PMID: 

Pak J Biol Sci. 2019 Jan ;22(12):614-622. PMID: 31930861

Abstract Title: 

Antiviral Activity of Curcumin Loaded Milk Proteins Nanoparticles on Potato Virus Y.

Abstract: 

BACKGROUND AND OBJECTIVE: Potato is one of the world's leading vegetable crops. Potato viral diseases cause adversely effects on the agricultural sector. Recently there is a growing interest to control plant viruses using spices and herbs (including curcumin). Poor solubility of curcumin in water limited its applications. Therefore, the main objective of the present study was to evaluate the effect of antiviral activity of curcumin-milk proteins nanoparticles against potato virus Y (PVY).MATERIALS AND METHODS: Curcumin-milk proteins nanoparticles were prepared via ionic gelation method. The antiviral activity of the resultant nanoparticles against PVY was evaluated at different concentrations (500, 1000 and 1500 mg/100 mL). Chlorophyll content as well as the activity of peroxidase (POX) and polyphenol oxidase (PPO) was examined.RESULTS: Curcumin-milk proteins nanoparticles showed inhibitory effect on PVY in a concentration dependent manner.CONCLUSION: Curcumin-milk proteins nanoparticles displayed a successful tool to control the PVY under green house conditions.

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Plants (Basel). 2020 Feb 18 ;9(2). Epub 2020 Feb 18. PMID: 32085514

Abstract Title: 

In Vitro Anti-HSV-1 Activity of Polyphenol-Rich Extracts and Pure Polyphenol Compounds Derived from Pistachios Kernels (L.).

Abstract: 

Natural compounds are a prominent source of novel antiviral drugs. Several reports have previously shown the antimicrobial activity of pistachio polyphenol extracts. Therefore, the aim of our research was to investigate the activity of polyphenol-rich extracts of natural shelled (NPRE) pistachios kernels (L.) on herpes simplex virus type 1 (HSV-1) replication. The Vero cell line was used to assess the cytotoxicity and antiviral activity. The cell viability was calculated by detection of cellular ATP after treatment with various concentrations of NPRE. For antiviral studies, five nontoxic-concentrations (0.1, 0.2, 0.4, 0.6, 0.8 mg/mL) were tested. Our study demonstrated that treatment with NPRE (0.4, 0.6, 0.8 mg/mL) reduced the expression of the viral proteins ICP8 (infected cell polypeptide 8), UL42 (unique long UL42 DNA polymerase processivity factor) , and US11 (unique short US11 protein), and resulted in a decrease of viral DNA synthesis. The 50% cytotoxic concentration (CC), 50% inhibitory concentration (EC), and the selectivity index (SI) values for NPRE were 1.2 mg/mL, 0.4mg/mL, and 3, respectively. Furthermore, we assessed the anti-herpetic effect of a mix of pure polyphenol compounds (NS MIX) present in NPRE. In conclusion, our findings indicate that natural shelled pistachio kernels have remarkable inhibitory activity against HSV-1.

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J Ethnopharmacol. 2019 Oct 5 ;242:111699. Epub 2019 Apr 18. PMID: 31005632

Abstract Title: 

In vitro and in vivo Study on Glioma Treatment Enhancement by Combining Temozolomide with Calycosin and Formononetin.

Abstract: 

ETHNOPHARMACOLOGICAL RELEVANCE: Astragalina alpestris is a traditional Chinese herbal medicine with anti-inflammatory, anti-immune, anti-tumor and other pharmacological effects. Calycosin and formononetin (FMN) are two natural compounds isolated from astragalus. It has been shown that calycosin and FMN are active anti-tumor ingredient.AIM OF THE STUDY: The aim of this current work was to study the therapeutic enhancement of temozolomide (TMZ) on gliomavia combining with calycosin and FMN.MATERIALS AND METHODS: The effect of co-administration via hematoxylin-eosin staining (HE staining) was determined by measuring cell proliferation toxicity with the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, Thiazolyl Blue Tetrazolium Bromide (MTT) assay and sequentially observing the cell morphology. To synchronously explore the effect of migration on C6, transwell assay and wound healing assay were performed. Apoptosis was measured by Annexin V/propidium iodide (PI) staining. Meanwhile, western blot was used to investigate proteins involved in the mechanisms for migration and apoptosis. Furthermore, HE staining and immunohistochemistry were also analyzed for curative effect in vivo.RESULTS: The efficacy of TMZ on glioma could be enhanced by combining with calycosin and FMN through inhibiting the proliferation and migration of glioma cells and promoting their apoptosis. Western blot assays indicated that expression of apoptotic proteins (Bcl-2 Associated XProtein (Bax), Cleaved Caspase-3, Cleaved Caspase-9) were up-regulated. Anti-apoptotic protein (B-cell lymphoma-2,Bcl-2) was down-regulated. The migratory proteins (Matrix metallopeptidase 2, 9, MMP-2, MMP-9) was downregulated. In vivo study, this kind of co-administration (calycosin, FMN, and TMZ) exhibited the marked therapeutic effect on glioma.CONCLUSIONS: This study has identified that calycosin and FMN can increase the treatment effect of TMZ in vitro and in vivo. These attractive features substantially broadened the application range of TMZ as a glioma treatment medicine.

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PMID: 

Metabolomics. 2019 11 25 ;15(12):153. Epub 2019 Nov 25. PMID: 31768751

Abstract Title: 

The anti-inflammatory effects of formononetin and ononin on lipopolysaccharide-induced zebrafish models based on lipidomics and targeted transcriptomics.

Abstract: 

INTRODUCTION: Formononetin (MBHS) and its glycosylated derivative ononin (MBHG), as the major isoflavones, have exhibited the anti-inflammatory impacts on the lipopolysaccharide (LPS)-induced inflammation. Although various researches have focused on interpreting the pharmaceutical activities of MBHG and MBHS, the molecular mechanisms in zebrafish models are still unclear.OBJECTIVE: The purpose of the present work is to investigate the molecular mechanisms of the anti-inflammatory effects of MGHG and MBHS based on lipidomics and targeted transcriptomics.METHODS: UHPLC-MS was applied for the lipid analyses and RT-PCR was adopted for the mRNA analyses, and the results of different groups were compared for exploring the significantly changed lipids and mRNAs.RESULTS: The results of lipidomics revealed that phosphatidylcholines (PCs) were drastically down-regulated in the MBHG or MBHS treated LPS-induced inflammatory zebrafish models. Besides, MBHS can also decrease the levels of triacylglycerols (TAGs). For the targeted transcriptomics analyses, 4 cytokines (TNF-α, IL-1β, IL-6 and IFN-γ) and 3 mRNA (JNK1, ERK1 and p38a) involved in the MAPK pathway were down-regulated and IL-10 was up-regulated under the treatment of MBHG or MBHS.CONCLUSION: Combining the results of lipidomics and targeted transcriptomics, we indicated that MBHG and MBHS exerted potent anti-inflammatory effects on the LPS-induced zebrafish models through the MyD88 or TRIF MAPK/ERK and MAPK/JNK pathways and the glycerophospholipid, glycosylphosphatidylinositol (GPI)-anchor biosynthesis and glycerolipid metabolisms. Our results provided new insights into the anti-inflammatory mechanisms of MBHG or MBHS and supplied an effective method to interpret the pharmacological mechanisms of drugs.

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PMID: 

Oncol Rep. 2020 Feb ;43(2):700-710. Epub 2019 Dec 13. PMID: 31894318

Abstract Title: 

Formononetin induces apoptotic cell death through the suppression of mitogen‑activated protein kinase and nuclear factor‑κB phosphorylation in FaDu human head and neck squamous cell carcinoma cells.

Abstract: 

Formononetin, a phytoestrogen extracted from various herbal plants, has been investigated as an anticancer agent against diverse types of cancer. The aim of the present study was to investigate the induction of apoptotic cell death by formononetin in the FaDu pharyngeal squamous cell carcinoma cell line. Formononetin significantly increased FaDu cell death, with an estimated IC50 value of 50 µM; however, it did not affect the viability of normal L929 mouse fibroblasts used as normal control at 5‑25 µM. Typical characteristics of apoptosis, such as morphological alterations, chromatin condensation, DNA fragmentation and the size of the apoptotic cell population, were increased inFaDu cells treated with formononetin for 24 h. Furthermore, formononetin‑induced FaDu cell death involved the death receptor‑mediated extrinsic and the mitochondria‑dependent intrinsic apoptotic pathways by activating the caspase cascade. The chemotherapeutic effects of formononetin were mediated by the suppression of mitogen‑activated protein kinases, including extracellular signal‑regulated kinase 1/2 and p38, and nuclear factor‑κB phosphorylation in FaDu cells. Finally, the oral administration of formononetin decelerated tumor growth through the expression of cleaved caspase‑3 in a FaDu cell xenograft animal model. Taken together, these findings indicate that formononetin holds promise as a chemotherapeutic agent and may be of value in the treatment of human head and neck squamous cell carcinoma.

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PMID: 

Mol Med Rep. 2020 Mar ;21(3):1192-1200. Epub 2020 Jan 3. PMID: 31922224

Abstract Title: 

Inhibitory effects of formononetin on the monocrotaline‑induced pulmonary arterial hypertension in rats.

Abstract: 

Pulmonary arterial hypertension (PAH) is a fatal syndrome resulting from enhanced pulmonary arterial pressure and pulmonary vessel resistance. Perivascular inflammation and extracellular matrix deposition are considered to be the crucial pathophysiologic bases of PAH. Formononetin (FMN), a natural phytoestrogen isolated from red clover (Trifolium pratense), has a variety of proapoptotic, anti‑inflammatory and anti‑tumor activities. However, the therapeutic effectiveness of FMN for PAH remains unclear. In the present study, 60 mg/kg monocrotaline (MCT) was first used to induce PAH in rats, and then all rats were treated with differentconcentrations of FMN (10, 30 and 60 mg/kg/day). At the end of this study, the hemodynamics and pulmonary vascular morphology of rats were evaluated. Specifically, matrix metalloproteinase (MMP)2, transforming growth factor β1 (TGFβ1) and MMP9 were measured using western blot and immunohistochemical staining. Collagen type I, collagen type III, fibronectin, monocyte chemotactic protein‑1, tumor necrosis factor‑α, interleukin‑1β, ERK and NF‑κB were quantified using western blotting. The results demonstrated that FMN significantly alleviated the changes of hemodynamics and pulmonary vascular morphology, and decreased the MCT‑induced upregulations of TGFβ1, MMP2 and MMP9 expression levels. Meanwhile, the expression levels of collagen type I, collagen type III and fibronectin in rat lungs decreased after FMN treatment. Furthermore, the phosphorylated ERK and NF‑κB also decreased after FMN treatment. Taken together, the present study indicated that FMN serves a therapeutic role in the MCT‑induced PAH in rats via suppressing pulmonary vascular remodeling, which may be partially related to ERK and NF‑κB signals.

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PMID: 

Biochem Biophys Res Commun. 2020 Feb 17. Epub 2020 Feb 17. PMID: 32081422

Abstract Title: 

Formononetin recovered injured nerve functions by enhancing synaptic plasticity in ischemic stroke rats.

Abstract: 

BACKGROUND AND OBJECTIVES: Formononetin has protective effect against ischemic stroke. It's unclear whether it can restore the nerve functions after stroke.METHODS: SD rats were subjected with middle cerebral artery occlusion (MCAO), and divided into sham, model and formononetin (30 mg/kg) groups. Neurobehavioral tests (modified Neurological Severity Score [mNSS] and rotarod) were performed before and at 1, 3, 7 and 14 days after MCAO. Then, the rats were sacrificed and the brain sections were processed for neuronal differentiation and synaptic plasticity.RESULTS: Compared with the sham group, the scores of mNSS were significantly increased, and the residence time on the rotating drum was significantly decreased in the MCAO rats. Compared with the model group, the scores of mNSS were significantly decreased, and the residence time on the rotating drum was increased in the formononetin (30 mg/kg) group. Formononetin significantly increased the number of neuronal dendritic spines and the expression of β III-tubulin, GAP-43, NGF, BDNF, p-Trk A, p-Trk B, p-AKT and p-ERK 1/2.CONCLUSIONS: Formononetin recovered injured nerve functions after ischemic stroke. PI3K/AKT/ERK pathway might involve in the beneficial effect of formononetin on the neuronal differentiation and synaptic plasticity.

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PMID: 

Neurosci Lett. 2017 02 3 ;639:36-42. Epub 2016 Dec 26. PMID: 28034780

Abstract Title: 

Formononetin attenuates Aβ-induced cytotoxicity in HT22 cells via PI3K/Akt signaling and non-amyloidogenic cleavage of APP.

Abstract: 

Amyloid beta (Aβ) is the main component of the amyloid plaques that accumulate in the brains of Alzheimer patients. Here, we reported the protective role of Formononetin (Form) against Aβ-induced neurotoxicity in HT22 cells. We found that Form significantly increased the viability of HT22 cells but decreased the cell apoptosis when challenging with AβThe inhibitory effects of Form were associated with PI3K/Akt signaling pathway as PI3K inhibitor (LY294002) or ERα specific inhibitor (MPP) blocked the effects. Form also accelerated the non-amyloidogenic process of amyloid precursor protein (APP) by enhancing α-secretase activity and sAPPα release. Altogether, our findings may provide a novel therapeutic target to treat AD sufferers.

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PMID: 

Med Sci Monit. 2019 Jun 8 ;25:4273-4277. Epub 2019 Jun 8. PMID: 31175839

Abstract Title: 

Pharmacological Targets and the Biological Mechanisms of Formononetin for Alzheimer's Disease: A Network Analysis.

Abstract: 

BACKGROUND This study aimed to identify the pharmacological targets and mechanisms of action of the traditional Chinese medicine, formononetin, in the treatment of Alzheimer's disease (AD) using network pharmacological analysis. MATERIAL AND METHODS Targets of AD were obtained by using DisGeNET gene discovery platform, the herbal ingredients target (HIT) database, the SuperPred, and the SwissTargetPrediction compound target prediction platforms. Pathogenic and therapeutic targets were imported to the STRING biological database, and Cytoscape network integration software was used to construct component-target and disease-target interaction networks. Core targets were identified by topological analysis and were further tested to identify the biological processes and signaling pathways. RESULTS Seven key target genes for formononetin in the treatment of patients with AD were identified, including estrogen receptor alpha (ESR1), peroxisome proliferator-activated receptor gamma (PPARG), tumor protein p53 (TP53), sirtuin 1 (SIRT1), tumor necrosis factor (TNF), cytochrome P450 19A1 (CYP19A1), and nuclear factor (erythroid-derived 2)-like 2 (NFE2L2). The biological processes included hormone metabolism, regulation of nucleoside, nucleotide and nucleic acid metabolism, apoptosis, energy pathways, metabolism, cell communication, and signal transduction. The signaling pathways included histone acetylation and deacetylation (HDAC) class I, regulation of p38-alpha/beta, p38 mitogen-activated protein kinase (MAPK) signaling pathway, bone morphogenetic protein (BMP) receptor signaling, interleukin-1 (IL1) mediated signaling events, the tumor necrosis factor (TNF) receptor signaling pathway, and cytoplasmic and nuclear Smad2/3 signaling. CONCLUSIONS Pharmacological network analysis was used to identify the gene targets and mechanisms of formononetin treatment in patients with AD.

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PMID: 

Theranostics. 2020 ;10(3):1090-1106. Epub 2020 Jan 1. PMID: 31938053

Abstract Title: 

Formononetin attenuates atherosclerosis via regulating interaction between KLF4 and SRA in apoEmice.

Abstract: 

: Atherosclerosis is an underlying cause of coronary heart disease. Foam cell, a hallmark of atherosclerosis, is prominently derived from monocyte-differentiated macrophage, and vascular smooth muscle cells (VSMCs) through unlimitedly phagocytizing oxidized low-density lipoprotein (oxLDL). Therefore, the inhibition of monocyte adhesion to endothelium and uptake of oxLDL might be a breakthrough point for retarding atherosclerosis. Formononetin, an isoflavone extracted from, has exhibited multiple inhibitory effects on proatherogenic factors, such as obesity, dyslipidemia, and inflammation in different animal models. However, its effect on atherosclerosis remains unknown. In this study, we determined if formononetin can inhibit atherosclerosis and elucidated the underlying molecular mechanisms.: ApoE deficient mice were treated with formononetin contained in high-fat diet for 16 weeks. After treatment, mouse aorta, macrophage and serum samples were collected to determine lesions, immune cell profile, lipid profile and expression of related molecules. Concurrently, we investigated the effect of formononetin on monocyte adhesion, foam cell formation, endothelial activation, and macrophage polarizationand.: Formononetin reducedand aortic root sinus lesions size. Formononetin enhanced lesion stability by changing the composition of plaque. VSMC- and macrophage-derived foam cell formation and its accumulation in arterial wall were attenuated by formononetin, which might be attributed to decreased SRA expression and reduced monocyte adhesion. Formononetin inhibited atherogenic monocyte adhesion and inflammation. KLF4 negatively regulated the expression of SRA at transcriptional and translational level.: Our study demonstrate that formononetin can substantially attenuate the development of atherosclerosis via regulation of interplay between KLF4 and SRA, which suggests the formononetin might be a novel therapeutic approach for inhibition of atherosclerosis.

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