Metabolic Activity Research Articles

The Influence of Dietary Isothiocyanates on the Effectiveness of Mitomycin C and Bacillus Calmette-Guérin in Treating Nonmuscle-Invasive Bladder Cancer.

Nonmuscle-invasive bladder cancer (NMIBC) has high recurrence rates and is often treated with mitomycin C (MMC) and bacillus Calmette-Guérin (BCG). Their efficacy relies on phase 2 enzyme metabolism and immune response activation, respectively. Dietary isothiocyanates, phytochemicals in cruciferous vegetables, are phase 2 enzyme inducers and immunomodulators, and may impact treatment outcomes. We investigated the modifying effects of cruciferous vegetable and isothiocyanate intake on recurrence risk following MMC or BCG treatment. Self-reported cruciferous vegetable intake, estimated isothiocyanate intake, and urinary isothiocyanate metabolites were collected from 1158 patients with incident NMIBC in the prospective Be-Well Study. Hazard ratios (HRs) and 95% CIs were calculated from Cox proportional hazards regression models for risk of first recurrences, and random effects Cox shared frailty models for multiple recurrences. Over median follow-up of 23 months, 343 (30%) recurrences occurred. Receipt of MMC and BCG was associated with decreased risks of first recurrence (MMC: HR = 0.58; 95% CI: 0.46-0.73; BCG: HR = 0.66; 95% CI: 0.49-0.88) and multiple recurrences (MMC: HR = 0.55; 95% CI: 0.44-0.68; BCG: HR = 0.72; 95% CI: 0.55-0.95). Patients receiving BCG and having high intake (>2.4 servings/mo), but not low intake, of raw cruciferous vegetables had reduced risk of recurrence (HR: 0.56; 95% CI: 0.36-0.86; P for interaction = .02) and multiple recurrences (HR: 0.51; 95% CI: 0.34-0.77; P for interaction < .001). The inverse association between MMC receipt and recurrence risk was not modified. For NMIBC patients who receive induction BCG, increasing consumption of raw cruciferous vegetables could be a promising strategy to attenuate recurrence risk.

Metabolic Reprogramming and AMPK Activation: Key Players in the Therapeutic Effects of Cooling Blood and Detoxicating Formular on Psoriasis

Metabolic Reprogramming and AMPK Activation: Key Players in the Therapeutic Effects of Cooling Blood and Detoxicating Formular on Psoriasis

Mechanistic insights into behavioral clusters associated with cancer-related systemic inflammatory response.

This focused, narrative review mostly describes our team's investigations into the potential inflammatory mechanisms that contribute to the development of cancer-related gastrointestinal (GI) mucositis and its associated symptoms. This review summarizes details of our clinical and preclinical findings to test the role of inflammation in the development and occurrence of these cancer-related conditions. GI mucositis (GIM) is a common, distressing condition reported by cancer patients. GIM is often clustered with other behaviors including fatigue, pain, anorexia, depression, and diarrhea. It is hypothesized that there is a common biologic mechanism underpinning this symptom cluster. Our multi-platform investigations revealed that GIM and its associated cluster of behaviors may be triggered by local inflammation spreading systemically causing pro-inflammatory-mediated toxicities, leading to alterations in immune, metabolic, and nervous system functions and activities. For example, behavioral toxicities related to local irradiation for non-metastatic cancer may be triggered by mGluR5 activation influencing prolonged T cell as well as NF-κB transcription factor activities. Thus, interventions targeting inflammation and associated pathways may be a reasonable strategy to alleviate GIM and its symptom cluster. GIM may be a sign of a broader systemic inflammatory response triggered by cancer or its treatment. Addressing GIM and its associated symptoms primarily involves supportive care strategies focused on relieving symptoms, promoting healing, and preventing complications.

Improving Reliability of Immunological Assays by Defining Minimal Criteria for Cell Fitness.

Human PBMC-based assays are often used as biomarkers for the diagnosis and prognosis of disease, as well as for the prediction and tracking of response to biological therapeutics. However, the development and use of PBMC-based biomarker assays is often limited by poor reproducibility. Complex immunological assays can be further complicated by variation in cell handling before analysis, especially when using cryopreserved cells. Variation in postthaw viability is further increased if PBMC isolation and cryopreservation are done more than a few hours after collection. There is currently a lack of evidence-based standards for the minimal PBMC viability or "fitness" required to ensure the integrity and reproducibility of immune cell-based assays. In this study, we use an "induced fail" approach to examine the effect of thawed human PBMC fitness on four flow cytometry-based assays. We found that cell permeability-based viability stains at the time of thawing did not accurately quantify cell fitness, whereas a combined measurement of metabolic activity and early apoptosis markers did. Investigation of the impact of different types and levels of damage on PBMC-based assays revealed that only when cells were >60-70% live and apoptosis negative did biomarker values cease to be determined by cell fitness rather than the inherent biology of the cells. These data show that, to reproducibly measure immunological biomarkers using cryopreserved PBMCs, minimal acceptable standards for cell fitness should be incorporated into the assay protocol.

P21-60 Metabolic activities in Rainbow trout (Oncorhynchus mykiss) S9 fractions from liver and extrahepatic organs as an alternative in vitro ecotoxicity assessment approach

P21-60 Metabolic activities in Rainbow trout (Oncorhynchus mykiss) S9 fractions from liver and extrahepatic organs as an alternative in vitro ecotoxicity assessment approach

Evaluating the potential prebiotic effects of umbu-cajá (Spondias spp.) fruit processing by-product flour on the human intestinal microbiota

This study evaluated the potential prebiotic properties of umbu-cajá (Spondias spp.) fruit processing by-product flour (UCF) on the human intestinal microbiota by monitoring the relative abundance of specific intestinal bacterial populations, microbial metabolic behavior, and antioxidant activity during 48 h of in vitro colonic fermentation using fecal inoculum donated from healthy adult individuals. UCF had a high insoluble fiber content and flavonols, especially quercetin-3-O-glucoside, as the most prevalent phenolic compounds, besides showing antioxidant activity. Medium with UCF increased the relative abundance of Lactobacillus spp./Enterococcus spp., Bifidobacterium spp., and Clostridium histolyticum during the colonic fermentation and decreased the relative abundance of Bacteroides spp./Prevotella spp. and Eubacterium rectale/Clostridium coccoides. Medium with UCF maintained a higher relative abundance of Ruminococcus albus/R. flavefaciens than negative control during the colonic fermentation. UCF stimulated intense metabolic activity of the intestinal microbiota during the colonic fermentation, evidenced by decreased pH values, sugar consumption, and production of several metabolites linked to host health promotion, concomitant with high antioxidant activity. The results characterize UCF as a candidate for prebiotic use and a novel value-added circular ingredient to functionalize foods and nutraceuticals.

Modified biochar affects CO2 and N2O emissions from coastal saline soil by altering soil pH and elemental stoichiometry

The application of biochar in degraded farmland improves soil productivity while achieving the recycling of agricultural waste. The collapse of the physical structure of coastal saline soils will greatly reduce the carbon sequestration potential of biochar. Phosphorus- and magnesium-modified biochar greatly improve the stability of biochar, which endows them with the potential to greatly improve the organic carbon pool of coastal saline soil. However, changes in the properties of modified biochar increase the uncertainty of microbial driven CO2 and N2O release by affecting soil chemistry properties. In this study, through laboratory soil microcosmic experiment, we investigated the effects of magnesium-modified biochar (BCMg) and phosphorus-modified biochar (BCP) on CO2 and N2O releases from coastal saline soils, and further uncovered their potential mechanisms. Compared with unapplied biochar (CK) and unmodified biochar (BC) treatment, BCMg reduced both the releases of CO2 and N2O, and BCP decreased N2O release but enhanced CO2 release. pH is the medium through which BCMg affects the release of CO2 and N2O. Specifically, BCMg increased soil pH above 8.5, which reduced the metabolic activity of the microbial community, and the abundance of bacteria directly or indirectly involved in N2O production, thereby decreasing the releases of CO2 and N2O. The amendment of BCP changed soil elemental stoichiometry causing microbial N-limitation. Increasing CO2 release and decreasing N2O release were strategies for microorganisms to cope with N-limitation. These findings suggested that BCMg is superior to BCP in mitigating greenhouse gas emissions, providing a basis for the application of modified biochar to improve the carbon pool and reduce greenhouse gas emissions of coastal saline soil.

Shift of microbial taxa and metabolisms relying on carbon sources of rhizodeposits and straw of Zea mays L

Decoding the fundamental taxa that decompose crop rhizodeposits (rhizo-C) and/or straw residue (straw-C) is crucial for understanding the role of plant-derived carbon (C) in driving microbial community assembly and consequent C decomposition. Here, a parallel 13C-labeling design, DNA-SIP, and metagenomics techniques were combined to separate maize rhizo-C utilizers from straw-C utilizers in agriculture soils containing both C sources. Also, by comparing bacterial utilizers and their C metabolisms in soils amended with a single C source (e.g., straw-13C only) and two C sources (e.g., straw-13C and rhizo-12C), we investigated the shift of composition and metabolisms of soil bacterial utilizers responding to C sources shift (e.g., compositional and metabolic changes of straw-13C utilizers from soil containing straw-13C to soil containing both straw-13C and rhizo-12C). We revealed i) Proteobacteria predominantly utilized rhizo-13C, while Firmicutes dominated the community specializing in straw-13C decomposition in soil containing both straw-C and rhizo-C; ii) the planted maize (i.e. rhizo-C input) changed community composition and metabolisms of straw-C utilizers, which shifted from K-strategists characterized by an enrichment of lignin-degrading genes to r-strategists which exhibited an enrichment of genes related to polysaccharide degradation. This metabolic shift of straw-C utilizer ultimately reduced straw-13C mineralization by 25.6% when maize was planted. This study identified the distinct utilizers of rhizo-C and straw-C in soils containing both C sources, and shed light on the shift of bacterial community and their metabolic activities responding to the changes of maize-derived C sources.

Study on synergistic effect of carrier combined with micro-aeration on anaerobic digestion of food waste

Enhancing the conversion efficiency of methane production from food waste (FW) is always a hot issue. Biological carriers and micro-aeration had demonstrated notable advantages in enhancing anaerobic digestion (AD) efficiency, but their synergistic potential remained largely untapped. This study introduced polyurethane carriers into micro-aeration assisted AD, trying to explore their synergism in enhancing the digestive efficiency of FW. Results revealed that an optimal blend of carriers and micro-aeration pose significant improvement to the digestive performance. Their combination enhanced microbial metabolic activity, accelerated the consumption or conversion of dissolved organic matter (DOM) molecules, promoted the aggregation of microorganisms, which improved their tolerance capacity under the oxygen stress brought by the micro-aeration, ensuring the system stability. It also enriched methane-producing microorganisms, and balanced methane-producing pathways. Additionally, the combination of micro-aeration and carriers promoted key enzyme expression in metabolic pathways, providing ample support for methane production. These findings held significance for optimizing FW treatment, improving methane production efficiency, and reducing the burden of organic waste treatment.

The Impact of CYP 2C9 rs1799853 and rs1057910 Polymorphism on Plasma Losartan Metabolic Ratio in a Sample of Iraqi Hypertensive Patients

Background: The challenge associated with interindividual diversity in CYP2C9 enzyme activity is primarily related to genetic variations among individuals. Polymorphisms in the CYP2C9 gene can lead to different enzyme activity, affecting how individuals metabolize drugs. The understanding of interindividual diversity in CYP2C9 enzyme activity has implications for personalized medicine. Objective: To examine the impact of CYP2C9 gene polymorphisms (rs1799853 and rs1057910) on the losartan metabolism in Iraqi hypertensive patients. Methods: This prospective interventional study was conducted on a sample of hypertension patients from Babylon governorate, Iraq. All patients received 100 mg of losartan once daily. After 4 weeks, blood samples were obtained for genetic analysis and measuring losartan and its carboxylic acid (LCA) metabolite levels. The plasma losartan-to-LCA ratio is used as an indirect determinant of CYP2C9 activity within CYP2C9 SNP genotypes. Results: Two major allelic polymorphisms, CYP2C9 rs1799853 (T allele 15.5%) on exon 3 and rs1057910 (C allele 8.5%) on exon 7, have been identified among the patients. Plasma losartan/E3174 metabolic ratio was significantly higher in patients with a CT genotype of rs1799853 SNP (1.65) than in patients with a CC wild-type genotype (1.03). The losartan/E3174 metabolic ratio in heterozygous mutant AC genotypes of rs1057910 (1.18) was also higher than in those with wild-type AA genotypes (1.15); however, these differences are not statistically significant. Conclusions: The rs1799853 SNP variant, but not the rs1057910 SNP variant, significantly impacts CYP2C9 metabolic activity. The plasma losartan/E3174 metabolic ratio appears to be a practical and reliable measure for CYP2C9 activity.

Design, synthesis, and evaluation of novel oxyacanthine derivatives for anti-SARS-CoV-2 activity

Here, we report the synthesis of a series of oxyacanthine derivatives and evaluation for their anti-SARS-CoV-2 activity in Vero E6 cells. In order to eliminate the potential metabolic activation caused by para-methylene phenol moiety in oxyacanthine, totally 29 derivatives were designed and synthesized, resulting in 23 compounds with antivirus IC50 below 5.00 μM and 9 compounds with antivirus IC50 below 1.00 μM. Among them, amides compound 4a and 4d exhibited potent anti-SARS-CoV-2 activity and the most favorable selectivity index (SI) in vitro with the SI values of 115 and 70, respectively. The pharmacokinetic properties of 4a and 4d were also assessed. Much more improved exposure in mice, longer half-life (T1/2), and increased oral bioavailability were observed for both compounds 4a and 4d compared with oxyacanthine.

Bioconversion of pure CO2 to caproic acid with zero valent iron: Optimizing carbon flux distribution in co-cultures of Acetobacterium woodii and Megasphaera hexanoica

Acetobacterium woodii and Megasphaera hexanoica were co-cultured for caproic acid (CA) production from Lactic acid (LA) and CO2. Also, various concentrations (1 g/L, 3 g/L, 5 g/L, and 10 g/L) of Zero Valent Iron (ZVI) were introduced to study its impact on the co-culture system. In flask experiments, 10 g/L LA and 1.0 bar CO2 produced 0.6 g/L CA with some biomass growth. ZVI increased LA consumption and CA production. Indeed, 3 g/L ZVI boosted CA production by 186 % and biomass accumulation by 103 %, suggesting that ZVI controls the carbon flux. Subsequent automated bioreactor studies showed that 3 g/L ZVI produced 1.842 g/L CA at stable pH, compared to 0.969 g/L without ZVI (control). Further, metabolic activity showed that both bacteria could directly use H2, generated by ZVI (3 g/L), as electron donor. Higher ZVI concentrations (10 g/L) resulted in Fe2+ causing excessive oxidation pressure on M. hexanoica, with its carbon flux flowing preferentially towards biomass. Enzyme assays confirmed that A. woodii preferred 10 g/L ZVI while M. hexanoica preferred 3 g/L for optimal bioconversion

Comparative analysis of phosphorylated proteomes between plerocercoid and adult Spirometra mansoni reveals phosphoproteomic profiles of the medical tapeworm

BackgroundPlerocercoid larvae of the tapeworm Spirometra mansoni can infect both humans and animals, leading to severe parasitic zoonosis worldwide. Despite ongoing research efforts, our understanding of the developmental process of S. mansoni remains inadequate. To better characterize posttranslational regulation associated with parasite growth, development, and reproduction, a comparative phosphoproteomic study was conducted on the plerocercoid and adult stages of S. mansoni.MethodsIn this study, site-specific phosphoproteomic analysis was conducted via 4D label-free quantitative analysis technology to obtain primary information about the overall phosphorylation status of plerocercoids and adults.ResultsA total of 778 differentially abundant proteins (DAPs) were detected between adults and plerocercoids, of which 704 DAPs were upregulated and only 74 were downregulated. DAPs involved in metabolic activity were upregulated in plerocercoid larvae compared with adults, whereas DAPs associated with binding were upregulated in adults. Gene Ontology (GO) and Kyoto Encyclopedia of Genes (KEGG) analyses indicated that most DAPs involved in signal transduction and environmental information processing pathways were highly active in adults. DAPs upregulated in the plerocercoid group were enriched mainly in metabolic activities. The kinases PKACA, GSK3B, and smMLCK closely interact, suggesting potential active roles in the growth and development of S. mansoni.ConclusionsThe dataset presented in this study offers a valuable resource for forthcoming research on signaling pathways as well as new insights into functional studies on the molecular mechanisms of S. mansoni.Graphical abstract

Brassinosteroids enhance the tolerance, production, and fruit quality of covered table grape vines

ABSTRACT Plastic covering (PC) is used to speed up the ripening and harvesting of grapes while also shielding grapevines from unfavourable climatic conditions. This study aimed to determine how PC induced abiotic stress on covered vines and assess the role of brassinosteroids (Brs) in alleviating these impacts. The results showed that PC caused a substantial rise in soluble sugar, MDA, proline, total phenol, and antioxidant enzymes (catalase and ascorbate peroxidase) and decreased insoluble sugars and carbohydrates in ‘Superior' seedless grape leaves. Applying Brs at concentrations of 0, 1, 2, and 3 mg/l twice during the berry development stages (pea and veraison) enhanced the plants’ ability to withstand PC-induced stress. The concentration of 3 mg/l Brs elevated some metabolic activities, including insoluble sugar, total carbohydrates, proline, and total phenol. Additionally, it increased the antioxidant enzyme activity. Meanwhile, 2 mg/l appeared to be the most effective concentration in achieving the highest cluster and berry weight, enhanced total soluble solids (TSS) and firmness, and reduced weight loss over shelf life. In conclusion, applying Brs could be a promising strategy to alleviate the adverse effect of abiotic stress on table grapes.

Inhibitory Effects of Lactobionic Acid on Biofilm Formation and Virulence of Staphylococcus aureus.

Staphylococcus aureus biofilm is a common bio-contaminant source that leads to food cross-contamination and foodborne disease outbreaks. Hence, there is a need for searching novel antibiofilm agents with potential anti-virulence properties to control S. aureus contamination and infections in food systems. In this study, the antibiofilm effects of lactobionic acid (LBA) against S. aureus and its influence on virulence were explored. The minimum inhibition concentration of LBA on S. aureus was 8 mg/mL. Viable count and crystal violet assays revealed that LBA inhibited and inactivated S. aureus biofilms. Microscopic observations further confirmed the antibiofilm activity of LBA on S. aureus that disrupted the biofilm architecture and inactivated the viable cells in biofilms. Moreover, LBA decreased the release of extracellular DNA (eDNA) and extracellular polysaccharide (EPS) in S. aureus biofilms. LBA suppressed biofilm formation by intervening metabolic activity and reduced virulence secretion by repressing the hemolytic activity of S. aureus. Furthermore, LBA altered the expressions of biofilm- and virulence-related genes in S. aureus, further confirming that LBA suppressed biofilm formation and reduced the virulence secretion of S. aureus. The results suggest that LBA might be useful in preventing and controlling biofilm formation and the virulence of S. aureus to ensure food safety.

Antibacterial Activity of Novel Agent N-2-Hydroxypropyl Trimethyl Ammonium Chloride Chitosan against Streptococcus mutans.

Dental caries (DC) is one of the most common oral diseases and is mainly caused by Streptococcus mutans (S. mutans). The use of antibiotics against S. mutans usually has side effects, including developing resistance. N-2-Hydroxypropyl trimethyl ammonium chloride chitosan (N-2-HACC), a natural product, has great potential utility in antibacterial agents owing to its low toxicity and good biocompatibility. Thus, the purpose of the present study was to explore the antimicrobial activity of N-2-HACC against S. mutans through the permeability of the cell wall, integrity of cell membrane, protein and nucleic acid synthesis, respiratory metabolism, and biofilm formation. Our results confirmed that the MIC of N-2-HACC against S. mutans was 0.625 mg/mL with a 90.01 ± 1.54% inhibition rate. SEM observed the formation of cavities on the surface of S. mutans after 12 h N-2-HACC treatment. The level of alkaline phosphatase (AKP) activity was higher in the N-2-HACC treatment group than in the control group, indicating that N-2-HACC can improve the permeability of the cell wall. Also, N-2-HACC treatment can destroy the cell membrane of S. mutans by increasing conductivity and absorbance at 260 nm, decreasing cell metabolic activity, and enhancing the fluorescence at 488 nm. Respiratory metabolism revealed that the activities of the Na+-K+-ATP enzyme, pyruvate kinase (PK), succinate dehydrogenase (SDH), and malate dehydrogenase (MDH) were decreased after N-2-HACC treatment, revealing that N-2-HACC can inhibit glycolysis and the tricarboxylic acid cycle (TCA cycle) of S. mutans. Moreover, N-2-HACC can also decrease the contents of the nucleic acid and solution protein of S. mutans, interfere with biofilm formation, and decrease the mRNA expression level of biofilm formation-related genes. Therefore, these results verify that N-2-HACC has strong antibacterial activity against S. mutans, acting via cell membrane integrity damage, increasing the permeability of cell walls, interfering with bacterial protein and nucleic acid synthesis, perturbing glycolysis and the TCA cycle, and inhibiting biofilm formation. It is suggested that N-2-HACC may represent a new potential synthetically modified antibacterial material against S. mutans.

Z-Spectral MRI Quantifies the Mass and Metabolic Activity of Adipose Tissues With Fat-Water-Fraction and Amide-Proton-Transfer Contrasts.

Brown adipose tissue (BAT) is metabolically activatable and plays an important role in obesity and metabolic diseases. With reduced fat-water-fraction (FWF) compared with white adipose tissue (WAT), BAT mass and its functional activation may be quantified with Z-spectra MRI, with built-in FWF and the metabolic amide proton transfer (APT) contrasts. To investigate if Z-spectral MRI can quantify the mass and metabolic activity of adipose tissues. Prospective. Seven groups of 8-week-old male rats, including two groups (n = 7 per group) for in vivo MRI study and five groups (n = 5 per group) for ex vivo validation; 12 young and healthy volunteers with 6 male and 6 female. The 7 T small animal and 3 T clinical systems, T2-weighted imaging, Rapid Acquisition with Relaxation Enhancement (RARE) readout based chemical exchange saturation transfer (CEST) Z-spectral MRI sequence. Quantified FWF and APT from Z-spectra in rats before and after norepinephrine (NE) stimulation and in healthy human subjects; ex vivo measurements of total proteins in BAT from rats. Two-tailed unpaired Student's t-tests and repeated measures ANOVA. P-value <0.05 was considered significant. Decreased FWF (from 39.6% ± 7.2% before NE injection to 16.4% ± 7.2% 120 minutes after NE injection, P < 0.0001) and elevated APT (from 1.1% ± 0.5% before NE injection to 2.9% ± 0.5% 120 minutes after NE injection, P < 0.0001) signals in BAT were observed with in vivo Z-spectral MRI in rats injected with NE at 7 T MRI. At clinical 3 T, Z-spectral MRI was used to quantify the FWF (58.5% ± 7.2% in BAT and 73.7% ± 6.5% in WAT with P < 0.0001) and APT (2.6% ± 0.8% in BAT and 0.9% ± 0.3% in WAT with P < 0.0001) signals in healthy volunteers. APT signals of BAT were negatively correlated with the BMI in humans (r = 0.71). Endogenous Z-spectral MRI was demonstrated to simultaneously quantify BAT mass and function based on its FWF and APT contrasts. 1.

The Role of Amide Proton Transfer (APT)-Weighted Imaging in Glioma: Assessment of Tumor Grading, Molecular Profile and Survival in Different Tumor Components.

Amide Proton Transfer-weighted (APTw) imaging is a molecular MRI technique used to quantify protein concentrations in gliomas, which have heterogeneous components with varying cellularity and metabolic activity. This study aimed to assess the correlation between the component-specific APT signal of the neoplasm and WHO grade, molecular profile and survival status. Sixty-one patients with adult-type diffuse gliomas were retrospectively analyzed. APT values were semi-automatically extracted from tumor solid and, whenever present, necrotic components. APT values were compared between groups stratified by WHO grade, IDH-mutation, MGMT promoter methylation and 1- and 2-year survival status using Wilcoxon rank-sum test, adjusting for multiple comparisons. Overall survival (OS) was analyzed in the subgroup of 48 patients with grade 4 tumors using Cox proportional-hazards models. Random-effects models were used to assess inter-subject heterogeneity of the mean APT values in each tumor component. APT values of the solid component significantly differed between patients with grades 2-3 and 4 tumors (mean 1.58 ± 0.50 vs. 2.04 ± 0.56, p = 0.028) and correlated with OS after 1 year (1.81 ± 0.58 in survivors vs. 2.17 ± 0.51 in deceased patients, p = 0.030). APT values did not differ by IDH-mutation, MGMT methylation, and 2-year survival status. Within grade 4 glioma patients, higher APT kurtosis of the solid component was a negative prognostic factor (hazard ratio = 1.60, p = 0.040). Mean APT values of the necrosis showed high inter-subject variability, although most necrotic tumors were grade 4 and IDH wildtype. In conclusion, APTw imaging in the solid component provided metrics associated with glioma grade and survival status but showed weak correlation with IDH-mutation and MGMT promoter methylation status, in contrast to previous works. Further research is needed to understand APT signal variability within the necrotic component of high-grade gliomas.

Neural acetylcholinesterase and monoamine oxidase deregulation during streptozotocin-induced behavioral, metabolic and redox modification in Nauphoeta cinerea.

Genetic and environmental factors have been linked with neurodegeneration, especially in the elderly. Yet, efforts to impede neurodegenerative processes have at best addressed symptoms instead of underlying pathologies. The gap in the understanding of neuro-behavioral plasticity is consistent from insects to mammals, and cockroaches have been proven to be effective models for studying the toxicity mechanisms of various chemicals. We therefore used head injection of 74 and 740 nmol STZ in Nauphoeta cinerea to elucidate the mechanisms of chemical-induced neurotoxicity, as STZ is known to cross the blood-brain barrier. Neurolocomotor assessment was carried out in a new environment, while head homogenate was used to estimate metabolic, neurotransmitter and redox activities, followed by RT-qPCR validation of relevant cellular signaling. STZ treatment reduced the distance and maximum speed travelled by cockroaches, and increased glucose levels while reducing triglyceride levels in neural tissues. The activity of neurotransmitter regulators - AChE and MAO was exacerbated, with concurrent upregulation of glucose sensing and signaling, and increased mRNA levels of redox regulators and inflammation-related genes. Consequently, STZ neurotoxicity is conserved in insects, with possible implications for using N. cinerea to target the multi-faceted mechanisms of neurodegeneration and test potential anti-neurodegenerative agents.

Acidity induces durable enhancement of Treg cell suppressive functions for tumor immune evasion

The microenvironment within solid tumors often becomes acidic due to various factors associated with abnormal metabolism and cellular activities, including increased lactate production as a result of dysregulated tumor glycolysis. Recently, we have identified multiple tumor microenvironment (TME) factors that potentiate regulatory T (Treg) cell function in evading anti-tumor immunosurveillance. Despite the strong correlation between lactate and acidity, the potential roles of acidity in intratumoral Treg cell adaptation and underlying molecular mechanisms have gone largely unstudied. In this study, we demonstrate that acidity significantly enhances immunosuppressive functions of nTreg cells, but not iTreg cells, without altering the expression of either FoxP3 or the cell surface receptors CD25, CTLA4, or GITR in these cells. Surprisingly, the addition of lactate, often considered a major contributor to increased acidity of the TME, completely abolished the acidity-induced enhancement of nTreg suppressive functions. Consistently, metabolic flux analyses showed elevated basal mitochondrial respiratory capacity and ATP-coupled respiration in acidity-treated nTreg cells without altering glycolytic capacity. Genome-wide transcriptome and metabolomics analyses revealed alterations in multiple metabolic pathways, particularly the one-carbon folate metabolism pathway, with reduced SAM, folate, and glutathione, in nTreg cells exposed to low pH conditions. Addition of a one-carbon metabolic contributor, formate, diminished the acidity-induced enhancement in nTreg cell suppressive functions, but neither SAM nor glutathione could reverse the phenotype. Remarkably, in vitro transient treatment of nTreg cells resulted in sustained enhancement of their functions, as evidenced by more vigorous tumor growth observed in mice adoptively receiving acidity-treated nTreg cells. Further analysis of intratumoral infiltrated T cells confirmed a significant reduction in CD8+ T cell frequency and their granzyme B production. In summary, our study elucidates how acidity-mediated metabolic reprogramming leads to sustained Treg-mediated tumor immune evasion.