Search Results (126)

Skin aging is closely related to mitochondrial dysfunction and cell cycle abnormalities, and developing intervention strategies targeting mitochondrial quality control is an important direction for anti-aging research. In this study, we investigated the anti-aging mechanism of Camellia japonica flower (CJF) extract and its active ingredient hyperoside based on a doxorubicin (DOX)-induced endogenous senescence model in human skin fibroblasts (HSFs). LC-MS proteomics analysis revealed that CJF extract and hyperoside specifically activated the FUNDC1-mediated mitochondrial autophagy pathway, significantly ameliorated the DOX-induced decrease in mitochondrial membrane potential and the accumulation of reactive oxygen species (ROS), and alleviated the cellular S-phase blockade and reversed the high expression of senescence-associated β-galactosidase (SA-β-gal). Further studies showed that the two cleared damaged mitochondria by enhancing mitochondrial autophagy and restoring cellular energy metabolism homeostasis while promoting type III collagen and elastin synthesis and repairing the expression of Claudin 1 related to skin barrier function. For the first time, the present study reveals the molecular mechanism of CJF extract in delaying skin aging by regulating the FUNDC1-dependent mitochondrial autophagy pathway, which provides a theoretical basis and a candidate strategy for developing novel anti-aging agents targeting mitochondrial quality control. Full article

Background: The candidate therapeutic peptide TnP demonstrates broad, system-level regulatory capacity, revealed through integrated network analysis from transcriptomic data in zebrafish. Our study primarily identifies TnP as a multifaceted modulator of drug metabolism, wound healing, proteolytic activity, and pigmentation pathways. Results: Transcriptomic profiling of TnP-treated larvae following tail fin amputation revealed 558 differentially expressed genes (DEGs), categorized into four functional networks: (1) drug-metabolizing enzymes (cyp3a65, cyp1a) and transporters (SLC/ABC families), where TnP alters xenobiotic processing through Phase I/II modulation; (2) cellular trafficking and immune regulation, with upregulated myosin genes (myhb/mylz3) enhancing wound repair and tlr5-cdc42 signaling fine-tuning inflammation; (3) proteolytic cascades (c6ast4, prss1) coupled to autophagy (ulk1a, atg2a) and metabolic rewiring (g6pca.1-tg axis); and (4) melanogenesis-circadian networks (pmela/dct-fbxl3l) linked to ubiquitin-mediated protein turnover. Key findings highlight TnP’s unique coordination of rapid (protease activation) and sustained (metabolic adaptation) responses, enabled by short network path lengths (1.6–2.1 edges). Hub genes, such as nr1i2 (pxr), ppara, and bcl6aa/b, mediate crosstalk between these systems, while potential risks—including muscle hypercontractility (myhb overexpression) or cardiovascular effects (ace2-ppp3ccb)—underscore the need for targeted delivery. The zebrafish model validated TnP-conserved mechanisms with human relevance, particularly in drug metabolism and tissue repair. TnP’s ability to synchronize extracellular matrix remodeling, immune resolution, and metabolic homeostasis supports its development for the treatment of fibrosis, metabolic disorders, and inflammatory conditions. Conclusions: Future work should focus on optimizing tissue-specific delivery and assessing genetic variability to advance clinical translation. This system-level analysis positions TnP as a model example for next-generation multi-pathway therapeutics. Full article

Transcranial direct current stimulation (tDCS) can modulate cortical excitability in a polarity-specific manner, yet identical protocols often produce inconsistent outcomes across sessions or individuals. This narrative review proposes that much of this variability arises from the brain’s intrinsic temporal landscape. Integrating evidence from chronobiology, sleep research, and non-invasive brain stimulation, we argue that tDCS produces reliable, polarity-specific after-effects only within a circadian–homeostatic “window of efficacy”. On the circadian (Process C) axis, intrinsic alertness, membrane depolarisation, and glutamatergic gain rise in the late biological morning and early evening, whereas pre-dawn phases are marked by reduced excitability and heightened inhibition. On the homeostatic (Process S) axis, consolidated sleep renormalises synaptic weights, widening the capacity for further potentiation, whereas prolonged wakefulness saturates plasticity and can even reverse the usual anodal/cathodal polarity rules. Human stimulation studies mirror this two-process fingerprint: sleep deprivation abolishes anodal long-term-potentiation-like effects and converts cathodal inhibition into facilitation, while stimulating at each participant’s chronotype-aligned (phase-aligned) peak time amplifies and prolongs after-effects even under equal sleep pressure. From these observations we derive practical recommendations: (i) schedule excitatory tDCS after restorative sleep and near the individual wake-maintenance zone; (ii) avoid sessions at high sleep pressure or circadian troughs; (iii) log melatonin phase, chronotype, recent sleep and, where feasible, core temperature; and (iv) consider mild pre-heating or time-restricted feeding as physiological primers. By viewing Borbély’s two-process model and allied metabolic clocks as adjustable knobs for plasticity engineering, this review provides a conceptual scaffold for personalised, time-sensitive tDCS protocols that could improve reproducibility in research and therapeutic gain in the clinic. Full article

In acute myeloid leukemia (AML) it is important to elucidate the biological events that lead from remission to relapse, which have a high probability of leading to an adverse disease outcome. The cancer stem cell marker aldehyde dehydrogenase 1 (ALDH1A1) is underexpressed in AML cells when compared to healthy cells, both at the RNA level and at the protein level, and at least in the former, both in the bone marrow and in peripheral blood. Nonetheless, ALDH1A1/ALDH1A2 activity increases in AML cells during disease relapse and is higher in adverse prognosis AML in comparison with favorable prognosis AML. Furthermore, especially in relapsed AML and in unfavorable AML, AML cells rich in ALDH1A1 can contain high levels of reactive oxygen species (ROS), in parallel with high ALDH1A1/2 activity. This metabolic feature is clearly incompatible with normal stem cells. The term “stem-like” therefore is useful to coin malignant cells with a variety of genetic makeups, metabolic programming and biomarkers that converge in the function of survival of clones sufficient to sustain, spread and re-establish neoplastic disease. Therefore, AML “stem-like” cells survive cancer treatment that eradicates other malignant cell clones. This fact differentiates AML “stem-like” cells from normal stem and progenitor cells that function in tissue regeneration as part of a distinct hierarchical order of cell phenotypes. The ODYSSEY clinical trial is a Phase I/II study designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ABD-3001, a novel therapeutic agent, in patients with AML who have relapsed or are refractory to standard treatments. In this context, ABD-3001 is used as an inhibitor of cytosolic ALDH1 enzymes, such as ALDH1A1 and ALDH1A2. Full article

Obesity and type 2 diabetes mellitus (T2DM) are global health crises with significant morbidity and mortality. Retatrutide, a novel triple receptor agonist targeting glucagon-like peptide-1 (GLP-1), Glucose-Dependent Insulinotropic Polypeptide (GIP), and glucagon receptors, represents a groundbreaking advancement in obesity and T2DM pharmacotherapy. This review synthesizes findings from preclinical and clinical studies, highlighting retatrutide’s mechanisms, efficacy, and safety profile. Retatrutide’s unique molecular structure enables potent activation of GLP-1, GIP, and glucagon receptors, leading to significant weight reduction, improved glycemic control, and favorable metabolic outcomes. Animal studies demonstrate retatrutide’s ability to delay gastric emptying, reduce food intake, and promote weight loss, with superior efficacy compared to other incretin-based therapies. Phase I and II clinical trials corroborate these findings, showing dose-dependent weight loss, reductions in Glycated Hemoglobin (HbA1c) levels, and improvements in liver steatosis and diabetic kidney disease. Common adverse effects are primarily gastrointestinal and dose-related. Ongoing Phase III trials, such as the TRIUMPH studies, aim to further evaluate retatrutide’s long-term safety and efficacy in diverse patient populations. While retatrutide shows immense promise, considerations regarding cost and the quality of weight loss beyond BMI reduction warrant further investigation. Retatrutide heralds a new era in obesity and T2DM treatment, offering hope for improved patient outcomes. Full article

This study employed shotgun metagenomics to investigate microbial dynamics, phage-bacteria interactions, and functional genes throughout a three-month apple vinegar fermentation process. A total of 5621 microbial species were identified, revealing three distinct phases: (i) Enterobacteria and non-Saccharomyces species dominated the initial substrate; (ii) S. cerevisiae and Leuconostoc pseudomesenteroides prevailed in the intermediate phase; and (iii) acetic acid bacteria (Acetobacter ghanesis and Gluconobacter spp.), alongside non-Saccharomyces species (Pichia kudriavzevii and Malassezia restricta), dominated the final stages. Bacteriophage analysis revealed the presence of phages targeting spoilage bacteria, such as Pseudomonas and Erwinia, suggesting a role in regulating microbial stability and enhancing fermentation control. Functional metagenomic analysis highlighted key pathways associated with microbial growth and metabolite production, including carbohydrate and amino acid metabolism, energy production, and glycan biosynthesis. Enzymes involved in stress adaptation and secondary metabolism, including oxidative phosphorylation and phenolic compound synthesis, demonstrated microbial resilience and their potential role in shaping the product’s sensory and functional properties. Moreover, Enterobacteriaceae species were associated with pectin degradation during the early stages, aiding substrate breakdown. These findings are crucial for microbial and phage management in fermentation technology, offering valuable insights for innovation in the vinegar industry. Full article

Background: Obesity and type 2 diabetes (T2D) are major public health concerns. Tirzepatide has shown promise in recent clinical trials. This systematic review and meta-analysis aim to evaluate the efficacy and safety of tirzepatide in adults with obesity or type 2 diabetes, compared to placebo, GLP-1 receptor agonists (GLP-1 RAs), and insulin. Method: PubMed, Embase, and the Cochrane Library were searched on 17 January 2024, focusing on phase II and III randomized controlled trials (RCTs). We included studies involving adults with T2D or obesity, comparing tirzepatide to placebo, GLP-1 RAs, or insulin. The primary outcomes were the proportion of participants achieving ≥5%, ≥10%, and ≥15% weight loss targets. Secondary outcomes included changes in body weight, waist circumference, HbA1c levels, and blood pressure. Safety outcomes focused on adverse event rates. Meta-analyses were performed, and risk of bias was assessed using the Cochrane Risk-of-Bias tool version 2. Results: Fourteen RCTs involving 14,713 patients were included. Tirzepatide significantly increased the proportion of participants achieving weight loss targets, and reduced body weight, waist circumference, HbA1c, and blood pressure versus placebo and insulin. Compared with GLP-1 RAs, tirzepatide provided comparable or better outcomes in weight loss, waist circumference, and glycemic control. The incidence of gastrointestinal adverse events was significantly higher at all doses of tirzepatide compared to placebo and insulin. When compared with GLP-1 RAs, higher doses of tirzepatide were associated with increased risk of nausea, diarrhea, and decreased appetite, but not vomiting. Conclusions: Tirzepatide is an effective option for managing weight and improving metabolic outcomes in patients with T2D or obesity. However, it is associated with an increased risk of gastrointestinal adverse events, especially at higher doses. Therefore, close monitoring should be considered in clinical practice. Registration: PROSPERO CRD42021283449. Full article

Chromobacterium spp. use a density-dependent cell-to-cell communication mechanism (quorum sensing, QS) to control various traits, including the pigment violacein biosynthesis. Recently, one of the type strains of this genus, previously deposited in the American Type Culture Collection under accession number C. violaceum 31532, was reclassified as C. subtsugae, making the QS data obtained for the first species irrelevant to the second. The goal of this study is to conduct transcriptomic and genomic analyses of the C. subtsugae ATCC 31532 (formerly C. violaceum ATCC 31532) strain to identify density-dependent regulated genes and the mechanisms of their QS control. Whole transcriptome dataset analysis comparing QS-negative mid-log phase and QS-positive early stationary phase samples revealed 35 down-regulated and 261 up-regulated genes, including 44 genes that increased transcription activity the most (log2 (fold change) > 4.0). In addition to the violacein biosynthesis, QS-controlled traits in C. subtsugae ATCC 31532 included the following: (i) cdeAB-oprM efflux pump; (ii) RND efflux transporter; (iii) chuPRSTUV iron acquisition system; (iv) polyamine transport system; (v) carbohydrate (semialdehydes) metabolic pathways; (vi) SAM/SPASM maturase system XYE (predicted); (vii) prophage proteins; and (viii) fucose-binding lectin II. Subsequent screening of the promoter regions of the up-regulated genes and operons in most cases showed the presence of CsuR AHL-receptor/transcriptional regulator binding sites with 56.25–68.75% similarity to the ideal 16-base-pair palindrome 5′-CTGTCCGATAGGACAG-3′ sequence, supporting the concept of QS control in C. subtsugae ATCC 31532 by the csuI-csuR gene pair. Notably, several transcriptional regulators (MarR, TetR/AcrR, HU family DNA-binding protein, helix-turn-helix domain-containing protein) were found to be under QS control. Based on these data, a hierarchical QS regulatory network in C. subtsugae ATCC 31532 was hypothesized that provides direct control of the target genes via a canonical autoinduction mechanism and further dissemination of the effect via the activity of QS-controlled transcriptional regulators. Full article

Background/Objectives: The urea-to-creatinine ratio (UCR) serves as a biochemical marker for catabolism in the intensive care unit (ICU). UCR increases mainly due to an elevated urea generation from increased protein metabolism. This study aimed to evaluate the impact of protein intake on UCR progression in ICU patients. Methods: The inclusion criteria of this retrospective, single-center analysis required an ICU stay of at least 14 days without requirement of renal replacement therapy (n = 346 patients). Patients were grouped based on daily mean protein intake per kilogram between days 5 and 14: low (≤0.8 g/kg/d, n = 120), medium (0.9–1.2 g/kg/d, n = 132), and high (≥1.3 g/kg/d, n = 94). Data on daily protein and calorie intake, calorie deficit, urea generation rate, serum creatinine, urea, UCR and creatinine clearances were analysed. Risk factors for developing a high UCR were determined via logistic regression analysis adjusted for sex, age, bodyweight, disease severity (SAPS III admission score) as well as mean protein intake and calorie deficit during day 5 and 14 on ICU. Results: Higher protein intake was associated with increased calorie intake, lower calorie deficit, and led to an elevated urea generation rate and higher UCR. Renal function and serum urea trends were comparable between all groups, while creatinine was significantly lower in the high-protein group. Risk factors for developing an elevated UCR included older age, female sex and higher protein intake. Conclusions: An elevated UCR in the early ICU phase may indicate an increased protein metabolism, not only deriving from catabolism but also from a high protein feed. Full article

Anthocyanins (ACNs) from dark sweet cherries (DSCs) have shown efficacy against breast cancer (BC) cells, particularly triple-negative breast cancer (TNBC) cells, without affecting normal breast cells. This study investigated the impact of ACNs on TNBC cells, focusing on drug resistance mechanisms involving drug metabolism and transport enzymes. Specifically, it was examined whether ACNs influenced Doxorubicin (DOX) metabolism by targeting drug metabolism enzymes (phase I metabolism) and drug transport enzymes (phase III metabolism) in TNBC cells. 4T1 TNBC cells were treated with ACNs, DOX, and the combination of both (ACN-DOX). Results showed a synergistic inhibition of cell viability by ACNs and DOX. In addition, the modulation of phase I drug-metabolizing enzymes was exerted by ACNs, reducing the activity of cytochrome P450 (CYP) enzymes induced by DOX. A reduction of drug efflux by ACNs was shown by decreasing P-glycoprotein (P-gp) activity, leading to a higher intracellular accumulation of DOX. These effects were confirmed using CYP and P-gp inducers and inhibitors, showing their impact on cell viability. In conclusion, the combination of ACNs with DOX has the potential to lower DOX doses, enhance its efficacy, and possibly reduce side effects, offering a promising approach for TNBC treatment. Full article

Soybean seeds with similar germination rates may exhibit subtle differences in physiological quality, influencing field performance and storage longevity. This study used a shotgun proteomics approach to characterize the proteomic profile of two commercial soybean seed lots (higher- and lower-quality) during germination, aiming to identify biomarkers associated with vigor and deterioration. Proteins were analyzed across three germination phases: imbibition (Phase I, 0.5 h), metabolic activation (Phase II, 20 h), and radicle protrusion (Phase III, 51 h). A total of 777 proteins were identified, and of these differentially abundant proteins (DAPs), the following totals were detected: 12 in Phase I, 17 in Phase II, and 28 in Phase III. In Phase I, ribosomal proteins were more abundant in high-quality seeds, indicating efficient translation and preparation for germination. Conversely, in Phase III, low-quality seeds showed increased levels of storage proteins and stress-response proteins, including alcohol dehydrogenase (ADH), heat shock proteins, and annexins, reflecting delayed germination and more deterioration. These findings highlight the dynamic nature of protein expression during germination and demonstrate the potential of proteomics to detect subtle differences in physiological quality. The identified biomarkers provide insights for seed quality assessment and offer practical applications for improving classification and management of commercial soybean seed lots. Full article

Background/Objectives: There is controversy about the health risks of sugary diets. A recent study reported that chronic consumption of 11% sugar solutions improved glycemic control in lean mice. Based on this finding, we hypothesized that chronic consumption of the same 11% sugar solutions would also improve glycemic control in metabolically deranged mice. Methods: We exposed mice to a high-fat/high-sugar diet for 12 weeks. Then, we switched the mice to a control (i.e., standard chow) or one of four experimental diets for 8 weeks. The experimental diets contained standard chow plus an 11% solution of glucose or high-fructose syrup. The sugar syrups were derived from corn or cellulose. We included the cellulosic syrups because they contain polyphenols, which are thought to promote glycemic control. We measured body weight, adiposity, glucose tolerance, insulinemia, insulin sensitivity, body composition, and avidity for sweeteners. Results: Mice switched to the control diet lost weight, whereas mice switched to the experimental diets remained obese and hyperinsulinemic. Thus, the experimental diets did not cause the mice to regain normal metabolic health. Nevertheless, we observed (i) improvements in glucose tolerance in mice on both the control and experimental diets; (ii) reduced insulinemia and enhanced insulin sensitivity in mice offered the cellulosic syrups; (iii) elevations in cephalic-phase insulin responses in mice on the experimental diets; and (iv) increased avidity for sweeteners in mice on the control but not the experimental diets. Conclusions: Switching metabolically deranged mice to the experimental diets, particularly those with cellulosic sugars, improved glucose tolerance and insulin sensitivity. Full article

Dual PPARα/γ agonists can normalize both glucose and lipid metabolism in patients with type 2 diabetes mellitus. The development of such drugs faced the detection of various toxic effects in phase III clinical trials. However, two drugs of this class managed to pass all stages of clinical trials, which makes the search for new dual PPARα/γ agonists promising. In the present study, a series of dihydrobetulonic acid amides differing in the length of the amino-alcohol linker and incorporating a pharmacophore fragment of (S)-2-ethoxy-3-phenylpropanoic acid were synthesized. The in vitro study showed that the length of the aminoalcohol linker dramatically affects the level of activation of PPAR-α and γ receptors. The synthesized compounds were tested for their ability to improve glycemic control and to counter lipid abnormalities in C57Bl/6 Ay/a mice at a dose of 30 mg/kg. Of all the compounds tested, the dihydrobetulonic acid derivative with an aminoethanol linker (15a) had the most pronounced effect in improving insulin sensitivity and glucose tolerance, and in reducing blood triglyceride levels. In addition, 15a dramatically counteracted the pathological changes in the liver, pancreas, kidney, and brown fat tissue that are characteristic of type 2 diabetes. Full article

Background/Objectives: Obesity is influenced by biological, hormonal, and social factors, contributing to chronic diseases and burdening the healthcare system. Chronic stress and emotional eating are linked to weight gain, affecting eating behaviors and metabolism. This study aimed to assess the association between stress, eating behavior, and adiposity in obese women. Methods: This cross-sectional study included 132 obese women from Viçosa, Minas Gerais, Brazil. The participants completed the Lipp Stress Symptoms Inventory and the Dutch Eating Behavior Questionnaire. Blood samples were collected to measure plasma cortisol, and Body Mass Index (BMI) was calculated from weight and height measurements. Body fat was assessed using dual-energy X-ray absorptiometry (DXA). Associations between stress, eating behavior, and adiposity were evaluated using linear regression models, and interactions between stress and eating behavior subscales were tested. Results: Positive associations were observed between Phases I (alert), II (resistance), and III (exhaustion) of stress with emotional and external eating. A negative association was identified between dietary restraint and body fat, especially in women with lower cortisol levels (<13.7 mg/dL). Additionally, the alert phase was associated with higher android fat in these women. Conclusions: The findings support the hypothesis that stress and eating behavior are associated with body adiposity and that stress is linked to emotional and external eating. An inverse association between restrained eating and body fat was observed in women with lower cortisol levels. These results highlight the importance of an interdisciplinary approach that incorporates emotional and stress conditions in obesity treatment. Full article

Maize is among the world’s three most important cereals because it is used for human consumption and agricultural feed. The embryo in monocotyledons contains a cotyledon that is the scutellum, which in Chalqueño maize constitutes approximately 80% of the embryo’s mass. The activation of metabolism during germination is accompanied by the production of reactive oxygen species, which must be maintained at a low level to avoid damage. Little is known about the oxidative state of the scutellum, but it is important to understand the control of oxidative stress during the final phase of germination and the embryo–seedling transition. Among the enzymes involved are class III peroxidase (POX), catalase (CAT), and superoxide dismutase (SOD), which were observed in the scutella of isolated imbibed embryos between 0 and 36 h. The activity of SOD fluctuated over a baseline value. The activity of class III POX was greater than that of CAT, showing differences between them in germination and postgermination. The activities of CAT and POX increased during germination (0 to 18 h), stabilized towards the final phase of germination (18 to 24 h), and then increased again in postgermination (24 to 36 h). The POX activity is a biochemical marker of the scutellum metabolism and marks the transition from germination to the embryo–seedling transition. Full article