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N‐acetylcysteine (NAC) is an antidote to prevent acetaminophen (paracetamol‐APAP)‐induced acute liver injury (ALI). The 3‐bag licensed 20.25 h standard regimen, and a 12 h modified regimen, are used to treat APAP overdose. This study evaluated the redox thiol response and APAP metabolites, in patients with a single APAP overdose treated with either the 20.25 h standard or 12 h modified regimen. We used liquid chromatography tandem mass spectrometry to quantify clinically important oxidative stress biomarkers and APAP metabolites in plasma samples from 45 patients who participated in a randomized controlled trial (SNAP trial). We investigated the time course response of plasma metabolites at predose, 12 h, and 20.25 h post‐start of NAC infusion. The results showed that the 12 h modified regimen resulted in a significant elevation of plasma NAC and cysteine concentrations at 12 h post‐infusion. We found no significant alteration in the metabolism of APAP, mitochondrial, amino acids, and other thiol biomarkers with the two regimens. We examined APAP and purine metabolism in overdose patients who developed ALI. We showed the major APAP‐metabolites and xanthine were significantly higher in patients with ALI. These biomarkers correlated well with alanine aminotransferase activity at admission. Receiver operating characteristic analysis showed that at admission, plasma APAP‐metabolites and xanthine concentrations were predictive for ALI. In conclusion, a significantly higher redox thiol response with the modified NAC regimen at 12 h postdose suggests this regimen may produce greater antioxidant efficacy. At baseline, plasma APAP and purine metabolites may be useful biomarkers for early prediction of APAP‐induced ALI.

Background/Objectives: Although systematic reviews and meta-analyses have examined immune-inflammatory indices in cardiovascular disease (CVD), the evidence remains scattered and inconsistent. This umbrella review aims to synthesize findings and evaluate the overall predictive value of these indices for clinical outcomes. Methods: We systematically searched PubMed, Cochrane Library, Web of Science, Embase, Scopus, and Medline for systematic reviews with meta-analyses assessing neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), platelet-to-lymphocyte ratio (PLR), and systemic inflammation response index (SIRI) in patients with CVD. Study quality and certainty of evidence were appraised using AMSTAR-2 and GRADE, respectively. Results: A total of 35 meta-analyses covering 106 unique outcomes were included, of which 87 showed significant associations. Elevated NLR and SII were consistently linked to higher risks of CVD mortality, major adverse cardiovascular events, myocardial infarction, heart failure, and stroke. PLR and SIRI were primarily associated with poor recovery from stroke and increased mortality in ST-elevation myocardial infarction. Specifically, the methodological quality of the included reviews was generally moderate to high according to AMSTAR-2, whereas none of the associations reached high certainty based on GRADE, with most rated as low or very low and about one-quarter as moderate certainty. Conclusions: The overall certainty of evidence remains limited according to GRADE, alongside methodological heterogeneity, population variability, and inconsistent thresholds that further restrict the direct applicability of these findings in clinical practice. Nevertheless, available evidence indicates that elevated immune-inflammatory indices are likely associated with worse clinical outcomes in patients with CVD. Future research should prioritize establishing standardized cutoffs, improving methodological consistency, and validating these indices across diverse populations to support their integration into clinical risk-stratification frameworks.

Despite anti-tuberculous treatment (ATT), central nervous system tuberculosis (CNS-TB) still causes permanent neurological deficits and death. To identify prognostic factors, we profiled a prospective cohort of pediatric HIV-negative tuberculous meningitis (TBM) and non-TBM patients. We found significantly increased cerebrospinal fluid (CSF) matrix metalloproteinases (MMPs) and neutrophil extracellular traps (NETs) in TBM patients with neuroradiological abnormalities and poor outcomes. To dissect mechanisms, we used our existing CNS-TB murine model, which shows neutrophil-rich necrotizing pyogranulomas with MMP-9 and NETs colocalizing, as observed in human CNS-TB pathology. Spatial transcriptomic analysis of both human and murine CNS-TB demonstrates a highly-inflamed and neutrophil-rich microenvironment of inflammatory immune responses, extracellular matrix degradation and angiogenesis within CNS-TB granulomas. Murine CNS-TB treated with ATT and MMP inhibitors SB-3CT or doxycycline show significantly suppressed NETs with improved survival. MMP inhibition arms show attenuated inflammation and well-formed blood vessels within granulomas. Adjunctive doxycycline is highly promising to improve CNS-TB outcomes and survival. Graphical abstract

Incorporating β-glucan-rich oat bran (OB) can attenuate postprandial glycemic response (PPGR) in solid foods, but its effect in liquid matrices is unclear. This study investigated the ability of differently processed low-dose-β-glucan-containing beverages to lower PPGR, and the mechanisms of action. Twenty participants consumed five malt beverages made from cocoa powder: intact OB (Intact), OB treated with enzymatic hydrolysis (EnzymA, EnzymB) or extrusion (Extr), or no OB (Ctrl). Four-hour postprandial incremental areas under the curve (iAUC) and peak incremental concentrations (iCmax) of glucose, insulin, glucagon-like peptide 1 (GLP-1), gastric inhibitory polypeptide (GIP), and paracetamol were evaluated. The molecular weight (MW) and extractability of the β-glucan in all the test products were also assessed. The three-hour glucose iAUC significantly decreased by −26%, −28%, −32%, and −38% in Intact, EnzymA, EnzymB, and Extr, respectively, and the insulin levels of the oat-containing products were also significantly lower compared to Ctrl. Intact and Extr elicited a lower insulin iCmax and GLP-1 3 h iAUC compared to Ctrl. However, the GIP and paracetamol levels were not changed. All the processed OBs improved β-glucan extractability and lowered the MW of β-glucan compared to Intact. In conclusion, low-dose oat β-glucan in a beverage significantly reduced PPGR, with effects maintained across different oat processing methods.

Eating late in the day is associated with circadian desynchrony, resulting in dysregulated metabolism and increased cardiometabolic disease risk. However, the underlying mechanisms remain unclear. Using targeted metabolomics of postprandial plasma samples from a secondary analysis of a randomised 2 × 2 crossover study in 36 healthy older Chinese adults, we have compared postprandial metabolic responses between high (HI) glycemic index (GI) or low-GI (LO) meals, consumed either at breakfast (BR) or at dinner (DI). 29 out of 234 plasma metabolites exhibited significant differences (p < 0.05) in postprandial AUC between BR and DI sessions, whereas only five metabolites were significantly different between HI and LO sessions. There were no significant interactions between intake timing and meal GI. Lower glutamine: glutamate ratio, lower lysine and higher trimethyllysine (TML) levels were found during DI compared with BR, along with greater postprandial reductions (δAUC) in creatine and ornithine levels during DI, indicating a worse metabolic state during the evening DI period. Greater reductions (δAUC) in postprandial creatine and ornithine were also observed during HI compared with LO (both p < 0.05). These metabolomic changes may indicate potential molecular signatures and/or pathways linking metabolic responses with cardiometabolic disease risk between different meal intake timings and/or meals with variable GI.

We aimed to determine primary markers of oxidative stress (OS) in ED patients which predict hospital length of stay (LoS), intensive care unit (ICU) LoS, and sepsis severity. This prospective, single center observational study was conducted in adult patients recruited from the ED who were diagnosed with either sepsis, infection without sepsis, or non-infectious, age-matched controls. 290 patients were admitted to the hospital and 24 patients had direct admission to the ICU. A panel of 269 OS and related metabolic markers were profiled for each cohort. Clinical outcomes were direct ICU admission, hospital LoS, ICU LoS, and , adjudicated sepsis severity scoring. Bonferroni correction was used for pairwise comparisons. Principal component regression was used for dimensionality reduction and selection of plasma metabolites associated with sepsis. Multivariable negative binomial regression was applied to predict admission, hospital, and ICU LoS. Homoarginine (hArg) was the top discriminator of sepsis severity [sepsis vs. control: ROC-AUC = 0.86 (95% CI 0.81-0.91)], [sepsis vs. infection: ROC-AUC = 0.73 (95% CI 0.68-0.78)]. The 25th percentile of hArg [odds ratio (OR) = 8.57 (95% CI 1.05-70.06)] was associated with hospital LoS [IRR = 2.54 (95% CI 1.83-3.52)] and ICU LOS [IRR = 18.73 (95% CI 4.32-81.27)]. In prediction of outcomes, hArg had superior performance compared to arginine (Arg) [hArg ROC-AUC = 0.77 (95% CI 0.67-0.88) vs. Arg ROC-AUC = 0.66 (95% CI 0.55-0.78)], and dimethylarginines [SDMA ROC-AUC 0.68 (95% CI 0.55-0.79) and ADMA ROC-AUC = 0.68 (95% CI 0.56-0.79)]. Ratio of hArg and Arg/NO metabolic markers and creatinine clearance provided modest improvements in clinical prediction. Homoarginine is associated with sepsis severity and predicts hospital and ICU LoS, making it a useful biomarker in guiding treatment decisions for ED patients.

Reproductive aging is a major cause of fertility decline, attributed to decreased oocyte quantity and developmental potential. A possible cause is aging of the surrounding follicular somatic cells that support oocyte growth and development by providing nutrients and regulatory factors. Here, by creating chimeric follicles, whereby an oocyte from one follicle was transplanted into and cultured within another follicle whose native oocyte was removed, we show that young oocytes cultured in aged follicles exhibited impeded meiotic maturation and developmental potential, whereas aged oocytes cultured within young follicles were significantly improved in rates of maturation, blastocyst formation and live birth after in vitro fertilization and embryo implantation. This rejuvenation of aged oocytes was associated with enhanced interaction with somatic cells, transcriptomic and metabolomic remodeling, improved mitochondrial function and higher fidelity of meiotic chromosome segregation. These findings provide the basis for a future follicular somatic cell-based therapy to treat female infertility. Oocyte quality declines during aging. Here the authors show that oocytes from aged mice cultured within follicles from young mice have improved developmental potential. Aged oocytes cultured within young follicles have enhanced interaction with somatic cells, improved mitochondrial function and better meiotic chromosome segregation.

[...]our pilot study uncovered highly discriminative proteins and metabolites for early neuroprognostication after OHCA, with 24-hours post-ROSC as the optimal timepoint. Abbreviations ATP6V1F: V-type proton ATPase subunit F AUC: area under receiver operating curve CALCA: calcitonin related polypeptide alpha CALR: calreticulin CPC: Cerebral Performance Category FC: fold-change Gal-4: galectin-4 GSTP1: glutathione s-transferase Pi 1 I/R: ischemia-reperfusion LC-MS/MS: liquid chromatography-coupled triple quadrupole mass spectrometry LC-MS: liquid chromatography-coupled mass spectrometry NfL: neurofilament light chain NOS3: nitric oxide synthase 3 OHCA: out-of-hospital cardiac arrest PSME1: proteasome activator complex subunit 1 PVALB: parvalbumin ROSC: return of spontaneous circulation TIGAR:

Reproductive aging is a major cause of fertility decline, attributed to decreased oocyte quantity and competence. Follicular somatic cells play crucial roles in the growth and development of the oocyte by providing nutrients and regulatory factors. Here we investigated how oocyte quality is affected by its somatic cell environment by creating chimeric follicles, whereby an oocyte from one follicle was transplanted into and cultured within another follicle whose native oocyte was removed. Somatic cells within the chimeric follicle re-establish connections with the oocyte and support oocyte growth and maturation in a three-dimensional (3D) culture system. We show that young oocytes transplanted into aged follicles exhibited reduced meiotic maturation and developmental potential, whereas the young follicular environment significantly improved the rates of maturation, blastocyst formation and live birth of aged oocytes. Aged oocytes cultured within young follicles exhibited enhanced interaction with somatic cells, more youth-like transcriptome, remodelled metabolome, improved mitochondrial function, and enhanced fidelity of meiotic chromosome segregation. These findings provide the basis for a future follicular somatic cell-based therapy to treat age-associated female infertility.

The biosynthesis of mono/dimannosyldiacylglycerol (Man1–2 -DAG), mannosylphosphorylundecaprenol (Man-P-Und) and a membrane-associated lipomannan (LM) in Micrococcus luteus was documented over 30 years ago. Structural and topological studies have been conducted to learn more about the possible role of these mannolipids in LM assembly. The major mannolipid has been purified and characterized as α-D-mannosyl-(1 → 3)-α-D-mannosyl-(1 → 3)-diacylglycerol (Man2-DAG) by ESI-MSn. The fragmentation patterns indicate that the sn-1-position is predominantly acylated with a 12-methyltetradecanoyl group and the sn-2 position is acylated with a myristoyl group. Evidence that LM is located on the exterior face of the cytoplasmic membrane, and not exposed on the surface of intact cells, was obtained by staining intact protoplasts with fluorescein isothiocyanate-linked concanavalin A. In vitro studies with amphomycin, an inhibitor of Man-P-Und synthesis, indicate that GDP-Man is the direct mannosyl donor during Man 1–2-DAG synthesis, and that LM is formed when the DAG-linked disaccharide is elongated by 48 additional α-mannosyl units donated by Man-P-Und. Protease-sensitivity studies with intact and lysed protoplasts indicate that the active sites of the mannosyltransferases catalyzing the formation of Man1–2DAG and Man-P-Und are exposed on the inner face of the cytoplasmic membrane, and the Man-P-Und-mediated reactions occur on the outer leaflet. These results form the basis of a topological model that involves membrane proteins (flippases) in the transverse diffusion of Man2-DAG and Man-P-Und. To isolate temperature-sensitive micrococcal mutants defective for growth and LM synthesis, a [3H]mannose-suicide selection was used. In vivo and in vitro biochemical studies confirm that mms1 are defective for Man2-DAG synthesis and accumulate Man-DAG, while mms2 are defective for Man-P-Und synthesis and accumulate Man2-DAG at the non-permissive temperature (37°C). Since mms1 cells are deficient in endogenous Man 2-DAG, membrane fractions from this mutant efficiently converted exogenous [3H]Man2-DAG to [3H]LM by a GDP-Man/Man-P-Und dependent process inhibited by amphomycin. Consistent with Man2-DAG serving as a lipid anchor precursor for LM assembly, endogenous, pre-labeled [3H]Man2-DAG was converted to [3H]LM when mms2 membranes were incubated with exogenous Man-P-Und. These studies provide the first direct proof for the role of Man2-DAG as the lipid anchor precursor for LM, and that Man2-DAG is essential for normal growth of M. luteus cells.