Alzheimer's Disease: In Vitro and In Vivo Evidence of Activation of the Plasma Bradykinin-Forming Cascade and Implications for Therapy.

The plaques associated with Alzheimer's disease are formed as a result of the aggregation of Aβ peptides, which vary in length from 38 to 43 amino acids. The 1-40 peptide is the most abundant, while the 1-42 peptide appears to be the most destructive to neurons and/or glial cells in a variety of assays. We have demonstrated that aggregated Aβ, a state prior to plaque formation, will activate the plasma bradykinin-forming pathway when tested in vitro.

Omics analysis reveals galectin-3 to be a potential key regulator of allergic inflammation in hereditary angioedema.

Background: Hereditary angioedema (HAE) is a rare inherited disorder that predisposes an individual to develop vasogenic edema. Bradykinin release, which increases vascular permeability, results in angioedema. C1 esterase inhibitor (C1-INH) is a major regulator of critical enzymes involved in bradykinin generation and mutations in genes that encode the C1 inhibitor of complement factor 1, which prevent its synthesis (type I HAE), form a dysfunctional protein (type II HAE), or have normal functioning C1-INH (type III HAE, aka HAE-III).

The C1q and gC1qR axis as a novel checkpoint inhibitor in cancer.

Understanding at the molecular level of the cell biology of tumors has led to significant treatment advances in the past. Despite such advances however, development of therapy resistance and tumor recurrence are still unresolved major challenges. This therefore underscores the need to identify novel tumor targets and develop corresponding therapies to supplement existing biologic and cytotoxic approaches so that a deeper and more sustained treatment responses could be achieved.

Complement protein C1q stimulates hyaluronic acid degradation gC1qR/HABP1/p32 in malignant pleural mesothelioma.

Complement component C1q can act as a pro-tumorigenic factor in the tumor microenvironment (TME). The TME in malignant pleural mesothelioma (MPM) is rich in C1q and hyaluronic acid (HA), whose interaction enhances adhesion, migration and proliferation of malignant cells. HA-bound C1q is also capable of modulating HA synthesis.

Complement component C1q initiates extrinsic coagulation via the receptor for the globular head of C1q in adventitial fibroblasts and vascular smooth muscle cells.

Background: Vascular diseases are highly associated with inflammation and thrombosis. Elucidating links between these two processes may provide a clearer understanding of these diseases, allowing for the design of more effective treatments. The activation of complement component 1 (C1) is a crucial contributor to innate immunity and is associated with significant concentrations of circulating C1q.

The complex role of kininogens in hereditary angioedema.

Human high molecular weight kininogen (HK) is the substrate from which bradykinin is released as a result of activation of the plasma "contact" system, a cascade that includes the intrinsic coagulation pathway, and a fibrinolytic pathway leading to the conversion of plasminogen to plasmin. Its distinction from low molecular weight kininogen (LK) was first made clear in studies of bovine plasma. While early studies did suggest two kininogens in human plasma also, their distinction became clear when plasma deficient in HK or both HK and LK were discovered.

gC1qR/C1qBP/HABP-1: Structural Analysis of the Trimeric Core Region, Interactions With a Novel Panel of Monoclonal Antibodies, and Their Influence on Binding to FXII.

The protein gC1qR/C1qBP/HABP-1 plays an essential role in mitochondrial biogenesis, but becomes localized at the cellular surface in numerous pathophysiological states. When this occurs on endothelial cells, surface-exposed gC1qR activates the classical pathway of complement. It also promotes assembly of a multi-protein complex comprised of coagulation factor XII (FXII), pre-kallikrein (PK), and high-molecular weight kininogen (HMWK) that activates the contact system and the kinin-generating system.

Microbial Protein Binding to gC1qR Drives PLA2G1B-Induced CD4 T-Cell Anergy.

The origin of the impaired CD4 T-cell response and immunodeficiency of HIV-infected patients is still only partially understood. We recently demonstrated that PLA2G1B phospholipase synergizes with the HIV gp41 envelope protein in HIV viremic plasma to induce large abnormal membrane microdomains (aMMDs) that trap and inactivate physiological receptors, such as those for IL-7. However, the mechanism of regulation of PLA2G1B activity by the cofactor gp41 is not known.

The role of complement in the tumor microenvironment.

Tumorigenesis has long been linked to the evasion of the immune system and the uncontrolled proliferation of transformed cells. The complement system, a major arm of innate immunity, is a key factor in the progression of cancer because many of its components have critical regulatory roles in the tumor microenvironment. For example, complement anaphylatoxins directly and indirectly inhibit antitumor T-cell responses in primary and metastatic sites, enhance proliferation of tumor cells, and promote metastasis and tumor angiogenesis.

SARS-CoV-2 Exacerbates COVID-19 Pathology Through Activation of the Complement and Kinin Systems.

Infection with SARS-CoV-2 triggers the simultaneous activation of innate inflammatory pathways including the complement system and the kallikrein-kinin system (KKS) generating in the process potent vasoactive peptides that contribute to severe acute respiratory syndrome (SARS) and multi-organ failure. The genome of SARS-CoV-2 encodes four major structural proteins - the spike (S) protein, nucleocapsid (N) protein, membrane (M) protein, and the envelope (E) protein. However, the role of these proteins in either binding to or activation of the complement system and/or the KKS is still incompletely understood.

gC1qR Antibody Can Modulate Endothelial Cell Permeability in Angioedema.

Angioedema is characterized by swelling of the skin or mucous membranes. Overproduction of the vasodilator bradykinin (BK) is an important contributor to the disease pathology, which causes rapid increase in vascular permeability. BK formation on endothelial cells results from high molecular weight kininogen (HK) interacting with gC1qR, the receptor for the globular heads of C1q, the first component of the classical pathway of complement.

SARS-CoV-2 Structural Proteins Exposure Alter Thrombotic and Inflammatory Responses in Human Endothelial Cells.

Introduction: We have experienced a pandemic induced by the interaction of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) structural proteins with innate structures. These interactions are especially prevalent for patients with underlying pathologies, such as cardiovascular diseases. However, there has been limited work to uncover the range of responses induced by SARS-CoV-2 structural proteins.

Low Glucose Mediated Fluconazole Tolerance in .

Chronic meningoencephalitis is caused by and is treated in many parts of the world with fluconazole (FLC) monotherapy, which is associated with treatment failure and poor outcome. In the host, propagates predominantly under low glucose growth conditions. We investigated whether low glucose, mimicked by growing in synthetic media (SM) with 0.

SARS-CoV-2 proteins regulate inflammatory, thrombotic and diabetic responses in human arterial fibroblasts.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for many pathological processes, including altered vascular disease development, dysfunctional thrombosis and a heightened inflammatory response. However, there is limited work to determine the underlying cellular responses induced by exposure to SARS-CoV-2 structural proteins. Thus, our objective was to investigate how human arterial adventitial fibroblasts inflammation, thrombosis and diabetic disease markers are altered in response to Spike, Nucleocapsid and Membrane-Envelope proteins.

Yao Syndrome: A Potential Role and Association of Vasoactive Intestinal Peptide with .

Nucleotide-binding oligomerization domain containing protein 2 (NOD2) is a cytosolic receptor. Both NOD2 and vasoactive intestinal peptide (VIP) are critical in regulation of immune and inflammatory response. Yao syndrome (YAOS, OMIM 617321) is an autoinflammatory disease associated with specified NOD2 mutations.

Heterozygous // Polymorphism Reduces Mitochondrial Oxidative Phosphorylation and Is Expressed in Low-grade Colorectal Carcinomas.

Rapid proliferation of cancer cells is enabled by favoring aerobic glycolysis over mitochondrial oxidative phosphorylation (OXPHOS). P32 (/gC1qR) is essential for mitochondrial protein translation and thus indispensable for OXPHOS activity. It is ubiquitously expressed and directed to the mitochondrial matrix in almost all cell types with an excessive up-regulation of p32 expression reported for tumor tissues.

SLE: Novel Postulates for Therapeutic Options.

Genetic deficiency in C1q is a strong susceptibility factor for systemic lupus erythematosus (SLE). There are two major hypotheses that potentially explain the role of C1q in SLE. The first postulates that C1q deficiency abrogates apoptotic cell clearance, leading to persistently high loads of potentially immunogenic self-antigens that trigger autoimmune responses.

GC1qR Cleavage by Caspase-1 Drives Aerobic Glycolysis in Tumor Cells.

Self-sustained cell proliferation constitutes one hallmark of cancer enabled by aerobic glycolysis which is characterized by imbalanced glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) activity, named the Warburg effect. The C1q binding protein (; gC1qR) is pivotal for mitochondrial protein translation and thus OXPHOS activity. Due to its fundamental role in balancing OXPHOS and glycolysis, mice display embryonic lethality, while gC1qR is excessively up-regulated in cancer.

Anti gC1qR/p32/HABP1 Antibody Therapy Decreases Tumor Growth in an Orthotopic Murine Xenotransplant Model of Triple Negative Breast Cancer.

gC1qR is highly expressed in breast cancer and plays a role in cancer cell proliferation. This study explored therapy with gC1qR monoclonal antibody 60.11, directed against the C1q binding domain of gC1qR, in a murine orthotopic xenotransplant model of triple negative breast cancer.

Complement and coagulation: key triggers of COVID-19-induced multiorgan pathology.

In a stunningly short period of time, the unexpected coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has turned the unprepared world topsy-turvy. Although the rapidity with which the virus struck was indeed overwhelming, scientists throughout the world have been up to the task of deciphering the mechanisms by which SARS-CoV-2 induces the multisystem and multiorgan inflammatory responses that, collectively, contribute to the high mortality rate in affected individuals. In this issue of the JCI, Skendros and Mitsios et al.