Search Results (7,933)

Background/Objectives: Metabolic alterations, including dyslipidemia, may influence tumor biology and treatment outcomes in neuroendocrine tumors. However, the clinical relevance of dyslipidemia and lipid-lowering therapy in bronchopulmonary neuroendocrine tumors (BP-NETs) treated with somatostatin analogues (SSAs) remains poorly defined. This translational proof-of-concept study evaluated progression-free survival (PFS) in patients with advanced BP-NETs receiving SSAs according to dyslipidemia and statin therapy and explored the effects of statin-SSA combination treatment in vitro. Methods: We retrospectively analyzed 24 patients with advanced well-differentiated BP-NETs treated with SSAs as first-line therapy. Fourteen patients (58.3%) had dyslipidemia, and 11 of them were receiving statins. In parallel, NCI-H727 cells were treated with atorvastatin (10 µM), lanreotide (5 or 10 µM), or their combination for 48–72 h. Cell viability, proliferation, cell death, apoptosis, DNA damage, and ATP production were assessed. Results: Median PFS was 22.5 months overall. A trend toward longer PFS was observed in non-dyslipidemic vs. dyslipidemic patients (70 vs. 36 months, p = 0.08). Among dyslipidemic patients, statin therapy was associated with a non-significant trend toward longer PFS compared with no statin therapy (36 vs. 18 months, p = 0.30). In vitro, combined atorvastatin–lanreotide treatment reduced cell viability and proliferation, increased cell death, enhanced cleaved caspase-3 and p-γH2AX expression, and reduced ATP production. Conclusions: These findings support the potential relevance of lipid metabolism modulation as an adjunct strategy in advanced BP-NETs while highlighting the need for larger prospective studies and dedicated biochemical investigation of the underlying lipid-related pathways. Full article

Ultraviolet A (UVA) radiation induces oxidative stress and mitochondrial dysfunction in dermal fibroblasts, contributing to photodamage and skin aging. This study investigated the protective effects of Yeast/rice fermentation filtrate (RFF) and sialic acid (SA), both individually and in combination, against UVA-induced damage in human dermal fibroblasts. Cell viability, reactive oxygen species (ROS) levels, intracellular ATP and NAD⁺ contents, and mitochondrial membrane potential (ΔΨm) were evaluated following treatment. RFF, SA, and their combination significantly improved cell viability in UVA-damaged fibroblasts and reduced ROS generation. Notably, the combined treatment increased intracellular ATP levels by 201.2% (p < 0.05), with enhancements of 62.3% and 285.4% compared to RFF and SA alone, respectively. Additionally, the combined treatment significantly restored NAD⁺ levels and effectively preserved mitochondrial membrane potential. Transcriptomic analysis revealed modulation of pathways related to cellular energy metabolism, particularly AMPK, and upregulation of SIRT1, SIRT3, and SIRT5 expression. The RFF–SA combination confers robust UVA photoprotection by enhancing mitochondrial resilience, providing a foundation for the development of protective cosmetic formulations. Full article

The global rise in the incidence and severity of invasive fungal infections, particularly among immunocompromised and immunodeficient patients, has created an urgent need for rapid and accurate diagnostic techniques. Therefore, fungal-specific positron emission tomography imaging agents are increasingly in demand, as they offer the potential for early-stage detection of fungal infections. Recently, 2-deoxy-2-[¹⁸F]fluorocellobiose ([¹⁸F]FCB), a fluorine-18-labeled analog of cellobiose that is selectively metabolized by fungal pathogens possessing cellulose-degrading mechanisms (cellulolytic), was developed for the targeted imaging of Aspergillus infections. However, the final [¹⁸F]FCB contained less than 2% unreacted 2-deoxy-2-[¹⁸F]fluoroglucose ([¹⁸F]FDG), which can potentially interfere with image interpretation. Accordingly, this study aims to eliminate residual [¹⁸F]FDG from the final product by enzymatically converting it to [¹⁸F]FDG-6-phosphate through hexokinase-mediated phosphorylation. A Trasis AllInOne (Trasis AIO) module was used to automate the radiolabeling procedure. The reagent vials contain [¹⁸F]FDG, glucose-1-phosphate, cellobiose phosphorylase, adenosine triphosphate (ATP), and hexokinase. A Sep-Pak cartridge was used to purify the tracer. The overall radiochemical yield was 45–50% (n = 3, decay-corrected) in a 40 min synthesis time, with a radiochemical purity of >99% (no detectable [¹⁸F]FDG). This is a highly reliable protocol to produce current good manufacturing practice (cGMP)-compliant [¹⁸F]FCB for clinical PET imaging. Full article

Background: The cochlea is a specialized sensory organ essential for hearing. To elucidate its cellular and molecular architecture and prioritize candidate genes associated with hearing loss (HL), we constructed a cross-species single-cell transcriptomic atlas of human fetal and postnatal mouse cochleae. Methods: We integrated single-cell and single-nucleus RNA sequencing datasets from human fetal cochleae and postnatal mouse cochleae to build a comprehensive cross-species single-cell transcriptomic atlas. Cell-type annotation, transcriptional regulator analysis, intercellular communication, and disease phenotypes were performed to dissect the cochlear cellular landscape, regulatory programs, and potential HL gene candidates. Results: A total of 19 major cochlear cell types were identified in both species, with conserved cellular composition and transcriptional programs. Comparative analysis revealed strong transcriptional conservation between matched human and mouse cell types, particularly in supporting, schwann cells and hair cells. Cell–cell communication analysis revealed conserved signaling pathways, including the BDNF-NTRK2 axis, potentially involved in cochlear development and auditory function. Regulatory network inference uncovered conserved and previously undercharacterized transcription factors, such as SKOR1, RFX2, and PAX2, predicted to be associated with hair cell identity and function. We further defined a conserved gene module of 3138 hair cell-enriched genes, from which 24 candidate HL-associated genes (e.g., ATP8B1, BDNF, and SOD1) were prioritized through integration with human disease databases and mouse auditory phenotype annotations. Conclusions: This study provides a high-resolution cross-species cochlear atlas, revealing conserved molecular programs and candidate HL-associated genes, offering valuable insights into auditory biology and potential avenues for further investigation. Full article

Shallow groundwater in saline soils creates a self-reinforcing cycle where waterlogging-induced root hypoxia impairs the ATP-dependent sodium exclusion mechanisms that plants rely on for salt tolerance. We conducted a two-year field experiment to test whether subsurface drainage must precede root-zone aeration for oxygen delivery to be effective. The experimental site was located in Heyang County, Weinan City, on the Guanzhong Plain of Shaanxi Province, north-central China—a major alluvial agricultural region representative of shallow-groundwater-induced salinization. The site had saturated paste electrical conductivity of 6.0 dS m⁻¹ and groundwater depth fluctuating between 0.5 and 1.4 m. A randomized complete block design with 2 × 2 factorial arrangement compared four treatments: control (CK), subsurface drainage only (SD), root-zone aeration only (RA), and both interventions combined (SD + RA). Drainage increased air-filled porosity from 5.8% to 13.5%, crossing the 10.2% threshold (95% CI: 9.1–11.3%) where gas-phase continuity emerges according to segmented regression analysis. Without drainage, aeration achieved only 4.2 mg L⁻¹ dissolved oxygen with high spatial variability (CV 12.5%), while the combined treatment reached 6.8 mg L⁻¹ (CV 6.8%). Root ATP content increased by 89% in SD + RA compared to control, accompanied by 56% lower root Na⁺ and 185% higher K⁺/Na⁺ ratio. These physiological changes correlated with 31% higher grain yield (7580 vs. 5798 kg ha⁻¹). The synergy index of 1.40 (95% CI: 1.28–1.52) indicated that combined effects exceeded the sum of individual treatments by 40%. Methane emissions declined by 62%, and the system achieved a 2.9-year payback period with a benefit–cost ratio of 4.08. These results establish drainage as a physical prerequisite for effective oxygenation, providing a mechanistic explanation for the variable performance of aeration systems reported in previous studies. Full article

Background: Bedaquiline (BDQ) resistance poses a serious threat to its long-term efficacy, particularly in high-burden settings like South Africa, where data remain scattered and largely non-synthesized. Objective: This study aimed to estimate the trends of BDQ resistance in drug resistant tuberculosis (DR-TB), characterize associated resistance mechanisms, and evaluate implications for treatment outcomes in South Africa. Eligibility criteria: We included primary studies reporting BDQ resistance, resistance mechanisms, minimum inhibitory concentrations (MICs), or treatment outcomes among patients with MDR- or XDR-TB treated with BDQ-containing regimens in South Africa. Information sources: PubMed, Web of Science, and Embase were searched for studies published between January 2016 and July 2024. Risk of bias: Study quality was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist. Synthesis of results: Random-effects meta-analysis with Freeman–Tukey double-arcsine transformation was used to estimate pooled BDQ resistance prevalence. Heterogeneity, sensitivity analyses, and publication bias were assessed. Results: Twenty-eight studies were included. The pooled prevalence of BDQ resistance was 6.0% (95% CI: 4.1–7.9%; I² = 62%). Treatment success averaged 63.5%, and culture conversion reached 84.1%. Resistance-associated mutations were most frequently reported in Rv0678, followed by atpE and pepQ, often associated with elevated MICs (≥2–4 μg/mL). Evidence of small-study effects was observed (Egger’s test, p = 0.0012). A pooled prevalence estimate was calculated; however, evidence of small-study effects suggests that estimates should be interpreted cautiously. Limitations: Heterogeneity in study design, outcome definitions, and resistance testing methods limited comparability across studies. Conclusions: Bedaquiline remains effective for DR-TB treatment in South Africa; however, emerging resistance and its molecular drivers pose a growing threat to regimen sustainability, including BPaL. Strengthened surveillance and standardized resistance testing are urgently needed. Full article

The large yellow croaker (Larimichthys crocea) is a high-value marine fish, but stress during live transport often leads to physiological disturbance and deterioration of muscle quality. This study investigated the effects of pre-transport temporary rearing at three temperatures (8, 10, and 12 °C) over 48 h on stress response, energy allocation, and muscle quality in this fish species. Temporary rearing at 8 °C induced stronger cold stress, characterised by elevated cortisol, marked lipid mobilisation, late lactate rebound, and greater loss of polyunsaturated fatty acids, indicating enhanced stress–catabolism coupling and higher risk of quality deterioration. In contrast, 12 °C did not sufficiently suppress metabolic turnover, resulting in continuous glycogen depletion, rapid ATP degradation, and accelerated accumulation of bitter-tasting nucleotide metabolites such as hypoxanthine. Among the tested temperatures, 10 °C showed the most coordinated response, with relatively stable endocrine status, moderate substrate utilisation, lower accumulation of undesirable degradation products, and better preservation of texture, water-holding capacity, and flavour-related precursors. These findings suggest that 10 °C is a promising pre-transport temporary rearing temperature for large yellow croakers under the present 48 h experimental conditions. The advantage of this temperature appears to lie in achieving a more favourable balance between metabolic suppression and physiological homeostasis, thereby providing a scientific basis for improving pre-transport rearing management and supporting safer, more stable live transport. Future studies incorporating behavioural and molecular indicators are needed to further clarify the regulatory effects of 10 °C during pre-transport rearing. Full article

Objective: This study aims to investigate the protective effect of Shengmai San (SMS) against high-glucose (HG)-induced injury in neonatal rat ventricular myocytes (NRVMs) and to elucidate the underlying pharmacological molecular mechanisms. We hypothesize that SMS ameliorates HG-induced calcium homeostasis imbalance in NRVMs by improving mitochondrial energy metabolism disorder, and this protective effect is associated with the downregulation of oxidized and phosphorylated CaMKII expression to inhibit CaMKII signaling pathway overactivation. Herein, we verify this hypothesis by assessing mitochondrial function, calcium transients, sarcoplasmic reticulum (SR) calcium handling and CaMKII phosphorylation levels in NRVMs. Methods: First, ultra-high performance liquid chromatography–high resolution mass spectrometry was used to identify the chemical components of SMS to clarify its material basis. Primary NRVMs were then cultured under low-glucose (LG) or HG conditions, with 2% SMS-medicated serum (SMS-MS) as the experimental intervention, and NAC (ROS scavenger) and KN93 (CaMKII inhibitor) as positive controls. Following intervention, we sequentially detected key indicators corresponding to the proposed pathological pathway: intracellular reactive oxygen species (ROS) levels (oxidative stress), mitochondrial ROS, mitochondrial function indices including oxygen consumption rate (OCR) (energy metabolism), calcium transients and diastolic intracellular free calcium concentration (global calcium homeostasis), sarcoplasmic reticulum (SR) calcium leak (calcium handling disorder), and, finally, the phosphorylation, oxidation levels of CaMKII and RyR2 phosphorylation (Ser2814) (p-RyR2) (key regulatory pathway) via Western blot to systematically elucidate the mechanistic link between SMS intervention and HG-induced NRVM injury. Results: Quantitative analysis revealed that high-glucose (HG) induction significantly reduced calcium transient amplitude and prolonged the decay time constant (tau) in NRVMs at 72 h (p < 0.01 vs. LG), with these parameters normalizing by 120 h—an effect indicative of a compensatory adaptive response. The 2%SMS-MS markedly ameliorated HG-induced calcium transient abnormalities at 72 h (p < 0.01 vs. HG). Additionally, 2%SMS-MS significantly enhanced mitochondrial basal oxygen consumption rate, spare respiratory capacity, ATP production, and maximal respiration in HG-exposed NRVMs (p < 0.01 vs. HG). SMS also significantly reduced intracellular reactive oxygen species (ROS) levels (p < 0.01 vs. HG), mitochondrial ROS levels (p < 0.01 vs. HG), diastolic intracellular free calcium concentration (p < 0.01 vs. HG), and SR calcium leak (p < 0.05 vs. HG). Western blot analysis revealed that 2%SMS-MS intervention effectively downregulated the expression of oxidized CaMKII (Ox-CaMKII) (p < 0.01 vs. HG), phosphorylated CaMKII (p-CaMKII) (p < 0.01 vs. HG), and RyR2 phosphorylation (Ser2814) (p < 0.05 vs. HG), which may be the potential mechanism in maintaining calcium homeostasis in HG-induced NRVMs. Conclusions: This study suggests that SMS enhances mitochondrial energy metabolism and exerts a protective effect against high-glucose-induced calcium homeostasis imbalance in NRVMs, which supports our proposed hypothesis. Its potential mechanism indicates that the protective effects of SMS are associated with its ability to downregulate the expression of oxidized and phosphorylated CaMKII. These findings highlight SMS as a potential therapeutic candidate for alleviating HG-related myocardial injury and provide evidence for its application in the prevention of early diabetic cardiomyopathy. Full article

(1) Background: Erlotinib is a tyrosine kinase inhibitor (TKI) widely used in cancer therapy; however, its potential adverse effects on ovarian tissue have not been fully elucidated. The present study aimed to investigate erlotinib-induced ovarian injury and to evaluate the protective effects of adenosine triphosphate (ATP) and flunarizine, administered alone or in combination, using biochemical and histopathological analyses in a rat model. (2) Methods: Thirty female rats were randomly allocated into five groups (n = 6 per group): healthy control, erlotinib, ATP + erlotinib, flunarizine + erlotinib, and ATP + flunarizine + erlotinib. ATP (5 mg/kg, intraperitoneal) and flunarizine (5 mg/kg, oral gavage) were administered daily for two weeks, while erlotinib (5 mg/kg) was given orally every two days for two weeks. Ovarian tissues were collected for oxidative stress analysis and histopathological evaluation, and blood samples were obtained for the measurement of serum prolactin and AMH levels. (3) Results: Erlotinib administration resulted in significant oxidative stress and histopathological alterations in ovarian tissue, accompanied by a reduction in serum AMH levels, while prolactin levels remained unchanged. Treatment with ATP or flunarizine partially attenuated these alterations. (4) Conclusions: Combined ATP and flunarizine administration showed stronger protective effects, improving biochemical parameters and preserving ovarian histology, suggesting a protective role against erlotinib-induced ovarian injury. Full article

Environmental pH plays a critical role in microbial fermentation processes. Weizmannia coagulans attracts particular attention for exceptional acid tolerance and lactic acid productivity. Yet acidic stress impacts on its cell division regulation remain unclear. Here, a critical pH value (pH 4.20) for growth inhibition of the Gram-positive bacterium Weizmannia coagulans strain BC99 was first established. Transcriptomic analysis of metabolic pathways was then performed. The multi-layered regulatory network underlying acid stress-induced cell division was elucidated. Integrated transcriptomic and physiological analyses reveal that acid stress triggers multigene expression reprogramming. This drives core metabolic network reorganization, coordinately regulating division processes. RNA-seq analysis demonstrated acid stress triggered differential expression of division genes (FtsZ/Q downregulation), ATP synthase suppression, and peptidoglycan transport reduction, while enhancing membrane rigidification (Cfa) and magnesium homeostasis (CorA). The PhoPR dual-component system emerged as a central regulator, inhibiting septal assembly via RipA hydrolase and RpsU ribosomal suppression while rerouting carbon flux to glycolysis, elucidating bacterial acid adaptation mechanisms. Collectively, these adaptive changes prioritize cell survival over active proliferation under acidic conditions. This study provides molecular insights into how W. coagulans preserves viability under acid stress, offering a theoretical basis for optimizing its performance in probiotic applications. Full article

Background: Uterus transplantation (UTx) is an emerging treatment for absolute uterine factor infertility. However, the use of deceased donors is limited, and donation after circulatory death (DCD) has not yet been utilized. Ischemic injury remains a major barrier, particularly compared with living donor procedures. Hypothermic oxygenated perfusion (HOPE), which has shown protective effects in heart, liver, and kidney transplantation, may offer similar benefits for uterine grafts. Methods: We report the first series applying HOPE to human uteri to improve preservation and enable metabolic injury assessment during perfusion. Six uteri (3 DBD, 3 DCD; median donor age 53 years) underwent 8 h of HOPE following procurement, while paired tissue controls were preserved using static cold storage (SCS). Perfusion was delivered using a pressure-controlled system (15 mmHg, 10 ± 1 °C, VitaSmart^®). Perfusate and tissue samples were analyzed for mitochondrial injury, inflammation, and transcriptional responses. Results: HOPE maintained stable flows (70–150 mL/min), delivered high oxygen levels (pO₂ ≈ 1000 hPa), and increased tissue ATP levels. Stratification based on perfusate flavin mononucleotide (FMN) release identified grafts with greater Complex I/II injury. HOPE was associated with lower levels of mitochondrial injury markers and inflammatory signals, preserved tissue architecture, and promoted gene expression patterns consistent with metabolic recovery compared with paired SCS tissue controls. Conclusions: These findings suggest that HOPE may serve as a preservation approach that enables metabolic and ischemic injury assessment and may facilitate broader use of deceased donor uteri for transplantation. Full article

Glioblastoma (GBM) remains among the most treatment-refractory human malignancies. It is characterized by profound radioresistance and a highly immunosuppressive tumor microenvironment, limiting the durable efficacy of radiotherapy. Beyond direct cytotoxicity, ionizing radiation can induce immunogenic cell death and the release of damage-associated molecular patterns (DAMPs), including surface-exposed calreticulin, HMGB1, extracellular ATP/adenosine, and tumor-derived DNA. These signals engage pattern-recognition receptors and cGAS–STING–type I interferon pathways, transiently promoting antigen presentation and immune activation. In GBM, however, DAMP signaling frequently evolves toward chronic inflammation and immune suppression, characterized by myeloid cell recruitment, adenosine accumulation, and immune checkpoint upregulation, thereby contributing to tumor regrowth and radioresistance. This dual immune-regulatory role of DAMPs highlights the importance of temporal and contextual interpretation of radiation-induced immune responses. In this review, we summarize current mechanistic and translational evidence on DAMP-mediated immunomodulation in GBM radiotherapy; discuss modality-dependent considerations across photon, proton, and high-LET irradiation; and evaluate the emerging potential of DAMPs as dynamic biomarkers of treatment response. We further outline how integration of DAMP profiling with liquid biopsy, imaging, and nanotheranostic platforms may support biologically informed and adaptive radiotherapy strategies for glioblastoma. Full article

Halogenated derivatives of polycyclic aromatic hydrocarbons (PAHs), such as chlorinated PAHs (ClPAHs), are an emerging class of contaminants that are being detected in the environment as well as in wildlife and human populations. Previous studies have shown that chemical substitution of PAHs, including chlorination, may alter the toxicity of parent PAHs; however, whether chlorination affects their endocrine-disrupting potential remains unexplored. In this study, we examined the effects of phenanthrene (Phe), one of the most prevalent PAHs, and its chlorinated congeners, 9-chlorophenanthrene (9ClPhe) and 9,10-dichlorophenanthrene (9,10Cl₂Phe), on hormone production in granulosa cells, key hormone-secreting cells of the ovary. We observed that Phe and its chlorinated congeners differentially altered anti-Müllerian hormone (AMH), estradiol (E2), and progesterone (P4) secretion. Since mitochondria are central to steroidogenesis, we further evaluated mitochondrial function. While Phe increased ATP production, both 9ClPhe and 9,10Cl₂Phe increased ROS, decreased mitochondrial membrane potential, and reduced the expression of markers for mitochondrial dynamics and mitophagy without altering ATP levels. We further tested impacts on cell fate and found that neither Phe nor its chlorinated congeners altered granulosa cell apoptosis. Together, these results suggest that chlorination of Phe leads to dose-dependent, differential effects on hormone production and mitochondrial pathways without inducing cell death in granulosa cells. This study highlights the potential adverse impacts of ClPAH exposure on ovarian follicle development and female fertility by disrupting steroidogenesis and mitochondrial quality control. Full article

Background: Parental imprinting plays a crucial role in epigenetic regulation and is increasingly recognized for its involvement in neurodevelopmental disorders. Although ATP8A2 is considered a non-imprinted gene; However, the marked phenotypic variability observed across related disorders suggests that additional regulatory layers may influence its expression. Methods: We investigated the imprinting-like status of ATP8A2 through functional analyses of a splicing variant (c.1580-3C>G) identified in a patient diagnosed with Cerebellar Ataxia, Mental Retardation, and Disequilibrium syndrome type 4 (CAMRQ4). Sanger sequencing was used to assess allelic expression and identify aberrant transcripts. Results: Our analyses revealed an allelic expression imbalance suggestive of parental imprinting of ATP8A2. Moreover, Sanger sequencing led to the identification of a novel ATP8A2–RAB3GAP2 chimeric transcript, pointing to a previously unreported transcriptional event, the functional relevance of which remains to be determined. Conclusions: These findings indicate that ATP8A2 may be subject to imprinting-like regulation and involved in atypical splicing events with unknown significance. This highlights the need for further investigation into the epigenetic and transcriptional complexity of ATP8A2-related neurodevelopmental disorders. Full article

This study investigated the effects of dietary supplementation with α-mangostin (α-Ma), a bioactive xanthone derived from mangosteen pericarp, on production performance and egg quality in late-phase laying hens. The experiment was conducted using a completely randomized design. In total, 576 healthy 51-week-old Beinong No. 2 laying hens were randomly assigned to 4 dietary treatments (n = 12): a basal diet (CON) or the basal diet supplemented with 80, 120, or 160 mg/kg α-Ma. The experiment lasted for 4 weeks, after which production performance, egg quality, serum biochemical and antioxidant parameters, inflammatory markers, and uterine gene expression were evaluated. Dietary supplementation with α-mangostin, particularly at 120 mg/kg, significantly improved feed efficiency (p < 0.05), as evidenced by a reduced feed-to-egg ratio from week 2 onward, without affecting average daily feed intake or egg production rate. After 4 weeks, hens receiving 120 mg/kg α-Ma exhibited significantly greater egg weight and eggshell strength (p < 0.05). Serum and hepatic antioxidant capacities were significantly enhanced, with increased glutathione peroxidase and catalase activities, elevated total antioxidant capacity, and decreased malondialdehyde levels (p < 0.05). Moreover, α-Ma at 120 mg/kg specifically lowered the concentration of the pro-inflammatory cytokine interleukin-1β in both serum and uterine tissue (p < 0.05). At the molecular level, this dosage significantly upregulated uterine genes essential for eggshell formation (p < 0.05), including calcium transporters (TRPV6, ATP2B2), the matrix protein gene OC-116, and other key genes (LYZ, CA2, SLC4A9, and ATP6V0D2). In conclusion, dietary supplementation with 120 mg/kg α-Ma effectively enhances feed efficiency, strengthens antioxidant and anti-inflammatory defenses, and upregulates uterine genes involved in biomineralization, thereby improving eggshell quality in aging laying hens. These findings support α-Ma as a promising plant-based feed additive for maintaining productivity and egg quality in antibiotic-free layer production systems. Full article