Osteoinductive biomaterials: current knowledge of properties, experimental models and biological mechanisms

The transport of drugs across the placenta is a point of great importance in pharmacotherapy during pregnancy. However, the knowledge of drug transport in pregnancy is mostly based on experimental clinical data, and the underlying biological mechanisms are not fully understood. In this review, we summarize the current knowledge of drug transporters in the human placenta. We only refer to human data since the placenta demonstrates great diversity among species. In addition, we describe the experimental models that have been used in human placental transport studies and discuss their availability. A better understanding of placental drug transporters will be beneficial for the health of pregnant women who need drug treatment and their fetuses.

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Experimental Rodent Models of Vascular Dementia: A Systematic Review

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527319666210108123438 ◽

2021 ◽

Vol 19 ◽

Author(s):

Nidhi Tiwari ◽

Jyoti Upadhyay ◽

Mohd Nazam Ansari ◽

Syed Shadab Raza ◽

Wasim Ahmad ◽

...

Keyword(s):

Vascular Dementia ◽

Small Vessel Disease ◽

Current Knowledge ◽

Vascular Cognitive Impairment ◽

Experimental Models ◽

New Drugs ◽

Amyloid Angiopathy ◽

Vessel Disease ◽

The Brain ◽

Large Vessel Disease

: Vascular dementia (VaD) occurs due to cerebrovascular insufficiency, which leads to decreased blood circulation to the brain, thereby resulting in mental disabilities. The main causes of vascular cognitive impairment (VCI) are severe hypoperfusion, stroke, hypertension, large vessel disease (cortical), small vessel disease (subcortical VaD), strategic infarct, hemorrhage (microbleed), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and cerebral amyloid angiopathy (CAA),which leads to decreased cerebrovascular perfusion. Many metabolic disorders such as diabetes mellitus (DM), dyslipidemia, and hyperhomocysteinemia are also related to VaD. The rodent experimental models provide a better prospective for the investigation of the molecular mechanism of new drugs. A plethora of experimental models are available that mimic the pathological conditions and lead to VaD. This review article updates the current knowledge on the basis of VaD, risk factors, pathophysiology, mechanism, advantages, limitations, and the modification of various available rodent experimental models.

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Disparities in Health Between Black and White Americans: Current Knowledge and Directions for Future Research

The Oxford Handbook of Integrative Health Science ◽

10.1093/oxfordhb/9780190676384.013.33 ◽

2018 ◽

pp. 456-478

Author(s):

Thomas E. Fuller-Rowell ◽

David S. Curtis ◽

Adrienne M. Duke

Keyword(s):

Health Disparities ◽

Current Knowledge ◽

Public Investment ◽

The United States ◽

Future Research ◽

Sociocultural Factors ◽

White Americans ◽

Biological Mechanisms ◽

Black And White ◽

Racial Ethnic

Conceptual frameworks for racial/ethnic health disparities are abundant, but many have received insufficient empirical attention. As a result, there are substantial gaps in scientific knowledge and a range of untested hypotheses. Particularly lacking is specificity in behavioral and biological mechanisms for such disparities and their underlying social determinants. Alongside lack of political will and public investment, insufficient clarity in mechanisms has stymied efforts to address racial health disparities. Capitalizing on emergent findings from the Midlife in the United States (MIDUS) study and other longitudinal studies of aging, this chapter evaluates research on health disparities between black and white US adults. Attention is given to candidate behavioral and biological mechanisms as precursors to group differences in morbidity and mortality and to environmental and sociocultural factors that may underlie these mechanisms. Future research topics are discussed, emphasizing those that offer promise with respect to illuminating practical solutions to racial/ethnic health disparities.

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Upregulation of the Renin–Angiotensin System Pathways and SARS-CoV-2 Infection: The Rationale for the Administration of Zinc-Chelating Agents in COVID-19 Patients

Cells ◽

10.3390/cells10030506 ◽

2021 ◽

Vol 10 (3) ◽

pp. 506

Author(s):

Loris Zamai

Keyword(s):

Chelating Agents ◽

Ethylenediaminetetraacetic Acid ◽

Current Knowledge ◽

Clinical Manifestations ◽

Renin Angiotensin System ◽

Experimental Models ◽

Zinc Metalloprotease ◽

Previous Hypothesis ◽

Zinc Metalloproteases

The article describes the rationale for the administration of zinc-chelating agents in COVID-19 patients. In a previous work I have highlighted that the binding of the SARS-CoV spike proteins to the zinc-metalloprotease ACE2 has been shown to induce ACE2 shedding by activating the zinc-metalloprotease ADAM17, which ultimately leads to systemic upregulation of ACE2 activity. Moreover, based on experimental models, it was also shown the detrimental effect of the excessive systemic activity of ACE2 through its downstream pathways, which leads to “clinical” manifestations resembling COVID-19. In this regard, strong upregulation of circulating ACE2 activity was recently reported in COVID-19 patients, thus supporting the previous hypothesis that COVID-19 may derive from upregulation of ACE2 activity. Based on this, a reasonable hypothesis of using inhibitors that curb the upregulation of both ACE2 and ADAM17 zinc-metalloprotease activities and consequent positive feedback-loops (initially triggered by SARS-CoV-2 and subsequently sustained independently on viral trigger) is proposed as therapy for COVID-19. In particular, zinc-chelating agents such as citrate and ethylenediaminetetraacetic acid (EDTA) alone or in combination are expected to act in protecting from COVID-19 at different levels thanks to their both anticoagulant properties and inhibitory activity on zinc-metalloproteases. Several arguments are presented in support of this hypothesis and based on the current knowledge of both beneficial/harmful effects and cost/effectiveness, the use of chelating agents in the prevention and therapy of COVID-19 is proposed. In this regard, clinical trials (currently absent) employing citrate/EDTA in COVID-19 are urgently needed in order to shed more light on the efficacy of zinc chelators against SARS-CoV-2 infection in vivo.

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Rho-Proteins and Downstream Pathways as Potential Targets in Sepsis and Septic Shock: What Have We Learned from Basic Research

Cells ◽

10.3390/cells10081844 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1844

Author(s):

Maria Luísa da Silveira Hahmeyer ◽

José Eduardo da Silva-Santos

Keyword(s):

Septic Shock ◽

Actin Polymerization ◽

Current Knowledge ◽

Cecal Ligation ◽

Experimental Models ◽

Rho Proteins ◽

Growing Cell ◽

Sepsis And Septic Shock

Sepsis and septic shock are associated with acute and sustained impairment in the function of the cardiovascular system, kidneys, lungs, liver, and brain, among others. Despite the significant advances in prevention and treatment, sepsis and septic shock sepsis remain global health problems with elevated mortality rates. Rho proteins can interact with a considerable number of targets, directly affecting cellular contractility, actin filament assembly and growing, cell motility and migration, cytoskeleton rearrangement, and actin polymerization, physiological functions that are intensively impaired during inflammatory conditions, such as the one that occurs in sepsis. In the last few decades, Rho proteins and their downstream pathways have been investigated in sepsis-associated experimental models. The most frequently used experimental design included the exposure to bacterial lipopolysaccharide (LPS), in both in vitro and in vivo approaches, but experiments using the cecal ligation and puncture (CLP) model of sepsis have also been performed. The findings described in this review indicate that Rho proteins, mainly RhoA and Rac1, are associated with the development of crucial sepsis-associated dysfunction in different systems and cells, including the endothelium, vessels, and heart. Notably, the data found in the literature suggest that either the inhibition or activation of Rho proteins and associated pathways might be desirable in sepsis and septic shock, accordingly with the cellular system evaluated. This review included the main findings, relevance, and limitations of the current knowledge connecting Rho proteins and sepsis-associated experimental models.

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Nuclear receptor Nur77: its role in chronic inflammatory diseases

Essays in Biochemistry ◽

10.1042/ebc20210004 ◽

2021 ◽

Author(s):

Sanne C. Lith ◽

Carlie J.M. de Vries

Keyword(s):

Nuclear Receptor ◽

Inflammatory Disease ◽

Inflammatory Responses ◽

Current Knowledge ◽

Inflammatory Diseases ◽

Cell Types ◽

Experimental Models ◽

Therapeutic Interventions ◽

Alternative Mechanism ◽

Signaling Complex

Abstract Nur77 is a nuclear receptor that has been implicated as a regulator of inflammatory disease. The expression of Nur77 increases upon stimulation of immune cells and is differentially expressed in chronically inflamed organs in human and experimental models. Furthermore, in a variety of animal models dedicated to study inflammatory diseases, changes in Nur77 expression alter disease outcome. The available studies comprise a wealth of information on the function of Nur77 in diverse cell types and tissues. Negative cross-talk of Nur77 with the NFκB signaling complex is an example of Nur77 effector function. An alternative mechanism of action has been established, involving Nur77-mediated modulation of metabolism in macrophages as well as in T cells. In this review, we summarize our current knowledge on the role of Nur77 in atherosclerosis, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, and sepsis. Detailed insight in the control of inflammatory responses will be essential in order to advance Nur77-targeted therapeutic interventions in inflammatory disease.

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Pharmacological Rationale for Targeting IL-17 in Asthma

Frontiers in Allergy ◽

10.3389/falgy.2021.694514 ◽

2021 ◽

Vol 2 ◽

Author(s):

Siti Farah Rahmawati ◽

Maurice te Velde ◽

Huib A. M. Kerstjens ◽

Alexander S. S. Dömling ◽

Matthew Robert Groves ◽

...

Keyword(s):

Severe Asthma ◽

Inhaled Corticosteroids ◽

Current Knowledge ◽

Experimental Models ◽

Airflow Limitation ◽

Interleukin 17 ◽

Asthma Phenotype ◽

T Helper 2 ◽

Bronchial Biopsies

Asthma is a respiratory disease that currently affects around 300 million people worldwide and is defined by coughing, shortness of breath, wheezing, mucus overproduction, chest tightness, and expiratory airflow limitation. Increased levels of interleukin 17 (IL-17) have been observed in sputum, nasal and bronchial biopsies, and serum of patients with asthma compared to healthy controls. Patients with higher levels of IL-17 have a more severe asthma phenotype. Biologics are available for T helper 2 (Th2)-high asthmatics, but the Th17-high subpopulation has a relatively low response to these treatments, rendering it a rather severe asthma phenotype to treat. Several experimental models suggest that targeting the IL-17 pathway may be beneficial in asthma. Moreover, as increased activation of the Th17/IL-17 axis is correlated with reduced inhaled corticosteroids (ICS) sensitivity, targeting the IL-17 pathway might reverse ICS unresponsiveness. In this review, we present and discuss the current knowledge on the role of IL-17 in asthma and its interaction with the Th2 pathway, focusing on the rationale for therapeutic targeting of the IL-17 pathway.

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Could Mycolactone Inspire New Potent Analgesics? Perspectives and Pitfalls

Toxins ◽

10.3390/toxins11090516 ◽

2019 ◽

Vol 11 (9) ◽

pp. 516

Author(s):

Marie-Line Reynaert ◽

Denis Dupoiron ◽

Edouard Yeramian ◽

Laurent Marsollier ◽

Priscille Brodin

Keyword(s):

Current Knowledge ◽

Experimental Models ◽

Mycobacterium Ulcerans ◽

Nerve Degeneration ◽

Medical Attention ◽

Common Symptom ◽

Angiotensin Ii Receptor ◽

Promising Alternative ◽

Limited Effectiveness ◽

Wide Range

Pain currently represents the most common symptom for which medical attention is sought by patients. The available treatments have limited effectiveness and significant side-effects. In addition, most often, the duration of analgesia is short. Today, the handling of pain remains a major challenge. One promising alternative for the discovery of novel potent analgesics is to take inspiration from Mother Nature; in this context, the detailed investigation of the intriguing analgesia implemented in Buruli ulcer, an infectious disease caused by the bacterium Mycobacterium ulcerans and characterized by painless ulcerative lesions, seems particularly promising. More precisely, in this disease, the painless skin ulcers are caused by mycolactone, a polyketide lactone exotoxin. In fact, mycolactone exerts a wide range of effects on the host, besides being responsible for analgesia, as it has been shown notably to modulate the immune response or to provoke apoptosis. Several cellular mechanisms and different targets have been proposed to account for the analgesic effect of the toxin, such as nerve degeneration, the inhibition of inflammatory mediators and the activation of angiotensin II receptor 2. In this review, we discuss the current knowledge in the field, highlighting possible controversies. We first discuss the different pain-mimicking experimental models that were used to study the effect of mycolactone. We then detail the different variants of mycolactone that were used in such models. Overall, based on the results and the discussions, we conclude that the development of mycolactone-derived molecules can represent very promising perspectives for new analgesic drugs, which could be effective for specific pain indications.

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Skin Immunity to Dermatophytes: From Experimental Infection Models to Human Disease

Frontiers in Immunology ◽

10.3389/fimmu.2020.605644 ◽

2020 ◽

Vol 11 ◽

Author(s):

Verónica L. Burstein ◽

Ignacio Beccacece ◽

Lorena Guasconi ◽

Cristian J. Mena ◽

Laura Cervi ◽

...

Keyword(s):

Immune Response ◽

Human Disease ◽

Current Knowledge ◽

Skin Inflammation ◽

Experimental Models ◽

Fungal Virulence ◽

Lectin Receptors ◽

Immunological Mechanisms ◽

Human Infections ◽

Cellular Immune

Dermatophytoses (ringworms) are among the most frequent skin infections and are a highly prevalent cause of human disease worldwide. Despite the incidence of these superficial mycoses in healthy people and the compelling evidence on chronic and deep infections in immunocompromised individuals, the mechanisms controlling dermatophyte invasion in the skin are scarcely known. In the last years, the association between certain primary immunodeficiencies and the susceptibility to severe dermatophytosis as well as the evidence provided by novel experimental models mimicking human disease have significantly contributed to deciphering the basic immunological mechanisms against dermatophytes. In this review, we outline the current knowledge on fungal virulence factors involved in the pathogenesis of dermatophytoses and recent evidence from human infections and experimental models that shed light on the cells and molecules involved in the antifungal cutaneous immune response. The latest highlights emphasize the contribution of C-type lectin receptors signaling and the cellular immune response mediated by IL-17 and IFN-γ in the anti-dermatophytic defense and skin inflammation control.

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Manganese promotes the aggregation and prion-like cell-to-cell exosomal transmission of α-synuclein

Science Signaling ◽

10.1126/scisignal.aau4543 ◽

2019 ◽

Vol 12 (572) ◽

pp. eaau4543 ◽

Cited By ~ 41

Author(s):

Dilshan S. Harischandra ◽

Dharmin Rokad ◽

Matthew L. Neal ◽

Shivani Ghaisas ◽

Sireesha Manne ◽

...

Keyword(s):

Potential Role ◽

Neuronal Model ◽

Experimental Models ◽

Bimolecular Fluorescence Complementation ◽

Wild Type ◽

Biological Mechanisms ◽

Extracellular Medium ◽

Cell To Cell Transfer ◽

Serum Exosomes

The aggregation of α-synuclein (αSyn) is considered a key pathophysiological feature of certain neurodegenerative disorders, collectively termed synucleinopathies. Given that a prion-like, cell-to-cell transfer of misfolded αSyn has been recognized in the spreading of αSyn pathology in synucleinopathies, we investigated the biological mechanisms underlying the propagation of the disease with respect to environmental neurotoxic stress. Considering the potential role of the divalent metal manganese (Mn2+) in protein aggregation, we characterized its effect on αSyn misfolding and transmission in experimental models of Parkinson’s disease. In cultured dopaminergic neuronal cells stably expressing wild-type human αSyn, misfolded αSyn was secreted through exosomes into the extracellular medium upon Mn2+ exposure. These exosomes were endocytosed through caveolae into primary microglial cells, thereby mounting neuroinflammatory responses. Furthermore, Mn2+-elicited exosomes exerted a neurotoxic effect in a human dopaminergic neuronal model (LUHMES cells). Moreover, bimolecular fluorescence complementation (BiFC) analysis revealed that Mn2+ accelerated the cell-to-cell transmission of αSyn, resulting in dopaminergic neurotoxicity in a mouse model of Mn2+ exposure. Welders exposed to Mn2+ had increased misfolded αSyn content in their serum exosomes. Stereotaxically delivering αSyn-containing exosomes, isolated from Mn2+-treated αSyn-expressing cells, into the striatum initiated Parkinsonian-like pathological features in mice. Together, these results indicate that Mn2+ exposure promotes αSyn secretion in exosomal vesicles, which subsequently evokes proinflammatory and neurodegenerative responses in both cell culture and animal models.

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