Chad Hancock | Brigham Young University (original) (raw)

Papers by Chad Hancock

In periodontitis, there is a disruption in the homeostasis of the oral microbiome by peridontopat... more In periodontitis, there is a disruption in the homeostasis of the oral microbiome by peridontopathogenic bacteria. However, while bacteria is essential for periodontitis to occur, the severity, pattern and progression of the disease is not solely determined by the microbial burden, and in fact has a lot to do with the overwhelming host inflammatory response. The response can vary even in two individuals with similar periodontopathogenic profiles. The host response leads to extracellular matrix (ECM) destruction, loss of attachment, alveolar bone resorption and eventually, edentulism. The host's reaction is orchestrated by proinflammatory cytokines and chemokines and matrix metalloproteinases (MMPs). MMPs are proteolytic enzymes capable of degrading collagen fibers from the extracellular matrix and are the main responsible for tissue damage and gingival recession in periodontitis. As a response to the limitations of the traditional therapies, new agents have been used in preclinical and clinical studies, namely host-modulatory agents, including anti-proteinase agents, anti-inflammatory agents and anti-resorptive agents. Focusing on changing the inflammatory process, as opposed to the microbial insult, can slow down the disease progression, improve clinical outcomes and even prevent tooth loss in severely compromised patients. This work examines the role of pro-inflammatory markers homocysteine in chronic inflammation and periodontitis. Homocysteine (Hcy) is a non-protein amino acid derived from the metabolism of the essential amino acid methionine via methyl group metabolism. Controlling Homocysteine as a potential inductor of MMPs, and hence of tissue destruction, can lead to new adjuvant therapies to improve clinical outcomes and prevent activation of the disease

AMP-activated protein kinase (AMPK), a metabolic regulator, acts in opposition to many of the eff... more AMP-activated protein kinase (AMPK), a metabolic regulator, acts in opposition to many of the effects of aging and may provide insights into the development of sarcopenia. However, the effect of aging on AMPK activation is unclear. The purpose of this dissertation was to: 1) clarify the controversy concerning the activation of AMPK in response to endurance-like exercise in aged skeletal muscle; 2) address mechanisms for the age-associated alterations in AMPK activation; and 3) address the known benefits of chronic AICAR treatment in aged skeletal muscle. First, to clarify the effect of age on AMPK activation, young adult (YA) (8 mo.) and old (O) (30 mo.) male Fischer 344 x Brown Norway F1 hybrid rats received an in situ bout of endurance-type contractions produced via electrical stimulation of the sciatic nerve (STIM). AMPK activation was attenuated in aging muscle as demonstrated by decreased AMPKα phosphorylation and AMPKα2 protein content and activity in O vs. YA muscle after STI...

The thesis of Jacob D. Brown is acceptable in its final form including (1) its format, citations,... more The thesis of Jacob D. Brown is acceptable in its final form including (1) its format, citations, and bibliographical style are consistent and acceptable and fulfill university and department style requirements; (2) its illustrative materials including figures, tables, and charts are in place; and (3) the final manuscript is satisfactory and ready for submission. The Liver Kinase B1 (LKB1)/AMP-Activated Protein Kinase (AMPK) signaling pathway is a major regulator of skeletal muscle metabolic processes. During exercise, LKB1-mediated phosphorylation of AMPK leads to its activation, promoting mitochondrial biogenesis and glucose transport, among other effects. The roles of LKB1 and AMPK have not been fully characterized in the diaphragm. Two methods of AMPK activation were used to characterize LKB1/AMPK signaling in diaphragms from muscle-specific LKB1 knockout (KO) and littermate control (C) mice: (1) acute injection of 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) and (2) 5-...

Overexpression of HDAC1 Induces Functional β-cell Mass Type 2 diabetes is a metabolic disorder th... more Overexpression of HDAC1 Induces Functional β-cell Mass Type 2 diabetes is a metabolic disorder that results in β-cell dysfunction and ultimate destruction, and leads to impaired glucose homeostasis. High rates of proliferation and differentiation of pancreatic β-cells occurs mostly during neonatal development. However, research shows these mechanisms remain intact as β-cell proliferation has been observed during pregnancy and obesity. We have shown that overexpression of the β-cell transcription factor Nkx6.1 is sufficient to induce β-cell proliferation. Exploration of the transcriptional targets of Nkx6.1 has identified histone deacetylase 1 (HDAC1) as a downstream target of Nkx6.1. Here we demonstrate that HDAC1 overexpression is sufficient to induce β-cell proliferation, enhance β-cell survival upon exposure to apoptotic stimuli and maintains glucose stimulated insulin secretion (GSIS). Our data suggests overexpression of HDAC1 leads to p15/INK4b suppression, a cell cycle inhibit...

induces an increase in glucose transport in muscle. As the acute increase in glucose transport re... more induces an increase in glucose transport in muscle. As the acute increase in glucose transport reverses, it is replaced by an increase in insulin sensitivity. Interleukin-6 (IL-6) increases with exercise and has been reported to activate AMP-activated protein kinase (AMPK). Based on this information, we hypothesized that IL-6 would result in an increase in muscle insulin sensitivity. Rat epitrochlearis and soleus muscles were incubated with 120 ng/ml IL-6. Exposure to IL-6 induced a modest acute increase in glucose transport and was fol-lowed 3.5 h later by an increase in insulin sensitivity in epitrochlearis but not soleus muscles. IL-6 also brought about an increase in AMPK phosphorylation in epitrochlearis muscles. We conclude that exposure of fast-twitch muscle to 120 ng/ml IL-6 increases insulin sensitivity by activating AMPK. However, exposure of epitrochlearis muscles to 10 ng/ml IL-6, a concentration 100-fold higher than that attained in plasma during exercise, had no effect...

The FASEB Journal, 2014

Recent work has linked increased circulating iron and cellular iron status with insulin resistanc... more Recent work has linked increased circulating iron and cellular iron status with insulin resistance and type 2 diabetes. An increase in cellular iron is also associated with chronic inflammation. To further explore this association we examined free iron, and proteins important for cellular iron management, in liver tissue from Zucker Diabetic Fatty (ZDF) rats and ZDF rats treated with Rosiglitazone (ZDF ROSI). Rosiglitazone (ROSI) is known to improve insulin sensitivity and has recently been shown to reduce certain inflammatory signals. We hypothesized that ROSI treatment of ZDF rats would cause a reduction in free iron and related changes in proteins involved in cellular iron regulation. Six week old ZDF rats were fed ad libitum a chow diet or a chow diet with 100 mg of ROSI/kg of diet for 6 weeks. The free iron concentration in liver tissue was reduced by 26% ± 4% (p=0.02) in response to ROSI treatment compared to ZDF controls. Ferritin protein levels in ZDF ROSI were significantly...

International Journal of Molecular Sciences

Though effective in treating various types of cancer, the chemotherapeutic doxorubicin (DOX) is a... more Though effective in treating various types of cancer, the chemotherapeutic doxorubicin (DOX) is associated with skeletal muscle wasting and fatigue. The purpose of this study was to assess muscle function in situ following DOX administration in mice. Furthermore, pre-treatments with exercise (EX) or metformin (MET) were used in an attempt to preserve muscle function following DOX. Mice were assigned to the following groups: control, DOX, DOX + EX, or DOX + MET, and were given a single injection of DOX (15 mg/kg) or saline 3 days prior to sacrifice. Preceding the DOX injection, DOX + EX mice performed 60 min/day of running for 5 days, while DOX + MET mice received 5 daily oral doses of 500 mg/kg MET. Gastrocnemius–plantaris–soleus complex function was assessed in situ via direct stimulation of the sciatic nerve. DOX treatment increased time to half-relaxation following contractions, indicating impaired recovery (p < 0.05). Interestingly, EX prevented any increase in half-relaxatio...

American Journal of Physiology-Endocrinology and Metabolism

Doxorubicin (DOX) is an effective chemotherapeutic treatment with lasting side effects in heart a... more Doxorubicin (DOX) is an effective chemotherapeutic treatment with lasting side effects in heart and skeletal muscle. DOX is known to bind with iron, contributing to oxidative damage resulting in cardiac and skeletal muscle toxicity. However, major cellular changes to iron regulation in response to DOX are poorly understood in liver, heart, and skeletal muscle. Additionally, two cotreatments, exercise (EX) and metformin (MET), were studied for their effectiveness in reducing DOX toxicity by ameliorating iron dysregulation and preventing oxidative stress. The purposes of this study were to 1) characterize the DOX-induced changes of the major iron regulation pathway in liver, heart, and skeletal muscle and 2) to determine whether EX and MET exert their benefits by minimizing DOX-induced iron dysregulation. Mice were assigned to receive saline or DOX (15 mg/kg) treatments, paired with either EX (5 days) or MET (500 mg/kg), and were euthanized 3 days after DOX treatment. Results suggest ...

The Faseb Journal, Apr 1, 2014

Obesity is associated with increased risk of developing insulin resistance, inflammation, heart d... more Obesity is associated with increased risk of developing insulin resistance, inflammation, heart disease, and cancer. The accumulation of fat can be influenced by a variety of factors, including diet and activity. There is evidence that soy isoflavones may prevent fat gain by increasing thermogenesis. We hypothesized that rats fed a high isoflavone (HIF) diet would have decreased fat accumulation and improved basal glucose tolerance compared to animals fed a low isoflavone (LIF) control diet. Male Wistar rats were fed a low isoflavone control diet (LIF) diet for 72 days. Intraperitoneal glucose tolerance tests were performed, and body fat percentage was determined via Dual-energy X-ray absorptiometry (DXA). There were no differences in body weight (p=0.125), body fat percentage (p=0.218), fat pad weight as a percentage of body weight, or glucose tolerance area under the curve (AUC) (p=0.401). These findings suggest that the effects of an HIF diet may be strain-dependent. Moreover, a metabolic challenge suc...

American journal of physiology. Endocrinology and metabolism, Jan 24, 2016

Iβ-cell insulin secretion is dependent on proper mitochondrial function. Various studies have cle... more Iβ-cell insulin secretion is dependent on proper mitochondrial function. Various studies have clearly shown that the Nr4a family of orphan nuclear receptors is essential for fuel utilization and mitochondrial function in liver, muscle and adipose. We have previously demonstrated that overexpression of Nr4a1 or Nr4a3 is sufficient to induce proliferation of pancreatic β-cells. In this study we examined whether Nr4a expression impacts pancreatic β-cell mitochondrial function. Here we show that β-cell mitochondrial respiration is dependent on the nuclear receptors Nr4a1 and Nr4a3. Mitochondrial respiration in permeabilized cells was significantly decreased in β-cells lacking Nr4a1 or Nr4a3. Furthermore, respiration rates of intact cells deficient for Nr4a1 or Nr4a3 in the presence of 16mM glucose resulted in decreased glucose mediated oxygen consumption. Consistent with this reduction in respiration, a significant decrease in glucose stimulated insulin secretion rates is observed with ...

The Faseb Journal, Mar 1, 2008

Journal of applied physiology (Bethesda, Md. : 1985), Jan 21, 2016

Skeletal muscle specific liver kinase B1 (LKB1) knockout mice (skmLKB1-KO) exhibit elevated mitog... more Skeletal muscle specific liver kinase B1 (LKB1) knockout mice (skmLKB1-KO) exhibit elevated mitogen-activated protein kinase (MAPK) signaling after treadmill running. MAPK activation is also associated with inflammation-related signaling in skeletal muscle. Since exercise can induce muscle damage, and inflammation is a response triggered by damaged tissue, we therefore hypothesized that LKB1 plays an important role in dampening the inflammatory response to muscle contraction, and that this may be due in part to increased susceptibility to muscle damage with contractions in LKB1-deficient muscle. Here we studied the inflammatory response and muscle damage with in situ muscle contraction or downhill running. After in situ muscle contractions, the phosphorylation of both NF-κB and STAT3 was increased more in skmLKB1-KO vs. WT muscles. Analysis of gene expression via microarray and RT-PCR show that expression of many inflammation-related genes increased after contraction only in skmLKB1...

The Faseb Journal, Apr 1, 2010

BioMed Research International, 2013

Journal of Nutrition, 2011

The effects of supplemental Se in rodent models may depend upon composition of the basal diet to ... more The effects of supplemental Se in rodent models may depend upon composition of the basal diet to which it is added. Wild-type male littermates of Transgenic Adenocarcinoma of Mouse Prostate mice were fed until 18 wk of age 1 of 2 Seadequate stock diets high in soy (HS) or low in phytoestrogens (LP) or the same diets supplemented with 3.0 mg Se/kg diet as seleno-methylselenocysteine. Body and abdominal fat pad weights were lower (P , 0.01) in mice fed the HS diet. Supplemental Se reduced fat pad weights in mice receiving the LP diet but increased body and fat pad weights in mice consuming the HS formulation (P-interaction , 0.005). Serum free triiodothyronine concentrations were unaffected by supplemental Se in mice fed the LP diet but were decreased by Se supplementation of mice given the HS feed (Pinteraction , 0.02). Free thyroxine concentrations were higher in mice consuming the HS diet regardless of Se intake (P , 0.001). Hepatic mRNA for iodothyronine deiodinase I was lower (P , 0.001) in mice fed the HS diet. Supplementation of Se increased this mRNA (P , 0.001) in both diet groups. Results from this study show a significant interaction between the composition of basal diets and the effects of supplemental Se with respect to body composition. These findings have important implications for future studies in rodent models of the effects of supplemental Se on heart disease, cancer, diabetes, and other conditions related to body weight and composition.

The FASEB Journal, 2011

It has been reported that 30% calorie restriction (CR) for 3 mo results in large increases in mit... more It has been reported that 30% calorie restriction (CR) for 3 mo results in large increases in mitochondrial biogenesis in heart, brain, liver, and adipose tissue, with concomitant increases in respiration and ATP synthesis. We found these results surprising, and performed this study to determine whether 30% CR does induce an increase in mitochondria in heart, brain, liver, adipose tissue, and/or skeletal muscle. To this end, we measured the levels of a range of mitochondrial proteins, and mRNAs. With the exception of long-chain acyl-CoA dehydrogenase protein level, which was increased ∼60% in adipose tissue, none of the mitochondrial proteins or mRNAs that we measured were increased in rats subjected to 30% CR for 14 wk. There was also no increase in citrate synthase activity. Because it is not possible to have an increase in mitochondria without any increase in key mitochondrial proteins, we conclude that 30% CR does not induce an increase in mitochondria in heart, brain, liver, adipose tissue, or skeletal muscle in laboratory rodents.

PLoS ONE, 2011

Background: It has been proposed that muscle insulin resistance in type 2 diabetes is due to a se... more Background: It has been proposed that muscle insulin resistance in type 2 diabetes is due to a selective decrease in the components of the mitochondrial electron transport chain and results from accumulation of toxic products of incomplete fat oxidation. The purpose of the present study was to test this hypothesis. Methodology/Principal Findings: Rats were made severely iron deficient, by means of an iron-deficient diet. Iron deficiency results in decreases of the iron containing mitochondrial respiratory chain proteins without affecting the enzymes of the fatty acid oxidation pathway. Insulin resistance was induced by feeding iron-deficient and control rats a high fat diet. Skeletal muscle insulin resistance was evaluated by measuring glucose transport activity in soleus muscle strips. Mitochondrial proteins were measured by Western blot. Iron deficiency resulted in a decrease in expression of iron containing proteins of the mitochondrial respiratory chain in muscle. Citrate synthase, a non-iron containing citrate cycle enzyme, and long chain acyl-CoA dehydrogenase (LCAD), used as a marker for the fatty acid oxidation pathway, were unaffected by the iron deficiency. Oleate oxidation by muscle homogenates was increased by high fat feeding and decreased by iron deficiency despite high fat feeding. The high fat diet caused severe insulin resistance of muscle glucose transport. Iron deficiency completely protected against the high fat diet-induced muscle insulin resistance. Conclusions/Significance: The results of the study argue against the hypothesis that a deficiency of the electron transport chain (ETC), and imbalance between the ETC and b-oxidation pathways, causes muscle insulin resistance.