Molecular Hydrogen: Emerging Treatment for Stroke Management.

Ischemic stroke is a major cause of death and disability worldwide. However, only intravenous thrombolysis using mechanical thrombectomy or tissue plasminogen activator is considered an effective and approved treatment. Molecular hydrogen is an emerging therapeutic agent and has recently become a research focus. Molecular hydrogen is involved in antioxidative, anti-inflammatory, and antiapoptotic functions in normal physical processes and may play an important role in stroke management; it has been evaluated in numerous preclinical and clinical studies in several administration formats, including inhalation of hydrogen gas, intravenous or intraperitoneal injection of hydrogen-enriched solution, or drinking of hydrogen-enriched water. In addition to investigation of the underlying mechanisms, the safety and efficacy of using molecular hydrogen have been carefully evaluated, and favorable outcomes have been achieved. All available evidence indicates that molecular hydrogen may be a promising treatment option for stroke management in the future. This review aimed to provide an overview of the role of molecular hydrogen in the management of stroke and possible further modifications of treatment conditions and procedures in terms of dose, duration, and administration route.

Movement pattern and upper extremity muscle activation during fast and slow continuous steering movement.

Continuous steering movement (CSM) is an essential component of the upper extremity (UE) task during vehicle driving, and could be a suitable candidate for multi-joint rehabilitation programs for patients with UE disabilities. This study aims to evaluate the UE muscle activation during CSM and how the rotating speed and direction affect CSM's kinematic and kinetic performance. Surface electromyography (EMG), hand contact information, and steering torque were measured under fast (180°/s) and slow (60°/s) constant-velocity CSM to reveal the activation of shoulder and elbow muscles, temporal characteristics, and force exertion during the stance and swing phases of a CSM cycle. Data from 24 normal young adults showed that shorter contact duration but higher force exertion occurred in the hand moving in an outward steering direction during only fast CSM in either the clockwise (CW) or counterclockwise (CCW) direction. During a steering cycle (either fast or slow speed), the triceps brachii, sternal part of the pectoralis major (PS), and posterior deltoid play major roles in generating steering torque in the CW direction of the CSM. In contrast, the PS, clavicular part of the pectoralis major (PC), and anterior deltoid (AD) largely contribute to torque generation during the CCW CSM. During the swing phase of CSM, AD, PC, and PS are the major muscles that move the hand for the next grasping of the steering wheel in all four conditions. Using the mean activation profiles of the major contributing muscles, the functional roles of these elbow and shoulder muscles were analyzed and are discussed herein. These findings help us to further understand the activation patterns of UE muscles and the kinematic and kinetic changes during two rotating directions and two speeds of CSM, and suggest important implications for future practice in clinical training.

Effects of virtual reality-based motor control training on inflammation, oxidative stress, neuroplasticity and upper limb motor function in patients with chronic stroke: a randomized controlled trial.

BACKGROUND: Immersive virtual reality (VR)-based motor control training (VRT) is an innovative approach to improve motor function in patients with stroke. Currently, outcome measures for immersive VRT mainly focus on motor function. However, serum biomarkers help detect precise and subtle physiological changes. Therefore, this study aimed to identify the effects of immersive VRT on inflammation, oxidative stress, neuroplasticity and upper limb motor function in stroke patients. METHODS: Thirty patients with chronic stroke were randomized to the VRT or conventional occupational therapy (COT) groups. Serum biomarkers including interleukin 6 (IL-6), intracellular adhesion molecule 1 (ICAM-1), heme oxygenase 1 (HO-1), 8-hydroxy-2-deoxyguanosine (8-OHdG), and brain-derived neurotrophic factor (BDNF) were assessed to reflect inflammation, oxidative stress and neuroplasticity. Clinical assessments including active range of motion of the upper limb and the Fugl-Meyer Assessment for upper extremity (FMA-UE) were also used. Two-way mixed analyses of variance (ANOVAs) were used to examine the effects of the intervention (VRT and COT) and time on serum biomarkers and upper limb motor function. RESULTS: We found significant time effects in serum IL-6 (p = 0.010), HO-1 (p = 0.002), 8-OHdG (p = 0.045), and all items/subscales of the clinical assessments (ps < 0.05), except FMA-UE-Coordination/Speed (p = 0.055). However, significant group effects existed only in items of the AROM-Elbow Extension (p = 0.007) and AROM-Forearm Pronation (p = 0.048). Moreover, significant interactions between time and group existed in item/subscales of FMA-UE-Shoulder/Elbow/Forearm (p = 0.004), FMA-UE-Total score (p = 0.008), and AROM-Shoulder Flexion (p = 0.001). CONCLUSION: This was the first study to combine the effectiveness of immersive VRT using serum biomarkers as outcome measures. Our study demonstrated promising results that support the further application of commercial and immersive VR technologies in patients with chronic stroke.

Practice Effects, Test-Retest Reliability, and Minimal Detectable Change of the Ruff 2 and 7 Selective Attention Test in Patients with Schizophrenia.

BACKGROUND: The Ruff 2 and 7 Selective Attention Test (RSAT) is designed to measure selective attention. It tests automatic detection speed (ADS), automatic detection errors (ADE), automatic detection accuracy (ADA), controlled search speed (CSS), controlled search errors (CSE), and controlled search accuracy (CSA). The purpose of this study was to examine the test-retest reliability, practice effect, and minimum detectable change (MDC) of the RSAT in patients with schizophrenia. METHODS: A total of 101 patients with schizophrenia completed the RSAT twice at a 4-week interval. The intra-class correlation coefficient (ICC), paired t test, and effect size were used to examine the test-retest reliability and practice effect. The standard error of measurement (SEM) and MDC were calculated. RESULTS: The difference scores between the two assessments were significant in all the indexes. The absolute effect sizes were 0.14 to 0.30. The ICCs of the RSAT ranged from 0.69 to 0.91. The MDC% in the indexes of ADS, ADA, and CSA of the RSAT were <30%. CONCLUSIONS: The RSAT is reliable for assessing selective attention in patients with schizophrenia. The RSAT has good to excellent test-retest reliability, a trivial to small practice effect, and indexes of ADS, ADA, and CSA, representing acceptable random measurement error.

A Systematic Review of the Current Measures of Theory of Mind in Adults with Schizophrenia.

Adults with schizophrenia usually have impairments in theory of mind (ToM), which subsequently cause them problems in social interaction. Therefore, it is important for healthcare providers to assess their ToM using adequate measures. This systematic review evaluated current ToM measures (or ToM tasks) for adults with schizophrenia and summarized their specific characteristics, including the concept and construct, administration, and psychometric properties. From a review of 117 articles, 13 types of ToM tasks were identified, and the findings from these articles were qualitatively synthesized. The results showed that ToM tasks are diverse in their presentation modalities, answer modes, strategies of controlling cognitive confounders, and scoring. Most tasks employ cognitive and affective dimensions and target a specific, single ToM concept. The present systematic review found that psychometric evidence supporting the ToM tasks, such as internal consistency, test-retest reliability, unidimensionality, and convergent, criterion, and ecological validities, is insufficient. Based on the results, we propose several principles for selecting appropriate ToM tasks in practice, e.g., selecting a task with multiple ToM concepts, or an exclusive ToM construct containing the cognitive and affective dimensions. Moreover, future studies are needed to provide more psychometric evidence on each type of ToM task applied in people with schizophrenia.

Measurement Invariance of the Drivers of COVID-19 Vaccination Acceptance Scale: Comparison between Taiwanese and Mainland Chinese-Speaking Populations.

The impacts of novel coronavirus disease-2019 (COVID-19) on human life continue to be serious. To control the spread of COVID-19, the production of effective vaccines is likely to be one of the best solutions. However, vaccination hesitancy may decrease individuals' willingness to get vaccinated. The Drivers of COVID-19 Vaccination Acceptance Scale (DrVac-COVID19S) was recently developed to help healthcare professionals and researchers better understand vaccination acceptance. The present study examined whether DrVac-COVID19S is measurement invariant across different subgroups (Taiwanese vs. mainland Chinese university students; males vs. females; and health-related program majors vs. non-health-related program majors). Taiwanese (n = 761; mean age = 25.51 years; standard deviation (SD) = 6.42; 63.5% females) and mainland Chinese university students (n = 3145; mean age = 20.72 years; SD = 2.06; 50.2% females) were recruited using an online survey between 5 January and 21 February 2021. Factor structure and measurement invariance of the two DrVac-COVID19S scales (nine-item and 12-item) were tested using confirmatory factor analysis (CFA). The findings indicated that the DrVac-COVID19S had a four-factor structure and was measurement invariant across the subgroups. The DrVac-COVID19S's four-factor structure was supported by the CFA results is a practical and valid instrument to quickly capture university students' willingness to get COVID-19 vaccination. Moreover, the DrVac-COVID19S can be used to compare university students' underlying reasons to get COVID-19 vaccination among different subgroups.

Alternative Motor Task-Based Pattern Training With a Digital Mirror Therapy System Enhances Sensorimotor Signal Rhythms Post-stroke.

Mirror therapy (MT) facilitates motor learning and induces cortical reorganization and motor recovery from stroke. We applied the new digital mirror therapy (DMT) system to compare the cortical activation under the three visual feedback conditions: (1) no mirror visual feedback (NoMVF), (2) bilateral synchronized task-based mirror visual feedback training (BMVF), and (3) reciprocal task-based mirror visual feedback training (RMVF). During DMT, EEG recordings, including time-dependent event-related desynchronization (ERD) signal amplitude in both mu and beta bands, were obtained from the standard C3 (ispilesional hemisphere, IH), C4 (contralesional hemisphere, CH), and Cz scalp sites (supplementary motor area, SMA). The entire ERD curve was separated into three time-phases: P0 (-2 to 0 s), P1 (0 to 2 s), and P2 (2 to 4 s). Four-way and subsequent repeated-measures analyses of variance were used to examine the effects of group (stroke vs. control group), test condition (NoMVF, BMVF, and RMVF), time-phase (P0, P1, and P2), and brain area (IH, CH, SMA) on the ERD areas (%) in mu and beta bands. For the mu band, generally, ERD areas (%) were larger in the control than in the stroke group. The ERD areas (%) were largest under the RMVF condition, followed by BMVF and NoMVF conditions. Similar results were found in the beta bands. The main effects of group, time-phase, and test condition on the ERD areas (%) were significant for the three brain areas, except the main effect of group in the SMA (Cz) and CH (C4) brain area. The ERD areas (%) were larger in the control than in the stroke group. The ERD area (%) was significantly larger during P1 than during P0 and P2 (ps < 0.02), and during P2 than during P0 (ps < 0.01). The ERD area (%) under the RMVF condition was significantly larger than that under the BMVF condition and NoMVF condition (ps < 0.05). The present study suggests that cortical activation particularly in the SMA (Cz) of the brain increases in the RMVF condition in both healthy subjects and stroke patients. This result supports the hypothesis that stroke patients may benefit from RMVF training.

TDP-43 proteolysis is associated with astrocyte reactivity after traumatic brain injury in rodents.

The aggregation and deposition of transactivation response DNA-binding protein 43 (TDP-43) in neurons and astrocytes is characteristic in a number of neurodegenerative diseases including Alzheimer's disease, frontotemporal lobar degeneration, and amyotrophic lateral sclerosis. Nevertheless, the exact role of TDP-43 in astrocytes is unknown. Recently, TDP-43 was identified in neurons but not astrocytes after traumatic brain injury (TBI) in humans. In the present study, we evaluated TDP-43 expression and proteolysis in astrocytes in a rat model of TBI. We assessed TDP-43 fragment expression, astrocyte morphology, neuronal population numbers, and motor function after TBI with or without intracerebroventricular administration of a caspase-3 inhibitor. Motor dysfunction was observed after TBI in potential association astrocytic TDP-43 short fragment mislocalization and accumulation, astrogliosis, and neuronal loss. Notably, caspase-3 inhibition prevented these changes after TBI. Our findings suggest that TDP-43 proteolysis in astrocytes is related to astrogliosis and subsequent neuronal loss in TBI, and that TDP-43 may be an important therapeutic target for preventing motor dysfunction after TBI.

Risk factors for myocardial dysfunction after traumatic brain injury: A one-year follow-up study.

INTRODUCTION: Traumatic brain injury has been associated with an increased risk of myocardial dysfunction. Common abnormalities accompanying this pathology include electrocardiographic abnormalities, elevated creatine kinase levels, arrhythmias, and pathologic changes of the myocardium. The aim of this study was to determine if TBI patients have a higher risk of myocardial dysfunction than the general population and to identify the risk factors of myocardial dysfunction in TBI patients. PATIENTS AND METHODS: The study sample was drawn from Taiwan's National Health Insurance Research Database of reimbursement claims, and comprised 26,860 patients who visited ambulatory care centers or were hospitalized with a diagnosis of TBI. The comparison group consisted of 134,300 randomly selected individuals. The stratified Fine and Gray regression was performed to evaluate independent risk factors for myocardial dysfunction in all patients and to identify risk factors in TBI patients. RESULTS: During a 1-year follow-up period, 664 patients with TBI and 1494 controls developed myocardial dysfunction. TBI was independently associated with increased risk of myocardial dysfunction. Diabetes, hypertension, peptic ulcer disease, chronic liver disease and chronic renal disease were risk factors of myocardial dysfunction in TBI patients. CONCLUSIONS: Individuals with TBI are at greater risk of developing myocardial dysfunction after adjustments for possible confounding factors. Early monitor should be initiated to decrease disability and dependence in patients with TBI.

Endothelial differentiation of bone marrow mesenchyme stem cells applicable to hypoxia and increased migration through Akt and NFκB signals.

BACKGROUND: Bone marrow mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs) are used to repair hypoxic or ischemic tissue. However, the underlining mechanism of resistance in the hypoxic microenvironment and the efficacy of migration to the injured tissue are still unknown. The current study aims to understand the hypoxia resistance and migration ability of MSCs during differentiation toward endothelial lineages by biochemical and mechanical stimuli. METHOD: MSCs were harvested from the bone marrow of 6-8-week-old Sprague-Dawley rats. The endothelial growth medium (EGM) was added to MSCs for 3 days to initiate endothelial differentiation. Laminar shear stress was used as the fluid mechanical stimulation. RESULTS: Application of EGM facilitated the early endothelial lineage cells (eELCs) to express EPC markers. When treating the hypoxic mimetic desferrioxamine, both MSCs and eELCs showed resistance to hypoxia as compared with the occurrence of apoptosis in rat fibroblasts. The eELCs under hypoxia increased the wound closure and C-X-C chemokine receptor type 4 (CXCR4) gene expression. Although the shear stress promoted eELC maturation and aligned cells parallel to the flow direction, their migration ability was not superior to that of eELCs either under normoxia or hypoxia. The eELCs showed higher protein expressions of CXCR4, phosphorylated Akt (pAkt), and endogenous NFκB and IκBα than MSCs under both normoxia and hypoxia conditions. The potential migratory signals were discovered by inhibiting either Akt or NFκB using specific inhibitors and revealed decreases of wound closure and transmigration ability in eELCs. CONCLUSION: The Akt and NFκB pathways are important to regulate the early endothelial differentiation and its migratory ability under a hypoxic microenvironment.

The GLP-1 receptor agonists exendin-4 and liraglutide alleviate oxidative stress and cognitive and micturition deficits induced by middle cerebral artery occlusion in diabetic mice.

BACKGROUND: Glucagon-like peptide 1 (GLP-1) analogs protect a variety of cell types against oxidative damage and vascular and neuronal injury via binding to GLP-1 receptors. This study aimed to investigate the effects of the GLP-1 analogs exendin-4 and liraglutide on cerebral blood flow, reactive oxygen species production, expression of oxidative stress-related proteins, cognition, and pelvic sympathetic nerve-mediated bladder contraction after middle cerebral artery occlusion (MCAO) injury in the db/db mouse model of diabetes. RESULTS: Sixty minutes of MCAO increased blood and brain reactive oxygen species counts in male db/db mice, as revealed by dihydroethidium staining. MCAO also increased nuclear factor-κB and intercellular adhesion molecule-1 expression and decreased cerebral microcirculation. These effects were attenuated by treatment with exendin-4 or liraglutide. MCAO did not affect basal levels of phosphorylated Akt (p-Akt) or endothelial nitric oxide synthase (p-eNOS); however, exendin-4 and liraglutide treatments significantly enhanced p-Akt and p-eNOS levels, indicating activation of the p-Akt/p-eNOS signaling pathway. MCAO-induced motor and cognitive deficits and micturition dysfunction, indicated by reduced pelvic nerve-mediated voiding contractions and increased nonvoiding contractions, were also partially attenuated by exendin-4 treatment. CONCLUSIONS: The above data indicate that treatment with GLP-1 agonists exerts protective effects against oxidative, inflammatory, and apoptotic damage in brain areas that control parasympathetic/pelvic nerve-mediated voiding contractions and cognitive and motor behaviors in a diabetic mouse model.

Immediate Effects of Smoking on Cardiorespiratory Responses During Dynamic Exercise: Arm Vs. Leg Ergometry.

PURPOSE: This study compared the immediate effects of smoking on cardiorespiratory responses to dynamic arm and leg exercises. METHODS: This randomized crossover study recruited 14 college students. Each participant underwent two sets of arm-cranking (AC) and leg-cycling (LC) exercise tests. The testing sequences of the control trial (participants refrained from smoking for 8 h before testing) and the experimental trial (participants smoked two cigarettes immediately before testing) were randomly chosen. We observed immediate changes in pulmonary function and heart rate variability after smoking and before the exercise test. The participants then underwent graded exercise tests of their arms and legs until reaching exhaustion. We compared the peak work achieved and time to exhaustion during the exercise tests with various cardiorespiratory indices [i.e., heart rate, oxygen consumption (VO2), minute ventilation (VE)]. The differences between the smoking and control trials were calculated using paired t-tests. For the exercise test periods, VO2, heart rate, and VE values were calculated at every 10% increment of the maximal effort time. The main effects of the time and trial, as well as their trial-by-time (4 × 10) interaction effects on the outcome measures, were investigated using repeated measure ANOVA with trend analysis. RESULTS: 5 min after smoking, the participants exhibited reduced forced vital capacities and forced expiratory volumes in the first second (P < 0.05), in addition to elevated resting heart rates (P < 0.001). The high-frequency, low-frequency, and the total power of the heart rate variability were also reduced (P < 0.05) at rest. For the exercise test periods, smoking reduced the time to exhaustion (P = 0.005) and the ventilatory threshold (P < 0.05) in the LC tests, whereas no significant effects were observed in the AC tests. A trend analysis revealed a significant trial-by-time interaction effect for heart rate, VO2, and VE during the graded exercise test (all P < 0.001). Lower VO2 and VE levels were exhibited in the exercise response of the smoking trial than in those of the control LC trials, whereas no discernable inter-trial difference was observed in the AC trials. Moreover, the differences in heart rate and VE response between the LC and AC exercises were significantly smaller after the participants smoked. CONCLUSION: This study verified that smoking significantly decreased performance and cardiorespiratory responses to leg exercises. However, the negative effects of smoking on arm exercise performance were not as pronounced.

Delayed mirror visual feedback presented using a novel mirror therapy system enhances cortical activation in healthy adults.

BACKGROUND: Mirror visual feedback (MVF) generated in mirror therapy (MT) with a physical mirror promotes the recovery of hemiparetic limbs in patients with stroke, but is limited in that it cannot provide an asymmetric mode for bimanual coordination training. Here, we developed a novel MT system that can manipulate the MVF to resolve this issue. The aims of this pilot study were to examine the feasibility of delayed MVF on MT and to establish its effects on cortical activation in order to understand how it can be used for clinical applications in the future. METHODS: Three conditions (no MVF, MVF, and 2-s delayed MVF) presented via our digital MT system were evaluated for their time-course effects on cortical activity by event-related desynchronization (ERD) of mu rhythm electroencephalography (EEG) during button presses in 18 healthy adults. Phasic ERD areas, defined as the areas of the relative ERD curve that were below the reference level and within -2-0 s (P0), 0-2 s (P1), and 2-4 s (P2) of the button press, were used. RESULTS: The overall (P0 to P2) and phasic ERD areas were higher when MVF was provided compared to when MVF was not provided for all EEG channels (C3, Cz, and C4). Phasic ERD areas in the P2 phase only increased during the delayed-MVF condition. Significant enhancement of cortical activation in the mirror neuron system and an increase in attention to the unseen limb may play major roles in the response to MVF during MT. In comparison to the no MVF condition, the higher phasic ERD areas that were observed during the P1 phase in the delayed-MVF condition indicate that the image of the still hand may have enhanced the cortical activation that occurred in response to the button press. CONCLUSIONS: This study is the first to achieve delayed MVF for upper-limb MT. Our approach confirms previous findings regarding the effects of MVF on cortical activation and contributes additional evidence supporting the use of this method in the future for upper-limb motor training in patients with stroke.

Exendin-4-loaded PLGA microspheres relieve cerebral ischemia/reperfusion injury and neurologic deficits through long-lasting bioactivity-mediated phosphorylated Akt/eNOS signaling in rats.

Glucagon-like peptide-1 (GLP-1) receptor activation in the brain provides neuroprotection. Exendin-4 (Ex-4), a GLP-1 analog, has seen limited clinical usage because of its short half-life. We developed long-lasting Ex-4-loaded poly(D,L-lactide-co-glycolide) microspheres (PEx-4) and explored its neuroprotective potential against cerebral ischemia in diabetic rats. Compared with Ex-4, PEx-4 in the gradually degraded microspheres sustained higher Ex-4 levels in the plasma and cerebrospinal fluid for at least 2 weeks and improved diabetes-induced glycemia after a single subcutaneous administration (20 µg/day). Ten minutes of bilateral carotid artery occlusion (CAO) combined with hemorrhage-induced hypotension (around 30 mm Hg) significantly decreased cerebral blood flow and microcirculation in male Wistar rats subjected to streptozotocin-induced diabetes. CAO increased cortical O2(-) levels by chemiluminescence amplification and prefrontal cortex edema by T2-weighted magnetic resonance imaging analysis. CAO significantly increased aquaporin 4 and glial fibrillary acidic protein expression and led to cognition deficits. CAO downregulated phosphorylated Akt/endothelial nitric oxide synthase (p-Akt/p-eNOS) signaling and enhanced nuclear factor (NF)-κBp65/intercellular adhesion molecule-1 (ICAM-1) expression, endoplasmic reticulum (ER) stress, and apoptosis in the cerebral cortex. PEx-4 was more effective than Ex-4 to improve CAO-induced oxidative injury and cognitive deficits. The neuroprotection provided by PEx-4 was through p-Akt/p-eNOS pathways, which suppressed CAO-enhanced NF-κB/ICAM-1 signaling, ER stress, and apoptosis.

Glucagon-like peptide-1 receptor agonist activation ameliorates venous thrombosis-induced arteriovenous fistula failure in chronic kidney disease.

High shear stress that develops in the arteriovenous fistula of chronic kidney diseases (CKD) may increase H2O2 and thromboxane A2 (TXA2) release, thereby exacerbating endothelial dysfunction, thrombosis, and neointimal hyperplasia. We investigated whether glucagon-like peptide-1 receptor agonist/exendin-4, a potentially cardiovascular protective agent, could improve TXA2-induced arteriovenous fistula injury in CKD. TXA2 administration to H2O2-exposed human umbilical vein endothelial cells increased apoptosis, senescence, and detachment; these phenotypes were associated with the downregulation of phosphorylated endothelial nitric oxide synthase/heme oxygenase-1 (eNOS/HO-1) signalling. Exendin-4 reduced H2O2/TXA2-induced endothelial injury via inhibition of apoptosis-related mechanisms and restoration of phosphorylated eNOS/HO-1 signalling. Male Wistar rats subjected to right common carotid artery-external jugular vein anastomosis were treated with exendin-4 via cervical implant osmotic pumps for 16-42 days. High shear stress induced by the arteriovenous fistula significantly increased venous haemodynamics, blood and tissue H2O2 and TXB2 levels, macrophage/monocyte infiltration, fibrosis, proliferation, and adhesion molecule-1 expression. Apoptosis was also increased due to NADPH oxidase gp91 activation and mitochondrial Bax translocation in the proximal end of the jugular vein of CKD rats. Exendin-4-treatment of rats with CKD led to the restoration of normal endothelial morphology and correction of arteriovenous fistula function. Exendin-4 treatment or thromboxane synthase gene deletion in CKD mice markedly reduced ADP-stimulated platelet adhesion to venous endothelium, and prevented venous occlusion in FeCl3-injured vessels by upregulation of HO-1. Together, these data reveal that the use of glucagon-like peptide-1 receptor agonists is an effective strategy for treatment of CKD-induced arteriovenous fistula failure.

Dietary Monascus adlay supplements facilitate suppression of cigarette smoke-induced pulmonary endoplasmic reticulum stress, autophagy, apoptosis and emphysema-related PLGF in the rat.

Cigarette smoke (CS) exposure may cause oxidative stress in the lung, leading to cell death and long-term injury. Monascus adlay (MA) with antioxidant components produced by inoculating adlay (Cois lachrymal-jobi L. var. ma-yuen Stapf) with Monascus purpureus may protect lung against CS-induced lung injuries in rats. MA and lovastatin had higher antioxidant activities than either M. purpureus or adlay. CS exposure caused significant lung damage, as evidenced by higher levels of reactive oxygen species (ROS), neutrophil infiltration, dityrosine and 4-HNE, as well as lower levels of Mn-superoxide dismutase and catalase expression. Lung tissues with CS exposure had higher levels of ER stress, apoptosis, autophagy and emphysema-related placenta growth factor (PlGF) expressions. All CS-induced injuries were significantly suppressed by MA supplements. MA would be a beneficial nutritional therapy to ameliorate CS-induced lung injury via preserving antioxidant defense mechanisms, decreasing oxidative stress and inhibiting ER stress, autophagy, apoptosis and emphysema-related risk factor.

Therapeutic potential of traditional chinese medicine on inflammatory diseases.

Increased oxidative stress induces inflammation to several tissues/organs leading to cell death and long-term injury. Traditional Chinese Medicine (TCM) with antioxidant, anti-inflammatory, anti-apoptotic, and autophagic regulatory functions has been widely used as preventive or therapeutic strategy in modern medicine. Oxidative stress and inflammation have been widely reported to contribute to cigarette smoke-induced lung inflammation, hepatotoxicity, or sympathetic activation-induced liver inflammation, lipopolysaccharide-induced renal inflammation, and substance P-mediated neurogenic hyperactive bladder based on clinical findings. In this review, we introduce several evidences for TCM treatment including Monascus adlay (MA) produced by inoculating adlay (Cois lachrymal-jobi L. var. ma-yuen Stapf) with Monascus purpureus on lung injury, Amla (Emblica officinalis Gaertn. of Euphorbiaceae family) on hepatotoxin-induced liver inflammation, Virgate Wormwood Decoction (Yin Chén Hao tang) and its active component genipin on sympathetic activation-induced liver inflammation, and green tea extract and its active components, catechins, or a modified TCM formula Five Stranguries Powder (Wǔ Lén Sǎn) plus Crataegi Fructus (Shan Zha) on hyperactive bladder. The pathophysiologic and molecular mechanisms of TCM on ameliorating inflammatory diseases are discussed in the review.

Green tea extract supplementation ameliorates CCl4-induced hepatic oxidative stress, fibrosis, and acute-phase protein expression in rat.

BACKGROUND/PURPOSE: We evaluated the long-term effects of green tea extract (GTE) supplementation on oxidative stress, biliary acute phase protein expression, and liver function in CCl(4)-induced chronic liver injury. METHODS: We evaluated the antioxidant activity of GTE in comparison with those of vitamin C, vitamin E, and ß-carotene in vitro by using an ultrasensitive chemiluminescence analyzer. Chronic liver injury was induced by intraperitoneally administering carbon tetrachloride (CCl(4)) (1 mL/kg body weight, twice weekly) to female Wistar rats for 8 weeks. The effects of low (4 mg/kg body weight per day) and high (20 mg/kg body weight per day) doses of intragastric GTE on CCl(4)-induced liver dysfunction and fibrosis were examined by measuring the bile and blood reactive oxygen species levels and biochemical parameters by using Western blot and two-dimensional polyacrylamide gel electrophoresis techniques. RESULTS: GTE has greater scavenging activity against O(2)(-), H(2)O(2), and Hypochlorous acid (HOCl) in vitro than vitamin C, vitamin E, and ß-carotene do. In vivo, CCl(4) markedly increased bile and blood reactive oxygen species production, lipid accumulation, number of infiltrated leukocytes, fibrosis, hepatic hydroxyproline content, and plasma alanine aminotransferase and aspartate aminotransferase activities, and reduced plasma albumin levels. Two-dimensional polyacrylamide gel electrophoresis revealed that CCl(4) increased the acute-phase expression of six biliary proteins and decreased hepatic B-cell lymphoma 2 (Bcl-2), catalase, and CuZn superoxide dismutase protein expression. GTE supplementation attenuated CCl(4)-enhanced oxidative stress, levels of biochemical parameters, pathology, and acute-phase protein secretion, and preserved antioxidant/antiapoptotic protein expression. CONCLUSION: GTE supplementation attenuates CCl(4)-induced hepatic oxidative stress, fibrosis, acute phase protein excretion, and hepatic dysfunction via the antioxidant and antiapoptotic defense mechanisms.

Inhibitory effect of botulinum toxin type A on the NANC system in rat respiratory models of neurogenic inflammation.

This study investigated whether botulinum toxin type A (BTX-A) inhibits respiratory neurogenic inflammation in the non-adrenergic, non-cholinergic (NANC) transmitter system in rats. Neurogenic inflammation models were induced in Sprague Dawley (SD) rats through bilateral cerebral artery occlusion (BCAO) for different times (0, 30 and 60 min) or by stimulation with capsaicin at different doses (5 or 15 g/kg). Pre-Bötzinger Complex-Spikes and the expression of substance P, synaptosomal-associated protein-25 (SNAP-25), and reactive oxygen species (ROS) were detected with or without pretreatment of rats with BTX-A (15 or 30 U/kg). BCAO reduced pre-Bot C spike activity (spike/s) and increased the breath rate (breaths/s) in an unstable pattern in comparison to controls, while pretreatment with BTX-A slightly reduced this phenomenon. Pretreatment with BTX-A inhibited BCAO- or capsaicin-induced increases in expression of SNAP-25, substance P, and ROS in a dose-dependent manner in brainstem and lung tissue. BTX-A exerts a suppressive effect on neurogenic inflammation via non-adrenergic, non-cholinergic transmitters. These results add to the body of evidence elucidating the non-cholinergic effects of BTX-A in the context of neurogenic inflammation.

Repetitive progressive thermal preconditioning hinders thrombosis by reinforcing phosphatidylinositol 3-kinase/Akt-dependent heat-shock protein/endothelial nitric oxide synthase signaling.

OBJECTIVE: We compared the effects of modified progressive thermal preconditioning (PTP) and whole-body thermal preconditioning (TP) on stress responses, oxidative stress biomarkers, and arterial thrombosis formation, and explored their possible actions through phosphatidylinositol 3-kinase (PI3K)/Akt-dependent heat-shock protein (Hsp)/endothelial nitric oxide synthase (eNOS) pathways. METHODS: We divided four groups of 249 male Wistar rats into nonimmersed controls, TP, and one (1-PTP) and three consecutive cycles (3-PTP) of PTP in a 42°C water bath. We evaluated the stress responses, including hemodynamics, total energy transfer, endoplasmic reticulum (ER) stress marker glucose-regulated protein (GRP78), and blood reactive oxygen species level during TP or PTP treatment. We compared 1-PTP, 3-PTP, or TP effects on oxidative stress, intercellular adhesion molecule 1 (ICAM-1), Hsp70, tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) activity, and vascular phosphorylated Akt (p-Akt) and eNOS (p-eNOS) expressions in a model of topical ferric chloride (FeCl(3))-induced carotid artery thrombosis. RESULTS: PTP significantly (P < .05) induced less hemodynamic fluctuations, total energy transfer, ER, and oxidative stress than TP did. After 24 or 72 hours of treatment, 1-PTP, 3-PTP, and TP significantly (P < .05) elevated carotid arterial Hsp70, p-Akt, and p-eNOS expression, significantly (P < .05) depressed FeCl(3)-enhanced vascular 2',7'-dichlorodihydrofluorescein diacetate, chemokine (C-X3-C motif) ligand 1 (CX3CL1), 3-nitrotyrosine, 4-hydroxynonenal, and ICAM-1 stain, PAI-1, and t-PA activity, leukocyte infiltration and thrombus size, and significantly (P < .05) delayed thrombus formation compared with controls. 3-PTP and TP had a higher (P < .05) protection than 1-PTP. PI3K/Akt, Hsp70, or N(G)-nitro-l-arginine methyl ester hydrochloride (L-NAME) inhibitors significantly (P < .05) depressed 3-PTP and TP-induced vascular protection. CONCLUSIONS: Repetitive PTP is better than single PTP to hinder thrombosis formation via reinforcing PI3K/Akt-dependent Hsp70/eNOS signaling.