PubMed

Heliyon. 2024 Aug 3;10(15):e35755. doi: 10.1016/j.heliyon.2024.e35755. eCollection 2024 Aug 15.ABSTRACTIntestinal flora metabolites played a crucial role in immunomodulation by influencing host immune responses through various pathways. Macrophages, as a type of innate immune cell, were essential in chemotaxis, phagocytosis, inflammatory responses, and microbial elimination. Different macrophage phenotypes had distinct biological functions, regulated by diverse factors and mechanisms. Advances in intestinal flora sequencing and metabolomics have enhanced understanding of how intestinal flora metabolites affect macrophage phenotypes and functions. These metabolites had varying effects on macrophage polarization and different mechanisms of influence. This study summarized the impact of gut microbiota metabolites on macrophage phenotype and function, along with the underlying mechanisms associated with different metabolites produced by intestinal flora.PMID:39170251 | PMC:PMC11337042 | DOI:10.1016/j.heliyon.2024.e35755

Heliyon. 2024 Aug 6;10(15):e35861. doi: 10.1016/j.heliyon.2024.e35861. eCollection 2024 Aug 15.ABSTRACTThe issue of non-renewable energy scarcity has persisted over an extended period, primarily due to the depletion of fossil fuel reserves and the adverse effects of their utilization. This scarcity stems from the finite nature of fossil energy resources. The development of oil energy or biofuels aims to utilize oil-producing plants such as Jatropha curcas to develop alternative energy resources. However, metabolomic studies in Jatropha curcas are limited and need more investigations. Therefore, this research was essential to find biomarkers of metabolites among the fruit, leaf, and stem of Jatropha curcas using the GC-MS technique. We tested the metabolite profile with the R program, especially the metaboanalystR package, to determine fold change metabolite and pathway analysis. We found that 54 metabolites were detected in both fruit, leaf, and stem tissues of Jatropha curcas L, of which 19 metabolites were upregulated in the fruit, 20 metabolites in the leaf, and 15 up-regulated metabolites in the stem. The metabolites found formed three clusters based on correlation and networking metabolites analysis. The three clusters showed a relationship with the lipid biosynthesis pathway. In this study, provisional information was obtained that there was a different pattern of expression of metabolites between fruit, leaf, and stem tissues in Jatropha curcas, which was thought to be related to the critical metabolites of oleic acid and methylcyclohexane carboxylate in the biosynthetic pathway of fatty acids and unsaturated fatty acids. This information is essential as an initial reference for genetic engineering Jatropha curcas so that it can be used to transform plants, especially lipid-producing plants, as a source of oil.PMID:39170246 | PMC:PMC11337045 | DOI:10.1016/j.heliyon.2024.e35861

Heliyon. 2024 Jul 30;10(15):e35394. doi: 10.1016/j.heliyon.2024.e35394. eCollection 2024 Aug 15.ABSTRACTPolygonati Rhizoma (PR, Huangjing in Chinese) and its processed product (PRP), which are used in Traditional Chinese medicine (TCM) for cognitive enhancement and treatment of Alzheimer's disease (AD), have not been fully explored in terms of the different mechanisms underlying their anti-AD effects. Therefore, we used APP/PS1 mice as an AD model to assess the effects of PR and PRP on anxiety-like behaviors, cognitive function, memory performance, and pathological changes in the murine brain. UPLC-HRMS was applied to identify the components of PR and PRP that entered into the blood and brain. Network pharmacology was used to elucidate potential mechanisms underlying the improvement of AD. Differences in the intestinal flora composition between mice treated with PR and PRP were investigated using 16S rRNA sequencing, establishing a correlation between pharmacological components and distinct flora profiles. The results revealed that both PR and PRP interventions ameliorated cognitive deficits and attenuated Amyloid β (Aβ) plaque deposition in the brains of AD mice. Seven specific blood-entering components, namely glutamic acid, Phe-Phe, and uridine, etc., were associated with PR intervention, whereas ten specific blood-entering components including (2R,3S)-3-isopropylmalate, 3-methylhexahydropyrrolo[1,2-a]pyrazine-1,4-dione, and 3-methoxytyrosine were related to PRP intervention. Uridine was identified as a common brain-penetrating component in both PR and PRP interventions. Network pharmacology analysis suggested that the NOD-like receptor signaling pathway, Calcium signaling pathway and Alzheimer's disease were specific pathways targeted in AD treatment using PR intervention. Moreover, the apoptosis pathway was specifically linked to AD treatment during PRP intervention. Furthermore, the administration of both PR and PRP enhanced the abundance and diversity of the intestinal flora in APP/PS1 mice. Western blotting confirmed that PR excels in regulates inflammation, whereas PRP balances autophagy and apoptosis to alleviate the progression of AD. This study offers valuable insights and establishes a robust foundation for further comprehensive exploration of the intrinsic correlation between TCM and AD.PMID:39170207 | PMC:PMC11336570 | DOI:10.1016/j.heliyon.2024.e35394

Heliyon. 2024 Jul 9;10(15):e34317. doi: 10.1016/j.heliyon.2024.e34317. eCollection 2024 Aug 15.ABSTRACTBACKGROUND: Gastric cancer (GC) is one of the most common malignant tumors in the world. It has become increasingly difficult to meet the needs of precision therapy using the existing molecular typing system. Therefore, developing a more effective molecular typing system for GC is urgent.METHODS: In this study, 100 Chinese GC patients were included. Whole-exome sequencing (WES) and metabolomics analysis were performed to reveal the characteristics of genomic and metabolic changes.RESULTS: In WES, nonsynonymous mutations accounted for the majority. Based on metabolomics, GC has been divided into three subtypes with distinct metabolic features. Importantly, we ultimately divided GC into four subtypes with different metabolic characteristics, genomic alterations, and clinical prognoses by incorporating biomics analysis.CONCLUSIONS: Integrating biological features, we constructed a novel molecular system for GC that was closely related to genetics and metabolism, providing new insights for further understanding the heterogeneity and formulating precise treatment strategies.PMID:39170180 | PMC:PMC11336309 | DOI:10.1016/j.heliyon.2024.e34317

Phytochem Anal. 2024 Aug 21. doi: 10.1002/pca.3436. Online ahead of print.ABSTRACTINTRODUCTION: Cannabis sativa is a highly versatile plant with a long history of cultivation and domestication. It produces multiple compounds that exert distinct and valuable therapeutic effects by modulating diverse biological systems, including the endocannabinoid system (ECS). Access to standardized, metabolically diverse, and reproducible C. sativa chemotypes and chemovars is essential for physicians to optimize individualized patient treatment and for industries to conduct drug-discovery campaigns.OBJECTIVE: This study aimed to characterize and assess the phytochemical diversity of C. sativa chemotypes in diverse ecological regions of Colombia, South America.METHODOLOGY: Ten cannabinoids and 23 terpenes were measured using liquid and gas chromatography, in addition to other phenotypic traits, in 156 C. sativa plants that were grown in diverse ecological regions in Colombia, a hotspot for global biodiversity.RESULTS: Our results reveal significant phytochemical diversity in Colombian-grown C. sativa plants, with four distinct chemotypes based on cannabinoid profile. The significant amount of usually uncommon terpenes suggests that Colombia's environments may have unique capabilities that allow the plant to express these compounds. Colombia's diverse climates offer enormous cultivation potential, making it a key player in both domestic and international medicinal and recreational C. sativa trade.CONCLUSION: These findings underscore Colombia's capacity to pioneer global C. sativa production diversification, particularly in South America with new emerging markets.PMID:39169651 | DOI:10.1002/pca.3436

J Sep Sci. 2024 Aug;47(16):e2400436. doi: 10.1002/jssc.202400436.ABSTRACTSteroids can be used as biomarkers in clinical metabolomics and other fields related to human toxicology. This chemical group is known for its complexity, considering its number of isobaric compounds and the wide variety of phases I and II metabolic pathways that parent compounds can undergo. For a successful analysis of steroids in biological samples, liquid chromatography separation must be finely tuned. It is especially challenging for glucuronidated and sulfated steroids derivatives that bear polar heads and can be affected by non-specific adsorption. The benefits of a biphenyl stationary phase chemistry for the selectivity of the separation of steroids and their phase II metabolites and the extent to which nonspecific adsorption phenomena could degrade chromatographic performance were investigated. Replacing a conventional hardware by a passivated hardware allowed to considerably reduce peaks width and asymmetry of sulfated species. The addition of weak ion pairing agents in the mobile phase could also help to reduce non-specific adsorption but are detrimental to mass spectrometry detection. As confirmed by the successful detection of 52 steroids in plasma, the use of a biphenyl stationary phase complemented by a passivated column hardware is of great help for a successful biomedical analysis of steroids and their phase II metabolites.PMID:39169650 | DOI:10.1002/jssc.202400436

Arthritis Care Res (Hoboken). 2024 Aug 21. doi: 10.1002/acr.25420. Online ahead of print.ABSTRACTOBJECTIVES: Our objective was to prospectively investigate pre-diagnostic population-based metabolome for risk of hospitalized gout (i.e., most accurate, severe, and costly cases), accounting for serum urate.METHODS: We conducted pre-diagnostic metabolome-wide analyses among 249,677 UK Biobank participants with NMR metabolomic profiling (N=168 metabolites, including eight amino acids) from baseline blood samples (2006-2010), without a history of gout. We calculated multivariable hazard ratios (HRs) for incident hospitalized gout, before and after adjusting for serum urate levels; we included non-hospitalised incident gout cases in a sensitivity analysis. Potential causal effects were evaluated with two-sample Mendelian randomization.RESULTS: Correcting for multiple testing, 107 metabolites were associated with incidence of hospitalized gout (N=2735) before urate adjustment, including glycine and glutamine (inversely; HR=0.64 [95% CI: 0.54, 0.75], P=8.3x10-8 and HR=0.69 [0.61, 0.78], P=3.3x10-9 between extreme quintiles, respectively), and glycoprotein acetyls (GlycA; HR=2.48 [2.15, 2.87], P=1.96x10-34). Associations remained significant and directionally-consistent following urate adjustment (HR=0.83 [0.70, 0.98], 0.86 [0.76, 0.98], 1.41 [1.21, 1.63] between extreme quintiles), respectively; corresponding HR per SD were 0.91 (0.86, 0.97), 0.94 (0.91, 0.98), and 1.10 (1.06, 1.14). Findings persisted when including non-hospitalised incident gout cases. Mendelian randomization corroborated their potential causal role on hyperuricemia or gout risk; with change in urate levels of -0.05 mg/dL (-0.08, -0.01), and -0.12 mg/dL (-0.22, -0.03), per SD of glycine and glutamine, respectively, and ORs 0.94 (0.88, 1.00), and 0.81 (0.67, 0.97), for gout.CONCLUSION: These prospective findings with causal implications could lead to biomarker-based risk prediction and potential supplementation-based interventions with glycine or glutamine.PMID:39169570 | DOI:10.1002/acr.25420

Bioresour Technol. 2024 Aug 19:131312. doi: 10.1016/j.biortech.2024.131312. Online ahead of print.ABSTRACTMicrobial oils have been of considerable interest as food additives and biofuel resources due to high lipid contents, but lipid accumulation of oleaginous microorganisms can be induced by environmental stresses, such as dissolved oxygen (DO), which limit large-scale lipid production. Here, DO stress gave rise to the endogenous nitric oxide (NO) level to mediate S-nitrosylation of SpAsg1, regulating the lipid accumulation in Saitozyma podzolica zwy-2-3. Notably, qRT-PCR, yeast one-hybrid, dual-luciferase reporter assays, and metabolomics analysis exhibited that overexpression of SpAsg1 promoted lipid synthesis by directly regulation of glucose metabolism, enhancing glucose uptake, ATP and NADPH contents under DO stress. Meanwhile, SpAsg1 improved the antioxidant capacity to reduce the intracellular reactive oxygen species (ROS) and NO levels. Overall, we systematically investigated the regulation of SpAsg1 on lipid metabolism of S. podzolica zwy-2-3 under DO stress, which sheds light on further studies for alleviating oxygen limitation of lipid production in microbial industry.PMID:39168414 | DOI:10.1016/j.biortech.2024.131312

Int J Biol Macromol. 2024 Aug 19:134823. doi: 10.1016/j.ijbiomac.2024.134823. Online ahead of print.ABSTRACTIn our previous study, bile Arisaema was elucidated to have a significant anti-febrile effect, but the pharmacodynamic material basis of this effect remains uncertain. Herein, we found that the soluble polysaccharide fraction from bile Arisaema presents a remarkable antipyretic effect through balancing the gut microbiota and regulating metabolic profiling. Bile Arisaema polysaccharide (BAP) was characterized for its monosaccharide composition with arabinose, galactose, glucose, mannose and xylose (0.028:0.072:0.821:0.05:0.029, molar ratios) and amino acid composition with arginine, threonine, alanine, glycine, serine, proline and tyrosine (109.33, 135.78, 7.22, 8.86, 21.07, 4.96, 12.31 μg/mg). A total of 50 peptides were identified from BAP using Ltq-Orbitrap MS/MS. The oral administration of 100 mg/kg BAP significantly increased the antipyretic effect in yeast-induced fever rats by comparing the rectal temperature. Mechanistically, the inflammation and disorders of neurotransmitters caused by fever were improved by treatment with BAP. The western blotting results suggested that BAP could suppress fever-induced inflammation by down-regulating the NF-κB/TLR4/MyD88 signaling pathway. We also demonstrated that BAP affects lipid metabolism, amino acid metabolism and carbohydrate metabolism and balances the gut microbiota. In summary, the present study provides a crucial foundation for determining polysaccharide activity in bile Arisaema and further investigating the underlying mechanism of action.PMID:39168226 | DOI:10.1016/j.ijbiomac.2024.134823

Comput Biol Med. 2024 Aug 20;181:109040. doi: 10.1016/j.compbiomed.2024.109040. Online ahead of print.ABSTRACTThe integration of multi-omics data offers a robust approach to understanding the complexity of diseases by combining information from various biological levels, such as genomics, transcriptomics, proteomics, and metabolomics. This integrated approach is essential for a comprehensive understanding of disease mechanisms and for developing more effective diagnostic and therapeutic strategies. Nevertheless, most current methodologies fail to effectively extract both shared and specific representations from omics data. This study introduces MOSDNET, a multi-omics classification framework that effectively extracts shared and specific representations. This framework leverages Simplified Multi-view Deep Discriminant Representation Learning (S-MDDR) and Dynamic Edge GCN (DEGCN) to enhance the accuracy and efficiency of disease classification. Initially, MOSDNET utilizes S-MDDR to establish similarity and orthogonal constraints for extracting these representations, which are then concatenated to integrate the multi-omics data. Subsequently, MOSDNET constructs a comprehensive view of the sample data by employing patient similarity networks. By incorporating similarity networks into DEGCN, MOSDNET learns intricate network structures and node representations, which enables superior classification outcomes. MOSDNET is trained through a multitask learning approach, effectively leveraging the complementary knowledge from both the data integration and classification components. After conducting extensive comparative experiments, we have conclusively demonstrated that MOSDNET outperforms leading state-of-the-art multi-omics classification models in terms of classification accuracy. Simultaneously, we employ MOSDNET to identify pivotal biomarkers within the multi-omics data, providing insights into disease etiology and progression.PMID:39168014 | DOI:10.1016/j.compbiomed.2024.109040

Drug Resist Updat. 2024 Aug 16;77:101138. doi: 10.1016/j.drup.2024.101138. Online ahead of print.ABSTRACTAIMS: To investigate the molecular events associated with acquiring macrolide resistance genes [mefE/mel (Mega) or ermB] in Streptococcus pneumoniae (Spn) during nasopharyngeal colonization.METHODS AND RESULTS: Genomic analysis of 128 macrolide-resistant Spn isolates revealed recombination events in genes of the conjugation apparatus, or the competence system, in strains carrying Tn916-related elements. Studies using confocal and electron microscopy demonstrated that during the transfer of Tn916-related elements in nasopharyngeal cell biofilms, pneumococcal strains formed clusters facilitating their acquisition of resistance determinants at a high recombination frequency (rF). Remarkably, these aggregates comprise both encapsulated and nonencapsulated pneumococci that span extracellular and intracellular compartments. rF assessments showed similar rates regardless Mega was associated with large integrative and conjugative elements (ICEs) (>23 kb) or not (∼5.4 kb). The rF for Mega Class IV(c) insertion region (∼53 kb) was three orders of magnitude higher than the transformation of the capsule locus. Metabolomics studies of the microenvironment created by colonization of human nasopharyngeal cells revealed a link between the acquisition of ICEs and the pathways involving nicotinic acid and sucrose.CONCLUSIONS: Pneumococcal clusters, both extracellular and intracellular, facilitate macrolide resistance acquisition, and ICEs were acquired at a higher frequency than the capsule locus. Metabolic changes could serve as intervention targets.PMID:39167981 | DOI:10.1016/j.drup.2024.101138

J Exp Clin Cancer Res. 2024 Aug 21;43(1):239. doi: 10.1186/s13046-024-03141-5.ABSTRACTOral squamous cell carcinoma (OSCC) accounts for around 90% of all oral cancers and is the eighth most common cancer worldwide. Despite progress in managing OSCC, the overall prognosis remains poor, with a survival rate of around 50-60%, largely due to tumor size and recurrence. The challenges of late-stage diagnosis and limitations in current methods emphasize the urgent need for less invasive techniques to enable early detection and treatment, crucial for improving outcomes in this aggressive form of oral cancer. Research is currently aimed at unraveling tumor-specific metabolite profiles to identify candidate biomarkers as well as discover underlying pathways involved in the onset and progression of cancer that could be used as new targets for diagnostic and therapeutic purposes. Metabolomics is an advanced technological approach to identify metabolites in different sample types (biological fluids and tissues). Since OSCC promotes metabolic reprogramming influenced by a combination of genetic predisposition and environmental factors, including tobacco and alcohol consumption, and viral infections, the identification of distinct metabolites through screening may aid in the diagnosis of this condition. Moreover, studies have shown the use of metabolites during the catalysis of epigenetic modification, indicating a link between epigenetics and metabolism. In this review, we will focus on the link between environmental, genetic, and epigenetic influences in metabolomic alterations in OSCC. In addition, we will discuss therapeutic targets of tumor metabolism, which may prevent oral tumor growth, metastasis, and drug resistance.PMID:39169426 | DOI:10.1186/s13046-024-03141-5

J Cachexia Sarcopenia Muscle. 2024 Aug 21. doi: 10.1002/jcsm.13567. Online ahead of print.ABSTRACTBACKGROUND: The pathophysiology of sarcopenia is complex and multifactorial and has not been fully elucidated. The impact of resistance training and nutritional support (RTNS) on metabolomics and lipodomics in older adults with sarcopenia remains uncertain. This study aimed to explore potential biomarkers of sarcopenia and clinical indicators of RTNS in older sarcopenic adults.METHODS: Older individuals diagnosed with sarcopenia through routine health checkups at a community hospital were recruited for a 12-week randomized controlled trial focusing on RTNS. Plasma metabolomic and lipidomic profiles of 45 patients with sarcopenia and 47 matched controls were analysed using 1H-nuclear magnetic resonance (1H-NMR) and liquid chromatography-mass spectrometer (LC-MS).RESULTS: At baseline, the patient and control groups had similar age, sex, and height distribution. The patient group had significantly lower weight, BMI, grip strength, gait speed, skeletal muscle index, lean mass of both the upper and lower limbs, and lower limb bone mass. There was a significant difference in 12 metabolites between the control and patient groups. They are isoleucine (patient/control fold change [FC] = 0.86 ± 0.04, P = 0.0005), carnitine (FC = 1.05 ± 0.01, P = 0.0110), 1-methylhistamine/3-methylhistamine (FC = 1.24 ± 0.14, P = 0.0039), creatinine (FC = 0.71 ± 0.04, P < 0.0001), carnosine (FC = 0.71 ± 0.04, P = 0.0007), ureidopropionic acid (FC = 0.61 ± 0.10, P = 0.0107), uric acid (FC = 0.88 ± 0.03, P = 0.0083), PC (18:2/20:0) (FC = 0.69 ± 0.03, P = 0.0010), PC (20:2/18:0) (FC = 0.70 ± 0.06, P = 0.0014), PC (18:1/20:1) (FC = 0.74 ± 0.05, P = 0.0015), PI 32:1 (FC = 4.72 ± 0.17, P = 0.0006), and PI 34:3 (FC = 1.88 ± 0.13, P = 0.0003). Among them, carnitine, 1-methylhistamine/3-methylhistamine, creatinine, ureidopropionic acid, uric acid, PI 32:1, and PI 34:3 were first identified. Notably, PI 32:1 had highest diagnostic accuracy (0.938) for sarcopenia. 1-Methylhistamine/3-methylhistamine, carnosine, PC (18:2/20:0), PI 32:1, and PI 34:3 levels were not different from the control group after RTNS. These metabolites are involved in amino acid metabolism, lipid metabolism, and the PI3K-AKT/mTOR signalling pathway through the ingenuity pathway analysis.CONCLUSIONS: These findings provide information on metabolic changes, lipid perturbations, and the role of RTNS in patients with sarcopenia. They reveal new insights into its pathological mechanisms and potential therapies.PMID:39169398 | DOI:10.1002/jcsm.13567

Cell Commun Signal. 2024 Aug 21;22(1):409. doi: 10.1186/s12964-024-01784-7.ABSTRACTBACKGROUND: Melanoma, one of the most lethal forms of skin cancer, has the potential to develop in any area where melanocytes are present. Currently, postoperative recurrence due to the emergence of systemic drug resistance represents a significant challenge in the treatment of melanoma. In this study, terphenyllin (TER), a distinctive inhibitory impact on melanoma cells was identified from the natural p-terphenyl metabolite. This study aimed to elucidate the intrinsic mechanism of this inhibitory effect, which may facilitate the discovery of novel chemotherapeutic agents.METHODS: A transcriptome sequencing and metabolomic analysis of TER-treated A375 cells was conducted to identify potential pathways of action. The key proteins were knocked out and backfilled using CRISPR-Cas9 technology and molecular cloning. Subsequently, the results of cytosolic viability, LDH release, immunofluorescence and flow cytometry were employed to demonstrate the cell death status of the drug-treated cells.RESULTS: The p53 signalling pathway was markedly upregulated following TER treatment, leading to the activation of CASP3 via the intrinsic apoptotic pathway. The activated CASP3 initiated apoptosis, while simultaneously continuing to cleave the GSDME, thereby triggering pyroptosis. The knockout of p53, a key protein situated upstream of this pathway, resulted in a significant rescue of TER-induced cell death, as well as an alleviation of the decrease in cell viability. However, the knockout of key proteins situated downstream of the pathway (CASP3 and GSDME) did not result in a rescue of TER-induced cell death, but rather a transformation of the cells from apoptosis and pyroptosis.CONCLUSIONS: The induction of apoptosis and pyroptosis in A375 cells by TER is mediated via the p53-BAX/FAS-CASP3-GSDME signalling pathway. This lays the foundation for TER as a potential anti-melanoma drug in the future. It should be noted that CASP3 and GSDME in this pathway solely regulate the mode of cell death, rather than determine whether cell death occurs. This distinction may prove valuable in future studies of apoptosis and pyroptosis.PMID:39169379 | DOI:10.1186/s12964-024-01784-7

Sci Rep. 2024 Aug 21;14(1):19417. doi: 10.1038/s41598-024-70600-6.ABSTRACTSo far, a variety of metabolite components of kiwifruit have been elucidated. However, the identification and analysis of flavonoids in different tissues of kiwifruit are rarely carried out. In this study, we performed transcriptome and metabolome analyses of roots (Gkf_R), stems (Gkf_T), leaves (Gkf_L), and fruits (Gkf_F) to provide insights into the differential accumulation and regulation mechanisms of flavonoids in kiwifruit. Results showed that a total of 301 flavonoids were identified, in four tissues with different accumulation trends, and a large proportion of flavonoids had high accumulation in Gkf_L and Gkf_R. A total of 84 genes have been identified involved in the flavonoid biosynthesis pathway, and the expression levels of five LAR, two DFR, and one HCT were significantly correlated with the accumulation of 16 flavonoids and co-localized in the flavonoid biosynthesis pathway. In addition, a total of 2362 transcription factor genes were identified, mainly MYBs, bHLHs, ERFs, bZIPs and WRKYs, among which the expression level of bHLH74, RAP2.3L/4L/10L, MYB1R1, and WRKY33 were significantly correlated with 25, 56, 43, and 24 kinds of flavonoids. Our research will enrich the metabolomic data and provide useful information for the directed genetic improvement and application in the pharmaceutical industry of kiwifruit.PMID:39169238 | DOI:10.1038/s41598-024-70600-6

Sci Rep. 2024 Aug 21;14(1):19351. doi: 10.1038/s41598-024-70386-7.ABSTRACTThe most devastating feature of cancer cells is their ability to metastasize to distant sites in the body. HER2 + and TN breast cancers frequently metastasize to the brain and stay potentially dormant for years until favorable conditions support their proliferation. The sheltered and delicate nature of the brain prevents, however, early disease detection and effective delivery of therapeutic drugs. Moreover, the challenges associated with the acquisition of brain biopsies add compounding difficulties to exploring the mechanistic aspects of tumor development. To provide insights into the determinants of cancer cell behavior at the brain metastatic site, this study was aimed at exploring the early response of HER2 + breast cancer cells (SKBR3) to factors present in the brain perivascular niche. The neural microenvironment was simulated by using the secretome of a set of brain cells that come first in contact with the cancer cells upon crossing the blood brain barrier, i.e., endothelial cells, astrocytes, and microglia. Cytokine microarrays were used to investigate the secretome mediators of intercellular communication, and proteomic technologies for assessing the changes in the behavior of cancer cells upon exposure to the brain cell-secreted factors. The cytokines detected in the brain secretomes were supportive of inflammatory conditions, while the SKBR3 cells secreted numerous cancer-promoting growth factors that were either absent or present in lower abundance in the brain cell cultures, indicating that upon exposure the SKBR3 cells may have been deprived of favorable conditions for optimal growth. Altogether, the results suggest that the exposure of SKBR3 cells to the brain cell-secreted factors altered their growth potential and drove them toward a state of quiescence, with broader overall outcomes that affected cellular metabolism, adhesion and immune response processes. The findings of this study underscore the key role played by the neural niche in shaping the behavior of metastasized cancer cells, provide insights into the cellular cross-talk that may lead cancer cells into dormancy, and highlight novel opportunities for the development of metastatic breast cancer therapeutic strategies.PMID:39169222 | DOI:10.1038/s41598-024-70386-7

EMBO Mol Med. 2024 Aug 21. doi: 10.1038/s44321-024-00119-w. Online ahead of print.ABSTRACTChemotherapy induced ovarian failure and infertility is an important concern in female cancer patients of reproductive age or younger, and non-invasive, pharmacological approaches to maintain ovarian function are urgently needed. Given the role of reduced nicotinamide adenine dinucleotide phosphate (NADPH) as an essential cofactor for drug detoxification, we sought to test whether boosting the NAD(P)+ metabolome could protect ovarian function. We show that pharmacological or transgenic strategies to replenish the NAD+ metabolome ameliorates chemotherapy induced female infertility in mice, as measured by oocyte yield, follicle health, and functional breeding trials. Importantly, treatment of a triple-negative breast cancer mouse model with the NAD+ precursor nicotinamide mononucleotide (NMN) reduced tumour growth and did not impair the efficacy of chemotherapy drugs in vivo or in diverse cancer cell lines. Overall, these findings raise the possibility that NAD+ precursors could be a non-invasive strategy for maintaining ovarian function in cancer patients, with potential benefits in cancer therapy.PMID:39169162 | DOI:10.1038/s44321-024-00119-w

Clin Exp Nephrol. 2024 Aug 22. doi: 10.1007/s10157-024-02545-z. Online ahead of print.ABSTRACTBACKGROUND: CKD currently affects 8.2% to 9.1% of the global population and the CKD mortality rate has increased during recent decades, making it necessary to identify new therapeutic targets. This study investigated the role of nicotinamide N-methyltransferase (NNMT) in renal fibrosis following ischemia-reperfusion injury (IRI), a key factor in chronic kidney disease (CKD) progression.METHODS: We established a mouse model with a knockdown of NNMT to investigate the impact of this enzyme on renal fibrosis after unilateral IRI. We then utilized histology, immunohistochemistry, and metabolomic analyses to investigate fibrosis markers and sphingolipid metabolism in NNMT-deficient mice. We also utilized an Nnmt lentivirus interference vector or an Nnmt overexpression plasmid to transfect mouse kidney proximal tubule cells, stimulated these cells with TGF-β1, and then measured the pro-fibrotic response and the expression of the methylated and unmethylated forms of Sphk1.RESULTS: The results demonstrated that reducing NNMT expression mitigated fibrosis, inflammation, and lipid deposition, potentially through the modulation of sphingolipid metabolism. Histology, immunohistochemistry, and metabolomic analyses provided evidence of decreased fibrosis and enhanced sphingolipid metabolism in NNMT-deficient mice. NNMT mediated the TGF-β1-induced pro-fibrotic response, knockdown of Nnmt decreased the level of unmethylated Sphk1 and increased the level of methylated Sphk1 in renal tubular epithelial cells.CONCLUSIONS: Our findings suggest that NNMT functions in sphingolipid metabolism and has potential as a therapeutic target for CKD. Further research is needed to elucidate the mechanisms linking NNMT to sphingolipid metabolism and renal fibrosis.PMID:39168882 | DOI:10.1007/s10157-024-02545-z

Biomed Pharmacother. 2024 Aug 20;179:117305. doi: 10.1016/j.biopha.2024.117305. Online ahead of print.ABSTRACTNumerous natural substances have anti-cancer properties. Especially indigenous people use aqueous plant extracts for tea or ointments including Dioscorea sansibarensis Pax to treat various diseases. The aim of this study was to evaluate the cytotoxic and radiosensitizing potential of aqueous extracts from Dioscorea sansibarensis Pax collected from Kenya in a panel of HPV-negative and -positive head and neck squamous cell carcinoma (HNSCC) cells grown in three-dimensional laminin-rich extracellular matrix (3D lrECM). The results show cytotoxicity, radiosensitization and increased levels of residual double strand breaks (DBS) by Dioscorea sansibarensis Pax extracts in HPV-negative and -positive HNSCC models in a concentration- and cell model-dependent manner. Application of ROS scavengers indicated an association between ROS-induced DSB and radiosensitization through Dioscorea sansibarensis Pax pretreatment. High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) based characterization of Dioscorea sansibarensis Pax identified the main components of the extract including camptothecin. Overall, Dioscorea sansibarensis Pax aqueous extracts alone and in combination with X-ray irradiation showed effective anticancer properties, which are worthy of further mechanistic investigation.PMID:39167841 | DOI:10.1016/j.biopha.2024.117305

Ann Am Thorac Soc. 2024 Aug 21. doi: 10.1513/AnnalsATS.202311-955OC. Online ahead of print.ABSTRACTRationale: Growing evidence suggests that air pollution exposure is a major risk factor in chronic obstructive pulmonary disease (COPD) that is associated with an increased prothrombotic state and adverse cardiovascular outcomes. However, much of this work is based on observational data or human exposure studies involving younger participants. The biological causality and mechanism of air pollution-induced prothrombotic response in patients with COPD remain to be explored. Objective: The main aim of this work was to investigate the impact of short-term diesel exhaust (DE) exposure on circulating prothrombotic markers-fibrinogen and plasminogen activator inhibitor-1 (PAI-1)-and urinary eicosanoids in patients with COPD. Methods: Twenty-nine research participants were recruited in this randomized, double-blinded, crossover, controlled human exposure study to DE. Participants included former smokers with and without mild or moderate COPD (ES and COPD group) and healthy never-smokers without COPD (NS group). Each participant was exposed to DE (300 µg/m3 of PM2.5) and filtered air (FA) for 2 hours on different occasions, in randomized order, separated by a 4-week washout. Blood and urine samples were collected prior to and 24 hours after each exposure. Plasma fibrinogen and serum PAI-1 concentrations were quantified using ELISAs. Urinary eicosanoid concentrations were quantified using ultra- performance liquid chromatography coupled to tandem mass spectrometry. Linear mixed-effects models were used for statistical comparisons. Results: Participants with COPD showed an increase in plasma fibrinogen (effect estimate: 1.27 [1.06 to 1.53], p=0.01) after DE relative to FA, but no significant DE-associated change in serum PAI-1 (0.95 [0.87 to 1.04], p=0.26). In never-smokers and ex-smokers without COPD, fibrinogen (NS group: 1.10 [0.99 to 1.23], p=0.08; ES group: 0.86 [0.68 to 1.09], p=0.08] and PAI-1 (NS group: 1.12 [ 0.96 to 1.32], p=0.15; ES group: 0.90 [0.79 to 1.03], p=0.13) were not changed after DE exposure. COPD participants showed a DE-attributable increase in urinary thromboxane B2 (TXB2) metabolites concentrations as follows: 11-dehydro TXB2 (1.45 [1.02 to 2.08], p=0.04); 2,3-dinor-TXB2 (1.45 [1.05 to 2.00], p=0.03). Conclusions: Participants with COPD had increased plasma fibrinogen and urinary TXB2 metabolites after short-term DE exposure, suggesting they may be more susceptible to pollution-attributable prothrombotic response compared to healthy controls or ex-smokers without COPD. Clinical trial registration available at www.clinicaltrials.gov, ID: NCT02236039.PMID:39167788 | DOI:10.1513/AnnalsATS.202311-955OC