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1.
J Strength Cond Res ; 38(6): 1144-1148, 2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38781471

ABSTRACT

ABSTRACT: Dos'Santos, T, Evans, DT, and Read, DB. Validity of the Hawkin dynamics wireless dual force platform system against a piezoelectric laboratory grade system for vertical countermovement jump variables. J Strength Cond Res 38(6): 1144-1148, 2024-The aim of this study was to determine the criterion validity of the Hawkin Dynamics (HD) wireless dual force platform system for assessing vertical countermovement jump (CMJ) variables, compared with those derived from a Kistler piezoelectric laboratory grade force platform system. During a single testing session, HD force platforms were placed directly on top of 2 adjacent Kistler force platforms to simultaneously collect vertical ground reaction forces produced by 2 male recreational soccer players (age: 29.0 ± 2.8 years, height: 1.79 ± 0.01 m, mass: 85.6 ± 4.7 kg) that performed 25 vertical CMJs each. Sixteen vertical CMJ variables pertaining to jump height (JH), flight time (FT), time-to-take off (TTT), countermovement depth, body weight (BW), propulsive and braking mean, and peak powers, forces, and impulses were compared between systems. Fixed bias was observed for 6 of 16 variables (peak and mean braking power, mean propulsion force, TTT, FT, and BW), while proportional bias was present for 10 of 16 variables (peak and mean propulsive and braking force, TTT, FT, peak and mean braking power, mean propulsive power, and BW). For all variables regardless of fixed or proportional bias, percentage differences were ≤3.4% between force platform systems, with near perfect to perfect correlations (r or ρ = 0.977-1.000) observed for 15 of 16 variables. The HD dual wireless force platform system can be considered a valid alternative to a piezoelectric laboratory grade force platform system for the collection of vertical CMJ variables, particularly outcome (i.e., JH, reactive strength index modified) and strategy variables (countermovement depth).


Subject(s)
Soccer , Humans , Male , Adult , Soccer/physiology , Exercise Test/instrumentation , Biomechanical Phenomena , Reproducibility of Results , Muscle Strength/physiology , Athletic Performance/physiology , Plyometric Exercise , Wireless Technology/instrumentation
2.
Cell Rep ; 43(4): 114120, 2024 Apr 23.
Article in English | MEDLINE | ID: mdl-38625796

ABSTRACT

Border-associated macrophages (BAMs) are tissue-resident macrophages that reside at the border of the central nervous system (CNS). Since BAMs originate from yolk sac progenitors that do not persist after birth, the means by which this population of cells is maintained is not well understood. Using two-photon microscopy and multiple lineage-tracing strategies, we determine that CCR2+ monocytes are significant contributors to BAM populations following disruptions of CNS homeostasis in adult mice. After BAM depletion, while the residual BAMs possess partial self-repopulation capability, the CCR2+ monocytes are a critical source of the repopulated BAMs. In addition, we demonstrate the existence of CCR2+ monocyte-derived long-lived BAMs in a brain compression model and in a sepsis model after the initial disruption of homeostasis. Our study reveals that the short-lived CCR2+ monocytes transform into long-lived BAM-like cells at the CNS border and subsequently contribute to BAM populations.


Subject(s)
Brain , Macrophages , Monocytes , Receptors, CCR2 , Animals , Receptors, CCR2/metabolism , Monocytes/metabolism , Macrophages/metabolism , Mice , Brain/pathology , Brain/metabolism , Mice, Inbred C57BL , Homeostasis
3.
Neuron ; 112(12): 1959-1977.e10, 2024 Jun 19.
Article in English | MEDLINE | ID: mdl-38614103

ABSTRACT

Microglial calcium signaling is rare in a baseline state but strongly engaged during early epilepsy development. The mechanism(s) governing microglial calcium signaling are not known. By developing an in vivo uridine diphosphate (UDP) fluorescent sensor, GRABUDP1.0, we discovered that UDP release is a conserved response to seizures and excitotoxicity across brain regions. UDP can signal through the microglial-enriched P2Y6 receptor to increase calcium activity during epileptogenesis. P2Y6 calcium activity is associated with lysosome biogenesis and enhanced production of NF-κB-related cytokines. In the hippocampus, knockout of the P2Y6 receptor prevents microglia from fully engulfing neurons. Attenuating microglial calcium signaling through calcium extruder ("CalEx") expression recapitulates multiple features of P2Y6 knockout, including reduced lysosome biogenesis and phagocytic interactions. Ultimately, P2Y6 knockout mice retain more CA3 neurons and better cognitive task performance during epileptogenesis. Our results demonstrate that P2Y6 signaling impacts multiple aspects of myeloid cell immune function during epileptogenesis.


Subject(s)
Calcium Signaling , Epilepsy , Mice, Knockout , Microglia , Phagocytosis , Receptors, Purinergic P2 , Animals , Microglia/metabolism , Microglia/immunology , Mice , Receptors, Purinergic P2/metabolism , Receptors, Purinergic P2/genetics , Calcium Signaling/physiology , Epilepsy/metabolism , Epilepsy/immunology , Epilepsy/genetics , Uridine Diphosphate/metabolism , Lysosomes/metabolism , Neurons/metabolism , Mice, Inbred C57BL , Male , Hippocampus/metabolism , Neuroimmunomodulation/physiology
4.
Clin Obstet Gynecol ; 67(2): 304-314, 2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38343037

ABSTRACT

Life sometimes provides unannounced challenges that threaten the structure of our existence. This personal account of an ob-gyn's encounter with paralysis will illustrate the impact of one such experience.


Subject(s)
Paralysis , Humans , Female , Paralysis/etiology , Obstetrics , Gynecology , Physician-Patient Relations
5.
bioRxiv ; 2024 Jan 02.
Article in English | MEDLINE | ID: mdl-38260601

ABSTRACT

In the central nervous system, triggering receptor expressed on myeloid cells 2 (TREM2) is exclusively expressed by microglia and is critical for microglial proliferation, migration, and phagocytosis. TREM2 plays an important role in neurodegenerative diseases, such as Alzheimer's disease and amyotrophic lateral sclerosis. However, little is known about the role TREM2 plays in epileptogenesis. To investigate this, we utilized TREM2 knockout (KO) mice within the murine intra-amygdala kainic acid seizure model. Electroencephalographic analysis, immunocytochemistry, and RNA sequencing revealed that TREM2 deficiency significantly promoted seizure-induced pathology. We found that TREM2 KO increased both acute status epilepticus and spontaneous recurrent seizures characteristic of chronic focal epilepsy. Mechanistically, phagocytic clearance of damaged neurons by microglia was impaired in TREM2 KO mice and the reduced phagocytic capacity correlated with increased spontaneous seizures. Analysis of human tissue from patients who underwent surgical resection for drug resistant temporal lobe epilepsy also showed a negative correlation between microglial phagocytic activity and focal to bilateral tonic-clonic generalized seizure history. These results indicate that microglial TREM2 and phagocytic activity may be important to epileptogenesis and the progression of focal temporal lobe epilepsy.

6.
Brain Behav Immun ; 115: 406-418, 2024 01.
Article in English | MEDLINE | ID: mdl-37926132

ABSTRACT

Microglia are key players in maintaining brain homeostasis and exhibit phenotypic alterations in response to epileptic stimuli. However, it is still relatively unknown if these alterations are pro- or anti-epileptic. To unravel this dilemma, we employed chemogenetic manipulation of microglia using the artificial Gi-Dreadd receptor within a kainic acid (KA) induced murine seizure model. Our results indicate that acute Gi-Dreadd activation with Clozapine-N-Oxide can reduce seizure severity. Additionally, we observed increased interaction between microglia and neuronal soma, which correlated with reduced neuronal hyperactivity. Interestingly, prolonged activation of microglial Gi-Dreadds by repeated doses of CNO over 3 days, arrested microglia in a less active, homeostatic-like state, which associated with increased neuronal loss after KA induced seizures. RNAseq analysis revealed that prolonged activation of Gi-Dreadd interferes with interferon ß signaling and microglia proliferation. Thus, our findings highlight the importance of microglial Gi signaling not only during status epilepticus (SE) but also within later seizure induced pathology.


Subject(s)
Microglia , Status Epilepticus , Mice , Animals , Microglia/pathology , Seizures/chemically induced , Status Epilepticus/chemically induced , Anticonvulsants , Brain/pathology , Kainic Acid/pharmacology
7.
Neuro Oncol ; 2023 Nov 06.
Article in English | MEDLINE | ID: mdl-37941134

ABSTRACT

BACKGROUND: Myeloid cells comprise up to 50% of the total tumor mass in glioblastoma (GBM) and have been implicated in promoting tumor progression and immunosuppression. Modulating the response of myeloid cells to the tumor has emerged as a promising new approach for cancer treatment. In this regard, we focus on the Triggering Receptor Expressed on Myeloid cells 2 (TREM2), which has recently emerged as a novel immune modulator in peripheral tumors. METHODS: We studied the TREM2 expression profile in various patient tumor samples and conducted single-cell transcriptomic analysis in both glioblastoma patients and the GL261 mouse glioma model. We utilized multiple mouse glioma models and employed state-of-the-art techniques such as in vivo two-photon imaging, spectrum flow cytometry, and in vitro co-culture assays to study TREM2 function in myeloid cell-mediated phagocytosis of tumor cells, antigen presentation, and response of CD4+ T cells within the tumor hemispheres. RESULTS: Our research revealed significantly elevated levels of TREM2 expression in brain tumors compared to other types of tumors in patients. TREM2 was predominantly localized in tumor-associated myeloid cells and was highly expressed in nearly all microglia, as well as various subtypes of macrophages. Surprisingly, in pre-clinical glioma models, TREM2 deficiency did not confer a beneficial effect; instead, it accelerated glioma progression. Through detailed investigations, we determined that TREM2 deficiency impaired the ability of tumor-myeloid cells to phagocytose tumor cells and led to reduced expression of MHCII. This deficiency further significantly decreased the presence of CD4+ T cells within the tumor hemispheres. CONCLUSIONS: Our study unveiled a previously unrecognized protective role of tumor-myeloid TREM2. Specifically, we found TREM2 enhance the phagocytosis of tumor cells and promote an immune response by facilitating MHCII-associated CD4+ T cell responses against gliomas.

8.
Metabolites ; 13(8)2023 Aug 14.
Article in English | MEDLINE | ID: mdl-37623888

ABSTRACT

This article illustrates how dietary flaxseed can be used to reduce cancer risk, specifically by attenuating obesity, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD). We utilize a targeted metabolomics dataset in combination with a reanalysis of past work to investigate the "metabo-bioenergetic" adaptations that occur in White Leghorn laying hens while consuming dietary flaxseed. Recently, we revealed how the anti-vitamin B6 effects of flaxseed augment one-carbon metabolism in a manner that accelerates S-adenosylmethionine (SAM) biosynthesis. Researchers recently showed that accelerated SAM biosynthesis activates the cell's master energy sensor, AMP-activated protein kinase (AMPK). Our paper provides evidence that flaxseed upregulates mitochondrial fatty acid oxidation and glycolysis in liver, concomitant with the attenuation of lipogenesis and polyamine biosynthesis. Defatted flaxseed likely functions as a metformin homologue by upregulating hepatic glucose uptake and pyruvate flux through the pyruvate dehydrogenase complex (PDC) in laying hens. In contrast, whole flaxseed appears to attenuate liver steatosis and body mass by modifying mitochondrial fatty acid oxidation and lipogenesis. Several acylcarnitine moieties indicate Randle cycle adaptations that protect mitochondria from metabolic overload when hens consume flaxseed. We also discuss a paradoxical finding whereby flaxseed induces the highest glycated hemoglobin percentage (HbA1c%) ever recorded in birds, and we suspect that hyperglycemia is not the cause. In conclusion, flaxseed modifies bioenergetic pathways to attenuate the risk of obesity, type 2 diabetes, and NAFLD, possibly downstream of SAM biosynthesis. These findings, if reproducible in humans, can be used to lower cancer risk within the general population.

9.
Sports Med ; 53(9): 1789-1803, 2023 09.
Article in English | MEDLINE | ID: mdl-37410360

ABSTRACT

BACKGROUND: Augmented feedback is often used during resistance training to enhance acute physical performance and has shown promise as a method of improving chronic physical adaptation. However, there are inconsistencies in the scientific literature regarding the magnitude of the acute and chronic responses to feedback and the optimal method with which it is provided. OBJECTIVE: This systematic review and meta-analysis aimed to (1) establish the evidence for the effects of feedback on acute resistance training performance and chronic training adaptations; (2) quantify the effects of feedback on acute kinematic outcomes and changes in physical adaptations; and (3) assess the effects of moderating factors on the influence of feedback during resistance training. METHODS: Twenty studies were included in this systematic review and meta-analysis. This review was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Four databases were searched, and studies were included if they were peer-reviewed investigations, written in English, and involved the provision of feedback during or following dynamic resistance exercise. Furthermore, studies must have evaluated either acute training performance or chronic physical adaptations. Risk of bias was assessed using a modified Downs and Black assessment tool. Multilevel meta-analyses were performed to quantify the effects of feedback on acute and chronic training outcomes. RESULTS: Feedback enhanced acute kinetic and kinematic outputs, muscular endurance, motivation, competitiveness, and perceived effort, while greater improvements in speed, strength, jump performance, and technical competency were reported when feedback was provided chronically. Furthermore, greater frequencies of feedback (e.g., following every repetition) were found to be most beneficial for enhancing acute performance. Results demonstrated that feedback improves acute barbell velocities by approximately 8.4% (g = 0.63, 95% confidence interval [CI] 0.36-0.90). Moderator analysis revealed that both verbal (g = 0.47, 95% CI 0.22-0.71) and visual feedback (g = 1.11, 95% CI 0.61-1.61) were superior to no feedback, but visual feedback was superior to verbal feedback. For chronic outcomes, jump performance might have been positively influenced (g = 0.39, 95% CI - 0.20 to 0.99) and short sprint performance was likely enhanced (g = 0.47, 95% CI 0.10-0.84) to a greater extent when feedback is provided throughout a training cycle. CONCLUSIONS: Feedback during resistance training can lead to enhanced acute performance within a training session and greater chronic adaptations. Studies included in our analysis demonstrated a positive influence of feedback, with all outcomes showing superior results than when no feedback is provided. For practitioners, it is recommended that high-frequency, visual feedback is consistently provided to individuals when they complete resistance training, and this may be particularly useful during periods of low motivation or when greater competitiveness is beneficial. Alternatively, researchers must be aware of the ergogenic effects of feedback on acute and chronic responses and ensure that feedback is standardised when investigating resistance training.


Subject(s)
Resistance Training , Humans , Resistance Training/methods , Muscle Strength/physiology , Exercise/physiology , Adaptation, Physiological , Acclimatization
10.
iScience ; 26(5): 106588, 2023 May 19.
Article in English | MEDLINE | ID: mdl-37138776

ABSTRACT

Microglia exhibit diverse phenotypes in various central nervous system disorders and metabolic pathways exert crucial effects on microglial activation and effector functions. Here, we discovered two novel distinct microglial clusters, functionally associated with enhanced phagocytosis (PEMs) and myelination (MAMs) respectively, in human patients with multiple sclerosis by integrating public snRNA-seq data. Microglia adopt a PEMs phenotype during the early phase of demyelinated lesions, predominated in pro-inflammatory responses and aggravated glycolysis, while MAMs mainly emerged during the later phase, with regenerative signatures and enhanced oxidative phosphorylation. In addition, microglial triggering receptor expressed on myeloid cells 2 (Trem2) was greatly involved in the phenotype transition in demyelination, but not indispensable for microglia transition toward PEMs. Rosiglitazone could promote microglial phenotype conversion from PEMs to MAMs, thus favoring myelin repair. Taken together, these findings provide insights into therapeutic interventions targeting immunometabolism to switch microglial phenotypes and facilitate regenerative capacity in demyelination.

11.
Biomolecules ; 12(12)2022 11 26.
Article in English | MEDLINE | ID: mdl-36551185

ABSTRACT

BACKGROUND: Breast cancer is the most common cancer in women and the leading cause of female cancer deaths worldwide. Obesity causes chronic inflammation and is a risk factor for post-menopausal breast cancer and poor prognosis. Obesity triggers increased infiltration of macrophages into adipose tissue, yet little research has focused on the effects of macrophages in early stages of breast tumor development in obese patients. In this study, the effects of pro-inflammatory macrophages on breast cancer-adipocyte crosstalk were investigated. METHODS: An innovative human cell co-culture system was built and used to model the paracrine interactions among adipocytes, macrophages, and breast cancer cells and how they facilitate tumor progression. The effects on cancer cells were examined using cell counts and migration assays. Quantitative reverse-transcription polymerase chain reaction was used to measure the expression levels of several cytokines and proteases to analyze adipocyte cancer association. RESULTS: Macrophage-conditioned media intensified the effects of breast cancer-adipocyte crosstalk. Adipocytes became delipidated and increased production of pro-inflammatory cytokines, even in the absence of cancer cells, although the expression levels were highest with all three cell components. As a result, co-cultured breast cancer cells became more aggressive, with increased proliferation and migration compared to adipocyte-breast cancer co-cultures treated with unconditioned media. CONCLUSIONS: A novel co-culture model was built to evaluate the crosstalk among human macrophages, adipocytes, and breast cancer cells. We found that macrophages may contribute to adipocyte inflammation and cancer association and thus promote breast cancer progression.


Subject(s)
Breast Neoplasms , Female , Humans , Breast Neoplasms/metabolism , Culture Media, Conditioned/pharmacology , Adipocytes , Macrophages/metabolism , Inflammation/metabolism , Cytokines/metabolism , Obesity/metabolism , Cell Proliferation
12.
Elife ; 112022 12 19.
Article in English | MEDLINE | ID: mdl-36533901

ABSTRACT

Following infection of bacterial cells, bacteriophage modulate double-stranded DNA break repair pathways to protect themselves from host immunity systems and prioritise their own recombinases. Here, we present biochemical and structural analysis of two phage proteins, gp5.9 and Abc2, which target the DNA break resection complex RecBCD. These exemplify two contrasting mechanisms for control of DNA break repair in which the RecBCD complex is either inhibited or co-opted for the benefit of the invading phage. Gp5.9 completely inhibits RecBCD by preventing it from binding to DNA. The RecBCD-gp5.9 structure shows that gp5.9 acts by substrate mimicry, binding predominantly to the RecB arm domain and competing sterically for the DNA binding site. Gp5.9 adopts a parallel coiled-coil architecture that is unprecedented for a natural DNA mimic protein. In contrast, binding of Abc2 does not substantially affect the biochemical activities of isolated RecBCD. The RecBCD-Abc2 structure shows that Abc2 binds to the Chi-recognition domains of the RecC subunit in a position that might enable it to mediate the loading of phage recombinases onto its single-stranded DNA products.


Subject(s)
Bacteriophages , Escherichia coli Proteins , Escherichia coli Proteins/metabolism , Escherichia coli/genetics , Escherichia coli/metabolism , Bacteriophages/genetics , Bacteriophages/metabolism , Exodeoxyribonuclease V/genetics , DNA/metabolism , DNA, Single-Stranded/metabolism , Recombinases/metabolism , Exodeoxyribonucleases/chemistry , Exodeoxyribonucleases/genetics , Exodeoxyribonucleases/metabolism , DNA, Bacterial/metabolism
13.
Cancer Cell ; 40(9): 986-998.e5, 2022 09 12.
Article in English | MEDLINE | ID: mdl-36055226

ABSTRACT

Platelets, the often-overlooked component of the immune system, have been shown to promote tumor growth. Non-alcoholic fatty liver disease (NAFLD) is a common disease in the Western world and rising risk for hepatocellular carcinoma (HCC). Unexpectedly, we observed that platelets can inhibit the growth of established HCC in NAFLD mice. Through pharmacological inhibition and genetic depletion of P2Y12 as well as in vivo transfusion of wild-type (WT) or CD40L-/- platelets, we demonstrate that the anti-tumor function of platelets is mediated through P2Y12-dependent CD40L release, which leads to CD8+ T cell activation by the CD40 receptor. Unlike P2Y12 inhibition, blocking platelets with aspirin does not prevent platelet CD40L release nor accelerate HCC in NAFLD mice. Similar findings were observed in liver metastasis models. All together, our study reveals a complex role of platelets in tumor regulation. Anti-platelet treatment without inhibiting CD40L release could be considered for liver cancer patients with NAFLD.


Subject(s)
Blood Platelets/immunology , Carcinoma, Hepatocellular , Liver Neoplasms , Non-alcoholic Fatty Liver Disease , Receptors, Purinergic P2Y12/metabolism , Animals , CD40 Ligand/genetics , Carcinoma, Hepatocellular/genetics , Liver Neoplasms/drug therapy , Liver Neoplasms/genetics , Mice , Non-alcoholic Fatty Liver Disease/drug therapy , Non-alcoholic Fatty Liver Disease/genetics
15.
Life (Basel) ; 12(4)2022 Apr 09.
Article in English | MEDLINE | ID: mdl-35455053

ABSTRACT

Endometrial carcinoma (EC) is the most common type of gynecologic malignant epithelial tumor, with the death rate from this disease doubling over the past 20 years. Mitochondria provide cancer cells with necessary anabolic building blocks such as amino acids, lipids, and nucleotides, and EC samples have been shown to increase mitochondrial biogenesis. In cancer, mitochondrial DNA (mtDNA) heteroplasmy studies suggest that heteroplasmic variants encode predicted pathogenic proteins. We investigated the mtDNA genotypes within peri-normal and tumor specimens obtained from three individuals diagnosed with EC. DNA extracts from peri-normal and tumor tissues were used for mtDNA-specific next-generation sequencing and analyses of mtDNA content and topoisomers. The three tumors harbor heteroplasmic somatic mutations, and at least one mutation in each carcinoma is predicted to deleteriously alter a mtDNA-encoded protein. Somatic heteroplasmy linked to two mtDNA tRNA genes was found in separate tumors, and two heteroplasmic non-coding variants were identified in a single EC tumor. While two tumors had altered mtDNA content, all three displayed increased mtDNA catenanes. Our findings support that EC cells require wild-type mtDNA, but heteroplasmic mutations may alter mitochondrial metabolism to help promote cancer cell growth and proliferation.

16.
Sci Med Footb ; 6(1): 60-65, 2022 02.
Article in English | MEDLINE | ID: mdl-35236226

ABSTRACT

The purpose was to investigate the effects of travel on performance in the National Rugby League (NRL). A total of 4,704 observations from 2,352 NRL matches (2007-2019) were analysed. The effect of travel on match outcome (i.e., win/loss) was analysed using a generalized linear mixed model, and the points difference using a linear mixed model. For every 1,000 km travelled in the NRL, the estimated probability of winning a match was reduced by -2.7% [-5.7 to 0.3%] and the estimated points difference by -1.1 [-2.0 to -0.2] points. In relation to every 1,000 km travelled, the 2007-2009 seasons had the greatest reduction in the likelihood of winning a match (-2.7% [-4.7 to -0.6%]), with the 2018-2019 seasons having the greatest likelihood (1.1% [-1.2 to 3.3%]). Regarding inter-state travel, teams from the state of Queensland had the greatest reduction in the likelihood of winning a match while the team from the state of Victoria had the greatest likelihood, although there were no clear differences between states. These data suggest that travel has impacted performance in NRL matches although this effect has reduced over time. These findings are useful for practitioners that prepare athletes in sports where frequent short-haul travel is required.


Subject(s)
Athletic Performance , Football , Athletes , Humans , Linear Models , Rugby
17.
Signal Transduct Target Ther ; 7(1): 6, 2022 01 07.
Article in English | MEDLINE | ID: mdl-34992208

ABSTRACT

Revascularization and angiogenesis, as substrates of sustained collateral circulation, play a crucial role in determining the severity and clinical outcome of acute ischemic stroke (AIS) due to large vessel occlusion (LVO). Developing an adjunct biomarker to help identify and monitor collateral status would aid stroke diagnosis and prognosis. To screen the potential biomarkers, proteomic analysis was performed in this study to identify those distinct plasma protein profiles in AIS due to LVO with different collateral status. Interestingly, we found that levels of Plasma Factor VII Activating Protease (FSAP) significantly increased in those AIS patients with poor collaterals, and were correlated with worse neurological outcome. Furtherly, both in vitro and in vivo models of ischemic stroke were used to explore pathological mechanisms of FSAP in endothelial dysfunction. We demonstrated that the FSAP inhibitor, high-molecular-weight hyaluronan (HMW-HA), enhanced the pro-angiogenic vascular factors, improved the integrity of brain blood barrier, and promoted newly formed cerebral microvessels in the ischemic penumbra, consequently improving neurological function. To elucidate the pathways that might contribute to revascularization during LVO, we applied transcriptomic analysis via unbiased RNA sequencing and showed that Wnt signaling was highly involved in FSAP mediated endothelial dysfunction. Notably, inhibition of Wnt5a largely reversed the protective effects from HMW-HA treatment, implying that FSAP might aggravate endothelial dysfunction and neurological deficits by regulating Wnt5a signaling. Therefore, FSAP may represent a potential biomarker for collateral status after LVO and a promising therapeutic target to be explored in the treatment of stroke.


Subject(s)
Cerebrovascular Disorders/enzymology , Endothelium, Vascular/enzymology , Ischemic Stroke/enzymology , Serine Endopeptidases/metabolism , Animals , Humans , Mice
18.
Nat Neurosci ; 25(1): 26-38, 2022 01.
Article in English | MEDLINE | ID: mdl-34916658

ABSTRACT

Triggering receptor expressed on myeloid cell 2 (TREM2) is linked to risk of neurodegenerative disease. However, the function of TREM2 in neurodegeneration is still not fully understood. Here, we investigated the role of microglial TREM2 in TAR DNA-binding protein 43 (TDP-43)-related neurodegeneration using virus-mediated and transgenic mouse models. We found that TREM2 deficiency impaired phagocytic clearance of pathological TDP-43 by microglia and enhanced neuronal damage and motor impairments. Mass cytometry analysis revealed that human TDP-43 (hTDP-43) induced a TREM2-dependent subpopulation of microglia with high CD11c expression and phagocytic ability. Using mass spectrometry (MS) and surface plasmon resonance (SPR) analysis, we further demonstrated an interaction between TDP-43 and TREM2 in vitro and in vivo as well as in human tissues from individuals with amyotrophic lateral sclerosis (ALS). We computationally identified regions within hTDP-43 that interact with TREM2. Our data highlight that TDP-43 is a possible ligand for microglial TREM2 and that this interaction mediates neuroprotection of microglia in TDP-43-related neurodegeneration.


Subject(s)
DNA-Binding Proteins , Membrane Glycoproteins , Microglia , Neurodegenerative Diseases , Receptors, Immunologic , Animals , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Membrane Glycoproteins/genetics , Membrane Glycoproteins/metabolism , Mice , Mice, Transgenic , Microglia/metabolism , Neurodegenerative Diseases/metabolism , Neuroprotection , Receptors, Immunologic/genetics , Receptors, Immunologic/metabolism
19.
Dev Neurobiol ; 82(1): 125-137, 2022 01.
Article in English | MEDLINE | ID: mdl-34874625

ABSTRACT

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is an aggressive motor neuron degenerative disease characterized by selective loss of both upper and lower motor neurons. The mechanisms underlying disease initiation and progression are poorly understood. The involvement of nonmotor neuraxis emphasizes the contribution of glial cells in disease progress. Microglia comprise a unique subset of glial cells and are the principal immune cells in the central nervous system (CNS). Triggering receptor expressed on myeloid cell 2 (TREM2) is a surface receptor that, within the CNS, is exclusively expressed on microglia and plays crucial roles in microglial proliferation, migration, activation, metabolism, and phagocytosis. Genetic evidence has linked TREM2 to neurodegenerative diseases including ALS, but its function in ALS pathogenesis is largely unknown. In this review, we summarize how microglial activation, with a specific focus on TREM2 function, affects ALS progression clinically and experimentally. Understanding microglial TREM2 function will help pinpoint the molecular target for ALS treatment.


Subject(s)
Amyotrophic Lateral Sclerosis , Membrane Glycoproteins , Microglia , Neurodegenerative Diseases , Receptors, Immunologic , Amyotrophic Lateral Sclerosis/genetics , Amyotrophic Lateral Sclerosis/metabolism , Amyotrophic Lateral Sclerosis/pathology , Central Nervous System/metabolism , Humans , Membrane Glycoproteins/genetics , Membrane Glycoproteins/metabolism , Microglia/metabolism , Motor Neurons/metabolism , Neurodegenerative Diseases/genetics , Neurodegenerative Diseases/metabolism , Neurodegenerative Diseases/pathology , Receptors, Immunologic/genetics , Receptors, Immunologic/metabolism
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