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Recent landmark trials showed that colchicine provides a substantial benefit in reducing major cardiovascular events in patients with coronary artery disease. Yet, its exact mechanism of action is still poorly understood. This study aimed to unravel the effect of colchicine on monocyte and neutrophil phenotype and function. A randomized double‐blind placebo‐controlled cross‐over intervention study was executed in patients with a history of myocardial infarction. In neutrophils, colchicine treatment decreased CD62L expression and NGAL release upon ex vivo stimulation and increased PMA‐induced ROS production. The effects of colchicine on monocytes were limited to a decrease in HLA‐DR expression in the intermediate and nonclassical monocytes. Also, on the level of RNA expression, colchicine did not affect monocyte phenotype, while affecting various immunomodulating genes in neutrophils. Overall, our study suggests that treatment with colchicine affects neutrophil function, particularly by reducing neutrophil recruitment, lowering concentrations of NGAL, and changing the expression of various genes with immunomodulatory potential, whereas the effect on monocytes is limited. [ABSTRACT FROM AUTHOR]

Patients with coronavirus disease 2019 (COVID-19) often experience acute kidney injury, linked to disease severity or mortality, along with renal tubular dysfunction and megalin loss in proximal tubules. Megalin plays a crucial role in kidney vitamin D metabolism. However, the impact of megalin loss on vitamin D metabolism during COVID-19 is unclear. This study investigated whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection reduces megalin expression in proximal tubules and its subsequent effect on vitamin D metabolism in mice expressing human angiotensin converting enzyme 2 (K18-hACE2 mice). Histological and immunohistochemical staining analyses revealed glomerular and capillary congestion, and elevated renal neutrophil gelatinase-associated lipocalin levels, indicative of acute kidney injury in K18-hACE2 mice. In SARS-CoV-2-infected mice, immunohistochemical staining revealed suppressed megalin protein levels. Decreased vitamin D receptor (VDR) localization in the nucleus and increased mRNA expression of VDR, CYP27B1, and CYP24A1 were observed by quantitative PCR in SARS-CoV-2-infected mice. Serum vitamin D levels remained similar in infected and vehicle-treated mice, but an increase in tumor necrosis factor-alpha and a decrease in IL-4 mRNA expression were observed in the kidneys of the SARS-CoV-2 group. These findings suggest that megalin loss in SARS-CoV-2 infection may impact the local role of vitamin D in kidney immunomodulation, even when blood vitamin D levels remain unchanged. [ABSTRACT FROM AUTHOR]

Introduction: Approximately 20-40% of patients with systemic lupus erythematosus (SLE) experience neuropsychiatric SLE (NPSLE), which often manifests as cognitive dysfunction and depression. Currently, there are no approved treatments for NPSLE because its underlying mechanisms are unclear. Identifying relevant mediators and understanding their contribution to pathogenesis are crucial for developing targeted treatment options. Lipocalin 2 (LCN2) is a multifunctional acute-phase protein that plays important roles in immune cell differentiation, migration, and function. LCN2 has been implicated in models of neuroinflammatory disease. Methods: We generated an LCN2-deficient MRL/lpr mouse to evaluate the effects of LCN2 on this classic NPSLE model. To evaluate the effects of LCN2 deficiency on behavior, the mice underwent a battery of behavioral tests evaluating depression, memory, and anxiety. Flow cytometry was used to quantify immune cell populations in the brain, blood, and secondary lymphoid organs. Cutaneous disease was quantified by scoring lesional skin, and skin infiltrates were quantified through immunofluorescent staining. Systemic disease was evaluated through measuring anti-nuclear antibodies by ELISA. Results: In this study, we found that LCN2 deficiency significantly attenuates neuropsychiatric and cutaneous disease in MRL/lpr lupus prone mice, likely by decreasing local infiltration of immune cells into the brain and skin and reducing astrocyte activation in the hippocampus. Anti-nuclear antibodies and kidney disease were not affected by LCN2. Discussion: As there was no effect on systemic disease, our results suggest that the inflammatory effects of LCN2 were localized to the skin and brain in this model. This study further establishes LCN2 as a potential target to ameliorate organ injury in SLE, including neuropsychiatric and cutaneous disease. [ABSTRACT FROM AUTHOR]

Drug-induced kidney injury (DIKI) is of significant concern, both during drug development and in clinical practice. We report a patient-centric approach for clinical implementation of the FDA-qualified kidney safety biomarker panel, highlighting Phase 1 and 2 trials for candidate therapeutics in Pfizer's portfolio (PFE-1 and PFE-2, respectively) that induced kidney tubular injury in rat toxicity studies. Clusterin (CLU), cystatin-C (CysC), kidney injury molecule-1 (KIM-1), N -acetyl-beta- d -glucosaminidase (NAG), neutrophil gelatinase-associated lipocalin (NGAL), and osteopontin (OPN) were measured in urine samples from (i) Phase 1 healthy volunteers (HVs; n  = 12) dosed with PFE-1, (ii) Phase 2 rheumatoid arthritis (RA) patients (n  = 266) dosed with PFE-2, (iii) lupus patients on standard-of-care therapies (n  = 121), and (iv) healthy volunteers (n  = 60). The FDA-defined composite measure (CM), calculated as the geometric mean response across the 6 biomarkers, was increased ∼30% in HVs administered 100 mg PFE-1 relative to placebo, providing evidence of DIKI. In contrast, the CM for RA patients dosed with PFE-2 was comparable to placebo controls, helping to de-risk the concern for DIKI at clinically relevant doses. Comparing individual biomarker concentrations across disease states revealed that CLU, KIM-1, NAG, NGAL, and OPN are elevated in the urine of RA and lupus patients (those without severe active proliferative lupus nephritis) relative to HVs. Overall, these case studies demonstrate the value of using the FDA-qualified kidney biomarker panel to guide risk assessment, dose selection, and clinical decision making for novel therapeutics, both in HVs and patient populations. [ABSTRACT FROM AUTHOR]

Objective: To determine whether the urinary excretion of podocyte degradation products varies according to PCOS phenotype and metabolic syndrome (MetS). Methods: The concentrations of podocalyxin (PDX) and nephrin, chronic markers of podocyte damage, and neutrophil gelatinase-associated lipocalin (NGAL), a marker of acute glomerular damage, were analyzed in the morning urine samples of 50 PCOS patients and 50 healthy controls matched by age and BMI. Albuminuria was assessed by calculating the urine albumin–creatinine ratio (uACR). Results: The PDX, nephrin and NGAL concentrations of PCOS participants were significantly higher than those of the control group. While PDX, nephrin and NGAL levels of classic phenotypes were similar, they were higher than ovulatory and non-hyperandrogenic phenotypes. Significant increases in urinary levels of each podocyte protein were detected in PCOS patients with MetS compared to patients without MetS. A positive significant correlation between podocyte proteins and BMI, systolic blood pressure, testosterone, glucose, HOMA-IR and uACR. After adjusting for age and BMI, podocyte proteins were an independent risk factor for microalbuminuria. The incidence of microalbuminuria in PCOS increased 6-fold compared to controls. The frequency of microalbuminuria was higher in classical phenotypes than in ovulatory phenotype. The frequency of microalbuminuria in PCOS patients with MetS was 6.5 times higher than in PCOS patients without MetS. Conclusions: In PCOS accompanied by hyperandrogenemia or metabolic syndrome, leakage of acute and chronic podocyte breakdown products into the urine becomes more pronounced. [ABSTRACT FROM AUTHOR]

To identify potentially transplantable organs in a pool of marginal kidneys, 33 porcine slaughterhouse kidneys were perfused for 4 h with whole blood. During the normothermic perfusion, plasma, urine, and tissue samples were taken. Several biomarkers for tubule injury, endothelial activation, and inflammatory response were evaluated for a potential correlation with macroscopic appearance, histology, and filtration activity. Generally, biomarker levels increased during perfusion. TLR-4, EDN-1, and NGAL were not associated with any classification. In contrast, a steeper increase in NAG and IL-6 in plasma correlated with a poor macroscopic appearance at 4 h, indicating a higher inflammatory response in the kidneys with worse macroscopy early on, potentially due to more damage at the tubules. Although long-term effects on the graft could not be assessed in this setting, early observation under machine perfusion with whole blood was feasible. It allowed the assessment of kidneys under conditions comparable to reperfusion. This setting could give surgeons further insight into the quality of marginal kidneys and an opportunity to pre-treat them. [ABSTRACT FROM AUTHOR]

Crohn's disease (CD) is an autoimmune intestinal disease characterised by chronic and non-specific inflammation, and the exact etiology and pathogenesis are still unclear. Neutrophil gelatinase associated lipocalin (NGAL), a secreted glycoprotein and isolated from neutrophils, is widely involved in pathophysiological processes such as intestinal inflammation response, apoptosis and tumour progression. It has been found that NGAL has the potential to be a clinical biological marker in clinical diagnosis and monitoring of CD activity. Therefore, this paper reviews the application value of NGAL in different clinical samples of CD, in order to provide reference for clinical diagnosis and treatment of CD. [ABSTRACT FROM AUTHOR]

Purpose: Prolonged work in the heat increases the risk of acute kidney injury (AKI) in young men. Whether aging and age-associated chronic disease may exacerbate the risk of AKI remains unclear. Methods: We evaluated plasma neutrophil gelatinase-associated lipocalin (NGAL) and serum kidney injury molecule-1 (KIM1) before and after 180 min of moderate-intensity work (200 W/m2) in temperate (wet-bulb globe temperature [WBGT] 16 °C) and hot (32 °C) environments in healthy young (n = 13, 22 years) and older men (n = 12, 59 years), and older men with type 2 diabetes (T2D; n = 9, 60 years) or hypertension (HTN; n = 9, 60 years). Results: There were no changes in NGAL or KIM1 concentrations following prolonged work in temperate conditions in any group. Despite a similar work tolerance, the relative change in NGAL was greater in the older group when compared to the young group following exercise in the hot condition (mean difference + 82 ng/mL; p < 0.001). Baseline concentrations of KIM1 were ~ 22 pg/mL higher in the older relative to young group, increasing by ~ 10 pg/mL in each group after exercise in the heat (both p ≤ 0.03). Despite a reduced work tolerance in the heat in older men with T2D (120 ± 40 min) and HTN (108 ± 42 min), elevations in NGAL and KIM1 were similar to their healthy counterparts. Conclusion: Age may be associated with greater renal stress following prolonged work in the heat. The similar biomarker responses in T2D and HTN compared to healthy older men, alongside reduced exercise tolerance in the heat, suggest these individuals may exhibit greater vulnerability to heat-induced AKI if work is prolonged. [ABSTRACT FROM AUTHOR]

Lipocalin-2 (Lcn2), a protein secreted by immune-activated cells, including reactive astrocytes, is detrimental to the brain and induces neurodegeneration. We previously showed that Lcn2 levels are reduced in primary mouse astrocytes after treatment with the proteasome inhibitor bortezomib (BTZ). However, it remains unknown whether a decrease in Lcn2 levels after BTZ treatment can also be observed in vivo and whether it reduces neurotoxicity during lipopolysaccharide (LPS)-induced systemic inflammation in vivo. To answer these questions, we performed LPS challenge experiments by intraperitoneal injection in mice and found that Lcn2 levels were significantly increased in the brain, recapitulating in vitro experiments using astrocytes. Co-administration of LPS and BTZ reduced the Lcn2 levels compared to the levels in LPS-treated controls. Upon LPS challenge, the expression levels of glial marker genes were upregulated in the mouse brain. Of note, this upregulation was hampered by the co-administration of BTZ. Taken together, our results suggested that BTZ can reduce LPS-induced Lcn2 levels and may alleviate LPS-induced neuroinflammation and neurotoxicity in mice. [ABSTRACT FROM AUTHOR]

Background: Polymyxins have been revived as a last-line therapeutic option for multi-drug resistant bacteria and continue to account for a significant proportion of global antibiotic usage. However, kidney injury is often a treatment limiting event with kidney failure rates ranging from 5 to 13%. The mechanisms underlying polymyxin-induced nephrotoxicity are currently unclear. Researches of polymyxin-associated acute kidney injury (AKI) models need to be more standardized, which is crucial for obtaining consistent and robust mechanistic results. Methods: In this study, male C57BL/6 mice received different doses of polymyxin B (PB) and polymyxin E (PE, also known as colistin) by different routes once daily (QD), twice daily (BID), and thrice daily (TID) for 3 days. We continuously monitored the glomerular filtration rate (GFR) and the AKI biomarkers, including serum creatinine (Scr), blood urea nitrogen (BUN), neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1). We also performed histopathological examinations to assess the extent of kidney injury. Results: Mice receiving PB (35 mg/kg/day subcutaneously) once daily exhibited a significant decrease in GFR and a notable increase in KIM-1 two hours after the first dose. Changes in GFR and KIM-1 at 24, 48 and 72 h were consistent and demonstrated the occurrence of kidney injury. Histopathological assessments showed a positive correlation between the severity of kidney injury and the changes in GFR and KIM-1 (Spearman's rho = 0.3167, P = 0.0264). The other groups of mice injected with PB and PE did not show significant changes in GFR and AKI biomarkers compared to the control group. Conclusion: The group receiving PB (35 mg/kg/day subcutaneously) once daily consistently developed AKI at 2 h after the first dose. Establishing an early and stable AKI model facilitates researches into the mechanisms of early-stage kidney injury. In addition, our results indicated that PE had less toxicity than PB and mice receiving the same dose of PB in the QD group exhibited more severe kidney injury than the BID and TID groups. [ABSTRACT FROM AUTHOR]

Introduction: We focused on neutrophil gelatinase‐associated lipocalin (NGAL) and autosomal dominant polycystic kidney disease (ADPKD) progression. Methods: ADPKD patients with an estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2 were included. Serum NGAL level and NGAL to eGFR ratio (NGR), height‐adjusted total kidney volume (hTKV) were assessed initially. Patients were followed‐up for 5 years. Results: Sixty one patients were enrolled and initial eGFR was 73.6 (48.9–101.5) ml/min/1.73m2. EGFR declined by 3.7 mL/min/1.73m2 per year. Thirty four patients (55.7%) exhibited rapid progression. Rapid progression group had lower serum NGAL levels (p < 0.001) and higher hTKV (p < 0.001). Lower serum NGAL level was a risk factor for rapid progression (p < 0.001). NGR was not associated with rapid progression. Serum NGAL level was predictive in for rapid progression ROC analysis (cut‐off <10.62 ng/mL). Conclusion: Relatively lower serum NGAL levels can predict worse outcomes in ADPKD and can provide risk stratification in patients with ADPKD. [ABSTRACT FROM AUTHOR]

This article presents a study on the use of urinary guanidino compounds (GCs) and ureido compounds (UCs) as biomarkers for cardiac surgery-associated acute kidney injury (CSA-AKI). The study utilized a benzylic rearrangement reaction and high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) to analyze the concentrations of GCs/UCs in urine samples from patients with CSA-AKI at different stages. The findings suggest that certain GC/UC metabolites show significant changes in concentration during CSA-AKI and could potentially serve as biomarkers for different stages of AKI. This research provides valuable resources and new therapeutic targets for further study on CSA-AKI. [Extracted from the article]

Sepsis associated Acute kidney injury (AKI) is a common clinical syndrome characterized by suddenly decreased in renal function and urinary volume. This study was designed to investigate the role of Aquaporin 1 (AQP1) and P53 in the development of sepsis-induced AKI and their potential regulatorymechanisms. Firstly, transcriptome sequencing analysis of mice kidney showed AQP1 expression was reduced and P53 expression was elevated in Cecal ligation and puncture (CLP)- induced AKI compared with controls. Bioinformatics confirmed that AQP1 expression was remarkably decreased and P53 expression was obviously elevated in renal tissues or peripheral blood of septic AKI patients. Moreover, we found in vivo experiments that AQP1mRNA levels were dramatically decreased and P53mRNA significantly increased following the increased expression of inflammation, apoptosis, fibrosis, NGAL and KIM-1 at various periods in septic AKI. Meanwhile, AQP1 and P53 protein levels increased significantly first and then decreased gradually in kidney tissue and serum of rats in different stages of septic AKI. Most importantly, in vivo and vitro experiments demonstrated that silencing of AQP1 greatly exacerbates renal or cellular injury by upregulating P53 expression promoting inflammatory response, apoptosis and fibrosis. Overexpression of AQP1 prevented the elevation of inflammation, apoptosis and fibrosis by down-regulating P53 expression in Lipopolysaccharide (LPS)-induced AKI or HK-2 cells. Therefore, our results suggested that AQP1 plays a protective role in modulating AKI and can attenuate inflammatory response, apoptosis and fibrosis via downregulating P53 in septic AKI or LPS-induced HK-2cells. The pharmacological targeting of AQP1mediated P53 expressionmight be identified as potential targets for the early treatment of septic AKI. [ABSTRACT FROM AUTHOR]

Background: Individuals with non-celiac gluten/wheat sensitivity (NCGWS) experience improvement in gastrointestinal symptoms following a gluten-free diet. Although previous results have indicated that fructo-oligosaccharides (FOS), a type of short-chain fructans, were more likely to induce symptoms than gluten in self-reported NCGWS patients, the underlying mechanisms are unresolved. Methods: Our main objective was therefore to investigate whether FOS-fructans and gluten affect the composition and diversity of the faecal microbiota (16S rRNA gene sequencing), faecal metabolites of microbial fermentation (short-chain fatty acids [SCFA]; gas chromatography with flame ionization detector), and a faecal biomarker of gut inflammation (neutrophil gelatinase-associated lipocalin, also known as lipocalin 2, NGAL/LCN2; ELISA). In the randomised double-blind placebo-controlled crossover study, 59 participants with self-reported NCGWS underwent three different 7-day diet challenges with gluten (5.7 g/day), FOS-fructans (2.1 g/day), and placebo separately (three periods, six challenge sequences). Results: The relative abundances of certain bacterial taxa were affected differently by the diet challenges. After the FOS-fructan challenge, Fusicatenibacter increased, while Eubacterium (E.) coprostanoligenes group, Anaerotruncus, and unknown Ruminococcaceae genera decreased. The gluten challenge was primarily characterized by increased abundance of Eubacterium xylanophilum group. However, no differences were found for bacterial diversity (α-diversity), overall bacterial community structure (β-diversity), faecal metabolites (SCFA), or NGAL/LCN2. Furthermore, gastrointestinal symptoms in response to FOS-fructans were generally not linked to substantial shifts in the gut bacterial community. However, the reduction in E. coprostanoligenes group following the FOS-fructan challenge was associated with increased gastrointestinal pain. Finally, correlation analysis revealed that changes in gastrointestinal symptoms following the FOS-fructan and gluten challenges were linked to varying bacterial abundances at baseline. Conclusions: In conclusion, while FOS-fructans induced more gastrointestinal symptoms than gluten in the NCGWS patients, we did not find that substantial shifts in the composition nor function of the faecal microbiota could explain these differences in the current study. However, our results indicate that individual variations in baseline bacterial composition/function may influence the gastrointestinal symptom response to both FOS-fructans and gluten. Additionally, the change in E. coprostanoligenes group, which was associated with increased symptoms, implies that attention should be given to these bacteria in future trials investigating the impact of dietary treatments on gastrointestinal symptoms. Trial registration: Clinicaltrials.gov as NCT02464150. [ABSTRACT FROM AUTHOR]

Introduction. Acute kidney injury (AKI) is a prevalent complication of liver transplantation, leading to prolonged hospital or intensive care unit stay and significant morbidity. Recently, biomarkers such as neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C have been investigated for their potential role in the early detection of AKI in liver transplantation patients. Method. Our study comprised 60 patients with end-stage liver disease undergoing living donor liver transplantation. Based on the postoperative development of AKI, the patients were categorised into two groups: the AKI group comprising 22 patients and the non-AKI group comprising 38 patients. Serum cystatin C and urine NGAL levels were measured twice: immediately after induction of anaesthesia (baseline) and at the end of the surgery. Results. The overall incidence of AKI was 36.66%. The mean cystatin C level measured at the end of the surgery was significantly higher in the AKI group (1.12 ± 0.40 mg/L) than in the non-AKI group (0.82 ± 0.27 mg/L) [P = .001]. The receiver operating characteristic curve for the postoperative cystatin C biomarker demonstrated a significant difference between the AKI and non-AKI groups [area under the curve: 0.71, P = .007]. However, baseline cystatin C and urine NGAL levels did not significantly differ between the groups. Conclusion. Cystatin C levels measured at the end of the surgery showed a better predictive value and higher accuracy in identifying post-liver transplantation patients with AKI than baseline cystatin C and urine NGAL. [ABSTRACT FROM AUTHOR]

This study presents a comprehensive review of the literature regarding the use of urinary neutrophil gelatinase-associated lipocalin (uNGAL) as a diagnostic tool for urinary tract infection (UTI) in children. Meta-analysis was conducted to evaluate the effectiveness of uNGAL in diagnosing UTI and differentiating acute pyelonephritis (APN) from other sites infection in pediatric patients. We searched PubMed, Web of Science, the Cochrane Library and EMBASE for reports published up to January 2023. We only included published literature that addressed the diagnosis of UTI and APN with the use of uNGAL in children aged 0-18 years. Two authors independently reviewed the included studies and extracted the corresponding data according to the inclusion and exclusion criteria. The sensitivity, specificity and area under the curve for each study were pooled by using a bivariate mixedeffects model. A total of 13 studies met the inclusion criteria for this review: 8 reported on uNGAL diagnosis of UTI, 2 on uNGAL diagnosis of APN, and 3 on both UTI and APN. Among all included studies, uNGAL had good sensitivity (0.88, 95% CI 0.79-0.94) and good specificity (0.86, 95% CI 0.78-0.92) for the diagnosis of UTI. The sensitivity and specificity of uNGAL for the diagnosis of APN were 0.79 (95% CI 0.72-0.85) and 0.78 (95% CI 0.50-0.93), respectively. uNGAL has good sensitivity and specificity in the diagnosis of UTI in children and is a promising marker. However, the use of uNGAL still does not provide significant advantages in the diagnosis of APN in children. Consequently, there is a need to optimize and further explore the assay for improved diagnostic accuracy. [ABSTRACT FROM AUTHOR]

AIM: To explore the mechanisms behind the inhibition of lymphangiogenesis in pregnant rats with obstructive nephropathy and assess the protective effects on kidney function. METHODS: Forty nulliparous female Wi-star rats were randomly assigned to four groups: sham operation, sham operation + pregnancy, model, and Esaxerenone groups, with 10 rats in each group. Renal injury was induced in the model and Esaxerenone groups via unilateral ureteral obstruction (UUO). The other two groups underwent ureteral dissociation without ligation. Nine weeks post-UUO, female rats in the sham operation+pregnancy, model, and Esaxerenone groups were mated with male rats (2:1 ratio) to establish a rat model of obstructive nephropathy during pregnancy. Starting the day after UUO, rats in the Esaxerenone group received Esaxerenone at 1 mg⋅kg-1⋅d-1. On the 18th day of pregnancy, 24-hour urine was collected using metabolic cages. The following day, the rats were sacrificed, serum samples collected, and the contralateral kidney removed. Blood urea nitrogen (BUN) was measured using standard biochemical methods, and endogenous creatinine clearance rate (Ccr) was calculated. Kidney tissue pathology was assessed using HE, Masson, and Sirius red staining. Serum aldosterone levels were determined via ELISA. Immunohistochemistry, real-time PCR, and Western blot were employed to assess mineralo-corticoid receptor (MR) activation, lymphangiogenesis, signaling pathways, and fibrosis-related markers. RESULTS: Renal function tests revealed increased BUN levels and decreased Ccr in the model group (P<0. 01). Pathological examination showed dilated renal tubules, significant collagen deposition, and inflammatory cell infiltration in the model group. ELISA results indicated a significant increase in serum aldosterone levels in the model group (P<0. 01). Immunohisto-chemistry showed enhanced nuclear translocation of MR in the kidneys of the model group post-activation. Western blot and real-time PCR demonstrated a marked increase in neutrophil gelatinase-associated lipocalin (NGAL) expression in the model group (P<0. 01). Additionally, the expression of vascular endothelial growth factor C (VEGF-C) and its receptor VEGFR3 was significantly elevated in the renal tubulointerstitium of the model group, as shown by both immunohistochemistry and real-time PCR (P < 0. 01). The PI3K/Akt signaling pathway was activated in the model group, with significantly increased phosphorylation levels observed primarily in renal tubular epithelial and interstitial cells (P<0. 01). Collagen type III (Col III) expression, primarily in the renal tubulointerstitium, was also significantly upregulated in the model group, consistent with real-time PCR results (P<0. 01). Esaxerenone treatment improved renal function, reduced pathological damage, inhibited aldosterone secretion, and downregulated the expression of MR, NGAL, VEGF-C, VEGFR3, phosphorylated PI3K, phosphorylated Akt, and Col III (P<0. 01). CONCLUSION: Esaxerenone mitigates aldosterone-induced MR activation, modulates the PI3K/Akt signaling pathway, reduces lymphangiogenesis in the contralateral kidney of pregnant rats with obstructive nephropathy, decreases collagen deposition, and delays the progression of renal interstitial fibrosis. [ABSTRACT FROM AUTHOR]

Simple Summary: Our understanding of methods by which dietary interventions can be used to modify the established gut microbiota in adult humans is rudimentary. In this intervention trial, a person's gut microbial diversity and intestinal inflammatory markers remained unchanged across four weeks of daily consumption of 80 g of wheat crackers, regardless of wheat-flour type. Consumers must understand that shifting their gut microbiota and inflammatory state with a single dietary constituent may be difficult with mild and short-term interventions. Consumption of whole-grain wheat has been associated with positive health outcomes, but it remains unclear whether different types of wheat elicit varying effects on the gut microbiome and intestinal inflammation. The objectives of this research were to investigate the effect of two whole-grain wheat flours versus refined wheat flour on the diversity of the human gut microbiota, as well as on butyrate production capacity and gastrointestinal inflammation, using one-week dietary interventions. For this study, 28 participants were recruited, with ages ranging from 18 to 55 years and a mean BMI of 26.0 kg/m2. For four weeks, participants were provided 80 g daily servings of different wheat crackers: Week A was a run-in period of crackers made from soft white wheat flour, Week B crackers were whole-grain soft white wheat flour, Week C crackers were a wash-out period identical to Week A, and Week D crackers were whole-grain soft red wheat flour. At the end of each week, participants provided fecal samples that were analyzed for markers of intestinal inflammation, including lipocalin and calprotectin, using enzyme-linked immunosorbent assays and quantitative real-time PCR. The primary outcome, gut bacterial community alpha and beta diversity, was similar across timepoints. Three taxa significantly differed in abundance following both whole-grain wheat flour interventions: Escherichia/Shigella and Acidaminococcus were significantly depleted, and Lachnospiraceae NK4A136 group was enriched. Secondary outcomes determined that protein markers of intestinal inflammation and genes related to putative butyrate production capacity were similar throughout the study period, with no significant changes. Lipocalin concentrations ranged from 14.8 to 22.6 ng/mL while calprotectin ranged from 33.2 to 62.5 ng/mL across all 4 weeks. The addition of wheat crackers to the adult human subjects' usual diet had a minimal impact on their gastrointestinal inflammation or the gut microbiota. [ABSTRACT FROM AUTHOR]

Background: Cell cycle arrest biomarkers (tissue inhibitor of metalloproteinase‐2 [uTIMP‐2] and insulin‐like growth factor binding protein 7 [uIGFBP7]), and neutrophil gelatinase‐associated lipocalin (NGAL) variables are valuable biomarkers for early diagnosis of acute kidney injury (AKI) in people. Objectives: To evaluate uTIMP‐2, uIGFBP7, fractional excretion of NGAL (FeNGAL), and urinary to serum NGAL ratio (u/sNGAL) in healthy dogs, dogs with AKI, dogs with chronic kidney disease (CKD), and critically ill (CI) dogs. Animals: Forty‐two client‐owned dogs (healthy, n = 10; AKI, n = 11; CKD, n = 11; CI, n = 10). Methods: Prospective, observational study. After assessment of routine renal biomarkers, stress (uTIMP‐2, uIGFBP7) and damage (NGAL) biomarkers were measured, using ELISA kits, and normalized to urinary creatinine (uCr). Results: Normalized uTIMP‐2 and [uTIMP‐2] × [uIGFBP7]/uCr were significantly higher in the AKI group (median 151.9 [range, 2.2‐534.2] and 62.9 [1.1‐266.8] pg/mL respectively), compared to healthy dogs (0.3 [0.2‐74.7]; P <.001 and 0.16 [0.1‐58.1] pg/mL; P <.001), dogs with CKD (0.7 [0.3‐742.5]; P =.04 and 0.37 [0.2‐180.1] pg/mL; P =.03) and CI dogs (1.9 [0.2‐37.0]; P =.03 and 0.8 [0.1‐16.1] pg/mL; P =.02). Fractional excretion of NGAL was significantly higher in dogs with AKI (54.17 [7.93‐155.32] %), than in healthy (0.03 [0.01‐0.21] %; P <.001) and CI dogs (3.05 [0.05‐28.86] %; P =.02). Conclusions and Clinical Importance: Normalized uTIMP‐2, [uTIMP‐2] × [uIGFBP7]/uCr, and FeNGAL can be valuable renal biomarkers for early diagnosis of AKI in dogs. [ABSTRACT FROM AUTHOR]

Depression is a prevalent and debilitating mental disorder that affects millions worldwide. Current treatments, such as antidepressants targeting the serotonergic system, have limitations, including delayed onset of action and high rates of treatment resistance, necessitating novel therapeutic strategies. Ginsenoside Rc (G-Rc) has shown potential anti-inflammatory and neuroprotective effects, but its antidepressant properties remain unexplored. This study investigated the antidepressant effects of G-Rc in an L-alpha-aminoadipic acid (L-AAA)-induced mouse model of depression, which mimics the astrocytic pathology and neuroinflammation observed in major depressive disorder. Mice were administered G-Rc, vehicle, or imipramine orally after L-AAA injection into the prefrontal cortex. G-Rc significantly reduced the immobility time in forced swimming and tail suspension tests compared to vehicle treatment, with more pronounced effects than imipramine. It also attenuated the expression of pro-inflammatory cytokines (TNF-α, IL-6, TGF-β, lipocalin-2) and alleviated astrocytic degeneration, as indicated by increased GFAP and decreased IBA-1 levels. Additionally, G-Rc modulated apoptosis-related proteins, decreasing caspase-3 and increasing Bcl-2 levels compared to the L-AAA-treated group. These findings suggest that G-Rc exerts antidepressant effects by regulating neuroinflammation, astrocyte–microglia crosstalk, and apoptotic pathways in the prefrontal cortex, highlighting its potential as a novel therapeutic agent for depression. [ABSTRACT FROM AUTHOR]

Objectives Neurosurgical patients often receive 0.9% normal saline (NS) during the perioperative period. Theoretically, a balanced salt solution (BSS) is better than 0.9% saline. We compared the effects of two different fluids on acid–base balance, renal function, and neurological outcome in patients who underwent clipping following subarachnoid hemorrhage from a ruptured intracranial aneurysm. Materials and Methods Patients in group NS (n = 30) received 0.9% saline and group BSS (N = 30) received BSS (Plasmalyte-A) in the perioperative period for 48 hours. Comparison of arterial pH, bicarbonate, and base deficit measured preoperatively, intraoperatively (first and second hour), and postoperatively (at 24 and 48 hours) was the primary outcome of the study. The secondary outcome compared serum electrolytes, renal function tests, urine neutrophil gelatinase-associated lipocalin (NGAL), serum cystatin C, and the neurological outcome using modified Rankin score (MRS) at discharge, 1, and 3 months. Results In group NS, significantly low pH at 1-hour intraoperative period was seen compared with group BSS (7.37 ± 0.06 vs. 7.40 ± 0.05, p = 0.024). The bicarbonate level in group NS was significantly lower and the base deficit was higher at second intraoperative hour (bicarbonate: 17.49 vs. 21.99 mEq/L, p = 0.001; base deficit: 6.41 mmol/L vs. 1.89 mmol/L, p = 0.003) and at 24 hours post-surgery (bicarbonate: 20.38 vs. 21.96 mEq/L, p = 0.012; base deficit: 3.56 mmol/L vs. 2.12 mmol/L, p = 0.034)). Serum creatinine was higher in group NS at 24 hours (0.66 vs. 0.52 mg/dL, p = 0.013) and 48 hours (0.62 vs. 0.53 mg/dL, p = 0.047). Serum urea, electrolytes, cystatin, urine NGAL, and MRS were comparable. Conclusion In neurosurgical patients undergoing clipping for ruptured intracranial aneurysm, using a BSS during the perioperative period is associated with a better acid–base and renal profile. However, the biomarkers of kidney injury and long-term outcomes were comparable. [ABSTRACT FROM AUTHOR]

Increasing evidence implicates that inflammatory factors do play a crucial role in the pathophysiology of schizophrenia. However, the association between inflammatory markers and different symptom dimensions and cognitive function of schizophrenia remains unclear. A total of 140 drug-naïve patients with schizophrenia and 69 healthy controls matched for age and gender were enrolled. Peripheral blood plasma concentrations of S-100 calcium-binding protein B (S100B), neutrophil gelatinase-associated lipocalin (NGAL), and interferon-γ (IFN-γ) were detected by enzyme-linked immunosorbent assay (ELISA). Psychotic symptoms were measured using the Positive and Negative Syndrome Scale (PANSS), and cognitive function was assessed by the MATRICS Consensus Cognitive Battery (MCCB). Compared with healthy controls, patients with schizophrenia had significantly worse cognitive function and lower levels of NGAL and IFN-γ (P < 0.001). In schizophrenia, plasma NGAL and IFN-γ levels negatively correlated with positive symptom scores (all P < 0.05). There was a positive correlation between plasma levels of NGAL and IFN-γ with visual learning, neurocognition, and MCCB total score (all P < 0.05). We found that NGAL levels (β = 0.352, t = 5.553, 95% CI 0.228–0.477, P < 0.001) and negative symptoms subscale scores (β = − 0.321, OR = 0.725, 95% CI 648–0.811, P < 0.001) were independently associated with the MCCB total score. Further, binary logistic regression analysis indicated that the concentrations of NGAL (β = − 0.246, OR = 0.782, 95% CI 0.651–0.939, P = 0.008) were independently associated with the diagnosis of schizophrenia. There was a positive correlation between NGAL and IFN-γ levels and MCCB total score in schizophrenia. NGAL level was an independent protective factor for cognitive function and an independent risk factor for the diagnosis of schizophrenia. [ABSTRACT FROM AUTHOR]

The management of acute kidney injury (AKI) in cirrhosis is challenging. The EASL guidelines proposed an algorithm for the management of AKI, but this has never been validated. We aimed to prospectively evaluate this algorithm in clinical practice. We performed a prospective cohort study in consecutive hospitalized patients with cirrhosis and AKI. The EASL management algorithm includes identification/treatment of precipitating factors, 2-day albumin infusion in patients with AKI ≥stage 1B, and treatment with terlipressin in patients with hepatorenal syndrome (HRS-AKI). The primary outcome was treatment response, which included both full and partial response. Secondary outcomes were survival and adverse events associated with terlipressin therapy. A total of 202 AKI episodes in 139 patients were included. Overall treatment response was 80%, while renal replacement therapy was required in only 8%. Response to albumin infusion was achieved in one-third of episodes. Of patients not responding to albumin, most (74%) did not meet the diagnostic criteria of HRS-AKI, with acute tubular necrosis (ATN) being the most common phenotype. The response rate in patients not meeting the criteria for HRS-AKI was 70%. Only 30 patients met the diagnostic criteria for HRS-AKI, and their response rate to terlipressin was 61%. Median time from AKI diagnosis to terlipressin initiation was only 2.5 days. While uNGAL (urinary neutrophil gelatinase-associated lipocalin) could differentiate ATN from other phenotypes (AUROC 0.78), it did not predict response to therapy in HRS-AKI. Ninety-day transplant-free survival was negatively associated with MELD-Na, ATN and HRS-AKI as well as uNGAL. Three patients treated with terlipressin developed pulmonary edema. The application of the EASL AKI algorithm is associated with very good response rates and does not significantly delay initiation of terlipressin therapy. The occurrence of acute kidney injury (AKI) in patients with cirrhosis is associated with poor short-term mortality. Improving its rapid identification and prompt management was the focus of the recently proposed EASL AKI algorithm. This is the first prospective study demonstrating that high AKI response rates are achieved with the use of this algorithm, which includes identification of AKI, treatment of precipitating factors, a 2-day albumin challenge in patients with AKI ≥1B, and supportive therapy in patients with persistent AKI not meeting HRS-AKI criteria or terlipressin with albumin in those with HRS-AKI. These findings support the use of this algorithm in clinical practice. [Display omitted] • In 2018, EASL published an algorithm for the diagnosis/management of acute kidney injury in patients with cirrhosis. • This algorithm had not been validated in real-world practice. • In this prospective study, this algorithm was associated with high renal response rates, both overall and in different phenotypes. • The use of the algorithm resulted in the swift diagnosis and treatment of hepatorenal syndrome. • These results support the use of this algorithm in clinical practice. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Modern Laboratory Medicine is the property of Journal of Modern Laboratory Medicine Editorial Department and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Chinese Journal of Contemporary Pediatrics is the property of Xiangya Medical Periodical Press and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Chung Hyun Nahm,1 Moon Hee Lee,2 Noriyoshi Fujii,3 Tatsuyoshi Fujii,4 Jong Weon Choi1 1Department of Laboratory Medicine, College of Medicine, Inha University, Incheon, Republic of Korea; 2Department of Internal Medicine, College of Medicine, Inha University, Incheon, Republic of Korea; 3Department of Dermatology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan; 4Department of Internal Medicine, Teikyo University Chiba Medical Center, Chiba, JapanCorrespondence: Jong Weon Choi, Department of Laboratory Medicine, College of Medicine, Inha University, Inhang-ro 27, Jung-gu, Incheon, Republic of Korea, Tel +82-32-890-2503, Fax +82-32-890-2529, Email jwchoi@inha.ac.krBackground: Nitric oxide (NO) is a bioactive signaling molecule that mediates various physiological and biological processes. Type 2 diabetes mellitus (T2DM) can be categorized into several subgroups according to fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) levels. Few studies have closely examined the effect of NO and lipocalin-2 on albuminuria and insulin resistance in T2DM subgroups. This study investigated the role of NO, lipocalin-2, and proinflammatory cytokines on the development of proteinuria and insulin resistance in patients with T2DM subgroups.Methods: A total of 256 subjects, including 191 patients with T2DM and 65 non-diabetic healthy individuals, were evaluated. NO metabolites (NOx), lipocalin-2, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) levels were measured. Patients with T2DM were classified into three subgroups: patients with FPG-defined diabetes (PG-DM), those with HbA1c-defined diabetes (HA-DM), and those who met the criteria for both FPG and HbA1c (PG/HA-DM). The albumin-to-creatinine ratio (ACR) and the homeostasis model assessment of β-cell function (HOMA-B) and insulin resistance (HOMA-IR) were calculated.Results: NOx, lipocalin-2, and TNF-α levels were significantly higher in patients with T2DM than in healthy individuals. Patients with PG/HA-DM had significantly higher NOx levels than those with PG-DM or HA-DM. Of the patients with high NOx levels, patients with lipocalin-2 elevation exhibited higher ACR and HOMA-IR than those without lipocalin-2 elevation. NOx was positively correlated with lipocalin-2, ACR, HOMA-IR, and TNF-α but not with HOMA-B and IL-6. The upper quartile of NOx levels led to a 1.2-fold increase in the risk of albuminuria (odds ratio: 1.215; 95% CI: 1.012– 2.418; p < 0.001).Conclusion: NO plays a crucial role in proteinuria and insulin resistance by collaborating with lipocalin-2 and TNF-α, showing significantly higher levels in patients with PG/HA-DM than in those with PG-DM or HA-DM.Keywords: nitric oxide, lipocalin-2, proteinuria, insulin resistance, diabetes subgroups

Abstract Lipocalin-2 (Lcn2), a protein secreted by immune-activated cells, including reactive astrocytes, is detrimental to the brain and induces neurodegeneration. We previously showed that Lcn2 levels are reduced in primary mouse astrocytes after treatment with the proteasome inhibitor bortezomib (BTZ). However, it remains unknown whether a decrease in Lcn2 levels after BTZ treatment can also be observed in vivo and whether it reduces neurotoxicity during lipopolysaccharide (LPS)-induced systemic inflammation in vivo. To answer these questions, we performed LPS challenge experiments by intraperitoneal injection in mice and found that Lcn2 levels were significantly increased in the brain, recapitulating in vitro experiments using astrocytes. Co-administration of LPS and BTZ reduced the Lcn2 levels compared to the levels in LPS-treated controls. Upon LPS challenge, the expression levels of glial marker genes were upregulated in the mouse brain. Of note, this upregulation was hampered by the co-administration of BTZ. Taken together, our results suggested that BTZ can reduce LPS-induced Lcn2 levels and may alleviate LPS-induced neuroinflammation and neurotoxicity in mice.

Chronic liver disease is a common and important clinical problem.Hepatorenal syndrome (HRS) is a life threatening complication. Serum creatinine (Cr) remains the only conventional indicator of renal function. However, the interpretation of serum Cr level can be confounded by malnutrition and reduced muscle mass often observed in patients with severe liver disease. Here, we present a cross-sectional study to explore the sensitivity and specificity of other markers as urinary KIM-1 and NGAL for cases of HRS. Cross-sectional study was conducted on 88 patients who were admitted to Alexandria main university hospital. Enrolled patients were divided in two groups; group 1: patients with advanced liver cirrhosis (child B and C) who have normal kidney functions while group 2: patients who developed HRS. Stata© version 14.2 software package was used for analysis. Group 1 included 18 males and 26 females compared to 25 males and 19 females in group 2 (p = 0.135). Only the urinary KIM-1 showed a statistically significant difference between both groups in the multivariate logistic regression analysis adjusted for gender, serum bilirubin, serum albumin, INR, serum K, AST and ALT levels. In conclusion, our study aligns with prior research, as seen in the consistent findings regarding Urinary NGAL elevation in cirrhotic patients with AKI. Urinary KIM-1, independent of Urinary NGAL, may have a role in precisely distinguishing between advanced liver cirrhosis and HRS and merits further exploration. [ABSTRACT FROM AUTHOR]

Sepsis-associated acute kidney injury (S-AKI) is a common disease in pediatric intensive care units (ICU) with high morbidity and mortality. The newly discovered results indicate that microRNAs (miRNAs) play an important role in the diagnosis and treatment of S-AKI and can be used as markers for early diagnosis. In this study, the expression level of miR-16-5p was found to be significantly upregulated about 20-fold in S-AKI patients, and it also increased by 1.9 times in the renal tissue of S-AKI mice. Receiver operating characteristic (ROC) curve analysis showed that miR-16-5p had the highest predictive accuracy in the diagnosis of S-AKI (AUC = 0.9188). In vitro, the expression level of miR-16-5p in HK-2 cells treated with 10 μg/mL lipopolysaccharide (LPS) increased by more than 2 times. In addition, LPS-exposed renal tissue and HK-2 cells lead to upregulation of inflammatory cytokines IL-6, IL-1β, TNF-a, and kidney damage molecules kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL). However, inhibition of miR-16-5p significantly mitigated LPS expose-mediated kidney injury and inflammation. Furthermore, LPS-exposed HK-2 cells increased more than 1.7-fold the expression levels of Bax and caspase-3, decreased 3.2-fold the expression level of B-cell lymphoma-2 (Bcl-2), and significantly promoted the occurrence of apoptosis. MiR-16-5p mimic further increased LPS-induced apoptosis in HK-2 cells. Nevertheless, inhibition of miR-16-5p significantly attenuated this effect. In summary, up-regulation of miR-16-5p expression can significantly aggravate renal injury and apoptosis in S-AKI, which also proves that miR-16-5p can be used as a potential biomarker to promote early identification of S-AKI. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) can progress to renal fibrosis and chronic kidney disease (CKD), which reduces quality of life and increases the economic burden on patients. However, the molecular mechanisms underlying renal fibrosis following AKI remain unclear. This study tested the hypothesis that the Krüppel-like factor 4 (KLF4)/miR-101/Collagen alpha-1X (COL10A1) axis could inhibit epithelial-mesenchymal transition (EMT) and renal fibrosis after AKI in a mouse model of ischemia-reperfusion (I/R)-induced renal fibrosis and HK-2 cells by gene silencing, overexpression, immunofluorescence, immunohistochemistry, real-time quantitative PCR, Western blotting, dual-luciferase reporter assay, fluorescence in situ hybridization (FISH) and ELISA. Compared with the Sham group, I/R induced renal tubular and glomerular injury and fibrosis, and increased the levels of BUN, serum Scr and neutrophil gelatinase-associated lipocalin (NGAL), Col10a1 and Vimentin expression, but decreased E-cadherin expression in the kidney tissues of mice at 42 days post-I/R. Similarly, hypoxia promoted fibroblastic morphological changes in HK-2 cells and enhanced NGAL, COL10A1, Vimentin, and α-SMA expression, but reduced E-cadherin expression in HK-2 cells. These pathological changes were significantly mitigated in COL10A1-silenced renal tissues and HK-2 cells. KLF4 induces miR-101 transcription. More importantly, hypoxia upregulated Vimentin and COL10A1 expression, but decreased miR-101, KLF4, and E-cadherin expression in HK-2 cells. These hypoxic effects were significantly mitigated or abrogated by KLF4 over-expression in the HK-2 cells. Our data indicate that KLF4 up-regulates miR-101 expression, leading to the downregulation of COL10A1 expression, inhibition of EMT and renal fibrosis during the pathogenic process of I/R-related renal fibrosis. [ABSTRACT FROM AUTHOR]

Abstract Background Systemic inflammation is believed to contribute to small cell lung cancer (SCLC) progression, but the underlying relationship remains unclear. Lipocalin‐2, a potential biomarker of inflammation, has been implicated in various cancers but its prognostic value in SCLC is underexplored. Methods We retrospectively analyzed 191 patients with SCLC (72 with limited‐stage [LD] and 119 with extensive‐stage) treated using platinum‐based chemotherapy. Lipocalin‐2 expression was evaluated using immunohistochemistry. Optimal cutoff values for lipocalin‐2 and neutrophil‐to‐lymphocyte ratio (NLR) were determined using time‐dependent receiver operating characteristic curve analysis. The pectoralis muscle index was used to assess sarcopenia. Results In LD‐SCLC, high lipocalin‐2 expression was associated with worse progression‐free survival (PFS; median: 7.0 vs. 15.9 months, p = 0.015) and overall survival (OS; median: 12.9 vs. 30.3 months, p = 0.035) compared with low lipocalin‐2 expression. Patients were stratified into three prognostic groups by combining lipocalin‐2 with NLR: low lipocalin‐2/low NLR, high lipocalin‐2/low NLR or low lipocalin‐2/high NLR, and high lipocalin‐2/high NLR (median PFS: 17.3 vs. 11.0 vs. 6.3 months, p = 0.004; median OS: 30.5 vs. 17.3 vs. 8.6 months, p = 0.002). Similar trends were observed when combining lipocalin‐2 with the pectoralis muscle index. High lipocalin‐2 expression was also associated with lower complete response rates (18.9% vs. 34.3%, p = 0.035). No significant prognostic implications were found for lipocalin‐2 in extensive‐stage SCLC. Conclusions High lipocalin‐2 expression is potentially associated with poorer survival in LD‐SCLC. Combining lipocalin‐2 with other inflammation‐related markers could improve prognostic stratification.

Breast cancer is the leading cancer diagnosed in women globally, with brain metastasis emerging as a major cause of death, particularly in human epidermal growth factor receptor 2 positive and triple-negative breast cancer subtypes. Comprehensive understanding of the molecular foundations of central nervous system metastases is imperative for the evolution of efficacious treatment strategies. Lipocalin-2 (LCN2), a secreted iron transport protein with multiple functions, has been linked to the progression of breast cancer brain metastasis (BCBM). In primary tumors, LCN2 promotes the proliferation and angiogenesis of breast cancer cells, triggers the epithelial-mesenchymal transition, interacts with matrix metalloproteinase-9, thereby facilitating the reorganization of the extracellular matrix and enhancing cancer cell invasion and migration. In brain microenvironment, LCN2 undermines the blood-brain barrier and facilitates tumor seeding in the brain by modulating the behavior of key cellular components. In summary, this review meticulously examines the fuel role of LCN2 in BCBM cascade, and investigates the potential mechanisms involved. It highlights the potential of LCN2 as both a therapeutic target and biomarker, indicating that interventions targeting LCN2 may offer improved outcomes for patients afflicted with BCBM. [ABSTRACT FROM AUTHOR]

Simple Summary: Early detection of kidney diseases in dogs is crucial. While many studies focus on urine biomarkers, this study explored the potential of plasma biomarkers. We investigated plasma neutrophil gelatinase-associated lipocalin (pNGAL) and plasma kidney injury molecule-1 (pKIM-1) in small-breed dogs for detecting chronic kidney disease (CKD). Our findings suggest that pNGAL and pKIM-1 can identify CKD stages and risk groups effectively. These biomarkers showed better diagnostic accuracy than traditional indicators like serum creatinine. Therefore, pNGAL and pKIM-1 could be valuable tools for early CKD detection in veterinary practice. Multiple diagnostic modalities are urgently needed to identify early-stage kidney diseases. Various molecules have been investigated; however, most studies have focused on identifying specific biomarkers in urine. Considering that assessing the symmetrical dimethylarginine (SDMA) plasma concentration is more suitable as an early diagnostic test for chronic kidney disease (CKD) in routine veterinary practice, we aimed to investigate the clinical usefulness of plasma neutrophil gelatinase-associated lipocalin (pNGAL) and plasma kidney injury molecule-1 (pKIM-1) concentrations for CKD detection in small-breed dogs. Through a retrospective analysis, we found that numerous clinicopathological data showed a log-normal distribution, even when they satisfied normality tests. Moreover, the log-transformed pNGAL and pKIM-1 concentrations successfully identified CKD International Renal Interest Society (IRIS) stages 1–4 and the risk group with underlying CKD risk factors. Correlation analysis and group comparison of other factors confirmed the possibility of using these two biomarkers for detecting the CKD risk group and IRIS stage 1. Receiver operating characteristic curve analysis revealed that the diagnostic accuracy for discriminating the risk group was superior in the order of pKIM-1, pNGAL, SDMA, and serum creatinine levels. In conclusion, these results suggest that pKIM-1 and pNGAL are possible early or quantifiable markers of insignificant CKD or can be at least used as an adjunct with traditional indicators. [ABSTRACT FROM AUTHOR]

In rats with unilateral nephrectomy and cardiac dysfunction, renal function deteriorates at an accelerated rate, as evidenced by increased proteinuria. Whether myocardial infarct-induced heart failure (HF) exacerbates renal injury in hypertensive rats with mild renal injury has not been reported. Rats underwent either coronary ligation or sham surgery. Thirty spontaneously hypertensive rats (SHRs) aged 8 weeks were randomly divided into two groups. Group 1 was the sham group, in which the rats underwent thoracotomy without ligation of the coronary artery. Group 2 underwent coronary artery ligation. The rats in group 2 underwent coronary artery ligation on week 0. The experiment lasted 12 weeks. Urine was collected in metabolic cages over a 24-h period. Urine was collected from the rats 2 days before the end of the experiment, and the ratio of urinary protein to urinary creatinine was measured in the clinical laboratory. All rats were examined by echocardiogram one day before the end of the experiment. On the last day of the experiment, blood was collected and sent to the laboratory for analysis. Hematoxylin–eosin (HE) and periodic acid-Schiff (PAS) staining were performed on heart and kidney sections. The ejection fraction in group 2 was lower than that in group 1 (P < 0.001). The urinary albumin to creatinine ratio in group 2 was greater than that in group 1 (P < 0.001). The urea and creatinine levels in group 1 were significantly lower than those in group 2 (P < 0.01). The levels of brain natriuretic peptide (BNP), neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C were greater in the second group than in the first group (P < 0.05). The interleukin-1β (IL-1β) and interleukin-6 (IL-6) levels in group 2 were significantly greater than those in group 1 (P < 0.001). The malondialdehyde (MDA) levels in Group 2 were greater than those in Group 1 (P < 0.01). The glutathione peroxidase (GSH-Px) levels in Group 2 were lower than those in Group 1 (P < 0.05). The level of angiotensin II (AT-II) in group 1 was lower than that in group 2 (P < 0.001). Cardiac dysfunction secondary to myocardial infarction could induce cardiorenal interactions in SHRs. It could be interpreted by the activation of oxidative stress, changes in inflammation and alteration of renin–angiotensin–aldosterone system. [ABSTRACT FROM AUTHOR]

The primary aim of this research was to explore the functions of Wtap and Ythdf1 in regulating neuronal Lipocalin-2 (Lcn2) through m6A modification in traumatic brain injury (TBI). By employing transcriptome sequencing and enrichment analysis, we identified the Wtap/Ythdf1-mediated Lcn2 m6A modification pathway as crucial in TBI. In our in vitro experiments using primary cortical neurons, knockout of Wtap and Ythdf1 led to the inhibition of Lcn2 m6A modification, resulting in reduced neuronal death and inflammation. Furthermore, overexpression of Lcn2 in cortical neurons induced the activation of reactive astrocytes and M1-like microglial cells, causing neuronal apoptosis. In vivo experiments confirmed the activation of reactive astrocytes and microglial cells in TBI and importantly demonstrated that Wtap knockdown improved neuroinflammation and functional impairment. These findings underscore the significance of Wtap/Ythdf1-mediated Lcn2 regulation in TBI secondary injury and suggest potential therapeutic implications for combating TBI-induced neuroinflammation and neuronal damage. [ABSTRACT FROM AUTHOR]

Acute kidney injury following trauma impacts patient recovery critically, necessitating an integrated approach to emergency care and nephrology. This review aims to provide a comprehensive understanding of trauma-induced nephropathy, highlighting recent advancements in pathophysiological insights, diagnostic techniques, and strategic interventions. Our key findings emphasize the role of biomarkers, like Neutrophil Gelatinase-Associated Lipocalin and Liver Fatty Acid-Binding Protein, and imaging techniques, such as contrast-enhanced ultrasound, in early AKI detection. Preventive strategies, including aggressive fluid resuscitation, avoidance of nephrotoxic agents, and hemodynamic optimization, are essential for mitigating AKI progression. Integrating these approaches into trauma care frameworks aims to enhance patient outcomes and set a foundation for future research and clinical improvements. [ABSTRACT FROM AUTHOR]

Objective(s): Rhabdomyolysis, a potentially life-threatening condition, occurs when myoglobin is released from damaged muscle cells, leading to acute kidney injury (AKI). Alpha lipoic acid (ALA), an organosulfur compound known for its anti-oxidant and anti-inflammatory properties, was examined in this study for its potential impact on rhabdomyolysis-induced AKI in rats. Materials and Methods: Six groups of rats were included in the study, with each group consisting of six rats (n=6): Control, rhabdomyolysis, rhabdomyolysis treated with different doses of ALA (5, 10, and 20 mg/kg), and ALA alone (20 mg/kg) groups. Rhabdomyolysis was induced by intramuscular injection of glycerol on the first day of the experiment, while ALA was administered intraperitoneally for four consecutive days. Renal function parameters, oxidative stress markers, and histological changes in the kidneys were evaluated. Western blot analysis was performed to measure the levels of neutrophil gelatinase-associated lipocalin (NGAL) and tumor necrosis factor-alpha (TNF-α) proteins. Results: A significant increase in serum urea, creatinine, renal malondialdehyde, NGAl, and TNF-a protein levels was observed in glycerol-injected rats. In addition, a significant decrease in glutathione was recorded. Compared to the rhabdomyolysis group, treatment with ALA recovered kidney histological and biochemical abnormalities. Conclusion: Results suggest that rhabdomyolysis-induced AKI is associated with increased oxidative stress and inflammation. Treatment with ALA improved kidney histological abnormalities and reduced oxidative stress markers in rats. Therefore, ALA may have a potential protective effect against rhabdomyolysis-induced AKI. [ABSTRACT FROM AUTHOR]

Background and Aims: Data focussing on acute kidney injury (AKI) in obstetric patients admitted to the intensive care unit (ICU) are scarce and even more so regarding the role of neutrophil gelatinase-associated lipocalcin (NGAL) in detecting AKI or predicting outcomes in these patients. Hence, we aim to evaluate the incidence of AKI in obstetric ICU patients and validate the role of urinary and serum NGAL in predicting the onset of AKI and mortality. Methods: This prospective observational cohort included 45 obstetric patients admitted in ICU, excluding those with prior renal dysfunction. Serum creatinine and urine output were monitored for the occurrence of AKI during the ICU stay. The outcome of the patient (survival or death) in the ICU and hospital was recorded, and serum and urinary NGAL were determined at the time of ICU admission. Results: AKI occurred in 32 [71.1%; 95% confidence interval (CI): 55.4%, 86.8%] patients during their ICU stay. Serum NGAL showed an area under receiver operating characteristic curve (AUROCC) of 0.630 (95% CI: 0.417, 0.842) (P = 0.231) for AKI and 0.486 (95% CI: 0.295, 0.676) (P = 0.883) for ICU mortality. Urinary NGAL showed AUROC = 0.472 (95% CI: 0.285, 0.660) (P = 0.772) to predict AKI and 0.430 (95% CI: 0.268, 0.652) (P = 0.684) for ICU mortality. Conclusions: AKI is common amongst critically ill obstetric ICU patients. However, serum and urinary NGAL cannot be advocated to discriminate between patients with or without AKI or between survivors and non-survivors in critically ill obstetric patients. [ABSTRACT FROM AUTHOR]

Introduction: Tachycardia caused by sympathetic overactivity impairs myocardial function and raises septic patients' mortality. This study examined whether tachycardia is associated with acute kidney injury (AKI) period-prevalence among critically ill patients with and without sepsis. Methods: In 328 patients (119 sepsis and 209 non-sepsis) admitted to our intensive care unit (ICU), we assessed heart rate at ICU admission, plasma neutrophil gelatinase-associated lipocalin (NGAL) and N-terminal pro-B-type natriuretic peptide, and urinary L-type fatty acid-binding protein and N-acetyl-β-d-glucosaminidase (NAG) at 0 and 48 h after admission. Tachycardia was defined as a heart rate above 100 beats/min. Results: Tachycardia was independently correlated with AKI prevalence during the first week after ICU admission in the septic patients, but not in the non-septic patients. A dose-dependent increase in AKI period-prevalence was observed across ascending heart rate ranges. Furthermore, we discovered a dose-dependent increase in renal biomarker-positive patients regarding plasma NGAL and urinary NAG over increasing heart rate ranges 48 h after admission. Conclusion: The findings revealed an independent relationship between tachycardia and AKI prevalence during the first week of ICU in septic patients. Heart rate was found to have a dose-dependent effect on AKI prevalence and renal insult monitored by biomarkers. [ABSTRACT FROM AUTHOR]

Previous studies reported that peripheral inflammation was associated with cognitive performance and brain structure in schizophrenia. However, the moderating effect of inflammation has not been extensively studied. This study investigated whether inflammation markers moderated the association between negative symptoms and neurocognition in schizophrenia. This cross-sectional study included 137 drug-naïve schizophrenia patients (DNS) and 67 healthy controls (HC). We performed the Measurements and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) for cognitive assessment and the Positive and Negative Syndrome Scale (PANSS) for psychiatric symptoms. Plasma concentrations of interferon-gamma (IFN-γ), neutrophil gelatinase-associated lipocalin (NGAL), and nuclear factor kappa B (NF-κB) were measured. The MCCB neurocognition score, social cognition score, and total score; the plasma concentrations of NGAL, IFN-γ, and NF-κB were significantly decreased in DNS than in HC (all P's < 0.001). PANSS negative subscale (PNS), PANSS reduced expressive subdomain (RES) negatively correlated with neurocognition score (P = 0.007; P = 0.011, respectively). Plasma concentrations of IFN-γ and NGAL positively correlated with neurocognition score (P = 0.043; P = 0.008, relatively). The interactions of PNS × NGAL; PNS × IFN-γ; RES × IFN-γ accounted for significant neurocognition variance (P = 0.025; P = 0.029, P = 0.007, respectively). Simple slope analysis showed that all the above moderating effects only occurred in patients with near normal IFN-γ and NGAL levels. Plasma concentrations of IFN-γ and NGAL moderated the relationship between negative symptoms (especially RES) and neurocognition in schizophrenia. Treatment targeting inflammation may contribute to neurocognition improvement in schizophrenia. [ABSTRACT FROM AUTHOR]

A growing body of research is categorizing sex differences in both sickle cell anemia (SCA) and acute kidney injury (AKI); however, most of this work is being conducted in high-resource settings. Here, we evaluated risk factors and clinical parameters associated with AKI and AKI severity, stratified by sex, in a cohort of children hospitalized with SCA and vaso-occlusive pain crisis (VOC). The purpose of this study was to explore sex disparities in a high-risk, vulnerable population. This study was a secondary analysis of data collected from a cohort of Ugandan children between 2 and 18 yr of age prospectively enrolled. A total of 185 children were enrolled in the primary study; 41.6% were female and 58.4% were male, with a median age of 8.9 yr. Incident or worsening AKI (P = 0.026) occurred more frequently in female compared with male children, despite no differences in AKI on admission. Female children also had altered markers of renal function including higher creatinine levels at admission (P = 0.03), higher peak creatinine (P = 0.006), and higher urine neutrophil gelatinase-associated lipocalin (NGAL) at admission (P = 0.003) compared with male children. Female children had elevated total (P = 0.045) and conjugated bilirubin at admission (P = 0.02) compared with male children and higher rates of hematuria at admission (P = 0.004). Here, we report sex differences in AKI in children with SCA and VOC, including increased incidence and worsening of AKI in female pediatric patients, in association with an increase in biological indicators of poor renal function including creatinine, estimated glomerular filtration rate, and NGAL. NEW & NOTEWORTHY: In this study, we report an increased risk of developing acute kidney injury (AKI) during hospitalization, worsening AKI, and death among females with sickle cell anemia (SCA) hospitalized with an acute pain crisis compared with males. The sex differences in AKI were not explained by socioeconomic differences, severity of pain, or disease severity among females compared with males. Together, these data suggest that female children with SCA may be at increased risk of AKI. [ABSTRACT FROM AUTHOR]

Perinatal asphyxia (PA) poses a significant threat to multiple organs, particularly the kidneys. Diagnosing PA-associated kidney injury remains challenging, and treatment options are inadequate. Furthermore, there is a lack of long-term follow-up data regarding the renal implications of PA. In this study, 7-day-old male Wistar rats were exposed to PA using a gas mixture (4% O2; 20% CO2 in N2 for 15 min) to investigate molecular pathways linked to renal tubular damage, hypoxia, angiogenesis, heat shock response, inflammation, and fibrosis in the kidney. In a second experiment, adult rats with a history of PA were subjected to moderate renal ischemia-reperfusion (IR) injury to test the hypothesis that PA exacerbates renal susceptibility. Our results revealed an increased gene expression of renal injury markers (kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin), hypoxic and heat shock factors (hypoxia-inducible factor-1α, heat shock factor-1, and heat shock protein-27), proinflammatory cytokines (interleukin-1β, interleukin-6, tumor necrosis factor-α, and monocyte chemoattractant protein-1), and fibrotic markers (transforming growth factor-β, connective tissue growth factor, and fibronectin) promptly after PA. Moreover, a machine learning model was identified through random forest analysis, demonstrating an impressive classification accuracy (95.5%) for PA. Post-PA rats showed exacerbated functional decline and tubular injury and more intense hypoxic, heat shock, proinflammatory, and profibrotic response after renal IR injury compared with controls. In conclusion, PA leads to subclinical kidney injury, which may increase the susceptibility to subsequent renal damage later in life. In addition, the parameters identified through random forest analysis provide a robust foundation for future biomarker research in the context of PA. NEW & NOTEWORTHY: This article demonstrates that perinatal asphyxia leads to subclinical kidney injury that permanently increases renal susceptibility to subsequent ischemic injury. We identified major molecular pathways involved in perinatal asphyxia-induced renal complications, highlighting potential targets of therapeutic approaches. In addition, random forest analysis revealed a model that classifies perinatal asphyxia with 95.5% accuracy that may provide a strong foundation for further biomarker research. These findings underscore the importance of multiorgan follow-up for perinatal asphyxia-affected patients. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is one of the most important causes of chronic pediatric morbidity and mortality and places an important burden on the medical system. Current diagnosis and progression monitoring techniques have numerous sensitivity and specificity limitations. New biomarkers for monitoring CKD progression have been assessed. Neutrophil gelatinase-associated lipocalin (NGAL) has had some promising results in adults, but in pediatric patients, due to the small number of patients included in the studies, cutoff values are not agreed upon. The small sample size also makes the statistical approach limited. The aim of our study was to develop a fuzzy logic approach to assess the probability of pediatric CKD progression using both NGAL (urinary and plasmatic) and routine blood test parameters (creatinine and erythrocyte sedimentation rate) as input data. In our study, we describe in detail how to configure a fuzzy model that can simulate the correlations between the input variables ESR, NGAL-P, NGAL-U, creatinine, and the output variable Prob regarding the prognosis of the patient's evolution. The results of the simulations on the model, i.e., the correlations between the input and output variables (3D graphic presentations) are explained in detail. We propose this model as a tool for physicians which will allow them to improve diagnosis, follow-up, and interventional decisions relative to the CKD stage. We believe this innovative approach can be a great tool for the clinician and validates the feasibility of using a fuzzy logic approach in interpreting NGAL biomarker results for CKD progression. [ABSTRACT FROM AUTHOR]

Purpose: Sepsis-associated acute kidney injury (S-AKI) is associated with increased morbidity and mortality. We aimed to develop a nomogram for predicting the risk of S-AKI patients. Patients and Methods: We collected data from septic patients admitted to the Provincial Hospital Affiliated with Shandong First Medical University from January 2019 to September 2022. Septic patients were divided into two groups based on the occurrence of AKI. A nomogram was developed by multiple logistic regression analyses. The performance of the nomogram was evaluated using C-statistics, calibration curves, and decision curve analysis (DCA). The validation cohort contained 70 patients between December 2022, and March 2023 in the same hospital. Results: 198 septic patients were enrolled in the training cohort. Multivariate logistic regression analysis showed that neutrophil gelatinase-associated lipocalin (NGAL), platelet-to-lymphocyte ratio (PLR), and vasopressor use were independent risk factors for S-AKI. A nomogram was developed based on these factors. C-statistics for the training and validation cohorts were respectively 0.873 (95% CI 0.825– 0.921) and 0.826 (95% CI 0.727– 0.924), indicating high prediction accuracy. The calibration curves showed good concordance. DCA revealed that the nomogram was of great clinical value. Conclusion: The nomogram presents early and effective prediction for the S-AKI patients, and provides optimal intervention to improve patient outcomes. [ABSTRACT FROM AUTHOR]

Lipocalin-2, a neutrophil gelatinase-associated lipocalin, is a 25-kDa secreted protein implicated in a broad range of inflammatory diseases affecting the brain and periphery. It is a pleotropic protein expressed by various immune and nonimmune cells throughout the body. Importantly, the surge in lipocalin-2 levels in disease states has been associated with a myriad of undesirable effects, further exacerbating the ongoing pathological processes. In the brain, glial cells are the principal source of lipocalin-2, which plays a definitive role in determining their functional phenotypes. In different central nervous system pathologies, an increased expression of glial lipocalin-2 has been linked to neurotoxicity. Lipocalin-2 mediates a crosstalk between central and peripheral immune cells under neuroinflammatory conditions. One intriguing aspect is that elevated lipocalin-2 levels in peripheral disorders, such as cancer, metabolic conditions, and liver diseases, potentially incite an inflammatory activation of glial cells while disrupting neuronal functions. This review comprehensively summarizes the influence of lipocalin-2 on the exacerbation of neuroinflammation by regulating various cellular processes. Additionally, this review explores lipocalin-2 as a mediator of neuroimmune crosstalk in various central nervous system pathologies and highlights the role of lipocalin-2 in carrying inflammatory signals along the neuroimmune axis. [ABSTRACT FROM AUTHOR]

Background and Aim: Neutrophil gelatinase‐associated lipocalin (NGAL) is characterized by increased expression before the rise in serum creatinine and has been used as a biomarker for the early prediction of acute kidney injury (AKI). However, there have been no comprehensive analyses of its significance in gastrointestinal diseases. This study aimed to analyze the usefulness of measuring urinary NGAL levels in patients with gastrointestinal diseases. Methods: This study included 171 patients with a wide range of gastrointestinal diseases. Urinary NGAL levels were measured in all patients within 24 h of admission and 72 h later. Results: Urinary NGAL levels were higher in patients with acute pancreatitis and acute cholangitis/cholecystitis than in those with other diseases. Although lower than in these diseases, urinary NGAL tends to be higher in inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease, as well as in acute and chronic liver diseases, and is higher in liver cirrhosis as the Child–Pugh grade increases. Furthermore, we found that the group with higher urinary NGAL levels, which continued to increase over time, had worse hospital stays and prognosis. Conclusion: Urinary NGAL could be used as an indicator of infectious diseases rather than an indicator of AKI in inflammatory bowel diseases and cirrhosis, and could predict the prognosis of patients with gastrointestinal diseases. [ABSTRACT FROM AUTHOR]

Key points Renal ischaemia and reperfusion (I/R) is caused by a sudden temporary impairment of the blood flow. I/R is a prevalent cause of acute kidney injury. As nitric oxide generated by inducible nitric oxide synthase (iNOS) has detrimental effects during I/R, the pharmacological blockade of iNOS has been proposed as a potential strategy to prevent I/R injury. The aim of this study was to improve the understanding of 1400W (an iNOS inhibitor) on renal I/R as a pharmacological strategy against kidney disease. BALB/c mice received 30 min of bilateral ischaemia, followed by 48 h or 28 days of reperfusion. Vehicle or 1400W (10 mg/kg) was administered 30 min before inducing ischaemia. We found that after 48 h of reperfusion 1400W decreased the serum creatinine, blood urea nitrogen, neutrophil gelatinase‐associated lipocalin and proliferating cell nuclear antigen 3 in the I/R animals. Unexpectedly, we observed mRNA upregulation of genes involved in kidney injury, cell‐cycle arrest, inflammation, mesenchymal transition and endothelial activation in the renal medulla of sham animals treated with 1400W. We also explored if 1400W promoted chronic kidney dysfunction 28 days after I/R and did not find significant alterations in renal function, fibrosis, blood pressure or mortality. The results provide evidence that 1400W may have adverse effects in the renal medulla. Importantly, our data point to 1400W‐induced endothelial dysfunction, establishing therapeutic limitations for its use. Acute kidney injury is a global health problem associated with high morbidity and mortality. The pharmacological blockade of inducible nitric oxide synthase (iNOS) has been proposed as a potential strategy to prevent AKI induced by ischaemia and reperfusion (I/R). Our main finding is that 1400W, a selective and irreversible iNOS inhibitor with low toxicity that is proposed as a therapeutic strategy to prevent kidney I/R injury, produces aberrant gene expression in the medulla associated to tissue injury, cell cycle arrest, inflammation, mesenchymal transition and endothelial activation. The negative effect of 1400W observed in the renal medulla at 48 h from drug administration, is transient as it did not translate into a chronic kidney disease condition. [ABSTRACT FROM AUTHOR]

Objective: Early diagnosis and prediction of organ dysfunction are critical for intervening and improving the outcomes of septic patients. The study aimed to find novel diagnostic and predictive biomarkers of organ dysfunction for perioperative septic patients. Method: This is a prospective, controlled, preliminary, and single-center study of emergency surgery patients. Mass spectrometry, Gene Ontology (GO) functional analysis, and the protein-protein interaction (PPI) network were performed to identify the differentially expressed proteins (DEPs) from sepsis patients, which were selected for further verification via enzyme-linked immunosorbent assay (ELISA). Logistic regression analysis was used to estimate the relative correlation of selected serum protein levels and clinical outcomes of septic patients. Calibration curves were plotted to assess the calibration of the models. Results: Five randomized serum samples per group were analyzed via mass spectrometry, and 146 DEPs were identified. GO functional analysis and the PPI network were performed to evaluate the molecular mechanisms of the DEPs. Six DEPs were selected for further verification via ELISA. Cathepsin B (CatB), vascular cell adhesion protein 1 (VCAM-1), neutrophil gelatinase-associated lipocalin (NGAL), protein S100-A9, prosaposin, and thrombospondin-1 levels were significantly increased in the patients with sepsis compared with those of the controls (p < 0.001). Logistic regression analysis showed that CatB, S100-A9, VCAM-1, prosaposin, and NGAL could be used for preoperative diagnosis and postoperative prediction of organ dysfunction. CatB and S100-A9 were possible predictive factors for preoperative diagnosis of renal failure in septic patients. Internal validation was assessed using the bootstrapping validation. The preoperative diagnosis of renal failure model displayed good discrimination with a C-index of 0.898 (95% confidence interval 0.843–0.954) and good calibration. Conclusion: Serum CatB, S100-A9, VCAM-1, prosaposin, and NGAL may be novel markers for preoperative diagnosis and postoperative prediction of organ dysfunction. Specifically, S100-A9 and CatB were indicators of preoperative renal dysfunction in septic patients. Combining these two biomarkers may improve the accuracy of predicting preoperative septic renal dysfunction. Trial registration: The study was registered at the Chinese Clinical Trials Registry (ChiCTR2200060418) on June 1, 2022. [ABSTRACT FROM AUTHOR]

Repetitive exposure of innate immune cells to a subthreshold dosage of endotoxin components may modulate inflammatory responses. However, the regulatory mechanisms in the interactions between the central nervous system (CNS) and the immune system remain unclear. This study aimed to investigate the effects of lipopolysaccharide (LPS) preconditioning in repeated social defeat stress (RSDS)-induced abnormal immune responses and behavioral impairments. This study aimed to elucidate the mechanisms that underlie the protective effects of repeated administration of a subthreshold dose LPS on behavioral impairments using the RSDS paradigm. LPS preconditioning improved abnormal behaviors in RSDS-defeated mice, accompanied by decreased monoamine oxidases and increased glucocorticoid receptor expression in the hippocampus. In addition, pre-treated with LPS significantly decreased the recruited peripheral myeloid cells (CD11b+CD45hi), mainly circulating inflammatory monocytes (CD11b+CD45hiLy6ChiCCR2+) into the brain in response to RSDS challenge. Importantly, we found that LPS preconditioning exerts its protective properties by regulating lipocalin-2 (LCN2) expression in microglia, which subsequently induces expressions of chemokine CCL2 and pro-inflammatory cytokine. Subsequently, LPS-preconditioning lessened the resident microglia population (CD11b+CD45intCCL2+) in the brains of the RSDS-defeated mice. Moreover, RSDS-associated expressions of leukocytes (CD11b+CD45+CCR2+) and neutrophils (CD11b+CD45+Ly6G+) in the bone marrow, spleen, and blood were also attenuated by LPS-preconditioning. In particular, LPS preconditioning also promoted the expression of endogenous antioxidants and anti-inflammatory proteins in the hippocampus. Our results demonstrate that LPS preconditioning ameliorates lipocalin 2-associated microglial activation and aberrant immune response and promotes the expression of endogenous antioxidants and anti-inflammatory protein, thereby maintaining the homeostasis of pro-inflammation/anti-inflammation in both the brain and immune system, ultimately protecting the mice from RSDS-induced aberrant immune response and behavioral changes. [ABSTRACT FROM AUTHOR]

Background: Systemic inflammation is believed to contribute to small cell lung cancer (SCLC) progression, but the underlying relationship remains unclear. Lipocalin‐2, a potential biomarker of inflammation, has been implicated in various cancers but its prognostic value in SCLC is underexplored. Methods: We retrospectively analyzed 191 patients with SCLC (72 with limited‐stage [LD] and 119 with extensive‐stage) treated using platinum‐based chemotherapy. Lipocalin‐2 expression was evaluated using immunohistochemistry. Optimal cutoff values for lipocalin‐2 and neutrophil‐to‐lymphocyte ratio (NLR) were determined using time‐dependent receiver operating characteristic curve analysis. The pectoralis muscle index was used to assess sarcopenia. Results: In LD‐SCLC, high lipocalin‐2 expression was associated with worse progression‐free survival (PFS; median: 7.0 vs. 15.9 months, p = 0.015) and overall survival (OS; median: 12.9 vs. 30.3 months, p = 0.035) compared with low lipocalin‐2 expression. Patients were stratified into three prognostic groups by combining lipocalin‐2 with NLR: low lipocalin‐2/low NLR, high lipocalin‐2/low NLR or low lipocalin‐2/high NLR, and high lipocalin‐2/high NLR (median PFS: 17.3 vs. 11.0 vs. 6.3 months, p = 0.004; median OS: 30.5 vs. 17.3 vs. 8.6 months, p = 0.002). Similar trends were observed when combining lipocalin‐2 with the pectoralis muscle index. High lipocalin‐2 expression was also associated with lower complete response rates (18.9% vs. 34.3%, p = 0.035). No significant prognostic implications were found for lipocalin‐2 in extensive‐stage SCLC. Conclusions: High lipocalin‐2 expression is potentially associated with poorer survival in LD‐SCLC. Combining lipocalin‐2 with other inflammation‐related markers could improve prognostic stratification. [ABSTRACT FROM AUTHOR]