VEGF controls lung Th2 inflammation via the miR-1–Mpl (myeloproliferative leukemia virus oncogene)–P-selectin axis

Asthma, the prototypic Th2-mediated inflammatory disorder of the lung, is an emergent disease worldwide. Vascular endothelial growth factor (VEGF) is a critical regulator of pulmonary Th2 inflammation, but the underlying mechanism and the roles of microRNAs (miRNAs) in this process have not been defined. Here we show that lung-specific overexpression of VEGF decreases miR-1 expression in the lung, most prominently in the endothelium, and a similar down-regulation occurs in lung endothelium in Th2 inflammation models. Intranasal delivery of miR-1 inhibited inflammatory responses to ovalbumin, house dust mite, and IL-13 overexpression. Blocking VEGF inhibited Th2-mediated lung inflammation, and this was restored by antagonizing miR-1. Using mRNA arrays, Argonaute pull-down assays, luciferase expression assays, and mutational analysis, we identified Mpl as a direct target of miR-1 and showed that VEGF controls the expression of endothelial Mpl during Th2 inflammation via the regulation of miR-1. In vivo knockdown of Mpl inhibited Th2 inflammation and indirectly inhibited the expression of P-selectin in lung endothelium. These experiments define a novel VEGF–miR-1–Mpl–P-selectin effector pathway in lung Th2 inflammation and herald the utility of miR-1 and Mpl as potential therapeutic targets for asthma.Asthma, the prototypic type 2 inflammatory disorder of the lung, is an emergent disease worldwide (Asher et al., 2006; Kim et al., 2010). Several studies have demonstrated that vascular endothelial growth factor (VEGF) and endothelial signaling play critical roles in the lung Th2 inflammation (Hoshino et al., 2001a,b; Lee et al., 2004; Simcock et al., 2007; Tuder and Yun, 2008; Asosingh and Erzurum, 2009). Most prominent were studies demonstrating that transgenic expression of VEGF in the lung leads to eosinophil-rich inflammation, mucus metaplasia, and airway remodeling and that selective VEGF receptor 2 (VEGFR2) blockade abrogates aeroallergen-induced pulmonary inflammation (Lee et al., 2004). However, the mechanisms of VEGF contribution to this inflammatory cascade are poorly understood (Voelkel et al., 2006; Tuder and Yun, 2008).MicroRNAs (miRNAs) regulate gene expression by base pairing with conserved sites within the 3′ untranslated region (UTR) of their target mRNAs (Bartel, 2009). Each miRNA can potentially bind to hundreds of mRNAs in the cell and thus regulate a multitude of functional and structural changes in a cell- and organ-specific manner (Giraldez et al., 2005; Chen and Rajewsky, 2006; Sokol et al., 2008). Although the mechanisms of translational regulation by miRNAs have not been fully defined, it is known that miRNAs function through formation of a ribonucleoprotein complex called the miRNA-induced silencing complex (mi-RISC). mi-RISC contains a guide miRNA bound to one of four mammalian Argonaute proteins and is one of the effector arms of the RNA interference pathway causing mRNA deadenylation and decay or inhibition of translation (Jackson and Standart, 2007). Of these, Argonaute 2 (Ago2) is the most abundantly expressed Argonaute in mammalian tissues (Wang et al., 2012) and is the only mammalian Argonaute with endonucleolytic activity (Liu et al., 2004). Recent studies have demonstrated that miRNAs play important roles in a wide variety of biological processes (Giraldez et al., 2005; Chen and Rajewsky, 2006; Sokol et al., 2008; Fish et al., 2008; Wang et al., 2008; Suárez et al., 2008; Bonauer et al., 2009; Nicoli et al., 2010). However, the roles of miRNA in Th2 inflammation and the inflammatory effects of VEGF have not been investigated.We hypothesized that the effects of VEGF in Th2 inflammation are mediated by its ability to alter endothelial miRNA and their downstream targets. To test this hypothesis, we evaluated the miRNA and miRNA target alterations in VEGF transgenic mice and models of aeroallergen-induced Th2 inflammation. We found that lung-targeted VEGF down-regulated miR-1, most prominently in the endothelium, and that a similar down-regulation takes place in lung-targeted IL-13 transgenic and aeroallergen-sensitized and challenged mice. We next demonstrated that intranasal delivery of miR-1 decreased Th2- and IL-13–stimulated inflammation and that antagonizing miR-1 rescued Th2 immunity in the context of VEGFR2 blockade. We also found a direct target of miR-1, Mpl, and defined the critical role of Mpl in Th2 inflammation by silencing this gene in Th2-inflamed lungs. Lastly, we showed that Mpl, similar to its role in platelets, regulates the expression of P-selectin in the lung endothelium. Overall, these experiments define a novel VEGF-driven, miR-1–Mpl–P-selectin effector pathway in lung Th2 inflammation.     

The RAGE axis in systemic inflammation, acute lung injury and myocardial dysfunction: an important therapeutic target?

Background  

The sepsis syndromes, frequently complicated by pulmonary and cardiac dysfunction, remain a major cause of death amongst the critically ill. Targeted therapies aimed at ameliorating the systemic inflammation that characterises the sepsis syndromes have largely yielded disappointing results in clinical trials. Whilst there are many potential reasons for lack of success of clinical trials, one possibility is that the pathways targeted, to date, are only modifiable very early in the course of the illness. More recent approaches have therefore attempted to identify pathways that could offer a wider therapeutic window, such as the receptor for advanced glycation end-products (RAGE) and its ligands.     

The concept of “baby lung”

Background The baby lung concept originated as an offspring of computed tomography examinations which showed in most patients with acute lung injury/acute respiratory distress syndrome that the normally aerated tissue has the dimensions of the lung of a 5- to 6-year-old child (300–500 g aerated tissue).Discussion The respiratory system compliance is linearly related to the baby lung dimensions, suggesting that the acute respiratory distress syndrome lung is not stiff but instead small, with nearly normal intrinsic elasticity. Initially we taught that the baby lung is a distinct anatomical structure, in the nondependent lung regions. However, the density redistribution in prone position shows that the baby lung is a functional and not an anatomical concept. This provides a rational for gentle lung treatment and a background to explain concepts such as baro- and volutrauma.Conclusions From a physiological perspective the baby lung helps to understand ventilator-induced lung injury. In this context, what appears dangerous is not the V_T/kg ratio but instead the V_T/baby lung ratio. The practical message is straightforward: the smaller the baby lung, the greater is the potential for unsafe mechanical ventilation.     

The oxysterol–CXCR2 axis plays a key role in the recruitment of tumor-promoting neutrophils

Tumor-infiltrating immune cells can be conditioned by molecules released within the microenvironment to thwart antitumor immune responses, thereby facilitating tumor growth. Among immune cells, neutrophils play an important protumorigenic role by favoring neoangiogenesis and/or by suppressing antitumor immune responses. Tumor-derived oxysterols have recently been shown to favor tumor growth by inhibiting dendritic cell migration toward lymphoid organs. We report that tumor-derived oxysterols recruit protumor neutrophils in a liver X receptor (LXR)–independent, CXCR2-dependent manner, thus favoring tumor growth by promoting neoangiogenesis and immunosuppression. We demonstrate that interfering with the oxysterol–CXCR2 axis delays tumor growth and prolongs the overall survival of tumor-bearing mice. These results identify an unanticipated protumor function of the oxysterol–CXCR2 axis and a possible target for cancer therapy.Tumor formation is the result of molecular alterations involving cellular regulators (Hanahan and Weinberg, 2011) as well as the ability of tumor cells to affect the tumor microenvironment by smoldering inflammation (de Visser et al., 2006; Mantovani et al., 2008) or even taking advantage of inflammation to grow and metastasize (Zitvogel et al., 2006; Grivennikov et al., 2010). Indeed, targeted therapies aimed to inhibit molecular alterations in tumor cells even though inducing antitumor responses have improved overall survival only slightly, indicating that antitumor strategies comprehensive of drugs targeting molecular as well as microenvironment alterations might be more effective (Vanneman and Dranoff, 2012). Tumor microenvironment is composed of various cell types, including tumor-associated macrophages endowed with phenotypes and functions of alternatively activated or M2 macrophages (i.e., expressing IL-10, TGF-β, ARG1, and mannose receptor; Mantovani and Sica, 2010), which have been shown to promote tumor initiation/formation through the induction of immune suppression, matrix remodeling, and angiogenesis (Murdoch et al., 2008), and the heterogeneous CD11b⁺Gr1⁺ myeloid cells, also termed myeloid-derived suppressor cells, comprising immature myeloid progenitors for neutrophils, monocytes, and DCs (Gabrilovich and Nagaraj, 2009). CD11b⁺Gr1⁺ myeloid cells are present in the tumor as well as in bone marrow, peripheral blood, and spleen of tumor-bearing mice (Bronte and Zanovello, 2005). In particular, the immature CD11b⁺Gr1⁺ bone marrow–derived cells, as well as the CD11b^highGr1^highLy6G⁺ neutrophils, have been recognized as playing an important protumorigenic role by promoting neoangiogenesis (Yang et al., 2004) through the release of MMP9 (Nozawa et al., 2006) and Bv8 (Shojaei et al., 2008), thus mediating refractoriness to anti-VEGF therapy (Shojaei et al., 2007a). Neutrophils have also been shown to suppress antitumor immune responses (Fridlender et al., 2009; De Santo et al., 2010).Several tumor-derived molecules induce immune suppression by affecting tumor-infiltrating immune cells (Vesely et al., 2011). Some of these molecules are intermediate or final products of the cellular metabolism, such as kynurenine, which, alone or together with the depletion of tryptophan, has been reported to promote T cell anergy (Mellor et al., 2003). Similarly, it has been shown that the increased metabolism of l-arginine by myeloid cells can result in the impairment of lymphocyte responses to tumor cells (Bronte and Zanovello, 2005). Other metabolic pathways have recently emerged as protumorigenic. Products of lipid and cholesterol metabolism have been demonstrated to damage the function of DC both in mouse and in human tumor models. As an example, lipid-loaded DCs are not able to effectively stimulate allogeneic T cells or to present tumor-associated antigens as the result of a reduced antigen processing capability (Herber et al., 2010).Liver X receptor (LXR) ligands, also named oxysterols, are involved in cholesterol homeostasis (Repa and Mangelsdorf, 2000) and in modulating immune responses (Bensinger and Tontonoz, 2008). The oxysterol 7α,25-HC, which is unable to activate LXRs, has recently been involved in B cell migration to follicles of lymphoid organ through the engagement of EBI2 receptor (Hannedouche et al., 2011; Liu et al., 2011). We have recently shown that LXR ligands/oxysterols are released by cancer cells and inhibit CCR7 expression on maturing DCs, therefore dampening DC migration to draining lymph nodes and antitumor immune responses (Villablanca et al., 2010). Indeed, tumor cells engineered to express the oxysterol inactivating enzyme sulfotransferase 2B1b (SULT2B1b; Fuda et al., 2007), fail to activate LXRs in vitro and are delayed or rejected when infused in immunocompetent mice (Villablanca et al., 2010). Whether tumor-derived LXR ligands/oxysterols are endowed with other protumorigenic functions, thus favoring the formation of hostile microenvironments for immune cells, remains elusive.Here, we show that tumor-derived oxysterols contribute to recruit neutrophils in a CXCR2-dependent manner within tumor microenvironment, thus favoring neoangiogenesis and/or immunosuppression and tumor growth. Importantly, we show that oxysterol inactivation, as well as CXCR2 inactivation, controls tumor growth, thus identifying a new protumor role of oxysterols and a new therapeutic target for cancer patients.     

Plasma glutamate–modulated interaction of A2AR and mGluR5 on BMDCs aggravates traumatic brain injury–induced acute lung injury

The bone marrow–derived cell (BMDC)–associated inflammatory response plays a key role in the development of acute lung injury (ALI). Activation of adenosine A_2A receptor (A_2AR) is generally considered to be antiinflammatory, inhibiting BMDC activities to protect against ALI. However, in the present study, we found that in a mouse model of neurogenic ALI induced by severe traumatic brain injury (TBI), BMDC A_2AR exerted a proinflammatory effect, aggravating lung damage. This is in contrast to the antiinflammatory effect observed in the mouse oleic acid–induced ALI model (a nonneurogenic ALI model.) Moreover, the A_2AR agonist {"type":"entrez-protein","attrs":{"text":"CGS21680","term_id":"878113053","term_text":"CGS21680"}}CGS21680 aggravated, whereas the antagonist ZM241385 attenuated, the severe TBI-induced lung inflammatory damage in mice. Further investigation of white blood cells isolated from patients or mouse TBI models and of cultured human or mouse neutrophils demonstrated that elevated plasma glutamate after severe TBI induced interaction between A_2AR and the metabotropic glutamate receptor 5 (mGluR5) to increase phospholipase C–protein kinase C signaling, which mediated the proinflammatory effect of A_2AR. These results are in striking contrast to the well-known antiinflammatory and protective role of A_2AR in nonneurogenic ALI and indicate different therapeutic strategies should be used for nonneurogenic and neurogenic ALI treatment when targeting A_2AR.Traumatic brain injury (TBI) is a life-threatening syndrome that can be complicated by the dysfunction of peripheral organs such as lung, liver, kidney, or intestine. Among these, the association between TBI and subsequent acute lung injury (ALI) has been increasingly recognized (Dettbarn and Davidson, 1989; Bratton and Davis, 1997; Contant et al., 2001; Bronchard et al., 2004; Mascia et al., 2008). Mackersie et al. (1983) reported that 9 of 18 comatose victims with isolated TBI developed pulmonary edema, defined as increased extravascular lung fluid content measured by thermal green dye. Two studies have reported that 20–25% of patients with isolated TBI developed respiratory insufficiency (Fulton and Jones, 1975; Bratton and Davis, 1997). Moreover, Holland et al. (2003) investigated 137 patients with TBI and found that ∼31% developed ALI. In fact, TBI-induced ALI and its development may not only influence the lung epithelium, but may also impair brain function, aggravate the neurogenic injury, and cause higher mortality and worse prognosis. Although there is evidence to suggest that inflammation is the key pathological mechanism in TBI-induced ALI (Kalsotra et al., 2007; Jin et al., 2009), as it is in nonneurogenic ALI (such as ALI induced by lung trauma, shock, and sepsis; Wheeler and Bernard, 2007; Parekh et al., 2011; Qian et al., 2012), it is unclear how TBI triggers the lung inflammatory response.BMDCs, including neutrophils, lymphocytes, monocytes, and eosinophils (also called WBCs), are the critical response cells for progression of inflammation in ALI/acute respiratory distress syndrome (Abraham, 2003; Nakajima et al., 2010; Grommes and Soehnlein, 2011). Adenosine A_2A receptor (A_2AR), one of four G protein–coupled adenosine receptors (A₁R, A_2AR, A_2BR, and A₃R), is found to be expressed on BMDCs and can regulate the function of BMDCs in several pathological conditions. Previous studies in multiple nonneurogenic ALI animal models such as LPS-induced ALI, lung ischemia-reperfusion injury, and lung injury in laparotomy-induced hemorrhagic shock have shown that activation of A_2AR plays an antiinflammatory role via inhibition of BMDC activities (Thiel et al., 2005; Haskó et al., 2006; Reutershan et al., 2007; Sharma et al., 2010). Accordingly, this receptor is considered an attractive potential target for therapeutic approaches to human ALI (Schepp and Reutershan, 2008). Conversely, in TBI and some other central nervous system injury models, A_2AR on BMDCs has been found to promote the inflammation of brain or spinal cord (Yu et al., 2004; Dai et al., 2010a). This leads us to speculate that in severe TBI-induced ALI (a neurogenic ALI), the role of BMDC A_2AR may be different from that in nonneurogenic ALI and may be involved in the progression of TBI-induced ALI.To confirm this hypothesis, we created BM chimeras to determine the role of BMDC A_2AR in a mouse model of severe TBI-induced ALI, comparing it with the oleic acid–induced ALI model (a nonneurogenic model). In human and mouse WBCs and neutrophils, the major components of BMDCs and the key reactive cells in ALI, we further investigated the mechanisms of BMDC A_2AR effects on inflammation associated with TBI-induced ALI.     

The role of circulating sex hormones in menstrual cycle–dependent modulation of pain-related brain activation

Sex differences in pain sensitivity have been consistently found, but the basis for these differences is incompletely understood. The present study assessed how pain-related neural processing varies across the menstrual cycle in normally cycling, healthy women, and whether menstrual cycle effects are based on fluctuating sex hormone levels. Fifteen subjects participated in 4 test sessions during their menstrual, midfollicular, ovulatory, and midluteal phases. Brain activity was measured while nonpainful and painful stimuli were applied with a pressure algometer. Serum hormone levels confirmed that scans were performed at appropriate cycle phases in 14 subjects. No significant cycle phase differences were found for pain intensity or unpleasantness ratings of stimuli applied during functional magnetic resonance imaging scans. However, lower pressure pain thresholds were found for follicular compared with other phases. Pain-specific brain activation was found in several regions traditionally associated with pain processing, including the medial thalamus, anterior and middle insula, midcingulate, primary and secondary somatosensory cortices, cerebellum, and frontal regions. The inferior parietal lobule, occipital gyrus, cerebellum, and several frontal regions showed interaction effects between stimulus level and cycle phase, indicating differential processing of pain-related responses across menstrual cycle phases. Correlational analyses indicated that cycle-related changes in pain sensitivity measures and brain activation were only partly explained by varying sex hormone levels. These results show that pain-related cerebral activation varies significantly across the menstrual cycle, even when perceived pain intensity and unpleasantness remain constant. The involved brain regions suggest that cognitive pain or more general bodily awareness systems are most susceptible to menstrual cycle effects.     

Heart–lung interactions during neurally adjusted ventilatory assist

Introduction

Assist in unison to the patient’s inspiratory neural effort and feedback-controlled limitation of lung distension with neurally adjusted ventilatory assist (NAVA) may reduce the negative effects of mechanical ventilation on right ventricular function.

Methods

Heart–lung interaction was evaluated in 10 intubated patients with impaired cardiac function using esophageal balloons, pulmonary artery catheters and echocardiography. Adequate NAVA level identified by a titration procedure to breathing pattern (NAVAal), 50% NAVAal, and 200% NAVAal and adequate pressure support (PSVal, defined clinically), 50% PSVal, and 150% PSVal were implemented at constant positive end-expiratory pressure for 20 minutes each.

Results

NAVAal was 3.1 ± 1.1cmH₂O/μV and PSVal was 17 ± 2 cmH₂0. For all NAVA levels negative esophageal pressure deflections were observed during inspiration whereas this pattern was reversed during PSVal and PSVhigh. As compared to expiration, inspiratory right ventricular outflow tract velocity time integral (surrogating stroke volume) was 103 ± 4%, 109 ± 5%, and 100 ± 4% for NAVAlow, NAVAal, and NAVAhigh and 101 ± 3%, 89 ± 6%, and 83 ± 9% for PSVlow, PSVal, and PSVhigh, respectively (p < 0.001 level-mode interaction, ANOVA). Right ventricular systolic isovolumetric pressure increased from 11.0 ± 4.6 mmHg at PSVlow to 14.0 ± 4.6 mmHg at PSVhigh but remained unchanged (11.5 ± 4.7 mmHg (NAVAlow) and 10.8 ± 4.2 mmHg (NAVAhigh), level-mode interaction p = 0.005). Both indicate progressive right ventricular outflow impedance with increasing pressure support ventilation (PSV), but no change with increasing NAVA level.

Conclusions

Right ventricular performance is less impaired during NAVA compared to PSV as used in this study. Proposed mechanisms are preservation of cyclic intrathoracic pressure changes characteristic of spontaneous breathing and limitation of right-ventricular outflow impedance during inspiration, regardless of the NAVA level.

Trial registration

Clinicaltrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT00647361","term_id":"NCT00647361"}}NCT00647361, registered 19 March 2008

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-014-0499-8) contains supplementary material, which is available to authorized users.     

Chitinase 3–like–1 and its receptors in Hermansky-Pudlak syndrome–associated lung disease

Hermansky-Pudlak syndrome (HPS) comprises a group of inherited disorders caused by mutations that alter the function of lysosome-related organelles. Pulmonary fibrosis is the major cause of morbidity and mortality in patients with subtypes HPS-1 and HPS-4, which both result from defects in biogenesis of lysosome-related organelle complex 3 (BLOC-3). The prototypic chitinase-like protein chitinase 3–like–1 (CHI3L1) plays a protective role in the lung by ameliorating cell death and stimulating fibroproliferative repair. Here, we demonstrated that circulating CHI3L1 levels are higher in HPS patients with pulmonary fibrosis compared with those who remain fibrosis free, and that these levels associate with disease severity. Using murine HPS models, we also determined that these animals have a defect in the ability of CHI3L1 to inhibit epithelial apoptosis but exhibit exaggerated CHI3L1-driven fibroproliferation, which together promote HPS fibrosis. These divergent responses resulted from differences in the trafficking and effector functions of two CHI3L1 receptors. Specifically, the enhanced sensitivity to apoptosis was due to abnormal localization of IL-13Rα2 as a consequence of dysfunctional BLOC-3–dependent membrane trafficking. In contrast, the fibrosis was due to interactions between CHI3L1 and the receptor CRTH2, which trafficked normally in BLOC-3 mutant HPS. These data demonstrate that CHI3L1-dependent pathways exacerbate pulmonary fibrosis and suggest CHI3L1 as a potential biomarker for pulmonary fibrosis progression and severity in HPS.     

The immunoneuroendocrine axis in critical illness: beneficial adaptation or neuroendocrine exhaustion?

PURPOSE OF REVIEW: Over the last years, endocrinology has been incorporated in critical care medicine, and acknowledgment of the complex neuro-endocrine adaption of critical illness has led to new insights and major breakthroughs in clarifying pathophysiological mechanisms and the targeting of therapeutic strategies. This review focuses on the important role of the hypothalamic-pituitary-adrenal (HPA) axis during critical illness and the occurrence of neuroendocrine failure. RECENT FINDINGS: The distinction between acute (activated anterior pituitary function and inactivated peripheral anabolic pathways) and prolonged (reduced neuroendocrine stimulation) critical illness as different neuroendocrine paradigms has brought a new approach to the critically ill patient. The HPA adaptation in the prolonged phase is characterized by hypercortisolism induced by non-ACTH driven pathways as ACTH levels are low. In spite of the high-normal (total) cortisol levels, HPA insufficiency appears to be quite common. On the other hand, there is a marked depletion of corticosteroid-binding globulin (CBG) in the acute phase of critical illness, resulting in increased free and biologically active cortisol. There is a persistent marked depletion of dehydroeplandrosterone sulfate, possibly indicating adrenal exhaustion, while macrophage inhibitory factor is upregulated in sepsis, affecting and contraregulating the biological effects of glucocorticoids. SUMMARY: The endocrine system is highly interrelated with the immune and neural systems, the neuroimmunoendocrine axis is subject to clear biphasic changes in the acute and chronic phases of critical illness, most likely reflecting a beneficial adaptation. These neuroendocrine dynamics should be considered when assessing the neuroendocrine system, in particular the HPA axis.     

Primary lung tumor segmentation from PET–CT volumes with spatial–topological constraint

Purpose

Accurate lung tumor segmentation is a prerequisite for effective radiation therapy and surgical planning. However, tumor delineation is challenging when the tumor boundaries are indistinct on PET or CT. To address this problem, we developed a segmentation method to improve the delineation of primary lung tumors from PET–CT images.

Methods

We formulated the segmentation problem as a label information propagation process in an iterative manner. Our model incorporates spatial–topological information from PET and local intensity changes from CT. The topological information of the regions was extracted based on the metabolic activity of different tissues. The spatial–topological information moderates the amount of label information that a pixel receives: The label information attenuates as the spatial distance increases and when crossing different topological regions. Thus, the spatial–topological constraint assists accurate tumor delineation and separation. The label information propagation and transition model are solved under a random walk framework.

Results

Our method achieved an average DSC of \(0.848 \pm 0.036\) and HD (mm) of \(8.652 \pm 4.532\) on 40 patients with lung cancer. The t test showed a significant improvement (p value \(<\) 0.05) in segmentation accuracy when compared to eight other methods. Our method was better able to delineate tumors that had heterogeneous FDG uptake and which abutted adjacent structures that had similar densities.

Conclusions

Our method, using a spatial–topological constraint, provided better lung tumor delineation, in particular, when the tumor involved or abutted the chest wall and the mediastinum.

     

The microheterogeneity of α1-acid glycoprotein in inflammatory lung disease,cancer of the lung and normal health

The concentration of α₁-acid glycoprotein (AGP, orosomucoid) was measured in sera from 19 patients with primary squamous cell carcinoma of the lung, 16 patients with an inflammatory lung disease and 17 persons with normal health. All sera were further subjected to crossed immuno-affinoelectrophoresis with addition of Con A in the first dimension and sugar in the second dimension. The distribution of AGP into four microheterogeneity forms, which were the result of this analysis, was estimated by measuring the area under the precipitation curve. The microheterogeneity patterns of AGP in the three groups were significantly different from each other (p< 0.001). The total concentration of AGP in the two groups of patients was significantly different from the concentration in the healthy group (p < 0.001).     

Impact of gut–brain interaction in emerging neurological disorders

The central nervous system(CNS) is a reservoir of immune privilege. Specialized immune glial cells are responsible for maintenance and defense against foreign invaders. The blood–brain barrier(BBB) prevents detrimental pathogens and potentially overreactive immune cells from entering the periphery. When the double-edged neuroinflammatory response is overloaded, it no longer has the protective function of promoting neuroregeneration. Notably, microbiota and its derivatives may emerge as pathogen-...