PMID: 

J Neuroimmune Pharmacol. 2019 Jul 18. Epub 2019 Jul 18. PMID: 31321663

Abstract Title: 

Neuroprotective Effects of Genistein in a SOD1-G93A Transgenic Mouse Model of Amyotrophic Lateral Sclerosis.

Abstract: 

Oxidant toxicity has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), an insidiously progressive neurodegenerative disorder involving upper and lower motor neurons. Here, we investigated the cellular and molecular mechanisms underlying the neuroprotective effects of an anti-oxidant genistein in SOD1-G93A transgenic mouse model of ALS. Rotarod test, hanging wire test and hindlimb clasping test were used to determined disease onset and assess motor performance. Immunostaining together with neuronal size measurement were used to count viable motor neurons. In addition, immunostaining procedure and ELISA kit were used to assess the inflammatory response in the spinal cord. Our results showed that Genistein administration suppressed the production of pro-inflammatory cytokines and alleviated gliosis in the spinal cord of SOD1-G93A mice. In addition, genistein administration induced autophagic processes and enhanced the viability of spinal motor neurons. As a result, genistein alleviated ALS-related symptoms and slightly prolonged the lifespan of SOD1-G93A mice. Taken together, our results indicate that genistein is neuroprotective in SOD1-G93A mice, suggesting genistein could be a promising treatment for human ALS. Graphical Abstract Genistein protects impariments in SOD1-G93A transgenic mouse model.

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PMID: 

J Food Drug Anal. 2018 04 ;26(2):761-768. Epub 2017 Nov 10. PMID: 29567247

Abstract Title: 

Antibacterial activity of propolins from Taiwanese green propolis.

Abstract: 

Taiwanese green propolis is a prenylated flavonoid rich honeybee product and propolins isolated from Taiwanese green propolis exert a broad spectrum of biological activities, such as anti-cancer and anti-oxidant. However, the anti-bacterial effects of Taiwanese green propolis or propolins are still poorly understood. In the current study, the antibacterial effects of Taiwanese green propolis and propolins were evaluated. Results show that the maximum dry matter yields of Taiwanese green propolis were observed in the 95% and 99.5% ethanol extracts compared to other extraction methods. Consistently, the highest concentration of propolins C, D, F and G from Taiwanese green propolis was obtained in 95% and 99.5% ethanol extracts. Propolins inhibited the growth of gram-positive bacterial strains (Staphylococcus aureus, Bacillus subtilis, Listeria monocytogenes and Paenibacillus larvae). The average minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of propolins from ethanol extracts were 20 μg/ml. Among the propolins, propolin C had the highest antibacterial activity. Furthermore, Taiwanese green propolis also showed antibacterial activity against methicillin-resistant S. aureus (MRSA). In conclusion, these results demonstrate that Taiwanese green propolis and propolins have significant antibacterial activity, particularly against gram-positive bacterial strains.

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PMID: 

Front Immunol. 2019 ;10:936. Epub 2019 May 1. PMID: 31118933

Abstract Title: 

Naringenin Produces Neuroprotection Against LPS-Induced Dopamine Neurotoxicity via the Inhibition of Microglial NLRP3 Inflammasome Activation.

Abstract: 

Parkinson's disease (PD) is the second most prevalent central nervous system (CNS) degenerative disease and characterized by slow and progressive loss of dopamine (DA) neurons in the midbrain substantia nigra. Microglia-mediated neuroinflammation has been considered as the major central event in the process of DA neuronal loss. Thus, inhibition of neuroinflammation could possess a more viable strategy for PD treatment. Naringenin (NAR), a natural flavanoid contained in citrus fruit and grapefruits, possesses amounts of pharmacological activities. Recent studies indicated that NAR produced neuroprotection against several neurological disorders. However, the mechanisms underlying NAR-generated neuroprotection are not fully illuminated.In the present study, rat nigral stereotaxic injection of lipopolysaccharide (LPS)-induced DA neuronal loss was performed to investigate NAR-mediated neuroprotection. In addition, BV-2 and MN9D cell lines were applied to explore the underlying mechanisms.NAR protected DA neurons against LPS-induced neurotoxicity. Also, NAR suppressed microglial nod-like receptor protein 3 (NLRP3) inflammasome signaling activation and the subsequent pro-inflammatory factors release. In addition, NAR-mediated DA neuroprotection was dependent on the inhibition of microglial NLRP3 inflammasome activation, as evidenced by the observations that NAR-reduced pro-inflammatory factors production and further NAR-exerted DA neuroprotection against LPS-induced neuronal damage was not discerned after microglial NLRP3 siRNA treatment.This study demonstrated that NAR targeted microglial NLRP3 inflammasome to protect DA neurons against LPS-induced neurotoxicity. These findings suggest NAR might hold a promising therapeutic potential for PD.

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PMID: 

Int J Med Sci. 2019 ;16(5):644-653. Epub 2019 May 7. PMID: 31217731

Abstract Title: 

Naringenin Ameliorates Renovascular Hypertensive Renal Damage by Normalizing the Balance of Renin-Angiotensin System Components in Rats.

Abstract: 

Naringenin, a member of the dihydroflavone family, has been shown to have a protective function in multiple diseases. We previously demonstrated that naringenin played a protective role in hypertensive myocardial hypertrophy by decreasing angiotensin-converting enzyme (ACE) expression. The kidney is a primary target organ of hypertension. The present study tested the effect of naringenin on renovascular hypertensive kidney damage and explored the underlying mechanism.An animal model of renovascular hypertension was established by performing 2-kidney, 1-clip (2K1C) surgery in Sprague Dawley rats. Naringenin (200 mg/kg/day) or vehicle was administered for 10 weeks. Blood pressure and urinary protein were continuously monitored. Plasma parameters, renal pathology and gene expression of nonclipped kidneys were evaluated by enzyme-linked immunosorbent assay, histology, immunohistochemistry, real-time polymerase chain reaction, and Western blot at the end of the study. Rats that underwent 2K1C surgery exhibited marked elevations of blood pressure and plasma Ang II levels and renal damage, including mesangial expansion, interstitial fibrosis, and arteriolar thickening in the nonclipped kidneys. Naringenin significantly ameliorated hypertensive nephropathy and retarded the rise of Ang II levels in peripheral blood but had no effect on blood pressure. 2K1C rats exhibited increases in the ACE/ACE2 protein ratio and AT1R/AT2R protein ratio in the nonclipped kidney compared with sham rats, and these increases were significantly suppressed by naringenin treatment.Naringenin attenuated renal damage in a rat model of renovascular hypertension by normalizing the imbalance of renin-angiotensin system activation. Our results suggest a potential treatment strategy for hypertensive nephropathy.

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PMID: 

J Nat Med. 2019 Jun 19. Epub 2019 Jun 19. PMID: 31218550

Abstract Title: 

Naringenin suppresses neutrophil infiltration into adipose tissue in high-fat diet-induced obese mice.

Abstract: 

Recruitment of immune cells to adipose tissue is altered dramatically in obesity, which results in chronic inflammation of the adipose tissue that leads to metabolic disorders, such as insulin resistance and type 2 diabetes mellitus. The regulation of immune cell infiltration into adipose tissue has prophylactic and therapeutic implications for obesity-related diseases. We previously showed that naringenin, a citrus flavonoid, suppressed macrophage infiltration into adipose tissue by inhibiting monocyte chemoattractant protein-1 (MCP-1) expression in the progression phase to high-fat diet (HFD)-induced obesity. In the current study, we evaluated the effects of naringenin on neutrophil infiltration into adipose tissue, because neutrophils also infiltrate into adipose tissue in the progression phase to obesity. Naringenin suppressed neutrophil infiltration into adipose tissue induced by the short-term (2 weeks) feeding of a HFD to mice. Naringenin tended to inhibit the HFD-induced expression of several chemokines, including MCP-1 and MCP-3, in adipose tissue. Naringenin also inhibited MCP-3 expression in 3T3-L1 adipocytes and a co-culture of 3T3-L1 adipocytes and RAW264 macrophages. However, naringenin did not affect the expression of macrophage inflammatory protein-2 (MIP-2), an important chemokine for neutrophil migration and activation, in macrophages or in a co-culture of adipocytes and macrophages. Our results suggest that naringenin suppresses neutrophil infiltration into adipose tissue via the regulation of MCP-3 expression and macrophage infiltration.

PMID: 

J Nutr Biochem. 2019 Aug ;70:215-226. Epub 2019 May 21. PMID: 31252288

Abstract Title: 

Naringenin ameliorates progression of endometriosis by modulating Nrf2/Keap1/HO1 axis and inducing apoptosis in rats.

Abstract: 

Endometriosis is mainly characterized by the presence of endometrial tissue exterior to the uterus, however, the exact pathophysiology of this disease still remains uncertain. Moreover, the incidence significantly contributes to infertility among women and hence, a novel treatment for endometriosis is widely investigated. Naringenin is a plant-derived flavonoid having anti-proliferative, anti-inflammatory, and anti-angiogenic properties in chronic and metabolic diseases. The current study was planned with an objective to demonstrate the anti-endometriotic therapeutic potential of naringenin in rats and to examine its impact on various cellular aspects with a view to define the mechanism involved. The endometrial lesion volumes, weight, serum TNF-α level and the histopathologic scores were significantly reduced in the naringenin- treated group as compared to the endometriotic control group. Naringenin ameliorated the expression of prognostic markers (TAK1, PAK1, VEGF and PCNA) involved in development and progression of endometriotic cells.Naringenin caused dose-dependent loss of mitochondrial membrane potential, induced apoptosis and inhibited proliferation in these cells. Further, a significant increase in level of Nrf2 and its downstream molecules (NQO1, HO-1) was found in endometriotic lesion, with a subsequent decrease in its repressor molecule Keap-1. Naringenin significantly modulated the expression of Nrf2 and its effector molecules downstream. It also inhibited the invasion of endometrial cells by reducing the expression of MMP-2 and MMP-9 in in-vitro primary culture. We conclude that naringenin may have a therapeutic potential in the treatment of endometriosis via induction of ROS-mediated apoptosis and its anti-invasive effects.

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PMID: 

Mol Nutr Food Res. 2019 Jul 25:e1900224. Epub 2019 Jul 25. PMID: 31343820

Abstract Title: 

Anti-Diabetic, Anti-Inflammatory, and Anti-Oxidant Effects of Naringenin in an In Vitro Human Model and an In Vivo Murine Model of Gestational Diabetes Mellitus.

Abstract: 

SCOPE: Gestational diabetes mellitus (GDM), which affects up to 20% of pregnant women, is associated with maternal peripheral insulin resistance, low-grade inflammation, and oxidative stress. The flavonoid naringenin has potent anti-diabetic, anti-inflammatory, and anti-oxidative properties; however, its effects in GDM remain unknown. The study aimed to determine the effects of naringenin on glucose metabolism, inflammation, and oxidative stress associated with GDM both in vitro and in vivo.METHODS AND RESULTS: In vitro, human tissue samples obtained at term elective Caesarean section are stimulated with tumour necrosis factor alpha (TNF) to develop a GDM-like environment. Naringenin treatment significantly improves TNF-impaired glucose uptake in skeletal muscle. In placenta and visceral adipose tissue (VAT), naringenin significantly reduces expression of pro-inflammatory cytokines and chemokines and increases antioxidant mRNA expression. Mechanistically, naringenin suppresses nuclear factorκB activation. In vivo, pregnant heterozygous db/+ mice are used to model GDM. Daily intraperitoneal injections of GDM mice with naringenin from gestational day 10-17 significantly improve glucose tolerance, reduces IL1A mRNA expression, and increases antioxidant mRNA expression in placenta, VAT, and subcutaneous adipose tissue.CONCLUSION: Naringenin is shown to improve insulin sensitivity, inflammation, and oxidative stress associated with GDM and shows promise as a novel preventive therapeutic.

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PMID: 

J Food Biochem. 2019 Jul ;43(7):e12885. Epub 2019 May 7. PMID: 31353690

Abstract Title: 

Erectile dysfunction attenuation by naringenin in streptozotocin-induced diabetic rats.

Abstract: 

Diabetes mellitus is associated with sexual dysfunction, which leads to infertility in animal models. The aim of this study was to evaluate sexual behavior in diabetic rats administered with naringenin. Rats were classified into five groups including healthy controls, those with STZ-induced diabetes, and those with STZ-induced diabetes then treated with 25, 50, or 100 mg kg dayof naringenin. Male rats were introduced to sexually receptive females, and data were collected regarding sexual behavior and erectile activity. Blood samples were taken and histopathological analyses were carried out. ANOVA and the Student-Newman-Keuls t test were used for statistical comparisons. Sexual behavioral, mount latency, intromission latency, ejaculation latency, and postejaculatory interval were significantly increased in diabetic rates compared with controls (p 

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PMID: 

Environ Toxicol Pharmacol. 2019 Jul 23 ;71:103224. Epub 2019 Jul 23. PMID: 31376681

Abstract Title: 

Neuroprotective role of naringenin against methylmercury induced cognitive impairment and mitochondrial damage in a mouse model.

Abstract: 

Human exposure to organomercurials like methylmercury (MeHg) may occur by consumption of contaminated seafood, affecting various vital organs especially, brain contributing to neuro disorders. The citrus flavanone, naringenin (NAR) has shown strong antioxidant and anti-inflammatory effects and therefore may exert cytoprotective effect against xenobiotic agents. Herein, we investigated the neuroprotective role of NAR against MeHg induced functional changes in mitochondria, neuronal cell death and cognitive impairment in a mouse model. A neurotoxic dose of MeHg (4 mg/kg.b.wt.) was administered orally to mice for 15 days. This resulted in the reduction of GSH and GST, an increase in mitochondrial DNA damage and memory impairment. On the contrary, NAR pre-treatment (100 mg/kg.b.wt.), helped in lowering the oxidative burden which in turn maintained mitochondrial function and prevented induced neuronal cell death, ultimately improving the cognitive impairment. As MeHg intoxication occurs chronically, consumption of the dietary components rich in NAR may have its positive human health impact, ultimately improving the quality of life.

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PMID: 

Cell Mol Biol (Noisy-le-grand). 2019 Jun 30 ;65(5):38-42. Epub 2019 Jun 30. PMID: 31304904

Abstract Title: 

Naringin inhibits lipopolysaccharide-induced activation of microglia cells.

Abstract: 

The purpose of this study was to investigate the effect of naringin on lipopolysaccharide (LPS)-induced activation of BV2 microglia and inflammatory factor release, and the mechanism involved. Different concentrations of naringin were used to pretreat BV2 cells for 30 min, after which they were stimulated with 100 ng/mL LPS for different durations. The levels of NO, IL-1β and TNF-α in the cell culture medium was determined with ELISA and Griess method. The mRNA expressions of IL-1β and TNF-α was determined with RT-PCR. Changes in ERK and p65/NF-κB signaling pathway proteins were assayed with Western blotting. After 12 h stimulation of BV2 cells with LPS, the levels of IL-1β and TNF-α in the cell culture medium were significantly increased, but naringin had no significant effect on these inflammatory factors. In the cells pretreated with naringin, LPS stimulated the activation of microglia to produce IL-1β and TNF-α in a dose-dependent manner. Naringin inhibited LPS-induced release of IL-1β, to a certain extent. The TNF-α gene was overexpressed. In addition, LPS stimulated a dose-dependent decrease in NO production by BV2 after pretreatment with different concentrations of naringin. Naringin pretreatment of cells significantly inhibited the activation of p65/NF-κB in a concentration-dependent manner. In BV2 microglia, naringin inhibits LPO-induced production of NO and inflammatory factors, through a mechanism involving inhibition of activation of the p65/NF-κB signaling pathway.

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