Search Results (2,081)

Circadian desynchronization is increasingly linked to metabolic, immune, neurocognitive, and oncological disease, but integrated clinical phenotyping across endocrine, microbiome, metabolic, and neuroimaging domains remains limited. We conducted a prospective, single-centre, observational study in 179 symptomatic patients referred for chronic multisystem features consistent with circadian dysregulation and 107 practically healthy controls. Circadian melatonin status was assessed using fractionated 24 h urinary 6-sulfatoxymelatonin (aMT6s) and standardized dim-light plasma sampling at daytime (14:00–16:00) and nocturnal (02:00–04:00) windows. Microbiome composition was assessed by 16S rRNA sequencing, urolithin A by targeted metabolomics, and putative glymphatic/perivascular clearance by MRI-derived DTI-ALPS index, perivascular space scoring, and white-matter-hyperintensity (WMH) volumetry. Patients showed markedly reduced nocturnal melatonin output and loss of day–night contrast (night aMT6s 10.2 vs. 40.6 ng/mL; urinary aMT6s day/night ratio 0.81 vs. 0.14; plasma nocturnal melatonin 12.7 vs. 54.4 pg/mL; all p < 0.0001), accompanied by altered cortisol day–night patterning. Patients also showed reduced microbiome diversity, depletion of Gordonibacter and Ellagibacter, lower plasma urolithin A, higher WMH volume and perivascular space scores, and a lower DTI-ALPS index. Age distributions broadly overlapped in the individual-level dataset, and key biomarkers were not significantly correlated with chronological age within the patient cohort; however, this finding is interpreted as an exploratory absence of detectable age gradient within the symptomatic cohort, not as proof of biological age-independence. Overall, the data support a coherent cross-sectional association among blunted nocturnal melatonin rhythmicity, dysbiosis/urolithin depletion, and MRI markers compatible with impaired perivascular clearance. The MGM axis framework should be regarded as hypothesis-generating; causal direction, melatonin receptor involvement, and AQP4-related mechanisms require longitudinal and mechanistic validation. Full article

This study systematically investigated the alkali activation behavior of construction waste micro-powder (CWM) to develop a low-carbon, high-performance cementitious material. The activator formulation was optimized, the hydration thermodynamics were analyzed, and a kinetics model was constructed to reveal the reaction mechanism. The composite activator (sodium silicate and Portland cement) exhibited a significant synergistic effect, outperforming single activators. The optimal ratio was determined: 40% CWM, 60% Portland cement, and 8% water glass (modulus 1.0), which balances the system’s alkalinity and silicate modulus. Thermogravimetric analysis revealed a notable net weight gain at 3 days, indicating an ongoing secondary hydration reaction. By 7 days, the main hydration was complete, accompanied by microstructural densification, which confirmed the efficiency of the composite activator. A key contribution was the successful application of the Krstulović–Dabić (KD) model to quantify the hydration mechanism. The hydration process evolved sequentially through nucleation and growth (NG, dominant before 0.05~0.15 h), phase boundary reaction (I), and diffusion (D). The period of 0.21–50 h was governed by both I and D, after which D became the sole rate-limiting step. The model yielded the rate constants (K_NG, K_I, K_D), Avrami exponent (n), and transition points (α1, α2), providing a kinetic explanation for the ‘early strength and rapid hardening’ characteristic. In conclusion, this work establishes a material design framework guided by activator optimization, supported by thermodynamics, and explained by kinetics. The KD model proves to be a powerful tool for deciphering the hydration behavior of alkali-activated CWM, offering theoretical guidance for developing sustainable cementitious materials with controllable performance. Full article

Background/Objectives: Familial hyperaldosteronism type IV (FH-IV) is an extremely rare, clinically heterogeneous condition representing the least characterized familial subtype of primary aldosteronism (PA) caused by germline gain-of-function CACNA1H mutations. Despite growing molecular insights, optimal diagnostic and therapeutic strategies remain poorly defined. This systematic review aims to synthesize available evidence regarding the clinical, biochemical, and genetic characteristics of FH-IV, and to evaluate the efficacy of current pharmacological and surgical treatments. Methods: A systematic review was conducted in accordance with PRISMA guidelines and preregistered in PROSPERO (CRD420261324945). A comprehensive search of MEDLINE, Embase, and Web of Science identified studies reporting genetically confirmed FH-IV patients. Data concerning clinical phenotypes, diagnostic evaluations, treatment outcomes, and genetic backgrounds were extracted and analyzed. Results: The primary cohort included 31 fully characterized symptomatic patients, alongside 8 mutation-positive relatives (4 asymptomatic carriers and 4 symptomatic individuals). The genetic landscape was remarkably heterogeneous, encompassing 17 distinct CACNA1H mutations. Clinically, diagnosis was frequently delayed, often complicated by atypical normokalaemic presentations and misleading adrenal imaging. Surgical treatment was generally ineffective, frequently resulting in persistent or recurrent hypertension and biochemical dysregulation. Pharmacologically, patients often required multiple antihypertensive drugs, most frequently a combination of mineralocorticoid receptor antagonists (MRAs) and calcium channel blockers (CCBs). Conclusions: FH-IV is best conceptualized as a systemic adrenal channelopathy. While standard screening parameters are usually elevated, atypical biochemical profiles and misleading structural imaging can complicate the diagnostic process. Optimal management relies on multigene Next-Generation Sequencing (NGS) panels for definitive diagnosis and cascade screening of relatives. Finally, while the combination of MRAs and CCBs is commonly used in PA, it represents a valuable therapy for FH-IV, with dual L-/T-type CCBs emerging as a potential disease-specific option. Full article

Severe traumatic brain injury (TBI) is a leading cause of mortality and long-term disability in polytrauma (PT) patients, and its clinical outcome remains difficult to predict due to clinical heterogeneity and secondary injury mechanisms. Current diagnostic and prognostic approaches based on clinical assessment and imaging are limited, particularly in PT where neurological evaluation is often impaired. This study aimed to compare plasma- and extracellular vesicle (EV)-associated microRNA (miRNA) signatures in patients with severe TBI and healthy controls to identify their potential as minimally invasive biomarkers and to improve understanding of molecular responses. For profiling circulating miRNAs, blood samples were collected at ≤3 h and at 48 h after admission. In the screening phase, plasma samples of n = 15 patients with severe isolated TBI (Abbreviated Injury Scale [AIS]Head ≥ 4, all other AIS ≤ 1) and n = 15 age- and sex-matched healthy controls were pooled (n = 5/pool) and subjected to next-generation sequencing (NGS). In the following validation phase, n = 25 severely injured trauma patients (Injury Severity Score [ISS] ≥ 16) were enrolled and stratified into PT without TBI (PT; AISHead = 0; n = 13) and isolated TBI (n = 12). Differentially expressed candidate miRNAs identified in the screening phase were validated in individual plasma and EV samples using reverse transcription droplet digital polymerase chain reaction (RT-ddPCR). Functional enrichment and pathway analyses were performed using miRNet. NGS identified more differentially expressed miRNAs in plasma (ER: 103; 48 h: 65) than in EVs (Emergency Room [ER]: 14; 48 h: 32). Functional enrichment analysis indicated associations with pathways related to cellular stress, senescence, growth factor signaling, transcriptional regulation, and apoptosis. In validation, 12 of 16 plasma and 10 of 15 EV-miRNAs were confirmed as differentially expressed in TBI patients; among these, three plasma and four EV miRNAs differed between TBI and PT. After adjustment, most plasma miRNAs were associated with injury severity rather than group status. EV miRNA profiles showed heterogeneous patterns, with miR-1469 associated with TBI group status in adjusted analysis, while miR-1237-5p was linked to injury severity and other EV miRNAs showed no consistent group-specific effects. Plasma miRNAs mainly correlated with systemic injury markers, whereas EV miR-1469 showed a moderate association with the Glasgow Coma Scale (GCS). Overall, circulating miRNA profiles after injury appear to be predominantly influenced by systemic trauma severity rather than TBI-specific effects. Plasma miRNAs mainly reflected general injury burden, whereas EV-associated miRNAs showed more heterogeneous patterns, with miR-1469 emerging as a candidate associated with TBI after adjustment for clinical covariates. These findings suggest that EV-derived miRNAs, particularly miR-1469, may provide more targeted signals related to brain injury and warrant further investigation. Full article

Atmospheric arsenic (As) poses significant health threats in heavily polluted urban environments. However, the size-resolved distribution of water-soluble arsenic (WSAs) in atmospheric particulate matter, as well as the size-dependent variation in As concentration and solubility under contrasting haze and non-haze conditions, remains insufficiently characterized. This study investigated the concentration, size distribution, water solubility, sources, and health risks of particulate-bound As and WSAs in Beijing from April 2014 to February 2015. The annual mean PM_0.1–18 concentration was 136.96 ± 54.21 μg·m⁻³, with significantly higher levels observed during haze episodes (179.61 ± 41.71 μg·m⁻³) compared to non-haze periods (118.00 ± 49.42 μg·m⁻³). The annual mean concentration of As was 6.42 ± 3.69 ng·m⁻³, exceeding both WHO guidelines and Chinese standards during haze periods, while WSAs averaged 4.54 ± 2.50 ng·m⁻³. Distinct size distribution patterns were observed: As displayed, a unimodal fine-mode peak (0.32–0.56 μm) was observed during haze periods and a bimodal distribution during non-haze conditions, whereas WSAs followed comparable size-dependent behavior, reflecting shifts in dominant emission sources and atmospheric processes. The average WSAs/As ratio (0.72 ± 0.07) indicated high As solubility and strong associations with secondary species and anthropogenic emissions. Size-resolved analysis revealed that As was preferentially enriched in fine particles, particularly during haze episodes, whereas coarse particles became more prominent under non-haze conditions, especially in spring, likely driven by regional dust transport and its interactions with anthropogenic emissions. Deposition modeling based on the ICRP framework showed that As and WSAs were primarily deposited in the headway (HA: 0.68 and 0.32 ng·h⁻¹, respectively), followed by the alveolar region (AR: 0.29 and 0.20 ng·h⁻¹, respectively). Fine particles enhanced deposition in deeper lung regions during haze episodes, whereas coarse particles contributed more to upper airway deposition under non-haze conditions. Although inhalation carcinogenic risks remained within acceptable limits (10⁻⁶–10⁻⁴), risks were 1.60 times higher during haze periods, with adults bearing the greatest exposure burden. These findings demonstrate that haze conditions substantially alter the size distribution, solubility, and health risks of atmospheric arsenic, and provide a scientific basis for developing size-resolved and haze-targeted heavy metal monitoring strategies in urban environments subject to significant anthropogenic pollution. Full article

This study was conducted to support the development of a novel generic veterinary formulation by performing a comparative pharmacokinetic analysis against an approved reference product (Bravecto^® Plus). Sensitive and selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods were developed and validated for the quantification of fluralaner and moxidectin in cat plasma. A single topical dose (40 mg/kg fluralaner and 2 mg/kg moxidectin) of either the test or reference formulation was administered to 20 healthy cats in a parallel study. A validated LC-MS/MS method was used to determine plasma concentrations. Key pharmacokinetic parameters—including peak plasma concentration (C_max), time to C_max (t_max), and area under the curve (AUC_0–∞)—were calculated and statistically compared. The C_max of fluralaner was 1527.62 ± 905.94 ng/mL, t_max was 14.00 (interquartile range (IQR): 5.00–28.00) days and AUC_0–∞ was 1,415,464.8 ± 822,873.6 ng·h/mL. The C_max of moxidectin was 27.85 ± 38.78 ng/mL, t_max was 6.00 (IQR: 1.00–14.00) days, AUC_0–∞ was 16,807.2 ± 12,885.6 ng·h/mL. Compared with the reference veterinary drug (Bravecto^® Plus), the relative bioavailability (F) of both fluralaner (118.89% (90% CI: 96.5–145.3%)) and moxidectin (102.00% (90% CI: 85.2–118.8%)) exceeded 100%, and there was no statistical difference in the time to peak concentration (t_max). The test and reference formulations exhibit similar pharmacokinetic profiles in cats. These results provide critical pharmacokinetic data supporting the bioequivalence and therapeutic potential of the new generic formulation, thereby facilitating its further development and regulatory evaluation. Full article

Toxicological testing for drugs of abuse (DOAs) is an essential tool for healthcare practitioners and law enforcement agencies. Oral fluid (OF) is an alternative biological fluid for detecting recent DOA intake and is widely employed in forensic investigations. In the current study, a relatively novel and “green” fabric phase sorptive extraction (FPSE) procedure for sample preparation was coupled to liquid chromatography–tandem mass spectrometry (LC–MS/MS) to provide simplicity, cost-effectiveness, rapidity, low solvent consumption, and high analytical performance for the quantitative determination of ten commonly encountered DOAs and metabolites: amphetamine, benzoylecgonine, cocaine, codeine, ecgonine methyl ester, methadone, methamphetamine, 3,4-methylenedioxyamphetamine, 6-monoacetylmorphine, and morphine. The FPSE procedure was optimized by testing different filters, pH, extraction time, and solvents. The validated method demonstrated excellent linearity for all analytes, selectivity, acceptable precision, and high sensitivity (ranges for limits of detection (LODs) and quantification (LOQs) were 0.01–2 ng/mL and 0.03–6 ng/mL, respectively). Autosampler and short-term freeze stability exceeded 95% and 90% for all analytes, respectively. Overall, the combination of FPSE with LC–MS/MS provided a sensitive, selective, and environmentally friendly innovative analytical approach for the determination of DOA in OF and is suitable for both screening and confirmatory forensic and clinical applications. Full article

The development of highly sensitive and reliable strategies for microcystin-LR (MC-LR) monitoring remains critical for environmental safety and public health protection. Herein, we report a metallene-enabled electrochemiluminescence (ECL) biosensing platform based on ultrathin PdMoCu trimetallic metallenes for femtogram-level MC-LR detection. The two-dimensional PdMoCu metallenes provide abundant active sites and accelerated interfacial charge-transfer kinetics through synergistic electronic modulation among Pd, Mo, and Cu atoms, significantly enhancing the Ru(bpy)₃²⁺/TPrA ECL efficiency. By integrating a programmable H1–aptamer duplex interface, electrostatic enrichment of Ru(bpy)₃²⁺ was achieved, enabling target-responsive luminophore release via aptamer-triggered structural switching. This cooperative amplification mechanism, combining catalytic acceleration and DNA-mediated signal modulation, results in a sensitive signal-off detection mode. Under optimized conditions, the biosensor exhibited a wide linear response from 0.1 pg mL⁻¹ to 50 ng mL⁻¹ with a detection limit as low as 37 fg mL⁻¹. The platform demonstrated excellent selectivity against structural analogues, high reproducibility, and satisfactory recovery (99.3–102.0%) in real tap water samples. This work not only highlights the catalytic potential of trimetallic metallenes in ECL systems but also establishes a generalizable interfacial engineering strategy for ultrasensitive detection of trace environmental contaminants. Full article

In this paper, SiQDs were synthesized using 3-aminopropyltrimethoxysilane, an organosilicon source, via the room temperature stirring method under atmospheric pressure. Based on the “Turn-off” and “Turn-on” fluorescence response mechanisms, the SiQDs/Fe³⁺ fluorescent probe was constructed to quantitatively detect glyphosate according to the interaction between Fe³⁺ and glyphosate. Subsequently, the impacts of pH, incubation temperature, and reaction time on the detection of glyphosate were systematically investigated. Under the optimized detection parameters, the fluorescent probe exhibited a linear range of 2–10 μg/mL and a detection limit of 394.74 ng/mL. The constructed fluorescent probe demonstrated outstanding anti-interference performance. It was applied to actual samples of potato and yam, yielding satisfactory detection results with recovery values between 91.69% and 104.53%. These findings provide novel ideas and theoretical support for glyphosate residue detection. Full article

Invasive pulmonary mold infections (IPMIs) are critical complications in immunocompromised patients, contributing significantly to morbidity and mortality. Diagnosing pathogens like Aspergillus species (spp.) and the Mucorales remains challenging due to non-specific clinical presentations and the limitations of traditional culture methods. This review provides an up-to-date synopsis of IPMI diagnostic tools, focusing on their diagnostic performance, turnaround time (TAT), and cost-effectiveness. We conducted a narrative review of the current literature regarding clinical evaluation, radiographic findings, invasive diagnostics, and non-invasive assays, including next-generation sequencing (NGS) and volatile organic compounds (VOCs). Chest computerized tomography (CT) remains a vital first step, though classic signs like the “halo” or “reverse halo” are neither sensitive nor specific. Traditional diagnostics are limited by low sensitivity and delayed results. While plasma microbial cell-free DNA (mcfDNA) NGS offers rapid TAT (24–48 h) and high specificity, its suboptimal sensitivity for Aspergillus spp. (<50%) and high cost remain significant barriers. Investigational VOC “breath tests” show promising sensitivity (77–96%) but lack standardization. Future research must prioritize the standardization of non-invasive microbiologic testing modalities, particularly those with rapid TAT such as bedside “breath tests” and high-throughput mcfDNA NGS. Development of clinical algorithms that balance cost-effectiveness with timely pathogen diagnosis based on the patient’s degree of immunosuppression is essential to improve survival in high-risk populations. Full article

Ertugliflozin is a sodium-glucose co-transporter-2 inhibitor that has demonstrated promise as a treatment for hyperinsulinaemia in horses. Despite the frequent use of ertugliflozin in equine clinical practice, the pharmacokinetics of this drug in horses has not been established. The aim of the present study was to determine the pharmacokinetics of one supratherapeutic dose (0.25 mg/kg) of ertugliflozin in eight horses. Horses were defined as being healthy by physical examination, haematological, blood biochemical and oral sugar test (OST) results. Plasma concentrations of ertugliflozin were quantified using high-performance liquid chromatography–tandem mass spectrometry 0, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10, 14, 18, 24, 30, 36, 48, 60, 72, 96, and 120 h after drug administration enterally. Non-compartmental analysis led to determination of key pharmacokinetic variables, including mean ± SD time to maximum concentration (T_max) of 0.91 ± 0.13 h, maximum measured concentration (C_max) of 267.52 ± 25.37 ng/mL, terminal elimination half-life (T_1/2) of 17.65 ± 3.15 h and apparent oral clearance (CL/F) of 106.95 ± 27.53 mL/h/kg. No clinical signs of adverse effects or blood biochemical abnormalities occurred after drug administration. The results of this study suggest that a single supratherapeutic dose of ertugliflozin in healthy horses is safe. The pharmacokinetics of enterally administered ertugliflozin in horses are similar to pharmacokinetics of the drug in humans and the long T_1/2 makes ertugliflozin suitable for once daily dosing in horses. It is proposed that a starting dose for ertugliflozin in horses be in the range 0.05–0.1 mg/kg. Further pharmacokinetic studies are required to optimise the dose regimen for treating horses with hyperinsulinaemia. Full article

Background/Objectives: Scrub typhus, a life-threatening infection caused by Orientia tsutsugamushi, is treated with doxycycline or azithromycin. In severe disease, combination therapy with azithromycin and doxycycline had better clinical outcomes than either drug alone. However, it is not clear what causes the improved efficacy. To understand the same, we examined the plasma concentrations, intracellular concentrations, and efficacy of doxycycline, azithromycin, and both drugs in combination in 51 patients with severe scrub typhus. Methods: A randomly selected subset of adult (>18 years) participants from the INTREST trial (Clinical Trials Registry–India, number CTRI/2018/08/015159), who had been randomized in a 1:1:1 ratio to receive doxycycline, azithromycin, or both drugs, respectively, were included in this study for comparative drug concentration analysis. Blood samples were collected on days 0, 1, 3, and 7 to monitor bacterial load using quantitative polymerase chain reaction (PCR). Five milliliters of sterile blood were collected 3–10 h after the final dose on day 7 for comparative drug concentration measured using high-resolution multiple reaction monitoring. Data were analyzed in GraphPad Prism v.10.0.3. Results: Fifty-one patients (males, 59%; median age, 52 years) were enrolled. Fifteen, seventeen, and nineteen patients received azithromycin, doxycycline, and both, respectively. Doxycycline achieved a median plasma concentration of 1112 (42.51–5697) ng/mL and was undetectable intracellularly. The intracellular concentration of azithromycin (1127 [16.78–19,250] ng/mL) surpassed its plasma concentration (227.1 [48.78–1022] ng/mL). On day 3, PCR negativity rates were 56.24%, 93.3%, and 94.7% in the doxycycline, azithromycin, and combination groups, respectively. Conclusions: The high plasma concentrations of doxycycline and intracellular accumulation of azithromycin may contribute to improved clinical outcomes when used in combination. Full article

Introduction: Intermittent fasting (IF) is becoming increasingly popular as a method of weight management, but it is unknown whether it affects plasticiser intake with resultant changes in glycaemic control in diabetes and vitamin D (VitD) levels; therefore, this study was undertaken in a cohort of control and type-2 diabetic (T2D) subjects during Ramadan time-restricted feeding (TRF). Methods: In T2D subjects (n = 19) and controls (n = 31) undertaking TRF, 24 h urinary levels of phthalate metabolites, bisphenols and serum VitD were determined pre- and post-TRF by liquid chromatography–tandem mass spectrometry (LC-MS/MS). Anthropometric data and glycosylated haemoglobin (HbA1c) were measured. Results: T2D subjects were older (52 versus 36.73 years, p < 0.001), and had higher BMI (36.54 versus 27.67 kg/m², p < 0.001), body weight (101.77 versus 80.36 kg, p < 0.001), and HbA1c (8.38 versus 5.46%, p < 0.001) compared to controls, while VitD levels did not differ (60.43 versus 63.95 nmol/L, p > 0.05). Post-TRF, HbA1c was unchanged in T2D subjects and there was no difference in weight, BMI or VitD. Increased mono-iso-butyl phthalate (MiBP) in T2D subjects (10 versus 6.1 ng/mL, p = 0.001) and mono-n-butyl phthalate (MnBP) in T2D subjects (37 versus 13 ng/mL, p = 0.018) and controls (8.3 versus 5.4 ng/mL, p = 0.007) were observed post-TRF; however, significance was lost after adjusting for baseline differences in age, BMI, and HbA1c using a general linear model (GLM) repeated-measures ANOVA. Despite having no median differences in DEHP (di-2-ethylhexyl phthalate) metabolites pre- and post-TRF, analyses revealed a significant time × HbA1c interaction for [mono(2-ethyl-5-carboxypentyl) phthalate, MECPP: F(1,42) = 4.79, p = 0.03, mono(2-ethyl-5-hydroxyhexyl) phthalate, MEHHP: F(1,42) = 8.56, p = 0.006, mono(2-ethylhexyl) phthalate, MEHP: F(1,42) = 4.64, p = 0.03 and mono(2-ethyl-5-oxohexyl) phthalate, MEOHP: F(1,42) = 8.19, p = 0.007] and time × group interactions [MEHHP: F(1,42) = 14.27, p < 0.001, MEHP: F(1,42) = 6.35, p = 0.01 and MEOHP: F(1,42) = 10.30, p = 0.003]. Estimated marginal means (adjusted for age, BMI, HbA1c, and VitD) further confirmed higher concentrations of DEHP metabolites [MECPP, MEHHP, MEHP, and MEOHP] in T2D participants over time compared with controls. Additionally, monomethyl phthalate (MMP) trajectories were significantly influenced by the time × group interaction (F(1,42) = 4.28, p = 0.04), with post-TRF elevations observed in T2D subjects. Vitamin D status was observed to modify MCPP and MEP trajectories over time. Conclusion: Ramadan TRF is associated with changes in plasticiser metabolite levels, with estimated increased levels in T2D subjects versus healthy controls. Metabolite levels were influenced by HbA1c and vitamin D, though BMI was not observed to be a contributing factor. Full article

Background: Endotoxin tolerance describes the phenomenon whereby prior lipopolysaccharide (LPS) exposure attenuates inflammatory responses to subsequent LPS challenge. Studies have reported the involvement of different mediators of the toll-like receptor (TLR)-4 signaling pathway in endotoxin tolerance. Methods: We first examined dose- and time-dependent production of cytokines following LPS treatment and then examined cytokine production in BV2 cells pretreated with 5 ng/mL LPS for 24 h, followed by secondary challenge with 1 µg/mL LPS for four hours. To examine which inflammatory cytokine could induce tolerance, we pretreated BV2 cells with 1 µg/mL IL-1β, IL-6, or TNF-α for 24 h, followed by secondary challenge with 1 μg/mL LPS for four hours, and then examined cytokine production by ELISA. Results: Our data showed that LPS induced dose- and time-dependent production of IL-1β, IL-6, and TNF-α. Pretreatment with 5 ng/mL LPS significantly reduced the production of IL-1β and TNF-α in response to secondary challenge, while IL-6 production was slightly enhanced. We also found that pretreatment with IL-1β did not attenuate production of TNF-α but slightly enhanced IL-6 following secondary challenge with 1 µg/mL LPS. In contrast, pretreatment with IL-6 or TNF-α significantly attenuated subsequent LPS-induced IL-1β production without affecting the production of the other. Conclusions: Endotoxin tolerance in BV2 microglial cells selectively suppresses IL-1β and TNF-α while preserving IL-6 production. Both IL-6 and TNF-α independently induce tolerance specifically to IL-1β, suggesting negative feedback regulations. These findings reveal that endotoxin tolerance involves selective rather than global suppression of inflammatory mediators and cross-regulation between LPS and cytokine-induced signaling pathways. Full article

Lupus nephritis (LN) is a severe immune-mediated renal disorder causing significant morbidity and mortality in patients with systemic lupus erythematosus (SLE). Traditional biomarkers (serum complement components C3 and C4 and anti-dsDNA antibodies) have limited sensitivity and specificity for detecting renal flares; thus, new markers are needed to improve relapse detection and therapeutic response monitoring. We conducted a cross-sectional study including 71 women with SLE and 20 age- and sex-matched controls. Clinical data were collected, global activity was evaluated using the SLEDAI, and renal activity was evaluated using the renal SLEDAI (rSLEDAI). Serum syndecan-1 (SDC-1) and anti-dsDNA were measured using ELISA, and 24 h proteinuria was quantified. According to the rSLEDAI, 38 patients (53.5%) had LN flare, with a mean SDC-1 level of 108.5 ± 69.3 ng/mL and anti-dsDNA level of 113.1 ± 148.8 IU/mL. SDC-1 was correlated with the rSLEDAI (r = 0.32; p = 0.006), prednisone dose (r = 0.37; p = 0.002), proteinuria (r = 0.33; p = 0.005), and anti-dsDNA (r = 0.33; p = 0.006), while anti-dsDNA was positively correlated with proteinuria (r = 0.39; p = 0.001 and SDC-1 (r = 0.33; p = 0.006) and negatively correlated with age (r = −0.33; p = 0.006). High SDC-1 (cutoff ≥ 89 ng/mL) had higher sensitivity for detecting renal flares than anti-dsDNA (66% vs. 45%). In the multivariable analysis, high SDC-1 levels had around a 3-fold higher risk of being associated with LN flares, independently of anti-dsDNA and complement component levels. These results support serum SDC-1 as a promising biomarker for identifying renal flares in SLE patients, and it should be combined with traditional biomarkers to increase its value as a clinical tool. Follow-up studies are required to determine its value for predicting long-term renal outcomes. Full article