Modern scientific research focuses on the identification of subclinical metabolicdisorders and mechanisms of their regulation, as the initial links of many systemicdiseases. The respiratory system deserves attention especially after the COVID-19pandemic. Numerous scientific publications claim a complicated course of the diseaseagainst the background of diabetes mellitus, thyroid pathology development in the postCOVID period. Due to the prevalence of endocrine diseases and preclinical disordersof thyroid and carbohydrate homeostasis, influence of alimentary-dependent endocrinedisorders on the course of biochemical processes in the respiratory part of the lungs isinteresting to study. Changes in metabolic processes are most likely accompanied by theactivation of nitroso-oxidative processes, violation of the prooxidant/antioxidantbalance.Purpose – to investigate the intensity of inducible NO-synthase synthesis in therespiratory part of lungs and antioxidant potential of blood serum of rats, which iodinedeficiency, insulin resistance and their combinations were modelled to.Materials and methods. The study was carried out on sexually mature outbred whitemale rats weighing 150-180 g. The animals were divided randomly into four groups andfed for 90 days with a standard diet (n=15, 1st group, control), a diet low in iodine(n=15, 2nd research group), standard diet, replacing drinking water with a 20 %fructose solution (n=15, 3rd research group), a diet low in iodine combined with afructose solution of drinking water instead (n=15, 4th research group). The animalswere withdrawal from the experiment under thiopental sodium anesthesia. Tissuecollection, analysis of biochemical parameters of blood and respiratory section of thelungs was carried out taking into consideration generally accepted and special researchmethods in accredited laboratories of Ivano-Frankivsk National Medical University.The study was carried out in compliance with the provisions of the Council of EuropeConvention for the Protection of Vertebrate Animals, which are used in experiments andother scientific purposes (1986), EEC Directives № 609 (1986), of the Order of theMinistry of Health of Ukraine № 281 from 01.11.2000, "Measures to furtherimprovement of the organizational norms of work with the use of experimental animals"and the Law of Ukraine № 3447-IV «The protection of animals from cruelty» (2006). Apositive conclusion of the Ethics Commission of Ivano-Frankivsk National MedicalUniversity was received (Protokol № 109/19 from 29.05.2019). Statistical values aredetermined taking into account the standard error (m), of the mathematical mean sample(M), using the Shapiro-Wilk and Kolmogorov-Smirnov criteria. Biochemical parametersin samples with normal distribution were evaluated using Student's t criterion. The resultp<0.05 was determined to be reliable.Results. As a result of the study, a significant increase in the synthesis of nitrite ion in blood serum under conditions of iodine deprivation was found – in 80.5 % (р<0.02),insulin resistance – in 2.3 time (р<0.01) and their combination – in 2.1 time (р<0.02)according control. Excessive nitric oxide synthesis may be coursed with the expressionof inducible NO synthase (iNOS). In particular, activity of the enzyme in blood serumincreased by two to three times (р<0.02) regarding the values in intact animals. Theincrease in iNOS activity in the respiratory part of the lungs under the studied conditionsdraws attention. An increase of enzyme activity in the 33.5 % (р<0.02) in the animalson a low iodine installed, under conditions of high-carbohydrate feeding – in 17.6 %(р<0.02), and against the background of combined endocrine pathology - in 23.5 %(р<0.05) regarding the values of a similar indicator in intact animals. Such changesreflect the development of the inflammatory process, which is a risk factor for asignificant decrease in oxygen consumption and a trigger for a hypometabolic responseto food rations. It is important, that such changes in the nitric oxide system wereobserved against the background of an imbalance of antioxidant enzymes: an increasein catalase activity (in 2.5 – 3.1 times, р<0.02) regardless of diet, inhibition of theglutathione system enzymes (decrease by 21.3 – 33.0 %, р<0.01), especially inconditions of excessive carbohydrate intake and in combination with iodine deprivation.Conclusions. Diet-induced iodine deficiency and insulin resistance are accompanied byexcessive synthesis of nitric oxide and INOS activation, including in the respiratory partof the lungs. Such nitric oxide metabolism disorders are caused by the inhibition of theantioxidant potential of blood serum. The detected changes may characterize thedevelopment of nitroso-oxidative stress, inflammation and endothelial dysfunction,suppress the immune response and is a risk factor for damage to the respiratory system,the likelihood of which increases significantly against the background of comorbidendocrine pathology.

Transcriptional changes in organism and muscles especially during development of metabolic syndrome (MetS) is still highly understudied. Role of p38 MAPK activation during MetS is highly debatable. The aim of this study is to evaluate influence of administration of selective inhibitor of p38 MAPK on production and metabolism of nitric oxide in rat biceps femoris during metabolic syndrome modelling. Materials and methods. The study was conducted on 24 mature male Wistar rats weighing 200–260 g, which were divided into 4 groups of 6 animals each: I – control group; II – MetS (received 20 % fructose for 60 days); III – SB203580 administration (received SB203580 intraperitoneally in a dose 2 mg/kg once every 3 days for 60 days); IV –SB203580 + MetS modelling. We studied activity of enzymes responsible for NOS-dependent and NOS-independent NO production and content of nitrites, peroxynitrites and nitrosothiols in rat biceps femoris. Results. MetS modelling increased production of nitric oxide from NO-synthases and nitrtate-nitrite reductive pathway, elevated content of nitrosothiols and peroxynitrite, while SB203580 during MetS modelling attenuated these changes in production of nitric oxide and nitrosothiols and peroxynitrite content. Conclusions. P38 MAPK activation during MetS modelling increases NOS-dependent and NOS-independent NO production and leads to accumulation of nitrosothiols and peroxynitrite in rat biceps femoris.

Cationic amino acid transporter 1 (CAT1) transports cationic amino acids and plays pivotal roles in cancer proliferation, immune modulation, and nitric oxide metabolism. It also serves as the specific cellular receptor for certain murine leukemia viruses. Here, we report the cryo-electron microscopy (cryo-EM) structure of mammalian CAT1 in complex with its substrate ornithine and the receptor-binding domain (RBD) of Friend murine leukemia virus (FrMLV). CAT1 specifically recognizes the side-chain amino group of ornithine via residue S347 on transmembrane helix 8 (TM8), capturing the transporter in an inward-facing occluded conformation. Notably, the FrMLV RBD (frRBD) primarily engages the third extracellular loop (ECL3) of CAT1-a region marked by substantial species-specific variation that likely governs cross-species viral tropism. Together, our structural and biochemical results elucidate the molecular mechanism of substrate recognition and transport by mCAT1, and unveil the molecular basis for FrMLV receptor specificity. These findings provide a valuable framework for structure-based drug design targeting CAT1 in cancer and infectious diseases.

Oxygen (O₂) availability in plant tissues is dynamically shaped by photosynthesis and respiration and is linked to plant stress responses and development. While mitochondria are the primary consumers of cellular O₂, their impact on chloroplast functions under low-oxygen conditions remains insufficiently understood. Mitochondrial retrograde signaling activates expression of nuclear genes encoding alternative oxidases and other respiratory components, and high abundance of these enzymes coincides not only with changes in respiration but also with alterations in chloroplast functions. For example, plants with induced mitochondrial signaling are tolerant to methyl viologen, which catalyzes the Mehler reaction. The mechanism of this inter-organelle interaction remains unclear. Here, we investigated respiration, photosynthesis, and in vivo O₂ levels in Arabidopsis (Arabidopsis thaliana) mutants and transgenic lines with perturbations in diverse mitochondrial functions, including defects in respiratory complex I, ATP synthase, mitochondrial protein processing, transcription, nucleoid organization, and organelle architecture; as well as in lines with altered mitochondrial signaling, alternative oxidase activities, and nitric oxide metabolism. Increased abundance and capacity of alternative oxidases correlated with elevated O₂ consumption in darkness, slower O₂ re-accumulation in light, and reduced effects of methyl viologen on chloroplasts. The changes are likely mediated by multiple stress-induced alternative respiratory components. Our results support the hypothesis that enhanced mitochondrial O₂ consumption under stress lowers tissue O₂ levels, thereby modifying chloroplastic electron transfer and ROS metabolism. These data provide insights into the establishment and sensing of hypoxia in plants, plant adaptation to mitochondrial stress and low-oxygen environments, and the roles of chloroplasts in these processes.

Background Reliable molecular biomarkers for predicting cerebral infarction outcomes remain limited, highlighting the need for integrative approaches that bridge bioinformatic discovery with clinical validation. Objective To identify key differentially expressed genes (DEGs) prognostic for cerebral infarction and evaluate their clinical utility for risk stratification through integrated bioinformatic analysis and prospective cohort validation. Methods Functional annotation employed GO enrichment and protein-protein interaction network analysis. A prospective cohort enrolled 151 cerebral infarction patients, with peripheral blood samples subjected to qPCR analysis of candidate genes. Prognostic predictive capacity was assessed via multivariable Cox regression, Kaplan-Meier survival analysis, and ROC curve analysis with clinical follow-up data. Results Five candidate DEGs (VIM, OSM, PTGS2, SOD2, SAMSN1) were identified, enriched in inflammatory response, nitric oxide metabolism, and lipopolysaccharide response pathways. qPCR confirmed significantly elevated VIM, OSM, and PTGS2 expression in poor prognosis group (p < 0.01). Multivariable Cox regression identified VIM (HR = 4.475), OSM (HR = 2.800), and homocysteine (Hcy; HR = 1.120) as independent prognostic risk factors. Kaplan-Meier analysis demonstrated significantly reduced survival in high-expression groups (all p < 0.01). The combined model integrating VIM, OSM, and Hcy achieved superior predictive performance (AUC = 0.811; sensitivity 72.55%, specificity 78.00%, Youden’s index 0.506) compared to VIM alone (AUC = 0.760). Conclusion VIM and OSM exhibit robust bioinformatic associations and stable expression with independent prognostic value in clinical cohorts.

Rheumatoid arthritis (RA) is associated with elevated cardiovascular risk. Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor and marker of endothelial dysfunction, has been implicated in inflammation-driven vascular injury. However, the association between ADMA and micro- and macrovascular function in RA remains unclear. Patients with RA underwent nailfold videocapillaroscopy (NVC) to assess microvascular alterations in the dermal capillary network. Macrovascular function was evaluated with well-known markers of arterial stiffness [carotid-femoral pulse wave velocity (PWV), augmentation index], and subclinical atherosclerosis [carotid intima-media thickness]. Serum ADMA was measured using enzyme-linked immunosorbent assay (ELISA). A total of 103 consecutive RA patients (61.1 ± 11.6years, 76.7% female) were studied with median disease duration 6 (12) years. Patients were under methotrexate (54.4%), corticosteroids (35.9%) and biologics (38.8%). A considerable portion had been previously diagnosed with hypertension (38.8%) and dyslipidemia (31.1%), and 41.7% were smokers. ADMA was not significantly associated with cardiovascular risk factors or markers of vascular injury in the total cohort. However, in the subgroup of patients not receiving cardiovascular medication (n = 48), ADMA significantly correlated with PWV, venous limb diameter and capillary tortuosity, even after adjustment for other variables in multivariate analysis. Circulating ADMA was not associated with markers of vascular impairment in a real-life RA cohort presenting with various treatments and comorbidities. However, ADMA independently correlated with arterial stiffness and NVC abnormalities in the subgroup of RA patients not on cardiovascular medications. These findings are consistent with a role of impaired NO homeostasis in vascular injury in RA. Key Points • This study is the first to investigate the association between circulating ADMA levels and both micro- and macrovascular injury in rheumatoid arthritis using nailfold videocapillaroscopy and markers of arterial stiffness and subclinical atherosclerosis. • Significant correlations between ADMA, pulse wave velocity, and nailfold videocapillaroscopic abnormalities were observed in patients not receiving cardiovascular medications. • These findings suggest that impaired nitric oxide metabolism may contribute to peripheral microangiopathy and vascular dysfunction in rheumatoid arthritis.

Polybacterial infections associated with periodontitis are increasingly linked to systemic vascular complications, yet the underlying endothelial mechanisms remain unclear. This study investigated how a consortium of red-complex bacteria (Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola) and orange complex (Fusobacterium nucleatum) affects oxidative stress, inflammation, metabolism, and apoptosis in endothelial cells, and whether L-Sepiapterin [a tetrahydrobiopterin (BH4) precursor via salvage pathway] or bardoxolone methyl (CDDO-Me) [a potent nuclear factor erythroid 2-related factor 2 (Nrf2) activator)] could provide protection. Human umbilical vein endothelial cells (HUVECs) were infected for 12-72 h and treated with L-Sepiapterin or CDDO-Me. Nitric oxide (NO), BH4, and reactive oxygen species (ROS) levels were quantified, and mRNA expression of key genes regulating nitric oxide synthase activity, antioxidant defense, inflammation (TLR4/NF-κB, cytokines), metabolism (PI3K-AKT-PEA-15), and apoptosis (FAS-caspase pathway) was analyzed. Infection markedly reduced NO and BH4, elevated ROS, activated TLR4/NF-κB and proinflammatory cytokines, disrupted PI3K/AKT signaling, and triggered endothelial apoptosis. Treatments with L-Sepiapterin and CDDO-Me restored NO bioavailability, reduced oxidative and inflammatory responses, normalized metabolic gene expression, and attenuated apoptosis, with CDDO-Me showing more promising effects. This study provides the mechanistic insight linking periodontal polybacterial infection to endothelial dysfunction and metabolic impairment such as diabetes, suggesting that redox-modulating strategies such as L-Sepiapterin and CDDO-Me may help prevent vascular damage associated with periodontal disease.

Background: Sepsis is a leading cause of mortality in intensive care units, with liver dysfunction representing a critical determinant of poor outcome, mainly associated with excessive inflammation and oxidative stress. Lycopene, a carotenoid with potent antioxidant and anti-inflammatory properties, has been proposed as a potential therapeutic agent. This study investigated whether lycopene supplementation mitigates lipopolysaccharide-induced oxidative and inflammatory liver injury in rats. Methods: Male Wistar rats, divided into four groups, were exposed to either lipopolysaccharide or a combination of lipopolysaccharide (10 mg/kg) and lycopene (6 mg/kg). In order to assess liver damage induced by lipopolysaccharide, hepatocellular injury markers, oxidative stress indices, nitric oxide metabolism, glutathione redox status, apoptotic enzyme activity, and inflammatory mediators were assessed in serum and liver tissue. Results: Lipopolysaccharide induced marked hepatocellular damage, characterized by elevated serum liver-cell damage parameters, and liver tissue xanthine oxidase, myeloperoxidase, thiobrabituric reactive substances, protein carbonyl content, deoxyribonuclease I/II activity, nuclear factor kappa B, tumor necrosis factor-α, and interleukin-6, alongside depletion of reduced glutathione and reduced glutathione reductase and glutathione peroxidase activities. Lyc pretreatment significantly attenuated liver enzyme leakage, oxidative damage, and cytokine release while restoring reduced glutathione and glutathione reductase activity. In contrast, lycopene had limited effects on glutathione peroxidase activity, nitric oxide/inducible nitric oxide synthase signaling, and nuclear factor erythroid 2-related factor 2 expression. Conclusions: These findings demonstrate that lycopene confers partial hepatoprotection in endotoxemic rats, primarily through suppression of oxidative damage and nuclear factor kappa B-mediated inflammation. Further studies are needed to clarify tissue-specific mechanisms and optimize dosing strategies in order to increase the efficacy of this carotenoid.

The Interplay of Gibberellin, Nitric Oxide and Reactive Oxygen Species Metabolism in Smoke-Induced Seed Dormancy Release

Background and Objectives: Obesity represents a major public health concern worldwide, particularly in economically challenged regions, and is often associated with metabolic comorbidities such as type 2 diabetes mellitus, hypertension, and metabolic-associated fatty liver disease. Oxidative stress plays a central role in obesity pathophysiology through the accumulation of reactive oxygen and nitrogen species. This study aimed to investigate changes in specific oxidative stress biomarkers in patients with obesity before and one year after bariatric surgery, with a lean control group as reference. Methods: This observational cohort study included 50 patients with morbid obesity undergoing bariatric surgery (laparoscopic sleeve gastrectomy or one-anastomosis gastric bypass) and 50 patients without obesity undergoing other surgical procedures. Plasma levels of malondialdehyde (MDA), reduced and oxidized glutathione (GSH and GSSG), nitrite (NO2−), and nitrate (NO3−) were measured preoperatively and one year postoperatively in the bariatric group, and once in the control group. Quantification was performed using HPLC-based techniques. Results: Postoperative analysis revealed a significant reduction in oxidative stress markers. MDA levels decreased from 21.58 to 16.62 ng/mL after surgery, while GSH levels increased significantly, although they remained lower than in the control group. GSH/GSSG ratio improved slightly, indicating enhanced antioxidant capacity. Nitrite and nitrate levels showed a marked reduction postoperatively, which may reflect both diminished NO production and complex metabolic adaptations following weight loss. Correlation analysis showed that reductions in BMI were significantly associated with increases in GSH levels and decreases in MDA. Conclusions: Bariatric surgery led to significant improvements in key oxidative stress biomarkers in patients with obesity, supporting the hypothesis that weight loss mitigates oxidative damage. However, the reduction in nitrite suggests potential trade-offs in nitric oxide metabolism that warrant further investigation. Long-term studies are needed to determine the clinical significance and sustainability of these biochemical improvements.

After peripheral nerve lesion, the role of reactive oxygen species (ROS) has not been clarified during Wallerian degeneration. The present study examined the participation of oxidant stress after rat sciatic nerve injury induced by two experimental models (crush and transection). Here, biochemical parameters indicative of oxidant stress, nitric oxide (NO) metabolism, cell proliferation, apoptosis, and bioenergetics were determined in injured and contralateral sciatic nerves and caudofemoralis muscle. After crushing, we found two peaks of increased lipid peroxidation (LP) by-products and carbonylation of proteins in crushed nerves. In transected nerves, increases in LP showed similar patterns in both proximal and distal nerve. In both models, NO production was decreased and accompanied by an early increase in cell proliferation. Moreover, caspase-3 activity increased later only in crushed nerves. NAD availability and mitochondrial cytochrome oxidase activity were increased in transected but not in crushed nerves. The contralateral nerves also had changes in these parameters, but in a differential manner depending on the type of nerve lesion. In conclusion, present data suggest that changes in the patterns of LP may play a regulatory role in cell damage and death, somehow exerting a control in the progression of Wallerian degeneration.

BackgroundMeaB is a bZIP-type transcription factor in fungi. This protein is known to regulate nitrogen metabolism, contribute to nitrite susceptibility and determine virulence in aspergilli. We hypothesized that MeaB is required for proper nitric oxide (NO) metabolism of fungi. Here, we tested this hypothesis on the human pathogenic fungus Aspergillus fumigatus using a transcriptomics approach.ResultsDeletion of the meaB gene increased nitrite, diethylamine NONOate and menadione-sodium bisulfite stress sensitivity, but not that of terc-butyl hydroperoxide or H2O2. The conidia of the ΔmeaB mutant showed no altered susceptibility to human macrophages. When the transcriptome of the ΔmeaB strain was compared with the wild-type strain (Af293), genes involved in siderophore biosynthesis or glucanases were enriched in the up-regulated gene set, whereas genes encoding heme-binding proteins or chitinases were enriched in the down-regulated gene set. The 90 mM NaNO2-induced stress elicited a response in the ΔmeaB gene deletion mutant that was very similar to that of the wild-type strain in the presence of 135 mM NaNO2. These stress responses included the downregulation of mitotic cell cycle and ribosomal protein genes, and the upregulation of nitrosative stress response (fhpA, fhpB, gnoA), nitrate utilization (niaD, niiA), several iron acquisition and ergosterol biosynthesis genes, as well as the alternative oxidase gene aoxA. These stress treatments also altered the transcriptional activity of secondary metabolite cluster and carbohydrate-active enzyme (CAZyme) genes. Nitrite treatment upregulated arginine metabolism genes only in the wild-type strain. The observed transcriptional changes were associated with reduced growth, increased redox imbalance, increased sterol content in both strains and increased nitrite sensitivity of the ΔmeaB mutant on arginine as sole C and N source.ConclusionsTranscriptomic data implies that MeaB affected fine-tuned regulation of arginine metabolism genes, and the alteration in arginine dependent processes (including siderophore production and possibly NO homeostasis) was responsible for the altered phenotype of the ΔmeaB mutant. Our results also suggest that, although inhibition of A. fumigatus defense against nitrosative stress may not be an effective antifungal therapy for all A. fumigatus strains, a combined approach based on disruption of both iron and NO homeostasis is promising.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12864-025-11990-3.

Aging-associated decline in brown adipose tissue (BAT) function and mass contributes to energy and metabolic homeostasis disruption. Alcohol dehydrogenase 5 (ADH5) is a major denitrosylase that prevents cellular nitro-thiol redox imbalance, an essential feature of aging. However, the functional significance of BAT ADH5 in the context of aging is largely unknown. Here, we aimed to investigate the role of BAT ADH5 in protecting against age-related metabolic dysfunction. We show that aging promotes aberrant BAT protein S-nitrosylation modification and downregulates ADH5 in mice. Furthermore, BAT ADH5-deletion accelerates BAT senescence and aging-associated declines in metabolic homeostasis and cognition. Mechanistically, we found that aging inactivates BAT Adh5 by suppressing heat shock factor 1 (HSF1), a well-recognized proteostasis regulator. Moreover, pharmacologically enhancing HSF1 improved BAT senescence, metabolic decline, and cognitive dysfunction in aged mice. Together, these findings suggest that the BAT HSF1-ADH5 signaling cascade plays a key role in protecting against age-related systemic functional decline. Ultimately, unraveling the role of thermogenic adipose nitrosative signaling will provide novel insights into the interplay between BAT nitric oxide bioactivity and metabolism in the context of aging.

The microbiota influence disease pathogenesis and treatment, however we have limited ability to assess patient status in relation to the microbiota. Here we find that the nitric oxide generating enzyme, nitric oxide synthase 2 (Nos2), is transcriptionally primed in intestinal epithelial cells (IECs), as opposed to immune cells, in inflammatory bowel disease (IBD) patients. Generation of IEC-specific Nos2 knockout mice revealed that epithelial Nos2 activity promoted susceptibility to intestinal disease and sustained a colitogenic microbiota. Epithelial Nos2 increased levels of nitric oxide-derived nitrates and nitrate-metabolizing bacteria in the intestine. Unexpectedly, extra-intestinal nitrates also reflected IEC-intrinsic Nos2 expression, and systemic nitrate concentrations in patients paralleled intestinal Nos2 activation. In fact, temporally inhibiting epithelial Nos2 was sufficient to alter intestinal nitrate homeostasis and inflammation in mice, as well as restrict nitrate production by human intestinal organoids. These data reveal that epithelial nitric oxide metabolism directs host-microbiota dynamics that can alter disease and that monitoring and targeting this axis may benefit patients with IBD.

BackgroundArginase and ceruloplasmin are enzymes of redox balance involved in the metabolism of nitric oxide. Arginase competes with nitric oxide synthase (NOS) for L-arginine and hence plays a crucial role in the arginase/NOS balance of maintaining proteins and the appropriate nitric oxide (NO•) level in the serum. On the other hand, ceruloplasmin (CP) is an acute- phase protein responsible for the metabolic balance of copper and iron. For this study it was to investigate the serum concentrations of enzymes involved in the redox balance, namely arginase type I (Arg1) and CP, in a group of patients with and without sleep bruxism (SB), which was diagnosed by polysomnographic examination.Methods75 adults (35 women and 40 men, mean age 49.12) underwent a full- night of video polysomnography according to standards set out by the American Academy of Sleep Medicine. The concentration of Arg1 and CP in the serum, was determined using ELISA Kits.ResultsThe results showed that the concentration of Arg1 and CP was significantly lower in individuals with SB, irrespective of bruxism severity. Regression analysis revealed that only in the group of patients with higher Arg1 and CP concentrations, was there a negative linear relationship with the bruxism episode index (BEI).ConclusionThe results suggest that there is an oxidative imbalance in patients with SB, independent of the severity of bruxism. Higher plasma levels of Arg1 and CP were related to a lower BEI, potentially as the result of a protective biochemical balance against oxidative stress and inflammation in the SB.

An integrated microbial genome-wide association studies-based characterization of nitric oxide homeostasis by probiotic Bacillus subtilis on aging and neurodegeneration using Caenorhabditis elegans and mouse models.

20-HETE: Its potential role in physiological and pathophysiological processes.

ABSTRACTGlutathione S transferase pi-1 (GSTP1) is a detoxification enzyme essential for oxidative homeostasis. In cancer, GSTP1 has been implicated in tumorigenicity, cell cycle progression, and chemoresistance. While GSTP1 depletion has been associated with decreased cancer growth in various models, the mechanism remains poorly understood. This study investigates GSTP1 as a therapeutic target for pancreatic ductal adenocarcinoma (PDAC) using inducible knockdown models. We demonstrate that GSTP1 loss disrupts redox balance, impairs cell survival, and induces metabolic adaptations. Multiomics analysis characterized the global impact of inducible GSTP1 knockdown on the transcriptome and proteome of PDAC cells, identifying 550 differentially expressed genes and 62 proteins. Notably, 43 of these showed consistent regulation at both the mRNA and protein levels. We identify dysregulation of key stress response proteins, including dimethylarginine dimethylaminohydrolase 1 (DDAH1), involved in nitric oxide metabolism, and protein disulfide isomerase A6 (PDIA6), which maintains protein homeostasis. The interplay between GSTP1, DDAH1 and PDIA6 highlights the complexity of redox regulation in pancreatic cancer and suggests that targeting GSTP1 may offer a new therapeutic approach for PDAC.

In this study, we conducted a targeted quantitative metabolomic analysis of 630 metabolites in the plasma of 78 West African patients at the time of breast cancer diagnosis and prior to any treatment. Most of these patients were at an advanced stage of the disease. The data were compared with those of 79 healthy controls using a combination of several machine learning approaches and statistical analyses. The predictive models obtained with the machine learning algorithms were comparable, with the best AUC of 0.878 obtained with ridge logistic regression using Boruta feature selection. The most consistently identified discriminating metabolites across univariate analyses with Benjamini-Hochberg correction, OPLS-DA analyses, and the best machine learning approach were thirteen, out of a total of 63 discriminating metabolites identified cumulatively by the three approaches. This signature highlights several key biological processes, including oxidative stress, disrupted neurotransmitter profiles, altered nitric oxide and xanthine oxidase metabolism, and impaired energy metabolism. The involvement of new metabolites significantly deregulated in breast cancer, such as asymmetric dimethylarginine and hexosylceramides, have also been identified. The identified metabolomic signature provides a comprehensive and global view of the blood biochemical phenotype associated with advanced breast cancer at the time of diagnosis.

BackgroundAlfalfa (Medicago sativa L.) is a vital forage crop with substantial economic and ecological significance in agriculture and animal husbandry. However, atrazine, a widely used herbicide, negatively impacts the growth and yield of alfalfa due to its residual presence in the environment. Transcriptomic analysis was performed to investigate the differences in tolerance and uncover the potential molecular regulatory mechanisms between the tolerant variety JN5010 and the sensitive variety WL363 when subjected to atrazine stress, using RNA-seq on pooled samples.ResultsBased on the analysis of gene expression profiles, significant differences were observed between the tolerant variety JN5010 and the sensitive variety WL363 under atrazine stress: 2,297 upregulated and 3,167 downregulated in the shoot parts, and 3,232 upregulated and 4,907 downregulated in the roots of JN5010. In WL363, 2,937 genes were upregulated and 4,237 genes were downregulated in the shoot parts, while 5,316 genes were upregulated and 7,977 genes were downregulated in the roots. The DEGs in the shoot parts were mainly involved in biological regulation, metabolic processes, and cellular processes, including proline metabolic processes and S-adenosylmethionine cycle. The DEGs in the roots were predominantly associated with nitric oxide synthesis and metabolism, as well as processes related to cell wall biosynthesis and degradation. In the shoot parts of JN5010, six DEGs were mapped onto the proline metabolic pathway, including four upregulated genes involved in proline biosynthesis and two downregulated genes involved in proline catabolism. In the roots of WL363, eleven DEGs were mapped onto the phenylpropanoid biosynthesis pathway, including seven upregulated genes involved in flavonoid biosynthesis and four downregulated genes associated with lignin biosynthesis. These findings highlight the distinct genetic responses of the two alfalfa varieties to atrazine stress, with JN5010 exhibiting more consistent gene expression patterns compared to the sensitive variety WL363.ConclusionsThe tolerant variety JN5010 shows improved tolerance to atrazine stress by maintaining stable gene expression and precise regulation in various pathways, such as antioxidant processes, signaling, photosynthesis, and toxin removal. This differential gene expression helps JN5010 maintain stability in its functions under stress, demonstrating better adaptability. These findings enhance our understanding of how alfalfa tolerates atrazine stress and provide important insights for developing atrazine-tolerant varieties.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12870-025-07129-x.