Adipocyte Fatty Acid-binding Protein Research Articles

FABP4 Enhances Lipidic and Fibrotic Cardiac Structural and Ca2+ Dynamic Changes.

Adipocyte FABP4 (fatty acid-binding protein 4) is augmented in the epicardial stroma of patients with long-standing persistent atrial fibrillation. Because this molecule is released mainly by adipocytes, our objective was to study its role in atrial cardiomyopathy, focusing our attention on fibrosis, metabolism, and electrophysiological changes. These results might clarify the role of adiposity as a mediator of atrial cardiomyopathy. We used several preclinical cellular models, epicardial and subcutaneous stroma primary cell cultures from patients undergoing open heart surgery, human atrial fibroblasts, atrial cardiomyocytes derived from human induced pluripotent stem cells and isolated from adult mice, and Nav1.5 transfected Chinese hamster ovary cells. Fibrosis, glucose, mitochondrial and adipogenesis activity, gene expression, and proteomics were determined by wound healing, enzymatic, colorimetric, fluorescence assays, real-time quantitative polymerase chain reaction, and TripleTOF proteomics. Molecular changes were analyzed by Raman confocal microspectroscopy, calcium dynamics by confocal microscopy, and ion currents by patch clamp. Epicardial, subcutaneous, and atrial fibroblasts and cardiomyocytes were incubated with FABP4 at 100 ng/mL. Our results showed that FABP4 induced fibrosis, glucose metabolism, and lipid accumulation on epicardial and subcutaneous stroma cells and atrial fibroblasts. Besides, it modified lipid content and calcium dynamics in atrial cardiomyocytes without effects on INa. FABP4 exerts fibrotic and metabolic changes on epicardial stroma and modifies lipid content and calcium dynamic on atrial cardiomyocytes. These results suggest its possible role as an atrial cardiomyopathy mediator.

The association of initial and changes in serum A-FABP level with the development and improvement of pre-sarcopenia.

Several cross-sectional studies have reported the association between serum adipocyte fatty acid binding protein (A-FABP) level and pre-sarcopenia. However, data on the impacts of serum A-FABP level and its changes over time on the development and improvement of pre-sarcopenia are scarce. This longitudinal cohort study included 1496 adults (41.2% men; median age, 58 [53-63] years) in 2013-2014 and was followed up to 2015-2016. Participants underwent serum A-FABP level measurements at baseline and follow-up visit. Visceral fat area (VFA) was measured using magnetic resonance imaging. Skeletal muscle mass (SMM) was estimated by bioelectrical impedance analysis and converted to skeletal muscle index (SMI). Pre-sarcopenia was defined as SMI < 1 standard deviation of the sex-specific mean for the young reference group. During an average follow-up period of 2.1 years, baseline serum A-FABP level was positively associated with the incidence of pre-sarcopenia (standardized by weight: risk ratio [RR] 3.22, 95% confidence interval [CI] 1.96-5.38; standardized by VFA: RR 2.11, 95%CI 1.29-3.51) and negatively associated with the improvement of pre-sarcopenia (standardized by weight: RR 0.66, 95%CI 0.45-0.97; standardized by VFA: RR 0.71, 95%CI 0.54-0.94), regardless of whether SMM was standardized by weight or VFA. Moreover, changes in serum A-FABP level provided additional information on the incidence and improvement of pre-sarcopenia, independent of baseline serum A-FABP level (all P < 0.05). Baseline serum A-FABP level and its changes were positively associated with the incidence, and negatively associated with the improvement of pre-sarcopenia.

Adipocyte fatty acid-binding protein (FABP4) as a potential biomarker for predicting metabolically driven low-grade and organ damage in thalassemia syndromes

Adipocyte fatty acid-binding protein (A-FABP; FABP4) plays a significant role in the pathogenesis and progression of metabolically driven low-grade inflammation and organ damage. This study aimed to evaluate the performance of circulating FABP4 as a predictive and diagnostic biomarker for thalassemia-associated cardiometabolic events. This case-control study enrolled 50 adults with β-thalassemia and 30 age-, sex-, and body mass index-matched controls. Participants underwent a comprehensive evaluation, including complete blood count, liver and kidney function tests, serum blood glucose, lipid profile, and ferritin levels, pelviabdominal ultrasound, ECG, and echocardiography after taking a full medical history and conducting a clinical examination. Serum levels of FABP4 were measured using an Enzyme-Linked-Immunosorbent-Assay. The diagnostic performance of FABP4 was assessed using receiver operator characteristic (ROC) curve analysis to determine optimal values for excluding and confirming cardiometabolic metflammation. The thalassemia cohort exhibited a statistically significant higher concentration of FABP4 compared to the control group (p-value < 0.001). Positive correlations were found between FABP4 and ferritin serum levels above 800 or 1000 ug/L, as well as with ALT, TGS, and LDL (p-value < 0.05). Circulating FABP4 was identified as a statistically significant risk factor for thalassemia-associated cardiometabolic comorbidities (OR = 84.00, 95%CI:18.6–378.6, p-value < 0.001). ROC analysis determined that the FABP4 exclusionary cut-off value > 2.30 ng/ml could effectively discriminate between thalassemia-associated adverse metaflammation and controls, while the FABP4 confirmatory cut-off value was > 2.58 ng/ml. In conclusion, circulating FABP4 appears to be a potential risk factor for predicting progression to cardiometabolic events in thalassemia-associated adverse metaflammation. FABP4 holds promise as a diagnostic and prognostic biomarker for disease monitoring and risk stratification. Further validation through large-scale, multicenter, prospective studies is warranted.

Concomitant decrease of E- and A-FABP expression predicts worse survival in urothelial bladder cancer patients

Non-muscle invasive bladder cancers (NMIBC) pTa-pT1 are depicted by a high risk of recurrence and/or progression with an unpredictable clinical evolution. Our aim was to identify, from the original resection specimen, tumors that will progress to better manage patients. We previously showed that A-FABP (Adipocyte- Fatty Acid Binding Protein) loss predicted NMIBC progression. Here we determined by immunohistochemistry the prognostic value of E-FABP (Epidermal-Fatty Acid Binding Protein) expression in 210 tumors (80 pTa, 75 pT1, 55 pT2-T4). Thus, E-FABP low expression was correlated with a high grade/stage, the presence of metastatic lymph nodes, and visceral metastases (p < 0.001). Unlike A-FABP in NMIBC, E-FABP low expression was not associated with RFS or PFS in Kaplan–Meier analysis. But patients of the overall cohort with a high E-FABP expression had a longer mOS (53.8 months vs. 29.3 months, p = 0.029). The immunohistochemical analysis on the same NMIBC tissue sections revealed that when A-FABP is absent, a high E-FABP expression is detected. E-FABP could compensate A-FABP loss. Interestingly, patients, whose original tumor presents both low E-FABP and negative A-FABP, had the worse survival, those maintaining the expression of both markers had better survival. To conclude, the combined evaluation of A- and E-FABP expression allowed to stratify patients with urothelial carcinoma for optimizing treatment and follow-up.

Association of selected adipokines with vitamin D deficiency in children with inflammatory bowel disease

BackgroundAdipose tissue is significantly involved in inflammatory bowel disease (IBD). Vitamin D can affect both adipogenesis and inflammation. The aim of this study was to compare the production of selected adipokines, potentially involved in the pathogenesis of IBD - adiponectin, resistin, retinol binding protein 4 (RBP-4), adipocyte fatty acid binding protein and nesfatin-1 in children with IBD according to the presence of 25-hydroxyvitamin D (25(OH)D) deficiency.MethodsThe study was conducted as a case-control study in pediatric patients with IBD and healthy children of the same sex and age. In addition to adipokines and 25(OH)D, anthropometric parameters, markers of inflammation and disease activity were assessed in all participants.ResultsChildren with IBD had significantly higher resistin levels regardless of 25(OH)D levels. IBD patients with 25(OH)D deficiency only had significantly lower RBP-4 compared to healthy controls and also compared to IBD patients without 25(OH)D deficiency. No other significant differences in adipokines were found in children with IBD with or without 25(OH)D deficiency. 25(OH)D levels in IBD patients corelated with RBP-4 only, and did not correlate with other adipokines.ConclusionsWhether the lower RBP-4 levels in the 25(OH)D-deficient group of IBD patients directly reflect vitamin D deficiency remains uncertain. The production of other adipokines does not appear to be directly related to vitamin D deficiency.

Serum adipocyte fatty acid binding protein (AFABP) level in different trimesters of gestational diabetes mellitus

Serum adipocyte fatty acid binding protein (AFABP) level in different trimesters of gestational diabetes mellitus

Meat Characteristics, Expression of Myosin Heavy Chain and Metabolism-Related Genes in Thai Native Pigs.

This study investigated the meat quality, expression of myosin heavy chain (MyHC) and metabolism-related genes, ribonucleotides and fatty acids in Longissimus thoracis of Thai native pigs (TNPs) from different geographical regions (GR). Forty-one 9-10-month-old castrated TNPs (BW 60 kg), consisting of 18, 11 and 12 pigs from Northern (NT), Southern (ST) and Northeastern (NE) regions, respectively, were slaughtered. GR did not affect (p > 0.05) the expression of MyHC, phosphoglycerate mutase 1, cytosolic glycerol-3-phosphate dehydrogenase, triosephosphate isomerase 1 and adipocyte fatty acid binding protein genes. The trend of MyHC was MyHC IIx > MyHC IIb > MyHC IIa > MyHC I. The NT loin had higher (p < 0.05) glycogen, C18:2n6, C20:4n6 and cooking loss, lower inosine, inosine monophosphate and hypoxanthine and a shorter sarcomere length than the ST and NE loins. The ST loin had a lower (p < 0.05) a* compared to other loins. Principal component analysis established significant relationships between the TNP and specific meat quality traits. This finding suggests that GR affected the meat quality, ribonucleotides and selected fatty acids in TNPs. These results provide relevant information that can be used to optimize the use of Thai native pork.

The tandem of Fibroblast Growth Factor (FGF21) and Adipocyte Fatty Acid Binding Protein (A-FABP) as a physiological macronutrient signal to prevent insulin resistance

The tandem of Fibroblast Growth Factor (FGF21) and Adipocyte Fatty Acid Binding Protein (A-FABP) as a physiological macronutrient signal to prevent insulin resistance

A-FABP and E-FABP as cutaneous biomarkers of Metabolic Syndrome

Introduction: In Metabolic syndrome (MetS), tissues such as adipose, liver, and skin with very active lipid metabolism are dysfunctional, making it diffcult to store the excess fat. Fatty acid binding proteins (FABPs) are cytosolic proteins that can reversibly bind to lipids and transport them to different cell organelles. In this work, we focus on adipocyte (A-FABP) and epidermal (E-FABP) FABPs, which have been proposed as potential biomarkers of MetS due to their different tissue expression patterns. When MetS impacts the skin, the integrity of the barrier is affected, such as changes in the structure and function of collagen fibers, changes in microcirculation and macrocirculation, damage to lymphatic vessels, diffculty in wound healing, increased production of sebum and sweat. All those changes seem to depend on the abnormal function of lipids and FABPs. In MetS, E-FABP and A-FABP increase significantly in serum and probably in the skin in order to facilitate lipid transport. For this reason, they can be considered a molecular sensors of the inflammation induced in the skin by MetS. Objective: Analyze the concentrations of A-FABP and E-FABP in the skin of a MetS model to determine their value as biomarkers. Methods: We used a Wistar rat model (N=32) of MetS with a 41% extra fat diet during 8, 18, 28, and 52 weeks. The protocol was approved by the "Internal Committee for the Care and Use of Laboratory Animals of the Faculty of Medicine of the Autonomous University of San Luis Potosí" (assigned code: BGFMUASLP -07-19). At the end of every period of time (8, 18, etc) a biopsy of the skin (1 cm2) was took and cleaned from connective and subcutaneous adipose tissue. For Western Blot (WB) experiments the protein extraction was performed using cell lysis and homogenization, and 50 μg of protein of each sample was used. The WB was performed following the supplier's specifications and the standardized protocol in our laboratory. The primary antibodies used for incubation were rat A-FABP antibody (R&amp;D Systems, AF1443) and rat E-FABP antibody (R&amp;D Systems, AF1476). The secondary antibody was Goat IgG HRP-conjugated Antibody (R&amp;D Systems, HAF017). As a control gene, GAPDH reconstituted as indicated by the supplier. Bands were visualized using chemiluminescent detection, and their density in each group was analyzed using ImageJ software. Results: animals developed MetS after being 28 weeks in high fat diet showing excess of abdominal fat, hypertension, high triglycerides, and low cholesterol-HDL. At 52 weeks, we observed an increase in total cholesterol and in the severity of the blood lipids mentioned. Also, 40% of the animals showed visible skin lesions characterized by redness, eruptions, scratching marks, and wounds that do not heal, mainly in the cervical region, suggesting an inflammatory process. A-FABP expression was increased in MetS rats at 8 and 18 weeks and remained high at 28 and 52 weeks, although the increase was not significant. On the other hand E-FABP expression increased in MetS rats from week 18 and 28 but decreasing at 52. It suggests a greater presence of the protein and a probable participation of it in the inflammatory processes and skin lesions observed. Conclusions: E-FABP and A-FABP, increase significantly in the skin of MetS rats, mainly in the in the initial stages of MetS. E-FABP can considered a molecular sensor of skin inflammation induced by obesity. We also observed the presence of A-FABP in the skin, probably from subcutaneous adipose tissue. We propose the feasibility of both FABPs as early markers of MetS. This work has been supported by the National Council of Science and Technology (CONAHCYT) Project No. 320024. GE Donjuán-Loredo thanks CONAHCYT CVU 775467. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Anti-Obesity Effect of Lactobacillus acidophilus DS0079 (YBS1) by Inhibition of Adipocyte Differentiation through Regulation of p38 MAPK/PPARγ Signaling.

Obesity is spawned by an inequality between the portion of energy consumed and the quantity of energy expended. Disease entities such as cardiovascular disease, arteriosclerosis, hypertension, and cancer, which are correlated with obesity, influence society and the economy. Suppression of adipogenesis, the process of white adipocyte generation, remains a promising approach for treating obesity. Oil Red O staining was used to differentiate 3T3-L1 cells for screening 20 distinct Lactobacillus species. Among these, Lactobacillus acidophilus DS0079, referred to as YBS1, was selected for further study. YBS1 therapy decreased 3T3-L1 cell development. Triglyceride accumulation and mRNA expression of the primary adipogenic marker, peroxisome proliferator-activated receptor gamma (PPARγ), including its downstream target genes, adipocyte fatty acid binding protein 4 and adiponectin, were almost eliminated. YBS1 inhibited adipocyte differentiation at the early stage (days 0-2), but no significant difference was noted between the mid-stage (days 2-4) and late-stage (days 4-6) development. YBS1 stimulated the activation of p38 mitogen-activated protein kinase (p38 MAPK) during the early stages of adipogenesis; however, this effect was eliminated by the SB203580 inhibitor. The data showed that YBS1 administration inhibited the initial development of adipocytes via stimulation of the p38 MAPK signaling pathway, which in turn controlled PPARγ expression. In summary, YBS1 has potential efficacy as an anti-obesity supplement and requires further exploration.

Effects of mifepristone on adipocyte differentiation in mouse 3T3-L1 cells

BackgroundBoth glucocorticoid receptor and peroxisome proliferator-activated receptor-γ (PPARγ) play a critical role in adipocyte differentiation. Mifepristone is not only an antagonist of the glucocorticoid receptor but also an agonist of PPARγ. Therefore, the present study investigated the effect of mifepristone on adipocyte differentiation.MethodsMouse 3T3-L1 cells were used as a model for adipocyte differentiation. The lipid droplet formation was evaluated with Bodipy493/503 staining and the expression of adipocyte markers [adiponectin and adipocyte fatty acid binding protein-4 (Fabp4)] was evaluated with quantitative PCR and immunoblot analyses for indication of adipocyte differentiation. siRNA and neutralizing antibodies were used to elucidate the molecular mechanism of mifepristone-induced adipocyte differentiation. Luciferase reporter assay was used to examine the effect of mifepristone on the promoter activity of PPAR-response element (PPRE). The DNA microarray analysis was used to characterize the transcriptome of the mifepristone-induced adipocytes. In vivo adipogenic effect of mifepristone was examined in mice.ResultsMifepristone not only enhanced adipocyte differentiation induced by the conventional protocol consisting of insulin, dexamethasone and 3-isobutyl-1-methylxanthine but also induced adipocyte differentiation alone, as evidenced by lipid droplets formation and induction of the expression of adiponectin and Fabp4. These effects were inhibited by an adiponectin-neutralizing antibody and a PPARγ antagonist. Mifepristone activated the promoter activity of PPRE in a manner sensitive to PPARγ antagonist. A principal component analysis (PCA) of DNA microarray data revealed that the mifepristone-induced adipocytes represent some characteristics of the in situ adipocytes in normal adipose tissues to a greater extent than those induced by the conventional protocol. Mifepristone administration induced an increase in the weight of epididymal, perirenal and gluteofemoral adipose tissues.ConclusionsMifepristone alone is capable of inducing adipocyte differentiation in 3T3-L1 cells and adipogenesis in vivo. PPARγ plays a critical role in the mifepristone-induced adipocyte differentiation. Mifepristone-induced adipocytes are closer to the in situ adipocytes than those induced by the conventional protocol. The present study proposes a single treatment with mifepristone as a novel protocol to induce more physiologically relevant adipocytes in 3T3-L1 cells than the conventional protocol.

Abstract 5910: Developing a novel humanized anti-FABP4 antibody for breast cancer treatment

Abstract Circulating levels of adipocyte fatty acid binding protein (A-FABP, also known as FABP4) are linked with metabolic dysregulation. Our previous study demonstrated that high serum levels of FABP4 increased the risk of breast cancer, indicating that circulating FABP4 could be a potential therapeutic target for this disease. In this study, we generated mouse monoclonal antibodies (mAb) against FABP4 by immunizing C57BL/6 mice with recombinant human FABP4. After screening over 1300 hybridoma clones, we identified an FABP4 neutralizing mAb, named 12G2, which inhibited breast cancer growth in various mouse models. To facilitate clinical application, we engineered chimeric and humanized variants of the 12G2 mAb. Notably, the humanized variant, 12G2-variant 9 (12G2-vt9), effectively inhibited mammary tumor growth and progression by reducing the activity of FABP4/ALDH1 in different breast cancer mouse models. Our findings suggest that 12G2-Vt9 is a promising neutralizing mAb targeting FABP4-mediated cancer stemness through ALDH1 signaling, offering potential as a targeted therapeutic antibody for the clinical treatment of breast cancer. Citation Format: Jiaqing Hao, Matthew Yorek, Jian yu, Anthony Avellino, Bing Li. Developing a novel humanized anti-FABP4 antibody for breast cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5910.

Curcumin is a potential therapeutic agent that ameliorates diabetes among non-alcoholic fatty liver disease coexist with type 2 diabetes

Type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD) harmonize and act synergistically in clinical practices. About 70–80% of diabetic patients develop NAFLD. At the same time, NAFLD existence increases T2DM development. Meanwhile, the presence of T2DM increases the progression to liver disease such as NAFLD, and to non-alcoholic steatohepatitis (NASH). The most prevalent chronic liver disease worldwide is a NAFLD. NAFLD and (T2DM) have a two-way pathophysiologic relationship, with the latter driving the development of the former into NASH. Nonetheless, NASH enhances the threat of cirrhosis as well as hepatocellular carcinoma (HCC), both cases in turn need transplantation of the liver. The only treatment for NAFLD is still lifestyle management because there are no FDA-approved drugs for the condition. In the current study, we review how curcumin (a naturally occurring phytopolyphenol pigment) treats NAFLD. Also we showed broad insights on curcumin-based therapy, by severe reduction of hepatic inflammation. Thus, our review showed that curcumin ingestion considerably decreased glycemic parameters (fasting blood glucose, glycosylated hemoglobin, insulin resistance index (HOMA-IR), and free fatty acids) and adipocyte-fatty acid binding protein (A-FABP), and adipokine released from adipocytes. Clinical trials are needed to evaluate the effects of curcumin and its specific dosage on liver enzymes, glycemic consequences, among NAFLD coexist with T2DM patients.

Bacoside-A repressed the differentiation and lipid accumulation of 3T3-L1 preadipocytes by modulating the expression of adipogenic genes.

Obesity is one of the more complicated diseases, it can induce numerous life-threatening diseases mainly diabetes mellitus, cardiovascular disease, hypertension, and certain cancers. In this study, we assessed the efficacy of bacoside-A (a dammarane-type triterpenoid saponin derived from the plant Bacopa monniera Linn.) on the adipogenesis of 3T3-L1 preadipocytes. Results of this study illustrated that bacoside-A decreased the differentiation of 3T3-L1 cell, as evidenced by diminution of lipid droplets, which contains triglycerides and other lipids. During the differentiation process, transcription factors, which are mainly participating in adipogenesis such us CCAAT/enhancer-binding protein α (C/EBPα) and C/EBPβ, peroxisome proliferator-activated receptor-γ (PPARγ), and sterol regulatory element-binding protein-1c (SREBP-1c), expressions were significantly suppressed by bacoside-A. In addition, bacoside-A showed a potent reduction in genes precise to adipocytes such as lipoprotein lipase (LPL), fatty acid synthase (FAS), adipocyte fatty acid-binding protein (FABP4), and leptin expressions. Further, bacoside-A stimulated the phosphorylation of acetyl CoA carboxylase (ACC) and AMP-activated protein kinase (AMPK). These results demonstrated that bacoside-A has anti-adipogenic effects by regulating the transcription factors involved in adipocyte differentiation. Therefore, bacoside-A might be considered as a potent therapeutic agent for alleviating obesity and hyperlipidemia.

Evaluation of Adipocyte Fatty acid Binding Protein (A-FABP) Serum Level in Male Androgenetic Alopecia Patients

Evaluation of Adipocyte Fatty acid Binding Protein (A-FABP) Serum Level in Male Androgenetic Alopecia Patients

Development of a therapeutic monoclonal antibody against circulating adipocyte fatty acid binding protein to treat ischaemic stroke.

Adipocyte fatty acid-binding protein (A-FABP) exacerbates cerebral ischaemia injury by disrupting the blood-brain barrier (BBB) through inducing expression of MMP-9. Circulating A-FABP levels positively correlate with infarct size in stroke patients. We hypothesized that targeting circulating A-FABP by a neutralizing antibody would alleviate ischaemic stroke outcome. Monoclonal antibodies (mAbs) against A-FABP were generated using mouse hybridoma techniques. Binding affinities of a generated mAb named 6H2 towards various FABPs were determined using Biacore. Molecular docking studies were performed to characterize the 6H2-A-FABP complex structure and epitope. The therapeutic potential and safety of 6H2 were evaluated in mice with transient middle cerebral artery occlusion (MCAO) and healthy mice, respectively. Replenishment of recombinant A-FABP exaggerated the stroke outcome in A-FABP-deficient mice. 6H2 exhibited nanomolar to picomolar affinities to human and mouse A-FABP, respectively, with minimal cross-reactivities with heart and epidermal FABPs. 6H2 effectively neutralized JNK/c-Jun activation elicited by A-FABP and reduced MMP-9 production in macrophages. Molecular docking suggested that 6H2 interacts with the "lid" of the fatty acid binding pocket of A-FABP, thus likely hindering the binding of its substrates. In mice with transient MCAO, 6H2 significantly attenuated BBB disruption, cerebral oedema, infarction, neurological deficits, and decreased mortality associated with reduced cytokine and MMP-9 production. Chronic 6H2 treatment showed no obvious adverse effects in healthy mice. These results establish circulating A-FABP as a viable therapeutic target for ischaemic stroke, and provide a highly promising antibody drug candidate with high affinity and specificity.

Levofloxacin alleviates blood-brain barrier disruption following cerebral ischemia and reperfusion via directly inhibiting A-FABP

Reperfusion therapy is currently the most effective treatment for acute ischemic stroke, but often results in secondary brain injury. Adipocyte fatty acid-binding protein (A-FABP, FABP4, or aP2) was shown to critically mediate cerebral ischemia/reperfusion (I/R) injury by exacerbating blood-brain barrier (BBB) disruption. However, no A-FABP inhibitors have been approved for clinical use due to safety issues. Here, we identified the therapeutic effect of levofloxacin, a widely used antibiotic displaying A-FABP inhibitory activity in vitro, on cerebral I/R injury and determined its target specificity and action mechanism in vivo. Using molecular docking and site-directed mutagenesis, we showed that levofloxacin inhibited A-FABP activity through interacting with the amino acid residue Asp76, Gln95, Arg126 of A-FABP. Accordingly, levofloxacin significantly inhibited A-FABP-induced JNK phosphorylation and expressions of proinflammatory factors and matrix metalloproteinase 9 (MMP-9) in mouse primary macrophages. In wild-type mice with transient middle cerebral artery occlusion, levofloxacin substantially mitigated BBB disruption and neuroinflammation, leading to reduced cerebral infarction, alleviated neurological outcomes, and improved survival. Mechanistically, levofloxacin decreased MMP-9 expression and activity, and thus reduced degradation of extracellular matrix and endothelial tight junction proteins. Importantly, the BBB- and neuro-protective effects of levofloxacin were abolished in A-FABP or MMP-9 knockout mice, suggesting that the therapeutic effects of levofloxacin highly depended on specific targeting of the A-FABP-MMP-9 axis. Overall, our study demonstrates that levofloxacin alleviates A-FABP-induced BBB disruption and neural tissue injury following cerebral I/R, and unveils its therapeutic potential for the treatment of ischemic stroke.

Late-life plasma proteins associated with prevalent and incident frailty: A proteomic analysis.

Proteomic approaches have unique advantages in the identification of biological pathways that influence physical frailty, a multifactorial geriatric syndrome predictive of adverse health outcomes in older adults. To date, proteomic studies of frailty are scarce, and few evaluated prefrailty as a separate state or examined predictors of incident frailty. Using plasma proteins measured by 4955 SOMAmers in the Atherosclerosis Risk in Community study, we identified 134 and 179 proteins cross-sectionally associated with prefrailty and frailty, respectively, after Bonferroni correction (p < 1 × 10-5 ) among 3838 older adults aged ≥65 years, adjusting for demographic and physiologic factors and chronic diseases. Among them, 23 (17%) and 82 (46%) were replicated in the Cardiovascular Health Study using the same models (FDR p < 0.05). Notably, higher odds of prefrailty and frailty were observed with higher levels of growth differentiation factor 15 (GDF15; pprefrailty = 1 × 10-15 , pfrailty = 2 × 10-19 ), transgelin (TAGLN; pprefrailty = 2 × 10-12 , pfrailty = 6 × 10-22 ), and insulin-like growth factor-binding protein 2 (IGFBP2; pprefrailty = 5 × 10-15 , pfrailty = 1 × 10-15 ) and with a lower level of growth hormone receptor (GHR, pprefrailty = 3 × 10-16 , pfrailty = 2 × 10-18 ). Longitudinally, we identified 4 proteins associated with incident frailty (p < 1 × 10-5 ). Higher levels of triggering receptor expressed on myeloid cells 1 (TREM1), TAGLN, and heart and adipocyte fatty-acid binding proteins predicted incident frailty. Differentially regulated proteins were enriched in pathways and upstream regulators related to lipid metabolism, angiogenesis, inflammation, and cell senescence. Our findings provide a set of plasma proteins and biological mechanisms that were dysregulated in both the prodromal and the clinical stage of frailty, offering new insights into frailty etiology and targets for intervention.

Effect of obesity, lipids and adipokines on allergic rhinitis risk: a Mendelian randomization study

ObjectivesObservational studies suggested that obesity may promote the development of allergic rhinitis. The aim of this study was to explore the association of obesity, lipids and adipokines with this allergic disease at the genetic level using Mendelian randomization strategies. MethodsSummary data for three obesity indicators (such as body mass index), eight lipid indicators (such as triglycerides) and six adipokines (such as interleukin-6 and adipocyte fatty acid-binding protein) were collected, and suitable instrumental variables were extracted from these summary data according to the three main assumptions of Mendelian randomization. Three Mendelian randomization methods (such as inverse variance weighted) were used to detect the casual effect of the above indicators on allergic rhinitis risk. Sensitivity analyses were performed to assess heterogeneity and horizontal pleiotropy. ResultsAfter Bonferroni correction, the inverse variance weighted reported that elevated levels of interleukin-6 and adipocyte fatty acid-binding protein were nominally associated with the decreased risk of allergic rhinitis (OR = 0.870, 95% CI 0.765–0.990, p = 0.035; OR = 0.732, 95% CI 0.551–0.973, p = 0.032). The other Mendelian randomization methods supported these results. Obesity, lipids and other adipokines were not related to this allergic disease. Sensitivity analyses found no heterogeneity and horizontal pleiotropy in the study. ConclusionThe study provided some interesting, but not sufficient, evidence to suggest that interleukin-6 and adipocyte fatty acid-binding protein might play a protective role in the development of allergic rhinitis at the genetic level. These findings should be validated by more research. Level of evidenceThis was a Mendelian randomized study with a level of evidence second only to clinical randomized trials, and higher than cohort and case-control studies.

Pathophysiological Insight into Fatty Acid-Binding Protein-4: Multifaced Roles in Reproduction, Pregnancy, and Offspring Health.

Fatty acid-binding protein-4 (FABP4), commonly known as adipocyte-fatty acid-binding protein (A-FABP), is a pleiotropic adipokine that broadly affects immunity and metabolism. It has been increasingly recognized that FABP4 dysfunction is associated with various metabolic syndromes, including obesity, diabetes, cardiovascular diseases, and metabolic inflammation. However, its explicit roles within the context of women's reproduction and pregnancy remain to be investigated. In this review, we collate recent studies probing the influence of FABP4 on female reproduction, pregnancy, and even fetal health. Elevated circulating FABP4 levels have been found to correlate with impaired reproductive function in women, such as polycystic ovary syndrome and endometriosis. Throughout pregnancy, FABP4 affects maternal-fetal interface homeostasis by affecting both glycolipid metabolism and immune tolerance, leading to adverse pregnancy outcomes, including miscarriage, gestational obesity, gestational diabetes, and preeclampsia. Moreover, maternal FABP4 levels exhibit a substantial linkage with the metabolic health of offspring. Herein, we discuss the emerging significance and potential application of FABP4 in reproduction and pregnancy health and delve into its underlying mechanism at molecular levels.