Research progress in association between angiopoietin-like protein 2 and inflammation-related diseases

Chronic low-grade inflammatory diseases are a subclinical process caused by innate system disorders. In recent years, with the study of chronic low-grade inflammatory diseases, inflammation has become a hot topic of major human diseases, including obesity, diabetes, cardiovascular diseases, cancer and autoimmune diseases. Angiopoietin-like protein 2 (ANGPTL2) is one of the emerging angiogenesis-related factors. Studies show that ANGPTL2 induces vascular inflammation, insulin resistance and other characteristics. The article reviews the research progress in association between angiopoietin-like protein 2 and inflammation-related diseases.     

Impact of particulate matter in air pollution on cardiovascular diseases

Impact of air pollution on cardiovascular diseases has been established. As the main source of city air pollution, particulate matter has been demonstrated an independent correlation with incidence and mortality of cardiovascular diseases. The mechanisms are not clear. Several plausible mechanistic pathways have been described, including inflammation induced by oxidative stress, the followed enhanced coagulation/thrombosis resulted in instability of atherosclerosis, the promotion of ischemic heart diseases and imbalance of autonomic nerve tone resulted in the occurrence of arrhythmia. The article provides a review of the mechanisms on air pollution and cardiovascular diseases and suggestions for further research.     

PPARs and TLR-NF-κB signaling pathway

Peroxisome proliferator-activated receptors(PPARs) influence Toll-like receptors(TLRs)-nuclear receptor-κB(NF-κB) signaling pathway through diverse mechanisms to negatively regulate TLR-NF-κB signaling-mediated inflammation and immune responses under para-inflammation condition. However, in pathological states, the balance between inhibition and promotion of inflammation, which is regulated by PPARs and TLR-NF-κB signaling pathway, respectively, has been broken down, resulting in inflammatory cascade and eventually causing chronic non-infectious inflammatory diseases, such as atherosclerosis, ulcerative colitis and rheumatoid arthritis. This review mainly focuses on the interaction between PPARs and TLR-NF-κB signaling pathway either in para-inflammatory status or pathological state, which highlights the importance of PPARs in the process of inflammation and immune responses and provides new interfering targets for the treatment of the diseases like coronary atherosclerotic heart disease.     

New progress in study of inflammatory reflex

Proinflammatory cytokines induced by peripheral immune challenge can activate the inflammatory reflex, which results in negative-feedback control of inflammation. Some recent studies revealed that it is the splanchnic nerve, not the vagus nerve, to constitute the efferent arm of the inflammatory reflex. Further researches are needed to identify the neural construction and regulatory mechanism of the inflammatory reflex, which might be harnessed for the treatment of inflammation and the development of anti-inflammatory drugs.     

Relationship between hypothermia and heart rate variability,blood pressure variability

AIM: To study the function of autonomic nervous system by the method of heart rate variability (HRV) and arterial blood pressure variability (BPV).METHODS: The rectal temperature of rats decreased gradually with their body surfaces contacted with ice,the range of the rectal temperature varied from 19 ℃ to 37 ℃.Both the dynamic electrocardiogram (ECG) signals and dynamic blood pressure signals were recorded,respectively.RESULTS: Using the method of HRV,there was an increase in RR interval (RRI),which implied a corresponding decrease in heart rate with the rectal temperature varying from 19 ℃ to 29 ℃ (P<0.01).There was a decrease in the value of normalized low frequency power (LFn) (P<0.05) and an increase in the value of normalized high frequency power (HFn) (P<0.01) with the rectal temperatures varying from 19 ℃ to 21 ℃.Therefore,the balance control of cardiac autonomic nervous was transferred to increase of vagal nerve drive (P<0.05).Using the method of BPV,there was an increase (P<0.01) in the value of HFn related to respiratory with the body temperatures falling to 31 ℃.While the body temperature varied from 19 ℃ to 29 ℃ (except 27 ℃),there was an increase in the value of HFn related to respiratory rates (P<0.05 or P<0.01) and the balance control of autonomic nervous was transferred to increase of vagal nerve drive (P<0.05).CONCLUSION: As the body temperature reduces,the vagal nerve activity in cardiovascular system increases,and the effect of hypothermia on HRV is sensitive to BPV.     

Relationship between QT dispersion and autonomic nerve of heart

QT dispersion (QTd, equals maximal minus minimal QT interval on a standard ECG) has been shown to reflect inhomogeneity of myocardial repolarization and cardial electrical instability, hence, been proposed to be associated with ventricular arrhythmias.But the intrinsical mechanism of QTd is incompletely understood. Contributing to QTd are differences of action potential duration (APD) in the three-dimensional structure of ventricular myocardium, which is identified to own three cell subtypes: endocardial, midmyocardial (M cells) and epicardial cells. And findings suggest that regional differences in the duration of the M cell action potential may lead transmural and spatial dispersion of repolarization. Autonomic nerves by combining receptors on the myocardial cells, especially M cells affect significantly the APD. Concordance between heterogeneity of ventricular myocardium and heterogeneity of autonomic innervation in heart provide support for the role of autonomic nerve in the generat ion of the QT dispersion.     

Effect of asymmetric dimethylarginine on blood pressure and renal function in sympathectomized spontaneously hypertensive rats

AIM: To investigate the effect of asymmetric dimethylarginine (ADMA) on blood pressure and renal function in sympathectomized spontaneously hypertensive rats (SHR). METHODS: The neonatal SHR were sympathectomized by guanethidine monosulfate. Systolic and diastolic blood pressure was monitored by tail-cuff method. Urine excretion of norepinephrine (NE) was measured by metabolic cage collection. The levels of ADMA and NE in the kidneys were analyzed by HPLC. Nitric oxide (NO) content in SHR kidney was detected by colorimetry. The protein expression of endothelial nitric oxide synthase (eNOS) was determined by Western blot. Glomerular filtration rate (GFR) was examined to evaluate the renal function. RESULTS: Neonatal chemical sympathectomy produced significant decreases in urinary NE excretion, renal NE and ADMA contents, and systolic and diastolic blood pressure compared with the sympathetically intact SHR (P<0.05). Moreover, the level of NO content and protein expression of eNOS in the kidneys were significantly increased (P<0.05). However, no significant difference was observed in microalbumin, urinary sodium excretion and GFR between the sympathetically intact SHR and the sympathectomized SHR. CONCLUSION: Inhibition of sympathetic nervous system affects blood pressure by reducing the release of ADMA and NE, and increasing NO synthesis and eNOS expression. The regulation of ADMA generation by sympathetic nervous system does not influence renal function.     

Fibroblasts function as "sentinel cell" in inflammatory reaction

The fibroblasts have long been considered as structural elements and playing a main role in wound healing. Recent studies indicated that fibroblasts are heterogenic cells and function as resident sentinel cells in inflammatory reaction. When activated by substances released during tissue injury or derived from infectious microorganisms or by proinflammatory cytokines, tissuespecific fibroblasts can transiently produce certain chemokines and initiate a cascade of inflammatory reaction. In addition fibroblasts can produce prostanoids that participate in inflammatory and immune responses. In this review, the new role of fibroblasts in regulation of inflammation and immune reactions and possible molecular mechanism will be discuss.     

Autonomic neuronal modulation of inflammation and its clinical significance

Enormous progresses have been made in recent years for the involvement of nervous system in particular the vagus nerve in inflammatory responses. The parasympathetic nerve can be activated by "inflammatory reflex" to inhibit macrophages, via their specific nicotinic receptor α-7 subunit, and hence to reduce the production of tumor necrosis factor (TNF) that plays a pivotal role in many inflammatory reactions and is a key mediator for septic shock. This cholinergic anti-inflammatory pathway has been utilized, with positive outcomes, by means of either pharmacological or electrical stimulation in animal models against inflammatory responses and septic shock. Monoclonal antibodies against TNF and other pro-inflammatory cytokines have also been developed and used against inflammation experimentally and clinically. Although clinical use of these new treatments have yielded primitive and only limited results, these new research findings and concepts are important for the advance of modern medicine, as well as for better comprehension of some theories and practices in traditional medicine. Future directions are discussed herewith.     

Role of central PGE2 on sympathetic excitation in chronic heart failure

AIM: To observe the effect of central prostaglandin E₂ (PGE₂) on sympathetic activation in chronic heart failure (CHF) and to explore the underlying mechanism. METHODS: Male SD rats were subjected to coronary artery ligation to induce heart failure (HF), and the intracerebroventricular infusion was performed by osmotic pump continuously. The rats in sham group and HF group were given artificial cerebrospinal fluid (0.25 μL/h). The rats in HF plus treatment group was given celecoxib (CLB; 20 mg/h). After 4 weeks, the levels of PGE₂ in cerebrospinal fluid (CSF), the sympathetic nerve excitability and cardiac function were measured, and the changes of corticotropin-hormone releasing hormone (CRH)-containing neurons activation and neurotransmitter contents in the hypothalamic paraventricular nucleus (PVN) were also determined. RESULTS: Compared with the sham-operated rats, the HF rats had raised level of PGE₂ in CSF, up-regulated renal sympathetic nerve activity and plasma norepinephrine, increased left ventricular end diastolic pressure, lung-to-body weight and right ventricular-to-body weight ratios, and decreased maximal increase and decreased rate of left ventricular pressure (P<0.05). In addition, the number of CRH positive neurons in PVN and the level of plasma adrenocorticotropic hormone were higher in HF rats than those in sham-operated rats (P<0.05). After administration of CLB into the lateral ventricle of HF rats, the contents of PGE₂ in CSF were significantly reduced, the number of activation CRH neurons in PVN was decreased, the excitability of sympathetic nerves was down-regulated and cardiac function was improved (P<0.05). Compared with the sham-operated rats, the content of glutamic acid in PVN of HF rats was increased, the content of γ-aminobutyric acid and the number of glutamate decarboxylase 67-positive neurons were decreased (P<0.05). After the CLB was given, the above indexes were reversed (P<0.05). CONCLUSION: These findings indicate that in CHF, the increased central PGE₂ may activate CRH-containing PVN neurons and contribute to the augmented sympathetic drive possibly by modulating the neurotransmitters within the PVN.     

Toll-like receptor 4 and damage of central nervous system

As a receptor mediating the transmembrane signal transduction in the innate immunity, Toll-like receptor 4 (TLR4) is a bridge between innate immunity and required immunity, and plays an important role when signal-transducing of some cells are activated. Recent reports show that TLR4 expresses in the different glial cells and strongly links to the innate immune activation and inflammatory response in the central nervous system (CNS). TLR4 plays a key role in the processes of brain damage by infection of the CNS, stroke, cerebral hemorrhage and trauma. In this review, we concentrate on recent findings regarding the progress of function and mechanism of TLR4 in the processes of the CNS damage in various diseases.     

NLRP3 inflammasome in pathogenesis of MS/EAE and its targeted therapy

Inflammasomes, the important component of innate immune system, play an important role in inflammatory diseases. NLRP3, the most studied inflammasome, is activated after recognizing danger-associated molecular patterns and pathogen-associated molecular patterns. The activated NLRP3 inflammasome promotes inflammation by maturation and release of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18. Involvement of the NLRP3 inflammasome in the development of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) was suggested in a number of studies. Therefore, targeting on NLRP3 inflammasome is one of the promising methods for treatment of related diseases. In this review, we summarize the main ways by which the NLRP3 inflammasome is activated in the cytosol. We also discuss the development and treatment of NLRP3 inflammasome in MS and EAE, and expect to provide reference for the treatment of MS.     

Effect of fractalkine on neuroprotection

The chemokine fractalkine primarily involves in chemotaxis,adherence and inflammation.Recently it has been discovered owning the ability of inhibiting cell death in neurons and glial cells,as well as protecting central nervous system from toxic damage.Fractalkine reduces the toxicity to neurons and glial cells mediated by excessive Fas L,glutamate (Glu) or lipopolysaccharide (LPS).In vivo neutralization of endogenous brain fractalkine signal pathway increases inflammatory cytokines secretion and neuronal cell death induced by LPS.Fractalkine may achieve its neuroprotective property through influencing expression of pro-apoptotic and anti-apoptotic proteins,intracellular Ca2+ level and inflammatory cytokines secretion via protein kinase B (PKB)/Akt and extracellular signal-regulated kinase (ERK)/MAPK pathways.     

Protective role of lipoxins in digestive diseases

Lipoxins, metabolites of arachidonic acid, are a strong “braking signal” towards inflammatory reaction. Due to their anti-inflammatory and pro-resolving properties, lipoxins have emerged to be the central targets in the research on inflammation. The present article reviews the research advances of synthesis, biological effects and the protective role of lipoxins in the diseases of liver, pancreas, stomach and colorectum, thus providing a novel approach for the treatment of digestive diseases.     

The effect of arachidonic acid and its derivatives on superoxide release of neutrophils primed by TNFα

AIM: TO study the control mechanism of the developing of inflammation diseases, two inflammatory mediators, TNFa and arachidonic acid(AA) and its derivatives have been used as stimuli to induce human peripheral blood neutrophils to produce superoxide radicals. METHODS: The method of lucigeni - dependent light release has been used to exam the ability of releasing superoxide of neutrophils induced by the cooperation of TNFa and high class fatty acids as well as their derivatives. RESULTS: TNFa pretreatment markedly augmented the amount of superoxide produced in response to AA. Similarly, polyunsaturated fatty acids(PUFA) such as eicosapentaenoic acid, docosahexaenoic acid, linoleic acid, linlenic acid as well as monounsaturated fatty acid oleic acid were effected by TNFa. However, hydroxide (C_20:4, n - 6 hydroxy) and hydroperoxide(C_20:4, n - 6 hydroperoxy) of AA were not effected by TNFa. Leukotriene B₄(LTB₄) and PGE₂ which are products of AA metabolism via the lipoxygenase and cyclooxygenase pathways respectively. The two major major of mediators are generated during an inflammatory response. The former acted on neutrophils in the generation of reactive oxygen species while the latter played an inhibition function. CONCLUSION: The complexity of the mediator network operating in various immune reactions and interaction between unsaturated lipids and cytokines may play an important role in disease processes and regulation of immune responses.     

Roles of SARS-CoV-2 receptor ACE2 in various diseases

It is well know that severe acute respiratory syndrome coronavirus 2 （SARS-CoV-2） can enter host cells through angiotensin-converting enzyme 2 （ACE2）, which is a key step in the development of coronavirus disease 2019 （COVID-19）. At the same time, ACE2 is expressed in a variety of tissues and regulates many biological functions, including inflammation, cell proliferation and oxidative stress, as a key negative regulator of the renin-angiotensin system. It plays an important role in the changes of physiological functions and pathological diseases of multiple systems and organs. Therefore, in addition to COVID-2019, ACE2 is also a potential therapeutic target for the diseases such as acute lung injury, cardiovascular diseases, cancer, and kidney diseases. This article reviews the mechanism of ACE2 in the above diseases and new strategies for therapeutic application.     

Over-expression of SK2 channel in PVN reduces renal sympathetic nerve activity in chronic heart failure rats

AIM：To investigate the effect of over-expression of small-conductance calcium-activated potassium channel subtype 2 (SK2) in the paraventricular nucleus (PVN) of hypothalamus on heart rate(HR), mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) of the rats with chronic heart failure (CHF). METHODS：Adenovirus vector encoding SK2 (pDC316-mCMV-EGFP-rKCNN2) was constructed.The CHF model of the male Sprague Dawley (SD) rats was established by the ligation of anterior descending coronary artery. Echocardiogram was used at the 6th week after the operation to identify the CHF model. Adenovirus vector encoding SK2 (pDC316-mCMV-EGFP-rKCNN2) or control adenovirus vector (pDC316-mCMV-EGFP) were transfected into the PVN in vivo. The cardiac function was monitored by echocardiogram. The expression of SK2 at mRNA and protein levels was determined by RT-PCR, Western blotting and immunofluorescence. The HR, MAP and RSNA were measured by PowerLab 8/30 in anesthetized rats with bilateral PVN microinjection of SK channel blocker apamin. RESULTS：Treatment with pDC316-mCMV-EGFP-rKCNN2 significantly decreased the renal sympathetic nerve activity in the rat with CHF. Injection of pDC316-mCMV-EGFP did not change the renal sympathetic nerve activity in the rats in sham group. CONCLUSION：The expression and function of SK channels in PVN in the heart failure rats were decreased, suggesting a reduced negative regulation of sympathetic activity in central neural system. Increased expression of SK2 in the PVN leads to a reduction in sympathetic outflow under the condition of CHF, which may provide a new target for the treatment of heart failure.