Ziwei Wang

All Publications

• (-)-Epicatechin mitigates anxiety-related behavior in a mouse model of high fat diet-induced obesity. The Journal of nutritional biochemistry Kang, J., Wang, Z., Cremonini, E., Gall, G. L., Pontifex, M. G., Muller, M., Vauzour, D., Oteiza, P. I. 2022: 109158

  Abstract

  Mounting evidence demonstrates that consumption of high fat diet (HFD) and subsequent development of obesity leads to alterations in cognition and mood. While obesity can affect brain function, consumption of select dietary bioactives may help prevent obesity-related cognitive decline. This study investigated the capacity of the dietary flavonoid (-)-epicatechin (EC) to mitigate HFD-induced obesity-associated alterations in memory and mood. Healthy 8-week old male C57BL/6J mice were maintained on either a control diet (10 kCal% from fat) or a HFD (45 kCal% from fat) and were supplemented with EC at 2 or 20 mg/kg body weight (B.W.) for a 24 week period. Between week 20 and 22, anxiety-related behavior, recognition memory, and spatial memory were measured. Underlying mechanisms were assessed by measuring the expression of selected genes in the hippocampus and by 16S rRNA sequencing and metabolomic analysis of the gut microbiota. 24 weeks of HFD feeding resulted in obesity, which was not affected by EC supplementation. HFD-associated increase in anxiety-related behavior was mitigated by EC in a dose-response manner and was accompanied by increased hippocampal brain-derived neurotrophic factor, as well as partial or full restoration of glucocorticoid receptor, mineralocorticoid receptor and 11β-HSD1 expression. Higher EC dosage (20 mg/kg B.W.) also restored aberrant Lactobacillus and Enterobacter abundance altered by HFD and/or the associated obesity. Together, these results demonstrate how EC mitigates anxiety-related behaviors, revealing a connection between BDNF- and glucocorticoids-mediated signaling . Our findings link changes in the hippocampus and the gut microbiota in a context of HFD-induced obesity and anxiety.

  View details for DOI 10.1016/j.jnutbio.2022.109158

  View details for PubMedID 36150679

• A randomized placebo-controlled cross-over study on the effects of anthocyanins on inflammatory and metabolic responses to a high-fat meal in healthy subjects. Redox biology Cremonini, E., Daveri, E., Iglesias, D. E., Kang, J., Wang, Z., Gray, R., Mastaloudis, A., Kay, C. D., Hester, S. N., Wood, S. M., Fraga, C. G., Oteiza, P. I. 2022; 51: 102273

  Abstract

  This study investigated the effects of supplementation with a cyanidin- and delphinidin-rich extract (CDRE) on the postprandial dysmetabolism, inflammation, and redox and insulin signaling, triggered by the consumption of a high fat meal (HFM) in healthy individuals. Participants (n = 25) consumed a 1026-kcal HFM simultaneously with either the CDRE providing 320.4 mg of anthocyanins (90% cyanidin and delphinidin) or placebo. Diets were randomly assigned in a double blind, placebo-controlled crossover design. Blood was collected prior to (fasted, time 0), and for 5 h after meal consumption; plasma, serum, and peripheral blood mononuclear cells (PBMC) were isolated. AC metabolites were detected in serum as early as 30 min after CDRE consumption. The CDRE mitigated HFM-induced endotoxemia, reducing increases in plasma LPS and LPS-binding protein. The CDRE also reduced other events associated with HFM-triggered postprandial dysmetabolism including: i) plasma glucose and triglyceride increases; ii) TNFα and NOX4 upregulation in PBMC; and iii) JNK1/2 activation in PBMC. The CDRE did not significantly affect HFM-mediated increases in plasma insulin, GLP-1, GLP-2, GIP, and LDL- and HDL-cholesterol, and IKK phosphorylation in PBMC. In summary, dietary AC, i.e. cyanidin and delphinidin, exerted beneficial actions against unhealthy diets by modulating the associated postprandial dysmetabolism, endotoxemia, alterations of glycemia and lipidemia, and redox and insulin signaling.

  View details for DOI 10.1016/j.redox.2022.102273

  View details for PubMedID 35255426

  View details for PubMedCentralID PMC8902616

• Faeces from malnourished colorectal cancer patients accelerate cancer progression. Clinical nutrition (Edinburgh, Scotland) Chao, X., Lei, Z., Hongqin, L., Ziwei, W., Dechuan, L., Weidong, D., Lu, X., Haitao, C., Bo, Z., Haixing, J., Qinghua, Y. 2022; 41 (3): 632-644

  Abstract

  BACKGROUD: Malnutrition has been confirmed to play an important role in colorectal cancer (CRC) progression via the gut microenvironment. However, the characteristics of the gut microbiota or its potential biological mechanism in CRC remain inconclusive.METHODS: In this work, Patient-Generated Subjective Global Assessment (PG-SGA) tool and 16sRNA sequencing were prepared to detect the variation in gut microbiota and the association between nutrition status and gut microbiota. RDA/CCA analysis was used to evaluate the relationship between faecal microbiota from malnourished CRC and clinical nutrition indicators. To investigate the mechanism of the gut microbiota in CRC, faecal samples from malnourished CRC patients were transplanted into C57BL/6J and DSS/AOM mouse models. Moreover, FACS and IHC were prepared to detect the infiltration of B cells and macrophages. qPCR and Elisa assays were performed to explore the expression of cytokines.RESULT: We found dramatic variation in the faecal microbiota among patients with different nutritional statuses, discovering that specific microbiota species, namely, Atopobium vaginae, Selenomonas sputigena and Faecalibacterium prausnitzii, may be considered diagnostic biomarkers in malnutrition and indicate poor prognosis. High expression level of A.vaginae in CRC tissues revealed the poorer overall survival compared with low expression level (Mean survival: 23.0 months vs 29.0 months). Faecal from malnourished colorectal cancer were found to be protumorigenic. More importantly, our evidence suggests that after faecal microbiota transplantation, B cells and macrophages are recruited to activate specific tumour immunity in CRC. Depletion of B cells significantly suppressed faecal microbiota-induced M2b polarization as well as the protumorigenic activity of tumour-associated macrophages invivo.CONCLUSION: Faecal microbiota in CRC under malnutrition conditions exhibits specific characteristics that accelerate CRC progression and regulate B cells and macrophages. The use of specific faecal microbial species could be a feasible approach for identifying the malnutrition status of patients and demonstrating the poor prognosis of CRC.

  View details for DOI 10.1016/j.clnu.2022.01.001

  View details for PubMedID 35124471

• (-)-Epicatechin and the comorbidities of obesity. Archives of biochemistry and biophysics Cremonini, E., Iglesias, D. E., Kang, J., Lombardo, G. E., Mostofinejad, Z., Wang, Z., Zhu, W., Oteiza, P. I. 2020; 690: 108505

  Abstract

  Obesity has major adverse consequences on human health contributing to the development of, among others, insulin resistance and type 2 diabetes, cardiovascular disease, non-alcoholic fatty liver disease, altered behavior and cognition, and cancer. Changes in dietary habits and lifestyle could contribute to mitigate the development and/or progression of these pathologies. This review will discuss current evidence on the beneficial actions of the flavan-3-ol (-)-epicatechin (EC) on obesity-associated comorbidities. These benefits can be in part explained through EC's capacity to mitigate several common events underlying the development of these pathologies, including: i) high circulating levels of glucose, lipids and endotoxins; ii) chronic systemic inflammation; iii) tissue endoplasmic reticulum and oxidative stress; iv) insulin resistance; v) mitochondria dysfunction and vi) dysbiosis. The currently known underlying mechanisms and cellular targets of EC's beneficial effects are discussed. While, there is limited evidence from human studies supplementing with pure EC, other studies involving cocoa supplementation in humans, pure EC in rodents and in vitro studies, support a potential beneficial action of EC on obesity-associated comorbidities. This evidence also stresses the need of further research in the field, which would contribute to the development of human dietary strategies to mitigate the adverse consequences of obesity.

  View details for DOI 10.1016/j.abb.2020.108505

  View details for PubMedID 32679195

• (-)-Epicatechin mitigates high fat diet-induced neuroinflammation and altered behavior in mice. Food & function Kang, J., Wang, Z., Oteiza, P. I. 2020; 11 (6): 5065-5076

  Abstract

  Obesity is characterized by a condition of low-level chronic inflammation that can lead to altered cognition and behavior. The flavanol (-)-epicatechin (EC) has been shown to have anti-inflammatory actions in mouse models of diet-induced obesity. This study investigated the capacity of dietary EC to mitigate hippocampal inflammation and impaired memory in high fat diet (HFD)-fed mice. Healthy 6 weeks old male C57BL/6J mice (10 mice per group) were fed for 13 weeks either: a control diet (10% total calories from fat), a high fat diet (60% total calories from fat), or the control and high fat diets supplemented with 20 mg EC per kg body weight. Short-term object recognition memory was evaluated by the novel object recognition (NOR) task and spatial memory by the object location memory (OLM) task and the Morris water maze (MWM). After 13 weeks on the dietary treatments, HFD-fed mice developed obesity, which was not affected by EC supplementation. HFD consumption caused metabolic endotoxemia, and increases in parameters of hippocampal inflammation, i.e. mRNA levels of TLR4, Iba-1, and NOX4. All these changes were mitigated by EC supplementation. EC supplementation also significantly improved recognition memory in HFD-fed mice while neither HFD consumption nor EC supplementation affected mouse spatial memory. Overall, EC supplementation prevented short-term recognition memory impairment in HFD-induced obese mice, which could be in part due to the capacity of EC to mitigate metabolic endotoxemia and associated hippocampal inflammation and oxidative stress.

  View details for DOI 10.1039/d0fo00486c

  View details for PubMedID 32432285

• (-)-Epicatechin and NADPH oxidase inhibitors prevent bile acid-induced Caco-2 monolayer permeabilization through ERK1/2 modulation. Redox biology Wang, Z., Litterio, M. C., Müller, M., Vauzour, D., Oteiza, P. I. 2020; 28: 101360

  Abstract

  Secondary bile acids promote gastrointestinal (GI) tract permeabilization both in vivo and in vitro. Consumption of high fat diets increases bile acid levels in the GI tract which can contribute to intestinal permeabilization and consequent local and systemic inflammation. This work investigated the mechanisms involved in bile acid (deoxycholic acid (DCA))-induced intestinal epithelial cell monolayer permeabilization and the preventive capacity of (-)-epicatechin (EC). While EC prevented high fat diet-induced intestinal permeabilization in mice, it did not mitigate the associated increase in fecal/cecal total and individual bile acids. In vitro, using differentiated Caco-2 cells as a model of epithelial barrier, EC and other NADPH oxidase inhibitors (VAS-2870 and apocynin) mitigated DCA-induced Caco-2 monolayer permeabilization. While EC inhibited DCA-mediated increase in cell oxidants, it did not prevent DCA-induced mitochondrial oxidant production. Prevention of DCA-induced ERK1/2 activation with EC, VAS-2870, apocynin and the MEK inhibitor U0126, also prevented monolayer permeabilization, stressing the key involvement of ERK1/2 in this process and its redox regulation. Downstream, DCA promoted myosin light chain (MLC) phosphorylation which was related to MLC phosphatase (MLCP) inhibition by ERK1/2. DCA also decreased the levels of the tight junction proteins ZO-1 and occludin, which can be related to MMP-2 activation and consequent ZO-1 and occludin degradation. Both events were prevented by EC, NADPH oxidase and ERK1/2 inhibitors. Thus, DCA-induced Caco-2 monolayer permeabilization occurs mainly secondary to a redox-regulated ERK1/2 activation and downstream disruption of TJ structure and dynamic. EC's capacity to mitigate in vivo the gastrointestinal permeabilization caused by consumption of high-fat diets can be in part related to its capacity to inhibit bile-induced NADPH oxidase and ERK1/2 activation.

  View details for DOI 10.1016/j.redox.2019.101360

  View details for PubMedID 31677553

  View details for PubMedCentralID PMC6920094

• (-)-Epicatechin protects the intestinal barrier from high fat diet-induced permeabilization: Implications for steatosis and insulin resistance. Redox biology Cremonini, E., Wang, Z., Bettaieb, A., Adamo, A. M., Daveri, E., Mills, D. A., Kalanetra, K. M., Haj, F. G., Karakas, S., Oteiza, P. I. 2018; 14: 588-599

  Abstract

  Increased permeability of the intestinal barrier is proposed as an underlying factor for obesity-associated pathologies. Consumption of high fat diets (HFD) is associated with increased intestinal permeabilization and increased paracellular transport of endotoxins which can promote steatosis and insulin resistance. This study investigated whether dietary (-)-epicatechin (EC) supplementation can protect the intestinal barrier against HFD-induced permeabilization and endotoxemia, and mitigate liver damage and insulin resistance. Mechanisms leading to loss of integrity and function of the tight junction (TJ) were characterized. Consumption of a HFD for 15 weeks caused obesity, steatosis, and insulin resistance in male C57BL/6J mice. This was associated with increased intestinal permeability, decreased expression of ileal TJ proteins, and endotoxemia. Supplementation with EC (2-20mg/kg body weight) mitigated all these adverse effects. EC acted modulating cell signals and the gut hormone GLP-2, which are central to the regulation of intestinal permeability. Thus, EC prevented HFD-induced ileum NOX1/NOX4 upregulation, protein oxidation, and the activation of the redox-sensitive NF-κB and ERK1/2 pathways. Supporting NADPH oxidase as a target of EC actions, in Caco-2 cells EC and apocynin inhibited tumor necrosis alpha (TNFα)-induced NOX1/NOX4 overexpression, protein oxidation and monolayer permeabilization. Together, our findings demonstrate protective effects of EC against HFD-induced increased intestinal permeability and endotoxemia. This can in part underlie EC capacity to prevent steatosis and insulin resistance occurring as a consequence of HFD consumption.

  View details for DOI 10.1016/j.redox.2017.11.002

  View details for PubMedID 29154190

  View details for PubMedCentralID PMC5691220