Experimental Biology And Medicine (Maywood, N.J.)[JOURNAL]
Sun
200 papers
Enhancing pharmacogenomic data accessibility and drug safety with large language models: a case study with Llama3.1.
Li D, Wu L, Lin YC … +7 more , Huang HY, Cotton E, Liu Q, Chen R, Huang R, Zhang Y, Xu J
Exp Biol Med (Maywood) · 2024 · PMID 39691764 · Full text
Pharmacogenomics (PGx) holds the promise of personalizing medical treatments based on individual genetic profiles, thereby enhancing drug efficacy and safety. However, the current landscape of PGx research is hindered by...
Pharmacogenomics (PGx) holds the promise of personalizing medical treatments based on individual genetic profiles, thereby enhancing drug efficacy and safety. However, the current landscape of PGx research is hindered by fragmented data sources, time-consuming manual data extraction processes, and the need for comprehensive and up-to-date information. This study aims to address these challenges by evaluating the ability of Large Language Models (LLMs), specifically Llama3.1-70B, to automate and improve the accuracy of PGx information extraction from the FDA Table of Pharmacogenomic Biomarkers in Drug Labeling (FDA PGx Biomarker table), which is well-structured with drug names, biomarkers, therapeutic area, and related labeling texts. Our primary goal was to test the feasibility of LLMs in streamlining PGx data extraction, as an alternative to traditional, labor-intensive approaches. Llama3.1-70B achieved 91.4% accuracy in identifying drug-biomarker pairs from single labeling texts and 82% from mixed texts, with over 85% consistency in aligning extracted PGx categories from FDA PGx Biomarker table and relevant scientific abstracts, demonstrating its effectiveness for PGx data extraction. By integrating data from diverse sources, including scientific abstracts, this approach can support pharmacologists, regulatory bodies, and healthcare researchers in updating PGx resources more efficiently, making critical information more accessible for applications in personalized medicine. In addition, this approach shows potential of discovering novel PGx information, particularly of underrepresented minority ethnic groups. This study highlights the ability of LLMs to enhance the efficiency and completeness of PGx research, thus laying a foundation for advancements in personalized medicine by ensuring that drug therapies are tailored to the genetic profiles of diverse populations.
Integrating artificial intelligence in strabismus management: current research landscape and future directions.
Wu D, Huang X, Chen L … +3 more , Hou P, Liu L, Yang G
Exp Biol Med (Maywood) · 2024 · PMID 39654660 · Full text
Advancements in artificial intelligence (AI) are transforming strabismus management through improved screening, diagnosis, and surgical planning. Deep learning has notably enhanced diagnostic accuracy and optimized surgi...
Advancements in artificial intelligence (AI) are transforming strabismus management through improved screening, diagnosis, and surgical planning. Deep learning has notably enhanced diagnostic accuracy and optimized surgical outcomes. Despite these advancements, challenges such as the underrepresentation of diverse strabismus types and reliance on single-source data remain prevalent. Emphasizing the need for inclusive AI systems, future research should focus on expanding AI capabilities with large model technologies, integrating multimodal data to bridge existing gaps, and developing integrated management platforms to better accommodate diverse patient demographics and clinical scenarios.
Association of immunity-related gene SNPs with Alzheimer's disease.
Bissar N, Kassir R, Salami A … +1 more , El Shamieh S
Exp Biol Med (Maywood) · 2024 · PMID 39651329 · Full text
Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by progressive cognitive decline. Genetic factors have been implicated in disease susceptibility as its etiology remains multifactorial. Th...
Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by progressive cognitive decline. Genetic factors have been implicated in disease susceptibility as its etiology remains multifactorial. The and the genes, involved in immune responses, have emerged as potential candidates influencing AD risk. In this study, 644 Lebanese individuals, including 127 AD patients and 250 controls, were genotyped, by KASP assay, for six SNPs selected from the largest GWAS study in 2021. Logistic regression analysis assessed the association between SNP genotypes and AD risk, adjusting for potential confounders. Among the six SNPs analyzed, rs1846190G>A in and rs1354106T>G in showed significant associations with AD risk in the Lebanese population ( < 0.05). Carriers of the AG and AA genotypes of rs1846190 in exhibited a protective effect against AD (AG: OR = 0.042, p = 0.026; AA: OR = 0.052, p = 0.031). The GT genotype of rs1354106T>G in was also associated with reduced risk (OR = 0.173, p = 0.005). Following Bonferroni correction, a significant correlation of rs1354106T > G with AD risk was established. Our results might highlight the complex interplay between genetic and immunological factors contributing to the development of the disease.
Engineering ADSCs by manipulating YAP for lymphedema treatment in a mouse tail model.
Hu L, Zhang N, Zhao C … +1 more , Pan J
Exp Biol Med (Maywood) · 2024 · PMID 39633684 · Full text
Secondary lymphedema is a chronic disease associated with deformity of limbs and dysfunction; however, conventional therapies are not curative. Adipose-derived stem cells (ADSCs) based therapy is a promising way, but a s...
Secondary lymphedema is a chronic disease associated with deformity of limbs and dysfunction; however, conventional therapies are not curative. Adipose-derived stem cells (ADSCs) based therapy is a promising way, but a single transplantation of ADSCs has limited efficacy. In this study, ADSCs were engineered and then transplanted into the site of lymphedema. Yes-associated protein (YAP), a crucial regulator of Hippo pathway, plays an important role in regulating stem cell functions. We examined the YAP expression in a mouse tail lymphedema model, and found that transplanted ADSCs exhibited high expression level of YAP and a large number of YAP positive cells existed in lymphedema environment. , the downregulation of YAP in ADSCs resulted in higher expression levels of genes related to lymphangiogenesis such as Lyve-1, VEGFR-3 and Prox-1. , YAP-engineered ADSCs generated abundant VEGFR-3-positive lymphatic vessels and significantly improved subcutaneous fibrosis. These results indicated that the transplantation of pre-engineered ADSCs by manipulating YAP is a promising strategy for lymphatic reconstruction.
Predicting severe COVID-19 using readily available admission indicators: SpO2/FiO2 ratio, comorbidity index, and gender.
Vu LD, Christofferson RC, O'Neal HR … +9 more , Hamer D, Phan ATQ, Vance KM, Turner EA, Kumar A, Yola IM, Lim N, Ogden B, Cormier SA
Exp Biol Med (Maywood) · 2024 · PMID 39633683 · Full text
The focus of this study was to identify risk factors for severe and critical COVID-19, evaluate local respiratory immune responses to SARS-CoV-2 infection, and develop a prognostic tool for COVID-19 severity using access...
The focus of this study was to identify risk factors for severe and critical COVID-19, evaluate local respiratory immune responses to SARS-CoV-2 infection, and develop a prognostic tool for COVID-19 severity using accessible early indicators. Using nasopharyngeal swab samples from hospitalized patients with COVID-19 of varying severity during the first wave of the pandemic from March to May 2020 in Louisiana, we evaluated the association between COVID-19 severity and viral load, respiratory immune mediators, and demographic/clinical factors. We found that the SpO/FiO ratio at triage, total comorbidity burden (represented by Charlson Comorbidity Index), and gender were significantly associated with COVID-19 severity. Using these early significant indicators, we developed a prognostic tool for COVID-19 severity that is simple and convenient. Additionally, our study demonstrated that elevated levels of respiratory immune mediators, including IL-10, IL-6, MCP-1, and MCP-3, were significantly associated with COVID-19 severity. We also found that viral load at the time of admission was associated with disease severity. Our findings highlight the feasibility and importance of evaluating the humoral component of local mucosal immune responses and viral load at the infected site using convenient nasopharyngeal swab samples, which could be an effective method to understand the relationship between viral infection and immune responses at the early stages of infection. Our proposed prognostic tool has the potential to be useful for COVID-19 management in clinical settings, as it utilizes accessible and easy-to-collect variables at the time of admission.
Neuroinflammation underlies the development of social stress induced cognitive deficit in male sickle cell mice.
DeVeaux SA, Vyshnya S, Propsom K … +8 more , Gbotosho OT, Singh AS, Horning RZ, Sharma M, Jegga AG, Niu L, Botchwey EA, Hyacinth HI
Exp Biol Med (Maywood) · 2024 · PMID 39629138 · Full text
Cognitive deficit is a debilitating complication of sickle cell disease (SCD), with a multifactorial etiopathogenesis. Here we show that neuroinflammation and dysregulation in lipidomics and transcriptomics profiles are...
Cognitive deficit is a debilitating complication of sickle cell disease (SCD), with a multifactorial etiopathogenesis. Here we show that neuroinflammation and dysregulation in lipidomics and transcriptomics profiles are major underlying mechanisms of social stress-induced cognitive deficit in SCD. Male Townes sickle cell (SS) mice and controls (AA) were exposed to social stress using the repeat social defeat (RSD) paradigm concurrently with or without treatment with minocycline. Mice were tested for cognitive deficit using novel object recognition and fear conditioning tests. SS mice exposed to RSD without treatment had worse performance on cognitive tests compared to SS mice exposed to RSD with treatment or to AA controls, irrespective of their RSD or treatment disposition. Additionally, compared to SS mice exposed to RSD with treatment, SS mice exposed to RSD without treatment had significantly more cellular evidence of neuroinflammation coupled with a significant shift in the differentiation of neural progenitor cells towards astrogliogenesis. Additionally, brain tissue from SS mice exposed to RSD was significantly enriched for genes associated with blood-brain barrier dysfunction, neuron excitotoxicity, inflammation, and significant dysregulation in sphingolipids important to neuronal cell processes. We demonstrate in this study that social stress induces cognitive deficit in SS mice, concurrently with neuroinflammation and lipid dysregulation.
STEMIN and YAP5SA, the future of heart repair?
Bejar N, Xiao S, Iyer D … +4 more , Muili A, Adeleye A, McConnell BK, Schwartz RJ
Exp Biol Med (Maywood) · 2024 · PMID 39544432 · Full text
This review outlines some of the many approaches taken over a decade or more to repair damaged hearts. We showcase the recent breakthroughs in organ regeneration elicited by reprogramming factors OCT3/4, SOX2, KLF4, and...
This review outlines some of the many approaches taken over a decade or more to repair damaged hearts. We showcase the recent breakthroughs in organ regeneration elicited by reprogramming factors OCT3/4, SOX2, KLF4, and C-MYC (OKSM). Transient OKSM transgene expression rejuvenated senescent organs in mice. OKSM transgenes also caused murine heart cell regeneration. A triplet alanine mutation of the N-terminus of Serum Response Factor's MADS box SRF153(A3), termed STEMIN, and the YAP mutant, YAP5SA synergized and activated OKSM and NANOG in adult rat cardiac myocytes; thus, causing rapid nuclear proliferation and blocked myocyte differentiation. In addition, ATAC seq showed induced expression of growth factor genes , , , and non-canonical Injected STEMIN and YAP5SA synthetic modifying mRNA (mmRNA) into infarcted adult mouse hearts, brought damaged hearts back to near normal contractility without severe fibrosis. Thus, STEMIN and YAP5SA mmRNA may exert additional regenerative potential than OKSM alone for treating heart diseases.
Fructose metabolism is unregulated in cancers and placentae.
Bazer FW, Wu G, Johnson GA
Exp Biol Med (Maywood) · 2024 · PMID 39529665 · Full text
Fructose and lactate are present in high concentrations in uterine luminal fluid, fetal fluids and fetal blood of ungulates and cetaceans, but their roles have been ignored and they have been considered waste products of...
Fructose and lactate are present in high concentrations in uterine luminal fluid, fetal fluids and fetal blood of ungulates and cetaceans, but their roles have been ignored and they have been considered waste products of pregnancy. This review provides evidence for key roles of both fructose and lactate in support of key metabolic pathways required for growth and development of fetal-placental tissues, implantation and placentation. The uterus and placenta of ungulates convert glucose to fructose via the polyol pathway. Fructose is sequestered within the uterus and cannot be transported back into the maternal circulation. Fructose is phosphorylated by ketohexokinase to fructose-1-PO4 (F1P) by that is metabolized via the fructolysis pathway to yield dihydoxyacetone phosphate and glyceraldehyde-3-PO4 that are downstream of phosphofructokinase. Thus, there is no inhibition of the fructolysis pathway by low pH, citrate or ATP which allows F1P to continuously generate substrates for the pentose cycle, hexosamine biosynthesis pathway, one-carbon metabolism and tricarboxylic acid cycle, as well as lactate. Lactate sustains the activity of hypoxia-inducible factor alpha and its downstream targets such as vascular endothelial growth factor to increase utero-placental blood flow critical to growth and development of the fetal-placental tissues and a successful outcome of pregnancy. Pregnancy has been referred to as a controlled cancer and this review addresses similarities regarding metabolic aspects of tumors and the placenta.
Subunit-specific mechanisms of isoflurane-induced acute tonic inhibition in dentate gyrus granule neuron.
Yu Z, Chen X, Liu Z … +2 more , Ding R, Xu J
Exp Biol Med (Maywood) · 2024 · PMID 39529664 · Full text
Prolonged exposure to volatile anesthetics may raise the risk of developing cognitive impairment by acting on gamma-a Aminobutyric acid A receptors (GABAAR). The dentate gyrus plays an important role in the hippocampus a...
Prolonged exposure to volatile anesthetics may raise the risk of developing cognitive impairment by acting on gamma-a Aminobutyric acid A receptors (GABAAR). The dentate gyrus plays an important role in the hippocampus and has a high potential for neural plasticity. However, it is unknown whether prolonged anesthesia induces a change in acute phasic or tonic inhibition in dentate gyrus granule cells (DGGCs) by acting on GABAAR. In order to verify the effects of volatile anesthetics on the current in DGGCs, a whole-cell patch was applied to record acute brain slices, and this study indicated that 4 h but not 2 h of isoflurane (ISO) exposure induced significantly larger tonic currents in DGGCs other than hippocampal CA1 pyramidal and thalamic relay neurons. Furthermore, this study demonstrated that the increased tonic current in DGGCs was dependent on the δ subunit-containing GABAARs by using transgenic δ subunit knockout mice. In conclusion, the δ subunit specific GABAAR is the key element that increased acute tonic inhibition in DGGCs of mice after prolonged ISO exposure, which may be one of the mechanisms of ISO neurotoxicity to the developing brain.
Quantitative characterization of retinal features in translated OCTA.
Badhon RH, Thompson AC, Lim JI … +2 more , Leng T, Alam MN
Exp Biol Med (Maywood) · 2024 · PMID 39507240 · Full text
This study explores the feasibility of quantitative Optical Coherence Tomography Angiography (OCTA) features translated from OCT using generative machine learning (ML) for characterizing vascular changes in retina. A gen...
This study explores the feasibility of quantitative Optical Coherence Tomography Angiography (OCTA) features translated from OCT using generative machine learning (ML) for characterizing vascular changes in retina. A generative adversarial network framework was employed alongside a 2D vascular segmentation and a 2D OCTA image translation model, trained on the OCT-500 public dataset and validated with data from the University of Illinois at Chicago (UIC) retina clinic. Datasets are categorized by scanning range (Field of view) and disease status. Validation involved quality and quantitative metrics, comparing translated OCTA (TR-OCTA) with ground truth OCTAs (GT-OCTA) to assess the feasibility for objective disease diagnosis. In our study, TR-OCTAs showed high image quality in both 3 and 6 mm datasets (high-resolution and contrast quality, moderate structural similarity compared to GT-OCTAs). Vascular features like tortuosity and vessel perimeter index exhibits more consistent trends compared to density features which are affected by local vascular distortions. For the validation dataset (UIC), the metrics show similar trend with a slightly decreased performance since the model training was blind on UIC data, to evaluate inference performance. Overall, this study presents a promising solution to the limitations of OCTA adoption in clinical practice by using vascular features from TR-OCTA for disease detection. By making detailed vascular imaging more widely accessible and reducing reliance on expensive OCTA equipment, this research has the potential to significantly enhance the diagnostic process for retinal diseases.
Immunization with recombinant PgdA protects mice against lung invasion.
Xiao J, Liu B, Yin Y … +1 more , Zhang X
Exp Biol Med (Maywood) · 2024 · PMID 39469203 · Full text
Current pneumococcal vaccines, including the pneumococcal polysaccharide (PPV23) and conjugate (PCV13) vaccines, offer protection against specific serotypes but pose risks of serotype replacement that can alter the compo...
Current pneumococcal vaccines, including the pneumococcal polysaccharide (PPV23) and conjugate (PCV13) vaccines, offer protection against specific serotypes but pose risks of serotype replacement that can alter the composition of the nasopharyngeal microbiota. To address this challenge, a novel strategy has been proposed to provide effective protection without disrupting the colonization of other bacterial populations. In our study, we found that subcutaneous immunization with recombinant peptidoglycan N-acetylglucosamine deacetylase A (rPgdA) elicited robust humoral and cellular immune responses, significantly reducing the invasion of pneumoniae in the lungs without affecting nasopharyngeal carriage. Furthermore, rPgdA antisera were shown to diminish bacterial invasion of lung epithelial cells . Notably, sera from patients with invasive pneumococcal infections exhibited higher levels of antibodies against the PgdA protein compared to sera from healthy adults, suggesting that a natural immune response to this protein occurs during infection. These results suggest a promising new target for the development of pneumococcal vaccines.
Exosomal circPTPRK promotes angiogenesis after radiofrequency ablation in hepatocellular carcinoma.
Zhu Y, He Q, Qi M
Exp Biol Med (Maywood) · 2024 · PMID 39469202 · Full text
Radiofrequency ablation (RFA) is an effective treatment for hepatocellular carcinoma (HCC), but the recurrence rate remains high due to angiogenesis in residual cancer cells. We used thermal stimulation to simulate the p...
Radiofrequency ablation (RFA) is an effective treatment for hepatocellular carcinoma (HCC), but the recurrence rate remains high due to angiogenesis in residual cancer cells. We used thermal stimulation to simulate the post-RFA microenvironment. The expression profile of circRNAs between normal control HCC cell-derived exosomes and exosomes after heat stimulation were analyzed by RNA sequencing. Quantitative real-time PCR was applied to evaluate the expression of circPTPRK in exosomes and human umbilical vein endothelial cells (HUVECs). Then, the functions of heat-stimulated HCC cell-derived exosomes and exosomal circPTPRK on HUVECs were unveiled. Transcriptome sequencing was utilized to determine targeted genes of circPTPRK. Heat-stimulated HCC cell-derived exosomes augmented cell proliferation, migration, and angiogenesis of HUVECs. In total, 229 differentially expressed circRNAs were obtained, including 211 upregulated circRNAs and 18 downregulated circRNAs in heat-stimulated HCC cell-derived exosomes. The expression of circPTPRK was remarkably increased in heat-stimulated HCC cell-derived exosomes and the HUVECs incubated with them. Heat-stimulated HCC cell-derived exosomes with circPTPRK knockdown significantly inhibited cell proliferation, migration, and angiogenesis of HUVECs. Mechanistic studies indicated that PLA2G4E is a downstream target of circPTPRK, and PLA2G4E overexpression reversed the inhibitory effect of circPTPRK knockdown on HUVEC angiogenesis. Our results indicated that exosomal circPTPRK activated HUVEC angiogenesis by upregulating PLA2G4E expression.
Bridging the gap: a translational perspective in spinal cord injury.
Hassan OI, Takamiya S, Asgarihafshejani A … +1 more , Fehlings MG
Exp Biol Med (Maywood) · 2024 · PMID 39391076 · Full text
Traumatic spinal cord injury (SCI) is a devastating and complex condition to treat with no curative options. In the past few decades, rapid advancements in our understanding of SCI pathophysiology as well as the mergence...
Traumatic spinal cord injury (SCI) is a devastating and complex condition to treat with no curative options. In the past few decades, rapid advancements in our understanding of SCI pathophysiology as well as the mergence of new treatments has created more optimism. Focusing on clinical translation, this paper provides a comprehensive overview of SCI through its epidemiology, pathophysiology, currently employed management strategies, and emerging therapeutic approaches. Additionally, it emphasizes the importance of addressing the heavy quality of life (QoL) challenges faced by SCI patients and their desires, providing a basis to tailor patient-centric forms of care. Furthermore, this paper discusses the frequently encountered barriers in translation from preclinical models to clinical settings. It also seeks to summarize significant completed and ongoing SCI clinical trials focused on neuroprotective and neuroregenerative strategies. While developing a cohesive regenerative treatment strategy remains challenging, even modest improvements in sensory and motor function can offer meaningful benefits and motivation for patients coping with this highly debilitating condition.
Integrated multi-omics profiling reveals the ZZZ3/CD70 axis is a super-enhancer-driven regulator of diffuse large B-cell lymphoma cell-natural killer cell interactions.
Li X, Cui J, Wang L … +2 more , Cao C, Liu H
Exp Biol Med (Maywood) · 2024 · PMID 39376717 · Full text
Tumor immune microenvironment is crucial for diffuse large B-cell lymphoma (DLBCL) development. However, the mechanisms by which super-enhancers (SEs) regulate the interactions between DLBCL cells and tumor-infiltrating...
Tumor immune microenvironment is crucial for diffuse large B-cell lymphoma (DLBCL) development. However, the mechanisms by which super-enhancers (SEs) regulate the interactions between DLBCL cells and tumor-infiltrating immune cells remains largely unknown. This study aimed to investigate the role of SE-controlled genes in regulating the interactions between DLBCL cells and tumor-infiltrating immune cells. Single-cell RNA-seq, bulk RNA-seq and H3K27ac ChIP-seq data were downloaded from the Heidelberg Open Research Data database and Gene Expression Omnibus database. HOMER algorithm and Seurat package in R were used for bioinformatics analysis. Cell proliferation and lactate dehydrogenase (LDH) release was detected by MTS and LDH release assays, respectively. Interaction between B cell cluster and CD8 T cell and NK cell cluster was most obviously enhanced in DLBCL, with CD70-CD27, MIF-CD74/CXCR2 complex, MIF-CD74/CD44 complex and CCL3-CCR5 interactions were significantly increased. NK cell sub-cluster showed the strongest interaction with B cell cluster. ZZZ3 upregulated the transcription of by binding to its SE. Silencing CD70 in DOHH2 cells significantly promoted the proliferation of co-cultured NK92 cells and LDH release from DOHH2 cells, which was counteracted by ZZZ3 overexpression in DOHH2 cells. CD70 silencing combined with PD-L1 blockade promoted LDH release from DOHH2 cells co-cultured with NK92 cells. In conclusion, DLBCL cells inhibited the proliferation and killing of infiltrating NK cells by regulating ZZZ3/CD70 axis. Targeting ZZZ3/CD70 axis combined with PD-L1 blockade is expected to be a promising strategy for DLBCL treatment.
Corrigendum: Genome-wide association study identifying variants related to performance and injury in high-performance athletes.
Ebert JR, Magi A, Unt E … +3 more , Prans E, Wood DJ, Koks S
Exp Biol Med (Maywood) · 2024 · PMID 39364093 · Full text
[This corrects the article DOI: 10.1177/15353702231198068.].
[This corrects the article DOI: 10.1177/15353702231198068.].
Development of a comprehensive open access "molecules with androgenic activity resource (MAAR)" to facilitate risk assessment of chemicals.
Dong F, Hardy B, Liu J … +7 more , Mohoric T, Guo W, Exner T, Tong W, Dohler J, Bachler D, Hong H
Exp Biol Med (Maywood) · 2024 · PMID 39364092 · Full text
The increasing prevalence of endocrine-disrupting chemicals (EDCs) and their potential adverse effects on human health underscore the necessity for robust tools to assess and manage associated risks. The androgen recepto...
The increasing prevalence of endocrine-disrupting chemicals (EDCs) and their potential adverse effects on human health underscore the necessity for robust tools to assess and manage associated risks. The androgen receptor (AR) is a critical component of the endocrine system, playing a pivotal role in mediating the biological effects of androgens, which are male sex hormones. Exposure to androgen-disrupting chemicals during critical periods of development, such as fetal development or puberty, may result in adverse effects on reproductive health, including altered sexual differentiation, impaired fertility, and an increased risk of reproductive disorders. Therefore, androgenic activity data is critical for chemical risk assessment. A large amount of androgenic data has been generated using various experimental protocols. Moreover, the data are reported in different formats and in diverse sources. To facilitate utilization of androgenic activity data in chemical risk assessment, the Molecules with Androgenic Activity Resource (MAAR) was developed. MAAR is the first open-access platform designed to streamline and enhance the risk assessment of chemicals with androgenic activity. MAAR's development involved the integration of diverse data sources, including data from public databases and mining literature, to establish a reliable and versatile repository. The platform employs a user-friendly interface, enabling efficient navigation and extraction of pertinent information. MAAR is poised to advance chemical risk assessment by offering unprecedented access to information crucial for evaluating the androgenic potential of a wide array of chemicals. The open-access nature of MAAR promotes transparency and collaboration, fostering a collective effort to address the challenges posed by androgenic EDCs.
Single-cell RNA sequencing data locate ALDH1A2-mediated retinoic acid synthetic pathway to glomerular parietal epithelial cells.
Liu WB, Fermin D, Xu AL … +2 more , Kopp JB, Xu Q
Exp Biol Med (Maywood) · 2024 · PMID 39360029 · Full text
Aldehyde dehydrogenase 1, family member A2, is a retinoic acid-synthesizing enzyme encoded by in mice and in humans. This enzyme is indispensable for kidney development, but its role in kidney physiology and pathophysi...
Aldehyde dehydrogenase 1, family member A2, is a retinoic acid-synthesizing enzyme encoded by in mice and in humans. This enzyme is indispensable for kidney development, but its role in kidney physiology and pathophysiology remains to be fully defined. In this review, we mined single-cell and single-nucleus RNA sequencing databases of mouse and human kidneys and found that glomerular parietal epithelial cells (PECs) express a full set of genes encoding proteins needed for cellular vitamin A uptake, intracellular transport, and metabolism into retinoic acid. In particular, mRNAs are selectively enriched in mouse and human PECs. expression in PECs is greatly increased in a mouse model of anti-glomerular basement membrane glomerulonephritis and moderately induced in a mouse model of ischemia-reperfusion acute kidney injury. expression in PECs is substantially repressed in a chronic kidney disease mouse model combining diabetes, hypertension, and partial nephrectomy and is moderately repressed in mouse models of focal segmental glomerulosclerosis and diabetic nephropathy. Single-nucleus RNA sequencing data show that mRNA expression in PECs is diminished in patients with chronic kidney disease associated with diabetes, hypertension and polycystic kidney disease. In addition to data mining, we also performed Spearman's rank correlation coefficient analyses and identified gene transcripts correlated with transcripts in mouse PECs and PEC subtypes, and in human PECs of healthy subjects and patients with AKI or CKD. Furthermore, we conducted Gene Ontology pathway analyses and identified the biological pathways enriched among these -correlated genes. Our data mining and analyses led us to hypothesize that ALDH1A2mediated retinoic acid synthesis in PECs plays a yet-undefined role in the kidney and that its dysregulation mediates injury. Conditional, PEC-selective knockout, RNA silencing and transgenic mouse models will be useful tools to test this hypothesis. Clinical studies on genetics, epigenetics, expression and functions of and other genes needed for retinoic acid biosynthesis and signaling are also warranted.
Experimental Biology and Medicine: a global journal with rigorous publication standards.
Goodman SR
Exp Biol Med (Maywood) · 2024 · PMID 39318792 · Full text
Abstract loading — click title to view on PubMed.
Collagen II enrichment through scAAV6-RNAi-mediated inhibition of matrix-metalloproteinases 3 and 13 in degenerative nucleus-pulposus cells degenerative disc disease and biological treatment strategies.
Mern DS, Thomé C
Exp Biol Med (Maywood) · 2024 · PMID 39286594 · Full text
Intervertebral disc (IVD) degeneration damaging the extracellular matrix (ECM) of IVDs is the main cause of spine-associated disorders. Degenerative disc disease (DDD) is a multifaceted disorder, where environmental fact...
Intervertebral disc (IVD) degeneration damaging the extracellular matrix (ECM) of IVDs is the main cause of spine-associated disorders. Degenerative disc disease (DDD) is a multifaceted disorder, where environmental factors, inflammatory cytokines and catabolic enzymes act together. DDD starts typically due to imbalance between ECM biosynthesis and degradation within IVDs, especially through unbalanced degradation of aggrecan and collagen II in nucleus pulposus (NP). Current treatment approaches are primarily based on conservative or surgical therapies, which are insufficient for biological regeneration. The disintegrins and metalloproteinases with thrombospondin motifs (ADAMTSs) and matrix metalloproteinases (MMPs) are the key proteolytic enzymes for degradation of aggrecan and collagens. Previously, high expression levels of ADAMTS4, ADAMTS5, MMP3 and MMP13, which are accompanied with low levels of aggrecan and collagen II, were demonstrated in degenerative human NP cells. Moreover, self-complementary adeno-associated virus type 6 (scAAV6) mediated inhibitions of ADAMTS4 and ADAMTS5 by RNA-interference (RNAi) could specifically enhance aggrecan level. Thus, MMPs are apparently the main degrading enzymes of collagen II in NP. Furthermore, scAAV6-mediated inhibitions of MMP3 and MMP13 have not yet been investigated. Therefore, we attempted to enhance the level of collagen II in degenerative NP cells by scAAV6-RNAi-mediated inhibitions of MMP3 and MMP13. MRI was used to determine preoperative grading of IVD degeneration in patients. After isolation and culturing of NP cells, cells were transduced with scAAV6-shRNAs targeting MMP3 or MMP13; and analysed by fluorescence microscopy, FACS, MTT assay, RT-qPCR, ELISA and western blotting. scAAV6-shRNRs have no impact on cell viability and proliferation, despite high transduction efficiencies (98.6%) and transduction units (1383 TU/Cell). Combined knockdown of MMP3 (92.8%) and MMP13 (90.9%) resulted in highest enhancement of collagen II (143.2%), whereby treatment effects were significant over 56 days ( < 0.001). Conclusively, scAAV6-RNAi-mediated inhibitions of MMP3 and MMP13 help to progress less immunogenic and enduring biological treatments in DDD.
Ultrasound-assisted laser therapy for selective removal of melanoma cells.
Subramanian Karthikesh M, Martinez-Rivera N, Rosa-Molinar E … +2 more , Wang X, Yang X
Exp Biol Med (Maywood) · 2024 · PMID 39170033 · Full text
The current study explores the potential of ultrasound-assisted laser therapy (USaLT) to selectively destroy melanoma cells. The technology was tested on an melanoma model, which was established by growing melanoma cell...
The current study explores the potential of ultrasound-assisted laser therapy (USaLT) to selectively destroy melanoma cells. The technology was tested on an melanoma model, which was established by growing melanoma cells in chicken breast tissue. Ultrasound-only and laser-only treatments were used as control groups. USaLT was able to effectively destroy melanoma cells and selectively remove 66.41% of melanoma cells in the tumor model when an ultrasound peak negative pressure of 2 MPa was concurrently applied with a laser fluence of 28 mJ/cm at 532 nm optical wavelength for 5 min. The therapeutic efficiency was further improved with the use of a higher laser fluence, and the treatment depth was improved to 3.5 mm with the use of 1,064 nm laser light at a fluence of 150 mJ/cm. None of the laser-only and ultrasound-only treatments were able to remove any melanoma cells. The treatment outcome was validated with histological analyses and photoacoustic imaging. This study opens the possibility of USaLT for melanoma that is currently treated by laser therapy, but at a much lower laser fluence level, hence improving the safety potential of laser therapy.
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