Elevated Serum Research Articles

Proposing Bromo-epi-androsterone (BEA) for perioperative neurocognitive disorders with Interleukin-6 as a druggable target.

Cognitive impairment following surgery is a significant complication, affecting multiple neurocognitive domains. The term "perioperative neurocognitive disorders" (PND) is recommended to encompass this entity. Individuals who develop PND are typically older and have increases in serum and brain pro-inflammatory cytokines notwithstanding the type of surgery undergone. Surgical trauma induces production of small biomolecules, damage-associated molecular patterns (DAMP), particularly the DAMP known as high molecular group box 1 protein (HMGB1). Mechanistically, peripheral surgical trauma promotes pro-inflammatory cytokines that stimulate central nervous system (CNS) inflammation by disrupting the blood-brain barrier (BBB) causing functional neuronal disruption that leads to PND. PND is strongly linked to elevations in serum and CNS pro-inflammatory cytokines interleukin-1 beta (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα); these cytokines cause further release of HMGB1 creating a positive feedback loop that amplifies the inflammatory response. The cytokine IL-6 is necessary and sufficient for PND. Dehydroepiandrosterone (DHEA) is a principal component of the steroid metabolome and is involved in immune homeostasis. DHEA has been shown to suppress expression of several pro-inflammatory cytokines by regulation of the NF-kB pathway. Bromo-epi-androsterone (BEA) is a potent synthetic analog of DHEA; unlike DHEA, it is non-androgenic, non-anabolic and is an effective modulator of immune dysregulation. In a randomized, placebo-controlled clinical trial, BEA effected significant and sustained decreases in IL-1β, TNFα and IL-6. This article presents BEA as a potential candidate for clinical trials targeting PND and further suggests the use of BEA in elective total hip arthroplasty as a well-documented surgical entity relevant to the management of PND.

Comparative analysis of the performance, egg quality and ovarian immune function of fast and slow feather strains in tianfu green shell laying hens at various stages of egg production.

This objective of this experiment was to compare and evaluate the performance, egg quality, and immune function of Tianfu green shell laying hens with varying feather growth rates, in order to provide a reference for their rational utilization. A total of 120 one-day-old healthy Tianfu green shell laying hens were classified into the early-feathering (EF) and late-feathering (LF) groups through phenotypic identification of feather length and qPCR molecular identification. Each group was subdivided into four replicates, with 30 chickens in each replicate. Under the identical feeding and management conditions, the live weight, tibial length, egg production performance, egg quality, serum biochemical indexes, immune protein content, and the expression of related genes in uterine and ovarian tissues were assessed and analyzed. The results indicated that LF hens exhibited significantly greater live weights at 4, 16, 27, and 43 weeks (P < 0.05) and longer tibia lengths at 4 and 16 weeks (P < 0.05) compared to EF hens, suggesting enhanced early growth performance. Conversely, EF hens demonstrated superior egg-laying performance, characterized by a higher laying rate during both peak (27 weeks) and late (43 weeks) laying periods (P < 0.05), despite their eggs being lighter in weight (P < 0.05). Furthermore, EF hens exhibited the production of eggs with significantly thicker and stronger shells during the peak laying period (P < 0.05), while no notable differences were observed in other egg quality parameters. Immunologically, EF hens demonstrated elevated peak serum levels of IgA, IgG, and IgM compared to LF hens. Additionally, the expression levels of IFN-γ and interleukin 6 (IL-6) genes in the ovaries were markedly higher in EF hens. These findings indicate that although LF hens excel in early growth stages, EF hens exhibit superior egg production capabilities and enhanced immune responses.

Ningxiang pig-derived Lactobacillus reuteri improves the gut health of weaned piglets by regulating intestinal barrier function and cytokine profiles

Weaning stress in piglets can induce intestinal damage, resulting in impaired growth performance. Probiotics have emerged as significant contributors to enhancing gut health in piglets. This study aimed to evaluate the effects of Lactobacillus reuteri (L. reuteri) supplementation on growth performance, intestinal immunity, and intestinal barrier integrity in weaned piglets. In this investigation, fourteen healthy weaned piglets of similar age and weight, were randomly assigned to two groups (n = 7), receiving either normal saline (Control group) or L. reuteri (L-treatment group) over a 16-day period. The findings revealed no significant impact of L. reuteri on growth performance compared to controls. However, it lowered serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels (P < 0.05) and elevated serum concentrations of Immunoglobulin A (IgA), immunoglobulin G (IgG), and secretory immunoglobulin A (sIgA) (P < 0.05). Additionally, L. reuteri notably enhanced the villus height-to-crypt depth ratio in the ileum (P < 0.05) and increased mRNA expression of zonula occludens-1 (ZO-1), Claudin-1, and ZO-1 in ileal tissue (P < 0.05). Furthermore, L. reuteri reduced mRNA expression of pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) (P < 0.05) in the jejunum and colon while enhancing the expression of the anti-inflammatory cytokine interleukin-10 (IL-10) (P < 0.05) in both the ileum and colon. This study demonstrates that L. reuteri isolated from Ningxiang pigs can improve the intestinal health of weaned piglets by modulating gut barrier function and cytokine levels.

Long-term effects of Nε-carboxymethyllysine intake on intestinal barrier permeability: Associations with gut microbiota and bile acids.

Advanced glycation end products (AGEs) in processed foods are closely linked to intestinal injury. However, the long-term effects of exposure to free Nɛ-carboxymethyl lysine (CML), a prevalent AGE molecule, on intestinal barrier integrity have been rarely evaluated. This study investigated the temporal effects of CML exposure on intestinal barrier permeability in C57BL/6N mice at diet-related doses over 12, 14, and 16weeks. No significant changes were observed at 12weeks, but CML exposure significantly increased intestinal permeability at 14 and 16weeks, accompanied by elevated serum LPS levels, colonic histological damage, and reduced tight junction protein expression at 16weeks. CML exposure also altered gut microbiota composition and intestinal bile acid (BA) profiles, specifically reducing TDCA, GDCA, and GCDCA levels. Given the important role of colonic BA receptor signaling in maintaining the intestinal barrier integrity, the impact of CML on BA receptor signaling was assessed. CML exposure significantly downregulated BA receptor TGR5-YAP signaling in mice, while no significant effects were observed in vitro, suggesting that the changes observed in TGR5-YAP signaling in vivo may not result from the direct effects of CML. Spearman's correlation analysis revealed strong associations between altered gut microbiota, BA levels, TGR5-YAP signaling, and intestinal barrier injury. This study highlighted the chronic health risks of long-term CML intake and provided new insights into the links between CML-induced intestinal toxicity, gut microbiota, BA profiles, and BA receptor signaling.

Effects of chronic cold stress and thermal stress on growth performance, hepatic apoptosis, oxidative stress, immune response and gut microbiota of juvenile hybrid sturgeon (Acipenser baerii ♀ × A. schrenkii ♂)

The current study was conducted to investigate the effects of chronic cold stress and thermal stress on the growth performance, hepatic oxidative status, immune response, apoptosis and gut microbiota in juvenile hybrid sturgeon. The fish (initial mean weight: 21.4 ± 0.3 g) was reared at three temperatures (14 °C, 22 °C, and 30 °C) for 16 d, which were termed as low temperature group (LT), moderate temperature group (MT), and high temperature group (HT), respectively, and the second group was regarded as control group in this study. Each group was assigned randomly to three tanks with 15 fish per replica. The results indicated that cold stress resulted in a significant reduction of growth metrics and a significant increase of feed conversion ratio in fish compared with MT group. Interestingly, cold stress increased hepatocyte apoptosis revealed by TUNEL staining, along with nuclear disappearance in H&E-stained sections and elevated serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Transcriptional levels of apoptosis-related genes and toll-like receptor signaling pathway components were significantly up-regulated in liver under cold stress. Compared with control group, in terms of thermal stress, the growth performance and feed utilization of fish were declined to some extent compared with MT group. Moreover, high temperature significantly elevated hepatic productions of malondialdehyde and hydrogen peroxide, as well as increased activities of some antioxidant enzymes in liver. In addition, low and high temperature induce changes in the composition of gut microbiota. Overall, the results suggested that cold stress decelerated growth performance, induced hepatocyte apoptosis, and enhanced innate immunity in hybrid sturgeon to cope with additional stressors. Whereas, thermal stress resulted in hepatic oxidative stress in liver and the protective responses in the antioxidant enzymes in fish were activated. These results provided insights into the different physiological adaptation strategies in responsive to cold stress and thermal stress in this cold-water fish.

Efficacy of Second-line Nivolumab Versus Tyrosine Kinase Inhibitors for Renal Cell Carcinoma With Bone Metastases.

Combination therapy with immune checkpoint inhibitors has become the standard first-line treatment for metastatic renal cell carcinoma (mRCC), leading to changes in second-line treatment options, such as nivolumab or tyrosine kinase inhibitors (TKIs). However, very few studies have compared the efficacy of these drugs in patients with mRCC, particularly those with bone metastases (BM), which are associated with a poor prognosis. This study compared the efficacy of nivolumab and TKIs as second-line treatments for mRCC patients with BM and examined the microenvironments of primary tumors and BM lesions. This multi-institutional retrospective study included 87 mRCC patients with BM who received either nivolumab or TKIs as second-line treatments. We analyzed tumor-infiltrating immune cells expressing CD8 and CD20, along with PD-L1, HIF2α, c-MET, VEGFR2, and AXL, in primary tumors and BM sites using immunohistochemistry. This analysis indicated that poor-risk classification, as per the International Metastatic RCC Database Consortium criteria (p<0.01), and elevated serum alkaline phosphatase levels (p=0.031) were significantly associated with poor prognosis. No significant difference in overall survival was observed between patients receiving nivolumab and those receiving TKIs. However, the objective response rate of patients with BM lesions was significantly higher when receiving TKIs than when receiving nivolumab (p=0.014). Immunohistochemistry revealed significantly higher VEGFR2 expression in BM lesions than primary tumors. TKIs could be a promising second-line treatment option for mRCC patients with bone-limited metastases.

Cardiac secreted HSP90α exacerbates pressure overload myocardial hypertrophy and heart failure.

Sustained myocardial hypertrophy or left ventricular hypertrophy (LVH) triggered by pressure overload is strongly linked to adverse cardiovascular outcomes. Here, we investigated the clinical relationship between serum HSP90α (an isoform of HSP90) levels and LVH in patients with hypertension or aortic stenosis (AS) and explored underlying mechanisms in pressure overload mouse model. We built a pressure overload mouse model via transverse aortic constriction (TAC). Compared to controls, elevated serum HSP90α levels were observed in patients with hypertension or AS, and the levels positively correlated with LVH. Similarly, HSP90α levels increased in heart tissues from patients with obstructive hypertrophic cardiomyopathy (HCM), and in mice post-TAC. TAC induced the enhanced cardiac expression and secretion of HSP90α from cardiomyocytes and cardiac fibroblasts. Knockdown of HSP90α or blockade of extracellular HSP90α (eHSP90α) attenuated cardiac hypertrophy and dysfunction by inhibition of β-catenin/TCF7 signaling under pressure overload. Further analysis revealed that eHSP90α interacted with EC1-EC2 region of N-cadherin to activate β-catenin, enhancing the transcription of hypertrophic genes by TCF7, resulting in cardiac hypertrophy and dysfunction under pressure overload. These insights suggest the therapeutic potential of targeting HSP90α-initiated signaling pathway against cardiac hypertrophy and heart failure under pressure overload.

Abstract TMP78: Beyond Recanalization: Predicting Poor Outcomes in Successful Vertebrobasilar Thrombectomy

Background: Successful recanalization following endovascular thrombectomy (EVT) in vertebrobasilar artery occlusions (VBAOs) does not uniformly translate into favorable functional outcomes. Identifying predictors of futile recanalization is critical for improving patient selection and treatment strategies. This study aimed to compare patients with good versus poor functional outcomes despite successful recanalization in VBAO and to establish predictive factors for futile recanalization. Methods: We retrospectively analyzed patients who achieved successful recanalization after EVT for VBAO from a prospectively maintained database between 2014-2024. Functional outcomes were assessed using the modified Rankin Scale (mRS) at 90 days; dichotomized into good (mRS 0-3) and poor (mRS 4-6) outcomes. Demographic data, clinical characteristics, procedural variables, and imaging findings were compared between the groups using pairwise comparisons and multivariable logistic regression models to identify predictors of futile recanalization. Results: Among the 163 patients who qualified for final analysis, 73 (44.8%) had good functional outcomes, while 90 (55.2%) had poor outcomes despite successful recanalization. Age (72 years vs. 64 years, p=0.0014), baseline NIHSS score (22 vs. 14, p&lt;0.0001), and serum glucose levels (142 mg/dL vs. 124 mg/dL, p=0.0109) were significantly higher in patients with poor outcomes. In addition, intubation (57.1% vs. 25.4%, p&lt;0.001) and prior history of diabetes mellitus (34.4% vs. 17.8%, p=0.017) and coronary artery disease (33.3% vs. 16.4%, p=0.014) were more prevalent in the poor outcome group. Multivariable analysis confirmed that advanced age (OR 0.73, 95% CI: 0.57-0.93, p=0.012), higher serum glucose (OR 0.90, 95% CI: 0.82-0.99, p=0.025), NIHSS at 24-36 hours post-last known well (OR 0.61, 95% CI: 0.38-0.98, p=0.039), and mRS at discharge (OR 0.0001, 95% CI: 0.0002-0.064, p=0.005) were independent predictors of poor functional outcomes, indicating futile recanalization. A subgroup analysis of patients with complete recanalization (mTICI 2c/3) further validated these findings. Conclusion: Futile recanalization after EVT for VBAO is linked to older age, elevated serum glucose levels, higher NIHSS scores at 24-36 hours, and poor mRS at discharge. These factors should be carefully considered in clinical decision-making to improve patient selection for EVT in VBAO.

Persistent elevated serum parathyroid hormone levels with normocalcaemia after parathyroidectomy: Secondary hyperparathyroidism or pseudo- hyperparathyroidism?

Persistent elevated serum parathyroid hormone levels with normocalcaemia after parathyroidectomy: Secondary hyperparathyroidism or pseudo- hyperparathyroidism?

Clinical Impact of Cellular Senescence and RNA Dysregulation in HCC Is Associated With MASLD and HCV-SVR.

The incidence of hepatocellular carcinoma (HCC) associated with metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatitis C virus sustained virologic response (HCV-SVR) are increasing. However, the mechanisms driving HCC development in these patients remain unclear. This study aimed to evaluate the role of cellular senescence and RNA editing in HCC by examining cyclin-dependent kinase inhibitor 2A (p16) and adenosine deaminase acting on RNA (ADAR1) expression. HCC specimens from patients with MASLD or HCV-SVR were analyzed by immunohistochemistry to assess p16 and ADAR1 expression. Statistical analyses were conducted using the Chi-squared test, Fisher's exact test, and Mann-Whitney U-test. Survival analyses were performed using the Kaplan-Meier method, the log-rank test, and Cox regression analysis. Among 122 patients, 59 (48.4%) had MASLD and 63 (51.6%) had HCV-SVR. p16 expression was observed in 69 cases (57.0%) in the noncancerous areas and 53 cases (44.5%) in the cancerous areas. ADAR1 expression was positive in 28 cases (23.5%) in the cancerous areas and significantly associated with p16 expression in the cancerous areas (p=0.039). Patients with p16 expression in the noncancerous areas were older (p=0.045) and had elevated serum ALT levels (p=0.024). p16 expression in the cancerous areas were correlated with a shorter recurrence-free survival (HR=1.65, 95%CI=1.00-2.73, p=0.046). Cellular senescence and RNA editing may play a key role in MASLD- and HCV-SVR-related HCC. p16 expression in the cancerous areas may serve as a prognostic biomarker for surgical outcomes.

Inverse Relationship Between Serum Carotenoid Levels and Cardiovascular-Kidney-Metabolic Syndrome Among the General Adult Population.

To examine the relationship between serum carotenoid levels and cardiovascular-kidney-metabolic (CKM) syndrome in a representative sample of US adults. Data from the fasting subsample of the NHANES 2017-2018 were analyzed using a survey-weighted approach to ensure the findings are representative of the broader US adult population. Serum levels of α-carotene, β-carotene, β-cryptoxanthin, lutein/zeaxanthin, and lycopene were measured using high-performance liquid chromatography. CKM syndrome stages were defined according to the 2023 American Heart Association guidelines, with advanced CKM syndrome categorized as stages 3 or 4. Associations between serum carotenoids and advanced CKM syndrome were assessed using logistic regression and weighted quantile sum (WQS) regression. The study included 1671 adults aged 20 years and older, with a mean age of 48.7 years and a gender distribution of 50.9% female and 49.1% male. Higher serum levels of α-carotene, β-carotene, α-cryptoxanthin, lutein/zeaxanthin, and lycopene were inversely associated with advanced CKM syndrome. Specifically, compared to the lowest quartile, the highest quartile of α-carotene had an odds ratio (OR) of 0.29 (95% CI: 0.16-0.55), β-carotene 0.35 (95% CI: 0.16-0.78), α-cryptoxanthin 0.23 (95% CI: 0.11-0.49), lutein/zeaxanthin 0.26 (95% CI: 0.14-0.48), and lycopene 0.58 (95% CI: 0.35-0.98). However, β-cryptoxanthin did not show a significant association. Moreover, the combined effect of all carotenoids was significantly negatively correlated with advanced CKM syndrome (OR = 0.67, 95% CI: 0.53-0.86), with lutein/zeaxanthin contributing the most (44.56%). Elevated serum carotenoid levels are inversely associated with the prevalence of advanced CKM syndrome in a dose-dependent manner, with this association remaining consistent across diverse demographic and health subgroups.

Impact of Bambusa vulgaris-supplemented diet on Nile tilapia challenged with Pseudomonas putida: Hematological, immune, and oxidative responses.

This study investigated the effects of bamboo shoot extract (Bambusa vulgaris) as a feed additive on the health profiles and infection resistance of Nile tilapia (Oreochromis niloticus) against Pseudomonas putida. Bamboo shoot extract was added at levels of 0g, 40g, and 60g per 1000g of diet over a 60-day period. The fish were then challenged with a pathogenic P. putida strain. Chemical analysis of the bamboo shoot extract identified 3,5-dinitrophenol and hydroquinone as the two most abundant compounds. Results showed that fish fed bamboo-enriched diets exhibited significantly enhanced levels of red blood cells, hemoglobin, hematocrit, white blood cells, and platelets, and improved erythrocyte cellular and nuclear morphologies, indicating improved health profiles after the challenge. Liver function indicators, including AST, ALT, and ALP, were notably balanced in fish receiving bamboo shoot extract post-challenge (p<0.05). Blood levels of K+ were lower in the bamboo-fed groups. Additionally, blood levels of Ca++ and Na+ were reduced in fish fed 40g and 60g of bamboo, respectively, compared to the control group (p<0.01). The bamboo extract also enhanced immune and oxidative capacities, as demonstrated by increased catalase, superoxide dismutase, lysozyme activity, and phagocytic activity, along with reduced malondialdehyde levels and elevated serum immunoglobulin M (p<0.01). Gene expression analysis revealed significant effects of Bambusa vulgaris extract, Pseudomonas infection, and their interaction on the expression of interleukin-1β, interleukin-10, and NK-lysin genes, with varying expression levels at 1, 3, and 7 days post-challenge (p<0.05). The liver bacterial load in fish exposed to P. putida significantly decreased in the bamboo-fed groups, with the lowest count observed in the 60g bamboo group. Additionally, survival rates were markedly higher in the bamboo-fed groups compared to the control, with no significant difference between the two bamboo-fed groups. In conclusion, dietary supplementation with bamboo shoot extract enhances hematological parameters, blood cell and nuclear morphology, and increases survival rates in Nile tilapia following infection.

Relapse detection in the Danish surveillance program of patients with clinical stage I seminoma: a nationwide study.

Active surveillance is a recommended management strategy for patients with clinical stage I (CSI) seminoma. This study aims to identify patterns of relapse detection methods in an unselected population-based cohort of CSI patients and provide evidence for a risk-adapted follow-up program. A total of 924 patients with CSI seminoma were identified in the prospective Danish Testicular Cancer database. Retrospectively collected clinical data were used for descriptive analyses of patterns in detection methods. Additionally, we explored a risk-adapted surveillance approach based on recently identified risk factors for relapse, classifying patients into low- and non-low-risk groups. At 60 months, the 5-year cumulative relapse risk was 16%, with 146 relapses during surveillance. Relapses were detected by imaging alone in 71% of cases, imaging combined with elevated serum tumor markers (STMs) in 18%, isolated elevation of STMs in 8%, and by self-referral due to symptoms in 3%. No relapses were detected by abnormal findings at a physical examination. In total, 134 (92%) relapses were localized to retroperitoneal lymph nodes, primarily without additional spread. The 5-year relapse risk in patients with low risk of relapse was 9% compared to 28% in patients in the non-low-risk group. This study highlights that the surveillance program can detect relapses at an early stage. Reduction of visits and omission of routine physical examinations can safely be considered for patients with a low risk of relapse, while further research is needed to optimize follow-up and treatment for patients at higher risk of relapse.

Single- and multiple-dose pharmacokinetics and safety of the SARS-CoV-2 3CL protease inhibitor RAY1216: a phase 1 study in healthy participants.

Coronavirus disease 2019, which leads to pneumonia, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). RAY1216 is a 3C-like protease inhibitor that targets SARS-CoV-2. The aim of our study was to assess the pharmacokinetics (PK) and safety of RAY1216 in healthy volunteers. This was a randomized, placebo-controlled, double-blind study consisting of four components: a single ascending dose study, a drug-drug interaction study, a multiple ascending dose study, and a food-effect study. All participants were randomly assigned to receive either a single dose or multiple doses of RAY1216 or placebo. A total of 88 healthy adult participants (male-to-female ratio of 1:1) aged 18-50 years were enrolled. A total of 37 participants (42%) experienced at least one adverse event (AE). All AEs were mild or moderate and were resolved without additional treatment. The most commonly reported adverse drug reactions were hypertriglyceridemia, hyperuricemia, and elevated serum creatinine levels. RAY1216 was well-absorbed after administration with exposure increasing in a dose-dependent manner. Food appeared to increase exposure and delay the absorption of RAY1216. Ritonavir significantly inhibited drug metabolism, and increased drug exposure increased the associated safety risks. RAY1216 was found to be well tolerated and safe in healthy participants. On the basis of preclinical results, PK characteristics, and the safety profile of RAY1216, a dosage of 400 mg three times daily was selected, thereby establishing a foundation for future research and for the clinical application of RAY1216.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT05829551.

Progesterone sulfates are enterohepatically recycled and stimulate G protein-coupled bile acid receptor 1-mediated gut hormone release.

Sulfated progesterone metabolites (PMxS) increase during gestation and are raised further in intrahepatic cholestasis of pregnancy (ICP), a disorder characterised by pruritus and elevated serum bile acids. PMxS interact with bile acid receptor G protein-coupled bile acid receptor 1 (GPBAR1) to cause itch. We investigated whether PMxS could undergo enterohepatic recycling and stimulate intestinal GPBAR1-mediated release of gut hormones glucagon-like peptide-1 (GLP-1) and peptide YY (PYY). PMxS were quantified in pre-/postprandial serum samples (n=21) and feces (n=18) by ultra-performance liquid chromatography-tandem mass spectrometry in prospectively recruited third trimester of pregnancy outpatients with uncomplicated pregnancy or ICP. Ussing chambers were used to evaluate colonic ion secretion changes (ΔIsc) in wildtype, GPBAR1-/-, and PYY-/- mice by PMxS metabolites, PM3S and PM5S, and in wildtype mice with or without apical sodium bile acid transporter (ASBT) inhibition (n=6/condition). PM3S/PM5S stimulation of GLP-1 release from wildtype and GPBAR1-/- murine crypts and human colonoids was measured by ELISA (n=3). Serum PMxS increase postprandially in women with ICP but are unaltered in uncomplicated pregnancies. PMxS are present in feces. Apical and basolateral PM3S and PM5S stimulated PYY-mediated -ΔIsc in wildtype (p<0.01) but not GPBAR1-/- or PYY-/- colons. PM3S and PM5S caused GLP-1 secretion in murine crypts and human colonoids (p<0.001). ASBT inhibition blunted -ΔIsc by 68% after apical PM3S and PM5S addition (p<0.001). Serum PMxS, elevated in women with ICP and particularly postprandially, can undergo ASBT-mediated intestinal reuptake and activate GPBAR1 to stimulate gut hormone release. PMxS may therefore augment GPBAR1-mediated metabolic responses during pregnancy.

Partially hydrolyzed guar gum alleviates neurological deficits and gastrointestinal dysfunction in mice with traumatic brain injury.

Traumatic brain injury (TBI)-associated neuroinflammation and neurotoxicity can induce gastrointestinal dysfunction through the brain-gut axis. Partially hydrolyzed guar gum (PHGG) was demonstrated to exert beneficial health effects by altering gut microbiota and short-chain fatty acids (SCFAs) production. Our study aimed to explore the effects of PHGG on gastrointestinal dysfunction in TBI mouse models. Controlled cortical impact (CCI)-induced TBI mouse models were administrated with PHGG (600mg/kg/d) for 21 consecutive days. Behavioral tests (modified neurological severity score and beam walk test) and Y‑maze assay were performed to evaluate neurological functions and cognitive impairment. Enzyme-linked immunosorbent assay, reverse transcription-quantitative polymerase chain reaction, and western blotting examined the levels of inflammatory cytokines, intestinal mucosal damage markers, intestinal tight junction proteins, and NLRP3 inflammasome-related molecules in the serum, cerebral cortex, and colon tissues. The histological changes in the cerebral cortex and colon tissues were observed through hematoxylin and eosin and Nissl staining. Liquid chromatography/mass spectrometry analyzed SCFA amounts in the cecum contents and bile acid levels in the serum. PHGG administration alleviated neurological deficits and cognitive perturbations, reduced neuroinflammation, and attenuated cortical tissue damage and neuron loss in TBI mice. PHGG ameliorated intestinal barrier impairment, upregulated intestinal production of SCFAs, and elevated serum bile acid levels in TBI mice. Besides, PHGG treatment repressed NLRP3 inflammasome activation in TBI mice. Overexpressing NLRP3 reversed the beneficial effects of PHGG against TBI in mice. PHGG ameliorates neuroinflammation and gastrointestinal dysfunction in TBI murine models by inhibiting NLRP3 inflammasome activation.

Risk factors and machine learning prediction models for intrahepatic cholestasis of pregnancy

BackgroundIntrahepatic cholestasis of pregnancy (ICP) is a liver disorder that occurs in the second and third trimesters of pregnancy and is associated with a significant risk of fetal complications, including premature birth and fetal death. In clinical practice, the diagnosis of ICP is predominantly based on the presence of pruritus in pregnant women and elevated serum total bile acid. However, this approach may result in missed or delayed diagnoses. Therefore, it is essential to explore the risk factors associated with ICP and to accurately identify affected individuals to enable timely prophylactic interventions. The existing literature exhibits a paucity of studies employing artificial intelligence to predict ICP. Therefore, developing machine learning-based diagnostic and severity classification models for ICP holds significant importance.MethodsThis study included ICP patients and some healthy pregnant women from Jiaxing Maternity and Child Health Care Hospital in China between July 2020 and October 2023. We collected clinical data during their pregnancies and selected the top 11 critical risk factors through univariable and lasso regression analysis. The dataset was randomly divided into training and testing cohorts. Thirteen machine learning techniques, including Random Forest, Support Vector Machine, and Artificial Neural Network, were employed. Based on their various classification performances on the training set, the top five models were selected for internal validation.ResultsThe dataset included 798 participants (300 normal, 312 mild, and 186 severe cases). Through univariable and lasso regression analysis, total bile acid, gamma-glutamyl transferase, multiple pregnancy, lymphocyte percentage, hematocrit, neutrophil percentage, prothrombin time, Aspartate aminotransferase, red blood cell count, lymphocyte count and platelet count were identified as risk factors of ICP. The AUCs of the selected top five models ranged from 0.9509 to 0.9614. The CatBoost model achieved the best performance, with an AUC of 0.9614 (95% confidence interval, 0.9377–0.9813), an accuracy of 0.9085, a precision of 0.8930, a recall of 0.9059, and a F1-score of 0.8981.ConclusionsWe identified risk factors for ICP and developed machine learning models based on these factors. These models demonstrated good performance and can be used to help predict whether pregnant women have ICP and the degree of ICP (mild or severe).

Mechanistic study of the effect of a high-salt diet on the intestinal barrier

Despite the established link between chronic high salt diet (HSD) and an increase in gut inflammation, the effect of HSD on the integrity of the intestinal barrier remains understudied. The present study aims to investigate the impact of HSD on the intestinal barrier in rats, encompassing its mechanical, mucous, and immune components. Expression levels of intestinal tight junction proteins and mucin-2 (MUC2) in SD rats were analyzed using immunofluorescence. The expression area of goblet cell mucopolysaccharides was assessed through PAS staining. Additionally, serum D-lactic acid, SIgA, β-defensin, and colonic tissue cytokines were measured using ELISA. Rats fed with HSD exhibited decreased expression of tight junction proteins, particularly Occludin, resulting in impairment of the intestinal epithelial barrier and an elevated serum D-lactic acid level. Furthermore, a notable reduction in the expression of goblet cell mucopolysaccharides, along with lower β-defensin and MUC2 levels, was observed. Notably, the SIgA and immune-related cytokines were significantly reduced in the HSD group. HSD disrupts the intestinal barrier in rats, leading to increased permeability and the entry of inflammatory factors into the bloodstream. This finding suggests that HSD may contribute to the pathogenesis of various diseases.

Unlocking the full potential of resistance training: a comparative analysis of low- and high-intensity effects on neurotrophic growth factors and homocysteine

ObjectiveResistance training has been demonstrated an effective approach for preventing the cognitive function decline through physiological mechanisms; however, the effect of acute resistance training at different intensities on growth factor and homocysteine levels remains unclear. This study aimed to compare the impact of resistance training at varying intensities on peripheral neurobiological factors and homocysteine levels in young adults.MethodsTwelve young male adults, predominantly engaged in various sports activities but without prior strength training experience, were recruited to participate in a randomized controlled cross-over trial. They implemented two different resistance training protocols: high intensity (HIRT, 12 repetitions at 80% 1RM) and low intensity (LIRT, 24 repetitions at 40% 1RM). Blood samples were collected at three time points: pre-training, post training, and after 30 min of rest to measure changes in serum lactate, serum brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1), vascular endothelial growth factor (VEGF), irisin, and plasma homocysteine (Hcy) levels.ResultsBoth resistance training protocols significantly increased blood lactate and perceived exertion compared to pre-training (HIRT, p < 0.01; LIRT, p < 0.01), with higher levels observed in HIRT. Acute HIRT significantly elevated serum BDNF, IGF-1, and VEGF levels post training compared to LIRT (p < 0.05), while no difference was observed in irisin levels between the two protocols at any time point. Both training protocols significantly reduced plasma Hcy levels post training (p < 0.01) and maintained lower levels than pre-training and after 30 min of rest (p < 0.05), with no significant differences between the two protocols.ConclusionsThis study demonstrates that high intensity training appears to have a greater impact on specific neurobiological factors; however, regardless of intensity, resistance training can significantly decrease plasma homocysteine.Trial registration ClinicalTrials.gov ID: NCT06114550. Date of registration 01/30/2024. https://clinicaltrials.gov/study/NCT06114550.

Microalbuminuria, neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1) as predictors of preeclampsia and gestational diabetes mellitus

Background: The health of young women of reproductive age is a key factor that directly influences the health of future generations. Therefore, early detection of chronic diseases, including chronic kidney disease, in this category of patients is one of the primary objectives of healthcare services. From an obstetric perspective, preventing chronic kidney disease can be linked to the early detection and prediction of preeclampsia and gestational diabetes mellitus. In the literature, there are studies that investigate microalbuminuria, neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1) as predictors of these obstetric complications. Aim: The aim of this study was to evaluate microalbuminuria, KIM-1, and NGAL as markers for the development of gestational diabetes mellitus and preeclampsia. Materials and methods: This prospective study was conducted at the Department of Obstetrics and Gynecology, Academician I.P. Pavlov First Saint Petersburg State Medical University (Saint Petersburg, Russia) and involved 280 pregnant women during the first trimester at 6-13 weeks of gestation. The concentrations of microalbuminuria, KIM-1, and NGAL were measured. The second stage involved assessing the course of pregnancy and the development of obstetric complications in the participants. ROC analysis was performed to assess biological markers as predictors of preeclampsia, and predictive value was evaluated by the area under the ROC curve. Results: The urinary KIM-1 levels in all patients were within the reference values. Microalbuminuria in the range from 30 to 300 mg/L was detected in 20 patients (7.14%). Gestational diabetes mellitus was more common in patients with microalbuminuria above 30 mg/L (p = 0.0358). Elevated serum NGAL levels above the reference values (106 ng/L) were observed in 96 patients (34.2%). Urinary NGAL levels exceeded 9.8 ng/L in 203 patients (72.5%). Moderate or severe preeclampsia developed in 63 (22.5%) pregnant women. ROC analysis of NGAL’s predictive ability showed high sensitivity and specificity for preeclampsia prediction (sensitivity 95.24%, specificity 93.09%, area under the ROC curve 0.93). Conclusions: The data obtained suggest that the assessment of albuminuria, serum NGAL, and urinary NGAL levels in the blood serum and urine of pregnant women during the first trimester of gestation may serve as early prognostic biomarkers for gestational diabetes mellitus and preeclampsia.