PMID: 

Biomed Pharmacother. 2018 Jul ;103:1223-1230. Epub 2018 May 7. PMID: 29864902

Abstract Title: 

Cyanidin-3-O-glucoside ameliorates diabetic nephropathy through regulation of glutathione pool.

Abstract: 

Diabetic nephropathy (DN) is a common complication of diabetes and the major cause of chronic kidney disease. Cyanidin 3-glucoside (C3G) is the most widespread anthocyanin in nature. In the present study, we aimed to investigate the possible effects of C3G on DN in db/db mice. We found that body weights and high levels of fasting blood glucose, serum insulin, C-peptide, glycosylated hemoglobin A1c, and systolic blood pressure in diabetic mice were significantly reduced by C3G. C3G also reduced the ratio of kidney to body weight and the levels of blood urea nitrogen (BUN), serum creatinine, urinary albumin content and albumin/creatinine ratio (ACR), ameliorated the pathological changes of kidneys, reduced the surface area of Bowman's capsule, glomerular tuft, Bowman's space, and decreased renal expression of collagen IV, fibronectin, transforming growth factorβ 1 (TGFβ1), matrix metalloprotein 9 (MMP9) and α-smooth muscle actin (α-SMA) in db/db mice. The Lee's index, perirenal white adipose tissue weight, and high levels of blood and renal triglyceride and cholesterol were decreased by C3G. Moreover, C3G reduced systemic levels and renal expression of tumor necrosis factor ɑ (TNFɑ), IL-1ɑ, and monocyte chemotactic protein-1 (MCP-1), indicating the inhibition of inflammation. Furthermore, C3G increased glutathione (GSH) level and decreased GSSG level in kidneys of diabetic mice. The renal mRNA expression of glutamate-cysteine ligase catalyticsubunit (GCLC) and glutamate-cysteine ligase modifier subunit (GCLM) was increased by C3G in diabetic mice. Buthionine sulphoximine (BSO), an inhibitor of GSH synthesis, inhibited the effects of C3G on glucose metabolic dysfunction and DN. The data demonstrates that enhancement of GSH pool is involved in the renal-protective effects of C3G. Overall, C3G could be a promising therapeutic option for attenuation of diabetes and DN.

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PMID: 

Food Funct. 2018 Jun 20 ;9(6):3466-3480. PMID: 29878020

Abstract Title: 

Cyanidin 3-O-glucoside prevents the development of maladaptive cardiac hypertrophy and diastolic heart dysfunction in 20-week-old spontaneously hypertensive rats.

Abstract: 

The present study investigated the effects of cyanidin 3-O-glucoside (C3G) in cardiomyocytes (CM) and fibroblasts exposed to endothelin 1 (ET1), as well as in the spontaneously hypertensive rat (SHR) model, alone or in combination with hydrochlorothiazide (HCT). Adult rat CM and cardiac fibroblasts (CF) were pretreated with C3G and co-incubated with ET1 (10-7 M) for 24 hours. Five-week-old male SHR and their normotensive controls, Wistar-Kyoto rats (WKY), received one of 4 treatments via oral gavage daily for 15 weeks: (1) water (control); (2) C3G (10 mg per kg per day); (3) HCT (10 mg per kg per day); (4) C3G + HCT (10 mg per kg per day each). Blood pressure (BP) was measured at 1, 8 and 15 weeks. Echocardiography measurements were performed at 15 weeks. C3G prevented ET1-induced CM death and hypertrophy. Stimulating CF with ET1 did not induce their phenoconversion; nevertheless, C3G inhibited un-stimulated CF differentiation. HCT slowed the rise of systolic BP (SBP) in the SHR over time (week 1: SHRs control = 161± 6.3 mmHg, SHRs HCT = 129 ± 6.3 mmHg; week 15: SHRs control = 201 ± 7.3 mmHg, SHRs HCT = 168 ± 7.3 mmHg), but C3G had no effect on SBP (week 1: SHRs control = 161 ± 6.3 mmHg, SHRs C3G = 126 ± 6.3 mmHg; week 15: SHRs control = 201 ± 7.3 mmHg, SHRs C3G = 186 ± 7.3 mmHg). SHRs treated with C3G, HCT, and C3G + HCT had lower left ventricular mass and shorter isovolumetric relaxation time compared to control SHRs. C3G ameliorated cardiac hypertrophy and diastolic dysfunction in SHRs.

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PMID: 

Biomed Pharmacother. 2018 Sep ;105:625-632. Epub 2018 Jun 10. PMID: 29898429

Abstract Title: 

Cyanidin-3-O-β-glucoside regulates the activation and the secretion of adipokines from brown adipose tissue and alleviates diet induced fatty liver.

Abstract: 

AIM: Cyanidin-3-O-β-glucoside (Cy-3-G) the most abundant monomer of anthocyanins has multiple protective effects on many diseases. To date, whether Cy-3-G could regulate the function of brown adipose tissue (BAT) is still unclear and whether this regulation could influence the secretion of adipokines from BAT to prevent non-alcoholic fatty liver disease (NAFLD) indirectly remains to be explored. In this study we investigated the effect of Cy-3-G on BAT and the potential role of Cy-3-G to prevent fatty liver through regulating the secretion of BAT.METHODS: Male C57BL/6 J mice were fed with a high fat high cholesterol (HFC) diet with or without 200 mg/kg B.W Cy-3-G for 8 weeks. In in vitro experiments, the differentiated brown adipocytes (BAC) and C3H10T1/2 clone8 cells were treated with 0.2 mM palmitate with or without Cy-3-G for 72 or 96 h. Then the culture media of C3H10T1/2 clone8 cells were collected for measuring the adipokines secretion by immunoblot assay and were applied to culture HepG2 cells or LO2 cells for 24 h. Lipid accumulation in HepG2 cells or LO2 cells were evaluated by oil red O staining.RESULTS: Here we found that Cy-3-G regulated the activation of BAT and the expression of adipokines in BAT which were disrupted by HFC diet and alleviated diet induced fatty liver in mice. In in vitro experiments, Cy-3-G inhibited the release of adipokines including extracellular nicotinamide phosphoribosyltransferase (eNAMPT) and fibroblast growth factor 21 (FGF21) from differentiated C3H10T1/2 clone8 cells induced by palmitate, which was accompanied by a reduction of lipid accumulation in HepG2 cells and LO2 cells cultured by the corresponding collected media of C3H10T1/2 clone8 cells.CONCLUSIONS: These results indicate that Cy-3-G can regulate the thermogenic and secretory functions of BAT. Furthermore, our data suggest that the protective effect of Cy-3-G on hepatic lipid accumulation is probably via regulating the secretion of adipokines from BAT.

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PMID: 

Z Naturforsch C. 2018 Jul 26 ;73(7-8):281-289. PMID: 29924740

Abstract Title: 

Cyanidin-3-rutinoside protects INS-1 pancreaticβ cells against high glucose-induced glucotoxicity by apoptosis.

Abstract: 

Exposure to high levels of glucose may cause glucotoxicity, leading to pancreaticβ cell dysfunction, including cell apoptosis and impaired glucose-stimulated insulin secretion. The aim of this study was to explore the effect of cyanidin-3-rutinoside (C3R), a derivative of anthocyanin, on glucotoxicity-induced apoptosis in INS-1 pancreatic β cells. Glucose (30 mM) treatment induced INS-1 pancreatic β cell death, but glucotoxicity and apoptosis significantly decreased in cells treated with 50 μM C3R compared to that observed in 30 mM glucose-treated cells. Furthermore, hyperglycemia increased intracellular reactive oxygen species (ROS), lipid peroxidation, and nitric oxide (NO) levels, while C3R treatment reduced these in a dose-dependent manner. C3R also increased the activity of antioxidant enzymes, markedly reduced the expression of pro-apoptotic proteins (such as Bax, cytochrome c, caspase 9 and caspase 3), and increased the expression of the anti-apoptotic protein, Bcl-2, in hyperglycemia-exposed cells. Finally, cell death was examined using annexin V/propidium iodide staining, which revealed that C3R significantly reduced high glucose-induced apoptosis. In conclusion, C3R may have therapeutic effects against hyperglycemia-induced β cell damage in diabetes.

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PMID: 

Cytotechnology. 2018 Dec ;70(6):1519-1528. Epub 2018 Aug 28. PMID: 30155610

Abstract Title: 

Cyanidin-3-glucoside enhances mitochondrial function and biogenesis in a human hepatocyte cell line.

Abstract: 

Mitochondrial dysfunction has been identified as one of the primary factors contributing to liver diseases. Pathways that control mitochondrial biogenesis are potential therapeutic targets for the amelioration of hepatocyte dysfunction and liver disease. Research on natural pharmacological agents that ameliorate liver diseases has intensified over the last two decades. Cyanidin-3-glucoside (Cy3g), a dietary flavonoid compound extracted from a wide variety of fruits and vegetables, reportedly has several beneficial health effects. In this study, we used an adult human hepatoma cell line (HuH7) to investigate the effects of the Cy3g polyphenolic compound on mitochondrial function and biogenesis in vitro. An increase in intracellular mitochondrial reductase levels was observed after treatment with Cy3g, but cytotoxicity was not induced. In addition, mitochondrial membrane potential and ATP production were increased following Cy3g treatment. Cy3g treatment also resulted in a dose- and time-dependent upregulation of the gene expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a transcription factor considered a master regulator of mitochondrial biogenesis and metabolism. Additionally, the expression of sirtuin 1 (SIRT1), which plays a key role in deacetylating PGC-1α, was also increased in a dose- and time-dependent manner. Cy3g treatment also increased the expression of downstream PGC-1α genes, nuclear respiratory factor 1 and mitochondrial transcription factor A (TFAM). Our results suggest that Cy3g has potential as a hepatoprotective therapeutic agent that enhances mitochondrial function and biogenesis in hepatocytes.

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PMID: 

Phytother Res. 2019 Jan ;33(1):81-89. Epub 2018 Sep 25. PMID: 30251280

Abstract Title: 

Cyanidin-3-glucoside attenuates the angiogenesis of breast cancer via inhibiting STAT3/VEGF pathway.

Abstract: 

Angiogenesis plays a pivotal role in breast cancer progression. Cyanidin-3-glucoside (C3G), one of the most widely distributed anthocyanins in edible fruits, shows antioxidative and anti-inflammatory property as well as induction of breast cancer cells apoptosis. However, the effect of C3G on breast cancer-induced angiogenesis remains unknown. In the present study, we found that C3G could attenuate breast cancer-induced angiogenesis via inhibiting VEGF, a key cytokine for angiogenesis, expression and secretion. Furthermore, signal transducer and activator of transcription 3 (STAT3) could transcriptionally activate VEGF, and C3G reduced STAT3 expression at both mRNA and protein level. Subsequently, our data showed that C3G induced miR-124 expression. Moreover, miR-124 could directly repress STAT3 expression, and miR-124-mediated STAT3 down-regulation was responsible for the inhibition of C3G on VEGF and angiogenesis. Taken together, we supplied more evidence to the anti-breast cancer property of C3G.

PMID: 

J Agric Food Chem. 2018 Dec 5 ;66(48):12675-12684. Epub 2018 Oct 30. PMID: 30376326

Abstract Title: 

Cyanidin-3- O-glucoside at Low Doses Protected against 3-Chloro-1,2-propanediol Induced Testis Injury and Improved Spermatogenesis in Male Rats.

Abstract: 

In recent decades, the capability of mankind spermatogenesis is declining due to various threats. Anthocyanins as colorful polyphenols possess beneficial functions for the organisms, including Leydig cells, but their effects on male spermatogenesis remain underexplored. In our study, the protective effect of cyanidin-3- O-glucoside (C3G) was investigated on the 3-chloro-1,2-propanediol (3-MCPD) caused rat spermatogenic disorders. At low doses, C3G improved the number and motility of the sperms, alleviating the seminiferous tubule injury. Interestingly, C3G showed no influence on sexual hormone but increased the androgen receptor expression. Meanwhile, C3G reduced the oxidative stress and number of apoptotic cells and promoted the integrity of the blood-testis barrier in the testis. Additionally, C3G mediated the activation of p-ERK, p-JNK, and p53, which are related to the protection of Sertoli cells and spermatogenesis. In conclusion, C3G protected against the 3-MCPD caused testis damage and spermatogenic disorders under appropriate doses, which indicates the potential protection of anthocyanins on male reproduction.

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PMID: 

Korean J Physiol Pharmacol. 2018 Nov ;22(6):689-696. Epub 2018 Oct 25. PMID: 30402029

Abstract Title: 

Cyanidin-3-glucoside inhibits amyloidβ-induced neuronal cell death in cultured rat hippocampal neurons.

Abstract: 

Increasing evidence implicates changes in [Ca]and oxidative stress as causative factors in amyloid beta (Aβ)-induced neuronal cell death. Cyanidin-3-glucoside (C3G), a component of anthocyanin, has been reported to protect against glutamate-induced neuronal cell death by inhibiting Caand Znsignaling. The present study aimed to determine whether C3G exerts a protective effect against Aβ-induced neuronal cell death in cultured rat hippocampal neurons from embryonic day 17 fetal Sprague-Dawley rats using MTT assay for cell survival, and caspase-3 assay and digital imaging methods for Ca, Zn, MMP and ROS. Treatment with Aβ(20µM) for 48 h induced neuronal cell death in cultured rat pure hippocampal neurons. Treatment with C3G for 48 h significantly increased cell survival. Pretreatment with C3G for 30 min significantly inhibited Aβ-induced [Zn]increases as well as [Ca]increases in the cultured rat hippocampal neurons. C3G also significantly inhibited Aβ-induced mitochondrial depolarization. C3G also blocked the Aβ-induced formation of ROS. In addition, C3G significantly inhibited the Aβ-induced activation of caspase-3. These results suggest that cyanidin-3-glucoside protects against amyloidβ-induced neuronal cell death by reducing multiple apoptotic signals.

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PMID: 

Int Immunopharmacol. 2019 Apr ;69:1-10. Epub 2019 Jan 17. PMID: 30660871

Abstract Title: 

Cyanidin-3-O-β-glucoside attenuates allergic airway inflammation by modulating the IL-4Rα-STAT6 signaling pathway in a murine asthma model.

Abstract: 

Cyanidin-3-O-β-glucoside (Cy-3-g), a typical and abundant monomer of anthocyanins, exhibits a variety of biological activities, such as anti-atherosclerosis, anti-obesity, and anticancer effects. However, to date little is known about its effects on asthma. This study aimed to investigate the efficacy of dietary Cy-3-g on allergic asthma in an animal model. BALB/c mice were sensitized and challenged with ovalbumin (OVA) to induce allergic asthma. The pathological changes of the lung tissues, type 2 helper (Th2)-associated cytokine production in bronchoalveolar lavage fluid (BALF), and the interleukin 4 receptor alpha (IL-4Rα)-signal transducer and activator of transcription 6 (STAT6) signaling pathway activities were assessed. We found that Cy-3-g significantly inhibited OVA-induced inflammatory cell infiltration and mucus hyper-production in lung tissues, reduced the production of interleukin 4 (IL-4), interleukin 5 (IL-5) and interleukin 13 (IL-13) in BALF. Furthermore, Cy-3-g effectively suppressed OVA-induced up-regulation of the IL-4Rα-STAT6 signaling pathway activity of the lung tissues. These results demonstrated that dietary Cy-3-g could attenuate allergic airway inflammation in a murine asthma model, and Cy-3-g might be used as an agent for asthma prevention and/or treatment in the future.

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PMID: 

Toxins (Basel). 2019 Sep 17 ;11(9). Epub 2019 Sep 17. PMID: 31533259

Abstract Title: 

Astaxanthin Protects OTA-Induced Lung Injury in Mice through the Nrf2/NF-κB Pathway.

Abstract: 

The aim of this research was to evaluate the potential protective mechanism of astaxanthin (ASTA) against oxidative damage and inflammation caused by ochratoxin (OTA) in mouse lung. We divided mice into a control group (CG), an OTA group (PG), an astaxanthin group (AG), and an OTA+ASTA group (JG). Oxidative indices (malondialdehyde (MDA), total superoxide dismutase (T-SOD), and reduced glutathione (GSH)) and inflammatory markers (interleukin 1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α)) were assayed in the lung, and the lung-weight-to-body-weight ratio was calculated. Apoptosis was detected in pathological sections by the TdT-mediated dUTP nick-end labeling (TUNEL) assay. Oxidative damage and inflammation were detected in the lung of mice after exposure to OTA. Besides, Nrf2- and NF-κB-pathway-associated proteins were detected by Western blot. In contrast with OTA, ASTA significantly raised the expression of Nrf2, HO-1, and MnSOD, while the expression of other proteins (Keap1, TLR4, and NF-κB) was significantly decreased. These results indicate that ASTA exerted protective effects against OTA-induced oxidative damage and inflammation in the lung by regulating the Nrf2 and NF-κB pathways.

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