Circulating immune complexes and complement C3 and C4 levels in a selected group of patients with rhinitis in Lebanon

BACKGROUND: A number of reports indicate that circulating immune complexes (CIC) and activation of the complement system contribute to the pathogenesis of Type I allergy. The aim of this study was to investigate the status of CIC in 113 patients with rhinitis in Lebanon and determine complement components C3 and C4 serum levels in the CIC-positive patients. Serum specific IgE antibodies were previously detected and reported in 74 of the 113 patients. METHODS: CIC were detected by polyethylene glycol precipitation and serum C3 and C4 levels quantified by radial immunodiffusion. RESULTS: CIC was positive in 20 of the specific IgE-positive and 13 of the specific IgE-negative patients. C3 and C4 levels were within the normal range in all the 33 CIC-positive patients. CONCLUSIONS: The antibody class that constitutes the complexes does not seem to be IgG or IgM. Moreover, complement activation does not seem to be involved in the allergic reaction since both C3 and C4 levels were normal in all patients. The role of these complexes, if any, in the pathogenesis of rhinitis is yet to be determined

Editorial: biomarkers in neurology

Neurological disorders constitute a major health and socioeconomic problem. They represent the second cause of death and the leading cause of disability throughout the world. Despite the implementation of strategies and intervention programs to reduce the burden, over the past 25 years, the incidence, prevalence, mortality, and disability rates of neurological disorders are rising globally, mainly due to population aging and growth (1). This has placed heavy pressure on health-care systems pointing out the urgent need to identify new strategies to improve patient outcomes and reduce health costs by enabling more effective drug development and establishing a more personalized medicine approach. Rapid scientific and technical advances have enabled reliable and affordable measurement of novel biomarkers—biological indicators that objectively measure and evaluate physiological or pathophysiological processes or pharmacological responses to a therapeutic intervention (2)—which have been suggested to help assessment and management of patients with neurological disorders beyond current practice standards (3–5). Evidence suggests a potential variety of clinical applications, including enhancing diagnostic and prognostic accuracy, improving the existing decision criteria for early diagnosis and risk stratification, as well as assisting in disease monitoring, and acting as surrogate endpoints in experimental studies and clinical trials (6–10). In addition, biomarkers may reliably capture the different aspects of disease heterogeneity and pathogenesis, helping characterize patients, and thereby informing targeted tailored treatments and predicting response outcomes to interventions (11–18). However, despite large numbers of candidate biomarkers have been proposed and extensively evaluated, very few are currently integrated into routine clinical practice and the quest for novel brain injury markers in still ongoing (19)

Dual vulnerability of tau to calpains and caspase-3 proteolysis under neurotoxic and neurodegenerative conditions

Axonally specific microtubule-associated protein tau is an important component of neurofibrillary tangles found in AD (Alzheimer's disease) and other tauopathy diseases such as CTE (chronic traumatic encephalopathy). Such tau aggregate is found to be hyperphosphorylated and often proteolytically fragmented. Similarly, tau is degraded following TBI (traumatic brain injury). In the present study, we examined the dual vulnerability of tau to calpain and caspase-3 under neurotoxic and neurodegenerative conditions. We first identified three novel calpain cleavage sites in rat tau (four-repeat isoform) as Ser130↓Lys131, Gly157↓Ala158 and Arg380↓Glu381. Fragment-specific antibodies to target the major calpain-mediated TauBDP-35K (35 kDa tau-breakdown product) and the caspase-mediated TauBDP-45K respectively were developed. In rat cerebrocortical cultures treated with excitotoxin [NMDA (N-methyl-d-aspartate)], tau is significantly degraded into multiple fragments, including a dominant signal of calpain-mediated TauBDP-35K with minimal caspase-mediated TauBDP-45K. Following apoptosis-inducing EDTA treatment, tau was truncated only to TauBDP-48K/45K-exclusively by caspase. Cultures treated with another apoptosis inducer STS (staurosporine), dual fragmentation by calpain (TauBDP-35K) and caspase-3 (TauBDP-45K) was observed. Tau was also fragmented in injured rat cortex following TBI in vivo to BDPs of 45–42 kDa (minor), 35 kDa and 15 kDa, followed by TauBDP-25K. Calpain-mediated TauBDP-35K-specific antibody confirmed robust signals in the injured cortex, while caspase-mediated TauBDP-45K-specific antibody only detected faint signals. Furthermore, intravenous administration of a calpain-specific inhibitor SNJ-1945 strongly suppressed the TauBDP-35K formation. Taken together, these results suggest that tau protein is dually vulnerable to calpain and caspase-3 proteolysis under different neurotoxic and injury conditions

CSF and Plasma Amyloid-beta Temporal Profiles and Relationships with Neurological Status and Mortality after Severe Traumatic Brain Injury

The role of amyloid-β (Aβ) neuropathology and its significant changes in biofluids after traumatic brain injury (TBI) is still debated. We used ultrasensitive digital ELISA approach to assess amyloid-β1-42 (Aβ42) concentrations and time-course in cerebrospinal fluid (CSF) and in plasma of patients with severe TBI and investigated their relationship to injury characteristics, neurological status and clinical outcome. We found decreased CSF Aβ42 levels in TBI patients acutely after injury with lower levels in patients who died 6 months post-injury than in survivors. Conversely, plasma Aβ42 levels were significantly increased in TBI with lower levels in patients who survived. A trend analysis showed that both CSF and plasma Aβ42 levels strongly correlated with mortality. A positive correlation between changes in CSF Aβ42 concentrations and neurological status as assessed by Glasgow Coma Scale (GCS) was identified. Our results suggest that determination of Aβ42 may be valuable to obtain prognostic information in patients with severe TBI as well as in monitoring the response of the brain to injury

G protein estrogen receptor as a potential therapeutic target in Raynaud’s phenomenon

Exaggerated cold-induced vasoconstriction can precipitate a pathogenesis called Raynaud’s phenomenon (RP). Interestingly, RP is significantly more prevalent in females than age-matched men, highlighting the potential implication of 17β-estradiol (E2) in the etio-pathogenesis of this disease. Indeed, we have previously reported that E2 stimulates the expression of vascular alpha 2C-adrenoceptors (α2C-AR), the sole mediator of cold-induced constriction of cutaneous arterioles. This induced expression occurs through the cyclic adenosine monophosphate → exchange protein activated by cAMP→ Ras-related protein 1→ c-Jun N-terminal kinase→ activator protein-1 (cAMP/Epac/Rap/JNK/AP-1 pathway). On the basis that estrogen-induced rapid cAMP accumulation and JNK activation occurs so rapidly we hypothesized that a non-classic, plasma membrane estrogen receptor was the mediator. We then showed that an impermeable form of E2, namely E2:BSA, mimics E2 effects suggesting a role for the membranous G-protein coupled estrogen receptor (GPER) in E2-induced α2C-AR expression. Our current working hypothesis and unpublished observations further cement this finding, as G1, a GPER agonist, mimics while G15, a GPER antagonist, abrogates estrogen’s effect on the expression of vascular α2C-AR. These, and other observations, highlight the potential of GPER as a tractable target in the management of RP, particularly in pre-menopausal women.APCs for this paper have been offset by a generous support from Frontiers as part of the support offered to women in pharmacology, for the specific invitation to Women in Translational Pharmacology: 2021

Acute NMDA toxicity in cultured rat cerebellar granule neurons is accompanied by autophagy induction and late onset autophagic cell death phenotype

<p>Abstract</p> <p>Background</p> <p>Autophagy, an intracellular response to stress, is characterized by double membrane cytosolic vesicles called autophagosomes. Prolonged autophagy is known to result in autophagic (Type II) cell death. This study examined the potential role of an autophagic response in cultured cerebellar granule neurons challenged with excitotoxin N-methyl-D-aspartate (NMDA).</p> <p>Results</p> <p>NMDA exposure induced light chain-3 (LC-3)-immunopositive and monodansylcadaverine (MDC) fluorescent dye-labeled autophagosome formation in both cell bodies and neurites as early as 3 hours post-treatment. Elevated levels of Beclin-1 and the autophagosome-targeting LC3-II were also observed following NMDA exposure. Prolonged exposure of the cultures to NMDA (8-24 h) generated MDC-, LC3-positive autophagosomal bodies, concomitant with the neurodegenerative phase of NMDA challenge. Lysosomal inhibition studies also suggest that NMDA-treatment diverted the autophagosome-associated LC3-II from the normal lysosomal degradation pathway. Autophagy inhibitor 3-methyladenine significantly reduced NMDA-induced LC3-II/LC3-I ratio increase, accumulation of autophagosomes, and suppressed NMDA-mediated neuronal death. ATG7 siRNA studies also showed neuroprotective effects following NMDA treatment.</p> <p>Conclusions</p> <p>Collectively, this study shows that autophagy machinery is robustly induced in cultured neurons subjected to prolonged exposure to excitotoxin, while autophagosome clearance by lysosomal pathway might be impaired. Our data further show that prolonged autophagy contributes to cell death in NMDA-mediated excitotoxicity.</p