Psychological stress-induced cerebrovascular dysfunction: the role of metabolic syndrome and exercise.

NEW FINDINGS: What is the central question of this study? How does chronic stress impact cerebrovascular function and does metabolic syndrome accelerate the cerebrovascular adaptations to stress? What role does exercise training have in preventing cerebrovascular changes to stress and metabolic syndrome? What is the main finding and its importance? Stressful conditions lead to pathological adaptations of the cerebrovasculature via an oxidative nitric oxide pathway, and the presence of metabolic syndrome produces a greater susceptibility to stress-induced cerebrovascular dysfunction. The results also provide insight into the mechanisms that may contribute to the influence of stress and the role of exercise in preventing the negative actions of stress on cerebrovascular function and structure. ABSTRACT: Chronic unresolvable stress leads to the development of depression and cardiovascular disease. There is a high prevalence of depression with the metabolic syndrome (MetS), but to what extent the MetS concurrent with psychological stress affects cerebrovascular function is unknown. We investigated the differential effect of MetS on cerebrovascular structure/function in rats (16-17 weeks old) following 8 weeks of unpredictable chronic mild stress (UCMS) and whether exercise training could limit any cerebrovascular dysfunction. In healthy lean Zucker rats (LZR), UCMS decreased (28%, P < 0.05) ex vivo middle cerebral artery (MCA) endothelium-dependent dilatation (EDD), but changes in MCA remodelling and stiffness were not evident, though cerebral microvessel density (MVD) decreased (30%, P < 0.05). The presence of UCMS and MetS (obese Zucker rats; OZR) decreased MCA EDD (35%, P < 0.05) and dilatation to sodium nitroprusside (20%, P < 0.05), while MCA stiffness increased and cerebral MVD decreased (31%, P < 0.05), which were linked to reduced nitric oxide and increased oxidative levels. Aerobic exercise prevented UCMS impairments in MCA function and MVD in LZR, and partly restored MCA function, stiffness and MVD in OZR. Our data suggest that the benefits of exercise with UCMS were due to a reduction in oxidative stress and increased production of nitric oxide in the cerebral vessels. In conclusion, UCMS significantly impaired MCA structure and function, but the effects of UCMS were more substantial in OZR vs. LZR. Importantly, aerobic exercise when combined with UCMS prevented the MCA dysfunction through subtle shifts in nitric oxide and oxidative stress in the cerebral microvasculature.

Circulating leucocytes perpetuate stroke-induced aortic dysfunction.

NEW FINDINGS: What is the central question of this study? Does a stroke event influence aortic endothelial function; and what is the role of peripheral circulating leucocytes in stroke on the vascular reactivity of the aorta? What is the main finding and its importance? In vitro co-culture experiments demonstrated that aortic endothelium-dependent relaxation was impaired when rat aortic rings were co-cultured with leucocytes stimulated with serum from stroke patients. Impaired vascular reactivity was not observed in aortic rings without leucocytes stimulated with serum from stroke patients or age-matched control patients with or without leucocytes. These data suggest that leucocyte-dependent altered aortic endothelium-dependent relaxation with stroke and the systemic consequences of stroke on vascular inflammation may occur in the aorta. Post-stroke inflammation has been linked to poor stroke outcomes. The vascular endothelium senses and responds to circulating factors, in particular inflammatory cytokines. Although stroke-associated local cerebrovascular dysfunction is well reported, the effects of a stroke on conduit artery function are not fully understood. We tested the hypothesis that serum from stroke patients triggers leucocyte-dependent aortic endothelial dysfunction that is associated with elevated concentrations of cytokines. Total leucocytes were isolated from healthy individuals, and the cells were incubated in serum from control subjects or stroke patients for 6 h. The quantity of cytokines in media was determined using an immunoassay. Vascular reactivity was determined by the rat aortic rings that were co-cultured with or without leucocytes and stimulated with serum samples from control subjects or stroke patients. Endothelium-dependent dilatation was significantly impaired in aortic rings co-cultured with leucocytes plus serum from stroke patients (50 ± 30 versus 85 ± 13%, P < 0.05) versus serum from control subjects. In contrast, no difference was observed in aortic function stimulated with serum from control subjects or stroke patients without total leucocytes. Likewise, total leucocyte-derived cytokine concentrations were significantly increased in a time-dependent manner on stimulation with serum from stroke patients (P < 0.05). These observations support the concept that the increased response of leucocytes drives the development of stroke-associated vascular endothelial dysfunction. As such, pharmacologically targeting the source of inflammatory cytokines might alleviate stroke-associated peripheral vascular dysfunction.

Therapeutic Potential of Cerium Oxide Nanoparticles for the Treatment of Peritonitis Induced by Polymicrobial Insult in Sprague-Dawley Rats.

OBJECTIVES: Peritonitis is a life-threatening disease that is associated with high mortality. The purpose of this study was to determine if cerium oxide nanoparticles can be used to diminish intra-abdominal infection-induced mortality and systemic inflammatory response syndrome in the laboratory rat. DESIGN: Randomized, controlled animal study and cell culture study. SETTING: University research laboratory. SUBJECTS: Male Sprague-Dawley rats aged 12 weeks, RAW 246.7 macrophage cell line. INTERVENTIONS: Intra-abdominal infection or peritonitis was induced by intraperitoneal injection of cecal material (600 mg/kg in 5% sterile dextrose water at a dosage of 5 mL/kg) obtained from healthy donors. Rats in control and peritonitis groups received 200 µL of sterile deionized water IV via the tail vein, whereas rats in cerium oxide-only group and peritonitis+cerium oxide group received cerium oxide nanoparticles (0.5 mg/kg) IV at the time of polymicrobial injection. Survival rate was monitored for 14 days, while in other experiments, animals were killed at 3 and 18 hours after induction of peritonitis for biochemical analysis. MEASUREMENTS AND MAIN RESULTS: Administration of a single dose (0.5 mg/kg) of cerium oxide nanoparticles IV to rats in the peritonitis group significantly improved survival rates and functioned to restore core body temperature toward baseline. Treatment-induced increases in animal survivability were associated with reduced systemic and hepatic oxidative stress, diminished serum cytokines, and chemokine levels. Changes in serum inflammatory markers with treatment were accompanied by decreased monocyte and lymphocyte extravasation into the peritoneal cavity along with decreased infiltration of macrophages into liver. In the heart, treatment diminished extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase-Stat-3 signaling and attenuated endothelial expression of P-selectin and vascular cell adhesion molecule-1. CONCLUSIONS: Cerium oxide nanoparticles attenuate the systemic inflammatory response associated with peritonitis, suggesting potential use as a novel therapeutic agent for the treatment of severe intra-abdominal infection.

Cerium oxide nanoparticles attenuate acute kidney injury induced by intra-abdominal infection in Sprague-Dawley rats.

BACKGROUND: Intra-abdominal infection or peritonitis is a cause for great concern due to high mortality rates. The prognosis of severe intra-abdominal infection is significantly diminished in the presence of acute kidney injury (AKI) which is often characterized by renal tubular cell death that can lead to renal failure. The purpose of the current study is to examine the therapeutic efficacy of cerium oxide (CeO2) nanoparticles for the treatment of peritonitis-induced AKI by polymicrobial insult. RESULTS: A one-time administration of CeO2 nanoparticles (0.5 mg/kg) in the absence of antibiotics or other supportive care, attenuated peritonitis-induced tubular dilatation and the loss of brush border in male Sprague-Dawley rats. These improvements in renal structure were accompanied by decreases in serum cystatin-C levels, reduced renal oxidative stress, diminished Stat-3 phosphorylation and an attenuation of caspase-3 cleavage suggesting that the nanoparticle treatment improved renal glomerular filtration rate, diminished renal inflammation and reduced renal apoptosis. Consistent with these data, further analysis demonstrated that the CeO2 nanoparticle treatment diminished peritonitis-induced increases in serum kidney injury molecule-1 (KIM-1), osteopontin, ß-2 microglobulin and vascular endothelial growth factor-A (VEGF-A) levels. In addition, the nanoparticle attenuated peritonitis-induced hyperglycemia along with increases in blood urea nitrogen (BUN), serum potassium and sodium. CONCLUSION: CeO2 nanoparticles scavenge reactive oxygen species and attenuate polymicrobial insult induced increase in inflammatory mediators and subsequent AKI. Taken together, the data indicate that CeO2 nanoparticles may be useful as an alternative therapeutic agent or in conjunction with standard medical care for the treatment of peritonitis induced acute kidney injury.

Interactions between A(2A) adenosine receptors, hydrogen peroxide, and KATP channels in coronary reactive hyperemia.

Myocardial metabolites such as adenosine mediate reactive hyperemia, in part, by activating ATP-dependent K(+) (K(ATP)) channels in coronary smooth muscle. In this study, we investigated the role of adenosine A(2A) and A(2B) receptors and their signaling mechanisms in reactive hyperemia. We hypothesized that coronary reactive hyperemia involves A(2A) receptors, hydrogen peroxide (H(2)O(2)), and KATP channels. We used A(2A) and A(2B) knockout (KO) and A(2A/2B) double KO (DKO) mouse hearts for Langendorff experiments. Flow debt for a 15-s occlusion was repaid 128 ± 8% in hearts from wild-type (WT) mice; this was reduced in hearts from A(2A) KO and A(2A)/(2B) DKO mice (98 ± 9 and 105 ± 6%; P < 0.05), but not A(2B) KO mice (123 ± 13%). Patch-clamp experiments demonstrated that adenosine activated glibenclamide-sensitive KATP current in smooth muscle cells from WT and A(2B) KO mice (90 ± 23% of WT) but not A(2A) KO or A(2A)/A(2B) DKO mice (30 ± 4 and 35 ± 8% of WT; P < 0.05). Additionally, H(2)O(2) activated KATP current in smooth muscle cells (358 ± 99%; P < 0.05). Catalase, an enzyme that breaks down H(2)O(2), attenuated adenosine-induced coronary vasodilation, reducing the percent increase in flow from 284 ± 53 to 89 ± 13% (P < 0.05). Catalase reduced the repayment of flow debt in hearts from WT mice (84 ± 9%; P < 0.05) but had no effect on the already diminished repayment in hearts from A(2A) KO mice (98 ± 7%). Our findings suggest that adenosine A(2A) receptors are coupled to smooth muscle KATP channels in reactive hyperemia via the production of H(2)O(2) as a signaling intermediate.

Penitrem A as a tool for understanding the role of large conductance Ca(2+)/voltage-sensitive K(+) channels in vascular function.

Large conductance, Ca(2+)/voltage-sensitive K(+) channels (BK channels) are well characterized, but their physiological roles, often determined through pharmacological manipulation, are less clear. Iberiotoxin is considered the "gold standard" antagonist, but cost and membrane-impermeability limit its usefulness. Economical and membrane-permeable alternatives could facilitate the study of BK channels. Thus, we characterized the effect of penitrem A, a tremorigenic mycotoxin, on BK channels and demonstrate its utility for studying vascular function in vitro and in vivo. Whole-cell currents from human embryonic kidney 293 cells transfected with hSlo α or α + ß1 were blocked >95% by penitrem A (IC(50) 6.4 versus 64.4 nM; p < 0.05). Furthermore, penitrem A inhibited BK channels in inside-out and cell-attached patches, whereas iberiotoxin could not. Inhibitory effects of penitrem A on whole-cell K(+) currents were equivalent to iberiotoxin in canine coronary smooth muscle cells. As for specificity, penitrem A had no effect on native delayed rectifier K(+) currents, cloned voltage-dependent Kv1.5 channels, or native ATP-dependent K(ATP) current. Penitrem A enhanced the sensitivity to K(+)-induced contraction in canine coronary arteries by 23 ± 5% (p < 0.05) and increased the blood pressure response to phenylephrine in anesthetized mice by 36 ± 11% (p < 0.05). Our data indicate that penitrem A is a useful tool for studying the role of BK channels in vascular function and is practical for cell and tissue (in vitro) studies as well as anesthetized animal (in vivo) experiments.

COVID-19-Related Trends and Characteristics of Type 2 Diabetes Mellitus and Metabolic Syndrome.

Background Although there have been several studies associating obesity with severe coronavirus disease 2019 (COVID-19) outcomes, the potential impact of the pandemic on type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) incidence is less clear. Furthermore, reports on the characteristics of these patients during the pandemic have been scarce. Objectives The purpose of this retrospective study was 1) to explore the impact of the COVID-19 pandemic on T2DM and MetS incidence, and 2) to describe sex-based differences in the characteristics of T2DM and MetS patients during the COVID-19 pandemic. Methods Using electronic health records (EHRs) obtained from the USA-based TriNetX research database (TriNetX, Cambridge, MA), the incidence and the total number of patients with "T2DM (ICD-10-CM: E11)" and "MetS (ICD-10-CM: E88.81)" prior to and during the COVID-19 pandemic were determined. Aggregate lab data from EHRs were extracted and statistical analyses on the lab values and patient demographics including sex, race/ethnicity, and comorbidities were performed. Results After analyzing T2DM and MetS patient data from 2018, 2019, and 2020, we observed a considerable decrease in both T2DM and MetS incidence, with data in April 2020 exhibiting the largest decrease when compared to other months. Furthermore, monthly male T2DM and MetS patients' lab data revealed worsening parameters in April 2020, such as hemoglobin A1c (HbA1C) and blood glucose, when compared to females. Demographic data during 2020 revealed that male T2DM and MetS patients had a significantly higher prevalence of comorbidities including hypertension, ischemic heart disease, and heart failure, but female T2DM and MetS patients had significantly higher asthma comorbidity. Conclusions During 2020, there was a marked decrease in T2DM and MetS diagnosis. Due to a lack of screening, these data may suggest a subsequent increase in T2DM and MetS-related heart disease in the future and may magnify the existing sex-related differences identified in these patients.

A Culinary Medicine Elective Course Incorporating Lifestyle Medicine for Medical Students.

OBJECTIVE: The purpose of this study is to describe our culinary medicine elective course with a lifestyle modification focus and to evaluate the students' perceived knowledge and attitudes in lifestyle medicine. METHODS: Pre- and post-surveys including quantitative assessment, Likert-type questions, and one open-ended response question to assess students' perceived knowledge of nutrition and lifestyle medicine were distributed to osteopathic medical students who participated in the culinary medicine elective course. The Mann-Whitney U test and dependent t test were used where appropriate based on normality. RESULTS: Compared to the pre-course survey, students who responded "strongly agree" in questions related to nutrition counseling in the post-course survey were 26.5 to 31.3% higher (p < 0.05). Based on the post-course survey (n = 34), 33 students responded either "strongly agree" (n = 25, 73.5%) or "agree" (n = 8, 23.5%) to the question of "increased my knowledge of nutrition." CONCLUSIONS: Culinary medicine courses with a lifestyle medicine focus may be effective in increasing medical students' confidence and perceived knowledge of nutrition and lifestyle medicine.

Utilization of myosin and actin bundles for the transport of molecular cargo.

The utilization of motor proteins for the movement and assembly of synthetic components is currently a goal of nanoengineering research. Application of the myosin actin motor system for nanotechnological uses has been hampered due to the low flexural rigidity of individual F-actin filaments. Here it is demonstrated how actin bundling can be used to affect the translational behavior of myosin-propelled filaments, transport molecules across a motor-patterned surface, and that the movement of bundled actin can be regulated photonically. These data suggest that actin bundling may significantly improve the applicability of the myosin motor for future nanotechnological applications.

Perivascular adipose tissue mediated aortic reactivity data: Female lean and obese Zucker rats.

Perivascular adipose tissue (PVAT) is recognized as a paracrine organ that controls vascular function. One of the early data demonstrated PVAT from male Sprague-Dawley rats altered aortic vascular reactivity [1]. Subsequent studies have suggested PVAT mediated vascular reactivity is impaired in a variety of vascular beds with animal models of metabolic syndrome [2]. Findings in these experimental animals are generally reported by only male data. Here we report the new data on the effects of PVAT on the aortic reactivity of female lean zucker rats (LZR) and obese zucker rats (OZR). The data presented here is related to a recent manuscript entitled "Aortic dysfunction in metabolic syndrome mediated by perivascular adipose tissue TNFα- and NOX2-dependent pathway" [3] which demonstrated PVAT from male obese Zucker rats (OZR) impaired endothelial function of aorta which is associated with altered PVAT inflammatory signaling.

Impaired function of coronary BK(Ca) channels in metabolic syndrome.

The role of large-conductance Ca(2+)-activated K(+) (BK(Ca)) channels in regulation of coronary microvascular function is widely appreciated, but molecular and functional changes underlying the deleterious influence of metabolic syndrome (MetS) have not been determined. Male Ossabaw miniature swine consumed for 3-6 mo a normal diet (11% kcal from fat) or an excess-calorie atherogenic diet that induces MetS (45% kcal from fat, 2% cholesterol, 20% kcal from fructose). MetS significantly impaired coronary vasodilation to the BK(Ca) opener NS-1619 in vivo (30-100 microg) and reduced the contribution of these channels to adenosine-induced microvascular vasodilation in vitro (1-100 microM). MetS reduced whole cell penitrem A (1 microM)-sensitive K(+) current and NS-1619-activated (10 microM) current in isolated coronary vascular smooth muscle cells. MetS increased the concentration of free intracellular Ca(2+) and augmented coronary vasoconstriction to the L-type Ca(2+) channel agonist BAY K 8644 (10 pM-10 nM). BK(Ca) channel alpha and beta(1) protein expression was increased in coronary arteries from MetS swine. Coronary vascular dysfunction in MetS is related to impaired BK(Ca) channel function and is accompanied by significant increases in L-type Ca(2+) channel-mediated coronary vasoconstriction.

High-frequency electrical stimulation (HFES) Data Lean and Obese Zucker Rat Soleus Muscle: Regulation of p70S6kinase Associated Proteins.

Anaerobic exercise has been advocated as a prescribed treatment for the management of diabetes: however, alterations in exercise-induced signaling remain largely unexplored in the diabetic muscle. Here, we compare the basal and the in situ contraction-induced phosphorylation of the AKT, GSK3beta, mTor, p70s6K, Pten, and Shp2 proteins in the lean and obese (fa/fa) Zucker rat soleus muscle following a single bout of contractile stimuli. This article represents data associated with prior publications from our lab (Katta et al., 2009a, 2009b; Tullgren et al., 1991) [1-3] and concurrent Data in Brief articles (Ginjupalli et al., 2017a, 2017b; Rice et al., 2017a, 2017b) [4-7].

Diabetic Zucker rat Tibialis anterior muscle high-frequency electrical stimulation (HFES) data: Regulation of MAPKs associated proteins.

Anaerobic exercise has been advocated as a prescribed treatment for the management of diabetes: however, alterations in exercise-induced signaling remain largely unexplored in the diabetic muscle. Here, we compare the basal and the in situ contraction-induced phosphorylation of the mitogen-activated protein kinases (MAPKs) ERK 1/2, p38, and JNK in the lean and obese (fa/fa) Zucker rat tibialus anterior (TA) muscle following a single bout of contractile stimuli. This article represents data associated with prior publications from our lab (Katta et al., 2009, Katta et al., 2009, Tullgren et al., 1991) [1-3] and concurrent Data in Brief articles (Ginjupalli et al., 2017, Rice et al., 2017, Rice et al., 2017, Rice et al., 2017) [4-7].

Lean and Obese Zucker Rat Extensor Digitorum Longus Muscle high-frequency electrical stimulation (HFES) Data: Regulation of MAPKs Associated Proteins.

Anaerobic exercise has been advocated as a prescribed treatment for the management of diabetes: however, alterations in exercise-induced signaling remain largely unexplored in the diabetic muscle. Here, we compare the basal and the in situ contraction-induced phosphorylation of the mitogen-activated protein kinases (MAPKs) ERK 1/2, p38, and JNK in the lean and obese (fa/fa) Zucker rat extensor digitorum longus (EDL) muscle following a single bout of contractile stimuli. This article represents data associated with prior publications from our (Katta et al., 2009a, 2009b, 2008) [1-3] and concurrent Data in Brief articles (Ginjupalli et al., 2017a, 2017b; Rice et al., 2017a, 2017b) [4-7].

High-frequency electrical stimulation (HFES) data lean and obese Zucker rat tibialis anterior muscle: Regulation of glycogen synthase kinase 3 beta (GSK3B) associated proteins.

Anaerobic exercise has been advocated as a prescribed treatment for the management of diabetes: however, alterations in exercise-induced signaling remain largely unexplored in the diabetic muscle. Here, we compare the basal and the in situ contraction-induced phosphorylation of the AMPK, GSK3beta, and Shp2 in the lean and obese (fa/fa) Zucker rat tibialis anterior (TA) muscle following a single bout of contractile stimuli. This article represents data associated with prior publications from our lab (Katta et al., 2009; Katta et al., 2009; Tullgren et al., 1991) [1-3] and concurrent Data in Brief articles (Ginjupalli et al., 2017; Rice et al., 2017; Rice et al., 2017; Rice et al., 2017) [4-7].

Lean and Obese Zucker Rat Extensor Digitorum Longus Muscle high-frequency electrical stimulation (HFES) Data: Regulation of p70S6kinase Associated Proteins.

Anaerobic exercise has been advocated as a prescribed treatment for the management of diabetes: however, alterations in exercise-induced signaling remain largely unexplored in the diabetic muscle. Here, we compare the basal and the in situ contraction-induced phosphorylation of the AKT, GSK3beta, mTor, p70s6K, Pten, and Shp2 in the lean and obese (fa/fa) Zucker rat Extensor Digitorum Longus (EDL) muscle following a single bout of contractile stimuli. This article represents data associated with prior publications from our lab (Katta et al., 2009a, 2009b; Tullgren et al., 1991) [1-3] and concurrent Data in Brief articles (Ginjupalli et al., 2017a, 2017b; Rice et al., 2017a, 2017b) [4-7].

Dietary resveratrol confers apoptotic resistance to oxidative stress in myoblasts.

High levels of reactive oxygen species (ROS) contribute to muscle cell death in aging and disuse. We have previously found that resveratrol can reduce oxidative stress in response to aging and hindlimb unloading in rodents in vivo, but it was not known if resveratrol would protect muscle stem cells during repair or regeneration when oxidative stress is high. To test the protective role of resveratrol on muscle stem cells directly, we treated the C2C12 mouse myoblast cell line with moderate (100 µM) or very high (1 mM) levels of H2O2 in the presence or absence of resveratrol. The p21 promoter activity declined in myoblasts in response to high ROS, and this was accompanied a greater nuclear to cytoplasmic translocation of p21 in a dose-dependent matter in myoblasts as compared to myotubes. Apoptosis, as indicated by TdT-mediated dUTP nick-end labeling, was greater in C2C12 myoblasts as compared to myotubes (P<.05) after treatment with H2O2. Caspase-9, -8 and -3 activities were elevated significantly (P<.05) in myoblasts treated with H2O2. Myoblasts were more susceptible to ROS-induced oxidative stress than myotubes. We treated C2C12 myoblasts with 50 µM of resveratrol for periods up to 48 h to determine if myoblasts could be rescued from high-ROS-induced apoptosis by resveratrol. Resveratrol reduced the apoptotic index and significantly reduced the ROS-induced caspase-9, -8 and -3 activity in myoblasts. Furthermore, Bcl-2 and the Bax/Bcl-2 ratio were partially rescued in myoblasts by resveratrol treatment. Similarly, muscle stem cells isolated from mouse skeletal muscles showed reduced Sirt1 protein abundance with H2O2 treatment, but this could be reversed by resveratrol. Reduced apoptotic susceptibility in myoblasts as compared to myotubes to ROS is regulated, at least in part, by enhanced p21 promoter activity and nuclear p21 location in myotubes. Resveratrol confers further protection against ROS by improving Sirt1 levels and increasing antioxidant production, which reduces mitochondrial associated apoptotic signaling, and cell death in myoblasts.

Gene expression profiling in stroke: relevance of blood-brain interaction.

Biomarker profiling is utilized to identify diagnostic and prognostic candidates for stroke. Clinical and preclinical biomarker data suggest altered circulating immune responses may illuminate the mechanisms of stroke recovery. However, the relationship between peripheral blood biomarker profile(s) and brain profiles following stroke remains elusive. Data show that neutrophil lymphocyte ratio (NLR) predicts stroke outcome. Neutrophils release Arginase 1 (ARG1) resulting in T lymphocyte suppression in peripheral blood. Interestingly, the cellular response to stroke may have implications for known biomarker profiles. Conversely, preclinical evidence suggests that upregulation of ARG1 in microglia is a marker of M2 macrophages and may influence neuroprotection. Comparing clinical and preclinical studies creates opportunities to explore the molecular mechanisms of blood and brain biomarker interactions in stroke.

Cecal inoculum peritonitis: An alternative model for sepsis vascular dysfunction study.

AIMS: Sepsis is a life threatening condition that is characterized by the loss of vascular reactivity. The factor(s) responsible for the diminished vascular function seen in sepsis are not well understood. The purpose of this study was to characterize the vascular dysfunction from the rat cecal inoculum (CI) sepsis model using cecal ligation and puncture (CLP), and lipopolysaccharide (LPS) sepsis as reference models. MATERIALS AND METHODS: Experiments were performed on isolated aorta from CI, CLP and LPS treated rats using a combination of pharmacological approaches. KEY FINDINGS: Phenylephrine (PE)-induced aortic contraction was significantly decreased in each model (p<0.05) and not normalized by L-NAME or indomethacin. The vascular response elicited in the CI model for acetylcholine (Ach) was more similar to that seen in the CLP than the LPS model. The removal of the endothelial layer increased sensitivity to L-NAME (p<0.05) in aortae from CI group. Inhibition of the large conductance Ca(2+)/voltage sensitive K(+) (BKCa) channel did not normalize PE hyporesponsiveness but did abolish sepsis-induced contractile oscillation. Inhibition of the voltage dependent Kv1.5 channel was not able to reverse the vascular hyporesponsiveness, however, inhibition of the ATP dependent (KATP) channel inhibition partially restored the contractile response (p<0.05). Elevation of VCAM expression and aortic structural alternation were observed in each model. SIGNIFICANCE: These results suggest that the CI model may be an additional tool that could be used to investigate the mechanisms of vascular hyporesponsiveness in sepsis.

Cerium oxide nanoparticle treatment ameliorates peritonitis-induced diaphragm dysfunction.

The severe inflammation observed during sepsis is thought to cause diaphragm dysfunction, which is associated with poor patient prognosis. Cerium oxide (CeO2) nanoparticles have been posited to exhibit anti-inflammatory and antioxidative activities suggesting that these particles may be of potential use for the treatment of inflammatory disorders. To investigate this possibility, Sprague Dawley rats were randomly assigned to the following groups: sham control, CeO2 nanoparticle treatment only (0.5 mg/kg iv), sepsis, and sepsis+CeO2 nanoparticles. Sepsis was induced by the introduction of cecal material (600 mg/kg) directly into the peritoneal cavity. Nanoparticle treatment decreased sepsis-associated impairments in diaphragmatic contractile (P(o)) function (sham: 25.6±1.6 N/cm(2) vs CeO2: 23.4±0.8 N/cm(2) vs Sep: 15.9±1.0 N/cm(2) vs Sep+CeO2: 20.0±1.0 N/cm(2), P<0.05). These improvements in diaphragm contractile function were accompanied by a normalization of protein translation signaling (Akt, FOXO-1, and 4EBP1), diminished proteolysis (caspase 8 and ubiquitin levels), and decreased inflammatory signaling (Stat3 and iNOS). Histological analysis suggested that nanoparticle treatment was associated with diminished sarcolemma damage and diminished inflammatory cell infiltration. These data indicate CeO2 nanoparticles may improve diaphragmatic function in the septic laboratory rat.