Alcohol is a molecule whose multiple effects in living organisms exemplify how profound biological complexity can arise from an exceptionally simple chemical structure interacting with the cellular biochemical machinery. This review was conceived to provide an up-to-date synthesis of the current knowledge on the multifaceted consequences of alcohol oxidative metabolism and alcohol-derived oxidative stress, ranging from disruption of subcellular and cellular homeostasis to impairment of organ function. This study primarily focuses on the consequences of alcohol metabolism and on the mechanisms by which the rise of its main metabolite, acetaldehyde, and of reactive oxygen species (ROS), generates oxidative stress by-products and molecular adducts responsible for compromising cellular energy balance and antioxidant defense mechanisms. In particular, this review aims to provide an exhaustive representation of the mechanisms, causes, and consequences of alcohol oxidative metabolism: this is accomplished by taking into account alcohol-induced modifications of gene expression of cellular antioxidant determinants, the role of epigenetic mechanisms, and that of gene polymorphisms linked to alcohol-dependent oxidative stress and responsible for serious diseases such as, among others, alcoholic hepatitis, cirrhosis, and hepatocellular carcinoma. In addition, this review highlights the role of alcohol oxidative metabolism in the brain, which, in the acute setting, activates the dopaminergic system mainly involved in alcohol reinforcing properties and, upon chronic exposure, contributes to neurodegenerative disorders. Finally, a dedicated paragraph explores autophagy as an integrative mechanism underlying the effects of alcohol-related oxidative stress across multiple organs, including the liver, heart, and brain.

Hepatectomy is an effective and widely adopted surgical technique for treating various liver diseases. However, owing to the liver's unique anatomical structure and rich blood supply, hepatectomy poses considerable challenges. The most critical challenge is intraoperative bleeding, which is closely associated with postoperative complications and patient mortality. This has driven the pursuit of effective and safe strategies to minimize bleeding during hepatectomy. Managing a low central venous pressure of <5 cm H2O or 3 mmHg has been shown to significantly reduce hepatic vein bleeding and provide optimal surgical visibility during hepatectomy. Before the routine application of low central venous pressure management, bleeding during hepatectomy was often associated with unacceptably high morbidity and mortality rates. Although this technique has been demonstrated to be safe and effective in multiple studies of hepatectomy and transplantation, its widespread adoption remains limited. Concerns have been raised regarding morbidity related to insufficient perfusion to vital organs during the low central venous pressure phase of hepatectomy. This review has discussed recent developments concerning the effects of low central venous pressure management during hepatectomy on the function of critical organs.

Organic molecule functionalization of Cu single-atom catalysts for enhanced electrocatalytic CO2 reduction to methane

The Drosophila larval salivary gland, a simple and elegant model system to understand secretory organ development and function.

Adjuvant camrelizumab combined with capecitabine in patients with intrahepatic cholangiocarcinoma after surgical resection in China (ACC): a single-arm, single-centre, open-label, phase 2 trial.

Chemotherapy resistance remains a major challenge in the treatment of uveal melanoma, necessitating the identification of novel therapeutic strategies. In this study, we established chemoresistant uveal melanoma cell lines by exposing parental cells to dacarbazine, cisplatin, or gemcitabine and performed high-throughput drug screening incorporating normal human epidermal melanocytes (NHEMs) as a normal control to assess both efficacy and selectivity. Our screening identified temsirolimus and selumetinib as top candidates, with temsirolimus exhibiting strong tumor-selective cytotoxicity. Further in-vitro studies confirmed that temsirolimus induced apoptosis and suppressed clonogenic potential in chemoresistant uveal melanoma cells while having minimal effects on NHEM. Combination studies demonstrated synergy between temsirolimus and cisplatin or gemcitabine, reinforcing its role as an effective chemosensitizer. In a chemoresistant uveal melanoma xenograft model, temsirolimus significantly inhibited tumor growth without inducing systemic toxicity, as evidenced by stable biochemical markers of organ function. Mechanistically, temsirolimus downregulated mammalian target of rapamycin (mTOR) signaling, as indicated by reduced p-mTOR, p-S6, and p-4EBP1 expression in tumor tissues. These findings demonstrate that temsirolimus selectively targets chemoresistant uveal melanoma cells, enhances chemotherapy efficacy, and suppresses tumor growth via mTOR inhibition, supporting its potential clinical application as a novel therapeutic strategy for chemoresistant uveal melanoma.

Clinico-pathological findings in a series of gastrointestinal endoscopic submucosal dissection specimens: A retrospective 5-year study.

The potential protective role of L-citrulline against cadmium-induced renal dysfunction in male albino rats: The implications of the Nrf2/HO-1 antioxidant signaling pathway.

Sarcoidosis: Disease mechanisms, diagnostic pathway and treatment.

Sepsis has emerged as a major threat to human mortality. Increasing evidence explores the impact of mitochondrial metabolism on the prognosis of sepsis patients and its therapeutic potential. To enhance risk stratification and identify potential targets, we conducted a retrieval and analysis of differential expression of mitochondrial metabolism related genes (MMRG) between sepsis and normal samples from public databases. Immune infiltration analysis was preformed to gain comprehensive knowledge of features of the established risk model. Additionally, single-cell sequencing results suggested MTHFD2 may be a critical target in sepsis for regulating immune infiltration characteristics, potentially altering platelet metabolism pathways significantly, thereby influencing sepsis occurrence and progression. Utilizing molecular docking, we further screened Ginsenoside Rb1 (Grb1) as a key pharmacological target interacting with MTHFD2. Further animal experiments preliminarily indicated that Grb1 administration was associated with reduced MTHFD2 expression and improved organ function and survival in CLP-induced septic rats. These findings provide new insights and potential therapeutic targets for clinical treatment of sepsis in the future.

Kinetics, tolerability and safety of (R)-1,3-butanediol (S)-lactate ester (LaKe): A randomized controlled cross-over trial in adults with obesity.

Abstract Introduction Novel total-body positron emission tomography (PET) scanners offer a unique possibility to simultaneously measure various organ functions in the body. Adenosine is routinely used as a pharmacological vasodilator in myocardial perfusion imaging. Purpose The study aimed to investigate sex differences in brain perfusion at rest and during adenosine stress. Methods A total of 130 patients with suspected coronary artery disease and without prior stroke were prospectively recruited to undergo total-body [15O]H2O PET perfusion imaging at rest and during adenosine stress. The brain and the heart were analysed using organ-specific models. K1-derived absolute perfusion for different brain regions was measured using a single-tissue-compartment model. Comparison of regional brain perfusion between sexes was adjusted with the volume of the regions of interest. k2-derived absolute myocardial perfusion was measured for the heart. Results Myocardial perfusion was significantly lower in males (rest median 0.84 [25th-75th percentiles 0.75–0.94] mL/min/g and stress 2.54 [2.15–2.95] mL/min/g) compared with females (rest 1.13 [0.96–1.30] mL/min/g and stress 3.44 [2.75–3.81] mL/min/g) both at rest (p&amp;lt;0.0001) and during adenosine stress (p&amp;lt;0.0001). In males, global brain perfusion was mean 0.42 (SD 0.07) mL/min/mL at rest and 0.30 (0.05) mL/min/mL during adenosine stress (p&amp;lt;0.0001). In females global brain perfusion was 0.46 (0.07) mL/min/mL at rest and 0.34 (0.06) mL/min/mL during adenosine stress (p&amp;lt;0.0001). Volume-adjusted global brain perfusion was significantly higher in females compared to males during adenosine stress (p=0.013), but did not differ between sexes at rest (p=0.7). In the grey matter cortex, brain perfusion during adenosine stress was also significantly lower in males than in females (0.30 (0.05) mL/min/mL vs 0.34 (0.05) mL/min/mL, p=0.03). No difference was observed in white matter at rest (p=0.11) or during adenosine stress (p=0.11). Conclusions Adenosine decreases brain perfusion in both sexes as compared with the resting state. Brain perfusion differs between sexes during adenosine stress. Males appear to have lower volume-adjusted global brain perfusion than females during adenosine stress. Males also had lower brain perfusion during adenosine stress in the grey matter cortex compared to females. The clinical significance of sex differences in brain perfusion warrants further study.

Slightly acidic electrolyzed water (SAEW) has been shown to possess strong bactericidal and virucidal properties, making it a promising candidate for spatial disinfection. In this study, we rigorously evaluated the efficacy and safety of SAEW for aerosol disinfection under controlled conditions. Laser particle size distribution analysis confirmed uniform aerosolization. Additionally, analysis of chlorine concentration ensured stable disinfection conditions. Moreover, SAEW exhibited potent sterilization effects against the model organism Escherichia coli in both direct-contact and aerosol-disinfection experiments. Notably, long-term exposure assessments in rats revealed no adverse effects on body weight, food and water intake, and organ function and histology. Conclusively, these results indicate that SAEW is a highly effective and safe disinfectant for controlling airborne and droplet-mediated infections. In addition to preventing the spread of infectious diseases, including coronaviruses, SAEW is expected to be effectively utilized in the veterinary, agricultural, and food industries.

Depletion of CX3CR1+ macrophages results in disrupted functionality and immune surveillance within epididymis and testis.

The pivotal clinical trials, CARTITUDE-1 and KarMMa-3, showed promising response rates in relapsed and refractory multiple myeloma (RRMM) with use of BCMA-directed CAR T-cell therapy; however, a major challenge is determining suitability in patients who do not meet trial inclusion criteria due to suboptimal organ function. In this multicenter retrospective study, we evaluated the safety and efficacy of BCMA CAR-T therapy in patients with RRMM and renal impairment (RI), defined as creatinine clearance (CrCL) of less than 45 mL/min. We evaluated 223 patients treated with idecabtagene vicleucel (ide-cel) or ciltacabtagene autoleucel (cilta-cel) between May 2021 and April 2024. Outcomes were compared between baseline RI (11.2%) and normal renal function (nRF) cohorts. Response rates were similar at 1 month (p = 0.09), 3 months (p &gt; 0.9), and 6 months (p = 0.8). Progression-free survival (PFS) was 21.9 months in the RI group compared to 15 months in the nRF group (p = 0.32), while overall survival (OS) was 27.9 months for patients with RI versus not reached for patients with nRF (p = 0.87). Patients with RI had higher rates of immune effector cell-associated neurotoxicity syndrome (ICANS) (60% vs. 19%, p = 0.04) and infections (44% vs. 20%, p = 0.008). We found that BCMA CAR-T demonstrated comparable efficacy in RRMM patients with baseline RI, although these patients exhibited increased rates of neurotoxicity and infections.

Three silica-based porous adsorbents, MCM-41 (pure silica), vinyl-MCM-41 (hybrid silica), and Ph-PMO (periodic mesoporous phenylene-silica), were tested to evaluate the effect of organic functionalities on removing the hormone disruptor 17α-ethinylestradiol (EE2) from water. Different adsorbent dosages were tested in ultrapure water spiked with 200 μg L-1 EE2, and the results revealed that adsorbent concentrations higher than 500 mg L-1 did not significantly enhance the EE2 removal efficiency. Both materials containing organic functionalities (using a dose of 500 mg L-1) were tested in ultrapure water, phosphate buffer at pH 5, 7, and 9, and wastewater effluent to evaluate the pH impact and the effect of different water matrices on their adsorption performance. An increase in pH significantly improved the EE2 adsorption capacity of Ph-PMO, reaching 94 ± 2% at pH 9, while it decreased the adsorption efficiency of vinyl-MCM-41 to 14 ± 7% at the same pH. Following a comprehensive characterization of the materials, including assessments of chemical stability across varying pH conditions, point of zero charge, hydrophobicity, and textural properties such as specific surface area, pore volume, and pore diameter, the findings suggest that the homogeneous distribution of organic functionalities in Ph-PMO enhances surface interactions, such as π-π stacking and hydrophobic interactions, with the EE2 hormone. Ph-PMO demonstrated superior performance in wastewater effluents, and kinetic studies showed rapid EE2 adsorption across all matrices, reaching equilibrium within 5 min. This study highlights the potential of Ph-PMO for the advanced-stage removal of EE2 from water effluents.

Hibernators rely on endogenous supplies of amino acids (AAs) and other nutrients to sustain organ function and skeletal muscle mass. Gut microbiota-mediated recycling of urea-nitrogen into AAs has long been considered a mechanism to assist in conserving nitrogen; however, the relevance of urea nitrogen salvage (UNS) to overall host physiology and metabolism is debated. We hypothesized that incorporation of microbially-liberated urea-nitrogen (MLUN) into AAs would be higher in host tissues of hibernating arctic ground squirrels compared to those of summer active squirrels, and that MLUN would support synthesis of anabolic AAs that regulate protein balance. To test this, we injected [13C, 15N2]-urea into summer squirrels and into squirrels hibernating at an ecologically relevant ambient temperature (-16 °C). We found greater incorporation of MLUN into non-essential AAs and specific essential AAs in several tissues of hibernating squirrels compared to summer. We also observed increased 15N enrichment in leucine-isoleucine, citrulline and glutamine, anabolic AAs known to influence protein balance and trans-organ nitrogen balance. Compared to studies in which ground squirrels hibernated at ambient temperatures above 0 °C, our results suggest that squirrels hibernating at subzero temperatures may up modulate synthesis of AAs that preserve protein and nitrogen balance during prolonged fasting and inactivity.

Cardiometabolic diseases, including hypertension, type 2 diabetes, dyslipidemia, and obesity, along with their cardiovascular complications, remain leading causes of morbidity and mortality worldwide, imposing significant public health, economic, and societal burdens. Conventional pharmacological therapies often show limited efficacy and increased adverse effects because they do not account for the body’s intrinsic circadian rhythms, which regulate organ function, drug absorption, and metabolism. Chronopharmacology, which aligns treatment timing with these biological rhythms, offers a strategy to enhance therapeutic outcomes. This review presents a comprehensive analysis of chronopharmacology principles applied to cardiometabolic disease management, integrating molecular, physiological, and clinical perspectives. It examines how core clock genes and tissue-specific circadian patterns influence drug action and absorption and summarizes evidence-based time-optimized interventions for hypertension, diabetes, dyslipidemia, obesity, and multimorbid patients. Furthermore, the review highlights emerging innovations, including artificial intelligence-guided dosing, circadian-biomarker-informed therapy selection, and wearable digital devices for real-time monitoring of biological rhythms. By synthesizing mechanistic and clinical insights, circadian-aligned treatment strategies are shown to improve drug efficacy, reduce adverse effects, and support the development of precision, rhythm-based therapeutics, offering a practical framework for personalized cardiometabolic disease care.

Chronic kidney disease (CKD) is a significant challenge in pediatric care, as it can lead to substantial long-term comorbidities, reduced quality of life and reduced lifetime. Early detection of pediatric CKD is vital for preventive care and maintaining organ function. Therefore, there is a critical need for biomarkers that should ideally offer early detection (before glomerular filtration rate (GFR) decline), possess high specificity for the underlying renal disease process (e.g. tubular or glomerular damage), and show strong prognostic value for predicting disease progression. This narrative review examines the role of Dickkopf-3 (DKK3), a pro-fibrotic protein released by renal tubular cells during pathophysiological stress, in the context of pediatric CKD. In experimental models, DKK3has been shown to drive renal tubulointerstitial fibrosis by modulating the WNT/β-catenin signaling pathway. There is increasing evidence suggesting that urinary DKK3 (uDKK3) levels could serve as a valuable biomarker for identifying pediatric CKD patients at high risk for rapid disease progression, regardless of the underlying etiology. This review highlights uDKK3 as a potential marker for the early detection and risk stratification of pediatric patients with CKD, which could lead to a personalized approach to monitor CKD beyond estimated GFR and albuminuria.

Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by loss of the SMN1 gene, reduced levels of SMN protein, and motor neuron degeneration. However, increasing evidence shows that SMA is a multisystemic disease with immune system involvement. We investigated how SMN deficiency affects lymphoid organ development and function using a severe SMA mouse model (SMNΔ7) and postmortem human fetal and postnatal tissues lacking SMN1 and carrying one or two SMN2 copies, consistent with type 0–I SMA. Histology, immunostaining, and flow cytometry were used to examine tissue architecture and immune cell composition. SMNΔ7 mice displayed thymus, spleen, and bone marrow abnormalities, including mislocalization of T- and B-cells and expansion of resident macrophages. Bone marrow analysis revealed impaired B-cell development, suggesting intrinsic hematopoietic defects rather than apoptosis. Early treatment with a nusinersen-like antisense oligonucleotide, administered intracerebroventricularly or subcutaneously, restored SMN2 splicing, improved survival, motor function, and prevented lymphoid pathology. Human SMA samples exhibited similar, though milder, splenic alterations compared to SMNΔ7 mice, while thymic organization remained largely preserved. These findings demonstrate that SMN deficiency disrupts lymphoid organ development through defective bone marrow output and impaired immune cell maturation. Early SMN restoration prevents these abnormalities, highlighting immune dysfunction as a key component of SMA pathology.