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Expert Opinion on Investigational Drugs May 2024Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common inherited kidney condition caused by a single-gene mutation. It leads patients to kidney failure... (Review)
Review
INTRODUCTION
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common inherited kidney condition caused by a single-gene mutation. It leads patients to kidney failure in more than 50% of cases by the age of 60, and, given the dominant inheritance, this disease is present in the family history in more than 90% of cases.
AREAS COVERED
This review aims to analyze the set of preclinical and early-phase studies to provide a general view of the current progress on ADPKD therapeutic options. Articles from PubMed and the current status of the trials listed in clinicaltrials.gov were examined for the review.
EXPERT OPINION
Many potential therapeutic targets are currently under study for the treatment of ADPKD. A few drugs have reached the clinical phase, while many are currently still in the preclinical phase. Organoids could be a novel approach to the study of drugs in this phase. Other than pharmacological options, very important developing approaches are represented by gene therapy and the use of MiRNA inhibitors.
Topics: Humans; Polycystic Kidney, Autosomal Dominant; Animals; Drugs, Investigational; Drug Development; Genetic Therapy; Mutation; MicroRNAs
PubMed: 38618918
DOI: 10.1080/13543784.2024.2342327 -
Biochemical and Biophysical Research... Apr 2024Nicotinamide adenine dinucleotide (NAD) is the fundamental molecule that performs numerous biological reactions and is crucial for maintaining cellular homeostasis.... (Review)
Review
Nicotinamide adenine dinucleotide (NAD) is the fundamental molecule that performs numerous biological reactions and is crucial for maintaining cellular homeostasis. Studies have found that NAD decreases with age in certain tissues, and age-related NAD depletion affects physiological functions and contributes to various aging-related diseases. Supplementation of NAD precursor significantly elevates NAD levels in murine tissues, effectively mitigates metabolic syndrome, enhances cardiovascular health, protects against neurodegeneration, and boosts muscular strength. Despite the versatile therapeutic functions of NAD in animal studies, the efficacy of NAD precursors in clinical studies have been limited compared with that in the pre-clinical study. Clinical studies have demonstrated that NAD precursor treatment efficiently increases NAD levels in various tissues, though their clinical proficiency is insufficient to ameliorate the diseases. However, the latest studies regarding NAD precursors and their metabolism highlight the significant role of gut microbiota. The studies found that orally administered NAD intermediates interact with the gut microbiome. These findings provide compelling evidence for future trials to further explore the involvement of gut microbiota in NAD metabolism. Also, the reduced form of NAD precursor shows their potential to raise NAD, though preclinical studies have yet to discover their efficacy. This review sheds light on NAD therapeutic efficiency in preclinical and clinical studies and the effect of the gut microbiota on NAD metabolism.
Topics: Mice; Animals; NAD; Dietary Supplements; Aging; Niacinamide; Nicotinamide Mononucleotide
PubMed: 38340651
DOI: 10.1016/j.bbrc.2024.149590 -
Neural Regeneration Research Dec 2023Patients with potential spinal stenosis are susceptible to central cord syndrome induced by blunt trauma. Suitable animal models are helpful for studying the...
Patients with potential spinal stenosis are susceptible to central cord syndrome induced by blunt trauma. Suitable animal models are helpful for studying the pathogenesis and treatment of such injuries. In this study, we established a mouse model of acute blunt traumatic spinal cord injury by compressing the C6 spinal cord with 5 and 10 g/mm compression weights to simulate cervical central cord syndrome. Behavioral testing confirmed that this model exhibited the characteristics of central cord syndrome because motor function in the front paws was impaired, whereas basic motor and sensory functions of the lower extremities were retained. Hematoxylin-eosin staining showed that the diseased region of the spinal cord in this mouse model was restricted to the gray matter of the central cord, whereas the white matter was rarely affected. Magnetic resonance imaging showed a hypointense signal in the lesion after mild and severe injury. In addition, immunofluorescence staining showed that the degree of nerve tract injury in the spinal cord white matter was mild, and that there was a chronic inflammation reaction. These findings suggest that this mouse model of central cord syndrome can be used as a model for preclinical research, and that gray matter is most vulnerable to injury in central cord syndrome, leading to impaired motor function.
PubMed: 37449640
DOI: 10.4103/1673-5374.373718 -
Pediatrics Jan 2024Increased intestinal permeability seems to be a key factor in the pathogenesis of autoimmune diseases, including celiac disease (CeD). However, it is unknown whether...
OBJECTIVES
Increased intestinal permeability seems to be a key factor in the pathogenesis of autoimmune diseases, including celiac disease (CeD). However, it is unknown whether increased permeability precedes CeD onset. This study's objective was to determine whether intestinal permeability is altered before celiac disease autoimmunity (CDA) in at-risk children. We also examined whether environmental factors impacted zonulin, a widely used marker of gut permeability.
METHODS
We evaluated 102 children in the CDGEMM study from 2014-2022. We included 51 CDA cases and matched controls, who were enrolled for 12 months or more and consumed gluten. We measured serum zonulin from age 12 months to time of CDA onset, and the corresponding time point in controls, and examined clinical factors of interest. We ran a mixed-effects longitudinal model with dependent variable zonulin.
RESULTS
Children who developed CDA had a significant increase in zonulin in the 18.3 months (range 6-78) preceding CDA compared to those without CDA (slope differential = β = 0.1277, 95% CI: 0.001, 0.255). Among metadata considered, zonulin trajectory was only influenced by increasing number of antibiotic courses, which increased the slope of trajectory of zonulin over time in CDA subjects (P = .04).
CONCLUSIONS
Zonulin levels significantly rise in the months that precede CDA diagnosis. Exposure to a greater number of antibiotic courses was associated with an increase in zonulin levels in CDA subjects. This suggests zonulin may be used as a biomarker for preclinical CeD screening in at-risk children, and multiple antibiotic courses may increase their risk of CDA by increasing zonulin levels.
Topics: Biomarkers; Celiac Disease; Humans; Infant; Child, Preschool; Child; Haptoglobins; Male; Female; Anti-Bacterial Agents; Protein Precursors
PubMed: 38062791
DOI: 10.1542/peds.2023-063050 -
ACS Pharmacology & Translational Science Nov 2023- Several C-tracers have demonstrated high potential in early diagnostic PET imaging applications of neurodegenerative diseases including Alzheimer's and Parkinson's... (Review)
Review
- Several C-tracers have demonstrated high potential in early diagnostic PET imaging applications of neurodegenerative diseases including Alzheimer's and Parkinson's disease. These radiotracers often track critical biomarkers in disease pathogenesis such as tau fibrils ([C]PBB3) or β-amyloid plaques ([C]PiB) associated with such diseases. - The short review aims to serve as a guideline in the future development of radiotracers for students, postdocs and/or new radiochemists who will be synthesizing clinical grade or novel research C-tracers, including knowledge of regulatory requirements. We aim to bridge the gap between novel and established C-tracer quality control (QC) processes through exploring the design process and regulatory requirements for C-pharmaceuticals. - A literature survey was undertaken to identify articles with a detailed description of the QC methodology and characterization for each of the sections of the review. - First a general summary of C-tracer production was presented; this was used to establish possible places for contamination or assurances for a sterile final product. The key mandated QC analyses for clinical use were then discussed. Further, we assessed the QC methods used for established C-tracers and then reviewed the routine QC tests for preclinical translational and validation studies. Therefore, both mandated QC methods for clinical and preclinical animal studies were reviewed. Last, some examples of optimization and automation were reviewed, and implications of the QC practices associated with such procedures were considered. - All of the common QC parameters associated with C-tracers under clinical and preclinical settings (along with a few exceptions) were discussed in detail. While it is important to establish standard, peer-reviewed QC testing protocols for a novel C-tracer entering the clinical umbrella, equal importance is needed on preclinical applications to address credibility and repeatability for the study.
PubMed: 37974626
DOI: 10.1021/acsptsci.3c00200 -
Critical Reviews in Oncology/hematology Sep 2023Preclinical models are extensively employed in cancer research because they can be manipulated in terms of their environment, genome, molecular biology, organ systems,... (Review)
Review
Preclinical models are extensively employed in cancer research because they can be manipulated in terms of their environment, genome, molecular biology, organ systems, and physical activity to mimic human behavior and conditions. The progress made in in vivo cancer research has resulted in significant advancements, enabling the creation of spontaneous, metastatic, and humanized mouse models. Most recently, the remarkable and extensive developments in genetic engineering, particularly the utilization of CRISPR/Cas9, transposable elements, epigenome modifications, and liquid biopsies, have further facilitated the design and development of numerous mouse models for studying cancer. In this review, we have elucidated the production and usage of current mouse models, such as xenografts, chemical-induced models, and genetically engineered mouse models (GEMMs), for studying esophageal cancer. Additionally, we have briefly discussed various gene-editing tools that could potentially be employed in the future to create mouse models specifically for esophageal cancer research.
Topics: Animals; Mice; Humans; Gene Editing; Genetic Engineering; Disease Models, Animal; Esophageal Neoplasms
PubMed: 37468084
DOI: 10.1016/j.critrevonc.2023.104068 -
Phytotherapy Research : PTR Nov 2023Resveratrol (RES) has extensively been utilized to treat osteoporosis (OP) in animal models. However, the anti-OP effects of RES have not been tested during clinical... (Meta-Analysis)
Meta-Analysis
Resveratrol (RES) has extensively been utilized to treat osteoporosis (OP) in animal models. However, the anti-OP effects of RES have not been tested during clinical application due to the lack of evidence and poor knowledge of the underlying mechanisms. Moreover, there is little preclinical evidence to support the use of RES in the management of OP. In the present paper, we conducted a preclinical systematic review and meta-analysis to assess the efficacy of RES in animal OP models. The potential mechanisms underlying the efficacy of RES against OP were summarized. The online databases PubMed, CNKI, EMBASE, Wanfang, Web of Science, Chinese Biomedical Literature, Cochrane Library, and Chinese VIP were retrieved from inception to December 2021. The CAMARADES 10-item quality checklist was utilized to assess the risk of bias of the included studies. STATA 12.0 software was employed to analyze the data. The quality of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. Thirteen studies containing 248 animals were included yielding a mean risk of bias score of 5.54 (range 4-7). The pooled estimates showed that the administration of RES could significantly elevate the bone mineral density (BMD) both at femur (SMD = 2.536; 95% CI = 1.950-3.122; p < 0.001) and lumbar spine (SMD = 1.363; 95% CI = 0894-1.832; p < 0.001), bone volume over total volume (BV/TV) (SMD = 2.543; 95% CI = 2.023-3.062; p < 0.001), trabecular linear density (Tb.N) (SMD = 2.724; 95% CI = 2.186-3.262; p < 0.001) and trabecular thickness (Tb.Th) (SMD = 1.745; 95% CI = 1.294-2.196; p < 0.001), while serum phosphorus (S-P) (SMD = -2.168; 95% CI = -2.753 to -1.583; p < 0.001) and trabecular separation (Tb.Sp) (SMD = -2.856; 95% CI = -4.218 to -1.494; p < 0.001) were significantly reduced in animal OP models. No significant change in serum calcium (S-Ca) (SMD = -2.448; 95% CI = -5.255-0.360; p = 0.087) was observed after RES treatment. Furthermore, RES could significantly improve the bone biomechanical indexes: bone maximum load (BML) (SMD = 2.563; 95% CI = 1.827-3.299; p < 0.001) and connectivity density (Conn.D) (SMD = 1.512; 95% CI = 0.909-2.116; p < 0.001) and decrease the structural model index (SMI) (SMD = -2.522; 95% CI = -3.243 to -1.801; p < 0.001). Overall, the present study revealed that RES has huge prospects as a medicine or dietary supplement for the clinical treatment of OP. High-quality studies with stringent designs and larger sample sizes are warranted to substantiate our conclusion.
Topics: Animals; Resveratrol; Osteoporosis; Bone Density; Bone and Bones; Models, Animal
PubMed: 37482965
DOI: 10.1002/ptr.7954 -
Journal of Neurochemistry Nov 2023Psilocybin is the main psychoactive compound found in hallucinogenic/magic mushrooms and can bind to both serotonergic and tropomyosin receptor kinase b (TrkB)... (Review)
Review
Psilocybin is the main psychoactive compound found in hallucinogenic/magic mushrooms and can bind to both serotonergic and tropomyosin receptor kinase b (TrkB) receptors. Psilocybin has begun to show efficacy for a range of neuropsychiatric conditions, including treatment-resistant depression and anxiety disorders; however, neurobiological mechanisms are still being elucidated. Clinical research has found that psilocybin can alter functional connectivity patterns in human brains, which is often associated with therapeutic outcomes. However, preclinical research affords the opportunity to assess the potential cellular mechanisms by which psilocybin may exert its therapeutic effects. Preclinical rodent models can also facilitate a more tightly controlled experimental context and minimise placebo effects. Furthermore, where there is a rationale, preclinical researchers can investigate psilocybin administration in neuropsychiatric conditions that have not yet been researched clinically. As a result, we have systematically reviewed the knowledge base, identifying 82 preclinical studies which were screened based on specific criteria. This resulted in the exclusion of 44 articles, with 34 articles being included in the main review and another 2 articles included as Supporting Information materials. We found that psilocybin shows promise as a lead candidate molecule for treating a variety of neuropsychiatric conditions, albeit showing the most efficacy for depression. We discuss the experimental findings, and identify possible mechanisms whereby psilocybin could invoke therapeutic changes. Furthermore, we critically evaluate the between-study heterogeneity and possible future research avenues. Our review suggests that preclinical rodent models can provide valid and translatable tools for researching novel psilocybin-induced molecular and cellular mechanisms, and therapeutic outcomes.
PubMed: 38019032
DOI: 10.1111/jnc.16017 -
Intensive Care Medicine Experimental Jul 2023Preclinical sepsis models have been criticized for their inability to recapitulate human sepsis and suffer from methodological shortcomings that limit external validity...
Development and characterization of a fecal-induced peritonitis model of murine sepsis: results from a multi-laboratory study and iterative modification of experimental conditions.
BACKGROUND
Preclinical sepsis models have been criticized for their inability to recapitulate human sepsis and suffer from methodological shortcomings that limit external validity and reproducibility. The National Preclinical Sepsis Platform (NPSP) is a consortium of basic science researchers, veterinarians, and stakeholders in Canada undertaking standardized multi-laboratory sepsis research to increase the efficacy and efficiency of bench-to-bedside translation. In this study, we aimed to develop and characterize a 72-h fecal-induced peritonitis (FIP) model of murine sepsis conducted in two independent laboratories. The experimental protocol was optimized by sequentially modifying dose of fecal slurry and timing of antibiotics in an iterative fashion, and then repeating the experimental series at site 1 and site 2.
RESULTS
Escalating doses of fecal slurry (0.5-2.5 mg/g) resulted in increased disease severity, as assessed by the modified Murine Sepsis Score (MSS). However, the MSS was poorly associated with progression to death during the experiments, and mice were found dead without elevated MSS scores. Administration of early antibiotics within 4 h of inoculation rescued the animals from sepsis compared with late administration of antibiotics after 12 h, as evidenced by 100% survival and reduced bacterial load in peritoneum and blood in the early antibiotic group. Site 1 and site 2 had statistically significant differences in mortality (60% vs 88%; p < 0.05) for the same dose of fecal slurry (0.75 mg/g) and marked differences in body temperature between groups.
CONCLUSIONS
We demonstrate a systematic approach to optimizing a 72-h FIP model of murine sepsis for use in multi-laboratory studies. Alterations to experimental conditions, such as dose of fecal slurry and timing of antibiotics, have clear impact on outcomes. Differences in mortality between sites despite rigorous standardization warrants further investigations to better understand inter-laboratory variation and methodological design in preclinical studies.
PubMed: 37460911
DOI: 10.1186/s40635-023-00533-3 -
Brain Stimulation Jun 2024Low-intensity transcranial ultrasound has surged forward as a non-invasive and disruptive tool for neuromodulation with applications in basic neuroscience research and... (Review)
Review
BACKGROUND
Low-intensity transcranial ultrasound has surged forward as a non-invasive and disruptive tool for neuromodulation with applications in basic neuroscience research and the treatment of neurological and psychiatric conditions.
OBJECTIVE
To provide a comprehensive overview and update of preclinical and clinical transcranial low intensity ultrasound for neuromodulation and emphasize the emerging role of functional brain mapping to guide, better understand, and predict responses.
METHODS
A systematic review was conducted by searching the Web of Science and Scopus databases for studies on transcranial ultrasound neuromodulation, both in humans and animals.
RESULTS
187 relevant studies were identified and reviewed, including 116 preclinical and 71 clinical reports with subjects belonging to diverse cohorts. Milestones of ultrasound neuromodulation are described within an overview of the broader landscape. General neural readouts and outcome measures are discussed, potential confounds are noted, and the emerging use of functional magnetic resonance imaging is highlighted.
CONCLUSION
Ultrasound neuromodulation has emerged as a powerful tool to study and treat a range of conditions and its combination with various neural readouts has significantly advanced this platform. In particular, the use of functional magnetic resonance imaging has yielded exciting inferences into ultrasound neuromodulation and has the potential to advance our understanding of brain function, neuromodulatory mechanisms, and ultimately clinical outcomes. It is anticipated that these preclinical and clinical trials are the first of many; that transcranial low intensity focused ultrasound, particularly in combination with functional magnetic resonance imaging, has the potential to enhance treatment for a spectrum of neurological conditions.
PubMed: 38880207
DOI: 10.1016/j.brs.2024.06.005