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Inflammatory breast cancer (IBC) is an aggressive form of primary breast cancer characterized by rapid onset and high risk of metastasis and poor clinical outcomes. The biological basis for the aggressiveness of IBC is still not well understood and no IBC‐specific targeted therapies exist. In this study, we report that lipocalin 2 (LCN2), a small secreted glycoprotein belonging to the lipocalin superfamily, is expressed at significantly higher levels in IBC vs non‐IBC tumors, independently of molecular subtype. LCN2 levels were also significantly higher in IBC cell lines and in their culture media than in non‐IBC cell lines. High expression was associated with poor‐prognosis features and shorter overall survival in IBC patients. Depletion of LCN2 in IBC cell lines reduced colony formation, migration, and cancer stem cell populations in vitro and inhibited tumor growth, skin invasion, and brain metastasis in mouse models of IBC. Analysis of our proteomics data showed reduced expression of proteins involved in cell cycle and DNA repair in LCN2‐silenced IBC cells. Our findings support that LCN2 promotes IBC tumor aggressiveness and offer a new potential therapeutic target for IBC. In this study, the authors demonstrate that lipocalin 2 (LCN2) is highly upregulated in inflammatory breast cancer (IBC), a rare, rapidly‐progressing and aggressive variant of primary breast cancer. Depletion of LCN2 in IBC cell lines reduced colony formation, migration, and cancer stem cell populations in vitro and inhibited tumor growth, skin invasion, and brain metastasis in mouse models of IBC.

The signaling network between cancer and stromal cells plays a crucial role in tumor microenvironment. The fate of tumor progression mainly depends on the huge amount of information that these cell populations exchange from the onset of neoplastic transformation. Interfering with such signaling has been producing exciting results in cancer therapy: just think of anti-PD-1/anti-PD-L1/anti-CTLA-4 antibodies that, acting as immune checkpoint inhibitors, interrupt the inhibitory signaling exerted by cancer cells on immune cells or the CAR-T technology that fosters the reactivation of anti-tumoral immunity in a restricted group of leukemias and lymphomas. Nevertheless, many types of cancers, in particular solid tumors, are still refractory to these treatments, so the identification of novel molecular targets in tumor secretome would benefit from implementation of current anti-cancer therapeutical strategies. Neutrophil Gelatinase-Associated Lipocalin (NGAL) is a secreted protein abundantly expressed in the secretome of various human tumors. It represents a promising target for the multiple roles that are played inside cancer and stromal cells, and also overall in their cross-talk. The review focuses on the different roles of NGAL in tumor microenvironment and in cancer senescence-associated secretory phenotype (SASP), highlighting the most crucial functions that could be eventually targetable in cancer therapy.

Sodium-glucose transporter-2 (SGLT2) inhibitors reduced the incidence of acute kidney injury in large cardiovascular outcome trials in patients with chronic heart and kidney failure. Acute kidney injury is a common complication following cardiac surgery. We hypothesized that perioperative SGLT2 inhibition could reduce kidney injury after cardiac surgery, measured with the biomarker neutrophil gelatinase-associated (NGAL). In this open-label phase IV, randomized, parallel-group, pilot study, adult patients undergoing elective cardiac surgery with cardiopulmonary bypass were randomized to receive either an SGLT2 inhibitor, empagliflozin (10 mg; oral) once daily, from three days before surgery until postoperative day two, or standard-of-care. The primary outcome was the between-group difference of serum NGAL on the second postoperative day. Moreover, other biomarkers for acute kidney injury were measured, including serum kidney injury molecule-1 (KIM-1), hypoxia-inducible factor-1 alpha (HIF-1α), and urine NGAL/Creatinine and KIM-1/Creatinine ratios. Additional outcomes included acute kidney injury incidence within the first seven days following cardiac surgery according to Kidney Disease: Improving Global Outcomes criteria and metabolic parameters, including ketone body concentrations and glycemic control. Between March 2022 and April 2023, 55 patients were included (sex: 73 % male, age: 66 ± 10 years, BMI: 28 ± 4 kg/m2, empagliflozin n = 25, control n = 30) in the intention-to-treat analysis. There were no significant between-group differences in serum and urine NGAL or KIM-1. However, empagliflozin significantly reduced the incidence of acute kidney injury (20 % vs 66.7 %; absolute difference 46.7 %, 95 % CI, −69.7 – -23.6; P < .001). A significant increase in serum HIF-1α after surgery was solely observed in the control group. We observed no between-group differences in the incidence of (euglycemic) ketoacidosis or hypoglycemic events. In this pilot study, perioperative SGLT2 inhibition was not associated with lower NGAL levels. We observed that SGLT2 inhibition reduced the incidence of acute kidney injury in this small study population. As the results of this pilot study are hypotheses-generating, further validation is needed in a large-scale, double-blind, placebo-controlled, randomized trial, which is currently ongoing. •This pilot trial showed that empagliflozin reduced the AKI incidence.•Perioperative empagliflozin did not result in ketoacidosis.•Findings warrant validation in large, double-blind, placebo-controlled trial.

Immune and inflammatory responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contribute to disease severity of coronavirus disease 2019 (COVID-19). However, the utility of specific immune-based biomarkers to predict clinical outcome remains elusive. Here, we analyzed levels of 66 soluble biomarkers in 175 Italian patients with COVID-19 ranging from mild/moderate to critical severity and assessed type I IFN-, type II IFN-, and NF-κB-dependent whole-blood transcriptional signatures. A broad inflammatory signature was observed, implicating activation of various immune and nonhematopoietic cell subsets. Discordance between IFN-α2a protein and IFNA2 transcript levels in blood suggests that type I IFNs during COVID-19 may be primarily produced by tissue-resident cells. Multivariable analysis of patients' first samples revealed 12 biomarkers (CCL2, IL-15, soluble ST2 [sST2], NGAL, sTNFRSF1A, ferritin, IL-6, S100A9, MMP-9, IL-2, sVEGFR1, IL-10) that when increased were independently associated with mortality. Multivariate analyses of longitudinal biomarker trajectories identified 8 of the aforementioned biomarkers (IL-15, IL-2, NGAL, CCL2, MMP-9, sTNFRSF1A, sST2, IL-10) and 2 additional biomarkers (lactoferrin, CXCL9) that were substantially associated with mortality when increased, while IL-1α was associated with mortality when decreased. Among these, sST2, sTNFRSF1A, IL-10, and IL-15 were consistently higher throughout the hospitalization in patients who died versus those who recovered, suggesting that these biomarkers may provide an early warning of eventual disease outcome.

Acute kidney injury (AKI) complicates recovery from cardiac surgery in up to 30 % of patients, injures and impairs the function of the brain, lungs, and gut, and places patients at a 5-fold increased risk of death during hospitalization. Renal ischemia, reperfusion, inflammation, hemolysis, oxidative stress, cholesterol emboli, and toxins contribute to the development and progression of AKI. Preventive strategies are limited, but current evidence supports maintenance of renal perfusion and intravascular volume while avoiding venous congestion, administration of balanced salt as opposed to high-chloride intravenous fluids, and the avoidance or limitation of cardiopulmonary bypass exposure. AKI that requires renal replacement therapy occurs in 2–5 % of patients following cardiac surgery and is associated with 50 % mortality. For those who recover from renal replacement therapy or even mild AKI, progression to chronic kidney disease in the ensuing months and years is more likely than for those who do not develop AKI. Cardiac surgery continues to be a popular clinical model to evaluate novel therapeutics, off-label use of existing medications, and nonpharmacologic treatments for AKI, since cardiac surgery is fairly common, typically elective, provides a relatively standardized insult, and patients remain hospitalized and monitored following surgery. More efficient and time-sensitive methods to diagnose AKI are imperative to reduce this negative outcome. The discovery and validation of renal damage biomarkers should in time supplant creatinine-based criteria for the clinical diagnosis of AKI.

Chemoresistance is a major cause of cancer progression and the mortality of cancer patients. Developing a safe strategy for enhancing chemosensitivity is a challenge for biomedical science. Recent studies have suggested that vitamin D supplementation may decrease the risk of many cancers. However, the role of vitamin D in chemotherapy remains unknown. We found that vitamin D sensitised oral cancer cells to cisplatin and partially reversed cisplatin resistance. Using RNA-seq, we discovered that lipocalin 2 (LCN2) is an important mediator. Cisplatin enhanced the expression of LCN2 by decreasing methylation at the promoter, whereas vitamin D enhanced methylation and thereby inhibited the expression of LCN2. Overexpression of LCN2 increased cell survival and cisplatin resistance both in vitro and in vivo. High LCN2 expression was positively associated with differentiation, lymph node metastasis, and T staging and predicted a poor prognosis in oral squamous cell carcinoma (OSCC) patients. LCN2 was also associated with post-chemotherapy recurrence. Moreover, we found that LCN2 promoted the activation of NF-κB by binding to ribosomal protein S3 (RPS3) and enhanced the interaction between RPS3 and p65. Our study reveals that vitamin D can enhance cisplatin chemotherapy and suggests that vitamin D should be supplied during chemotherapy; however, more follow-up clinical studies are needed.

Lipocalin-2 (LCN2) is a secreted glycoprotein linked to several physiological roles, including transporting hydrophobic ligands across cell membranes, modulating immune responses, maintaining iron homeostasis, and promoting epithelial cell differentiation. Although LNC2 is expressed at low levels in most human tissues, it is abundant in aggressive subtypes of cancer, including breast, pancreas, thyroid, ovarian, colon, and bile duct cancers. High levels of LCN2 have been associated with increased cell proliferation, angiogenesis, cell invasion, and metastasis. Moreover, LCN2 modulates the degradation, allosteric events, and enzymatic activity of matrix metalloprotease-9, a metalloprotease that promotes tumor cell invasion and metastasis. Hence, LCN2 has emerged as a potential therapeutic target against many cancer types. This review summarizes the most relevant findings regarding the expression, biological roles, and regulation of LCN2, as well as the proteins LCN2 interacts with in cancer. We also discuss the approaches to targeting LCN2 for cancer treatment that are currently under investigation, including the use of interference RNAs, antibodies, and gene editing.

Background Patients with type 2 diabetes often face early tubular injury, necessitating effective treatment strategies. This study aimed to evaluate the impact of the SGLT2 inhibitor empagliflozin on early tubular injury biomarkers in type 2 diabetes patients with normoalbuminuria. Methods A randomized controlled clinical study comprising 54 patients selected based on specific criteria was conducted. Patients were divided into an intervention group (empagliflozin, n  = 27) and a control group ( n  = 27) and treated for 6 weeks. Tubular injury biomarkers KIM-1 and NGAL were assessed pre- and post-treatment. Results Both groups demonstrated comparable baseline characteristics. Post-treatment, fasting and postprandial blood glucose levels decreased similarly in both groups. The intervention group exhibited better improvements in total cholesterol, low-density lipoprotein, and blood uric acid levels. Renal function indicators, including UACR and eGFR, showed greater enhancements in the intervention group. Significant reductions in KIM-1 and NGAL were observed in the intervention group. Conclusion Treatment with empagliflozin in type 2 diabetes patients with normoalbuminuria led to a notable decrease in tubular injury biomarkers KIM-1 and NGAL. These findings highlight the potential of SGLT2 inhibitors in early tubular protection, offering a new therapeutic approach.

There are few effective pharmacological interventions for intracerebral hemorrhage (ICH). Atorvastatin (Ato) has been shown to exert a substantial protective effect on ischemic stroke and is effective in alleviating neuroinflammation. Lipocalin-2 (LCN2), an important inflammation-regulating protein, has been demonstrated to play pivotal roles in post-ICH neuroinflammation. However, the exact role of Ato and whether LCN2 is involved after ICH remain largely unknown. In the current study, the BV2 (microglia) cell line, which was transfected with or without LCN2 for overexpression/interference, was co-cultured with primary cultured neurons and received blood infusion from C57BL/6 mice in vitro. For the in vivo study, atorvastatin was injected peritoneally into an ICH mouse model, and LCN2 specific knockout using the flox/cre system was performed in mice for mechanism study. Behavioral tests were conducted before ICH and on days 1, 3, and 7 post—ICH, and the brains and cultured cells were collected for protein, histological, and morphological studies. Our results showed that atorvastatin treatment alleviates neural damage and promotes neurological outcomes after ICH. Moreover, M1 activation and pro—inflammatory polarization are inhibited by atorvastatin. In both in vivo and in vitro models, the upregulation of LCN2 after ICH is substantially inhibited by atorvastatin. Studies on LCN2 transgenic mice and LCN2 overexpression/interference cells demonstrated that the suppression of macrophage/microglia (M/M) LCN2 participates in atorvastatin-mediated anti-neuroinflammation and neural protection effects. Therefore, our study suggests that atorvastatin treatment attenuates M/M-related neuroinflammation and protects neural recovery by down—regulating LCN2 after ICH. This study identified a potential novel therapeutic target for ICH treatment. Graphical Abstract Atorvastatin treatment counteracts M/M-related neuroinflammation, marked by M1 phenotype marker expression and pro-inflammatory cytokines IL-1β and TNF release, and protects neural recovery, marked by facilitated clot reduction, alleviated neural damage and neurologic functional recovery, after ICH via down-regulation M/M LCN2 expression.

Inflammatory Breast Cancer (IBC) is an aggressive form of invasive breast cancer, highly metastatic, representing 2–4% of all breast cancer cases in the United States. Despite its rare nature, IBC is responsible for 7–10% of all breast cancer deaths, with a 5-year survival rate of 40%. Thus, targeted and effective therapies against IBC are needed. Here, we proposed Lipocalin-2 (LCN2)—a secreted glycoprotein aberrantly abundant in different cancers—as a plausible target for IBC. In immunoblotting, we observed higher LCN2 protein levels in IBC cells than non-IBC cells, where the LCN2 levels were almost undetectable. We assessed the biological effects of targeting LCN2 in IBC cells with small interference RNAs (siRNAs) and small molecule inhibitors. siRNA-mediated LCN2 silencing in IBC cells significantly reduced cell proliferation, viability, migration, and invasion. Furthermore, LCN2 silencing promoted apoptosis and arrested the cell cycle progression in the G0/G1 to S phase transition. We used in silico analysis with a library of 25,000 compounds to identify potential LCN2 inhibitors, and four out of sixteen selected compounds significantly decreased cell proliferation, cell viability, and the AKT phosphorylation levels in SUM149 cells. Moreover, ectopically expressing LCN2 MCF7 cells, treated with two potential LCN2 inhibitors (ZINC00784494 and ZINC00640089) showed a significant decrease in cell proliferation. Our findings suggest LCN2 as a promising target for IBC treatment using siRNA and small molecule inhibitors.