hederagenin, XZK and simvastatin reduced effectively TC, TG, LDL-C and MDA content, and increased HDL-C, SOD and GSH-PX in HFD rats. Moreover, the phosphorylation level of p38 MAPK was inhibited after administration of hederagenin, XZK and simvastatin. Our results revealed that hederagenin possessed beneficial potentials for hypolipidemic effects, especially in TG clearance. The mechanism might be associated with inhibition of lipid absorption, reduction of lipid oxidation, and down-regulation of p38MAPK phosphorylation.

The aim of this study was to investigate the phytochemical constituents and antioxidant potentials of the ethanol extract and fractions of Irvingia gabonensis root bark in order to establish the scientific basis and rationale for its folkloric use. The powdered root bark of I. gabonensis was macerated with 70% ethanol and then partitioned with different solvents based on their polarity to afford 4 fractions. The extract and fractions were subjected to phytochemical analysis. The in vitro antioxidant activity was evaluated using DPPH assay. The quantitative phytochemical determination showed that ethyl acetate fraction of I. gabonensis root bark (EFIGR) had the highest content of tannins (154.44 mg/GAE g), phenol (106.26 mg/GAE g and flavonoid (76.07 mg/QE g). The in vitro antioxidant activity of the extract and the fractions had IC50 values of 76.0±0.03, 27.0± 0.05, 39.0±0.07 and 28.0±0.10 μg/mL for Ethanol extract, EFIGR, Butanol fraction and Aqueous fraction respectively while the standard had 29.0±0.03 μg/mL.Further fractionation of EFIGR led to the isolation of hederagenin which was characterized using 1D-NMR and mass spectrometric data. The present study revealed that root bark of I. gabonensis is a potential source of natural antioxidant which justified its uses in the traditional medicine. [ABSTRACT FROM AUTHOR]

Swiss chard is a vegetable valued not only for the taste of its leaves but also because of its health-promoting properties. To date, nothing is known regarding the occurrence of saponins in the Swiss chard plant, even though they could be at least partially responsible for the nutraceutical activities of this plant. This research aimed to describe saponins from the leaves of four Swiss chard ( Beta vulgaris L.) cultivars. Saponin structures were analyzed by UHPLC-CAD/QTOF-MS/MS. Based on the fragmentation patterns, we tentatively identified 16 triterpene saponins in B. vulgaris , including two that had not been detected previously. The observed compounds were glycosides of five different, tentatively identified aglycones, i.e ., oleanolic acid, hederagenin, gypsogenin, akebonoic acid, and serjanic acid. Moreover, the structure of four saponins detected in Swiss chard leaves included dioxolane-type and six acetal-type substituents. Eleven, eight, eleven, and eight saponins were observed in saponin fractions obtained from Rhubarb, Bulls Blood, Perpetual Spinach, and White Silver cultivars, respectively. Furthermore, the content of all identified triterpene derivatives in the investigated cultivars was estimated using a method based on the UHPLC coupled with QTOF-MS/MS and charged aerosol detector (CAD). The analyzed cultivars differed in the total and individual saponin content. The total saponin content ranged from 125.53 to 397.09 μg/g DW.

Due to their manifold biological activities, natural products such as triterpenoids have advanced to represent excellent leading structures for the development of new drugs. For this reason, we focused on the syntheses and cytotoxic evaluation of derivatives obtained from gypsogenin, hederagenin, and madecassic acid, cytotoxicity increased—by and large—from the parent compounds to their acetates. Another increase in cytotoxicity was observed for the acetylated amides (phenyl, benzyl, piperazinyl, and homopiperazinyl), but a superior cytotoxicity was observed for the corresponding rhodamine B conjugates derived from the (homo)-piperazinyl amides. In particular, a madecassic acid homopiperazinyl rhodamine B conjugate 24 held excellent cytotoxicity and selectivity for several human tumor cell lines. Thus, this compound was more than 10,000 times more cytotoxic than parent madecassic acid for A2780 ovarian cancer cells. We assume that the presence of an additional hydroxyl group at position C–6 in derivatives of madecassic, as well as the (2α, 3β) configuration of the acetates in ring A, had a beneficial effect onto the cytotoxicity of the conjugates, as well as onto tumor/non-tumor cell selectivity. [ABSTRACT FROM AUTHOR]

Depression is a prevalent psychiatric disorder and a leading cause of disability worldwide. Despite a variety of available treatments currently being used in the clinic, a substantial proportion of patients is unresponsive to these treatments, urging the development of more effective therapeutic approaches. Hederagenin (Hed), a triterpenoid saponin extracted from Fructus Akebiae, has several biological activities including anti-apoptosis, anti-hyperlipidemic and anti-inflammatory properties. Over the years, its potential therapeutic effect in depression has also been proposed, but the information is limited and the mechanisms underlying its antidepressant-like effects are unclear. The present study explored the neuroprotective effects and the potential molecular mechanisms of Hederagenin action in corticosterone (CORT)-injured PC12 cells. Obtained results show that Hederagenin protected PC12 cells against CORT-induced damage in a concentration dependent manner. In adittion, Hederagenin prevented the decline of mitochondrial membrane potential, reduced the production of intracellular reactive oxygen species (ROS) and decreased the apoptosis induced by CORT. The protective effect of Hederagenin was reversed by a specific phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002 and AKT (also known as protein kinase B) inhibitor MK2206, suggesting that the effect of Hederagenin is mediated by the PI3K/AKT pathway. In line with this, western blot analysis results showed that Hederagenin stimulated the phosphorylation of AKT and its downstream target Forkhead box class O 3a (FoxO3a) and Glycogen synthase kinase-3-beta (GSK3β) in a concentration dependent manner. Taken together, these results indicate that the neuroprotective effect of Hederagenin is likely to occur via stimulation of the PI3K/AKT pathway.

Depression is a prevalent psychiatric disorder and a leading cause of disability worldwide. Despite a variety of available treatments currently being used in the clinic, a substantial proportion of patients is unresponsive to these treatments, urging the development of more effective therapeutic approaches. Hederagenin (Hed) , a triterpenoid saponin extracted from Fructus Akebiae, has several biological activities including anti-apoptosis, anti-hyperlipidemic and anti-inflammatory properties. Over the years, its potential therapeutic effect in depression has also been proposed, but the information is limited and the mechanisms underlying its antidepressant-like effects are unclear. The present study explored the neuroprotective effects and the potential molecular mechanisms of Hederagenin action in corticosterone (CORT)-injured PC12 cells. Obtained results show that Hederagenin protected PC12 cells against CORT-induced damage in a concentration dependent manner. In adittion, Hederagenin prevented the decline of mitochondrial membrane potential, reduced the production of intracellular reactive oxygen species (ROS) and decreased the apoptosis induced by CORT. The protective effect of Hederagenin was reversed by a specific phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002 and AKT (also known as protein kinase B) inhibitor MK2206, suggesting that the effect of Hederagenin is mediated by the PI3K/AKT pathway. In line with this, western blot analysis results showed that Hederagenin stimulated the phosphorylation of AKT and its downstream target Forkhead box class O 3a (FoxO3a) and Glycogen synthase kinase-3-beta (GSK3β) in a concentration dependent manner. Taken together, these results indicate that the neuroprotective effect of Hederagenin is likely to occur via stimulation of the PI3K/AKT pathway. [ABSTRACT FROM AUTHOR]

Lung cancer poses a significant threat globally, especially in China. This puts higher demands on the treatment methods and drugs for lung cancer. Natural plants provide valuable resources for the development of anti-cancer drugs. Hederagenin (Hed) is a triterpenoid compound extracted from ivy leaves and has anti-tumor activity against multifarious cancers, including lung cancer. However, the regulatory mechanism of Hed in lung cancer remains unclear. In this study, we used Hed to treat lung cancer cells, and observed the effect of Hed on cell proliferation (including CCK-8 and colony formation experiments), apoptosis (including flow cytometry and apoptosis gene detection (BAX and Bcl-2)). The results showed that Hed induced lung cancer cell death (inhibiting proliferation and promoting apoptosis). Next, we performed bioinformatics analysis of the expression profile GSE186218 and found that Hed treatment significantly increased the expression of CHAC1 gene. CHAC1 is a ferroptosis-inducing gene. RT-qPCR detection of lung cancer clinical tissues and related cell lines also showed that CHAC1 was lowly expressed in lung cancer. Therefore, we knocked down and overexpressed CHAC1 in lung cancer cells, respectively. Subsequently, cell phenotype experiments showed that down-regulating CHAC1 expression inhibited lung cancer cell death (promoting proliferation and inhibiting apoptosis); on the contrary, up-regulating CHAC1 expression promoted lung cancer cell death. To further verify that Hed exerts anti-tumor effects in lung cancer by promoting CHAC1 expression, we performed functional rescue experiments. The results showed that down-regulating CHAC1 expression reversed the promoting effect of Hed on lung cancer cell death. Mechanistically, in vitro and in vivo experiments jointly demonstrated that Hed exerts anti-cancer effects by promoting CHAC1-induced ferroptosis. In summary, our study further enriches the regulatory mechanism of Hed in lung cancer. • Hederagenin (Hed) inhibits lung cancer progression. • Hed activates CHAC1 and inhibits lung cancer progression. • Hed inhibits lung cancer progression by activating CHAC1 mediated ferroptosis. [ABSTRACT FROM AUTHOR]

• Hederagenin significantly improves renal injury and fibrosis in diabetic nephropathy mice. • Hederagenin ameliorates renal injury in diabetic nephropathy mice by alleviating ferroptosis in renal tubule cells. • Smad3 is an upstream regulatory gene of NOX4/SLC7A11 that promotes iron death in renal tubule cells. • The ameliorative effect of Hederagenin on renal fibrosis in diabetic nephropathy depends on the inhibition of Smad3. Diabetic nephropathy (DN) is a common complication of diabetes, characterized by renal fibrosis and poor patient prognosis. Hederagenin (HDG) has shown promising improvement in chronic kidney disease (CKD) kidney fibrosis, but its mechanism in DN-induced kidney fibrosis remains unclear. In this study, a model of diabetic nephropathy (DN) in mice was induced by intraperitoneal injection of streptozocin (50 mg/kg), while in vitro , high glucose (25 mM) was used to induce HK2 cell damage, simulating tubular injury in DN kidneys. The improvement of HDG treatment intervention was evaluated by observing changes in renal function, pathological structural damage, and the expression of fibrosis-related proteins in renal tubular cells. The results demonstrate that HDG intervention alleviates renal dysfunction and pathological damage in DN mice, accompanied by reduced expression of fibrotic markers α-smooth muscle actin (α-SMA), fibronectin (FN) and Collagen-I. Mechanistically, this study found that HDG can inhibit ferroptosis and fibrosis induced by the ferroptosis inducer Erastin (1 μM) in renal tubular cells. Phosphorylation of Smad3 promotes ferroptosis in renal tubular cells. After using its specific inhibitor SIS3 (4 μM), the expression of downstream target protein NADPH oxidase 4 (NOX4) significantly decreases, while the level of glutathione peroxidase 4 (GPX4) is notably restored, mitigating ferroptosis. Smad3 overexpression attenuates the therapeutic effect of HDG on tubular cell fibrosis induced by high glucose. These results demonstrate HDG inhibits Smad3 phosphorylation, thereby reducing the expression of NOX4 and enhancing the expression of GPX4, ultimately attenuating ferroptosis induced renal fibrosis. These findings suggest that HDG offer therapeutic potential for DN renal fibrosis by targeting Smad3-mediated ferroptosis in renal tubular cells. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) continues to be a worldwide health concern, demanding innovative therapeutic approaches. This study investigates the neuroprotective potential of herbal compounds by scrutinizing their interactions with Beta-Secretase-1 (BACE1). Through comprehensive molecular docking analyses, three compounds, Masticadienonic acid (ΔG: −9.6 kcal/mol), Hederagenin (ΔG: −9.3 kcal/mol), and Anthocyanins (ΔG: −8.1 kcal/mol), emerge as promising BACE1 ligands, displaying low binding energies and strong affinities. ADME parameter predictions, drug-likeness assessments, and toxicity analyses reveal favorable pharmacokinetic profiles for these compounds. Notably, Masticadienonic Acid exhibits optimal drug-likeness (−3.3736) and negligible toxicity concerns. Hederagenin (drug-likeness: −5.3272) and Anthocyanins (drug-likeness: −6.2041) also demonstrate promising safety profiles. Furthermore, pharmacophore modeling elucidates the compounds' unique interaction landscapes within BACE1′s active site. Masticadienonic acid showcases seven hydrophobic interactions and a hydrogen bond acceptor interaction with Thr232. Hederagenin exhibits a specific hydrogen bond acceptor interaction with Trp76, emphasizing its selective binding. Anthocyanins reveal a multifaceted engagement, combining hydrophobic contacts and hydrogen bond interactions with key residues. In conclusion, Masticadienonic acid, Hederagenin, and Anthocyanins stand out as promising candidates for further experimental validation, presenting a synergistic balance of efficacy and safety in combating AD through BACE1 inhibition. [ABSTRACT FROM AUTHOR]

Toxoplasma gondii infection is widespread worldwide, not only posing a serious threat to human food safety and animal husbandry, but also endangering human health. The selectivity index was employed to measure anti-T. gondii activity. Hederagenin (HE) exhibited potent anti-T. gondii activity and low cytotoxicity. For this reason, HE was selected for in vivo experiments. HE showed 64.8%±13.1% inhibition for peritoneal tachyzoites in mice, higher than spiramycin 56.8%±6.0%. Biochemical parameters such as alanine aminotransferase, aspartate aminotransferase, glutathione, and malondialdehyde, illustrated that HE was a good inhibitor of T. gondii in vivo. This compound was also effective in relieving T. gondii-induced liver damage. Collectively, it was demonstrated that HE had potential as an anti-T. gondii agent. [ABSTRACT FROM AUTHOR]

Swiss chard is a vegetable valued not only for the taste of its leaves but also because of its health-promoting properties. To date, nothing is known regarding the occurrence of saponins in the Swiss chard plant, even though they could be at least partially responsible for the nutraceutical activities of this plant. This research aimed to describe saponins from the leaves of four Swiss chard (Beta vulgaris L.) cultivars. Saponin structures were analyzed by UHPLC-CAD/QTOF-MS/MS. Based on the fragmentation patterns, we tentatively identified 16 triterpene saponins in B. vulgaris, including two that had not been detected previously. The observed compounds were glycosides of five different, tentatively identified aglycones, i.e., oleanolic acid, hederagenin, gypsogenin, akebonoic acid, and serjanic acid. Moreover, the structure of four saponins detected in Swiss chard leaves included dioxolane-type and six acetal-type substituents. Eleven, eight, eleven, and eight saponins were observed in saponin fractions obtained from Rhubarb, Bulls Blood, Perpetual Spinach, and White Silver cultivars, respectively. Furthermore, the content of all identified triterpene derivatives in the investigated cultivars was estimated using a method based on the UHPLC coupled with QTOF-MS/MS and charged aerosol detector (CAD). The analyzed cultivars differed in the total and individual saponin content. The total saponin content ranged from 125.53 to 397.09 µg/g DW. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disease characterized by memory loss and cognitive impairment. β-amyloid (Aβ) is one of the typical pathological features of AD, and its accumulation leads to neuronal death from oxidative stress. Here, we found that hederagenin (HG), a natural product, exhibits anti-tumor, anti-inflammatory, anti-depressant, anti-neurodegenerative biological activities. However, whether HG has anti-Aβ activity remains unclear. Based on the characteristics of HG, it is hypothesized that HG has biological activity against Aβ injury. Therefore, Aβ-injured SH-SY5Y cells were constructed, and the protective effect of HG against Aβ injury was further evaluated using C. elegans. The results showed that HG increased superoxide dismutase activity, effectively reduced Aβ-induced oxidative damage, and reduced apoptosis via the PI3 K/Akt signaling pathway. HG inhibited Aβ deposition and delayed senescence and paralysis in the C. elegans strain, CL4176. HG showed inhibitory effects on Aβ; therefore, more natural active products are expected to be applied in AD therapy., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Leukocyte Biology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Cerebral ischaemia/reperfusion (CI/R) injury is a major challenge due to the lack of effective neuroprotective drugs. Hederagenin (HE) is the aglycone part of saponins extracted from Hedera helix Linné that has exhibited anti-apoptotic and anti-inflammatory effects; however, the role of HE in CI/R has not been elucidated. In this study, mice were intraperitoneally (i.p.) injected with HE (26.5, 53, or 106 μmol/kg body weight) for 3 days after middle cerebral artery occlusion (MCAO). Neural function and brain infarct volume were evaluated. HE treatment attenuated CI/R-induced apoptosis and inflammatory cytokine expression within the infarcted areas. HE treatment also decreased the activation of the MLK3 signalling pathway, which potentiates CI/R damage via the MAPK and NFκB pathways. Due to HE’s safety profile, it has potential to be used for the clinical treatment of ischaemic stroke.

• Hederagenin and gypsogenin have been isolated from plant material. • Both compounds can be interconverted in good yields. • Oxidation of gypsogenin followed by decarboxylation led to 4- epi -hedragonic acid. Gypsogenin (1) and hederagenin (2) were isolated by extracting the powdered roots of Saponaria officinalis and the pericarp of Sapindus saponaria , respectively. While the gypsophila derived saponin can be obtained easily and in large quantities as a technical product, the plant material from Sapindus saponaria is difficult to obtain in Europe and the North-Americas, whereas in Latin America it is readily available (unlike the gypsophila saponin). In order to achieve a better accessibility of both aglycones, gypsogenin (1) and hederagenin (2), a simple synthesis for their interconversion was developed. Modification of the reaction conditions led to the first synthesis of 4- epi -hedragonic acid (3). [ABSTRACT FROM AUTHOR]

Cerebral ischaemia/reperfusion (CI/R) injury is a major challenge due to the lack of effective neuroprotective drugs. Hederagenin (HE) is the aglycone part of saponins extracted from Hedera helix Linné that has exhibited anti-apoptotic and anti-inflammatory effects; however, the role of HE in CI/R has not been elucidated. In this study, mice were intraperitoneally (i.p.) injected with HE (26.5, 53, or 106 μmol/kg body weight) for 3 days after middle cerebral artery occlusion (MCAO). Neural function and brain infarct volume were evaluated. HE treatment attenuated CI/R-induced apoptosis and inflammatory cytokine expression within the infarcted areas. HE treatment also decreased the activation of the MLK3 signalling pathway, which potentiates CI/R damage via the MAPK and NFκB pathways. Due to HE's safety profile, it has potential to be used for the clinical treatment of ischaemic stroke. [ABSTRACT FROM AUTHOR]

As a respiratory disease with high morbidity and mortality, pulmonary fibrosis (PF) has been a serious threat to people's health. Hederagenin (HDG) is a pentacyclic triterpenoid saponin widely distributed in various plants. This study explored the role of HDG in Bleomycin (BLM)-induced PF and the molecular mechanism. The results showed that HDG reduced BLM-induced pulmonary dysfunction, pathological damage in a dose-dependent manner. Besides, HDG reduced BLM-induced collagen deposition by decreasing the levels of α-SMA, Collagen I and hydroxproline. Furthermore, HDG reduced the levels of inflammatory cytokines (TNF-α and IL-6), TGF-β1 and connective tissue growth factor (CTGF) in bronchoalveolar lavage fluid (BALF) or serum. Further mechanism analysis indicated that HDG inhibited the expression of Ras and phosphorylation of JNK and NFAT4 in a dose-dependent manner. However, the JNK pathway activator Anisomycin reversed this inhibitory effect. In conclusion, these findings suggest that HDG may be a potential target drug for PF therapy. Hederagenin alleviates bleomycin-induced pulmonary fibrosis by regulating Ras/JNK/NFAT4 pathway in rats [ABSTRACT FROM AUTHOR]

Objective: This study aims to elucidate anti-liver cancer components and potential mechanisms of Curcumae Rhizoma and Hedyotis diffusa Willd (CR-HDW)., Methods: Effective components and targets of CR-HDW were identified from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. Liver cancer-related genes were collected from GeneCards, Gene-Disease Association (DisGeNET), and National Center for Biotechnology Information (NCBI). Protein-protein interaction networks, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment were conducted to analyze the identified genes. Molecular docking was used to simulate binding of the active components and their target proteins. Cell activity assay, western blot, and senescence-associated β-galactosidase (SA-β-gal) experiments were conducted to validate core targets identified from molecular docking., Results: Ten active compounds of CR-HDW were identified including quercetin, 3-epioleanic acid and hederagenin. The primary core proteins comprised Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), Protein Kinase B(AKT1), etc. The pathways for Phosphoinositide 3-kinase (PI3K)/ AKT, cellular senescence, Fork head boxO (FOXO) were revealed as important for anti-cancer activity of CR-HDW. Molecular docking demonstrated strong binding between liver cancer target proteins and major active components of CR-HDW. In-vitro experiments confirmed that hederagenin and 3-epioleolic acid inhibited HuH-7 cell growth, reduced expression of PI3K, AKT, and mechanistic target of rapamycin (mTOR) proteins. Hederagenin also induced HuH-7 senescence., Conclusions: In summary, The authors' results suggest that the CR-HDW component (Hederagenin, 3-epoxy-olanolic acid) can inhibit the proliferation of HuH-7 cells by decreasing PI3K, AKT, and mTOR. Hederagenin also induced HuH-7 senescence., Competing Interests: The author(s) of this work have nothing to disclose.Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

In this study, three of the saponins present in leaves of Hedera helix L., α-hederin, hederagenin, and hederacoside C were studied for their antiproliferative activity. The three saponins were analyzed in different concentrations by in vitro tests on normal fibroblasts cells and cervix ephitelial tumor cells. Determination of cytotoxicity and antitumor effects was performed using the MTT method. From the tested saponins, α-hederin was biocompatible in normal fibroblasts cells at concentrations between 2–10 μg/mL. Its antiproliferative activity was exerted in the concentration range of 10–400 μg/mL in cervix ephitelial tumor cells. Similarly, hederagenin presented antiproliferative activity at concentrations between 25–400 μg/mL. In turn, hederacoside C was shown to be noncytotoxic in normal fibroblasts and cervix ephitelial tumor cell culture at all the tested concentrations. The obtained experimental results were analyzed by "Mixture design", a specialized form of the response surface method (RSM) provided by the Design Expert 11 software, and the optimal composition of obtained saponins mixture was selected and verified in vitro for antiproliferative activity. The results showed that an optimal saponins mixture has the potential to be used in pharmacological applications. [ABSTRACT FROM AUTHOR]

A phytochemical investigation of Blighia unijugata led to the isolation of eleven hederagenin glycosides. Among these compounds, six are previously undescribed, two are described in their native forms for the first time and three are known whereas firstly isolated from Blighia unijugata. The structure of the undescribed compounds was elucidated on the basis of 2D NMR and mass spectrometry analyses as 3 -O- β-D-xylopyranosyl-(1 → 3)-α-L-arabinopyranosyl-(1 → 4)-β-D-glucopyranosyl-(1 → 3)-α-L-rhamnopyranosyl-(1 → 2)-α-L-arabinopyranosylhederagenin, 3 -O- β-D-xylopyranosyl-(1 → 3)-α-L-arabinopyranosyl-(1 → 4)-3 -O- acetyl-β-D-glucopyranosyl - (1 → 3)-α-L-rhamnopyranosyl-(1 → 2)-α-L-arabinopyranosylhederagenin, 3 -O- β-D-glucopyranosyl-(1 → 3)-α-L-arabinopyranosyl-(1 → 4)-β-D-glucopyranosyl-(1 → 3)-α-L-rhamnopyranosyl-(1 → 2)-α-L-arabinopyranosylhederagenin, 3 -O- β-D-xylopyranosyl-(1 → 3)-β-D-xylopyranosyl-(1 → 4)-β-D-glucopyranosyl-(1 → 3)-α-L-rhamnopyranosyl-(1 → 2)-α-L-arabinopyranosylhederagenin, 3 -O- β-D-xylopyranosyl-(1 → 3)-β-D-xylopyranosyl-(1 → 4)-3 -O- acetyl-β-D-glucopyranosyl-(1 → 3)-α-L-rhamnopyranosyl-(1 → 2)-α-L-arabinopyranosylhederagenin, 3 -O- α-L-arabinopyranosyl-(1 → 4)-β-D-glucopyranosyl-(1 → 3)-α-L-rhamnopyranosyl-(1 → 2)-α-L-arabinopyranosylhederagenin 28 -O- β-D-glucopyranosyl-(1 → 6)-β-D-glucopyranosyl ester, 3 -O- α-L-arabinopyranosyl-(1 → 4)-β-D-glucopyranosyl-(1 → 3)-α-L-rhamnopyranosyl-(1 → 2)-α-L-arabinopyranosylhederagenin 28 -O- β-D-glucopyranosyl ester and 3 -O- β-D-xylopyranosyl-(1 → 4)-β-D-glucopyranosyl-(1 → 3)-α-L-rhamnopyranosyl-(1 → 2)-α-L-arabinopyranosylhederagenin 28 -O- β-D-glucopyranosyl ester. These results revealed the existence of several conserved structural features that could be used as chemotaxonomic markers for the Blighia genus such as the glycosidic sequence 3 -O- α-L-arabinopyranosyl-(1 → 4)-β-D-glucopyranosyl-(1 → 3)-α-L-rhamnopyranosyl-(1 → 2)-α-L-arabinopyranosyl, the occurrence of 3 -O- acetylated β-D-glucopyranosyl units and the systematic presence of hederagenin as aglycone. Image 1 • Eight undescribed hederagenin glycosides were isolated from Blighia unijugata. • Their structures were determined by spectroscopic methods. • Chemotaxonomic conclusions were discussed. [ABSTRACT FROM AUTHOR]

A triterpenoid isolated from the plant Hedera helix , hederagenin was discovered to have anti-cancer, anti-inflammatory, anti-depressant and anti-fibrosis properties both in vivo and in vitro. In this study, the relationship between mitochondrial fission and hederagenin-induced apoptosis in ovarian cancer (OC) was investigated and the underlying mechanisms were deciphered. Hederagenin's cytotoxicity on OC cells was analyzed using colony formation and CCK-8 assays. The effect of hederagenin on OC cells was also verified by a mouse xenograft tumor model. Flow cytometric analysis was conducted to examine hederagenin's effects on mitochondrial membrane potential, apoptosis, and cell cycle OC cells. MitoTracker Red (CMXRos) staining was performed to observe the mitochondrial morphology. The protein levels of Bak, Bcl-2, Caspase 3, Caspase 9, Cyclin D1 and Bax were measured by Western blot. This study found that hederagenin could suppress the in vivo and in vitro SKOV3 and A2780 cell proliferation in an effective manner. Besides, hederagenin altered the mitochondrial membrane potential, induced S-phase and G0/G1-phase arrest, mitochondrial morphology changes, and apoptosis in OC cells. Additionally, our findings further demonstrated that hederagenin changed the mitochondrial morphology by suppressing dynamin-related protein 1 (Drp1), a crucial mitochondrial division factor. Moreover, Drp1 overexpression could reverse hederagenin-induced apoptosis, whereas the Drp1 knockdown had the opposite effect. Furthermore, hederagenin may trigger BAX mitochondrial translocation and apoptosis in OC cells. These results provided a novel perspective on the relationship between the modulation of mitochondrial morphology and the suppression of ovarian cancer by hederagenin. • The inhibitory effect of hederagenin on ovarian cancer.The relationship between mitochondrial morphology modulation and suppression of ovarian cancer process in response to hederagenin.After treatment with hederagenin, Bax translocated from the cytoplasm to the mitochondrial membrane, triggering apoptosis and leading to cell death. • After treatment with hederagenin, Bax translocated from the cytoplasm to the mitochondrial membrane, triggering apoptosis and leading to cell death. [ABSTRACT FROM AUTHOR]

Hederagenin is a pentacyclic triterpenoid that is widely distributed as the main pharmaceutical ingredient in various medicinal plants. Similarly as other pentacyclic triterpenoids, hederagenin has various pharmacological effects such as anti-tumor, anti-inflammatory, anti-depressant, and anti-viral activities. In particular, the anti-tumor activity of hederagenin indicates its potential for development into highly effective chemotherapeutic agents. Studies revealed that hederagenin effectively suppresses the growth of various tumor cell lines in vitro and interacts with several molecular targets that play essential roles in various cellular signaling pathways. The compound suppresses transformation, inhibits proliferation, and induces apoptosis in tumor cells. In this review, we highlight research progress on the source, pharmacokinetics, pharmacological activity, and mechanism of action of hederagenin and the anti-tumor activity of its analogs by integrating and analyzing relevant domestic and international studies and providing a basis for their further development and application. [ABSTRACT FROM AUTHOR]

Context: Cussonia arborea Hochst. ex A. Rich (Araliaceae) is a folk medicine used to treat various diseases. However, there is no report of the root phytochemistry. Objective: This study isolates and identifies the immunomodulatory compounds from root-bark of C. arborea. Materials and methods: The methanol extract (18 g) was subjected to repeated column chromatography resulting in isolation of five compounds (1–5). Structure determination was achieved by analysis of their 1 D and 2 D NMR, and mass spectroscopy. The compounds (100–1.0 μg/mL) were examined immunomodulatory for effect on production of reactive oxygen species (ROS) from whole blood phagocytes and on proliferation of T-cells. The compounds cytotoxicity (100–1.0 μg/mL) was evaluated on NIH-3T3 normal fibroblast cells. Results: Three pentacyclic triterpenoids [3, 23-dihydroxy-12-oleanen-28-oic acid (1), 3β-hydroxylolean-12-en-28-oic (2) and 23-hydoxy-oxo-urs-12-en-28-oic acid (5)], two phytosterols: [stigmasterol (3)] and [3-O-β-d-glucopyranosyl stigmasterol (4)] were all isolated from the methanol soluble extract. All the tested compounds (1–4) were found to be nontoxic on NIH-3T3 cells. Compound 1 and 2 moderately inhibited the production of ROS (IC50 = 24.4 ± 4.3 and 37.5 ± 0.1 μg/mL, respectively) whereas compound 2 exhibited the highest inhibitory effect (IC50 = 12.6 ± 0.4 μg/mL) on proliferation of phytoheamagglutinin (PHA) activated T-cells. Conclusions: The isolated compounds (1–5) are reported for the first time from this species. In addition, compound 2 with suppressive potential on production of intracellular ROS and proliferation of T-cells could be of immense value in control of autoimmune diseases as well as in immune compromised patients.

Aims and Objectives: This study aimed to evaluate the pharmacological mechanism of Hederagenin (HD) combined with oxaliplatin (L-OHP) in treating gastric cancer (GC) through network pharmacology combined with experimental verification., Material and Methods: Network pharmacology methods were used to screen potential targets for HD, L-OHP, and GC-related targets from public databases, and the intersection of the three gene sets was taken. Cross genes were analyzed through protein-protein interaction (PPI) networks to predict core targets, and related pathways were predicted through GO and KEGG enrichment analysis. The experimental results were verified by the in vitro experiments. HD was applied on AGS/L-OHP cells, and then cellular chemosensitivity and the expressions of P-gp, Survivin, Bcl-2, p-Akt, and p-PI3K genes were detected. Wound assay and Transwell Chamber assay were employed to detect the effect of HD on AGS/L-OHP cells. Nude mice xenograft models transfected using AGS/L-OHP cells were also treated with HD in order to verify the results. The size and weight of the tumor, as well as the expressions of P-gp, Survivin, Bcl-2, p- Akt and p-PI3K genes, were also measured., Results: KEGG analysis showed that the anti-gastric cancer effect of HD was mediated mainly by PI3K-Akt signaling pathways. The PI3K-Akt signaling pathway containing more enriched genes may play a greater role in anti-gastric cancer. It was observed that for AGS/L-OHP cells jointly treated with HD and L-OHP, their activity, migration and invasion were significantly lower than those treated only using HD or L-OHP group. Moreover, expressions of p-Akt, p- PI3K, Bcl-2, P-gp, and Survivin for the HD+L-OHP group decreased significantly. Results of the in vivo experiments showed that the sizes and weights of tumors in the HD+L-OHP group were the lowest compared to the HD group and L-OHP group., Conclusion: Our findings suggest that HD may reduce the resistance of AGS/L-OHP cells to LOHP by regulating the PI3K/Akt signaling pathway., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objective: The objective of this study is to assess the antitumor effects of hederagenin (HDG) in liver cancer (LC) cells and explore the related mechanisms., Materials and Methods: HepG2 cells were treated with HDG and cisplatin, respectively. The CCK8 assay was used to detect cell activity, DAPI staining was used to detect the proportion of living cells, TUNEL assay to detect the proportion of apoptotic cells, flow cytometry to detect the membrane potential, fluoroscopic electron microscopy to detect microstructural changes to the mitochondrial, and western blot analysis and high-content screening to detect apoptosisrelated proteins., Results: Treatment with HDG inhibited the growth of HepG2 cells, decreased the proportion of viable cells, increased the proportion of apoptotic cells, and significantly increased the proportion of cells in the G1 phase. Fluorescence staining showed that HDG damaged the mitochondria of HepG2 cells and significantly decreased the number of mitochondria. Flow cytometry showed that HDG decreased the mitochondrial membrane potential of HepG2 cells. Observations by electron microscopy showed that HDG caused swelling and vacuole formation of the mitochondria of HepG2 cells. HDG significantly reduced the average fluorescence intensity of Bcl-2 in HepG2 cells and significantly increased that of the pro-apoptosis proteins Bax, Cytochrome-c, and Caspase-3., Conclusion: HDG induced apoptosis of HepG2 cells via the mitochondrial pathway., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Kalopanax septemlobus, commonly named the castor aralia tree, is a highly valued woody medicinal tree belonging to the family Araliaceae. Kalopanax septemlobus contains approximately 15 triterpenoid saponins primarily constituted of hederagenin aglycones. Hederagenin is a representative precursor for hemolytic saponin in plants. In the present study, transcriptome analysis was performed to discover genes involved in hederagenin saponin biosynthesis in K. septemlobus. De novo assembly generated 82,698 unique sequences, including 17,747 contigs and 64,951 singletons, following 454 pyrosequencing. Oxidosqualene cyclases (OSCs) are enzymes that catalyze the formation of diverse triterpene skeletons from 2,3-oxidosqualene. Heterologous expression of an OSC sequence in yeast revealed that KsBAS is a β-amyrin synthase gene. Cytochrome P450 genes (CYPs) make up a supergene family in the plant genome and play a key role in the biosynthesis of sapogenin aglycones. In total, 95 contigs and 110 singletons annotated as CYPs were obtained by sequencing the K. septemlobus transcriptome. By heterologous expression in yeast, we found that CYP716A94 was β-amyrin 28-oxidase involved in oleanolic acid production from β-amyrin, and CYP72A397 was oleanolic acid 23-hydroxylase involved in hederagenin production from oleanolic acid. Engineered yeast co-expressing KsBAS, CYP716A94 and CYP72A397 produced hederagenin. Kalopanax septemlobus CYP72A397 is a novel CYP enzyme that synthesizes hederagenin aglycone from oleanolic acid as a single product. In conclusion, we characterized three genes participating in sequential steps for hederagenin biosynthesis from β-amyrin, which are likely to play a major role in hederagenin saponin biosynthesis in K. septemlobus. [ABSTRACT FROM AUTHOR]

Context:Cussonia arboreaHochst. ex A. Rich (Araliaceae) is a folk medicine used to treat various diseases. However, there is no report of the root phytochemistry. Objective:This study isolates and identifies the immunomodulatory compounds from root-bark ofC. arborea. Materials and methods:The methanol extract (18 g) was subjected to repeated column chromatography resulting in isolation of five compounds (1–5). Structure determination was achieved by analysis of their 1 D and 2 D NMR, and mass spectroscopy. The compounds (100–1.0 μg/mL) were examined immunomodulatory for effect on production of reactive oxygen species (ROS) from whole blood phagocytes and on proliferation of T-cells. The compounds cytotoxicity (100–1.0 μg/mL) was evaluated on NIH-3T3 normal fibroblast cells. Results:Three pentacyclic triterpenoids [3, 23-dihydroxy-12-oleanen-28-oic acid (1), 3β-hydroxylolean-12-en-28-oic (2) and 23-hydoxy-oxo-urs-12-en-28-oic acid (5)], two phytosterols: [stigmasterol (3)] and [3-O-β-d-glucopyranosyl stigmasterol (4)] were all isolated from the methanol soluble extract. All the tested compounds (1–4) were found to be nontoxic on NIH-3T3 cells. Compound1and2moderately inhibited the production of ROS (IC50 = 24.4 ± 4.3 and 37.5 ± 0.1 μg/mL, respectively) whereas compound2exhibited the highest inhibitory effect (IC50 = 12.6 ± 0.4 μg/mL) on proliferation of phytoheamagglutinin (PHA) activated T-cells. Conclusions:The isolated compounds (1–5) are reported for the first time from this species. In addition, compound2with suppressive potential on production of intracellular ROS and proliferation of T-cells could be of immense value in control of autoimmune diseases as well as in immune compromised patients. [ABSTRACT FROM PUBLISHER]

Aiming to obtain new potent leishmanicidal and cytotoxic compounds from natural sources, the triterpene hederagenin was converted into several new 1,2,3-triazolyl derivatives tethered at C-23 and C-28. For this work hederagenin was isolated from fruits of Sapindus saponaria and reacted with propargyl bromide to afford as a major product bis-propargylic derivative 1 in 74%. Submitting this compound to Huisgen 1,3-dipolar cycloaddition reactions with several azides afforded the derivatives 2 – 19 with yields in the range of 40–87%. All compounds have been screened for in vitro cytotoxic activity in a panel of five human cancer cell lines by a SRB assay. The bioassays showed that compound 19 was the most cytotoxic against all human cancer cell lines with EC 50 = 7.4–12.1 μM. Moreover, leishmanicidal activity was evaluated through the in vitro effect in the growth of Leishmania infantum , and derivatives 1 , 2 , 5 and 17 were highly effective preventing proliferation of intracellular amastigote forms of L. infantum (IC 50 = 28.8, 25.9, 5.6 and 7.4 μM, respectively). All these compounds showed a higher selectivity index and low toxicity against two strains of kidney BGM and liver HepG2 cells. Compound 5 has higher selectivity (1780 times) in comparison with the commercial antimony drug and is around 8 times more selective than the most active compound previously reported hederagenin derivative. Such high activity associated with low toxicities make the new bis-traiazolyl derivatives promising candidates for the treatment of leishmaniasis. In addition, hederagenin and some derivatives ( 2 , 5 and 17 ) showed interaction in the binding site of the enzyme CYP51 Li . [ABSTRACT FROM AUTHOR]

The pentacyclic triterpenoid hederagenin (1) was subjected to biotransformation byCunninghamella echinulateCGMCC 3.2000,Mucor subtilissimusCGMCC 3.2454 andPseudomonas oleovoransCGMCC 1.1641. Three metabolites were obtained. On the basis of nuclear magnetic resonance and high-resolution mass spectral analyses, their structures were characterized as 3β, 23-dihydroxyolean-12-en-28-oic acid 28-O-β-D-glucopyranosyl ester (2), 3β, 15α, 23-trihydroxyolean-12-en-28-oic acid (3), 1β, 3β, 23-trihydroxyolean-12-en-28-oic acid (4), and metabolite (3) was a new compound. This was the first report on the biotransformation of hederagenin. [ABSTRACT FROM PUBLISHER]

The antiprotozoal effect of saponins is transitory, as when saponins are deglycosylated to the sapogenin by rumen microorganisms they become inactive. We postulated that the substitution of the sugar moiety of the saponin with small polar residues would produce sapogen-like analogs which might be resistant to degradation in the rumen as they would not be enzymatically cleaved, allowing the antiprotozoal effect to persist over time. In this study, we used an acute assay based on the ability of protozoa to break down [14C] leucine-labeled Streptococcus bovis and a longer term assay based on protozoal motility over 24 h to evaluate both the antiprotozoal effect and the stability of this effect with fifteen hederagenin bis-esters esterified with two identical groups, and five cholesterol and cholic acid based derivatives carrying one to three succinate residues. The acute antiprotozoal effect of hederagenin derivatives was more pronounced than that of cholesterol and cholic acid derivatives. Modifications in the structure of hederagenin, cholesterol, and cholic acid derivatives resulted in compounds with different biological activities in terms of acute effect and stability, although those which were highly toxic to protozoa were not always the most stable over time. Most of the hederagenin bis-esters, and in particular hederagenin bis-succinate (TSB24), hederagenin bis-betainate dichloride (TSB37) and hederagenin bis-adipate (TSB47) had a persistent effect against rumen protozoa in vitro, shifting the fermentation pattern toward higher propionate and lower butyrate. These chemically modified triterpenes could potentially be used in ruminant diets as an effective defaunation agent to, ultimately, increase nitrogen utilization, decrease methane emissions, and enhance animal production. Further trials in vivo or in long term rumen simulators are now needed to confirm the in vitro observations presented. [ABSTRACT FROM AUTHOR]

A rapid and sensitive liquid chromatography tandem mass spectrometry (LC-MS/MS) was developed and validated for simultaneous quantification of oleanolic acid and hederagenin in rat plasma. After the two analytes were extracted with liquid-liquid extraction, chromatographic separation was performed on a C18 column with acetonitrile and water (85:15, v/v) as mobile phase at a flow rate of 0.4 mL/min. Calibration curves exhibited good linearity ( r > 0.995) over the ranges of 0.41-82.0 ng/mL for oleanolic acid and 0.32-64.0 ng/mL for hederagenin, respectively. The lower limit of quantifications (LLOQs) in plasma were 0.41 ng/mL for oleanolic acid and 0.32 ng/mL for hederagenin. The established LLOQs were within the concentration needed for the assay in plasma, which met the requirements to evaluate their pharmacokinetics of oleanolic acid and hederagenin. This developed assay was successfully applied in the pharmacokinetic study of oleanolic acid and hederagenin in rats after oral administration of Rhizoma Clematidis extract. [ABSTRACT FROM AUTHOR]

• HDG significantly improves renal fibrosis caused by IRI and UUO. • Inhibition of ISG15 in vivo and in vitro can significantly reduce the renal tubule fibrosis. • ISG15 promotes renal fibrosis by activating the JAK/SATAT signaling pathway. • HDG improves renal fibrosis in CKD through inhibiting ISG15 regulated JAK/STAT signaling. Interstitial fibrosis is the key pathological characteristics of chronic kidney diseases (CKD). In this study, we reported that hederagenin (HDG) can effectively improve the renal interstitial fibrosis and its mechanism. We constructed CKD animal models of ischemia reperfusion injury (IRI) and unilateral ureteral obstruction (UUO) respectively to observe the improvement effect of HDG on CKD. The results showed that HDG can effectively improve the pathological structure of kidney and the renal fibrosis in CKD mice. Meanwhile, HDG can also significantly reduce the expression of α-SMA and FN induced by TGF-β in Transformed C3H Mouse Kidney-1 (TCMK1) cells. Mechanistically, we performed transcriptome sequencing on UUO kidneys treated with HDG. By real time PCR screening of the sequencing results, we determined that ISG15 plays an important role in the intervention of HDG in CKD. Subsequently, we knocked-down ISG15 in TCMK1 and found that ISG15 knock-down significantly inhibited TGF-β-induced fibrotic protein expression and JAK/STAT activation. Finally, we performed electrotransfection and used liposomes to transfect ISG15 overexpression plasmids to up-regulate ISG15 in kidney and cells, respectively. We found that ISG15 can aggravate renal tubular cell fibrosis and abolish the protection of HDG on CKD. These results indicated that HDG significantly improves renal fibrosis in CKD by inhibiting ISG15 and its downstream JAK/STAT signaling pathway, which provides a new drug and research target for the subsequent treatment of CKD. [ABSTRACT FROM AUTHOR]