Metabolic Characteristics Research Articles

Uncovering the features of rhodium metabolism in China during 2011–2022

Rhodium has unique properties, such as high-temperature oxidation resistance and catalytic activity, making it irreplaceable in various domains such as automobile exhaust purification and chemical production. Given its pivotal role in facilitating China's green and low-carbon transition and the advancement of high-tech industries, rhodium has become a strategic resource. However, China heavily relies on importing rhodium to meet its domestic demand due to its limited rhodium reserve. This study employs dynamic material flow analysis (DMFA) to trace the rhodium flows throughout its entire life cycle in China for the period of 2011–2022 so that the key features of rhodium metabolism can be uncovered, including rhodium production, consumption, trade, in-use stock, and recycling. Our results show that the domestic demand for rhodium increased by 2.18 times during this study period. The cumulative rhodium consumption reached 82,890 kg, of which automobile three-way catalysts (TWCs) accounted for 71.85% of the total rhodium consumption, followed by the chemical sector (13.64%) and the glass sector (8.95%). China's accumulative imported rhodium reached 77,447 kg, meaning an import reliance rate (IRR) of 91.81%. The total recycled rhodium reached 21,184 kg, meaning a recycling rate (RR) of 58.63%. These findings reflect that China is facing several challenges in achieving sustainable rhodium resource management, such as a significant supply risk, and inadequate recycling. Consequently, China should establish a comprehensive rhodium recycling system and diversify its rhodium supply both domestically and internationally to ensure the sustainable supply of rhodium resources.

Production of polyhydroxybutyrate with photosynthetic bacteria treating artificial kitchen waste: Effect of light intensity

Kitchen waste can be used as a cheap carbon source for photosynthetic bacteria (PSB) to produce polyhydroxybutyrate (PHB). Light intensity is one of the most important factors in PSB growth. This paper investigated the efficiency and mechanism of PSB growth and PHB production from fermented kitchen waste under different light intensities. Results showed that PSB could grow well and produce PHB within the light intensity range of 1000-4000 lux using fermented kitchen waste as substrate. The 2000 lux was the optimal for PHB production, and PHB content and concentration reached 41.6% dry cell weight and 675.3mg/L, respectively, much higher than other light intensities. The corresponding PHB yield and productivity were 0.33g PHB/g chemical oxygen demand (COD) and 51.9mg/L/d, respectively. Removal of COD and NH4+ were 89.6% and 44.7%, respectively. Microbial community analysis showed that diversity and richness of bacterial community increased with time, and Rhodopseudomona and unclassified_f_Enterobacteriaceae were the dominant bacterial genera at the 2000 lux. Metabolic characteristics in fatty acid degradation, tricarboxylic acid cycle, pyruvate metabolism, photosynthesis, and pyruvate metabolism increased at the 2000 lux. Also, the key enzyme (PhaC, butyryl-CoA dehydrogenase, etc.) for synthesizing PHB was highly expressed, which corresponded to the large amount of PHB accumulation. This study provides a theoretical reference for treatment of kitchen waste with PSB for PHB production.

Metabolic pathways, pharmacokinetic, and brain neurochemicals effects of capsaicin: Comprehensively insights from in vivo studies

BackgroundCapsaicin (CAP), a prominent component of chili pepper known for its potent agonistic effects on TRPV1, has attracted significant attention for its diverse physiological effects. Nevertheless, there remains a paucity of data concerning its in vivo distribution, metabolism, pharmacodynamic properties, and influence on the metabolic profile of the brain. MethodsStable isotope tracing, in vitro enzyme incubation, microdialysis coupled with UHPLC-MS/MS techniques were employed to investigate the in vivo metabolic pathways, distribution, and pharmacokinetic properties of CAP, and the potential biases in metabolic pathways was elucidate through molecular docking. Furthermore, the effect of CAP on brain metabolic profiles was assessed using untargeted metabolomics, and spatial visualization analysis was conducted through mass spectrometry imaging. ResultsCAP was distributed predominantly in the kidneys, with lower content in the liver, heart, lungs, brain, and spleen following peripheral administration, and the absorption half-life in the body was about 20 minutes. CAP primarily underwent alkyl terminal dehydrogenation, hydroxylation, and macrocyclization metabolic pathways under the action of CYP2C9, CYP2C19 and CYP2D6, resulting in at least four metabolites. Among them, the hydroxylation products were main metabolites and the dehydrogenation product 16,17-dihydrocapsaicin could interact with the key binding sites Leu515 and Thr550 of TRPV1 like CAP. CAP quickly diffused to various brain regions and the metabolic characteristics in the striatum were relatively different from that in the blood. The distribution of CAP in the brain primarily triggered the release of neurotransmitters in areas associated with reward, cognition, and memory. Both acute and chronic exposure to CAP elevated amino acid levels in cortical regions, while producing contrasting effects on nucleotide metabolites. ConclusionThis study offers an initial in-depth analysis of the distribution patterns, metabolic pathways and pharmacodynamic properties of CAP in the body and brain. These findings established a basis for further studies on CAP's pharmacology properties and its influence on the central nervous system.

Assessment of protective effect of Vitamin E supplementation on oxidative damage of diabetic rat spleen induced by Streptozotocin

AimsIncreased oxidative stress in diabetes mellitus may lead to splenic damage, contributing to decreased immunity. This study aims to evaluate the potential of vitamin E supplements as a protective agent against spleen injury by examining physiological, hematological, biochemical, and histological changes in diabetic rat model. MethodsDiabetes was induced in male wistar albino rats through an intraperitoneal injection of 50mg/kg Streptozotocin, and the rats were randomly divided into five groups. The rats were then administered varying doses of vitamin E for 14 consecutive days. Assessments included renal function tests, blood glucose levels, complete blood counts, lipid profiles, tissue oxidative stress and spleen histology. An acute toxicity study was also conducted on normal rats. ResultsVitamin E supplementation did not result in any mortality up to 5000mg/kg body weight. The treated diabetic group showed improved metabolic characteristics, such as normal body weight, food and water intake and a reduced spleen index compared to the untreated diabetic group. Significant improvements were observed in hematological parameters like packed cell volume (PCV), hemoglobin concentration, RBC (red blood cells) and WBC (white blood cells) counts. HCA (Hierarchical Cluster Analysis) of these parameters indicated that doses of 100mg/kg and 150mg/kg were most similar to normal condition. Catalase and MDA (Malondialdehyde) assays showed a substantial reduction in oxidative stress in spleen tissue and histopathological examination revealed significant regenerative effects. ConclusionThis study demonstrated that vitamin E supplementation significantly enhanced various metabolic, hematological, biochemical, and histological parameters in the diabetic group compared to those who did not receive the treatment. Among the doses tested, 100mg/kg and 150mg/kg body weight were found to yield the most favorable outcomes.

Radioiodinated Nanobody immunoPET probe for in vivo detection of CD147 in pan-cancer.

To develop the extracellular matrix metalloproteinase inducer (CD147)-targeting therapeutic strategies, accurate detection of CD147 expression in tumors is crucial. Owing to their relatively low molecular weights and high affinities, nanobodies (Nbs) may be powerful candidates for cancer diagnosis and therapy. In this study, we developed a novel CD147-targeted nanobody radiotracer, [124I]I-NB147, which provides guidance for the noninvasive detection of CD147-overexpressing cancers. CD147 expression in human cancers was detected via immunohistochemistry (IHC) on tissue microarrays (TMAs). Western blot (WB) and flow cytometry were used to screen CD147-positive malignant melanoma (MM), triple-negative breast cancer (TNBC), and pancreatic cancer (PCA) cell lines. The CD147 nanobody (NB147) was labeled with [124I]INa using Iodogen as the oxidizing agent and was purified by the PD-10 column. The physicochemical properties, affinity, metabolic characteristics, biodistribution, and immunoPET imaging of [124I]I-NB147 were evaluated Moreover, [18F]F-FDG was used as a control. Finally, CD147 expression analysis was performed via multiplex immunofluorescence (MxIF) and autoradiography on human cancer specimens and tumor-bearing mice tissues. TMAs results revealed that CD147 is highly expressed in MM, TNBC, and PCA. A CD147-specific nanobody, NB147, was successfully generated with excellent in vitro binding characteristics. [124I]I-NB147 was obtained with high radiochemical yield and purity, and was stable for at least 4h in vitro. WB and FCM revealed that CD147 was positive in A375, MDA-MB-435 and ASPC1 cells, whereas SK-MEL-28, 4T1 and BXPC3 cells presented low expression levels. The radio-ELISA results indicated that [124I]I-NB147 had a high binding affinity to CD147. The uptake of [124I]I-NB147 was significantly different between CD147 high-expression cells and CD147 low-expression cells (P < 0.001). The biological half-life of the distribution and clearance phases were 0.05h and 1.58h, respectively. In CD147-positive tumor models, the [124I]I-NB147 accumulated in A375, MDA-MB-435, and ASPC1 tumors, and the uptake value was significantly higher than that of [18F]F-FDG. Uptake in SK-MEL-28, BXPC3, and 4T1 tumors was not clearly observed. Finally, through autoradiography and histological studies, the correlation analysis between tumor uptake and CD147 expression level was determined. The high expression of CD147 in MM, TNBC, and PCA tissuesand in tumor cells was verified. The CD147 nanobody, NB147 was produced and radiolabeled to obtain the immunoPET probe, [124I]I-NB147, which showed high affinity to CD147 and precise visualization for accurate diagnosis of CD147-expressing lesions in different cancers. These results provide insight into the imaging and binding properties of nanobody NB147 over extended periods of time, reinforcing its potential in developing radionuclide therapies for CD147-positive cancer patients.

Exploring the impact of mitochondrial-targeting anthelmintic agents with GLUT1 inhibitor BAY-876 on breast cancer cell metabolism.

Cancer cells alter their metabolic phenotypes with nutritional change. Single agent approaches targeting mitochondrial metabolism in cancer have failed due to either dose limiting off target toxicities, or lack of significant efficacy in vivo. To mitigate these clinical challenges, we investigated the potential utility of repurposing FDA approved mitochondrial targeting anthelmintic agents, niclosamide, IMD-0354 and pyrvinium pamoate, to be combined with GLUT1 inhibitor BAY-876 to enhance the inhibitory capacity of the major metabolic phenotypes exhibited by tumors. To test this, we used breast cancer cell lines MDA-MB-231 and 4T1 which exhibit differing basal metabolic rates of glycolysis and mitochondrial respiration, respectively. Metabolic characterization was carried out using Seahorse XFe96 Bioanalyzer and statistical analysis was carried out via ANOVA. Here, we found that specific responses to mitochondrial and glycolysis targeting agents elicit responses that correlate with tested cell lines basal metabolic rates and fuel preference, highlighting the potential to cater metabolism targeting treatment regimens based on specific tumor nutrient handling. Inhibition of GLUT1 with BAY-876 potently inhibited glycolysis in both MDA-MB-231 and 4T1 cells, and niclosamide and pyrvinium pamoate perturbed mitochondrial respiration that resulted in potent compensatory glycolysis in the cell lines tested. In this regard, combination of BAY-876 with both mitochondrial targeting agents resulted in inhibition of compensatory glycolysis and subsequent metabolic crisis. These studies highlight targeting tumor metabolism as a combination treatment regimen that can be tailored by basal and compensatory metabolic phenotypes.

Acute tear versus chronic-degenerated rotator cuff pathologies are associated with divergent tendon metabolite profiles

ABSTRACT Purpose/Aim Metabolic disorders are risk factors for rotator cuff injuries, which suggests that the rotator cuff is sensitive to local metabolic fluctuations. However, the link between the metabolic microenvironment and pathologic features of acute tear versus chronic degeneration is currently unknown. The overarching goal of this study was to evaluate alterations in tendon metabolite profiles following acute tear or chronic degeneration of the rotator cuff. We hypothesized that injury types (acute tear vs. chronic degeneration) would result in distinct metabolite profiles relative to clinically unaffected tendon controls. Materials and Methods We utilized untargeted metabolomics to identify pathways that were altered at the time of rotator cuff repair (RCR; acute tear) or reverse total shoulder arthroplasty (rTSA; chronic degeneration) relative to total shoulder arthroplasty controls (TSA; tendon clinically unaffected). Results Acute tears to the rotator cuff were associated with an overall decrease in tendon metabolites. This global decrease was primarily associated with glycolic acid and decreased tricarboxylic acid (TCA) cycle activity. Conversely, chronic tendon specimens from patients undergoing rTSA showed an overall increase in metabolites. Most notably, chronic injury was associated with increased levels of multiple amino acids including alanine, aspartate, lysine, and proline. Conclusions Overall, this study demonstrates that distinct metabolite profiles are associated with injury types, and that therapeutic strategies should address both cellular and matrix components regardless of injury induction. The specific pathways identified paired with validated, established, treatment methods may serve as novel therapeutic targets for patients who suffer from rotator cuff injuries.

A Comparative Metabolomics Study of the Potential Marker Compounds in Feces from Different Hybrid Offspring of Huainan Pigs

As a notable native Chinese genetic population, the Huainan pig has an exceptional meat quality but a low percentage of lean meat and subpar genetic performance. To better exploit the superior genetic traits of the Huainan pig and address knowledge gaps regarding the optimization of its hybrid offspring, this study used Huainan pigs as the maternal line and bred them with Yorkshire, Landrace, and Berkshire sires. This approach produced three hybrid combinations: Yorkshire × Huainan (YH), Landrace × Huainan (LH), and Berkshire × Huainan (BH). The body size, fat ratio, and average backfat thickness of these hybrid progeny were evaluated under the same feeding management and nutritional circumstances. The results revealed that the average backfat thickness of YH was significantly lower than that of LH and BH. In order to better understand the causes of these variations, fecal samples were taken from three pigs in each group for metabolomic analysis. A total of 2291 metabolites were identified, including benzene derivatives (16.6%), amino acids and their metabolites (14.5%), and organic acids (13.4%), with pyruvaldehyde and norethindrone acetate elevated in YH compared to LH and BH. In addition, the three hybrid pig groups commonly exhibited differences in the “glycerophospholipid metabolism” pathway. This variation may also contribute to differences in their fat ratio and backfat thickness. Our findings provide a novel perspective on the role of hybrid vigor in advancing the genetic population of Huainan pigs, while also revealing the unique metabolic characteristics of the YH with regard to fat deposition. This study is expected to enhance the conservation and effective utilization of genetic resources within the Huainan pig population.

Correlation between glucose metabolism and body mass index in tumor lesions of patients with lung cancer.

Lung cancer, along with various other cancers, is characterized by increased glucose metabolism. The maximum standardized uptake value (SUVmax), derived from positron emission tomography-computed tomography (PET-CT), serves as an indicator of glucose metabolic activity in tumor lesions. This study aimed to evaluate the correlation between body mass index (BMI) and SUVmax in individuals with lung cancer. This study included 41 patients with lung cancer, who were divided into two groups: Group 1 (n = 21), with a BMI greater than 22.4, and Group 2 (n = 20), with a BMI less than 22.4. All participants underwent 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET-CT) imaging. The SUVmax was calculated by manually delineating the regions of interest. A t-test was performed to assess whether the differences in SUVmax between the two groups were statistically significant. The mean SUVmax for Group 1 was 11.20 ± 5.45, while for Group 2 it was 10.65 ± 5.96. Although the mean SUVmax was higher in Group 1 compared to Group 2, the difference between the groups was not statistically significant (P = 0.757). The findings indicate a non-significant difference in glucose metabolism in lung cancer lesions between patients with different BMI levels. These results offer valuable insights into the metabolic characteristics of lung cancer and contribute to a deeper understanding of its pathophysiology.

Herbal formula xuling-jiangu improves bone metabolic balance in rats with ovariectomy-induced osteoporosis via the gut-bone axis

IntroductionThe XuLing JianGu recipe (XLJGR) is an empirical traditional Chinese medicine formula used for the treatment of osteoporosis. This study aims to explore the effects of XLJGR on the intestinal microbiota composition and endogenous metabolites in ovariectomized (OVX) rats.MethodsAn OVX rat model was established to evaluate the intervention effects of XLJGR. The measured indicators included bone density, serum bone metabolism markers, and an analysis of the types and abundances of intestinal microbiota, along with changes in endogenous metabolites. Additionally, MC3T3-E1 cells were used to validate the differential metabolites.ResultsXLJGR significantly reduced the abundance of Bacteroides, Butyricicoccus, and other bacterial strains in the gut. KEGG metabolic pathway enrichment analysis showed that XLJGR intervention led to notable changes in pathways such as peptidoglycan biosynthesis, carbapenem biosynthesis, and vancomycin resistance. Moreover, XLJGR significantly upregulated key intestinal microbiota metabolites, including gabapentin(GAB), camphoric acid(CAA), and nonanedioic acid(AZA), thereby promoting the proliferation and osteogenic differentiation of MC3T3-E1 cells.DiscussionThis study highlights the potential biomedical applications of XLJGR in promoting bone health by positively affecting intestinal microbiota and metabolic characteristics. These findings suggest that XLJGR may serve as a viable alternative in the treatment of osteoporosis, warranting further exploration of its therapeutic mechanisms and clinical applications.

GlutaR: AHigh-Performance Fluorescent Protein-Based Sensor for Spatiotemporal Monitoring of Glutamine Dynamics In Vivo.

Glutamine is the most abundant amino acid in human blood and muscle, and is integral to a wide variety of functions in cancer cells. However, the inability to monitor the subcellular distribution of glutamine in real-time has obscured understanding of glutamine metabolism under physiological and pathological conditions. Here, we report the development of a genetically encoded fluorescent sensor and demonstrate how this GlnBP-cpYFP fusion "GlutaR sensor" undergoes glutamine-induced conformational changes reflected in detectable fluorescence responses. Obtained after iterative screening of approximately 1,600 variants, GlutaR exhibits a ratiometric readout, fast response kinetics, and high responsivity, and we demonstrate its selectivity for monitoring glutamine fluctuations in multiple cell types. Additionally, using digitonin permeabilization of GlutaR HeLa cells, we generated a calibration curve and performedin situtitration to quantify free glutamine concentrations in subcellular compartments (cytosol, nucleus, mitochondria). Subsequently, we applied GlutaR to investigate how chemical and genetic inhibition of GS and GLS differentially alter glutamine levels in subcellular compartments. Finally, we demonstrate GlutaR's ability to monitor dynamic glutamine levels in muscle and liver tissues of diabetic micein vivo.These findings collectively demonstrate GlutaR as a versatile tool for the spatiotemporal characterization of glutamine metabolism in living cells and tissues.

Abstract PR001: The CTC RPL/RPS gene signature: Targeting translation and the cell cycle inversely affects CTC metabolism but not metastasis

Abstract Melanoma brain metastasis (MBM) is the most devastating consequence of melanoma, is increasing in frequency, and is linked to poor prognosis and dismal survival. By employing an unbiased, multipronged approach, we discovered a CTC gene signature for ribosomal protein large/small subunits (RPL/RPS) which associated with MBM onset and progression. Experimental strategies involved capturing, transcriptional profiling, and interrogating CTCs, either directly isolated from blood of melanoma patients at distinct stages of progression, from CTC-driven MBM in experimental animals, or by developing/applying the first MRI CTC- derived MBM xenograft model (MRI-MBM CDX) to discriminate MBM spatial and temporal growth, thus faithfully recreating its clinical presentation. Accordingly, we hypothesized that targeting CTC ribogenesis can prevent melanoma metastasis in general, MBM in particular. We treated CDX cohorts with FDA-approved protein translation inhibitor omacetaxine in the presence or absence of CDK4/CDK6 inhibitor palbociclib, and monitored metastatic development and cell proliferation. Necropsies and IVIS imaging showed decreased MBM/extracranial metastasis in drug-treated mice, and RNA-Seq on mouse-blood-derived CTCs revealed downregulation of four RPL/RPS genes of the CTC signature. Notably, by performing the first-ever functional metabolic characterization of circulating neoplastic cells/CTCs in real- time, coupled with confirmatory RT-qPCR, we found that omacetaxine and palbociclib inversely affected glycolytic metabolism, and demonstrated that dual targeting of cell translation and proliferation is critical to suppress plasticity in metastasis-competent CTCs. This study identifies the relevance of targeting the CTC RPL/RPS signature to suppress melanoma metastasis, and set forward notions for novel therapies to affect metastasis by the deregulation of translation controlling CTC states. Studies involving structural and mechanistic analyses of CTC dormant vs active ribosomes by cryogenic electron microscopy are in progress. Citation Format: Dario Marchetti. The CTC RPL/RPS gene signature: Targeting translation and the cell cycle inversely affects CTC metabolism but not metastasis [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr PR001.

Swill and Pig Manure Substrates Differentially Affected Transcriptome and Metabolome of the Black Soldier Fly Larvae

Black soldier fly larvae (Hermetia illucens) (BSFL) are insect larvae with significant ecological and economic value. This study aims to investigate whether swill and manure had any effects on the transcriptome and metabolome of BSFL. Through high-throughput transcriptome sequencing, we found that larvae fed with swill exhibited higher levels of gene expression, especially with the upregulation of genes related to energy metabolism, amino acid metabolism, and redox reactions. Metabolomics analysis showed a significant increase in energy metabolism-related metabolites, such as organic acids and amino acids, in the swill-fed larvae. In contrast, gene expression and metabolic characteristics in the pig manure-fed group indicated a higher stress response, with relevant genes and metabolites (such as short-chain fatty acids and antioxidants) showing significant upregulation. GO and KEGG enrichment analyses further supported these results, suggesting that swill promotes larval growth and metabolism, whereas pig manure induces the activation of stress response mechanisms. These findings offer clear molecular and physiological insights into the optimization of substrate selection for enhancing the performance of BSFL in waste management.

Gut microbiota and metabolic profiles in adults with unclassified diabetes: a cross-sectional study

AimsOur study, employing a multi-omics approach, aimed to delineate the distinct gut microbiota and metabolic characteristics in individuals under 30 with unclassified diabetes, thus shedding light on the underlying pathophysiological mechanismsMethodsThis age- and sex-matched case-control study involved 18 patients with unclassified diabetes, 18 patients with classic type 1 diabetes, 13 patients with type 2 diabetes, and 18 healthy individuals. Metagenomics facilitated the profiling of the gut microbiota, while untargeted liquid chromatography-mass spectrometry was used to quantify the serum lipids and metabolites.ResultsOur findings revealed a unique gut microbiota composition in unclassified diabetes patients, marked by a depletion of Butyrivibrio proteoclasticus and Clostridium and an increase in Ruminococcus torques and Lachnospiraceae bacterium 8_1_57FAA. Comparative analysis identified the combined marker panel of five bacterial species, seven serum biomarkers, and three clinical parameters could differentiate patients with UDM from HCs with an AUC of 0.94 (95% CI 0.85–1). Notably, the gut microbiota structure of patients with unclassified diabetes resembled that of type 2 diabetes patients, especially regarding disrupted lipid and branched-chain amino acid metabolism.ConclusionsDespite sharing certain metabolic features with type 2 diabetes, unclassified diabetes presents unique features. The distinct microbiota and metabolites in unclassified diabetes patients suggest a significant role in modulating glucose, lipid, and amino acid metabolism, potentially influencing disease progression. Further longitudinal studies are essential to explore therapeutic strategies targeting the gut microbiota and metabolites to modify the disease trajectory.

NIMG-69. INTERROGATION OF GLIOBLASTOMA FATTY-ACID SYNTHESIS AND METABOLISM WITH DEUTERIUM METABOLIC IMAGING

Abstract Glioblastoma, an invariably lethal brain tumor, undergoes marked metabolic alterations during tumorigenesis and is extraordinarily difficult to treat. Detecting recurrence after treatment and understanding metabolic alterations within the tumor microenvironment are extremely challenging. An exciting and emerging imaging methodology, deuterium metabolic imaging (DMI), detects metabolic adaptations via non-radioactively labeled deuterated substrates. This study developed approaches to image lipid synthesis with deuterium oxide (D2O) and metabolism with D31-palmitate (D31-Pal) in glioblastoma. A fatty-acid phantom was generated for characterization of lipid DMI signal at 12 T. DMI was performed in mice orthotopically implanted with GL261 glioblastoma utilizing either orally administered D31-Pal or D2O and was correlated with pharmacokinetic metabolic measurements from mouse serum. Mice were either orally gavaged with an emulsion of D31-Pal prior to imaging or provided 16% D2O for ad libitum consumption following tumor implantation. Although D2O administration resulted in robust enrichment of lipid signal in GBM, D31-Pal uptake and metabolism were not significantly detected within intracranial tumors. Interestingly, D31-Pal uptake and metabolism were detected in normal tissues, indicating preferential utilization of fatty acids in non-neoplastic tissues. These findings suggest de novo lipogenesis within GBM, rather than uptake of administered long chain fatty acids, is the preferential pathway for cellular lipids. DMI can assist in interrogating GBM fatty-acid synthesis and metabolism, as well as furthering our understanding of lipid distribution within the body by providing a non-invasive scaffold for dynamic interrogation of fatty-acid distribution in an oncologic model. Developing a non-invasive method for characterization of tumor fatty-acid synthesis and metabolism may improve our understanding of tumor metabolism and could dynamically guide selection of patient-tailored metabolic therapies in the future.

Women With Polycystic Ovary Syndrome and Excess Body Fat Exhibit Atypical Sympathetic Autonomic Modulation That is Partially Reversed by Aerobic Physical Training.

The aetiology of impairments in autonomic modulation of heart rate variability (HRV) in polycystic ovary syndrome (PCOS) remains unclear, as does the impact of aerobic physical training (APT) on controlling endocrine-metabolic disorders and HRV. This is because these women often present excess body fat. Therefore, we assessed whether the dysregulation in autonomic modulation of HRV in women with PCOS is due to endocrine-metabolic disorders and whether the combination of excess body fat with endocrine-metabolic disorders amplifies cardiovascular autonomic deficits. We also investigated whether APT positively influences autonomic modulation of HRV in PCOS. Non-randomised clinical trial. Women with and without PCOS with different percentages of body fat. Participants were divided into four groups: women without PCOS with a body fat percentage between 22% and 29% (CONTROL group; 22%-29%); CONTROL (30%-37%) group; PCOS (22%-29%) group; and PCOS (30%-37%) group. Hemodynamic, metabolic, and hormonal characteristics and HRV parameters were obtained before and after 16 weeks of APT. The PCOS (22%-29%) group exhibited lower vagal modulation than the CONTROL (22%-29%) group. In contrast, no significant differences were observed between the CONTROL (30%-37%) and PCOS (30%-37%) groups. Furthermore, the PCOS (30%-37%) group demonstrated lower sympathetic modulation than the PCOS (22%-29%) group. After APT, the PCOS (22%-29%) group increased in vagal modulation, while the PCOS (30%-37%) group increased in sympathetic modulation. PCOS affects vagal modulation; however, this effect may be masked at elevated levels of body fat. Additionally, the combination of excess body fat with endocrine-metabolic dysregulation appears to reduce sympathetic modulation, possibly due to sympathetic drive hyperactivity. APT positively affected HRV in both PCOS groups.

TMET-37. TARGETING LIPID MEDIATED NON-CANONICAL CELL DEATH IN MALIGNANT GLIOMA

Abstract Resistance to canonical cell death mechanisms (e.g. apoptosis) is a hallmark of glioma and consequently driving the dismal outcomes of patients with glioma. Recent work has demonstrated gliomas are susceptible to non-apoptotic forms of cell death mediated by rewired lipid metabolism. Here we explored whether gliomas are vulnerable to other lipid-dependent forms of cell death. Our investigation revealed a large subset of patient-derived glioma cells that are exquisitely sensitive to a novel cell death pathway dependent on palmitate. Intriguingly, sensitivity to this type of cell death was linked to glioma tumor cells having a proneural identity and a specific enrichment in sphingolipid metabolic features. The catabolism of glioma sphingolipids established palmitate pools for protein S-palmitoylation, a necessary requirement to trigger palmitate mediated cell death in glioma, which was coupled to the exclusive expression of palmitoyl acyltransferases unique to proneural glioma tumors. Ongoing efforts aim to explore the mechanistic link between glioma identity, lipotype and susceptibility to palmitate dependent lethality. Taken together, these results identify a new approach to drive glioma cell death by targeting non-canonical cell death mediated by rewired glioma lipid metabolism.

Effects of Deficit Irrigation on Spring Wheat Lignification Process, Yield Productivity and Stalk Strength

Moderate deficit irrigation can improve lignin metabolism, thereby increasing wheat yield and lodging resistance. The moisture-sensitive variety Xinchun 22 (XC22) and drought-resistant variety Xinchun 6 (XC6) were used as experimental materials. We set mild drought (T1, J1 and 60–65% FC, where FC is the field capacity) and moderate drought (T2, J2 and 45–50% FC) during the tillering stage (T) and the jointing stage (J). We used conventional drip irrigation as a control (CK and 75–80% FC). The results show that the activity of lignin synthesis-related enzymes decreased with the growth process, while the accumulation and monomer content of lignin increased under different water treatments. The lignin metabolism and morphological characteristics of XC6 were higher than those of XC22. Under the same processing conditions, the indicators of XC22 showed more significant changes and were more sensitive to changes in the moisture content. Compared with other treatments, the stem thickness and wall thickness of the J1 treatment increased by 0.86–23.49% and 1.72–23.58%. The yield of the T1 treatment was the highest, increasing by 3.05–44.06% compared to other treatments. In addition, by improving PAL, H-type lignin monomers, S-type lignin monomers, stem thickness and lignin metabolism, grain yield can be increased. After mild drought during the jointing stage, J1 significantly improved the lignin metabolism capacity of the stem, increased stem thickness and wall thickness, and was beneficial for improving lodging resistance. The T1 treatment favored the improvement of the production capacity of assimilates, thus promoting a high yield of spring wheat.

The Metabolic Characteristics and Bioavailability of Resveratrol Based on Metabolic Enzymes.

The natural polyphenol resveratrol (RV) has garnered fame for its extensive pharmacological properties. Although clinical studies have shown some positive results, many contradictory outcomes remain. An important obstacle to the development of therapeutic applications for RV is its low bioavailability in vivo. This may be partially attributed to biotransformation mediated by phase I and II enzymes, such as cytochrome P450s, UDP-glucuronosyltransferases, and sulfotransferases. To date, more than 20 different types of metabolites have been detected after catalysis by these enzymes. Notably, RV and some of its metabolites serve as substrates for these enzymes. Conversely, RV can directly regulate the expression or activity of these enzymes. Given the increasing number of studies investigating the bioactivity of RV, this review summarizes its physicochemical and pharmacokinetic characteristics and describes the metabolism of RV and the bioactivities of its metabolites, with emphasis on the interaction between RV and its related metabolic enzymes. In addition to hepatic metabolism, the crucial roles of RV metabolism in multiple other tissues and organs cannot be overlooked, and they reveal the relationship between RV metabolism and its biological potential.

Characterization of Nonclinical Drug Metabolism and Pharmacokinetic Properties of Phosphorodiamidate Morpholino Oligonucleotides, a Novel Drug Class for Duchenne Muscular Dystrophy.

Eteplirsen, golodirsen, and casimersen are phosphorodiamidate morpholino oligomers (PMOs) that are approved in the United States for the treatment of patients with Duchenne muscular dystrophy (DMD) with mutations in the DMD gene that are amenable to exon 51, 53, and 45 skipping, respectively. Here we report a series of in vivo and in vitro studies characterizing the drug metabolism and pharmacokinetic (DMPK) properties of these three PMOs. Following a single intravenous dose, plasma exposure was consistent for all three PMOs in mouse, rat, and nonhuman primate (NHP), and plasma half-lives were similar for eteplirsen (2.0-4.1 h) and golodirsen (2.1-8.7 h) across species and more variable for casimersen (3.2-18.1 h). Plasma protein binding was low (<40%) for all three PMOs in mouse, rat, NHP, and human and was largely concentration independent. In the mdx mouse model of DMD, following a single intravenous injection, extensive biodistribution was observed in the target skeletal muscle tissues and the kidney for all three PMOs; consistent with the latter finding, the predominant route of elimination was renal. In vitro studies using liver microsomes showed no evidence of hepatic metabolism, and none of the PMOs were identified as inhibitors or inducers of the human cytochrome P450 enzymes or membrane drug transporters tested at clinically relevant concentrations. These findings suggest that key DMPK features are consistent for eteplirsen, golodirsen, and casimersen and provide evidence for the concept of a PMO drug class with potential application to novel exon-skipping drug candidates. SIGNIFICANCE STATEMENT: The PMOs eteplirsen, golodirsen, and casimersen share similar absorption, distribution, metabolism, and excretion and DMPK properties, which provides evidence for the concept of a PMO treatment class. A PMO drug class may support a platform approach to enhance understanding of the pharmacokinetic and pharmacodynamic behavior of these molecules. The grouping of novel agent series into platforms could be beneficial in the development of drug candidates for populations in which traditional clinical trials are not feasible.