In response to severe tissue trauma several danger sensing and signalling cascades are activated, including the complement and the apoptosis systems. In polytrauma patients, both the early activation of the complement cascade with an excessive generation of the potent anaphylatoxin C5a and the induction of apoptosis have been shown to ...

Macrophage-stimulating protein (MSP) circulates as a proform protein and requires proteolytic processing for activation. Respiratory ciliated cells express the MSP receptor, recepteur d'origine nantais (RON), at the apical surface, which reportedly has an important role in ciliary function. Like RON, human airway trypsin-like protease (HAT) is also expressed at the ...

Ebola (EBOV) and Marburg virus (MARV) cause severe hemorrhagic fever. The host cell proteases cathepsin B and L activate the Zaire ebolavirus glycoprotein (GP) for cellular entry and constitute potential targets for antiviral intervention. However, it is unclear if different EBOV species and MARV equally depend on cathepsin B/L activity ...

Secreted papain-like Cys proteases are important players in plant immunity. We previously reported that the C14 protease of tomato is targeted by cystatin-like EPIC proteins that are secreted by the oomycete pathogen Phytophthora infestans (Pinf) during infection. C14 has been under diversifying selection in wild potato species coevolving with Pinf ...

The CUB domain-containing protein-1 (CDCP1) is a transmembrane molecule that has recently been implicated in cancer progression. In this study we have established a novel mechanism for initiation of CDCP1-mediated signaling in vivo and demonstrated that specific 135→70-kDa processing of cell-surface CDCP1 by extracellular serine proteases is a prerequisite for ...

Atopic dermatitis (AD) is a chronically relapsing, noncontagious pruritic skin disease with two phases: acute and chronic. Previous studies have shown that the cysteine protease cathepsin S (CTSS) is linked to inflammatory processes, including atherosclerosis and asthma. The possibility that this or other cysteine proteases might cause itching or be ...

The level of proteolysis within phagosomes of dendritic cells (DCs) is thought to be tightly regulated, as it directly impacts the cell's efficiency to process antigen. Activity of the antimicrobial effector NADPH oxidase (NOX2) has been shown to reduce levels of proteolysis within phagosomes of both macrophages and DCs. However, ...

Granzyme B is a cytotoxic lymphocyte-derived protease that plays a central role in promoting apoptosis of virus-infected target cells, through direct proteolysis and activation of constituents of the cell death machinery. However, previous studies have also implicated granzymes A and B in the production of proinflammatory cytokines, via a mechanism ...

Mammalian epithelial, endothelial and various other cell types, upon their detachment from the extracellular matrix (ECM) undergo a specialized kind of apoptosis, known as anoikis. Entameba histolytica cysteine proteases have been implicated in degradation of the host ECM, which may induce anoikis in host cells. To explore this hypothesis, supernatant ...

Streptococcus pneumoniae meningitis causes brain damage through inflammation-related pathways whose identity and mechanisms of action are yet unclear. We previously identified caspase-1, which activates precursor IL-1 type cytokines, as a central mediator of inflammation in pneumococcal meningitis. In this study, we demonstrate that lack of the inflammasome components ASC or ...

OBJECTIVE: SirT1 has been previously implicated in the regulation of human cartilage homeostasis and chondrocyte survival. Exposing human osteoarthritic chondrocytes to TNFα generates a stable and enzymatically inactive 75kDa form of SirT1 (75SirT1) via Cathepsin B-mediated cleavage. Because 75SirT1 is resistant to further degradation, we assumed it has a distinct ...

Cathepsin B and urokinase plasminogen activator receptor (uPAR) are postulated to play key roles in glioma invasion. Calcineurin is one of the key regulators of mitochondrial-dependent apoptosis, but its mechanism is poorly understood. Hence, we studied subcellular localization of calcineurin after transcriptional downregulation of uPAR and cathepsin B in glioma. ...

Macrophage tissue infiltration is a hallmark of several pathological situations including cancer, neurodegenerative disorders and chronic inflammation. Hence, deciphering the mechanisms of macrophage migration across a variety of tissues holds great potential for novel anti-inflammatory therapies. Leukocytes have long been thought to migrate through tissues by using the amoeboid (protease-independent) ...

The baker's yeast, Saccharomyces cerevisiae, is also capable of undergoing programmed cell death or apoptosis, for example in response to viral infection as well as during chronological and replicative aging. Intrinsically, programmed cell death in yeast can be induced by, for example, H2O2, acetic acid or the mating-type pheromone. A ...

The yeast apoptosis field emerged with the finding that key components of the apoptotic machinery are conserved in these simple eukaryotes. Thus it became possible to exploit these genetically tractable organisms to improve our understanding of the intricate mechanisms of cell death in higher eukaryotes and of severe human diseases ...

Inhalation of single-walled carbon nanotubes (SWCNTs) has raised serious concerns related to potential toxic effects in the respiratory system. This study examined possible SWCNTs-induced toxic mechanisms in vivo in mice. The results indicated that a single intra-tracheal instillation of SWCNTs could induce airway hyper-reactivity and airflow obstruction, and confirmed previous ...

Telomerase is a ribonucleoprotein complex that is essential for persistent cellular proliferation. The catalytic subunit of human telomerase, hTERT, functions as a reverse transcriptase and promotes vitality by maintaining telomeric DNA length. hTERT is tightly regulated with complex but poorly understood positive and negative regulation at several levels including transcription, ...

Pathogenesis of blister formation in bullous pemphigoid (BP) and dermatitis herpetiformis (DH) is associated with destruction of numerous components of the dermal-epidermal junction. Proteolytic enzymes (PE) are involved in a multitude of physiological reactions and may have impact on the epidermal-dermal integrity. Involvement of various PE in inflammation and blister ...

Microglia are important innate immune effectors against invading CNS pathogens, such as Staphylococcus aureus (S. aureus), a common etiological agent of brain abscesses typified by widespread inflammation and necrosis. The NLRP3 inflammasome is a protein complex involved in IL-1β and IL-18 processing following exposure to both pathogen- and danger-associated molecular ...

Lysosomes are the key degradative compartments of the cell. Lysosomal cathepsins, which are enclosed in the lysosomes, help to maintain the homeostasis of the cell's metabolism by participating in the degradation of heterophagic and autophagic material. Following the targeted lysosomal membrane's destabilization, the cathepsins can be released into the cytosol ...

Trypanosoma cruzi is the causative agent of Chagas' disease. Novel chemotherapy with the drug K11777 targets the major cysteine protease cruzain and disrupts amastigote intracellular development. Nevertheless, the biological role of the protease in infection and pathogenesis remains unclear as cruzain gene knockout failed due to genetic redundancy. A role ...

We recently showed that serine proteases in German cockroach (GC) feces (frass) decreased experimental asthma through the activation of protease-activated receptor (PAR)-2. Since dendritic cells (DCs) play an important role in the initiation of asthma, we queried the role of GC frass proteases in modulating CCL20 (chemokine C-C motif ligand ...

We previously reported that curcumin inhibited lung cancer A549 cells growth and promoted cell apoptosis in vitro. In this study, we further examined the apoptosis-related parameters, including lysosomal damage and cathepsin activation, in A549 cells exposed to curcumin. We found that curcumin caused lysosomal membrane permeabilization (LMP) and cytosolic relocation ...

Calpains are proteolytic enzymes that modulate cellular function through cleavage of targets, thereby modifying their actions. An important role is emerging for calpains in regulating inflammation and immune responses, although specific mechanisms by which this occurs have not been clearly defined. In this study, we identify a novel target of ...

Serine protease inhibitor Kazal (SPIK) is an inflammatory protein whose levels are elevated in numerous cancers. However, the role of this protein in cancer development is unknown. We have recently found that SPIK suppresses serine protease-dependent cell apoptosis. Here, we report that anti-SPIK antibodies can co-immmuneprecipitate serine protease granzyme A ...

In response to viral infection, reactive oxygen species (ROS) mediate innate immune signaling or generate danger signals to activate immune cells. The mechanisms of virally induced ROS are poorly defined, however. We demonstrate that ROS are produced within minutes of adenovirus type 5 (Ad5) infection of macrophages and that oxidative ...

The ficolin-mediated complement pathway plays an important role in vertebrate immunity, but it is not clear whether this pathway exists in invertebrates. Here we identified homologs of ficolin pathway components from the cephalochordate amphioxus and investigated if they had been co-opted into a functional ficolin pathway. Four of these homologs, ...

The obligate intracellular bacterial pathogen Chlamydia trachomatis injects numerous effector proteins into the epithelial cell cytoplasm to manipulate host functions important for bacterial survival. In addition, the bacterium secretes a serine protease, chlamydial protease-like activity factor (CPAF). Although several CPAF targets are reported, the significance of CPAF-mediated proteolysis is unclear ...

Macrophages play a pivotal role in the pathophysiology of atherosclerosis. These cells express cathepsin L (CatL), a cysteine protease that has been implicated in atherogenesis and the associated arterial remodeling. In addition, macrophages highly express peroxisome proliferator-activated receptor (PPAR) γ, a transcription factor that regulates numerous genes important for lipid ...

Enterovirus 71 (EV71) causes hand-foot-and-mouth disease and neurological complications in young children. Although the underlying mechanisms remain obscure, impaired or aberrant immunity is thought to play a role. In infected cells, EV71 suppresses type I interferon responses mediated by retinoid acid inducible gene-I (RIG-I). This involves the EV71 3C protein ...

α1-Antichymotrypsin (α1-ACT) is a specific inhibitor of leukocyte-derived chymotrypsin-like proteases with largely unknown functions in tissue repair. By examining human and murine skin wounds, we showed that following mechanical injury the physiological repair response is associated with an acute phase response of α1-ACT and the mouse homologue Spi-2, respectively. In ...

Both CpG oligodeoxynucleotides and double-stranded RNA (poly I:C) have documented effects as treatments against several viral diseases in fish. However, as stand-alone treatments their effects have been modest. We have tested here whether CpG and poly I:C, alone or in combination induce protection against Salmonid Alphavirus (SAV), the causative agent ...

Although infectiological stimuli, environmental factors and genotypic features are known to contribute to the initiation and perpetuation of systemic sclerosis (SSc), its etiology still remains to be enigmatic, and less elusive insights are to be achieved by ongoing and future investigations. Being characterized, however, as chronic autoimmune disease with excessive ...

Lipopolysaccharide (LPS) is a bacterial molecule that induces nitric oxide (NO) production and triggers defense systems in plant-pathogen interactions. NO production is induced in the roots of Lotus japonicus after inoculation of the roots with its microsymbiont Mesorhizobium loti. However, the rhizobial molecule that induces NO production has not yet ...

Apart from reducing plasma lipids, ezetimibe may produce non-lipid-related pleiotropic effects. The aim of this paper was to compare the effect of ezetimibe and simvastatin on monocyte cytokine release and systemic inflammation in isolated hypercholesterolemic patients. One hundred thirty-four subjects with isolated hypercholesterolemia were allocated into one of four treatment ...

Early studies of the immune system disclosed that, generally, females exhibit stronger responses to a variety of antigens than males. Perhaps as a result of this response, women are more prone to developing autoimmune diseases than men. Yet, the precise cellular and molecular mechanisms remain under investigation. Recently, interferon-gamma and ...

The proinflammatory cytokine interleukin-17A (IL-17A) is produced primarily by the CD4+ T cell subset called Th17 cells, which is involved in host defense, inflammation, and autoimmune disorders. This study was undertaken to investigate the effect of a high-affinity RNA molecule, called an aptamer, against human IL-17A on IL-17A-induced signal transduction ...

The predominant prevalence of autoimmune diseases in women of reproductive age has led to the investigation of the effects of sex hormones on immune regulation and in autoimmune diseases, in particular the prototypic systemic autoimmune disease lupus. The female hormone prolactin has receptors beyond the reproductive axis including immune cells, ...

Due to the female predominance of autoimmune diseases, the role of gender and sex hormones in the immune system is of long-term interest. Estrogen's primary effects are mediated via estrogen receptors alpha and beta (ER α/β) that are expressed on most immune cells. ERs are nuclear hormone receptors that can ...

Aims Doxorubicin (DOX) is an anthracycline drug with a wide spectrum of clinical antineoplastic activity, but increased apoptosis has been implicated in its cardiotoxicity. Resveratrol (RES) was shown to harbor major health benefits in diseases associated with oxidative stress. In this study we hope to determine the effect of RES ...

Melanoma is the deadliest form of skin cancer, which is notoriously aggressive and chemo-resistant, and for which there is little effective treatment available if it goes undetected. Curcumin from the tumeric spice (Curcuma longa) has long been used in Southeast Asian medicine to alleviate ailments and cure an array of ...

Transforming growth factor (TGF-β1) is a pleiotropic cytokine, secreted by immune and nonhematopoietic cells. TGF-β is involved in many different critical processes, such as embryonal development, cellular maturation and differentiation, wound healing, and immune regulation. It maintains immune homeostasis by acting as a potent immune suppressor through inhibition of proliferation, ...

Caspases, a family of aspartate-specific cysteine proteases, play a major role in apoptosis and a variety of physiological and pathological processes. Fourteen mammalian caspases have been identified and can be divided into two groups: inflammatory caspases and apoptotic caspases. Based on the structure and function, the apoptotic caspases are further ...

Eosinophils are multifunctional leukocytes implicated in the pathogenesis of allergic diseases. An association between eosinophilic inflammation and infection or colonization by fungi has also been long recognized. However, the mechanisms underlying how eosinophils are activated and how they release proinflammatory and immunomodulatory mediators such as major basic protein (MBP) and ...

Programmed cell death-1 (PD-1) is a member of the CD28 superfamily that delivers negative signals upon interaction with its two ligands, PD-L1 or PD-L2. PD-1 and its ligands are broadly expressed and exert a wider range of immunoregulatory roles in T cells activation and tolerance compared with other CD28 members. ...

In mammals, cysteine proteases are essential for the induction and development of both innate and adaptive immune responses. These proteases play a role in antigen-and pathogen-recognition and elimination, signal processing and cell homeostasis. Many pathogens also secrete cysteine proteases that often act on the same target proteins as the mammalian ...

The lysosomal endoprotease cathepsin D (CatD) is an essential player in general protein turnover and specific peptide processing. CatD-deficiency is associated with neurodegenerative diseases, whereas elevated CatD levels correlate with tumor malignancy and cancer cell survival. Here, we show that the CatD ortholog of the budding yeast Saccharomyces cerevisiae (Pep4p) ...

Granzyme K (GrK) is a trypsin-like serine protease that is elevated in patients with sepsis and acute lung inflammation. While GrK was originally believed to function exclusively as a pro-apoptotic protease, recent studies now suggest that GrK may possess other non-cytotoxic functions. In the context of acute lung inflammation, we ...

Mast cells are best known for their role in allergic reactions but are also now recognized for their important contributions to a number of disparate inflammatory conditions through the release of inflammatory mediators, serglycin and other proteoglycans, and proteases. Because these tissue resident inflammatory cells express proteases in such great ...

The ATP-dependent ClpQY protease system in Plasmodium falciparum is a prokaryotic machinery in the parasite. In the present study, we have identified the complete ClpQY system in P. falciparum and elucidated its functional importance in survival and growth of asexual stage parasites. We characterized the interaction of P. falciparum ClpQ ...