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BioRxiv : the Preprint Server For... Aug 2023The development of diverse spatial profiling technologies has provided an unprecedented insight into molecular mechanisms driving cancer pathogenesis. Here, we conducted...
Integrated spatial transcriptomics and lipidomics of precursor lesions of pancreatic cancer identifies enrichment of long chain sulfatide biosynthesis as an early metabolic alteration.
BACKGROUND
The development of diverse spatial profiling technologies has provided an unprecedented insight into molecular mechanisms driving cancer pathogenesis. Here, we conducted the first integrated cross-species assessment of spatial transcriptomics and spatial metabolomics alterations associated with progression of intraductal papillary mucinous neoplasms (IPMN), cystic precursors of pancreatic ductal adenocarcinoma (PDAC).
METHODS
Matrix Assisted Laster Desorption/Ionization (MALDI) mass spectrometry (MS)-based spatial imaging and Visium spatial transcriptomics (ST) (10X Genomics) was performed on human resected IPMN tissues (N= 23) as well as pancreata from a mutant mouse model of IPMN. Findings were further compared with lipidomic analyses of cystic fluid from 89 patients with histologically confirmed IPMNs, as well as single-cell and bulk transcriptomic data of PDAC and normal tissues.
RESULTS
MALDI-MS analyses of IPMN tissues revealed long-chain hydroxylated sulfatides, particularly the C24:0(OH) and C24:1(OH) species, to be selectively enriched in the IPMN and PDAC neoplastic epithelium. Integrated ST analyses confirmed that the cognate transcripts engaged in sulfatide biosynthesis, including , and , were co-localized with areas of sulfatide enrichment. Lipidomic analyses of cystic fluid identified several sulfatide species, including the C24:0(OH) and C24:1(OH) species, to be significantly elevated in patients with IPMN/PDAC compared to those with low-grade IPMN. Targeting of sulfatide metabolism via the selective galactosylceramide synthase inhibitor, UGT8-IN-1, resulted in ceramide-induced lethal mitophagy and subsequent cancer cell death , and attenuated tumor growth of mutant allografts. Transcript levels of and were also selectively enriched in PDAC transcriptomic datasets compared to non-cancerous areas, and elevated tumoral was prognostic for poor overall survival.
CONCLUSION
Enhanced sulfatide metabolism is an early metabolic alteration in cystic pre-cancerous lesions of the pancreas that persists through invasive neoplasia. Targeting sulfatide biosynthesis might represent an actionable vulnerability for cancer interception.
PubMed: 37645752
DOI: 10.1101/2023.08.14.553002 -
Molecules (Basel, Switzerland) Mar 2024During the life activities of microorganisms, a variety of secondary metabolites are produced, including antimicrobials and antitumor drugs, which are widely used in... (Review)
Review
During the life activities of microorganisms, a variety of secondary metabolites are produced, including antimicrobials and antitumor drugs, which are widely used in clinical practice. In addition to exploring new antibiotics, this makes it one of the research priorities of to effectively increase the yield of antibiotics in production strains by various means. Most antibiotic-producing strains have a variety of functional regulatory factors that regulate their growth, development, and secondary metabolite biosynthesis processes. Through the study of precursor substances in antibiotic biosynthesis, researchers have revealed the precursor biosynthesis process and the mechanism by which precursor synthesis regulators affect the biosynthesis of secondary metabolites, which can be used to obtain engineered strains with high antibiotic production. This paper summarizes the supply of antibiotic biosynthesis precursors and the progress of research on the role of regulators in the process of precursors in biosynthesis. This lays the foundation for the establishment of effective breeding methods to improve antibiotic yields through the manipulation of precursor synthesis genes and related regulators.
Topics: Anti-Bacterial Agents; Actinobacteria; Actinomyces; Secondary Metabolism
PubMed: 38474644
DOI: 10.3390/molecules29051132 -
Neuroimmunomodulation 2024T-cell acute lymphoblastic leukemia (T-ALL) is a malignant hematologic disease caused by the transformation and uncontrolled proliferation of T-cell precursors. T-ALL is... (Review)
Review
BACKGROUND
T-cell acute lymphoblastic leukemia (T-ALL) is a malignant hematologic disease caused by the transformation and uncontrolled proliferation of T-cell precursors. T-ALL is generally thought to originate in the thymus since lymphoblasts express phenotypic markers comparable to those described in thymocytes in distinct stages of development. Although around 50% of T-ALL patients present a thymic mass, T-ALL is characterized by peripheral blood and bone marrow involvement, and central nervous system (CNS) infiltration is one of the most severe complications of the disease.
SUMMARY
The CNS invasion is related to the expression of specific adhesion molecules and receptors commonly expressed in developing T cells, such as L-selectin, CD44, integrins, and chemokine receptors. Furthermore, T-ALL blasts also express neurotransmitters, neuropeptides, and cognate receptors that are usually present in the CNS and can affect both the brain and thymus, participating in the crosstalk between the organs.
KEY MESSAGES
This review discusses how the thymus-brain connections, mediated by innervation and common molecules and receptors, can impact the development and migration of T-ALL blasts, including CNS infiltration.
Topics: Humans; Thymus Gland; Brain; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Animals
PubMed: 38272012
DOI: 10.1159/000536419 -
Virulence Dec 2024Persistent human papillomavirus HPV infection is a necessary but insufficient condition for cervical cancer. Microorganisms are crucial environmental factors in cancers...
Persistent human papillomavirus HPV infection is a necessary but insufficient condition for cervical cancer. Microorganisms are crucial environmental factors in cancers susceptibility and progression, recently attracting considerable attention. This study aimed to determine the infection status and relationship between high-risk HPV (HR-HPV) and lower genital tract infectious pathogens in cervical cancer and its precursors. From a retrospective and a prospective cohort analysis, () dominated the pathogens isolated from cervical discharges, and an isolation rate uptrend has been shown recently. HPV16 and 's coinfection rate gradually increased with the severity of cervical intraepithelial neoplasia. The adhesion and invasion abilities of the isolated to HPV16-positive SiHa cells were evaluated . The TCGA database and cervical tissues samples analysis showed that IL-10 was upregulated in cervical cancer. IL-10 expression levels increased in tissue samples with the severity of cervical cancer and its precursors with HPV16 and coinfection. Although no significant changes in IL-10 production were observed in the co-culture supernatant, we hypothesized that Treg immune cells in the tumour microenvironment might be responsible for the local IL-10 upregulation, according to our data showing Foxp3 upregulation and an upward trend with the cervical intraepithelial neoplasia grading to cancer and tumours with and HPV16 coinfection. Our data provide insights into the possible role of in cervical cancer progression and suggest that the application of HPV and screening programs may be an effective strategy to relieve the burden of cervical cancer and its precursor lesions.
Topics: Female; Humans; Uterine Cervical Neoplasms; Interleukin-10; Human papillomavirus 16; Escherichia coli; Papillomavirus Infections; Retrospective Studies; Coinfection; Prospective Studies; Uterine Cervical Dysplasia; Tumor Microenvironment
PubMed: 38380669
DOI: 10.1080/21505594.2024.2319962 -
BioRxiv : the Preprint Server For... Sep 2023Riboflavin (vitamin B) is the precursor of the flavin coenzymes, FAD and FMN, which play a central role in cellular redox metabolism. While humans must obtain riboflavin...
Riboflavin (vitamin B) is the precursor of the flavin coenzymes, FAD and FMN, which play a central role in cellular redox metabolism. While humans must obtain riboflavin from dietary sources, certain microbes, including (Mtb), can biosynthesize riboflavin . Riboflavin precursors have also been implicated in the activation of mucosal-associated invariant T (MAIT) cells which recognize metabolites derived from the riboflavin biosynthesis pathway complexed to the MHC-I-like molecule, MR1. To investigate the biosynthesis and function of riboflavin and its pathway intermediates in mycobacterial metabolism, physiology and MAIT cell recognition, we constructed conditional knockdowns (hypomorphs) in riboflavin biosynthesis and utilization genes in (Msm) and Mtb by inducible CRISPR interference. Using this comprehensive panel of hypomorphs, we analyzed the impact of gene silencing on viability, on the transcription of (other) riboflavin pathway genes, on the levels of the pathway proteins and on riboflavin itself. Our results revealed that (i) despite lacking a canonical transporter, both Msm and Mtb assimilate exogenous riboflavin when supplied at high concentration; (ii) there is functional redundancy in lumazine synthase activity in Msm; (iii) silencing of or is profoundly bactericidal in Mtb; and (iv) in Msm, silencing results in concomitant knockdown of other pathway genes coupled with RibA2 and riboflavin depletion and is also bactericidal. In addition to their use in genetic validation of potential drug targets for tuberculosis, this collection of hypomorphs provides a useful resource for investigating the role of pathway intermediates in MAIT cell recognition of mycobacteria.
PubMed: 37693561
DOI: 10.1101/2023.08.30.555301 -
Inorganic Chemistry Oct 2023Currently, two approaches dominate the large-scale production of MoS: liquid-phase exfoliation, referred to as the top-down approach, and bottom-up colloidal synthesis...
Currently, two approaches dominate the large-scale production of MoS: liquid-phase exfoliation, referred to as the top-down approach, and bottom-up colloidal synthesis from molecular precursors. Known colloidal synthesis approaches utilize toxic precursors. Here, an alternative green route for the bottom-up synthesis of MoS nanoflakes (NFs) is described. The NFs were synthesized by colloidal synthesis using [Mo(CHCOO)] and a series of sulfur (S)-precursors including thioacetamide (TAA), 3-mercaptopropionic acid (3-MPA), l-cysteine (L-CYS), mercaptosuccinic acid (MSA), 11-mercaptoundecanoic acid (MUA), 1-dodecanethiol (DDTH), and di--butyl disulfide (DTBD). While TAA, an S-precursor most commonly used for MoS NF preparation, is a known carcinogen, the other investigated S-precursors have low or no known toxicity. High-resolution scanning transmission electron microscopy (HR-STEM) and grazing incidence wide-angle X-ray scattering (GIWAXS) confirmed that in all cases, the syntheses yielded single-layer MoS NFs with lateral sizes smaller than 15 nm and a well-defined crystal structure. Electronic absorption and Raman spectra showed characteristic features associated with the MoS monolayers. The evolution of the absorption spectra of the growth solution during the syntheses reveals how the kinetics of the NF formation is affected by the S-precursor as well as the nature of the coordinating ligands.
PubMed: 37751900
DOI: 10.1021/acs.inorgchem.3c02420 -
Frontiers in Aging Neuroscience 2023Dementias and mild cognitive impairment (MCI) are associated with variously combined changes in the neurotransmitter system and signaling, from neurotransmitter...
Several dementia subtypes and mild cognitive impairment share brain reduction of neurotransmitter precursor amino acids, impaired energy metabolism, and lipid hyperoxidation.
OBJECTIVE
Dementias and mild cognitive impairment (MCI) are associated with variously combined changes in the neurotransmitter system and signaling, from neurotransmitter synthesis to synaptic binding. The study tested the hypothesis that different dementia subtypes and MCI may share similar reductions of brain availability in amino acid precursors (AAPs) of neurotransmitter synthesis and concomitant similar impairment in energy production and increase of oxidative stress, i.e., two important metabolic alterations that impact neurotransmission.
MATERIALS AND METHODS
Sixty-five demented patients (Alzheimer's disease, AD, = 44; frontotemporal disease, FTD, = 13; vascular disease, VaD, = 8), 10 subjects with MCI and 15 control subjects (CTRL) were recruited for this study. Cerebrospinal fluid (CSF) and plasma levels of AAPs, energy substrates (lactate, pyruvate), and an oxidative stress marker (malondialdehyde, MDA) were measured in all participants.
RESULTS
Demented patients and subjects with MCI were similar for age, anthropometric parameters, biohumoral variables, insulin resistance (HOMA index model), and CSF neuropathology markers. Compared to age-matched CTRL, both demented patients and MCI subjects showed low CSF AAP tyrosine (precursor of dopamine and catecholamines), tryptophan (precursor of serotonin), methionine (precursor of acetylcholine) limited to AD and FTD, and phenylalanine (an essential amino acid largely used for protein synthesis) ( = 0.03 to <0.0001). No significant differences were found among dementia subtypes or between each dementia subtype and MCI subjects. In addition, demented patients and MCI subjects, compared to CTRL, had similar increases in CSF and plasma levels of pyruvate (CSF: = 0.023 to <0.0001; plasma: < 0.002 to <0.0001) and MDA (CSF: < 0.035 to 0.002; plasma: < 0.0001). Only in AD patients was the CSF level of lactate higher than in CTRL ( = 0.003). Lactate/pyruvate ratios were lower in all experimental groups than in CTRL.
CONCLUSION
AD, FTD, and VaD dementia patients and MCI subjects may share similar deficits in AAPs, partly in energy substrates, and similar increases in oxidative stress. These metabolic alterations may be due to AAP overconsumption following high brain protein turnover (leading to phenylalanine reductions), altered mitochondrial structure and function, and an excess of free radical production. All these metabolic alterations may have a negative impact on synaptic plasticity and activity.
PubMed: 37655338
DOI: 10.3389/fnagi.2023.1237469 -
Journal of Cerebral Blood Flow and... Nov 2023Nicotinamide adenine dinucleotide (NAD) is a redox cofactor critical for oxidative phosphorylation. Nicotinamide (NAM) and nicotinamide riboside (NR) are NAD precursors...
Nicotinamide adenine dinucleotide (NAD) is a redox cofactor critical for oxidative phosphorylation. Nicotinamide (NAM) and nicotinamide riboside (NR) are NAD precursors widely used as nutritional supplements to augment oxidative phosphorylation. Indeed, NAD precursors have been reported to improve outcomes in ischemic stroke when administered as a rescue therapy after stroke onset. However, we have also reported that enhanced reliance on oxidative phosphorylation before ischemia onset might worsen outcomes. To address the paradox, we examined how NAD precursors modulate the outcome of middle cerebral artery occlusion in mice, when administered either 20 minutes after reperfusion or daily for three days before ischemia onset. A single post-ischemic dose of NAM or NR indeed improved tissue and neurologic outcomes examined at 72 hours. In contrast, pre-ischemic treatment for three days enlarged the infarcts and worsened neurological deficits. As a possible explanation for the diametric outcomes, a single dose of NAM or NR augmented tissue AMPK, PGC1α, SIRT1, and ATP in both naïve and ischemic brains, while the multiple-dose paradigm failed to do so. Our data suggest that NAD precursor supplements may sensitize the brain to subsequent ischemic events, despite their neuroprotective effect when administered after ischemia onset.
Topics: Mice; Animals; NAD; Dietary Supplements; Brain; Stroke; Ischemia
PubMed: 37434361
DOI: 10.1177/0271678X231156500 -
Biochemical and Biophysical Research... Apr 2024Nicotinamide adenine dinucleotide (NAD) is the fundamental molecule that performs numerous biological reactions and is crucial for maintaining cellular homeostasis.... (Review)
Review
Nicotinamide adenine dinucleotide (NAD) is the fundamental molecule that performs numerous biological reactions and is crucial for maintaining cellular homeostasis. Studies have found that NAD decreases with age in certain tissues, and age-related NAD depletion affects physiological functions and contributes to various aging-related diseases. Supplementation of NAD precursor significantly elevates NAD levels in murine tissues, effectively mitigates metabolic syndrome, enhances cardiovascular health, protects against neurodegeneration, and boosts muscular strength. Despite the versatile therapeutic functions of NAD in animal studies, the efficacy of NAD precursors in clinical studies have been limited compared with that in the pre-clinical study. Clinical studies have demonstrated that NAD precursor treatment efficiently increases NAD levels in various tissues, though their clinical proficiency is insufficient to ameliorate the diseases. However, the latest studies regarding NAD precursors and their metabolism highlight the significant role of gut microbiota. The studies found that orally administered NAD intermediates interact with the gut microbiome. These findings provide compelling evidence for future trials to further explore the involvement of gut microbiota in NAD metabolism. Also, the reduced form of NAD precursor shows their potential to raise NAD, though preclinical studies have yet to discover their efficacy. This review sheds light on NAD therapeutic efficiency in preclinical and clinical studies and the effect of the gut microbiota on NAD metabolism.
Topics: Mice; Animals; NAD; Dietary Supplements; Aging; Niacinamide; Nicotinamide Mononucleotide
PubMed: 38340651
DOI: 10.1016/j.bbrc.2024.149590 -
The Journal of Steroid Biochemistry and... Feb 2024Prostate cancer (PC) is dependent on androgen receptor (AR) activation by testosterone and 5α-dihydrotestosterone (DHT). Intratumoral androgen accumulation and...
Prostate cancer (PC) is dependent on androgen receptor (AR) activation by testosterone and 5α-dihydrotestosterone (DHT). Intratumoral androgen accumulation and activation despite systemic androgen deprivation therapy underlies the development of castration-resistant PC (CRPC), but the precise pathways involved remain controversial. Here we investigated the differential contributions of de novo androgen biosynthesis and androgen precursor conversion to androgen accumulation. Steroid flux analysis by liquid chromatography-tandem mass spectrometry (LC-MS/MS) was performed on (CR)PC cell lines and fresh patient PC tissue slices after incubation with classic and alternative biosynthesis intermediates, alongside quantitative PCR analysis for steroidogenic enzyme expression. Activity of CYP17A1 was undetectable in all PC cell lines and patient PC tissue slices. Instead, steroid flux analysis confirmed the generation of testosterone and DHT from adrenal precursors and reactivation of androgen metabolites. Precursor steroids upstream of DHEA were converted down the first steps of the alternative DHT biosynthesis pathway, but did not proceed through to active androgen generation. Comprehensive steroid flux analysis of (CR)PC cells provides strong evidence against intratumoral de novo androgen biosynthesis and demonstrates that androgen precursor steroids downstream of CYP17A1 activities constitute the major source of intracrine androgen generation.
Topics: Male; Humans; Prostatic Neoplasms; Androgens; Androgen Antagonists; Chromatography, Liquid; Tandem Mass Spectrometry; Testosterone; Dihydrotestosterone; Receptors, Androgen; Steroids; Cell Line, Tumor; Steroid 17-alpha-Hydroxylase
PubMed: 38104728
DOI: 10.1016/j.jsbmb.2023.106446