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Hsieh DY, Lai YR, Huang CC, Chen YN, Wu SY, Chiu WC, Cheng BC, Lin TY, Chiang HC, Lu CH. Baroreflex Sensitivity as a Surrogate Biomarker for Concurrently Assessing the Severity of Arterial Stiffness and Cardiovascular Autonomic Neuropathy in Individuals with Type 2 Diabetes. J Pers Med 2024; 14:491. [PMID: 38793073 PMCID: PMC11122369 DOI: 10.3390/jpm14050491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 04/22/2024] [Accepted: 04/29/2024] [Indexed: 05/26/2024] Open
Abstract
This study aimed to investigate whether baroreflex sensitivity (BRS) could serve as a reliable metric for assessing cardiovascular autonomic neuropathy (CAN) and concurrently act as a surrogate biomarker for evaluating the severity of arterial stiffness and CAN in individuals diagnosed with type 2 diabetes mellitus (T2DM). Participants underwent brachial-ankle pulse wave velocity (baPWV) as well as autonomic function evaluations encompassing the Sudoscan-based modified composite autonomic scoring scale (CASS), baroreflex sensitivity, and heart rate variability in time domains and frequency domains. Linear regression analysis was performed to evaluate the influence of independent variables on baPWV and modified CASS. Participants with higher baPWV values were older, with longer diabetes duration, lower body weight, body mass index, waist circumference, elevated systolic and diastolic blood pressure, and mean arterial blood pressure. They also exhibited a higher prevalence of retinopathy as the underlying disease and reduced estimated glomerular filtration rate. Multiple linear regression analysis revealed that age and BRS were significantly associated with baPWV while diabetes duration, UACR, and BRS were significantly associated with modified CASS. Our study confirms the significant association of BRS with baPWV and modified CASS in T2DM, highlighting its pivotal role in linking microvascular and macrovascular complications. This supports BRS as a surrogate marker for assessing both the severity of arterial stiffness and cardiovascular autonomic neuropathy in T2DM, enabling the early identification of complications.
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Affiliation(s)
- Dong-Yi Hsieh
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung City 83301, Taiwan; (D.-Y.H.); (Y.-R.L.); (H.-C.C.)
| | - Yun-Ru Lai
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung City 83301, Taiwan; (D.-Y.H.); (Y.-R.L.); (H.-C.C.)
- Department of Hyperbaric Oxygen Therapy Center, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung City 83301, Taiwan
| | - Chih-Cheng Huang
- Department of Neurology, Chi-Mei Medical Center, Tainan City 73657, Taiwan;
| | - Yung-Nien Chen
- Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung City 83301, Taiwan; (Y.-N.C.); (W.-C.C.); (B.-C.C.)
| | - Szu-Ying Wu
- Department of Chinese Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung City 83301, Taiwan;
| | - Wen-Chan Chiu
- Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung City 83301, Taiwan; (Y.-N.C.); (W.-C.C.); (B.-C.C.)
| | - Ben-Chung Cheng
- Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung City 83301, Taiwan; (Y.-N.C.); (W.-C.C.); (B.-C.C.)
| | - Ting-Yin Lin
- Department of Nursing, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung City 83301, Taiwan;
| | - Hui-Ching Chiang
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung City 83301, Taiwan; (D.-Y.H.); (Y.-R.L.); (H.-C.C.)
| | - Cheng-Hsien Lu
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung City 83301, Taiwan; (D.-Y.H.); (Y.-R.L.); (H.-C.C.)
- Department of Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung City 83301, Taiwan
- Department of Biological Science, National Sun Yat-Sen University, Kaohsiung City 80424, Taiwan
- Department of Neurology, Xiamen Chang Gung Memorial Hospital, Xiamen 361126, China
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Cardiorespiratory Interaction and Autonomic Sleep Quality Improve during Sleep in Beds Made from Pinus cembra (Stone Pine) Solid Wood. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:ijerph18189749. [PMID: 34574675 PMCID: PMC8472742 DOI: 10.3390/ijerph18189749] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Revised: 09/02/2021] [Accepted: 09/08/2021] [Indexed: 12/27/2022]
Abstract
Cardiorespiratory interactions (CRIs) reflect the mutual tuning of two important organismic oscillators—the heartbeat and respiration. These interactions can be used as a powerful tool to characterize the self-organizational and recreational quality of sleep. In this randomized, blinded and cross-over design study, we investigated CRIs in 15 subjects over a total of 253 nights who slept in beds made from different materials. One type of bed, used as control, was made of melamine faced chipboard with a wood-like appearance, while the other type was made of solid wood from stone pine (Pinus cembra). We observed a significant increase of vagal activity (measured by respiratory sinus arrhythmia), a decrease in the heart rate (as an indicator of energy consumption during sleep) and an improvement in CRIs, especially during the first hours of sleep in the stone pine beds as compared to the chipboard beds. Subjective assessments of study participants’ well-being in the morning and sub-scalar assessments of their intrapsychic stability were significantly better after they slept in the stone pine bed than after they slept in the chipboard bed. Our observations suggest that CRIs are sensitive to detectable differences in indoor settings that are relevant to human health. Our results are in agreement with those of other studies that have reported that exposure to volatile phytochemical ingredients of stone pine (α-pinene, limonene, bornyl acetate) lead to an improvement in vagal activity and studies that show a reduction in stress parameters upon contact with solid wood surfaces.
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Vidak E, Javoršek U, Vizovišek M, Turk B. Cysteine Cathepsins and their Extracellular Roles: Shaping the Microenvironment. Cells 2019; 8:cells8030264. [PMID: 30897858 PMCID: PMC6468544 DOI: 10.3390/cells8030264] [Citation(s) in RCA: 260] [Impact Index Per Article: 43.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Revised: 03/12/2019] [Accepted: 03/15/2019] [Indexed: 12/17/2022] Open
Abstract
For a long time, cysteine cathepsins were considered primarily as proteases crucial for nonspecific bulk proteolysis in the endolysosomal system. However, this view has dramatically changed, and cathepsins are now considered key players in many important physiological processes, including in diseases like cancer, rheumatoid arthritis, and various inflammatory diseases. Cathepsins are emerging as important players in the extracellular space, and the paradigm is shifting from the degrading enzymes to the enzymes that can also specifically modify extracellular proteins. In pathological conditions, the activity of cathepsins is often dysregulated, resulting in their overexpression and secretion into the extracellular space. This is typically observed in cancer and inflammation, and cathepsins are therefore considered valuable diagnostic and therapeutic targets. In particular, the investigation of limited proteolysis by cathepsins in the extracellular space is opening numerous possibilities for future break-through discoveries. In this review, we highlight the most important findings that establish cysteine cathepsins as important players in the extracellular space and discuss their roles that reach beyond processing and degradation of extracellular matrix (ECM) components. In addition, we discuss the recent developments in cathepsin research and the new possibilities that are opening in translational medicine.
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Affiliation(s)
- Eva Vidak
- Jozef Stefan Institute, Department of Biochemistry and Molecular and Structural Biology, Jamova 39, SI-1000 Ljubljana, Slovenia.
- International Postgraduate School Jozef Stefan, Jamova 39, SI-1000 Ljubljana, Slovenia.
| | - Urban Javoršek
- Jozef Stefan Institute, Department of Biochemistry and Molecular and Structural Biology, Jamova 39, SI-1000 Ljubljana, Slovenia.
- International Postgraduate School Jozef Stefan, Jamova 39, SI-1000 Ljubljana, Slovenia.
| | - Matej Vizovišek
- Jozef Stefan Institute, Department of Biochemistry and Molecular and Structural Biology, Jamova 39, SI-1000 Ljubljana, Slovenia.
- Department of Biology, Institute of Molecular Systems Biology, ETH Zürich Otto-Stern-Weg 3, 8093 Zürich, Switzerland.
| | - Boris Turk
- Jozef Stefan Institute, Department of Biochemistry and Molecular and Structural Biology, Jamova 39, SI-1000 Ljubljana, Slovenia.
- Faculty of Chemistry and Chemical Technology, University of Ljubljana, Vecna pot 113, SI-1000 Ljubljana, Slovenia.
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Dou Y, Luo J, Wu X, Wei Z, Tong B, Yu J, Wang T, Zhang X, Yang Y, Yuan X, Zhao P, Xia Y, Hu H, Dai Y. Curcumin attenuates collagen-induced inflammatory response through the "gut-brain axis". J Neuroinflammation 2018; 15:6. [PMID: 29306322 PMCID: PMC5756354 DOI: 10.1186/s12974-017-1047-7] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Accepted: 12/20/2017] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Previous studies have demonstrated that oral administration of curcumin exhibited an anti-arthritic effect despite its poor bioavailability. The present study aimed to explore whether the gut-brain axis is involved in the therapeutic effect of curcumin. METHODS The collagen-induced arthritis (CIA) rat model was induced by immunization with an emulsion of collagen II and complete Freund's adjuvant. Sympathetic and parasympathetic tones were measured by electrocardiographic recordings. Unilateral cervical vagotomy (VGX) was performed before the induction of CIA. The ChAT, AChE activities, and serum cytokine levels were determined by ELISA. The expression of the high-affinity choline transporter 1 (CHT1), ChAT, and vesicular acetylcholine transporter (VAChT) were determined by real-time PCR and immunohistochemical staining. The neuronal excitability of the vagus nerve was determined by whole-cell patch clamp recording. RESULTS Oral administration of curcumin restored the imbalance between the sympathetic and parasympathetic tones in CIA rats and increased ChAT activity and expression of ChAT and VAChT in the gut, brain, and synovium. Additionally, VGX eliminated the effects of curcumin on arthritis and ACh biosynthesis and transport. Electrophysiological data showed that curcumin markedly increased neuronal excitability of the vagus nerve. Furthermore, selective α7 nAChR antagonists abolished the effects of curcumin on CIA. CONCLUSIONS Our results demonstrate that curcumin attenuates CIA through the "gut-brain axis" by modulating the function of the cholinergic system. These findings provide a novel approach for mechanistic studies of anti-arthritic compounds with low oral absorption and bioavailability.
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Affiliation(s)
- Yannong Dou
- Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China
| | - Jinque Luo
- Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China
| | - Xin Wu
- Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China
| | - Zhifeng Wei
- Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China
| | - Bei Tong
- Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China
| | - Juntao Yu
- Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China
| | - Ting Wang
- Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China
| | - Xinyu Zhang
- Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China
| | - Yan Yang
- Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China
| | - Xusheng Yuan
- Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China
| | - Peng Zhao
- Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China
| | - Yufeng Xia
- Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China
| | - Huijuan Hu
- Department of Pharmacology and Physiology, Drexel University College of Medicine, 245 N. 15th Street, Philadelphia, PA, 19102, USA.
| | - Yue Dai
- Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China.
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Dantzer R. Neuroimmune Interactions: From the Brain to the Immune System and Vice Versa. Physiol Rev 2018; 98:477-504. [PMID: 29351513 PMCID: PMC5866360 DOI: 10.1152/physrev.00039.2016] [Citation(s) in RCA: 572] [Impact Index Per Article: 81.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Revised: 06/05/2017] [Accepted: 06/18/2017] [Indexed: 12/14/2022] Open
Abstract
Because of the compartmentalization of disciplines that shaped the academic landscape of biology and biomedical sciences in the past, physiological systems have long been studied in isolation from each other. This has particularly been the case for the immune system. As a consequence of its ties with pathology and microbiology, immunology as a discipline has largely grown independently of physiology. Accordingly, it has taken a long time for immunologists to accept the concept that the immune system is not self-regulated but functions in close association with the nervous system. These associations are present at different levels of organization. At the local level, there is clear evidence for the production and use of immune factors by the central nervous system and for the production and use of neuroendocrine mediators by the immune system. Short-range interactions between immune cells and peripheral nerve endings innervating immune organs allow the immune system to recruit local neuronal elements for fine tuning of the immune response. Reciprocally, immune cells and mediators play a regulatory role in the nervous system and participate in the elimination and plasticity of synapses during development as well as in synaptic plasticity at adulthood. At the whole organism level, long-range interactions between immune cells and the central nervous system allow the immune system to engage the rest of the body in the fight against infection from pathogenic microorganisms and permit the nervous system to regulate immune functioning. Alterations in communication pathways between the immune system and the nervous system can account for many pathological conditions that were initially attributed to strict organ dysfunction. This applies in particular to psychiatric disorders and several immune-mediated diseases. This review will show how our understanding of this balance between long-range and short-range interactions between the immune system and the central nervous system has evolved over time, since the first demonstrations of immune influences on brain functions. The necessary complementarity of these two modes of communication will then be discussed. Finally, a few examples will illustrate how dysfunction in these communication pathways results in what was formerly considered in psychiatry and immunology to be strict organ pathologies.
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Affiliation(s)
- Robert Dantzer
- Department of Symptom Research, University of Texas MD Anderson Cancer Center , Houston, Texas
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6
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Sui HX, Ke SZ, Xu DD, Lu NN, Wang YN, Zhang YH, Gao FG. Nicotine induces TIPE2 upregulation and Stat3 phosphorylation contributes to cholinergic anti-inflammatory effect. Int J Oncol 2017; 51:987-995. [PMID: 28766689 DOI: 10.3892/ijo.2017.4080] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2017] [Accepted: 07/24/2017] [Indexed: 11/06/2022] Open
Abstract
Cholinergic anti-inflammatory pathway has therapeutic effect on inflammation-associated diseases. However, the exact mechanism of nicotine-mediated anti-inflammatory effect is still unclear. TIPE2, a new member of tumor necrosis factor-α-induced protein-8 family, is a negative regulator of immune homeostasis. However, the roles of TIPE2 in cholinergic anti-inflammatory effect are still uncertain. Here, we demonstrated that nicotine exerts its anti-inflammatory effect by TIPE2 upregulation and phosphorylated stat3 mediated the inhibition of NF-κB activation, which was supported by the following evidence: firstly, both nicotine and TIPE2 inhibit pro-inflammatory cytokine release via NF-κB inactivation. Secondly, nicotine upregulates TIPE2 expression via α7 nicotinic acetylcholine receptor. Moreover, the enhancement of stat3 phosphorylation and decrease of LPS-induced p65 translocation were achieved by nicotine treatment. Importantly, nicotine treatment augments the interaction of phosphorylated stat3 and p65, indicating that the inhibitory effect of nicotine on NF-κB activation was mediated with protein-protein interactions. Hence, this study revealed that TIPE2 upregulation and stat3 phosphorylation contribute to nicotine-mediated anti-inflammation effect, indicating that TIPE2 and stat3 might be potential molecules for dealing with inflammation-associated diseases.
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Affiliation(s)
- Hua Xiu Sui
- Department of Immunology, Basic Medicine Science, Medical College, Xiamen University, Xiamen, Fujian 361102, P.R. China
| | - Shi Zhong Ke
- Department of Immunology, Basic Medicine Science, Medical College, Xiamen University, Xiamen, Fujian 361102, P.R. China
| | - Dan Dan Xu
- Department of Immunology, Basic Medicine Science, Medical College, Xiamen University, Xiamen, Fujian 361102, P.R. China
| | - Nan Nan Lu
- Department of Immunology, Basic Medicine Science, Medical College, Xiamen University, Xiamen, Fujian 361102, P.R. China
| | - Yi Nan Wang
- Department of Immunology, Basic Medicine Science, Medical College, Xiamen University, Xiamen, Fujian 361102, P.R. China
| | - Yue Hua Zhang
- Department of Immunology, Basic Medicine Science, Medical College, Xiamen University, Xiamen, Fujian 361102, P.R. China
| | - Feng Guang Gao
- Department of Immunology, Basic Medicine Science, Medical College, Xiamen University, Xiamen, Fujian 361102, P.R. China
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Payne P, Fiering S, Leiter JC, Zava DT, Crane-Godreau MA. Effectiveness of a Novel Qigong Meditative Movement Practice for Impaired Health in Flight Attendants Exposed to Second-Hand Cigarette Smoke. Front Hum Neurosci 2017; 11:67. [PMID: 28270757 PMCID: PMC5318411 DOI: 10.3389/fnhum.2017.00067] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2016] [Accepted: 02/01/2017] [Indexed: 12/12/2022] Open
Abstract
This single-arm non-randomized pilot study explores an intervention to improve the health of flight attendants (FA) exposed to second-hand cigarette smoke prior to the smoking ban on commercial airlines. This group exhibits an unusual pattern of long-term pulmonary dysfunction. We report on Phase I of a two-phase clinical trial; the second Phase will be a randomized controlled trial testing digital delivery of the intervention. Subjects were recruited in the Northeastern US; testing and intervention were administered in 4 major cities. The intervention involved 12 h of training in Meditative Movement practices. Based on recent research on the effects of nicotine on fear learning, and the influence of the autonomic nervous system on immune function, our hypothesis was that this training would improve autonomic function and thus benefit a range of health measures. Primary outcomes were the 6-min walk test and blood levels of C-reactive protein. Pulmonary, cardiovascular, autonomic, and affective measures were also taken. Fourteen participants completed the training and post-testing. There was a 53% decrease in high sensitivity C-Reactive Protein (p ≤ 0.05), a 7% reduction in systolic blood pressure (p ≤ 0.05), a 13% increase in the 6-min walk test (p ≤ 0.005), and significant positive changes in several other outcomes. These results tend to confirm the hypothesized benefits of MM training for this population, and indicate that autonomic function may be important in the etiology and treatment of their symptoms. No adverse effects were reported. This trial is registered at ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT02612389/), and is supported by a grant from the Flight Attendant Medical Research Institute (FAMRI).
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Affiliation(s)
- Peter Payne
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth Lebanon, NH, USA
| | - Steven Fiering
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth Lebanon, NH, USA
| | - James C Leiter
- Department of Molecular and System Biology, Geisel School of Medicine at Dartmouth Lebanon, NH, USA
| | | | - Mardi A Crane-Godreau
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth Lebanon, NH, USA
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Abstract
Although many studies have demonstrated that components of the hemostatic system may be involved in signaling leading to cancer progression, the potential mechanisms by which they contribute to cancer dissemination are not yet precisely understood. Among known coagulant factors, tissue factor (TF) and thrombin play a pivotal role in cancer invasion. They may be generated in the tumor microenvironment independently of blood coagulation and can induce cell signaling through activation of protease-activated receptors (PARs). PARs are transmembrane G-protein-coupled receptors (GPCRs) that are activated by a unique proteolytic mechanism. They play important roles in vascular physiology, neural tube closure, hemostasis, and inflammation. All of these agents (TF, thrombin, PARs—mainly PAR-1 and PAR-2) are thought to promote cancer invasion and metastasis at least in part by facilitating tumor cell migration, angiogenesis, and interactions with host vascular cells, including platelets, fibroblasts, and endothelial cells lining blood vessels. Here, we discuss the role of PARs and their activators in cancer progression, focusing on TF- and thrombin-mediated actions. Therapeutic options tailored specifically to inhibit PAR-induced signaling in cancer patients are presented as well.
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Payne P, Zava D, Fiering S, Crane-Godreau M. Meditative Movement as a Treatment for Pulmonary Dysfunction in Flight Attendants Exposed to Second-Hand Cigarette Smoke: Study Protocol for a Randomized Trial. Front Psychiatry 2016; 7:38. [PMID: 27047398 PMCID: PMC4801846 DOI: 10.3389/fpsyt.2016.00038] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2015] [Accepted: 02/29/2016] [Indexed: 12/03/2022] Open
Abstract
A study protocol is presented for the investigation of meditative movement (MM) as a treatment for pulmonary dysfunction in flight attendants (FA) who were exposed to second-hand cigarette smoke while flying before the smoking ban. The study will have three parts, some of which will run concurrently. The first is a data gathering and screening phase, which will gather data on pulmonary and other aspects of the health of FA, and will also serve to screen participants for the other phases. Second is an exercise selection phase, in which a variety of MM exercises will be taught, over a 16-week period, to a cohort of 20 FA. A subset of these exercises will be selected on the basis of participant feedback on effectiveness and compliance. Third is a 52-week randomized controlled trial to evaluate the effectiveness of a digitally delivered form of the previously selected exercises on a group of 20 FA, as compared with an attention control group. Outcome measures to be used in all three parts of the study include the 6-min walk test as a primary measure, as well as a range of biomarkers, tests, and questionnaires documenting hormonal, cardio-respiratory, autonomic, and affective state. This study is registered at ClinicalTrials.gov. Identifier: NCT02612389.
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Affiliation(s)
- Peter Payne
- Microbiology and Immunology, Geisel School of Medicine at Dartmouth , Hanover, NH , USA
| | | | - Steven Fiering
- Microbiology and Immunology, Geisel School of Medicine at Dartmouth , Hanover, NH , USA
| | - Mardi Crane-Godreau
- Microbiology and Immunology, Geisel School of Medicine at Dartmouth , Hanover, NH , USA
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Ba L, Wu DQ, Qian AY, Zhang M, Xiong B. Dynamic changes of serum cholinesterase activity after severe trauma. J Zhejiang Univ Sci B 2015; 15:1023-31. [PMID: 25471831 DOI: 10.1631/jzus.b1400129] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
OBJECTIVE The aim of the present study was to examine dynamic changes in serum cholinesterase (ChE) activity during early-stage severe trauma and the clinical significance of these changes. METHODS This prospective, observational study included 81 patients with severe trauma who were treated between October 2011 and April 2013 in the emergency intensive care unit (EICU) of a university-affiliated, tertiary-care, grade A general hospital in China. Serum ChE activity was measured on Days 1, 3, and 7 post-injury. The correlation of dynamic changes in serum ChE activity with trauma severity and prognosis was assessed. Correlations between changes in serum ChE activity after injury and albumin (ALB), prealbumin (PAB), transferrin (TRF), and C-reactive protein (CRP) levels were also analyzed. RESULTS Serum ChE activity in trauma patients was 42.3%-50.2% lower on Days 1, 3, and 7 compared with the control (P<0.001 for all time points), and it continued to decrease after Day 7 in both the survival and death subgroups. In the subgroup with an injury severity score (ISS) of ≤25, serum ChE activity initially decreased, but eventually increased. However, activity decreased continuously in the ISS>25 subgroup. ChE activity was significantly lower in both the death and the ISS>25 subgroups than in the survival and ISS≤25 subgroups on Days 1, 3, and 7 after injury. Activity was negatively correlated with ISS and acute physiology and chronic health evaluation III (APACHE III) at all time points. When comparing the receiver operating characteristic (ROC) curves for predicting prognosis, the area under the curve (AUC) in the plot of serum ChE was similar to the AUCs in plots of ISS and APACHE III, but significantly smaller than the AUC in the plot of the trauma and injury severity score (TRISS). Serum ChE activity was positively correlated with ALB, PAB, and TRF at all time points post-injury. Activity was not significantly correlated with CRP on Day 1, but was significantly and negatively correlated with CRP on Days 3 and 7. CONCLUSIONS There is a significant decrease in serum ChE activity after severe trauma. Serum ChE may be regarded as a negative acute phase protein (APP) and the dynamic changes in serum ChE may be useful as an auxiliary indicator for evaluating trauma severity and predicting prognosis.
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Affiliation(s)
- Li Ba
- Department of Emergency Medicine, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China; Department of Rehabilitation Medicine, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310052, China
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Yang C, Gao W, Yang X, Wang H, Du J, Zhong H, Zhou L, Zhou J, Zhang Y, Jiang J. CRH knockout inhibits the murine innate immune responses in association with endoplasmic reticulum stress after thermal injury. Surgery 2015; 158:255-65. [DOI: 10.1016/j.surg.2015.01.024] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2014] [Revised: 12/18/2014] [Accepted: 01/29/2015] [Indexed: 01/07/2023]
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Nyitray CE, Chang R, Faleo G, Lance KD, Bernards DA, Tang Q, Desai T. Polycaprolactone Thin-Film Micro- and Nanoporous Cell-Encapsulation Devices. ACS NANO 2015; 9:5675-82. [PMID: 25950860 PMCID: PMC4628825 DOI: 10.1021/acsnano.5b00679] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/25/2023]
Abstract
Cell-encapsulating devices can play an important role in advancing the types of tissue available for transplantation and further improving transplant success rates. To have an effective device, encapsulated cells must remain viable, respond to external stimulus, and be protected from immune responses, and the device itself must elicit a minimal foreign body response. To address these challenges, we developed a micro- and a nanoporous thin-film cell encapsulation device from polycaprolactone (PCL), a material previously used in FDA-approved biomedical devices. The thin-film device construct allows long-term bioluminescent transfer imaging, which can be used for monitoring cell viability and device tracking. The ability to tune the microporous and nanoporous membrane allows selective protection from immune cell invasion and cytokine-mediated cell death in vitro, all while maintaining typical cell function, as demonstrated by encapsulated cells' insulin production in response to glucose stimulation. To demonstrate the ability to track, visualize, and monitor the viability of cells encapsulated in implanted thin-film devices, we encapsulated and implanted luciferase-positive MIN6 cells in allogeneic mouse models for up to 90 days. Lack of foreign body response in combination with rapid neovascularization around the device shows promise in using this technology for cell encapsulation. These devices can help elucidate the metrics required for cell encapsulation success and direct future immune-isolation therapies.
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Affiliation(s)
- Crystal E. Nyitray
- Program in Chemistry and Chemical Biology, University of California, San Francisco, 1700 4th Street, Byers Hall, Box 2520, San Francisco, California 94158, United States
| | - Ryan Chang
- UCB/UCSF Joint Program in Bioengineering, University of California, San Francisco, 1700 4th Street, Byers Hall, Box 2520, San Francisco, California 94158, United States
| | - Gaetano Faleo
- Department of Surgery, University of California, San Francisco, 513 Parnassus Avenue HSE520 Box 0780, San Francisco, California 94143, United States
| | - Kevin D. Lance
- UCB/UCSF Joint Program in Bioengineering, University of California, San Francisco, 1700 4th Street, Byers Hall, Box 2520, San Francisco, California 94158, United States
| | - Daniel A. Bernards
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, 1700 4th Street, Byers Hall, Box 2520, San Francisco, California 94158, United States
| | - Qizhi Tang
- Department of Surgery, University of California, San Francisco, 513 Parnassus Avenue HSE520 Box 0780, San Francisco, California 94143, United States
| | - TejalA Desai
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, 1700 4th Street, Byers Hall, Box 2520, San Francisco, California 94158, United States
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Francoeur RB. Using an innovative multiple regression procedure in a cancer population (Part II): fever, depressive affect, and mobility problems clarify an influential symptom pair (pain-fatigue/weakness) and cluster (pain-fatigue/weakness-sleep problems). Onco Targets Ther 2015; 8:57-72. [PMID: 25565866 PMCID: PMC4278791 DOI: 10.2147/ott.s68859] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
Background Most patients with advanced cancer experience symptom pairs or clusters among pain, fatigue, and insomnia. However, only combinations where symptoms are mutually influential hold potential for identifying patient subgroups at greater risk, and in some contexts, interventions with “cross-over” (multisymptom) effects. Improved methods to detect and interpret interactions among symptoms, signs, or biomarkers are needed to reveal these influential pairs and clusters. I recently created sequential residual centering (SRC) to reduce multicollinearity in moderated regression, which enhances sensitivity to detect these interactions. Methods I applied SRC to moderated regressions of single-item symptoms that interact to predict outcomes from 268 palliative radiation outpatients. I investigated: 1) the hypothesis that the interaction, pain × fatigue/weakness × sleep problems, predicts depressive affect only when fever presents, and 2) an exploratory analysis, when fever is absent, that the interaction, pain × fatigue/weakness × sleep problems × depressive affect, predicts mobility problems. In the fever context, three-way interactions (and derivative terms) of the four symptoms (pain, fatigue/weakness, fever, sleep problems) are tested individually and simultaneously; in the non-fever context, a single four-way interaction (and derivative terms) is tested. Results Fever interacts separately with fatigue/weakness and sleep problems; these comoderators each magnify the pain–depressive affect relationship along the upper or full range of pain values. In non-fever contexts, fatigue/weakness, sleep problems, and depressive affect comagnify the relationship between pain and mobility problems. Conclusion Different mechanisms contribute to the pain × fatigue/weakness × sleep problems interaction, but all depend on the presence of fever, a sign/biomarker/symptom of proinflammatory sickness behavior. In non-fever contexts, depressive affect is no longer an outcome representing malaise from the physical symptoms of sickness, but becomes a fourth symptom of the interaction. In outpatient subgroups at heightened risk, single interventions could potentially relieve multiple symptoms when fever accompanies sickness malaise and in non-fever contexts with mobility problems. SRC strengthens insights into symptom pairs/clusters.
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Affiliation(s)
- Richard B Francoeur
- School of Social Work and the Center for Health Innovation, Adelphi University, Garden City, NY, USA ; Center for the Psychosocial Study of Health and Illness, Columbia University, New York, NY, USA
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14
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Wang Y, Xiao C, Indersmitten T, Freedman R, Leonard S, Lester HA. The duplicated α7 subunits assemble and form functional nicotinic receptors with the full-length α7. J Biol Chem 2014; 289:26451-26463. [PMID: 25056953 DOI: 10.1074/jbc.m114.582858] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The α7 nicotinic acetylcholine receptor gene (CHRNA7) is linked to schizophrenia. A partial duplication of CHRNA7 (CHRFAM7A) is found in humans on 15q13-14. Exon 6 of CHRFAM7A harbors a 2-bp deletion polymorphism, CHRFAM7AΔ2bp, which is also associated with schizophrenia. To understand the effects of the duplicated subunits on α7 receptors, we fused α7, dupα7, and dupΔα7 subunits with various fluorescent proteins. The duplicated subunits co-localized with full-length α7 subunits in mouse neuroblastoma cells (Neuro2a) as well as rat hippocampal neurons. We investigated the interaction between the duplicated subunits and full-length α7 by measuring Förster resonance energy transfer using donor recovery after photobleaching and fluorescence lifetime imaging microscopy. The results revealed that the duplicated proteins co-assemble with α7. In electrophysiological studies, Leu at the 9'-position in the M2 membrane-spanning segment was replaced with Cys in dupα7 or dupΔα7, and constructs were co-transfected with full-length α7 in Neuro2a cells. Exposure to ethylammonium methanethiosulfonate inhibited acetylcholine-induced currents, showing that the assembled functional nicotinic acetylcholine receptors (nAChRs) included the duplicated subunit. Incorporation of dupα7 and dupΔα7 subunits modestly changes the sensitivity of receptors to choline and varenicline. Thus, the duplicated proteins are assembled and transported to the cell membrane together with full-length α7 subunits and alter the function of the nAChRs. The characterization of dupα7 and dupΔα7 as well as their influence on α7 nAChRs may help explain the pathophysiology of schizophrenia and may suggest therapeutic strategies.
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Affiliation(s)
- Ying Wang
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125 and
| | - Cheng Xiao
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125 and
| | - Tim Indersmitten
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125 and
| | - Robert Freedman
- Department of Psychiatry, University of Colorado at Denver, Denver, Colorado 80045
| | - Sherry Leonard
- Department of Psychiatry, University of Colorado at Denver, Denver, Colorado 80045
| | - Henry A Lester
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125 and.
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Involvement of α7 nAChR subtype in rat oxaliplatin-induced neuropathy: Effects of selective activation. Neuropharmacology 2014; 79:37-48. [DOI: 10.1016/j.neuropharm.2013.10.034] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2013] [Revised: 10/14/2013] [Accepted: 10/28/2013] [Indexed: 12/12/2022]
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Park JY, Park JJ, Jeon S, Doo AR, Kim SN, Lee H, Chae Y, Maixner W, Lee H, Park HJ. From peripheral to central: the role of ERK signaling pathway in acupuncture analgesia. THE JOURNAL OF PAIN 2014; 15:535-49. [PMID: 24524846 DOI: 10.1016/j.jpain.2014.01.498] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 12/11/2013] [Revised: 01/23/2014] [Accepted: 01/29/2014] [Indexed: 01/04/2023]
Abstract
UNLABELLED Despite accumulating evidence of the clinical effectiveness of acupuncture, its mechanism remains largely unclear. We assume that molecular signaling around the acupuncture needled area is essential for initiating the effect of acupuncture. To determine possible bio-candidates involved in the mechanisms of acupuncture and investigate the role of such bio-candidates in the analgesic effects of acupuncture, we conducted 2 stepwise experiments. First, a genome-wide microarray of the isolated skin layer at the GB34-equivalent acupoint of C57BL/6 mice 1 hour after acupuncture found that a total of 236 genes had changed and that extracellular signal-regulated kinase (ERK) activation was the most prominent bio-candidate. Second, in mouse pain models using formalin and complete Freund adjuvant, we found that acupuncture attenuated the nociceptive behavior and the mechanical allodynia; these effects were blocked when ERK cascade was interrupted by the mitogen-activated protein kinase kinase (MEK)/mitogen-activated protein kinase (MAPK) inhibitor U0126 (.8 μg/μL). Based on these results, we suggest that ERK phosphorylation following acupuncture needling is a biochemical hallmark initiating the effect of acupuncture including analgesia. PERSPECTIVE This article presents the novel evidence of the local molecular signaling in acupuncture analgesia by demonstrating that ERK activation in the skin layer contributes to the analgesic effect of acupuncture in a mouse pain model. This work improves our understanding of the scientific basis underlying acupuncture analgesia.
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Affiliation(s)
- Ji-Yeun Park
- Studies of Translational Acupuncture Research, Acupuncture and Meridian Science Research Center, Kyung Hee University, Seoul, Republic of Korea; Department of Korean Medical Science, Graduate School of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Jongbae J Park
- Asian Medicine and Acupuncture Research, Department of Physical Medicine and Rehabilitation, Chapel Hill, North Carolina; Center for Pain Research and Innovation, UNC School of Dentistry, Chapel Hill, North Carolina
| | - Songhee Jeon
- Dongguk University Research Institute of Biotechnology, Seoul, Republic of Korea
| | - Ah-Reum Doo
- Studies of Translational Acupuncture Research, Acupuncture and Meridian Science Research Center, Kyung Hee University, Seoul, Republic of Korea
| | - Seung-Nam Kim
- Studies of Translational Acupuncture Research, Acupuncture and Meridian Science Research Center, Kyung Hee University, Seoul, Republic of Korea; Department of Korean Medical Science, Graduate School of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Hyangsook Lee
- Studies of Translational Acupuncture Research, Acupuncture and Meridian Science Research Center, Kyung Hee University, Seoul, Republic of Korea
| | - Younbyoung Chae
- Studies of Translational Acupuncture Research, Acupuncture and Meridian Science Research Center, Kyung Hee University, Seoul, Republic of Korea; Department of Korean Medical Science, Graduate School of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - William Maixner
- Center for Pain Research and Innovation, UNC School of Dentistry, Chapel Hill, North Carolina
| | - Hyejung Lee
- Studies of Translational Acupuncture Research, Acupuncture and Meridian Science Research Center, Kyung Hee University, Seoul, Republic of Korea; Department of Korean Medical Science, Graduate School of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Hi-Joon Park
- Studies of Translational Acupuncture Research, Acupuncture and Meridian Science Research Center, Kyung Hee University, Seoul, Republic of Korea; Carolina Asia Center, UNC-Chapel Hill, Chapel Hill, North Carolina.
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Jung SJ, Bae KH, Nam MH, Kwon HM, Song YK, Soh KS. Primo vascular system floating in lymph ducts of rats. J Acupunct Meridian Stud 2013; 6:306-18. [PMID: 24290795 DOI: 10.1016/j.jams.2013.09.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2013] [Accepted: 09/03/2013] [Indexed: 11/29/2022] Open
Abstract
An epoch-making development in the gross anatomy of the lymph system has emerged: the observation of the primo vascular system (PVS), which is a threadlike structure floating in lymph ducts. The PVS, which was proposed as the conduit for the acupuncture Qi, is a complex network distributed throughout an animal's body. The lymph-PVS, which is a subsystem of the PVS, is one of the most convincing visual demonstrations of the PVS. Because its existence is not easily demonstrated, even with a microscope, due to its transparency, in current anatomy its existence is largely unknown despite its potential significance in physiology and medicine. The lymph-PVS has been observed in rabbits, rats, and mice by several independent teams. Because the involved techniques are rather complicated, we provide detailed protocols for surgery, for injection of the staining dye, and for detection, extraction, and identification of the PVS in a rat.
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Affiliation(s)
- Sharon Jiyoon Jung
- Nano Primo Research Center, Advanced Institute of Convergence Technology, Seoul National University, Suwon, South Korea; Graduate School of Convergence Science and Technology, Seoul National University, Suwon, South Korea
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Abstract
Inflammatory bowel disease is associated with industrialization, and its incidence has increased markedly over time. The prospect of reversing these trends motivates the search for the agent(s) involved. Modernity entails several physical and behavioral modifications that compromise both the photosynthesis of cholecalciferol in the skin and of its bioavailability. Although deficiency in this "vitamin" has therefore emerged as a leading candidate, and despite the publication of a randomized control trial that showed a trend toward statistically significant benefit in Crohn's disease, its causal agency has yet to be demonstrated by an adequately powered study. We discuss the strengths and weaknesses of the case being made by epidemiologists, geneticists, clinicians, and basic researchers, and consolidate their findings into a model that provides mechanistic plausibility to the claim. Specifically, converging data sets suggest that local activation of vitamin D coordinates the activity of the innate and adaptive arms of immunity, and of the intestinal epithelium, in a manner that promotes barrier integrity, facilitates the clearance of translocated flora, and diverts CD4 T cell development away from inflammatory phenotypes. Because smoking is an important risk-altering exposure, we also discuss its newly established melanizing effect and other emerging evidence linking tobacco use to immune function through vitamin D pathways.
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Effects of Acupuncture on 1-Chloro-2,4-dinitrochlorobenzene-Induced Atopic Dermatitis. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2013; 2013:982095. [PMID: 23997805 PMCID: PMC3755411 DOI: 10.1155/2013/982095] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/16/2013] [Revised: 07/03/2013] [Accepted: 07/05/2013] [Indexed: 11/18/2022]
Abstract
Though the effects of acupuncture in atopic dermatitis have been proven in clinical studies, its mechanism remains unclear. In this study, we investigate the effectiveness and mechanism of action for acupuncture treatment on the LI11 meridian point for treatment of allergic contact dermatitis. BALB/c mice received 1-chloro-2,4-dinitrobenzene (DNCB) application to induce skin inflammation. Acupuncture treatment on LI11 significantly inhibited cutaneous hyperplasia, serum IgE levels, and expression of proinflammatory cytokine (IL-4, IL-8, and TNF- α ) mRNA and NF- κ B, ERK1/2, JNK, and p38 proteins. Acupuncture treatment of local points also inhibited cutaneous hyperplasia and serum IgE levels; however, it was not effective in regulating proinflammatory cytokines and proteins. In addition, LI11 treatment is more effective at reducing serum IgE levels and pro-inflammatory cytokines and proteins than local point treatment. These results suggest that acupuncture treatment is effective in alleviating allergic contact dermatitis by reducing pro-inflammatory cytokines and proteins.
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20
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Zhang Z, Liu X, Lu S, Yu A, Fu Z. Increased pain in response to mechanical or thermal stimulation in a rat model of incision-induced pain with nicotine dependence and withdrawal. Exp Ther Med 2013; 5:1063-1066. [PMID: 23596472 PMCID: PMC3627443 DOI: 10.3892/etm.2013.963] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2012] [Accepted: 01/08/2013] [Indexed: 11/21/2022] Open
Abstract
The aim of this study was to observe the changes in mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) in a rat model of incisional pain with nicotine dependence and withdrawal. Twelve Wistar rats were randomly divided into a control and a withdrawal group, with 6 rats per group. In the control group, the rats were raised in normal conditions for 7 days without any treatment. A model of plantar incisional pain was established in the right lower extremity and changes in the plantar MWT and TWL of the healthy and operative sides were observed for 7 successive days. In the withdrawal group, the rats were raised in normal conditions and treated with a subcutaneous injection of pure nicotine (3 mg/kg), 3 times each day for 7 days. The model of plantar incisional pain in the right lower extremity was established, and changes in bilateral plantar MWT and TWL were observed for 7 days. The operative side plantar MWT and TWL in the withdrawal group were significantly lower than those in the control group on postoperative days 1–7, respectively (P<0.05). Compared with the healthy side in the control group, the healthy plantar MWT was significantly reduced on postoperative days 1–7 (P<0.05) and TWL was significantly decreased in postoperative days 1–6 (P<0.05) in the withdrawal group. The pain sensitivity to mechanical and thermal stimulation significantly increased in the rat model of incisional pain with nicotine dependence and withdrawal. This is consistent with the clinical increase of postoperative pain observed in patients after quitting smoking.
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Affiliation(s)
- Zongwang Zhang
- Department of Anesthesiology, Shangdong Province-owned Hospital Affiliated to Shandong University, Jinan 250000; ; Department of Anesthesiology, Liaocheng People's Hospital, Liaocheng 252000
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21
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Li S, Sun Y, Gao D. Role of the nervous system in cancer metastasis. Oncol Lett 2013; 5:1101-1111. [PMID: 23599747 PMCID: PMC3629128 DOI: 10.3892/ol.2013.1168] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2012] [Accepted: 10/17/2012] [Indexed: 12/17/2022] Open
Abstract
The notion that tumors lack innervation was proposed several years ago. However, nerve fibers are irregulatedly found in some tumor tissues. Their terminals interaction with cancer cells are considered to be neuro-neoplastic synapses. Moreover, neural-related factors, which are important players in the development and activity of the nervous system, have been found in cancer cells. Thus, they establish a direct connection between the nervous system and tumor cells. They modulate the process of metastasis, including degradation of base membranes, cancer cell invasion, migration, extravasation and colonization. Peripheral nerve invasion provides another pathway for the spread of cancer cells when blood and lymphatic metastases are absent, which is based on the interactions between the microenvironments of nerve fibers and tumor cells. The nervous system also modulates angiogenesis, the tumor microenvironment, bone marrow, immune functions and inflammatory pathways to influence metastases. Denervation of the tumor has been reported to enhance cancer metastasis. Stress, social isolation and other emotional factors may increase distant metastasis through releasing hormones from the brain, the hypothalamic-pituitary-adrenal axis and autonomic nervous system. Disruption of circadian rhythms will also promote cancer metastasis through direct and indirect actions of the nervous system. Therefore, the nervous system plays an important role in cancer metastasis.
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Affiliation(s)
- Sha Li
- Department of Radiation Oncology, Lanzhou General Hospital of PLA, Lanzhou, Gansu 730050
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22
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Protocol for the observation of the primo vascular system in the lymph vessels of rabbits. J Acupunct Meridian Stud 2012; 5:234-40. [PMID: 23040104 DOI: 10.1016/j.jams.2012.07.007] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2012] [Revised: 05/23/2012] [Accepted: 05/30/2012] [Indexed: 11/23/2022] Open
Abstract
Molecular-level understanding of the structure and the functions of the lymphatic system has greatly enhanced the importance of this second circulation system, especially in connection with cancer metastasis and inflammation. Recently, a third circulatory system, the primo vascular system (PVS) was found in various parts of an animal's body, especially as threadlike structures floating in the lymphatic flow in lymph vessels. Although the medical significance of this emerging system will require much work in the future, at present, several important suggestions in connection with immune cells, stem cells, and cancer metastasis have already appeared. Experiments to observe the PVS in the lymph vessels near the caudal vena cava of rabbits and rats have been performed by several independent teams, but reproduction requires considerable skill and technical know-how. In this article, we provide a detailed protocol to detect the PVS inside the lymph vessels of a rabbit. Detection and isolation are the first steps in unraveling the physiological functions of the PVS, which awaits intensive research.
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23
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Stefanov M, Kim J. Primo Vascular System as a New Morphofunctional Integrated System. J Acupunct Meridian Stud 2012; 5:193-200. [DOI: 10.1016/j.jams.2012.07.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2012] [Revised: 06/13/2012] [Accepted: 07/16/2012] [Indexed: 11/17/2022] Open
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Chen JK, Zhao T, Ni M, Li DJ, Tao X, Shen FM. Downregulation of alpha7 nicotinic acetylcholine receptor in two-kidney one-clip hypertensive rats. BMC Cardiovasc Disord 2012; 12:38. [PMID: 22682236 PMCID: PMC3507811 DOI: 10.1186/1471-2261-12-38] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2012] [Accepted: 05/18/2012] [Indexed: 01/11/2023] Open
Abstract
Background Inflammation processes are important participants in the pathophysiology of hypertension and cardiovascular diseases. The role of the alpha7 nicotinic acetylcholine receptor (α7nAChR) in inflammation has recently been identified. Our previous study has demonstrated that the α7nAChR-mediated cholinergic anti-inflammatory pathway is impaired systemically in the genetic model of hypertension. In this work, we investigated the changes of α7nAChR expression in a model of secondary hypertension. Methods The 2-kidney 1-clip (2K1C) hypertensive rat model was used. Blood pressure, vagus nerve function, serum tumor necrosis factor-α (TNF-α) and both the mRNA and protein levels of α7nAChR in tissues from heart, kidney and aorta were measured at 4, 8 and 20 weeks after surgery. Results Compared with age-matched control, it was found that vagus nerve function was significantly decreased in 2K1C rats with the development of hypertension. Serum levels of TNF-α were greater in 2K1C rats than in age-matched control at 4, 8 and 20 weeks. α7nAChR mRNA in the heart was not altered in 2K1C rats. In the kidney of 2K1C rats, α7nAChR expression was significantly decreased at 8 and 20 weeks, but markedly increased at 4 weeks. α7nAChR mRNA was less in aorta of 2K1C rats than in age-matched control at 4, 8 and 20 weeks. These findings were confirmed at the protein levels of α7nAChR. Conclusions Our results suggested that secondary hypertension may induce α7nAChR downregulation, and the decreased expression of α7nAChR may contribute to inflammation in 2K1C hypertension.
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Affiliation(s)
- Ji-Kuai Chen
- Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, 200433, China
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Phillips RJ, Powley TL. Macrophages associated with the intrinsic and extrinsic autonomic innervation of the rat gastrointestinal tract. Auton Neurosci 2012; 169:12-27. [PMID: 22436622 DOI: 10.1016/j.autneu.2012.02.004] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2012] [Revised: 02/22/2012] [Accepted: 02/23/2012] [Indexed: 12/28/2022]
Abstract
Interactions between macrophages and the autonomic innervation of gastrointestinal (GI) tract smooth muscle have received little experimental attention. To better understand this relationship, immunohistochemistry was performed on GI whole mounts from rats at three ages. The phenotypes, morphologies, and distributions of gut macrophages are consistent with the cells performing extensive housekeeping functions in the smooth muscle layers. Specifically, a dense population of macrophages was located throughout the muscle wall where they were distributed among the muscle fibers and along the vasculature. Macrophages were also associated with ganglia and connectives of the myenteric plexus and with the sympathetic innervation. Additionally, these cells were in tight registration with the dendrites and axons of the myenteric neurons as well as the varicosities along the length of the sympathetic axons, suggestive of a contribution by the macrophages to the homeostasis of both synapses and contacts between the various elements of the enteric circuitry. Similarly, macrophages were involved in the presumed elimination of neuropathies as indicated by their association with dystrophic neurons and neurites which are located throughout the myenteric plexus and smooth muscle wall of aged rats. Importantly, the patterns of macrophage-neuron interactions in the gut paralleled the much more extensively characterized interactions of macrophages (i.e., microglia) and neurons in the CNS. The present observations in the PNS as well as extrapolations from homologous microglia in the CNS suggest that GI macrophages play significant roles in maintaining the nervous system of the gut in the face of wear and tear, disease, and aging.
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Affiliation(s)
- Robert J Phillips
- Department of Psychological Sciences, Purdue University, West Lafayette, Indiana 47907-2081, USA
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Hu SX, Sui HX, Jin HJ, Ni XY, Liu XX, Xue MQ, Zhang Y, Gao FG. Lipopolysaccharide and dose of nicotine determine the effects of nicotine on murine bone marrow-derived dendritic cells. Mol Med Rep 2012; 5:1005-10. [PMID: 22245993 PMCID: PMC3493033 DOI: 10.3892/mmr.2012.751] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2011] [Accepted: 12/19/2011] [Indexed: 11/05/2022] Open
Abstract
The reported effects of nicotine on dendritic cells (DCs) are controversial. To investigate the factors which determine the effects of nicotine on DCs, immature dendritic cells (imDCs) induced from murine bone marrow were treated with different doses of nicotine with or without lipopolysaccharides (LPS). The morphology and expression of the co-stimulatory molecules CD80, CD86, CD40 and CD54 were observed and determined by microscopy and flow cytometry, respectively. The results showed that, firstly, nicotine treatment promoted the development of DC precursors into imDCs with a semi-mature phenotype revealed by a higher expression of CD11c and more branched projections. Secondly, lower doses of nicotine (16.5 ng/ml), but not higher (200 μg/ml), up-regulated the expression of the co-stimulatory molecules CD80, CD40 and CD54 on imDCs. Co-administration of LPS and nicotine revealed differential effects on co-stimulatory molecule expression on imDCs. Thirdly and importantly, treatment with lower doses of nicotine (16.5 ng/ml) did not augment expression of the CD80, CD86, CD40 and CD54 molecules in mature DCs. Fourthly and interestingly, high doses of nicotine (more than 165 μg/ml) revealed pro-apoptotic activity but lower doses of nicotine (16.5–0.165 ng/ml) achieved an anti-apoptotic effect on imDCs. All data presented here indicate that the controversial effects of nicotine on DCs may be due to the LPS of the nicotinic environment and the dose of nicotine used.
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Affiliation(s)
- Su Xian Hu
- Department of Respiratory Medicine, The First Affiliated Hospital of Xiamen University, Xiamen 361003, PR China
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Editorial comment. Urology 2011; 78:1378-9; author reply 1379. [PMID: 22137707 DOI: 10.1016/j.urology.2011.06.047] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2011] [Revised: 06/09/2011] [Accepted: 06/10/2011] [Indexed: 11/22/2022]
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Zhao T, Li DJ, Liu C, Su DF, Shen FM. Beneficial effects of anisodamine in shock involved cholinergic anti-inflammatory pathway. Front Pharmacol 2011; 2:23. [PMID: 21687515 PMCID: PMC3108475 DOI: 10.3389/fphar.2011.00023] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2011] [Accepted: 04/11/2011] [Indexed: 11/29/2022] Open
Abstract
Anisodamine, an antagonist of muscarinic receptor, has been used therapeutically to improve blood flow in circulatory disorders such as septic shock in China since 1965. The main mechanism of anisodamine for anti-shock proposed in Pharmacology for Chinese medical students is to improve blood flow in the microcirculation. Here, we suggest a new mechanism for its anti-shock effect. That is, anisodamine, by blocking muscarinic receptor, results in rerouting of acetylcholine to α7 nicotinic acetylcholine receptor (α7nAChR) bringing about increased acetylcholine-mediated activation of α7nAChR and the cholinergic anti-inflammatory pathway.
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Affiliation(s)
- Ting Zhao
- Department of Pharmacology, School of Pharmacy, Second Military Medical University Shanghai, China
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Su DF. Parasympathetic nervous system: A new therapeutic target in cardiovascular disease? Clin Exp Pharmacol Physiol 2011; 38:290-1. [DOI: 10.1111/j.1440-1681.2011.05500.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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Backward conditioning of tumor necrosis factor-α in a single trial: Changing intervals between exposures to lipopolysaccharide and saccharin taste. Physiol Behav 2011; 102:239-44. [DOI: 10.1016/j.physbeh.2010.11.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2009] [Revised: 10/18/2010] [Accepted: 11/08/2010] [Indexed: 11/18/2022]
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Li DJ, Evans RG, Yang ZW, Song SW, Wang P, Ma XJ, Liu C, Xi T, Su DF, Shen FM. Dysfunction of the cholinergic anti-inflammatory pathway mediates organ damage in hypertension. Hypertension 2010; 57:298-307. [PMID: 21173343 DOI: 10.1161/hypertensionaha.110.160077] [Citation(s) in RCA: 89] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Inflammatory responses are associated with the genesis and progression of end-organ damage (EOD) in hypertension. A role for the α7 nicotinic acetylcholine receptor (α7nAChR) in inflammation has recently been identified. We tested the hypothesis that α7nAChR dysfunction contributes to hypertensive EOD. In both spontaneously hypertensive rats (SHRs) and rats with abdominal aorta coarctation-induced hypertension, atropine-induced tachycardia was blunted compared with normotensive controls. Both models of hypertension were associated with deficits in expression of the vesicular acetylcholine transporter and the α7nAChR in cardiovascular tissues. In hypertension induced by abdominal aorta coarctation, deficits in aortic vesicular acetylcholine transporter and α7nAChR were present both above and below the coarctation site, indicating that they were independent of the level of arterial pressure itself. Hypertension in 40-week-old SHRs was associated with cardiac and aortic hypertrophy. Morphological abnormalities consistent with EOD, along with elevated tissue levels of proinflammatory cytokines (tumor necrosis factor-α, interleukin-1β, and interleukin-6) were observed in the heart, kidney, and aorta. Chronic treatment of SHRs with the α7nAChR agonist PNU-282987 relieved EOD and inhibited tissue levels of proinflammatory cytokines and activation of nuclear factor κB. Greater serum levels of proinflammatory cytokines and more severe damage in the heart, aorta, and kidney were seen in α7nAChR(-/-) mice subjected to 2-kidney-1-clip surgery than in wild-type mice. A deficit in the cholinergic anti-inflammatory pathway appears to contribute to the pathogenesis of EOD in models of hypertension of varying etiology. This pathway may provide a new target for preventing cardiovascular disease resulting from hypertension.
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Affiliation(s)
- Dong-Jie Li
- Department of Pharmacology, Second Military Medical University, Shanghai 200433, China
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Gao FG, Li HT, Li ZJ, Gu JR. Nicotine stimulated dendritic cells could achieve anti-tumor effects in mouse lung and liver cancer. J Clin Immunol 2010; 31:80-8. [PMID: 20957418 DOI: 10.1007/s10875-010-9459-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2010] [Accepted: 09/02/2010] [Indexed: 11/25/2022]
Abstract
INTRODUCTION Our previous studies have revealed that nicotine-treated immature dendritic cells (imDCs) have anti-tumor effects in murine lymphoma models. The present study is to explore the preventive and therapeutic anti-tumor effects of nicotine-treated imDCs in murine lung and liver cancer. MATERIALS AND METHODS To address this objection, bone marrow-derived imDCs were firstly stimulated by nicotine in vitro and the expressions of CD80, CD86, CD40, CD11b, MHC class I and II were determined by flow cytometry. Then, DCs-dependent tumor-lysate-specific T cell proliferation, IL-12(p40+p70) secretion were determined by BrdU cell proliferation assay and enzyme-linked immunosorbent assay, respectively. The anti-tumor effects of such imDCs were further explored by intraperitoneal transfer against tumor challenge or implantation. By using kinase inhibitors, the mechanism of nicotine upregulating CD80 was finally explored by flow cytometry. RESULTS The results showed that: firstly, nicotine could upregulate the expressions of CD80, CD86, CD40,CD11b, MHC class I and II molecules in imDCs. Secondly, nicotine could promote imDCs-dependent T cell priming and IL-12 secretion. Most importantly, systemic transfer of ex vivo nicotine-stimulated imDCs, which enhanced CD80 expression through PI3K activation, could reveal preventive and effectively therapeutic effects on tumor development. CONCLUSIONS Ex vivo nicotine stimulation can significantly improve imDCs efficacy for adaptive therapy of cancer. Nicotine-treated imDCs might be considered as a potential candidate for therapeutic tumor immunotherapy for lung and liver cancer.
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Affiliation(s)
- Feng Guang Gao
- Department of Basic Medicine Science, Medical College, Xiamen University, Xiamen 361005, People's Republic of China.
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Abstract
Our digestive tract has an autonomous functioning but also has a bidirectional relation with our brain known as brain-gut interactions. This communication is mediated by the autonomous nervous system, i.e., the sympathetic and parasympathetic nervous systems, with a mixed afferent and efferent component, and the circumventricular organs located outside the blood-brain barrier. The vagus nerve, known as the principal component of the parasympathetic nervous system, is a mixed nerve composed of 90% afferent fibers, which has physiological roles due to its putative vegetative functions. The vagus nerve has also anti-inflammatory properties both through the hypothalamic pituitary adrenal axis (through its afferents) and the cholinergic anti-inflammatory pathway (through its efferents). The sympathetic nervous system has a classical antagonist effect on the parasympathetic nervous system at the origin of an equilibrated sympathovagal balance in normal conditions. The brain is able to integrate inputs coming from the digestive tract inside a central autonomic network organized around the hypothalamus, limbic system and cerebral cortex (insula, prefrontal, cingulate) and in return to modify the autonomic nervous system and the hypothalamic pituitary adrenal axis in the frame of physiological loops. A dysfunction of these brain-gut interactions, favoured by stress, is most likely involved in the pathophysiology of digestive diseases such as irritable bowel syndrome or even inflammatory bowel diseases. A better knowledge of these brain-gut interactions has therapeutic implications in the domain of pharmacology, neurophysiology, behavioural and cognitive management.
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Affiliation(s)
- B Bonaz
- Clinique universitaire d'hépato-gastroentérologie, CHU de Grenoble, BP 217, 38043 Grenoble cedex 9, France.
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ACE-inhibitor therapy and survival among patients with multiorgan dysfunction syndrome (MODS) of cardiac and non-cardiac origin. Int J Cardiol 2010; 140:296-303. [DOI: 10.1016/j.ijcard.2008.11.104] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2008] [Accepted: 11/15/2008] [Indexed: 01/18/2023]
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LAI XS, TONG Z. A Study on the Classification and the ‘Catching’ of the ‘Arrived Qi’ in Acupuncture. J TRADIT CHIN MED 2010. [DOI: 10.1016/s0254-6272(10)60001-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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Vasilescu C, Rossi S, Shimizu M, Tudor S, Veronese A, Ferracin M, Nicoloso MS, Barbarotto E, Popa M, Stanciulea O, Fernandez MH, Tulbure D, Bueso-Ramos CE, Negrini M, Calin GA. MicroRNA fingerprints identify miR-150 as a plasma prognostic marker in patients with sepsis. PLoS One 2009; 4:e7405. [PMID: 19823581 PMCID: PMC2756627 DOI: 10.1371/journal.pone.0007405] [Citation(s) in RCA: 244] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2009] [Accepted: 09/17/2009] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND The physiopathology of sepsis continues to be poorly understood, and despite recent advances in its management, sepsis is still a life-threatening condition with a poor outcome. If new diagnostic markers related to sepsis pathogenesis will be identified, new specific therapies might be developed and mortality reduced. Small regulatory non-coding RNAs, microRNAs (miRNAs), were recently linked to various diseases; the aim of our prospective study was to identify miRNAs that can differentiate patients with early-stage sepsis from healthy controls and to determine if miRNA levels correlate with the severity assessed by the Sequential Organ Failure Assessment (SOFA) score. METHODOLOGY/PRINCIPAL FINDINGS By using genome-wide miRNA profiling by microarray in peripheral blood leukocytes, we found that miR-150, miR-182, miR-342-5p, and miR-486 expression profiles differentiated sepsis patients from healthy controls. We also proved by quantitative reverse transcription-polymerase chain reaction that miR-150 levels were significantly reduced in plasma samples of sepsis patients and correlated with the level of disease severity measured by the SOFA score, but were independent of the white blood counts (WBC). We found that plasma levels of tumor necrosis factor alpha, interleukin-10, and interleukin-18, all genes with sequence complementarity to miR-150, were negatively correlated with the plasma levels of this miRNA. Furthermore, we identified that the plasma levels ratio for miR-150/interleukin-18 can be used for assessing the severity of the sepsis. CONCLUSIONS/SIGNIFICANCE We propose that miR-150 levels in both leukocytes and plasma correlate with the aggressiveness of sepsis and can be used as a marker of early sepsis. Furthermore, we envision miR-150 restoration as a future therapeutic option in sepsis patients.
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Affiliation(s)
- Catalin Vasilescu
- Department of Surgery, Fundeni Clinical Hospital, Bucharest, Romania
| | - Simona Rossi
- Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America
| | - Masayoshi Shimizu
- Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America
| | - Stefan Tudor
- Department of Surgery, Fundeni Clinical Hospital, Bucharest, Romania
| | - Angelo Veronese
- Department of Experimental and Diagnostic Medicine, Interdepartmental Center for Cancer Research, University of Ferrara, Ferrara, Italy
| | - Manuela Ferracin
- Department of Experimental and Diagnostic Medicine, Interdepartmental Center for Cancer Research, University of Ferrara, Ferrara, Italy
| | - Milena S. Nicoloso
- Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America
| | - Elisa Barbarotto
- Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America
| | - Monica Popa
- Department of Surgery, Fundeni Clinical Hospital, Bucharest, Romania
| | - Oana Stanciulea
- Department of Surgery, Fundeni Clinical Hospital, Bucharest, Romania
| | - Michael H. Fernandez
- Department of Hematopathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America
| | - Dan Tulbure
- Department of Anesthesiology, Fundeni Clinical Hospital, Bucharest, Romania
| | - Carlos E. Bueso-Ramos
- Department of Hematopathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America
| | - Massimo Negrini
- Department of Experimental and Diagnostic Medicine, Interdepartmental Center for Cancer Research, University of Ferrara, Ferrara, Italy
| | - George A. Calin
- Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America
- * E-mail:
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Oke SL, Tracey KJ. The inflammatory reflex and the role of complementary and alternative medical therapies. Ann N Y Acad Sci 2009; 1172:172-80. [PMID: 19743552 PMCID: PMC4533858 DOI: 10.1196/annals.1393.013] [Citation(s) in RCA: 106] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The body's first defense against invading pathogens or tissue injury is the innate immune system. Since excessive immune responses can be damaging, anti-inflammatory mechanisms function to control the pro-inflammatory response and prevent injury. The cholinergic anti-inflammatory pathway is a neural mechanism that suppresses the innate inflammatory response. Knowledge concerning innervation of the immune system offers a unique opportunity to explore previously unrecognized techniques to treat disease. It also enables consideration of the neurological basis of complementary and alternative medical therapies, such as meditation and acupuncture. This evolving area of research has implications for the pathogenesis of chronic inflammatory conditions including inflammatory bowel disease, rheumatoid arthritis, type 2 diabetes, and other conditions of excessive cytokine release.
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Affiliation(s)
- Stacey L Oke
- Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, New York, USA
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Werdan K, Schmidt H, Ebelt H, Zorn-Pauly K, Koidl B, Hoke RS, Heinroth K, Müller-Werdan U. Impaired regulation of cardiac function in sepsis, SIRS, and MODS. Can J Physiol Pharmacol 2009; 87:266-74. [PMID: 19370080 DOI: 10.1139/y09-012] [Citation(s) in RCA: 103] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
In sepsis, systemic inflammatory response syndrome (SIRS), and multiorgan dysfunction syndrome (MODS), a severe prognostically relevant cardiac autonomic dysfunction exists, as manifested by a strong attenuation of sympathetically and vagally mediated heart rate variability (HRV). The mechanisms underlying this attenuation are not limited to the nervous system. They also include alterations of the cardiac pacemaker cells on a cellular level. As shown in human atrial cardiomyocytes, endotoxin interacts with cardiac hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels, which mediate the pacemaker current If and play an important role in transmitting sympathetic and vagal signals on heart rate and HRV. Moreover, endotoxin sensitizes cardiac HCN channels to sympathetic signals. These findings identify endotoxin as a pertinent modulator of the autonomic nervous regulation of heart function. In MODS, the vagal pathway of the autonomic nervous system is particularly compromised, leading to an attenuation of the cholinergic antiinflammatory reflex. An amelioration of the blunted vagal activity appears to be a promising novel therapeutic target to achieve a suppression of the inflammatory state and thereby an improvement of prognosis in MODS patients. Preliminary data revealed therapeutic benefits (increased survival rates and improvements of the depressed vagal activity) of the administration of statins, beta-blockers, and angiotensin-converting enzyme inhibitors in patients with MODS.
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Affiliation(s)
- Karl Werdan
- Department of Medicine III, Martin Luther University Halle-Wittenberg, Ernst-Grube Str. 40, D-06097 Halle, Saale, Germany.
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Bohdjalian A, Prager G, Rosak C, Weiner R, Jung R, Schramm M, Aviv R, Schindler K, Haddad W, Rosenthal N, Ludvik B. Improvement in glycemic control in morbidly obese type 2 diabetic subjects by gastric stimulation. Obes Surg 2009; 19:1221-7. [PMID: 19575272 DOI: 10.1007/s11695-009-9901-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2009] [Accepted: 06/02/2009] [Indexed: 12/28/2022]
Abstract
BACKGROUND Gastric electrical stimulation synchronized to the refractory period of gastric electrical activity and applied during meals was evaluated for safety and for improvement of body weight and glycemic control in obese type 2 diabetes. METHODS The study involved obese diabetic type 2 (ODM) patients in a multicenter open-label European feasibility trial. A total of 24 ODM (nine males, 15 females) treated with insulin and/or oral hyperglycemic agents and body mass index between 33.3 to 49.7 kg/m(2) were implanted laparoscopically with a TANTALUS system. RESULTS There were 18 adverse events related to the implant procedure or the device reported in 12 subjects. All were short lived and resolved with no sequelae. In the 21 subjects that reached the 1-year visit weight was reduced by 4.5 +/- 2.7 kg (p < 0.05) and HbA1c by 0.5 +/- 0.3% (p < 0.05). In a subgroup (n = 11) on stable or reduced oral medication, weight was reduced by 6.3 +/- 3.4 kg (p < 0.05) and HbA1c by 0.9 +/- 0.4% (p < 0.05). The group on insulin (n = 6) had no significant changes in weight and HbA1c. CONCLUSIONS The TANTALUS system is well tolerated in obese type 2 diabetic subjects. Gastric electrical stimulation can potentially improve glucose metabolism and induce weight loss in obese diabetic patients, who are not well controlled on oral antidiabetic therapy. Further evaluation is required to determine whether this effect is due to induced weight loss and/or to direct signal dependent mechanisms.
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Affiliation(s)
- Arthur Bohdjalian
- Department of Surgery, Medical University of Vienna, Waehringer Guertel 18-20, Vienna 1090, Austria
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Soh KS. Bonghan Circulatory System as an Extension of Acupuncture Meridians. J Acupunct Meridian Stud 2009; 2:93-106. [PMID: 20633480 DOI: 10.1016/s2005-2901(09)60041-8] [Citation(s) in RCA: 140] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2009] [Accepted: 04/08/2009] [Indexed: 12/31/2022] Open
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Cerutti S, Hoyer D, Voss A. Multiscale, multiorgan and multivariate complexity analyses of cardiovascular regulation. PHILOSOPHICAL TRANSACTIONS. SERIES A, MATHEMATICAL, PHYSICAL, AND ENGINEERING SCIENCES 2009; 367:1337-1358. [PMID: 19324712 DOI: 10.1098/rsta.2008.0267] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/27/2023]
Abstract
Cardiovascular system complexity is confirmed by both its generally variegated structure of physiological modelling and the richness of information detectable from processing of the signals involved in it, with strong linear and nonlinear interactions with other biological systems. In particular, this behaviour may be accordingly described by means of what we call MMM paradigm (i.e. multiscale, multiorgan and multivariate). Such an approach to the cardiovascular system emphasizes where the genesis of its complexity is potentially allocated and how it is possible to detect information from it. No doubt that processing signals from multi-leads of the same system (multivariate), from the interaction of different physiological systems (multiorgan) and integrating all this information across multiple scales (from genes, to proteins, molecules, cells, up to the whole organ) could really provide us with a more complete look at the overall phenomenon of cardiovascular system complexity, with respect to the one which is obtainable from its single constituent parts. In this paper, some examples of approaches are discussed for investigating the cardiovascular system in different time and spatial scales, in studying a different organ involvement (such as sleep, depression and multiple organ dysfunction) and in using a multivariate approach via various linear and nonlinear methods for cardiovascular risk stratification and pathology assessment.
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Affiliation(s)
- Sergio Cerutti
- Department of Bioengineering, IIT UNIT, Politecnico di Milano, Milano 20133, Italy.
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Lee BC, Bae KH, Jhon GJ, Soh KS. Bonghan System as Mesenchymal Stem Cell Niches and Pathways of Macrophages in Adipose Tissues. J Acupunct Meridian Stud 2009; 2:79-82. [DOI: 10.1016/s2005-2901(09)60020-0] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2008] [Accepted: 01/14/2009] [Indexed: 01/31/2023] Open
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The Consequences of Cardiac Autonomic Dysfunction in Multiple Organ Dysfunction Syndrome. Intensive Care Med 2009. [DOI: 10.1007/978-0-387-77383-4_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Liu AJ, Ling G, Wu J, Shen FM, Wang DS, Lin LL, Liu JG, Su DF. Arterial baroreflex function is an important determinant of acute cerebral ischemia in rats with middle cerebral artery occlusion. Life Sci 2008; 83:388-93. [DOI: 10.1016/j.lfs.2008.06.021] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2008] [Revised: 06/05/2008] [Accepted: 06/05/2008] [Indexed: 11/28/2022]
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Kim MS, Hong JY, Hong S, Lee BC, Nam CH, Woo HJ, Kang DI, Soh KS. Bong-Han Corpuscles as Possible Stem Cell Niches on the Organ-Surfaces. J Pharmacopuncture 2008. [DOI: 10.3831/kpi.2008.11.1.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
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Schmidt H, Hoyer D, Wilhelm J, Söffker G, Heinroth K, Hottenrott K, Said SM, Buerke M, Müller-Werdan U, Werdan K. The alteration of autonomic function in multiple organ dysfunction syndrome. Crit Care Clin 2008; 24:149-63, ix. [PMID: 18241783 DOI: 10.1016/j.ccc.2007.10.003] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Autonomic dysfunction is associated with the severity of illness and mortality in patients with multiple organ dysfunction syndrome (MODS) and may contribute significantly to the pathogenesis of this syndrome. Several treatment approaches may possibly restore autonomic function in MODS and thus cause the survival benefit.
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Affiliation(s)
- Hendrik Schmidt
- Martin-Luther-University Halle-Wittenberg, Klinikum Kröllwitz, Ernst-Grube-Strasse 40, D-06097 Halle/Saale, Germany.
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Enhanced in vitro activation of immunocompetent cells in healthy individuals being subcutaneously ‘vaccinated’ with placebo (physiological saline). Clin Immunol 2008; 126:322-31. [DOI: 10.1016/j.clim.2007.09.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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Abstract
An enhanced inflammatory state - i.e. "inflammatory/pathogen burden" - in the elderly on the one hand results from physiological immunosenescence and on the other hand is modified by the individual immune history: the latter is determined by sequential infectious/pathogenic events ("multiple hits"). Immunosenescence may prompt ageing of other organs. Cardiac ageing can be assessed by analysing heart rate variability. We present our hypothesis that the increasing "inflammatory/pathogen burden" of each organism during a lifetime significantly contributes to the cardiac ageing process. This hypothesis is grounded on the fact that a characteristic feature of the ageing heart - a narrowed heart rate variability - can be experimentally induced in humans by an inflammatory stimulus (endotoxin).
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Affiliation(s)
- U Müller-Werdan
- Universitätsklinik und Poliklinik für Innere Medizin III, Klinikum der Martin-Luther-Universität Halle-Wittenberg, Ernst-Grube-Strasse 40, 06097, Halle, Germany.
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Hoyer D, Frank B, Baranowski R, Zebrowski JJ, Stein PK, Schmidt H. Autonomic information flow rhythms. From heart beat interval to circadian variation. ACTA ACUST UNITED AC 2008; 26:19-24. [PMID: 18189082 DOI: 10.1109/emb.2007.907091] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Affiliation(s)
- Dirk Hoyer
- Biomagnetic Center, Department of Neurology, University Hospital, Friedrich Schiller University, Jena, Germany.
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