scholarly journals A Critical Temporal Window for Selectin-dependent CD4+ Lymphocyte Homing and Initiation of Late-Phase Inflammation in Contact Sensitivity

2004 ◽  
Vol 199 (9) ◽  
pp. 1223-1234 ◽  
Author(s):  
John M. Hwang ◽  
Jun Yamanouchi ◽  
Pere Santamaria ◽  
Paul Kubes
Keyword(s):  
Early Phase ◽  
Molecular Mechanisms ◽  
Late Phase ◽  
Leukocyte Recruitment ◽  
Late Response ◽  
Inflammatory Disorder ◽  
Contact Sensitivity ◽  
Microscopy Technique ◽  
Cd4 Lymphocyte ◽  
Cd4 Lymphocytes

Contact sensitivity (CS) is an inflammatory disorder characterized by early and late phases of leukocyte recruitment. We used a noninvasive intravital microscopy technique allowing for the direct visualization of leukocyte rolling and adhesion on blood vessel endothelium. By blocking specific adhesion molecules, we elucidated the molecular mechanisms mediating early leukocyte recruitment to be E- and P-selectin and demonstrated that leukocyte recruitment in the late phase had a different adhesive profile (mainly α4-integrin). Complete blockade of E- and P-selectin within the first 2 h of leukocyte–endothelial cell interactions (but not later) eliminated selectin-independent leukocyte recruitment at 24 h. Despite the predominance of neutrophils in the early phase, specific elimination of CD4+ lymphocytes in the early phase eliminated the late response. CD4+ lymphocytes homed to skin via E- and P-selectin within the early phase and induced the late phase response. Addition of these same CD4+ lymphocytes 2 h after antigen challenge was too late for these cells to home to the skin and induce late phase responses. Our data clearly demonstrate that the antigen-challenged microenvironment is only accessible to CD4+ lymphocytes for the first 2 h, and that this process is essential for the subsequent recruitment of other leukocyte populations in late phase responses.

scholarly journals Heterotypic adherence between human B-lymphoblastic and pre-B- lymphoblastic cells and marrow stromal cells is a biphasic event: integrin very late antigen-4 alpha mediates only the early phase of the heterotypic adhesion

Blood ◽  
1995 ◽  
Vol 85 (1) ◽  
pp. 168-178 ◽  
Author(s):  
CW Jr Patrick ◽  
HS Juneja ◽  
S Lee ◽  
FC Schmalstieg ◽  
LV McIntire
Keyword(s):  
Cell Line ◽  
Adhesion Molecules ◽  
Stromal Cells ◽  
Early Phase ◽  
Molecular Mechanisms ◽  
Late Phase ◽  
Marrow Stromal Cells ◽  
Major Player ◽  
Late Antigen ◽  
Lymphoblastic Cells

Heterotypic adherence between marrow stromal cells (MSC) and lymphoblastic cells is essential for normal lymphopoiesis and malignant lymphoblastic development. However, the detailed molecular mechanisms by which this heterotypic adherence occurs are poorly understood. The cell-cell interactions between a B-lymphoblastic cell line (UTMB-460) and a pre-B-cell line (NALM-6) with MSC were chosen as models to investigate potential mechanisms and adhesion molecules involved in the apposition between normal and malignant lymphoblastic cells and MSC. A parallel-flow detachment assay (PFDA) and a 51Cr detachment assay, coupled with monoclonal antibody (MoAb) blocking experiments, were used to quantify the attachment of lymphoblastic cells to confluent monolayers of MSC. The apposition between MSC and B-lymphoblastic cells (UTMB-460 cells) was investigated for variable time periods, ranging from 1 minute to 4 hours. Results from the temporal study suggest that the heterotypic adherence of the B-lymphoblastic cells to MSC is a biphasic event and the interactions occur rapidly (< or = 1 minute) after the two cells come into contact. More specifically, the early phase of adherence (< or = 15 minutes) solely involves very late antigen-4 alpha (VLA-4 alpha)/vascular cell adhesion molecule 1 (VCAM- 1) interactions, as evidenced by the nearly complete inhibition (93%) of UTMB-460 cell adherence in the presence of anti-VLA-4 alpha. The late phase (> or = 30 minutes) proceeds despite the continuous presence of anti-VLA-4 alpha. In addition, the late-phase adherence is not affected by MoAbs to LFA-1, CD44, VCAM-1, E-selectin, or L-selectin, which suggests the possible involvement of other adhesion molecules. Adherence of pre-B-lymphoblastic cells (NALM-6) to MSC is also biphasic. Integrin VLA-4 is again a major player in the early phase of pre-B-lymphoblastic cell/MSC interactions. The early phase of adherence may be important in homing of the malignant lymphoblastic cells to the MSC and the late phase in retention of malignant lymphoblastic cells in the bone marrow.

scholarly journals Maternal high-fat diet induces long-term obesity with sex-dependent metabolic programming of adipocyte differentiation, hypertrophy and dysfunction in the offspring

2020 ◽  
Vol 134 (7) ◽  
pp. 921-939 ◽  
Author(s):  
Thorsten Litzenburger ◽  
Eva-Kristina Huber ◽  
Katharina Dinger ◽  
Rebecca Wilke ◽  
Christina Vohlen ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
High Fat Diet ◽  
Early Phase ◽  
Molecular Mechanisms ◽  
Maternal Obesity ◽  
Late Phase ◽  
Metabolic Programming ◽  
Dependent Manner ◽  
Adipocyte Size ◽  
High Fat

Abstract Maternal obesity determines obesity and metabolic diseases in the offspring. The white adipose tissue (WAT) orchestrates metabolic pathways, and its dysfunction contributes to metabolic disorders in a sex-dependent manner. Here, we tested if sex differences influence the molecular mechanisms of metabolic programming of WAT in offspring of obese dams. To this end, maternal obesity was induced with high-fat diet (HFD) and the offspring were studied at an early phase [postnatal day 21 (P21)], a late phase (P70) and finally P120. In the early phase we found a sex-independent increase in WAT in offspring of obese dams using magnetic resonance imaging (MRI), which was more pronounced in females than males. While the adipocyte size increased in both sexes, the distribution of WAT differed in males and females. As mechanistic hints, we identified an inflammatory response in females and a senescence-associated reduction in the preadipocyte factor DLK in males. In the late phase, the obese body composition persisted in both sexes, with a partial reversal in females. Moreover, female offspring recovered completely from both the adipocyte hypertrophy and the inflammatory response. These findings were linked to a dysregulation of lipolytic, adipogenic and stemness-related markers as well as AMPKα and Akt signaling. Finally, the sex-dependent metabolic programming persisted with sex-specific differences in adipocyte size until P120. In conclusion, we do not only provide new insights into the molecular mechanisms of sex-dependent metabolic programming of WAT dysfunction, but also highlight the sex-dependent development of low- and high-grade pathogenic obesity.

scholarly journals Genetic mapping in Diversity Outbred mice identifies aTrpa1variant influencing late phase formalin response

2018 ◽  
Author(s):  
Jill M. Recla ◽  
Jason A. Bubier ◽  
Daniel M. Gatti ◽  
Jennifer L. Ryan ◽  
Katie H. Long ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Genetic Mapping ◽  
Molecular Mechanisms ◽  
Late Phase ◽  
Cation Channel ◽  
Chromosome 1 ◽  
Formalin Injection ◽  
Late Response ◽  
Diversity Outbred ◽  
Isoform Expression

ABSTRACTIdentification of genetic variants that influence susceptibility to chronic pain is key to identifying molecular mechanisms and targets for effective and safe therapeutic alternatives to opioids. To identify genes and variants associated with chronic pain, we measured late phase response to formalin injection in 275 male and female Diversity Outbred (DO) mice genotyped for over 70 thousand SNPs. One quantitative trait locus (QTL) reached genome-wide significance on chromosome 1 with a support interval of 3.1 Mb. This locus,Nociq4(nociceptive sensitivity inflammatory QTL 4; MGI:5661503), harbors the well-known pain geneTrpa1(transient receptor potential cation channel, subfamily A, member 1).Trpa1is a cation channel known to play an important role in acute and chronic pain in both humans and mice. Analysis of DO founder strain allele effects revealed a significant effect of the CAST/EiJ allele atTrpa1, with CAST/EiJ carrier mice showing an early, but not late, response to formalin relative to carriers of the seven other inbred founder alleles (A/J, C57BL/6J, 129S1/SvImJ, NOD/ShiLtJ, NZO/HlLtJ, PWK/PhJ, and WSB/EiJ). We characterized possible functional consequences of sequence variants inTrpa1by assessing channel conductance,Trpa1/Trpv1interactions, and isoform expression. The phenotypic differences observed in CAST/EiJ relative to C57BL/6J carriers were best explained byTrpa1isoform expression differences, implicating a splice junction variant as the causal functional variant. This study demonstrates the utility of advanced, high-precision genetic mapping populations in resolving specific molecular mechanisms of variation in pain sensitivity.

Improved Stage Categorization of PTZ-Induced Kindling and Late Enhanced Neurogenesis in PTZ Kindled Mice

2019 ◽  
Vol 8 ◽  
pp. 1511
Author(s):  
Marzieh Shahpari ◽  
Hadi Aligholi ◽  
Mohammad Reza Namavar ◽  
Farzaneh Vafaee ◽  
Masoumeh Emamghoreishi
Keyword(s):  
Subventricular Zone ◽  
Early Phase ◽  
Hind Limb ◽  
Late Phase ◽  
The Other ◽  
Myoclonic Jerk ◽  
Ptz Kindling ◽  
First Occurrence ◽  
Tonic Extension ◽  
Behavioral Index

Background: There is no universally accepted behavioral scoring to define the early development of phenothiazine (PTZ) kindling. Therefore, studies investigating alterations of neurogenesis in the PTZ model were mainly focused on full kindled animals rather than early stages of kindling. This study aimed to determine an appropriate behavioral index for categorizing stages of PTZ kindling progress and to evaluate neurogenesis during PTZ kindling. Materials and Methods: Twenty-four mice were intraperitoneally injected with a sub convulsive dose of PTZ (40mg/kg) every other day until they became full kindled. The first occurrence of different seizure behaviors and their durations were recorded during kindling development, and the different stages of kindling were categorized. Neurogenesis was evaluated in the lateral subventricular zone (SVZ) at each stage of kindling by immunofluorescence staining. Results: First occurrence of restlessness, motionless staring, hind limb tonic extension, Straub’s tail, myoclonic jerk, and tonic-clonic were sequentially observed in more than 80% of animals with increasing PTZ injections. The duration of the myoclonic jerk was significantly longer than the other seizure behaviors. The significantly higher percentage of BrdU-positive cells was found in SVZ of mice showing tonic-clonic in comparison to other seizure behaviors. Conclusion: A hierarchy behavior was observed during the kindling process when considering the first occurrence of seizure behaviors. We defined the first occurrence of restlessness, motionless, hind limb tonic extension and Straub’s tail behaviors as an early phase, myoclonic jerk as a borderline phase and tonic-clonic as a late phase of PTZ-induced kindling. Our results indicated an enhanced SVZ neurogenesis at the late phase of kindling. [GMJ.2019;8:e1511]

Relationship Between Gamma-glutamyl Transpeptidase Activity and Inflammatory Response in Lichen Planus

2018 ◽  
Vol 69 (3) ◽  
pp. 739-743 ◽  
Author(s):  
Madalina Irina Mitran ◽  
Ilinca Nicolae ◽  
Corina Daniela Ene ◽  
Cristina Iulia Mitran ◽  
Clara Matei ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Lichen Planus ◽  
Inflammatory Process ◽  
Molecular Mechanisms ◽  
Functional Adaptation ◽  
Physical Factors ◽  
Inflammatory Disorder ◽  
Gamma Glutamyl Transpeptidase ◽  
Gamma Glutamyl ◽  
Glutamyl Transpeptidase

Chemicals used in the manufacture of synthetic fibers have been associated with undesirable side effects such as itching or skin lesions and it seems that they are involved in the induction of pathological processes such as oxidative stress and inflammation. Lichen planus (LP) can be regarded as an inflammatory disorder, chemical and physical factors playing an important role in the perpetuation of the inflammatory process. Gamma-glutamyl transpeptidase (GGT) plays an important role in the preservation of skin architecture and modulation of skin inflammation. In this study, we found that GGT activity is increased in LP patients with mild inflammation, whilst GGT is inactivated under conditions of severe inflammation. Therefore, GGT is involved in the inflammatory process, but there is no a positive correlation between its activity and the intensity of the inflammatory response. This functional adaptation of the enzyme may be due to down-regulation of its synthesis under free radical overload conditions. Understanding the molecular mechanisms involved in the modulation of intracellular redox homeostasis is an important step in the pharmacological management of patients with LP.

Role of Resveratrol in Modulating microRNAs in Human Diseases: From Cancer to Inflammatory Disorder

2020 ◽  
Vol 28 (2) ◽  
pp. 360-376 ◽  
Author(s):  
Atefeh Amiri ◽  
Maryam Mahjoubin-Tehran ◽  
Zatollah Asemi ◽  
Alimohammad Shafiee ◽  
Sarah Hajighadimi ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Antioxidant Activities ◽  
Natural Compounds ◽  
Therapeutic Effects ◽  
Inflammatory Disorder ◽  
Inflammatory Disorders ◽  
Therapeutic Modalities ◽  
Anti Cancer ◽  
Current Therapies ◽  
Anti Inflammatory

: Cancer and inflammatory disorders are two important public health issues worldwide with significant socio.economic impacts. Despite several efforts, the current therapeutic platforms are associated with severe limitations. Therefore, developing new therapeutic strategies for the treatment of these diseases is a top priority. Besides current therapies, the utilization of natural compounds has emerged as a new horizon for the treatment of cancer and inflammatory disorders as well. Such natural compounds could be used either alone or in combination with the standard cancer therapeutic modalities such as chemotherapy, radiotherapy, and immunotherapy. Resveratrol is a polyphenolic compound that is found in grapes as well as other foods. It has been found that this medicinal agent displays a wide pharmacological spectrum, including anti-cancer, anti-inflammatory, anti-microbial, and antioxidant activities. Recently, clinical and pre-clinical studies have highlighted the anti-cancer and anti-inflammatory effects of resveratrol. Increasing evidence revealed that resveratrol exerts its therapeutic effects by targeting various cellular and molecular mechanisms. Among cellular and molecular targets that are modulated by resveratrol, microRNAs (miRNAs) have appeared as key targets. MiRNAs are short non-coding RNAs that act as epigenetic regulators. These molecules are involved in many processes that are involved in the initiation and progression of cancer and inflammatory disorders. Herein, we summarized various miRNAs that are directly/indirectly influenced by resveratrol in cancer and inflammatory disorders.

Nucleolin Improves Heart Function During Recovery From Myocardial Infarction by Modulating Macrophage Polarization

2021 ◽  
pp. 107424842198957
Author(s):  
Yuting Tang ◽  
Xiaofang Lin ◽  
Cheng Chen ◽  
Zhongyi Tong ◽  
Hui Sun ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Early Phase ◽  
Heart Function ◽  
Macrophage Polarization ◽  
Late Phase ◽  
Macrophage Infiltration ◽  
Enzyme Linked Immunosorbent Assay ◽  
M2 Macrophage ◽  
M2 Macrophage Polarization ◽  
Nucleolin Expression

Background: Nucleolin has multiple functions within cell survival and proliferation pathways. Our previous studies have revealed that nucleolin can significantly reduce myocardial ischemia-reperfusion injury by promoting myocardial angiogenesis and reducing myocardial apoptosis. In this study, we attempted to determine the role of nucleolin in myocardial infarction (MI) injury recovery and the underlying mechanism. Methods: Male BALB/c mice aged 6–8 weeks were used to set up MI models by ligating the left anterior descending coronary artery. Nucleolin expression in the heart was downregulated by intramyocardial injection of a lentiviral vector expressing nucleolin-specific small interfering RNA. Macrophage infiltration and polarization were measured by real-time polymerase chain reaction, flow cytometry, and immunofluorescence. Cytokines were detected by enzyme-linked immunosorbent assay. Results: Nucleolin expression in myocardium after MI induction decreased a lot at early phase and elevated at late phase. Nucleolin knockdown impaired heart systolic and diastolic functions and decreased the survival rate after MI. Macrophage infiltration increased in the myocardium after MI. Most macrophages belonged to the M1 phenotype at early phase (2 days) and the M2 phenotype increased greatly at late phase after MI. Nucleolin knockdown in the myocardium led to a decrease in M2 macrophage polarization with no effect on macrophage infiltration after MI. Furthermore, Notch3 and STAT6, key regulators of M2 macrophage polarization, were upregulated by nucleolin in RAW 264.7 macrophages. Conclusions: Lack of nucleolin impaired heart function during recovery after MI by reducing M2 macrophage polarization. This finding probably points to a new therapeutic option for ischemic heart disease.

scholarly journals Decoding the temporal nature of brain GR activity in the NFκB signal transition leading to depressive-like behavior

2021 ◽  
Author(s):  
Young-Min Han ◽  
Min Sun Kim ◽  
Juyeong Jo ◽  
Daiha Shin ◽  
Seung-Hae Kwon ◽  
...  
Keyword(s):  
Inhibitory Action ◽  
Time Course ◽  
Molecular Mechanisms ◽  
Late Phase ◽  
Fine Tuning ◽  
Dependent Manner ◽  
Middle Phase ◽  
Temporal Shift

AbstractThe fine-tuning of neuroinflammation is crucial for brain homeostasis as well as its immune response. The transcription factor, nuclear factor-κ-B (NFκB) is a key inflammatory player that is antagonized via anti-inflammatory actions exerted by the glucocorticoid receptor (GR). However, technical limitations have restricted our understanding of how GR is involved in the dynamics of NFκB in vivo. In this study, we used an improved lentiviral-based reporter to elucidate the time course of NFκB and GR activities during behavioral changes from sickness to depression induced by a systemic lipopolysaccharide challenge. The trajectory of NFκB activity established a behavioral basis for the NFκB signal transition involved in three phases, sickness-early-phase, normal-middle-phase, and depressive-like-late-phase. The temporal shift in brain GR activity was differentially involved in the transition of NFκB signals during the normal and depressive-like phases. The middle-phase GR effectively inhibited NFκB in a glucocorticoid-dependent manner, but the late-phase GR had no inhibitory action. Furthermore, we revealed the cryptic role of basal GR activity in the early NFκB signal transition, as evidenced by the fact that blocking GR activity with RU486 led to early depressive-like episodes through the emergence of the brain NFκB activity. These results highlight the inhibitory action of GR on NFκB by the basal and activated hypothalamic-pituitary-adrenal (HPA)-axis during body-to-brain inflammatory spread, providing clues about molecular mechanisms underlying systemic inflammation caused by such as COVID-19 infection, leading to depression.

scholarly journals AFP and eGFR are related to early and late recurrence of HCC following antiviral therapy

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Takao Watanabe ◽  
Yoshio Tokumoto ◽  
Kouji Joko ◽  
Kojiro Michitaka ◽  
Norio Horiike ◽  
...  
Keyword(s):  
Risk Factors ◽  
Confidence Interval ◽  
Early Phase ◽  
Late Phase ◽  
Previous History ◽  
Late Recurrence ◽  
Early Recurrence ◽  
Hazard Ratio ◽  
Post Treatment ◽  
Hcc Recurrence

Abstract Background An unexpected recurrence of hepatocellular carcinoma (HCC) sometimes occurs in patients with hepatitis C virus (HCV) after treatment with direct-acting antivirals (DAAs). However, the characteristics of patients with HCC recurrence may differ depending on time after DAA treatment. We aimed to identify risk factors related to HCC recurrence according to time after DAA treatment. Methods Of 1663 patients with HCV treated with a DAA, 199 patients had a previous history of HCC. We defined HCC recurrence within 1 year after DAA treatment as ‘early recurrence’, and recurrence more than 1 year after as ‘late recurrence’. The different risk factors between the early and late phases of HCC recurrence after the end of DAA therapy were investigated. Results Ninety-seven patients experienced HCC recurrence during the study period. Incidences of recurrence were 29.8, 41.0, and 53.4% at 1, 2, and 3 years, respectively, after the end of DAA therapy. Multivariate analysis identified post-treatment α-fetoprotein (AFP) as an independent factor contributing to HCC recurrence in the early phase (hazard ratio, 1.056; 95% confidence interval, 1.026–1.087, p < 0.001) and post-treatment estimated glomerular filtration rate (eGFR) (hazard ratio, 0.98; 95% confidence interval, 0.96–0.99, p = 0.032) as a predictor of HCC recurrence in the late phase. Conclusion Patients with higher post-treatment AFP in the early phase and those with lower post-treatment eGFR in the late phase had a high risk of HCC recurrence. The risk factors associated with HCC recurrence after DAA treatment were different between the early and late phases.

scholarly journals Tim-3 enhances FcεRI-proximal signaling to modulate mast cell activation

2015 ◽  
Vol 212 (13) ◽  
pp. 2289-2304 ◽  
Author(s):  
Binh L. Phong ◽  
Lyndsay Avery ◽  
Tina L. Sumpter ◽  
Jacob V. Gorman ◽  
Simon C. Watkins ◽  
...  
Keyword(s):  
T Cells ◽  
Mast Cell ◽  
Signaling Pathways ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Late Phase ◽  
Cell Types ◽  
Mast Cell Activation ◽  
Positive Role ◽  
Ample Evidence

T cell (or transmembrane) immunoglobulin and mucin domain protein 3 (Tim-3) has attracted significant attention as a novel immune checkpoint receptor (ICR) on chronically stimulated, often dysfunctional, T cells. Antibodies to Tim-3 can enhance antiviral and antitumor immune responses. Tim-3 is also constitutively expressed by mast cells, NK cells and specific subsets of macrophages and dendritic cells. There is ample evidence for a positive role for Tim-3 in these latter cell types, which is at odds with the model of Tim-3 as an inhibitory molecule on T cells. At this point, little is known about the molecular mechanisms by which Tim-3 regulates the function of T cells or other cell types. We have focused on defining the effects of Tim-3 ligation on mast cell activation, as these cells constitutively express Tim-3 and are activated through an ITAM-containing receptor for IgE (FcεRI), using signaling pathways analogous to those in T cells. Using a variety of gain- and loss-of-function approaches, we find that Tim-3 acts at a receptor-proximal point to enhance Lyn kinase-dependent signaling pathways that modulate both immediate-phase degranulation and late-phase cytokine production downstream of FcεRI ligation.

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