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In this study, we investigated the effects and molecular mechanisms by which Scutellaria barbata flavonoids (SBFs) enhance neurogenesis and ameliorate memory impairment mediated by CREB phosphorylation in rats, using a network pharmacology approach. The active ingredients of SBFs and their targets were identified using the Traditional Chinese Medicine Systems Pharmacology platform. An Alzheimer's disease (AD) model was established by intracerebroventricular injection of Aβ25-35 combined with AlCl₃ and RHTGF-β1 (composited Aβ) in rats. The Morris water maze was used to confirm the successful establishment of the AD rat model. Successfully modeled rats were randomly divided into three groups: a model group and two treatment groups receiving either 140 mg/kg SBFs or 0.5 mg/kg Rolipram (positive control). After 38 days, the Morris water maze test was performed to assess learning and memory abilities. Hematoxylin-eosin (HE) staining, immunohistochemistry, quantitative PCR (qPCR), and Western blotting (WB) were conducted to evaluate neuronal morphology, NeuN protein expression, the mRNA levels of TrkB, RSK, CREB, and BDNF, and the protein expression of NeuN, TrkB, RSK, P-CREB-Ser133, and BDNF in the hippocampus and cerebral cortex of the rats. These results indicate that SBFs and Rolipram ameliorate learning and memory impairment, reduce neuropathological changes, promote neurogenesis, and upregulate the BDNF- RSK-CREB signaling pathway through the activation of CREB phosphorylation. The findings suggest that the effects of SBFs are similar to those of Rolipram and that SBFs may also act as activators of CREB phosphorylation. Overall, SBFs promote neurogenesis and improve learning and memory deficits, possibly by enhancing CREB phosphorylation. This study identified the key targets and signaling pathways of SBFs in AD, indicating that SBFs represent a promising multitarget therapeutic candidate for the treatment of AD. However, our research has some limitations. Further studies are needed to determine the absorption route, major active components, and metabolic forms of the bioactive substances in SBFs. In future work, we aim to clarify the potential mechanisms of SBFs in AD by integrating multiple omics approaches and to evaluate the safety and efficacy of SBFs in AD treatment. Thirty-seven targets were identified based on the intersection between AD-related targets and the components of SBFs. SBFs were involved in anti-AD activity through the MAPK signaling pathway, including the BDNF-RSK-CREB pathway. SBFs attenuated memory impairment, ameliorated neuropathological changes, increased NeuN protein expression, and regulated the mRNA expression of TrkB, RSK, CREB, and BDNF, as well as the protein expression of NeuN, TrkB, RSK, P-CREB-Ser133, and BDNF. Rolipram produced similar effects to SBFs. Network pharmacology analysis and animal experiments confirmed that SBFs promote neurogenesis and ameliorate learning and memory impairment in AD model rats, primarily by facilitating CREB phosphorylation, similar to Rolipram. This study indicates that SBFs may be a promising therapeutic candidate for the treatment of AD. Show less

Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder characterized by severe hypertriglyceridemia and caused by mutations in genes involved in chylomicron metabolism. Dietary management includes a very-low-fat diet, restriction of simple carbohydrates and alcohol, supplementation with medium-chain triglycerides, essential fatty acids, and fat-soluble vitamins; however, long-term adherence is often poor and nutritional therapy alone is insufficient. We report two adult Chilean sisters with FCS caused by the homozygous Q97X mutation in the APOA5 gene. Both patients experienced severe hypertriglyceridemia (>5,000 mg/dL) and recurrent episodes of acute pancreatitis. One sister was treated with volanesorsen, an antisense oligonucleotide, receiving a weekly dose of 285 mg, which was repeated every 3 weeks due to thrombocytopenia. When combined with structured nutritional counseling, pharmacological treatment achieved a marked reduction in plasma triglycerides to <250 mg/dL and a substantial improvement in quality of life. The other sister was managed with conventional therapy due to a lack of health insurance coverage for volanesorsen. She presented persistent hypertriglyceridemia and recurrent hospitalizations, underscoring the challenges of access to advanced therapies in limited-resource settings. While volanesorsen offers a promising therapeutic alternative, equitable access remains a critical issue, particularly in health systems of low-to middle-income regions. Show less

Congenital heart defects represent a major global health burden, affecting nearly one million newborns annually. Identifying the underlying genetic causes is essential for improved diagnosis, patient management, and genetic counseling. We conducted a cytogenetic study integrating conventional karyotyping, fluorescence in situ hybridization (FISH), and chromosomal microarray analysis (CMA 44 K) in 20 Tunisian patients presenting syndromic CHDs and referred to our Genetics Department. CMA identified pathogenic copy number variations in four patients. These included an inherited 11 Mb deletion at 9p24.2 together with a 10 Mb duplication of 20pter; a de novo 1.2 Mb deletion at 15q26.2 with an 11 Mb duplication at 2q36.3; a de novo 113 kb deletion at 17q21.32; and a de novo 48 Mb duplication at 8q22. Several CNVs overlapped known deletion/duplication syndromes, some with previously infrequent cardiac involvement. Genotype-phenotype correlations enabled prioritization of CHD relevant genes including DOCK8, HTR2B, KANSL1, ZFPM2, and TRPS1, whose dosage sensitivity and interactions with cardiac developmental pathways may contribute to the observed phenotypes. This study reinforces the clinical utility of CMA in detecting cryptic chromosomal abnormalities in syndromic CHD. The identified CNVs and gene candidates offer new insights into CHD genetic architecture and support CMA as a first-tier diagnostic tool. These findings highlight the contribution of rare, pathogenic CNVs in syndromic cases and suggest their integration into refined diagnostic and counseling strategies. Further functional studies are necessary to elucidate the roles of these candidates in cardiogenesis. Show less

Skin aging arises from intrinsic processes and extrinsic insults (e.g., ultraviolet exposure and oxidative stress). Mesenchymal stromal cell (MSC)-derived secretome offers a cell-free approach to skin regeneration. Wharton's jelly-derived MSCs (WJ-MSCs) may outperform adipose-derived (AD-MSCs) and bone marrow-derived MSCs (BM-MSCs). Secretomes from WJ-MSCs, AD-MSCs, and BM-MSCs were compared in vitro for human dermal fibroblast proliferation, scratch-wound closure, extracellular-matrix (ECM) remodeling, and type I procollagen secretion. Anti-inflammatory and antioxidant activities were assessed by IL-6, IL-1β, TNF-α, COX-2 and intracellular reactive oxygen species (ROS). Antibody arrays profiled secreted factors. An exploratory, single-arm human pilot ( The WJ-MSC secretome increased fibroblast proliferation, ECM remodeling, and type I procollagen, and reduced cytokines and ROS, exceeding the effects of AD-MSC and BM-MSC secretomes. Profiling highlighted apolipoprotein A4 (ApoA4) and SERPINH1 as enriched, functionally active mediators; recombinant ApoA4 and SERPINH1 enhanced fibroblast activity, collagen-related readouts, and accelerated in vitro wound closure. In the pilot study, within-subject increases in instrument-derived hydration and elasticity were observed over one week (paired tests). No treatment-related adverse events were noted. Patch testing showed no irritation (ICDRG scores all 0; non-irritant classification). The WJ-MSC secretome demonstrated consistent in-vitro pro-regenerative, anti-inflammatory, and antioxidant activities, with ApoA4 and SERPINH1 as candidate mediators. Human findings are preliminary/exploratory and suggest potential short-term benefits that require confirmation in adequately powered, controlled trials. Show less

Apolipoprotein E (APOE) genotype influences the presence, course and severity of sporadic cerebral amyloid angiopathy (sCAA). We investigated the effect of the APOE ε4-allele on clinical and neuroradiological outcomes in mutation-carriers with Dutch-type hereditary (D-)CAA. Participants with D-CAA from a prospective cohort study, with data collected on history of symptomatic intracerebral hemorrhages (sICH) and vascular risk factors, underwent 3 Tesla magnetic resonance imaging (MRI) scans to assess macrobleeds, cerebral microbleeds (CMBs), cortical superficial siderosis (cSS), enlarged perivascular spaces (EPVS), white matter hyperintensity (WMH) volume and WMH multispot lesions. Global cognition was measured using Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE) scores. Associations between ≥1 APOE ε4-allele and age of first sICH, time to recurrence, cognition and radiological data were analyzed with adjustments for confounders. Eighty-one participants (mean age 47 years, 54% women, 38% with sICH history) were included. The APOE ε4-allele was not associated with earlier sICH onset (median age 56 versus 57 years; p = 0.6) or time to recurrence (5.0 versus 3.9 years; p = 0.4), nor was it associated with macrobleeds (β 2.0; 95%CI 2.4- -2.7; p = 0.4), CMBs (β 2.9; 95%CI 1.0-8.9; p = 0.06), cSS (aOR 0.5; 95%CI 0.1-2.0; p = 0.3), EPVS (aOR 0.4; 95%CI 0.1-1.5; p = 0.6), WMH volume (β 6.8; 95%CI -1.9-15.4; p = ), a multispot pattern (OR 0.7; 95%CI 0.2-2.7, p = 0.6), or cognition (β -0.3; 95%CI -0.4- -0.5; p = 0.5). APOE ε4 does not affect key clinical parameters or D-CAA neuroradiological markers and therefore does not explain the large variation in disease course in D-CAA. Show less

Fatigue persists as a dominant and debilitating phenomenon in long-COVID, yet its underlying biological mechanisms remain unclear. While inflammatory variables tend to normalize within months post-infection, fatigue continues to significantly impact quality of life. Understanding whether specific biomarkers associate with long-COVID fatigue could shed light on pathophysiological mechanisms and potential therapeutic targets. In this single-center, cross-sectional controlled study, we enrolled 48 individuals with long-COVID (according to NICE criteria) and 48 age- and sex-matched recovered controls with prior SARS-CoV-2 infection but no persistent symptoms. We carefully excluded all subjects with other diseases or conditions that could influence fatigue levels. Fatigue severity was assessed using three validated instruments: Fatigue Visual Analog Scale (fVAS), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), and SF-36 vitality subscale. Blood samples were analyzed for pro-inflammatory markers (CRP, TNF-α, IL-6, IL-1β) and biomarkers associated with cellular stress responses and neuroprotection (HSP90α, APOA4, Serpin F1/PEDF, Hemopexin). Anti-nuclear antibodies (ANA) were tested to assess potential autoimmune mechanisms. Depression was assessed using the Hospital Anxiety and Depression Scale, Depression Subscale (HADS-D). Long-COVID patients demonstrated significantly higher fatigue severity across all instruments compared to recovered controls: fVAS median scores 63 versus 5 (p < 0.001), FACIT-F scores 21.5 versus 49 (p < 0.001), and SF-36 vitality scores 25 versus 72.5 (p < 0.001). Depression scores were also significantly elevated in long-COVID cases. However, none of the measured biomarkers differed significantly between groups: HSP90α, Serpin F1, Hemopexin, APOA4, and CRP showed no differences, while TNF-α and IL-6 showed only tendencies toward higher levels in long-COVID (p = 0.07 and p = 0.07, respectively). IL-1β concentrations were in most cases below the lower limit of detection and were excluded from further analysis. ANA positivity was 10.4% in cases versus 4.2% in controls (p = 0.38) and did not influence fatigue levels. Multivariable regression analysis revealed no significant associations between biomarkers and fatigue severity. Fatigue in long-COVID represents severe, persistent disability comparable to observations in chronic inflammatory diseases and chronic fatigue syndrome but is not associated with traditional inflammatory biomarkers or cellular stress response proteins measured in peripheral blood. The absence of biomarker associations suggests that long-COVID fatigue may involve more complex mechanisms, potentially including persistent neuro-immune dysregulation, epigenetic changes, or pathophysiological processes not reflected in systemic biomarker concentrations including neurobiological mechanisms such as altered predictive processing and central nervous system-confined neuroinflammation. These findings highlight the need for alternative approaches to understanding and treating long-COVID fatigue beyond conventional inflammatory paradigms. Show less

Pregnant women have a high incidence of perinatal mood and anxiety disorders (PMADs). To explore the influence factor on perinatal psychology, we analysed the SCFAs, lipids, cognition, emotion, and cytokines in the late pregnant women. The mood, cognition, SCFAs of the non-pregnant group were compared to those in the late pregnancy. The differences in SCFAs, lipids, cognition, and cytokines between the high-risk and low-risk groups for affective disorders among women in the late pregnancy were analysed, and the risk factors were sought. Compared with the non-pregnant group, the pregnant group scored lower on the SDMT (P < 0.001), DST (P = 0.035), VRT (P = 0.001), and VFT (P < 0.001), and took longer on the TMTA (P = 0.004). Acetate (P = 0.001) and butyrate (P = 0.002) were higher, while propionate (P < 0.001) and isobutyrate (P = 0.001) were lower in the pregnant group than in the non-pregnant group. Among the pregnant women, CRP was higher in the high-risk group for mood disorders than in the low-risk group (P = 0.048). Meanwhile, HDL was positively associated with DST (P = 0.000), VRT (P = 0.015), and VFT (P < 0.001). Longer TMTA completion times were associated with reduced propionate (P = 0.072) and LPa (P = 0.022). Longer TMTB completion time was associated with lower life satisfaction (P = 0.037), as well as decreased cholesterol (P = 0.026). Pregnant women experience changes in cognition and SCFAs. CRP is a sensitive indicator for monitoring affective disorder. Regulation of SCFAs and lipids may be beneficial for cognition and affect. Show less

Human ApolipoproteinB (ApoB) exists in two isoforms that are packaged into low density lipoprotein particles and are major contributors to atherosclerosis. Alternatively, Drosophila Apolipoprotein Lipophorin (ApoLpp) also exists in two isoforms packaged into lipoprotein particles that cross the blood-brain barrier (BBB) in second instar larvae where they deliver lipids to neuroblasts. To extend our understanding of ApoLpp function to adult brains and suggest new hypotheses for human ApoB, we document evolutionary conservation between the two N-terminal isoforms human ApoB48 and fly ApoLppII. Then our tissue-specific analyses including rescue of apolpp lethality and apolpp RNAi showed that apolpp expression in the fat body is both necessary and sufficient for survival to adulthood. Our imaging studies of ApoLpp in the adult brain employed endogenous isoform-specific tagged proteins generated by the Fourth Chromosome Resource Project. Images revealed that both ApoLpp isoforms are present in the adult brain with ApoLppII accumulation prominent near glia. Nanobody morphotrap experiments that blocked tagged ApoLpp at the BBB demonstrated that ApoLpp detected inside the adult brain is exogenous. An N- and C-terminal tagged ApoLpp transgene expressed solely in the fat body facilitated tracking of each isoform from fat body secretion to the BBB and then inside the adult brain. Overall, our data suggest that the known role of ApoLpp in lipid delivery to larval brains likely continues in adults. Strong conservation between ApoLppII and ApoB48 supports the hypothesis that ApoB48 may have a role in the brain outside the circulatory system. Show less

Postoperative cognitive dysfunction (POCD) in older adults is strongly linked to neuroinflammation driven by microglial activation and NF-κB signaling. Runx1 has emerged as an upstream regulator of NF-κB, but its role in POCD is unknown. Dendrobine, a sesquiterpenoid alkaloid from Dendrobium species, exhibits anti-inflammatory and neuroprotective activity. POCD was induced in aged C57BL/6 mice via sevoflurane anesthesia combined with exploratory laparotomy. Dendrobine (10 or 20 mg/kg) was administered, and cognitive outcomes were evaluated by Morris Water Maze and Novel Object Recognition. RNA sequencing, Western blotting, immunofluorescence, and in vitro microglia-neuron co-culture systems were employed to investigate inflammatory responses, apoptosis, synaptic plasticity, and signaling pathway activation. Functional roles of Runx1 were validated via siRNA knockdown, pharmacological inhibition (Ro5-3335), and overexpression in BV2 cells. Dendrobine improved spatial and recognition memory in POCD mice, reduced hippocampal microglial activation, proinflammatory cytokine expression (TNF-α, IL-1β, IL-6), and neuronal apoptosis while enhancing synaptic protein levels (BDNF, PSD95, SYN1). Transcriptomic and KEGG analyses revealed suppression of NF-κB signaling by dendrobine, with Runx1 identified as an upstream modulator. Dendrobine downregulated Runx1 expression in vivo and in vitro. Runx1 inhibition enhanced dendrobine's anti-inflammatory effects, whereas RUNX1 overexpression abolished them. Dendrobine ameliorates POCD by inhibiting the Runx1/NF-κB signaling pathway, suppressing neuroinflammation, promoting synaptic resilience, and preventing neuronal apoptosis. Runx1 appears to act as a key upstream mediator of NF-κB signaling in POCD. Targeting the Runx1/NF-κB axis represents a promising strategy for perioperative neuroprotection. Show less

Fibrillary glomerulonephritis is a rare cause of proteinuric kidney disease characterized by Congo red-negative fibrillary deposits and typically shows DNAJB9 positivity on immunohistochemistry. Amyloidosis is defined by Congo red positivity and can be typed by laser microdissection-tandem mass spectrometry when routine studies are inconclusive. We report the case of a 64-year-old man with proteinuria and declining kidney function whose kidney biopsy showed DNAJB9-positive fibrillary glomerulonephritis in glomeruli, but Congo red-positive deposits confined to the medulla were DNAJB9 negative. Laser microdissection-tandem mass spectrometry of the medullary deposits identified apolipoprotein A-IV amyloidosis, establishing concurrent fibrillary glomerulonephritis and apolipoprotein A-IV amyloidosis in the same biopsy. Apolipoprotein A-IV amyloidosis is often medullary predominant and, in rare hereditary forms related to autosomal dominant Show less

This study examined how different photoperiods affect net energy partitioning and explored the mechanisms via blood biochemistry, gut microbiota, and fecal metabolites. Twelve healthy crossbred pigs (47.7 ± 7.5 kg) were randomly allocated to two groups and subjected to a self-controlled crossover design. Following an 8-day baseline under a normal photoperiod (12L:12D, 12 h light:12 h dark), pigs were assigned to two photoperiod treatment groups: prolonged photoperiod (18L:6D, 18 h light:6 h dark; P group) and shortened photoperiod (6L:18D, 6 h light:18 h dark; S group). Measurements during the baseline (12L:12D) and treatment phases are designated as N1/P (for the P group) and N2/S (for the S group), respectively. The treatment periods were interspersed with the baseline 12L:12D photoperiod and repeated six times. It was observed that, compared to N2, shortened photoperiod (S) had significantly higher net energy deposition, net energy for protein deposition, and net energy for fat deposition ( Show less

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver condition, closely associated with obesity and type 2 diabetes mellitus. Despite its prevalence, there are no approved pharmacotherapies, making the search for effective treatments crucial. This study investigates the impact of vertical sleeve gastrectomy (VSG) on NAFLD, focusing on changes in bile acid metabolism as a potential therapeutic mechanism. We employed an ApoE-/- mouse model to simulate human NAFLD conditions. Mice were divided into two groups: one underwent VSG and the other served as a control. We monitored body weight, food intake, liver function, lipid profiles, and histological changes in hepatic tissues. Bile acid profiles were analyzed using Ultra Performance Liquid Chromatography coupled with Tandem Mass Spectrometry (UPLC-MS/MS). Post-VSG, mice exhibited significant weight loss and reduced food intake. Biochemical analyses showed substantial improvements in liver function tests (ALT and AST), lipid profiles (cholesterol and triglycerides), and glucose regulation. Histological examination revealed marked reductions in hepatic steatosis and inflammation. Notably, VSG led to significant alterations in bile acid profiles, particularly increased primary bile acids and decreased secondary bile acids, correlating with improved liver histology and metabolic parameters. Our findings suggest that VSG, beyond its role in weight reduction, significantly improves NAFLD. The surgery alters bile acid metabolism, which may contribute to its therapeutic effects. These results highlight the potential of VSG as a metabolic surgery for NAFLD and open avenues for exploring bile acid-related therapies. Show less

Angiopoietin-like protein 8 (ANGPTL8), a member of the angiopoietin-like protein (ANGPTL) family, is a physiological inhibitor of lipoprotein lipase (LPL), and plays a critical role in lipoprotein and triglyceride metabolism in response to nutritional cues. ANGPTL8 is implicated in a wide range of systemic and cellular processes and is closely associated with metabolic and cardiovascular diseases (CVD). Circulating ANGPTL8 is primarily secreted by the liver, with adipose tissue as a secondary source. Its expression is regulated by multiple transcription factors and microRNAs, and is responsive to fasting/refeeding states, hormonal signals, and stress conditions. In lipid metabolism, ANGPTL8 forms complexes with ANGPTL3 and ANGPTL4 to modulate LPL activity under fasting and feeding conditions. In glucose metabolism, ANGPTL8 plays a complex role. While some studies suggest it may improve glucose tolerance and insulin resistance, others indicate it could exacerbate glucose metabolism disorders and diabetes, or have no effect. Cardiovascular diseases are intricately linked to metabolic disorders and diseases. Increasing evidence also links ANGPTL8 to various cardiovascular pathologies, including atherosclerosis, hypertension, cardiomyopathy, cardiac hypertrophy, aortic aneurysm, and dissection. Given the strong interplay between metabolic dysregulation and CVDs, elucidating the role of ANGPTL8 in these processes is of significant interest. This review provides a balanced assessment of ANGPTL8's roles in key pathophysiological processes, highlighting its established functions in metabolism alongside its emerging involvement in CVDs. Understanding the diverse functions of ANGPTL8 in various tissues and metabolic states will lead to new opportunities for therapeutic intervention in cardiometabolic disorders. Show less

Apolipoprotein A-IV amyloidosis (AApoA-Ⅳ) is a rare subtype of cardiac amyloidosis (CA) and is often overlooked because of its clinical similarity to transthyretin (ATTR) CA. An 82-year-old man presented with heart failure with preserved ejection fraction. His clinical features, including grade 1 uptake on Although the pathologic significance of the unique histologic features remains unclear, they may represent distinguishing characteristics of AApoA-IV amyloidosis. AApoA-IV CA typically presents with elderly-onset heart failure with preserved ejection fraction and may show positive uptake on bone scintigraphy. Differentiation from ATTR CA is possible based on characteristic histopathologic findings and mass spectrometry-based proteomic analysis. Show less

Genetic variations in the lipoprotein lipase (LPL) gene including the HindIII polymorphism (rs320) have been reported to modify fat metabolism, adiposity, and body weight. However, little attention has been given to the African population. The present study aimed to investigate the relationship between the rs320 gene polymorphism and a number of metabolic and anthropometric parameters in a sample of the Nigerian population. We recruited 236 participants for the study. The participants were required to sign informed consent forms after which information related to their calorie intake and utilization as well as anthropometric measurements were recorded. Plasma metabolic parameters were subsequently determined using an autoanalyzer. Genotyping for HindIII polymorphism was performed using the PCR-RFLP method. The frequencies (n) of T and G alleles were 0.841 (397) and 0.158 (75), while the frequencies (n) of TT, TG, and GG were 0.691(163), 0.301(71), and 0.01(2), respectively. The population was not in Hardy-Weinberg equilibrium (χ Show less

Elite training induces profound physiological adaptations, yet whether these changes manifest as stable circulating proteomes remains unclear. This study characterized serum proteomic profiles in male and female Olympic-level athletes to identify biomarkers associated with long-term endurance and strength training. Cross-sectional study in Olympic-level athletes and sedentary controls. Resting serum samples were collected from male and female marathon runners and weightlifters (with 5-15 years of training), alongside age- and sex-matched sedentary individuals. Proteomic profiling was performed using tandem mass spectrometry. Data were processed with MaxQuant and analyzed using Perseus. Selected proteins were confirmed using antibody-based assays. Among 301 identified protein groups, 36 showed significant differences between groups. Apolipoprotein A-IV (APOA4) was elevated in athletes, particularly marathoners, suggesting cardiovascular adaptation to endurance training. Fibronectin 1 (FN1) was reduced in weightlifters, consistent with vascular remodeling associated with resistance training. Marathoners exhibited higher levels of von Willebrand factor (VWF) and glycosylphosphatidylinositol-specific phospholipase D1 (GPLD1), and lower levels of galectin-3-binding protein (LGAS3BP) and leucine-rich alpha-2-glycoprotein 1 (LRG1), indicating immunomodulatory effects of oxidative training. Weightlifters showed reduced levels of GPLD1 and extracellular matrix protein 1 (ECM1), reflecting distinct remodeling pathways. FN1, APOA4, VWF, LGALS3BP and ECM1 levels were further confirmed. Endurance and resistance training elicit modality-specific serum proteomic adaptations that reflect vascular, endothelial, and hemostatic remodeling. These molecular signatures, observed in both sexes, highlight stable changes induced by chronic training and may inform cardiovascular prevention strategies and evidence-based approaches in sports science to optimize training and performance. Show less

Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone traditionally known for its insulinotropic and adipogenic effects. However, its role in immune modulation and inflammation has recently gained attention, particularly in the context of metabolic diseases. By conducting a comprehensive search into the scientific literature since the discovery of GIP hormone, this review examines the biological evidences linking GIP and inflammation in pre-clinical and clinical studies. Pharmacological approaches targeting the GIP receptor (GIPR) with effects on inflammatory processes are discussed as well, including the latest GIP-based multi-target approaches. The impact of GIP on inflammation appears context-dependent and influenced by tissue-specific receptor expression and metabolic status. While GIP has been shown to exert both pro- and anti-inflammatory effects in experimental models, clinical data are still limited. The success of GIP/glucagon-like peptide-1 (GLP-1) dual agonists in improving glycometabolic and inflammatory outcomes, highlighted the need to disentangle the individual contributions of each pathway. GIPR remains a promising, yet understudied, target in immunometabolism. Future studies are needed to clarify the molecular mechanisms underpinning GIP’s immunomodulatory actions and evaluate the anti-inflammatory potential of GIP-targeting therapies in clinical settings. Show less

Carbamoyl phosphate synthetase 1 (CPS1) is primarily expressed in hepatocytes as a highly abundant mitochondrial matrix enzyme that catalyses the first step of the urea cycle that leads to renal nitrogen disposal. CPS1 is a member of the CPS family that manifests broad evolutionary expression from bacteria to humans. CPS1 expression and enzyme activity are highly regulated transcriptionally and post-translationally. Its autosomal recessive mutation leads to CPS1 deficiency, which causes encephalopathy and coma, typically neonatally, due to severe hyperammonaemia. CPS1 is physiologically secreted, apically, into bile likely via mitochondria-derived vesicles. Normally absent from serum, it is released by basolateral mistargeting and cellular injury and becomes readily detectable in serum during acute liver failure (ALF). Injury-triggered CPS1 release into blood, or media in cultured hepatocytes, is selective as compared with other mitochondrial proteins. This, coupled with its abundance and short (1-2 hours) serum half-life, renders it a prognostic serum biomarker, particularly in human acetaminophen-related ALF. Its rapid turnover is explained by its non-enzymatic role as an immune modulator via its uptake by circulating monocytes leading to differentiation of anti-inflammatory cells that home to, and protect, the injured liver. CPS1 also plays a growing role in several cancers, by CPS1 upregulation or downregulation, particularly via metabolic reprogramming which alters the tumour microenvironment and impacts cancer growth and progression. Therefore, CPS1 has multiple enzymatic and non-enzymatic touch points spanning a wide range of cellular and extracellular functions and roles, with important physiological, homoeostatic, genetic disease, diagnostic and potential therapeutic clinical implications. Show less

Carbamoyl phosphate synthetase 1 (CPS-1) deficiency is a rare autosomal recessive disorder that disrupts the proximal mitochondrial phase of the urea cycle, resulting in impaired ureagenesis, hyperammonaemia and metabolic decompensation during the neonatal period. This condition is linked to significant neurological impairment and poses a considerable risk of mortality, especially in newborns. This case underscores the importance of recognising urgent clinical presentation and the intricate management challenges encountered in the treatment of early-onset CPS-1 deficiency. Show less

Lipoprotein(a) [Lp(a)] is a highly atherogenic particle that significantly increases overall cardiovascular risk. Evidence regarding concentrations of Lp(a) in the Polish general population remains limited, as well as the association between Lp(a) and various clinical characteristics. The aim in this study was to analyze Lp(a) concentration in a Polish population hospitalized in a tertiary referral hospital, compare clinical characteristics between patients with low and high Lp(a) and find the predictors of increased Lp(a) concentrations. This was an observational, cross-sectional study. All patients hospitalized in the Clinical Department of Internal Medicine, Endocrinology, Diabetology, and Nephrology in the Czerniakowski Hospital between 01.03.2024 and 08.10.2024 and with measured Lp(a) concentration were consecutively included. Patients were divided into two groups: those with high Lp(a) (≥ 30 mg/dL) and those with low Lp(a) ( < 30 mg/dL). The groups were compared in terms of multiple clinical characteristics. Multiple logistic regression was used to determine independent predictors of high Lp(a). The p-value below 0.05 was considered statistically significant. Out of 562 patients, 117 had high Lp(a) concentration (20.8%). The groups did not differ in terms of age, sex, or clinical examination findings. In a multiple logistic regression, male sex was associated with a decreased odds ratio of high Lp(a) (OR = 0.2857, 95% CI: 0.1107 to 0.6468, p = 0.01). High Lp(a) is prevalent in the Polish population, and thus it is important to measure it routinely in each individual at least once in a lifetime and control all other known cardiovascular risk factors to decrease the overall risk. Show less

Attention-deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder in children. Long Mu Ning Xin Decoction (LMNXD) shows established clinical efficacy against ADHD, yet its mechanistic basis is not fully elucidated. This study investigates the therapeutic potential of LMNXD for ADHD and explores its underlying mechanisms of action. Thirty spontaneously hypertensive rats (SHRs/NCrl) were randomly divided into five groups: a model (SHR) group, low-, medium-, and high-dose LMNXD (LMNXD-LD, LMNXD-MD, LMNXD-HD)groups, and a methylphenidate hydrochloride (MPH) group. Additionally, six Wistar Kyoto (WKY/NCrl) rats were designated as the control group.Behavioral performance was assessed using the open field test and Morris water maze. The expression levels of glial fibrillary acidic protein (GFAP), dopamine deceptor D1 (DRD1), and brain-derived neurotrophic factor (BDNF) in the rat hippocampus, prefrontal cortex (PFC), and striatum were evaluated by immunofluorescence, immunohistochemistry, and Western blot. Potential targets and mechanisms were explored through transcriptomic sequencing and network pharmacology, with subsequent validation by reverse transcription quantitative polymerase chain reaction (RT-qPCR). Compared to the SHR group, LMNXD ameliorated hyperactivity, impulsivity, deficits in spatial memory and learning ability in SHR/NCrl rats. It also effectively reduced GFAP expression in the hippocampus while increasing DRD1 expression in the PFC and BDNF levels in the striatum. Network pharmacology predicted that LMNXD might alleviate ADHD by acting on pathways including phosphatidylinositide 3-kinase-Akt (PI3K-Akt), calcium signaling, and cyclic adenosine monophosphate (cAMP) signaling. Consistent with this prediction, transcriptomic analysis of rat hippocampi showed that LMNXD influences the cAMP and PI3K-Akt signaling pathways, as well as serotonergic and cholinergic synapses. RT-qPCR further confirmed that LMNXD likely exerts its therapeutic effect by regulating the mRNA expression of ATPase Plasma Membrane Ca LMNXD may ameliorates hyperactive-impulsive behaviors and improves spatial memory and learning in SHRs/NCrl rats by modulating ATP2B4, GRIN3A, OXTR, COL6A2, and ITGA1 within the cAMP and PI3K-Akt signaling pathways. This intervention also upregulates DRD1 and BDNF expression while downregulating GFAP levels. Show less

The APOE4 is a well-established and significant genetic risk factor associated with the accumulation of β-amyloid (Aβ) plaques and hyperphosphorylated tau (p-tau) in the pathogenesis of Alzheimer's disease (AD). Our previous research has implicated circular RNA FoxO3 (circ-FoxO3) in the clearance of aggregated proteins in ischemic stroke. However, the role of circ-FoxO3 in the accumulation of abnormal proteins during AD development remains unclear. In this study, we demonstrate that circ-FoxO3 mitigates APOE4-driven neurotoxic protein aggregation by enhancing FoxO3-mediated autophagy. Specifically, transgenic mice expressing human APOE4 exhibited elevated levels of p-tau and Aβ, and these pathological alterations were significantly ameliorated by circ-FoxO3. Mechanistically, we found that circ-FoxO3 upregulates its host gene FoxO3, leading to activation of autophagy and subsequent clearance of neurotoxic protein aggregates. The findings highlight a critical role for circ-FoxO3 in counteracting APOE4-induced brain damage and suggest its potential as a therapeutic target for mitigating APOE4-related neuropathology. Show less

Familial hypercholesterolemia (FH) is the most common monogenic lipid disorder, primarily resulting from mutations in LDLR, APOB, and PCSK9 genes. These mutations cause persistently high levels of low-density lipoprotein cholesterol (LDL-C), predisposing affected individuals to premature atherosclerotic cardiovascular disease (ASCVD). Homozygous FH (HoFH), a rare but severe form, manifests early in life with cutaneous xanthomas and accelerated coronary and aortic disease. Early diagnosis and aggressive, lifelong management are crucial, yet challenges remain, particularly when follow-up is interrupted. We report the case of a 20-year-old female diagnosed with HoFH at age 13 after presenting with xanthomas. Initial evaluation revealed mild to moderate aortic stenosis and early coronary artery involvement. Genetic testing confirmed a homozygous LDLR mutation. Despite treatment with atorvastatin and evolocumab, partial lipid control was achieved, and follow-up was disrupted during the COVID-19 pandemic. At 20 years, she presented with worsening dyspnea, paroxysmal nocturnal dyspnea, and orthopnea. Advanced imaging documented severe heart failure with an ejection fraction of 20%, significant ventricular dilation, severe mitral regurgitation, and calcified aortic stenosis. Coronary angiography demonstrated critical coronary stenoses, while subsequent adjustments in her lipid-lowering regimen, including rosuvastatin, ezetimibe, increased evolocumab dosing, and bempedoic acid, failed to stabilize her condition. Despite recommendations for surgical intervention, the patient's critical status precluded operative management, and she tragically died on the day of her scheduled follow-up. This case underscores the aggressive natural history of HoFH and the dire consequences of interrupted follow-up care. Early detection and sustained, multidisciplinary management are essential to mitigate rapid cardiovascular deterioration in HoFH patients. Consistent monitoring and prompt therapeutic adjustments remain pivotal in improving outcomes and reducing the high mortality risk associated with advanced aortic and coronary complications in these patients. Show less

Xinjiang Brown cattle are an important beef breed in Northwest China. Although multigenerational selective breeding has improved their growth performance, the accompanying molecular adaptations and potential physiological trade- ofs remain insufficiently elucidated at the systemic level. This study aimed to decipher the dynamic serum proteomic profiles shaped by both ontogeny and generational selection in Xinjiang Brown cattle, and to identify the associated key proteins and pathways. Serum samples from 18 bulls across three genera- tions (A, B, C) at 3 and 9 months of age were analyzed using Tandem Mass Tag (TMT)-based quantitative proteomics. Under stringent quality control (FDR < 1%), 583 high-confidence proteins were identified. Diferentially expressed proteins (DEPs) were screened using thresholds of |fold change| ≥ 1.2 and This study reveals that the breeding strategy for Xinjiang Brown cattle prioritizes shaping a proteomic landscape that promotes growth and metabolism, potentially at the cost of atten- uated immune-vascular reactivity. The identified panel of candidate proteins pro- vides a molecular framework for evaluating breeding outcomes and designing balanced selection strategies. Follow-up research should further investigate the functions of these candidate proteins and validate their predictive value for health and production performance in independent herds. Show less

Breast cancer is the leading cause of cancer-related mortality in African American (AA) women. In this study we evaluated the serum proteomic profile of AA women with breast cancer using an integrated proteomic framework with multivariate pattern analysis. Using 2D-DIGE, thousands of serum protein spots were detected across 33 gels; 46 spots met criteria for presence, statistical significance, and differential expression. Proteins from the spots were identified by MALDI-TOF/TOF and matched in curated databases, highlighting serum biomarkers including ceruloplasmin, alpha-2-macroglobulin, complement component C3 and C6, alpha-1-antitrypsin, alpha-1B-glycoprotein, alpha-2-HS-glycoprotein and haptoglobin-related protein. LC-MS/MS analysis revealed 163 differentiating peptides after imputing and filtering 286 peptides. These were evaluated using cumulative distribution function (CDF) analysis, a nonparametric method suited for limited sample sizes. Peptide patterns were explored with Random Forest, showing concordance with CDF. The model achieved an AUC of 0.85 at the peptide level. This workflow identified differentiating proteins (CERU, A2MG, CO3, VTDB, HEMO, APOB, APOA4, CFAH, CO4A, AACT, K1C10, ITIH2, ITIH4), highlighting CERU, A2MG, and CO3 with overexpression and reproducible identification across platforms. We present an integrated, non-invasive serum protein biomarker signature panel specific to AA women, through reproducible proteomic sensor framework to support early detection and breast cancer prevention. Show less

CNS diseases are a prevailing cause of morbidity and mortality worldwide, and are influenced by environmental and biological factors, including genetic risk. Here, we generated genome-wide genetic data on a large cohort of brain tissue donors with in-depth clinical and neuropathological phenotyping, allowing for broad investigations into the risk and mechanisms of these neurological, neurodevelopmental, and psychiatric conditions. This resource consists of 9,663 donors with array-based genotyping and 9,543 donors with whole-genome sequencing completed. The clinical diagnoses of these donors include 148 central nervous system diseases clustered into 15 broad categories by International Classification of Diseases-10 (ICD-10) coding. These donors were collected by six repositories comprising the National Institutes of Health NeuroBioBank, with an average participant age of 60 years. While primarily older individuals of European descent, the cohort also contains younger donors and individuals from non-European backgrounds. Variants were detected in whole-genome sequencing (WGS), normalized and annotated to describe their functional impact, resulting in 171,121,209 unique variants and 1,078,774 non-silent variants. These raw and normalized data have been made available as a neurogenomics resource in the National Institute of Mental Health Data Archive (NIMH NDA) (nda.nih.gov), combined with donor-matched deep demographic and phenotypic data from the NeuroBioBank Portal (neurobiobank.nih.gov). To illustrate applications, we replicated the strong association observed in previous studies between pathogenic CAG nucleotide repeat expansions in the HTT gene with the clinical diagnosis of Huntington's disease, as well as associations of the APOE gene with Alzheimer's disease, and examined the association of polygenic risk scores with the three most common disease diagnoses in the cohort. Show less

APOE genotype may affect statin therapy response. We conducted a meta-analysis to update and quantify this association across various outcomes. We searched seven databases (MEDLINE, Scopus, Web of Science, the Cochrane Library, APA PsycINFO, CINAHL Plus and ClinicalTrials.gov) on 9 May 2024. Screening and data extraction were performed by two reviewers and a machine learning tool (ASReview). From 4352 de-duplicated records, 52 studies were included in the meta-analysis. Biomarkers analysed included low-density lipoprotein cholesterol (LDLC), total cholesterol (TC), triglycerides (TG) and high-density lipoprotein cholesterol (HDLC). Compared to ε3 carriers, ε2 carriers showed greater reductions in LDLC in response to statin treatment (mean difference in percentage change: -2.98%, 95% CI: -5.88% to -0.08%) and similar reductions in TC (-2.73%, -5.62% to 0.16%), and TG (-4.95%, -11.93% to 2.04%) with no significant difference in HDLC (-0.09%, -3.10% to 2.91%). After adjusting for publication bias, ε4 carriers showed less pronounced statin effects, with smaller reductions in LDLC (mean difference: 10.04%, 6.04% to 14.04%), TC (8.99%, 5.08% to 12.90%) and TG (8.24%, 2.15% to 14.33%), along with a smaller increase in HDLC (-10.08%, -15.30% to -4.85%) compared to ε3 carriers. Study quality was unclear, and heterogeneity (partly explained by sex and Familial hypercholesterolemia) was high, especially for the percentage changes. A stronger genotype effect was seen in males. Our meta-analysis shows that APOE genotype may influence statin response, emphasizing the need to incorporate known genetic factors into personalized treatment regimens. Show less

We report the case of a 47-year-old woman with severe hypertriglyceridemia due to a homozygous APOA5 c.553G>T (p.Gly185Cys) mutation. She presented with markedly elevated triglyceride levels (TG, 1,047 mg/dL) that were unresponsive to lifestyle modifications. Lipoprotein fractionation revealed increased chylomicrons (CMs, 21%) and very-low-density lipoprotein (35%), consistent with type V hyperlipoproteinemia. Secondary causes, such as diabetes, alcohol intake, and hypothyroidism, were excluded. The post-heparinization lipoprotein lipase (PH-LPL) level was reduced (104 ng/mL), indicating impaired lipolysis. Genetic testing revealed no pathogenic variants in LPL or other major genes related to triglyceride metabolism. A homozygous APOA5 c.553G>T variant was identified. Pemafibrate (0.2 mg/day), a selective PPARα modulator (SPPARMα), was initiated. After 2 months, the blood lipid levels had markedly improved, with the complete disappearance of CMs, and the PH-LPL level had normalized to 173 ng/mL. This case highlights the potential pathogenic role of APOA5 mutations in LPL-related hypertriglyceridemia. Furthermore, it demonstrates the multifaceted therapeutic effects of pemafibrate, suggesting a potential role for SPPARMα therapy in the management of hereditary hypertriglyceridemia. Homozygous APOA5 mutations can cause reduced LPL protein levels, leading to severe hypertriglyceridemia with elevated CMs and VLDL. Pemafibrate may improve both LPL levels and lipid profiles, even in cases with reduced LPL protein and chylomicronemia. ApoA5-related chylomicronemia can resemble familial chylomicronemia syndrome but may respond to therapies such as pemafibrate, highlighting the importance of accurate genetic diagnosis. Show less