PMID: 

Front Microbiol. 2019 ;10:2489. Epub 2019 Nov 5. PMID: 31749783

Abstract Title: 

Antibacterial Effect and Mode of Action of Flavonoids From Licorice Against Methicillin-Resistant.

Abstract: 

is a bacterial pathogen that causes food poisoning, various infections, and sepsis. Effective strategies and new drugs are needed to controlassociated infections due to the emergence and rapid dissemination of antibiotic resistance. In the present study, the antibacterial activity, potential mode of action, and applications of flavonoids from licorice were investigated. Here, we showed that glabrol, licochalcone A, licochalcone C, and licochalcone E displayed high efficiency against methicillin-resistant(MRSA). Glabrol, licochalcone A, licochalcone C, and licochalcone E exhibited low cytotoxicity without hemolytic activity based on safety evaluation. Glabrol displayed rapid bactericidal activity with low levels of resistance development. Meanwhile, glabrol rapidly increased bacterial membrane permeability and dissipated the proton move force. Furthermore, we found that peptidoglycan, phosphatidylglycerol, and cardiolipin inhibited the antibacterial activity of glabrol. Molecular docking showed that glabrol binds to phosphatidylglycerol and cardiolipin through the formation of hydrogen bonds. Lastly, glabrol showed antibacterial activity against MRSA in bothandmodels. Altogether, these results suggest that glabrol is a promising lead compound for the design of membrane-active antibacterial agents against MRSA and can be used as a disinfectant candidate as well.

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PMID: 

Cells. 2019 Nov 14 ;8(11). Epub 2019 Nov 14. PMID: 31739642

Abstract Title: 

Licochalcone A-Induced Apoptosis Through the Activation of p38MAPK Pathway Mediated Mitochondrial Pathways of Apoptosis in Human Osteosarcoma Cells In Vitro and In Vivo.

Abstract: 

BACKGROUND: Licochalcone A (LicA) is isolated from the roots ofand possesses antitumor and anti-invasive activities against several tumor cells. However, the antitumor effects of LicA on human osteosarcoma cells have yet to be demonstrated either in vitro or in vivo.METHODS: Cell viability was measured by MTT assay. Apoptosis and mitochondrial dysfunction were detected with Annexin V/PI staining and JC-1 staining by flow cytometry. The expressions of caspase- or mitochondrial-related proteins were demonstrated by western blotting. Antitumor effect of LicA on 143B xenograft mice in vivo.RESULTS: LicA could inhibit cell proliferation and induce apoptosis in human osteosarcoma cells, as evidenced by a decrease in cell viability, loss of mitochondrial membrane potentials, and activation of caspases. LicA treatment substantially reduced the expression of Bcl-2 and Mcl-1 and increased the expression of cleaved-caspase-3, cleaved-caspase-9, cleaved-PARP, and Bax in HOS and U2OS cells. Moreover, mitochondrial membrane potential and apoptosis suppression mediated by Z-VAD or tauroursodeoxycholic acid significantly reduced LicA-induced mitochondria-dependent apoptosis. The study also determined that LicA treatment induced p38MAPK phosphorylation, but siRNA-p38 or BIRB796 substantially reversed cell viability through the inhibition of mitochondria-dependent apoptosis pathways. Finally, an in vivo study revealed that LicA significantly inhibited 143B xenograft tumor growth.CONCLUSIONS: These findings demonstrate that LicA has antitumor activities against human osteosarcoma cells through p38MAPK regulation of mitochondria-mediated intrinsic apoptotic pathways in vitro and in vivo.

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PMID: 

Phytother Res. 2019 Dec 2. Epub 2019 Dec 2. PMID: 31793097

Abstract Title: 

Licochalcone A restrains microphthalmia-associated transcription factor expression and growth by activating autophagy in melanoma cells via miR-142-3p/Rheb/mTOR pathway.

Abstract: 

Licochalcone A (LCA) was found to possess anticancer effects. This study aimed to investigate the anticancer effects and mechanisms of LCA in melanoma. A375 and B16 melanoma cells were stimulated with LCA, MTT assay was used to assess cell proliferation. Expression of miR-142-3p, microphthalmia-associated transcription factor (MITF, which regulates melanin production) and autophagy-related genes was determined by Real-time PCR or western blot. The apoptosis was analyzed by flow cytometry and caspase-3 activity. The roles of miR-142-3p and Ras homolog enriched in brain (Rheb) in LCA-affected cells were investigated by gain- and loss-of functions. LCA inhibited proliferation and MITF expression, but increased apoptosis and autophagy of melanoma cells. Moreover, LCA elevated miR-142-3p expression, but decreased its target gene Rheb expression. The effects of LCA on melanoma cells were abrogated by miR-142-3p inhibitor or Rheb overexpression. LCA suppressed mTOR signaling activation via Rheb. Additionally, rapamycin (a mTOR antagonist) notably attenuated the effects of Rheb on the autophagy, proliferation, apoptosis, and MITF expression in LCA-treated melanoma cells. In conclusion, LCA restrained MITF expression and growth by activating autophagy in melanoma cells via miR-142-3p/Rheb/mTOR pathway. This study suggested that LCA might be a potential therapeutic candidate for prevention and treatment of melanoma.

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PMID: 

Bioorg Med Chem Lett. 2020 Jan 15 ;30(2):126825. Epub 2019 Nov 30. PMID: 31836442

Abstract Title: 

Licochalcone A suppresses the proliferation of sarcoma HT-1080 cells, as a selective R132C mutant IDH1 inhibitor.

Abstract: 

IDH1 mutations are closely related to the development and progression of various human cancers, such as glioblastoma, sarcoma, and acute myeloid leukemia. By screening dozens of reported natural compounds using both wild-type and mutant IDH1 enzymatic assays, we discovered Licochalcone A is a selective inhibitor to the R132C-mutant IDH1 with an ICvalue of 5.176 μM, and inhibits the proliferation of sarcoma HT-1080 cells with an ICvalue of 10.75 μM. Suggested by the molecular docking results, Licochalcone A might occupy the allosteric pocket between the two monomers of IDH1 homodimer, and the R132H mutation was unfavorable for the binding of Licochalcone A with the IDH1 protein, as compared to the R132C mutation. Revealed by the RNA-Seqdata analysis, the Cell Cycle pathway was the most over-represented pathway for HT-1080 cells treated with Licochalcone A. Consistent with these results, Licochalcone A induced apoptosis and cell cycle arrest of HT-1080 cells, while it showed minimal effect against the proliferation of normal RCTECcells. The discovery of Licochalcone A as a mutation-selective IDH1 inhibitor can serve as a promising starting point for the development of mutation-selective anti-tumor lead compounds targeting IDH1.

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PMID: 

J Nutr. 2020 Jan 9. Epub 2020 Jan 9. PMID: 31919508

Abstract Title: 

Substitution of Milk with Whole-Fat Yogurt Products or Cheese Is Associated with a Lower Risk of Myocardial Infarction: The Danish Diet, Cancer and Health cohort.

Abstract: 

BACKGROUND: Food-based dietary guidelines recommend replacement of whole-fat dairy products with low-fat variants based on data suggesting that diets high in saturated fat are associated with a higher risk of ischemic heart disease. However, the health effects of saturated fat may depend on the source.OBJECTIVES: The aim was to investigate substitutions between different subgroups of dairy products and the risk of myocardial infarction (MI).METHODS: Data were from the Danish Diet, Cancer and Health cohort and included 54,903 men and women aged 50-64 y at enrollment and without an MI diagnosis. Information about intake of dairy products was obtained by a semiquantitative food-frequency questionnaire. Incident MI cases were identified through nationwide registries. We used Cox proportional hazards regression to estimate associations between specified substitutions of dairy products and MI risk.RESULTS: During a median follow-up of 15.9 y, 3033 cases were identified. Whole-fat yogurt products in place of low-fat or whole-fat milk were associated with a lower risk of MI (HR: 0.89; 95% CI: 0.80, 0.99 per 200 g/d replaced; and HR: 0.87; 95% CI: 0.78, 0.98 per 200 g/d replaced, respectively). Substitution of 20 g/d of cheese for 200 g/d of low-fat or whole-fat milk was also associated with a lower risk of MI (HR: 0.96; 95% CI: 0.92, 0.99; and HR: 0.95; 95% CI: 0.89, 0.99, respectively).CONCLUSIONS: Among middle-aged Danish men and women, intake of whole-fat yogurt products or cheese in place of milk, regardless of fat content, was associated with a lower risk of development of MI.

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PMID: 

Nutrients. 2019 Dec 27 ;12(1). Epub 2019 Dec 27. PMID: 31892189

Abstract Title: 

Pterostilbene Prevents Early Diabetic Retinopathy Alterations in a Rabbit Experimental Model.

Abstract: 

Oxidative stress generated by diabetes plays a key role in the development of diabetic retinopathy (DR), a common diabetic complication. DR remains asymptomatic until it reaches advanced stages, which complicate its treatment. Although it is known that good metabolic control is essential for preventing DR, knowledge of the disease is incomplete and an effective treatment with no side effects is lacking. Pterostilbene (Pter), a natural stilbene with good antioxidant activity, has proved to beneficially affect different pathologies, including diabetes. Therefore, our study aimed to analyse the protective and/or therapeutic capacity of Pter against oxidant damage by characterising early retinal alterations induced by hyperglycaemia, and its possible mechanism of action in a rabbit model of type 1 diabetes mellitus. Pter reduced lipid and protein oxidative damage, and recovered redox status and the main activities of antioxidant enzymes. Moreover, the redox regulation by Pter was associated with activation of the PI3K/AKT/GSK3β/NRF2 pathway. Our results show that Pter is a powerful protective agent that may delay early DR development.

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PMID: 

Molecules. 2020 Jan 2 ;25(1). Epub 2020 Jan 2. PMID: 31906449

Abstract Title: 

Pterostilbene Enhances Endurance Capacity via Promoting Skeletal Muscle Adaptations to Exercise Training in Rats.

Abstract: 

It has been demonstrated that skeletal muscle adaptions, including muscle fibers transition, angiogenesis, and mitochondrial biogenesis are involved in the regular exercise-induced improvement of endurance capacity and metabolic status. Herein, we investigated the effects of pterostilbene (PST) supplementation on skeletal muscle adaptations to exercise training in rats. Six-week-old male Sprague Dawley rats were randomly divided into a sedentary control group (Sed), an exercise training group (Ex), and exercise training combined with 50 mg/kg PST (Ex + PST) treatment group. After 4 weeks of intervention, an exhaustive running test was performed, and muscle fiber type transformation, angiogenesis, and mitochondrial content in the soleus muscle were measured. Additionally, the effects of PST on muscle fiber transformation, paracrine regulation of angiogenesis, and mitochondrial function were tested in vitro using C2C12 myotubes. In vivo study showed that exercise training resulted in significant increases in time-to-exhaustion, the proportion of slow-twitch fibers, muscular angiogenesis, and mitochondrial biogenesis in rats, and these effects induced by exercise training could be augmented by PST supplementation. Moreover, the in vitro study showed that PST treatment remarkably promoted slow-twitch fibers formation, angiogenic factor expression, and mitochondrial function in C2C12 myotubes. Collectively, our results suggest that PST promotes skeletal muscle adaptations to exercise training thereby enhancing the endurance capacity.

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PMID: 

Molecules. 2019 Jul 2 ;24(13). Epub 2019 Jul 2. PMID: 31269698

Abstract Title: 

Licochalcone A Suppresses the Proliferation of Osteosarcoma Cells through Autophagy and ATM-Chk2 Activation.

Abstract: 

Licochalcone A, a flavonoid extracted from licorice root, has been shown to exhibit broad anti-inflammatory, anti-bacterial, anticancer, and antioxidative bioactivity. In this study, we investigated the antitumor activity of Licochalcone A against human osteosarcoma cell lines. The data showed that Licochalcone A significantly suppressed cell viability in MTT assay and colony formation assay in osteosarcoma cell lines. Exposure to Licochalcone A blocked cell cycle progression at the G2/M transition and induced extrinsic apoptotic pathway in osteosarcoma cell lines. Furthermore, we found the Licochalcone A exposure resulted in rapid ATM and Chk2 activation, and high levels of nuclear foci of phosphorylated Chk2 at Thr 68 site in osteosarcoma cell lines. In addition, Licochalcone A exposure significantly induced autophagy in osteosarcoma cell lines. When Licochalcone A-induced autophagy was blocked by the autophagy inhibitor chloroquine, the expression of activated caspase-3 and Annexin V positive cells were reduced, and cell viability was rescued in Licochalcone A-treated osteosarcoma cell lines. These data indicate that the activation of ATM-Chk2 checkpoint pathway and autophagy may contribute to Licochalcone A-induced anti-proliferating effect in osteosarcoma cell lines. Our findings display the possibility that Licochalcone A may serve as a potential therapeutic agent against osteosarcoma.

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PMID: 

J Sci Food Agric. 2020 Jan 9. Epub 2020 Jan 9. PMID: 31916584

Abstract Title: 

Dietary apple polyphenols promote fat browning in high-fat diet-induced obese mice through activation of AMP-activated protein kinase (AMPK)α.

Abstract: 

BACKGROUND: Promoting brown and beige adipogenesis contributes to adaptive thermogenesis, which provides a defense against obesity and related disorders. Apple polyphenols (APs) play a significant role in treating variety of metabolic diseases. The present study was conducted to determine the effects of APs on the development of brown and beige adipocytes and thermogenesis and investigate whether these effects are mediated by AMP-activated protein kinase (AMPK). High-fat diet (HFD) induced obese mice and differentiated 3 T3-L1 adipocytes were subjected to APs treatment. The thermogenic program and associated regulatory factors, and the involvement of AMPKα was assessed.RESULTS: Dietary APs supplementation reduced adiposity and improved insulin sensitivity in HFD induced obese mice. Moreover, APs increased the oxygen consumption and heat production and decreased respiratory exchange ratio, which were accompanied by the upregulation of thermogenic genes expression and the activation of AMPKα in brown fat and inguinal white fat. Further, APs treatment directly increased expression of brown adipogenic markers and induced phosphorylation of AMPKα in differentiated 3 T3-L1 adipocytes, whereas the beneficial effects of APs were reversed by AMPK inhibition.CONCLUSION: Our results provide new insights into the function of APs in regulating brown/beige adipogenesis and adaptive thermogenesis and suggest the potential application of APs in the prevention and therapeutic of obesity and associated metabolic diseases. This article is protected by copyright. All rights reserved.

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PMID: 

Pharm Biol. 2020 Dec ;58(1):35-43. PMID: 31881157

Abstract Title: 

The seed offraction ameliorates hippocampal neuronal injury in an Aβ-induced Alzheimer's disease rat model via the AKT/GSK-3β pathway.

Abstract: 

The seed ofSonn., a famous traditional Chinese medicine, was recently reported to enhance cognitive function by inhibiting neuronal apoptosis in rats.We determined whether the seed offraction (SLF) can ameliorate hippocampal neuronal injury via the AKT/GSK-3β pathway.We established Alzheimer's disease (AD) model by infusing Aβinto the lateral ventricle of Sprague-Dawley (SD) rats and randomly divided into five groups ( = 10): sham, donepezil and SLF (120, 240 and 480 mg/kg/d). Rats were treated by intragastric administration for 28 consecutive days. Spatial learning and memory were evaluated with Morris water maze, while protein expression of AKT, GSK-3β and tau in the hippocampal neurons was measured by Western blotting and immunohistochemistry.On the fifth day, escape latency of the AD model group was 45.78 ± 2.52 s and that of the sham operative group was 15.98 ± 2.32 s. SLF could improve cognitive functions by increasing the number of rats that crossed the platform ( 

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