Search Results (202)

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the leading cause of chronic liver disease worldwide, driven by the global epidemics of obesity, type 2 diabetes, and metabolic syndrome. In this evolving nosological landscape, alcohol consumption—traditionally excluded from the diagnostic criteria of non-alcoholic fatty liver disease (NAFLD)—has regained central clinical importance. The recently defined MetALD phenotype acknowledges the co-existence of metabolic dysfunction and a significant alcohol intake, highlighting the synergistic nature of their pathogenic interactions. This narrative review provides a comprehensive analysis of the biochemical, mitochondrial, immunometabolic, and nutritional mechanisms through which alcohol exacerbates liver injury in MASLD. Central to this interaction is cytochrome P450 2E1 (CYP2E1), whose induction by both ethanol and insulin resistance enhances oxidative stress, lipid peroxidation, and fibrogenesis. Alcohol also promotes mitochondrial dysfunction, intestinal barrier disruption, and micronutrient depletion, thereby aggravating metabolic and inflammatory derangements. Furthermore, alcohol contributes to sarcopenia and insulin resistance, establishing a bidirectional link between hepatic and muscular impairment. While some observational studies have suggested a cardiometabolic benefit of a moderate alcohol intake, emerging evidence challenges the safety of any threshold in patients with MASLD. Accordingly, current international guidelines recommend alcohol restriction or abstinence in all individuals with steatotic liver disease and metabolic risk. The review concludes by proposing an integrative clinical model and a visual cascade framework for the assessment and management of alcohol consumption in MASLD, integrating counseling, non-invasive fibrosis screening, and personalized lifestyle interventions. Future research should aim to define safe thresholds, validate MetALD-specific biomarkers, and explore the efficacy of multidisciplinary interventions targeting both metabolic and alcohol-related liver injury. Full article

Background: Invasive fungal infections (IFIs) are a major complication in patients with acute myeloid leukemia (AML), particularly during chemotherapy-induced neutropenia. Posaconazole is the standard drug for primary antifungal prophylaxis (PAP), but its use is limited by oral bioavailability and CYP3A4 interactions. Study Objective: This study aims to evaluate the clinical efficacy and safety of intravenous caspofungin versus oral posaconazole as PAP in AML patients during their first cycle of chemotherapy and assess their subsequent impact on clinical outcomes. Methods: A retrospective, monocentric study was conducted on 75 consecutive AML patients treated at the Federico II University Medical School of Naples, Italy (2021–2025). Patients received either caspofungin or posaconazole as PAP based on the drug–drug interaction risk or clinical conditions. IFIs were diagnosed using EORTC/MSG criteria. Logistic and Cox regression models were used to assess risk factors and overall survival (OS). Results: IFI incidence was 13.3% overall (9.4% proven/probable). No significant difference was found between the caspofungin and posaconazole groups (six vs. four IFIs; p = 0.878). Post-chemotherapy refractory AML (OR = 11.9; p = 0.003) and liver disease (OR = 30.4; p = 0.004) independently predicted IFI development. Median OS did not significantly differ in patients receiving caspofungin versus posaconazole (29.3 vs. 32.1 months, p = 0.6). Conclusions: Caspofungin appears clinically comparable to posaconazole for PAP in AML during the induction phase, especially when azole use is contraindicated. Prospective studies are warranted to refine prophylactic strategies in the era of new AML therapies. Full article

The polyphagous aphid Aphis gossypii exhibits host-specific biotypes, notably the cotton (Hap1) and cucumber (Hap3) types. While both can adapt to new hosts via zucchini induction, the underlying molecular mechanisms remain unclear. Our investigation revealed that both Hap1 and Hap3 A. gossypii underwent significant body size enlargement following host transfer to zucchini. Transcriptomic analysis revealed that zucchini-mediated host adaptation in the A. gossypii biotypes (Hap1/Hap3) involves insulin metabolism and detoxification pathways, with 17 co-differentially expressed genes (e.g., Col-I (type I collagen), CYP450 6a13, peroxidase) potentially critical for adaptation. The findings provide new insights into the molecular mechanisms regulating A. gossypii phenotypic plasticity and contribute to the development of resistance management strategies. Full article

Centrilobular hepatocyte hypertrophy is frequently observed in animal studies for chemical safety assessment. Although its toxicological significance and precise mechanism remain unknown, it is considered an adaptive response resulting from the induction of drug-metabolizing enzymes (DMEs). This study aimed to elucidate the association between centrilobular hepatocyte hypertrophy and DME induction using machine learning on toxicogenomic data. Utilizing publicly available gene expression data and pathological findings from rat livers of 134 compounds, we developed six different types of machine learning models to predict the occurrence of centrilobular hepatocyte hypertrophy based on gene expression data as explanatory variables. Among these, a LightGBM-based model demonstrated the best performance with an accuracy of approximately 0.9. With this model, we assessed each gene’s contribution to predicting centrilobular hepatocyte hypertrophy using mean absolute SHAP values. The results revealed that Cyp2b1 had an extremely significant contribution, while other DME genes also displayed positive contributions. Additionally, enrichment analysis of the top 100 genes based on mean absolute SHAP values identified “Metabolism of xenobiotics by cytochrome P450” as the most significantly enriched term. In conclusion, the current results suggest that the induction of multiple DMEs, including CYP2B1, is crucial for the development of centrilobular hepatocyte hypertrophy. Full article

It is known that nutrient deprivation following detachment can cause non-chilling peel pitting (NCPP) in citrus fruits when stored under a non-stressful environment and that this damage is reduced by pretreating the fruit with ethylene (ETH) (4 d, 10 µL L⁻¹). The present work investigates the effect of this pretreatment on jasmonate (JA) accumulation and transcriptional regulation in mature Navelate oranges (Citrus sinensis L. Osbeck) stored under non-stressful conditions. ETH increased the expression of abundant genes participating in the synthesis of cis-(+)-12-oxo-phytodienoic acid (OPDA), jasmonic acid (JA), and methyl jasmonate (MeJA). ETH also upregulated genes involved in jasmonoyl–isoleucine (JAIle) synthesis (CsJAR1) and decrease (CsCYP94B3 and CYP94C1), and CsSTA2, related to JA sulfation. The levels of these JA metabolites increased during fruit holding in ETH and after shifting them to air, with MeJA accumulation being especially remarkable. Overall, the beneficial effect of ETH on reducing NCPP appears to be related not only to this redirection of OPDA and JA metabolism towards the formation of JA derivatives but also to the regulation of JA signalling. Indeed, the repression of the receptor CsCOI1 and upregulation of various CsJAZs repressors caused by nutrient deprivation, together with the ETH-mediated induction of CsCOI1, CsTOPLESS, and abundant CsJAZs during long-term storage, suggests the occurrence of an ETH-enhanced negative transcriptional regulatory feedback loop in JA metabolism and signalling, by which the susceptibility of detached Navelate oranges to NCPP might be reduced. Full article

Tea plants (Camellia sinensis) are among the world’s most significant economic tree species. Tissue culture serves as a crucial method in commercial breeding by facilitating the rapid propagation of valuable genotypes and the generation of disease-free clones. However, callus browning represents a prevalent challenge in tea plant tissue culture, and may adversely affect explant growth and development. Our research demonstrates that although anti-browning agents can effectively suppress browning, they induce distinct color changes in the callus. These color variations could significantly influence callus induction and subsequent growth patterns. In this study, callus tissues from C. sinensis var. Assamica cv. Mengku were employed as experimental materials and treated with three commonly used anti-browning agents: ascorbic acid (VC), activated carbon (AC), and polyvinylpyrrolidone (PVP). The results demonstrated that while these three reagents effectively inhibited browning, they also induced distinct color changes in the explants, which appeared red, green, and white, respectively. Furthermore, this study investigated the molecular mechanisms underlying callus color changes using transcriptomic and metabolomic approaches. Based on transcriptome analysis, it was revealed that photosynthesis and flavonoid biosynthesis pathways were significantly enriched. Metabolome analysis identified 14 phenolic acids, which exhibited significant variation in accumulation across calluses of different colors. The differential expression of genes involved in flavonoid biosynthesis pathways, coupled with the distinct accumulation patterns of metabolites, can effectively alleviate photooxidative damage and enhance the resistance of callus to browning. AC activates the photosynthesis of callus by regulating carbon source allocation and upregulating the expression of key genes in the psa, psb, and pet families within the photosynthetic system. This process promotes chlorophyll biosynthesis, thereby enabling the callus to grow green, while VC activates the expression of key genes such as CHS, F3H, C4H, CYP75B1, and ANR in the flavonoid pathway, which are involved in the regulation of pigment synthesis in red callus. This study elucidated the molecular mechanisms underlying the effects of anti-browning agents on color variations in C. sinensis callus, thereby providing a robust theoretical foundation for optimization, the establishment of tea plant tissue culture systems, and enhancing cultivar quality. Full article

Background/Objectives: The ineffective delivery of drugs into tumors and the existence of multidrug resistance (MDR) are the primary causes of chemotherapy failure. Downregulation of the Sonic Hedgehog (Shh) pathway has been shown to reduce P-glycoprotein (P-gp) expression on cell membranes and to resist MDR. Methods: In this study, we combine cyclopamine (CYP, a potent Shh antagonist) with paclitaxel (PTX, an antitumor drug that can produce MDR) in a nano-drug delivery system (CYP NP and PTX NP) for the treatment of drug-resistant breast cancer. Nanoparticles were characterized for size, zeta potential, and encapsulation efficiency. P-gp expression, nanoparticle accumulation, cytotoxicity, and apoptosis were evaluated in MCF-7 and MCF-7/Adr cells. Penetration ability was assessed using 3D multicellular tumor spheroids. Antitumor efficacy and nanoparticle biodistribution were validated in MCF-7/Adr-bearing nude mice models. Results: Our engineered CYP nanoparticles (~200 nm) demonstrated prolonged intratumoral retention, enabling sustained Shh pathway inhibition and P-gp functional suppression. This size-optimized formulation created a favorable tumor microenvironment for the smaller PTX nanoparticles (~30 nm), facilitating deeper tumor penetration and enhanced cellular uptake. Meanwhile, by down-regulating P-gp expression, CYP NPs could convert drug-resistant cells to PTX-sensitive cells in both cytotoxicity and apoptosis induction through the Shh pathway. The combination of CYP NP and PTX NP augmented the antitumor effects in MCF-7/Adr-bearing nude mice models. Conclusions: The CYP NP and PTX NP combination offers a new therapeutic strategy in cancer treatment. Full article

Background: Esketamine is a rapidly acting antidepressant with robust efficacy in treatment-resistant depression (TRD). Diminishing therapeutic effects and attenuated side effects have been reported after long-term use. This study aimed to investigate its long-term pharmacokinetics and factors that may contribute to reduced efficacy over time in patients with TRD by evaluating the potential role of auto-induction. Methods: Pharmacokinetic data were collected from 18 patients receiving oral esketamine for six weeks. A pharmacokinetic model was developed to predict esketamine and noresketamine plasma concentrations. Observed esketamine and noresketamine plasma concentrations were compared to model-predicted concentrations to assess deviations suggestive of auto-induction. Results: On day 39, plasma concentrations of esketamine and noresketamine were 59% and 35% lower than predicted, respectively, indicative of auto-induction of CYP3A4 and CYP2B6. Conclusions: Auto-induction appears to occur in oral esketamine treatment, which may contribute to reduced therapeutic efficacy and side effects in long-term treatment. Identifying auto-induction as a mechanism of tolerance potentially has important clinical implications. Further studies are warranted to confirm these findings and evaluate strategies to maintain therapeutic efficacy. Full article

One hazardous material that occurs naturally in the environment and induces oxidative stress is cadmium (Cd). Epidemiological data revealed that exposure to cadmium in the workplace and environment might be linked to many illnesses and serious testicular injuries. Aims: It is taught that antioxidants can protect different organs against environmental toxic compounds. Therefore, the current investigation aims to show the role of antioxidants (gallic acid and selenium) in the protection against cadmium toxicity, including the architecture of the testes, semen properties, steroid hormones, protein expression of cytochrome P450 [CYP 19 and 11A1] contributing to the production of steroid hormones, and antioxidant enzyme activities, in male rabbits. Methods: Male rabbits were given cadmium orally three times/week [1 mg/kg BW] for twelve weeks. In addition, gallic acid (20 mg/kg) or selenium (1 mg/kg BW) was administered two hours before cadmium treatment. This investigation included a spectrophotometer, histopathology, and Western immunoblotting techniques. Results: Cadmium treatment significantly reduced sperm counts, testosterone, and estrogen levels after four, eight, and twelve weeks of treatment. In addition, after a 12-week treatment of rabbits with cadmium, the activity of 17β-hydroxysteroid dehydrogenase and antioxidant enzymes, including catalase, superoxide dismutase, glutathione reductase, glutathione peroxidase, and glutathione S-transferase, as well as the glutathione levels, were inhibited in the testes tissue. On the other hand, following cadmium treatment, rabbit’s testes showed a discernible increase in free radical levels. Interestingly, the activity of antioxidant enzymes and level of free radicals were recovered in rabbits treated with gallic acid or selenium before cadmium treatment. In addition, after 12 weeks of cadmium treatment, the steroidogenic protein expressions of CYP 11A1 and CYP 19 were upregulated and downregulated in the testes, respectively. Interestingly, after pretreatment of rabbits with either gallic acid or selenium for two hours before cadmium administration, the downregulated CYP11A1 was restored to normal levels. In the histopathological investigation, immature spermatozoids and sloughed spermatogonium cells were observed in cadmium-treated rabbits’ testes. On the other hand, pretreatments of rabbits with gallic acid or selenium mitigated and alleviated the adverse effects of cadmium on testes architecture and increased the production of healthy sperm. Conclusions: The lower levels of steroid hormones could be due to the downregulation of CYP11A1, inhibition of 17β-hydroxysteroid dehydrogenase, antioxidant enzyme activities, and the induction of free radical levels. Furthermore, the pretreatment of rabbits with gallic acid or selenium mitigated the adverse effects of cadmium on the tissue architecture of testes and steroid hormone levels. Full article

Aromatase, a crucial enzyme for estrogen synthesis, plays a vital role in gender determination and differentiation. This study aimed to establish an inducible knockout model of the chicken CYP19A1 gene, which encodes aromatase, to support gender control in chickens. We selected the most efficient sgRNA target site and constructed an inducible knockout model based on the Tet-on system. The knockout efficiency reached 80% with 20 μg/mL DOX induction in vitro. The encapsulation of the plasmid with PEI and injection into eggs achieved a knockout efficiency of 45% in ovo. qRT-PCR analysis revealed a significant downregulation of female-related genes (CYP19A1, FOXL2, ESR1) and upregulation of male-related genes (DMRT1, SOX9, AMH) in female chicken embryos after induction. Western blotting showed decreased protein expression of CYP19A1 and FOXL2, and increased SOX9 expression in female embryos post-DOX induction. Elisa detection further confirmed lower estradiol levels in the gonads of induced female embryos compared to normal and non-induced females. These findings demonstrate the successful establishment of an inducible knockout system for the CYP19A1 gene in chickens, providing theoretical and technical support for the creation of new breeding materials for gender control. Full article

Background/Objective: The aryl hydrocarbon receptor (AHR) is an important mediator of intestinal homeostasis. The AHR senses certain classes of phytochemicals, including many flavonoids and tryptophan metabolites generated in the intestinal tract. Several in vitro studies demonstrate the presence of AHR ligands in numerous plants commonly consumed by humans. However, it has not been established that these foods can activate the AHR in vivo. The aim of this study was to evaluate how phytochemicals in foods can lead to AHR activation in vivo through modulating CYP1A1 activity. Methods: Freeze-dried spinach, corn, red potatoes, kidney beans, parsley, onion, carrots, bell peppers, and broccoli were fed to C57BL6/J female mice at 15% w/w in a semi-purified diet to evaluate the AHR activation potential. In vitro CYP1A1 microsomal assays were utilized to establish specific phytochemicals as CYP1A1 substrates. Results: Broccoli, onion, and carrots increased expression of the AHR target gene Cyp1a1 in the duodenum. Broccoli consumption led to the formation of the potent AHR ligand indolo[3,2-b]carbazole (ICZ), which is also a CYP1A1 substrate. Relative to the other vegetables, parsley contained a high concentration of apiin, a diglycoside of the flavone apigenin. Mice were fed a diet with either 10% parsley, 10% broccoli, or both vegetables. Parsley consumption increased broccoli-mediated Cyp1a1 induction in the duodenum, liver, and lung. Apigenin is a CYP1A1 substrate that can attenuate ICZ metabolism in vitro and increase broccoli-mediated Cyp1a1 expression in the lung. Conclusions: These results suggest that phytochemical competition for intestinal AHR binding and CYP1A1 metabolism modulates systemic AHR activity. Full article

The Aryl-hydrocarbon Receptor (AhR) is implicated in the regulation of several genes, including those encoding CYP1A1. Although it is an orphan receptor, the amount of data about its relationship with skin homeostasis and nosology is constantly increasing. Interestingly, 6-formylindolo[3,2-b]carbazole (6-FICZ), one of the most active AhR inducers and amongst the proposed receptor’s endogenous ligands, has been detected in Malassezia furfur isolates from lesional skin, as well as in skin scales from patients with seborrhoeic dermatitis. Aiming to study the structure–activity relationships of the indolo[3,2-b]carbazole (ICZ) scaffold and to clarify if the formyl group of 6-FICZ has any specific role in AhR induction, a series of analogues of ICZ (substituted at position 6 with methyl, formyl and hydroxymethyl groups) were synthesized and evaluated for their activity on AhR in cell lines of four different species. A new simple method for the synthesis of 6-FICZ was developed. 6-Methylindolo[3,2-b]carbazole (6-MICZ) showed higher activity than 6-FICZ in human, rat and guinea pig cell lines, and all synthesized derivatives showed comparable activity in the mouse cell line. Therefore, the formyl group does not seem to play a significantly specific role in the affinity for AhR, and 6-FICZ seems less likely to be an endogenous ligand. Full article

Children and young people (CYP) with special educational needs and disabilities (SEND) comprise over 1.6 million pupils in classrooms in England. However, evidence suggests pupils’ learning and wellbeing needs are often missed or unmet and legislation designed to increase families’ decision-making in education provision has not been translated into practice. The current participatory action research study investigated the perceptions and experiences of a specific population of SEND pupils in mainstream schooling—CYP with 22q11.2 deletion syndrome (22q). Participants included existing and previous mainstream pupils and their parents (n = 8 parent−CYP dyads). Data were collected through semi-structured interviews, and a hybrid inductive-deductive thematic analysis was conducted. Five superordinate themes were generated: minding the gaps in school support; my mental wellbeing story; power and influence; getting it wrong: failing CYP and families; and getting it right: from surviving to thriving. Findings provided authentic insights into the lived experiences of support for CYP with 22q which resonate with the wider SEND population. These findings can help to inform more inclusive practice in mainstream settings. An affirmative model which places SEND pupils and parents at the heart of meaningful reform is urgently needed in schools. Collaborative work among all key stakeholders is paramount to ensure that strategies are genuinely co-produced, co-owned and robustly evidence-based. Full article

The release of herbivore-induced plant volatiles (HIPVs) has been recognized to be an important strategy for plant adaptation to herbivore attack. However, whether these induced volatiles are beneficial to insect herbivores, particularly insect larvae, is largely unknown. We used the two important highly polyphagous lepidopteran pests Spodoptera frugiperda and S. litura to evaluate the benefit on xenobiotic detoxification of larval exposure to HIPVs released by the host plant maize (Zea mays). Larval exposure of the invasive alien species S. frugiperda to maize HIPVs significantly enhanced their tolerance to all three of the well-known defensive compounds 2,4-dihydroxy-7-methoxy-1,4-benzoxazin-3-one (DIMBOA), chlorogenic acid, and tannic acid in maize and the two commonly used insecticides methomyl and chlorpyrifos. HIPV exposure also improved the larval tolerance of S. litura third instars to chlorogenic and tannic acids. Furthermore, larval exposure to either maize HIPVs or DIMBOA induced the activities of cytochrome P450 enzymes (P450s), glutathione-s-transferase (GST), and carboxylesterase (CarE) in the midguts and fat bodies of the two insects, while the induction was significantly higher by the two components together. In addition, the expression of four genes encoding uridine diphosphate (UDP)-glycosyltransferases (UGT33F28, UGT40L8) and P450s (CYP4d8, CYP4V2) showed similar induction patterns in S. frugiperda. Cis-3-hexen-1-ol, an important component in maize HIPVs, also showed the same functions as maize HIPVs, and its exposure increased larval xenobiotic tolerance and induced the detoxification enzymes and gene expression. Our findings demonstrate that HIPVs released by the pest-infested host plants are conductive to the xenobiotic tolerance of lepidopteran insect larvae. Hijacking the host plant HIPVs is an important strategy of the invasive alien polyphagous lepidopteran pest to counter-defend against the host plant’s chemical defense. Full article

Rice allelopathy is a natural method of weed control that is regarded as an eco-friendly practice in agroecology. The root growth of allelopathic rice at the seedling stage plays an important role in its weed control. Our study characterizes a plant hormone that promotes root growth, abscisic acid (ABA), to explore its role in the induction of rice allelopathy. Increasing the root morphology traits (root length, root tip number, and root biomass) in rice using different concentrations of exogenous ABA resulted in increased inhibitory ratios against barnyard grass (Echinochloa crus-galli), both in a hydroponic experiment and pot test. In particular, the relative proportion of induced allelopathy to total allelopathy in non-allelopathic rice Lemont (Le) was higher than that in allelopathic rice PI31277 (PI). The total content of phenolic acid, which is an important allelochemical in rice, as previously reported, was significantly elevated in the root exudates of both PI and LE. The gene expression levels of OsPAL, OsC4H, and OsCOL related to phenolic acid synthesis were also up-regulated, with a higher regulatory fold in PI. ABA also increased the expression of OsKSL4 and CYP75B4 involved in the biosynthesis of momilactone B and tricin. Moreover, low concentrations of exogenous ABA mainly positively regulate the expression of OsIAA11, an AUX/IAA transcription factor gene, in the root of PI and Le. These findings suggest that the application of ABA could significantly enhance the weed-suppressive activity of both rice cultivars through regulating root growth and the synthesis of allelochemicals secreted by rice roots, providing an option for the improvement of rice allelopathy through chemical induction. Full article