Macro, Micro, and Molecular. Changes of the Osteochondral Interface in Osteoarthritis Development

Osteoarthritis (OA) is a long-term condition that causes joint pain and reduced movement. Notably, the same pathways governing cell growth, death, and differentiation during the growth and development of the body are also common drivers of OA. The osteochondral interface is a vital structure located between hyaline cartilage and subchondral bone. It plays a critical role in maintaining the physical and biological function, conveying joint mechanical stress, maintaining chondral microenvironment, as well as crosstalk and substance exchange through the osteochondral unit. In this review, we summarized the progress in research concerning the area of osteochondral junction, including its pathophysiological changes, molecular interactions, and signaling pathways that are related to the ultrastructure change. Multiple potential treatment options were also discussed in this review. A thorough understanding of these biological changes and molecular mechanisms in the pathologic process will advance our understanding of OA progression, and inform the development of effective therapeutics targeting OA.

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Emerging roles of the Hedgehog signalling pathway in inflammatory bowel disease

Cell Death Discovery ◽

10.1038/s41420-021-00679-7 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Zhuo Xie ◽

Mudan Zhang ◽

Gaoshi Zhou ◽

Lihui Lin ◽

Jing Han ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Molecular Mechanisms ◽

Treatment Options ◽

Critical Role ◽

Signalling Pathway ◽

Hedgehog Signalling Pathway ◽

Inflammatory Bowel ◽

Effective Drugs

AbstractThe Hedgehog (Hh) signalling pathway plays a critical role in the growth and patterning during embryonic development and maintenance of adult tissue homeostasis. Emerging data indicate that Hh signalling is implicated in the pathogenesis of inflammatory bowel disease (IBD). Current therapeutic treatments for IBD require optimisation, and novel effective drugs are warranted. Targeting the Hh signalling pathway may pave the way for successful IBD treatment. In this review, we introduce the molecular mechanisms underlying the Hh signalling pathway and its role in maintaining intestinal homeostasis. Then, we present interactions between the Hh signalling and other pathways involved in IBD and colitis-associated colorectal cancer (CAC), such as the Wnt and nuclear factor-kappa B (NF-κB) pathways. Furthermore, we summarise the latest research on Hh signalling associated with the occurrence and progression of IBD and CAC. Finally, we discuss the future directions for research on the role of Hh signalling in IBD pathogenesis and provide viewpoints on novel treatment options for IBD by targeting Hh signalling. An in-depth understanding of the complex role of Hh signalling in IBD pathogenesis will contribute to the development of new effective therapies for IBD patients.

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ERS International Congress, Madrid, 2019: highlights from the Basic and Translational Science Assembly

ERJ Open Research ◽

10.1183/23120541.00350-2019 ◽

2020 ◽

Vol 6 (1) ◽

pp. 00350-2019

Author(s):

Niki D. Ubags ◽

Jonathan Baker ◽

Agnes Boots ◽

Rita Costa ◽

Natalia El-Merhie ◽

...

Keyword(s):

Lung Disease ◽

Molecular Mechanisms ◽

Respiratory Infections ◽

Function Analysis ◽

Treatment Options ◽

Cell Types ◽

International Congress ◽

European Respiratory Society ◽

Lung Health

In this review, the Basic and Translational Sciences Assembly of the European Respiratory Society (ERS) provides an overview of the 2019 ERS International Congress highlights. In particular, we discuss how the novel and very promising technology of single cell sequencing has led to the development of a comprehensive map of the human lung, the lung cell atlas, including the discovery of novel cell types and new insights into cellular trajectories in lung health and disease. Further, we summarise recent insights in the field of respiratory infections, which can aid in a better understanding of the molecular mechanisms underlying these infections in order to develop novel vaccines and improved treatment options. Novel concepts delineating the early origins of lung disease are focused on the effects of pre- and post-natal exposures on neonatal lung development and long-term lung health. Moreover, we discuss how these early life exposures can affect the lung microbiome and respiratory infections. In addition, the importance of metabolomics and mitochondrial function analysis to subphenotype chronic lung disease patients according to their metabolic program is described. Finally, basic and translational respiratory science is rapidly moving forward and this will be beneficial for an advanced molecular understanding of the mechanisms underlying a variety of lung diseases. In the long-term this will aid in the development of novel therapeutic targeting strategies in the field of respiratory medicine.

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New treatment approaches to von Willebrand disease

Hematology ◽

10.1182/asheducation-2016.1.683 ◽

2016 ◽

Vol 2016 (1) ◽

pp. 683-689 ◽

Cited By ~ 13

Author(s):

Michelle Lavin ◽

James S. O’Donnell

Keyword(s):

Molecular Mechanisms ◽

Treatment Options ◽

Critical Role ◽

Bleeding Risk ◽

Von Willebrand Disease ◽

Assessment Tools ◽

Treatment Optimization ◽

New Treatment ◽

Molecular Aspects ◽

Von Willebrand

Abstract von Willebrand disease (VWD) is the commonest inherited bleeding disorder and results from either a quantitative or qualitative deficiency in the plasma glycoprotein von Willebrand factor (VWF). Recent large cohort studies have significantly enhanced our understanding of the molecular mechanisms involved in the pathogenesis of VWD. In contrast, however, there have been relatively few advances in the therapeutic options available for the treatment of bleeding in patients with VWD. Established treatment options include tranexamic acid, 1-deamino-8-d-arginine vasopressin (DDAVP), and plasma-derived VWF concentrates. In addition, a recombinant VWF has also recently been developed. In this review, we focus on how recent insights into the clinical and molecular aspects underpinning VWD are already beginning to influence treatment in the clinic. For example, a number of different bleeding assessment tools (BATs) have been developed to objectively assess bleeding symptoms in patients with VWD. Interestingly, however, these BAT scores may also have an important role to play in predicting bleeding risk in VWD. Furthermore, recent studies have demonstrated that enhanced VWF clearance plays a critical role in the etiology of both type 1 and type 2 VWD. These findings have direct translational relevance with respect to the use of DDAVP in patients with VWD. As understanding of the mechanisms involved in VWD pathogenesis continues to advance, novel treatment options are likely to emerge. Critically, however, large adequately powered and stratified clinical trials will be required to address the outstanding questions that remain regarding VWD treatment optimization.

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Infections

Operative Plastic Surgery ◽

10.1093/med/9780190499075.003.0099 ◽

2019 ◽

pp. 995-1002

Author(s):

Scott D. Oates

Keyword(s):

Human Activities ◽

Surgical Intervention ◽

Fungal Infections ◽

Treatment Options ◽

Healthcare Providers ◽

Signs And Symptoms ◽

The Body ◽

Early Surgical Intervention

Because of their exposed nature during human activities, infections of the hand are common. The anatomy of the hand and fingers also lends itself to unique types of infections that do not occur in other areas of the body, such as paronychia, felons, and fungal infections. Because of these unique types of infections, early surgical intervention is often necessary to prevent long-term functional sequelae. This requires healthcare providers to be knowledgeable of the signs and symptoms of these distinct infections in order to effectively treat these patients. This chapter describes many common hand infections and their treatment options.

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Impairments of Long-Term Synaptic Plasticity in the Hippocampus of Young Rats during the Latent Phase of the Lithium-Pilocarpine Model of Temporal Lobe Epilepsy

International Journal of Molecular Sciences ◽

10.3390/ijms222413355 ◽

2021 ◽

Vol 22 (24) ◽

pp. 13355

Author(s):

Tatyana Y. Postnikova ◽

Georgy P. Diespirov ◽

Dmitry V. Amakhin ◽

Elizaveta N. Vylekzhanina ◽

Elena B. Soboleva ◽

...

Keyword(s):

Synaptic Plasticity ◽

Temporal Lobe Epilepsy ◽

Temporal Lobe ◽

Molecular Mechanisms ◽

Critical Role ◽

Long Term Potentiation ◽

Control Group ◽

High Frequency Stimulation ◽

Pilocarpine Model

Status epilepticus (SE) causes persistent abnormalities in the functioning of neuronal networks, often resulting in worsening epileptic seizures. Many details of cellular and molecular mechanisms of seizure-induced changes are still unknown. The lithium–pilocarpine model of epilepsy in rats reproduces many features of human temporal lobe epilepsy. In this work, using the lithium–pilocarpine model in three-week-old rats, we examined the morphological and electrophysiological changes in the hippocampus within a week following pilocarpine-induced seizures. We found that almost a third of the neurons in the hippocampus and dentate gyrus died on the first day, but this was not accompanied by impaired synaptic plasticity at that time. A diminished long-term potentiation (LTP) was observed following three days, and the negative effect of SE on plasticity increased one week later, being accompanied by astrogliosis. The attenuation of LTP was caused by the weakening of N-methyl-D-aspartate receptor (NMDAR)-dependent signaling. NMDAR-current was more than two-fold weaker during high-frequency stimulation in the post-SE rats than in the control group. Application of glial transmitter D-serine, a coagonist of NMDARs, allows the enhancement of the NMDAR-dependent current and the restoration of LTP. These results suggest that the disorder of neuron–astrocyte interactions plays a critical role in the impairment of synaptic plasticity.

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Requirement for PINCH in Skeletal Myoblast Differentiation

10.21203/rs.3.rs-560801/v1 ◽

2021 ◽

Author(s):

Siyi Xie ◽

Chushan Fang ◽

Yujie Gao ◽

Jie Yan ◽

Lina Luo ◽

...

Keyword(s):

Skeletal Muscle ◽

Skeletal Muscles ◽

Molecular Mechanisms ◽

Myogenic Differentiation ◽

Critical Role ◽

The Body ◽

Myoblast Differentiation ◽

Skeletal Myogenesis ◽

Congenital Myopathies

Abstract Background: Skeletal muscle is composed of bundles of myofibers ensheathed by extracellular matrix networks. Malformation of skeletal muscle during embryonic development results in congenital myopathies. Disease mechanisms of congenital myopathies remain unclear. PINCH, an adaptor of focal adhesion complex, plays essential roles in multiple cellular processes and organogenesis. Elucidation of the molecular mechanisms underlying skeletal myogenesis will offer new insights into pathogenesis of myopathies.Methods: We generated muscle-specific PINCH knock-out mice to study the functional role of PINCH in skeletal myogenesis. Histologic and Transmission Electron Microscopy analysis demonstrated that Impaired myogenic differentiation and maturation in mice with PINCH1 being ablated in skeletal muscle progenitors, and Ablation of PINCH1 and PINCH2 resulted in reduced size of muscle fibers and impaired multinucleation; Cell culture and immunostaining showed that defects in myoblast fusion and cytoskeleton assembly in PINCH double mutant mice; Western blotting showed that defects in expression of cytoskeleton proteins and proteins involved in myogenesis in DMUT skeletal muscles.Results: Double ablation of PINCH1 and PINCH2 resulted in early postnatal lethality with reduced size of skeletal muscles and detachment of diaphragm muscles from the body wall. Myofibers of PINCH mutant myofibers failed to undergo multinucleation and exhibited disrupted sarcomere structures. The mutant myoblasts in culture were able to adhere to newly formed myotubes, but impeded in cell fusion and subsequent sarcomere genesis and cytoskeleton organization. Consistent with this, expression of integrin β1 and some cytoskeleton proteins, and phosphorylation of ERK and AKT were significantly reduced in PINCH mutants. Expression of MRF4, the most highly expressed myogenic factor at late stages of myogenesis, was abolished in PINCH mutants, that could contribute to observed phenotypes. In addition, mice with PINCH1 being ablated in myogenic progenitors exhibited only mild centronuclear myopathic changes, suggesting a compensatory role of PINCH2 in myogenic differentiation, indicating a critical role of PINCH proteins in myogenic differentiation.Conclusion: Our results demonstrated an essential role of PINCH in skeletal myogenic differentiation.

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Omics Derived Biomarkers and Novel Drug Targets for Improved Intervention in Advanced Prostate Cancer

Diagnostics ◽

10.3390/diagnostics10090658 ◽

2020 ◽

Vol 10 (9) ◽

pp. 658

Author(s):

Maria Frantzi ◽

Marie C. Hupe ◽

Axel S. Merseburger ◽

Joost P. Schanstra ◽

Harald Mischak ◽

...

Keyword(s):

Prostate Cancer ◽

Drug Targets ◽

Molecular Mechanisms ◽

Treatment Options ◽

Survival Rates ◽

Initial Therapy ◽

Clinical Settings ◽

Recommended Treatment ◽

Novel Drug

Prostate cancer (PCa) is one of the most frequently diagnosed malignancies, and the fifth leading cause of cancer related mortality in men. For advanced PCa, radical prostatectomy, radiotherapy, and/or long-term androgen deprivation therapy are the recommended treatment options. However, subsequent progression to metastatic disease after initial therapy results in low 5-year survival rates (29%). Omics technologies enable the acquisition of high-resolution large datasets that can provide insights into molecular mechanisms underlying PCa pathology. For the purpose of this article, a systematic literature search was conducted through the Web of Science Database to critically evaluate recent omics-driven studies that were performed towards: (a) Biomarker development and (b) characterization of novel molecular-based therapeutic targets. The results indicate that multiple omics-based biomarkers with prognostic and predictive value have been validated in the context of PCa, with several of those being also available for commercial use. At the same time, omics-driven potential drug targets have been investigated in pre-clinical settings and even in clinical trials, holding the promise for improved clinical management of advanced PCa, as part of personalized medicine pipelines.

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Distal renal tubular acidosis: a systematic approach from diagnosis to treatment

Journal of Nephrology ◽

10.1007/s40620-021-01032-y ◽

2021 ◽

Author(s):

Sabrina Giglio ◽

Giovanni Montini ◽

Francesco Trepiccione ◽

Giovanni Gambaro ◽

Francesco Emma

Keyword(s):

Metabolic Acidosis ◽

Renal Tubular Acidosis ◽

Molecular Mechanisms ◽

Clinical Symptoms ◽

Genetic Disorder ◽

Treatment Options ◽

Current Treatment ◽

Hydrogen Ions ◽

Renal Tubular

AbstractRenal tubular acidosis (RTA) comprises a group of disorders in which excretion of hydrogen ions or reabsorption of filtered HCO3is impaired, leading to chronic metabolic acidosis with normal anion gap. In the current review, the focus is placed on the most common type of RTA, Type 1 RTA or Distal RTA (dRTA), which is a rare chronic genetic disorder characterized by an inability of the distal nephron to secrete hydrogen ions in the presence of metabolic acidosis. Over the years, knowledge of the molecular mechanisms behind acid secretion has improved, thereby greatly helping the diagnosis of dRTA. The primary or inherited form of dRTA is mostly diagnosed in infancy, childhood, or young adulthood, while the acquired secondary form, as a consequence of other disorders or medications, can happen at any age, although it is more commonly seen in adults. dRTA is not as “benign” as previously assumed, and can have several, highly variable long-term consequences. The present review indeed reports and summarizes both clinical symptoms and diagnosis, long-term outcomes, genetic inheritance, epidemiology and current treatment options, with the aim of shedding more light onto this rare disorder. Being a chronic condition, dRTA also deserves attention in the transition between pediatric and adult nephrology care, and as a rare disease it has a place in the European and Italian rare nephrological diseases network.

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Dual binding capacity of mucosal immunoblasts to mucosal and synovial endothelium in humans: dissection of the molecular mechanisms.

Journal of Experimental Medicine ◽

10.1084/jem.181.1.137 ◽

1995 ◽

Vol 181 (1) ◽

pp. 137-149 ◽

Cited By ~ 85

Author(s):

M Salmi ◽

D P Andrew ◽

E C Butcher ◽

S Jalkanen

Keyword(s):

Molecular Mechanisms ◽

Binding Capacity ◽

Critical Role ◽

Cell Types ◽

The Body ◽

Minor Role ◽

Lymphocyte Function ◽

High Endothelial Venules ◽

Lamina Propria Lymphocyte ◽

The Impact

Lymphocytes continuously migrate throughout the body in search of antigens. Virgin lymphocytes recirculate freely between the blood and different lymphatic organs, whereas immunoblasts extravasate preferentially into sites similar to those where they initially responded to antigen. Tissue-specific extravasation of lymphocytes is largely controlled by distinct lymphocyte surface receptors that mediate lymphocyte binding to high endothelial venules (HEV). In the present study, the molecular mechanisms determining the specificity of human mucosal (lamina propria) lymphocyte binding to different endothelial recognition systems were analyzed. Mucosal immunoblasts adhered five times better than small mucosal lymphocytes to mucosal HEV. Importantly, mucosal immunoblasts also bound to synovial HEV almost as efficiently as to mucosal HEV, but they did not adhere to peripheral lymph node HEV. To study the impact of different homing-associated molecules in this dual endothelial binding, we used a gut-derived T cell line and freshly isolated mucosal immunoblasts. Both cell types expressed integrins alpha 4, beta 1, beta 7, and lymphocyte function associated antigen 1 (LFA-1), and were CD44 positive, but practically L-selectin negative. Binding of mucosal immunoblasts to mucosal HEV was almost completely abolished by pretreatment with anti-beta 7 monoclonal antibodies, but it was independent of alpha 4/beta 1 function. In contrast, alpha 4/beta 1 partially mediated immunoblast adherence to synovial HEV, whereas alpha 4/beta 7 had only a minor role in adherence of blasts at this site. CD44 and LFA-1 contributed to HEV-binding both in mucosa and synovium. Taken together, this is the first report that demonstrates a critical role for alpha 4/beta 7 in the binding of gut lymphocytes to mucosal venules in humans. Moreover, a hitherto unknown interaction between mucosal effector cells and synovial endothelial cells was shown to be only partially mediated by the currently known homing receptors. The dual endothelial binding capacity of mucosal blasts may help to explain the pathogenesis of reactive arthritis not uncommonly associated with inflammatory and infectious bowel disease.

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Serum Glycoproteomic Alterations in Patients with Diabetic Retinopathy

Proteomes ◽

10.3390/proteomes8030025 ◽

2020 ◽

Vol 8 (3) ◽

pp. 25

Author(s):

Ashok Sharma ◽

James Cox ◽

Joshua Glass ◽

Tae Jin Lee ◽

Sai Karthik Kodeboyina ◽

...

Keyword(s):

Extracellular Matrix ◽

Diabetic Retinopathy ◽

Protein Structure ◽

Molecular Mechanisms ◽

Inflammatory Diseases ◽

Treatment Options ◽

Critical Role ◽

Diabetic Patients ◽

Post Translational Modification ◽

Novel Therapeutic

The precise molecular mechanisms of diabetic retinopathy (DR) pathogenesis are unclear, and treatment options are limited. There is an urgent need to discover and develop novel therapeutic targets for the treatment of this disease. Glycosylation is a post-translational modification that plays a critical role in determining protein structure, function, and stability. Recent studies have found that serum glycoproteomic changes are associated with the presence or progression of several inflammatory diseases. However, very little is known about the glycoproteomic changes associated with DR. In this study, glycoproteomic profiling of the serum of diabetic patients with and without DR was performed. A total of 15 glycopeptides from 11 glycoproteins were found to be significantly altered (5 upregulated and 10 downregulated) within the serum glycoproteome of DR patients. These glycoproteins are known to be involved in the maintenance of the extracellular matrix and complement system through peptidolytic activity or regulation.

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