The mononuclear phagocyte system(MPS)consists of monocytes,dendritic cells and macrophages,which play vital roles in innate immune defense against cancer.Hepatocellular carcinoma(HCC)is a complex disease that is affec...The mononuclear phagocyte system(MPS)consists of monocytes,dendritic cells and macrophages,which play vital roles in innate immune defense against cancer.Hepatocellular carcinoma(HCC)is a complex disease that is affected or initiated by many factors,including chronic hepatitis B virus infection,hepatitis C virus infection,metabolic disorders or alcohol consumption.Liver function,tumor stage and the performance status of patients affect HCC clinical outcomes.Studies have shown that targeted treatment of tumor microenvironment disorders may improve the efficacy of HCC treatments.Cytokines derived from the innate immune response can regulate T-cell differentiation,thereby shaping adaptive immunity,which is associated with the prognosis of HCC.Therefore,it is important to elucidate the function of the MPS in the progression of HCC.In this review,we outline the impact of HCC on the MPS.We illustrate how HCC reshapes MPS cell phenotype remodeling and the production of associated cytokines and characterize the function and impairment of the MPS in HCC.展开更多
The mononuclear phagocyte system （MPS）, which con-sists of monocytes, dendritic cells （DCs）, and macro-phages, plays a vital role in the innate immune defense against pathogens. Hepatitis C virus （HCV） is effcie...The mononuclear phagocyte system （MPS）, which con-sists of monocytes, dendritic cells （DCs）, and macro-phages, plays a vital role in the innate immune defense against pathogens. Hepatitis C virus （HCV） is effcient in evading the host immunity, thereby facilitating its devel-opment into chronic infection. Chronic HCV infection is the leading cause of end-stage liver diseases, liver cirrhosis, and hepatocellular carcinoma. Acquired im-mune response was regarded as the key factor to era-dicate HCV. However, innate immunity can regulate the acquired immune response. Innate immunity-derived cytokines shape the adaptive immunity by regulating T-cell differentiation, which determines the outcome of acute HCV infection. Inhibition of HCV-specific T-cell responses is one of the most important strategies for im-mune system evasion. It is meaningful to illustrate the role of innate immune response in HCV infection. With the MPS being the important factor in innate immunity, therefore, understanding the role of the MPS in HCV infection will shed light on the pathophysiology of chronic HCV infection. In this review, we outline the impact of HCV infection on the MPS and cytokine production. We discuss how HCV is detected by the MPS and describe the function and impairment of MPS components in HCV infection.展开更多
Objective: To investigate the leishmanicidal effects of two antioxidants, caffeic acid and quercetin on Leishmania major(L.major) promastigotes in vitro, and their immunomodulatory effects on infected phagocytes deriv...Objective: To investigate the leishmanicidal effects of two antioxidants, caffeic acid and quercetin on Leishmania major(L.major) promastigotes in vitro, and their immunomodulatory effects on infected phagocytes derived from susceptible BALB/c mice.Methods: Caffeic acid and quercetin-induced cell death was examined by Pi-Hoechst double staining of L.major promastigotes and MTT assay, in the presence or absence of protease inhibitors in vitro.Caffeic acid or quercetin were administered subcutaneously to BALB/c mice infected with L.major promastigotes through a dorsal air pouch.Nitric oxide and superoxide anion production by phagocytes infiltrating the air pouch and the expression of inducible nitric oxide synthase(i NOS), tumor necrosis factor alpha(TNF-a) and nuclear factor kappa B in the air pouch membrane were therefore evaluated using appropriate methods.Results: Caffeic acid and quercetin displayed a dose-dependent cytotoxic effect against L.major promastigotes, and induced cell death via caspases-independent pathways.In vivo, L.major promastigotes inoculation into air pouch cavity of BALB/c mice leads to a sequential influx of neutrophils(hours), followed by macrophages(days).Results showed that L.major delayed apoptosis of infected neutrophils and macrophages by the cleavage of the nuclear factor kappa B p65^(RelA) subunit, and persisted by inhibiting TNF-a and i NOS expression and reactive oxygen species generation.Caffeic acid or quercetin restored reactive oxygen species production and TNF-a-induced i NOS activity, and abrogate apoptosis delay of infected phagocytes.Conclusions: The leishmanicidal effect of caffeic acid and quercetin on promastigotes and amastigotes, as well as reactivation of infected phagocytes apoptosis, suggested a potential therapeutic role against cutaneous leishmaniasis.展开更多
The aim of this work was a study of the functional activity of neutrophils and peripheral blood monocytes in rats with the transplanted Walker carcinosarcoma as potential predictors of the sensitivity of this tumor to...The aim of this work was a study of the functional activity of neutrophils and peripheral blood monocytes in rats with the transplanted Walker carcinosarcoma as potential predictors of the sensitivity of this tumor to doxorubicin treatment. This study provides an evidence that such indices of the functional activity of circulating phagocytes of the tumor-bearing rats as the quantity and the phagocytosis intensity of monocytes, as well as the intensity of ROS production by monocytes and neutrophils, may reflect the degree of sensitivity of the tumor to doxorubicin. So it was shown that the growth of the resistant tumor caused a significant increase of the number of circulating phagocytic cells and the intensity of phagocytosis by more than 100% (p < 0.001) compared with the corresponding indices of intact rats and rats with the parental variant of the tumor. The ability of blood mono-cytes and neutrophils of rats with a resistant tumor to produce ROS was also significantly different from that in intact rats and animals with the parental carcinosarcoma variant. The predictive value of these indices is especially important in the dynamic monitoring of the development of tumor drug resistance during long-term cancer chemotherapy. Considering the standard 2 - 3 week interval between the courses of cancer therapy and the short lifetime of circulating phagocytes, an assessment of the indices of their functional activity before each subsequent course can be considered as a pretreatment assessment. Meanwhile, further studies are needed to determine the spectrum of malignant neoplasms for which the degree of tumor drug resistance correlates with the functional activity of circulating phagocytes.展开更多
The study aimed to develop and characterize a microemulsified system based on cotton oil and verify its effect on superoxide release anion and microbicidal activity by human peripheral blood cells. Microemulsions were...The study aimed to develop and characterize a microemulsified system based on cotton oil and verify its effect on superoxide release anion and microbicidal activity by human peripheral blood cells. Microemulsions were formulated using distilled water, degummed cotton oil, Span 80 (SP), Tween 80 (TW), and 1-butanol (BT). The pseudo-ternary diagram delimited ME regions, and the points were pre-selected. The physical-chemical and rheological characterization of the microemulsions was carried out. The ME activity on the interactions between leukocytes and bacteria was analyzed by superoxide release, phagocytosis, and microbicidal activity. The developed formulation was classified as Oil/Water, with an average pH of 5.76, and the viscosity showed resistance to temperature changes. The rheological model of the Power Law classified the microemulsion as a non-Newtonian fluid with pseudoplastic characteristics. The cell viability of cotton oil microemulsion was greater than 90%. There was an increase in the superoxide release by MN phagocytes when treated with cotton oil microemulsion. The cotton oil microemulsion increased phagocytosis and microbicidal activity. The present study suggests that cotton oil is an alternative biomaterial for therapeutic applications, especially in treating infections.展开更多
Two-dimensional(2D)nanomaterials,known for their unique atomic arrangements and exceptional physicochemical properties,have garnered significant attention in biomedical applications,particularly in the realms of immun...Two-dimensional(2D)nanomaterials,known for their unique atomic arrangements and exceptional physicochemical properties,have garnered significant attention in biomedical applications,particularly in the realms of immunotherapy for tissue engineering and tumor therapy.These applications necessitate a thorough assessment of the potential influence of 2D nanomaterials on immune cells.Notably,the mononuclear phagocyte system(MPS)cells,which play pivotal roles in both innate and adaptive immunity,are essential for maintaining organismal homeostasis.MPS cells with phagocytic capability contribute to the prevention of foreign body invasion and the elimination of dead or senescent cells.Furthermore,MPS cells,including macrophages and dendritic cells,serve as vital bridges between innate and adaptive immune responses.Therefore,understanding the nano-bio interactions between 2D nanomaterials and MPS cells is imperative.These nano-bio interactions including cellular uptake,cytocompatibility,and immunological impact are invaluable forthe purposeful design of 2D nanomaterials.Herein,we provide an overview of the latest advancements in understanding the nano-bio interactions between 2D nanomaterials and MPS cells,and discuss the current challenges and future prospects of employing 2D nanomaterials in the field of nanomedicine.展开更多
The defense system of teleost fish organized on innate and adaptive immunity protects them against a wide variety of pathogenic microorganisms in the aquatic environment.Phagocytosis is one of the most effective defen...The defense system of teleost fish organized on innate and adaptive immunity protects them against a wide variety of pathogenic microorganisms in the aquatic environment.Phagocytosis is one of the most effective defense strategies against microbial challenge mainly performed by classical‘professional’phagocytes(including monocytes,macrophages and granulocytes).They contain,kill and process the internalized pathogens for antigen presentation by providing antigenic ligands to initiate activation and clonal expansion of T and B cells,which bridge the innate and adaptive immunity.The discovery of phagocytic B cells in teleost fish has broken the paradigm that primary vertebrate B cells are lack of phagocytosis of particulates,as well as led to the investigation of phagocytic activity of mammalian B-1 B cells.The active phagocytic,microbicidal capabilities and antigen presentation in teleost phagocytic B cell have demonstrated to be similar as professional phagocytes,providing a potential impact on development of new vaccination strategies to prevent and control infectious diseases.In this review,we aim to address current progress on the antimicrobial role of phagocytic B cells in teleost fish by comparing it with other professional phagocytes and mammalian B-1 B cells,and provide the application prospect of phagocytic B cells in developing vaccines as well as the prevention of fish diseases.展开更多
A recent study revealed a novel mechanism by which radiotherapy promotes distant metastatic growth by inducing amphiregulin(AREG)secretion from tumor cells.1 Specifically,tumor-derived AREG reprograms mononuclear phag...A recent study revealed a novel mechanism by which radiotherapy promotes distant metastatic growth by inducing amphiregulin(AREG)secretion from tumor cells.1 Specifically,tumor-derived AREG reprograms mononuclear phagocytes(MNPs)into an immunosuppressive phenotype by activating the epidermal growth factor receptor(EGFR)on their surface.Concurrently,AREG upregulates CD47 expression on tumor cells via the signal transducer and activator of transcription 3(STAT3)pathway,which inhibits phagocytic function and facilitates metastatic progression.This discovery challenges the conventional understanding of the systemic effects of radiotherapy.It also identifies combinatorial therapeutic targets that promise an improvement in radiotherapy efficacy and enable the formulation of personalized treatment strategies.展开更多
Hemophagocytic lymphohistiocytosis (HLH) is an aggressive and often fatal overactivation of the immune system. It is characterized by inappropriate and dysregulated activation of natural killer (NK) cells, CD8^(+)cyto...Hemophagocytic lymphohistiocytosis (HLH) is an aggressive and often fatal overactivation of the immune system. It is characterized by inappropriate and dysregulated activation of natural killer (NK) cells, CD8^(+)cytotoxic T cells, and macrophages. Ineffective interactions between NK cells, CD8^(+)T cells, and their pathogenic targets lead to massive cytokine accumulation and widespread macrophage activation. Resultant hemophagocytosis and excessive organdamaging infl ammation subsequently occur.HLH may be triggered by genetic or sporadic disorders,as well as specific events that alter immune homeostasis.These events include inflammatory or infectious disease processes and malignancy.展开更多
Objective: PulmonaryMycobacterium tuberculosis infection can trigger cellular and humoral innate immune responses, which may cause death of the pathogen and or host cells/tissue. We aimed to determine the cytotoxic re...Objective: PulmonaryMycobacterium tuberculosis infection can trigger cellular and humoral innate immune responses, which may cause death of the pathogen and or host cells/tissue. We aimed to determine the cytotoxic response of phagocytes in patients with pulmonaryMycobacterium tuberculosis infection based on plasma tumor necrosis factor-alpha (TNF-α), malondialdehyde (MDA), and superoxide dismutase (SOD) levels.Methods: In this observational study, patients newly infected with pulmonaryMycobacterium tuberculosis (n=31;age 37-62 years) and age-matched uninfected volunteers (n=50) were recruited as test and control volunteers, respectively in Owo, Nigeria. The study protocol was reviewed and approved by the Research and Ethics Committee of the Department of Medical Laboratory Science, Achievers University, Owo, Nigeria (AUO/MLS/VII/2009/212). Anti-hepatitis C virus, human immunodeficiency virus antigen/antibody, hepatitis B virus surface antigen, and plasma TNF-α were determined by enzyme-linked immunosorbent assay, SOD, and MDA were determined by colorimetry,Plasmodium by Giemsa thick blood film staining, and acid-fast bacilli in sputum were detected by Ziehl-Neelsen staining.Results: All participants had normal blood glucose levels and tested negative for human immunodeficiency virus antigen/antibody, anti-hepatitis C virus, hepatitis B virus surface antigen, andPlasmodium spp., and had no medical history of cancer. Infected patients had significantly higher plasma MDA and TNF-α levels and significantly lower SOD levels compared with control subjects (allP<0.05).Conclusion: Mycobacterium tuberculosis infection elicited a cytotoxic response by phagocytes, evidenced by significant increases in MDA and TNF-α and a significant decrease in SOD levels.展开更多
AIM:To study the effects of probiotic metabolites on maturation stage of antigen-presenting immune cells.METHODS:Ganeden Bacillus coagulans 30(GBC30) bacterial cultures in log phase were used to isolate the secreted m...AIM:To study the effects of probiotic metabolites on maturation stage of antigen-presenting immune cells.METHODS:Ganeden Bacillus coagulans 30(GBC30) bacterial cultures in log phase were used to isolate the secreted metabolite(MET) fraction.A second fraction was made to generate a crude cell-wall-enriched fraction,by centrifugation and lysis,followed by washing.A preparation of MET was subjected to size exclusion centrifugation,generating three fractions:< 3 kDa,3-30 kDa,and 30-200 kDa and activities were tested in comparison to crude MET and cell wall in primary cultures of human peripheral blood mononuclear cell(PBMC) as a source of antigen-presenting mononuclear phagocytes.The maturation status of mononuclear phagocytes was evaluated by staining with monoclonal antibodies towards CD14,CD16,CD80 and CD86 and analyzed by flow cytometry.RESULTS:Treatment of PBMC with MET supported maturation of mononuclear phagocytes toward both macrophage and dendritic cell phenotypes.The biological activity unique to the metabolites included a reduction of CD14+ CD16+ pro-inflammatory cells,and this property was associated with the high molecular weight metabolite fraction.Changes were also seen for the dendritic cell maturation markers CD80 and CD86.On CD14dim cells,an increase in both CD80 and CD86 expression was seen,in contrast to a selective increase in CD86 expression on CD14bright cells.The co-expression of CD80 and CD86 indicates effective antigen presentation to T cells and support of T helper cell differentiation.The selective expression of CD86 in the absence of CD80 points to a role in generating T regulatory cells.CONCLUSION:The data show that a primary mechanism of action of GBC30 metabolites involves support of more mature phenotypes of antigen-presenting cells,important for immunological decision-making.展开更多
Up to 15%of male in fertility has an immuno logical origi n,either due to repetitive infections or to autoimmune resp on ses mainly affecting the epididymis,prostate,and testis.Clinical observations and epidemiologica...Up to 15%of male in fertility has an immuno logical origi n,either due to repetitive infections or to autoimmune resp on ses mainly affecting the epididymis,prostate,and testis.Clinical observations and epidemiological data clearly contradict the idea that the testis confers immune protection to the whole male genital tract.As a consequenee,the epididymis,in which posttesticular spermatozoa mature and are stored,has raised some in terest in recent years when it comes to its immune mecha nisms.In deed,sperm cells are produced at puberty,long after the establishment of self-toleranee,and they possess unique surface proteins that cannot be recognized as self.These are potential targets of the immune system,with the risk of inducing autoantibodies and consequently male infertility.Epididymal immunity is based on a finely tuned equilibrium between efficient immune responses to pathogens and strong tolerance to sperm cells.These processes rely on incompletely described molecules and cell types.This review compiles recent studies focusing on the immune cell types populating the epididymis,and proposes hypothetical models of the organization of epididymal immunity with a special emphasis on the immune response,while also discussing important aspects of the epididymal immune regulation such as tolerance and tumour control.展开更多
Helicobacter pylori(H. pylori) is perhaps the most ubiquitous and successful human pathogen, since it colonizes the stomach of more than half of humankind. Infection with this bacterium is commonly acquired during chi...Helicobacter pylori(H. pylori) is perhaps the most ubiquitous and successful human pathogen, since it colonizes the stomach of more than half of humankind. Infection with this bacterium is commonly acquired during childhood. Once infected, people carry the bacteria for decades or even for life, if not treated. Persistent infection with this pathogen causes gastritis, peptic ulcer disease and is also strongly associated with the development of gastric cancer. Despite induction of innate and adaptive immune responses in the infected individual, the host is unable to clear the bacteria. One widely accepted hallmark of H. pylori is that it successfully and stealthily evades host defense mechanisms. Though the gastric mucosa is well protected against infection, H. pylori is able to reside under the mucus, attach to gastric epithelial cells and cause persistent infection by evading immune responses mediated by host. In this review, we discuss how H. pylori avoids innate and acquired immune response elements, uses gastric epithelial cells as mediators to manipulate host T cell responses and uses virulence factors to avoid adaptive immune responses by T cells to establish a persistent infection. We also discuss in this review how the genetic diversity of this pathogen helps for its survival.展开更多
Microglia, as the resident immune cells in the central nervous system, play important roles in regulating neuronal processes, such as neural excitability, synaptic activity, and apoptotic cell clearance. Growth factor...Microglia, as the resident immune cells in the central nervous system, play important roles in regulating neuronal processes, such as neural excitability, synaptic activity, and apoptotic cell clearance. Growth factors can activate multiple signaling pathways in central nervous system microglia and can regulate their immune effects, but whether growth factors can affect the morphological characteristics and ultrastructure of microglia has not been reported. After microinjecting 300 nL of a growth factor cocktail, including 10 μg/mL epidermal growth factor, 10 μg/mL basic fibroblast growth factor, 10 μg/mL hepatocyte growth factor and 10 μg/mL insulin-like growth factor into adult rat cortex, we found that the number of IBA1-positive microglia around the injection area increased significantly, indicating local activation of microglia. All CD68-positive labeling co-localized with IBA1 in microglia. Cell bodies and protrusions of CD68-positive cells were strongly attached to or were engulfing neurons. Characteristic huge phagosomes were observed in activated phagocytes by electron microscopy. The phagosomes generally included non-degraded neuronal protrusions and mitochondria, yet they contained no myelin membrane or remnants, which might indicate selective phagocytosis by the phagocytes. The remnant myelin sheath after phagocytosis still had regenerative ability and formed "myelin-like" structures around phagocytes. These results show that microinjection of a growth factor cocktail into the cerebral cortex of rodents can locally activate microglia and induce selective phagocytosis of neural structures by phagocytes. The study was approved by the Institute of Laboratory Animal Science, Beijing Institute of Basic Medical Sciences(approval No. IACUC-AMMS-2014-501) on June 30, 2014.展开更多
Background: Glucose is the main substrate for the generation of NADPH, the cofactor of the oxidative burst enzyme NADPH-oxidase of blood neutrophils. Changes in blood glucose are thus expected to modify the generation...Background: Glucose is the main substrate for the generation of NADPH, the cofactor of the oxidative burst enzyme NADPH-oxidase of blood neutrophils. Changes in blood glucose are thus expected to modify the generation of reactive oxygen species (ROS). The new blood ROS generation assay (BRGA) quantifies ROS changes induced by blood glucose concentrations as they are found in diabetes mellitus. Material and Methods: Citrated or EDTA blood of 6 healthy donors were analyzed in the BRGA: 10 μl sample in black polystyrene F-microwells (Brand 781608) were incubated in triplicate with 125 μl Hanks’ balanced salt solution, 40 μl 0 - 200 mM glucose in 0.9% NaCl (final added conc.: 0 - 41 mM;final basal glucose conc.: about4 mM), 10 μl5 mMluminol, and 10 μl zymosan A (final conc.: 1.9 μg/ml) in 0.9% NaCl. The plates were measured within 0 - 250 min (37℃) in a photons-multiplyer microtiter plate luminometer (LUmo) with an integration time of 1 s. Results: Up to about 30 min reaction time the mean ROS generation was 50% inhibited by about1 mMadded glucose (= approx. IC50). At ≥80 min reaction time (possibly necessary for full phosphorylation of glucose to glucose-6-phosphate (G6P), the substrate metabolized by G6P-dehydrogenase to generate NADPH, the cofactor of the NADPH-oxidase) the mean ROS generation approximately doubled at about1 mMadded glucose (= approx. SC200) in citrated blood. Discussion: Elevated glucose concentrations not only increase systemic thrombin generation, they can also diminish cellular fibrinolysis and increase systemic inflammation, resulting in a chronic pro-thrombotic state. The fascinating importance of NADPH-oxidases not only in phagocytes but also in the beta cells of pancreas points towards a new pathogenesis explication of diabetes mellitus type 1: whatever stimulus (e.g. a pancreas-tropic virus) could activate the beta cell’s autodestructive NADPH-oxidase.展开更多
Until recently,microglia were mainly known as the resident phagocytes of the brain,i.e.the‘immunological warriors’of the brain.However,extensive knowledge is being accumulated about the functions of microglia beyond...Until recently,microglia were mainly known as the resident phagocytes of the brain,i.e.the‘immunological warriors’of the brain.However,extensive knowledge is being accumulated about the functions of microglia beyond immunity.Nowadays,it is well accepted that microglial cells are highly dynamic and responsive,and that they intervene in a dual manner in many developmental processes that shape the central nervous system,including neurogenesis,gliogenesis,spatial patterning,synaptic formation and elimination,and neural circuit establishment and maturation.The differentiation and the pool of precursor cells were also shown to be under microglia regulation via bidirectional communication.In this concise review,I discuss our recent work in microglia-Pax6+cell interactions in one of the circumventricular organs,the pineal gland.An analogy with the rest of the central nervous system is also presented.In addition,I briefly examine mechanisms of interaction between microglia and non-microglial cells in both health and disease.New avenues are also introduced,which may lead us to better comprehend the impact of microglia in physiological and pathological conditions.展开更多
Dendrites and axons are delicate neuronal membrane extensions that undergo degeneration after physical injuries. In neurodegenerative diseases, they often degenerate prior to neuronal death. Understanding the mechanis...Dendrites and axons are delicate neuronal membrane extensions that undergo degeneration after physical injuries. In neurodegenerative diseases, they often degenerate prior to neuronal death. Understanding the mechanisms of neurite degeneration has been an intense focus of neurobiology research in the last two decades. As a result, many discoveries have been made in the molecular pathways that lead to neurite degeneration and the cell-cell interactions responsible for the subsequent clearance of neuronal debris. Drosophila melanogaster has served as a prime in vivo model system for identifying and characterizing the key molecular players in neurite degeneration, thanks to its genetic tractability and easy access to its nervous system. The knowledge learned in the fly provided targets and fuel for studies in other model systems that have further enhanced our understanding of neurodegeneration. In this review, we will introduce the experimental systems developed in Drosophila to investigate injuryinduced neurite degeneration, and then discuss the biological pathways that drive degeneration. We will also cover what is known about the mechanisms of how phagocytes recognize and clear degenerating neurites, and how recent findings in this area enhance our understanding of neurodegenerative disease pathology.展开更多
The aim of this study is to evaluate the effect of moderate physical exercise and treatment time on the organism’s response to NSC631570. The sensitivity of circulating phagocytes to the drug at different times of da...The aim of this study is to evaluate the effect of moderate physical exercise and treatment time on the organism’s response to NSC631570. The sensitivity of circulating phagocytes to the drug at different times of day was estimated in in vitro experiments. NSC631570 was administered intravenously to healthy volunteers (eleven men, 23 ± 2 years) in a single therapeutic dose in an inpatient and an outpatient setting. Blood samples were obtained before the drug administration, 30 min after the drug injection and every fourth hour throughout the 24 hour period. Biochemical parameters were determined using the hematological analyzer. Flow cytometry was used to evaluate phagocyte metabolism. Treatment of circulating phagocytes with NSC631570 in vitro resulted in an increase in ROS production along with a decrease in their phagocytic activity, most expressed in the morning time. Drug injection to sedentary persons resulted in pro-inflammatory metabolic polarization of circulating phagocytes. Introduction of NSC631570 to active persons was accompanied by a significant increase in phagocyte endocytosis along with a decrease in the daily mean of ROS generation. Significant oscillation (but in the normal ranges) of urea, creatinine, alanine aminotransferase and aspartate aminotransferase after NSC631570 introduction in the outpatient setting was shown during the day. Physical activity interferes with immunomodulatory action of NSC631570 and abrogates pro-inflammatory shift of circulating phagocytes. Biochemical parameters of blood from patients treated with NSC631570 in the outpatient setting must be interpreted cautiously considering the effect of physical activity on some metabolic biomarkers.展开更多
The capacities of phagocytes of subpopulation P1 (F) and morula cells (MC) of holothurian Eupentacta fraudatrix to modulate apoptosis of each other as well as cytokine-dependent mechanisms and hormonal regulation of t...The capacities of phagocytes of subpopulation P1 (F) and morula cells (MC) of holothurian Eupentacta fraudatrix to modulate apoptosis of each other as well as cytokine-dependent mechanisms and hormonal regulation of these cells’s interaction were studied. The 18-h treatment of F with supernatants, obtained after centrifugation of MC preincubated for 3 h with phosphate buffered saline (PSB) at the temperature of 22℃?(SMC3) resulted in a significant growth of apoptosis level. A 30-min incubation of F with supernatants of MC, preincubated for 24 h (SMC24), on the contrary, reduced the apoptosis level and increased the level of interleukine-1α (IL-1α)-like substances, and 24-h incubation did not influence apoptosis and reduced level of IL-1α-like substances. Thus, proapoptotic effects of MC’s supernatants in F inversely depended on time of their preincubation with PSB and directly on time of incubation with F. Additionally, this effect was opposite to variations in the level of IL-1α-like substances. The level of apoptosis declined after 30 min of incubation but elevated after 24 h at the inverse treatment of MC with supernatant, obtained after preincubation of F during 24 h (SF24). The level of IL-1α-like substances dropped after 30 min and insignificantly decreased after 24 h. Hence, SF24 proapoptotic effect directly depended on time of incubation with MC and did not correspond to variations in the level of IL-1α-like substances. 100 μM dexamethasone stimulated apoptosis in F and MC in an inverse time-dependent manner during 24-h preincubation, and supernatants of cell suspensions obtained after such preincubations, stimulated apoptosis and reduced the IL-1α-like substances level in target cells at both types of interaction. IL-1α-like substances are?supposed to be mediators for MC’s effects in F, but not for F’s action on MC. In holothurians, steroid hormones apparently may participate in the regulation of the immune response and cell cooperation.展开更多
Background: The neutrophils (PMN) are our main blood cells to combat fungi, bacteria, and fibrin. For normal function, an activated PMN generates a certain concentration of reactive oxygen species (ROS). If the genera...Background: The neutrophils (PMN) are our main blood cells to combat fungi, bacteria, and fibrin. For normal function, an activated PMN generates a certain concentration of reactive oxygen species (ROS). If the generated blood ROS concentration is too low, then fungi, bacteria or fibrin might threaten the life of the patient, and it could be of great medical interest to stimulate PMN by physiologic drugs. Granulocyte-Colony Stimulating Factor (G-CSF) is a cell hormone that increases the cell number of PMN and that stimulates the individual PMN. The blood ROS generation assay (BRGA) is an innovative physiologic test to monitor the ROS generation of PMN in blood. Here the ROS generating action of G-CSF on normal PMN is quantified. Material and Methods: 40 μl 0 - 10.3 ng/ml (final conc.) G-CSF (in 5% human albumin) in black Brand? 781608 high quality polystyrene F-microwells was incubated in triplicate with 125 μl Hanks’ balanced salt solution (HBSS;modified without phenol red) and 10 μl normal citrated blood. Immediately (BRGA) or after 60 min (BRGA-60-) 10 μl 5 mM luminol sodium salt in 0.9% NaCl and 10 μl 0 or 36 μg/ml zymosan A in 0.9% NaCl was added. The photons were counted within 0 - 318 min (37°C) in a photons-multiplying microtiter plate luminometer. At about 0.5 t-maxn (0.5 fold the time to normal maximum) the approx. SC200 of G-CSF was determined. Results and Discussion: The approx. SC200 of G-CSF on normal blood ROS generation was 0.2 μg/l (=20 IU/ml). In clinical situations where an increased blood ROS generation is pharmacologically required, few micrograms of G-CSF could be a sufficient dosage for an adult patient. The BRGA helps to find out the correct stimulating G-CSF dosage for each individual. An enhanced PMN function could favor a better clinical outcome in situations of wanted increase of the innate immunology or in cellular fibrinolysis. G-CSF plasma concentrations of 0.1 - 1 μg/l might favor singlet oxygen generation without immunosuppression or cell fragment-induced thrombin generation.展开更多
基金National Natural Science Foundation of China,No 81970529The Natural Science Foundation of Jilin Province,No.20200201387JC.
文摘The mononuclear phagocyte system(MPS)consists of monocytes,dendritic cells and macrophages,which play vital roles in innate immune defense against cancer.Hepatocellular carcinoma(HCC)is a complex disease that is affected or initiated by many factors,including chronic hepatitis B virus infection,hepatitis C virus infection,metabolic disorders or alcohol consumption.Liver function,tumor stage and the performance status of patients affect HCC clinical outcomes.Studies have shown that targeted treatment of tumor microenvironment disorders may improve the efficacy of HCC treatments.Cytokines derived from the innate immune response can regulate T-cell differentiation,thereby shaping adaptive immunity,which is associated with the prognosis of HCC.Therefore,it is important to elucidate the function of the MPS in the progression of HCC.In this review,we outline the impact of HCC on the MPS.We illustrate how HCC reshapes MPS cell phenotype remodeling and the production of associated cytokines and characterize the function and impairment of the MPS in HCC.
文摘The mononuclear phagocyte system （MPS）, which con-sists of monocytes, dendritic cells （DCs）, and macro-phages, plays a vital role in the innate immune defense against pathogens. Hepatitis C virus （HCV） is effcient in evading the host immunity, thereby facilitating its devel-opment into chronic infection. Chronic HCV infection is the leading cause of end-stage liver diseases, liver cirrhosis, and hepatocellular carcinoma. Acquired im-mune response was regarded as the key factor to era-dicate HCV. However, innate immunity can regulate the acquired immune response. Innate immunity-derived cytokines shape the adaptive immunity by regulating T-cell differentiation, which determines the outcome of acute HCV infection. Inhibition of HCV-specific T-cell responses is one of the most important strategies for im-mune system evasion. It is meaningful to illustrate the role of innate immune response in HCV infection. With the MPS being the important factor in innate immunity, therefore, understanding the role of the MPS in HCV infection will shed light on the pathophysiology of chronic HCV infection. In this review, we outline the impact of HCV infection on the MPS and cytokine production. We discuss how HCV is detected by the MPS and describe the function and impairment of MPS components in HCV infection.
基金Supported by the Research project “Implication of phagocytes dependent oxidative stress in inflammatory diseases and leishmaniasis” with project No.CNEPRU F00220130061Algerian Ministry of Higher Education and Scientific Research
文摘Objective: To investigate the leishmanicidal effects of two antioxidants, caffeic acid and quercetin on Leishmania major(L.major) promastigotes in vitro, and their immunomodulatory effects on infected phagocytes derived from susceptible BALB/c mice.Methods: Caffeic acid and quercetin-induced cell death was examined by Pi-Hoechst double staining of L.major promastigotes and MTT assay, in the presence or absence of protease inhibitors in vitro.Caffeic acid or quercetin were administered subcutaneously to BALB/c mice infected with L.major promastigotes through a dorsal air pouch.Nitric oxide and superoxide anion production by phagocytes infiltrating the air pouch and the expression of inducible nitric oxide synthase(i NOS), tumor necrosis factor alpha(TNF-a) and nuclear factor kappa B in the air pouch membrane were therefore evaluated using appropriate methods.Results: Caffeic acid and quercetin displayed a dose-dependent cytotoxic effect against L.major promastigotes, and induced cell death via caspases-independent pathways.In vivo, L.major promastigotes inoculation into air pouch cavity of BALB/c mice leads to a sequential influx of neutrophils(hours), followed by macrophages(days).Results showed that L.major delayed apoptosis of infected neutrophils and macrophages by the cleavage of the nuclear factor kappa B p65^(RelA) subunit, and persisted by inhibiting TNF-a and i NOS expression and reactive oxygen species generation.Caffeic acid or quercetin restored reactive oxygen species production and TNF-a-induced i NOS activity, and abrogate apoptosis delay of infected phagocytes.Conclusions: The leishmanicidal effect of caffeic acid and quercetin on promastigotes and amastigotes, as well as reactivation of infected phagocytes apoptosis, suggested a potential therapeutic role against cutaneous leishmaniasis.
文摘The aim of this work was a study of the functional activity of neutrophils and peripheral blood monocytes in rats with the transplanted Walker carcinosarcoma as potential predictors of the sensitivity of this tumor to doxorubicin treatment. This study provides an evidence that such indices of the functional activity of circulating phagocytes of the tumor-bearing rats as the quantity and the phagocytosis intensity of monocytes, as well as the intensity of ROS production by monocytes and neutrophils, may reflect the degree of sensitivity of the tumor to doxorubicin. So it was shown that the growth of the resistant tumor caused a significant increase of the number of circulating phagocytic cells and the intensity of phagocytosis by more than 100% (p < 0.001) compared with the corresponding indices of intact rats and rats with the parental variant of the tumor. The ability of blood mono-cytes and neutrophils of rats with a resistant tumor to produce ROS was also significantly different from that in intact rats and animals with the parental carcinosarcoma variant. The predictive value of these indices is especially important in the dynamic monitoring of the development of tumor drug resistance during long-term cancer chemotherapy. Considering the standard 2 - 3 week interval between the courses of cancer therapy and the short lifetime of circulating phagocytes, an assessment of the indices of their functional activity before each subsequent course can be considered as a pretreatment assessment. Meanwhile, further studies are needed to determine the spectrum of malignant neoplasms for which the degree of tumor drug resistance correlates with the functional activity of circulating phagocytes.
文摘The study aimed to develop and characterize a microemulsified system based on cotton oil and verify its effect on superoxide release anion and microbicidal activity by human peripheral blood cells. Microemulsions were formulated using distilled water, degummed cotton oil, Span 80 (SP), Tween 80 (TW), and 1-butanol (BT). The pseudo-ternary diagram delimited ME regions, and the points were pre-selected. The physical-chemical and rheological characterization of the microemulsions was carried out. The ME activity on the interactions between leukocytes and bacteria was analyzed by superoxide release, phagocytosis, and microbicidal activity. The developed formulation was classified as Oil/Water, with an average pH of 5.76, and the viscosity showed resistance to temperature changes. The rheological model of the Power Law classified the microemulsion as a non-Newtonian fluid with pseudoplastic characteristics. The cell viability of cotton oil microemulsion was greater than 90%. There was an increase in the superoxide release by MN phagocytes when treated with cotton oil microemulsion. The cotton oil microemulsion increased phagocytosis and microbicidal activity. The present study suggests that cotton oil is an alternative biomaterial for therapeutic applications, especially in treating infections.
基金National Key Research and Development Program of China,Grant/Award Numbers:2022YFB3203800,2022YFB3203801,2022YFB3203804CAS Interdisciplinary Innovation Team,Grant/Award Number:JCTD-2020-08+6 种基金Innovative Research Team of High-Level Local Universities in Shanghai,Grant/Award Number:SHSMU-ZDCX20210900Zhejiang Provincial Natural Science Foundation of China,Grant/Award Number:LR22C100001National Natural Science Foundation of China,Grant/Award Number:32071374Shanghai Municipal Science and Technology Commission,Grant/Award Number:21dz2210100Explorer Program of Science and Technology Commission of Shanghai Municipality,Grant/Award Number:22TS1400700Start-Up Funds from Shanghai Jiao Tong University,Grant/Award Number:22X010201631Program of Shanghai Academic Research Leader under the Science and Technology Innovation Action Plan,Grant/Award Number:21XD1422100。
文摘Two-dimensional(2D)nanomaterials,known for their unique atomic arrangements and exceptional physicochemical properties,have garnered significant attention in biomedical applications,particularly in the realms of immunotherapy for tissue engineering and tumor therapy.These applications necessitate a thorough assessment of the potential influence of 2D nanomaterials on immune cells.Notably,the mononuclear phagocyte system(MPS)cells,which play pivotal roles in both innate and adaptive immunity,are essential for maintaining organismal homeostasis.MPS cells with phagocytic capability contribute to the prevention of foreign body invasion and the elimination of dead or senescent cells.Furthermore,MPS cells,including macrophages and dendritic cells,serve as vital bridges between innate and adaptive immune responses.Therefore,understanding the nano-bio interactions between 2D nanomaterials and MPS cells is imperative.These nano-bio interactions including cellular uptake,cytocompatibility,and immunological impact are invaluable forthe purposeful design of 2D nanomaterials.Herein,we provide an overview of the latest advancements in understanding the nano-bio interactions between 2D nanomaterials and MPS cells,and discuss the current challenges and future prospects of employing 2D nanomaterials in the field of nanomedicine.
基金supported by the National Natural Science Foundation of China(32102827,31972818,31528019)China Postdoctoral Science Foundation(2019M662959)+1 种基金Guangdong Basic and Applied Basic Research Foundation(2019A1515110987)Special fund for promoting economic development(for modern fishery development)of Guangdong Province(grant number 2019A4).
文摘The defense system of teleost fish organized on innate and adaptive immunity protects them against a wide variety of pathogenic microorganisms in the aquatic environment.Phagocytosis is one of the most effective defense strategies against microbial challenge mainly performed by classical‘professional’phagocytes(including monocytes,macrophages and granulocytes).They contain,kill and process the internalized pathogens for antigen presentation by providing antigenic ligands to initiate activation and clonal expansion of T and B cells,which bridge the innate and adaptive immunity.The discovery of phagocytic B cells in teleost fish has broken the paradigm that primary vertebrate B cells are lack of phagocytosis of particulates,as well as led to the investigation of phagocytic activity of mammalian B-1 B cells.The active phagocytic,microbicidal capabilities and antigen presentation in teleost phagocytic B cell have demonstrated to be similar as professional phagocytes,providing a potential impact on development of new vaccination strategies to prevent and control infectious diseases.In this review,we aim to address current progress on the antimicrobial role of phagocytic B cells in teleost fish by comparing it with other professional phagocytes and mammalian B-1 B cells,and provide the application prospect of phagocytic B cells in developing vaccines as well as the prevention of fish diseases.
基金supported by the National Natural Science Foundation of China(32000799)the Natural Science Foundation of Zhejiang Province,China(D25H300005)+1 种基金Zhejiang Provincial Traditional Chinese Medicine Science and Technology Project(GZY-KJS-ZJ-2025-072)Wenzhou Basic Scientific Research Project(Y20240675).
文摘A recent study revealed a novel mechanism by which radiotherapy promotes distant metastatic growth by inducing amphiregulin(AREG)secretion from tumor cells.1 Specifically,tumor-derived AREG reprograms mononuclear phagocytes(MNPs)into an immunosuppressive phenotype by activating the epidermal growth factor receptor(EGFR)on their surface.Concurrently,AREG upregulates CD47 expression on tumor cells via the signal transducer and activator of transcription 3(STAT3)pathway,which inhibits phagocytic function and facilitates metastatic progression.This discovery challenges the conventional understanding of the systemic effects of radiotherapy.It also identifies combinatorial therapeutic targets that promise an improvement in radiotherapy efficacy and enable the formulation of personalized treatment strategies.
文摘Hemophagocytic lymphohistiocytosis (HLH) is an aggressive and often fatal overactivation of the immune system. It is characterized by inappropriate and dysregulated activation of natural killer (NK) cells, CD8^(+)cytotoxic T cells, and macrophages. Ineffective interactions between NK cells, CD8^(+)T cells, and their pathogenic targets lead to massive cytokine accumulation and widespread macrophage activation. Resultant hemophagocytosis and excessive organdamaging infl ammation subsequently occur.HLH may be triggered by genetic or sporadic disorders,as well as specific events that alter immune homeostasis.These events include inflammatory or infectious disease processes and malignancy.
文摘Objective: PulmonaryMycobacterium tuberculosis infection can trigger cellular and humoral innate immune responses, which may cause death of the pathogen and or host cells/tissue. We aimed to determine the cytotoxic response of phagocytes in patients with pulmonaryMycobacterium tuberculosis infection based on plasma tumor necrosis factor-alpha (TNF-α), malondialdehyde (MDA), and superoxide dismutase (SOD) levels.Methods: In this observational study, patients newly infected with pulmonaryMycobacterium tuberculosis (n=31;age 37-62 years) and age-matched uninfected volunteers (n=50) were recruited as test and control volunteers, respectively in Owo, Nigeria. The study protocol was reviewed and approved by the Research and Ethics Committee of the Department of Medical Laboratory Science, Achievers University, Owo, Nigeria (AUO/MLS/VII/2009/212). Anti-hepatitis C virus, human immunodeficiency virus antigen/antibody, hepatitis B virus surface antigen, and plasma TNF-α were determined by enzyme-linked immunosorbent assay, SOD, and MDA were determined by colorimetry,Plasmodium by Giemsa thick blood film staining, and acid-fast bacilli in sputum were detected by Ziehl-Neelsen staining.Results: All participants had normal blood glucose levels and tested negative for human immunodeficiency virus antigen/antibody, anti-hepatitis C virus, hepatitis B virus surface antigen, andPlasmodium spp., and had no medical history of cancer. Infected patients had significantly higher plasma MDA and TNF-α levels and significantly lower SOD levels compared with control subjects (allP<0.05).Conclusion: Mycobacterium tuberculosis infection elicited a cytotoxic response by phagocytes, evidenced by significant increases in MDA and TNF-α and a significant decrease in SOD levels.
基金Supported by A Research Sponsorship from Ganeden Biotech, Ohio,United States
文摘AIM:To study the effects of probiotic metabolites on maturation stage of antigen-presenting immune cells.METHODS:Ganeden Bacillus coagulans 30(GBC30) bacterial cultures in log phase were used to isolate the secreted metabolite(MET) fraction.A second fraction was made to generate a crude cell-wall-enriched fraction,by centrifugation and lysis,followed by washing.A preparation of MET was subjected to size exclusion centrifugation,generating three fractions:< 3 kDa,3-30 kDa,and 30-200 kDa and activities were tested in comparison to crude MET and cell wall in primary cultures of human peripheral blood mononuclear cell(PBMC) as a source of antigen-presenting mononuclear phagocytes.The maturation status of mononuclear phagocytes was evaluated by staining with monoclonal antibodies towards CD14,CD16,CD80 and CD86 and analyzed by flow cytometry.RESULTS:Treatment of PBMC with MET supported maturation of mononuclear phagocytes toward both macrophage and dendritic cell phenotypes.The biological activity unique to the metabolites included a reduction of CD14+ CD16+ pro-inflammatory cells,and this property was associated with the high molecular weight metabolite fraction.Changes were also seen for the dendritic cell maturation markers CD80 and CD86.On CD14dim cells,an increase in both CD80 and CD86 expression was seen,in contrast to a selective increase in CD86 expression on CD14bright cells.The co-expression of CD80 and CD86 indicates effective antigen presentation to T cells and support of T helper cell differentiation.The selective expression of CD86 in the absence of CD80 points to a role in generating T regulatory cells.CONCLUSION:The data show that a primary mechanism of action of GBC30 metabolites involves support of more mature phenotypes of antigen-presenting cells,important for immunological decision-making.
文摘Up to 15%of male in fertility has an immuno logical origi n,either due to repetitive infections or to autoimmune resp on ses mainly affecting the epididymis,prostate,and testis.Clinical observations and epidemiological data clearly contradict the idea that the testis confers immune protection to the whole male genital tract.As a consequenee,the epididymis,in which posttesticular spermatozoa mature and are stored,has raised some in terest in recent years when it comes to its immune mecha nisms.In deed,sperm cells are produced at puberty,long after the establishment of self-toleranee,and they possess unique surface proteins that cannot be recognized as self.These are potential targets of the immune system,with the risk of inducing autoantibodies and consequently male infertility.Epididymal immunity is based on a finely tuned equilibrium between efficient immune responses to pathogens and strong tolerance to sperm cells.These processes rely on incompletely described molecules and cell types.This review compiles recent studies focusing on the immune cell types populating the epididymis,and proposes hypothetical models of the organization of epididymal immunity with a special emphasis on the immune response,while also discussing important aspects of the epididymal immune regulation such as tolerance and tumour control.
基金Supported by National Institutes of Health grants K22AI68712,R56DK090090-01American Gastroenterological Association Research Scholar Award,NIH 1U54RR02614+3 种基金The University of Texas Medical Branch Clinical and Translational Sciences AwardThe American cancer society RSG-10-159-01-LIB,NIH 8UL1TR000041The University of New Mexico clinical and Translational Science CenterTaslima T Lina is funded by Sealy Centre for Vaccine Development Pre-doctoral fellowship and McLaughlin Pre-doctoral Fellowship,UTMB
文摘Helicobacter pylori(H. pylori) is perhaps the most ubiquitous and successful human pathogen, since it colonizes the stomach of more than half of humankind. Infection with this bacterium is commonly acquired during childhood. Once infected, people carry the bacteria for decades or even for life, if not treated. Persistent infection with this pathogen causes gastritis, peptic ulcer disease and is also strongly associated with the development of gastric cancer. Despite induction of innate and adaptive immune responses in the infected individual, the host is unable to clear the bacteria. One widely accepted hallmark of H. pylori is that it successfully and stealthily evades host defense mechanisms. Though the gastric mucosa is well protected against infection, H. pylori is able to reside under the mucus, attach to gastric epithelial cells and cause persistent infection by evading immune responses mediated by host. In this review, we discuss how H. pylori avoids innate and acquired immune response elements, uses gastric epithelial cells as mediators to manipulate host T cell responses and uses virulence factors to avoid adaptive immune responses by T cells to establish a persistent infection. We also discuss in this review how the genetic diversity of this pathogen helps for its survival.
基金supported by a grant from State Key Laboratory of Proteomics of China,No.SKLP-K201401(to SJL)the National Key Project of Basic Research of China,No.2009CB918301(to SJL)the National Natural Science Foundation of China,Nos.30430310,30140001,30370460(to SJL)
文摘Microglia, as the resident immune cells in the central nervous system, play important roles in regulating neuronal processes, such as neural excitability, synaptic activity, and apoptotic cell clearance. Growth factors can activate multiple signaling pathways in central nervous system microglia and can regulate their immune effects, but whether growth factors can affect the morphological characteristics and ultrastructure of microglia has not been reported. After microinjecting 300 nL of a growth factor cocktail, including 10 μg/mL epidermal growth factor, 10 μg/mL basic fibroblast growth factor, 10 μg/mL hepatocyte growth factor and 10 μg/mL insulin-like growth factor into adult rat cortex, we found that the number of IBA1-positive microglia around the injection area increased significantly, indicating local activation of microglia. All CD68-positive labeling co-localized with IBA1 in microglia. Cell bodies and protrusions of CD68-positive cells were strongly attached to or were engulfing neurons. Characteristic huge phagosomes were observed in activated phagocytes by electron microscopy. The phagosomes generally included non-degraded neuronal protrusions and mitochondria, yet they contained no myelin membrane or remnants, which might indicate selective phagocytosis by the phagocytes. The remnant myelin sheath after phagocytosis still had regenerative ability and formed "myelin-like" structures around phagocytes. These results show that microinjection of a growth factor cocktail into the cerebral cortex of rodents can locally activate microglia and induce selective phagocytosis of neural structures by phagocytes. The study was approved by the Institute of Laboratory Animal Science, Beijing Institute of Basic Medical Sciences(approval No. IACUC-AMMS-2014-501) on June 30, 2014.
文摘Background: Glucose is the main substrate for the generation of NADPH, the cofactor of the oxidative burst enzyme NADPH-oxidase of blood neutrophils. Changes in blood glucose are thus expected to modify the generation of reactive oxygen species (ROS). The new blood ROS generation assay (BRGA) quantifies ROS changes induced by blood glucose concentrations as they are found in diabetes mellitus. Material and Methods: Citrated or EDTA blood of 6 healthy donors were analyzed in the BRGA: 10 μl sample in black polystyrene F-microwells (Brand 781608) were incubated in triplicate with 125 μl Hanks’ balanced salt solution, 40 μl 0 - 200 mM glucose in 0.9% NaCl (final added conc.: 0 - 41 mM;final basal glucose conc.: about4 mM), 10 μl5 mMluminol, and 10 μl zymosan A (final conc.: 1.9 μg/ml) in 0.9% NaCl. The plates were measured within 0 - 250 min (37℃) in a photons-multiplyer microtiter plate luminometer (LUmo) with an integration time of 1 s. Results: Up to about 30 min reaction time the mean ROS generation was 50% inhibited by about1 mMadded glucose (= approx. IC50). At ≥80 min reaction time (possibly necessary for full phosphorylation of glucose to glucose-6-phosphate (G6P), the substrate metabolized by G6P-dehydrogenase to generate NADPH, the cofactor of the NADPH-oxidase) the mean ROS generation approximately doubled at about1 mMadded glucose (= approx. SC200) in citrated blood. Discussion: Elevated glucose concentrations not only increase systemic thrombin generation, they can also diminish cellular fibrinolysis and increase systemic inflammation, resulting in a chronic pro-thrombotic state. The fascinating importance of NADPH-oxidases not only in phagocytes but also in the beta cells of pancreas points towards a new pathogenesis explication of diabetes mellitus type 1: whatever stimulus (e.g. a pancreas-tropic virus) could activate the beta cell’s autodestructive NADPH-oxidase.
基金Supported by grants from CONICET(Argentina,EM,PIP-CONICET 112-201101-00247,http://www.conicet.gov.ar)ANPCyT(Argentina,EM,PICT 2012-174,PICT 2017-499+1 种基金http://www.agencia.mincyt.gob.ar)NIH-CONICET(Argentina and USA,EM and Stephen Noctor,F65096).
文摘Until recently,microglia were mainly known as the resident phagocytes of the brain,i.e.the‘immunological warriors’of the brain.However,extensive knowledge is being accumulated about the functions of microglia beyond immunity.Nowadays,it is well accepted that microglial cells are highly dynamic and responsive,and that they intervene in a dual manner in many developmental processes that shape the central nervous system,including neurogenesis,gliogenesis,spatial patterning,synaptic formation and elimination,and neural circuit establishment and maturation.The differentiation and the pool of precursor cells were also shown to be under microglia regulation via bidirectional communication.In this concise review,I discuss our recent work in microglia-Pax6+cell interactions in one of the circumventricular organs,the pineal gland.An analogy with the rest of the central nervous system is also presented.In addition,I briefly examine mechanisms of interaction between microglia and non-microglial cells in both health and disease.New avenues are also introduced,which may lead us to better comprehend the impact of microglia in physiological and pathological conditions.
基金supported by a Cornell start-up fund and NIH grants (R01NS099125 and R21OD023824) awarded to C.H.
文摘Dendrites and axons are delicate neuronal membrane extensions that undergo degeneration after physical injuries. In neurodegenerative diseases, they often degenerate prior to neuronal death. Understanding the mechanisms of neurite degeneration has been an intense focus of neurobiology research in the last two decades. As a result, many discoveries have been made in the molecular pathways that lead to neurite degeneration and the cell-cell interactions responsible for the subsequent clearance of neuronal debris. Drosophila melanogaster has served as a prime in vivo model system for identifying and characterizing the key molecular players in neurite degeneration, thanks to its genetic tractability and easy access to its nervous system. The knowledge learned in the fly provided targets and fuel for studies in other model systems that have further enhanced our understanding of neurodegeneration. In this review, we will introduce the experimental systems developed in Drosophila to investigate injuryinduced neurite degeneration, and then discuss the biological pathways that drive degeneration. We will also cover what is known about the mechanisms of how phagocytes recognize and clear degenerating neurites, and how recent findings in this area enhance our understanding of neurodegenerative disease pathology.
文摘The aim of this study is to evaluate the effect of moderate physical exercise and treatment time on the organism’s response to NSC631570. The sensitivity of circulating phagocytes to the drug at different times of day was estimated in in vitro experiments. NSC631570 was administered intravenously to healthy volunteers (eleven men, 23 ± 2 years) in a single therapeutic dose in an inpatient and an outpatient setting. Blood samples were obtained before the drug administration, 30 min after the drug injection and every fourth hour throughout the 24 hour period. Biochemical parameters were determined using the hematological analyzer. Flow cytometry was used to evaluate phagocyte metabolism. Treatment of circulating phagocytes with NSC631570 in vitro resulted in an increase in ROS production along with a decrease in their phagocytic activity, most expressed in the morning time. Drug injection to sedentary persons resulted in pro-inflammatory metabolic polarization of circulating phagocytes. Introduction of NSC631570 to active persons was accompanied by a significant increase in phagocyte endocytosis along with a decrease in the daily mean of ROS generation. Significant oscillation (but in the normal ranges) of urea, creatinine, alanine aminotransferase and aspartate aminotransferase after NSC631570 introduction in the outpatient setting was shown during the day. Physical activity interferes with immunomodulatory action of NSC631570 and abrogates pro-inflammatory shift of circulating phagocytes. Biochemical parameters of blood from patients treated with NSC631570 in the outpatient setting must be interpreted cautiously considering the effect of physical activity on some metabolic biomarkers.
文摘The capacities of phagocytes of subpopulation P1 (F) and morula cells (MC) of holothurian Eupentacta fraudatrix to modulate apoptosis of each other as well as cytokine-dependent mechanisms and hormonal regulation of these cells’s interaction were studied. The 18-h treatment of F with supernatants, obtained after centrifugation of MC preincubated for 3 h with phosphate buffered saline (PSB) at the temperature of 22℃?(SMC3) resulted in a significant growth of apoptosis level. A 30-min incubation of F with supernatants of MC, preincubated for 24 h (SMC24), on the contrary, reduced the apoptosis level and increased the level of interleukine-1α (IL-1α)-like substances, and 24-h incubation did not influence apoptosis and reduced level of IL-1α-like substances. Thus, proapoptotic effects of MC’s supernatants in F inversely depended on time of their preincubation with PSB and directly on time of incubation with F. Additionally, this effect was opposite to variations in the level of IL-1α-like substances. The level of apoptosis declined after 30 min of incubation but elevated after 24 h at the inverse treatment of MC with supernatant, obtained after preincubation of F during 24 h (SF24). The level of IL-1α-like substances dropped after 30 min and insignificantly decreased after 24 h. Hence, SF24 proapoptotic effect directly depended on time of incubation with MC and did not correspond to variations in the level of IL-1α-like substances. 100 μM dexamethasone stimulated apoptosis in F and MC in an inverse time-dependent manner during 24-h preincubation, and supernatants of cell suspensions obtained after such preincubations, stimulated apoptosis and reduced the IL-1α-like substances level in target cells at both types of interaction. IL-1α-like substances are?supposed to be mediators for MC’s effects in F, but not for F’s action on MC. In holothurians, steroid hormones apparently may participate in the regulation of the immune response and cell cooperation.
文摘Background: The neutrophils (PMN) are our main blood cells to combat fungi, bacteria, and fibrin. For normal function, an activated PMN generates a certain concentration of reactive oxygen species (ROS). If the generated blood ROS concentration is too low, then fungi, bacteria or fibrin might threaten the life of the patient, and it could be of great medical interest to stimulate PMN by physiologic drugs. Granulocyte-Colony Stimulating Factor (G-CSF) is a cell hormone that increases the cell number of PMN and that stimulates the individual PMN. The blood ROS generation assay (BRGA) is an innovative physiologic test to monitor the ROS generation of PMN in blood. Here the ROS generating action of G-CSF on normal PMN is quantified. Material and Methods: 40 μl 0 - 10.3 ng/ml (final conc.) G-CSF (in 5% human albumin) in black Brand? 781608 high quality polystyrene F-microwells was incubated in triplicate with 125 μl Hanks’ balanced salt solution (HBSS;modified without phenol red) and 10 μl normal citrated blood. Immediately (BRGA) or after 60 min (BRGA-60-) 10 μl 5 mM luminol sodium salt in 0.9% NaCl and 10 μl 0 or 36 μg/ml zymosan A in 0.9% NaCl was added. The photons were counted within 0 - 318 min (37°C) in a photons-multiplying microtiter plate luminometer. At about 0.5 t-maxn (0.5 fold the time to normal maximum) the approx. SC200 of G-CSF was determined. Results and Discussion: The approx. SC200 of G-CSF on normal blood ROS generation was 0.2 μg/l (=20 IU/ml). In clinical situations where an increased blood ROS generation is pharmacologically required, few micrograms of G-CSF could be a sufficient dosage for an adult patient. The BRGA helps to find out the correct stimulating G-CSF dosage for each individual. An enhanced PMN function could favor a better clinical outcome in situations of wanted increase of the innate immunology or in cellular fibrinolysis. G-CSF plasma concentrations of 0.1 - 1 μg/l might favor singlet oxygen generation without immunosuppression or cell fragment-induced thrombin generation.
