Role In Metabolism Research Articles

Juvenil İdiyopatik Artrit Tanılı Çocuklarda 25 Hidroksivitamin D Düzey Takibinin Önemi

Objective: In patients with juvenile idiopathic arthritis (JIA), bone metabolism may be negatively affected due to both the activity of the disease and the medications used. Our study aimed to investigate the necessity of evaluating 25 hydroxyvitamin D (25 (OH) Vit D), calcium (Ca), phosphorus (P), alkaline phosphatase (ALP) levels and possible related factors in the follow-up of patients diagnosed with JIA.
 Method: The records of 68 patients with JIA were retrospectively evaluated. Disease subtypes, medications used, and whether they were in remission or active disease were reviewed.
 Results: 25 OH Vit D levels were low in 14.7% of patients with JIA compared to the control group. 66.6% of the patients with systemic arthritis had high ALP levels. 25 OH Vit D level was low in 16.6% of steroid users, and Vitamin D level was low in 55.5% of the patients in the active disease group. It was determined that patients in the active disease group had the highest ALP and lowest vitamin D levels compared to patients in remission with and without medication.
 Conclusion: Bone metabolism in patients with JIA is negatively affected. Since vitamin D plays a crucial role in bone metabolism, it was emphasized that vitamin D levels should be evaluated especially during active disease and supplements should be provided for patients with low vitamin D levels.

Polyphosphate Nanoparticles: Balancing Energy Requirements in Tissue Regeneration Processes.

Nanoparticles of a particular, evolutionarily old inorganic polymer found across the biological kingdoms have attracted increasing interest in recent years not only because of their crucial role in metabolism but also their potential medical applicability: it is inorganic polyphosphate (polyP). This ubiquitous linear polymer is composed of 10-1000 phosphate residues linked by high-energy anhydride bonds. PolyP causes induction of gene activity, provides phosphate for bone mineralization, and serves as an energy supplier through enzymatic cleavage of its acid anhydride bonds and subsequent ATP formation. The biomedical breakthrough of polyP came with the development of a successful fabrication process, in depot form, as Ca- or Mg-polyP nanoparticles, or as the directly effective polymer, as soluble Na-polyP, for regenerative repair and healing processes, especially in tissue areas with insufficient blood supply. Physiologically, the platelets are the main vehicles for polyP nanoparticles in the circulating blood. To be biomedically active, these particles undergo coacervation. This review provides an overview of the properties of polyP and polyP nanoparticles for applications in the regeneration and repair of bone, cartilage, and skin. In addition to studies on animal models, the first successful proof-of-concept studies on humans for the healing of chronic wounds are outlined.

CYP14 family in Caenorhabditis elegans: Mitochondrial function, detoxification, and lifespan.

CYP-14 members of the Caenorhabditis elegans (C. elegans) Cytochrome P450 (CYP) enzyme family, plays important roles in mitochondrial dysfunction, detoxification, lipid metabolism, defense and lifespan regulation. The review identifies CYP-14 members: cyp-14A1, cyp-14A2, cyp-14A3, cyp-14A4, cyp-14A5 and their homology with human CYP families. Despite limited studies on C. elegans cyp-14 members, the findings unraveled their complex crosstalk between mitochondrial stress, detoxification mechanisms, and lifespan regulation, emphasizing the complexity of these interconnected pathways as well as how their regulation depends on environmental cues changes including pH, nutrients, ROS and chemical stressors. The review underscores the translational relevance to human health, shedding light on potential human homologues and their implications in age-related, metabolic and respiratory diseases. Among other genes, cyp-14A2 and cyp-14A4 predominate the mitochondrial function, heat resistance, lipid metabolism, detoxification and lifespan pathways. In conclusion, these insights pave the way for future research, offering promising avenues for therapeutic interventions targeting CYP-14 activity to address age-related diseases and promote healthy aging.

ROP GTPases with a geranylgeranylation motif modulate alkaloid biosynthesis in Catharanthus roseus.

Rho of Plant (ROP) GTPases function as molecular switches that control signaling processes essential for growth, development, and defense. However, their role in specialized metabolism is poorly understood. Previously, we demonstrated that inhibition of protein geranylgeranyl transferase (PGGT-I) negatively impacts the biosynthesis of monoterpenoid indole alkaloids (MIA) in Madagascar periwinkle (Catharanthus roseus), indicating the involvement of prenylated proteins in signaling. Here, we show through biochemical, molecular, and in planta approaches that specific geranylgeranylated ROPs modulate C. roseus MIA biosynthesis. Among the six C. roseus ROP GTPases (CrROPs), only CrROP3 and CrROP5, having a C-terminal CSIL motif, were specifically prenylated by PGGT-I. Additionally, their transcripts showed higher expression in most parts than other CrROPs. Protein-protein interaction studies revealed that CrROP3 and CrROP5, but not ΔCrROP3, ΔCrROP5, and CrROP2 lacking the CSIL motif, interacted with CrPGGT-I. Further, CrROP3 and CrROP5 exhibited nuclear localization, whereas CrROP2 was localized to the plasma membrane. In planta functional studies revealed that silencing of CrROP3 and CrROP5 negatively affected MIA biosynthesis, while their overexpression upregulated MIA formation. In contrast, silencing and overexpression of CrROP2 had no effect on MIA biosynthesis. Moreover, overexpression of ΔCrROP3 and ΔCrROP5 mutants devoid of sequence coding for the CSIL motif failed to enhance MIA biosynthesis. These results implicate that CrROP3 and CrROP5 have a positive regulatory role on MIA biosynthesis and thus shed light on how geranylgeranylated ROP GTPases mediate the modulation of specialized metabolism in C. roseus.

The relation between plasma apelin 36 and insulin resistance in obese type 2 diabetic Egyptian population

ABSTRACT Background Obesity causes changes in the production of adipose tissue secreted factors, which are responsible for metabolism modulation. One of these factors is Apelin, a small peptide that interacts with a specific cell-surface receptor to modulate various cells signaling processes. Apelin is regarded as a new player because of its powerful role in energy metabolism and improvement of insulin sensitivity. Aim of the Work This study investigates the plasma apelin 36 role and to what extent it can impact the insulin resistance in obese Egyptians diagnosed with type 2 diabetes (T2DM). Subjects and Methods The study involved 90 participants, with 30 assigned to each of the three study involved categories: obese individuals with diabetes, obese individuals without diabetes, and healthy controls (n = 30 for each group). Measurements of skin fold thickness, body mass index (BMI), waist/hip ratio, and body fat % were obtained along with a comprehensive clinical examination and history. The following were investigated: plasma insulin, Hb A1c, lipid profile, plasma apelin (ELISA), plasma leptin (ELISA), and plasma adiponectin (ELISA). Results The median value of serum leptin in obese subjects (groups I and II) was higher significantly than healthy control group (group III) (p = <0.001). A significant decrease in serum adiponectin could be detected in obese subjects (groups I and II) compared to control subjects (Group III) (p = 0.004). When compared to the healthy control group (group III), the mean serum apelin level was significantly higher in the obese participants (groups I and II) and much higher among obese diabetic group (p = <0.001). A statistically significant correlation (p = 0.001) was observed between fasting serum insulin and both HOMA-IR and serum apelin among the non-diabetic obese participants involved in the study. Conclusions Obese people have raised serum apelin levels; those with T2DM have significantly greater serum apelin levels. While it showed a positive correlation with insulin level and HOMA-IR among the obese non-diabetic individuals.

A Novel Fluorogenic Probe Reveals Lipid Droplet Dynamics in ME/CFS Fibroblasts

AbstractLipid droplets (LDs) are dynamic cellular organelles that play an essential role in lipid metabolism and storage. LD dysregulation has been implicated in various diseases. However, investigations into the cellular LD dynamics under disease conditions have been rarely reported, possibly due to the absence of high performing LD imaging agents. Here a novel fluorogenic probe, AM‐QTPA, is reported for specific LD imaging. AM‐QTPA demonstrates viscosity sensitivity and aggregation‐induced emission enhancement characteristics. It is live cell permeable and can specifically light up LDs in cells, with low background noise and superior signals that can be quantified. After validation in cell model with LD accumulation induced by oleic acid treatment, AM‐QTPA is applied in a small proof‐of‐concept number of human fibroblast samples derived from people diagnosed with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a complex and debilitating disease with unknown cause. The results indicate the presence of larger but fewer LDs in ME/CFS fibroblasts compared to the healthy counterparts, accompanying with frequent LD‐mitochondria contacts, suggesting potential upregulation of lipolysis in ME/CFS connective tissue like fibroblasts. Overall, AM‐QTPA provides new understanding of the anomalous LD dynamics in disease status, which, potentially, will facilitate in‐depth investigation of the pathogenesis of ME/CFS.

Possible Role of Cellular Polyamine Metabolism in Neuronal Apoptosis.

Recent studies have shown that cellular levels of polyamines (PAs) are significantly altered in neurodegenerative diseases. Evidence from in vivo animal and in vitro cell experiments suggests that the cellular levels of various PAs may play important roles in the central nervous system through the regulation of oxidative stress, mitochondrial metabolism, cellular immunity, and ion channel functions. Dysfunction of PA metabolism related enzymes also contributes to neuronal injury and cognitive impairment in many neurodegenerative diseases. Therefore, in the current work, evidence was collected to determine the possible associations between cellular levels of PAs, and related enzymes and the development of several neurodegenerative diseases, which could provide a new idea for the treatment of neurodegenerative diseases in the future.

HOW DOES VITAMIN D SUPPLEMENTATION CHANGE THE OUTCOME FOR MOTHER AND CHILD?

Introduction: Pregnancy represents a period in which rapid bodily changes occur, which include a wide range of physiological interactions occurring in both the mother and the developing foetus. The role of vitamin D3 metabolism within pregnancy is an over-shadowed but very important aspect for the normal and healthy muscoskeletal development of the foetus and for the various alternative functions associated with vitamin D3 for the pregnant female. The purpose: To provide a detailed understanding ofhe current status of vitamin D3 and the role it has within pregnancy and to identify the efficacy and the wide range of effects that vitamin D3 has for both the mother and foetus. Materials and methods: We conducted a review of the available literature at PubMed, Google Scholar, and Science Direct, which included observational studies, prospective and controlled trials, reports and guidelines for appropriate dosages of vitamin D3 to be used within pregnant females. Results and Discussion: Our review of the scientific literature showed evidence of the benefits of vitamin D3 within pregnant women and the effect, if any, on the numerous physiological processes taking place within both the mother and the foetus. We found data indicating that vitamin D3 can prove to be very important in preventingreeclampsia, gestational diabetes and congenital malformations of the foetus. Conclusion: The administration of vitamin D3 may be a potential technique to prevent complications to the mother and the developing foetus both during and after pregnancy, either solely or as a combined therapy.

Restoration of fertility in nonablated recipient mice after spermatogonial stem cell transplantation

Spermatogonial stem cell (SSC) transplantation is a valuable tool for studying stem cell-niche interaction. However, the conventional approach requires the removal of endogenous SSCs, causing damage to the niche. Here we introduce WIN18,446, an ALDH1A2 inhibitor, to enhance SSC colonization in nonablated recipients. Pre-transplantation treatment with WIN18,446 induced abnormal claudin protein expression, which comprises the blood-testis barrier and impedes SSC colonization. Consequently, WIN18,446 increased colonization efficiency by 4.6-fold compared with untreated host. WIN18,446-treated testes remained small despite the cessation of WIN18,446, suggesting its irreversible effect. Offspring were born by microinsemination using donor-derived sperm. While WIN18,446 was lethal to busulfan-treated mice, cyclophosphamide- or radiation-treated animals survived after WIN18,446 treatment. Although WIN18,446 is not applicable to humans due to toxicity, similar ALDH1A2 inhibitors may be useful for SSC transplantation into nonablated testes, shedding light on the role of retinoid metabolism on SSC-niche interactions and advancing SSC research in animal models and humans.

Variation of sugar compounds in Phoebe chekiangensis seeds during natural desiccation.

To investigate the role of sugar metabolism in desiccation-sensitive seeds, we performed a natural desiccation treatment on Phoebe chekiangensis seeds in a room and systematically analyzed the changes in seed germination, sugar compounds, malondialdehyde, and relative electrical conductivity during the seed desiccation. The results revealed that the initial moisture content of P. chekiangensis seed was very high (37.06%) and the seed was sensitive to desiccation, the germination percentage of the seed decreased to 5.33% when the seed was desiccated to 22.04% of moisture content, therefore, the seeds were considered recalcitrant. Based on the logistic model, we know that the moisture content of the seeds is 29.05% when the germination percentage drops to 50% and that it is desirable to keep the seed moisture content above 31.74% during ambient transportation. During seed desiccation, sucrose and trehalose contents exhibited increasing trends, and raffinose also increased during the late stage of desiccation, however, low levels of the non-reducing sugar accumulations may not prevent the loss of seed viability caused by desiccation. Glucose and fructose predominated among sugar compounds, and they showed a slight increase followed by a significant decrease. Their depletion may have contributed to the accumulation of sucrose and raffinose family oligosaccharides. Correlation analysis revealed a significant relationship between the accumulation of sucrose, trehalose, and soluble sugars, and the reduction in seed viability. Sucrose showed a significant negative correlation with glucose and fructose. Trehalose also exhibited the same pattern of correlation. These results provided additional data and theoretical support for understanding the mechanism of sugar metabolism in seed desiccation sensitivity.

Identification and Validation of Key Genes Related to Preferred Flavour Profiles in Australian Commercial Papaya (Carica papaya L.).

Commercial papaya varieties grown in Australia vary greatly in taste and aroma. Previous profiling has identified undesirable 'off tastes' in existing varieties, discouraging a portion of the population from consuming papayas. Our focus on enhancing preferred flavours led to an exploration of the genetic mechanisms and biosynthesis pathways that underlie these desired taste profiles. To identify genes associated with consumer-preferred flavours, we conducted whole RNA sequencing and de novo genome assembly on papaya varieties RB1 (known for its sweet flavour and floral aroma) and 1B (less favoured due to its bitter taste and musty aroma) at both ripe and unripe stages. In total, 180,368 transcripts were generated, and 118 transcripts related to flavours were differentially expressed between the two varieties at the ripe stage. Five genes (cpBGH3B, cpPFP, cpSUS, cpGES and cpLIS) were validated through qPCR and significantly differentially expressed. These genes are suggested to play key roles in sucrose metabolism and aromatic compound production pathways, holding promise for future selective breeding strategies. Further exploration will involve assessing their potential across broader germplasm and various growth environments.

MYC: there is more to it than cancer.

MYC is a pleiotropic transcription factor involved in multiple cellular processes. While its mechanism of action and targets are not completely elucidated, it has a fundamental role in cellular proliferation, differentiation, metabolism, ribogenesis, and bone and vascular development. Over 4decades of research and some 10,000 publications linking it to tumorigenesis (by searching PubMed for "MYC oncogene") have led to MYC becoming a most-wanted target for the treatment of cancer, where many of MYC's physiological functions become co-opted for tumour initiation and maintenance. In this context, an abundance of reviews describes strategies for potentially targeting MYC in the oncology field. However, its multiple roles in different aspects of cellular biology suggest that it may also play a role in many additional diseases, and other publications are indeed linking MYC to pathologies beyond cancer. Here, we review these physiological functions and the current literature linking MYC to non-oncological diseases. The intense efforts towards developing MYC inhibitors as a cancer therapy will potentially have huge implications for the treatment of other diseases. In addition, with a complementary approach, we discuss some diseases and conditions where MYC appears to play a protective role and hence its increased expression or activation could be therapeutic.

The Role of Ferroptosis in Inflammatory Bowel Disease: Mechanisms and Therapeutic Implications

Inflammatory Bowel Disease (IBD), encompassing Crohn's disease and ulcerative colitis, is characterized by chronic inflammation of the gastrointestinal tract, with an increasing incidence worldwide. Recent advancements in cellular biology have identified ferroptosis, a form of programmed cell death driven by iron-dependent lipid peroxidation, as a critical player in the pathology of IBD. This article reviews the current understanding of ferroptosis and its distinctive mechanisms, including the role of GPx4, Nrf2-HO-1 pathways, and iron metabolism in the context of IBD. It also examines the dual nature of iron in intestinal health and disease, contributing to both physiological functions and pathological processes through oxidative stress and inflammation. The implications of ferroptosis in the intestinal epithelial cell death, barrier function, and immune response are discussed, highlighting its potential as a novel therapeutic target. Despite the promising insights, the article underscores the need for further research to elucidate the complex mechanisms of ferroptosis in IBD and to translate these findings into effective therapeutic strategies. The emerging evidence positions ferroptosis at the crossroads of metabolic, inflammatory, and cell death pathways, offering a unique perspective on the interplay between nutrition, genetics, and immunity in intestinal health and disease.

Identification of Stress Responsive NAC Genes in Casuarina equisetifolia L. and Its Expression Analysis under Abiotic Stresses

NAC (NAM, ATAF and CUC)-like transcription factors, a class of plant-specific transcription factors, play a pivotal role in plant growth, development, metabolism, and stress response. Notably, a specific subclass of NAC family, known as SNAC (stress-responsive NAC), is particularly involved in the plant’s response to abiotic stress. As a very useful tree, Casuarina equisetifolia L. also has excellent stress resistance properties. To explore gene resources of C. equisetifolia which are associated with stress resistance and the molecular mechanisms that it employed is very helpful to its molecular-assisted breeding. In this study, 10 CeSNAC transcription factors were identified by constructing the phylogenetic tree of 94 CeNACs from the genome of C. equisetifolia L. together with 79 SNAC in different plant species. Phylogenetic tree analysis revealed that these 10 CeSNAC genes are classified into the ATAF (Arabidopsis transcription activation factor), NAP (NAC-like, activated by AP3/P1), and AtNAC3 subfamilies of the NAC family, all featuring the typical NAM (no apical meristem) domain, with the exception of CeSNAC7. In addition, all NAC transcription factors, except CeSNAC9, were localized in the nucleus. Examination of the CeSNAC promoter unveiled the presence of stress response elements such as a STRE (stress responsive element), an MBS (MYB binding site), an ABRE (abscisic acid responsive element) and a LTR (low temperature responsive element). Under various stress treatments, the majority of CeSNAC expressions exhibited induction in response to low temperature, drought, and high salt treatments, as well as ABA (abscisic acid) treatment. However, CeSNAC6, CeSNAC7, and CeSNAC9 were found to be inhibited specifically by drought treatment. Additionally, only CeSNAC3 and CeNAC9 expression was hindered while the rest of the CeSNAC expression were induced by MeJA (methyl jasmonate) treatment. These findings shed light on the relationship between different CeSNAC genes and their responses to abiotic stress conditions, providing valuable insights for further research into CeSNAC functions and aiding the development of stress-resistant varieties in C. equisetifolia.

Glutamine Supplementation as an Anticancer Strategy: A Potential Therapeutic Alternative to the Convention.

Glutamine, a multifaceted nonessential/conditionally essential amino acid integral to cellular metabolism and immune function, holds pivotal importance in the landscape of cancer therapy. This review delves into the intricate dynamics surrounding both glutamine antagonism strategies and glutamine supplementation within the context of cancer treatment, emphasizing the critical role of glutamine metabolism in cancer progression and therapy. Glutamine antagonism, aiming to disrupt tumor growth by targeting critical metabolic pathways, is challenged by the adaptive nature of cancer cells and the complex metabolic microenvironment, potentially compromising its therapeutic efficacy. In contrast, glutamine supplementation supports immune function, improves gut integrity, alleviates treatment-related toxicities, and improves patient well-being. Moreover, recent studies highlighted its contributions to epigenetic regulation within cancer cells and its potential to bolster anti-cancer immune functions. However, glutamine implementation necessitates careful consideration of potential interactions with ongoing treatment regimens and the delicate equilibrium between supporting normal cellular function and promoting tumorigenesis. By critically assessing the implications of both glutamine antagonism strategies and glutamine supplementation, this review aims to offer comprehensive insights into potential therapeutic strategies targeting glutamine metabolism for effective cancer management.

Abstract A010: Prostate-specific membrane antigen use in glioma management: past, present, and future

Abstract Introduction: Prostate-Specific Membrane Antigen (PSMA) is a type II membrane-bound zinc metallopeptidase expressed in various tissues, including the prostate, renal tubular epithelium, small and large intestinal mucosa, and brain. It plays a role in cell proliferation pathways and folate and glutamate metabolism. PSMA has been utilized for imaging and treatment of prostate cancer and is also expressed in solid tumor neovasculature of other cancers. Gliomas, which are central nervous system neoplasms of glial tissue, represent a challenging group of tumors with limited treatment options due to their invasive nature. PSMA's ability to internalize and location makes it a promising diagnostic and therapeutic target for gliomas. This review synthesizes the literature surrounding the use of PSMA in gliomas to inform current and future directions of study. Methods: A review of the literature was conducted using PubMed and Scopus databases in June 2023. Seventy-one relevant studies, including histopathological, imaging, and therapeutic investigations, were identified. These publications were categorized by year of publication to analyze the evolution of PSMA research in glioma management. Additionally, clinicaltrials.gov was searched for ongoing clinical trials involving PSMA and gliomas. Results: Histopathological studies have demonstrated PSMA's high expression in glioma vasculature, particularly in glioblastoma (GBM), a high-grade glioma (HGG). Studies have investigated PSMA's role in tumor metabolism and its interplay with other tumor markers. Some research suggests that high PSMA expression in GBM endothelium may promote angiogenesis and correlates with poor prognosis. PSMA PET imaging has shown promise in diagnosing and differentiating HGGs and low-grade gliomas (LGGs). Studies have reported high sensitivity and diagnostic accuracy of PSMA PET for HGGs, making it a potentially useful screening tool for radioligand therapy patient selection. Mouse models have also been employed to evaluate the utility of PSMA PET imaging in GBM, with some studies suggesting its application in defining non-enhancing portions of tumors and recurrence volume. PSMA-targeted therapies, particularly PSMA-targeted radiotherapy using radionuclide agents like 177Lu-PSMA-617, have been explored for the treatment of gliomas. Case reports and preliminary studies have demonstrated potential efficacy and tumor response to such therapies, warranting further investigation. Conclusion: The evolving literature indicates that PSMA holds promise as a valuable tool in the diagnosis, prognosis, and treatment of gliomas. Studies have highlighted PSMA PET imaging's high diagnostic accuracy and its potential in patient selection for targeted therapies. However, more research is needed to fully understand the role of PSMA in glioma behavior and to optimize treatment strategies. Ongoing clinical trials and future investigations will further our knowledge of PSMA's potential in managing gliomas and improving patient outcomes. Citation Format: Joshua D. McBriar, Neeva Shafiian, Steven Scharf, A. Gabriella Wernicke. Prostate-specific membrane antigen use in glioma management: past, present, and future [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr A010.

Abstract A110: Targeting methionine metabolism inhibits ovarian cancer stem cells

Abstract Ovarian cancer (OC) is the leading cause of gynecologic cancer death. Platinum (Pt)- based chemotherapy can reprogram cancer cells to ovarian cancer stem cells (OCSCs) and contribute to disease recurrence. In the current study, we demonstrated that platinum drugs can enrich for OCSCs. In high grade serous ovarian cancer (HGSOC) cell lines, cisplatin treatment (IC50 for 16hrs) increased the percentage of cells with high aldehyde dehydrogenase (ALDH+) activity, a known OCSCs marker, and altered methionine (Met) metabolism. Extracellular Met uptake is converted to S-adenosyl-methionine (SAM) by methionine adenosyltransferase 2A (MAT2A), the rate-limiting enzyme of Met utilization. Short-term cisplatin treatment decreased SAM level and increased expression of MAT2A. It has been reported that CSCs have a high-flux metabolic state and are dependent on Met metabolism. We observed higher MAT2A expression in ALDH+ cells compared to the whole cell population, and Met depletion blocked the cisplatin-induced increase in %ALDH+ cells and spheroid formation ability. Furthermore, both MAT2A siRNA knockdown and the MAT2A inhibitor FIDAS-5 prevented cisplatin-induced increase in %ALDH+ cells, suggesting that blocking Met metabolism phenotypically inhibited the platinum enrichment of OCSCs. MAT2A inhibition also downregulated Cyclin E and arrested HGSOC cells in G1/S phase, indicating that a lower level of Met utilization re-established G1/S checkpoint in p53-mutant OC. As SAM is the universal methyl-group donor, it was of interest to examine whether the observed cisplatin-induced alterations in SAM level resulted in changes in DNA methylation. Methylation specific-PCR analysis demonstrated that siMAT2A or FIDAS-5 treatment of HGSOC cells inhibited cisplatin-induced hypermethylation of CpG islands of BRCA1 and ALDH1L1, a folate metabolic enzyme of which promoter hypermethylation is associated to tumor progression. Collectively, these results demonstrated a crucial role of Met metabolism in cisplatin-induced OCSCs enrichment. MAT2A has been recognized as a therapeutic target for the treatment of solid tumors and Met inhibition by targeting MAT2A could represent a therapeutic approach for inhibiting CSC in ovarian cancer. Citation Format: Shu Zhang, Tara X. Metcalfe, Christiane A. Hassel, Heather M. O'Hagan, Kenneth P. Nephew. Targeting methionine metabolism inhibits ovarian cancer stem cells [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A110.

Betaine Alleviates High-Fat Diet Induced Excessive Lipid Deposition in Gibel Carp Hepatopancreas and L8824 Cells by Enhancing VLDL Secretion through HNF4α/MTTP Pathway.

Betaine, a methyl donor, plays a crucial role in lipid metabolism. Previous studies have shown that appropriate betaine supplementation in a high-fat diet reduces triglycerides (TG) of serum and hepatopancreas in fish. However, the underlying mechanism remains unclear. This study examined whether betaine can enhance the secretion of very low-density lipoprotein (VLDL) and sought to identify the specific mechanisms through which this enhancement occurs. A lipid accumulation model was established in gibel carp and L8824 cells using a high-fat diet and oleic acid, respectively. Different doses of betaine (1, 4, and 16 g/kg in the diet; 400 μmol in cell culture) were administered, and measurements were taken for lipid deposition, gene expression of HNF4α, MTTP, and ApoB, as well as the regulation of Mttp and Apob promoters by HNF4α. The results showed that betaine supplementation mitigated lipid droplet accumulation, TG levels, and VLDL production induced by the high-fat diet in gibel carp hepatopancreas and L8824 cells. Moreover, betaine not only increased VLDL content in the cell culture supernatant but also reversed the inhibitory effects of the high-fat diet on protein expression of MTTP, ApoB, and HNF4α in both gibel carp hepatopancreas and L8824 cells. Additionally, HNF4α exhibits transactivating activity on the promoter of Mttp in gibel carp. These findings suggest that betaine supplementation exerts its effects through the HNF4α/MTTP/ApoB pathway, promoting the assembly and secretion of VLDL and effectively reducing lipid accumulation in the hepatopancreas of farmed gibel carp fed a high-fat diet.

Cysteine and thiosulfate promoted cadmium immobilization in strain G303 by the formation of extracellular CdS

Bacteria have evolved a variety of strategies to defend themselves against cadmium toxicity, however, the specific mechanisms involved in the enhancement of bacterial cadmium resistance by sulfur sources are unclear. In this study, a novel cadmium (Cd)-tolerant bacterium, Stenotrophomonas geniculata G303, was isolated from activated sludge. The growth of strain G303 under diverse Cd concentrations was investigated, and the minimum inhibitory concentration of Cd was found to be 1 mM. Strain G303 effectively remove 94.7 % of Cd after 96 h of culture. Extracellular CdS was detected using multiple methods, with the CdS formed being aggregated in the biofilm. The addition of cysteine and thiosulfate to the medium significantly enhanced the Cd resistance and removal capacity of strain G303. Integrated genomic and proteomic analyses revealed that heavy metal transporters cooperate to resist Cd stress. Cysteine and thiosulfate improved Cd tolerance in strain G303 by upregulating nitrogen and energy metabolism. Proteins associated with nitrate reduction likely played a pivotal role in cysteine and thiosulfate metabolism. Notably, cysteine synthase and the SUF system played crucial roles in CdS formation. This study systematically explored the impact of cysteine and thiosulfate on the Cd resistance of strain G303, deepening our understanding of the microbial response mechanism to heavy metals.

Functional characterization of HNF4A gene variants identify promoter and cell line specific transactivation effects.

Hepatocyte nuclear factor-4 alpha (HNF-4A) regulates genes with roles in glucose metabolism and β-cell development. Although pathogenic HNF4A variants are commonly associated with maturity-onset diabetes of the young (MODY1; HNF4A-MODY), rare phenotypes also include hyperinsulinemic hypoglycemia, renal Fanconi syndrome and liver disease. While the association of rare functionally damaging HNF1A variants with HNF1A-MODY and type 2 diabetes is well established owing to robust functional assays, the impact of HNF4A variants on HNF-4A transactivation in tissues including the liver and kidney is less known, due to lack of similar assays. Our aim was to investigate the functional effects of seven HNF4A variants, located in the HNF-4A DNA binding domain and associated with different clinical phenotypes, by various functional assays and cell lines (transactivation, DNA binding, protein expression, nuclear localization) and in silico protein structure analyses. Variants R85W, S87N and R89W demonstrated reduced DNA binding to the consensus HNF-4A binding elements in the HNF1A promoter (35, 13 and 9%, respectively) and the G6PC promoter (R85W ~10%). While reduced transactivation on the G6PC promoter in HepG2 cells was shown for S87N (33%), R89W (65%) and R136W (35%), increased transactivation by R85W and R85Q was confirmed using several combinations of target promoters and cell lines. R89W showed reduced nuclear levels. In silico analyses supported variant induced structural impact. Our study indicates that cell line specific functional investigations are important to better understand HNF4A-MODY genotype-phenotype correlations, as our data supports ACMG/AMP interpretations of loss-of-function variants and propose assay-specific HNF4A control variants for future functional investigations.