Studies In Animal Models Research Articles

Mechanism and Application of Chinese Herb Medicine in Treatment of Peripheral Nerve Injury.

Peripheral nerve injury (PNI) encompasses damage to nerves located outside the central nervous system, adversely affecting both motor and sensory functions. Although peripheral nerves possess an intrinsic capacity for self-repair, severe injuries frequently result in significant tissue loss and erroneous axonal junctions, thereby impeding complete recovery and potentially causing neuropathic pain. Various therapeutic strategies, including surgical interventions, biomaterials, and pharmacological agents, have been developed to enhance nerve repair processes. While preclinical studies in animal models have demonstrated the efficacy of certain pharmacological agents in promoting nerve regeneration and mitigating inflammation, only a limited number of these agents have been translated into clinical practice to expedite nerve regeneration. Chinese herb medicine (CHM) possesses a longstanding history in the treatment of various ailments and demonstrates potential efficacy in addressing PNI through its distinctive, cost-effective, and multifaceted methodologies. This review critically examines the advancements in the application of CHM for PNI treatment and nerve regeneration. In particular, we have summarized the most commonly employed and rigorously investigated CHM prescriptions, individual herbs, and natural products, elucidating their respective functions and underlying mechanisms in the context of PNI treatment. Furthermore, we have deliberated on the prospective development of CHM in both clinical practice and fundamental research.

Akkermansia muciniphila: A promising probiotic against inflammation and metabolic disorders.

Metabolic disease is a worldwide epidemic that has become a public health problem. Gut microbiota is considered to be one of the important factors that maintain human health by regulating host metabolism. As an abundant bacterium in the host gut, A. muciniphila regulates metabolic and immune functions, and protects gut health. Multiple studies have indicated that alterations in the abundance of A. muciniphila are associated with various diseases, including intestinal inflammatory diseases, obesity, type 2 diabetes mellitus, and even parasitic diseases. Beneficial effects were observed not only in live A. muciniphila, but also in pasteurized A. muciniphila, A. muciniphila-derived extracellular vesicles, outer membrane, and secreted proteins. Although numerous studies have only proven the simple correlation between multiple diseases and A. muciniphila, an increasing number of studies in animal models and preclinical models have demonstrated that the beneficial impacts shifted from correlations to in-depth mechanisms. In this review, we provide a comprehensive view of the beneficial effects of A. muciniphila on different diseases and summarize the potential mechanisms of action of A. muciniphila in the treatment of diseases. We provide a comprehensive understanding of A. muciniphila for improving host health and discuss the perspectives of A. muciniphila in the future studies.

Antibacterial and anti-biofilm activities of gold-curcumin nanohybrids and its polydopamine form upon photo-sonotherapy of Staphylococcus aureus infected implants: In vitro and animal model studies

Implant-related infections are among the major post-surgery problems, and treatment of these infections is challenging due to the formation of biofilms by microorganisms such as Staphylococcus aureus. Herein, a novel gold-curcumin nanohybrid (GCNH) was synthesized for the first time and characterized. GCNH had a band gap energy of 2.41 eV, a zeta potential of −15 mV, and comprised uniform spherical particles with a mean diameter of 8 ± 2 nm. The biological macromolecule of polydopamine was then coated on GCNH to prepare a gold-curcumin-polydopamine nanohybrid (GCDNH). The nanohybrids were employed as novel dual photo-sonosensitizers for bacterial eradication by near-infrared (NIR) light and ultrasound (US) irradiations. GCNH and GCDNH represented photothermal conversion efficiencies of 26 and 32 %, respectively, and GCDNH represented a hemolysis rate of 2.3 % under both near-infrared (NIR) light and ultrasound (US) irradiations. NIR light and US irradiations (photo-sonotherapy) of Staphylococcus aureus using GCDNH depicted anti-bacterial and anti-biofilm efficiencies of 98 and 99 %, respectively, in synergistic manners, which are higher or as high as other sensitizers reported previously. The mechanism of photo-sonotherapy was related to generation of high levels of reactive oxygen species (ROS), and protein and nucleic acid leakages. In an in vivo infection model, NIR light and US irradiations annihilated Staphylococcus aureus on GCDNH-covered implants with high efficiency, without causing damage to normal tissues.

TRAIL as a Warrior in Nano-Sized Trojan Horse: Anticancer and Anti-Metastatic Effects of Nano-Formulations of TRAIL in Cell Culture and Animal Model Studies

Cancer is a therapeutically challenging and genomically complicated disease. Pioneering studies have uncovered multifaceted aspects of cancer, ranging from intra- and inter-tumor heterogeneity, drug resistance, and genetic/epigenetic mutations. Loss of apoptosis is another critical aspect that makes cancer cells resistant to death. A substantial fraction of mechanistic information gleaned from cutting-edge studies has enabled researchers to develop near-to-complete resolution of the apoptotic pathway. Within the exciting frontiers of apoptosis, TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) has garnered phenomenal appreciation by interdisciplinary researchers principally because of its unique capability to target cancer cells. TRAIL-based monotherapies and combinatorial therapies have reached phase II and phase III clinical trials. Rapidly upgrading the list of clinical trials substantiates the clinically valuable role of TRAIL-based therapeutics in cancer therapy. However, there is a growing concern about the poor bioavailability and rapid clearance of TRAIL-based therapeutics. Excitingly, the charismatic field of nanotechnology offers solutions for different problems, and we have witnessed remarkable breakthroughs in the efficacy of TRAIL-based therapeutics using nanotechnological approaches. In this review, we have attempted to provide a summary about different nanotechnologically assisted delivery methods for TRAIL-based therapeutics in cell culture studies and animal model studies for the inhibition/prevention of cancer.

Comparison of pathomorphologic properties of non-resorbable and partially resorbable implants for reconstructive surgery of pelvic organ prolapse and stress urinary incontinence: an animal model study

Introduction. It is well-known that the use of transvaginal mesh implants is not devoid of specific complications that meaningfully impair the quality of life of female patients. The volume of permanent material used has been shown to correlate closely with the risk of implant-associated complications. Thus, there is a need to develop a new generation of implants that retain the advantages of a permanent mesh implant but with minimal risk of implant-associated complications. Meanwhile, there are insufficient data on the organism's response to this type of synthetic implant.Objective. To compare the histological changes in the soft tissues of the rabbit anterior abdominal wall in the implantation zone of the new generation partially resorbable implant and non-absorbable polypropylene mesh implant on the animal model.Materials & methods. We have previously developed a partially resorbable ligature delivery system for axial fixation of pelvic floor structures, performed technical analysis, and compared biomechanical and pathomorphological properties after implantation in an animal model experiment. The present study was conducted on 39 male rabbits of Chinchilla breed, randomised into three groups according to the type of implanted material: a partially resorbable ligature delivery system Axilen and Axilen Rapid [Lintex, LLC], and a non-resorbable polypropylene mesh implant Urosling. After the rabbits were removed from the experiment, the obtained biomaterial was subjected to histological study.Results. In the group with partially resorbable implants Axilen and Axilen Rapid, less inflammation and better tissue integration were observed compared to the polypropylene implant Urosling. This indicates a potential reduction in the risk of postoperative complications and an improvement in the quality of life for patients.Conclusion. The results of the experimental study confirm the advantages of using partially resorbable implants over traditional polypropylene meshes in pelvic floor reconstructive surgery. However, further research is needed to confirm the long-term safety and effectiveness of the new generation of implants.

Serum proteome profiling reveals HGFA as a candidate biomarker for pulmonary arterial hypertension

BackgroundIdentification and validation of potential biomarkers could facilitate the identification of pulmonary arterial hypertension (PAH) and thus aid to study their roles in the disease process.MethodsWe used the isobaric tag for relative and absolute quantitation approaches to compare the protein profiles between the serum of PAH patients and the controls. Bioinformatics analyses and enzyme-linked immunosorbent assay (ELISA) identification of PAH patients and the controls were performed to identify the potential biomarkers. The receiver operating characteristic curve (ROC) analysis was used to evaluate the diagnostic performance of these potential biomarkers. Mendelian randomization (MR) analysis further clarified the relationship between the potential biomarkers and PAH. Additionally, the expression levels of the potential biomarkers were further validated in two PAH animal models (monocrotaline-PH and Sugen5416 plus hypoxia-PH) using ELISA and reverse transcription-quantitative PCR (RT-qPCR).ResultsWe identified significant changes in three proteins including heparanase (HPSE), gelsolin (GSN), and hepatocyte growth factor activator (HGFA) in PAH patients. The ROC analysis showed that the areas under the curve of HPSE, GSN, and HGFA in differentiating PAH patients from controls were 0.769, 0.777, and 0.964, respectively. HGFA was correlated with multiple parameters of right ventricular functions in PAH patients. Besides proteomic analysis, we also used MR method to demonstrate the causal link between genetically reduced HGFA levels and an increased risk of PAH. In subsequent validation study in PAH animal models, the mRNA expression levels of HGFA in the lung tissues were significantly lower in PAH rat models than in controls. In the rat models, serum levels of HGFA were lower compared to the control group and showed a negative correlation with right ventricular systolic pressure.ConclusionThe study demonstrated that HGFA might be a promising biomarker for noninvasive detection of PAH.

Investigation of anticancer potential of a novel bioactive molecule from Trichosporon asahii VITSTB1 in breast cancer cell lines: an in vitro study.

The current study investigates the anticancer activity of protein derived from yeast against breast cancer. Yeast-derived proteins illustrate potential as an anticancer agent through mechanisms, such as immune system stimulation via beta-glucans, cytotoxic effects, and modulation of gut microbiota by probiotic strains. The antioxidant activity of yeast-derived proteins can aid in anticancer activity by neutralizing free radicals, thereby reducing oxidative stress and preventing damage to cellular DNA. Employing a comprehensive methodology encompassing yeast isolation, antioxidant screening, molecular characterization, bioactive protein purification, and MTT assay, the research provides crucial insights into the anticancer attributes of the protein extracted from the yeast. The findings reveal significant antioxidant activity that reduces reactive oxygen species (ROS) levels, which are implicated in cancer development. The MTT assay on MCF-7 breast cancer cell lines, characterized by estrogen receptor and progesterone receptor positivity and HER-2 negativity, determined an IC50 value of 54.89µg/ml, indicating a dose-dependent decrease in cytotoxic effects. These results suggest that the protein derived from Trichosporon asahii VITSTB1 exhibits promising anti-breast cancer properties. Further research is necessary to elucidate the underlying mechanisms, assess efficacy and safety profiles, explore synergies with existing therapies, and conduct animal model studies. Advancing this line of inquiry will significantly contribute to biomedical research and industrial innovation.

Gut Microbiota and Gut–Brain Axis in Hypertension: Implications for Kidney and Cardiovascular Health—A Narrative Review

Introduction: Arterial hypertension is a major contributor to a wide range of health complications, with cardiac hypertrophy and chronic kidney disease being among the most prevalent. Consequently, novel strategies for the treatment and prevention of hypertension are actively being explored. Recent research has highlighted a potential link between hypertension and the gut–brain axis. A bidirectional communication between the microbiota and the brain via the vagus nerve, enteric nervous system, hypothalamus–pituitary–adrenal axis, secreted short-chain fatty acids, and neurotransmitter metabolism. Materials and methods: A comprehensive literature search was conducted using databases such as PubMed to identify studies exploring the relationship between gut microbiota and hypertension, along with the effects of dietary interventions and probiotics on blood pressure regulation. Discussion: Studies in both animal models and human subjects have demonstrated a strong correlation between alterations in gut microbiota composition and the development of hypertension. By influencing blood pressure, the gut microbiota can potentially affect the progression of cardiovascular and kidney disorders. Modulating gut microbiota through dietary interventions and probiotics has shown promise in regulating blood pressure and reducing systemic inflammation, offering a novel approach to managing hypertension. Diets such as the Mediterranean diet, which is rich in polyphenols and omega-3 fatty acids and low in sodium, promote the growth of beneficial gut bacteria that support cardiovascular health. Additionally, probiotics have been found to enhance gut barrier function, reduce inflammation, and modulate the Renin–Angiotensin System, all of which contribute to lowering blood pressure. Conclusions: Further research is needed to determine the mechanisms of action of the microbiota in hypertension. The aim of this study was to evaluate the influence of gut microbiota on blood pressure regulation and the progression of hypertension-related complications, such as cardiovascular and kidney disorders.

Self-assembled Lipid Nanoparticles for Killing Triple Negative Breast Cancer Cells.

Triple negative breast cancers (TNBCs) lacking estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) on their cell surfaces are highly aggressive, difficult-to-treat and often relapse. Herein, we report on the self-assembled lipid nanoparticles (LNPs) of two new pegylated lipopeptides for killing TNBCs (MDA-MB-231). The pegylated lipopeptides were synthesized by conjugating an n-hexadecyl hydrophobic tail to one end of a (PEG)27 unit the other distal end of which was covalently grafted with two previously reported tumor targeting RGDK- and CGKRK- peptides. The SEM images of the self-assembled LNPs formed upon dissolution of the pegylated lipopeptides in aqueous medium revealed formation of spherical aggregates. The degree of cellular uptake for the self-assembled LNPs formed by the pegylated CGKRK-lipopeptide were found to be significantly higher than that for the self-assembled LNPs formed by the pegylated RGDK-lipopeptide in MCF-7, MDA-MB-231, HEK-293 and HFF cells. Notably, about 60 % TNBCs (MDA-MB-231 cells) were killed upon treatment with commercially available potent JAK2 inhibitor (WP 1066) loaded LNPs of the pegylated RGDK-lipopeptide. Contrastingly, the same treatment killed only about 20 % non-cancerous HEK-293 cells. The self-assembled pegylated LNPs described herein open the door for undertaking preclinical studies in animal models for TNBCs.

Therapeutic efficacy of brown propolis fromAraucaria sp.in modulating rheumatoid arthritis.

Rheumatoid arthritis is a systemic inflammatory autoimmune disease with prevalence estimated at 0.5% to 1% of the population. As one of the treatment routes of rheumatoid arthritis is based on the use of nonsteroidal anti-inflammatory drugs, the use of natural products with anti-inflammatory potential becomes relevant. Brown propolis has several biological properties, including immunomodulatory and anti-inflammatory effects. Thus, the present study evaluated the therapeutic efficacy of the crude extract of brown propolis from Araucaria sp. through experimental models of analgesia, anti-inflammatory activity, and rheumatoid arthritis. Hyperalgesia was evaluated by mechanical and thermal sensitivity. Anti-inflammatory activity was evaluated by plantar volume, cell migration and NF-kB expression in carrageenan-induced paw oedema. In collagen-induced rheumatoid arthritis, it was evaluated by mechanical and thermal nociception on the plantar surface, and mechanical nociception in the femorotibial and caudal joints, evaluation of plantar volume, radiography, weight gain and biochemical profile. The results demonstrated that the oral administration of brown propolis can modulate the course of rheumatoid arthritis, and it can inhibit pain through the modulation of mechanical sensitivity. The anti-arthritic effect of propolis may be due to its anti-inflammatory capacity, which includes inhibiting oedema formation, cell migration, and NF-kB expression, as well as preserving joint space and normalizing urea levels. This was an animal model study. Therefore, brown propolis should be evaluated in studies of human RA to determine efficacy.

Development of a Clinically Relevant Preclinical Animal Model to Mimic Suburethral Implantation of Support Materials for Stress Urinary Incontinence.

Following the severe complications widely reported in some women following polypropylene suburethral mesh implantation for the treatment of stress urinary incontinence, it has become clear that careful preclinical study in an appropriate animal model is essential. The preclinical model described here allows the postoperative clinical and histochemical assessment of material implanted in the sheep vagina and represents a model that allows prediction of the potential vaginal tissue responses to suburethral mesh implantation before implantation into humans. To develop and evaluate a relevant preclinical animal model to mimic suburethral implantation of support materials for stress urinary incontinence. Fourteen parous ewes of 30-40 kg were used. Under general anesthetic, animals were placed in the lithotomy position. A 12-French Foley catheter was inserted. The ventral vaginal wall was longitudinally incised. The space between the vaginal wall and the urethra was developed, with lateral retropubic dissection. Either a standard transvaginal polypropylene tape (seven animals) or a fascia mimetic microfibre spun polyurethane tape (seven animals) were inserted using an introducer either via a suprapubic (seven animals) or a transvaginal approach (seven animals) into the suburethral and retropubic space. The incisions were closed, and the catheter was removed. A betadine vaginal pack was placed and removed after 24 h. Postoperatively, the animals were observed carefully for pain and complications and allowed access to water and food under continuous veterinary supervision adhering to USA-approved protocols. On the second postoperative day, all the animals passed urine freely and had regular bowel motions. No procedure related complications were observed. This is the first large animal model which has been designed for suburethral implantation. and which can be effectively used for the preoperative evaluation of novel materials designed for suburethral implantation. We believe that this technique in this large animal model accurately reproduces the surgical technique used to treat stress urinary incontinence in women. It provides a new and effective in vivo model for the objective evaluation of new materials to treat female stress incontinence.

USE OF APITOXIN AS AN INTERVENTION IN THE TREATMENT OF DERMATOLOGICAL INFLAMMATIONS

Bee venom (BV), produced by the species Apis mellifera, is one of the most recognized and widely studied natural toxins, with increasing use in integrative medicine. This venom contains a variety of chemical substances, including peptides such as melittin, apamin, adolapin and the MCD peptide, as well as enzymes such as phospholipase A2 (PLA2), hyaluronidase, acid phosphomonoesterase and lysophospholipase. Amines, such as histamine, dopamine and norepinephrine, are also present, which contribute to its antimicrobial, anti-inflammatory, immunomodulatory and anticancer properties. Studies suggest that it has promising pharmacological effects, especially in the treatment of inflammation. OBJECTIVE: This study aims to investigate the therapeutic effects of bee venom in the treatment of dermatological inflammation, exploring its potential as a natural alternative with proven anti-inflammatory properties. METHODOLOGY: A systematic review of the literature was carried out, focusing on primary articles and results of randomized clinical trials (RCTs) conducted in vivo and in vitro, published between 2014 and 2024. RESULTS: In models with induced atopic dermatitis (AD) such as mice, phospholipase A2 (PLA2), a compound derived from BV, was shown to significantly reduce skin thickness and inflammatory cytokine levels, both in animal models and humans, highlighting the importance of confirming its clinical applicability. Therefore, therapies may include everything from topical application of BV to the use of emollients and cosmetics with these compounds, based on their pharmacological properties. CONCLUSION: This review highlighted the potential of bee venom as a promising alternative in the treatment of dermatological inflammations, due to its anti-inflammatory and immunomodulatory properties. Studies in animal models and in vitro suggest that compounds such as melittin and phospholipase A2 (PLA2) inhibit inflammatory mediators and alleviate symptoms of atopic dermatitis and acne. In addition, research indicates that VB can block inflammatory signaling pathways, such as NF-κB and MAPK, reinforcing its therapeutic potential in the management of skin inflammation, especially in topical applications.

Whole-brain responses to visual and auditory stimuli in anesthetized and minimally restrained awake mice using quiet zero echo time fMRI

Abstract Functional MRI (fMRI) is a flexible tool for sensory perception studies in animal models. However, animal fMRI studies are generally performed under anesthesia. Unfortunately, anesthesia affects brain function and sensory processing, complicating the interpretation of the findings. Since there is a growing need for fMRI protocols applicable for awake animals, we optimized a zero echo time Multi-Band Sweep Imaging with a Fourier Transformation (MB-SWIFT) fMRI approach for imaging awake mice. We implemented a 14-day habituation protocol that resulted in merely moderate motion of the mice while being head-fixed with the animals’ body and limbs being free-to-move. The sensory responsiveness between different states of consciousness was compared by imaging mice with visual and auditory stimulation schemes in the awake state and under ketamine-xylazine anesthesia. In awake mice, we observed a robust whole-brain activation of the ascending auditory and visual pathways, as well as higher sensory processing areas. Under ketamine-xylazine anesthesia, auditory responses were suppressed, and the temporal shapes of fMRI responses were different from those obtained in awake mice. Our results suggest that the quiet and motion-tolerant zero echo time MB-SWIFT approach allows complex behavioral fMRI designs in the awake state that promise to improve our understanding of the underlying mechanisms of perception.

Beneficial Effects of Xanthohumol on Metabolic Syndrome: Evidence from In Vitro and Animal Model Studies.

Metabolic syndrome refers to the simultaneous occurrence of several disorders that have been associated with other co-morbidities, such as a pro-inflammatory state and non-alcoholic fatty liver disease. Nowadays, it is a growing public health problem that contributes to the development of non-communicable diseases, such as type 2 diabetes, cardiovascular disease, and cognitive deficits among others. Its incidence has been related to modifiable lifestyle factors, mainly dietary patterns and physical activity. In addition, numerous studies have observed the potential beneficial effects of polyphenols in the prevention and treatment of metabolic syndrome components in both animals and humans. In this line, the aim of this review is to present the scientific evidence available about the beneficial effects of the phenolic compound xanthohumol in the prevention and/or treatment of obesity, dyslipidemia, insulin resistance, and fatty liver, which are important components of metabolic syndrome. All the potential beneficial effects described in this manuscript have been observed in vitro and in animal models, there are no published clinical trials in this context yet.

Modular and Fast Assembly of Self-Immobilizing Fluorogenic Probes for β-Galactosidase Detection.

β-Galactosidase (β-gal) has emerged as a pivotal biomarker in primary ovarian cancer. Despite the existence of numerous fluorescent probes for β-gal activity detection, quinone methide-based immobilizing probes were shown to avoid rapid diffusion of the activated fluorophore and improve the resolution. However, the synthesis of these fluorophores, particularly near-infrared fluorophores, still exhibits lower efficiency. In this study, we introduce modular and rapidly assembled self-immobilizing fluorogenic probes, capitalizing on the proximity labeling properties of quinone methide (QM). Compared to conventional fluorescent probes, these new probes not only exhibit a fluorogenic response but also achieve permanent retention, demonstrating improved detection sensitivity, particularly after cell fixation and in vivo animal model studies. This straightforward synthesis approach holds promise for broader applications in detecting other analytes.

Bioinformatics analysis to design a multi-epitope mRNA vaccine against S. agalactiae exploiting pathogenic proteins

Antibiotic resistance in bacterial pathogen infections is a growing global issue that occurs due to their adaptation to changing environmental conditions. Therefore, producing an efficient vaccine as an alternative approach can improve the immune system, eradicate related pathogens, and overcome this growing problem. Streptococcus agalactiae belongs to group B Streptococcus (GBS). Colonization of GBS during pregnancy is a significant risk factor for infants and young children. S. agalactiae infected population exhibits resistance to beta-lactams, including penicillin and the second-line antibiotics erythromycin and clindamycin. On the other hand, there are currently no commercial vaccines against this pathogen. Vaccination of pregnant women is a highly effective method to protect newborns and infants from S. agalactiae infection, and it has been identified as an urgent demand by the World Health Organization. This study employed various immunoinformatic tools to develop an effective vaccine that could trigger both humoral and cell-mediated immunity and prevent disease. For this purpose, three conserved antigenic proteins of the main pathogenic strains of S. agalactiae were utilized to predict CTL, HTL, and B-cell epitopes for producing an mRNA vaccine against different strains of S. agalactiae. The selected epitopes were fused using proper linkers. The Resuscitation promoting factor E (RpfE) sequence was incorporated in the designed vaccine construct as an adjuvant to boost its immune response. Different physicochemical characteristics of the final designed vaccine, modeling of the three-dimensional structure, molecular docking, molecular dynamics simulation, and immunological response simulation were screened following vaccine administration in an in vivo model. Computational immune simulation data identified that IgG1, IgM, INF γ, IL-2, T helper, and B-cell populations increased significantly after vaccination. These findings suggested that the vaccine candidate may provide good protection against S. agalactiae infection. However, experimental and animal model studies are required for additional validation and implementation in human vaccination programs.

A systematic review of progenitor survival and maturation in Parkinsonian models

Stem cell–based brain repair is a promising emergent therapy for Parkinson's disease based on years of foundational research using human fetal donors as a cell source. Unlike current therapeutic options for patients, this approach has the potential to provide long-term stem cell–derived reconstruction and restoration of the dopaminergic input to denervated regions of the brain allowing for restoration of certain functions to patients. The ultimate clinical success of stem cell–derived brain repair will depend on both the safety and efficacy of the approach and the latter is dependent on the ability of the transplanted cells to survive and differentiate into functional dopaminergic neurons in the Parkinsonian brain. Because the pre-clinical literature suggests that there is considerable variability in survival and differentiation between studies, the aim of this systematic review was to assess these parameters in human stem cell–derived dopaminergic progenitor transplant studies in animal models of Parkinson's disease. A defined systematic search of the PubMed database was completed to identify relevant studies published up to March 2024. After screening, 76 articles were included in the analysis from which 178 separate transplant studies were identified. From these, graft survival could be assessed in 52 studies and differentiation in 129 studies. Overall, we found that graft survival ranged from < 1% to 500% of cells transplanted, with a median of 51% of transplanted cells surviving in the brain; while dopaminergic differentiation of the cells ranged from 0% to 46% of cells transplanted with a median of 3%. This systematic review suggests that there is considerable scope for improvement in the differentiation of stem cell–derived dopaminergic progenitors to maximize the therapeutic potential of this approach for patients.

IEPA, a novel radiation countermeasure, alleviates acute radiation syndrome in rodents

Repurposing therapeutic agents with existing clinical data is a common strategy for developing radiation countermeasures. IEPA (imidazolyl ethanamide pentandioic acid) is an orally bioavailable small molecule pseudopeptide with myeloprotective properties, a good clinical safety profile, and stable chemical characteristics facilitating stockpiling. Here, we evaluated IEPA’s radiomitigative efficacy in the hematopoietic subsyndrome of acute radiation syndrome (H-ARS) using total-body irradiation (TBI) models in C57BL/6J mice and WAG/RijCmcr rats, applying various posology schemes and introducing syringe feeding of the IEPA formulation in the pudding. Additionally, we assessed IEPA in the delayed effects of acute radiation exposure (DEARE) model after partial-body irradiation (PBI) in WAG/RijCmcr rats. Endpoints included survival, body weight, hematology, and pulmonary parameters, depending on the model. Results from mouse and rat TBI models demonstrated survival improvements with repeated IEPA dosing at 10 mg/kg, with the largest benefits observed in the bi-daily (BID) treatment over the 30-day ARS phase in female rats. Survival across PBI-DEARE subsyndromes was comparable between IEPA and vehicle groups, though IEPA improved pulmonary parameters in female rats during the lung-DEARE phase. Sex-related differences in response to irradiation and IEPA were noted, with females showing a survival advantage. IEPA treatment is compatible with Neulasta® (Pegfilgrastim; PEG-G-CSF); adequately powered studies are needed to confirm the trend toward improved survival over standard care alone. IEPA is a promising development candidate as a medical countermeasure against the effects of acute radiation syndrome. Further confirmatory studies in small and large animal models should validate the robustness and translatability of preliminary rodent data on IEPA’s radiomitigative efficacy.

The Lymphatic Vasculature in Lung Homeostasis and Disease.

The lymphatic vasculature maintains lung homeostasis via fluid drainage in the form of lymph and by facilitating immune surveillance and leukocyte trafficking to the draining lymph nodes. Previous studies in both humans and animal models have demonstrated an important role for lymphatics in lung function from the neonatal period through adulthood. In addition, changes in the lymphatic vasculature have been observed in many respiratory diseases, and there is emerging evidence of a causative role for lymphatic dysfunction in the initiation and progression of lung pathology. Despite advances in the field, there are still many unanswered questions, and a more comprehensive understanding of the mechanisms by which the lymphatics affect lung homeostasis and the response to lung injury is needed. In this review, we discuss our current knowledge of the structure, function, and role of the lymphatics in the lung and how these vessels are involved in respiratory disease.

NCMP-13. EXPLORING THE PATHOPHYSIOLOGY OF HYDROCEPHALUS IN CHOROID PLEXUS PAPILLOMA

Abstract BACKGROUND Choroid plexus papilloma (CPP) is a benign intraventricular lesion associated with hydrocephalus and ventricular outflow obstruction. However, the molecular mechanism by which cerebrospinal fluid (CSF) is produced by choroid plexus (CP), or by which CSF production is altered in the setting of CPP to cause hydrocephalus, is unknown. METHODS A PRISMA systematic literature review was conducted to identify gene targets associated with CSF production. Primary tissue samples of CP and CPP from the same patient were obtained, and expression of target genes was assessed using immunohistochemistry and quantified using QuPath software H-scoring. Single-nucleus sequencing of both CP and CPP was also completed, and differential expression of identified target genes was evaluated by calculating log fold change. RESULTS Systematic literature review yielded 25 studies in animal models and 18 unique gene targets. 16 targets were expressed in primary CP and CPP tissue samples upon immunohistochemistry staining. 11 of 18 targets revealed significant differential expression between CP and CPP on single-nucleus sequencing. Genes with notable expression increases in CPP included ion transporters NKCC1 (Na-K-Cl cotransporter) and TRPV4 (non-selective cation channel), as well as carbonic anhydrase II. CONCLUSIONS We present evidence that choroid plexus papilloma has altered expression of genes previously implicated in CSF production. Upregulation of membrane transporters and cytoplasmic enzymes involved in Na+, K+, Cl-, and HCO3- transport may provide a mechanistic explanation for the development of hydrocephalus in CPP. Pharmacologic inhibition of CSF production may offer a route for non-surgical management of CPP, as well as other pathologies causing hydrocephalus.