Search Results (792)

Background and Objectives: People living with HIV (PLWH) have excess osteoporosis and fractures not fully captured by dual-energy X-ray absorptiometry (DXA). We evaluated whether trabecular bone score (TBS), calcaneal quantitative ultrasound (QUS) and bone turnover markers improve vertebral fracture risk assessment beyond areal bone mineral density (BMD) in PLWH. Methods: In this cross-sectional study, 87 antiretroviral-treated adults undergoing DXA had lumbar spine TBS and calcaneal QUS. Morphometric vertebral fractures were identified, correlates of degraded TBS were analyzed using multivariable regression, and sequential logistic models quantified the incremental contribution of TBS and CTX to discriminate for prevalent morphometric vertebral fractures. Results: Low BMD (osteopenia/osteoporosis) was present in 62% of participants, degraded TBS in 37% and morphometric vertebral fractures in 17%. Degraded versus normal TBS was associated with older age (49.1 vs. 39.7 years), longer HIV duration and lower nadir CD4+ count, as well as more frequent tenofovir disoproxil fumarate exposure (66% vs. 52%; all p ≤ 0.04). In multivariable analysis, age (per 10-year increase; adjusted odds ratio [aOR] 1.78; 95% CI 1.13–2.83) and nadir CD4+ < 200 cells/mm³ (aOR 2.29; 95% CI 1.06–4.97) independently predicted degraded TBS. In sequential cross-sectional models for prevalent morphometric vertebral fractures, the area under the curve increased from 0.71 (clinical variables) to 0.79 after adding lumbar spine T-score and to 0.85 after adding TBS; adding CTX yielded 0.87 without a statistically significant incremental gain. Conclusions: In PLWH, TBS captures bone quality deficits and improves vertebral fracture risk discrimination beyond BMD, supporting its integration alongside DXA in routine HIV care. Full article

Sharp declines in temperature pose a significant risk for mass mortality events in the Chinese soft-shelled turtle (Pelodiscus sinensis). To assess the effects of acute cold stress on intestinal health, turtles were exposed to temperatures of 28 °C (control), 14 °C, and 7 °C for 1, 2, 4, 8, and 16 days. The results showed that acute cold stress at 14 °C and 7 °C induced time-dependent alterations in intestinal morphology and histopathology. The damage was more severe at 7 °C, characterized by inflammatory cell infiltration, lymphoid hyperplasia, and extensive detachment and necrosis across the villi, muscle layer, and submucosa. 16S rDNA sequencing revealed significant shifts in intestinal microbiota composition in the 7 °C group, dominated by Helicobacter and Citrobacter. Transcriptomic analysis identified differentially expressed genes (DEGs) that respond to acute cold stress and are involved in the Toll-like receptor signaling pathway (Tlr2, Tlr4, Tlr5, Tlr7, and Tlr8), the NOD-like receptor signaling pathway (Traf6, Traf2, Casr, Rnasel, Pstpip1, Plcb2, Atg5, and Mfn2), apoptosis (Tuba1c, Ctsz, Ctsb, Kras, Hras, Pik3ca, Bcl2l11, Gadd45a, Pmaip1, Ddit3, and Fos), and the p53 signaling pathway (Serpine1, Sesn2, Ccng2, Igf1, Mdm2, Gadd45a, Pmaip1, and Cdkn1a). Metabolomic profiling highlighted differentially expressed metabolites (DEMs) that cope with acute cold stress, such as organic acids (oxoglutaric acid, L-aspartic acid, fumaric acid, DL-malic acid, and citric acid) and amino acids (including L-lysine, L-homoserine, and allysine). The integrated analysis of DEGs and DEMs underscored three key pathways modulated by acute cold stress: linoleic acid metabolism, neuroactive ligand–receptor interaction, and the FoxO signaling pathway. This study provides a comprehensive evaluation of intestinal health in Chinese soft-shelled turtles under acute cold stress and elucidates the underlying mechanisms. Full article

Currently, the differences in the responses of the organic acid metabolism in rapeseed (Brassica napus L.) roots to saline and alkaline stresses are still unknown. To clarify the differences, different saline (100 (LS) and 200 (HS) mmol/L NaCl) and alkaline (20 (LA) and 40 (HA) mmol/L Na₂CO₃) treatments were applied to rapeseed. Then, targeted metabolomics was used to quantitatively analyze the changes in organic acid metabolism in the root system. The results showed that compared with the control group without stress (CK), 21, 18, 27, and 20 differentially accumulated organic acid metabolites were detected in the rapeseed roots under LS, HS, LA, and HA, respectively. In addition, 26, 6, 34, and 14 differentially accumulated organic acids were detected in the rapeseed root exudates under LS, HS, LA, and HA, respectively. Based on the activities of key enzymes related to the tricarboxylic acid cycle (TCA), antioxidant enzyme activities, organic acid metabolism, and KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analysis in rapeseed roots, rapeseed mainly resisted saline and alkaline stresses by increasing organic acid synthesis and scavenging reactive oxygen species. Specifically, rapeseed resisted saline stress mainly by increasing the secretion of TCA cycle-related organic acids such as succinic acid, L-malic acid, fumaric acid, and cis-aconitic acid. In addition to secreting organic acids, rapeseed also resisted alkaline stress by increasing the secretion of phenolic acids such as 4-hydroxybenzoic acid, ferulic acid, and 4-coumaric acid. Notably, the number of secreted organic acid types and the increase in organic acid content under alkaline stress were higher than those under saline stress. The results of this study provide an important basis for the breeding of saline and alkaline stress-tolerant rapeseed varieties. Full article

The REPRIEVE Trial recently reported high rates of sudden cardiac death (SCD) middle-aged people living with HIV-1 infection (PWH) using the WHO/NIH-recommended two nucleoside reverse transcriptase inhibitors (NRTIs)/one integrase strand inhibitor (INSTI) regimen to manage HIV-1 viremia. To date, clinically relevant animal models to delineate underlying causes for this remain limited. Here, we assessed if HIV-1-infected NOD.Cg-Prkdc^scidIl2rg^tm1Wjl/SzJ humanized mice (Hu-mice) treated with the WHO/NIH-recommended antiretroviral regimen, dolutegravir (DTG, INSTI)/tenofovir disoproxil fumarate (TDF, NRTIs)/emtricitabine (FTC, NRTIs), can recapitulate abnormalities in the ECG and subclinical structural heart disease that serve as harbingers of SCD in middle-aged PWH. HIV-1-infected and uninfected Hu-mice served as controls. After one month of infection (HIV-1_ADA), ECG intervals/segments were significantly altered. ECG changes progressively worsened as the duration of untreated infection increased. Treating HIV-1-infected animals with the DTG/TDF/FTC for eight weeks, starting four weeks after infection, prevented worsening, but did not restore ECG intervals/segments to those before infection. In hearts from DTG/TDF/FTC-treated animals, steady-state levels of the sarco-(endo) plasmic reticulum Ca²⁺ ATPase (SERCA2) were reduced by 35%. Steady-state levels of type 2 ryanodine receptor (RyR2) did not change, but its phosphorylation status at Ser2808 was 2-fold higher than that of uninfected controls, indicative of a gain-of-function. The density of perfused micro vessels and fibrosis in hearts of DTG/TDF/FTC-treated animals was not significantly different from that of HIV-1-infected and uninfected Hu-mice. These data show for the first time that HIV-1 infection is triggering abnormalities in the ECG of Hu-mice, and changes in ECG persisted with DTG/TDF/FTC treatment, independent of ischemia and/or fibrosis. They also indicate that chronic DTG/TDF/FTC treatment did not worsen ECG changes, including the QT interval. Since phosphorylation of RyR2 at Ser2808 occurs via β-adrenergic activation of protein kinase A, these new data also suggest that chronic hyperadrenergic activity may be increasing the risk of SCD via Ca²⁺ leak through RyR2. Full article

Nuclear factor erythroid 2-related factor 2 (NRF2) orchestrates redox balance, metabolism, and cellular stress responses, acting as both a tumor suppressor and promoter depending on the disease stage. In advanced cancers, persistent NRF2 activation—through KEAP1/NFE2L2 mutations or oxidative adaptation—drives epithelial-to-mesenchymal transition, metabolic reprogramming, and immune evasion, promoting tumor invasion (T) and metastasis (M). Recent pharmacologic efforts seek to exploit this duality. NRF2 inhibitors such as brusatol, halofuginone, and ML385 suppress NRF2 transcriptional activity or disrupt DNA binding, reducing motility, invasion, and metastatic dissemination in preclinical models. In contrast, NRF2 activators, such as bardoxolone methyl (CDDO-Me), sulforaphane, and dimethyl fumarate, exhibit chemopreventive effects by enhancing detoxification and mitigating oxidative DNA damage during early tumorigenesis. Furthermore, metabolic interventions, such as glutaminase or G6PD inhibitors, target NRF2-driven anabolic and antioxidant pathways essential for metastatic fitness. Therefore, understanding the temporal and contextual effects of NRF2 signaling is crucial for therapeutic design. The aim of this review is to examine how pharmacological modulation of NRF2 influences the invasive and metastatic dimensions of tumor progression, in addition to discussing its potential integration into TNM-based prognostic and treatment frameworks. Full article

Bee pollen is a natural nutrient substance collected by bees from plants. Its metabolites have been extensively studied, yet the characteristic metabolites of bee pollen from different floral sources have not been clearly identified. In this study, we collected four types of bee pollen (tea, rose, rapeseed, and corn pollen) from across China and analyzed their volatile and non-volatile metabolites using liquid chromatography-high-resolution mass spectrometry (LC-HRMS) and gas chromatography-mass spectrometry (GC-MS). At the same time, the nutritional substances (Including polyphenols, organic acids, and sugars) were precisely quantified. The results showed that the total phenols (5 mg GAE/g) and total flavonoids (0.27 mg RE/g) content of corn pollen were significantly higher (p < 0.05) than those of other pollens, and the contents of polyphenols such as naringenin were relatively high, indicating strong antioxidant potential. Rose pollen was rich in protein (0.04 g/g) and flavonoid glycosides. Tea pollen was prominent in the content of polyphenol glycosides and amino acid derivatives, while rapeseed pollen performed well in phenolic acids (Ferulic acid), as well as specific sugar (Mannose). We identified the differential metabolites of these bee pollen through orthogonal partial least squares discriminant analysis (OPLS-DA) (VIP > 1). It was also stipulated that metabolites with a VIP value greater than 1.5 showed significant differences and could be used as characteristic metabolites for differentiating pollen (p < 0.05). The representative metabolites of bee pollen were as follows: rapeseed pollen—ferulic acid; tea pollen—malic acid; corn pollen—epicatechin; and rose pollen—fumaric acid. This study provides a research basis for evaluating the quality, traceability, and metabolite exploration of bee pollen. Full article

Isosorbide fatty acid diesters constitute a novel class of bioactive compounds with emerging therapeutic applications in inflammatory and barrier-compromised disorders. Among them, isosorbide dicaprylate (IDC) and isosorbide di-linoleate/oleate (IDL) synergistically strengthen epidermal barrier integrity, enhance stratum corneum hydration, regulate keratinocyte differentiation, suppress proinflammatory signaling, and beneficially modulate the skin microbiome. Randomized, double-blind clinical trials in both pediatric and adult populations with atopic dermatitis (AD) demonstrate that topical IDC + IDL formulations significantly reduce pruritus, corticosteroid dependence, and Staphylococcus aureus colonization while improving sleep quality, disease severity scores, and overall quality of life. Extending applications within and even beyond dermatology, isosorbide dimethyl fumarate (IDMF)—a next-generation fumarate derivative designed to mitigate sensitization risk—exhibits potent anti-inflammatory and antioxidant activities through NRF2 activation and NF-κB/IRF1 suppression. Preclinical studies in psoriasis and neuroinflammatory models, including multiple sclerosis, reveal robust modulation of oxidative stress and immune pathways with improved safety and mechanistic precision compared to conventional fumarates, although its systemic use remains exploratory and requires clinical validation. Collectively, isosorbide diesters emerge as multifunctional therapeutic agents offering barrier repair, immune modulation, and inflammation control, representing promising alternatives to corticosteroids and systemic immunosuppressants across dermatologic and systemic inflammatory disorders. Full article

Diroximel fumarate (DRF) is an orally administered prodrug used in multiple sclerosis (MS) treatment. Although it exhibits better gastrointestinal (GI) tolerability than its analogues, many patients still discontinue therapy due to frequent GI adverse events. To overcome these limitations, alternative drug delivery systems that bypass the GI tract are needed. Direct nose-to-brain delivery represents a promising approach to circumvent the blood–brain barrier and target the central nervous system; however, limited nasal mucosal absorption and the small volume of the nasal cavity pose significant challenges. Solid lipid nanoparticles (SLNs) can potentially overcome these obstacles by enhancing drug bioavailability and protecting against enzymatic degradation. This research aimed to develop an innovative intranasal nanoformulation of DRF to improve brain targeting and patient compliance. DRF-loaded SLNs were prepared using a solvent-diffusion technique with stearic acid as the lipid phase and Poloxamer 188 as the surfactant. The obtained nanoparticles displayed favorable technological characteristics, with a mean diameter of 210 nm, a polydispersity index of 0.17, and a zeta potential of −36 mV, suggesting good long-term stability. Interactions between SLNs and biomembrane models (MLV) were also studied to elucidate their cellular uptake mechanism. Future work will focus on evaluating the in vivo efficacy of this novel nanoformulation. Full article

Enteric methane (CH₄) emissions from ruminants contribute significantly to agricultural greenhouse gases. Anti-methanogenic feed additives (AMFA), such as Asparagopsis spp. and 3-nitrooxypropanol (3-NOP), reduce CH₄ emissions by inhibiting methanogenic enzymes. However, CH₄ inhibition often leads to dihydrogen (H₂) accumulation, which can impact rumen fermentation and decrease dry matter intake (DMI). Recent studies suggest that co-supplementation of CH₄ inhibitors with alternative electron acceptors, such as phloroglucinol, fumaric acid, or acrylic acid, can redirect excess H₂ during methanogenesis inhibition into fermentation products nutritionally beneficial for the host. This review summarizes findings from rumen simulation experiments and in vivo trials that have investigated the effects of combining a CH₄ inhibitor with an alternative H₂ acceptor to achieve effective methanogenesis inhibition. These trials demonstrate variable outcomes depending on additive combinations, inclusion rates, and adaptation periods. The use of phloroglucinol in vivo consistently decreased H₂ emissions and altered fermentation patterns, promoting acetate production, compared with fumaric acid or acrylic acid as alternative electron acceptors. As a proof-of-concept, phloroglucinol shows promise as a co-supplement for reducing CH₄ and H₂ emissions while enhancing volatile fatty acid profiles in vivo. Optimizing microbial pathways for H₂ utilization through targeted co-supplementation and microbial adaptation could enhance the sustainability of CH₄ mitigation strategies using feed additive inhibitors in ruminants. Further research using multi-omics approaches is needed to elucidate the microbial mechanisms underlying the redirection of H₂ toward beneficial fermentation products during enteric methanogenesis inhibition. This knowledge will help guide the formulation of novel co-supplements designed to reduce CH₄ emissions and improve energy efficiency for sustainable livestock production. Full article

The design of sustainable polymer systems with tunable properties is essential for next-generation functional materials. This study examines the influence of a phenol-free modified rosin resin (Unik Print™ 3340, UP)—a maleic anhydride- and fumaric acid-modified gum rosin—on the structural, thermal, rheological, and mechanical behavior of four poly(lactic acid) (PLA) grades with different molecular weights and crystallinity. Blends containing 3 phr of UP were prepared by melt compounding. Thermogravimetric analysis showed that the incorporation of UP did not alter the thermal degradation of PLA, confirming stability retention. In contrast, differential scanning calorimetry revealed that UP affected thermal transitions, suppressing crystallization and melting in amorphous PLA grades and shifting the crystallization temperature to lower values in semi-crystalline grades. The degree of crystallinity decreased for low-molecular-weight semi-crystalline PLA but slightly increased in higher-molecular-weight samples. Mechanical tests indicated that UP acted as a physical modifier, increasing toughness by over 25% for all PLA grades and up to 60% in the amorphous, low-molecular-weight grade. Rheological measurements revealed moderate viscosity variations, while FESEM analysis confirmed microstructural features consistent with improved ductility. Overall, UP resin enables fine tuning of the structure–property relationships of PLA without compromising stability, offering a sustainable route for developing bio-based polymer systems with enhanced mechanical performance and potential use in future biomimetic material designs. Full article

Background/Objectives: Metabolites are low-molecular-weight organic compounds (<1 kDa) that act as intermediates and end products of cellular metabolism. Their characterization provides valuable information on the nutritional quality, functionality, and potential health impacts of food products. In the dairy sector, proton nuclear magnetic resonance (¹H NMR) spectroscopy has emerged as a powerful tool for metabolite profiling, enabling the simultaneous identification and quantification of diverse compounds. In this study, ¹H NMR was applied to characterize and compare the metabolic composition of whey, a major by-product of cheese and yogurt production, and whey protein concentrate (WPC-80), a whey derivative containing approximately 80% protein by weight and rich in essential amino acids. Methods: Five whey and four WPC-80 samples from a single Parmigiano Reggiano dairy plant were collected, each representing a biologically independent sample. Statistical evaluation was performed using Mann–Whitney U tests to identify significantly different metabolites between groups, while principal component analysis and partial least squares discriminant analysis were employed to assess group separation and determine discriminant metabolites. Results: The results revealed marked compositional differences: whey was higher in dimethyl sulfone, succinate, orotate, fumarate, and lactose (p < 0.05), whereas WPC-80 contained significantly higher levels of histidine, formate, glucose + glucose-6-phosphate, acetate, and choline (p < 0.05). Moreover, metabolites such as hippurate, valine, lactate + threonine, and uracil were exclusively found on whey and not in WPC-80, likely due to processing steps such as ultrafiltration. Conclusions: These findings highlight the metabolic distinctions introduced by WPC-80 processing from Parmigiano Reggiano whey and provide insights into the nutritional and functional characteristics of whey-derived products. Such knowledge can inform the design of innovative dairy ingredients and functional foods, with potential benefits for both industry applications and consumer health. Full article

Background/Objectives: Fumarate hydratase-deficient leiomyomas (dFH-LMs) are a rare subtype of uterine smooth muscle tumors (USMTs) with implications for hereditary leiomatosis and renal cell carcinoma (HLRCC). Although several morphologic clues have been proposed, their diagnostic reproducibility is poorly defined. We aimed to determine the diagnostic significance of histopathologic features associated with fumarase deficiency and the reproducibility of key morphologic criteria for defining dFH-LMs. Methods: A retrospective analysis was performed on 45 USMTs that were initially classified as atypical leiomyomas (ALMs). The cohort comprised patients aged 21 to 75 years who had surgery at one tertiary medical care center from 2016 to 2025. Hematoxylin–eosin (H&E) slides were independently examined by three pathologists for features associated with FH deficiency, including eosinophilic globules, staghorn-like vessels, diffuse nuclear atypia, “bizarre” nuclei, and prominent nucleoli with halos. Molecular status was determined by immunohistochemistry (IHC) for fumarate hydratase (FH) and S-(2-succino)-cysteine (2SC). Interobserver agreement was quantified using Fleiss’s κ and Cohen’s κ. Results: Loss of FH expression was detected in 26/45 tumors (57.7%). Eosinophilic globules occurred in 88.5% of dFH-LMs, but only in 15.8% of ALMs (p < 0.001). By majority consensus (≥2 of 3 reviewers), the eosinophilic globules predicted FH deficiency with a sensitivity of 88.0% and a specificity of 85.0%; interobserver reproducibility was substantial (κ = 0.63). Staghorn-like vessels occurred in 73.1% of dFH-LMs vs. 26.3% of ALMs (p = 0.02) and diffuse nuclear atypia (84.6%) was also more frequent in dFH-LMs (p = 0.01). Patients with dFH-LMs were significantly younger than those with ALMs (Median, 34 vs. 41 years). Conclusions: Eosinophilic globules, staghorn-like vessels and diffuse nuclear atypia have been shown to have high diagnostic value and could be considered morphologic indicators of dFH-LMs. The substantial interobserver reproducibility of eosinophilic globules makes this feature particularly promising for routine clinical practice. Full article

Chronic obstructive pulmonary disease (COPD) is a major health burden in India with limited real-world data on triple inhaler therapy. This prospective, open-label, multi-center, single-arm, phase 4 study (October 2023–August 2024) assessed the effectiveness and safety of glycopyrronium/formoterol fumarate/budesonide (GFB) triple therapy, administered as metered-dose inhaler (MDI) or dry-powder inhaler (DPI), in Indian COPD patients. Symptomatic patients aged ≥40 years with minimum one exacerbation in the past year and receiving dual or monotherapy were included. GFB was delivered as MDI or DPI based on physician and patient preference. Primary outcomes were changes from baseline in trough forced expiratory volume in 1 s (FEV₁), forced vital capacity (FVC), and modified medical research council (mMRC) score over 24 weeks, with assessment of exacerbations, hospitalizations, rescue medication use, and safety. In 184 patients (70.65% male, mean age 53.7 years), GFB significantly improved FEV₁, FVC, and mMRC scores. Eleven mild exacerbations were reported without hospitalization; 17.39% used rescue salbutamol largely in the first 4 weeks. GFB was well tolerated, with mild-to-moderate adverse events in 14.67%, and outcomes were comparable between MDI and DPI. Our findings support GFB as safe and effective treatment in real-world COPD management. Full article

Dimethyl fumarate (DMF) has established a significant position among therapies for multiple sclerosis and psoriasis and is now being investigated for repurposing to many other non-malignant diseases. Despite decades of preclinical research, some issues about its pharmacology remain unresolved, with ongoing debate over which of the methyl esters of fumarate, whether DMF or monomethyl fumarate (MMF), is the active ingredient. It is generally accepted that DMF undergoes enzymatic hydrolysis to MMF and methanol. However, there is disagreement regarding its exact site, its extent, and the responsible enzyme(s). The enzymatic mechanisms, particularly the roles of carboxylesterases-1 and 2, vary across tissues and species, complicating the translation of in vitro and in vivo preclinical findings into clinical practice. In addition, the impact of DMF and MMF is often not clearly distinguishable and sometimes overlaps, making the true molecular mediators of therapeutic and side effects unclear. Thus, the interpretation of some results obtained in studies is inconsistent because of interchanging of in vitro and in vivo observed features of fumarate esters: while DMF demonstrates rapid and strong effects in cell culture studies, including nuclear factor erythroid 2-related factor 2 (NRF2) function activation and glutathione depletion, these observations may not exactly reflect systemic pharmacology and physiology dominated by MMF. Moreover, methanol, the co-product of DMF metabolism, may contribute to the observed DMF effects through increased production of reactive oxygen species, which could result in activation of NRF2-dependent mechanisms. This review highlights specific unresolved issues in DMF metabolism, which are sometimes overlooked. Full article

Recurrent Clostridioides difficile infection (rCDI) remains a major therapeutic challenge. Although faecal microbiota transplantation (FMT) is highly effective and thought to restore microbial composition and metabolic function, the mechanisms underlying its success are not fully understood. In particular, the contribution of non-bacterial components such as soluble metabolites remains unclear. Therefore, further investigation is needed to identify the mechanistic drivers of FMT efficacy and clarify how non-bacterial factors contribute to therapeutic outcomes. Here, we applied untargeted three-dimensional Orbitrap secondary ion mass spectrometry (3D OrbiSIMS) to profile faecal metabolic reprogramming in rCDI patients pre- and post-FMT, alongside C. difficile cultures exposed to sterile faecal filtrates. FMT induced extensive metabolic shifts, restoring glyoxylate/dicarboxylate and glycerophosphoinositol pathways and normalising disrupted bile acid and amino acid profiles. Faecal filtrate exposure caused strain-specific metabolic disruption in C. difficile, depleting proline, fumarate and succinate while enriching tryptophan. While multiple metabolite classes were profiled, the most significant functional changes were observed in lipids. Lipidomics identified >3.8-fold enrichment of phosphatidylinositol (PI) species, which localised to bacterial membranes and conferred cytoprotection against C. difficile toxins and other epithelial insults. Spatial metabolomics imaging revealed, for the first time, metabolite compartmentalisation within C. difficile, with proline and succinate broadly distributed across the cell surface and fumarate confined to distinct microdomains, highlighting functional heterogeneity in pathogen metabolism. Collectively, these findings demonstrate that soluble metabolites within faecal filtrates mediate pathogen suppression and epithelial barrier protection, establishing metabolite-driven mechanisms underlying FMT efficacy and identifying PI lipids as candidate post-biotic therapeutics for rCDI. Full article