Iron is an essential element that is indispensable for life. The delicate physiological body iron balance is maintained by both systemic and cellular regulatory mechanisms. The iron-regulatory hormone hepcidin assures maintenance of adequate systemic iron levels and is regulated by circulating and stored iron levels, inflammation and erythropoiesis. The kidney has an important role in preventing iron loss from the body by means of reabsorption. Cellular iron levels are dependent on iron import, storage, utilization and export, which are mainly regulated by the iron response element-iron regulatory protein (IRE-IRP) system. In the kidney, iron transport mechanisms independent of the IRE-IRP system have been identified, suggesting additional mechanisms for iron handling in this organ. Yet, knowledge gaps on renal iron handling remain in terms of redundancy in transport mechanisms, the roles of the different tubular segments and related regulatory processes. Disturbances in cellular and systemic iron balance are recognized as causes and consequences of kidney injury. Consequently, iron metabolism has become a focus for novel therapeutic interventions for acute kidney injury and chronic kidney disease, which has fuelled interest in the molecular mechanisms of renal iron handling and renal injury, as well as the complex dynamics between systemic and local cellular iron regulation.

The multifaceted role of iron in renal health and disease.

Over the last two decades, a novel subgroup of serine proteases, the cell surface-anchored serine proteases, has emerged as an important component of the human degradome, and several members have garnered significant attention for their roles in cancer progression and metastasis. A large body of literature describes that cell surface-anchored serine proteases are deregulated in cancer and that they contribute to both tumor formation and metastasis through diverse molecular mechanisms. The loss of precise regulation of cell surface-anchored serine protease expression and/or catalytic activity may be contributing to the etiology of several cancer types. There is therefore a strong impetus to understand the events that lead to deregulation at the gene and protein levels, how these precipitate in various stages of tumorigenesis, and whether targeting of selected proteases can lead to novel cancer intervention strategies. This review summarizes current knowledge about cell surface-anchored serine proteases and their role in cancer based on biochemical characterization, cell culture-based studies, expression studies, and in vivo experiments. Efforts to develop inhibitors to target cell surface-anchored serine proteases in cancer therapy will also be summarized.

Cell surface–anchored serine proteases in cancer progression and metastasis

The development of refractory tumor cells limits therapeutic efficacy in cancer by activating mechanisms that promote cellular proliferation, migration, invasion, metastasis, and survival. Benzimidazole anthelmintics have broad-spectrum action to remove parasites both in human and veterinary medicine. In addition to being antiparasitic agents, benzimidazole anthelmintics are known to exert anticancer activities, such as the disruption of microtubule polymerization, the induction of apoptosis, cell cycle (G2/M) arrest, anti-angiogenesis, and blockage of glucose transport. These antitumorigenic effects even extend to cancer cells resistant to approved therapies and when in combination with conventional therapeutics, enhance anticancer efficacy and hold promise as adjuvants. Above all, these anthelmintics may offer a broad, safe spectrum to treat cancer, as demonstrated by their long history of use as antiparasitic agents. The present review summarizes central literature regarding the anticancer effects of benzimidazole anthelmintics, including albendazole, parbendazole, fenbendazole, mebendazole, oxibendazole, oxfendazole, ricobendazole, and flubendazole in cancer cell lines, animal tumor models, and clinical trials. This review provides valuable information on how to improve the quality of life in patients with cancers by increasing the treatment options and decreasing side effects from conventional therapy.

/pdf/the-antitumor-potentials-of-benzimidazole-anthelmintics-as-45o7ihyyjj.pdf

The Antitumor Potentials of Benzimidazole Anthelmintics as Repurposing Drugs.

Proteases are a diverse group of hydrolytic enzymes, ranging from single-domain catalytic molecules to sophisticated multi-functional macromolecules. Human proteases are divided into five mechanistic classes: aspartate, cysteine, metallo, serine and threonine proteases, based on the catalytic mechanism of hydrolysis. As a protective mechanism against uncontrolled proteolysis, proteases are often produced and secreted as inactive precursors, called zymogens, containing inhibitory N-terminal propeptides. Protease propeptide structures vary considerably in length, ranging from dipeptides and propeptides of about 10 amino acids to complex multifunctional prodomains with hundreds of residues. Interestingly, sequence analysis of the different protease domains has demonstrated that propeptide sequences present higher heterogeneity compared with their catalytic domains. Therefore, we suggest that protease inhibition targeting propeptides might be more specific and have less off-target effects than classical inhibitors. The roles of propeptides, besides keeping protease latency, include correct folding of proteases, compartmentalization, liganding, and functional modulation. Changes in the propeptide sequence, thus, have a tremendous impact on the cognate enzymes. Small modifications of the propeptide sequences modulate the activity of the enzymes, which may be useful as a therapeutic strategy. This review provides an overview of known human proteases, with a focus on the role of their propeptides. We review propeptide functions, activation mechanisms, and possible therapeutic applications.

Protease propeptide structures, mechanisms of activation, and functions.

Solid tumors carry out the formation of new vessels providing blood supply for growth, tumor maintenance, and metastasis. Several processes take place during tumor vascularization. In angiogenesis, new vessels are derived from endothelial cells of pre-existing vessels; while in vasculogenesis, new vessels are formed de novo from endothelial progenitor cells, creating an abnormal, immature, and disorganized vascular network. Moreover, highly aggressive tumor cells form structures similar to vessels, providing a pathway for perfusion; this process is named vasculogenic mimicry (VM), where vessel-like channels mimic the function of vessels and transport plasma and blood cells. VM is developed by numerous types of aggressive tumors, including ovarian carcinoma which is the second most common cause of death among gynecological cancers. VM has been associated with poor patient outcome and survival in ovarian cancer, although the involved mechanisms are still under investigation. Several signaling molecules have an important role in VM in ovarian cancer, by regulating the expression of genes related to vascular, embryogenic, and hypoxic signaling pathways. In this review, we provide an overview of the current knowledge of the signaling molecules involved in the promotion and regulation of VM in ovarian cancer. The clinical implications and the potential benefit of identification and targeting of VM related molecules for ovarian cancer treatment are also discussed.

/pdf/mechanisms-of-vasculogenic-mimicry-in-ovarian-cancer-1w4y5a7rv6.pdf

Mechanisms of Vasculogenic Mimicry in Ovarian Cancer

Altered microRNA (miRNA) expression has been reported in patients with immune thrombocytopenic purpura (ITP). However, the detailed expression profiling of cell-free circulating miRNAs in ITP patients has not been fully investigated. In this study, we aimed to examine plasma miRNAs in ITP patients and evaluate their diagnostic values. Plasma samples from 74 ITP patients and 58 healthy controls were obtained and allocated into discovery, validation, and therapy-response sets. Initial screen with a miRNA microarray assay identified 23 miRNAs with different levels between ITP patients and healthy controls (>1.5-fold changes; p

Plasma microRNAs characterising patients with immune thrombocytopenic purpura

Multiple studies have indicated that albendazole (ABZ) can disrupt the microtubule in worms and have anti-tumor potential in a variety of tumors. However, the therapeutic effect of ABZ on triple-negative breast cancer (TNBC) is largely unknown, and the therapeutic evaluation of ABZ by 18F-FDG PET imaging remains relatively unexplored. The effects of ABZ on TNBC cell lines (MDA-MB-231 cells) were investigated in vitro using MTT, wound-healing, transwell migration, flow cytometry and Western blotting analyses. In vivo treatment was conducted in an MDA-MB-231 tumor-bearing nude mouse model. Mouse body weight loss was also evaluated. PET imaging was performed before and after 3 days of treatment. Tumor tissues were harvested for immunofluorescence analysis. ABZ treatment inhibited the proliferation and migration and triggered the apoptosis in MDA-MB-231 cells. Furthermore, Western blotting analysis showed that ABZ induced the apoptosis in MDA-MB-231 cells via GLUT1/AMPK/P53 signaling pathway. Long-term treatment studies found that the tumor volume of the treatment group was smaller compared with the control group, and the survival time was prolonged. In vivo 18F-FDG PET imaging showed that 3-day ABZ treatment reduced standardized uptake value (SUV) values in MDA-MB-231 xenografts compared with the controls, and immunofluorescence analysis showed more TUNEL-positive cells in the ABZ-treated mice. Our study suggested that ABZ induced the apoptosis of MDA-MB-231 cells by inhibiting glucose uptake, and it could be considered as a potential drug for TNBC cells. Moreover, 18F-FDG PET imaging could be used to monitor the early anti-tumor effect of ABZ on MDA-MB-231 tumors.

18F-FDG PET imaging for monitoring the early anti-tumor effect of albendazole on triple-negative breast cancer.

Vascular endothelial cadherin (VE‑cadherin) was first found in vascular endothelial cells to maintain normal vascular structures and regulate endothelial cell permeability by homology adhesion. New evidence indicates that certain invasive tumor cells also express VE‑cadherin, which is involved in vasculogenic mimicry to provide a blood supply required for tumor growth and metastasis. EC1 and EC3 domains of VE‑cadherin were reported to be important for intercellular homology adhesion. In the present study, a monoclonal antibody specific to the outer-membrane immunoglobulin-like domains of VE‑cadherin was generated and the binding epitope was identified as peptide LDREVVPWYNLTVEA in the EC4 domain. This antibody inhibited proliferation and capillary-like structure formation of lung cancer Glc‑82 cells in 3D Matrigel culture in vitro. This effect was mediated by the inhibition of AKT phosphorylation. Our results suggested that the EC4 domain participates in VE‑cadherin clustering and the antibody targeting the EC4 domain of VE‑cadherin may be a promising anti‑vasculogenic mimicry agent for cancer treatment.

/pdf/a-novel-monoclonal-antibody-targeting-a-novel-epitope-of-ve-39oj9j96cw.pdf

A novel monoclonal antibody targeting a novel epitope of VE‑cadherin inhibits vasculogenic mimicry of lung cancer cells

OBJECTIVE To examine the expression level of B7-H6 in chronic myeloid leukemia (CML) patients and to explore its clinical significance. METHODS Two hundred twenty-eight CML patients were included and peripheral blood (PB) and bone marrow (BM) mononuclear cells were collected for B7-H6 mRNA expression analyses by quantitative real time polymerase chain reaction (PCR). RESULTS The expression of B7-H6 mRNA was successfully detected in all PB and BM samples. According to the clinical characteristics of CML patients, no difference was found in the B7-H6 level of PBMCs. However, a significantly decreased B7-H6 level was noted in BM samples from CML with BCR-ABL1/ABL > 0.1% (10 copies of BCR-ABL1/10000 copies of ABL) compared to ≤ 0.1% (P < 0.0001), and a negative correlation was found between the expression level of B7-H6 in BM and the number of BCR-ABL1/ABL transcripts (r = -0.26, P = 0.0057). A significant difference in PFS was observed between patients with high expression level of B7-H6 and low expression level in BM (χ2 = 12.53, P = 0.0004). CONCLUSION The expression of the B7-H6 gene in CML is correlated with BCR-ABL1 copy number and responsiveness to treatment, and monitoring of B7-H6 expression may be used to predict CML prognosis, progression, and treatment efficacy evaluation.

Expression of B7-H6 in chronic myeloid leukemia and its clinical significance.

The invention relates to the technical fields of molecular biology and immunology and especially relates to a vascular endothelial cadherin epitope, an antibody and an application thereof. The invention provides the vascular endothelial cadherin epitope, the antibody and the application thereof, wherein the amino acid sequence of the epitope is represented as the SEQ ID No.1. The epitope is located at the N-terminal of a CDH5 protein and has higher conservatism. The epitope belongs to a neutralizing epitope and can specifically recognize tumor blood vessels and inhibit generation thereof. A test proves that the epitope can specially recognize the vascular endothelial cadherin in the tumor blood vessels, thereby inhibiting the generation of the tumor blood vessels.

Vascular endothelial cadherin epitope, antibody and application thereof

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