PubMed

J Cell Mol Med. 2023 Dec 23. doi: 10.1111/jcmm.18059. Online ahead of print.ABSTRACTMetastasis is an important contributor to increased mortality rates in non-small cell lung cancer (NSCLC). The TGF-β signalling pathway plays a crucial role in facilitating tumour metastasis through epithelial-mesenchymal transition (EMT). Glycolysis, a key metabolic process, is strongly correlated with NSCLC metastasis. Pirfenidone (PFD) has been shown to safely and effectively inhibit TGF-β1 in patients with lung diseases. Furthermore, TGF-β1 and glycolysis demonstrate an interdependent relationship within the tumour microenvironment. Our previous study demonstrated that PFD effectively inhibited glycolysis in NSCLC cells, prompting further investigation into its potential antitumour effects in this context. Therefore, the present study aims to investigate the potential antitumour effect of PFD in NSCLC and explore the relationship among TGF-β1, glycolysis and EMT through further experimentation. The antitumour effects of PFD were evaluated using five different NSCLC cell lines and a xenograft tumour model. Notably, PFD demonstrated a significant antitumour effect specifically in highly glycolytic H1299 cells. To elucidate the underlying mechanism, we compared the efficacy of PFD after pretreatment with either TGF-β1 or a TGF-β receptor inhibitor (LY2109761). The energy metabolomics analysis of tumour tissue demonstrated that PFD, a chemosensitizing agent, reduced lactate and ATP production, thereby inhibiting glycolysis and exerting synergistic antineoplastic effects. Additionally, PFD combined with cisplatin targeted TGF-β1 to inhibit glycolysis during EMT and enhanced the chemosensitization of A549 and H1299 cells. The magnitude of the anticancer effect exhibited by PFD was intricately linked to its metabolic properties.PMID:38140828 | DOI:10.1111/jcmm.18059

FEBS Lett. 2023 Dec 23. doi: 10.1002/1873-3468.14795. Online ahead of print.ABSTRACTAmong the spatial omics techniques available, mass spectrometry imaging (MSI) represents one of the most promising owing to its capability to map the distribution of hundreds of peptides and proteins, as well as other classes of biomolecules, within a complex sample background in a multiplexed and relatively high-throughput manner. In particular, matrix-assisted laser desorption/ionisation (MALDI-MSI) has come to the fore and established itself as the most widely used technique in clinical research. However, the march of this technique towards clinical utility has been hindered by issues related to method reproducibility, appropriate biocomputational tools, and data storage. Notwithstanding these challenges, significant progress has been achieved in recent years regarding multiple facets of the technology and have rendered it more suitable for a possible clinical role. As such, there is now more robust and extensive evidence to suggest that the technology has the potential to support clinical decision-making processes under appropriate circumstances. In this review, we will discuss some of the recent developments that have facilitated this progress and outline some of the more promising clinical proteomics applications which have been developed with a clear goal towards implementation in mind.PMID:38140823 | DOI:10.1002/1873-3468.14795

Plants (Basel). 2023 Dec 15;12(24):4168. doi: 10.3390/plants12244168.ABSTRACTPhytophthora capsici, a destructive fungal pathogen, poses a severe threat to pepper (Capsicum annuum L.) crops worldwide, causing blights that can result in substantial yield losses. Traditional control methods often come with environmental concerns or entail substantial time investments. In this research, we investigate an alternative approach involving ferrous sulfate (FeSO4) application to combat P. capsici and promote pepper growth. We found that FeSO4 effectively inhibits the growth of P. capsici in a dose-dependent manner, disrupting mycelial development and diminishing pathogenicity. Importantly, FeSO4 treatment enhances the biomass and resistance of pepper plants, mitigating P. capsici-induced damage. Microbiome analysis demonstrates that FeSO4 significantly influences soil microbial communities, particularly fungi, within the pepper root. Metabolomics data reveal extensive alterations in the redox metabolic processes of P. capsici under FeSO4 treatment, leading to compromised cell membrane permeability and oxidative stress in the pathogen. Our study presents FeSO4 as a promising and cost-effective solution for controlling P. capsici in pepper cultivation while simultaneously promoting plant growth. These findings contribute to a deeper understanding of the intricate interactions between iron, pathogen control, and plant health, offering a potential tool for sustainable pepper production.PMID:38140495 | DOI:10.3390/plants12244168

Plants (Basel). 2023 Dec 13;12(24):4155. doi: 10.3390/plants12244155.ABSTRACTShort-term drought events occur more frequently and more intensively under global climate change. Biochar amendment has been documented to ameliorate the negative effects of water deficits on plant performance. Moreover, biochar can alter the soil microbial community, soil properties and soil metabolome, resulting in changes in soil functioning. We aim to reveal the extent of biochar addition on soil nutrients and the soil microbial community structure and how this improves the tolerance of legume crops (peanuts) to short-term extreme drought. We measured plant performances under different contents of biochar, set as a gradient of 2%, 3% and 4%, after an extreme experimental drought. In addition, we investigated how soil bacteria and fungi respond to biochar additions and how the soil metabolome changes in response to biochar amendments, with combined growth experiments, high-throughput sequencing and soil omics. The results indicated that biochar increased nitrites and available phosphorus. Biochar was found to influence the soil bacterial community structure more intensively than the soil fungal community. Additionally, the fungal community showed a higher randomness under biochar addition when experiencing short-term extreme drought compared to the bacterial community. Soil bacteria may be more strongly related to soil nutrient cycling in peanut agricultural systems. Although the soil metabolome has been documented to be influenced by biochar addition independent of soil moisture, we found more differential metabolites with a higher biochar content. We suggest that biochar enhances the resistance of plants and soil microbes to short-term extreme drought by indirectly modifying soil functioning probably due to direct changes in soil moisture and soil pH.PMID:38140481 | DOI:10.3390/plants12244155

Nutrients. 2023 Dec 14;15(24):5109. doi: 10.3390/nu15245109.ABSTRACTThe plant Allium hookeri, a member of the Allium genus, has a rich history of culinary and medicinal use. Recent studies have unveiled its potent antioxidant and anti-inflammatory properties. While research on A. hookeri has demonstrated its neuroprotective and anti-neuroinflammatory effects, the specific bioactive compounds responsible for these effects remain unidentified in prior research. This study utilized an untargeted metabolomic approach, employing HRESI-qTOF MS/MS-based molecular networking, to comprehensively profile the chemical composition of metabolites in A. hookeri and identify new compounds within the plant. As a result, ten compounds, comprising one novel flavonoid (2) and nine known compounds (1 and 3-10), were isolated and identified through NMR analysis. The inhibitory effects of all isolated compounds on the senescent cell-associated secretory phenotype (SASP), which is pivotal in neuroprotective actions, were evaluated. Biological activity testing revealed N-trans-feruloyltyramine (7) to be the most potent compound, effectively inhibiting SASP markers and contributing to the senomorphic activities of A. hookeri. These findings underscore the potential of phenolamides from A. hookeri as a promising source of bioactive compounds for mitigating senescence-associated diseases.PMID:38140368 | DOI:10.3390/nu15245109

Nutrients. 2023 Dec 9;15(24):5056. doi: 10.3390/nu15245056.ABSTRACTAtherosclerotic cardiovascular disease is the leading cause of mortality worldwide, and hypercholesterolemia is a central risk factor for atherosclerosis. This study evaluated the effects of Totum-070, a plant-based polyphenol-rich supplement, in hamsters with high-fat diet (HFD)-induced dyslipidemia. The molecular mechanisms of action were explored using human Caco2 enterocytes. Totum-070 supplementation reduced the total cholesterol (-41%), non-HDL cholesterol (-47%), and triglycerides (-46%) in a dose-dependent manner, compared with HFD. HFD-induced hepatic steatosis was also significantly decreased by Totum-070, an effect associated with the reduction in various lipid and inflammatory gene expression. Upon challenging with olive oil gavage, the post-prandial triglyceride levels were strongly reduced. The sterol excretion in the feces was increased in the HFD-Totum-070 groups compared with the HFD group and associated with reduction of intestinal cholesterol absorption. These effects were confirmed in the Caco2 cells, where incubation with Totum-070 inhibited cholesterol uptake and apolipoprotein B secretion. Furthermore, a microbiota composition analysis revealed a strong effect of Totum-070 on the alpha and beta diversity of bacterial species and a significant decrease in the Firmicutes to Bacteroidetes ratio. Altogether, our findings indicate that Totum-070 lowers hypercholesterolemia by reducing intestinal cholesterol absorption, suggesting that its use as dietary supplement may be explored as a new preventive strategy for cardiovascular diseases.PMID:38140315 | DOI:10.3390/nu15245056

Nutrients. 2023 Dec 7;15(24):5026. doi: 10.3390/nu15245026.ABSTRACTA healthy intestinal permeability facilitates the selective transport of nutrients, metabolites, water, and bacterial products, involving cellular, neural, hormonal, and immune factors. An altered intestinal permeability indicates pathologic phenotypes and is associated with the exacerbation of obesity and related comorbidities. To investigate the impact of altered permeability in obese patients undergoing a calorie-restrictive dietary regimen (VLCKD), we collected urinary and fecal samples from obese patients with both normal and altered permeability (determined based on the lactulose/mannitol ratio) before and after treatment. The analysis of volatile organic compounds (VOCs) aids in understanding the metabolites produced by the intestinal microbiota in this unique ecological niche. Furthermore, we examined clinical and anthropometric variables from the cohort and compared them to significant VOC panels. Consequently, we identified specific markers in the metabolomics data that differentiated between normal and altered profiles before and after the diet. These markers indicated how the variable contribution specifically accounted for interleukins and lipopolysaccharides (LPS). The targeted metabolomics experiment detected no differences in measured short-chain fatty acids (SCFA). In summary, our study evaluated metabolomic markers capable of distinguishing low-grade inflammation conditions, exacerbated in more advanced stages of obesity with altered intestinal permeability.PMID:38140285 | DOI:10.3390/nu15245026

Pharmaceutics. 2023 Dec 8;15(12):2746. doi: 10.3390/pharmaceutics15122746.ABSTRACTAlzheimer's disease (AD) is a complex neurodegenerative disease. Numerous investigations have demonstrated that medications that regulate the "brain-gut" axis can ameliorate disease symptoms of AD. Studies have shown that Ginkgo biloba extract (EGb) is involved in intestinal metabolism to meet the goal of illness treatment. EGb is currently utilized extensively in the clinical prevention and treatment of cardiovascular and cerebrovascular diseases. However, the regulatory effect of EGb on intestinal flora and its metabolites in AD pathology remains largely speculative. In this study, the Morris water maze test showed a significant improvement of spatial memory in the AD mouse model (APP/PS1 mice) after EGb treatment. We next confirmed the positive effects of EGb on the gut flora and metabolites of APP/PS1 mice and further showed that EGb treatment reshaped the disturbed gut microbiome, in particular by reducing the Firmicutes/Bacteroides ratio and increasing the abundance of Bacteroidetes, Uroviricota, Streptophyta, and Spirochaetes. Meanwhile, a non-targeted metabolomics analysis showed that EGb treatment significantly reversed the dysfunction of the microbial metabolic phenotype by altering Limosilactobacillus and Parvibacte, with 300 differential metabolites modulated (131 up-regulated, 169 down-regulated). Our findings highlight the significant regulatory impact of EGb on intestinal microflora and microbial metabolism in AD mice models and provide a potential therapeutic strategy for AD.PMID:38140087 | DOI:10.3390/pharmaceutics15122746

Pharmaceuticals (Basel). 2023 Dec 11;16(12):1717. doi: 10.3390/ph16121717.ABSTRACTMetformin is the first-line oral medication for treating type 2 diabetes mellitus (T2DM). In the current study, an untargeted lipidomic analytical approach was used to investigate the alterations in the serum lipidome of a cohort of 89 participants, including healthy lean controls and obese diabetic patients, and to examine the alterations associated with metformin administration. A total of 115 lipid molecules were significantly dysregulated (64 up-regulated and 51 down-regulated) in the obese compared to lean controls. However, the levels of 224 lipid molecules were significantly dysregulated (125 up-regulated and 99 down-regulated) in obese diabetic patients compared to the obese group. Metformin administration in obese diabetic patients was associated with significant dysregulation of 54 lipid molecule levels (20 up-regulated and 34 down-regulated). Levels of six molecules belonging to five lipid subclasses were simultaneously dysregulated by the effects of obesity, T2DM, and metformin. These include two putatively annotated triacylglycerols (TGs), one plasmenyl phosphatidylcholine (PC), one phosphatidylglycerol (PGs), one sterol lipid (ST), and one Mannosyl-phosphoinositol ceramide (MIPC). This study provides new insights into our understanding of the lipidomics alterations associated with obesity, T2DM, and metformin and offers a new platform for potential biomarkers for the progression of diabetes and treatment response in obese patients.PMID:38139843 | DOI:10.3390/ph16121717

Int J Mol Sci. 2023 Dec 18;24(24):17628. doi: 10.3390/ijms242417628.ABSTRACTThe tumor microenvironment in glioblastoma (GB) is considered to be "cold", i.e., the fraction of cytotoxic T cells, for instance, is low. Instead, macrophages are the major immune cell population in GB, which stem either from tissue response (resident microglia) or recruitment of macrophages from the periphery, thereby undergoing tumor-dependent "imprinting" mechanisms by which macrophages can adapt a tumor-supportive phenotype. In this regard, it is important to describe the nature of macrophages associated with GB, in particular under therapy conditions using the gold standard chemotherapy drug temozolomide (TMZ). Here, we explored the suitability of combining information from in vivo magnetic resonance spectroscopic (MRS) approaches (metabolomics) with in vitro molecular analyses to assess therapy response and characterize macrophage populations in mouse GB using an isogenic GL261 model. For macrophage profiling, expression levels of matrix metalloproteinases (MMPs) and A disintegrin and metalloproteinases (ADAMs) were determined, since their gene products affect macrophage-tumor cell communication by extensive cleavage of immunomodulatory membrane proteins, such as PD-L1. In tumor mice with an overall therapy response, expression of genes encoding the proteases ADAM8, ADAM10, and ADAM17 was increased and might contribute to the immunosuppressive phenotype of GB and immune cells. In tumors responding to therapy, expression levels of ADAM8 were upregulated by TMZ, and higher levels of PD-L1 were correlated significantly. Using a CRISPR/Cas9 knockout of ADAM8 in GL261 cells, we demonstrated that soluble PD-L1 (sPD-L1) is only generated in the presence of ADAM8. Moreover, primary macrophages from WT and ADAM8-deficient mice showed ADAM8-dependent release of sPD-L1, independent of the macrophage polarization state. Since ADAM8 expression is induced in responding tumors and PD-L1 shedding is likely to decrease the anti-tumor activities of T-cells, we conclude that immunotherapy resistance is caused, at least in part, by the increased presence of proteases, such as ADAM8.PMID:38139457 | DOI:10.3390/ijms242417628

Int J Mol Sci. 2023 Dec 18;24(24):17607. doi: 10.3390/ijms242417607.ABSTRACTCardiogenic shock (CS) portends a dismal prognosis if hypoperfusion triggers uncontrolled inflammatory and metabolic derangements. We sought to investigate metabolomic profiles and temporal changes in IL6, Ang-2, and markers of glycocalyx perturbation from admission to discharge in eighteen patients with heart failure complicated by CS (HF-CS). Biological samples were collected from 18 consecutive HF-CS patients at admission (T0), 48 h after admission (T1), and at discharge (T2). ELISA analytical techniques and targeted metabolomics were performed Seven patients (44%) died at in-hospital follow-up. Among the survivors, IL-6 and kynurenine were significantly reduced at discharge compared to baseline. Conversely, the amino acids arginine, threonine, glycine, lysine, and asparagine; the biogenic amine putrescine; multiple sphingolipids; and glycerophospholipids were significantly increased. Patients with HF-CS have a metabolomic fingerprint that might allow for tailored treatment strategies for the patients' recovery or stabilization.PMID:38139435 | DOI:10.3390/ijms242417607

Int J Mol Sci. 2023 Dec 18;24(24):17585. doi: 10.3390/ijms242417585.ABSTRACTLessertia frutescens is a multipurpose medicinal plant indigenous to South Africa that is used for the management of cancer, stomach ulcers, wounds, etc. The use and demand for the raw materials from this plant have been increasing steadily over the years, putting strain on the dwindling wild populations. Although cultivation may provide relief to the strained supply, the persistent drought climate poses a threat to the plant's growth and productivity. This study explored three plant-growth-promoting rhizobacteria isolates, TUTLFNC33, TUTLFNC37 and TUTLFWC74, obtained from the root nodules of Lessertia frutescens as potential bioinoculants that can improve yield, biological activities and the production of secondary metabolites in the host plant. Isolate TUTLFNC37 was identified as the most promising isolate for inoculation of Lessertia frutescens under drought conditions as it induced drought tolerance through enhanced root proliferation, osmolyte proline accumulation and stomatal closure. Superior biomass yield, phenolics, triterpenes and antioxidant activity were evident in the extracts of Lessertia frutescens inoculated with TUTLFNC37 and under different levels of drought. Furthermore, the metabolomics of the plant extracts demonstrated the ability of the isolate to withstand drastic changes in the composition of unique metabolites, sutherlandiosides A-D and sutherlandins A-D. Molecular families which were never reported in the plant (peptides and glycerolipids) were detected and annotated in the molecular networks. Although drought had deleterious effects on Lessertia frutescens, isolate TUTLFNC37 alleviated the impact of the stress. Isolate TUTLFNC37 is therefore the most promising, environmentally friendly alternative to harmful chemicals such as nitrate-based fertilizers. The isolate should be studied to establish its field performance, cross infectivity with other medicinal plants and competition with inherent soil microbes.PMID:38139414 | DOI:10.3390/ijms242417585

Int J Mol Sci. 2023 Dec 16;24(24):17556. doi: 10.3390/ijms242417556.ABSTRACTThis work investigated the mechanisms of action of conventional drugs, cisplatin and oxaliplatin, and the potentially less deleterious drug Pd2Spermine (Spm) and its Pt(II) analog, against osteosarcoma MG-63 cells, using nuclear-magnetic-resonance metabolomics of the cellular lipidome. The Pt(II) chelates induced different responses, namely regarding polyunsaturated-fatty-acids (increased upon cisplatin), suggesting that cisplatin-treated cells have higher membrane fluidity/permeability, thus facilitating cell entry and justifying higher cytotoxicity. Both conventional drugs significantly increased triglyceride levels, while Pt2Spm maintained control levels; this may reflect enhanced apoptotic behavior for conventional drugs, but not for Pt2Spm. Compared to Pt2Spm, the more cytotoxic Pd2Spm (IC50 comparable to cisplatin) induced a distinct phospholipids profile, possibly reflecting enhanced de novo biosynthesis to modulate membrane fluidity and drug-accessibility to cells, similarly to cisplatin. However, Pd2Spm differed from cisplatin in that cells had equivalent (low) levels of triglycerides as Pt2Spm, suggesting the absence/low extent of apoptosis. Our results suggest that Pd2Spm acts on MG-63 cells mainly through adaptation of cell membrane fluidity, whereas cisplatin seems to couple a similar effect with typical signs of apoptosis. These results were discussed in articulation with reported polar metabolome adaptations, building on the insight of these drugs' mechanisms, and particularly of Pd2Spm as a possible cisplatin substitute.PMID:38139388 | DOI:10.3390/ijms242417556

Int J Mol Sci. 2023 Dec 16;24(24):17552. doi: 10.3390/ijms242417552.ABSTRACTMelon (Cucumis melo L.) represents an agriculturally significant horticultural crop that is widely grown for its flavorful fruits. Downy mildew (DM), a pervasive foliar disease, poses a significant threat to global melon production. Although several quantitative trait loci related to DM resistance have been identified, the comprehensive genetic underpinnings of this resistance remain largely uncharted. In this study, we utilized integrative transcriptomics and metabolomics approaches to identify potential resistance-associated genes and delineate the strategies involved in the defense against DM in two melon cultivars: the resistant 'PI442177' ('K10-1') and the susceptible 'Huangdanzi' ('K10-9'), post-P. cubensis infection. Even in the absence of the pathogen, there were distinctive differentially expressed genes (DEGs) between 'K10-1' and 'K10-9'. When P. cubensis was infected, certain genes, including flavin-containing monooxygenase (FMO), receptor-like protein kinase FERONIA (FER), and the HD-ZIP transcription factor member, AtHB7, displayed pronounced expression differences between the cultivars. Notably, our data suggest that following P. cubensis infection, both cultivars suppressed flavonoid biosynthesis via the down-regulation of associated genes whilst concurrently promoting lignin production. The complex interplay of transcriptomic and metabolic responses elucidated by this study provides foundational insights into melon's defense mechanisms against DM. The robust resilience of 'K10-1' to DM is attributed to the synergistic interaction of its inherent transcriptomic and metabolic reactions.PMID:38139381 | DOI:10.3390/ijms242417552

Int J Mol Sci. 2023 Dec 16;24(24):17543. doi: 10.3390/ijms242417543.ABSTRACTBladder cancer (BC) stands as one of the most prevalent urological malignancies, with over 500 thousand newly diagnosed cases annually. Treatment decisions in BC depend on factors like the risk of recurrence, the type of tumor, and the stage of the disease. While standard therapeutic approaches encompass transurethral resection of the bladder tumor, radical cystectomy, and chemo- or immunotherapy, these methods exhibit limited efficacy in mitigating the aggressive and recurrent nature of bladder tumors. To overcome this challenge, it is crucial to develop innovative methods for monitoring and predicting treatment responses among patients with BC. Metabolomics is gaining recognition as a promising approach for discovering biomarkers. It has the potential to reveal metabolic disruptions that precisely reflect how BC patients respond to particular treatments, providing a revolutionary method to improve accuracy in monitoring and predicting outcomes. In this article, we present a comprehensive review of studies employing metabolomics approaches to investigate the metabolic responses associated with different treatment modalities for BC. The review encompasses an exploration of various models, samples, and analytical techniques applied in this context. Special emphasis is placed on the reported changes in metabolite levels derived from these studies, highlighting their potential as biomarkers for personalized medicine in BC.PMID:38139377 | DOI:10.3390/ijms242417543

Int J Mol Sci. 2023 Dec 15;24(24):17533. doi: 10.3390/ijms242417533.ABSTRACTThe disruption of mitochondrial dynamics has been identified in cardiovascular diseases, including pulmonary hypertension (PH), ischemia-reperfusion injury, heart failure, and cardiomyopathy. Mitofusin 2 (Mfn2) is abundantly expressed in heart and pulmonary vasculature cells at the outer mitochondrial membrane to modulate fusion. Previously, we have reported reduced levels of Mfn2 and fragmented mitochondria in pulmonary arterial endothelial cells (PAECs) isolated from a sheep model of PH induced by pulmonary over-circulation and restoring Mfn2 normalized mitochondrial function. In this study, we assessed the effect of increased expression of Mfn2 on mitochondrial metabolism, bioenergetics, reactive oxygen species production, and mitochondrial membrane potential in control PAECs. Using an adenoviral expression system to overexpress Mfn2 in PAECs and utilizing 13C labeled substrates, we assessed the levels of TCA cycle metabolites. We identified increased pyruvate and lactate production in cells, revealing a glycolytic phenotype (Warburg phenotype). Mfn2 overexpression decreased the mitochondrial ATP production rate, increased the rate of glycolytic ATP production, and disrupted mitochondrial bioenergetics. The increase in glycolysis was linked to increased hypoxia-inducible factor 1α (HIF-1α) protein levels, elevated mitochondrial reactive oxygen species (mt-ROS), and decreased mitochondrial membrane potential. Our data suggest that disrupting the mitochondrial fusion/fission balance to favor hyperfusion leads to a metabolic shift that promotes aerobic glycolysis. Thus, therapies designed to increase mitochondrial fusion should be approached with caution.PMID:38139362 | DOI:10.3390/ijms242417533

Int J Mol Sci. 2023 Dec 13;24(24):17442. doi: 10.3390/ijms242417442.ABSTRACTObesity prevalence is becoming a serious global health and economic issue and is a major risk factor for concomitant diseases that worsen the quality and duration of life. Therefore, the urgency of the development of novel therapies is of a particular importance. A previous study of ours revealed that the natural pterocarpan, maackiain (MACK), significantly inhibits adipogenic differentiation in human adipocytes through a peroxisome proliferator-activated receptor gamma (PPARγ)-dependent mechanism. Considering the observed anti-adipogenic potential of MACK, we aimed to further elucidate the molecular mechanisms that drive its biological activity in a Caenorhabditis elegans obesity model. Therefore, in the current study, the anti-obesogenic effect of MACK (25, 50, and 100 μM) was compared to orlistat (ORST, 12 μM) as a reference drug. Additionally, the hybrid combination between the ORST (12 μM) and MACK (100 μM) was assessed for suspected synergistic interaction. Mechanistically, the observed anti-obesogenic effect of MACK was mediated through the upregulation of the key metabolic regulators, namely, the nuclear hormone receptor 49 (nhr-49) that is a functional homologue of the mammalian PPARs and the AMP-activated protein kinase (aak-2/AMPK) in C. elegans. Collectively, our investigation indicates that MACK has the potential to limit lipid accumulation and control obesity that deserves future developments.PMID:38139270 | DOI:10.3390/ijms242417442

Int J Mol Sci. 2023 Dec 13;24(24):17437. doi: 10.3390/ijms242417437.ABSTRACTLipedema is a chronic condition characterized by disproportionate and symmetrical enlargement of adipose tissue, predominantly affecting the lower limbs of women. This study investigated the use of metabolomics in lipedema research, with the objective of identifying complex metabolic disturbances and potential biomarkers for early detection, prognosis, and treatment strategies. The study group (n = 25) comprised women diagnosed with lipedema. The controls were 25 lean women and 25 obese females, both matched for age. In the patients with lipedema, there were notable changes in the metabolite parameters. Specifically, lower levels of histidine and phenylalanine were observed, whereas pyruvic acid was elevated compared with the weight controls. The receiver operating characteristic (ROC) curves for the diagnostic accuracy of histidine, phenylalanine, and pyruvic acid concentrations in distinguishing between patients with lipedema and those with obesity but without lipedema revealed good diagnostic ability for all parameters, with pyruvic acid being the most promising (area under the curve (AUC): 0.9992). Subgroup analysis within matched body mass index (BMI) ranges (30.0 to 39.9 kg/m2) further revealed that differences in pyruvic acid, phenylalanine, and histidine levels are likely linked to lipedema pathology rather than BMI variations. Changes in low-density lipoprotein (LDL)-6 TG levels and significant reductions in various LDL-2-carried lipids of patients with lipedema, compared with the lean controls, were observed. However, these lipids were similar between the lipedema patients and the obese controls, suggesting that these alterations are related to adiposity. Metabolomics is a valuable tool for investigating lipedema, offering a comprehensive view of metabolic changes and insights into lipedema's underlying mechanisms.PMID:38139266 | DOI:10.3390/ijms242417437

Int J Mol Sci. 2023 Dec 13;24(24):17418. doi: 10.3390/ijms242417418.ABSTRACTPreviously, studies have shown that leukemic cells exhibit elevated glycolytic metabolism and oxidative phosphorylation in comparison to hematopoietic stem cells. These metabolic processes play a crucial role in the growth and survival of leukemic cells. Due to the metabolic plasticity of tumor cells, the use of natural products has been proposed as a therapeutic alternative due to their ability to attack several targets in tumor cells, including those that could modulate metabolism. In this study, the potential of Petiveria alliacea to modulate the metabolism of K562 cell lysates was evaluated by non-targeted metabolomics. Initially, in vitro findings showed that P. alliacea reduces K562 cell proliferation; subsequently, alterations were observed in the endometabolome of cell lysates treated with the extract, mainly in glycolytic, phosphorylative, lipid, and amino acid metabolism. Finally, in vitro assays were performed, confirming that P. Alliacea extract decreased the oxygen consumption rate and intracellular ATP. These results suggest that the anti-tumor activity of the aqueous extract on the K562 cell line is attributed to the decrease in metabolites related to cell proliferation and/or growth, such as nucleotides and nucleosides, leading to cell cycle arrest. Our results provide a preliminary part of the mechanism for the anti-tumor and antiproliferative effects of P. alliacea on cancer.PMID:38139247 | DOI:10.3390/ijms242417418

Int J Mol Sci. 2023 Dec 12;24(24):17400. doi: 10.3390/ijms242417400.ABSTRACTThis review examines the impact of childhood obesity on the kidney from an epidemiological, pathogenetic, clinical, and pathological perspective, with the aim of providing pediatricians and nephrologists with the most current data on this topic. The prevalence of childhood obesity and chronic kidney disease (CKD) is steadily increasing worldwide, reaching epidemic proportions. While the impact of obesity in children with CKD is less pronounced than in adults, recent studies suggest a similar trend in the child population. This is likely due to the significant association between obesity and the two leading causes of end-stage renal disease (ESRD): diabetes mellitus (DM) and hypertension. Obesity is a complex, systemic disease that reflects interactions between environmental and genetic factors. A key mechanism of kidney damage is related to metabolic syndrome and insulin resistance. Therefore, we can speculate about an adipose tissue-kidney axis in which neurohormonal and immunological mechanisms exacerbate complications resulting from obesity. Adipose tissue, now recognized as an endocrine organ, secretes cytokines called adipokines that may induce adaptive or maladaptive responses in renal cells, leading to kidney fibrosis. The impact of obesity on kidney transplant-related outcomes for both donors and recipients is also significant, making stringent preventive measures critical in the pre- and post-transplant phases. The challenge lies in identifying renal involvement as early as possible, as it is often completely asymptomatic and not detectable through common markers of kidney function. Ongoing research into innovative technologies, such as proteomics and metabolomics, aims to identify new biomarkers and is constantly evolving. Many aspects of pediatric disease progression in the population of children with obesity still require clarification. However, the latest scientific evidence in the field of nephrology offers glimpses into various new perspectives, such as genetic factors, comorbidities, and novel biomarkers. Investigating these aspects early could potentially improve the prognosis of these young patients through new diagnostic and therapeutic strategies. Hence, the aim of this review is to provide a comprehensive exploration of the pathogenetic mechanisms and prevalent pathological patterns of kidney damage observed in children with obesity.PMID:38139229 | DOI:10.3390/ijms242417400