Lipocalin-2 Levels Research Articles

Lipocalin 2 - mutation screen and serum levels in patients with anorexia nervosa or obesity and in lean individuals.

The bone-derived adipokine lipocalin-2 is relevant for body weight regulation by stimulating the leptin-melanocortin pathway. We aimed to (i) detect variants in the lipocalin-2 gene (LCN2) which are relevant for body weight regulation and/or anorexia nervosa (AN); (ii) describe and characterize the impact of LCN2 and MC4R variants on circulating lipocalin-2 level. Sanger sequencing of the coding region of LCN2 in 284 children and adolescents with severe obesity or 287 patients with anorexia nervosa. In-silico analyses to evaluate functional implications of detected LCN2 variants. TaqMan assays for rare non-synonymous variants (NSVs) in additional independent study groups. Serum levels of lipocalin-2 were measured by ELISA in 35 females with NSVs in either LCN2 or MC4R, and 33 matched controls without NSVs in the two genes. Fourteen LCN2-variants (five NSVs) were detected. LCN2-p.Leu6Pro and p.Gly9Val located in the highly conserved signal peptide region may induce functional consequences. The secondary structure change of lipocalin-2 due to LCN2-p.Val89Ile may decrease solubility and results in a low lipocalin-2 level in a heterozygotes carrier (female recovered from AN). Lean individuals had lower lipocalin-2 levels compared to patients with obesity (p = 0.033). Lipocalin-2 levels are positively associated with body mass index (BMI). Single LCN2-variants might have a profound effect on lipocalin-2 levels.

Lipocalin-2 and neutrophil activation in pancreatic cancer cachexia.

Cancer cachexia is a multifactorial syndrome characterized by body weight loss and systemic inflammation. The characterization of the inflammatory response in patients with cachexia is still limited. Lipocalin-2, a protein abundant in neutrophils, has recently been implicated in appetite suppression in preclinical models of pancreatic cancer cachexia. We hypothesized that lipocalin-2 levels could be associated with neutrophil activation and nutritional status of pancreatic ductal adenocarcinoma (PDAC) patients. Plasma levels of neutrophil activation markers calprotectin, myeloperoxidase, elastase, and bactericidal/permeability-increasing protein (BPI) were compared between non-cachectic PDAC patients (n=13) and cachectic PDAC patients with high (≥26.9 ng/mL, n=34) or low (<26.9 ng/mL, n=34) circulating lipocalin-2 levels. Patients' nutritional status was assessed by the patient-generated subjective global assessment (PG-SGA) and through body composition analysis using CT-scan slices at the L3 level. Circulating lipocalin-2 levels did not differ between cachectic and non-cachectic PDAC patients (median 26.7 (IQR 19.7-34.8) vs. 24.8 (16.6-29.4) ng/mL, p=0.141). Cachectic patients with high systemic lipocalin-2 levels had higher concentrations of calprotectin, myeloperoxidase, and elastase than non-cachectic patients or cachectic patients with low lipocalin-2 levels (calprotectin: 542.3 (355.8-724.9) vs. 457.5 (213.3-606.9), p=0.448 vs. 366.5 (294.5-478.5) ng/mL, p=0.009; myeloperoxidase: 30.3 (22.1-37.9) vs. 16.3 (12.0-27.5), p=0.021 vs. 20.2 (15.0-29.2) ng/mL, p=0.011; elastase: 137.1 (90.8-253.2) vs. 97.2 (28.8-215.7), p=0.410 vs. 95.0 (72.2-113.6) ng/mL, p=0.006; respectively). The CRP/albumin ratio was also higher in cachectic patients with high lipocalin-2 levels (2.3 (1.3-6.0) as compared to non-cachectic patients (1.0 (0.7-4.2), p=0.041). Lipocalin-2 concentrations correlated with those of calprotectin (rs =0.36, p<0.001), myeloperoxidase (rs =0.48, p<0.001), elastase (rs =0.50, p<0.001), and BPI (rs =0.22, p=0.048). Whereas no significant correlations with weight loss, BMI, or L3 skeletal muscle index were observed, lipocalin-2 concentrations were associated with subcutaneous adipose tissue index (rs =-0.25, p=0.034). Moreover, lipocalin-2 tended to be elevated in severely malnourished patients compared with well-nourished patients (27.2 (20.3-37.2) vs. 19.9 (13.4-26.4) ng/mL, p=0.058). These data suggest that lipocalin-2 levels are associated with neutrophil activation in patients with pancreatic cancer cachexia and that it may contribute to their poor nutritional status.

The link between bone-derived factors osteocalcin, fibroblast growth factor 23, sclerostin, lipocalin 2 and tumor bone metastasis.

The skeleton is the third most common site of metastatic disease, which causes serious bone complications and short-term prognosis in cancer patients. Prostate and breast cancers are responsible for the majority of bone metastasis, resulting in osteolytic or osteoblastic lesions. The crosstalk between bone cells and their interactions with tumor cells are important in the development of lesions. Recently, both preclinical and clinical studies documented the clinical relevance of bone-derived factors, including osteocalcin (OC) and its undercarboxylated form (ucOC), fibroblast growth factor 23 (FGF23), sclerostin (SCL), and lipocalin 2 (LCN2) as prognostic tumor biomarkers and potential therapeutic targets in bone metastasis. Both OC and ucOC could be useful targets for the prevention of bone metastasis in breast cancer. Moreover, elevated OC level may be a metastatic marker of prostate cancer. FGF23 is particularly important for those forms of cancer that primarily affect bone and/or are characterized by bone metastasis. In other tumor entities, increased FGF23 level is enigmatic. SCL plays a significant role in the pathogenesis of both osteolytic and osteoblastic lesions, as its levels are high in metastatic breast and prostate cancers. Elevated expression levels of LCN2 have been found in aggressive subtypes of cancer. However, its role in anti-metastasis varies significantly between different cancer types. Anyway, all aforementioned bone-derived factors can be used as promising tumor biomarkers. As metastatic bone disease is generally not curable, targeting bone factors represents a new trend in the prevention of bone metastasis and patient care.

Mucosal Genes Expression in Inflammatory Bowel Disease Patients: New Insights.

Individual differences in IBD illness severity, behavior, progression, and therapy response are evident. Since a break in the intestinal epithelial barrier causes IBD to begin, mucosal gene expression in IBD is crucial. Due to its high sensitivity and dynamic nature, molecular analysis of biomarkers in intestinal biopsies is feasible and provides a reliable means of evaluating localized inflammation. The goal of this investigation was to discover alterations in gene expression in the inflamed mucosa of IBD patients undergoing treatment with 5-amino salicylic acid (5ASA) (N = 39) or anti-TNF drugs (N = 22). The mucosal expression of numerous IBD-related genes was evaluated using qPCR. We discovered that the levels of the proteins Lipocalin-2 (LCN2), Nitric Oxide Synthase 2 (NOS2), Mucin 2 (MUC2), Mucin 5AC (MUC5AC), and Trefoil factor 1 (TFF1), which are overexpressed in untreated IBD patients compared to non-IBD subjects, are decreased by both therapy regimens. On the other hand, anti-TNF medicine helped the levels of ABCB1 and E-cadherin return to normal in IBD patients who were not receiving treatment.

Reduced secretion of LCN2 (lipocalin 2) from reactive astrocytes through autophagic and proteasomal regulation alleviates inflammatory stress and neuronal damage

ABSTRACT LCN2/neutrophil gelatinase-associated lipocalin/24p3 (lipocalin 2) is a secretory protein that acts as a mammalian bacteriostatic molecule. Under neuroinflammatory stress conditions, LCN2 is produced and secreted by activated microglia and reactive astrocytes, resulting in neuronal apoptosis. However, it remains largely unknown whether inflammatory stress and neuronal loss can be minimized by modulating LCN2 production and secretion. Here, we first demonstrated that LCN2 was secreted from reactive astrocytes, which were stimulated by treatment with lipopolysaccharide (LPS) as an inflammatory stressor. Notably, we found two effective conditions that led to the reduction of induced LCN2 levels in reactive astrocytes: proteasome inhibition and macroautophagic/autophagic flux activation. Mechanistically, proteasome inhibition suppresses NFKB/NF-κB activation through NFKBIA/IκBα stabilization in primary astrocytes, even under inflammatory stress conditions, resulting in the downregulation of Lcn2 expression. In contrast, autophagic flux activation via MTOR inhibition reduced the intracellular levels of LCN2 through its pre-secretory degradation. In addition, we demonstrated that the N-terminal signal peptide of LCN2 is critical for its secretion and degradation, suggesting that these two pathways may be mechanistically coupled. Finally, we observed that LPS-induced and secreted LCN2 levels were reduced in the astrocyte-cultured medium under the above-mentioned conditions, resulting in increased neuronal viability, even under inflammatory stress. Abbreviations: ACM, astrocyte-conditioned medium; ALP, autophagy-lysosome pathway; BAF, bafilomycin A1; BTZ, bortezomib; CHX, cycloheximide; CNS, central nervous system; ER, endoplasmic reticulum; GFAP, glial fibrillary acidic protein; GFP, green fluorescent protein; JAK, Janus kinase; KD, knockdown; LCN2, lipocalin 2; LPS, lipopolysaccharide; MACS, magnetic-activated cell sorting; MAP1LC3/LC3, microtubule-associated protein 1 light chain 3; MTOR, mechanistic target of rapamycin kinase; NFKB/NF-κB, nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105; NFKBIA/IκBα, nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor, alpha; OVEX, overexpression; SLC22A17, solute carrier family 22 member 17; SP, signal peptide; SQSTM1, sequestosome 1; STAT3, signal transducer and activator of transcription 3; TNF/TNF-α, tumor necrosis factor; TUBA, tubulin, alpha; TUBB3/β3-TUB, tubulin, beta 3 class III; UB, ubiquitin; UPS, ubiquitin-proteasome system

Reciprocal interactions between innate immune cells and astrocytes facilitate neuroinflammation and brain metastasis via lipocalin-2.

Brain metastasis still encompass very grim prognosis and therefore understanding the underlying mechanisms is an urgent need toward developing better therapeutic strategies. We uncover the intricate interactions between recruited innate immune cells and resident astrocytes in the brain metastatic niche that facilitate metastasis of melanoma and breast cancer. We show that granulocyte-derived lipocalin-2 (LCN2) induces inflammatory activation of astrocytes, leading to myeloid cell recruitment to the brain. LCN2 is central to inducing neuroinflammation as its genetic targeting or bone-marrow transplantation from LCN2-/- mice was sufficient to attenuate neuroinflammation and inhibit brain metastasis. Moreover, high LCN2 levels in patient blood and brain metastases in multiple cancer types were strongly associated with disease progression and poor survival. Our findings uncover a previously unknown mechanism, establishing a central role for the reciprocal interactions between granulocytes and astrocytes in promoting brain metastasis and implicate LCN2 as a prognostic marker and potential therapeutic target.

The genetic polymorphisms and levels of adipokines and adipocytokines that influence the risk of developing gestational diabetes mellitus in Thai pregnant women

IntroductionAberrant immune and inflammatory response is thought to be involved in the pathogenesis of gestational diabetes mellitus (GDM). ObjectiveTo investigate the genetic polymorphisms and levels of adipokines/adipocytokines that influence the risk of developing GDM in Thai women. Research design & methodsThis case-control recruited 400 pregnant Thai women. A total of 12 gene polymorphisms at ADIPOQ, adipsin, lipocalin-2, PAI-1, resistin, IL-1β, IL-4, IL-17A, TGF-β, IL-10, IL-6, and TNF-α were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay and RNase H2 enzyme-based amplification (rhAmp) SNP assay. Serum levels of adipokines/adipocytokines were evaluated using Luminex assays. ResultsMean age, weight before and during pregnancy, body mass index before and during pregnancy, blood pressure, gestational age at blood collection, and median 50 g glucose challenge test were significantly higher in GDM women than control. Significantly lower adiponectin and higher IL-4 levels were found in GDM compared to controls (p = 0.001 and p = 0.03, respectively). The genotype frequencies of IL-17A (rs3819025) were significantly different between GDM and controls (p = 0.01). Using additive models, IL-17A (rs3819025) and.TNF-α (rs1800629) were found to be independently associated with increased risk of GDM (odds ratio [OR]: 2.867; 95 % confidence interval [CI]: 1.171–7.017; p = 0.021; and OR: 12.163; 95 %CI: 1.368–108.153; p = 0.025, respectively). In GDM with IL-17A (rs3819025), there was a significant negative correlation with lipocalin-2 and PAI-1 levels (p = 0.038 and p = 0.004, respectively). ConclusionThe results of this study highlight the need for genetic testing to predict/prevent GDM, and the importance of evaluating adipokine/adipocytokine levels in Thai GDM women.

Insulin resistance is associated with increased circulating lipocalin-2 levels in polycystic ovary syndrome: a systematic review and meta-analysis.

This meta-analysis was conducted to compare the circulating lipocalin-2 levels in polycystic ovary syndrome (PCOS). Relevant studies were retrieved by online database and manual searching. The standardized mean differences (SMDs) with 95% confidence intervals (CIs) were obtained by a random-effects meta-analysis. The subgroup analysis based on the Body Mass Index (BMI) and the homeostasis model assessment-estimated insulin resistance (HOMA-IR) was conducted. Meta-analysis of correlations and meta-regression were performed for the associations of lipocalin-2 with the metabolic and hormonal covariates. The funnel plot analysis was used for publication bias. The combined effect size including a total of 13 studies showed no significant difference in lipocalin-2 levels between PCOS and control groups. However, the subgroup meta-analysis based on insulin resistance showed a significant difference in the circulatory lipocalin-2 levels in PCOS as compared to controls in both HOMA-IR<3 (SMD=-1.15, Z=2.42, P=0.02) and HOMA-IR>3 subgroups (SMD=0.91, Z=2.43, P=0.02). There were significant associations of lipocalin-2 with age, BMI, estrogen and hyperandrogenism in PCOS. Lipocalin-2 level alterations in PCOS are associated to insulin resistance. More is the insulin resistance, higher is the lipocalin-2 level in PCOS as compared to controls.

Lipocalin-2 promotes acute lung inflammation and oxidative stress by enhancing macrophage iron accumulation.

Lipocalin-2 (LCN2) is an acute-phase protein that regulates inflammatory responses to bacteria or lipopolysaccharide (LPS). Although the bacteriostatic role of LCN2 is well studied, the function of LCN2 in acute lung damage remains unclear. Here, LCN2 knockout (KO) mice were used to investigate the role of LCN2 in LPS-treated mice with or without recombinant LCN2 (rLCN2). In addition, we employed patients with pneumonia. RAW264.7 cells were given LCN2 inhibition or rLCN2 with or without iron chelator deferiprone. LCN2 KO mice had a higher survival rate than wild-type (WT) mice after LPS treatment. In addition to elevated LCN2 levels in serum and bronchoalveolar lavage fluid (BALF), LPS treatment also increased LCN2 protein in alveolar macrophage lysates of BALF. LCN2 deletion attenuated neutrophil and macrophage infiltration in the lungs of LPS-treated mice as well as serum and BALF interleukin-6 (IL-6). Circulating proinflammatory cytokines and LCN2-positive macrophages were prominently increased in the BALF of pneumonia patients. In addition to increase of iron-stained macrophages in pneumonia patients, increased iron-stained macrophages and oxidative stress in LPS-treated mice were inhibited by LCN2 deletion. In contrast, rLCN2 pretreatment aggravated lung inflammation and oxidative stress in LPS-treated WT mice and then resulted in higher mortality. In RAW264.7 cells, exogenous LCN2 treatment also increased inflammation and oxidative stress, whereas LCN2 knockdown markedly diminished these effects. Furthermore, deferiprone inhibited inflammation, oxidative stress, and phagocytosis in RAW264.7 cells with high LCN2 levels, as well as LPS-induced acute lung injury in WT and LCN2 KO mice. Thus, these findings suggest that LCN2 plays a key role in inflammation and oxidative stress following acute lung injury and that LCN2 is a potential therapeutic target for pneumonia or acute lung injury.

Lipocalin-2 Secreted by the Liver Regulates Neuronal Cell Function Through AKT-Dependent Signaling in Hepatic Encephalopathy Mouse Model.

Hepatic encephalopathy (HE) associated with liver failure is accompanied by hyperammonemia, severe inflammation, depression, anxiety, and memory deficits as well as liver injury. Recent studies have focused on the liver-brain-inflammation axis to identify a therapeutic solution for patients with HE. Lipocalin-2 is an inflammation-related glycoprotein that is secreted by various organs and is involved in cellular mechanisms including iron homeostasis, glucose metabolism, cell death, neurite outgrowth, and neurogenesis. In this study, we investigated that the roles of lipocalin-2 both in the brain cortex of mice with HE and in Neuro-2a (N2A) cells. We detected elevated levels of lipocalin-2 both in the plasma and liver in a bile duct ligation mouse model of HE. We confirmed changes in cytokine expression, such as interleukin-1β, cyclooxygenase 2 expression, and iron metabolism related to gene expression through AKT-mediated signaling both in the brain cortex of mice with HE and N2A cells. Our data showed negative effects of hepatic lipocalin-2 on cell survival, iron homeostasis, and neurite outgrowth in N2A cells. Thus, we suggest that regulation of lipocalin-2 in the brain in HE may be a critical therapeutic approach to alleviate neuropathological problems focused on the liver-brain axis.

Circulating markers of neutrophil activation and lung injury in pediatric pneumonia in low-resource settings

ABSTRACT Diagnostic biomarkers for childhood pneumonia could guide management and improve antibiotic stewardship in low-resource settings where chest x-ray (CXR) is not always available. In this cross-sectional study, we measured chitinase 3-like protein 1 (CHI3L1), surfactant protein D (SP-D), lipocalin-2 (LCN2), and tissue inhibitor of metalloproteinases-1 (TIMP-1) in Ugandan children under the age of five hospitalized with acute lower respiratory tract infection. We determined the association between biomarker levels and primary end-point pneumonia, indicated by CXR consolidation. We included 89 children (median age 11 months, 39% female). Primary endpoint pneumonia was present in 22 (25%). Clinical signs were similar in children with and without CXR consolidation. Broad-spectrum antibiotics (ceftriaxone) were administered in 83 (93%). Levels of CHI3L1, SP-D, LCN2 and TIMP-1 were higher in patients with primary end-point pneumonia compared to patients with normal CXR or other infiltrates. All markers were moderately accurate predictors of primary end-point pneumonia, with area under receiver operator characteristic curves of 0.66-0.70 (p<0.05 for all markers). The probability of CXR consolidation increased monotonically with the number of markers above cut-off. Among 28 patients (31%) in whom all four markers were below the cut-off, the likelihood ratio of CXR consolidation was 0.11 (95%CI 0.015 to 0.73). CHI3L1, SP-D, LCN2 and TIMP-1 were associated with CXR consolidation in children with clinical pneumonia in a low-resource setting. Combinations of quantitative biomarkers may be useful to safely withhold antibiotics in children with a low probability of bacterial infection.

Increased visinin-like protein-1, YKL-40, lipocalin-2, and IL-23 levels in patients with migraine

ABSTRACT Background Migraine is a type of primary headache caused by changes in the trigeminal system and has been reported to be associated with neurovascular inflammation of cerebral and extracerebral vessels. Objective It is known that inflammation is an important process in the pathogenesis of migraine. It has been shown that the molecules of visinin-like protein 1 (Vilip-1), YKL-40, lipocalin-2 and interleukin (IL)-23 play a role in the inflammatory process. Our aim is to investigate the role of this molecule in the metabolic pathway of migraine disease. Methods Fifty migraine patients with and without aura in the interictal period were included in the study. Vilip-1, YKL-40, lipocalin-2, and IL-23 levels were measured by ELISA method. Results Serum vilip-1, YKL-40, lipocalin-2, and IL-23 levels were found to be significantly higher in migraine patients compared to the control group. We found that this molecule increased significantly in migraine subgroups compared to the control group (p < 0.001). A positive significant correlation was found between vilip-1 level and YKL-40 and lipocalin-2 levels in migraine patients. In addition, a positive correlation was observed between visual analogue scale score, number of days with pain and vilip-1 level (p < 0.01). The results of our study showed that activation of inflammatory mediators may play a role in the pathogenesis of migraine disease. In addition, our study is valuable in that inflammatory molecules are high in the interictal period and these biomarkers have never been analyzed in migraine patients. However, we still believe that larger studies are needed to explain the role of vilip-1, YKL-40, lipocalin-2, and IL-23 in the molecular mechanism of migraine disease.

Serum lipocalin-2 levels are decreased in patients with leprosy.

Background Leprosy is an infectious disease caused by Mycobacterium leprae affecting the skin, peripheral nerves and mucosae. Lipocalin-2 is a key component of the immune system's antimicrobial defence - it prevents iron uptake by binding and sequestering iron-scavenging siderophores and thus inhibits bacterial growth. Aim We evaluated serum lipocalin-2 levels in leprosy patients and its relationship to the pathogenesis and prognosis of the disease. Materials and methods In this case-control study, serum lipocalin-2 levels were measured by ELISA in 20 patients with leprosy and 20 healthy controls. Results Serum levels of lipocalin-2 were significantly reduced (P < 0.001) in leprosy patients as compared to controls. The levels were significantly higher (P < 0.014) in patients with multibacillary leprosy than in those with paucibacillary leprosy. Although the levels of lipocalin-2 were higher in patients with multiple nerve involvement as compared to those with involvement of 1 or 2 nerves, the results were not statistically significant. Limitation of the study The small sample size and the lack of different ethnic groups in the study were the major limitations of this study. Conclusion The lower lipocalin-2 concentrations in leprosy patients point to the importance of the protective functions of lipocalin-2. The elevated levels of lipocalin-2 observed in leprosy patients with neural involvement may be related to the reported neurodegenerative role of lipocalin-2.

Evaluation of Lipocalin-2 and Vaspin Levels in In Iraqi Women with Type 2 Diabetes Mellitus

The main objective of this study would be that if serum lipocalin-2 and Vaspin levels may be utilized as indicators for chronic in Type 2 diabetes mellitus (T2DM) patients. T2DM treatment is to maintain a healthy glycemic level. If this goal is not met, diabetes consequences, both acute and chronic, may emerge, one of which is obesity. As a result, researchers have investigated the levels of Lipocalin-2 and Vaspin, as well as their connection to obesity and insulin resistance. In this study, we included 60 T2DM (ages 35 to 65 years) and 30 healthy controls. After an overnight fast, blood serum samples were collected, and routine biochemical parameters such as lipocalin-2, Vaspin, and glucose were measured in all samples. At a P &lt;0.05 level, the data were declared significant. Using an ELISA kit, the levels of serum Lipocalin-2 and Vaspin were measured. The results have shown that patients with T2DM had substantially greater blood serum levels of Lipocalin-2 and Vaspin than normal controls (P &lt;0.001 for all comparisons). Also, results revealed Lipocalin-2 and Vaspin have a high positive correlation with each of BMI and Homeostasis Model Assessment for insulin resistance HOMA-IR and moderate positive correlation between Vaspin and Fasting blood glucose.

Lipocalin 2 Reduces MET Levels by Inhibiting MEK/ERK Signaling to Inhibit Nasopharyngeal Carcinoma Cell Migration.

Nasopharyngeal carcinoma (NPC) is the most common cancer that occurs in the nasopharynx, and it is difficult to detect early. The main cause of death of NPC patients is cancer metastasis. Lipocalin 2 (LCN2) has been shown to be involved in a variety of carcinogenesis processes. Here, we aimed to study the role of LCN2 in NPC cells and determine its underlying mechanism. We found that LCN2 was expressed differently in NPC cell lines, namely HONE-1, NPC-39, and NPC-BM. The down-regulation of LCN2 levels by siRNA targeting LCN2 (siLCN2) increased cell migration and invasion in HONE-1 cells, while the up-regulation of LCN2 levels by transfection with the LCN2 expression plasmid decreased cell migration and invasion in NPC-BM cells. Furthermore, LCN2 levels negatively regulated the phosphorylation of MEK/ERK pathways. The treatment of the specific MEK/ERK inhibitor, U0126, reduced cell migration in HONE-1 cells, whereas the treatment of tBHQ, an ERK activator, enhanced cell migration in NPC-BM cells. Based on the bioinformatics data, there was a moderately negative correlation between LCN2 and MET in metastatic NPC tissues (r = -0.5946, p = 0.0022). Indeed, the manipulation of LCN2 levels negatively regulated MET levels in these NPC cells. The treatment of U0126 reduced siLCN2-increased MET levels, while the treatment of tBHQ enhanced LCN2-enhanced MET levels. Interestingly, the down-regulation of MET levels by siMET further decreased siLCN2-enhanced MET levels and cell migration. Therefore, LCN2 inhibits NPC cell migration by reducing MET levels through MEK/ERK signaling.

Increased plasma lipocalin-2 levels correlate with disease severity and may be a marker of acute inflammatory response in patients with psoriasis.

More than a skin disease, psoriasis is also considered a systemic disorder. Lipocalin-2, an adipokine, may be a link between psoriasis and systemic inflammation. We conducted this study to measure the plasma level of lipocalin-2 and investigate its relationship with the clinical manifestations in patients with psoriasis. We assessed 62 patients with psoriasis and 31 healthy controls. Their demographic information and clinical characteristics were determined by physical examination and review of the recorded medical history. Plasma lipocalin-2 levels were measured using an enzyme-linked immunosorbent assay. Plasma lipocalin-2 concentration was significantly higher in patients with psoriasis than in the control group (P<0.001). Patients with acute psoriatic subgroups, including psoriatic erythroderma and pustular psoriasis, had significantly higher plasma lipocalin-2 levels than those with the chronic plaque type. In addition, plasma lipocalin-2 concentration positively correlates with the disease severity index, including the psoriasis area severity index, body surface area, high-sensitivity C-reactive protein, nail psoriasis severity index, and pustular severity index. In patients with psoriasis, increased plasma lipocalin-2 levels correlated with severity and indicated an active disease state. These findings suggest that lipocalin-2 may play an important role in determining the pathogenesis of acute psoriasis and may serve as a valuable clinical biomarker of this disease.

Effect of polycaprolactone nanofibers loaded with oxytetracycline hydrochloride and zinc oxide as an adjunct to SRP on GCF lipocalin-2 levels in periodontitis patients: A clinical and laboratory study.

Background. The aim of this study was the clinical and laboratory evaluation of using polycaprolactone (PCL) nanofibers loaded with oxytetracycline hydrochloride (OTC) and zinc oxide (ZnO) as an adjunct to mechanical therapy in managing stage II grade A periodontitis patients concerning GCF lipocalin2- levels. Methods. Fifty stage II grade A periodontitis patients (27 women and 23 men, with an age range of 30‒60) were enrolled in the study. The patients were randomly assigned to five equal groups and treated with scaling and root planing (SRP), followed by local application of PCL nanofibers: group I: SRP + PCL loaded with OTC and ZnO, group II: SRP + PCL loaded with OTC, group III: SRP + PCL loaded with ZnO, group IV: SRP + unloaded PCL, and group V: SRP alone. Additionally, 10 healthy subjects with healthy periodontium (group VI) (age- and gender-matched) served as the negative control. Nanofibers were applied in the selected pockets of periodontitis patients in groups I to IV once weekly for two months. All the participants were examined clinically by assessing periodontal indices (gingival index, plaque index, pocket depth, and clinical attachment level), and biochemically by assessing GCF lipocalin-2 levels. Results. Compared to controls, periodontitis groups (I, II, III, IV, and V) showed significant elevation of both clinical parameters and GCF lipocalin2- levels at baseline. In addition, these parameters improved significantly after treatment, which was more pronounced in groups I, II-, and III) compared to groups IV and V. However, it did not reach normal values. Conclusion. In association with SRP, PCL nanofibers loaded with OTC and ZnO had beneficial therapeutic effects at both clinical and laboratory levels.

Mechanisms of Corticosteroid Resistance in Type 17 Asthma.

IL-17A plays an important role in the pathogenesis of asthma, particularly the neutrophilic corticosteroid (CS)-resistant subtype of asthma. Clinical studies suggest that a subset of asthma patients, i.e., Th17/IL-17A-mediated (type 17) CS-resistant neutrophilic asthma, may improve with Th17/IL-17A pathway blockade. However, little is known about the mechanisms underlying type 17 asthma and CS response. In this article, we show that blood levels of lipocalin-2 (LCN2) and serum amyloid A (SAA) levels are positively correlated with IL-17A levels and are not inhibited by high-dose CS usage in asthma patients. In airway cell culture systems, IL-17A induces these two secreted proteins, and their induction is enhanced by CS. Furthermore, plasma LCN2 and SAA levels are increased in mice on a preclinical type 17 asthma model, correlated to IL-17A levels, and are not reduced by glucocorticoid (GC). In the mechanistic studies, we identify CEBPB as the critical transcription factor responsible for the synergistic induction of LCN2 and SAA by IL-17A and GC. IL-17A and GC collaboratively regulate CEBPB at both transcriptional and posttranscriptional levels. The posttranscriptional regulation of CEBPB is mediated in part by Act1, the adaptor and RNA binding protein in IL-17A signaling, which directly binds CEBPB mRNA and inhibits its degradation. Overall, our findings suggest that blood LCN2 and SAA levels may be associated with a type 17 asthma subtype and provide insight into the molecular mechanism of the IL-17A-Act1/CEBPB axis on these CS-resistant genes.

Abstract B008: Lipocalin-2 expression modulates ferroptosis in pancreatic ductal adenocarcinoma

Abstract Background: Pancreatic Ductal Adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the US. Lipocalin 2 (LCN2) is upregulated in PDAC patients and promotes inflammation and tumor growth. LCN2 regulates iron levels, which are dysregulated in tumors as cancer cells uptake increased iron to support growth. High iron levels can lead to ferroptosis, an iron-catalyzed form of cell death that relies on the oxidation of poly-unsaturated fatty acids (PUFAs). Ferroptosis is usually inhibited in cancer to prevent cell death and promote tumor growth. Therefore, LCN2 expression might influence ferroptosis outcomes in PDAC. Objective: To determine whether LCN2 inhibits ferroptosis and whether modulating LCN2 levels and other targets can be leveraged as treatments to induce ferroptosis in PDAC. Methods: Lcn2 expression was deleted via CRISPR in a mouse PDAC cell line (mKPC) to generate control Lcn2+/+ and Lcn2-/- mKPC cells. Gene expression changes were analyzed with RNA sequencing. Human and mouse PDAC cells were treated with a ferroptosis inducer, LCN2 blockade, and various PUFAs. Treatment effects on cell proliferation and lipid peroxidation were measured via 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl) -2-(4-sulfophenyl)-2H-tetrazolium) (MTS) assay and BODIPY 581/591 C11 staining respectively. Gene expression of ferroptosis markers (SLC7A11, GPX4, and SLC11A2) and LCN2 were measured via RT-qPCR. Results: Deletion of Lcn2 in mKPC cells significantly decreased the expression of genes involved in ferroptosis-inhibiting antioxidant synthesis. Ferroptosis induction upregulated Lcn2 expression in PDAC cells and decreased the viability of mKPC Lcn2-/- and human PDAC cells, but not mKPC Lcn2+/+ or human pancreatic duct epithelial cells. LCN2 blockade treatment to PDAC cells modulated the expression SLC7A11, GPX4, and SLC11A2, key enablers and inhibitors of the ferroptosis antioxidant pathway. Conclusions: Ferroptosis decreases proliferation of PDAC cells, which might be mediated by LCN2 expression. LCN2 modulation has potential to induce ferroptosis and delay PDAC growth. Future studies will determine whether a combination approach with LCN2 modulation could induce ferroptosis in PDAC. Acknowledgments: This research is supported by the OSU Pelotonia Fellowship Program and the NCI R01CA223204. Citation Format: Valentina Pita Grisanti, Andrew W. Dangel, Maciej Pietrzak, Amy Hite, Zobeida Cruz-Monserrate. Lipocalin-2 expression modulates ferroptosis in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B008.

The level of adipokines in young people with hypertension and abdominal obesity

Objective. To investigate the adipokine blood profile in young people with hypertension (HTN) and abdominal obesity (AO). Design and methods. In total. 530 people were included in the study, including 267 people with HTN, of which 169 had AO. In the control group (without HTN) there were 263 people comparable to the study group by gender and age. Among them there were 106 people with AO. The blood levels of adiponectin, adipsin, lipocalin-2, resistin and plasminogen activator inhibitor-1 (PAI-1) were determined in all examined patients by multiplex analysis. Statistical data processing was carried out with the use of SPSS 13.0 program. Results. The levels of adiponectin and lipocalin-2 were lower in the group of HTN patients by 1,46 (p &lt; 0,01) and 1,14 times (p &lt; 0,05), respectively. The level of adipsin in HTN patients was significantly higher (p &lt; 0,01) by 19,14 % compared to the control. The levels of resistin and PAI- did not differ in the control group and the group with HTN. Adiponectin level was 1,35 times lower (p &lt; 0,05) in the group with AO compared to those without AO, the other indicators did not differ in the AO group and controls. In the HTN group, higher levels of PAI-1 were found in the subgroup with AO. When comparing the subgroup without HTN and without AO with the subgroup with HTN and AO, a significant decrease in concentration of adiponectin and lipocalin-2 was found. For the subgroups with AO, a decrease in adiponectin levels and an increase in adipsin levels (p &lt; 0,01) were found in HTN patients. No statistically significant difference was found for the remaining indicators. The relative chance of early onset HTN was associated with the decrease in adiponectin and lipocalin-2 levels, and with the increase in adipsin levels, regardless of gender, age and the presence of AO. Conclusions. Thus, an increased level of adipsin and a reduced level of adiponectin and lipocalin-2 can serve as potential biomarkers indicating a high probability of developing early HTN in people under 45 years of age.