scholarly journals Targeted deletions of complement lectin pathway genes improve outcome in traumatic brain injury, with MASP-2 playing a major role

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
D. Mercurio ◽  
M. Oggioni ◽  
S. Fumagalli ◽  
N. J. Lynch ◽  
S. Roscher ◽  
...  
Keyword(s):  
Functional Activity ◽  
Brain Inflammation ◽  
Neurological Deficits ◽  
Lectin Pathway ◽  
Histopathological Analysis ◽  
Gene Deletions ◽  
Degree Of Protection ◽  
Pharmacological Targets ◽  
Key Enzyme ◽  
Post Traumatic

Abstract The lectin pathway (LP) of complement activation is believed to contribute to brain inflammation. The study aims to identify the key components of the LP contributing to TBI outcome as possible novel pharmacological targets. We compared the long-term neurological deficits and neuropathology of wild-type mice (WT) to that of mice carrying gene deletions of key LP components after experimental TBI. WT or MASP-2 (Masp2−/−), ficolin-A (Fcna−/−), CL-11 (Colec11−/−), MASP-1/3 (Masp1−/−), MBL-C (Mbl2−/−), MBL-A (Mbl1−/−) or MBL−/− (Mbl1−/−/Mbl2−/−) deficient male C57BL/6J mice were used. Mice underwent sham surgery or TBI by controlled cortical impact. The sensorimotor response was evaluated by neuroscore and beam walk tests weekly for 4 weeks. To obtain a comparative analysis of the functional outcome each transgenic line was rated according to a health score calculated on sensorimotor performance. For selected genotypes, brains were harvested 6 weeks after injury for histopathological analysis. MASP-2−/−, MBL−/− and FCN-A−/− mice had better outcome scores compared to WT. Of these, MASP-2−/− mice had the best recovery after TBI, showing reduced sensorimotor deficits (by 33% at 3 weeks and by 36% at 4 weeks). They also showed higher neuronal density in the lesioned cortex with a 31.5% increase compared to WT. Measurement of LP functional activity in plasma from MASP-2−/− mice revealed the absence of LP functional activity using a C4b deposition assay. The LP critically contributes to the post-traumatic inflammatory pathology following TBI with the highest degree of protection achieved through the absence of the LP key enzyme MASP-2, underlining a therapeutic utility of MASP-2 targeting in TBI.

scholarly journals Impact of MASP2 gene polymorphism and gene-tea drinking interaction on susceptibility to tuberculosis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Zihao Li ◽  
Mian Wang ◽  
Hua Zhong ◽  
Xin Huang ◽  
Xinyin Wu ◽  
...  
Keyword(s):  
Additive Model ◽  
Lectin Pathway ◽  
Control Group ◽  
Single Nucleotide ◽  
Key Enzyme ◽  
Healthy Control ◽  
Tea Drinking ◽  
Mannan Binding Lectin ◽  
The Complement System ◽  
Negative Interactions

AbstractMannan-binding lectin-associated serine protease-2 (MASP-2) has been reported to play an important role as a key enzyme in the lectin pathway of the complement system. The objectives of our study were to determine whether the single-nucleotide polymorphism (SNPs) of MASP2 and the gene-tea drinking interaction were associated with the susceptibility to TB. In total, 503 patients and 494 healthy controls were contained. Three SNPs (rs12142107, rs12711521, and rs7548659) were genotyped. The association between the SNPs and susceptibility to TB were investigated by conducting multivariate unconditional logistic regression analysis. The gene-tea drinking interactions were analyzed by the additive model of marginal structural linear odds models. Both genotype AC + AA at rs12711521 of MASP2 genes and genotype GT + GG at rs7548659 of MASP2 genes were more prevalent in the TB patient group than the healthy control group (OR: 1.423 and 1.439, respectively, P < 0.05). In addition, The relative excess risk of interaction (RERI) between tea drinking and rs12142107, rs12711521, and rs7548659 of MASP2 genes was found to suggest negative interactions, which reached − 0.2311 (95% confidence interval (CI): − 0.4736, − 0.0113), − 0.7080 (95% CI − 1.3998, − 0.0163), and − 0.5140 (95% CI − 0.8988, − 0.1291), respectively (P < 0.05). Our finding indicated that the SNPs (rs12711521 and rs7548659) of MASP2 were associated with the susceptibility to TB. Furthermore, there were negative interactions between tea drinking and rs12142107, rs12711521, and rs75548659 of MASP2 gene, respectively. Our research provides a basis for studying the pathogenesis and prevention of tuberculosis.

A-78 Interdisciplinary Consultation in a Case of Herpes Simplex Encephalitis with Unique Neuropsychiatric Symptoms

2021 ◽  
Vol 36 (6) ◽  
pp. 1121-1122
Author(s):  
Danielle Kaplan ◽  
John B O'Hara ◽  
Carolina Posada ◽  
Kristin E Slyne
Keyword(s):  
Herpes Simplex ◽  
Herpes Simplex Encephalitis ◽  
Neuropsychiatric Symptoms ◽  
Executive Dysfunction ◽  
Brain Inflammation ◽  
Neurological Deficits ◽  
Cognitive Changes ◽  
Fluid Analysis ◽  
Intravenous Acyclovir ◽  
Neuropsychological Evaluations

Abstract Objective Herpes simplex encephalitis (HSE) is a rare neurological condition (~2–4 per million) marked by brain inflammation caused by herpes simplex virus (HSV). HSE is associated with both cognitive and neuropsychiatric symptoms, particularly memory and executive dysfunction. We present the case of a 63-year-old, right-handed, St. Lucian female who completed serial neuropsychological evaluations (NPE). Method The patient presented with a six-day history (per collateral) of fever, confusion, and nausea. The patient denied cognitive changes. Magnetic Resonance Imaging (MRI) revealed leptomeningeal enhancement in the right sylvian fissure, multiple right temporal sulci, and inferior right frontal lobe (Figure 1). There was no indication of seizures. Cerebrospinal fluid analysis was positive for HSV-1. A two-week course of intravenous acyclovir was initiated on hospital day three. Results (Table 1). Initial NPE results (day five) revealed global cognitive impairment with sparing of auditory attention; exam was limited secondary to significant fatigue. Following completion of antivirals, subsequent NPE (day 17) revealed similar findings, despite improved alertness; left neglect (Figure 2) and significant anosagnosia (i.e., lack of disease awareness) and anosodiaphoria (i.e., indifference reaction to neurological deficits) were noted. Two-month outpatient follow-up NPE revealed marginal improvement in aspects of language and learning, but continued memory impairment, dense anosagnosia, and anosodiaphoria. Conclusion In this case, the patient presented with salient neuropsychiatric sequelae of HSE that have not been commonly associated with this condition in the extant literature. Her denial of cognitive symptoms may have initially confounded the differential diagnosis, emphasizing the importance of multi-specialty collaboration. Limitations of available normative data also complicated examination.

scholarly journals Anti-Inflammatory Effects of the 70 kDa Heat Shock Protein in Experimental Stroke

2007 ◽  
Vol 28 (1) ◽  
pp. 53-63 ◽  
Author(s):  
Zhen Zheng ◽  
Jong Youl Kim ◽  
Hualong Ma ◽  
Jong Eun Lee ◽  
Midori A Yenari
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Brain Ischemia ◽  
Inflammatory Responses ◽  
Nuclear Factor Κb ◽  
Artery Occlusion ◽  
Brain Inflammation ◽  
Neurological Deficits ◽  
Experimental Stroke ◽  
Anti Inflammatory

The 70-kDa heat shock protein (Hsp70) is involved in protecting the brain from a variety of insults including stroke. Although the mechanism has been largely considered to be because of its chaperone functions, recent work indicates that Hsp70 also modulates inflammatory responses. To explore how and whether Hsp70 regulate immune responses in brain ischemia, mice overexpressing Hsp70 (Hsp Tg) were subjected to 2 h middle cerebral artery occlusion, followed by 24 h reperfusion. Parallel experiments were performed using a brain inflammation model. Hsp Tg microglia cocultured with astrocytes were used to evaluate the direct effects of Hsp70 on cytotoxicity of mcrigolia. Compared with wild-type (Wt) littermates, Hsp Tg mice showed decreased infarct size and improved neurological deficits. The number of activated microglia/macrophages were also reduced in ischemic brains of Hsp Tg mice. Similar observations were made in a model of brain inflammation that does not result in brain cell death. Overexpression of Hsp70 in microglia completely prevented microglia-induced cytotoxicity to astrocytes. Activation of the inflammatory transcription factor, nuclear factor-κB (NF-κB) was inhibited significantly in Hsp Tg mice and microglia. This was associated with decreased phosphorylation of NF-κB inhibitor protein, IκBα, and decreased expression of several NFκB-regulated genes. Co-immunoprecipitation studies revealed an interaction of Hsp70 with NF-κB and IκBα, but not with IkB kinase, IKKγ, suggesting that Hsp70 binds to the NF-κB:IκB complex preventing IκB phosphorylation by IKK. The findings of the present work establish an anti-inflammatory role for Hsp70 in the context of brain ischemia as a novel mechanism of protection.

scholarly journals Rosuvastatin revert memory impairment and anxiogenic-like effect in mice infected with the chronic ME-49 strain of Toxoplasma gondii

PLoS ONE ◽  
2021 ◽  
Vol 16 (4) ◽  
pp. e0250079
Author(s):  
Fernanda Ferreira Evangelista ◽  
Willian Costa-Ferreira ◽  
Francini Martini Mantelo ◽  
Lucimara Fátima Beletini ◽  
Amanda Hinobu de Souza ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Memory Impairment ◽  
Brain Inflammation ◽  
Long Term Memory ◽  
Histopathological Analysis ◽  
Term Memory ◽  
Anxiogenic Effect ◽  
Short And Long Term ◽  
The Brain

The aim of this study was to investigate the effect of rosuvastatin treatment on memory impairment, and anxiogenic-like effects in mice chronically infected with Toxoplasma gondii. For this, Balb/c mice were infected orally with chronic ME-49 strain of Toxoplasma gondii. Oral treatment with rosuvastatin (40mg/kg/day) started on the 51st day post-infection and was performed daily for 21 days. After completion of treatment, anxiety-like effects and locomotion were investigated in the open field (OF) test, whereas novel object recognition (NOR) test was used for evaluation of short- and long-term memory. At the end of the experiments, the brain was collected for Toxoplasma gondii DNA quantification and histopathological analysis. Infection with ME-49 strain decreased the time spent in the center of OF, indicating an anxiogenic effect, without affecting total and peripheral locomotion. Rosuvastatin treatment inhibited the change in the center time. Besides, pharmacological treatment increased total and central locomotion in both non-infected and infected animals. Infection also impaired both short- and long-term memory in the NOR test, and these effects were reverted by rosuvastatin treatment. In addition to effects in behavioral changes, rosuvastatin also reduced parasite load in the brain and attenuated signs of brain inflammation such as perivascular cuffs, inflammatory cell infiltration and tissue damage. These findings indicate for the first time the efficacy of rosuvastatin in treatment of memory impairment and anxiogenic effect evoked by infection with Toxoplasma gondii. These effects might be mediated by reduced cyst load, which in turn decrease inflammation and damage in the brain.

Formyl peptide receptor 1 signaling potentiates inflammatory brain injury

2021 ◽  
Vol 13 (605) ◽  
pp. eabe9890
Author(s):  
Zhiguo Li ◽  
Yulin Li ◽  
Jinrui Han ◽  
Zilong Zhu ◽  
Minshu Li ◽  
...  
Keyword(s):  
Brain Edema ◽  
Brain Inflammation ◽  
Formyl Peptide Receptor ◽  
Neurological Deficits ◽  
Peptide Receptor ◽  
Neurological Outcomes ◽  
Molecular Pattern ◽  
Formyl Peptide ◽  
Molecular Landscape ◽  
Formyl Peptides

Acute brain insults elicit pronounced inflammation that amplifies brain damage in intracerebral hemorrhage (ICH). We profiled perihematomal tissue from patients with ICH, generating a molecular landscape of the injured brain, and identified formyl peptide receptor 1 (FPR1) as the most abundantly increased damage-associated molecular pattern (DAMP) receptor, predominantly expressed by microglia. Circulating mitochondrial N-formyl peptides, endogenous ligands of FPR1, were augmented and correlated with the magnitude of brain edema in patients with ICH. Interactions of formyl peptides with FPR1 activated microglia, boosted neutrophil recruitment, and aggravated neurological deficits in two mouse models of ICH. We created an FPR1 antagonist T-0080 that can penetrate the brain and bind both human and murine FPR1. T-0080 attenuated brain edema and improved neurological outcomes in ICH models. Thus, FPR1 orchestrates brain inflammation after ICH and could be targeted to improve clinical outcome in patients.

The deficiency of the lectin pathway functional activity in MASP-2 deficient mice does not effect the survival from acute polymicrobial septic peritonitis

2008 ◽  
Vol 45 (16) ◽  
pp. 4164
Author(s):  
Mohammed Ali ◽  
Bernd Echtenacher ◽  
Cordula Stover ◽  
Daniela Maennel ◽  
Wilhelm Schwaeble
Keyword(s):  
Functional Activity ◽  
Lectin Pathway ◽  
Septic Peritonitis ◽  
Deficient Mice

scholarly journals Rectal foreign body insertion as a rare cause of persistent lumbosacral plexus injury

2017 ◽  
Vol 99 (6) ◽  
pp. e191-e192 ◽  
Author(s):  
FA Meister ◽  
I Amygdalos ◽  
UP Neumann ◽  
G Lurje
Keyword(s):  
Foreign Body ◽  
Urinary Retention ◽  
Traffic Accidents ◽  
Rectal Wall ◽  
Heavy Traffic ◽  
Loop Ileostomy ◽  
Rectal Mucosa ◽  
Neurological Deficits ◽  
Lumbosacral Plexus ◽  
Post Traumatic

Rectal foreign body insertion is a common condition in emergency surgery, which often requires surgical intervention. Here we report a clinical case of rectal foreign body insertion as a rare cause of persistent lumbosacral plexus injury. A 72-year-old man presented to the emergency department complaining of acute bilateral paraplegia with loss of sensation in both legs, as well as total urinary retention. The patient underwent abdominal computed tomography, which showed a rectal foreign body measuring 13 × 11.5 × 10 cm in the lower abdomen and pelvis. Extraluminal assistance through a median laparotomy was required after unsuccessful attempts at transanal recovery alone. After removal of the foreign body, the rectal wall and anorectal sphincter were massively dilated, with severe bruising of the rectal mucosa on proctoscopy. A protective loop-ileostomy was performed. The sacral plexus is located posteriorly in the pelvis. Physiologically, the nerves are well protected by surrounding anatomical structures. Post-traumatic lumbosacral plexus injuries with paraplegia, urinary retention and anorectal sphincter insufficiency occur quite frequently after heavy traffic accidents. Lumbosacral plexus injury as a result of rectal foreign body insertion is rare. Severe neurological deficits through rectal foreign body insertion are rare but known medical conditions. To the best of our knowledge, this is the first reported case of severe and persistent post-traumatic lumbosacral plexus injury through a rectal foreign body.

scholarly journals EVALUATION OF CHONDROPROTECTIVE EFFECTS OF INTRA ARTICULAR PIROXICAM IN POST-TRAUMATIC OSTEOARTHRITIS MODEL OF RAT

2021 ◽  
Vol 71 (2) ◽  
pp. 593-97
Author(s):  
Noaman Ishaq ◽  
Shabana Ali ◽  
Qurra Tul Ain Haider ◽  
Muhammad Abdul Basit Qaisrani ◽  
Komal Mumtaz Malik ◽  
...  
Keyword(s):  
Treatment Group ◽  
Cruciate Ligament ◽  
Positive Control ◽  
Control Group ◽  
P Value ◽  
Surgical Removal ◽  
Histopathological Analysis ◽  
Sprague Dawley ◽  
Group I ◽  
Post Traumatic

Objective: To evaluate the chondroprotective effect of piroxicam in post-traumatic osteoarthritis model of rat. Study Design: Laboratory based experimental study. Place and Duration of Study: Pharmacology department, Army Medical College, Rawalpindi, from Apr to Jun 2019. Methodology: Project included sixteen rats of Sprague Dawley breed. Osteoarthritis was induced in anesthetized rats by surgical removal of medial meniscus and anterior cruciate ligament resection. After that rats were randomly allocated in two groups with eight rats in each group. Rats of group I were positive control that received 0.2 ml saline intra articularly once weekly for four weeks. Meanwhile rats of group II (treatment group) received 50 µl piroxicam intra articularly once weekly for four weeks. One week after the drug intervention, radiograph of the right knee joint of all rats were taken. Animals were then sacrificed with inhaled chloroform and part of proximal tibia was obtained for histopathological analysis. Results: Comparison of radiographs of both groups depicted a significant p-value of <0.01. Meanwhile mean histopathological score of control group and treatment group were 11.50 ± 1.195 and 6.50 ± 1.195 respectively with a p-value of <0.01. Conclusion: Intra articular administration of piroxicam in post-traumatic Osteoarthritis model of rats resulted in improvement in radiographic grades and histopathology scores.

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