Metabolic Alterations Research Articles

Oncometabolites in pancreatic cancer: Strategies and its implications

Pancreatic cancer (PanCa) is a catastrophic disease, being third lethal in both the genders around the globe. The possible reasons are extreme disease invasiveness, highly fibrotic and desmoplastic stroma, dearth of confirmatory diagnostic approaches and resistance to chemotherapeutics. This inimitable tumor microenvironment ( TME) or desmoplasia with excessive extracellular matrix accumulation, create an extremely hypovascular, hypoxic and nutrient-deficient zone inside the tumor. To survive, grow and proliferate in such tough TME, pancreatic tumor and stromal cells transform their metabolism. Transformed glucose, glutamine, fat, nucleotide metabolism and inter-metabolite communication between tumor and TME in synergism, impart therapy resistance, and immunosuppression in PanCa. Thus, a finer knowledge of altered metabolism would uncover its metabolic susceptibilities. These unique metabolic targets may help to device novel diagnostic/prognostic markers and therapeutic strategies for better management of PanCa. In this review, we sum up reshaped metabolic pathways in PanCa to formulate detection and remedial strategies of this devastating disease.

Serum metabolic alterations in chickens upon infectious bursal disease virus infection

BackgroundInfectious bursal disease virus (IBDV) is a highly contagious immunosuppressive virus of chickens. Chickens acquire infection by the oral route under natural conditions. Although the histological and pathological changes after IBDV infection are well described, the alterations in serum metabolome have not been reported. In this study, SPF chickens were infected with attenuated IBDV (atIBDV) strain LM and very virulent IBDV (vvIBDV) strain LX, respectively. On the seventh day after oral infection, serum samples of experimental chickens were identified using ultra-high performance liquid chromatography-MS/MS (UHPLC-MS/MS). The serum metabolic profiles were analyzed by multivariate statistical methods. KEGG enrichment analysis was performed to evaluate the dysregulated biological pathways.ResultsWe identified 368 significantly altered metabolites in response to both atIBDV and vvIBDV infection. The metabolic disorder of amino acid and lipid was associated with IBDV infection, especially tryptophan, glycerophospholipid, lysine, and tyrosine metabolism. The differential metabolites enriched in the four metabolic pathways were PC(20:4(5Z,8Z,11Z,14Z)/18:0), PE(16:0/18:2(9Z,12Z)), PE(16:0/22:6(4Z,7Z,10Z,13Z,16Z,19Z)), PE(18:0/20:4(5Z,8Z,11Z,14Z)), PE(18:0/20:4(8Z,11Z,14Z,17Z)), PE(18:0/22:6(4Z,7Z,10Z,13Z,16Z,19Z)), PE(20:3(8Z,11Z,14Z)/16:0), PE(22:6(4Z,7Z,10Z,13Z,16Z,19Z)/16:0), PE-NMe(20:5(5Z,8Z,11Z,14Z,17Z)/18:0), PS(20:3(5Z,8Z,11Z)/18:2(9Z,12Z)), 2-aminobenzoic acid, 4-(2-aminophenyl)-2,4-dioxobutanoic acid, N-acetylserotonin, 5-hydroxyindoleacetate, indole-3-acetaldehyde, indole-3-acetate, p-coumaric acid, L-tyrosine, homovanillin, and S-glutaryldihydrolipoamide.ConclusionThe atIBDV and vvIBDV infection causes metabolic changes in chicken serum. The differential metabolites and dysregulated metabolic pathways reflect the host response to the IBDV infection.

Levels of Bile Acid Metabolism Are Associated With Alterations of Gut Microbes in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is viewed as a metabolism associated disease, and bile acid metabolism is reported to occupy a significant role in the progression of HCC. However, little is known about the association between gut microbes and bile acid metabolism in HCC. Our study was designed to clarify the role of bile acid metabolism and microbiome in the progression of HCC. We investigated the relationship between bile acid metabolism and prognosis and immune cells by mining GSE14520. We studied the microbial profiles and metabolic alterations between the low bile acid group and high bile acid group using 16S rRNA sequencing and metabolomics. HCC patients in the high bile acid metabolism group showed better survival outcome compared with those in the low bile acid metabolism. Immune analysis displayed the close correlation between low bile acid metabolism and infiltration of CD4 + T cells, and the close relationship between high bile acid metabolism and infiltration of CD8 + T cells, macrophage cells in HCC. 16S rRNA sequencing results demonstrated that Blautia, Ruminococcus_gnavus_group, Erysipelotrichaceae_UCG-003 were mostly enriched in the low bile acid group. Metabolomics of the 109 fecal samples showed that the most enriched metabolites in the low total bile acid group were dihydrocytochalasin B, cucurbic acid and 27-Norcholestanehexol. Finally, KEGG enrichment analysis identified secondary bile acid biosynthesis and endocrine resistance as the most significant metabolic pathways. High bile acid metabolism was associated with more infiltration of CD8 + T cells, macrophage cells, and better prognosis in HCC. Levels of bile acid were significantly associated with altered gut microbes and metabolites in HCC. Further research related to gut microbes and bile acid metabolism may provide a novel insight into the pathogenesis and therapeutic strategy of HCC.

Dog Aging: A Comprehensive Review of Molecular, Cellular, and Physiological Processes

The aging process is a multifactorial biological phenomenon starting at birth and persisting throughout life, characterized by a decline in physiological functions and adaptability. This decline results in the diminished capacity of aging organisms to respond to environmental changes and stressors, leading to reduced efficiency in metabolic, immune, and hormonal functions. As behavioral flexibility wanes, older individuals face longer recovery times and increased vulnerability to diseases. While early research proposed nine core hallmarks of mammalian aging, recent studies have expanded this framework to twelve key characteristics: epigenetic changes, genomic instability, telomere shortening, loss of proteostasis, altered metabolism, mitochondrial dysfunction, cellular senescence, disrupted intercellular communication, stem cell depletion, immune system dysfunction, accumulation of toxic metabolites, and dysbiosis. Given the growing interest in the aging area, we propose to add a new hallmark: impaired water homeostasis. This potential hallmark could play a critical role in aging processes and might open new directions for future research in the field. This review enhances our understanding of the physiological aspects of aging in dogs, suggesting new clinical intervention strategies to prevent and control issues that may arise from the pathological degeneration of these hallmarks.

Insulin resistance in childhood obesity: The role of dietary habits and their association with novel markers of cardiovascular disease

Background Childhood obesity presents numerous comorbidities such as insulin resistance (IR) and dyslipidemia, and could be associated with alterations in novel markers of cardiovascular (CV) risk like: (1) the activities of associated enzymes such as lipoprotein associated phospholipase A2 (Lp-PLA2) and paraoxonase 1 (PON 1), (2) reverse cholesterol transport (RCT), which comprises cellular cholesterol efflux (CCE), in addition to lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) activities, and (3) high density lipoprotein (HDL) antioxidant capacity. Moreover, IR could worsen these cardiometabolic alterations. The objective of the present study was to characterize the effect of IR on novel CV markers in a pediatric population with obesity. Methods Twenty-five obese children and adolescents with IR, and 25 without IR took part in the study. Anthropometric parameters, Tanner stage and dietary habits were registered. Glucose, insulin, non-esterified fatty acid (NEFA), lipid, and high sensitivity C reactive protein (hsCRP) levels, plus Lp-PLA2, LCAT, CETP and PON 1 activities, as well as CCE and HDL antioxidant capacity were measured. A cutoff point of 3.16 in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) determined the presence of IR. Results No differences were observed in age, sex and Tanner stage. Expectedly, the group with IR displayed higher insulin and NEFA levels (p < 0.05). They also presented increased Lp-PLA2 and decreased PON activities (p < 0.05). Importantly, these differences were associated with dietary habits (p < 0.05). Conclusion IR present in pediatric obesity associated with vascular specific inflammation and reduced PON 1 activity, in addition to alterations in glucose metabolism, thus increasing CV risk in adulthood. These proatherogenic disturbances were conditioned by dietary habits.

Metabolomic analysis reveals an important role of sphingosine 1-phosphate in the development of HFMD due to EV-A71 infection.

Hand, foot, and mouth disease (HFMD) is a serious pediatric infectious disease that causes immeasurable physical and mental health burdens. Currently, there is a lack of information on the mechanisms of HFMD severity and early diagnosis. We performed metabolomic profiling of sera from 84 Enterovirus A71 (EV-A71) infections and 45 control individuals. Targeted metabolomics assays were employed to further validate some of the differential metabolic molecules. We identified significant molecular changes in the sera of HFMD patients compared to healthy controls (HCs). A total of 54, 60, 35, and 62 differential metabolites were screened between mild cases and HCs, severe cases and HCs, severe cases and mild cases, and among the three groups, respectively. These differential metabolites implicated dysregulation of the tricarboxylic acid cycle, alanine, aspartate, and glutamate metabolism, and valine, leucine, and isoleucine biosynthesis. The diagnostic panel based on some overlapped differential metabolites could effectively discriminate severe cases from mild cases with an AUC of 0.912 (95% CI: 0.85-0.97) using the logistic regression model. Next, we found the elevation of serum sphingosine 1-phosphate (S1P) level in EV-A71 infection mice, which was similar to clinical observation. Importantly, after blocking the release of S1P by MK571, the clinical symptoms and survival of mice were significantly improved, involving the reduction of leukocyte infiltration in infected brain tissues. Collectively, our data provided a landscape view of metabolic alterations in EV-A71 infected children and revealed regulating S1P metabolism was an exploitable therapeutic target against EV-A71 infection.

STING exerts antiviral innate immune response by activating pentose phosphate pathway

BackgroundThe innate immune system serves as the host’s first line of defense against invading pathogens. Stimulator of interferon genes (STING) is a key component of this system, yet its relationship with glucose metabolism, particularly in antiviral immunity, remains underexplored.MethodsMetabolomics analysis was used for detecting metabolic alterations in spleens from STING knockout (KO) and wild-type (WT) mice. Co-immunoprecipitation was employed for determining ubiquitination of TKT. Mass spectrometry was used for detecting interaction proteins of STING. Enzyme activity kits were used for detecting the activities of TKT and G6PD.ResultsIn this study, we demonstrate that herpes simplex virus (HSV) infection activates the pentose phosphate pathway (PPP) in host cells, thereby initiating an antiviral immune response. Using STING-manipulated cells and systemic knockout mice, we show that STING positively regulates PPP, which, in turn, limits HSV infection. Inhibition of the PPP significantly reduced the production of antiviral immune factors and dampened STING-induced innate immune responses. Mechanistically, we discovered that STING interacts with transketolase (TKT), a key enzyme in the non-oxidative branch of the PPP, and reduces its ubiquitination via the E3 ubiquitin ligase UBE3A, stabilizing TKT. Silencing TKT or inhibiting its activity with oxythiamine diminished antiviral immune factor production.ConclusionOur findings reveal that the PPP plays a synergistic role in generating antiviral immune factors during viral infection and suggest that PPP activation could serve as an adjunct strategy for antiviral therapy.

Evaluating Morphometric Character Variations in Diploid and Triploid Common Carp (Cyprinus carpio) during Early Developmental Stages

Numerous techniques have been put out to differentiate between diploid and triploid organisms, but they are all too complicated and expensive for everyday handling. This study investigated the possibility of distinguishing between diploid and triploid common carp by using simple and cost-effective morphometric variations. This study examines morphometric variations between diploid and triploid common carp (Cyprinus carpio) at three initial developmental stages at 15-, 45- and 75-days post-hatch (dph) to evaluate the morphometric variations during the early developmental stages. Assessments of 11 morphometric characteristics indicated no significant differences between both the ploidy groups at 15 and 45 dph (P > .05), implying similar growth patterns during the early stages of development. However, by 75 dph, significant differences (P<.05) were observed in standard length (SL), eye diameter (ED), anterior myotomal height (AMH), and middle myotomal height (MMH). Triploid fish exhibited higher values in these characteristics. The findings imply that the growth benefits in triploids could be related to metabolic or genetic alterations associated with triploidy, particularly as physiological differences become more pronounced over time. The similarities in early morphometric characteristics between diploids and triploids likely signify shared genetic lineages, whereas the differences at later developmental stages highlight the effect of triploidy on growth characteristics.

Evaluating the Impact of Multimodal Prehabilitation with High Protein Oral Nutritional Supplementation (HP ONS) with Beta-Hydroxy Beta-Methylbutyrate (HMB) on Sarcopenic Surgical Patients—Interim Analysis of the HEROS Study

Background: Multimodal prehabilitation programs, which may incorporate nutritional supplementation and exercise, have been developed to combat sarcopenia in surgical patients to enhance post-operative outcomes. However, the optimal regime remains unknown. The use of beta-hydroxy beta-methylbutyrate (HMB) has beneficial effects on muscle mass and strength. However, its effect on muscle quality in the perioperative setting has yet to be established. This study aims to explore the impact of a multimodal prehabilitation program using a bundle of care that includes high-protein oral nutritional supplementation (HP ONS) with HMB and resistance exercise on muscle quality and functional outcomes in sarcopenic surgical patients. Methods: Sarcopenic adult patients undergoing elective major gastrointestinal surgeries were recruited for this pilot interventional cohort study. They were enrolled in a 2–4-week multimodal prehabilitation program comprising resistance exercise, nutritional supplementation, vitamin supplementation, comorbid optimization and smoking cessation. Participants were provided three units of HP ONS with HMB per day pre-operatively. The primary outcome was changes in intramuscular adipose tissue (IMAT) as a proxy of muscle quality, assessed using Artificial Intelligence (AI)-aided ultrasonography. Secondary outcomes include changes in anthropometric measurements and functional characteristics. Outcomes were measured before prehabilitation, after prehabilitation and 1 month post-operatively. Results: A total of 36 sarcopenic patients, with a median age of 71.5 years, were included in this study. There was an increase in the IMAT index after two weeks of prehabilitation (p = 0.032) to 1 month after surgery (p = 0.028). Among functional parameters, improvement was observed in gait speed (p = 0.01) after two weeks of prehabilitation, which returned to baseline post-operatively. The median length of hospital stay was 7 (range: 2–75) days. Conclusions: The increase in the IMAT index in a sarcopenic surgical cohort undergoing prehabilitation may be due to altered muscle metabolism in elderly sarcopenic patients. A prehabilitation regime in sarcopenic patients incorporating HP ONS with HMB and resistance exercise is feasible and is associated with increased gait speed.

Sulfur Amino Acid Restriction Mitigates High-Fat Diet-Induced Molecular Alterations in Cardiac Remodeling Primarily via FGF21-Independent Mechanisms

Background/Objectives: Dietary sulfur amino acid restriction (SAAR) elicits various health benefits, some mediated by fibroblast growth factor 21 (FGF21). However, research on SAAR’s effects on the heart is limited and presents mixed findings. This study aimed to evaluate SAAR-induced molecular alterations associated with cardiac remodeling and their dependence on FGF21. Methods: Male C57BL/6J wild-type and FGF21 knockout mice were randomized into four dietary regimens, including normal fat and high-fat diets (HFDs) with and without SAAR, over five weeks. Results: SAAR significantly reduced body weight and visceral adiposity while increasing serum FGF21 levels. In the heart, SAAR-induced molecular metabolic alterations are indicative of enhanced lipid utilization, glucose uptake, and mitochondrial biogenesis. SAAR also elicited opposing effects on the cardiac gene expression of FGF21 and adiponectin. Regarding cellular stress responses, SAAR mitigated the HFD-induced increase in the cardiac expression of genes involved in oxidative stress, inflammation, and apoptosis, while upregulating antioxidative genes. Structurally, SAAR did not induce alterations indicative of cardiac hypertrophy and it counteracted HFD-induced fibrotic gene expression. Overall, most alterations induced by SAAR were FGF21-independent, except for those related to lipid utilization and glucose uptake. Conclusions: Altogether, SAAR promotes cardiac alterations indicative of physiological rather than pathological remodeling, primarily through FGF21-independent mechanisms.

Trained innate immunity as a potential link between preeclampsia and future cardiovascular disease

Preeclampsia (PE) is a complex pregnancy syndrome characterized by hypertension with or without proteinuria, affecting 2–6% of pregnancies globally. PE is characterized by excessive release of damage-associated molecular patterns (DAMPs) into the maternal circulation. This DAMP-rich milieu acts on innate immune cells, inducing a proinflammatory state characterized by elevated cytokines such as IL-1β and IL-18. This proinflammatory state in the mother and placenta results in the endothelial dysfunction strongly associated with cardiovascular disorders. While the immediate maternal and fetal risks of PE are well-documented, accumulating evidence indicates that PE also confers long-term cardiovascular risks to the mother, including hypertension, coronary heart disease, stroke, and heart failure. The underlying mechanisms connecting PE to these chronic cardiovascular conditions remain unclear. This article explores the potential role of trained innate immunity (TRIM) as a mechanistic link between PE and increased long-term cardiovascular risk. We propose that the persistent exposure to DAMPs during PE may epigenetically reprogram maternal innate immune cells and their progenitors, leading to TRIM. This reprogramming enhances the inflammatory response to subsequent stimuli, potentially contributing to endothelial dysfunction and chronic inflammation that predispose women to cardiovascular diseases later in life. Understanding the role of TRIM in PE could provide novel insights into the pathophysiology of PE-related cardiovascular complications and identify potential targets for therapeutic intervention. Further research is warranted to investigate the epigenetic and metabolic alterations in innate immune cells induced by PE and to determine how these changes may influence long-term maternal cardiovascular health.

Pathology and Treatments of Alzheimer’s Disease Based on Considering Changes in Brain Energy Metabolism Due to Type 2 Diabetes

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with cognitive dysfunction, memory decline, and behavioral disturbance, and it is pathologically characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain. Although various hypotheses have been proposed to explain the pathogenesis of AD, including the amyloid beta hypothesis, oxidative stress hypothesis, and abnormal phosphorylation of tau proteins, the exact pathogenic mechanisms underlying AD remain largely undefined. Furthermore, effective curative treatments are very limited. Epidemiologic studies provide convincing evidence for a significant association between type 2 diabetes and AD. Here, we showed energy metabolism using glucose, lactate, ketone bodies, and lipids as energy substrates in a normal brain, and changes in such energy metabolism due to type 2 diabetes. We also showed the influences of such altered energy metabolism due to type 2 diabetes on the pathology of AD. Furthermore, we comprehensively searched for risk factors related with type 2 diabetes for AD and showed possible therapeutic interventions based on considering risk factors and altered brain energy metabolism due to type 2 diabetes for the development of AD.

Plastic is one of the root causes of endocrine disorders

Endocrine-disrupting chemicals (EDCs) found in various products, including electronics, carpets, paints, cosmetics, and plastics, can disrupt human endocrine systems, potentially affecting reproductive health, thyroid function, metabolic alterations, diabetes, cardiovascular disease, obesity, impaired brain development, compromised immune responses, and cancers in hormone-sensitive tissues. Exposure to EDCs during gestation and early postnatal life has significant impacts, and hazardous compounds in plastics can lead to further damage.

Metabolic response of Klebsiella oxytoca to ciprofloxacin exposure: a metabolomics approach

IntroductionRapid detection and identification of pathogens and antimicrobial susceptibility is essential for guiding appropriate antimicrobial therapy and reducing morbidity and mortality associated with sepsis.ObjectivesThe metabolic response of clinical isolates of Klebsiella oxytoca exposed to different concentrations of ciprofloxacin (the second generation of quinolones antibiotics) were studied in order to investigate underlying mechanisms associated with antimicrobial resistance (AMR).MethodsMetabolomics investigations were performed using Fourier-transform infrared (FT-IR) spectroscopy as a metabolic fingerprinting approach combined with gas chromatography-mass spectrometry (GC-MS) for metabolic profiling.ResultsOur findings demonstrated that metabolic fingerprints provided by FT-IR analysis allowed for the differentiation of susceptible and resistant isolates. GC-MS analysis validated these findings, while also providing a deeper understanding of the metabolic alterations caused by exposure to ciprofloxacin. GC-MS metabolic profiling detected 176 metabolic features in the cellular extracts cultivated on BHI broth, and of these, 137 could be identified to Metabolomics Standards Initiative Level 2. Data analysis showed that 40 metabolites (30 Level 2 and 10 unknown) were differentiated between susceptible and resistant isolates. The identified metabolites belonging to central carbon metabolism; arginine and proline metabolism; alanine, aspartate and glutamate metabolism; and pyruvate metabolism. Univariate receiver operating characteristic (ROC) curve analyses revealed that six of these metabolites (glycerol-3-phosphate, O-phosphoethanolamine, asparagine dehydrate, maleimide, tyrosine, and alanine) have a crucial role in distinguishing susceptible from resistant isolates (AUC > 0.84) and contributing to antimicrobial resistance in K. oxtytoca.ConclusionOur study provides invaluable new insights into the mechanisms underlying development of antimicrobial resistance in K. oxytoca suggests potential therapeutic targets for prevention and identification of AMR in K. oxytoca infections.

Alterations in Mitochondrial Function in Pulmonary Vascular Diseases.

Aims: Alterations of mitochondrial bioenergetics and arginine metabolism are universally present and mechanistically linked to pulmonary arterial hypertension (PAH), but there is little knowledge of arginine metabolism and mitochondrial functions across the different pulmonary hypertension (PH) groups. We hypothesize that abnormalities in mitochondrial functions are present across all PH groups and associated with clinical phenotypes. We test the hypothesis in PH patients and healthy controls from the Pulmonary Vascular Disease Phenomics Program cohort, who had comprehensive clinical phenotyping and follow-up for at least 4 years for death or transplant status. Mitochondrial transmembrane potential, superoxide production, and mass were measured by flow cytometry in fresh platelets. Metabolomics analysis was performed on plasma samples. Global arginine bioavailability was calculated as the ratio of arginine/(ornithine+citrulline). Results: Global arginine bioavailability is consistently lower than controls in all PH groups. Although the mitochondrial mass is similar across all PH groups and controls, superoxide production and transmembrane potential vary across groups. Mitochondrial superoxide is higher in group 1 PAH and lowest in group 3 compared with other groups, while transmembrane potential is lower in group 1 PAH than controls or group 3. The alterations in mitochondrial functions of group 1 PAH are associated with changes in fatty acid metabolism. Mitochondrial transmembrane potential in group 1 PAH is associated with transplant-free survival. Conclusion: While alterations in mitochondrial function are found in all PH groups, group 1 PAH has a unique mitochondrial phenotype with greater superoxide and lower transmembrane potential linked to fatty acid metabolism, and clinically to survival. Antioxid. Redox Signal. 00, 000-000.

Delta-9 desaturase reduction in gastrointestinal cells induced to senescence by doxorubicin.

The condition of cellular senescence has specific features, including an altered lipid metabolism. Delta-9 desaturase (Δ9) catalyzes the conversion of saturated fatty acids, such as palmitic acid and stearic acid, into their monounsaturated forms, palmitoleic and oleic acid, respectively. Δ9 activity is important for most lipid functions, such as membrane fluidity, lipoprotein metabolism and energy storage. The present study aimed to investigate differences in the expression of Δ9 in senescence-induced pancreatic (MIA-PaCa-2 and PANC-1) and hepatic (Hepa-RG and HLF) cancer cell lines. Cellular senescence was induced by growing cells in the presence of the chemotherapic drug doxorubicin. Senescence status was determined by the senescence-associated beta-galactosidase activity assay kit combined with the p21 and senescence associated secretory phenotype protein assay. Δ9 was downregulated in all senescence-induced cell lines compared to control cells, in both the lipidomic analysis and when measuring protein levels via western blotting. Hence, our findings demonstrate that the study of membrane lipid composition and the expression levels of Δ9 could potentially form the basis for future applications investigating the state of cellular senescence.

Genomic landscape of circulating tumor DNA in HER2-low metastatic breast cancer

The large population of HER2-low breast cancer patients necessitates further research to provide enhanced clinical guidance. In this study, we retrospectively analyzed 1071 metastatic breast cancer (MBC) patients and the circulating tumor DNA (ctDNA) to investigate clinicopathological and genetic alterations of HER2-low MBC patients. The effect of HER2-low status on different treatment modalities was explored in two prospective clinical trials (NCT03412383, NCT01917279) and a retrospective study. Our findings suggest TP53, PIK3CA, and ESR1 are frequently mutated genes in HER2-low MBC. Compared to the HER2-0 group, mutations observed in the HER2-low group are more closely associated with metabolic pathway alterations. Additionally, among patients with ERBB2 mutations and treated with pyrotinib, the HER2-low group may experience superior prognosis when compared to the HER2-0 group. Notably, we did not find any statistically significant disparity in the response to chemotherapy, endocrine therapy, or CDK4/6 inhibitor therapy between HER2-0 and HER2-low breast cancer patients. Interestingly, within the subgroup of individuals with metabolic pathway-related gene mutations, we found that HER2-low group exhibited a more favorable response to these treatments compared to HER2-0 group. Additionally, dynamic analysis showed the HER2-low MBC patients whose molecular tumor burden index decreased or achieved early clearance of ctDNA after the initial two treatment cycles, exhibited prolonged survival. Moreover, we classified HER2-low MBC into three clusters, providing a reference for subsequent treatment with enhanced precision. Our study offers valuable insights into the biology of HER2-low MBC and may provide reference for personalized treatment strategies.

Application of 1H NMR Metabolic Profiling of Serum in Canine Multicentric Lymphoma.

Canine lymphoma represents a biologically and metabolically heterogeneous group of neoplasms that arise from malignant transformation of lymphoid cells. An accurate diagnosis is crucial because of its impact on survival. Current diagnostic methods include clinical laboratory tests and imaging, most of which are invasive and lack sensitivity and specificity. Interestingly, recent work in cancer patients focuses on the search for biomarkers for diagnosis, investigation of treatment response mechanisms, treatment efficacy and prognosis and the discovery of tumour metabolic pathways using metabolomic analysis. In this study, we compare the metabolite profiles in serum from 37 dogs with multicentric lymphoma (22 B-cell lymphomas/LB, 9 CD45+ T-cell lymphomas/LTCD45+, 6 CD45- T-cell lymphomas/LTCD45-) and 25 healthy dogs using 1H nuclear magnetic resonance spectroscopy (NMR). 1H NMR-based metabolite profiling analysis recognised lipids and 22 metabolites, with 16 of them altered, and was shown to be an effective approach for differentiating samples from dogs with lymphoma and healthy controls based on principal component analysis of the NMR data. We also investigated variations in the serum metabolome between immunophenotypes and the control group through pairwise comparisons of the healthy against the LB, LTCD45+ and LTCD45- groups, respectively which showed similar metabolomic profiles. In addition, there were significant differences in the levels of five individual metabolites based on the univariate statistical analysis. Our results showed alterations in energy, protein and lipid metabolism, suggesting glucose, lactate, N-acetyl glycoproteins (NAGs), scyllo-inositol and choline as possible new candidate biomarkers in canine multicentric lymphoma.

Oxalis erythrorhiza Gillies ex Hooker et Arnott (Oxalidaceae): Chemical Analysis, Biological In Vitro and In Vivo Properties and Behavioral Effects

In this work, a decoction (DOe) and a methanolic global extract (MGEOe), obtained with the aerial parts of Oxalis erythrorhiza Gillies ex Hooker et Arnott (Oxalidaceae), were evaluated. The high-resolution liquid chromatography in conjunction with electrospray ionization quadrupole time-of-flight mass spectrometry (UHPLC-ESI-QTOF-MS) analysis showed forty compounds in MGEOe and twenty-nine in DOe, including flavones, C-glycosyl flavones, isoflavones, fatty acids, terpenes, phenolic acids, and sterols. The antioxidant properties were evaluated by DPPH, TEAC, FRAP, and ILP assays. Both DOe and MGEOe showed stronger antioxidant activities. The anti-inflammatory effects were evaluated by COX inhibition method, where DOe demonstrated a significant inhibitory effect. The cytotoxic effects were evaluated in the tumoral HCT-116 and non-tumoral HBL-100 cell lines, revealing a selective action from DOe and MGOe on cancer cells. DOe was evaluated in an animal model of insulin resistance, which is characterized by alterations in glucose and lipid metabolism, as well as cognitive impairments, including anxiety-like behavior and memory deficits. Male SD rats received sucrose (10% w/v, SUC), a half dilution of DOe (5% w/v) with sucrose (HDOeS) or DOe with sucrose (DOeS) from PND21 to PND61. Then, anxiety-like behavior and spatial memory were assessed using the open field (OF), elevated plus maze (EPM) and the novel object location (NOL) tests, respectively. Serum parameters basal glycemia, total cholesterol (TC) and tryglicerides were measured using commercial kits. The lipid peroxidation was determined in homogenates of cerebral cortex, hippocampus and hypothalamus by TBAR assay. Only HDOeS exhibited lower anxiety-like behavior in OF and improved performance in NOL compared to SUC. Furthermore, DOeS showed reduced serum parameters, while HDOeS presented lower TC levels than SUC. No differences were observed on TBAR assay. The beneficial properties of these preparations could be attributed to the identified metabolites. These findings highlighted O. erythrorhiza as a potential source of compounds to improve human health; however, further research is required to elucidate its mechanisms of action.

Comparative analysis of the effects of different hypoxia mimetic agents on the secretome contents of conditioned medium obtained from mesenchymal stem/stromal cells cultured in 2 or 3-dimensional cell culture systems.

Paracrine factors secreted by mesenchymal stem/stromal cells (MSCs) have been demonstrated to have significant therapeutic potential. The secretome profiles of MSCs variate depending on culture conditions. Generally, the effects of a single preconditioning strategy on secretome profiles of MSCs were investigated. However, until now, there has been no study examining the combinatory effects of different preconditioning strategies in a comparative manner. This study aimed to evaluate the secretome contents of conditioned media obtained from human umbilical cord-derived MSCs cultured in 2- or 3-dimensional (D) culture systems preconditioned with deferoxamine (DFS) or dimethyloxalylglycine (DMOG). Immunocytochemical analysis showed that MSCs preconditioned with DFS or DMOG have increased nuclear hypoxia-inducible factor-1α expression. Transmission electron microscopic analysis showed that cells preconditioned with DFS or DMOG have increased autophagic vesicles, which could be attributed to altered energy metabolism under hypoxic conditions. It was revealed that hypoxia-mimetic agents added to the 2D-, or 3D-culture environment raised total protein concentrations per cell along with vascular endothelial growth factor. The concentrations of glial cell-derived neurotrophic factor (GDNF) and nerve growth factor (NGF) were differentially regulated in 2D-, and 3D-culture system, that the secretions of GDNF and NGF per cell were more prominent in 3D- and 2D-culture systems, respectively. These findings indicate that hypoxic conditions alone significantly elevate total protein concentrations, while the contribution of the 3D environment is more modest than initially anticipated. However, concentrations of secreted growth factors may be affected differently depending on the topography of the culture condition and the types of hypoxia mimetic agents.