Browsing by Subject "Inflammation"

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An apoptotic body-inspired nanoparticle to modulate inflammatory macrophages
(2021-03-15) Kraynak, Chelsea Amanda; Suggs, Laura J.; Baker, Aaron; Cui, Zhengrong; Farrar, Roger
Chronic inflammation is a significant pathological process found in a range of disease states. Treatments to reduce inflammation in this family of diseases may improve symptoms and disease progression, but are largely limited by variable response rates, cost, and off-target effects. Macrophages are implicated in many inflammatory diseases for their critical role in the maintenance and resolution of inflammation. Macrophages exhibit significant plasticity to direct the inflammatory response by taking on an array of pro- and anti-inflammatory phenotypes based on extracellular cues. One robust anti-inflammatory physiologic cue is the engulfment of apoptotic cells. In this work, we have developed a nanoparticle to target and reduce macrophage-mediated inflammation by mimicking the anti-inflammatory effect of apoptotic cell engulfment. The nanoparticle, comprised of a poly(lactide-co-glycolide) core, is coated in phosphatidylserine (PS)-supplemented cell plasma membrane to emulate key characteristics of the apoptotic cell surface. We demonstrate that this particle can reduce the production of pro-inflammatory cytokines and drive an anti-inflammatory phenotype shift without the use of small molecules or other drugs. We additionally functionalized the particle surface with an acid-sensitive polyethylene glycol (PEG) moiety to increase the delivery of our particles to sites of chronic inflammation in a mouse model. Particles are preferentially taken up by macrophages at the site of inflammation to promote an anti-inflammatory phenotype shift. The development of a nanoparticle to drive this pro-to-anti-inflammatory macrophage phenotype transition, through the use of a physiologic anti-inflammatory pathway, illustrates a new potential strategy in the design of therapeutics for chronic inflammation.
Central adiposity and brain vulnerability in mid-life : evidence for early risk
(2017-08) Kaur, Sonya Sarjit; Haley, Andreana P.; Tanaka, Hiforumi; Holahan, Charles J; Josephs, Robert A; Schnyer, David M
This set of projects focused on visceral fat, measured using proximal and direct methods. Specifically, I was interested in the effects of visceral fat on brain structure and integrity in middle age. Study 1 looked at waist to hip ratio (WHR) as a proximal measure of visceral fat and used statistical mediation to directly examine a possible mechanism behind the relationship between visceral fat and cognitive decline. Reductions in executive function seen in middle-aged adults with high visceral fat were found to occur in the context of lowered serum brain derived neurotrophic factor (BDNF) a key neurotrophin involved in synaptic plasticity as well as neuronal regeneration. Study 2 utilized Dual Energy X Ray Absorptiometry (DXA) to directly estimate visceral fat mass and volume as well as thickness of the cortical mantle in middle age. High-resolution Magnetization Prepared Rapid Acquisition Gradient Echo (MPRAGE) images were used. High visceral fat was found to predict increased thickness in the posterior cingulate cortex independently of age and cardiovascular risk in a cognitively intact middle-aged sample. Study 3 examined changes in concentrations of crucial cerebral metabolites in the posterior cingulate cortex among individuals with high visceral fat. Results indicated that visceral fat predicted reduced concentrations of N Acetyl Asparate, a marker of neuronal viability and increased concentrations of myo-inositol, a glial marker that is implicated in a number of disease states including prodromal Alzheimer’s Disease and Multiple Sclerosis. Collectively, the 3 studies highlight important evidence for early brain vulnerability even in cognitively intact middle- aged adults with high levels of cognitive reserve. An important next step would be to examine modifiable mediators of these relationships, such as inflammation and BDNF so that targeted interventions may be developed.
Chronic and acute effects of hydroxytyrosol on antioxidant status and inflammation at rest and during exercise
(2012-05) Simpson, Ashlee Danielle; Ivy, John, 1945-; Farrar, Roger P.
Evidence shows that consumption of a Mediterranean diet can lower the risk of all-cause and cause-specific mortality suggesting that this diet has an overall effect on health. Antioxidants found within olive oil, the primary source of fat in the Mediterranean diet, may be leading contributors to the decreased disease risk. More specifically, hydroxytyrosol (HT), one of the most active and powerful antioxidants found in olive oil, has the ability to increase total antioxidant status and lower levels of lipid peroxidation. In addition to a healthy diet, physical activity decreases the risk of cardiovascular morbidity and mortality; however, aerobic exercise of sufficient intensity or duration can induce oxidative stress. Therefore, the purpose of this study was to investigate the effects of 6 weeks of HT supplementation on antioxidant status and markers of inflammation in healthy, recreationally active males before and throughout acute aerobic exercise bouts. Using a randomized, double-blind, repeated-measures, placebo-controlled design, sixty-one (n=61) participants were randomly assigned to consume a placebo (PLA), low dose of HT (LHT, 50 mg/day), or high dose of HT (HHT, 150 mg/day). Throughout the course of the study, the participants performed four time trial rides (TT1-TT4) on cycle ergometers. TT1 occurred before supplementation, TT2 halfway through the supplementation period, and TT3 and TT4 occurred in the sixth week and final two days of supplementation. Blood was drawn prior to (pre) and just before termination (end) of each time trial to measure markers of antioxidant status and inflammation during exercise. We did not observe significant main effects for treatment on any of the markers for antioxidant status (TEAC) or for markers of inflammation (oxLDL, CRP, 8IP, TNFα, IL-6, IL-10, IL-1β, or IL-1ra). Significant treatment-by-time interactions occurred for CRP, 8IP, and IL-6 although significant treatment differences in these measures were not detected. We conclude that chronic and acute HT supplementation does not improve antioxidant status nor decrease markers of inflammation in this population at rest, during, or following exercise.
Development of a nanoprobe for tracking stem cell viability
(2019-09-12) Dhada, Kabir Singh; Suggs, Laura J.; Emelianov, Stanislav; Zoldan, Janeta; Tunnell, James; Ghosh, Debadyuti
Adult stem cell therapy has demonstrated improved outcomes for treating cardiovascular diseases in preclinical and clinical. The development of novel imaging tools may increase our understanding of the mechanisms of stem cell therapy, and a variety of imaging tools have been developed to image transplanted stem cells in vivo; however, they lack the ability to interrogate stem cell function longitudinally. The objective of this dissertation was to develop a nanoprobe capable of tracking stem cell viability in vivo using photoacoustic imaging. The nanoprobe consists of inert gold nanorods coated with a reactive oxygen species (ROS) sensitive near-infrared dye. Upon cell death, stem cells produce ROS to degrade the cell. Using this feature of stem cells, the viability can be measured by comparing the dye signal to the ROS insensitive gold nanorod signal, which can also be used to track stem cell location. Demonstrated in this dissertation is the design and development of this nanoprobe, followed by characterization of the nanoparticle, and subsequent studies tracking mesenchymal stem cell viability in vivo. The nanoprobe was successfully loaded into mesenchymal stem cells and was capable of tracking cell viability in vivo over a period of 10 days using photoacoustic imaging. In addition, the nanoprobe was applied toward measuring inflammation due to ischemia. The results of this work can provide insights on stem cell therapy mechanisms and may be used for enhancing and optimization of cell therapy in the future
Dietary fiber linked to decreased inflammation in overweight minority youth
(2015-05) Miller, Samantha Jean; Davis, Jaimie Nicole; Bray, Molly S
Objective: To examine the relationship between diet and inflammation, and adiposity in minority youth. Design and Methods: A cross-sectional analysis of 142 overweight (≥85th BMI percentile) Hispanic and African American adolescents (14-18 y) with the following measures: anthropometrics, adiposity via magnetic resonance imagine (MRI), dietary intake via 24-hour dietary recalls, and inflammation markers from fasting blood draws utilizing a multiplex panel. Partial correlations were estimated and ANCOVA models fit to examine the relationship between dietary variables, inflammation markers, and adiposity measures with the following a priori covariates: Tanner stage, ethnicity, sex, total energy intake, total body fat, and total lean mass. Results: Inference based on ANCOVA models showed that the highest tertile of fiber intake (mean intake of 21.3 ± 6.1 g/d) versus the lowest tertile of fiber intake (mean intake of 7.4 ± 1.8 g/d) was associated with 36% lower plasminogen activator inhibitor-1 (PAI-1) (P = 0.02) and 43% lower resistin (P = 0.02), independent of covariates. Similar results were seen for insoluble fiber. No other dietary variables included in this study were associated with inflammation markers. Conclusions: These results suggest that increases in dietary fiber could play an important role in lowering inflammation and therefore metabolic disease risk in high-risk minority youth.
The dose dependent effects of polyphenol supplementation on inflammatory markers following eccentric exercise
(2012-05) Christmas, Kevin Michael; Coyle, Edward F., 1952-; Brothers, Matthew R.
Unaccustomed eccentric exercise can lead to decreases in muscle force production, increases in soreness, swelling, stiffness, and discomfort. The purpose of this study was to test the dose response of pomegranate juice concentrate on serum markers of muscle permeability, inflammation, and total anti-oxidant status. To test this hypothesis, 45 healthy recreationally active males (22.3 ± 0.5 y, 73.8 ± 1.71 kg, 174.9 ± 0.9 cm) were recruited from the local Austin community for participation in this study. Subjects were disqualified from participation in the study if in the past 6 months they were engaged in an exercise training program. Subjects were placed into either the placebo group, the once-daily, or twice-daily pomegranate juice concentrate supplementation group. Subjects performed a total of 8 days of supplementation. On day 4, all subjects came to the laboratory and underwent an eccentric exercise protocol consisting of 2 minutes of downhill running at -10% grade at 7.5 mph repeated 10 times, resulting in ~20 minutes of total downhill running. Thereafter, subjects performed 50 eccentric elbow extensions each lasting 5 seconds using a weight equal to their concentric one-repetition maximum. Blood measures were made pre-exercise (baseline), and 2, 24, 48, 72, and 96 hours post exercise and analyzed for interleukin-6, creatine kinase, myoglobin, and total anti-oxidant status. Creatine kinase was significantly elevated at 96 hours post exercise, but with no significant differences between treatments. Myoglobin was significantly elevated above baseline at 2 and 96 hours, but with no differences between treatments. There was no effect for time or treatment on the total anti-oxidant status of the serum. Il-6 was significantly higher at 2 and 24 hours after exercise, but with no difference between treatments. The percent increase in interleukin-6 from baseline was significantly lower in the twice-daily POM supplementation group versus placebo (124.3 ± 9.4, 188.6 ± 16.0% of baseline; respectively) during the 2-96 hours following eccentric exercise, but no statistical difference between 1x and 2x or 1x and placebo was observed. This suggests that 8 days of supplementation with pomegranate juice concentrate twice a day significantly reduces the percent increase in a marker of inflammation (interleukin-6) during the 96 hours following eccentric exercise; however, neither supplement was different than the placebo in regards to all other measures.
The effects of acute muscle damage and autoimmune disease on vascular function : the potential role of inflammation
(2009-08) Barnes, Jill Nicole; Tanaka, Hirofumi, Ph. D.
Inflammation has been implicated in the development of cardiovascular disease and a potential underlying mechanism in the pathogenesis of impaired vascular function. Two different but complementary approaches were utilized to determine the role of inflammation on vascular function. First, to evaluate the effect of acute inflammation, we induced muscle damage to both small and large muscle mass and measured vascular function every 24 hours for up to 5 days of recovery. Eccentric exercise-induced muscle damage, in both small and large muscle mass, resulted in a transient increase in central arterial stiffness. Next, patients with systemic lupus erythematosus (SLE) were studied as a model of chronic inflammation. Measurements of vascular function were compared in habitually-exercising and sedentary SLE patients, and age-matched healthy controls. Individuals with SLE demonstrated lower vascular function than healthy controls. When SLE patients were grouped by exercise status, habitually-exercising SLE patients exhibited similar vascular function to healthy controls, and lower overall disease activity compared with sedentary SLE patients, supporting the beneficial effect of regular exercise in this population. Inflammatory biomarkers were associated with measures of macro- and microvascular function. In conclusion, acute muscle damage and chronic disease-related inflammation have a potent effect on measures of vascular function, suggesting that inflammation plays a role in the pathogenesis of vascular dysfunction and is an important biomarker for cardiovascular risk.
Energy balance modulation and pancreatic tumor growth : the role of NF-kB
(2012-12) Hays, Drew; Hursting, Stephen D.
Obesity is a known risk factor for many types of cancer including pancreatic. Calorie restriction (CR), an anti-obesity diet regimen, has potent anticancer effects that may be mediated through its ability to reduce serum metabolic hormones and protumorigenic cytokines such as insulin-like growth factor (IGF)-1. IGF-1 is a metabolic hormone responsive to nutrient status that activates the inflammatory, cancer-related pathway, nuclear factor (NF)-[kappa]B. For this report, we tested the hypothesis that CR, via regulation of IGF-1, inhibits pancreatic tumor cell growth through modulation of NF-kB activation and protumorigenic gene expression. Male athymic nude mice were randomized to either a control diet consumed ad libitum (n=15) or a 30% CR diet (n=15) for 17 weeks, at which time, mice were injected with human pancreatic cancer cells (MiaPaca) and tumor growth was monitored for 6 weeks. Translocation of p65, a regulatory element of NF-[kappa]B, and expression of its downstream gene targets were analyzed in excised tumors. CR mice weighed less, (p<0.05), and had smaller tumors (p=0.022) relative to controls. Tumors from CR mice, relative to controls, demonstrated significant decreases in NF-[kappa]B downstream genes CCND1, RELA, Survivin, VEGF, and XIAP. These findings parallel our previous studies in pancreatic tumors from mouse origin, and suggest that the inhibitory effects of CR on MiaPaca pancreatic tumor growth are associated with decreased NF-kB activation.
Energy balance, inflammation, and tumor progression : the role of NF-[kappa]B
(2011-05) Harvey, Alison Elise; Hursting, Stephen D.; Kline, Kimberly; Sanders, Bob; Otto, Glen; Fischer, Susan
Obesity is an established risk and progression factor for many types of cancer, including pancreatic and colon cancer, and is characterized by abnormal metabolic hormone production and a chronic low-grade state of inflammation. However, the links between obesity, hormones, inflammation and tumorigenesis in colon and pancreatic tissue are poorly understood. Calorie restriction (CR), an anti-obesity dietary regimen with potent anticancer effects, reduces serum metabolic hormones and protumorigenic cytokines. Insulin-like growth factor (IGF)-1 is a metabolic hormone that activates NF-[kappa]B, a key regulator of inflammation. NF-[kappa]B is a transcription factor that mediates transcription of many cancer- and inflammation-related genes and is upregulated in both colon and pancreatic cancer. We hypothesized that CR inhibits colon and pancreatic tumor cell growth through modulation of hormone-stimulated NF-[kappa]B activation and protumorigenic gene expression. To test this hypothesis, we used CR and ad libitum feeding to generate a lean and overweight (control) phenotype, respectively; in C57BL/6 mice transplanted with MC38 colon cancer cells or Panc 02 pancreatic cancer cells, and analyzed the effect of diet on circulating hormone levels, markers of inflammation, and tumor growth. We also investigated the in vitro effects of IGF-1 on NF-[kappa]B activation and downstream protumorigenic gene expression in MC38 and Panc 02 cells. CR, relative to control diet, reduced body weight, circulating IGF-1 levels, and transplanted MC38 and Panc 02 tumor growth, as well as protumorigenic gene expression in the MC38 and Panc 02 tumor microenvironment. IGF-1 increased cell viability, NF-[kappa]B nuclear translocation and DNA binding, transcriptional activation, and downstream gene expression of inflammation and other protumorigenic genes in MC38 colon cancer cells and Panc 02 pancreatic cancer cells in vitro. Knockdown studies of NF-[kappa]B in Panc 02 cells using si-RNA established that the IGF-1-induced increase in protumorigenic gene expression is mediated, at least partially, through an NF-[kappa]B-dependent mechanism. In conclusion, these findings in models of pancreatic and colon cancer help clarify the links between obesity, IGF-1, NF-[kappa]B-mediated inflammation, and cancer. This work provides the underpinnings for several new molecular targets and strategies to test in model systems and translational studies for preventing or controlling obesity-related cancer.
Gender and race/ethnic disparities in markers of chronic inflammation among US adults
(2022-08-18) Davidson-Turner, KJ; Hayward, Mark D.
In the United States, diseases that emerge across the aging process are unequally distributed with women and minority racial and ethnic groups most impacted. Chronic inflammation is one of the biological pathways linked to these later life health disparities. C-reactive protein (CRP) and cytokines are inflammatory markers thought to be reflective of social and environmental conditions and are associated with health and aging across the life course. Using the Health and Retirement Study, this paper examines race/ethnic and gender patterns among CRP and new cytokine markers to provide a more in-depth understanding of differences in inflammatory markers linked to later-life health disparities prevalent in the United States. Key takeaways from this analysis include: (1) Black women are consistently at high risk of inflammation for each inflammatory marker; (2) US-born Hispanic adults and non-US born Hispanic adults have different inflammation risks, with US-born Hispanic adults having similar risk of inflammation levels compared to Black adults; and (3) women appear to have lower levels of inflammation compared to men for certain inflammatory markers. Given the different gender and race/ethnic patterns for CRP and the cytokine markers, it remains unclear what these measures are capturing in terms of biological risk. While still very useful, we should proceed with caution when using inflammatory markers to look at health disparities since it appears that certain markers may be more useful at capturing different parts of health risk.
Genome-Wide Expression Profiling of Five Mouse Models Identifies Similarities and Differences with Human Psoriasis
(Public Library of Science, 2011-04-04) Swindell, William R.; Johnston, Andrew; Carbajal, Steve; Han, Gangwen; Wohn, Christian; Lu, Jun; Xing, Xianying; Nair, Rajan P.; Voorhees, John J.; Elder, James T.; Wang, Xiao-Jing; Sano, Shigetoshi; Prens, Errol P.; DiGiovanni, John; Pittelkow, Mark R.; Ward, Nicole L.; Gudjonsson, Johann E.
Development of a suitable mouse model would facilitate the investigation of pathomechanisms underlying human psoriasis and would also assist in development of therapeutic treatments. However, while many psoriasis mouse models have been proposed, no single model recapitulates all features of the human disease, and standardized validation criteria for psoriasis mouse models have not been widely applied. In this study, whole-genome transcriptional profiling is used to compare gene expression patterns manifested by human psoriatic skin lesions with those that occur in five psoriasis mouse models (K5-Tie2, imiquimod, K14-AREG, K5-Stat3C and K5-TGFbeta1). While the cutaneous gene expression profiles associated with each mouse phenotype exhibited statistically significant similarity to the expression profile of psoriasis in humans, each model displayed distinctive sets of similarities and differences in comparison to human psoriasis. For all five models, correspondence to the human disease was strong with respect to genes involved in epidermal development and keratinization. Immune and inflammation-associated gene expression, in contrast, was more variable between models as compared to the human disease. These findings support the value of all five models as research tools, each with identifiable areas of convergence to and divergence from the human disease. Additionally, the approach used in this paper provides an objective and quantitative method for evaluation of proposed mouse models of psoriasis, which can be strategically applied in future studies to score strengths of mouse phenotypes relative to specific aspects of human psoriasis.
High resolution retinal imaging to evaluate laser and light safety in the retina for near and long term health effects
(2012-12) Pocock, Ginger Madeleine; Snodderly, D. Max; Rylander, H. Grady (Henry Grady), 1948-; Markey, Mia K.; Milner, Tom E.; Oliver, Jeffrey W.
The purpose of this research was to investigate detect and monitor laser-tissue interactions at threshold and potentially sub-threshold levels of injury. High resolution imaging modalities can provide a deeper understanding of candidate biomarkers disease and injury at the molecular, cellular, and tissue-levels which can be used to identify and diagnose early stages disease and damage. In addition, multi-scale and multi-modal imaging have also been used to identify inherent biomarkers of retinal disease and injury. Monitoring tissue changes can be mapped back to biological changes at the cellular and sub-cellular level. Diseases often alter tissue on the ultra-structural level yet retinal clinical diagnosis often monitor changes in tissue at the organ level. If injury and disease is detected and diagnosed during an “early” stage of development, treatments and drug interventions may prevent further spread of the pathology. Non-invasive imaging is expected to be a valuable tool for in vivo medical research as well as for the diagnosis and management of disease. In addition to developing new imaging tools and techniques to image the retina, the identification of inherent biomarkers of disease and health using diagnostic methods are almost equally as important. Using the inherent optical properties of retinal tissue, we can non- invasively quantify differences in the absorption and reflection of light to gauge the risk for visual disability or worse yet irreversible vision loss as a result of retinal disease and chronic light exposure. The research presented with in this dissertation is three separate studies aimed at identifying light injury and potential biomarkers indicating the risk of light mediated development of disease.
The impact of nonsteroidal anti-inflammatory drugs on endocrine therapy outcomes in breast cancer patients
(2013-05) Ximenes Frota Máximo, Ilane; DeGraffenried, Linda
Obesity is a known risk factor for postmenopausal breast cancer, and is associated with worse disease prognosis in pre- and postmenopausal women. Adjuvant hormonal therapies improve disease prognosis in obese women, but many still recur. Given that obesity induces inflammation and increases levels of cyclooxygenase-2 (COX-2) enzyme, resulting in tumor proliferation, this retrospective study investigated if women on anti-inflammatory drugs would have improved disease outcomes by reduced production of prostaglandins by COX-2 pathway. Four hundred and forty women treated for invasive breast cancer in San Antonio clinics were included. Cases were classified as NSAID users if notes included daily use of aspirin, ibuprofen, celecoxib or another COX-2 inhibitor; patients were categorized as NSAID nonusers if they were not taking any NSAIDs, or if they used COX-2 drugs for pain as needed rather than daily. Patients on NSAIDs were more likely to be older, be slightly more obese and postmenopausal. NSAID and NSAID nonusers did not statistically significantly differ in regards to BMI categories, tumor stage, hormone receptor status, type of invasive tumor, ethnicity/race and type of surgery. NSAID users had significantly less recurrence rates compared to nonusers (p=0.05). Further, time to disease progression was delayed by almost 28 months in patients who were NSAIDs users. Although this trend was non-significant statistically due to low number of total recurrences, it is promising in the clinical setting. In a logistic regression model using NSAID use, BMI categories and hormonal therapy drug as independent variables to predict recurrence, use of NSAID was only statistically significant in the univariate model. Overweight women were more likely to develop recurrence than normal weight when holding NSAID use and endocrine therapy constant. Obese women had increase recurrence risk, but the trend was not statistically significant. Females using aromatase inhibitors were less likely to recur than those on tamoxifen. The results of this exploratory study had limited power to determine multiple modulating factors, but because they suggest a major clinical benefit, further analyses in a larger sample size are needed to confirm these findings.
The impact of obesity on prostate cancer progression
(2012-08) Price, Ramona Salcedo; deGraffenried, Linda; Fischer, Susan M.; Hursting, Stephen D.; Sanders, Bob G.; Troyer, Dean
The link between obesity and the risk of prostate cancer (PCa) is inconclusive. However, studies demonstrate a correlation between obesity, advanced PCa and mortality. Investigating the underlying biological mechanisms by which obesity promotes advanced PCa is necessary to develop potential therapeutic targets that may aid in the efficacy of treating obese men. Obesity-associated changes in tumor biology may modulate key aspects of the hallmarks of cancer; acquisition of characteristics essential for the development and progression of cancer. We hypothesized obesity-induced inflammation promotes PCa progression. Our studies incorporated cell culture and murine models to investigate the role of obesity-related systemic factors on AR signaling, inflammation-stimulated invasive PCa, and the paracrine interaction of the tumor-microenvironment (TME). We sought to recapitulate the systemic effects of obesity to investigate characteristics of the metastatic cascade. Briefly, sera from mice fed 60% or 10% kcal from fat diet for 12 weeks were used for in vitro studies. PCa cells exposed to sera from obese mice increased AR transcriptional activity, proliferation, invasion, migration, MMP-9 activity and EMT: e-cadherin, vimentin and β-catenin. PCa cells exposed to sera from 1 hour maintained the invasive phenotypes similar to PCa cells directly exposed to sera from obese mice. IL-6 is associated with advanced PCa cancer. Depleting sera of IL-6 or IL-6 shRNA suppressed obesity-induced proliferation, invasion, migration and MMP-9 activity in LNCaP cells. Furthermore, in a PTEN spontaneous model of PCa, IL-6 protein and mRNA levels corresponded with progression of PCa in mice fed a high-fat diet. These results suggest IL-6 mediates obesity-induced PCa progression. Stromal cells that comprise the TME vary in their contribution to the growth of tumors. Our studies show macrophage-like and myofibroblasts increased NF-kB activity in PCa cells exposed to sera from obese mice. An increase in NF-kB activity corresponded with proliferation, prostaglandin E2, and invasion and recruitment of stromal cells by PCa cells. In summary, obesity-related systemic factors promote an invasive PCa phenotype, which may be mediated by Akt, AR, IL-6 and the TME. Obesity-induced changes in tumor biology and the microenvironment provide a niche suitable for invasive prostate cancer.
Investigating the interplay between early life stress, acute secondary pathogenesis, and chronic hippocampal impairments in young mice with traumatic brain injury
(2023-07-27) Parker, Kaila N.; Noble-Haeusslein, Linda J.; Curley, James P; Champagne, Frances A; Gore, Andrea C; Fonken, Laura K; Jones, Theresa A
While Traumatic brain injury (TBI) is the leading cause of disability in children, it is unclear how early life stress (ELS) may act as a determinant of long-term recovery in brain-injured children. A murine model of ELS preceding TBI at postnatal day (P)21 addressed the following: regionally specific acute pathogenesis of the hippocampus after ELS+TBI, are these early changes predictive of hippocampal damage and impairment at adulthood. Males and females were exposed to ELS (P2-9) with the limited bedding nestlet (LBN) model, randomized to TBI or sham, and euthanized at P22 or adulthood. At P22, ELISAs revealed an upregulation of IL1B, IL-6, TNFα, and IFNγ in both sexes after injury. ELS+TBI elevated IL-1B, IL-10, TNFα, and IFNγ in males compared to TBI. Iba-1 and caspase-3 were evaluated in hippocampal subregions. While TBI increased microglial density in both sexes, ELS+TBI increased microglial density in male CA2 and CA3 but only in the CA3 in females compared to TBI. Quantification of caspase-3 revealed apoptosis in males and females after TBI. ELS + TBI increased apoptosis in CA1 and CA3 in males and females compared to TBI. Adulthood learning and memory were assessed with the NOR and Barnes Maze. Compared to TBI, ELS+TBI reduced novelty preference in females and increased path length to target in both sexes. Hippocampal neuron loss after ELS+TBI was evaluated at adulthood. TBI significantly reduced neurons in all subregions; ELS+TBI reduced neurons in the CA1 region in females only. These findings highlight hippocampal vulnerability after ELS+TBI and ELS prior to a TBI may enhance acute pathogenesis in males. Correlation matrices determined hippocampal acute pathogenesis is predictive of neuronal loss at adulthood and is associated with learning and memory impairments. Males and females were assessed for all outcomes. Both sexes showed similar vulnerability to secondary pathogenesis following TBI and adulthood impairments in learning and memory; males showed greater vulnerability to acute pathogenesis and females showed greater vulnerability to adulthood outcomes. These findings may advocate for opportunities to tailor therapies specific to each sex. Thus, developing pre-clinical biomarkers to predict long-term recovery may continue to bolster care management.
Salmonella Uses Energy Taxis to Benefit from Intestinal Inflammation
(Public Library of Science, 2013-04-18) Rivera-Chávez, Fabian; Winter, Sebastian E.; Lopez, Christopher A.; Xavier, Mariana N.; Winter, Maria G.; Nuccio, Sean-Paul; Russell, Joseph M.; Laughlin, Richard C.; Lawhon, Sara D.; Sterzenbach, Torsten; Bevins, Charles L.; Tsolis, Renée M.; Harshey, Rasika M.; Adams, L. Garry; Bäumler, Andreas J.
Chemotaxis enhances the fitness of Salmonella enterica serotype Typhimurium (S. Typhimurium) during colitis. However, the chemotaxis receptors conferring this fitness advantage and their cognate signals generated during inflammation remain unknown. Here we identify respiratory electron acceptors that are generated in the intestinal lumen as by-products of the host inflammatory response as in vivo signals for methyl-accepting chemotaxis proteins (MCPs). Three MCPs, including Trg, Tsr and Aer, enhanced the fitness of S. Typhimurium in a mouse colitis model. Aer mediated chemotaxis towards electron acceptors (energy taxis) in vitro and required tetrathionate respiration to confer a fitness advantage in vivo. Tsr mediated energy taxis towards nitrate but not towards tetrathionate in vitro and required nitrate respiration to confer a fitness advantage in vivo. These data suggest that the energy taxis receptors Tsr and Aer respond to distinct in vivo signals to confer a fitness advantage upon S. Typhimurium during inflammation by enabling this facultative anaerobic pathogen to seek out favorable spatial niches containing host-derived electron acceptors that boost its luminal growth.
Suicide, machine learning, and the brain
(2021-11-30) Jackson, Nicholas Allen; Jabbi, Mbemba
Suicide causes around 800,000 deaths worldwide each year, making premature deaths due to suicide a significant public health problem (WHO 2018). The expression of suicidal behaviors is a complex phenotype with underlying biological, psychological, clinical, and sociocultural risk factors (Turecki et al., 2019). From a neurobiological perspective, suicidal behaviors (ideation, attempt) are associated with the degree of anatomical, physiological, and neurotranscriptomic dysregulations of a network of brain regions. This network includes the anterior insula, anterior cingulate, and prefrontal cortical regions that mediate emotional-regulatory behaviors. From a clinical perspective, diagnostic measures of depressive symptoms in major depressive disorder and bipolar disorders (i.e., mood disorders) are associated with over sixty percent of suicide deaths (WHO 2018). Of interest, the brain anatomical and related depressive symptoms associated with suicidal behavior are characterized by regionally specific brain measures of aberrant gene expression profiles in the post-mortem brains of suicide completed donors (Jabbi et al., 2020). These convergent neurobiological correlates for depressive illness and suicidal phenotypes lead me to ask: 1) are regional brain gene expression dysregulations underlying depressive illness in mood disorders differentially associated with suicide mortality? 2) And crucially, how do the brain’s gene expression dysregulations measured in post-mortem studies relate to diagnostic and demographic variables to confer risk for suicide across the psychiatric continuum? Answering these questions using a deterministic post-mortem sample with well-characterized suicide outcomes could help identify the convergent molecular and clinical risk factors for suicide deaths across the lifespan. Furthermore, this line of research could resolve the specificity of how such clinically defined molecular risk factors for suicide mortality may differ across mood disorders and other mental illnesses, ultimately aiding in diagnostically informed suicide prevention. I reviewed the extant literature on studies of brain gene expression correlates of suicide by focusing on unique suicide-related gene expression dysregulations in mood disorders. Moving forward, I propose using machine learning tools to integrate brain-based gene expression measures in conjunction with clinical/demographic variables to identify molecular and phenotypic risk predictors for suicide mortality.
The immunoregulation of dying cell components on macrophages and their therapeutic potential in ischemic muscle regeneration
(2021-11-29) Huang, Wenbai; Suggs, Laura J.; Farrar, Roger P.; Stone, Audrey; Zoldan, Janet; Ehrlich, Lauren
Skeletal muscle regeneration after serious injury highly relies on local stem cell proliferation and differentiation which are processes that are tightly regulated by macrophages. Utilization of tissue-derived and ex-vivo expanded mesenchymal stromal cells (MSCs) in skeletal muscle regeneration has been heavily researched for the past decades but the results have not been consistent and the potential therapeutic mechanism or mechanisms remains unclear. In this project, we characterized the cell components of MSCs after inducing cell death under different conditions and confirmed their anti-inflammatory and pro-regenerative effects on macrophage polarization in vitro. We further investigated the underlying mechanisms of macrophage polarization by different components resulting from cell death. We found potent therapeutic effects from freeze and thaw (F&T) induced cell debris, and these effects are dependent on the externalization of phosphatidylserine (PtS) on the plasma membrane. In contrast, effects from the supernatant of F&T induced cell death primarily depends on the released protein content. Based on the findings from our in vitro studies, we applied the F&T induced cell supernatant to an animal model of peripheral artery disease (PAD) to treat muscle injury caused by a severe ischemia. This treatment resulted in significantly improved muscle functional and histological recovery as well as increased blood flow to the affected muscles 2 weeks after the injury procedure, validating the therapeutic potential of cell components of MSCs induced by F&T process, obviating the need for a viable cell population to treat injury. This result has implications for cell-free therapeutic approaches for ischemic injury to muscle.
The interaction between obesity, immune response, and T cell metabolism
(2016-08) Chen, Honglin, M.A.; Jolly, Christopher A.; Bray, Molly S.
Obesity is the result of positive energy balance over a long period of time. Current research suggests that obesity is a multifactorial phenotype resulting from a combination of several factors, including genetic, epigenetic, sedentary behavior and dietary macronutrient composition. The major consequences of obesity include dyslipidemia, hyperglycemia, insulin resistance, altered adipokines, and altered immune function. Obesity increases fat deposition in tissues of the immune system such as bone marrow and thymus. Ectopic lipid metabolites change the individual immune cell profiles. In inflamed adipose tissues, anti-inflammatory M2 macrophages shift toward the M1 pro-inflammatory phenotype. The increase in CD8⁺ T cells precedes the accumulation of macrophages. Th1 and CD8⁺ T cells promote the development of insulin resistance (IR), while T-reg cells inhibit IR. The activation of naïve T cells is an energy-demanding activity that requires metabolic reprogramming. Proliferating cells switch to anabolic metabolism from catabolic metabolism, and nutrient substrates are utilized for biosynthesis of new daughter cells. Differentiated T effector cells, such as Th1/Th2, Th17 and Treg, display a more elevated rate of glycolysis than naïve T cells. Notably, Treg has the least glycolytic metabolism but an elevated rate of lipid oxidation. Naïve T cells utilize glucose and glutamine at a relatively low rate to maintain normal housekeeping functions, such as ion transport and membrane integrity. Resting T cells rely on oxidative phosphorylation for ATP production. Glutamine provides energy via oxidative metabolism and supports the biosynthetic processes by providing carbon and nitrogen precursors. In activated T cells, glucose-6-phosphate can enter the pentose phosphate pathway for the production of 5-carbon sugars for nucleotide biosynthesis and NADPH. Additionally, the TCA cycle can also serve as a center of biosynthesis in addition to providing proton carriers that facilitate in the generation of ATP from glucose in naïve T cells. In conclusion, obesity causes chronic inflammation that alters the immune cells profiles, particularly, T cells. Furthermore, T cell metabolism is also altered by the exposure to the major consequences of obesity, hyperlipidemia and hyperglycemia, shifting T cell population into Th17 subsets.
Towards targeted delivery of biologics to chronic inflammation sites using innovative nanosystems
(2018-09-13) Aldayel, Abdulaziz Mohammed; Cui, Zhengrong; Jolly, Christopher A; Ghosh, Debadyuti; Williams, III, Robert O; Smyth, Hugh D
Inflammation is a complex process that involves the infiltration of immune cells and pro-inflammatory mediators, such as tumor necrosis factor alpha (TNF-α), to the site of inflammation. Nanomedicines, including monoclonal antibodies and nanoparticles, are widely used in the treatment and diagnosis of chronic inflammatory diseases. However, repetitive use of biologics can render them ineffective or result in serious toxicities that may, in many cases, reduce the patient’s quality of life. In this dissertation, different nanotechnology approaches were utilized to overcome the inefficacy or toxicity of current medications; such approaches include small interfering RNA (siRNA)-based formulations and monoclonal antibody-chemical conjugation. There has been growing interest in utilizing siRNA specific to pro-inflammatory cytokines, such as TNF-α, in chronic inflammation therapy. However, delivery systems that can increase the distribution of siRNA in chronic inflammation sites after intravenous administration are needed. Herein we developed two innovative surface-functionalized siRNA-incorporated formulations that significantly increase the delivery of siRNA in chronic inflammation sites in a mouse model. The first formulation is an acid–sensitive sheddable PEGylated poly (lactic-co-glycolic) acid (PLGA) nanoparticle, which showed significantly higher accumulation or distribution of siRNA in chronic inflammation sites. However, the polymeric nanoparticles suffer from low encapsulation efficiency and high burst release of siRNA. Therefore, we designed a solid lipid nanoparticle (AS-TNF-α-siRNA-SLNs) formulation that has high siRNA encapsulation efficiency and minimum burst release of TNF-α siRNA, and can target inflamed tissues after intravenous administration. This novel composition was intended to avoid siRNA-burst release associated with our previous siRNA formulation. The developed AS-TNF-α-siRNA-SLNs resulted in significantly reduced paw thickness, bone loss, and histopathological scores in a mouse model of collagen antibody-induced arthritis that does not respond to methotrexate therapy. Finally, we investigated the effect of the size of nanoparticles on their specific distribution and retention in chronic inflammation sites. In this dissertation we discovered that larger nanoparticles (100-200 nm) and macromolecules (e.g. IgM) have a higher specificity to chronic inflammation sites than smaller nanoparticles (2-10 nm) and macromolecules (e.g. IgG); surprisingly, however, smaller nanoparticles of 2-10 nm have longer retention within chronic inflammation sites. Based on these findings, proteins were crosslinked to form redox-sensitive nanoparticles of around 100-200 nm, which were found to increase the specificity of the proteins toward chronic inflammation sites as well as their retention in chronic inflammation sites. The redox-sensitive nanoparticle platform technology can be potentially used to increase the specific distribution of monoclonal antibodies in chronic inflammation sites.