PMID: 

Mini Rev Med Chem. 2019 Oct 9. Epub 2019 Oct 9. PMID: 32134369

Abstract Title: 

A Review on the Pharmacokinetic Properties of Naringin and Its Therapeutic Efficacies in Respiratory Diseases.

Abstract: 

Flavonoids are an important class of phytopharmaceuticals in plants. Naringin (naringenin- 7-O-rhamnoglucoside) is a flavanone glycoside isolated from folk herbal medicine Exocarpium Citri grandis (called Huajuhong in Chinese). Massive experimental works have been performed on naringin describing its phytochemical, pharmacokinetic, and bioactive properties. Naringin was found to possess multiple pharmacological activities in relieving inflammation, diabetes, neurodegeneration, cardiovascular disorders, and metabolic syndrome. Recently, it has been approved as a potential antitussive and expectorant for clinical trials. However, the pharmacokinetic aspects of naringin and its therapeutic potentials in respiratory diseases have not been comprehensively reviewed. The present review provides highlights of naringin with respect to its absorption, distribution, metabolism, excretion and its therapeutic effects on cough, phlegm, and pulmonary inflammation. This review would be helpful for the interpretation of pharmacokinetics and pharmacodynamics of naringin in clinical trials.

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PMID: 

Int J Mol Cell Med. 2019 ;8(2):141-153. Epub 2019 Oct 25. PMID: 32215265

Abstract Title: 

Protective Effect of Naringin on Bisphenol A-Induced Cognitive Dysfunction and Oxidative Damage in Rats.

Abstract: 

Bisphenol A (BPA) is one of the highest volume chemicals produced worldwide, which is used in many plastic industries. The present study aimed to evaluate the effect of BPA on cognitive functions and oxidative stress, and determine whether the naringin (NG) co-administration can modify the effect of this compound on cognitive functions and inhibit any possible oxidative stress in the brain tissue of rats. Adult male Wistar rats were divided into six groups. Group I: control, Group II: BPA-treated rats (50 mg/kg/day), Group III, IV, V: BPA+NG (40, 80, 160 mg/kg/day), Group VI: NG (160 mg/kg/day) alone. Cognitive functions were evaluated using step-down latency (SDL) on a passive avoidance apparatus, and transfer latency (TL) in elevated plus-maze. A significant decrease in SDL, prolongation of TL, noticeable oxidative impairment and increase in acetylcholinesterase activity were observed in the BPA-treated in comparison with the control group. Also, the co-administration of NG (160 mg/kg) antagonized the effect of BPA on SDL and TL, attenuated oxidative damage by lowering malondialdehyde and nitrite concentrations and restored superoxide dismutase, catalase, and glutathione S-transferase activities. On the other hand, acetylcholinesterase activity was reduced in the groups co-administred with NG (80 or 160 mg/kg) and BPA in comparison with the BPA alone-treated group. The present study highlighted the therapeutic potential of NG against BPA-induced cognitive impairment and oxidative damage.

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PMID: 

Neuroscience. 2020 Mar 25. Epub 2020 Mar 25. PMID: 32222558

Abstract Title: 

Bisphenol-A exposure during gestation and lactation causes visual perception deficits in rat pups following a decrease in IL-1β expression in the primary visual cortex.

Abstract: 

Bisphenol-A (BPA) exposure can affect cognitive functions of rodents and humans. However, whether information inputs for these functions in the brain are perturbed by BPA remains unclear. Here, visual perception in rats was assessed by testing their ability to discriminate between vertical and horizontal grating. We found that BPA exposure (1 mg/kg/day) during gestation and lactation markedly decreased the grating discrimination ability in rat pups (postnatal 21 days). The results of neuronal functions in the primary visual cortex (V1) showed that the orientation selectivity and signal extraction ability and fidelity were notably decreased after BPA exposure. These effects were accompanied by a reduction in synaptic plasticity (i.e., spine density and maturity) in the V1. According to inflammatory factor expression and glial cell morphology, no increase in inflammatory activation was observed after BPA exposure. However, BPA-exposed rat pups exhibited a significant decrease in IL-1β expression in the V1, accompanied by a decline in P38 phosphorylation. After local injection of IL-1β (10 ng/ml) in the V1, these two visual properties recovered to normal levels. Thus, our findings imply that physiological dysfunction of IL-1β may contribute to orientation perception deficitsin BPA-exposed rats.

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PMID: 

Molecules. 2020 Mar 23 ;25(6). Epub 2020 Mar 23. PMID: 32210117

Abstract Title: 

Major Contribution of Caspase-9 to Honokiol-Induced Apoptotic Insults to Human Drug-Resistant Glioblastoma Cells.

Abstract: 

Temozolomide (TMZ)-induced chemoresistance to human glioblastomas is a critical challenge now. Our previous studies showed that honokiol, a major bioactive constituent of(Houpo), can kill human glioblastoma cells and suppresses glioblastoma growth. This study was further aimed to evaluate the effects of honokiol on human drug-resistant glioblastoma cells and the possible mechanisms. The results by data mining in the cancer genome atlas (TCGA) database and immunohistochemistry displayed that expression of caspase-9 mRNA and protein in human glioblastomas was induced. Human TMZ-resistant U87-MG-R9 glioblastoma cells were selected and prepared from human drug-sensitive U87-MG cells. Compared to human drug-sensitive U87-MG cells, TMZ did not affect viability of U87-MG-R9 glioblastoma cells. Interestingly, treatment with honokiol suppressed proliferation and survival of human drug-resistant glioblastoma cells in concentration- and time-dependent manners. Compared to caspase-8 activation, honokiol chiefly increased activity of caspase-9 in U87-MG-R9 cells. Successively, levels of cleaved caspase-3 and activities of caspase-3 and caspase-6 in human TMZ-tolerant glioblastoma cells were augmented following honokiol administration. In parallel, honokiol triggered DNA fragmentation of U87-MG-R9 cells. Accordingly, treatment of human TMZ-resistant glioblastoma cells with honokiol induced cell apoptosis but did not affect cell necrosis. Fascinatingly, suppressing caspase-9 activity using its specific inhibitors repressed honokiol-induced caspase-6 activation, DNA fragmentation, and cell apoptosis. Taken together, this study has shown the major roles of caspase-9 in transducing honokiol-induced mitochondria-dependent apoptosis in human drug-resistant glioblastoma cells. Thus, honokiol may be clinically applied as a drug candidate for treatment of glioblastoma patients with chemoresistance.

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PMID: 

Toxicol Appl Pharmacol. 2017 08 15 ;329:128-139. Epub 2017 May 27. PMID: 28558962

Abstract Title: 

Galangin ameliorates cisplatin-induced nephrotoxicity by attenuating oxidative stress, inflammation and cell death in mice through inhibition of ERK and NF-kappaB signaling.

Abstract: 

Cisplatin is a chemotherapeutic agent widely used in the treatment of various cancers. However, cisplatin can induce nephrotoxicity and neurotoxicity, limiting its dosage and usage. Galangin, a natural flavonol, has been found to exhibit anti-oxidant and anti-inflammatory effects in vivo. Here, we investigated the effects of galangin on cisplatin-induced acute kidney injury (AKI) and its molecular mechanisms in mice. Galangin administration reduced the cisplatin-induced oxidative stress by decreasing renal MDA and 3-NT formations. Galangin administration also increased renal anti-oxidative enzyme activities (SOD, GPx, and CAT) and GSH levels depleted by cisplatin. Furthermore, galangin administration inactivated stress-induced Nrf2 protein and its downstream products, HO-1 and GCLC. In terms of the inflammatory response, galangin administration reduced IκBα phosphorylation, NF-κB phosphorylation and nuclear translocation, and then inhibited cisplatin-induced secretions of pro-inflammatory TNF-α, IL-1β and IL-6. In addition, cisplatin-induced ERK and p38 phosphorylations were inhibited by galangin administration. In terms of cell death, galangin administration reduced levels of p53, pro-apoptotic Bax and activated caspase-3 to inhibit the cisplatin-induced apoptosis. Galangin administration also reduced the expression levels of RIP1 and RIP3 to inhibit cisplatin-induced RIP1/RIP3-dependent necroptosis. Therefore, galangin administration significantly ameliorates cisplatin-induced nephrotoxicity by attenuating oxidative stress, inflammation, and cell death through inhibitions of ERK and NF-κB signaling pathways. Galangin might be a potential adjuvant for clinical cisplatin therapy.

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PMID: 

Oncol Rep. 2017 Aug ;38(2):703-714. Epub 2017 Jun 29. PMID: 28677816

Abstract Title: 

Galangin suppresses human laryngeal carcinoma via modulation of caspase-3 and AKT signaling pathways.

Abstract: 

Laryngeal cancers are mostly squamous cell carcinomas. Although targeting radio-resistant cancer cells is important for improving the treatmental efficiency, the signaling pathway- and therapeutic strategy-related to laryngeal carcinoma still require further study. Galangin is an active pharmacological ingredient, isolated from propolis and Alpinia officinarum Hance, and has been reported to have anticancer and anti-oxidative properties through regulation of cell cycle, resulting in angiogenesis, apoptosis, invasion and migration without triggering any toxicity in normal cells. PI3K/AKT and p38 are important signaling pathways to modulate cancer cell apoptosis and proliferation through caspase-3, NF-κB and mTOR signal pathways. Autophagy is also enhanced by activating LC3s and Beclin 1. In the present study, galangin was found to suppress laryngeal cancer cell proliferation. Also, flow cytometry, immunohistochemical and western blotanalysis indicated that cell apoptosis was induced for galangin administration, promoting caspase-3 expression through regulating PI3K/AKT/NF-κB. Furthermore, galangin inhibited laryngeal cancer cell proliferation, related to p38 inactivation by galangin treatment. Additionally, mTOR activation regulated by PI3K/AKT was reduced by galangin, suppressing cancer cell transcription and proliferation. Our data also indicated that the tumor volume and weight in nude mice were reduced for galangin use in vivo accompanied by Ki-67 decrease and TUNEL increase in tumor tissues. Together, our data indicated that galangin has a potential role in suppressing human laryngeal cancer via inhibiting tumor cell proliferation, activating apoptosis and autophagy, which were regulated by p38 and AKT/NF-κB/mTOR pathways, providing a therapeutic strategy for human laryngeal cancer treatment.

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PMID: 

Biomed Pharmacother. 2017 Nov ;95:1295-1300. Epub 2017 Oct 6. PMID: 28938520

Abstract Title: 

Galangin suppresses hepatocellular carcinoma cell proliferation by reversing the Warburg effect.

Abstract: 

Hepatocellular carcinoma (HCC) is the sixth most common cancer. The Warburg effect is an important way by which HCC adapts to a hypoxic environment. The aim of the present study was to determine whether and how galangin reverses the Warburg effect in HCC cells. We treated three HCC cell lines, HepG2, Hep3B and PLC/PRF/5 with galangin for 24h, respectively. Cell proliferation was measured with MTT assay. Glucose uptake, lactate production and the oxygen consumption were measured. Pyruvate kinase activities were detected by measuring the consumption of NADH, and glycolytic pathway-related proteins were measured by Western blotting. The results showed that galangin suppressed proliferation of HCC cells, decreased glucose absorption and lactate production of HCC. In addition, galangin also gave rise to increased oxygen consumption in all three HCC cell lines. After treatment with galangin, the activity of pyruvate kinase was up-regulated and the expression levels of glycolytic pathway-related proteins were changed. These results suggest that galangin suppresses the Warburg effect in HCC cells, indicating that galangin might be a potential therapeutic agent for HCC.

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PMID: 

Biomed Pharmacother. 2018 Jan ;97:213-224. Epub 2017 Nov 6. PMID: 29091869

Abstract Title: 

Galangin (GG) combined with cisplatin (DDP) to suppress human lung cancer by inhibition of STAT3-regulated NF-κB and Bcl-2/Bax signaling pathways.

Abstract: 

Lung cancer represents a significant problem for public health worldwide. Galangin (GG), a natural active compound 3, 5, 7-trihydroxyflavone, is a type of bioflavonoid, which is isolated from the Alpinia galangal root and suggested to induce apoptosis in various cancers. We investigated the ability of Galangin (GG) to attenuate the drug resistance of human lung cancer cells, resistant to treatment of cisplatin (DDP). DDP is a pyrimidine analog, widely used in cancer treatment. Galangin and DDP co-treatment resulted in a dose-dependent suppression of the cell proliferation. Decreasing of p-STAT3 was included in p65 suppression by GG with DDP in combination. Additionally, the presence of GG potentiated the effects of DDP on apoptosis induction through suppressing Bcl-2 in DDP-resistant lung cancer cells. The pro-apoptotic proteins of Bax and Bid were up-regulated, accompanied with Caspases cleavage, leading to apoptosis. Moreover, in mice xenograft models, the combined therapy inhibited tumor growth compared to the GG or DDP treatment alone. Our data indicated a novel therapeutic strategy to potentiate DDP-induced anti-tumor effect in lung cancer cells with DDP resistance by GG through inactivating p-STAT3/p65 and Bcl-2 pathways.

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PMID: 

Chem Biol Interact. 2018 Jan 5 ;279:1-9. Epub 2017 Nov 4. PMID: 29113808

Abstract Title: 

Galangin induces cell death by modulating the expression of glyoxalase-1 and Nrf-2 in HeLa cells.

Abstract: 

The present study was designed to understand the anticancer property and molecular mechanisms associated with chemo preventive effects of galangin. The anticancer effect was evaluated in vitro using human cervical cancer cell line (HeLa). Galangin was found to be effective in inducing cell death and inhibiting proliferation&migration significantly. The inhibitory effect of galangin could be correlated with the increase in ROS production&induction of apoptosis. Besides this the activity of glyoxalase-1, an enzyme important for the detoxification of cytotoxic metabolite methy glyoxal and Nrf-2 (a trascription factor), involved in redox signalling were found to be decreased. We concluded that galangin exerts its chemo preventive effect via redox signalling by inhibiting glyoxalase-1&increasing oxidative&carbonyl stress.

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PMID: 

Mol Med Rep. 2018 Oct ;18(4):3619-3624. Epub 2018 Aug 22. PMID: 30152847

Abstract Title: 

Galangin protects human rheumatoid arthritis fibroblast‑like synoviocytes via suppression of the NF‑κB/NLRP3 pathway.

Abstract: 

Rheumatoid arthritis (RA) is a chronic autoimmune disease that significantly affects patient quality of life. Galangin is an extract with multiple health benefits, including anti‑oxidative, anti‑proliferative, immunoprotective and cardioprotective effects. However, to the best of the authors' knowledge, no detailed studies have investigated its regulatory effects on the nuclear factor (NF)‑κB/NLR family pyrin domain containing 3 (NLRP3) signaling pathway. The presentstudy aimed to investigate the protective mechanism of galangin in RA fibroblast‑like synoviocytes with regards to the NF‑κB/NLRP3 signaling pathway. Human RA fibroblast‑like synovium cells (RAFSCs) were treated with lipopolysaccharide (LPS) to induce inflammation. The levels of interleukin(IL)‑1β, tumor necrosis factor (TNF)‑α, IL‑18, inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)‑2, prostaglandin E2 (PGE2), and nitric oxide (NO) were measured by enzyme‑linked immunosorbent assay or western blotting in the absence or presence of different concentrations of galangin. Superoxide dismutase (SOD) activity and malondialdehyde (MDA) content were additionally evaluated. Furthermore, factors involved in the NF‑κB/NLRP3 pathway, including NLRP3, apoptosis‑associated speck‑like protein containing A, IL‑1β, pro‑caspase‑1, caspase‑1, phosphorylated(p)‑NF‑κB inhibitor α and p‑NF‑κB, were assessed by western blotting. The results revealed that LPS significantly stimulated IL‑1β, TNF‑α, IL‑18, PGE2, NO, iNOS, COX‑2 and NF‑κB/NLRP3 factor expression, compared with the control. SOD activity was reduced. Pre‑treatment with galangin significantly attenuated the effects of LPS, and galangin was demonstrated to have effective anti‑oxidative properties. In conclusion, galangin protected RAFSCs through downregulation of the NF‑κB/NLRP3 signaling pathway. These findings suggested that galangin may provide a novel direction for the development of RA therapies in the future.

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