3,4-dihydroxyphenylacetic acid, a microbiota-derived metabolite of quercetin, protects against pancreatic β-cells dysfunction induced by high cholesterol

Carrasco‐Pozo, Catalina; Gotteland, Martín; Castillo, Rodrigo; Chen, Chen

doi:10.1016/j.yexcr.2015.03.021

Cited by 70 publications

(71 citation statements)

References 77 publications

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“…This is in agreement with previous studies where 3,4-DHPA, at similar doses (20 μM), completely blocked the effect of peroxynitrite on tyrosine hydroxylase, an enzyme involved in Parkinson’s disease pathology (35). Furthermore, recent evidences showed a preventive action of this phenolic metabolite in dysfunctional pancreatic-β-cells (36), even at not physiologically relevant concentrations (up to 250 μM), as well as on mice liver after intragastrically administration of 3,4-DHPA (10, 20, or 50 mg/kg) for 3 days (37). Additionally, in the meanline of the redaction process of this paper, new evidence was reported showing the ability of a panel of phenolic metabolites, noting 3,4-DHPA among them, to prevent neuronal death after oxidative (H 2 O 2 ) induced injury in the SH-SY5Y cellular model at a similar range of concentrations (1–10 μM) (38).…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective Effects of Selected Microbial-Derived Phenolic Metabolites and Aroma Compounds from Wine in Human SH-SY5Y Neuroblastoma Cells and Their Putative Mechanisms of Action

et al. 2017

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Moderate wine consumption has shown the potential to delay the onset of neurodegenerative diseases. This study investigates the molecular mechanisms underlying the protective effects of wine-derived phenolic and aroma compounds in a neuroinflammation model based on SIN-1 stress-induced injury in SH-SY5Y neuroblastoma cells. Cell pretreatment with microbial metabolites found in blood after wine consumption, 3,4-dihydroxyphenylacetic (3,4-DHPA), 3-hydroxyphenylacetic acids and salicylic β-d-O-glucuronide, at physiologically concentrations (0.1–10 μM) resulted in increased cell viability versus SIN-1 control group (p < 0.05). Results also showed significant decreases in mitogen-activated protein kinase (MAPK) p38 and ERK1/2 activation as well as in downstream pro-apoptotic caspase-3 activity by some of the studied compounds. Moreover, pretreatment with p38, MEK, and ERK1/2-specific inhibitors, which have a phenolic-like structure, also resulted in an increase on cell survival and a reduction on caspase-3 activity levels. Overall, these results contribute with new evidences related to the neuroprotective actions of wine, pointing out that wine-derived human metabolites and aroma compounds may be effective at protecting neuroblastoma cells from nitrosative stress injury by inhibiting neuronal MAPK p38 and ERK1/2, as well as downstream caspase 3 activity.

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Section: Discussionmentioning

confidence: 99%

Neuroprotective Effects of Selected Microbial-Derived Phenolic Metabolites and Aroma Compounds from Wine in Human SH-SY5Y Neuroblastoma Cells and Their Putative Mechanisms of Action

et al. 2017

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“…A recent study showed that 3,4-dihydroxyphenylacetic acid, a microbial metabolite of quercetin and PACs, can protect against the mitochondrial dysfunction induced by CS in Min6 pancreatic β-cells (194). CS (320µM) decreased the mitochondrial membrane potential, the intracellular concentrations of ATP and the rate of oxygen consumption, while 3,4-dihydroxyphenylacetic acid (100–250µM) prevented, in a concentration-dependent manner, these mitochondrial function alterations.…”

Section: The Pacs In the Colonmentioning

confidence: 99%

The Gastrointestinal Tract as a Key Target Organ for the Health-Promoting Effects of Dietary Proanthocyanidins

et al. 2017

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Proanthocyanidins (PACs) are polymers of flavan-3-ols abundant in many vegetable foods and beverages widely consumed in the human diet. There is increasing evidence supporting the beneficial impact of dietary PACs in the prevention and nutritional management of non-communicable chronic diseases. It is considered that PACs with a degree of polymerization >3 remain unabsorbed in the gastrointestinal (GI) tract and accumulate in the colonic lumen. Accordingly, the GI tract may be considered as a key organ for the healthy-promoting effects of dietary PACs. PACs form non-specific complexes with salivary proteins in mouth, originating the sensation of astringency, and with dietary proteins, pancreatic enzymes, and nutrient transporters in the intestinal lumen, decreasing the digestion and absorption of carbohydrates, proteins, and lipids. They also exert antimicrobial activities, interfering with cariogenic or ulcerogenic pathogens in the mouth (Streptococcus mutans) and stomach (Helicobacter pylori), respectively. Through their antioxidant and antiinflammatory properties, PACs decrease inflammatory processes in animal model of gastric and colonic inflammation. Interestingly, they exert prebiotic activities, stimulating the growth of Lactobacillus spp. and Bifidobacterium spp. as well as some butyrate-producing bacteria in the colon. Finally, PACs are also metabolized by the gut microbiota, producing metabolites, mainly aromatic acids and valerolactones, which accumulate in the colon and/or are absorbed into the bloodstream. Accordingly, these compounds could display biological activities on the colonic epithelium or in extra-intestinal tissues and, therefore, contribute to part of the beneficial effects of dietary PACs.

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“…Mice with specific inactivation of ABCA1 (ATP-binding cassette transporter subfamily A member 1), a transporter that mediates reverse cholesterol efflux show impaired glucose tolerance and insulin secretion [1], [2]. Moreover, a direct link has been found between elevated cholesterol and reduced insulin secretion in islets isolated from C57BL/6J mice and in INS-1 rat pancreatic β-cells [3], as well as in Min6 cells [4], whereby insulin secretion can be normalized through cholesterol depletion [3]. LDL receptor deficient mice exhibit hypercholesterolemia with elevated cholesterol levels in pancreatic islets, which is associated with β-cell dysfunction, impaired glucose tolerance and reduced glucose-stimulated insulin secretion (GSIS) [5].…”

Section: Introductionmentioning

confidence: 99%

The deleterious effect of cholesterol and protection by quercetin on mitochondrial bioenergetics of pancreatic β-cells, glycemic control and inflammation: In vitro and in vivo studies

et al. 2016

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Studying rats fed high cholesterol diet and a pancreatic β-cell line (Min6), we aimed to determine the mechanisms by which quercetin protects against cholesterol-induced pancreatic β-cell dysfunction and impairments in glycemic control. Quercetin prevented the increase in total plasma cholesterol, but only partially prevented the high cholesterol diet-induced alterations in lipid profile. Quercetin prevented cholesterol-induced decreases in pancreatic ATP levels and mitochondrial bioenergetic dysfunction in Min6 cells, including decreases in mitochondrial membrane potentials and coupling efficiency in the mitochondrial respiration (basal and maximal oxygen consumption rate (OCR), ATP-linked OCR and reserve capacity). Quercetin protected against cholesterol-induced apoptosis of Min6 cells by inhibiting caspase-3 and -9 activation and cytochrome c release. Quercetin prevented the cholesterol-induced decrease in antioxidant defence enzymes from pancreas (cytosolic and mitochondrial homogenates) and Min6 cells and the cholesterol-induced increase of cellular and mitochondrial oxidative status and lipid peroxidation. Quercetin counteracted the cholesterol-induced activation of the NFκB pathway in the pancreas and Min6 cells, normalizing the expression of pro-inflammatory cytokines. Quercetin inhibited the cholesterol-induced decrease in sirtuin 1 expression in the pancreas and pancreatic β-cells. Taken together, the anti-apoptotic, antioxidant and anti-inflammatory properties of quercetin, and its ability to protect and improve mitochondrial bioenergetic function are likely to contribute to its protective action against cholesterol-induced pancreatic β-cell dysfunction, thereby preserving glucose-stimulated insulin secretion (GSIS) and glycemic control. Specifically, the improvement of ATP-linked OCR and the reserve capacity are important mechanisms for protection of quercetin. In addition, the inhibition of the NFκB pathway is an important mechanism for the protection of quercetin against cytokine mediated cholesterol-induced glycemic control impairment. In summary, our data highlight cellular, molecular and bioenergetic mechanisms underlying quercetin's protective effects on β-cells in vitro and in vivo, and provide a scientifically tested foundation upon which quercetin can be developed as a nutraceutical to preserve β-cell function.

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3,4-dihydroxyphenylacetic acid, a microbiota-derived metabolite of quercetin, protects against pancreatic β-cells dysfunction induced by high cholesterol

Cited by 70 publications

References 77 publications

Neuroprotective Effects of Selected Microbial-Derived Phenolic Metabolites and Aroma Compounds from Wine in Human SH-SY5Y Neuroblastoma Cells and Their Putative Mechanisms of Action

Neuroprotective Effects of Selected Microbial-Derived Phenolic Metabolites and Aroma Compounds from Wine in Human SH-SY5Y Neuroblastoma Cells and Their Putative Mechanisms of Action

The Gastrointestinal Tract as a Key Target Organ for the Health-Promoting Effects of Dietary Proanthocyanidins

The deleterious effect of cholesterol and protection by quercetin on mitochondrial bioenergetics of pancreatic β-cells, glycemic control and inflammation: In vitro and in vivo studies

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