PMID: 

Neuropsychiatr Dis Treat. 2019 ;15:3041-3050. Epub 2019 Oct 29. PMID: 31754303

Abstract Title: 

Extract Reduces Hippocampus Inflammatory Responses, Improves Cardiac Functions And Depressive Behaviors In A Heart Failure Mouse Model.

Abstract: 

Background: Depression has been shown to share an extremely high comorbidity with heart failure (HF).extract (GBE) is a widely used traditional Chinese medicine in cardiac disease. However, its potential therapeutic effect on depressive symptoms following HF largely remains unknown. In this article, we aimed to investigate its effects in reducing depressive behaviors of a HF mouse model. Moreover, we also discussed whether its effects are associated with changes in neural inflammation and 5-hydroxytryptamine (5-HT) signaling.Methods: Mice were randomly divided into three groups: sham, HF+saline and HF+GBE (150 mg/kg/d) (n=10 per group). Systolic heart failure was induced by ligating the left anterior descending coronary artery. Cardiac functions together with depressive-like behaviors were measured after 4 weeks' treatment. Levels of brain natriuretic peptide (BNP), 5-HT, 5-HT receptor 2A (5-HTR), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), vascular endothelial growth factor (VEGF), hypoxia inducible factor-1 (HIF-1), (cleaved) caspase-3, Bax and Bcl-2 were analyzed by Western blot, Elisa and immunohistochemistry at the end of the experiments.Results: GBE benefited antidepressant-like behaviors and improved cardiac functions in mice with heart failure. Levels of TNF-α, IL-1β and 5-HT were reduced in the hippocampus after the administration of GBE. Further experiments revealed that GBE also blocked the release of serotonin in the peripheral blood and triggered HIF-1 induced anti-apoptotic pathways.Conclusion: GBE has potential therapeutic effects in relieving depressive status of patients with HF.

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PMID: 

PLoS One. 2019 ;14(12):e0225761. Epub 2019 Dec 2. PMID: 31790465

Abstract Title: 

Ginkgo biloba extract increases neurite outgrowth and activates the Akt/mTOR pathway.

Abstract: 

BACKGROUND: Standardized Ginkgo biloba extract (GBE) has demonstrated efficacy in the cognitive functional neuropsychiatric symptoms of patients with Alzheimer's disease (AD). With regard to its underlying molecular mode of action, first evidence was provided that GBE was able to modulate neuronal outgrowth in vitro, but the mechanisms underlying GBE effects on neuroplasticity remain unclear.METHODOLOGY/PRINCIPAL FINDINGS: In this study, we investigated the effect of GBE on neurite outgrowth using SH-SY5Y neuroblastoma cells in a 2D and 3D surface culture. The effects of the GBE LI1370 on neuroplasticity and neurite outgrowth were compared to those of nerve growth factor (NGF, 50 ng/ml) which was used as a positive control. We evaluated several parameters of neurite outgrowth such as the neurite number, total neurite length and extend of branching. Our findings showed that GBE (10 and 100μg/ml) significantly increased neurite outgrowth in the 2D as well as 3D culture model after 3 days of treatment with a comparable effect than that NGF. The use of the 3D cell culture allowed us to better reproduce the in vivo neuronal microenvironment for the evaluation the neurite formation afterGBE treatment. In addition, we assessed the effects of GBE on the Akt/mTOR pathway, which is known to promote neuroplasticity induced by nerve growth factors. We showed that GBE treatment induced an increase of phosphorylated IGF1R (Tyr1135/Tyr1136), Akt (Ser473), TSC2 (Ser939), mTOR (Ser2448), PTEN (Ser380) and GSK3β (Ser9).CONCLUSION: Together, these findings indicate that GBE promotes neurite growth and activates the PI3K/Akt/mTOR pathway suggesting that this plant extract supports neuronal plasticity.

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PMID: 

Plants (Basel). 2019 Nov 29 ;8(12). Epub 2019 Nov 29. PMID: 31795413

Abstract Title: 

L. Leaf Extract Protects HepG2 Cells Against Paraquat-Induced Oxidative DNA Damage.

Abstract: 

L. leaf extracts and herbal infusions are used worldwide due to the health benefits that are attributed to its use, including anti-neoplastic, anti-aging, neuro-protection, antioxidant and others. The aim of this study was to evaluate the effect of an aqueousextract on HepG2 cell viability, genotoxicity and DNA protection against paraquat-induced oxidative damage. Exposure to paraquat (PQ), over 24 h incubation at 1.0 and 1.5µM, did not significantly reduce cell viability but induced concentration and time-dependent oxidative DNA damage.leaf extract produced dose-dependent cytotoxicity (IC= 540.8± 40.5 µg/mL at 24 h exposure), and short incubations (1 h) produced basal and oxidative DNA damage (>750 and 1500µg/mL, respectively). However, lower concentrations (e.g., 75 µg/mL) ofleaf extract were not cytotoxic and reduced basal DNA damage, indicating a protective effect at incubations up to 4 h. On the other hand, longer incubations (24 h) induced oxidative DNA damage. Co-incubation of HepG2 cells for 4 h, withleaf extract (75µg/mL) and PQ (1.0 or 1.5 µM) significantly reduced PQ-induced oxidative DNA damage. In conclusion, the consumption ofleaf extract for long periods at high doses/concentrations is potentially toxic; however, low doses protect the cells against basal oxidative damage and against environmentally derived toxicants that induce oxidative DNA damage.

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PMID: 

Environ Sci Pollut Res Int. 2019 Dec 14. Epub 2019 Dec 14. PMID: 31838678

Abstract Title: 

In vivo protective effects of Ginkgo biloba L. leaf extract against hydrogen peroxide toxicity: cytogenetic and biochemical evaluation.

Abstract: 

In this study, the protective effects of Ginkgo biloba leaf extract (GbE) against toxicity induced by hydrogen peroxide (HO) in Swiss albino mice were investigated. Abnormal metaphase number (AMn), mitotic index (MI), micronucleus (MN), and chromosomal abnormalities (CAs) were analyzed for cytogenetic effects. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), blood urea nitrogen (BUN), creatinine, glutathione (GSH), and malondialdehyde (MDA) levels in liver and kidney organs were investigated as indicators of biochemical toxicity. Six experimental groups were formed as a control and treatment group, each containing six animals. The mice in the control group were given tap water, while the mice in the administration group received two different doses of GbE and HOfor 45 consecutive days. It was observed that HOadministration caused a significant decrease in MI compared to the control group and caused a significant decrease in the frequency of AMn, MN, and CAs. Chromatid break was the most common type of CAs induced by HO, and the other CAs types observed in this study were chromosome break, fragment, dicentric, gap, and ring. It has been determined that GbE treatment decreases the clastogenic effects of HOand reduces the MN and CAs frequency and causes a re-increase in mitotic cell numbers. It was determined that HOadministration caused changes in biochemical parameters and resulted in significant increases in serum AST, ALP, ALT, BUN, and creatinine levels. However, the level of MDA, which is an indicator of oxidative damage, increased, and GSH level decreased in liver and kidney tissues. Oxidative damage caused by HOin liver and kidney tissues was improved, and all biochemical parameters tested were found to be ameliorated after GbE treatment. This improvement was dependent on the dose of GbE, and improvement in 150 mg/kg bw GbE was found to be more prominent. As a result, the GbE can be used as an antioxidant nutritional supplement to protect against the toxic effects of environmental agents such as HO.

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PMID: 

Neurochem Res. 2020 Jan 2. Epub 2020 Jan 2. PMID: 31894463

Abstract Title: 

Modulatory Effects of Ginkgo biloba Against Amyloid Aggregation Through Induction of Heat Shock Proteins in Aluminium Induced Neurotoxicity.

Abstract: 

Protein misfolding and aggregation of amyloid beta (Aβ) peptide, as well as formation of neurofibrillary tangles (NFTs) are the signature hallmarks of Alzheimer's disease (AD) pathology. To prevent this, molecular chaperones come into play as they facilitate the refolding of the misfolded proteins and cell protection under stress. Here, we have evaluated the possible effects of Ginkgo biloba (GBE) against aggregation of the Aβ through activation of heat shock proteins (HSPs) in the Aluminium (Al) induced AD based model. GBE (100 mg/kg body weight) was administered per oral to the female SD rats in conjunction with intraperitoneal (i.p.) injection of Al lactate (10 mg/kg body weight) for six weeks. Pretreated animals were administered GBE for additional two weeks prior to any exposure of Al. GBE administration resulted in decrease in Aβ aggregation, ubiquitin deposition, accompanying a significant decline in APP&Tau protein hyperphosphorylation which can be attributed to activation of Heat shock factor (HSF-1) and upregulation in the protein expression of HSPs. Histopathological investigation studies have also shown the decrease in aggregation of Aβ peptide by GBE administration. Additionally, the decrease in ROS levels and Aβ aggregation by GBE administration prohibited the decline in the neurotransmitter levels and monoamine oxidase levels in hippocampus and cortex. This further caused improvement in learning and memory of the animals. Inconclusion, our results indicate that GBE prevents the symptoms of Al induced AD like pathophysiology by upregulating the HSPs levels and decreasing the aggregation load.

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PMID: 

Neurochem Res. 2019 Nov 25. Epub 2019 Nov 25. PMID: 31768814

Abstract Title: 

Kaempferol Protects Against Cadmium Chloride-Induced Memory Loss and Hippocampal Apoptosis by Increased Intracellular Glutathione Stores and Activation of PTEN/AMPK Induced Inhibition of Akt/mTOR Signaling.

Abstract: 

This study investigated the protective effect of Kaempferol against CdCl-induced hippocampal damage and memory deficit in rats and investigated if such effects involve modulating the activity of AMPK/PTEN/Akt/mTOR axis. Adult male rats (n = 12/group) were divided into control or CdCl-treated rats received the vehicle of Kaempferol for consecutive 6 weeks. Also, hippocampal cells were treated with CdClin the presence or absence of Kaempferol for 24 h with or without 1 h pre-incubation with compound C, an AMPK inhibitor or with bpV a PTEN inhibitor. Kaempferol improved the behavioral of CdCl-treated rats, preserved hippocampus structure and reduced hippocampal levels of ROS and protein levels of Bax and cleaved caspase-3. In both control and CdCl-treated rats, Kaempferol significantly increased hippocampal levels of GSH levels and protein levels of Nfr2, Bcl2 and synaptic proteins (SNAP-25, PSD-25, and synapsin). Concomitantly, it increased the activity of PTEN and AMPK and subsequently, decreased the activity of Akt and mTOR. In cultured cells, individual pharmacological inhibition of PTEN by bpv or AMPK of compound C (CC) partially prevented the stimulatory effect of Kaempferol on Akt/mTOR and its inhibitory effect on cell death whereas a combination of both inhibitors completely prevented this. Also, inhibition of PTEN alone completely abolished the inhibitory effect of Kaempferol by synaptic proteins, whereas inhibition of AMPK completely abolished its stimulatory effect of Nfr2. In conclusion, Kaempferol protects against CdCl-induced memory deficits and hippocampal apoptosis by its antioxidant potential and inhibition of Akt/mTOR axis and requires the activation of PTEN and AMPK.

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PMID: 

Anal Cell Pathol (Amst). 2019 ;2019:1907698. Epub 2019 Dec 1. PMID: 31871879

Abstract Title: 

Kaempferol Promotes Apoptosis While Inhibiting Cell Proliferation via Androgen-Dependent Pathway and Suppressing Vasculogenic Mimicry and Invasion in Prostate Cancer.

Abstract: 

Kaempferol is a well-known natural flavonol reported to be a potential treatment for multiple cancers. In this study, we demonstrated that cell growth of androgen-sensitive LNCaP cells could be inhibited 33% by 5 M kaempferol, around 60% by 10 M kaempferol, and almost 100% by 15 M kaempferol. Also, kaempferol showed relatively limited effect on PC-3 cells and nonmalignant RWPE-1 cells. In the presence of DHT, the ICfor kaempferol was 28.8± 1.5 M in LNCaP cells, 58.3± 3.5 M in PC-3 cells, and 69.1± 1.2 M in RWPE-1 cells, respectively. Kaempferol promotes apoptosis of LNCaP cells in a dose-dependent manner in the presence of dihydrotestosterone (DHT). Then, luciferase assay data showed that kaempferol could inhibit the activation of androgen receptors induced by DHT significantly. The downstream targets of androgen receptors, such as PSA, TMPRSS2, and TMEPA1, were found decreased in the presence of kaempferol in qPCR data. It was then confirmed that the protein level of PSA was decreased. Kaempferol inhibits AR protein expression and nuclear accumulation. Kaempferol suppressed vasculogenic mimicry of PC-3 cells in an in vitro study. In conclusion, kaempferol is a promising therapeutic candidate for treatment of prostate cancer, where the androgen signaling pathway as well as vasculogenic mimicry are involved.

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PMID: 

Medicine (Baltimore). 2020 Jan ;99(2):e18568. PMID: 31914035

Abstract Title: 

Ginkgol Biloba extract as an adjunctive treatment for ischemic stroke: A systematic review and meta-analysis of randomized clinical trials.

Abstract: 

OBJECTIVE: Ginkgo biloba extract (GBE) is widely used as an adjunctive treatment for ischemic stroke. This meta-analysis aimed to evaluate the effectiveness and safety of GBE specifically for long-term users at the convalescence stage of ischemic stroke.METHODS: MEDLINE, Cochrane Central Register of Controlled Trials, Embase Database, WHO Clinical Trials Registration Platform, Chinese National Knowledge Infrastructure, Wanfang Database, and Chinese Scientific Journal Database were searched from inception to 20 September 2018. Risk ratio (RR) and mean difference (MD) with a 95% confidence interval (CI) were used as effect estimates using RevMan software (5.3; Review Manager [RevMan], Nordic Cochrane Centre, Copenhagen, Denmark). A meta-analysis was performed where data were available. A trial sequential analysis was used to control random errors for recurrence rate and the GRADE (grading of recommendations, assessment, development, and evaluations) approach was used to assess the quality of the body of evidence. The meta-analysis design was registered on PROSPERO (CRD42018110211, https://ift.tt/30bxbFu We identified 15 randomized clinical trials involving 1829 participants. The majority of the included trials were of high risk of bias in methodological quality. For acute ischemic stroke, adding GBE to conventional therapy led to higher Barthel index scores (MD: 5.72; 95% CI: 3.11-8.33) and lower neurological function deficit scores (MD: -1.39; 95% CI: -2.15 to -0.62). For patients in their convalescence (or sequelae) stage of ischemic stroke, GBE was superior in improving dependence (MD: 7.17; 95% CI: 5.96-8.38) and neurological function deficit scores (MD: -1.15; 95% CI: -1.76 to -0.53) compared with placebo or conventional therapy, but there was no difference in vascular events (RR: 0.70; 95% CI: 0.44-1.14), recurrence rate (RR: 0.57; 95% CI: 0.26-1.25; trial sequential analysis: conclusive) and mortality (RR: 1.07; 95% CI: 0.41-2.81).CONCLUSIONS: GBE appears to improve neurological function and dependence compared with conventional therapy for ischemic stroke at different stages and appears generally safe for clinical application. The lack of improvement in recurrence rate was confirmed by trial sequential analysis. Due to the generally weak evidence, further large, rigorous trials are warranted.

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PMID: 

Front Pharmacol. 2018 ;9:147. Epub 2018 Mar 23. PMID: 29628888

Abstract Title: 

Licochalcone A Upregulates Nrf2 Antioxidant Pathway and Thereby Alleviates Acetaminophen-Induced Hepatotoxicity.

Abstract: 

Acetaminophen (APAP) overdose-induced fatal hepatotoxicity is majorly characterized by overwhelmingly increased oxidative stress while enhanced nuclear factor-erythroid 2-related factor 2 (Nrf2) is involved in prevention of hepatotoxicity. Although Licochalcone A (Lico A) upregulates Nrf2 signaling pathway against oxidative stress-triggered cell injury, whether it could protect from APAP-induced hepatotoxicity by directly inducing Nrf2 activation is still poorly elucidated. This study aims to explore the protective effect of Lico A against APAP-induced hepatotoxicity and its underlying molecular mechanisms. Our findings indicated that Lico A effectively decreased-butyl hydroperoxide (-BHP)- and APAP-stimulated cell apoptosis, mitochondrial dysfunction and reactive oxygen species generation and increased various anti-oxidative enzymes expression, which is largely dependent on upregulating Nrf2 nuclear translocation, reducing the Keap1 protein expression, and strengthening the antioxidant response element promoter activity. Meanwhile, Lico A dramatically protected against APAP-induced acute liver failure by lessening the lethality; alleviating histopathological liver changes; decreasing the alanine transaminase and aspartate aminotransferase levels, malondialdehyde formation, myeloperoxidase level and superoxide dismutase depletion, and increasing the GSH-to-GSSG ratio. Furthermore, Lico A not only significantly modulated apoptosis-related protein by increasing Bcl-2 expression, and decreasing Bax and caspase-3 cleavage expression, but also efficiently alleviated mitochondrial dysfunction by reducing c-jun N-terminal kinase phosphorylation and translocation, inhibiting Bax mitochondrial translocation, apoptosis-inducing factor and cytochromerelease. However, Lico A-inhibited APAP-induced the lethality, histopathological changes, hepatic apoptosis, and mitochondrial dysfunction in WT mice were evidently abrogated in Nrf2mice. These investigations firstly implicated that Lico A has protective potential against APAP-induced hepatotoxicity which may be strongly associated with the Nrf2-mediated defense mechanisms.

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PMID: 

Int J Parasitol Drugs Drug Resist. 2018 08 ;8(2):238-245. Epub 2018 Mar 1. PMID: 29684680

Abstract Title: 

Licochalcone A: An effective and low-toxicity compound against Toxoplasma gondii in vitro and in vivo.

Abstract: 

Toxoplasma gondii, an obligate intracellular protozoan, is the causative agent of toxoplasmosis, which can cause serious public health problems. The current drugs used to treat toxoplasmosis have many limitations. This study evaluated the anti-T. gondii activity and potential mechanism of Licochalcone A (Lico A) in vitro and in vivo. The safe concentration of Lico A in HFF cells was determined by MTT cell viability assays. The presence of T. gondii was assessed by qPCR and Giemsa staining. Azithromycin and sulfadiazine, commonly used effective treatments, served as drug controls. T. gondii ultrastructural alterations were observed by electron microscopy. The anti-T. gondii activity of Lico A was evaluated using an in vivo mouse infection model. In vitro, Lico A had no negative effect on host cell viability at concentrations below 9 μg/mL; however, it did inhibit T. gondii proliferation in a dose-dependent manner, with a 50% inhibitory concentration (IC) of 0.848 μg/mL. Electron microscopy analyses indicated substantial structural and ultrastructural changes in tachyzoites after Lico A treatment. Nile Red staining assays demonstrated that Lico A caused lipid accumulation. Lico A treatment significantly increased the survival rate of BALB/c mice infectedwith T. gondii. Lico A achieved the same therapeutic effect as a commonly used clinical drugs (combination of sulfadiazine, pyrimethamine and folinic acid). In conclusion, Lico A has strong anti-T. gondii activity in vitro and in vivo and might be developed into a new anti-T. gondii drug. Moreover,Lico A may exert these effects by interfering with lipid metabolism in the parasite.

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