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Discover Oncology May 2024Cellular proliferation, function and survival is reliant upon maintaining appropriate intracellular polyamine levels. Due to increased metabolic needs, cancer cells... (Review)
Review
Cellular proliferation, function and survival is reliant upon maintaining appropriate intracellular polyamine levels. Due to increased metabolic needs, cancer cells elevate their polyamine pools through coordinated metabolism and uptake. High levels of polyamines have been linked to more immunosuppressive tumor microenvironments (TME) as polyamines support the growth and function of many immunosuppressive cell types such as MDSCs, macrophages and regulatory T-cells. As cancer cells and other pro-tumorigenic cell types are highly dependent on polyamines for survival, pharmacological modulation of polyamine metabolism is a promising cancer therapeutic strategy. This review covers the roles of polyamines in various cell types of the TME including both immune and stromal cells, as well as how competition for nutrients, namely polyamine precursors, influences the cellular landscape of the TME. It also details the use of polyamines as biomarkers and the ways in which polyamine depletion can increase the immunogenicity of the TME and reprogram tumors to become more responsive to immunotherapy.
PubMed: 38761252
DOI: 10.1007/s12672-024-01034-9 -
IScience May 2024Mitochondrial function relies on the coordinated transcription of mitochondrial and nuclear genomes to assemble respiratory chain complexes. Across species, the SIN3...
Mitochondrial function relies on the coordinated transcription of mitochondrial and nuclear genomes to assemble respiratory chain complexes. Across species, the SIN3 coregulator influences mitochondrial functions, but how its loss impacts mitochondrial homeostasis and metabolism in the context of a whole organism is unknown. Exploring this link is important because haploinsufficiency causes intellectual disability/autism syndromes and SIN3 plays a role in tumor biology. Here we show that loss of SIN-3 results in transcriptional deregulation of mitochondrial- and nuclear-encoded mitochondrial genes, potentially leading to mito-nuclear imbalance. Consistent with impaired mitochondrial function, mutants show extensive mitochondrial fragmentation by transmission electron microscopy (TEM) and imaging, and altered oxygen consumption. Metabolomic analysis of mutant animals revealed a mitochondria stress signature and deregulation of methionine flux, resulting in decreased S-adenosyl methionine (SAM) and increased polyamine levels. Our results identify SIN3 as a key regulator of mitochondrial dynamics and metabolic flux, with important implications for human pathologies.
PubMed: 38746662
DOI: 10.1016/j.isci.2024.109789 -
BioRxiv : the Preprint Server For... Apr 2024The gut microbiome has been proposed to influence many aspects of animal development and physiology. However, both the specific bacterial species and the molecular...
The gut microbiome has been proposed to influence many aspects of animal development and physiology. However, both the specific bacterial species and the molecular mechanisms by which bacteria exert these effects are unknown in most cases. Here, we established a high throughput screening platform using the model animal for identifying bacterial species and mechanisms that influence animal development and physiology. From our initial screens we found that many species can restore normal animal development to insulin signaling mutant animals that otherwise do not develop to adulthood. To determine how influence animal development we screened a complete non-essential gene knockout library of for mutants that no longer restored development to adulthood. We found the gene is required for animal development. In the absence of , produces excess N1-aminopropylagmatine. This polyamine is taken up by animal intestinal cells via the polyamine transporter CATP-5. When this molecule is taken up in sufficient quantities it inhibits animal mitochondrial function and causes diverse species of animals to arrest their development. To our knowledge, these are the first observations that can produce N1-aminopropylagmatine and that polyamines produced by intestinal microbiome species can antagonize animal development and mitochondrial function. Given that species are regularly isolated from animal intestinal microbiomes, including from humans, we propose that altered polyamine production from intestinal is likely to also influence animal development and metabolism in other species and potentially even contribute developmental and metabolic pathologies in humans. In addition, our findings demonstrate that can be used as a model animal to conduct high throughput screens for bacterial species and bioactive molecules that alter animal physiology.
PubMed: 38746390
DOI: 10.1101/2024.04.29.591726 -
Scientific Reports May 2024Ethylenediaminetetraacetic acid (EDTA), a classically used chelating agent of decalcification, maintains good morphological details, but its slow decalcification limits...
Ethylenediaminetetraacetic acid (EDTA), a classically used chelating agent of decalcification, maintains good morphological details, but its slow decalcification limits its wider applications. Many procedures have been reported to accelerate EDTA-based decalcification, involving temperature, concentration, sonication, agitation, vacuum, microwave, or combination. However, these procedures, concentrating on purely tissue-outside physical factors to increase the chemical diffusion, do not enable EDTA to exert its full capacity due to tissue intrinsic chemical resistances around the diffusion passage. The resistances, such as tissue inner lipids and electric charges, impede the penetration of EDTA. We hypothesized that delipidation and shielding electric charges would accelerate EDTA-based penetration and the subsequent decalcification. The hypothesis was verified by the observation of speedy penetration of EDTA with additives of detergents and hypertonic saline, testing on tissue-mimicking gels of collagen and adult mouse bones. Using a 26% EDTA mixture with the additives at 45°C, a conventional 7-day decalcification of adult mouse ankle joints could be completed within 24 h while the tissue morphological structure, antigenicity, enzymes, and DNA were well preserved, and mRNA better retained compared to using 15% EDTA at room temperature. The addition of hypertonic saline and detergents to EDTA decalcification is a simple, rapid, and inexpensive method that doesn't disrupt the current histological workflow. This method is equally or even more effective than the currently most used decalcification methods in preserving the morphological details of tissues. It can be highly beneficial for the related community.
Topics: Animals; Edetic Acid; Detergents; Mice; RNA, Messenger; Saline Solution, Hypertonic; Bone and Bones; Decalcification Technique
PubMed: 38740835
DOI: 10.1038/s41598-024-61459-8 -
Cell Death & Disease May 2024Precise polyamine metabolism regulation is vital for cells and organisms. Mutations in spermine synthase (SMS) cause Snyder-Robinson intellectual disability syndrome...
Precise polyamine metabolism regulation is vital for cells and organisms. Mutations in spermine synthase (SMS) cause Snyder-Robinson intellectual disability syndrome (SRS), characterized by significant spermidine accumulation and autophagy blockage in the nervous system. Emerging evidence connects polyamine metabolism with other autophagy-related diseases, such as Tauopathy, however, the functional intersection between polyamine metabolism and autophagy in the context of these diseases remains unclear. Here, we altered SMS expression level to investigate the regulation of autophagy by modulated polyamine metabolism in Tauopathy in Drosophila and human cellular models. Interestingly, while complete loss of Drosophila spermine synthase (dSms) impairs lysosomal function and blocks autophagic flux recapitulating SRS disease phenotype, partial loss of dSms enhanced autophagic flux, reduced Tau protein accumulation, and led to extended lifespan and improved climbing performance in Tauopathy flies. Measurement of polyamine levels detected a mild elevation of spermidine in flies with partial loss of dSms. Similarly, in human neuronal or glial cells, partial loss of SMS by siRNA-mediated knockdown upregulated autophagic flux and reduced Tau protein accumulation. Importantly, proteomics analysis of postmortem brain tissue from Alzheimer's disease (AD) patients showed a significant albeit modest elevation of SMS level. Taken together, our study uncovers a functional correlation between polyamine metabolism and autophagy in AD: SMS reduction upregulates autophagy, suppresses Tau accumulation, and ameliorates neurodegeneration and cell death. These findings provide a new potential therapeutic target for AD.
Topics: Autophagy; Animals; tau Proteins; Humans; Spermine Synthase; Drosophila melanogaster; Drosophila Proteins; Tauopathies; Neurons; Alzheimer Disease; Spermidine; Disease Models, Animal; Lysosomes; Drosophila; Mental Retardation, X-Linked
PubMed: 38740758
DOI: 10.1038/s41419-024-06720-8 -
Ecotoxicology and Environmental Safety Jun 2024The issue of mercury (Hg) toxicity has recently been identified as a significant environmental concern, with the potential to impede plant growth in forested and...
The issue of mercury (Hg) toxicity has recently been identified as a significant environmental concern, with the potential to impede plant growth in forested and agricultural areas. Conversely, recent reports have indicated that Fe, may play a role in alleviating HM toxicity in plants. Therefore, this study's objective is to examine the potential of iron nanoparticles (Fe NPs) and various sources of Fe, particularly iron sulfate (Fe SO or Fe S) and iron-ethylene diamine tetra acetic acid (Fe - EDTA or Fe C), either individually or in combination, to mitigate the toxic effects of Hg on Pleioblastus pygmaeus. Involved mechanisms in the reduction of Hg toxicity in one-year bamboo species by Fe NPs, and by various Fe sources were introduced by a controlled greenhouse experiment. While 80 mg/L Hg significantly reduced plant growth and biomass (shoot dry weight (36%), root dry weight (31%), and shoot length (31%) and plant tolerance (34%) in comparison with control treatments, 60 mg/L Fe NPs and conventional sources of Fe increased proline accumulation (32%), antioxidant metabolism (21%), polyamines (114%), photosynthetic pigments (59%), as well as root dry weight (25%), and shoot dry weight (22%), and shoot length (22%). Fe NPs, Fe S, and Fe C in plant systems substantially enhanced tolerance to Hg toxicity (23%). This improvement was attributed to increased leaf-relative water content (39%), enhanced nutrient availability (50%), improved antioxidant capacity (34%), and reduced Hg translocation (6%) and accumulation (31%) in plant organs. Applying Fe NPs alone or in conjunction with a mixture of Fe C and Fe S can most efficiently improve bamboo plants' tolerance to Hg toxicity. The highest efficiency in increasing biochemical and physiological indexes under Hg, was related to the treatments of Fe NPs as well as Fe NPs + FeS + FeC. Thus, Fe NPs and other Fe sources might be effective options to remove toxicity from plants and soil. The future perspective may help establish mechanisms to regulate environmental toxicity and human health progressions.
Topics: Iron; Mercury; Soil Pollutants; Metal Nanoparticles; Soil; Edetic Acid; Poaceae; Environmental Restoration and Remediation; Nutrients; Antioxidants
PubMed: 38718730
DOI: 10.1016/j.ecoenv.2024.116431 -
Frontiers in Immunology 2024The objective of this study was to investigate the impact of electro-acupuncture (EA) on sepsis-related intestinal injury and its relationship with macrophage...
OBJECTIVE
The objective of this study was to investigate the impact of electro-acupuncture (EA) on sepsis-related intestinal injury and its relationship with macrophage polarization.
METHODS
A sepsis model was established using cecal ligation and puncture (CLP) to assess the effectiveness of EA. The extent of pathological injury was evaluated using Chiu's score, the expression of ZO-1 and Ocludin, and the impact on macrophage polarization was examined through flow cytometry and immunofluorescence staining. The expression of spermidine, one type of polyamine, and ornithine decarboxylase (ODC) was measured using ELISA and PCR. Once the efficacy was determined, a polyamine depletion model was created, and the role of polyamines was reassessed by evaluating efficacy and observing macrophage polarization.
RESULTS
EA treatment reduced the Chiu's score and increased the expression of ZO-1 and Ocludin in the intestinal tissue of septic mice. It inhibited the secretion of IL-1β and TNF-α, promoted the polarization of M2-type macrophages, increased the secretion of IL-10, and upregulated the expression of Arg-1, spermidine, and ODC. However, after depleting polyamines, the beneficial effects of EA on alleviating intestinal tissue damage and modulating macrophage polarization disappeared.
CONCLUSION
The mechanism underlying the alleviation of intestinal injury associated with CLP-induced sepsis by EA involves with the promotion of M2-type macrophage polarization mediated by spermidine expression.
Topics: Animals; Sepsis; Mice; Macrophages; Electroacupuncture; Polyamines; Male; Disease Models, Animal; Macrophage Activation; Intestines; Mice, Inbred C57BL; Cytokines
PubMed: 38715602
DOI: 10.3389/fimmu.2024.1373876 -
Arthritis Research & Therapy May 2024Gout is caused by monosodium urate (MSU) crystals deposition to trigger immune response. A recent study suggested that inhibition of Class I Histone deacetylases (HDACs)...
BACKGROUND
Gout is caused by monosodium urate (MSU) crystals deposition to trigger immune response. A recent study suggested that inhibition of Class I Histone deacetylases (HDACs) can significantly reduce MSU crystals-induced inflammation. However, which one of HDACs members in response to MSU crystals was still unknown. Here, we investigated the roles of HDAC3 in MSU crystals-induced gouty inflammation.
METHODS
Macrophage specific HDAC3 knockout (KO) mice were used to investigate inflammatory profiles of gout in mouse models in vivo, including ankle arthritis, foot pad arthritis and subcutaneous air pouch model. In the in vitro experiments, bone marrow-derived macrophages (BMDMs) from mice were treated with MSU crystals to assess cytokines, potential target gene and protein.
RESULTS
Deficiency of HDAC3 in macrophage not only reduced MSU-induced foot pad and ankle joint swelling but also decreased neutrophils trafficking and IL-1β release in air pouch models. In addition, the levels of inflammatory genes related to TLR2/4/NF-κB/IL-6/STAT3 signaling pathway were significantly decreased in BMDMs from HDAC3 KO mice after MSU treatment. Moreover, RGFP966, selective inhibitor of HDAC3, inhibited IL-6 and TNF-α production in BMDMs treated with MSU crystals. Besides, HDAC3 deficiency shifted gene expression from pro-inflammatory macrophage (M1) to anti-inflammatory macrophage (M2) in BMDMs after MSU challenge.
CONCLUSIONS
Deficiency of HDAC3 in macrophage alleviates MSU crystals-induced gouty inflammation through inhibition of TLR2/4 driven IL-6/STAT3 signaling pathway, suggesting that HDAC3 could contribute to a potential therapeutic target of gout.
Topics: Animals; Uric Acid; Histone Deacetylases; Macrophages; Mice, Knockout; Gout; Mice; Mice, Inbred C57BL; Inflammation; Male; Arthritis, Gouty; Disease Models, Animal; Signal Transduction; Acrylamides; Phenylenediamines
PubMed: 38711064
DOI: 10.1186/s13075-024-03335-4 -
Spectrochimica Acta. Part A, Molecular... Sep 2024Over the years, osteosarcoma therapy has had a significative improvement with the use of a multidrug regime strategy, increasing the survival rates from less than 20 %...
Over the years, osteosarcoma therapy has had a significative improvement with the use of a multidrug regime strategy, increasing the survival rates from less than 20 % to circa 70 %. Different types of development of new antineoplastic agents are critical to achieve irreversible damage to cancer cells, while preserving the integrity of their healthy counterparts. In the present study, complexes with two and three Pd(II) centres linked by the biogenic polyamines: spermine (PdSpmCl) and spermidine (PdSpdCl) were tested against non-malignant (osteoblasts, HOb) and cancer (osteosarcoma, MG-63) human cell lines. Either alone or in combination according to the EURAMOS-1 protocol, they were used versus cisplatin as a drug reference. By evaluating the cytotoxic effects of both therapeutic approaches (single and drug combination) in HOb and MG-63 cell lines, the selective anti-tumoral potential is assessed. To understand the different treatments at a molecular level, Synchrotron Radiation Fourier Transform Infrared and Raman microspectroscopies were applied. Principal component analysis and hierarchical cluster analysis are applied to the vibrational data, revealing the major metabolic changes caused by each drug, which were found to rely on DNA, lipids, and proteins, acting as biomarkers of drug-to-cell impact. The main changes were observed for the B-DNA native conformation to either Z-DNA (higher in the presence of polynuclear complexes) or A-DNA (preferably after cisplatin exposure). Additionally, a higher effect upon variation in proteins content was detected in drug combination when compared to single drug administration proving the efficacy of the EURAMOS-1 protocol with the new drugs tested.
Topics: Humans; Osteosarcoma; Spectrum Analysis, Raman; Antineoplastic Agents; Cell Line, Tumor; Spectroscopy, Fourier Transform Infrared; Vibration; Spermine; Bone Neoplasms; Spermidine; Principal Component Analysis; Cell Survival
PubMed: 38710137
DOI: 10.1016/j.saa.2024.124389 -
Medicine May 2024Very few studies worldwide have assessed the estimated glomerular filtration rate (eGFR) using serum cystatin C (ScysC) in comparison to the gold standard measured...
Very few studies worldwide have assessed the estimated glomerular filtration rate (eGFR) using serum cystatin C (ScysC) in comparison to the gold standard measured glomerular filtration rate (mGFR) with a gamma camera technique using 99m-Technetium-Diethylene Triaminepentoacetic Acid (99mTc-DTPA). To determine the eGFR formula with the most accurate estimate of glomerular filtration rate when compared with mGFR in a healthy population in Vietnam. We conducted a cross-sectional descriptive study of more than 100 adults without hypertension. The study subjects were examined for general characteristics and blood biochemistry tests to assess eGFR, and the glomerular filtration rate was measured using 99mTc-DTPA with the Gates technique to record mGFR. The estimated values of the eGFR formula were evaluated and compared with the actual mGFR using 99mTechnetium-DTPA. Serum creatinine (Scr) concentration showed a significant difference between males and females: 0.9 ± 0.1 versus 0.8 ± 0.1 (P < .001), while ScysC concentration did not show this difference. The mGFR in the age groups < 40, 40 to 59, and ≥ 60: 105.0 ± 9.9, 94.8 ± 8.6, and 93.4 ± 10.6, respectively (P < .001). The eGFR-CKD-EPI-cystatin C 2012 formula showed the highest positive correlation with mGFR (ΔGFR = -1.6, R = 0.68, P < .001). eGFR calculated using cystatin C does not require sex adjustment, whereas, for creatinine, sex adjustment is necessary. The eGFR-CKD-Epi-CysC formula showed the lowest difference and a strong correlation with mGFR.
Topics: Humans; Cystatin C; Glomerular Filtration Rate; Female; Male; Creatinine; Middle Aged; Adult; Cross-Sectional Studies; Vietnam; Technetium Tc 99m Pentetate; Aged; Biomarkers; Radiopharmaceuticals; Southeast Asian People
PubMed: 38701272
DOI: 10.1097/MD.0000000000037997