Qu HQ, Goel K, Ostberg K
… +10 more, Slater DJ, Wang F, Snyder J, Hou C, Eister G, Connolly JJ, March M, Glessner JT, Kao C, Hakonarson H
Exp Biol Med (Maywood)
· 2025 · PMID 40893145
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Natural Killer (NK) cells are integral components of the innate immune system, recognizing and eliminating virus-infected cells. They may play a crucial role in the immune response and contribute to the complications ass...Natural Killer (NK) cells are integral components of the innate immune system, recognizing and eliminating virus-infected cells. They may play a crucial role in the immune response and contribute to the complications associated with Single Ventricle/Hypoplastic Left Heart Syndrome (SV/HLHS). Utilizing single-cell RNA sequencing (scRNA-seq), NK cells from peripheral blood mononuclear cells (PBMCs) were analyzed in three de-identified SV/HLHS cases and three healthy controls. This study identified two novel NK cell subpopulations that could not be detected by conventional scRNA-seq pipelines or traditional flow cytometry. These subpopulations exhibit distinct gene expression profiles linked to the heterogeneity of immune responsiveness and stress adaptation in NK cells. In SV/HLHS patients, one cluster showed a significant upregulation of androgen response and downregulation of heme metabolism compared to healthy controls. Our study offers new insights into the fine-tuning of immune modulation that could help mitigate complications in SV/HLHS. It suggests that while NK cells in SV/HLHS adapt to support survival in a challenging physiological environment, these adaptations may compromise their ability to effectively respond to additional stresses, such as infections and inflammation.
Kumar A, Guo C, Sarumi Q
… +4 more, Courtney C, Campagna S, Richmond-Bryant J, Cormier SA
Exp Biol Med (Maywood)
· 2025 · PMID 40893144
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Open burn/open detonation (OB/OD) disposes of explosive waste via uncontrolled combustion, releasing harmful pollutants like toxic gases and particulate matter. Colfax, Louisiana, houses the nation's only commercially OB...Open burn/open detonation (OB/OD) disposes of explosive waste via uncontrolled combustion, releasing harmful pollutants like toxic gases and particulate matter. Colfax, Louisiana, houses the nation's only commercially OB/OD thermal treatment (TT) facility, raising concerns about environmental and public health impacts due to its emissions. In this exploratory pilot study, we investigated metabolic alterations indicative of potential health impacts from exposure to emissions from a TT facility through an untargeted metabolomics analysis of urine samples obtained from local residents. Urine samples were collected from 51 residents living within a 30-km radius of the facility, with proximity, race, and sex as key variables. Samples were analyzed using ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry (UHPLC-HRMS) to identify metabolic alterations and potential biomarkers of exposure. A total of 217 metabolites were identified, with significant differences in abundance based on proximity to the facility. Key metabolic pathways affected included energy metabolism, amino acid metabolism, and oxidative stress-related pathways. Metabolites associated with oxidative stress, such as glutathione sulfonamide (GSA), were elevated in individuals residing closer to the facility, indicating increased oxidative stress. Alterations in the glutathione/glutathione disulfide (GSH/GSSG) ratio further highlighted redox imbalances. Pathway enrichment analyses revealed perturbations in glycolysis, citric acid cycle, sulfur metabolism, and nucleotide metabolism, which are linked to critical biological functions like energy production and DNA repair. Notable differences in metabolite profiles were also observed between sexes and racial groups, pointing to the interplay of intrinsic biological and environmental factors. These findings demonstrate that exposure to emissions from the TT facility may have significant impacts on human health, including disruptions in cellular metabolism and increased oxidative stress. Further research is crucial to understand the long-term health implications of these metabolic alterations and to develop strategies to mitigate the environmental and health risks associated with this facility.
Yanamadala Y, Muthumula CMR, Gokulan K
… +5 more, Karn K, Sutherland V, Cunny H, Santos JH, Khare S
Exp Biol Med (Maywood)
· 2025 · PMID 40881189
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The antiretroviral (ARV) drug combination of abacavir sulfate, dolutegravir, and lamivudine [ABC/DTG/3TC; Tri combination Anti-retroviral therapy (TC-ART)] has revolutionized HIV treatment by effectively targeting differ...The antiretroviral (ARV) drug combination of abacavir sulfate, dolutegravir, and lamivudine [ABC/DTG/3TC; Tri combination Anti-retroviral therapy (TC-ART)] has revolutionized HIV treatment by effectively targeting different stages of viral replication. Despite its therapeutic efficiency for maintaining low viremia in the mother during pregnancy, there are concerns for long-term liabilities in offspring that are indirectly exposed during vulnerable periods of development. The commensal microbiota plays a crucial role in maintaining overall gut health, and disruption of the microbiome is often linked to various extraintestinal effects such as immune dysregulation and inflammation. We recently reported the effects of this drug combination in altering fecal microbiome composition of aged rats perinatally exposed to ABC/DTG/3TC-ART. The fecal microbiome can provide only a snapshot of the composition of microbial community at the end of the digestive tract, which may not reflect the microbial population interacting with ileal mucosa. Thus, the current work reports the effects of this drug combination in the gut mucosa-associated microbiome of the same animals, which showed significant microbial diversity and species richness in high dose exposed female adult offspring, along with dose-dependent changes in Firmicutes/Bacteroidetes ratio. The high dose exposure also showed an increase in opportunistic bacterial species in male animals. Overall, we found that, similar to the fecal microbiome, perinatal exposure to TC-ART led to sex- and dose-dependent alterations in the gut mucosa-associated microbial population in aged rats, suggesting that early life exposure to these drugs may influence gut mucosa-associated immune responses and intestinal permeability.
Ma X, Xu J, Sun H
… +5 more, Liu J, Xia S, Zhang H, Cui C, Song C
Exp Biol Med (Maywood)
· 2025 · PMID 40851915
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Advanced glycation end products (AGEs) have been associated with vascular pathologies including abdominal aortic aneurysms (AAAs), although their causal role remains unclear. In this study, we observed significant accumu...Advanced glycation end products (AGEs) have been associated with vascular pathologies including abdominal aortic aneurysms (AAAs), although their causal role remains unclear. In this study, we observed significant accumulation of AGEs in human AAAs, particularly in cases associated with intraluminal thrombus (ILT). , AGE exposure induced vascular smooth muscle cell (VSMC) migration and suppressed contractility, accompanied by reduced expression of contractile markers (α-SMA and MYH11) and elevated MMP-2. This phenotypic transformation was linked to the activation of the NLRP3 inflammasome and RAGE/RhoA/ROCK signaling, and was reversible upon inhibition of RAGE, RhoA, or ROCK. In macrophages, AGE pretreatment had minimal effects on basal cytokine secretion but attenuated LPS-induced IL-6 and IL-1β release and NF-κB activation. Co-culture experiments further revealed that AGE-pretreated macrophages reduced LPS-driven pro-migratory effects on VSMCs. Spatial transcriptomics demonstrated enriched AGE-RAGE signaling in αSMA+ VSMCs and CD68+αSMA+ macrophage-like VSMCs in ILT-containing AAAs. Overall, these associative findings implicate AGE-RAGE signaling in AAA pathogenesis and warrant further investigation to establish causality.
Li C, Lu Y, Chen M
… +4 more, Zhang Q, Zhang Z, Xi W, Yang W
Exp Biol Med (Maywood)
· 2025 · PMID 40831670
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Cataract is the leading cause of blindness globally, imposing a significant socioeconomic burden. While diet is associated with various eye diseases, the causal relationship between dietary-related characteristics (DRCs)...Cataract is the leading cause of blindness globally, imposing a significant socioeconomic burden. While diet is associated with various eye diseases, the causal relationship between dietary-related characteristics (DRCs) and cataract remains unclear. This study investigates the causal associations between DRCs and cataract using Mendelian randomization (MR) to provide insights into potential dietary interventions for cataract prevention. We conducted a two-sample MR analysis using data from the open GWAS database, focusing on individuals of European descent. Instrumental variables were selected based on stringent criteria, and multiple MR methods were applied to estimate causal effects. Sensitivity analyses assessed the robustness of the findings. Significant causal associations were found between oily fish intake (OR = 0.86) and variation in diet (OR = 1.26) with cataract. Sensitivity analyses supported the robustness of these findings. Mediation effect analysis suggested that the intake of oily fish might indirectly influence cataract risk through metabolites. This study provides evidence for causal relationships between specific DRCs and cataract, highlighting the potential role of dietary interventions in cataract prevention.
Godinho IP, Dória ÍF, Rocha VM
… +7 more, Miranda BA, Salomão LFC, Stancioli B, Paim AAO, Coelho Dos Reis JGA, Pereira SH, da Fonseca FG
Exp Biol Med (Maywood)
· 2025 · PMID 40776978
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The Oropouche virus (OROV), an arbovirus transmitted primarily by the midge, has caused significant outbreaks in the Americas, especially in the Amazon region. The virus's spread is closely linked to a combination of en...The Oropouche virus (OROV), an arbovirus transmitted primarily by the midge, has caused significant outbreaks in the Americas, especially in the Amazon region. The virus's spread is closely linked to a combination of environmental, climatic, and ecological factors. These include deforestation, urbanization, and changes in rainfall patterns, which influence the proliferation of vectors, and, consequently, increase the chances of mutations and reassortment events to occur. In 2024 and 2025, the number of OROV cases increased significantly, with outbreaks extending beyond the traditionally endemic Amazon region, highlighting the growing geographic expansion of the disease throughout Brazil. Despite its growing dispersion, diagnostic and therapeutic tools for OROV remain limited. Current diagnostic strategies rely almost exclusively on molecular detection methods, and there are no vaccines for effective prevention. Additionally, immunological responses to OROV infection are not fully understood, and further studies are needed. The ecological dynamics influencing OROV transmission, particularly the role of environmental changes in shaping vector populations, highlight the need for more integrated surveillance and control strategies. The ongoing expansion of OROV outside its traditional hotspots may be indicative of broader environmental shifts that facilitate viral spread. Therefore, continuous monitoring of both environmental and epidemiological data is crucial to understanding and mitigating the impact of OROV in the future. Collaborative efforts among researchers, policymakers, and local communities will be essential to prevent further outbreaks and minimize the health burden caused by OROV. This review summarizes important and up-to-date data information to the ongoing epidemic of Oropouche fever, focusing on topics that are particularly important to Public Health.
Gulley Cox LI, Dias N, Zhang C
… +2 more, Zhang Y, Gorniak SL
Exp Biol Med (Maywood)
· 2025 · PMID 40776977
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The focus of this study was to evaluate motor unit number and size across the upper extremity in older adults (aged 60+ years) versus young healthy adults (aged 20-30 years). We hypothesized that older adults would have:...The focus of this study was to evaluate motor unit number and size across the upper extremity in older adults (aged 60+ years) versus young healthy adults (aged 20-30 years). We hypothesized that older adults would have: fewer motor units and increased motor unit size as compared to young healthy adults (H1), that motor unit size would differ across the upper extremity muscles as compared to young healthy adults (H2), and higher body mass index (BMI) would be associated with lower motor unit numbers (H3). Compound muscle action potential (CMAP), motor unit number index (MUNIX), and motor unit size index (MUSIX) were evaluated in five muscles of the upper extremity. Group differences in CMAP due to aging were accounted for by increased body mass index (BMI); group differences in MUSIX were not impacted by BMI. No difference in MUNIX was found; however, an influence of BMI was found across groups. While this data provides supporting evidence of age-related motor unit changes, body composition changes with age may confound these conclusions when surface electromyography is utilized as the measurement modality. Adiposity estimation should be considered in future EMG studies, particularly in populations with higher BMI values.
Shymanskyi I, Lisakovska O, Veliky M
… +7 more, Mezhenska O, Bilous V, Siromolot A, Khomenko A, Labudzynskyi D, Horid'ko T, Pasichna E
Exp Biol Med (Maywood)
· 2025 · PMID 40776976
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Our objective was to study the effect of vitamin D (VD) on hepatocellular oxidative-nitrosative stress and pro/anti-inflammatory cytokines in relation to nitric oxide (NO) formation and NO synthase (NOS) levels in type 2...Our objective was to study the effect of vitamin D (VD) on hepatocellular oxidative-nitrosative stress and pro/anti-inflammatory cytokines in relation to nitric oxide (NO) formation and NO synthase (NOS) levels in type 2 diabetes mellitus (T2DM). After T2DM induction by high-fat diet and a single streptozotocin injection (25 mg/kg b. w.), male Wistar rats were treated with/without VD (1,000 IU/kg b. w., 30 days). Oxidative stress/inflammation and NOS/NO were assessed by flow cytometry, RT-qPCR, western blotting, and ELISA. A 3.3-fold decrease in serum 25(OH)D was established in diabetic rats, suggesting their VD deficient status. T2DM was associated with excess reactive oxygen species (ROS; 2.4-fold) and NO (2.5-fold) production in hepatocytes paralleled by elevated levels of myeloperoxidase (1.7-fold), carbonylated (2.8-fold) and nitrotyrosylated (1.7-fold) proteins in liver tissue vs. control, indicative of oxidative-nitrosative stress. Low-grade inflammation in diabetic liver was confirmed by increased NF-κB transcriptional activity (1.24-fold) and mRNA expression of proinflammatory cytokines TNF-α (3.5-fold) and IL-1β (2.2-fold) with alleviating mRNAs of anti-inflammatory cytokines IL-4 (1.7-fold) and IL-10 (2.6-fold), while TGF-β1 expression raised 1.4-fold vs. control. Higher iNOS and eNOS mRNAs (2.7- and 3.3-fold, respectively) and protein (2.1- and 3.2-fold, respectively) levels, as well as NOS activity (1.6-fold) were found in diabetic liver. VD supplementation restored 25(OH)D, partially normalized NF-κB transcriptional activity and pro/anti-inflammatory cytokines, lowered hepatocellular ROS/NO, and oxidative protein modifications. However, VD had no effect on eNOS, IL-10 and TGF-β1 mRNAs. It also led to a further increase in myeloperoxidase, eNOS and iNOS proteins and NOS activity compared to diabetes. In conclusion, abnormal oxidative metabolism in T2DM is associated with enhanced NF-κB/NOS/NO response, which can be partially attenuated by VD treatment via normalization of pro-oxidative/pro-inflammatory processes. The paradoxical sustained increase in NOS expression in the presence of VD antioxidant activity likely improves hepatocellular NO bioavailability, ultimately reducing T2DM-associated liver injury.
Partey FD, Pobee ANA, Damptey IK
… +11 more, Osei F, Owusu-Amponsah MMAK, Ansah YAA, Ye C, Bradfute S, Hurwitz I, Quashie PK, Ofori MF, Kusi AK, Perkins DJ, Awandare GA
Exp Biol Med (Maywood)
· 2025 · PMID 40761773
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COVID-19 booster vaccinations are needed to enhance waning immunity and the emergence of new variants. In Africa, where COVID-19 vaccine coverage is low, there is a paucity of data on COVID-19 vaccine-induced immunity, p...COVID-19 booster vaccinations are needed to enhance waning immunity and the emergence of new variants. In Africa, where COVID-19 vaccine coverage is low, there is a paucity of data on COVID-19 vaccine-induced immunity, particularly in the post-omicron era. This study examined the functional activity of vaccine-induced antibody responses against different variants before and after booster vaccinations in adults in Ghana, between November 2022 and February 2023. SARS-CoV-2 nucleocapsid protein and spike receptor binding domain (RBD) antigen-specific IgG levels against different viral variants were determined in plasma. Plasma was tested for the ability to inhibit ACE-2 binding to RBD variants. N antigen-specific antibody levels were comparable between vaccinated and previously infected, but unvaccinated individuals. However, RBD IgG levels before booster vaccinations were significantly higher in vaccinated participants than in exposed, unvaccinated individuals, except for Omicron. RBD IgG levels remained unchanged after the booster in participants with three prior vaccine doses but were significantly higher than in those with only primary vaccinations (Wild type p = 0.0315, Alpha p = 0.0090, Beta p = 0.0020, Delta p = 0.0040) except Omicron (p = 0.09). Participants who received the Pfizer-BioNTech vaccine showed a significant increase (p < 0.05) in RBD IgG levels against all tested variants from baseline to 3 months. In contrast, participants who received the J&J vaccine only showed a significant increase in RBD IgG to Wildtype (p = 0.04), Alpha (p < 0.0001), and Beta (p < 0.0001), but not Delta and Omicron. The inhibition of ACE-2 binding and live virus neutralization titers were significantly higher in vaccinated individuals than in unvaccinated individuals before the booster (p < 0.001). Virus neutralization titers against Wildtype were significantly high 3 months after booster (p < 0.001), but neutralization titers against Omicron remained stable from baseline to 3 months after booster. Extended interval between vaccinations may enhance vaccine-induced antibody responses.
Sabetta E, Rallmann K, Bergquist J
… +6 more, Taba P, Pfaff AL, Poudel BH, Ferrari D, Locatelli M, Kõks S
Exp Biol Med (Maywood)
· 2025 · PMID 40746751
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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder presenting progressive weakness of the bulbar and extremity muscles, leading to a wide-ranging clinical phenotype. More than 30 genes have been associat...Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder presenting progressive weakness of the bulbar and extremity muscles, leading to a wide-ranging clinical phenotype. More than 30 genes have been associated to genetically inherited ALS yet, approximately 85%-90% of ALS cases are sporadic. Short tandem repeats expansions, have recently been found in clinically diagnosed ALS patients and are currently investigated as potential genetic biomarkers. In this paper we compare the investigation of pathological tandem repeat expansions on a group of ALS patients by comparing the standard short-read sequencing (SRS) technique with a long-read-sequencing (LRS) method which has recently become more accessible. Blood samples from 47 sporadic ALS cases were subjected to SRS by Illumina Whole Genome Sequencing. The genome-wide tandem repeat expansions were genotyped using GangSTR, while wANNOVAR was used for variant annotation. Uncertain cases were further explored using LRS. SRS identified pathological expansions in , , and genes in one patient, which were not confirmed with LRS. The latter identified large tandem repeat expansions in the C9orf72 gene of one patient that were missed by SRS. Our findings suggest that LRS should be preferred to SRS for accurate identification of pathological tandem repeat expansions.
Zhang LL, Wang Z, Zhou Y
… +5 more, Li DY, Tu XN, Li YX, Du KM, Zheng ZZ
Exp Biol Med (Maywood)
· 2025 · PMID 40718649
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Accurate identifying internal tandem duplication (ITD) mutation is indispensable for diagnosis and prognosis of acute myeloid leukemia (AML) patients, but specialized full-size detection tools are lacking. Therefore, we...Accurate identifying internal tandem duplication (ITD) mutation is indispensable for diagnosis and prognosis of acute myeloid leukemia (AML) patients, but specialized full-size detection tools are lacking. Therefore, we aimed to develop a reliable system for accurate assessment of ITD mutations of various size ranges and improve prognosis for AML. Bone marrow samples from AML patients from December 2021 to March 2022 were collected for methodology establishment. After a large-scale sample testing by next-generation sequencing (NGS), a short-read tandem duplication recognition system based on soft-clip was established. During performance validation, the lower detection limit was set to a parameter close to capillary electrophoresis ("gold standard") by adjusting reference values (sensitivity 3-5%). Data simulation was performed using the FLT3 gene CDS as wild-type data. Methodological concordance of this system with capillary electrophoresis was analyzed. The applicability to other pathogenic tandem duplication mutations was validated. We have developed an innovative NGS-based system named "ITDFinder" for accurate detection of ITD mutations, with the lower detection limit of 4%, corresponding to a sequencing depth of 1000X. Compared to capillary electrophoresis, ITDFinder exhibited good consistency (mean difference: -0.0085) in mutation detection and correlation across various length of ITD. Clinical case validation (n = 1,032) showed an overall agreement rate of 96.5% between the two approaches used for characterization. In addition, data simulation results suggested that the new system could observe BCOR-ITD and KMT2A-PTD mutations (depths, 500-1300X; mutation rates, 0.04-0.8). The innovative mutation detection system is appropriate to small-to large-sized ITDs and other pathogenic tandem duplication mutations, expected to save 96.3% of the workload. This offers significant potential for accurate clinical assessment of ITD mutations and subsequent prognosis in AML patients.
Zhao X, Yang Y, Du X
… +4 more, Li L, Hou C, Cai Y, Ma X
Exp Biol Med (Maywood)
· 2025 · PMID 40666727
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As an inflammatory disease, atherosclerosis is associated with acute ischemic stroke (AIS), but its early identification and intervention efficacy remain suboptimal. A new research direction may be to explore peripheral...As an inflammatory disease, atherosclerosis is associated with acute ischemic stroke (AIS), but its early identification and intervention efficacy remain suboptimal. A new research direction may be to explore peripheral atherosclerotic biomarkers from the perspective of mitochondrial dysfunction, which can induce inflammatory cell activation. Moreover, the degree of overall cervicocephalic atherosclerosis (namely, atherosclerotic burden) is more closely related to AIS prognosis than local atherosclerotic lesions. Therefore, this study investigated the relationship between mitochondrial dysfunction in peripheral blood mononuclear cells (PBMCs), including monocytes and lymphocytes, and overall cervicocephalic atherosclerotic burden and AIS outcome. Patients with AIS and cervicocephalic atherosclerosis were enrolled and followed up for 90 days. The reactive oxygen species (ROS) and the mitochondrial deoxyribonucleic acid copy number (mtDNA-CN) in PBMCs were measured respectively through a fluorescence probe and a droplet digital polymerase chain reaction to evaluate mitochondrial function. The overall intracranial and cervical atherosclerotic burden (ICAB) was quantified by summing up the atherosclerosis degree points in each arterial segment as assessed by computed tomography angiography. A modified Rankin Scale (mRS) score >2 was considered a 90-day unfavorable functional outcome. Five (4.9%) of the 103 patients with AIS were lost to follow-up. mtDNA-CN [adjusted β = -0.099, 95% confidence intervals (CIs) = -0.153 ∼ -0.044, < 0.001] and ROS content (adjusted β = 1.275, 95%CI = 0.885 ∼ 1.665, < 0.001) were correlated with ICAB. The risk of a 90-day unfavorable functional outcome increased with higher ROS content [adjusted odds ratio (OR) = 1.523, 95%CI = 1.172 ∼ 1.981, = 0.002] and decreased with higher mtDNA-CN (adjusted OR = 0.911, 95%CI = 0.850 ∼ 0.976, = 0.008). PBMC mitochondrial dysfunction was found to be independently associated with extensive and severe cervicocephalic atherosclerosis and a 90-day unfavorable functional outcome in patients with AIS, which may provide a novel approach to improving the early identification and risk stratification of cervicocephalic atherosclerosis, along with the prediction of the outcome of atherosclerotic AIS.
Exp Biol Med (Maywood)
· 2025 · PMID 40661101
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Peripheral nerve trauma commonly results in chronic neuropathic pain by up-regulating the synthesis and release of pro-inflammatory mediators from local and invading cells and inducing hyperexcitability of nociceptive ne...Peripheral nerve trauma commonly results in chronic neuropathic pain by up-regulating the synthesis and release of pro-inflammatory mediators from local and invading cells and inducing hyperexcitability of nociceptive neurons and spontaneous electrical activity. The pain decreases when these cells down-regulate genes supporting the pro-inflammatory state, up-regulate genes for expressing anti-inflammatory factors, and modulate genes that reduce nociceptive neuron spontaneous electrical activity. Pharmacological agents, the primary technique for reducing pain, do not eliminate pain, and <50% of patients achieve benefits because they do not address the underlying causes of pain. Alternative techniques providing longer lasting, but not complete or long-term pain relief include surgical interventions, electrical stimulation, and antibody treatment. Anti-inflammatory mediators can reduce pain, but the effect is not complete or long-lasting. Platelet-rich plasma (PRP) contains a readably available evolutionarily developed cocktail of factors that induce longer-lasting and more significant, but not complete, pain relief than other techniques. However, a novel study shows that unique formulations of PRP can induce long-term pain elimination. This review examines (1) the efficacy of drugs, regenerative peripheral nerve interface (RPNI), targeted muscle reinnervation (TMR), and PRP in reducing chronic neuropathic pain, (2) recent clinical data showing that a novel PRP application technique induces long-term chronic neuropathic pain reduction/elimination, and (3) discusses why the novel PRP may be more effective in reducing/eliminating chronic neuropathic pain.
Wang C, Sun J, Donakonda R
… +6 more, Beger R, Latham LE, Wu L, Liu S, Hanig JP, Liu F
Exp Biol Med (Maywood)
· 2025 · PMID 40636749
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Fentanyl is a potent and short-acting opioid that is often given to pediatric patients during surgery to relieve pain and as an adjunct to anesthesia. Its effects on the developing brain are yet to be determined. In the...Fentanyl is a potent and short-acting opioid that is often given to pediatric patients during surgery to relieve pain and as an adjunct to anesthesia. Its effects on the developing brain are yet to be determined. In the present study, commercially available human neural stem cells (NSCs) were used to model the effects of fentanyl on the developing human brain. We determined the dose dependent effects and temporal relationships between fentanyl exposures and NSC health, viability, and differentiation. Markers of mitochondrial health [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetra-zolium bromide (MTT)] and cell death/damage [lactate dehydrogenase (LDH)] were monitored to determine the dose response effects of fentanyl on NSC viability. In addition, lipidomics analysis was conducted to investigate lipid profile changes in differentiated neural cells treated with fentanyl. Fentanyl did not cause a significant increase in LDH release, nor MTT reduction after 24-h exposure at concentrations of 0.5, 1.0, 3.0, 10, or 100 μM, for both NSCs and differentiated neural cells. Lipidomics data showed the top 15 most variable important in projection (VIP) lipid species (the higher the VIP scores, the bigger changes in treated groups vs. controls), including lysophosphatidylcholines (LPCs), lysophosphatidylethanolamines (LPEs), ceramides (CER), cholesterol esters (ChEs) and sphingosine (SPH). The lipidomic data indicate that LPC (16:0), LPC (16:1), LPC (18:1), CER (d18:0_22:0), CER (d18:2_18:0), CER(d18:2_24:1) were significantly increased, and only ChE (24:5) and SPH (d18:1) were significantly decreased in the highest dose group versus control. These data indicated that fentanyl exposure (24-h) did not induce detectable cell death. However, a lipidomic analysis indicated that fentanyl may affect immature neural cell functions through modifying lipid composition and lipid metabolism. These data indicated that despite the absence of clear neurodegeneration, fentanyl may still have a negative impact on the developing brain.
Asuzu P, Feto NA, Wan J
… +3 more, Stentz F, Mandal N, Dagogo-Jack S
Exp Biol Med (Maywood)
· 2025 · PMID 40630937
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Ceramides and other sphingolipids are associated with diabetes risk. Here, we examined the association of plasma sphingolipids with insulin sensitivity and secretion in people without diabetes. We enrolled adults without...Ceramides and other sphingolipids are associated with diabetes risk. Here, we examined the association of plasma sphingolipids with insulin sensitivity and secretion in people without diabetes. We enrolled adults without diabetes based on 75-g oral glucose tolerance test. Assessments included clinical examination, insulin sensitivity (hyperinsulinemic euglycemic clamp), and insulin secretion (intravenous glucose tolerance test). Plasma levels of 58 sphingolipid species (including ceramides, monohexosylceramides, sphingomyelins, and sphingosine) were assayed using liquid chromatography tandem mass spectrometry. The study participants (N = 240; 129 Black, 111 White) had a mean age of 43.1 ± 12.0 y, body mass index (BMI) 29.4 ± 6.23 kg/m, fasting plasma glucose 91.4 ± 6.91 mg/dL, and 2-h plasma glucose 123 ± 26.3 mg/dL. Several of the 58 SPLs species assayed showed variable associations with insulin sensitivity (r = 0.17-0.35, P = 0.039 - <0.0001) and secretion (r = 0.14-0.27; P = 0.038 - <0.0001). After correction for multiple testing, plasma levels of very-long-chain (VLC) monohexosylceramide C34:0 (r = 0.31 - 0.43, P < 0.0001) and VLC sphingomyelins C28-C34 (r = 0.31-0.35, P = 0.0004 - <0.0001) were significantly associated with insulin sensitivity. Plasma VLC sphingomyelin level were inversely associated with insulin secretion, plasma glucose, BMI, and waist circumference. We conclude that circulating VLC sphingomyelins are associated positively with insulin action and inversely with insulin secretion and adiposity in normoglycemic adults, indicating a possible link to glucoregulation that precedes the development of dysglycemia.
Winkens T, Schweitzer P, Perkas O
… +5 more, Kühnel C, Ndum F, Pomraenke M, Greiser J, Freesmeyer M
Exp Biol Med (Maywood)
· 2025 · PMID 40612332
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In-ovo imaging using ostrich eggs has been described as an alternative to animal testing using rodents. This approach is not considered an animal experiment and it does not require small-animal imaging devices as ostrich...In-ovo imaging using ostrich eggs has been described as an alternative to animal testing using rodents. This approach is not considered an animal experiment and it does not require small-animal imaging devices as ostrich eggs provide good image quality on regular CT, MRI or PET used in humans. The aims of this study were 1) to describe methods of radiopharmaceutical injection, 2) to explore normal biodistribution of F-18-FDG during a 60-min list-mode-PET/CT examination and 3) to compare biodistribution in-ovo to existing literature considering chicken and rodents. Vessel access was successful in 54/78 ostrich eggs. Highest FDG-uptake was observed in epiphyseal plates (0.36 ± 0.06 IA%/g; range 0.29-0.48 IA%/g) and brain (0.25 ± 0.05 IA%/g; range 0.21-0.36 IA%/g). activity distribution on PET and activity distribution (well counter) showed comparable results (Spearman's Rho range 0.795-0.882). No significant differences were observed regarding previous isoflurane exposure. Normal biodistribution of F-18-FDG in ostrich embryos using a standard PET/CT system for humans was mainly found as expected with highest uptake in epiphyseal plates and brain which is comparable to results on rodents and chicken embryos. Isoflurane anesthesia did not reveal significant differences regarding organ uptake. The results of this normal distribution study allow for interpretation of future disease models (inflammation, tumor) in ostrich embryos using F-18-FDG as radiopharmaceutical.