Effects of Long-Term Pioglitazone Treatment on Peripheral and Central Markers of Aging

Blalock, Eric M.; Phelps, Jeremiah T.; Pancani, Tristano; Searcy, James L.; Anderson, Katie L.; Gant, John C.; Popović, Jelena; Avdiushko, Margarita; Cohen, Don A.; Chen, Kuey Chu; Porter, Nada M.; Thibault, Olivier

doi:10.1371/journal.pone.0010405

Cited by 48 publications

(48 citation statements)

References 128 publications

(176 reference statements)

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“…Consistent with clinical results, we observed that pioglitazone significantly increased the body weights of db/db mice, while G004 and glimepiride showed no difference (Desouza et al 2007;Blalock et al 2010).…”

Section: Discussionsupporting

confidence: 89%

Reno-protection of G004, a novel anti-diabetic sulfonylurea in db/db mice

Tong

Amadi

et al. 2015

Naunyn-Schmiedeberg's Arch Pharmacol

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1-[4-[2-(4-Bromobenzene-sulfonamino)ethyl]phenylsulfonyl]-3-(trans-4-methylcyclohexyl) urea (G004, CAS865483-06-3) is a synthetic sulfonylurea, incorporating the hypoglycemic active structure of glimepiride (CAS 93479-97-1) and anti-TXA2 receptor (TP) active structure of BM-531(CAS 284464-46-6). In this study, we evaluated the effect of G004 on hyperglycemia and dyslipidemia as well as diabetic nephropathy (DN) in db/db mice by gavage over 90 consecutive days of treatment. The fasting blood glucose (FBG), glucose, and insulin tolerance as well as dyslipidemia were effectively ameliorated in db/db mice treated with G004. Interestingly, renal histological results of db/db mice revealed that G004 markedly reversed the expansion of mesangial extracellular matrix (ECM), the early hallmark of DN. Indeed, G004 treatment downregulated the renal expressions of type 4 collagen (Col IV) and transforming growth factor-β1 (TGF-β1) in db/db mice. In addition, imbalance in expressions of matrix metalloproteinase-9 (MMP-9) and its tissue inhibitor-1 (TIMP-1) in db/db mice kidneys was observed. However, G004 increased and decreased the expressions of MMP-9 and TIMP-1, respectively. It is well known that TGF-β pathway signaling plays an essential role in hyperglycemia-induced cell protein synthesis. On the other hand, MMP/TIMP system is responsible for the breakdown and turnover of ECM. Thus, we speculate that G004 possibly attenuated ECM accumulation via remodeling the synthesis and degradation of ECM component Col IV through modulation in TGF-β1 and MMP-9/TIMP-1 expressions in kidneys of db/db mice. Results from this study provide a strong rationale for G004 to be an efficient glucose-controlling agent with significant reno-protective properties.

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Section: Discussionsupporting

confidence: 89%

Reno-protection of G004, a novel anti-diabetic sulfonylurea in db/db mice

Tong

Amadi

et al. 2015

Naunyn-Schmiedeberg's Arch Pharmacol

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“…MWM procedures were similar to the procedures previously described (96). Briefly, animals were trained to find a submerged platform in a pool of water (days 1-3).…”

Section: Methodsmentioning

confidence: 99%

“…1). Hippocampal slices were obtained, and LTP was recorded as previously described (96). I/O relationships were examined by recording fEPSPs in the CA1 region resulting from stimuli of increasing intensity.…”

Section: Methodsmentioning

confidence: 99%

Vitamin D prevents cognitive decline and enhances hippocampal synaptic function in aging rats

Latimer¹,

Brewer²,

Searcy³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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180

103

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Vitamin D is an important calcium-regulating hormone with diverse functions in numerous tissues, including the brain. Increasing evidence suggests that vitamin D may play a role in maintaining cognitive function and that vitamin D deficiency may accelerate agerelated cognitive decline. Using aging rodents, we attempted to model the range of human serum vitamin D levels, from deficient to sufficient, to test whether vitamin D could preserve or improve cognitive function with aging. For 5-6 mo, middle-aged F344 rats were fed diets containing low, medium (typical amount), or high (100, 1,000, or 10,000 international units/kg diet, respectively) vitamin D3, and hippocampal-dependent learning and memory were then tested in the Morris water maze. Rats on high vitamin D achieved the highest blood levels (in the sufficient range) and significantly outperformed low and medium groups on maze reversal, a particularly challenging task that detects more subtle changes in memory. In addition to calcium-related processes, hippocampal gene expression microarrays identified pathways pertaining to synaptic transmission, cell communication, and G protein function as being up-regulated with high vitamin D. Basal synaptic transmission also was enhanced, corroborating observed effects on gene expression and learning and memory. Our studies demonstrate a causal relationship between vitamin D status and cognitive function, and they suggest that vitamin D-mediated changes in hippocampal gene expression may improve the likelihood of successful brain aging.V itamin D, a secosteroid hormone known for its role in bone and calcium homeostasis, is now well recognized for its many diverse functions and actions on a variety of tissues and cell types (1, 2). Vitamin D typically refers to the precursor forms of the hormone obtained through the skin's exposure to sunlight [vitamin D3 (VitD3)] or from dietary sources (VitD3 or VitD2). A metabolite of vitamin D, 25-hydroxyvitamin D (25OHD), is a serum biomarker of vitamin D status or repletion. In recent years, there is particular concern that large segments of the population may have low levels of 25OHD, and therefore are vitamin D-deficient (3). Due to factors such as reduced intake, absorption, and decreased exposure to sunlight, aging adults (≥50 y of age) are especially susceptible (3-6). Notably, this predisposition for lower 25OHD levels in the elderly has been linked to higher risk for numerous age-related disorders, including cancer and metabolic and vascular diseases (7-10).Inadequate vitamin D status also correlates with a greater risk for cognitive decline in the elderly (4,(11)(12)(13)(14)(15), suggesting that optimal levels may promote healthy brain aging (16,17). Because the brain expresses vitamin D receptors (VDRs) and can synthesize the active form of the hormone, the possible cognitive enhancing effects of vitamin D may reflect a primary action in the brain rather than a result of secondary systemic effects (18)(19)(20)(21)(22). Indeed, we and others have shown that vitamin D, as ...

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“…Frozen samples were thawed immediately before analysis and then maintained on ice throughout the assay setup. Briefly, according to procedures recommended by the manufacturers and previously described (Blalock et al 2010), all plasma samples were diluted 1:5 in sample diluent and then incubated in duplicate overnight with capture beads specific to TNF-a,IL-6 and IL-10. The beads were subsequently washed and incubated for 2 h with a biotin-conjugated detection antibody and then for 30 min with streptavidin-phycoerythrin.…”

Section: Cardiac Hemodynamic Assessmentmentioning

confidence: 99%