Plasma Levels Research Articles

Exploring the relationship between the interleukin family and lung adenocarcinoma through Mendelian randomization and RNA sequencing analysis

BackgroundLung adenocarcinoma (LUAD) is still one of the most prevalent malignancies. Interleukin factors are closely associated with the initiation and progression of cancer. However, the relationship between interleukin factors and LUAD has not been fully elucidated. This study aimed to use Mendelian randomization (MR) and RNA sequencing (RNA-seq) analyses to identify the interleukin factors associated with the onset and progression of LUAD.MethodsExposure-related instrumental variables were selected from interleukin factor summary datasets. The LUAD summary dataset from FINGENE served as the outcome. MR and sensitivity analyses were conducted to screen for interleukin factors associated with LUAD occurrence. Transcriptome analyses revealed the role of interleukin factors in lung tissues. The results were validated through Western blotting and further confirmed with driver gene-negative patients from multiple centers. Potential mechanisms influencing LUAD occurrence and development were explored using bulk RNA-seq and single-cell RNA-seq data.ResultsMR analysis indicated that elevated plasma levels of IL6RB, IL27RA, IL22RA1, and IL16 are causally associated with increased LUAD risk, while IL18R1 and IL11RA exhibit the opposite effect. Transcriptome analyses revealed that IL11RA, IL18R1, and IL16 were downregulated in tumor tissues compared with normal lung tissue, but only higher expression of IL11RA correlated with improved prognosis in patients with LUAD from different centers and persisted even in driver-gene negative patients. The IL11RA protein level was lower in various LUAD cell lines than in human bronchial epithelial cells. The genes co-expressed with IL11RA were enriched in the Ras signaling pathway and glycosylation processes. Fibroblasts were the primary IL11RA-expressing cell population, with IL11RA+fibroblasts exhibiting a more immature state. The genes differentially expressed between IL11RA+and IL11RA- fibroblasts were involved in the PI3K-Akt/TNF signaling pathway.ConclusionAccording to the MR and transcriptome analyses, the downregulation of IL11RA was closely related to the occurrence and development of LUAD.Graphical

Association between blood-based protein biomarkers and brain MRI in the Alzheimer's disease continuum: a systematic review.

Blood-based biomarkers (BBM) are becoming easily detectable tools to reveal pathological changes in Alzheimer's disease (AD). A comprehensive and up-to-date overview of the association between BBM and brain MRI parameters is not available. This systematic review aimed to summarize the literature on the associations between the main BBM and MRI markers across the clinical AD continuum. A systematic literature search was carried out on PubMed and Web of Science and a total of 33 articles were included. Hippocampal volume was positively correlated with Aβ42 and Aβ42/Aβ40 and negatively with Aβ40 plasma levels. P-tau181 and p-tau217 concentrations were negatively correlated with temporal grey matter volume and cortical thickness. NfL levels were negatively correlated with white matter microstructural integrity, whereas GFAP levels were positively correlated with myo-inositol values in the posterior cingulate cortex/precuneus. These findings highlight consistent associations between various BBM and brain MRI markers even in the pre-clinical and prodromal stages of AD. This suggests a possible advantage in combining multiple AD-related markers to improve accuracy of early diagnosis, prognosis, progression monitoring and treatment response.

Glucagon receptor activation contributes to the development of kidney injury.

The underlying causes of diabetic kidney disease are still largely unknown. New insights into the contributing causes of diabetic nephropathy are important in order to prevent this complication. Hyperglycemia and hypertension are some of the risk factors for diabetic nephropathy. However, the incidence of diabetic nephropathy is increasing despite efforts to normalize blood-glucose levels and blood pressure. Therefore, other factors should be investigated as causes of diabetic nephropathy. We investigated whether long-term increased plasma levels of glucagon contribute to the development of pathophysiological changes in kidney function as seen in patients with diabetic nephropathy. Using mouse models of chronic activation and inactivation of glucagon receptor signaling, we investigated whether glucagon is involved in changes in renal function, renal structural and transcriptional changes. We found several histopathological changes in the kidney, such as thickening of the parietal layer of Bowman's capsule, glomerular mesangial cell expansion, and significant albuminuria in the mice with activated glucagon receptor signaling. Opposite effects on mesangial area expansion and the development of albuminuria were demonstrated in mice with glucagon receptor inactivation. RNA sequencing data revealed that transcription of genes related to fatty acid metabolism, podocytes, Na+/K+-ATPase, and sodium/glucose transport were significantly changed in mice with activated glucagon receptor signaling. These data implicate that the glucagon receptor signaling is involved in the development of kidney injury, as seen in type 2 diabetes and that glucagon receptor is a potential therapeutic target in the treatment of diabetes.

Pharmacokinetics of Psilocybin, a Tryptamine Alkaloid in Magic Mushroom (Psilocybe cubensis): A Systematic Review

ABSTRACT Psilocybin, a major indole alkaloid found in magic mushrooms (Psilocybe cubensis), has recently drawn attention as a breakthrough therapy to treat major depressive disorder. This review aimed to summarize and identify knowledge gaps concerning their pharmacokinetic characteristics of psilocybin and its active metabolite, psilocin. Original studies related to pharmacokinetics of psilocybin conducted in vitro, animals, and humans were systematically collected from PubMed, Scopus, and ScienceDirect, from their inceptions to November 2023. Twenty articles were included in this work and assessed for study quality. A comprehensive review of the pharmacokinetics of psilocybin and psilocin in both animals and humans was performed. Psilocybin is considered a prodrug that is dephosphorylated to psilocin by alkaline phosphatase. Following ingestion, the peak psilocin plasma and brain levels were rapidly achieved in a dose-dependent manner. Psilocin is metabolized primarily through both Phase I and Phase II processes with the half-life of 2–3 hours. This review also identified lack of some pharmacokinetic related information and limitations of available research that may help direct future investigations to better understand the pharmacokinetics and improve study design including dose selection and dosage optimization.

Factor XII signaling via uPAR-integrin β1 axis promotes tubular senescence in diabetic kidney disease

Coagulation factor XII (FXII) conveys various functions as an active protease that promotes thrombosis and inflammation, and as a zymogen via surface receptors like urokinase-type plasminogen activator receptor (uPAR). While plasma levels of FXII are increased in diabetes mellitus and diabetic kidney disease (DKD), a pathogenic role of FXII in DKD remains unknown. Here we show that FXII is locally expressed in kidney tubular cells and that urinary FXII correlates with kidney dysfunction in DKD patients. F12-deficient mice (F12-/-) are protected from hyperglycemia-induced kidney injury. Mechanistically, FXII interacts with uPAR on tubular cells promoting integrin β1-dependent signaling. This signaling axis induces oxidative stress, persistent DNA damage and senescence. Blocking uPAR or integrin β1 ameliorates FXII-induced tubular cell injury. Our findings demonstrate that FXII-uPAR-integrin β1 signaling on tubular cells drives senescence. These findings imply previously undescribed diagnostic and therapeutic approaches to detect or treat DKD and possibly other senescence-associated diseases.

S100A9 and HMGB1 orchestrate MDSC-mediated immunosuppression in melanoma through TLR4 signaling

BackgroundImmunotherapies for malignant melanoma are challenged by the resistance developed in a significant proportion of patients. Myeloid-derived suppressor cells (MDSC), with their ability to inhibit antitumor T-cell responses, are a...

Preparation and Preclinical Characterization of a Simple Ester for Dual Exogenous Supply of Lactate and Beta-hydroxybutyrate.

Elevation of the plasma levels of (S)-lactate (Lac) and/or (R)-beta-hydroxybutyrate (BHB) occurs naturally in response to strenuous exercise and prolonged fasting, respectively, resulting in millimolar concentrations of these two metabolites. It is increasingly appreciated that Lac and BHB have wide-ranging beneficial physiological effects, suggesting that novel nutritional solutions, compatible with high-level and/or sustained consumption, which allow direct control of plasma levels of Lac and BHB, are of strong interest. In this study, we present a molecular hybrid between (S)-lactate and the BHB-precursor (R)-1,3-butanediol in the form of a simple ester referred to as LaKe. We show that LaKe can be readily prepared on the kilogram scale and undergoes rapid hydrolytic conversion under a variety of physiological conditions to release its two constituents. Oral ingestion of LaKe, in rats, resulted in dose-dependent elevation of plasma levels of Lac and BHB triggering expected physiological responses such as reduced lipolysis and elevation of the appetite-suppressing compound N-L-lactoyl-phenylalanine (Lac-Phe).

Obstructive sleep apnea comorbid with insomnia symptoms and objective short sleep duration is associated with clinical and preclinical cardiometabolic risk factors: Clinical implications

BackgroundInsomnia with objective short sleep duration (ISSD) but not insomnia with normal sleep duration (INSD) is associated with cardiometabolic morbidity. It has been reported that sleep apnea comorbid with insomnia (COMISA) confers higher cardiovascular risk than each condition alone. We hypothesize that the association of COMISA with clinical (hypertension) and preclinical (inflammatory and metabolic) biomarkers is driven by the ISSD phenotype. MethodsA clinical sample of 101 adults with mild-to-moderate OSA (mmOSA) (5 ≤ AHI <30) and insomnia symptoms underwent polysomnography or home sleep apnea testing, blood pressure measures (BP), fasting blood glucose, insulin, CRP and IL-6 plasma levels. Insomnia was based on PSQI. Objective short sleep duration was based on the median total sleep time of the sample. Participants were classified into 2 groups based on objective sleep duration: mmOSA with ISSD vs. mmOSA with INSD. Analysis of covariance and logistic regression analysis were conducted controlling for confounders. ResultsSystolic and diastolic BP were elevated in the ISSD group compared to INSD group (p = 0.039 and p = 0.004, respectively). Also, the risk of hypertension was significantly higher in the ISSD (OR = 3.88, 95%CI = 1.26–11.95, p < 0.05) compared to INSD group. Plasma IL-6 concentrations and insulin resistance as indexed by glucose/insulin ratio were significantly higher in the ISSD group compared to INSD group (both p < 0.05). CRP levels were not different between the two groups. ConclusionIt appears that the additive adverse effects of COMISA on cardiometabolic risks are driven by the ISSD phenotype, a finding with potential implications for further phenotyping COMISA.

Per- and Polyfluoroalkyl Substances in the Duluth, Minnesota Area: Exposure to and Biomarker Responses in Tree Swallows Relative to Known Fire-Fighting Foam Sources.

Tree swallow nest boxes were deployed at sites proximal to two putative aqueous film forming foam (AFFF) sources in the Duluth, MN area, as well as along the St. Louis River and a reference lake for comparative purposes in 2019, 2020 and 2021. The two AFFF sites were the current Duluth Air National Guard Base (ANG) and the Lake Superior College Emergency Response Training Center. Between 13 and 40 per- and polyfluoroalkyl substances (PFAS), depending on year, were detected and quantified in tree swallow egg, nestling carcasses, and stomach contents. Assessments were made of oxidative stress and ethoxyresorufin-O-dealkylase activity in liver tissue, thyroid hormone levels in plasma and thyroid glands, DNA damage in red blood cells, and two measures of immune response (haptoglobin-like activity and immunoglobulin) in plasma of the nestlings. Additionally, other contaminants, such as polychlorinated biphenyls, legacy organochlorine pesticides, and trace elements, were assessed at sites with no previous data. Total egg PFAS concentrations at the ANG site and north of that site were 30-40 times higher than at the reference lake, while nestling PFAS concentrations were 10-15 times higher. In contrast, the St. Louis River sites had slightly, but non-statistically significant, elevated egg and nestling PFAS concentrations relative to the reference lake (2-5 times higher). One PFAS, perfluorohexane sulfonate (PFHxS), was higher, as a proportion of total PFAS, at sites with a known AFFF source compared to the reference lake, as well as compared to sites along the St. Louis River with mainly urban and industrial sources of PFAS. The ratio of total carboxylates to total sulfonates also distinguished between PFAS sources. There were few to no differences in biomarker responses among sites, and no association with PFAS exposure.

The &lt;i&gt;LGALS1&lt;/i&gt; gene polymorphism is not associated with galectin-1 levels in tumor tissue and blood of colon cancer patients

Background: Galectin-1 plays an important role in the pathogenesis of colorectal cancer (CRC). The blood and tumoral levels of galectin-1 could be dependent on the polymorphism of the promotor region of LGALS1 gene. Aim: To analyze an association between galectin-1 levels in tumor tissue and plasma and the genotype of the rs4820293 and rs4820294 polymorphisms of the LGALS1 gene in CRC patients. Materials and methods: The study included a total of 70 inpatients with pathologically verified CRC (International Classification of Diseases 10th Revision codes C18-C20, 39 men and 31 women, mean age 65.4 ± 5.7 years), who were receiving treatment in the Tomsk Regional Oncology Center and Cancer Research Institute of the Tomsk National Research Medical Center from 2020 to 2022. The control group consisted of 70 healthy volunteers (34 men and 36 women, mean age 62.3 ± 7.2 years). Venous blood samples were taken from all study participants and tumor tissue samples were obtained from the CRC patients. Galectin-1 expression in the tumor tissue was assessed by immunohistochemistry and plasma galectin-1 levels by enzyme-linked immunosorbent assay. The LGALS1 gene polymorphisms rs4820293 and rs4820294 were identified by restriction fragment length polymorphism analysis. Results: The distributions of genotype and allele frequencies of polymorphic variants rs4820293 and rs4820294 of the LGALS1 gene in the CRC patients and in the healthy donors were comparable (p 0.05). Calculation of odds ratios did not confirm any association between LGALS1 gene polymorphisms and CRC. However, the rs4820294 polymorphism had a strong association with regional metastasis and tumor differentiation grade (Cramer's V above 0.4, p 0.001). The plasma galectin-1 levels in the CRC patients with the AA genotype of the rs4820294 polymorphism were higher than in the healthy carriers (17.42 versus 12.92 ng/ml, p = 0.040). However, there were no significant differences in the content of galectin-1+ cells in the tumor and galectin-1 in plasma of the CRC patients depending on the genotype of the LGALS1 gene polymorphisms (p 0.05). Conclusion: The LGALS1 gene polymorphism is not associated with CRC, but in the carriers of the rs4820294 variant is related to clinical and morphological parameters of the tumor process. The intratumoral expression and blood levels of galectin-1 in CRC patients are not dependent on the genotype of rs4820293 and rs4820294 polymorphisms of the LGALS1 gene.

Endogenous tPA levels: A biomarker for discriminating hemorrhagic stroke from ischemic stroke and stroke mimics.

Stroke is the leading cause of death and disability. Timely differentiation between ischemic stroke, hemorrhagic stroke, and stroke mimics is critical for tailored treatment and triage. To accelerate the identification of stroke's subtype, we propose to use the levels of circulating tPA as a biomarker. Biostroke is an observational study performed at the Caen Hospital. We quantified tPA levels in 110 patients with ischemic strokes, 30 patients with hemorrhagic strokes, and 67 stroke mimic patients upon their arrival at the emergency. Two logistic regression models were formulated: one with parameters measurable in an ambulance (Model A) and one with parameters measurable at the hospital (Model H). These models were both tested with or without plasma tPA measurements. Our initial assessment involved evaluating the effectiveness of both models in distinguishing between hemorrhagic strokes, ischemic strokes, and stroke mimics within our study cohort. Plasmatic tPA levels exhibit significant distinctions between hemorrhagic, ischemic, and mimic stroke patients (1.8; 2.5; 2.4 ng/mL, respectively). The inclusion of tPA in model A significantly enhances the classification accuracy of hemorrhagic patients only, increasing identification from 0.67 (95% CI, 0.59 to 0.75) to 0.78 (95% CI, 0.7 to 0.85) (p = 0.0098). Similarly, in model H, classification accuracy of hemorrhagic patients significantly increased with the addition of tPA, rising from 0.75 (95% CI, 0.67 to 0.83) without tPA to 0.86 (95% CI, 0.81 to 0.91) with tPA (p = 0.024). Our findings underscore the valuable role of tPA levels in distinguishing between stroke subtypes.

Testosterone treatment impacts the intestinal microbiome of transgender individuals.

Medical modulation of sex hormone levels is a cornerstone of treatment for many conditions that impact well-being, including cancer, fertility/infertility, gender dysphoria, and chronic metabolic diseases such as diabetes and obesity. The microbial residents of the intestine, known as the microbiota, interact with sex hormones in the intestine, and there is correlative evidence that this interaction is bidirectional. Based on these published findings, we hypothesized that transgender individuals receiving exogenous testosterone as part of their gender-affirming medical treatment might undergo changes in their intestinal microbiome. To test this, we collected 26 stool samples from nine individuals before and up to 8 months after initiation of treatment with exogenous testosterone and subjected these samples to metagenomic analysis. While no species were significantly associated with the duration of testosterone therapy, pathways that generate glutamate increased in abundance, while those that consume glutamate decreased. Glutamate is a precursor of arginine, and testosterone is known to increase levels of arginine and its metabolites in the plasma. We hypothesize that testosterone increases the uptake of glutamate by enterocytes, thus decreasing access of the microbiota to this amino acid. While this pilot study establishes the impact of testosterone therapy on the intestinal microbiome, a more comprehensive study is necessary to establish the impact of testosterone-driven metagenomic shifts on the stool metatranscriptome, the stool metabolome, and the plasma metabolome.IMPORTANCEThe human intestine is inhabited by a large community of microbes known as the microbiome. Members of the microbiome consume the diet along with their human host. Thus, the metabolomes of the host and microbe are intricately linked. Testosterone alters the plasma metabolome. In particular, plasma levels of arginine and its metabolites and testosterone are positively correlated. To investigate the impact of exogenous testosterone on the microbiome, we analyzed the stool metagenomes of transgender individuals before and after the initiation of testosterone treatment. In this pilot project, we found a modest impact on the microbiome community structure but an increase in the abundance of metabolic pathways that generate glutamate and spare glutamate consumption. We propose that the host uses glutamate to generate arginine, decreasing the amount available for the microbiome.

Plasma NfL, GFAP, amyloid, and p-tau species as Prognostic biomarkers in Parkinson's disease.

The prognostic role of plasma neurofilament light chain (NfL), phospho-tau, beta-amyloid, and GFAP is still debated in Parkinson's disease (PD). Plasma p-tau181, p-tau231, Aβ1-40, Aβ1-42, GFAP, and NfL were measured by SIMOA in 136 PD with 2.9 + 1.7years of follow-up and 76 controls. Differences in plasma levels between controls and PD and their correlation with clinical severity and progression rates were evaluated using linear regression analyses. Patients exhibited similar distribution of plasma biomarkers but higher P-tau181, P-tau231 and lower Aβ1-42 compared with controls. NfL and GFAP correlated with baseline motor and non-motor severity measures. At follow-up, NfL emerged as the best predictor of progression with marginal effect of GFAP and p-tau181 adjusting for age, sex, disease duration, and baseline motor severity. The present findings confirmed plasma NfL as best predictor of progression in PD, with a marginal role of p-tau181 and GFAP.

Alpha B-crystallin Ameliorates Imbalance of Redox Homeostasis, Inflammation and Apoptosis in an Acute Lung Injury Model with Rats.

Ischemia-reperfusion (IR) of the aorta is a significant contributor to the development of postoperative acute lung damage after abdominal aortic surgery. The aim of the present study was to examine the effect of alpha B-crystallin, a small heat shock protein (known as HspB5), on lung injury induced by abdominal aortic IR in rats. Male Sprague-Dawley rats were divided into three groups: control, ischemia-reperfusion (IR, 90 min ischemia and 180 min reperfusion), and alpha B-crystallin +IR. Alpha B-crystallin (50 μg/100 g) was intraperitoneally administered 1 h before IR. Lung tissue samples were obtained for histological and biochemical analyses of oxidative stress and cytokine and apoptosis parameters in plasma, lung tissues, and bronchoalveolar lavage (BAL) fluid. The levels of malondialdehyde, reactive oxygen species, total oxidant status, tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), nuclear factor kappa B (NFKβ), caspase-9 (CASP-9), 8-hydroxy-2'-deoxyguanosine, total antioxidant status, superoxide dismutase, and interleukin-10 levels in lung tissues, plasma, and BAL fluid (p<0.05 versus control) increased in Aortic IR. However, alpha B-crystallin significantly reduced the lung tissue levels of oxidative, inflamatuvar, and apoptotic parameters in the plasma, lung tissues, and BAL fluid (p<0.05 versus aortic IR). Histopathological results showed that alpha B-crystallin ameliorated the morphological changes related to lung injury (p<0.001). Alpha B-crystallin substantially restored disrupted the redox balance, inflammation, and apoptotic parameters in rats exposed to IR. The cytoprotective effect of alpha B-crystallin on redox balance might be attributed to improved lung injury.

The simultaneous inhibition of SLC6A19 and BCRP transporters leads to an increase of indoxyl sulfate (a uremic toxin) in plasma and kidney.

SLC6A19 inhibitors are being studied as therapeutic agents for Phenylketonuria. In this work, a potent SLC6A19 inhibitor (RA836) elevated rat kidney uremic toxin indoxyl sulfate (IDS) levels by intensity (arbitrary unit) of 13.7{plus minus}7.7 compared to vehicle 0.3{plus minus}0.1 (P=0.01) as determined by tissue mass spectrometry imaging (tMSI) analysis. We hypothesized that increased plasma and kidney levels of IDS could be caused by the simultaneous inhibition of both Slc6a19 and a kidney IDS transporter responsible for excretion of IDS into urine. To test this, we first confirmed the formation of IDS through tryptophan metabolism by feeding rats a Trp-free diet. Inhibiting Slc6a19 with RA836 led to increased IDS in these rats. Next, RA836 and its key metabolites were evaluated in vitro for inhibiting kidney transporters OAT1, OAT3 and BCRP. RA836 inhibits BCRP with an IC50 of 0.045 µM but shows no significant inhibition of OAT1 or OAT3. Finally, RA836 analogs with either potent or no inhibition of SLC6A19 and/or BCRP were synthesized and administered to rats fed a normal diet. Plasma and kidney samples were collected to quantify IDS using LC-MS. Neither a SLC6A19 inactive but potent BCRP inhibitor nor a SLC6A19 active but weak BCRP inhibitor raised IDS levels, while compounds inhibiting both transporters caused IDS accumulation in rat plasma and kidney, supporting the hypothesis that rat Bcrp contributes to the excretion of IDS. In summary, we identified that inhibiting Slc6a19 increases IDS formation, while simultaneously inhibiting Bcrp results in IDS accumulation in the kidney and plasma. Significance Statement This is the first publication to decipher the mechanism for accumulation of IDS (a uremic toxin) in rats via inhibition of both Slc6a19 and Bcrp. Specifically, inhibition of Slc6a19 in the GI track increases IDS formation and inhibition of Bcrp in the kidney blocks IDS excretion. Therefore, we should avoid inhibiting both SLC6A19 and BCRP simultaneously in humans to prevent accumulation of IDS, a known risk factor for cardiovascular disease, psychic anxiety, and mortality in chronic kidney disease patients.

Immunological effects of post-operative epidural analgesia versus oral opioids in VATS.

Anaesthetic choices in cancer surgery, including the use of epidural analgesia, may affect immune function during the perioperative period and might play an important role in subsequent cancer spread and recurrence. This was a prospective, randomised, controlled, double-blinded, single-centre study allocating patients scheduled for video-assisted thoracoscopic surgery (VATS) lobectomy to post-operative pain management using either thoracic epidural analgesia or oral morphine. We compared pre-, per-, and post-operative plasma levels of interleukin (IL)-6, IL-10, IL-12, and interferon (IFN)-γ using regression analysis, and conducted a two-year survival follow-up. A total of 66 patients were randomised. Fifty-six received the allocated treatment and were analysed. None of the investigated cytokines exhibited significant between-group differences in plasma concentrations when adjusted for the chosen covariates (p ≥ 0.204). A two-year follow-up showed no difference in survival between the two groups (p = 0.5). Our study found no differences in the impact on the innate, non-specific immune system related to epidural analgesia for pain management in VATS. The Danish Cancer Society (R150-A10139). Oberstinde Kirsten Jensa la Cours Mindelegat (JSP-25076). University of Southern Denmark, Region of Southern Denmark and Department of Anaesthesia and Intensive Care, Odense University Hospital. NCT02359175 (ClinicalTrials.gov).

The relationship between sphingomyelin and ceramide levels and soft neurological signs in ADHD.

Attention deficit hyperactivity disorder (ADHD), characterized by attention deficit, hyperactivity, and impulsivity, has recently been associated with lipid metabolism. In particular, the roles of sphingomyelin, ceramide, andgalactosylceramidase in the pathophysiology of ADHD are being investigated. This study aims to explore the relationship between sphingolipid metabolism markers and soft neurological signs (SNS) in children diagnosed with ADHD who are not undergoing medication treatment. A cross-sectional analysis was conducted on 41 children and adolescents aged 7-12 years diagnosed with ADHD and 39 neurotypically developing controls. Plasma levels of ceramide, sphingomyelin, and galactosylceramidase were measuredusing Enzyme-Linked Immunosorbent Assay (ELISA). SNS were assessed using the Physical and Neurological Examination for Soft Signs (PANESS). Statistical analyses included Student's t-tests, Mann-Whitney U tests, and Multivariate Analysis ofCovariance (MANCOVA), along with logistic regression analysis. Plasma levels of ceramide and sphingomyelin in children with ADHD showed significant differences compared to the neurotypically developing control group; however, there were no significant differences in galactosylceramidase levels between the two groups. Positive correlations were found between plasma levels of ceramide and sphingomyelin and the PANESS subscales F1 (Total Gait and Station) and F3 (Total Dysrhythmia). Additionally, logistic regression analysis indicated that high ceramide levels were positively associated with ADHD. This study underscores a significant association between alterations in sphingolipid metabolism (specifically increased levels of ceramide and sphingomyelin) and the presence of SNS in children with ADHD. These findings elucidate the potential role of sphingolipid metabolism in the pathophysiology of ADHD and provide suggestions for future therapeutic research targeting sphingolipid metabolism in the treatment of ADHD.

Interleukin‐6 induces cognitive impairment via toll‐like receptor 4 (TLR4)‐mediated neuroinflammation and neurodegeneration in mice with chronic kidney disease

AbstractBackgroundsPast epidemiological and experimental studies in rodents have demonstrated that chronic kidney disease (CKD) leads to cognitive impairment. However, the underlying mechanism requires further investigation. Herein, a mouse model of CKD was established using conventional 5/6 nephrectomy. We aimed to examine the relationship between CKD and cognitive impairment and elucidate the underlying mechanisms.MethodsCognitive behavior was assessed using the Morris water maze, novel object recognition test, and fear conditioning test. Further experiments were also conducted to investigate the underlying molecular mechanisms.ResultsOur clinical data revealed a decrease in cognitive function among patients with CKD, accompanied by elevated plasma levels of pro‐inflammatory cytokines. A positive correlation between cytokine concentrations and serum creatinine levels, as well as a significant positive correlation with cognitive dysfunction, were observed. Correlation analyzes demonstrated that hippocampal cytokine levels were positively correlated with serum creatinine levels and cognitive dysfunction in CKD model mice. Furthermore, 20 mg/mL interleukin‐6 (IL‐6) significantly decreased HT22 cell activity in vitro. Further, HT22 cells treated with IL‐6 showed increased expression levels of toll‐like receptor 4 (TLR4) and myeloid differentiation primary response gene 88 (MyD88), thereby inducing the nuclear factor kappa‐B p65 inflammatory pathway and mitochondria‐dependent apoptosis. The CKD mouse model showed increased expression of TLR4 and cytokines in the hippocampus. TLR4 knockdown antagonized the IL‐6‐mediated pro‐inflammatory and pro‐apoptotic effects in HT22 cells. TLR4 knockdown in the CKD model mice decreased hippocampal inflammation and increased the number of neuron dendrites, thus ameliorated cognitive impairment.ConclusionThese results suggest that IL‐6 triggers TLR4 activation to induce neuroinflammation and neurodegeneration in CKD, ultimately culminate in cognitive impairment.

Genome-wide association study meta-analysis of neurofilament light (NfL) levels in blood reveals novel loci related to neurodegeneration

Neurofilament light chain (NfL) levels in circulation have been established as a sensitive biomarker of neuro-axonal damage across a range of neurodegenerative disorders. Elucidation of the genetic architecture of blood NfL levels could provide new insights into molecular mechanisms underlying neurodegenerative disorders. In this meta-analysis of genome-wide association studies (GWAS) of blood NfL levels from eleven cohorts of European ancestry, we identify two genome-wide significant loci at 16p12 (UMOD) and 17q24 (SLC39A11). We observe association of three loci at 1q43 (FMN2), 12q14, and 12q21 with blood NfL levels in the meta-analysis of African-American ancestry. In the trans-ethnic meta-analysis, we identify three additional genome-wide significant loci at 1p32 (FGGY), 6q14 (TBX18), and 4q21. In the post-GWAS analyses, we observe the association of higher NfL polygenic risk score with increased plasma levels of total-tau, Aβ-40, Aβ-42, and higher incidence of Alzheimer’s disease in the Rotterdam Study. Furthermore, Mendelian randomization analysis results suggest that a lower kidney function could cause higher blood NfL levels. This study uncovers multiple genetic loci of blood NfL levels, highlighting the genes related to molecular mechanism of neurodegeneration.

Dosing Evaluation of Ceftazidime-Avibactam in Intensive Care Unit Patients Based on Pharmacokinetic/Pharmacodynamic (PK/PD) Modeling and Simulation.

P. aeruginosa is the most common microorganism involved in many ICU-acquired infections. A correct dosage regimen is pivotal to avoiding resistance development, worse outcomes and higher mortality rates. The aim of this study was to perform a pharmacokinetic-pharmacodynamic (PK/PD) evaluation of recommended dosing regimens of ceftazidime-avibactam (CAZ-AVI) in ICU patients with different degrees of renal function for a specific strain of Pseudomonas aeruginosa. A semi-mechanistic PK/PD model has been developed. It allows for the simulation of CAZ-AVI steady-state plasma level curves and the evolution of bacterial growth curves. The percentage of bacterial load reduction and the value of the recommended PK/PD indices have been taken into account to define the success or failure of the regimens. Probabilistic analysis was performed using Monte Carlo simulations of two populations: control and ICU. In both populations, dosing regimens endorsed for patients with CLcr higher than 10 mL/min reach the PK/PD indices recommended, T > MIC > 90% and Cmin/MIC > 1.3. While dosage regimens endorsed for patients with CLcr of 10 mL/min or lower fail (T > MIC < 60% and Cmin/MIC < 0.35). However, proposed dosing regimens based on shortening dosing intervals for these patients would be successful, increasing bacterial load reduction by almost 50% and reaching the proposed PK/PD indices. Therefore, CAZ-AVI dosing strategies based on model-informed precision dosing (MIPD) could directly influence the efficacy of results in ICU patients with renal insufficiency.