scholarly journals The Significance of the Enteric Microbiome on the Development of Childhood Disease: A Review of Prebiotic and Probiotic Therapies in Disorders of Childhood

2016 ◽  
Vol 10 ◽  
pp. CMPed.S38338 ◽  
Author(s):  
John Slattery ◽  
Derrick F. Macfabe ◽  
Richard E. Frye
Keyword(s):  
Clinical Trials ◽  
Gastrointestinal Disease ◽  
Probiotic Strain ◽  
Atopic Disease ◽  
Autism Spectrum ◽  
In Vitro Models ◽  
Duration Of Treatment ◽  
Childhood Diseases ◽  
Childhood Disease

Recent studies have highlighted the fact that the enteric microbiome, the trillions of microbes that inhabit the human digestive tract, has a significant effect on health and disease. Methods for manipulating the enteric microbiome, particularly through probiotics and microbial ecosystem transplantation, have undergone some study in clinical trials. We review some of the evidence for microbiome alteration in relation to childhood disease and discuss the clinical trials that have examined the manipulation of the microbiome in an effort to prevent or treat childhood disease with a primary focus on probiotics, prebiotics, and/or synbiotics (ie, probiotics + prebiotics). Studies show that alterations in the microbiome may be a consequence of events occurring during infancy and/or childhood such as prematurity, C-sections, and nosocomial infections. In addition, certain childhood diseases have been associated with microbiome alterations, namely necrotizing enterocolitis, infantile colic, asthma, atopic disease, gastrointestinal disease, diabetes, malnutrition, mood/anxiety disorders, and autism spectrum disorders. Treatment studies suggest that probiotics are potentially protective against the development of some of these diseases. Timing and duration of treatment, the optimal probiotic strain(s), and factors that may alter the composition and function of the microbiome are still in need of further research. Other treatments such as prebiotics, fecal microbial transplantation, and antibiotics have limited evidence. Future translational work, in vitro models, long-term and follow-up studies, and guidelines for the composition and viability of probiotic and microbial therapies need to be developed. Overall, there is promising evidence that manipulating the microbiome with probiotics early in life can help prevent or reduce the severity of some childhood diseases, but further research is needed to elucidate biological mechanisms and determine optimal treatments.

Modulation of Matrix Metalloproteinases by Plant-Derived Products

2020 ◽  
Vol 20 ◽  
Author(s):  
Nur Najmi Mohamad Anuar ◽  
Nurul Iman Natasya Zulkafali ◽  
Azizah Ugusman
Keyword(s):  
Clinical Trials ◽  
Natural Products ◽  
Matrix Metalloproteinases ◽  
Animal Studies ◽  
Current Knowledge ◽  
In Vitro Models ◽  
In Vivo Studies ◽  
Extracellular Matrix Components

: Matrix metalloproteinases (MMPs) are a group of zinc-dependent metallo-endopeptidase that are responsible towards the degradation, repair and remodelling of extracellular matrix components. MMPs play an important role in maintaining a normal physiological function and preventing diseases such as cancer and cardiovascular diseases. Natural products derived from plants have been used as traditional medicine for centuries. Its active compounds, such as catechin, resveratrol and quercetin, are suggested to play an important role as MMPs inhibitors, thereby opening new insights into their applications in many fields, such as pharmaceutical, cosmetic and food industries. This review summarises the current knowledge on plant-derived natural products with MMP-modulating activities. Most of the reviewed plant-derived products exhibit an inhibitory activity on MMPs. Amongst MMPs, MMP-2 and MMP-9 are the most studied. The expression of MMPs is inhibited through respective signalling pathways, such as MAPK, NF-κB and PI3 kinase pathways, which contribute to the reduction in cancer cell behaviours, such as proliferation and migration. Most studies have employed in vitro models, but a limited number of animal studies and clinical trials have been conducted. Even though plant-derived products show promising results in modulating MMPs, more in vivo studies and clinical trials are needed to support their therapeutic applications in the future.

The Use of Erythropoietin in the Treatment of Post-bone Marrow Transplatation Anemia

1993 ◽  
Vol 16 (5_suppl) ◽  
pp. 8-12 ◽  
Author(s):  
A.M. Vannucchi ◽  
A. Bosi ◽  
A. Grossi ◽  
S. Guidi ◽  
R. Saccardi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Clinical Trials ◽  
Bone Marrow Transplantation ◽  
Blood Transfusion ◽  
In Vitro Models ◽  
Immunosuppressive Drug ◽  
Number Of Patients

The issue of the role of erythropoietin (Epo) in the erythroid reconstitution after bone marrow transplantation (BMT) has been addressed in several recent studies. A defective Epo production in response to anemia has been shown to occur in patients undergoing allogeneic BMT unlike in most of those subjected to an autologous rescue. The factors involved in the inadeguate Epo production in BMT are discussed, with particular attention to the role of the immunosuppressive drug cyclosporin-A, which has been shown to inhibit Epo production in both in vivo and in vitro models. The observation of defective Epo production eventually led to the development of clinical trials of recombinant human Epo (rhEpo) administration in BMT patients; the aims of these studies were to stimulate erythroid engraftment, hence reducing blood transfusion exposure. Although the number of patients studied up to now is relatively small, a benefit from rhEpo administration in terms of accelerated erythroid engraftment seems very likely, and it may also be associated with decreased transfusional needs in most treated patients. However, further studies are needed to better define indications, dosages and schedules of rhEpo in BMT patients.

scholarly journals REDUCTION IN LIPOPROTEIN (A) WITH EVOLOCUMAB: ELUCIDATION OF THE ROLE OF THE LDL RECEPTOR FROM CLINICAL TRIALS AND IN-VITRO MODELS

2016 ◽  
Vol 67 (13) ◽  
pp. 1862 ◽  
Author(s):  
Frederick J. Raal ◽  
Robert P. Giugliano ◽  
Marc Sabatine ◽  
Michael Koren ◽  
Dirk Blom ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Ldl Receptor ◽  
In Vitro Models ◽  
Lipoprotein A

scholarly journals Human iPSC-Derived Glia as a Tool for Neuropsychiatric Research and Drug Development

2021 ◽  
Vol 22 (19) ◽  
pp. 10254
Author(s):  
Johanna Heider ◽  
Sabrina Vogel ◽  
Hansjürgen Volkmer ◽  
Ricarda Breitmeyer
Keyword(s):  
Drug Development ◽  
Neuropsychiatric Disorders ◽  
Autism Spectrum ◽  
In Vitro Models ◽  
Neuropsychiatric Diseases ◽  
Culture Models ◽  
Target Screening ◽  
Induced Pluripotent ◽  
The Impact

Neuropsychiatric disorders such as schizophrenia or autism spectrum disorder represent a leading and growing burden on worldwide mental health. Fundamental lack in understanding the underlying pathobiology compromises efficient drug development despite the immense medical need. So far, antipsychotic drugs reduce symptom severity and enhance quality of life, but there is no cure available. On the molecular level, schizophrenia and autism spectrum disorders correlate with compromised neuronal phenotypes. There is increasing evidence that aberrant neuroinflammatory responses of glial cells account for synaptic pathologies through deregulated communication and reciprocal modulation. Consequently, microglia and astrocytes emerge as central targets for anti-inflammatory treatment to preserve organization and homeostasis of the central nervous system. Studying the impact of neuroinflammation in the context of neuropsychiatric disorders is, however, limited by the lack of relevant human cellular test systems that are able to represent the dynamic cellular processes and molecular changes observed in human tissue. Today, patient-derived induced pluripotent stem cells offer the opportunity to study neuroinflammatory mechanisms in vitro that comprise the genetic background of affected patients. In this review, we summarize the major findings of iPSC-based microglia and astrocyte research in the context of neuropsychiatric diseases and highlight the benefit of 2D and 3D co-culture models for the generation of efficient in vitro models for target screening and drug development.

scholarly journals Drug-induced hepatotoxicity studied in a 3D, in vitro model of the liver

2021 ◽  
Vol 4 (s1) ◽  
Author(s):  
Giuseppe Guagliano ◽  
Manuela Legnardim ◽  
Cristina Volpini ◽  
Nora Bloise ◽  
Silvia Dotti ◽  
...  
Keyword(s):  
Clinical Trials ◽  
High Throughput ◽  
In Vitro Models ◽  
Rate Process ◽  
High Failure Rate ◽  
Drug Induced ◽  
Severe Hepatotoxicity ◽  
Preclinical Trials ◽  
3D Em

Drug development is a high failure rate process; too many drugs fail during clinical trials because of severe hepatotoxicity. This situation can be significantly improved by redesigning preclinical trials, and privileging the use of high-throughput in vitro models, by combining cell-based in vitro models and material-based models.

scholarly journals TZDs and Bone: A Review of the Recent Clinical Evidence

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-6 ◽  
Author(s):  
Ann V. Schwartz
Keyword(s):  
Clinical Trials ◽  
Bone Loss ◽  
Bone Formation ◽  
In Vitro Models ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Turnover Markers ◽  
Test Treatments ◽  
Bone Research

Over the past two years, evidence has emerged that the currently available thiazolidinediones (TZDs), rosiglitazone, and pioglitazone have negative skeletal consequences, at least in women, which are clinically important. Increased fracture risk in women, but not men, was reported for both TZDs, based on analyses of adverse event reports from clinical trials. In short-term clinical trials in women, both TZDs caused more rapid bone loss. In these trials, changes in bone turnover markers suggest a pattern of reduced bone formation without a change in resorption. Although limited, these results support the hypothesis based on rodent and in vitro models that reduced bone formation resulting from activation of peroxisome proliferator-activated receptor- (PPAR) is a central mechanism for TZDs_ effect on bone. Research is needed to better understand the mechanisms of bone loss with TZDs, to identify factors that influence susceptibility to TZD-induced osteoporosis, and to test treatments for its prevention.

scholarly journals Targeted therapies in CLL: mechanisms of resistance and strategies for management

Blood ◽  
2015 ◽  
Vol 126 (4) ◽  
pp. 471-477 ◽  
Author(s):  
Jennifer A. Woyach ◽  
Amy J. Johnson
Keyword(s):  
Clinical Trials ◽  
Targeted Therapy ◽  
Small Molecules ◽  
In Vitro Models ◽  
Lymphocytic Leukemia ◽  
Mechanisms Of Resistance ◽  
The Past ◽  
Genomic Risk ◽  
Generation Sequencing

Abstract The therapy of relapsed chronic lymphocytic leukemia (CLL) has changed dramatically in the past year with the regulatory approval of idelalisib and ibrutinib, with other therapeutic small molecules likely to become widely available in the next few years. Although durable remissions are being seen in many patients with these agents, it is becoming apparent that some patients with high genomic risk disease will relapse. Next-generation sequencing in patients as well as in vitro models is affording us the opportunity to understand the biology behind these relapses, which is the first step to designing rational therapies to prevent and treat targeted therapy-resistant CLL. These strategies are critical, as these relapses can be very difficult to manage, and a coordinated effort to put these patients on clinical trials will be required to efficiently determine the optimal therapies for these patients. In this review, we will describe mechanisms of resistance, both proven and hypothesized, for idelalisib, ibrutinib, and venetoclax, describe patterns of resistance that have been described with ibrutinib, and discuss potential strategies for management of disease resistant to these drugs as well as potential strategies to prevent resistance.

scholarly journals Human-induced pluripotent stem cell-derived cardiomyocytes, 3D cardiac structures, and heart-on-a-chip as tools for drug research

2021 ◽  
Author(s):  
Kalina Andrysiak ◽  
Jacek Stępniewski ◽  
Józef Dulak
Keyword(s):  
Clinical Trials ◽  
Pluripotent Stem Cell ◽  
Drug Research ◽  
Drug Effects ◽  
Induced Pluripotent Stem Cell ◽  
Cell Types ◽  
In Vitro Models ◽  
Cardiac Cell ◽  
Induced Pluripotent

AbstractDevelopment of new drugs is of high interest for the field of cardiac and cardiovascular diseases, which are a dominant cause of death worldwide. Before being allowed to be used and distributed, every new potentially therapeutic compound must be strictly validated during preclinical and clinical trials. The preclinical studies usually involve the in vitro and in vivo evaluation. Due to the increasing reporting of discrepancy in drug effects in animal and humans and the requirement to reduce the number of animals used in research, improvement of in vitro models based on human cells is indispensable. Primary cardiac cells are difficult to access and maintain in cell culture for extensive experiments; therefore, the human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) became an excellent alternative. This technology enables a production of high number of patient- and disease-specific cardiomyocytes and other cardiac cell types for a large-scale research. The drug effects can be extensively evaluated in the context of electrophysiological responses with a use of well-established tools, such as multielectrode array (MEA), patch clamp, or calcium ion oscillation measurements. Cardiotoxicity, which is a common reason for withdrawing drugs from marketing or rejection at final stages of clinical trials, can be easily verified with a use of hiPSC-CM model providing a prediction of human-specific responses and higher safety of clinical trials involving patient cohort. Abovementioned studies can be performed using two-dimensional cell culture providing a high-throughput and relatively lower costs. On the other hand, more complex structures, such as engineered heart tissue, organoids, or spheroids, frequently applied as co-culture systems, represent more physiological conditions and higher maturation rate of hiPSC-derived cells. Furthermore, heart-on-a-chip technology has recently become an increasingly popular tool, as it implements controllable culture conditions, application of various stimulations and continuous parameters read-out. This paper is an overview of possible use of cardiomyocytes and other cardiac cell types derived from hiPSC as in vitro models of heart in drug research area prepared on the basis of latest scientific reports and providing thorough discussion regarding their advantages and limitations.

scholarly journals CDK4/6 inhibitors in breast cancer – from in vitro models to clinical trials

2019 ◽  
Vol 59 (2) ◽  
pp. 219-232
Author(s):  
Lubaid Saleh ◽  
Caroline Wilson ◽  
Ingunn Holen
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
In Vitro Models
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