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Objective: To estimate the bone protective effect of alpinumisoflavone, a natural prenylated isoflavonoid, against glucocorticoid-induced osteoporosis in rats. Methods: Male Wistar rats received intramuscular administration of dexamethasone (4 mg/mL) at a dose level of 7 mg/kg for 5 weeks, and then alpinumisoflavone (5, 10, and 15 mg/kg) and alendronate (2 mg/kg) from 2 weeks. The body weight and organ weight (femoral, vagina, and uterus) were estimated. MicroCT analysis, bone turnover markers, bone parameters, oxidative stress parameters, and inflammatory cytokines were estimated. mRNA expressions of related genes were also estimated. Results: Alpinumisoflavone remarkably boosted body weight and organ weight (ureters and vagina), improved microCT analysis parameters, and boosted levels of bone markers. Besides, alpinumisoflavone considerably (P

Objective: To estimate the bone protective effect of alpinumisoflavone, a natural prenylated isoflavonoid, against glucocorticoid-induced osteoporosis in rats. Methods: Male Wistar rats received intramuscular administration of dexamethasone (4 mg/mL) at a dose level of 7 mg/kg for 5 weeks, and then alpinumisoflavone (5, 10, and 15 mg/kg) and alendronate (2 mg/kg) from 2 weeks. The body weight and organ weight (femoral, vagina, and uterus) were estimated. MicroCT analysis, bone turnover markers, bone parameters, oxidative stress parameters, and inflammatory cytokines were estimated. mRNA expressions of related genes were also estimated. Results: Alpinumisoflavone remarkably boosted body weight and organ weight (ureters and vagina), improved microCT analysis parameters, and boosted levels of bone markers. Besides, alpinumisoflavone considerably (P <0.001) restored the level of bone turnover markers and oxidative stress parameters, remarkably suppressed the level of cytokines such as interleukin-1β, interleukin-6, tumor necrosis factor-α, and increased transforming growth factor-β and insulin-like growth factor. It also significantly restored the osteoprotegerin (OPG, RANKL, and OPG/RANKL ratio) levels and the mRNA expression of Caspase (3, 6, 7, 9), BMP s, OPN , ALP , RUNX2 , and OCN. Conclusions: The current result suggests the bone protective effect of alpinumisoflavone against glucocorticoid-induced osteoporosis in rats. [ABSTRACT FROM AUTHOR]

Alpinumisoflavone is an isoflavonoid extracted from the Cudrania tricuspidate fruit and Genista pichisermolliana. It has various physiological functions, such as anti-inflammation, anti-proliferation, and apoptosis, in malignant tumors. However, the effect of alpinumisoflavone is still not known in chronic diseases and other benign reproductive diseases, such as endometriosis. In this study, we examined the cell death effects of alpinumisoflavone on the endometriosis cell lines, End1/E6E7 and VK2/E6E7. Results indicated that alpinumisoflavone inhibited cell migration and proliferation and led to cell cycle arrest, depolarization of mitochondria membrane potential, apoptosis, and disruption of calcium homeostasis in the endometriosis cell lines. However, the cellular proliferation of normal uterine epithelial cells was not changed by alpinumisoflavone. The alteration in Ca2+ levels was estimated in fluo-4 AM-stained End1/E6E7 and VK2/E6E7 cells after alpinumisoflavone treatment with or without calcium inhibitor, 2-aminoethoxydiphenyl borate (2-APB). The results indicated that a combination of alpinumisoflavone and a calcium inhibitor reduced the calcium accumulation in the cytosol of endometriosis cells. Additionally, alpinumisoflavone decreased oxidative phosphorylation (OXPHOS) in the endometriotic cells. Moreover, protein expression analysis revealed that alpinumisoflavone inactivated AKT signaling pathways, whereas it increased MAPK, ER stress, and autophagy regulatory proteins in End1/E6E7 and VK2/E6E7 cell lines. In summary, our results suggested that alpinumisoflavone could be a promising effective management agent or an adjuvant therapy for benign disease endometriosis. [ABSTRACT FROM AUTHOR]

Moreover, AIF treatment led to cell death via activation of the caspase-associated apoptotic pathway in PCa cells. Cell Growth Analysis To investigate the therapeutic effects of AIF on cell growth, PCa cells were seeded in the 96-well plates (1 × 10 SP 4 sp cells/well) and incubated overnight. As expected, targeting the emerging cancer hallmarks and PCa-specific vulnerability genes, such as FASN and HMGCR [[44]], AIF treatment caused the attenuation of PCa cell growth, migration, and invasion. [Extracted from the article]

Alpinumisoflavone is a natural prenylated isoflavonoid extracted from the raw fruit of Cudrania tricuspidata. Several studies have reported the beneficial characteristics of alpinumisoflavone, such as its antioxidant, anti-inflammation, anti-bacterial, osteoprotective, and neuroprotective effects. Alpinumisoflavone also has anti-cancer effects on thyroid, renal, and ovarian cancers, but its therapeutic effects on hepatocellular carcinoma (HCC) have not yet been demonstrated. We investigated the anti-cancer effects of alpinumisoflavone on HCC using human liver cancer cell lines, Hep3B and Huh7. Our results confirmed that alpinumisoflavone inhibited viability and regulated the MAPK/PI3K pathway in Hep3B and Huh7 cells. We also verified that alpinumisoflavone can depolarize the mitochondrial membrane potential and suppress the mitochondrial respiration in HCC cells. Moreover, we confirmed the dysregulation of the mitochondrial complexes I, III, and V involving mitochondrial oxidative phosphorylation at the mRNA level and the accumulation of calcium ions in the mitochondrial matrix. Lastly, we demonstrated that alpinumisoflavone induced mitochondria-mediated apoptosis via regulation of the Bcl-xL and BAK proteins. This study elucidates the anti-cancer effects of alpinumisoflavone on HCC. [ABSTRACT FROM AUTHOR]

Abstract Tuberculosis remains a major health problem worldwide. Drug-resistant and hypervirulent Mycobacterium tuberculosis (Mtb) strains can lead to a hyperinflammatory response and necrotic pathology in hyper-reactive individuals that require adjunctive treatment. Plant-derived substances have been investigated for TB treatment, among which flavonoids stand out. We evaluate the anti-Mtb, anti-inflammatory and cytotoxicity activities of fractions and substances 1, 2 and 3 isolated from Erythrina verna through a bioassay guided fractionation. Seven fractions (1, 3-5 and 7-9) obtained from dichloromethane E. verna extract inhibited NO production (IC50 ≤ 15 μg/mL) with none or poor cytotoxic effect, while the fractions 4 and 5 notably reduced TNF-a production. Fractions 4, 6 and 9 suppressed Mycobacterium growth with MIC50 ≤ 20 μg/mL. Fraction 4 was the most potent due to dual biological activities. Erythratidinone and alpinumisoflavone inhibited the growth of Mtb H37Rv and hypervirulent strain in bacterial cultures (MIC50 ≤ 20 μg/mL), with erythratidinone standing out in reducing intracellular growth of Mtb H37Rv (5.8 ± 1.1 μg/mL). Alpinumisoflavone and erythratidinone were capable of inhibiting NO and TNF-α production besides showing significant inhibitory effects against Mycobacterium tuberculosis strains with low toxicity in macrophages. Both substances are promising for further studies focusing on an anti-TB dual treatment approach.

Alpinumisoflavone is an isoflavonoid extracted from the Cudrania tricuspidate fruit and Genista pichisermolliana. It has various physiological functions, such as anti-inflammation, anti-proliferation, and apoptosis, in malignant tumors. However, the effect of alpinumisoflavone is still not known in chronic diseases and other benign reproductive diseases, such as endometriosis. In this study, we examined the cell death effects of alpinumisoflavone on the endometriosis cell lines, End1/E6E7 and VK2/E6E7. Results indicated that alpinumisoflavone inhibited cell migration and proliferation and led to cell cycle arrest, depolarization of mitochondria membrane potential, apoptosis, and disruption of calcium homeostasis in the endometriosis cell lines. However, the cellular proliferation of normal uterine epithelial cells was not changed by alpinumisoflavone. The alteration in Ca2+ levels was estimated in fluo-4 AM-stained End1/E6E7 and VK2/E6E7 cells after alpinumisoflavone treatment with or without calcium inhibitor, 2-aminoethoxydiphenyl borate (2-APB). The results indicated that a combination of alpinumisoflavone and a calcium inhibitor reduced the calcium accumulation in the cytosol of endometriosis cells. Additionally, alpinumisoflavone decreased oxidative phosphorylation (OXPHOS) in the endometriotic cells. Moreover, protein expression analysis revealed that alpinumisoflavone inactivated AKT signaling pathways, whereas it increased MAPK, ER stress, and autophagy regulatory proteins in End1/E6E7 and VK2/E6E7 cell lines. In summary, our results suggested that alpinumisoflavone could be a promising effective management agent or an adjuvant therapy for benign disease endometriosis.

[Display omitted] • AIF promotes cell proliferation by PCNA expression and migration in EVT cells. • AIF protects mitochondria from oxidative stress and improves mitochondrial function. • AIF modulates SIRT1-mediated proliferation and signaling pathways in EVT cells. • AIF alleviates H 2 O 2 -induced apoptosis and loss of MMP through SIRT1 in EVT cells. • Molecular docking analysis indicates strong binding affinity between AIF and SIRT1. Pre-eclampsia (PE) is classified as pregnancy-specific hypertensive disease and responsible for severe fetal and maternal morbidity and mortality, which influenced an approximate 3 ∼ 8 % of all pregnancies in both developed and developing countries. However, the exact pathological mechanism underlying PE has not been elucidated and it is urgent to find innovate pharmacotherapeutic agents for PE. Recent studies have reported that a crucial part of the etiology of PE is played by placental oxidative stress. Therefore, to treat PE, a possible treatment approach is to mitigate the placental oxidative stress. Alpinumisoflavone (AIF) is a prenylated isoflavonoid originated in mandarin melon berry called Cudrania tricuspidate, and is well known for its versatile pharmacotherapeutic properties, including anti-fibrotic, anti-inflammatory, anti-tumor, and antioxidant activity. However, protective property of AIF on extravillous trophoblast (EVT) under placental oxidative stress has not been elucidated yet. Therefore, we assessed stimulatory effects of AIF on the viability, invasion, migration, mitochondria function in the representative EVT cell line, HTR-8/SVneo cell. Moreover, protective activities of AIF from H 2 O 2 were confirmed, in terms of reduction in apoptosis, ROS production, and depolarization of mitochondrial membrane. Furthermore, we confirmed the direct interaction of AIF with sirtuin1 (SIRT1) using molecular docking analysis and SIRT1-mediated signaling pathways associated with the protective effects of AIF on HTR-8/SVneo cells under oxidative stress. Finally, beneficial efficacy of AIF against oxidative stress was further confirmed using BeWo cells, syncytiotrophoblast cell lines. These results suggest that AIF may ameliorate H 2 O 2 -induced intracellular damages through SIRT1 activation in human trophoblast cells. [ABSTRACT FROM AUTHOR]

Alpinumisoflavone is a prenylated isoflavonoid derived from the Cudrania tricuspidate fruit and Genista pichisermolliana. Alpinumisoflavone has anticancer properties in a variety of cancer cells, including colorectal, esophageal, renal and hepatocellular carcinoma. However, its mechanisms and effects in ovarian cancer remain unexplored. Our findings indicate that alpinumisoflavone triggers anti-proliferation in 2D- and 3D-cultured human ovarian cancer (ES2 and OV90) cells, including a reduction in the proliferating cell nuclear antigen expression and sub-G1 phase arrest of the cell cycle. Both alpinumisoflavone-treated ES2 and OV90 cells exhibited an augmentation in late apoptotic cells and the depolarization of mitochondrial membrane potential (MMP). We also observed a decrease in respiratory chain activity in ovarian cancer cells, owing to lower energy output by the alpinumisoflavone. In addition, combining cisplatin (a chemotherapeutic drug used in several malignancies) with alpinumisoflavone boosted apoptosis in ES2 and OV90 cells via a reduction in cell proliferation, induction of late apoptotic cells, and depolarization of MMP. Furthermore, alpinumisoflavone also regulated the PI3K/AKT, MAPK and endoplasmic reticulum (ER) stress regulatory signaling pathways, leading to cell death in both ES2 and OV90 cells. In general, our findings verified that alpinumisoflavone inhibited ovarian cancer cell growth via mitochondrial malfunction. [ABSTRACT FROM AUTHOR]

Alpinumisoflavone is a natural prenylated isoflavonoid extracted from the raw fruit of Cudrania tricuspidata. Several studies have reported the beneficial characteristics of alpinumisoflavone, such as its antioxidant, anti-inflammation, anti-bacterial, osteoprotective, and neuroprotective effects. Alpinumisoflavone also has anti-cancer effects on thyroid, renal, and ovarian cancers, but its therapeutic effects on hepatocellular carcinoma (HCC) have not yet been demonstrated. We investigated the anti-cancer effects of alpinumisoflavone on HCC using human liver cancer cell lines, Hep3B and Huh7. Our results confirmed that alpinumisoflavone inhibited viability and regulated the MAPK/PI3K pathway in Hep3B and Huh7 cells. We also verified that alpinumisoflavone can depolarize the mitochondrial membrane potential and suppress the mitochondrial respiration in HCC cells. Moreover, we confirmed the dysregulation of the mitochondrial complexes I, III, and V involving mitochondrial oxidative phosphorylation at the mRNA level and the accumulation of calcium ions in the mitochondrial matrix. Lastly, we demonstrated that alpinumisoflavone induced mitochondria-mediated apoptosis via regulation of the Bcl-xL and BAK proteins. This study elucidates the anti-cancer effects of alpinumisoflavone on HCC.

The objective of this study was to carry out a systematic review of the substances isolated from the African medicinal plant Erythrina senegalensis, focusing on compounds harboring activities against cancer models detailed in depth herein at both in vitro and in vivo preclinical levels. The review was conducted through Pubmed and Google Scholar. Nineteen out of the forty-two secondary metabolites isolated to date from E. senegalensis displayed interesting in vitro and/or in vivo antitumor activities. They belonged to alkaloid (Erysodine), triterpenes (Erythrodiol, maniladiol, oleanolic acid), prenylated isoflavonoids (senegalensin, erysenegalensein E, erysenegalensein M, alpinumisoflavone, derrone, warangalone), flavonoids (erythrisenegalone, senegalensein, lupinifolin, carpachromene) and pterocarpans (erybraedine A, erybraedine C, phaseollin). Among the isoflavonoids called “erysenegalensein”, only erysenealenseins E and M have been tested for their anticancerous properties and turned out to be cytotoxic. Although the stem bark is the most frequently used part of the plant, all pterocarpans were isolated from roots and all alkaloids from seeds. The mechanisms of action of its metabolites include apoptosis, pyroptosis, autophagy and mitophagy via the modulation of cytoplasmic proteins, miRNA and enzymes involved in critical pathways deregulated in cancer. Alpinumisoflavone and oleanolic acid were studied in a broad spectrum of cancer models both in vitro and in preclinical models in vivo with promising results. Other metabolites, including carpachromen, phaseollin, erybraedin A, erysenegalensein M and maniladiol need to be further investigated, as they display potent in vitro effects.

Cancer is the second cause of death after cardiovascular diseases in the world. Anticancer prevention used can cause undesirable things. Flavonoids are secondary metabolites derived from natural products that are useful for anticancer treatment. This study was performed to observe the cytotoxic activity of alpinumisoflavone from Erythrina poeppigiana, toward cervical cancer (Hela), colon cancer (WiDr), and hepatoma cancer (HepG2) cells. The cytotoxic activity of alpinumisoflavone was tested using (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide) assay. The percentage of cell mortality was calculated and the IC50 was calculated using probit analysis. The result shown that alpinumisoflavone has antiproliferative effect to colon cancer (WiDr), cervical cancer (Hela), and hepatoma cancer (HepG2) cells with the value of IC50 are 5.63, 7.18, and 18.08 µg/ml, respectively. Based on the value of IC50 alpinumisoflavone is very cytotoxic to colon cancer WiDr cell.

Over the last decade, several studies demonstrated that prenylation of flavonoids enhances various biological activities as compared to the respective nonprenylated compounds. In line with this, the natural prenylated isoflavonoid alpinumisoflavone (AIF) has been explored for a number of biological and pharmacological effects (therapeutic potential). In this review, we summarize the current information on health-promoting properties of AIF. Reported data evidenced that AIF has a multitherapeutic potential with antiosteoporotic, antioxidant and anti-inflammatory, antimicrobial, anticancer, estrogenic and antiestrogenic, antidiabetic, and neuroprotective properties. However, research on these aspects of AIF is not sufficient and needs to be reevaluated using more appropriate methods and methodology. Further series of studies are needed to confirm these pharmacological effects, and this review should lay the basis for the design of respective investigations. Overall, despite the drawbacks of studies recorded, AIF exhibits a potential as drug candidate.

Over the last decade, several studies demonstrated that prenylation of flavonoids enhances various biological activities as compared to the respective nonprenylated compounds. In line with this, the natural prenylated isoflavonoid alpinumisoflavone (AIF) has been explored for a number of biological and pharmacological effects (therapeutic potential). In this review, we summarize the current information on health-promoting properties of AIF. Reported data evidenced that AIF has a multitherapeutic potential with antiosteoporotic, antioxidant and anti-inflammatory, antimicrobial, anticancer, estrogenic and antiestrogenic, antidiabetic, and neuroprotective properties. However, research on these aspects of AIF is not sufficient and needs to be reevaluated using more appropriate methods and methodology. Further series of studies are needed to confirm these pharmacological effects, and this review should lay the basis for the design of respective investigations. Overall, despite the drawbacks of studies recorded, AIF exhibits a potential as drug candidate. [ABSTRACT FROM AUTHOR]

Cancer is the second cause of death after cardiovascular diseases in the world. Anticancer prevention used can cause undesirable things. Flavonoids are secondary metabolites derived from natural products that are useful for anticancer treatment. This study was performed to observe the cytotoxic activity of alpinumisoflavone from Erythrina poeppigiana, toward cervical cancer (Hela), colon cancer (WiDr), and hepatoma cancer (HepG2) cells. The cytotoxic activity of alpinumisoflavone was tested using (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide) assay. The percentage of cell mortality was calculated and the IC50 was calculated using probit analysis. The result shown that alpinumisoflavone has antiproliferative effect to colon cancer (WiDr), cervical cancer (Hela), and hepatoma cancer (HepG2) cells with the value of IC50 are 5.63, 7.18, and 18.08 µg/ml, respectively. Based on the value of IC50 alpinumisoflavone is very cytotoxic to colon cancer WiDr cell. [ABSTRACT FROM AUTHOR]

The skin is an important organ in the human body that protects the body from environmentally hazardous substances. Reactive oxygen species (ROS) cause inflammatory reactions and degradation of the extracellular matrix leading to skin aging and various cutaneous lesions. This study evaluated the potential of isoflavones isolated from Maclura tricuspidata fruit to prevent TNF-α-induced skin inflammation in normal human dermal fibroblasts (HDFs). It focused on alpinumisoflavone (AIF) that suppressed the accumulation of ROS and nitric oxide (NO) in tumor necrosis factor-alpha (TNF-α)-treated HDFs. AIF inhibited the TNF-α-induced increase in matrix metalloproteinase-1, decreased procollagen I α1, and suppressed pro-inflammatory mediators and pro-inflammatory cytokines, including NO synthase, cyclooxygenase-2, interleukin (IL)-1β, IL-6, and IL-8 that trigger inflammatory responses. AIF inhibited nuclear factor-κB and activating protein 1 mitogen-activated protein kinases that were increased by TNF-α stimulation. These results suggest that AIF may protect skin from aging and various cutaneous lesions.

Abstract Aims Colorectal Cancer (CRC) accounts for 6.1% incidence and 9.2% mortality worldwide. The current study aimed to investigate the effect of alpinumisoflavone (AIF) on CRC and its possible molecular mechanism. Methods HCT-116 and SW480 cells were chosen as cell model to study the anti-cancer activity of AIF in vitro experiments. Cells proliferative capacity and clonogenicity were examined by CCK-8 assay and colony formation assay, while cell apoptosis was detected by Hoechst 33258 staining and Flow cytometer. The protein expression levels of related gene were examined by western blotting. Transcriptome analyses were conducted to identify the differentially expressed genes in CRC cells, following AIF treatment. DNA damage was examined by γH2AX foci assay. The anti-cancer effect of AIF in vivo was validated in CRC xenograft model. Key findings We found that AIF inhibited CRC cell proliferation and promoted apoptosis in a dose-dependent manner, as well as increased the number of γ-H2AX foci. In addition, microarray analysis showed that the DNA-double strand break (DSB) repair gene RAD51 was aberrantly overexpressed in CRC tissues, and was positively correlated with lymph node metastasis, TNM stage and poor outcomes. Both in vitro and in vivo experiments confirm that AIF treatment significantly decreased RAD51 levels. Knockdown RAD51 could enhance the anti-cancer activity of AIF against CRC, while abrogated by RAD51 overexpression. Significance These findings suggest that AIF can be regarded as a potential anti-cancer drug and provide new insights into CRC treatment. [ABSTRACT FROM AUTHOR]

Alpinumisoflavone, a major compound in unripe Cudrania tricuspidata fruit is reported to exhibit numerous beneficial pharmacological activities, such as osteoprotective, antibacterial, estrogenic, anti-metastatic, atheroprotective, antioxidant, and anticancer effects. Despite its medicinal value, alpinumisoflavone is poorly soluble in water, which makes it difficult to formulate and administer intravenously (i.v.). To overcome these limitations, we used methoxy poly(ethylene glycol)-b-poly(d,l-lactide) (mPEG-b-PLA) polymeric micelles to solubilize alpinumisoflavone and increase its bioavailability, and evaluated their toxicity in vivo. Alpinumisoflavone-loaded polymeric micelles were prepared using thin-film hydration method, and their physicochemical properties were characterized for drug release, particle size, drug-loading (DL, %), and encapsulation efficiency (EE, %). The in vitro drug release profile was determined and the release rate of alpinumisoflavone from mPEG-b-PLA micelles was slower than that from drug solution, and sustained. Pharmacokinetic studies showed decreased total clearance and volume of distribution of alpinumisoflavone, whereas area under the curve (AUC) and bioavailability were significantly increased by incorporation in mPEG-b-PLA micelles. In vivo toxicity assay revealed that alpinumisoflavone-loaded mPEG-b-PLA micelles had no severe toxicity. In conclusion, we prepared an intravenous (i.v.) injectable alpinumisoflavone formulation, which was solubilized using mPEG-b-PLA micelles, and determined their physicochemical properties, pharmacokinetics, and toxicity profiles.

The long-term use of glucocorticoids is found to cause osteoporosis. This study is designed to evaluate the protective effect of alpinumisoflavone (AIF), a naturally occurring flavonoid compound, on dexamethasone(Dex)-induced osteoporosis. We use a rat model to investigate the apoptosis of osteoblastic and osteocytic cells. The results indicate that AIF effectively protects against dexamethasone-induced osteoporosis. Moreover, AIF effectively reversed dexamethasone-induced apoptosis in osteoblastic and osteocytic cells through inhibiting ROS overproduction and regulating the Nrf2 pathway. In conclusion, the AIF activated Nrf2 signaling pathway was observed to suppress Dex-induced ROS production in osteoblastic and osteocytic cells, which may explain its anti-osteoporotic effects against dexamethasone-induced osteoporosis. [ABSTRACT FROM AUTHOR]

Radiotherapy remains a mainstream treatment for patients with unresectable and locally advanced esophageal squamous cell carcinoma (ESCC). However, intrinsic radioresistance of ESCC tumors has largely compromised the efficacy of radiotherapy. The following study investigates the potential radiosensitizing effect of alpinumisoflavone (AIF) and explores its underlying mechanisms in ESCC. Briefly, our results showed that AIF could significantly increase radiosensitivity of ESCC cells both in vitro and in vivo, by increasing the effect of AIF on irradiation-induced DNA damage, apoptosis and cell cycle arrest. Mechanically, AIF aggravated irradiation-induced ROS generation in ESCC cells, which occurred via suppressing the expression of nuclear transcription factor Nrf2 and Nrf2-driven antioxidant molecule NQO-1 and HO-1. Collectively, we concluded that AIF functions as a potent radiosensitizer in human ESCC [ABSTRACT FROM AUTHOR]

Alpinumisoflavone (AIF), a naturally occurring flavonoid compound exacted from Derris eriocarpa, has been found to have a number of pharmacological activities. However, its role in bone disorder has not been investigated. The aim of this study is to evaluate the osteoprotective effect of AIF on ovariectomy-induced bone loss in mice model and related underlying mechanisms. Our study provides experimental evidence that AIF could regulate the remodeling process of bone and exert osteoprotective effect against ovariectomy-induced bone loss. Moreover, our results show that AIF suppresses osteoclast differentiation by attenuating RANKL-induced activation of p38, ERK and JNK pathways and consequently represses the expression of c-Fos and NFATc1. [ABSTRACT FROM AUTHOR]

Introduction: In medical oncology, multi-drug resistance (MDR) of cancer cells continues to be a major impediment. We are in quest of novel anti-proliferative agents to overcome drug-resistant tumor cells.Methods: In the present study, we investigated the cytotoxicity of 7 naturally occurring phenolic compounds including two isoflavonoids alpinumisoflavone (1) and laburnetin (2), one biflavonoid amentoflavone (3), three lignans pycnanthulignene A (4), pycnanthulignene B (5), and syringaresinol (7) and one xanthone, euxanthone (6) against 9 drug-sensitive and MDR cancer cell lines. The resazurin reduction assay was used to evaluate the cytotoxicity of these compounds, whilst caspase-Glo assay was used to detect caspase activation. Cell cycle, mitochondrial membrane potential (MMP) and levels of reactive oxygen species (ROS) were all analyzed via flow cytometry.Results: The IC50 values for the investigational phenolics ranged from 5.91 µM (towards leukemia CEM/ADR5000 cells) to 65.65 µM (towards drug-resistant breast adenocarcinoma MDA-MB-231-BCRP cells) for 1, 27.63 µM (towards leukemia CCRF-CEM cells) to 107.57 µM (towards MDA-MB-231-pcDNA cells) for 2, from 5.84 µM (towards CEM/ADR5000 cells) to 65.32 µM (towards colon carcinoma HCT116 (p53(-/-)) cells) for 4 and 0.20 µM (towards CCRF-CEM cells) to 195.12 µM (towards leukemia CEM/ADR5000) for doxorubicin. Phenolics 3, 5, 6 and 7 displayed selectivity cytotoxic effects on cancer cells lines. Compounds 1 and 4 induced apoptosis in CCRF-CEM cells, mediated by loss of MMP and increase ROS production.Conclusions: The studied phenolics and mostly isoflavonoid 1 and lignan 4 are potential cytotoxic natural products that deserve more investigations to develop novel antineoplastic drugs against multifactorial drug-resistant cancers. [ABSTRACT FROM AUTHOR]

Objectives E rythrina lysistemon was found to improve lipid profile in ovariectomized rats. Alpinumisoflavone ( AIF) and abyssinone V 4′-methylether ( AME) derived from this plant induced analogous effects on lipid profile and decreased atherogenic risks. To highlight the molecular mechanism of action of these natural products, we evaluated their effects on the expression of some estrogen-sensitive genes associated with cholesterol synthesis ( Esr1 and Apoa1) and cholesterol clearance ( Ldlr, Scarb1 and Cyp7a1). Methods Ovariectomized rats were subcutaneously treated for three consecutive days with either compound at the daily dose of 0.1, 1 and 10 mg/kg body weight ( BW). Animals were sacrificed thereafter and their liver was collected. The mRNA of genes of interest was analysed by quantitative real-time polymerase chain reaction. Key findings Both compounds downregulated the mRNA expression of Esr1, a gene associated with cholesterogenesis and cholesterol gallstone formation. AME leaned the Apoa1/Scarb1 balance in favour of Apoa1, an effect promoting high-density lipoprotein ( HDL)-cholesterol formation. It also upregulated the mRNA expression of Ldlr at 1 mg/kg/ BW per day (25%) and 10 mg/kg/ BW per day (133.17%), an effect favouring the clearance of low-density lipoprotein ( LDL)-cholesterol. Both compounds may also promote the conversion of cholesterol into bile acids as they upregulated Cyp7a1 mRNA expression. Conclusion AIF and AME atheroprotective effects may result from their ability to upregulate mechanisms promoting HDL-cholesterol and bile acid formation. [ABSTRACT FROM AUTHOR]

Background: The stem bark ethyl acetate extract of Erythrina lysistemon was found to induce vaginal proliferation in ovariectomized rats orally treated. Alpinumisoflavone (AIF) and abyssinone V-4′-methyl-ether (AME), isolated as its major constituents, were reported to separately provoke uterine growth and/or vaginal proliferation. The present study aimed at evaluating the effects of the mixture of AIF and AME (51 mg/kg [AIF]+153 mg/kg [AME]) following their relative abundance in the extract, in order to compare these effects to those of E. lysistemon. Methods: The study was performed in ovariectomized rats treated intraperitoneally for 3 days. Estradiol valerate (E2 V) and AME were used for positive controls. Morphological and histological changes of animals' uterus and vagina were used as the hallmark of estrogenicity. Results: E. lysistemon extract induced estrogen-like effects only on the uterus and significantly increased uterine wet weight (p<0.01) and uterine epithelial height (p<0.01). These results suggest a tissue-selective action of E. lysistemon extract depending on the route of administration. The mixture of AIF and AME induced E. lysistemon-like effects only at a dose of 1 mg/kg BW/d (0.25 mg/kg+0.75 mg/kg), although these effects were lower in magnitude (p<0.05) compared to those induced by E. lysistemon extract. Conclusions: Effects induced by the mixture of AIF and AME are analogous to those of E. lysistemon, but the low magnitude of these effects suggests that there are minor metabolites that interact with AIF and AME to provoke the specific effects of E. lysistemon. [ABSTRACT FROM AUTHOR]

Abstract: Plant-derived estrogen-like compounds, so called phytoestrogens, are given much attention due to their potential therapeutic use. In our previous work the ethylacetate extract of Erythrina lysistemon stem bark showed estrogenic effects on cell culture systems and ovariectomized Wistar rats. Using classical chromatographic methods, two constituents of Erythrina lysistemon have been isolated, referred to here as compounds 1 (alpinumisoflavone) and 2 (abyssinone V-4′-methyl-ether), and their structures successfully determined using spectroscopic techniques. To test their binding affinity, the ligand binding assay has been used on estrogen α receptor, and estrogen β receptor. Furthermore, transactivation assay in stably or transiently transfected human osteosarcoma (U2OS-estrogen α receptor and estrogen β receptor) cells were used to examine their estrogenic activity. The regulations of some estrogen receptor target genes were also investigated. Both compounds bind to estrogen α and β receptors. They significantly increased luciferase activity in a dose-dependent manner and induced the endogenous estrogen receptor–estrogen response element (ERE) interaction in U2OS-estrogen α receptor and estrogen β receptor cells. In contrast, when co-treated with E2, compound 2 did not antagonize E2 activity in both systems whereas, 1 significantly suppressed E2 activity despite its low binding affinity to estrogen β receptor. This result suggests a non-competitive mechanism. Both compounds also altered the expression of estrogen receptor target genes such as growth regulation by estrogen in breast cancer 1 (GREB1) and Cyclin D1 in breast cells. These results suggest that compounds 1 and 2 endow estrogenic activity and may be the active principles of Erythrina lysistemon. [Copyright &y& Elsevier]

The objective of this study was to carry out a systematic review of the substances isolated from the African medicinal plant Erythrina senegalensis, focusing on compounds harboring activities against cancer models detailed in depth herein at both in vitro and in vivo preclinical levels. The review was conducted through Pubmed and Google Scholar. Nineteen out of the forty-two secondary metabolites isolated to date from E. senegalensis displayed interesting in vitro and/or in vivo antitumor activities. They belonged to alkaloid (Erysodine), triterpenes (Erythrodiol, maniladiol, oleanolic acid), prenylated isoflavonoids (senegalensin, erysenegalensein E, erysenegalensein M, alpinumisoflavone, derrone, warangalone), flavonoids (erythrisenegalone, senegalensein, lupinifolin, carpachromene) and pterocarpans (erybraedine A, erybraedine C, phaseollin). Among the isoflavonoids called "erysenegalensein", only erysenealenseins E and M have been tested for their anticancerous properties and turned out to be cytotoxic. Although the stem bark is the most frequently used part of the plant, all pterocarpans were isolated from roots and all alkaloids from seeds. The mechanisms of action of its metabolites include apoptosis, pyroptosis, autophagy and mitophagy via the modulation of cytoplasmic proteins, miRNA and enzymes involved in critical pathways deregulated in cancer. Alpinumisoflavone and oleanolic acid were studied in a broad spectrum of cancer models both in vitro and in preclinical models in vivo with promising results. Other metabolites, including carpachromen, phaseollin, erybraedin A, erysenegalensein M and maniladiol need to be further investigated, as they display potent in vitro effects. [ABSTRACT FROM AUTHOR]

The skin is an important organ in the human body that protects the body from environmentally hazardous substances. Reactive oxygen species (ROS) cause inflammatory reactions and degradation of the extracellular matrix leading to skin aging and various cutaneous lesions. This study evaluated the potential of isoflavones isolated from Maclura tricuspidata fruit to prevent TNF-α-induced skin inflammation in normal human dermal fibroblasts (HDFs). It focused on alpinumisoflavone (AIF) that suppressed the accumulation of ROS and nitric oxide (NO) in tumor necrosis factor-alpha (TNF-α)-treated HDFs. AIF inhibited the TNF-α-induced increase in matrix metalloproteinase-1, decreased procollagen I α1, and suppressed pro-inflammatory mediators and pro-inflammatory cytokines, including NO synthase, cyclooxygenase-2, interleukin (IL)-1β, IL-6, and IL-8 that trigger inflammatory responses. AIF inhibited nuclear factor-κB and activating protein 1 mitogen-activated protein kinases that were increased by TNF-α stimulation. These results suggest that AIF may protect skin from aging and various cutaneous lesions. [ABSTRACT FROM AUTHOR]

Abstract: The aerial parts of Genista pichisermolliana Valsecchi (Fabaceae), an endemic plant of Sardinia, were extracted in Soxhlet apparatus and purified by several chromatographic methods. The new compound alpinumisoflavone 4′-O-glucopyranoside (6) was isolated together with nineteen flavonoids, p-coumaric methylester and d-pinitol, while no alkaloids were detected. All the chemical structures were elucidated by spectroscopic analysis. Since flavonoids represent the main constituents of this plant, the total flavonoid content was determined according to the Italian Pharmacopoeia IX Ed. method. [Copyright &y& Elsevier]

Esophageal squamous cell carcinoma (ESCC) presents a common human malignancy in the digestive system. We aimed to explore the critical effects of alpinumisoflavone (AIF) on ESCC in vitro and in vivo. The cell counting kit-8 assay was used to determine cell viability. Colony formation assay was employed to examine the effect of AIF on the long-term growth of ESCC cells. Cell apoptosis was determined by flow cytometry and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay. Cell morphologies were observed by light microscopy. The enzyme-linked immunosorbent assay was performed to examine the lactate dehydrogenase release from AIF-treated cells. Immunofluorescent labeling was utilized to examine AIF-induced GSDME expression. Western blot was employed to determine the expression levels of the associated proteins. Immunohistochemistry was performed to determine the localization and expression of the associated proteins in mice tumor tissues. AIF inhibited ESCC cell viability and suppressed cell growth in a dose- and time-dependent fashion. Results showed that AIF promoted apoptosis in ESCC cells. Meanwhile, our results also showed that AIF triggered pyroptotic cell death in ESCC, which was mediated by gasdermin E (GSDME) cleavage. In addition, our experiments provided experimental evidence that AIF-induced GSDME cleavage was dependent on caspase-3 activation. Moreover, the inhibition of GSDSE by knockdown was able to switch the form of cell death from pyroptosis to apoptosis. Furthermore, the results from the xenograft animal model also supported our findings in vitro that AIF was able to promote GSDME-mediated pyroptotic cell death in ESCC. AIF inhibited ESCC growth in vitro and in vivo by triggering GSDME-mediated pyroptotic cell death, which is dependent on caspase-3 activation., (© 2020 American Association for Anatomy.)

As a common subtype of malignant gliomas, glioblastoma multiforme (GBM) is associated with poor prognosis. This study is aimed to examine the anticancer activities of alpinumisoflavone (AIF) and its underlying mechanisms. Our results demonstrated that AIF inhibited the proliferation of GBM cells (U373 and T98G) in a time and dose-dependent manner. In addition, flow cytometry analysis not only confirmed AIF arrested cell cycle at the G0/G1 phase but also the induced apoptosis of U373 and T98G cells. Western blotting also confirmed that AIF altered the expression levels of cell cycle-related proteins. Further mechanism studies revealed that AIF inhibited cell proliferation, induced G0/G1 phase arrest and induced apoptosis of U373 and T98G cells through activating PPARγ, as evidenced by the fact that GW9662 (PPARγ inhibitor) could effectively reverse the effects of AIF on U373 and T98G cells. Furthermore, the in vivo study also revealed that AIF suppressed tumor growth and caused cell cycle arrest. Collectively, these results highlighted the potential use of AIF in the treatment of GBM., (© 2019 American Association for Anatomy.)

Glioblastoma multiforme (GBM, WHO grade IV astrocytoma) has become a public health burden worldwide. Alpinumisoflavone (AIF) is a flavonoid compound isolated from Derris eriocarpa. This study aims to examine the role of AIF in GBM. Our results showed that AIF could decrease the cell viability of both T98G and U373 GBM cell lines. AIF treatment also caused cell cycle arrest at G1/G0 phase along with upregulation of p27 and downregulation of cyclin D1. AIF could significantly induce apoptosis in GBM cells. Activation of caspase-9, disruption of mitochondrial membrane potential and loss of mitochondrial cytochrome C were also observed following AIF treatment. Inhibition of glycolysis by AIF was demonstrated by reducing glucose consumption and lactate output in GBM cells. Moreover, HK2 was identified as the molecular target responsible for the anticancer activities of AIF against GBM cells. The results showed that HK2 knockdown enhanced the anticancer activities of AIF whereas ectopic HK2 expression compromised its effect. Furthermore, the antineoplastic activities of AIF in vivo were also validated in xenograft murine model. Our results showed that AIF can exhibit anticancer activities in GBM by promoting apoptosis and inhibiting glycolysis via targeting HK2., (© 2019 American Association for Anatomy.)

Alpinumisoflavone (AIF) as a principal active ingredient of traditional Chinese herb Derris eriocarpa exerts a broad spectrum of anticancer activities against solid tumors. However, little is known about the effect of AIF on papillary thyroid cancer (PTC). Objectives of this study are to investigate the effect of AIF on cell growth, apoptosis, and metastasis of PTC cells and uncover its underlying mechanisms. Results showed that AIF treatment notably suppressed cell viability, migration, invasion, and epithelial-mesenchymal transition (EMT) process, as well as induced apoptotic cell death. In addition, microarray analysis results revealed that miR-141-3p level was dramatically elevated upon AIF insulation, suggesting that miR-141-3p may mediate the suppressive role of AIF against PTC. Moreover, miR-141-3p knockdown effectively reversed the effects of AIF on cell growth, migration, invasion, and EMT, while promoted PTC cell apoptosis escape. Furthermore, in vivo findings also confirmed that the antigrowth and antimetastasis activities of AIF were, at least partly, mediated by upregulation of miR-141-3p. Overall, AIF could serve as a potential anticancer compound for PTC treatment. Anat Rec, 2019. © 2019 American Association for Anatomy Anat Rec, 303:1842-1850, 2020. © 2019 American Association for Anatomy., (© 2019 American Association for Anatomy.)

Alpinumisoflavone, a major compound in unripe Cudrania tricuspidata fruit is reported to exhibit numerous beneficial pharmacological activities, such as osteoprotective, antibacterial, estrogenic, anti-metastatic, atheroprotective, antioxidant, and anticancer effects. Despite its medicinal value, alpinumisoflavone is poorly soluble in water, which makes it difficult to formulate and administer intravenously (i.v.). To overcome these limitations, we used methoxy poly(ethylene glycol)-b-poly(d,l-lactide) (mPEG-b-PLA) polymeric micelles to solubilize alpinumisoflavone and increase its bioavailability, and evaluated their toxicity in vivo. Alpinumisoflavone-loaded polymeric micelles were prepared using thin-film hydration method, and their physicochemical properties were characterized for drug release, particle size, drug-loading (DL, %), and encapsulation efficiency (EE, %). The in vitro drug release profile was determined and the release rate of alpinumisoflavone from mPEG-b-PLA micelles was slower than that from drug solution, and sustained. Pharmacokinetic studies showed decreased total clearance and volume of distribution of alpinumisoflavone, whereas area under the curve (AUC) and bioavailability were significantly increased by incorporation in mPEG-b-PLA micelles. In vivo toxicity assay revealed that alpinumisoflavone-loaded mPEG-b-PLA micelles had no severe toxicity. In conclusion, we prepared an intravenous (i.v.) injectable alpinumisoflavone formulation, which was solubilized using mPEG-b-PLA micelles, and determined their physicochemical properties, pharmacokinetics, and toxicity profiles. [ABSTRACT FROM AUTHOR]

Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer. The present study is aimed to investigate the role of alpinumisoflavone (AIF), a naturally occurring flavonoid compound, in ccRCC and the underlying mechanism. In this study, miR-101 has been identified as a novel therapeutic target, which exerts anti-tumor effect on ccRCC by directly targeting RLIP76. Moreover, our results showed that AIF was able to increase the expression of miR-101 by suppressing Akt signalling. Our findings in this study provided experimental evidence that AIF has the potential to be used as an agent in the treatment of ccRCC., Competing Interests: None.

Alpinumisoflavone (AIF) is a naturally occurring flavonoid that is a major bioactive component of the medicinal plant Derris eriocarpa . In this study we evaluated the antimetastatic effect of AIF and investigated the underlying mechanism of action using in vitro and in vivo models of melanoma. We found that AIF impaired the metastatic potential of A375 and SK-MEL-1 human melanoma cells by promoting cell differentiation as assessed by melanin content, protoporphyrin IX accumulation, and tissue transglutaminase activity. In addition, AIF inhibited cell adhesion, migration, and invasion in melanoma cells. We found that AIF treatment decreased cyclooxygenase-2 (COX-2) expression, and COX-2 overexpression attenuated the inhibitory effects of AIF on the metastatic behaviors of melanoma cells. AIF dose-dependently increased microRNA-124 (miR-124) levels and decreased levels of sphingosine kinase 1 (SPHK1), a target of miR-124. In a mouse model of melanoma, AIF suppressed lung metastasis. Taken together, our findings suggest that AIF inhibits metastasis in melanoma by modulating COX-2 expression, at least in part, through targeting the miR-124/SphK1 axis. Our study provides evidence that AIF may be useful as an antimetastatic agent in the treatment of melanoma.

Esophageal squamous cell carcinoma (ESCC) is the most prevalent type of esophageal cancer and accumulating evidence has confirmed the role of miRNAs in ESCC. One such miRNA, miR-370, was found to be aberrantly downregulated in various human malignancies. This study showed that the expression of miR-370 was significantly lower in ESCC tissues and cell lines, and miR-370 functioned as a tumor suppressor in ESCC. Moreover, this is the first report that showed miR-370 suppresses cell proliferation and tumor growth by directly targeting Pim family kinases 1 (PIM1). Furthermore, alpinumisoflavone, a naturally occurring flavonoid, could inhibit tumor growth of ESCC by targeting miR-370/PIM1 signaling.

Erythrina suberosa is an ornamental tall tree found in India, Pakistan, Nepal, Bhutan, Burma, Thailand and Vietnam. We have isolated four known distinct metabolites designated as α-Hydroxyerysotrine, 4'-Methoxy licoflavanone (MLF), Alpinumisoflavone (AIF) and Wighteone. Among the four isolated metabolites the two flavonoids, MLF and AIF were found to be the most potent cytotoxic agent with IC50 of ∼20μM in human leukemia HL-60 cells. We are reporting first time the anticancer and apoptotic potential of MLF and AIF in HL-60 cells. Both MLF and AIF inhibited HL-60 cell proliferation and induce apoptosis as measured by several biological endpoints. MLF and AIF induce apoptosis bodies formation, enhanced annexinV-FITC binding of the cells, increased sub-G0 cell fraction, loss of mitochondrial membrane potential (Δψm), release of cytochrome c, Bax, activation of caspase-9, caspase-3 and PARP (poly ADP Ribose polymers) cleavage in HL-60 cells. MLF and AIF also increase the expression of apical death receptor, Fas, with inhibition of anti-apoptotic protein Bid. All the above parameters revealed that these two flavonoids induce apoptosis through both extrinsic and intrinsic apoptotic pathways in HL-60 cells. In spite of apoptosis, these two flavonoids significantly inhibit nuclear transcription factor NF-κB and STAT (Signal Transducer and Activator of Transcription) signaling pathway, which are highly expressed in leukemia. The present study provide an insight of molecular mechanism of cell death induced by MLF and AIF in HL-60 cells which may be useful in managing and treating leukemia., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)