Browsing by Author "Jia, Zhenquan"

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    Dietary Anti-Aging Polyphenols and Potential Mechanisms
    Luo, Jing; Si, Hongwei; Jia, Zhenquan; Liu, Dongmin (MDPI, 2021-02-13)
    For years, the consumption of a diet rich in fruits and vegetables has been considered healthy, increasing longevity, and decreasing morbidities. With the assistance of basic research investigating the potential mechanisms, it has become clear that the beneficial effects of plant-based foods are mainly due to the large amount of bioactive phenolic compounds contained. Indeed, substantial dietary intervention studies in humans have supported that the supplementation of polyphenols have various health-promoting effects, especially in the elderly population. In vitro examinations on the anti-aging mechanisms of polyphenols have been widely performed, using different types of natural and synthetic phenolic compounds. The aim of this review is to critically evaluate the experimental evidence demonstrating the beneficial effects of polyphenols on aging-related diseases. We highlight the potential anti-aging mechanisms of polyphenols, including antioxidant signaling, preventing cellular senescence, targeting microRNA, influencing NO bioavailability, and promoting mitochondrial function. While the trends on utilizing polyphenols in preventing aging-related disorders are getting growing attention, we suggest the exploration of the beneficial effects of the combination of multiple polyphenols or polyphenol-rich foods, as this would be more physiologically relevant to daily life.
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    Genistein Induces Pancreatic beta-Cell Proliferation through Activation of Multiple Signaling Pathways and Prevents Insulin-Deficient Diabetes in Mice
    Fu, Zhuo; Zhang, Wen; Zhen, Wei; Lum, Hazel; Nadler, Jerry; Bassaganya-Riera, Josep; Jia, Zhenquan; Wang, Yanwen; Misra, Hara P.; Liu, Dongmin (Endocrine Society, 2010-07)
    Genistein, a flavonoid in legumes and some herbal medicines, has various biological actions. However, studies on whether genistein has an effect on pancreatic beta-cell function are very limited. In the present study, we investigated the effect of genistein on beta-cell proliferation and cellular signaling related to this effect and further determined its antidiabetic potential in insulin-deficient diabetic mice. Genistein induced both INS1 and human islet beta-cell proliferation after 24 h of incubation, with 5 mu M genistein inducing a maximal 27% increase. The effect of genistein on beta-cell proliferation was neither dependent on estrogen receptors nor shared by 17 beta-estradiol or a host of structurally related flavonoid compounds. Pharmacological or molecular intervention of protein kinase A (PKA) or ERK1/2 completely abolished genistein-stimulated beta-cell proliferation, suggesting that both molecules are essential for genistein action. Consistent with its effect on cell proliferation, genistein induced cAMP/PKA signaling and subsequent phosphorylation of ERK1/2 in both INS1 cells and human islets. Furthermore, genistein induced protein expression of cyclin D1, a major cell-cycle regulator essential for beta-cell growth. Dietary intake of genistein significantly improved hyperglycemia, glucose tolerance, and blood insulin levels in streptozotocin-induced diabetic mice, concomitant with improved islet beta-cell proliferation, survival, and mass. These results demonstrate that genistein may be a natural antidiabetic agent by directly modulating pancreatic beta-cell function via activation of the cAMP/PKA-dependent ERK1/2 signaling pathway. (Endocrinology 151: 3026-3037, 2010)
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    Natural Compound Resveratrol Attenuates TNF-Alpha-Induced Vascular Dysfunction in Mice and Human Endothelial Cells: The Involvement of the NF-κB Signaling Pathway
    Nallasamy, Palanisamy; Kang, Zi Yae; Sun, Xiaolun; Anandh Babu, Pon Velayutham; Liu, Dongmin; Jia, Zhenquan (MDPI, 2021-11-19)
    Resveratrol, a natural compound in grapes and red wine, has drawn attention due to potential cardiovascular-related health benefits. However, its effect on vascular inflammation at physiologically achievable concentrations is largely unknown. In this study, resveratrol in concentrations as low as 1 μm suppressed TNF-α-induced monocyte adhesion to human EA.hy926 endothelial cells (ECs), a key event in the initiation and development of atherosclerosis. Low concentrations of resveratrol (0.25–2 μm) also significantly attenuated TNF-α-stimulated mRNA expressions of MCP-1/CCL2 and ICAM-1, which are vital mediators of EC-monocyte adhesion molecules and cytokines for cardiovascular plaque formation. Additionally, resveratrol diminished TNF-α-induced IκB-α degradation and subsequent nuclear translocation of NF-κB p65 in ECs. In the animal study, resveratrol supplementation in diet significantly diminished TNF-α-induced increases in circulating levels of adhesion molecules and cytokines, monocyte adhesion to mouse aortic ECs, F4/80-positive macrophages and VCAM-1 expression in mice aortas and restored the disruption in aortic elastin fiber caused by TNF-α treatment. The animal study also confirmed that resveratrol blocks the activation of NF-κB In Vivo. In conclusion, resveratrol at physiologically achievable concentrations displayed protective effects against TNF-α-induced vascular endothelial inflammation in vitro and In Vivo. The ability of resveratrol in reducing inflammation may be associated with its role as a down-regulator of the NF-κB pathway.
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    Pesticides and Pesticide Mixtures Induce Neurotoxicity: Potentiation of Apoptosis and Oxidative Stress
    Jia, Zhenquan (Virginia Tech, 2006-07-07)
    Several epidemiological studies have suggested a role for environmental chemicals in the etiology of neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. Endosulfan (an organochlorine) and zineb (zinc-ethylene-bis-dithiocarbamate) are used as pesticides on a variety of crops worldwide and pose potential health risks to humans and animals. Both endosulfan and zineb are known to affect nervous system. Because the dopaminergic system continues to develop postnatally, we hypothesized that developmental exposure to endosulfan or zineb alone or in combination would result in alteration of nigrostrial neurotransmitters and would render the nigrostrial dopamine system more susceptible to chemical challenge later in life. The objectives of this study were (1) to determine the effects of endosulfan and zineb individually and in combination on dopaminergic or cholinergic pathways in vivo, (2) to investigate the effects of exposure to endosulfan, zineb and their mixtures administered in early life (during brain development) on subsequent exposure to these pesticides on the dopaminergic and cholinergic systems, in vivo, (3) to investigate the mechanism(s) of induction of neuronal cell death caused by these pesticides using human neuroblastoma SH-SY5Y cells in culture, (4) to define the role of oxidative stress in pesticide-induced neuronal cell death in vitro. Male C57Bl/6 mice of 7-9 months old exposed to zineb (50 and 100 mg/kg), endosulfan (1.55, 3.1 and 6.2 mg/kg) and their mixtures every other day over a 2-week period exhibited higher levels of dopamine accumulation in the striatum. Both pesticide-treated groups displayed significantly lower norepinephrine levels in the striatum (Ï ≤ 0.05) than the controls. The developmental exposure to zineb, endosulfan and their combination enhanced the vulnerability to subsequent neurotoxic challenges occurring later in life. Thus, C57BL/6 mice exposed to zineb, endosulfan and their mixtures as juveniles (postnatal days 5 to 19) and re-exposed at 8 months of age showed a significant depletion of striatal dopamine, to 22%, 16%, and 35% of control, respectively. Acetylcholinesterase activity in the cerebral cortex was found to be significantly increased in all pesticide treated groups. Mice given mixtures of pesticides also showed significantly increased levels of normal and aggregated alpha-synuclein, a hallmark of neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. The results of these studies indicate that exposure to these pesticides as neonates and re-exposure as adults could result in neurochemical changes that did not reveal at adulthood when the exposure was at juvenile age only. We further investigated the mechanism(s) of activation of pesticide-induced neuronal cell death in vitro. The characteristic of cell death in SH-SY5Y human neuroblastoma cells was examined. These cells are known to retain catecholaminergic phenotype. Cells were exposed to endosulfan, zineb and mixtures of two pesticides, in concentrations ranging from 50 μM to 400 μM. These exposures caused both apoptotic and necrotic cell death in SH-SY5Y cells as evaluated by lactate dehydrogenase release, 7-aminoactinomycin-D and Annexin-V/PI assays. Exposure to mixtures of the pesticides enhanced both the early apoptosis and late apoptosis/necrosis compared to either chemical alone. Visual evaluation using DNA ladder assay and fluorescence Annexin V/PI assay confirmed the contribution of both apoptotic and necrotic events. Furthermore, endosulfan and zineb alone and in combination altered the caspase-3 activity indicating that both pesticides exposure exert their apoptotic effect via the caspase-3 pathway. Because there has been increasing evidence of the role of reactive oxygen species (ROS) and oxidative stress in pesticide-induced neuronal cell death (apoptosis and necrosis), the levels of ROS and antioxidant enzymes were examined. Cells treated with pesticides were found to enhance the generation of superoxide anion and hydrogen peroxide both in a dose- and time-dependent manner. Mixture of pesticides significantly enhanced the production of these reactive oxygen species compared to cells exposed to individual pesticide. Cells treated with pesticides showed a decrease in superoxide dismutase, glutathione peroxidase, and catalase levels. These pesticides also induced lipid peroxides (thiobarbituric acid reactive products) formation in SH-SY5Y cells. Furthermore, cells exposed to these pesticides were found to have increased in the expression of NFkappaB activity in the nucleus. These data support the hypothesis that oxidative stress was induced in neuronal cells by exposing to these pesticides in vitro. Taken together, the results of this study support the above hypothesis and suggest that the cytotoxicity of endosulfan and zineb and their combinations may, at least in part, be associated with the generation of ROS. Furthermore, mice exposed at early age and re-exposed at adulthood become more susceptible to alteration of neurotransmitter levels compared to mice exposed to these pesticides only as juveniles. These findings could add to the growing body of knowledge on the mechanism of pesticide-induced dopaminergic neuronal cell death and could hold tremendous implication for the future understanding of the possible involvement of environmental risk factors in the pathogenesis of Parkinson's disease.
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    Small Molecule Kaempferol Promotes Insulin Sensitivity and Preserved Pancreatic β-Cell Mass in Middle-Aged Obese Diabetic Mice
    Alkhalidy, Hana; Moore, William B.; Zhang, Yanling; McMillan, Ryan P.; Wang, Aihua; Ali, Mostafa; Suh, Kyung-Shin; Zhen, Wei; Cheng, Zhiyong; Jia, Zhenquan; Hulver, Matthew W.; Liu, Dongmin (Hindawi, 2015-05-07)
    Insulin resistance and a progressive decline in functional β-cell mass are hallmarks of developing type 2 diabetes (T2D). Thus, searching for natural, low-cost compounds to target these two defects could be a promising strategy to prevent the pathogenesis of T2D. Here, we show that dietary intake of flavonol kaempferol (0.05% in the diet) significantly ameliorated hyperglycemia, hyperinsulinemia, and circulating lipid profile, which were associated with the improved peripheral insulin sensitivity in middle-aged obese mice fed a high-fat (HF) diet. Kaempferol treatment reversed HF diet impaired glucose transport-4 (Glut4) and AMP-dependent protein kinase (AMPK) expression in both muscle and adipose tissues from obese mice. In vitro, kaempferol increased lipolysis and prevented high fatty acid-impaired glucose uptake, glycogen synthesis, AMPK activity, and Glut4 expression in skeletal muscle cells. Using another mouse model of T2D generated by HF diet feeding and low doses of streptozotocin injection, we found that kaempferol treatment significantly improved hyperglycemia, glucose tolerance, and blood insulin levels in obese diabetic mice, which are associated with the improved islet β-cell mass. These results demonstrate that kaempferol may be a naturally occurring anti-diabetic agent by improving peripheral insulin sensitivity and protecting against pancreatic β-cell dysfunction.
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    Sulforaphane Ameliorates High-Fat-Diet-Induced Metabolic Abnormalities in Young and Middle-Aged Obese Male Mice
    Luo, Jing; Alkhalidy, Hana; Jia, Zhenquan; Liu, Dongmin (MDPI, 2024-03-29)
    Type 2 diabetes (T2D) is still a fast-growing health problem globally. It is evident that chronic insulin resistance (IR) and progressive loss of β-cell mass and function are key features of T2D etiology. Obesity is a leading pathogenic factor for developing IR. The aim of the present study was to determine whether sulforaphane (SFN), a natural compound derived from cruciferous vegetables, can prevent (prevention approach) or treat (treatment approach) obesity and IR in mouse models. We show that dietary intake of SFN (0.5 g/kg of HFD) for 20 weeks suppressed high-fat diet (HFD)-induced fat accumulation by 6.04% and improved insulin sensitivity by 23.66% in young male mice. Similarly, dietary provision of SFN (0.25 g/kg) significantly improved blood lipid profile, glucose tolerance, and insulin sensitivity of the middle-aged male mice while it had little effects on body composition as compared with the HFD group. In the treatment study, oral administration of SFN (40 mg/kg) induced weight loss and improved insulin sensitivity and plasma lipid profile in the diet-induced-obesity (DIO) male mice. In all three studies, the metabolic effects of SFN administration were not associated with changes in food intake. In vitro, SFN increased glucose uptake in C2C12 myotubes and increased fatty acid and pyruvate oxidation in primary human skeletal muscle cells. Our results suggest that SFN may be a naturally occurring insulin-sensitizing agent that is capable of improving the metabolic processes in HFD-induced obesity and IR and thereby may be a promising compound for T2D prevention.