Glycoreplica peptides to investigate molecular mechanisms of immune-mediated physiological versus pathological conditions

: Platelets are small blood cells known primarily for their ability to adhere and aggregate at injured vessels to arrest bleeding. However, when triggered under pathological conditions, the same adaptive mechanism of platelet adhesion and aggregation may cause thrombosis, a primary cause of heart attack and stroke. Over recent decades, research has made considerable progress in uncovering the intricate and dynamic interactions that regulate these processes. Integrins are heterodimeric cell surface receptors expressed on all metazoan cells that facilitate cell adhesion, movement, and signaling, to drive biological and pathological processes such as thrombosis and hemostasis. Recently, our group discovered that the plexinsemaphorin-integrin (PSI) domains of the integrin β subunits exert endogenous thiol isomerase activity derived from their two highly conserved CXXC active site motifs. Given the importance of redox reactions in integrin activation and its location in the knee region, this PSI domain activity may be critically involved in facilitating the interconversions between integrin conformations. Our monoclonal antibodies against the β3 PSI domain inhibited its thiol isomerase activity and proportionally attenuated fibrinogen binding and platelet aggregation. Notably, these antibodies inhibited thrombosis without significantly impairing hemostasis or causing platelet clearance. In this review, we will update mechanisms of thrombosis and hemostasis including platelet versatilities and immune-mediated thrombocytopenia, discuss critical contributions of the newly discovered PSI domain thiol isomerase activity, and its potential as a novel target for anti-thrombotic therapies and beyond.

Download Full-text

When the Balance Tips: Dysregulation of Mitochondrial Dynamics as a Culprit in Disease

International Journal of Molecular Sciences ◽

10.3390/ijms22094617 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4617

Author(s):

Styliana Kyriakoudi ◽

Anthi Drousiotou ◽

Petros P. Petrou

Keyword(s):

Insulin Resistance ◽

Mitochondrial Function ◽

Human Disease ◽

Molecular Mechanisms ◽

Mitochondrial Dynamics ◽

Mitochondrial Fusion ◽

Mitochondrial Morphology ◽

Disease Development ◽

Pathological Conditions ◽

Wide Range

Mitochondria are dynamic organelles, the morphology of which is tightly linked to their functions. The interplay between the coordinated events of fusion and fission that are collectively described as mitochondrial dynamics regulates mitochondrial morphology and adjusts mitochondrial function. Over the last few years, accruing evidence established a connection between dysregulated mitochondrial dynamics and disease development and progression. Defects in key components of the machinery mediating mitochondrial fusion and fission have been linked to a wide range of pathological conditions, such as insulin resistance and obesity, neurodegenerative diseases and cancer. Here, we provide an update on the molecular mechanisms promoting mitochondrial fusion and fission in mammals and discuss the emerging association of disturbed mitochondrial dynamics with human disease.

Download Full-text

BMP signaling alters aquaporin-4 expression in the mouse cerebral cortex

Scientific Reports ◽

10.1038/s41598-021-89997-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Kazuya Morita ◽

Naoyuki Matsumoto ◽

Kengo Saito ◽

Toshihide Hamabe-Horiike ◽

Keishi Mizuguchi ◽

...

Keyword(s):

Cerebral Cortex ◽

Molecular Mechanisms ◽

Water Movement ◽

Water Channel ◽

Bmp Signaling ◽

Aquaporin 4 ◽

Mammalian Brain ◽

Physiological Conditions ◽

Pathological Conditions ◽

Mouse Cerebral Cortex

AbstractAquaporin-4 (AQP4) is a predominant water channel expressed in astrocytes in the mammalian brain. AQP4 is crucial for the regulation of homeostatic water movement across the blood–brain barrier (BBB). Although the molecular mechanisms regulating AQP4 levels in the cerebral cortex under pathological conditions have been intensively investigated, those under normal physiological conditions are not fully understood. Here we demonstrate that AQP4 is selectively expressed in astrocytes in the mouse cerebral cortex during development. BMP signaling was preferentially activated in AQP4-positive astrocytes. Furthermore, activation of BMP signaling by in utero electroporation markedly increased AQP4 levels in the cerebral cortex, and inhibition of BMP signaling strongly suppressed them. These results indicate that BMP signaling alters AQP4 levels in the mouse cerebral cortex during development.

Download Full-text

An in vivo model allowing continuous observation of human vascular formation in the same animal over time

Scientific Reports ◽

10.1038/s41598-020-80497-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yohei Tsukada ◽

Fumitaka Muramatsu ◽

Yumiko Hayashi ◽

Chiaki Inagaki ◽

Hang Su ◽

...

Keyword(s):

Blood Vessel ◽

Blood Vessels ◽

Human Blood ◽

Molecular Mechanisms ◽

Human Tumor ◽

Continuous Observation ◽

In Vivo Models ◽

Cranial Window ◽

Pathological Conditions

AbstractAngiogenesis contributes to numerous pathological conditions. Understanding the molecular mechanisms of angiogenesis will offer new therapeutic opportunities. Several experimental in vivo models that better represent the pathological conditions have been generated for this purpose in mice, but it is difficult to translate results from mouse to human blood vessels. To understand human vascular biology and translate findings into human research, we need human blood vessel models to replicate human vascular physiology. Here, we show that human tumor tissue transplantation into a cranial window enables engraftment of human blood vessels in mice. An in vivo imaging technique using two-photon microscopy allows continuous observation of human blood vessels until at least 49 days after tumor transplantation. These human blood vessels make connections with mouse blood vessels as shown by the finding that lectin injected into the mouse tail vein reaches the human blood vessels. Finally, this model revealed that formation and/or maintenance of human blood vessels depends on VEGFR2 signaling. This approach represents a useful tool to study molecular mechanisms of human blood vessel formation and to test effects of drugs that target human blood vessels in vivo to show proof of concept in a preclinical model.

Download Full-text

Pharmacological Effects and Potential Clinical Usefulness of Polyphenols in Benign Prostatic Hyperplasia

Molecules ◽

10.3390/molecules26020450 ◽

2021 ◽

Vol 26 (2) ◽

pp. 450

Author(s):

Kensuke Mitsunari ◽

Yasuyoshi Miyata ◽

Tomohiro Matsuo ◽

Yuta Mukae ◽

Asato Otsubo ◽

...

Keyword(s):

Benign Prostatic Hyperplasia ◽

Molecular Mechanisms ◽

Prostatic Hyperplasia ◽

Pathological Conditions ◽

Urinary Tract Symptoms ◽

Anti Inflammatory ◽

Lower Urinary

Benign prostatic hyperplasia (BPH) is arguably the most common benign disease among men. This disease is often associated with lower urinary tract symptoms (LUTS) in men and significantly decreases the quality of life. Polyphenol consumption reportedly plays an important role in the prevention of many diseases, including BPH. In recent years, in addition to disease prevention, many studies have reported the efficacy and safety of polyphenol treatment against various pathological conditions in vivo and in vitro. Furthermore, numerous studies have also revealed the molecular mechanisms of the antioxidant and anti-inflammatory effects of polyphenols. We believe that an improved understanding of the detailed pharmacological roles of polyphenol-induced activities at a molecular level is important for the prevention and treatment of BPH. Polyphenols are composed of many members, and their biological roles differ. In this review, we first provide information regarding the pathological roles of oxidative stress and inflammation in BPH. Next, the antioxidant and anti-inflammatory effects of polyphenols, including those of flavonoids and non-flavonoids, are discussed. Finally, we talk about the results and limitations of previous clinical trials that have used polyphenols in BPH, with particular focus on their molecular mechanisms of action.

Download Full-text

Proopiomelanocortin, a polypeptide precursor with multiple functions: from physiology to pathological conditions

Acta Endocrinologica ◽

10.1530/eje.0.1490079 ◽

2003 ◽

Vol 149 (2) ◽

pp. 79-90 ◽

Cited By ~ 160

Author(s):

ML Raffin-Sanson ◽

Y de Keyzer ◽

X Bertagna

Keyword(s):

Anterior Pituitary ◽

Energy Homeostasis ◽

Molecular Mechanisms ◽

Single Gene ◽

Local Production ◽

Biological Functions ◽

Multiple Functions ◽

Pathological Conditions ◽

Recent Developments ◽

The Brain

Proopiomelanocortin (POMC) is the polypeptide precursor of ACTH. First discovered in anterior pituitary corticotroph cells, it has more recently been revealed to have many other physiological aspects. The fine molecular mechanisms of ACTH biosynthesis show that ACTH is but one piece of a puzzle which contains many other peptides. Present in various tIssues, among which are pituitary, hypothalamus, central nervous system and skin, POMC undergoes extensive post-translational processing. This processing is tIssue-specific and generates, depending on the case, various sets of peptides involved in completely diverse biological functions. POMC expressed in corticotroph cells of the pituitary is necessary for adrenal function. Recent developments have shown that POMC-expressing neurons in the brain play a major role in the control of pain and energy homeostasis. Local production of POMC-derived peptides in skin may influence melanogenesis. A still unknown function in the placenta is likely.POMC has become a paradigmatic polypeptide precursor model illustrating the variable roles of a single gene and its various products in different localities.

Download Full-text

Current Evidence for a Role of Neuropeptides in the Regulation of Autophagy

BioMed Research International ◽

10.1155/2017/5856071 ◽

2017 ◽

Vol 2017 ◽

pp. 1-10 ◽

Cited By ~ 7

Author(s):

Elisabetta Catalani ◽

Clara De Palma ◽

Cristiana Perrotta ◽

Davide Cervia

Keyword(s):

Molecular Mechanisms ◽

Current Evidence ◽

Pathological Conditions ◽

Organ Systems ◽

Intercellular Signalling ◽

Physiological Homeostasis ◽

Response To Stress ◽

Autophagic Process ◽

Regulatory Functions

Neuropeptides drive a wide diversity of biological actions and mediate multiple regulatory functions involving all organ systems. They modulate intercellular signalling in the central and peripheral nervous systems as well as the cross talk among nervous and endocrine systems. Indeed, neuropeptides can function as peptide hormones regulating physiological homeostasis (e.g., cognition, blood pressure, feeding behaviour, water balance, glucose metabolism, pain, and response to stress), neuroprotection, and immunomodulation. We aim here to describe the recent advances on the role exerted by neuropeptides in the control of autophagy and its molecular mechanisms since increasing evidence indicates that dysregulation of autophagic process is related to different pathological conditions, including neurodegeneration, metabolic disorders, and cancer.

Download Full-text

Novel in vitro Experimental Approaches to Study Myelination and Remyelination in the Central Nervous System

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.748849 ◽

2021 ◽

Vol 15 ◽

Author(s):

Davide Marangon ◽

Nicolò Caporale ◽

Marta Boccazzi ◽

Maria P. Abbracchio ◽

Giuseppe Testa ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Molecular Mechanisms ◽

Disease Modeling ◽

Brain Physiology ◽

Pathological Conditions ◽

Approaches To Study ◽

The Central Nervous System ◽

Experimental Approaches

Myelin is the lipidic insulating structure enwrapping axons and allowing fast saltatory nerve conduction. In the central nervous system, myelin sheath is the result of the complex packaging of multilamellar extensions of oligodendrocyte (OL) membranes. Before reaching myelinating capabilities, OLs undergo a very precise program of differentiation and maturation that starts from OL precursor cells (OPCs). In the last 20 years, the biology of OPCs and their behavior under pathological conditions have been studied through several experimental models. When co-cultured with neurons, OPCs undergo terminal maturation and produce myelin tracts around axons, allowing to investigate myelination in response to exogenous stimuli in a very simple in vitro system. On the other hand, in vivo models more closely reproducing some of the features of human pathophysiology enabled to assess the consequences of demyelination and the molecular mechanisms of remyelination, and they are often used to validate the effect of pharmacological agents. However, they are very complex, and not suitable for large scale drug discovery screening. Recent advances in cell reprogramming, biophysics and bioengineering have allowed impressive improvements in the methodological approaches to study brain physiology and myelination. Rat and mouse OPCs can be replaced by human OPCs obtained by induced pluripotent stem cells (iPSCs) derived from healthy or diseased individuals, thus offering unprecedented possibilities for personalized disease modeling and treatment. OPCs and neural cells can be also artificially assembled, using 3D-printed culture chambers and biomaterial scaffolds, which allow modeling cell-to-cell interactions in a highly controlled manner. Interestingly, scaffold stiffness can be adopted to reproduce the mechanosensory properties assumed by tissues in physiological or pathological conditions. Moreover, the recent development of iPSC-derived 3D brain cultures, called organoids, has made it possible to study key aspects of embryonic brain development, such as neuronal differentiation, maturation and network formation in temporal dynamics that are inaccessible to traditional in vitro cultures. Despite the huge potential of organoids, their application to myelination studies is still in its infancy. In this review, we shall summarize the novel most relevant experimental approaches and their implications for the identification of remyelinating agents for human diseases such as multiple sclerosis.

Download Full-text

Molecular signature of pruriceptive MrgprA3+ neurons

10.1101/727396 ◽

2019 ◽

Author(s):

Yanyan Xing ◽

Junyu Chen ◽

Henry Hilley ◽

Haley Steele ◽

Jingjing Yang ◽

...

Keyword(s):

Sensory Neurons ◽

Molecular Mechanisms ◽

Molecular Signature ◽

Neuronal Populations ◽

Pathological Conditions ◽

Chronic Itch ◽

Itch Sensation ◽

Profile Changes ◽

Allergic Contact

ABSTRACTItch, initiated by the activation of sensory neurons, is frequently associated with dermatological or systemic diseases and significantly affects patient quality of life. MrgprA3+ sensory neurons have been identified as one of the major itch-sensing neuronal populations. Mounting evidence has demonstrated that peripheral pathological conditions induce physiological regulations of sensory neurons, which is critical for the maintenance of chronic itch sensation. However, the underlying molecular mechanisms are not clear. Here we performed RNA sequencing of genetically labeled MrgprA3+ neurons under both naïve and allergic contact dermatitis condition. Our results revealed the unique molecular signature of itch-sensing neurons and the distinct transcriptional profile changes that result in response to dermatitis. We found enrichment of nine Mrgpr family members and two histamine receptors in MrgprA3+ neurons, suggesting that MrgprA3+ neurons are the main, direct neuronal target for histamine and Mrgprs agonists. In addition, Ptpn6 and Pcdh12 were identified as novel and highly selective markers of MrgprA3+ neurons. We also discovered that MrgprA3+ neurons respond to skin dermatitis in a way that is unique from other sensory neurons by regulating a combination of transcriptional factors, ion channels, and key molecules involved in synaptic transmission. These results significantly increase our knowledge of itch transmission and uncover potentially novel targets for combating itch.

Download Full-text

Unfulfilled Inflammatory Resolution: A Key Factor in the Pathogenesis of Psoriasis

Iranian Journal of Allergy Asthma and Immunology ◽

10.18502/ijaai.v19i4.4130 ◽

2020 ◽

Author(s):

Zohreh Jadali

Keyword(s):

Inflammatory Response ◽

Chronic Inflammation ◽

Molecular Mechanisms ◽

Inflammatory Responses ◽

Inflammatory Diseases ◽

Relevant Literature ◽

Regulatory Mechanisms ◽

Immune Mediated ◽

Key Factor ◽

Inflammation Resolution

Recent literature has highlighted the importance of chronic inflammation in psoriasis pathogenesis. Non-resolving inflammation can trigger progressive tissue damage and inflammatory mediator release which in turn perpetuate the inflammatory cycle. Under normal conditions, inflammatory responses are tightly controlled through several mechanisms that restore normal tissue function and structure. Defects in regulatory mechanisms of the inflammatory response can result in persistent unresolved inflammation and further increases of inflammation. Therefore, this review focuses on defects in regulatory mechanisms of inflammatory responses that lead to uncontrolled chronic inflammation in psoriasis. Databases such as Pubmed Embase, ISI, and Iranian databases including Iranmedex, and SID were researched to identify relevant literature. The results of this review indicate that dysregulation of the inflammatory response may be a likely cause of various immune-mediated inflammatory disorders such as psoriasis. Based on current findings, advances in understanding the cellular and molecular mechanisms involved in inflammation resolution are not only improving our knowledge of the pathogenesis of chronic inflammatory diseases but also supporting the development of new therapeutic strategies.

Download Full-text