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Objective: To investigate the relationship between serum a proliferation-inducing ligand (APRIL), leucine-rich a-2 glycoprotein 1 (LRG1), multiligand proteoglycan-1 (Syndecan-1) and renal function and short-term prognosis in patients with sepsis combined with acute kidney injury (AKI). Methods: 247 patients with sepsis admitted to Jinan Fifth People's Hospital from January 2021 to January 2023 were selected, and patients were divided into non-AKI group (122 cases) and AKI group (125 cases) according to whether AKI was combined, patients with sepsis combine with AKI were divided into death group and survival group according to the 30 days clinical outcome. Serum APRIL, LRGI and Syndecan-1 were detected by enzyme-linked immunosorbent assay, and renal function indexes [urinary albumin/creatinine ratio (UACR), estimated glomerular filtration rate (eGFR)] were calculated. The correlation between serum APRIL, LRGI, Syndecan-1 and UACR and eGFR in patients with sepsis combine with AKI were analyzed by Spearman correlation analysis. The influencing factors of short-term prognosis in patients with sepsis combine with AKI were analyzed by multivariate Logistic regression, the predictive value of serum APRIL, LRG1 and Syndecan-1 levels for short-term prognosis in patients with sepsis combine with AKI were analyzed by receiver operating characteristic (ROC) curve. Results: The levels of serum APRIL, LRG1, Syndecan-1 and UACR in AKI group were higher than those in non-AKI group, and eGFR was lower than that in non-AKI group (P<0.05). Spearman correlation analysis showed that, serum APRIL, LRG1 and Syndecan-1 were positively correlated with UACR and negatively correlated with eGFR in patients with sepsis combine with AKI (P<0.05). The 30 day mortality rate of 125 patients with sepsis combine with AKI was 40.80%. The levels of serum APRIL, LRG1, Syndecan-1 and UACR in death group were higher than those in survival group, and eGFR was lower than that in survival group (P<0.05). Multivariate Logistic regression analysis showed that, the increase of acute physiology and chronic health evaluation II (APACHE II) score, sequential organ failure assessment (SOFA) score, UACR, APRIL, LRG1 and Syndecan-1 were independent risk factors for short-term prognosis in patients with sepsis combine with AKI, and the increase of eGFR was an independent protective factor (P<0.05). The area under the curve of combined prediction of serum APRIL, LRG1 and Syndecan-1 levels was 0.908, which was greater than that of serum APRIL, LRG1 and Syndecan-1 levels alone. Conclusion: The increase of serum APRIL, LRG1 and Syndecan-1 levels are closely relate to the decrease of renal function in patients with sepsis combine with AKI, and are independent risk factors for poor short-term prognosis in patients with sepsis combined with AKI. The combination of serum APRIL, LRG1 and Syndecan-1 levels has a high value in predicting the short-term prognosis in patients with sepsis combine with AKI. [ABSTRACT FROM AUTHOR]

Atherosclerosis is a chronic inflammatory disease of the arterial wall characterized by the accumulation of cholesterol-rich lipoproteins in macrophages. How macrophages commit to proinflammatory polarization under atherosclerosis conditions is not clear. Report here that the level of a circulating protein, leucine-rich alpha-2 glycoprotein 1 (LRG1), is elevated in the atherosclerotic tissue and serum samples from patients with coronary artery disease (CAD). LRG1 stimulated macrophages to proinflammatory M1-like polarization through the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK) pathways. The LRG1 knockout mice showed significantly delayed atherogenesis progression and reduced levels of macrophage-related proinflammatory cytokines in a high-fat diet-induced Apoe-/- mouse atherosclerosis model. An anti-LRG1 neutralizing antibody also effectively blocked LRG1-induced macrophage M1-like polarization in vitro and conferred therapeutic benefits to animals with ApoE deficiency-induced atherosclerosis. LRG1 may therefore serve as an additional biomarker for CAD and targeting LRG1 could offer a potential therapeutic strategy for CAD patients by mitigating the proinflammatory response of macrophages. [ABSTRACT FROM AUTHOR]

Leucine-rich α-2 glycoprotein 1 (LRG1), a secreted glycoprotein, has been identified as significantly upregulated in renal fibrosis, potentially exacerbating the condition by enhancing TGF-β-Smad3-dependent signaling pathways. Herein, utilizing our developed LRG1-targeting peptide for LRG1 recruitment and lenalidomide for E3 ubiquitin ligase engagement, we developed an advanced proteolysis targeting chimera, ET TAC-2, specifically designed for LRG1 degradation. Our cellular degradation assays validated that ET TAC-2 effectively degraded LRG1 through a proteasome-dependent mechanism, achieving halfmaximal degradation at a concentration of 8.38 μM. Furthermore, anti-fibrotic experiments conducted both in vitro and in vivo revealed that ET TAC-2 efficiently induced LRG1 degradation in fibrotic kidneys. This action effectively inhibited the TGF-β-Smad3 signaling pathway and diminished the secretion of fibrosis-associated proteins, consequently attenuating the progression of renal fibrosis. Our study highlights the pivotal role of LRG1 in renal fibrosis and positions ET TAC-2 as a promising therapeutic candidate for targeted LRG1 intervention. [ABSTRACT FROM AUTHOR]

Introduction Cigarette smoking is one of the most important causes of COPD and could induce the apoptosis of pulmonary microvascular endothelial cells (PMVECs). The conditional knockout of LRG1 from endothelial cells reduced emphysema in mice. However, the mechanism of the deletion of LRG1 from endothelial cells rescued by cigarette smoke (CS) induced emphysema remains unclear. This research aimed to demonstrate whether LRG1 promotes the apoptosis of PMVECs through KLK10 in COPD. Methods Nineteen patients were divided into three groups: control non-COPD (n=7), smoker non-COPD (n=7), and COPD (n=5). The emphysema mouse model defined as the CS exposure group was induced by CS exposure plus cigarette smoke extract (CSE) intraperitoneal injection for 28 days. Primary PMVECs were isolated from the mouse by magnetic bead sorting method via CD31-Dynabeads. Apoptosis was detected by western blot and flow cytometry. Results LRG1 was increased in lung tissue of COPD patients and CS exposure mice, and CSE-induced PMVECs apoptosis model. KLK10 was over-expressed in lung tissue of COPD patients and CS exposure mice, and CSE-induced PMVECs apoptosis model. LRG1 promoted apoptosis in PMVECs. LRG1 knockdown reversed CSE-induced apoptosis in PMVECs. The mRNA and protein expression of KLK10 were increased after over-expressed LRG1 in PMVECs isolated from mice. Similarly, both the mRNA and protein levels of KLK10 were decreased after LRG1 knockdown in PMVECs. The result of co-immunoprecipitation revealed a protein-protein interaction between LRG1 and KLK10 in PMVECs. KLK10 promoted apoptosis via the down-regulation of Bcl-2/Bax in PMVECs. KLK10 knockdown could reverse CSE-induced apoptosis in PMVECs. Conclusions LRG1 promotes apoptosis via up-regulation of KLK10 in PMVECs isolated from mice. KLK10 promotes apoptosis via the down-regulation of Bcl-2/ Bax in PMVECs. There was a direct protein-protein interaction between LRG1 and KLK10 in PMVECs. Our novel findings provide insights into the understanding of LRG1/KLK10 function as a potential molecule in COPD.

Objective To investigate the role of lipopolysaccharide(LPS)in regulating the inflammatory response of neutrophil through the leucine-rich α-2 glycoprotein 1(LRG1)/ Rho-associated protein kinase(ROCK1)signaling. Methods HL-60 cells were treated with 1 μmol/L all-trans retinoic acid(ATRA)and 12.5 μL/mL dimethyl sulfoxide(DMSO)for 72 h and 96 h, and the morphological changes were observed by Wright-Giemsa staining. The expression of CD11b was detected by flow cytometry. LPS induced the activation of dHL-60 and human peripheral blood neutrophils. The transcription and secretion levels of LRG1, ROCK1 and inflammatory cytokines were detected by qPCR and ELISA, respectively. The expression levels of LRG1 and ROCK1 after the activation of dHL-60 were detected by Western blotting. Furthermore, dHL-60 was treated with the recombinant protein LRG1 and ROCK1 inhibitor Y-27632; the transcription levels of inflammatory cytokines were detected by qPCR. Results Neutrophils were activated by LPS. The expression levels of LRG1 and ROCK1 were significantly increased, and the transcription levels of inflammatory cytokines were significantly increased. The recombinant protein LRG1 activated dHL-60 in vitro, and the transcription levels of ROCK1 and inflammatory cytokines were significantly increased. Using the ROCK1 inhibitor Y-27632, the production levels of inflammatory cytokines were significantly reduced. Conclusion LPS can regulate the production levels of neutrophil inflammatory cytokines through activating the LRG1/ROCK1 signaling, thus exacerbating the inflammatory response. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The aim of this prospective, single-center cohort study was to analyze serum leucine-rich a-2-glycoprotein-1 (LRG1) expression in patients with acute cholecystitis (AC) and to investigate its variation depending on symptom duration. PATIENTS AND METHODS: Participants were divided into patients with AC and a healthy control group. At the time of diagnosis, blood samples were collected, and symptom onset times were questioned. Collected serum LRG1 levels were measured. RESULTS: 30 patients and 30 healthy volunteers were included in the study. LRG1 (p=0.008), white blood cells (WBC) (p<0.001), platelet (p=0.003), neutrophil (p<0.001), lymphocyte (p=0.001), and CRP (p=0.014) were significantly different in AC patients vs. the control group. When the correlations of serum laboratory values with the time of onset of symptoms were compared, LRG1 (p<0.001) was significantly correlated, while no significant correlation was observed in C-reactive protein (CRP) (p=0.572), WBC (p=0.155), and neutrophil (p=0.155). CONCLUSIONS: LRG1 expression increases after 24 hours in AC patients. Due to its correlation with symptom duration, we believe it can be helpful for timing cholecystectomy. [ABSTRACT FROM AUTHOR]

Abstract Background Currently, no useful serum markers exist for clear cell renal cell carcinoma (ccRCC), making early detection challenging as diagnosis relies solely on imaging tests. Radiation exposure is also a concern due to multiple required CT examinations during treatment. Renal cell carcinoma (RCC) histological types include ccRCC and non-clear cell RCC (non-ccRCC); however, treatment response to medications varies which necessitates accurate differentiation between the two. Therefore, we aimed to identify a novel serum marker of RCC. Increased LRG1 expression in the serum has been demonstrated in multiple cancer types. However, the expression of LRG1 expression in the serum and cancer tissues of patients with RCC has not been reported. Since ccRCC is a hypervascular tumor and LRG1 is capable of accelerating angiogenesis, we hypothesized that the LRG1 levels may be related to ccRCC. Therefore, we examined LRG1 expression in sera from patients with RCC. Methods Using an enzyme-linked immunosorbent assay, serum levels of leucine-rich-alpha-2-glycoprotein 1 (LRG1) were measured in 64 patients with ccRCC and 22 patients non-ccRCC who underwent radical or partial nephrectomy, as well as in 63 patients without cancer. Results Median values of serum LRG1 and their inter-quartile ranges were 63.2 (42.8–94.2) µg/mL in ccRCC, 23.4 (17.7–29.6) µg/mL in non-ccRCC, and 36.0 (23.7–56.7) µg/mL in patients without cancer, respectively (ccRCC vs. non-ccRCC or patients without cancer: P

Background: Currently, no useful serum markers exist for clear cell renal cell carcinoma (ccRCC), making early detection challenging as diagnosis relies solely on imaging tests. Radiation exposure is also a concern due to multiple required CT examinations during treatment. Renal cell carcinoma (RCC) histological types include ccRCC and non-clear cell RCC (non-ccRCC); however, treatment response to medications varies which necessitates accurate differentiation between the two. Therefore, we aimed to identify a novel serum marker of RCC. Increased LRG1 expression in the serum has been demonstrated in multiple cancer types. However, the expression of LRG1 expression in the serum and cancer tissues of patients with RCC has not been reported. Since ccRCC is a hypervascular tumor and LRG1 is capable of accelerating angiogenesis, we hypothesized that the LRG1 levels may be related to ccRCC. Therefore, we examined LRG1 expression in sera from patients with RCC. Methods: Using an enzyme-linked immunosorbent assay, serum levels of leucine-rich-alpha-2-glycoprotein 1 (LRG1) were measured in 64 patients with ccRCC and 22 patients non-ccRCC who underwent radical or partial nephrectomy, as well as in 63 patients without cancer. Results: Median values of serum LRG1 and their inter-quartile ranges were 63.2 (42.8–94.2) µg/mL in ccRCC, 23.4 (17.7–29.6) µg/mL in non-ccRCC, and 36.0 (23.7–56.7) µg/mL in patients without cancer, respectively (ccRCC vs. non-ccRCC or patients without cancer: P < 0.001). C-reactive protein (CRP) levels (P = 0.002), anemia (P = 0.037), hypercalcemia (P = 0.023), and grade (P = 0.031) were independent predictors of serum LRG1 levels in ccRCC. To assess diagnostic performance, the area under the receiver operating characteristic curve of serum LRG1 was utilized to differentiate ccRCC from non-cancer and non-ccRCC, with values of 0.73 (95% CI, 0.64–0.82) and 0.91 (95% CI, 0.82–0.96), respectively. Conclusions: LRG1 served as a serum marker associated with inflammation, indicated by CRP, anemia, hypercalcemia, and malignant potential in ccRCC. Clinically, serum LRG1 levels may assist in differentiating ccRCC from non-ccRCC with excellent diagnostic accuracy. [ABSTRACT FROM AUTHOR]

Most meningiomas, which are frequent central nervous system tumors, are classified as World Health Organization (WHO) grade 1 because of their slow‐growing nature. However, the recurrence rate varies and is difficult to predict using conventional histopathological diagnoses. Leucine‐rich α‐2 glycoprotein 1 (LRG1) is involved in cell signal transduction, cell adhesion, and DNA repair and is a predictive biomarker in different malignant tumors; however, such a relationship has not been reported in meningiomas. We examined tissue microarrays of histological samples from 117 patients with grade 1 and 2 meningiomas and assessed their clinical and pathological features, including expression of LRG1 protein. LRG1‐high meningiomas showed an increased number of vessels with CD3‐positive cell infiltration (P = 0.0328) as well as higher CD105‐positive vessels (P = 0.0084), as compared to LRG1‐low cases. They also demonstrated better progression‐free survival (hazard ratio [HR] 0.11, 95% confidence interval [CI] 0.016–0.841) compared to LRG1‐low patients (P = 0.033). Moreover, multivariate analysis indicated that high LRG1 expression was an independent prognostic factor (HR, 0.13; 95% CI, 0.018–0.991; P = 0.049). LRG1 immunohistochemistry may be a convenient tool for estimating the prognosis of meningiomas in routine practice. Further studies are required to elucidate the key role of LRG1 in meningioma progression. [ABSTRACT FROM AUTHOR]

Implant loosening is a severe complication after total joint replacement. Here, differential diagnosis between septic and aseptic cases is crucial for further surgical treatment, but low-grade periprosthetic joint infections (PJIs) in particular remain a challenge. In this study, we analyzed the synovial fluid proteome of 21 patients undergoing revision surgery for septic (eight cases) or aseptic (thirteen cases) implant failure using LC-MS/MS to identify potential new biomarkers as future diagnostic tools. Staphylococci were found in four cases, Streptococci in two cases, Serratia marcescens and Cutibacterium acnes in one case. Proteomic analysis of the synovial fluid resulted in the identification of 515 different proteins based on at least two peptides. A statistical comparison revealed 37 differentially abundant proteins (p < 0.05), of which 17 proteins (46%) showed a higher abundance in the septic group. The proteins with the highest fold change included the known marker proteins c-reactive protein (7.57-fold) and the calprotectin components protein S100-A8 (4.41-fold) and protein S100-A9 (3.1-fold). However, the protein with the highest fold change was leucine-rich alpha-2-glycoprotein 1 (LRG1) (9.07-fold), a currently discussed new biomarker for inflammatory diseases. Elevated LRG1 levels could facilitate the diagnosis of PJI in the future, but their significance needs to be further investigated. [ABSTRACT FROM AUTHOR]

Objective: To investigate the relationship between serum leucine-rich alpha-2 glycoprotein 1 (LRG1), glucose-regulated protein 78 (GRP78) and secondary acute lung injury (ALI) in patients with emergency sepsis. Methods: 155 patients with emergency sepsis who were treated in the emergency intensive care unit (EICU) of our hospital from January 2021 to October 2022 were retrospectively selected as observation group, patients were divided into ALI group (43 cases) and non-ALI group (112 cases) according to whether secondary ALI occurred, and 100 healthy subjects in our hospital during the same period were selected as control group. The levels of serum LRG1 and GRP78 were detected by enzyme-linked immunosorbent assay kit. The influencing factors of secondary ALI in patients with emergency sepsis were analyzed by univariate and multivariate logistic regression. The predictive value of serum LRG1 and GRP78 levels for secondary ALI in patients with emergency sepsis were analyzed by receiver operating characteristic (ROC) curve was used to analyze. Results: Compared with control group, the levels of serum LRG1 and GRP78 in observation group were increased (P<0.05). Univariate analysis showed that, ALI secondary to emergency sepsis was related to sepsis grade, EICU time, mechanical ventilation, sepsis-related organ failure assessment (SOFA) score, blood lactic acid, LRG1 and GRP78 (P<0.05). Multivariate logistic regression analysis showed that, septic shock, prolonged EICU time and increased SOFO score, blood lactic acid, LRG1 and GRP78 were independent risk factors for secondary ALI in patients with emergency sepsis (P<0.05). ROC curve analysis showed that, the area under the curve (AUC) of serum LRG1 and GRP78 levels alone and in combination in predicting ALI secondary to emergency sepsis were 0.790, 0.782 and 0.884 respectively, and the AUC of combined prediction was the largest (P<0.05). Conclusion: The increase of serum LRG1 and GRP78 levels in patients with emergency sepsis is closely relate to secondary ALI, and the combination of serum LRG1 and GRP78 levels has a higher value in predicting secondary ALI in patients with emergency sepsis. [ABSTRACT FROM AUTHOR]

Background: The diagnostic and prognostic value of the leucine-rich alpha-2-glycoprotein 1 (LRG1) gene in thyroid cancer remains unclear. Using the Cancer Genome Atlas (TCGA) database, we conducted a bioinformatics analysis to determine the role of LRG1 in thyroid cancer. Methods: Data from 512 patients with thyroid cancer and 59 normal individuals were collected from TCGA database. The Kruskal–Wallis test and logistic analysis were used to examine the relationship between LRG1 expression and clinicopathologic characteristics. Cox regression and Kaplan–Meier analysis were used to determine the predictive value of LRG1 on clinical outcomes. Single-sample gene set enrichment analysis (ssGSEA) was used to reveal associations between LRG1 expression and immune infiltration levels in thyroid cancer. Results: LRG1 was highly expressed in thyroid cancer (P < 0.001) and could effectively distinguish tumor tissue (area under the curve = 0.875) from normal tissue. Moreover, LRG1 was significantly correlated with pathological N stage (odds ratio (OR) = 2.411 (1.659–3.505), P < 0.001). Kaplan–Meier survival analysis revealed that patients with high LRG1 expression had better overall survival (hazard ratio (HR) = 0.30, P = 0.038). Cox regression analysis indicated that pathological M stage was a risk factor for progression-free interval (HR = 5.964 (2.010–17.694), P < 0.001). Using ssGSEA, we found that LRG1 expression was positively correlated with the number of T helper 1 cells (R = 0.435, P < 0.001), dendritic cells (R = 0.442, P < 0.001), and macrophages (R = 0.459, P < 0.001). Conclusion: LRG1 may be an important biomarker for predicting the prognosis of thyroid cancer and represent a suitable target for immunotherapy associated with immune infiltration.

Purpose: The primary objective was to establish whether blood-based leucine-rich alpha-2-glycoprotein (LRG1) can predict outcomes in patients with locally advanced prostate cancer undergoing androgen-deprivation therapy (ADT) and radiotherapy (RT) and to determine how it may relate to 92 immune-oncology (I-O)-related proteins in this setting. Methods: Baseline blood level of LRG1 from patients treated with ADT and RT enrolled in the CuPCa (n = 128) and IMRT (n = 81) studies was measured using ELISA. A longitudinal cohort with matched blood samples from start of ADT, start of RT, and end of RT protocol from 47 patients from the IMRT cohort was used to establish levels of I-O proteins by high-multiplexing Proximal Extension Assay by Olink Proteomics. Statistical analyses using Kaplan–Meier, Cox regression, and LIMMA analyses were applied to predict the prognostic value of LRG1 and its correlation to I-O proteins. Results: High baseline levels of LRG1 predicted a low frequency of treatment failure in patients undergoing ADT + RT in both the CuPCa and the IMRT cohorts. LRG1 was moderately correlated with CD4, IL6, and CSF1. We identified I-O proteins predicting metastatic failure (MF) at different timepoints. Conclusion: LRG1 biomarker is associated with I-O proteins and can be used to improve stratification and monitoring of prostate cancer patients undergoing ADT + RT. This work will require further in-depth analyses in independent cohorts with treatment outcome data. Study outline. A) Study cohorts. B) Sampling time points in a longitudinal cohort. [ABSTRACT FROM AUTHOR]

Atherosclerosis is the primary cause of cardiovascular disease. The development of plaque complications, such as calcification and neo-angiogenesis, strongly impacts plaque stability and is a good predictor of mortality in patients with atherosclerosis. Despite well-known risk factors of plaque complications, such as diabetes mellitus and chronic kidney disease, the mechanisms involved are not fully understood. We and others have identified that the concentration of circulating leucine-rich α-2 glycoprotein 1 (LRG1) was increased in diabetic and chronic kidney disease patients. Using apolipoprotein E knockout mice (ApoE−/−) (fed with Western diet) that developed advanced atherosclerosis and using human carotid endarterectomy, we showed that LRG1 accumulated into an atherosclerotic plaque, preferentially in calcified areas. We then investigated the possible origin of LRG1 and its functions on vascular cells and found that LRG1 expression was specifically enhanced in endothelial cells via inflammatory mediators and not in vascular smooth muscle cells (VSMC). Moreover, we identified that LRG1 was able to induce calcification and SMAD1/5-signaling pathways in VSMC. In conclusion, our results identified for the first time that LRG1 is a direct contributor to vascular calcification and suggest a role of this molecule in the development of plaque complications in patients with atherosclerosis. [ABSTRACT FROM AUTHOR]

Although the MAPK/MEK/ERK pathway is prevalently activated in colorectal cancer (CRC), MEK/ERK inhibitors show limited efficiency in clinic. As a downstream target of MAPK, ELK4 is thought to work primarily by forming a complex with SRF. Whether ELK4 can serve as a potential therapeutic target is unclear and the transcriptional regulatory mechanism has not been systemically analyzed. Here, it is shown that ELK4 promotes CRC tumorigenesis. Integrated genomics‐ and proteomics‐based approaches identified SP1 and SP3, instead of SRF, as cooperative functional partners of ELK4 at genome‐wide level in CRC. Serum‐induced phosphorylation of ELK4 by MAPKs facilitated its interaction with SP1/SP3. The pathological neoangiogenic factor LRG1 is identified as a direct target of the ELK4‐SP1/SP3 complex. Furthermore, targeting the ELK4‐SP1/SP3 complex by combination treatment with MEK/ERK inhibitor and the relatively specific SP1 inhibitor mithramycin A (MMA) elicited a synergistic antitumor effect on CRC. Clinically, ELK4 is a marker of poor prognosis in CRC. A 9‐gene prognostic model based on the ELK4‐SP1/3 complex‐regulated gene set showed robust prognostic accuracy. The results demonstrate that ELK4 cooperates with SP1 and SP3 to transcriptionally regulate LRG1 to promote CRC tumorigenesis in an SRF‐independent manner, identifying the ELK4‐SP1/SP3 complex as a potential target for rational combination therapy. [ABSTRACT FROM AUTHOR]

The establishment of new blood vessels, and their subsequent stabilization, is a critical process that facilitates tissue growth and organ development. Once established, vessels need to diversify to meet the specific needs of the local tissue and to maintain homeostasis. These processes are tightly regulated and fundamental to normal vessel and tissue function. The mechanisms that orchestrate angiogenesis and vessel maturation have been widely studied, with signaling crosstalk between endothelium and perivascular cells being identified as an essential component. In disease, however, new vessels develop abnormally, and existing vessels lose their specialization and function, which invariably contributes to disease progression. Despite considerable research into the vasculopathic mechanisms in disease, our knowledge remains incomplete. Accordingly, the identification of angiocrine and angiopathic molecules secreted by cells within the vascular microenvironment, and their effect on vessel behaviour, remains a major research objective. Over the last decade the secreted glycoprotein leucine-rich α-2 glycoprotein 1 (LRG1), has emerged as a significant vasculopathic molecule, stimulating defective angiogenesis, and destabilizing the existing vasculature mainly, but not uniquely, by altering both canonical and non-canonical TGF-β signaling in a highly cell and context dependent manner. Whilst LRG1 does not possess any overt homeostatic role in vessel development and maintenance, growing evidence provides a compelling case for LRG1 playing a pleiotropic role in disrupting the vasculature in many disease settings. Thus, LRG1 has now been reported to damage vessels in various disorders including cancer, diabetes, chronic kidney disease, ocular disease, and lung disease and the signaling processes that drive this dysfunction are being defined. Moreover, therapeutic targeting of LRG1 has been widely proposed to re-establish a quiescent endothelium and normalized vasculature. In this review, we consider the current status of our understanding of the role of LRG1 in vascular pathology, and its potential as a therapeutic target.

Abstract Although the MAPK/MEK/ERK pathway is prevalently activated in colorectal cancer (CRC), MEK/ERK inhibitors show limited efficiency in clinic. As a downstream target of MAPK, ELK4 is thought to work primarily by forming a complex with SRF. Whether ELK4 can serve as a potential therapeutic target is unclear and the transcriptional regulatory mechanism has not been systemically analyzed. Here, it is shown that ELK4 promotes CRC tumorigenesis. Integrated genomics‐ and proteomics‐based approaches identified SP1 and SP3, instead of SRF, as cooperative functional partners of ELK4 at genome‐wide level in CRC. Serum‐induced phosphorylation of ELK4 by MAPKs facilitated its interaction with SP1/SP3. The pathological neoangiogenic factor LRG1 is identified as a direct target of the ELK4‐SP1/SP3 complex. Furthermore, targeting the ELK4‐SP1/SP3 complex by combination treatment with MEK/ERK inhibitor and the relatively specific SP1 inhibitor mithramycin A (MMA) elicited a synergistic antitumor effect on CRC. Clinically, ELK4 is a marker of poor prognosis in CRC. A 9‐gene prognostic model based on the ELK4‐SP1/3 complex‐regulated gene set showed robust prognostic accuracy. The results demonstrate that ELK4 cooperates with SP1 and SP3 to transcriptionally regulate LRG1 to promote CRC tumorigenesis in an SRF‐independent manner, identifying the ELK4‐SP1/SP3 complex as a potential target for rational combination therapy.

Background: Biochanin A is an excellent dietary isoflavone that has the concomitant function of both medicine and foodstuff. The attenuation function of biochanin A on blood-brain barrier (BBB) damage induced by cerebral ischemia-reperfusion remains unclear. Methods: C57BL/6 mice were subjected to 1 h middle cerebral artery occlusion (MCAO) followed by 24 h reperfusion. The infarct volume of the brain was stained by TTC, while leakage of the brain was quantitatively stained by Evans blue, and the neurologic deficit score was measured. Microglial-induced morphologic changes were observed via immunofluorescence staining, and rolling and adhering leukocytes in venules were observed via two-photon imaging, while the inner fluorescein isothiocyanate-albumin of venules were compared with those of surrounding interstitial area through venular albumin leakage. Results: The attenuation effect of biochanin A on tight junction injury was compared in ischemia-reperfusion mice or conventional knockdown of leucine-rich α2-glycoprotein 1 (Lrg1) mice. Biochanin A could ameliorate BBB injury in mice with cerebral ischemiareperfusion in a dose-dependent manner by strengthening the immunostaining volume of occludin, claudin-5, and zonula occludens-1. The amoeba morphologic changes of microglial combined with the elevated expression of Lrg1 could be relieved under the treatment of biochanin A. Biochanin A played a countervailing role on the rolling leukocytes in the vessel, while the leakage of blood vessels was reduced. Biochanin A diminished its functions to further improved attenuation for tight junction injury on conventional Lrg1-knockout mice, as well as the inhibition effects on TGF-β1, and the phosphorylation of suppressor of mothers against decapentaplegic 2 (Smad2)/Smad2 via western blot assay. Conclusion: Biochanin A could alleviate tight junction injury induced by cerebral ischemiareperfusion and blocked the Lrg1/TGF-β/Smad2 pathway to modulate leukocyte migration patterns. [ABSTRACT FROM AUTHOR]

Leucine-rich alpha-2-glycoprotein 1 (LRG1) mediates skin repair and fibrosis by stimulating the transforming growth factor-beta (TGF-β) signaling pathway. In the present study, we investigated the effect of LRG1 on extracellular matrix (ECM) integrity in fibroblasts, as well as on skin aging. The treatment of dermal fibroblasts with purified recombinant human LRG1 increased type I collagen secretion and decreased matrix metalloproteinase-1 secretion. Additionally, LRG1 promoted SMAD2/SMAD3 phosphorylation in a pattern similar to that of TGF-β1 treatment. An inhibitor of TGF-β receptor 1 abolished LRG1-induced SMAD2 phosphorylation. RNA sequencing identified "extracellular region", "extracellular space", and "extracellular matrix" as the main Gene Ontology terms in the differentially expressed genes of fibroblasts treated with or without LRG1. LRG1 increased TGF-β1 mRNA levels, suggesting that LRG1 partially transactivates the expression of TGF-β1. Furthermore, an increased expression of type I collagen was also observed in fibroblasts grown in three-dimensional cultures on a collagen gel mimicking the dermis. LRG1 mRNA and protein levels were significantly reduced in elderly human skin tissues with weakened ECM integrity compared to in young human skin tissues. Taken together, our results suggest that LRG1 could retard skin aging by activating the TGF-β signaling pathway, increasing ECM deposition while decreasing its degradation. [ABSTRACT FROM AUTHOR]

Implant loosening is a severe complication after total joint replacement. Here, differential diagnosis between septic and aseptic cases is crucial for further surgical treatment, but low-grade periprosthetic joint infections (PJIs) in particular remain a challenge. In this study, we analyzed the synovial fluid proteome of 21 patients undergoing revision surgery for septic (eight cases) or aseptic (thirteen cases) implant failure using LC-MS/MS to identify potential new biomarkers as future diagnostic tools. Staphylococci were found in four cases, Streptococci in two cases, Serratia marcescens and Cutibacterium acnes in one case. Proteomic analysis of the synovial fluid resulted in the identification of 515 different proteins based on at least two peptides. A statistical comparison revealed 37 differentially abundant proteins (p < 0.05), of which 17 proteins (46%) showed a higher abundance in the septic group. The proteins with the highest fold change included the known marker proteins c-reactive protein (7.57-fold) and the calprotectin components protein S100-A8 (4.41-fold) and protein S100-A9 (3.1-fold). However, the protein with the highest fold change was leucine-rich alpha-2-glycoprotein 1 (LRG1) (9.07-fold), a currently discussed new biomarker for inflammatory diseases. Elevated LRG1 levels could facilitate the diagnosis of PJI in the future, but their significance needs to be further investigated.

The aim of this study was to analyze the diagnostic performance of Leucine-Rich Alpha-2-Glycoprotein (LRG1) in pediatric acute appendicitis (PAA). We conducted a systematic review of the literature in the main databases of medical bibliography. Two independent reviewers selected the articles and extracted relevant data. Methodological quality was assessed using the QUADAS2 index. A synthesis of the results, standardization of the metrics and 4 random-effect meta-analyses were performed. Eight studies with data from 712 participants (305 patients with confirmed diagnosis of PAA and 407 controls) were included in this review. The random-effect meta-analysis of serum LRG1 (PAA vs control) resulted in a significant mean difference (95% CI) of 46.76 μg/mL (29.26–64.26). The random-effect meta-analysis for unadjusted urinary LRG1 (PAA vs control) resulted in a significant mean difference (95% CI) of 0.61 μg/mL (0.30–0.93). The random-effect meta-analysis (PAA vs control) for urinary LRG1 adjusted for urinary creatinine resulted in a significant mean difference (95% CI) of 0.89 g/mol (0.11–1.66). Conlusion: Urinary LRG1 emerges as a potential non-invasive biomarker for the diagnosis of PAA. On the other hand, due to the high between-study heterogeneity, the results on serum LRG1 should be interpreted with caution. The only study that analyzed salivary LRG1 showed promising results. Further prospective studies are needed to confirm these findings. What is Known: • Pediatric acute appendicitis continues to be a pathology with a high rate of diagnostic error. • Invasive tests, although useful, are a source of stress for patients and their parents. What is New: • LRG1 emerges as a promising urinary and salivary biomarker for the noninvasive diagnosis of pediatric acute appendicitis. [ABSTRACT FROM AUTHOR]

Background: After radical prostatectomy (RP), depending on stage, up to 40% of patients with prostate cancer (PCa) will experience biochemical failure (BF). Despite salvage therapy, approximately one-third of these patients will need permanent hormone therapy (pHT) and are at risk of progression to castration-resistant PCa (CRPC). Prognostic markers herald the need for neoadjuvant, adjuvant, or multimodal treatment. Objective: To evaluate the added value of blood LRG1 in predicting treatment failure in patients who have undergone radical prostatectomy (RP). Design, setting, and participants: We quantified LRG1 in serum or plasma sampled before radical prostatectomy from patients from the Martini-Klinik (Martini; n = 423), the Danish CuPCa cohort (CuPCa; n = 182), and Oslo University Hospital (OUH; n = 145). Outcome measurements and statistical analysis: The endpoints were BF, pHT, and CRPC. The association between LRG1 and survival outcomes was evaluated using Kaplan-Meier estimation and Cox proportional-hazards modeling. The added predictive value of LRG1 in nested models was estimated using the concordance index, time-dependent area under the receiver operating characteristic curve, and decision curve analysis. Results and limitations: In multivariable Cox models using preoperative characteristics, LRG1 was associated with an estimated lower risk of BF in the Martini cohort (adjusted hazard ratio [aHR] 0.68, 95% confidence interval [CI] 0.52–0.90) and in the CuPCa cohort (aHR 0.47, 95% CI 0.30–0.73). Using preoperative prognostic variables, our data showed that doubling of LRG1 was also associated with a lower risk of pHT receipt in the CuPCa cohort (aHR 0.43, 95% CI 0.20–0.93) and of CRPC development in the OUH cohort (aHR 0.32, 95% CI 0.15–0.69). Similar aHR values were observed using either preoperative or postoperative variables for all endpoints. Conclusions: PCa patients with high blood LRG1 are at lower risk of BF, pHT receipt, and progression to CRPC. Since LRG1 adds value to established prognostic models, new prognostic factor combinations including LRG1 should be considered in future studies. Patient summary: We measured concentrations of the blood-based protein LRG1 before surgery for prostate cancer. Patients with high LRG1 levels had better disease-free survival, suggesting that LRG1 can help in predicting prognosis.

Abstract Background Lymphocytic leukemia (LL) is a primary malignant tumor of hematopoietic tissue, which seriously affects the health of children and the elderly. The study aims to establish a new detection method for screening acute/chronic LL using time-resolved fluorescence immunoassay (TRFIA) via quantitative detection of S100 calcium binding protein A8 (S100A8) and leucine-rich alpha-2-glycoprotein 1 (LRG1) in serum. Methods Here a sandwich TRFIA was optimized and established: Anti-S100A8/LRG1 caputre antibodies immobilized on 96-well plates captured S100A8/LRG1, and then banded together with the anti-S100A8/LRG1 detection antibodies labeled with Europium(III) (Eu3+)/samarium(III) (Sm3+) chelates. Finally time resolved fluorometry measured the fluorescence intensity. Results The sensitivity of S100A8 was 1.15 ng/mL(LogY = 3.4027 + 0.4091 × LogX, R 2 = 0.9828, P

Purpose: The aim of this study is to assess the diagnostic utility of serum leucine-rich α-2-glycoprotein 1 (LRG1) in pediatric patients with acute abdominal pain, admitted to the emergency surgical unit, in order to make a prompt and accurate diagnosis of acute appendicitis. Patients and methods: Pediatric patients older than 5 years of age who presented to the emergency department from 15 October 2021 to 30 June 2022 with acute abdominal pain and suspected acute appendicitis were prospectively recruited in the study. Demographic and clinical data, as well as operative and postoperative data, were recorded. A total of 92 patients were equally distributed into two groups: children with acute appendicitis who underwent laparoscopic appendectomy and non-appendicitis patients, presenting with non-specific abdominal pain. LRG1 levels were determined using a commercially available LRG1 enzyme-linked immunosorbent assay (ELISA) kit. Serum LRG1 levels, as well as other inflammatory markers (white blood cell count (WBC), C-reactive protein (CRP) and absolute neutrophil count) were compared between groups. Results: The median level of LRG1 in serum was significantly higher in the group of children with pathohistologically confirmed acute appendicitis than in the control group, at 350.3 µg/mL (interquartile range (IQR) 165.2–560.3) and 25.7 µg/mL (IQR 14.7–36.8) (p < 0.001), respectively. Receiver operating characteristic area under the curve for LRG1 from serum was 1.0 (95% CI 0.96–1.00; p < 0.001) and the value of >69.1 µg/mL was found to perfectly separate acute appendicitis cases from controls. Additionally, as expected, each of the examined laboratory inflammatory markers provided a significantly higher values in the acute appendicitis group compared to the control group: WBC 14.6 × 109/L (IQR 12.7, 18.7) vs. 7.0 × 109/L (IQR 5.4, 9.0) (p < 0.001), CRP 16.3 mg/dL (IQR 6.9, 50.4) vs. 2.2 mg/dL (IQR 2, 2) (p < 0.001) and absolute neutrophil count 84.6% (IQR 79.5, 89.0) vs. 59.5% (IQR 51.5, 68.6) (p < 0.001). Conclusions: LRG1 in the serum was found to be a promising novel biomarker, with excellent differentiation of acute appendicitis from non-appendicitis cases in children presenting with non-specific abdominal pain. [ABSTRACT FROM AUTHOR]

The aim of this study is to evaluate the diagnostic accuracy of leucine-rich α-2-glycoprotein 1 (LRG1) in saliva as a novel biomarker for acute appendicitis in the pediatric population. From October 2021 to June 2022, 92 children aged 5 to 17 years who presented with acute abdomen and suspected acute appendicitis were enrolled in this prospective study. The parameters documented included demographic and clinical information, as well as operative and postoperative data. Patients were divided into two groups: those with acute appendicitis who underwent laparoscopic appendectomy (n = 46) and those without appendicitis (n = 46). The total white blood cell (WBC) count, percent of neutrophils, C-reactive protein (CRP) level, and salivary LRG1 were compared between groups. A commercially available enzyme-linked immunosorbent assay (ELISA) LRG kit was used to measure the LRG levels. The median salivary LRG1 level was significantly higher in the group of children with pathohistologically confirmed acute appendicitis compared to the control group: 233.45 ng/mL (IQR 114.9, 531.2) vs. 55.95 ng/mL (IQR 51.5, 117.9), p < 0.001. LRG1 had an overall good receiver-operator characteristic area under the curve of 0.85 (95% CI 0.76–0.92; p < 0.001). The optimal LRG1 cutoff with best separation between acute appendicitis and the controls was >352.6 ng/mL (95% CI from >270.7 to >352.6). Although the specificity was 100% at this cutoff, the sensitivity for identifying appendicitis was 36%. In addition, a significant difference was found between groups in the laboratory values of all inflammatory markers tested: WBC, absolute neutrophil count, and CRP (p < 0.001 for all). Although LRG1 in saliva showed a good AUC parameter and significantly higher values in patients with acute appendicitis compared to the controls, its usefulness in the patient population who present at emergency departments with abdominal pain is debatable. Future studies should focus on investigating its diagnostic potential. [ABSTRACT FROM AUTHOR]

Atherosclerosis is the primary cause of cardiovascular disease. The development of plaque complications, such as calcification and neo-angiogenesis, strongly impacts plaque stability and is a good predictor of mortality in patients with atherosclerosis. Despite well-known risk factors of plaque complications, such as diabetes mellitus and chronic kidney disease, the mechanisms involved are not fully understood. We and others have identified that the concentration of circulating leucine-rich α-2 glycoprotein 1 (LRG1) was increased in diabetic and chronic kidney disease patients. Using apolipoprotein E knockout mice (ApoE−/−) (fed with Western diet) that developed advanced atherosclerosis and using human carotid endarterectomy, we showed that LRG1 accumulated into an atherosclerotic plaque, preferentially in calcified areas. We then investigated the possible origin of LRG1 and its functions on vascular cells and found that LRG1 expression was specifically enhanced in endothelial cells via inflammatory mediators and not in vascular smooth muscle cells (VSMC). Moreover, we identified that LRG1 was able to induce calcification and SMAD1/5-signaling pathways in VSMC. In conclusion, our results identified for the first time that LRG1 is a direct contributor to vascular calcification and suggest a role of this molecule in the development of plaque complications in patients with atherosclerosis.

Diabetic nephropathy (DN) has high prevalence and poor prognosis which make it a research priority for scientists. Since metformin, a hypoglycaemic drug, has been found to prolong the survival of mice with DN. This study aims at investigating the molecular mechanisms leading to DN in rats and to explore the role of leucine-rich α-2-glycoprotein-1 (LRG1), activin-like kinase1 (ALK1), and transforming growth factor–β (TGFβ1) in the pathologic alterations seen in DN. The aim was also extended to explore the protective action of metformin against DN in rats and its influence on LRG1and ALK1/TGFβ1 induced renal angiogenesis. 24 male rats were used. Rats were assigned as, the vehicle group, the diabetic control group and diabetic + metformin (100 and 200 mg/kg) groups. Kidney samples were processed for histopathology, immunohistochemistry and biochemical analysis. Bioinformatic analysis of studied proteins was done to determine protein-protein interactions. Metformin reduced serum urea and creatinine significantly, decreased the inflammatory cytokine levels and reduced LRG1, TGFβ1, ALK1 and vascular endothelial growth factor (VEGF) proteins in rat kidneys. Bioinformatic analysis revealed interactions between the studied proteins. Metformin alleviated the histopathological changes observed in the diabetic rats such as the glomerular surface area and increased Bowman’s space diameter. Metformin groups showed decreased VEGF immunostaining compared to diabetic group. Metformin shows promising renoprotective effects in diabetic model that was at least partly mediated by downregulation of LRG1 and TGFβ1/ALK1-induced renal angiogenesis. These results further explain the molecular mechanism of metformin in DN management.

Leucine-rich alpha-2-glycoprotein 1 (LRG1) mediates skin repair and fibrosis by stimulating the transforming growth factor-beta (TGF-β) signaling pathway. In the present study, we investigated the effect of LRG1 on extracellular matrix (ECM) integrity in fibroblasts, as well as on skin aging. The treatment of dermal fibroblasts with purified recombinant human LRG1 increased type I collagen secretion and decreased matrix metalloproteinase-1 secretion. Additionally, LRG1 promoted SMAD2/SMAD3 phosphorylation in a pattern similar to that of TGF-β1 treatment. An inhibitor of TGF-β receptor 1 abolished LRG1-induced SMAD2 phosphorylation. RNA sequencing identified “extracellular region”, “extracellular space”, and “extracellular matrix” as the main Gene Ontology terms in the differentially expressed genes of fibroblasts treated with or without LRG1. LRG1 increased TGF-β1 mRNA levels, suggesting that LRG1 partially transactivates the expression of TGF-β1. Furthermore, an increased expression of type I collagen was also observed in fibroblasts grown in three-dimensional cultures on a collagen gel mimicking the dermis. LRG1 mRNA and protein levels were significantly reduced in elderly human skin tissues with weakened ECM integrity compared to in young human skin tissues. Taken together, our results suggest that LRG1 could retard skin aging by activating the TGF-β signaling pathway, increasing ECM deposition while decreasing its degradation.

Abstract The secreted glycoprotein leucine-rich α-2 glycoprotein 1 (LRG1) was first described as a key player in pathogenic ocular neovascularization almost a decade ago. Since then, an increasing number of publications have reported the involvement of LRG1 in multiple human conditions including cancer, diabetes, cardiovascular disease, neurological disease, and inflammatory disorders. The purpose of this review is to provide, for the first time, a comprehensive overview of the LRG1 literature considering its role in health and disease. Although LRG1 is constitutively expressed by hepatocytes and neutrophils, Lrg1 −/− mice show no overt phenotypic abnormality suggesting that LRG1 is essentially redundant in development and homeostasis. However, emerging data are challenging this view by suggesting a novel role for LRG1 in innate immunity and preservation of tissue integrity. While our understanding of beneficial LRG1 functions in physiology remains limited, a consistent body of evidence shows that, in response to various inflammatory stimuli, LRG1 expression is induced and directly contributes to disease pathogenesis. Its potential role as a biomarker for the diagnosis, prognosis and monitoring of multiple conditions is widely discussed while dissecting the mechanisms underlying LRG1 pathogenic functions. Emphasis is given to the role that LRG1 plays as a vasculopathic factor where it disrupts the cellular interactions normally required for the formation and maintenance of mature vessels, thereby indirectly contributing to the establishment of a highly hypoxic and immunosuppressive microenvironment. In addition, LRG1 has also been reported to affect other cell types (including epithelial, immune, mesenchymal and cancer cells) mostly by modulating the TGFβ signalling pathway in a context-dependent manner. Crucially, animal studies have shown that LRG1 inhibition, through gene deletion or a function-blocking antibody, is sufficient to attenuate disease progression. In view of this, and taking into consideration its role as an upstream modifier of TGFβ signalling, LRG1 is suggested as a potentially important therapeutic target. While further investigations are needed to fill gaps in our current understanding of LRG1 function, the studies reviewed here confirm LRG1 as a pleiotropic and pathogenic signalling molecule providing a strong rationale for its use in the clinic as a biomarker and therapeutic target.

While dysregulation of adipocyte endocrine function plays a central role in obesity and its complications, the vast majority of adipokines remain uncharacterized. We employed bio-orthogonal non-canonical amino acid tagging (BONCAT) and mass spectrometry to comprehensively characterize the secretome of murine visceral and subcutaneous white and interscapular brown adip ocytes. Over 600 proteins were identified, the majority of which showed cell type-specific enrichment. We here describe a metabolic role for leucine-rich α–2 glycoprotein 1 (LRG1) as an obesity-regulated adipokine secreted by mature adipocytes. LRG1 overexpression significantly improved glucose homeostasis in diet-induced and genetically obese mice. This was associated with markedly reduced white adipose tissue macrophage accumulation and systemic inflammation. Mechanistically, we found LRG1 binds cytochrome c in circulation to dampen its pro-inflammatory effect. These data support a new role for LRG1 as an insulin sensitizer with therapeutic potential given its immunomodulatory function at the nexus of obesity, inflammation, and associated pathology.

Background: Lymphocytic leukemia (LL) is a primary malignant tumor of hematopoietic tissue, which seriously affects the health of children and the elderly. The study aims to establish a new detection method for screening acute/chronic LL using time-resolved fluorescence immunoassay (TRFIA) via quantitative detection of S100 calcium binding protein A8 (S100A8) and leucine-rich alpha-2-glycoprotein 1 (LRG1) in serum. Methods: Here a sandwich TRFIA was optimized and established: Anti-S100A8/LRG1 caputre antibodies immobilized on 96-well plates captured S100A8/LRG1, and then banded together with the anti-S100A8/LRG1 detection antibodies labeled with Europium(III) (Eu3+)/samarium(III) (Sm3+) chelates. Finally time resolved fluorometry measured the fluorescence intensity. Results: The sensitivity of S100A8 was 1.15 ng/mL(LogY = 3.4027 + 0.4091 × LogX, R2 = 0.9828, P < 0.001, dynamic range: 2.1–10,000 ng/mL), and 3.2 ng/mL for LRG1 (LogY = 3.3009 + 0.4082 × LogX, R2 = 0.9748, P < 0.001, dynamic range: 4.0–10,000 ng/mL). The intra-assay and inter-assay CVs were low, ranging from 5.75% to 8.23% for S100A8 and 5.30% to 9.45% for LRG1 with high specificity and affinity in serum samples. Bland–Altman plots indicated TRFIA and ELISA kits have good agreement in clinical serum samples. Additionally, the cutoff values for S100A8 and LRG1 were 1849.18 ng/mL and 588.08 ng/mL, respectively. Conclusion: The present TRFIA method could be used for the quantitative detection of S100A8 and LRG1 in serum, and it has high sensitivity, accuracy and specificity. Clinically, this TRFIA method could be suitable for screening of LL via the quantitative detection of S100A8 and LRG1. [ABSTRACT FROM AUTHOR]

Background: Prostate cancer (PC) is one of the most frequently diagnosed non-skin solid cancers and is a leading cause of cancer-related death and the incidence increasing. Early diagnosis of the disease improves the outcomes. There is an urgent need for new biomarkers with greater discriminative precision for diagnosis, risk-stratification and treatment. The aim of our study was to evaluate the diagnostic and prognostic potential of Fetuin-A and LRG1 in patients with PC., Methods: Serum levels of Fetuin-A and LRG1 were compared in patients with PC (n=46), a control group 1 including young, healthy subjects (n=26) and control group 2 including patients with negative prostate biopsy (n=46). In PC patients, the levels of both biomarkers were compared in subgroups with different tumour characteristics., Results: We demonstrated a statistically significant higher concentrations of Fetuin-A in PC patients compared to control group 2 (439 mg/L vs. 372 mg/L), P<0.001. No statistically significant difference was found between PC patients and control group 1, nor for LRG1 levels between the three groups. In PC patients, higher serum levels of LRG1 were found in M1 patients compared to M0 (98 mg/L vs. 42 mg/L), P=0.059., Conclusion: Fetuin-A levels are significantly higher in patients with prostate cancer than in patients without malignancy but LRG1 levels do not differ between patients with PC and controls., Competing Interests: The authors report no conflicts of interest in this work.

Renal fibrosis lacks effective nephroprotective drugs in clinical settings due to poor accumulation of therapeutic agents in damaged kidneys, underscoring the urgent need for advanced renal-targeted delivery systems. Herein, we exploited the significantly increased expression of the leucine-rich α-2 glycoprotein 1 (LRG1) protein during renal fibrosis to develop a novel drug delivery system. Our engineered nanocarrier, DEN NM , preferentially targets fibrotic kidneys via the decorated ET peptide's high affinity for LRG1. Once internalized by damaged renal cells, DEN NM releases its encapsulated nintedanib, triggered by the active caspase-3 protease, disrupting the nanomedicine's structural integrity. The released nintedanib effectively reduces the level of expression of the extracellular matrix and impedes the progression of renal fibrosis by inhibiting the transforming growth factor-β (TGF-β)-Smad2/3 pathway. Our comprehensive in vitro and in vivo studies validate DEN NM 's antifibrotic efficacy, emphasizing LRG1's potential in renal targeted drug delivery and introducing an innovative approach to nanomedicine for treating renal fibrosis.

Transforming growth factor (TGF)-β signaling is a well-established pathogenic mediator of diabetic kidney disease (DKD). However, owing to its pleiotropic actions, its systemic blockade is not therapeutically optimal. The expression of TGF-β signaling regulators can substantially influence TGF-β's effects in a cell- or context-specific manner. Among these, leucine-rich α2-glycoprotein 1 (LRG1) is significantly increased in glomerular endothelial cells (GECs) in DKD. As LRG1 is a secreted molecule that can exert autocrine and paracrine effects, we examined the effects of LRG1 loss in kidney cells in diabetic OVE26 mice by single-cell transcriptomic analysis. Gene expression analysis confirmed a predominant expression of Lrg1 in GECs, which further increased in diabetic kidneys. Loss of Lrg1 led to the reversal of angiogenic and TGF-β-induced gene expression in GECs, which were associated with DKD attenuation. Notably, Lrg1 loss also mitigated the increased TGF-β-mediated gene expression in both podocytes and mesangial cells in diabetic mice, indicating that GEC-derived LRG1 potentiates TGF-β signaling in glomerular cells in an autocrine and paracrine manner. Indeed, a significant reduction in phospho-Smad proteins was observed in the glomerular cells of OVE26 mice with LRG1 loss. These results indicate that specific antagonisms of LRG1 may be an effective approach to curb the hyperactive glomerular TGF-β signaling to attenuate DKD., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The American Society of Gene and Cell Therapy. All rights reserved.)

Atherosclerosis is a chronic inflammatory disease of the arterial wall characterized by the accumulation of cholesterol-rich lipoproteins in macrophages. How macrophages commit to proinflammatory polarization under atherosclerosis conditions is not clear. Report here that the level of a circulating protein, leucine-rich alpha-2 glycoprotein 1 (LRG1), is elevated in the atherosclerotic tissue and serum samples from patients with coronary artery disease (CAD). LRG1 stimulated macrophages to proinflammatory M1-like polarization through the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK) pathways. The LRG1 knockout mice showed significantly delayed atherogenesis progression and reduced levels of macrophage-related proinflammatory cytokines in a high-fat diet-induced Apoe -/- mouse atherosclerosis model. An anti-LRG1 neutralizing antibody also effectively blocked LRG1-induced macrophage M1-like polarization in vitro and conferred therapeutic benefits to animals with ApoE deficiency-induced atherosclerosis. LRG1 may therefore serve as an additional biomarker for CAD and targeting LRG1 could offer a potential therapeutic strategy for CAD patients by mitigating the proinflammatory response of macrophages., Competing Interests: Competing interests statement:The authors declare no competing interest.

Leucine-rich α-2 glycoprotein 1 (LRG1), a secreted glycoprotein, has been identified as significantly upregulated in renal fibrosis, potentially exacerbating the condition by enhancing TGF-β-Smad3-dependent signaling pathways. Herein, utilizing our developed LRG1-targeting peptide for LRG1 recruitment and lenalidomide for E3 ubiquitin ligase engagement, we developed an advanced proteolysis targeting chimera, ET TAC-2, specifically designed for LRG1 degradation. Our cellular degradation assays validated that ET TAC-2 effectively degraded LRG1 through a proteasome-dependent mechanism, achieving half-maximal degradation at a concentration of 8.38 µM. Furthermore, anti-fibrotic experiments conducted both in vitro and in vivo revealed that ET TAC-2 efficiently induced LRG1 degradation in fibrotic kidneys. This action effectively inhibited the TGF-β-Smad3 signaling pathway and diminished the secretion of fibrosis-associated proteins, consequently attenuating the progression of renal fibrosis. Our study highlights the pivotal role of LRG1 in renal fibrosis and positions ET TAC-2 as a promising therapeutic candidate for targeted LRG1 intervention., Competing Interests: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article., (© 2024 Shenyang Pharmaceutical University. Published by Elsevier B.V.)

Background: Rapid progression and early metastasis remain the main cause of high mortality in epithelial ovarian cancer (EOC) patients. The objective of this study was to explore the mechanisms of EOC progression and detect the function of leucine-rich alpha-2-glycoprotein 1 (LRG1) in modulating the pathologic process. Methods: Ultracentrifugation was initially performed to extract exosomes from the urine samples of EOC patients and healthy female subjects. Mass spectrometry (MS) was employed to analyze differentially expressed proteins. Survival analysis was performed to examine the association between LRG1 levels and the prognosis of EOC patients. LRG1 silencing ovarian cancer cell lines were built and cell migration was further evaluated via wound healing and transwell assays. Immunoblot, immunofluorescence and immunohistochemistry analyses were performed. A subcutaneous tumor model was established to study the function of LRG1 in vivo. Results: Exosomal LRG1 was specifically expressed in urine samples of EOC patients and high LRG1 levels were significantly associated with poor prognosis. Function analyses showed that LRG1 was associated with ovarian cancer migration and progression. Mechanistically, LRG1 was significantly related to the focal adhesion kinase/protein kinase B (FAK/AKT) signaling pathway. Conclusions: LRG1 participated in progression and metastasis of ovarian cancer via activation of the FAK/AKT pathway probably.

Background: Although ceramides are involved in the pathophysiology of cardiovascular disease and other inflammation-associated disorders, there is a paucity of data on the association between plasma ceramides and inflammatory biomarkers in type 2 diabetes mellitus (T2DM). Therefore, we explored whether there was an association between plasma leucine-rich α-2 glycoprotein 1 (LRG1) concentrations (i.e., a novel proinflammatory signaling molecule) and specific plasma ceramides in postmenopausal women with T2DM. Methods: We measured six previously identified plasma ceramides, which have been associated with increased cardiovascular risk [plasma Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/20:0), Cer(d18:1/22:0), Cer(d18:1/24:0) and Cer(d18:1/24:1)], amongst 99 Caucasian postmenopausal women with non-insulin-treated T2DM (mean age 72 ± 8 years, mean hemoglobin A1c 6.9 ± 0.7%), who consecutively attended our diabetes outpatient service during a 3-month period. Plasma ceramide and LRG1 concentrations were measured with a targeted liquid chromatography-tandem mass spectrometry assay and a Milliplex® MAP human cardiovascular disease magnetic bead kit, respectively. Results: In linear regression analyses, higher plasma LRG1 levels (1st tertile vs. 2nd and 3rd tertiles combined) were associated with higher levels of plasma Cer(d18:1/16:0) (standardized β coefficient: 0.289, p = 0.004), Cer(d18:1/18:0) (standardized β coefficient: 0.307, p = 0.002), Cer(d18:1/20:0) (standardized β coefficient: 0.261, p = 0.009) or Cer(d18:1/24:1) (standardized β coefficient: 0.343, p < 0.001). These associations remained significant even after adjusting for age, body mass index, systolic blood pressure, total cholesterol level, hemoglobin A1c, insulin resistance and statin use. Conclusions: The results of our pilot exploratory study suggest that higher plasma LRG1 concentration was associated with higher levels of specific high-risk plasma ceramide molecules in elderly postmenopausal women with metabolically well-controlled T2DM, even after adjusting for known cardiovascular risk factors and other potential confounding variables. [ABSTRACT FROM AUTHOR]

Background: Sepsis is a commonly seen severe case in clinical practice and the main cause of health loss worldwide. Objective: We investigated the biological function of LRG1 and its underlying molecular mechanisms in sepsis-renal injury. Mice of sepsis model group were subjected to cecal ligation and puncture (CLP) surgery after anesthetization. THP-1 cell was induced by LPS for vitro model. Results: The mRNA and protein levels of LRG1 in renal tissue of sepsis model were reduced. LRG1 could reduce the inflammation reaction in model of sepsis-renal injury. In addition, LRG1 up-regulation reduced inflammation reaction and ROS production levels in vitro model via the activation of HIF-1α and suppression of NLRP3 inflammasome. Knockout of LRG1 increased inflammation reaction and ROS production levels in vitro model via the inactivation of HIF-1α and induction of NLRP3 inflammasome. Furthermore, the inhibition of HIF-1α reduced the effects of LRG1 on NLRP3 inflammasome in vitro model. Conclusions: The present study suggests that LRG1 expression reduced inflammation of sepsis-renal injury via activation of NLRP3 inflammasome by HIF-1α, thereby may be a promising therapeutic target of sepsis-renal injury. [ABSTRACT FROM AUTHOR]

Abstract Autophagy is a conserved cellular process required to maintain homeostasis. The hallmark of autophagy is the formation of a phagophore that engulfs cytosolic materials for degradation and recycling to synthesize essential components. Basal autophagy is constitutively active under normal conditions and it could be further induced by physiological stimuli such as hypoxia, nutrient starvation, endoplasmic reticulum stress,energy depletion, hormonal stimulation and pharmacological treatment. In cancer, autophagy is highly context-specific depending on the cell type, tumour microenvironment, disease stage and external stimuli. Recently, the emerging role of autophagy as a double-edged sword in cancer has gained much attention. On one hand, autophagy suppresses malignant transformation by limiting the production of reactive oxygen species and DNA damage during tumour development. Subsequently, autophagy evolved to support the survival of cancer cells and promotes the tumourigenicity of cancer stem cells at established sites. Hence, autophagy is an attractive target for cancer therapeutics and researchers have been exploiting the use of autophagy modulators as adjuvant therapy. In this review, we present a summary of autophagy mechanism and controlling pathways, with emphasis on the dual-role of autophagy (double-edged sword) in cancer. This is followed by an overview of the autophagy modulation for cancer treatment and is concluded by a discussion on the current perspectives and future outlook of autophagy exploitation for precision medicine.

Leucine-rich α2-glycoprotein-1 (LRG1) is overexpressed in various cancers, including non-small cell lung cancer (NSCLC), but its role in NSCLC cell metastasis is not well understood. In this study, NSCLC cell exosomes were analyzed using different techniques, and the impact of exosomal LRG1 on NSCLC cell behavior was investigated through various assays both in vitro and in vivo. The study revealed that LRG1, found abundantly in NSCLC cells and exosomes, enhanced cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT). Exosomal LRG1 was shown to promote NSCLC cell metastasis in animal models. Additionally, the interaction between LRG1 and fibronectin 1 (FN1) in the cytoplasm was identified. It was observed that FN1 could counteract the effects of LRG1 knockdown on cell regulation induced by exosomes derived from NSCLC cells. Overall, the findings suggest that targeting exosomal LRG1 or FN1 may hold therapeutic potential for treating NSCLC. • Reducing the expression level of LRG1 decreases the ability of exosomes secreted by NSCLC cells to regulate cell proliferation, migration, invasion, and EMT. • LRG1 interacted with FN1 and regulated FN1, and FN1 can counteract the effects of exosomes with LRG1 knockdown on cell regulation. • LRG1 or FN1 may play a role in promoting NSCLC progression and metastasis. Therefore, targeting exosomal LRG1 or FN1 proteins could be a promising approach for NSCLC treatment. [ABSTRACT FROM AUTHOR]

The aim of this study is to evaluate the diagnostic accuracy of leucine-rich α-2-glycoprotein 1 (LRG1) in saliva as a novel biomarker for acute appendicitis in the pediatric population. From October 2021 to June 2022, 92 children aged 5 to 17 years who presented with acute abdomen and suspected acute appendicitis were enrolled in this prospective study. The parameters documented included demographic and clinical information, as well as operative and postoperative data. Patients were divided into two groups: those with acute appendicitis who underwent laparoscopic appendectomy (n = 46) and those without appendicitis (n = 46). The total white blood cell (WBC) count, percent of neutrophils, C-reactive protein (CRP) level, and salivary LRG1 were compared between groups. A commercially available enzyme-linked immunosorbent assay (ELISA) LRG kit was used to measure the LRG levels. The median salivary LRG1 level was significantly higher in the group of children with pathohistologically confirmed acute appendicitis compared to the control group: 233.45 ng/mL (IQR 114.9, 531.2) vs. 55.95 ng/mL (IQR 51.5, 117.9), p < 0.001. LRG1 had an overall good receiver-operator characteristic area under the curve of 0.85 (95% CI 0.76–0.92; p < 0.001). The optimal LRG1 cutoff with best separation between acute appendicitis and the controls was >352.6 ng/mL (95% CI from >270.7 to >352.6). Although the specificity was 100% at this cutoff, the sensitivity for identifying appendicitis was 36%. In addition, a significant difference was found between groups in the laboratory values of all inflammatory markers tested: WBC, absolute neutrophil count, and CRP (p < 0.001 for all). Although LRG1 in saliva showed a good AUC parameter and significantly higher values in patients with acute appendicitis compared to the controls, its usefulness in the patient population who present at emergency departments with abdominal pain is debatable. Future studies should focus on investigating its diagnostic potential.

Purpose: The aim of this study is to assess the diagnostic utility of serum leucine-rich α-2-glycoprotein 1 (LRG1) in pediatric patients with acute abdominal pain, admitted to the emergency surgical unit, in order to make a prompt and accurate diagnosis of acute appendicitis. Patients and methods: Pediatric patients older than 5 years of age who presented to the emergency department from 15 October 2021 to 30 June 2022 with acute abdominal pain and suspected acute appendicitis were prospectively recruited in the study. Demographic and clinical data, as well as operative and postoperative data, were recorded. A total of 92 patients were equally distributed into two groups: children with acute appendicitis who underwent laparoscopic appendectomy and non-appendicitis patients, presenting with non-specific abdominal pain. LRG1 levels were determined using a commercially available LRG1 enzyme-linked immunosorbent assay (ELISA) kit. Serum LRG1 levels, as well as other inflammatory markers (white blood cell count (WBC), C-reactive protein (CRP) and absolute neutrophil count) were compared between groups. Results: The median level of LRG1 in serum was significantly higher in the group of children with pathohistologically confirmed acute appendicitis than in the control group, at 350.3 µg/mL (interquartile range (IQR) 165.2–560.3) and 25.7 µg/mL (IQR 14.7–36.8) (p < 0.001), respectively. Receiver operating characteristic area under the curve for LRG1 from serum was 1.0 (95% CI 0.96–1.00; p < 0.001) and the value of >69.1 µg/mL was found to perfectly separate acute appendicitis cases from controls. Additionally, as expected, each of the examined laboratory inflammatory markers provided a significantly higher values in the acute appendicitis group compared to the control group: WBC 14.6 × 109/L (IQR 12.7, 18.7) vs. 7.0 × 109/L (IQR 5.4, 9.0) (p < 0.001), CRP 16.3 mg/dL (IQR 6.9, 50.4) vs. 2.2 mg/dL (IQR 2, 2) (p < 0.001) and absolute neutrophil count 84.6% (IQR 79.5, 89.0) vs. 59.5% (IQR 51.5, 68.6) (p < 0.001). Conclusions: LRG1 in the serum was found to be a promising novel biomarker, with excellent differentiation of acute appendicitis from non-appendicitis cases in children presenting with non-specific abdominal pain.

Background: Leucine-rich alpha-2-glycoprotein-1 (LRG1) is widely involved in proliferation, migration, and invasion of various tumor cells. Recent studies have evaluated the potential of LRG1 as both an early tumor and a prognostic biomarker. Method: The relevant literature from PubMed is reviewed in this article. Results: It has been found that LRG1 mainly acts on the regulatory mechanisms of angiogenesis, epithelial-mesenchymal transition (EMT), and apoptosis by transforming growth factor (TGF-β) signaling pathway as well as affecting the occurrence and development of the tumors. Moreover, with advancement of research, LRG1 regulation pathways which are independent of TGF-β signaling pathway have been gradually revealed in different tumor cells; There are several studies on the biological effects of LRG1 as an inflammatory factor, vascular growth regulator, cell adhesion, and a cell viability influencing factor. In addition, various tumor suppression methods which are based on regulation of LRG1 levels have also shown high potential clinical value. Conclusions: LRG1 are critical for the processes of tumorigenesis, development, and metastasis in various tumors. The present study reviewed the latest research on the achievements of LRG1 in tumor genesis and development. Further, this study also discussed the related molecular mechanisms of various biological functions of LRG1. [ABSTRACT FROM AUTHOR]

BACKGROUND: Lung cancer is the leading cause of cancer-related deaths worldwide. With the expectation of improved survival, tremendous efforts and resources have been invested in the discovery of specific biomarkers for early detection of the disease. Several investigators have reported the presence of cancer-associated autoantibodies in the plasma or serum of lung cancer patients. Previously, we used a monoclonal antibody (mAb) proteomics technology platform for the discovery of novel lung cancer-associated proteins. OBJECTIVE: The identification of specific protein epitopes associated with various cancers is a promising method in biomarker discovery. Here, in a preliminary study, we aimed to detect autoantibody-leucine-rich alpha-2-glycoprotein 1 (LRG1) immunocomplexes using epitope-specific monoclonal antibodies (mAbs). METHODS: We performed sandwich ELISA assays using the LRG1 epitope-specific capture mAbs, Bsi0352 and Bsi0392, and an IgG-specific polyclonal antibody coupled to a reporter system as the detection reagent. We tested the plasma of lung cancer patients and apparently healthy controls. RESULTS: Depending on the epitope specificity of the capture mAb, we were either unable to distinguish the control from LC-groups or showed a higher level of LRG1 and IgG autoantibody containing immunocomplexes in the plasma of non-small cell lung cancer and small cell lung cancer subgroups of lung cancer patients than in the plasma of control subjects. CONCLUSIONS: Our findings underline the importance of protein epitope-specific antibody targeted approaches in biomarker research, as this may increase the accuracy of previously described tests, which will need further validation in large clinical cohorts. [ABSTRACT FROM AUTHOR]

The secreted glycoprotein leucine-rich α-2 glycoprotein 1 (LRG1) was first described as a key player in pathogenic ocular neovascularization almost a decade ago. Since then, an increasing number of publications have reported the involvement of LRG1 in multiple human conditions including cancer, diabetes, cardiovascular disease, neurological disease, and inflammatory disorders. The purpose of this review is to provide, for the first time, a comprehensive overview of the LRG1 literature considering its role in health and disease. Although LRG1 is constitutively expressed by hepatocytes and neutrophils, Lrg1−/− mice show no overt phenotypic abnormality suggesting that LRG1 is essentially redundant in development and homeostasis. However, emerging data are challenging this view by suggesting a novel role for LRG1 in innate immunity and preservation of tissue integrity. While our understanding of beneficial LRG1 functions in physiology remains limited, a consistent body of evidence shows that, in response to various inflammatory stimuli, LRG1 expression is induced and directly contributes to disease pathogenesis. Its potential role as a biomarker for the diagnosis, prognosis and monitoring of multiple conditions is widely discussed while dissecting the mechanisms underlying LRG1 pathogenic functions. Emphasis is given to the role that LRG1 plays as a vasculopathic factor where it disrupts the cellular interactions normally required for the formation and maintenance of mature vessels, thereby indirectly contributing to the establishment of a highly hypoxic and immunosuppressive microenvironment. In addition, LRG1 has also been reported to affect other cell types (including epithelial, immune, mesenchymal and cancer cells) mostly by modulating the TGFβ signalling pathway in a context-dependent manner. Crucially, animal studies have shown that LRG1 inhibition, through gene deletion or a function-blocking antibody, is sufficient to attenuate disease progression. In view of this, and taking into consideration its role as an upstream modifier of TGFβ signalling, LRG1 is suggested as a potentially important therapeutic target. While further investigations are needed to fill gaps in our current understanding of LRG1 function, the studies reviewed here confirm LRG1 as a pleiotropic and pathogenic signalling molecule providing a strong rationale for its use in the clinic as a biomarker and therapeutic target. [ABSTRACT FROM AUTHOR]

Leucine-rich alpha⁃2 glycoprotein 1 (LRG1) is an important member of the leucine-rich repetitive sequence protein family. LRG1 was mainly involved in normal physiological activities of the nervous system, such as synapse formation, synapse growth, the development of nerve processes, neurotransmitter transfer and release, and cell adhesion molecules or ligand-binding proteins. Also, LRG1 affected the development of respiratory diseases, hematological diseases, endocrine diseases, tumor diseases, eye diseases, cardiovascular diseases, rheumatic immune diseases, infectious diseases, etc. LRG1 was a newly discovered important upstream signaling molecule of transforming growth factor⁃β (TGF⁃β) that affected various pathological processes through the TGF⁃β signaling pathway. However, research on LRG1 and its involvement in the occurrence and development of diseases was still in its infancy and the current studies were mainly focused on proteomic detection and basic animal experimental reports. We could reasonably predict that LRG1 might act as a new direction and strategy for the treatment of many diseases. [ABSTRACT FROM AUTHOR]