Apolipoprotein D modulates lipid mediators and osteopontin in an anti-inflammatory direction.

BACKGROUND: HDL has been proposed to possess anti-inflammatory properties; however, the detail mechanisms have not been fully elucidated. METHODS: We investigated the roles of Apolipoprotein D (ApoD) in the pathogenesis of inflammation in the mouse model of diet-induced obesity and that of lipopolysaccharide-induced sepsis and the in vitro experiments. Furthermore, we analyzed serum ApoD levels in human subjects. RESULTS: The overexpression of human ApoD decreased the plasma IL-6 and TNF-a levels in both mice models. Lipidomics analyses demonstrated association of ApoD with increase of arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid, as well as of their metabolites, and of the anti-inflammatory molecule sphingosine 1-phosphate, and decrease of proinflammatory lysophosphatidic acids and lysophosphatidylinositol. ApoD-containing lipoproteins might directly bind eicosapentaenoic acid and docosahexaenoic acid. The modulations of the lysophosphatidic acid and sphingosine 1-phosphate levels resulted from the suppression of autotaxin expression and elevation of apolipoprotein M (ApoM), respectively. Moreover, ApoD negatively regulated osteopontin, a proinflammatory adipokine. The activation of PPARg by ApoD might suppress autotaxin and osteopontin. Serum ApoD levels were negatively correlated with the serum osteopontin and autotaxin levels and, positively with serum ApoM levels. CONCLUSION: ApoD is an anti-inflammatory apolipoprotein, which modulates lipid mediators and osteopontin in an anti-inflammatory direction.

New Senolysis Approach via Antibody-Drug Conjugate Targeting of the Senescent Cell Marker Apolipoprotein D for Skin Rejuvenation.

Senescent cells accumulate in aging skin, causing age-related changes and a decline in functional efficiency. Therefore, senolysis, a treatment that specifically removes senescent cells and rejuvenates the skin, should be explored. We targeted apolipoprotein D (ApoD), a previously identified marker expressed on senescent dermal fibroblasts, and investigated a novel senolysis approach using a monoclonal antibody against this antigen and a secondary antibody conjugated with the cytotoxic drug pyrrolobenzodiazepine. Observations using fluorescently labeled antibodies revealed that ApoD functions as a surface marker of senescent cells and that the antibody is taken up and internalized only by such cells. The concurrent administration of the antibody with the PBD-conjugated secondary antibody specifically eliminated only senescent cells without harming young cells. The antibody-drug conjugate treatment of aging mice combined with the administration of antibodies reduced the number of senescent cells in the dermis of mice and improved the senescent skin phenotype. These results provide a proof-of-principle evaluation of a novel approach to specifically eliminate senescent cells using antibody-drug conjugates against senescent cell marker proteins. This approach is a potential candidate for clinical applications to treat pathological skin aging and related diseases via the removal of senescent cells.

Apolipoprotein D and transthyretin are reduced in female adolescent offspring of women with type 1 diabetes: The EPICOM study.

AIMS: Adolescent offspring exposed to maternal diabetes during intrauterine life show a less favourable metabolic profile than the background population. Here, we hypothesize that offspring of women with type 1 diabetes (T1D), possess sex-specific alterations in the serum profile of proteins involved in lipid, metabolic and transport processes and that these alterations are associated with lipid profile and indices of insulin sensitivity and secretion. METHODS: A prospective nationwide follow-up study (EPICOM) in a Danish population. Blood samples were assessed from offspring of women with T1D (index offspring, n = 267, 13-20 years), and matched control offspring (n = 290). Serum proteins were analysed using a 25-plex cardio-metabolic targeted proteomics assay, which includes 12 apolipoproteins and 13 transport and inflammatory proteins. RESULTS: Apolipoprotein D (ApoD) and transthyretin (TTR) were reduced in index females as compared to female controls (-8.1%, p < 0.001 and -6.1%, p = 0.006 respectively), but not in index males (2.2%, p = 0.476 and -2.4%, p = 0.731 respectively). Sex-dependent inverse associations between exposure to maternal T1D in utero and ApoD and TTR were significant after adjusting for age, BMI-SDS and Tanner stage (OR = 0.252 [95% CI 0.085, 0.745], p = 0.013 and OR = 0.149 [95% CI 0.040, 0.553], p = 0.004). ApoD correlated to indices of insulin sensitivity and secretion in a similar sex-specific pattern in crude and adjusted analyses. CONCLUSIONS: Low ApoD may be regarded as an early risk marker of metabolic syndrome. A possible link between ApoD and cardiovascular disease needs further investigation.

Cerebral Apolipoprotein D Exits the Brain and Accumulates in Peripheral Tissues.

Apolipoprotein D (ApoD) is a secreted lipocalin associated with neuroprotection and lipid metabolism. In rodent, the bulk of its expression occurs in the central nervous system. Despite this, ApoD has profound effects in peripheral tissues, indicating that neural ApoD may reach peripheral organs. We endeavor to determine if cerebral ApoD can reach the circulation and accumulate in peripheral tissues. Three hours was necessary for over 40% of all the radiolabeled human ApoD (hApoD), injected bilaterally, to exit the central nervous system (CNS). Once in circulation, hApoD accumulates mostly in the kidneys/urine, liver, and muscles. Accumulation specificity of hApoD in these tissues was strongly correlated with the expression of lowly glycosylated basigin (BSG, CD147). hApoD was observed to pass through bEnd.3 blood brain barrier endothelial cells monolayers. However, cyclophilin A did not impact hApoD internalization rates in bEnd.3, indicating that ApoD exit from the brain is either independent of BSG or relies on additional cell types. Overall, our data showed that ApoD can quickly and efficiently exit the CNS and reach the liver and kidneys/urine, organs linked to the recycling and excretion of lipids and toxins. This indicated that cerebral overexpression during neurodegenerative episodes may serve to evacuate neurotoxic ApoD ligands from the CNS.

Apolipoprotein D in Lepidoptera: Evolution and functional divergence.

Apolipoprotein D (ApoD) plays important roles in response to injury, cell differentiation, lifespan extension, and increasing stress resistance. However, the evolutionary mechanism of ApoD in insects remains largely unelucidated. We conducted a comprehensive study of the molecular evolution and functional divergence of ApoD in insects. A type I functional divergence analysis revealed significant differences among insect ApoD homologs, suggesting that they underwent functional divergence. We demonstrated that lepidopteran insects have three genes that are close homologs to ApoD and show divergences in sequence, expression pattern, and protein-protein interaction. Furthermore, positive selection was detected in lepidopteran ApoD2, and positively selected sites were located around the pocket and loop domains, which might result in conformational changes and affect binding properties. Moreover, we showed that the three ApoDs in Bombyx mori were significantly regulated by environmental stress. Thus, this work illustrates the dialectical relationship between genetic diversity and functional conservation of ApoD and highlights its unique functions in the stress response of Lepidoptera.

Apolipoprotein D: a potential biomarker for cerebral amyloid angiopathy.

AIMS: We investigated the potential of apolipoprotein D (apoD) as cerebrospinal fluid (CSF) biomarker for cerebral amyloid angiopathy (CAA) after confirmation of its association with CAA pathology in human brain tissue. METHODS: The association of apoD with CAA pathology was analysed in human occipital lobe tissue of CAA (n = 9), Alzheimer's disease (AD) (n = 11) and healthy control cases (n = 11). ApoD levels were quantified in an age- and sex-matched CSF cohort of CAA patients (n = 31), AD patients (n = 27) and non-neurological controls (n = 67). The effects of confounding factors (age, sex, serum levels) on apoD levels were studied using CSF of non-neurological controls (age range 16-85 years), and paired CSF and serum samples. RESULTS: ApoD was strongly associated with amyloid deposits in vessels, but not with parenchymal plaques in human brain tissue. CSF apoD levels correlated with age and were higher in men than women in subjects >50 years. The apoD CSF/serum ratio correlated with the albumin ratio. When controlling for confounding factors, CSF apoD levels were significantly lower in CAA patients compared with controls and compared with AD patients (P = 0.0008). CONCLUSIONS: Our data show that apoD is specifically associated with CAA pathology and may be a CSF biomarker for CAA, but clinical application is complicated due to dependency on age, sex and blood-CSF barrier integrity. Well-controlled follow-up studies are required to determine whether apoD can be used as reliable biomarker for CAA.

Elevated levels of tumour apolipoprotein D independently predict poor outcome in breast cancer patients.

AIMS: Apolipoprotein D (ApoD) is a protein that is regulated by androgen and oestrogen, and is a major constituent of breast cysts. Although ApoD has been reported to be a marker of breast cancer, its prognostic importance in invasive breast cancer is unclear. The aim of this study was to investigate the relationship between ApoD protein expression, oestrogen receptor-α (ERα) expression and androgen receptor (AR) expression in predicting breast cancer outcome. METHODS AND RESULTS: ApoD levels were measured by the use of immunohistochemistry and video image analysis on tissue sections from a breast cancer cohort (n = 214). We assessed the associations of ApoD expression with disease-free survival (DFS), metastasis-free survival (MFS), and overall survival (OS). We also assessed the relationship between ApoD expression, AR expression and ERα expression in predicting OS. ApoD expression (>1% ApoD positivity) was found in 72% (154/214) of tissues. High ApoD positivity (≥20.7%, fourth quartile) was an independent predictor of MFS and OS, and conferred a 2.2-fold increased risk of developing metastatic disease and a 2.1-fold increased risk of breast cancer-related death. ApoD positivity was not associated with AR or ERα nuclear positivity. However, patients with (≥1%) ERα-positive cancers with low (<20.7%) ApoD positivity, or those showing high (≥78%) AR positivity and low (<20.7%) ApoD positivity had better OS than other patient groups. CONCLUSIONS: ApoD expression could be used to predict breast cancer prognosis independently of ERα and AR expression.

Enrichment of apolipoprotein A-IV and apolipoprotein D in the HDL proteome is associated with HDL functions in diabetic kidney disease without dialysis.

BACKGROUND AND AIMS: Diabetic kidney disease (DKD) is associated with lipid derangements that worsen kidney function and enhance cardiovascular (CVD) risk. The management of dyslipidemia, hypertension and other traditional risk factors does not completely prevent CVD complications, bringing up the participation of nontraditional risk factors such as advanced glycation end products (AGEs), carbamoylation and changes in the HDL proteome and functionality. The HDL composition, proteome, chemical modification and functionality were analyzed in nondialysis subjects with DKD categorized according to the estimated glomerular filtration rate (eGFR) and urinary albumin excretion rate (AER). METHODS: Individuals with DKD were divided into eGFR> 60 mL/min/1.73 m2 plus AER stages A1 and A2 (n = 10) and eGFR< 60 plus A3 (n = 25) and matched by age with control subjects (eGFR> 60; n = 8). RESULTS: Targeted proteomic analyses quantified 28 proteins associated with HDL in all groups, although only 2 were more highly expressed in the eGFR< 60 + A3 group than in the controls: apolipoprotein D (apoD) and apoA-IV. HDL from the eGFR< 60 + A3 group presented higher levels of total AGEs (20%), pentosidine (6.3%) and carbamoylation (4.2 x) and a reduced ability to remove 14C-cholesterol from macrophages (33%) in comparison to HDL from controls. The antioxidant role of HDL (lag time for LDL oxidation) was similar among groups, but HDL from the eGFR< 60 + A3 group presented a greater ability to inhibit the secretion of IL-6 and TNF-alpha (95%) in LPS-elicited macrophages in comparison to the control group. CONCLUSION: The increase in apoD and apoA-IV could contribute to counteracting the HDL chemical modification by AGEs and carbamoylation, which contributes to HDL loss of function in well-established DKD.

Percutaneous Interstitial Nd:YAG Laser Therapy for Axillary Osmidrosis.

BACKGROUND AND OBJECTIVES: To investigate the effects of percutaneous interstitial Nd:YAG laser irradiation on the apocrine glands and molecules involved in odor production (apolipoprotein [ApoD], androgen receptor [AR]) in the subcutaneous tissue of a pig. STUDY DESIGN/MATERIALS AND METHODS: Skin on the back of healthy adult miniature pigs was exposed to pulsed Nd:YAG laser irradiation at 5 or 10 W, or continuous Nd:YAG laser irradiation at 10 W. Samples were taken 1 hour, 1 week, and 1 month after treatment for histology, western blot, and real-time quantitative polymerase chain reaction (qRT-PCR) analysis. RESULTS: One week and 1 month after irradiation, the apocrine glands in pigskin became rounded, glandular cells were shorter, and the glandular cavities were larger compared with controls, but there were no obvious changes in fat cell distribution of collagen around the apocrine glands. One month after irradiation at 10 W in continuous mode, there was a significant decrease in ApoD expression in apocrine cells and ApoD and AR protein and expression levels in pigskin compared with controls. There were also significant differences in ApoD and AR protein and expression levels between treatments. CONCLUSIONS: Percutaneous interstitial Nd:YAG laser irradiation has potential as a safe and efficacious treatment for axillary osmidrosis as it may decrease the production of volatile unsaturated fatty acids, steroids, and associated unpleasant odors in the axilla. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.

Cluster expansion of apolipoprotein D (ApoD) genes in teleost fishes.

BACKGROUND: Gene and genome duplication play important roles in the evolution of gene function. Compared to individual duplicated genes, gene clusters attract particular attention considering their frequent associations with innovation and adaptation. Here, we report for the first time the expansion of the apolipoprotein D (ApoD) ligand-transporter genes in a cluster manner specific to teleost fishes. RESULTS: Based on comparative genomic and transcriptomic analyses, protein 3D structure comparison, positive selection detection and breakpoints detection, the single ApoD gene in the ancestor expanded into two clusters following a dynamic evolutionary pattern in teleost fishes. Orthologous genes show conserved expression patterns, whereas lineage-specific duplicated genes show tissue-specific expression patterns and even evolve new gene expression profiles. Positive selection occurred in branches before and after gene duplication, especially for lineage-specific duplicated genes. Cluster analyses based on protein 3D structure comparisons, especially comparisons of the four loops at the opening side, show gene duplication-segregating patterns. Duplicated ApoD genes are predicted to be associated with forkhead transcription factors and MAPK genes. ApoD clusters are located next to the breakpoints of genome rearrangements. CONCLUSIONS: Here, we report the expansion of ApoD genes specific to teleost fishes in a cluster manner for the first time. Neofunctionalization and subfunctionalization were observed at both the protein and expression levels after duplication. Evidence from different aspects-i.e., abnormal expression-induced disease in humans, fish-specific expansion, predicted associations with forkhead transcription factors and MAPK genes, specific expression patterns in tissues related to sexual selection and adaptation, duplicated genes under positive selection and their location next to the breakpoints of genome rearrangements-suggests the potentially advantageous roles of ApoD genes in teleost fishes. The cluster expansion of ApoD genes specific to teleost fishes provides thus an ideal evo-devo model for studying gene duplication, cluster maintenance and new gene function emergence.

Dihydrotestosterone induces minor transcriptional alterations in genital skin fibroblasts of children with and without androgen insensitivity.

Endogenous and exogenous androgens induce masculinization of external genitalia through binding to the androgen receptor (AR). The target genes of androgens in external genitalia remain to be determined, although previous studies have shown that the apolipoprotein D gene (APOD) was significantly upregulated by dihydrotestosterone (DHT), the most potent androgen in humans. In the present study, we performed microarray analysis for genital skin fibroblasts obtained from four boys with buried penis (the control individuals) and a patient with partial androgen insensitivity syndrome (PAIS) due to a hypomorphic mutation in AR (the PAIS patient). We identified 24 transcripts that were upregulated or downregulated by DHT in all samples of control individuals and, to a lesser extent, in the sample of the PAIS patient. Differences between DHT-treated and -untreated samples were small; the results of 24 transcripts did not reach statistical significance. The 24 transcripts included CYP1B1, a gene possibly involved in the development of genital tubercle in mice, and APOD, as well as several genes that have been reported as androgen targets in prostate or other tissues. The results of this study indicate that androgen-mediated masculinization of external genitalia is unlikely to depend on massive transcriptional changes in specific AR target genes. Rather, minor transcriptional changes of several genes, and/or a complex molecular network may play a major role in penile development. Importantly, our data suggest the possible involvement of CYP1B1 in human genital development and confirm the clinical importance of APOD as a biomarker for AR function.

Secreted glycoprotein BmApoD1 plays a critical role in anti-oxidation and anti-apoptosis in Bombyx mori.

Recent studies highlighted that apolipoprotein D (ApoD) and its homologs exert neuroprotective and antioxidant functions in mammals and Drosophila. Unlike mammals and Drosophila, lepidopteran insects possess three distinct ApoD homologs. However, few information on their functions in lepidopteran insects are available. In this study, we investigated the protective potential of a novel ApoD homolog, BmApoD1, in Bombyx mori. Quantitative PCR analyses demonstrated that BmApoD1 is extensively expressed at low levels during the larval stage but abundantly expressed in the testis during the pupal and adult stages. Tryptophan fluorescence titration demonstrated that recombinant BmApoD1 protein can bind retinoic acid and ergosterol. In addition, we provided evidence that N-linked glycans of BmApoD1 are essential to BmApoD1 secretion, and three residues, namely, Asp69, Asp104, and Asp196, are the glycosylation sites of BmApoD1. Furthermore, we showed that BmApoD1 is significantly up-regulated in the larvae after oxidant or starvation treatment. The recombinant BmApoD1 protein can protect cells from oxidative stress induced by H2O2 and reduce actinomycin D-induced cell apoptosis. These observations, together with the transcriptional up-regulation of BmApoD1 in several tissues upon oxidative insult, identify BmApoD1 as a potent antioxidant. Our results demonstrate that BmApoD1 is critical for metabolic adaptation of B. mori to environmental challenges.

Apolipoprotein D Internalization Is a Basigin-dependent Mechanism.

Apolipoprotein D (apoD), a member of the lipocalin family, is a 29-kDa secreted glycoprotein that binds and transports small lipophilic molecules. Expressed in several tissues, apoD is up-regulated under different stress stimuli and in a variety of pathologies. Numerous studies have revealed that overexpression of apoD led to neuroprotection in various mouse models of acute stress and neurodegeneration. This multifunctional protein is internalized in several cells types, but the specific internalization mechanism remains unknown. In this study, we demonstrate that the internalization of apoD involves a specific cell surface receptor in 293T cells, identified as the transmembrane glycoprotein basigin (BSG, CD147); more particularly, its low glycosylated form. Our results show that internalized apoD colocalizes with BSG into vesicular compartments. Down-regulation of BSG disrupted the internalization of apoD in cells. In contrast, overexpression of basigin in SH-5YSY cells, which poorly express BSG, restored the uptake of apoD. Cyclophilin A, a known ligand of BSG, competitively reduced apoD internalization, confirming that BSG is a key player in the apoD internalization process. In summary, our results demonstrate that basigin is very likely the apoD receptor and provide additional clues on the mechanisms involved in apoD-mediated functions, including neuroprotection.

Production of a soluble and functional recombinant apolipoproteinD in the Pichia pastoris expression system.

ApolipoproteinD (ApoD) is a human glycoprotein from the lipocalin family. ApoD contains a conserved central motif of an 8-stranded antiparallel ß-sheet, which forms a beta-barrel that can be used for transport and storage of diverse hydrophobic ligands. Due to hydrophobic nature of ApoD, it has been difficult to generate a recombinant version of this protein. In the present work, we aimed at the production of ApoD in the robust Pichia pastoris expression system. To this end, the ApoD gene sequence was synthesized and subcloned for expression in the yeast host cells. Following integration of the ApoD gene into the yeast genomic region using homologous recombination, the ApoD recombinant protein was induced using methanol, reaching its maximum induction at 96 h. Having purified the ApoD recombinant protein by affinity chromatography, we measured the dissociation constant (KD) using its natural ligands: progesterone and arachidonic acid. Our results provide a viable solution to the production of recombinant ApoD protein in lieu of previous obstacles in generating soluble and functional ApoD protein.

The most valuable predictorsof endometrial receptivity.

OBJECTIVE: To investigate the predictive factors of insufficient endometrial quality. DESIGN: Review. SETTING: Department of Obstetrics and Gynecology, General Faculty Hospital Prague, 1st Faculty of Medicine, Charles University. RESULTS: This is the review on predictive factors of endometrial receptivity. There is a collected data on homeobox genes family, especially HOX 10 and HOX 11 members, that ensure implantation process by means of their interaction with estrogen and progesterone receptors via stimulatory proteins in the luminal epithelium in different periods of luteal phase. Moreover, the article describes appropriate secretion of osteoponin, cadherin, selectin, apopoliprotein D, mucin and balanced macrophage activity in endometrial epithelium in the proliferative phase of the menstrual cycle provide optimal conditions for implantation. CONCLUSION: Endometrial genes expressions along with the intrauterine environment macrophages activity maintain the tiny mechanism of endometrial receptivity.

The evolution and functional divergence of 10 Apolipoprotein D-like genes in Nilaparvata lugens.

Apolipoprotein D (ApoD), a member of the lipocalin superfamily of proteins, is involved in lipid transport and stress resistance. Whereas only a single copy of the ApoD gene is found in humans and some other vertebrates, there are typically several ApoD-like genes in insects. To date, there have been relatively few studies that have examined the evolution and functional differentiation of ApoD-like genes in insects, particularly hemi-metabolous insects. In this study, we identified 10 ApoD-like genes (NlApoD1-10) with distinct spatiotemporal expression patterns in Nilaparvata lugens (BPH), which is an important pest of rice. NlApoD1-10 were found to be distributed on 3 chromosomes in a tandem array of NlApoD1/2, NlApoD3-5, and NlApoD7/8, and show sequence and gene structural divergence in the coding regions, indicating that multiple gene duplication events occurred during evolution. Phylogenetic analysis revealed that NlApoD1-10 can be clustered into 5 clades, with NlApoD3-5 and NlApoD7/8 potentially evolving exclusively in the Delphacidae family. Functional screening using an RNA interference approach revealed that only NlApoD2 was essential for BPH development and survival, whereas NlApoD4/5 are highly expressed in testes, and might play roles in reproduction. Moreover, stress response analysis revealed that NlApoD3-5/9, NlApoD3-5, and NlApoD9 were up-regulated after treatment with lipopolysaccharide, H2 O2 , and ultraviolet-C, respectively, indicating their potential roles in stress resistance.

Apolipoprotein D facilitates rabies virus propagation by interacting with G protein and upregulating cholesterol.

Rabies virus (RABV) causes a fatal neurological disease, consisting of unsegmented negative-strand RNA, which encodes five structural proteins (3'-N-P-M-G-L-5'). Apolipoprotein D (ApoD), a lipocalin, is upregulated in the nervous system after injury or pathological changes. Few studies have focused on the role of ApoD during virus infection so far. This study demonstrated that ApoD is upregulated in the mouse brain (in vivo) and C8-D1A cells (in vitro) after RABV infection. By upregulating ApoD expression in C8-D1A cells, we found that ApoD facilitated RABV replication. Additionally, Co-immunoprecipitation demonstrated that ApoD interacted with RABV glycoprotein (G protein). The interaction could promote RABV replication by upregulating the cholesterol level. These findings revealed a novel role of ApoD in promoting RABV replication and provided a potential therapeutic target for rabies.

Chondroprotective effects of Apolipoprotein D in knee osteoarthritis mice through the PI3K/AKT/mTOR signaling pathway.

BACKGROUND: Because the pathophysiology of osteoarthritis (OA) has not been fully elucidated, targeted treatments are lacking. In this study, we assessed the role and underlying mechanism apolipoprotein D (APOD) on the development of OA. METHODS: To establish an in vitro OA model, we extracted primary chondrocytes from the cartilage of C57BL/6 mice and stimulated the chondrocytes with IL-1ß. After APOD intervention or incubation with an overexpressing plasmid, we detected inflammatory-related markers using RT-qPCR, Western blotting, and ELISA. To detect apoptosis and autophagy-related markers, we used flow cytometry, immunofluorescence, and transmission electron microscopy (TEM). Finally, we measured the level of oxidative stress. We also used RNA-seq to identify the APOD-regulated downstream signaling pathways. We used an in vivo mice OA model of the anterior cruciate ligament transection (ACLT) and administered intra-articular adenovirus overexpressing APOD. To examine cartilage damage severity, we used immunohistochemical analysis (IHC), micro-CT, scanning electron microscopy (SEM), and Safranin O-fast green staining. RESULTS: Our results showed that APOD inhibited chondrocyte inflammation, degeneration, and apoptosis induced by IL-1ß. Additionally, APOD reversed autophagy inhibition and oxidative stress and also blocked activation of the PI3K/AKT/mTOR signaling pathway induced by IL-1ß. Finally, overexpression of the APOD gene through adenovirus was sufficient to mitigate OA progression. CONCLUSIONS: Our findings revealed that APOD had a chondroprotective role in OA progression by the PI3K/AKT/mTOR signaling pathway.

Plasma Concentrations of High Mobility Group Box 1 Proteins and Soluble Receptors for Advanced Glycation End-Products Are Relevant Biomarkers of Cognitive Impairment in Alcohol Use Disorder: A Pilot Study.

Alcohol use disorder (AUD) is a major component in the etiology of cognitive decline and dementia. Underlying mechanisms by which long-term alcohol abuse causes cognitive dysfunction include excessive oxidative stress and inflammation in the brain, activated by increased reactive oxygen/nitrogen species (ROS/RNS), advanced glycation end-products (AGEs) and high-mobility group box 1 protein (HMGB1). In a pilot study, we examine the potential clinical value of circulating biomarkers of oxidative stress including ROS/RNS, HMGB1, the soluble receptor for AGE (sRAGE), the brain biomarker of aging apolipoprotein D (ApoD), and the antioxidant regulator nuclear factor erythroid 2-related factor 2 (NRF2) as predictive indices for cognitive impairment (CI) in abstinent patients with AUD (n = 25) compared to patients with established Alzheimer's disease (AD, n = 26) and control subjects (n = 25). Plasma concentrations of sRAGE were evaluated with immunoblotting; ROS/RNS with a fluorometric kit; and HMGB1, ApoD, and NRF2 by ELISA. Abstinent AUD patients had higher sRAGE, ROS/RNS (p < 0.05), and ApoD (p < 0.01) concentrations, similar to those of AD patients, and lower NRF2 (p < 0.01) concentrations, compared to controls. These changes were remarkable in AUD patients with CI. HMGB1, and sRAGE correlated positively with duration of alcohol use (rho = 0.398, p = 0.022; rho = 0.404, p = 0.018), whereas sRAGE correlated negatively with periods of alcohol abstinence (rho = -0.340, p = 0.045). A predictive model including ROS/RNS, HMGB1, sRAGE, alcohol use duration, and alcohol abstinence periods was able to differentiate AUD patients with CI (92.3% of correct predictions, ROC-AUC= 0.90) from those without CI. In conclusion, we propose ROS/RNS, HMGB1, and sRAGE as stress biomarkers capable of predicting cognitive impairment in AUD patients.

Contactin 5 and Apolipoproteins Interplay in Alzheimer's Disease.

Background: Apolipoproteins and contactin 5 are proteins associated with Alzheimer's disease (AD) pathophysiology. Apolipoproteins act on transport and clearance of cholesterol and phospholipids during synaptic turnover and terminal proliferation. Contactin 5 is a neuronal membrane protein involved in key processes of neurodevelopment. Objective: To investigate the interactions between contactin 5 and apolipoproteins in AD, and the role of these proteins in response to neuronal damage. Methods: Apolipoproteins (measured by Luminex), contactin 5 (measured by Olink's proximity extension assay), and cholesterol (measured by liquid chromatography mass spectrometry) were assessed in the cerebrospinal fluid (CSF) and plasma of cognitively unimpaired participants (n = 93). Gene expression was measured using polymerase chain reaction in the frontal cortex of autopsied-confirmed AD (n = 57) and control subjects (n = 31) and in the hippocampi of mice following entorhinal cortex lesions. Results: Contactin 5 positively correlated with apolipoproteins B (p = 5.4×10-8), D (p = 1.86×10-4), E (p = 2.92×10-9), J (p = 2.65×10-9), and with cholesterol (p = 0.0096) in the CSF, and with cholesterol (p = 0.02), HDL (p = 0.0143), and LDL (p = 0.0121) in the plasma. Negative correlations were seen between CNTN5, APOB (p = 0.034) and APOE (p = 0.015) mRNA levels in the brains of control subjects. In the mouse model, apoe and apoj gene expression increased during the reinnervation phase (p <  0.05), while apob (p = 0.023) and apod (p = 0.006) increased in the deafferentation stage. Conclusions: Extensive interactions were observed between contactin 5 and apolipoproteins and cholesterol, possibly due to neuronal damage. The alterations in gene expression of apolipoproteins suggest a role in axonal, terminal, and synaptic remodeling in response to entorhinal cortex damage.