Metabolic Processes Research Articles

Integrated Mechanism of Immune Response Modulation by Arctium Lappa L. Fructans Based on Microbiome and Metabolomics Technologies.

Arctium lappa L. is widely consumed for its various biological effects, and polysaccharides are its main functional components. The present study aimed to evaluate the immunoregulatory effects of the main polysaccharides from burdock (ALP-1) and reveal the underlying mechanisms. ALP-1 consisted of fructose and glucose (14.57:1) and had a molecular weight of 2757 Da, with typical characteristics of (1 → 2)-linked linear fructans. Oral intake of ALP-1 significantly increased the number of colonic goblet cells, serum immunoglobulin A and immunoglobulin G levels, and fecal secretory immunoglobulin A content as well as up-regulated antioxidant enzymes and increased short chain fatty acid production. In addition, ALP-1 administration regulated pro/anti-inflammatory cytokines (i.e., interleukin (IL)-1β, IL-6, tumor necrosis factor-α, interferon-γ, and IL-10), intestinal microbiota structure, and the spatial information on key metabolites. Some gut-microbiota-mediated metabolic processes were also significantly altered. These results indicated that ALP-1 could exert beneficial effects on immune responses and intestinal health in healthy mice.

Role of protein arginine methyltransferase 1 in obesity-related metabolic disorders: Research progress and implications.

Obesity has become a major global problem that significantly confers an increased risk of developing life-threatening complications, including type 2 diabetes mellitus, fatty liver disease and cardiovascular diseases. Protein arginine methyltransferases (PRMTs) are enzymes that catalyse the methylation of target proteins. They are ubiquitous in eukaryotes and regulate transcription, splicing, cell metabolism and RNA biology. As a key, epigenetically modified enzyme, protein arginine methyltransferase 1 (PRMT1) is involved in obesity-related metabolic processes, such as lipid metabolism, the insulin signalling pathway, energy balance and inflammation, and plays an important role in the pathology of obesity-related metabolic disorders. This review summarizes recent research on the role of PRMT1 in obesity-related metabolic disorders. The primary objective was to comprehensively elucidate the functional role and regulatory mechanisms of PRMT1. Moreover, this study attempts to review the pathogenesis of PRMT1-mediated obesity-related metabolic disorders, thereby offering pivotal information for further studies and clinical treatment.

Radionuclide Transfer in Tea Cultivation: Assessing Radiological Risks in the Largest and First Established Tea Garden in Bangladesh

ABSTRACT To address potential health risks associated with radioactivity in tea consumption, a study was conducted utilizing high purity germanium (HPGe) γ-ray spectrometry to measure the concentrations of 226Ra, 232Th, 40K, and 137Cs radionuclides in soil and tea leaves collected from several major tea gardens (including the Malnicherra tea garden which is the largest and first established tea garden in the Indian subcontinent) situated in Sylhet, Bangladesh. Although nearly all soil samples showed the presence of 137Cs (with a maximum activity of 6.5 ± 1.31 Bq/kg), none of the analyzed tea leaf samples exhibited its presence, which can be attributed to its restricted transferability from soil to plants. The range of transfer factors for 226Ra, 232Th and 40K from soil to tea leaves was calculated to be (0.39–0.54), (0.25–0.46) and (1.39–3.03), respectively. The heightened concentrations of 40K identified in the tea leaf samples can be mainly ascribed to specific metabolic processes associated with potassium, along with the heightened utilization of potassium chloride-based fertilizers aimed at enhancing tea production. The examination of hazard parameters, including the estimated committed effective dose and the excess lifetime cancer risk associated with tea consumption, reveals values that are comparatively lower than the recommended limits. Consequently, the radiation exposure from tea consumption does not present a significant radiological health concern for the general population.

Natural variations of heterosis-related allele-specific expression genes in promoter regions lead to allele-specific expression in maize

BackgroundHeterosis has successfully enhanced maize productivity and quality. Although significant progress has been made in delineating the genetic basis of heterosis, the molecular mechanisms underlying its genetic components remain less explored. Allele-specific expression (ASE), the imbalanced expression between two parental alleles in hybrids, is increasingly being recognized as a factor contributing to heterosis. ASE is a complex process regulated by both epigenetic and genetic variations in response to developmental and environmental conditions.ResultsIn this study, we explored the differential characteristics of ASE by analyzing the transcriptome data of two maize hybrids and their parents under four light conditions. On the basis of allele expression patterns in different hybrids under various conditions, ASE genes were divided into three categories: bias-consistent genes involved in basal metabolic processes in a functionally complementary manner, bias-reversal genes adapting to the light environment, and bias-specific genes maintaining cell homeostasis. We observed that 758 ASE genes (ASEGs) were significantly overlapped with heterosis quantitative trait loci (QTLs), and high-frequency variations in the promoter regions of heterosis-related ASEGs were identified between parents. In addition, 10 heterosis-related ASEGs participating in yield heterosis were selected during domestication.ConclusionsThe comprehensive analysis of ASEGs offers a distinctive perspective on how light quality influences gene expression patterns and gene-environment interactions, with implications for the identification of heterosis-related ASEGs to enhance maize yield.

Transcriptomic characteristics according to tumor size and SUVmax in papillary thyroid cancer patients

The SUVmax is a measure of FDG uptake and is related with tumor aggressiveness in thyroid cancer, however, its association with molecular pathways is unclear. Here, we investigated the relationship between SUVmax and gene expression profiles in 80 papillary thyroid cancer (PTC) patients. We conducted an analysis of DEGs and enriched pathways in relation to SUVmax and tumor size. SUVmax showed a positive correlation with tumor size and correlated with glucose metabolic process. The genes that indicate thyroid differentiation, such as SLC5A5 and TPO, were negatively correlated with SUVmax. Unsupervised analysis revealed that SUVmax positively correlated with DNA replication(r = 0.29, p = 0.009), pyrimidine metabolism(r = 0.50, p < 0.0001) and purine metabolism (r = 0.42, p = 0.0001). Based on subgroups analysis, we identified that PSG5, TFF3, SOX2, SL5A5, SLC5A7, HOXD10, FER1L6, and IFNA1 genes were found to be significantly associated with tumor aggressiveness. Both high SUVmax PTMC and macro-PTC are enriched in pathways of DNA replication and cell cycle, however, gene sets for purine metabolic pathways are enriched only in high SUVmax macro-PTC but not in high SUVmax PTMC. Our findings demonstrate the molecular characteristics of high SUVmax tumor and metabolism involved in tumor growth in differentiated thyroid cancer.

Inducible deletion of microRNA activity in kidney mesenchymal cells exacerbates renal fibrosis

MicroRNAs (miRNAs) are sequence-specific inhibitors of post-transcriptional gene expression. However, the physiological functions of these non-coding RNAs in renal interstitial mesenchymal cells remain unclear. To conclusively evaluate the role of miRNAs, we generated conditional knockout (cKO) mice with platelet-derived growth factor receptor-β (PDGFR-β)-specific inactivation of the key miRNA pathway gene Dicer. The cKO mice were subjected to unilateral ureteral ligation, and renal interstitial fibrosis was quantitatively evaluated using real-time polymerase chain reaction and immunofluorescence staining. Compared with control mice, cKO mice had exacerbated interstitial fibrosis exhibited by immunofluorescence staining and mRNA expression of PDGFR-β. A microarray analysis showed decreased expressions of miR-9-5p, miR-344g-3p, and miR-7074-3p in cKO mice compared with those in control mice, suggesting an association with the increased expression of PDGFR-β. An analysis of the signaling pathways showed that the major transcriptional changes in cKO mice were related to smooth muscle cell differentiation, regulation of DNA metabolic processes and the actin cytoskeleton, positive regulation of fibroblast proliferation and Ras protein signal transduction, and focal adhesion-PI3K/Akt/mTOR signaling pathways. Depletion of Dicer in mesenchymal cells may downregulate the signaling pathway related to miR-9-5p, miR-344g-3p, and miR-7074-3p, which can lead to the progression of chronic kidney disease. These findings highlight the possibility for future diagnostic or therapeutic developments for renal fibrosis using miR-9-5p, miR-344g-3p, and miR-7074-3p.

Phased Telomere-to-Telomere Reference Genome and Pangenome Reveal an Expansion of Resistance Genes during Apple Domestication.

The cultivated apple (Malus domestica Borkh.) is a cross-pollinated perennial fruit tree of great economic importance. Previous versions of apple reference genomes were unphased, fragmented, and lacked comprehensive insights into the highly heterozygous genome, which impeded genetic studies and breeding programs in apple. In this study, we assembled a haplotype-resolved telomere-to-telomere reference genome for the diploid apple cultivar Golden Delicious. Subsequently, we constructed a pangenome based on twelve assemblies from wild and cultivated apples to investigate different types of resistance gene analogs (RGAs). Our results revealed the dynamics of the gene gain and loss events during apple domestication. Compared with cultivated species, more gene families in wild species were significantly enriched in oxidative phosphorylation, pentose metabolic process, responses to salt, and abscisic acid biosynthesis process. Interestingly, our analyses demonstrated a higher prevalence of RGAs in cultivated apples than their wild relatives, partially attributed to segmental and tandem duplication events in certain RGAs classes. Other types of structural variations, mainly deletions and insertions, have affected the presence and absence of TIR-NB-ARC-LRR (TNL), NB-ARC-LRR (NL), and CC-NB-ARC-LRR (CNL) genes. Additionally, hybridization/introgression from wild species has also contributed to the expansion of resistance genes in domesticated apples. Our haplotype-resolved T2T genome and pangenome provide important resources for genetic studies of apples, emphasizing the need to study the evolutionary mechanisms of resistance genes in apple breeding programs.

In Vitro and In Vivo Biotransformation Profiling of 6PPD-Quinone toward Their Detection in Human Urine.

The antioxidant N-(1,3-Dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD) and its oxidized quinone product 6PPD-quinone (6PPD-Q) in rubber have attracted attention due to the ecological risk that they pose. Both 6PPD and 6PPD-Q have been detected in various environments that humans cohabit. However, to date, a clear understanding of the biotransformation of 6PPD-Q and a potential biomarker for exposure in humans are lacking. To address this issue, this study presents a comprehensive analysis of the extensive biotransformation of 6PPD-Q across species, encompassing both in vitro and in vivo models. We have tentatively identified 17 biotransformation metabolites in vitro, 15 in mice in vivo, and confirmed the presence of two metabolites in human urine samples. Interestingly, different biotransformation patterns were observed across species. Through semiquantitative analysis based on peak areas, we found that almost all 6PPD-Q underwent biotransformation within 24 h of exposure in mice, primarily via hydroxylation and subsequent glucuronidation. This suggests a rapid metabolic processing of 6PPD-Q in mammals, underscoring the importance of identifying effective biomarkers for exposure. Notably, monohydroxy 6PPD-Q and 6PPD-Q-O-glucuronide were consistently the most predominant metabolites across our studies, highlighting monohydroxy 6PPD-Q as a potential key biomarker for epidemiological research. These findings represent the first comprehensive data set on 6PPD-Q biotransformation in mammalian systems, offering insights into the metabolic pathways involved and possible exposure biomarkers.

Transcriptome analysis reveals the molecular mechanisms underlying the enhancement of salt-tolerance in Melia azedarach under salinity stress

Melia azedarach demonstrates strong salt tolerance and thrives in harsh saline soil conditions, but the underlying mechanisms are poorly understood. In this study, we analyzed gene expression under low, medium, and high salinity conditions to gain a deeper understanding of adaptation mechanisms of M. azedarach under salt stress. The GO (gene ontology) analysis unveiled a prominent trend: as salt stress intensified, a greater number of differentially expressed genes (DEGs) became enriched in categories related to metabolic processes, catalytic activities, and membrane components. Through the analysis of the category GO:0009651 (response to salt stress), we identified four key candidate genes (CBL7, SAPK10, EDL3, and AKT1) that play a pivotal role in salt stress responses. Furthermore, the KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway enrichment analysis revealed that DEGs were significantly enriched in the plant hormone signaling pathways and starch and sucrose metabolism under both medium and high salt exposure in comparison to low salt conditions. Notably, genes involved in JAZ and MYC2 in the jasmonic acid (JA) metabolic pathway were markedly upregulated in response to high salt stress. This study offers valuable insights into the molecular mechanisms underlying M. azedarach salt tolerance and identifies potential candidate genes for enhancing salt tolerance in M. azedarach.

Human Enteroid Monolayers: A Novel, Functionally-Stable Model for Investigating Oral Drug Disposition.

To further the development of an in vitro model which faithfully recapitulates drug disposition of orally administered drugs, we investigated the utility of human enteroid monolayers to simultaneously assess intestinal drug absorption and first-pass metabolism processes. We cultured human enteroid monolayers from three donors, derived via biopsies containing duodenal stem cells that were propagated and then differentiated atop permeable Transwell® inserts, and confirmed transformation into a largely enterocyte population via RNA-seq analysis and immunocytochemical (ICC) assays. Proper cell morphology was assessed and confirmed via bright field microscopy and ICC imaging of tight junction proteins and other apically and basolaterally localized proteins. Enteroid monolayer barrier integrity was demonstrated by elevated transepithelial electrical resistance (TEER) that stabilized after 10 days in culture and persisted for 42 days. These results were corroborated by low paracellular transport probe permeability at 7 and 21 days in culture. The activity of a prominent drug metabolizing enzyme, CYP3A, was confirmed at 7, 21, and 42 days culture under basal, 1α,25(OH)2 vitamin D3-induced, and 6',7'-dihydroxybergamottin-inhibited conditions. The duration of these experiments is particularly noteworthy, as this is the first study assessing drug metabolizing enzymes and transporters (DMET) expression/function for enteroids cultured for greater than 12 days. The sum of these results suggests enteroid monolayers are a promising ex vivo model to investigate and quantitatively predict an orally administered drug's intestinal absorption and/or metabolism. Significance Statement This study presents a novel ex vivo model of the human intestine, human intestinal organoid (enteroid) monolayers, that maintain barrier function and metabolic functionality for up to 42-days in culture. The incorporation of both barrier integrity and metabolic function over an extended period within the same model is an advancement over historically used in vitro systems, which either lack one or both of these attributes or have limited viability.

Comparative transcriptomic and physiological analyses unravel wheat source root adaptation to phosphorous deficiency

Phosphorus (P) is a crucial macronutrient for plant growth and development. Basic metabolic processes regulate growth; however, the molecular detail of these pathways under low phosphorous (LP) in wheat is still unclear. This study aims to elucidate the varied regulatory pathways responses to LP stress in wheat genotypes. Phenotypic, physiological, and transcriptome analyses were conducted on Fielder (P efficient) and Ardito (P inefficient) wheat genotypes after four days of normal phosphorous (NP) and LP stress. In response to LP, Fielder outperformed Ardito, displaying higher chlorophyll content-SPAD values (13%), plant height (45%), stem diameter (12%), shoot dry weight (42%), and root biomass (75%). Root structure analysis revealed that Fielder had greater total root length (50%), surface area (56%), volume (15%), and diameter (4%) than Ardito under LP. These findings highlight Fielder’s superior performance and adaptation to LP stress. Transcriptome analysis of wheat genotype roots identified 3029 differentially expressed genes (DEGs) in Fielder and 1430 in Ardito, highlighting LP-induced changes. Key DEGs include acid phosphatases (PAPs), phosphate transporters (PHT1 and PHO1), SPX, and transcription factors (MYB, bHLH, and WRKY). KEGG enrichment analysis revealed key pathways like plant hormones signal transduction, biosynthesis of secondary metabolites, and carbohydrate biosynthesis metabolism. This study unveils crucial genes and the intricate regulatory process in wheat’s response to LP stress, offering genetic insights for enhancing plant P utilization efficiency.

Transcriptional Profiling Underscores the Role of Preprocurement Allograft Metabolism and Innate Immune Status on Outcomes in Human Liver Transplantation

Objective: The adverse effects of ischemia-reperfusion injury (IRI) remain a principal barrier to a successful outcome after lifesaving orthotopic liver transplantation (OLT). Gene expression during different phases of IRI is dynamic and modified by individual exposures, making it attractive for identifying potential therapeutic targets for improving the number of suitable organs for transplantation and patient outcomes. However, data remain limited on the functional landscape of gene expression during liver graft IRI, spanning procurement to reperfusion and recovery. Therefore, we sought to characterize transcriptomic profiles of IRI during multiple phases in human OLT. Methods: We conducted clinical data analyses, histologic evaluation, and RNA sequencing of 17 consecutive human primary OLT. We performed liver allograft biopsies at 4 time points: baseline (B, before donor cross-clamp), at the end of cold ischemia (CI), during early reperfusion (ER, after revascularization), and during late reperfusion (LR). Data were generated and then recipients grouped by post-OLT outcomes categories: immediate allograft function (IAF; n = 11) versus early allograft dysfunction (EAD; n = 6) groups. Results: We observed that CI (vs B) modified a transcriptomic landscape enriched for a metabolic and immune process. Expression levels of hallmark inflammatory response genes were higher transitioning from CI to ER and decreased from ER to LR. IAF group predominantly showed higher bile and fatty acid metabolism activity during LR compared with EAD group, while EAD group maintained more immunomodulatory activities. Throughout all time points, EAD specimens exhibited decreased metabolic activity in both bile and fatty acid pathways. Conclusions: We report transcriptomic profiles of human liver allograft IRI from prepreservation in the donor to posttransplantation in the recipient. Immunomodulatory and metabolic landscapes across ER and LR phases were different between IAF and EAD allografts. Our study also highlights marker genes for these biological processes that we plan to explore as novel therapeutic targets or surrogate markers for severe allograft injury in clinical OLT.

Widespread and active piezotolerant microorganisms mediate phenolic compound degradation under high hydrostatic pressure in hadal trenches

AbstractPhenolic compounds, as well as other aromatic compounds, have been reported to be abundant in hadal trenches. Although high-throughput sequencing studies have hinted at the potential of hadal microbes to degrade these compounds, direct microbiological, genetic and biochemical evidence under in situ pressures remain absent. Here, a microbial consortium and a pure culture of Pseudomonas, newly isolated from Mariana Trench sediments, efficiently degraded phenol under pressures up to 70 and 60 MPa, respectively, with concomitant increase in biomass. By analyzing a high-pressure (70 MPa) culture metatranscriptome, not only was the entire range of metabolic processes under high pressure generated, but also genes encoding complete phenol degradation via ortho- and meta-cleavage pathways were revealed. The isolate of Pseudomonas also contained genes encoding the complete degradation pathway. Six transcribed genes (dmpKLMNOPsed) were functionally identified to encode a multicomponent hydroxylase catalyzing the hydroxylation of phenol and its methylated derivatives by heterogeneous expression. In addition, key catabolic genes identified in the metatranscriptome of the high-pressure cultures and genomes of bacterial isolates were found to be all widely distributed in 22 published hadal microbial metagenomes. At microbiological, genetic, bioinformatics, and biochemical levels, this study found that microorganisms widely found in hadal trenches were able to effectively drive phenolic compound degradation under high hydrostatic pressures. This information will bridge a knowledge gap concerning the microbial aromatics degradation within hadal trenches.

Cuproptosis in lung cancer: therapeutic options and prognostic models.

Lung cancer (LC) is a serious threat to mankind. The survival of LC patients is still poor despite the enormous efforts that have been made to develop novel treatments. A copper-dependent cell death termed cuproptosis is distinct from known programmed cell death (PCD). Cuproptosis is induced by the disruption of the binding of copper to lipoylated tricarboxylic acid (TCA) cycle proteins of mitochondrial respiratory chains. Potential approaches for treating LC are inducing cell cuproptosis and targeting cell copper death mechanisms. Thus, in this review, we summarize the systemic and cellular metabolic processes of copper. We highlight the possible therapeutic options of employing copper ionophores and chelators for inducing cuproptosis. Moreover, we summarize the prognostic models based on cuproptosis-related genes (CRGs) to identify promising biomarkers for tumor diagnosis and therapy. This review aims to provide a comprehensive summary of CRGs-based prognostic models and promising therapeutic options for cuproptosis induction in LC.

At the Basis of Brain Malformations: Brain Plasticity, Developmental Neurobiology, and Considerations for Rehabilitation

AbstractFrom early age in the human brain occurs plasticity process that influences its development. The functioning of the brain is governed by its neuronal connectivity and the synaptic dynamics of these connections. A neuron, over thousands of synapses, can receive a large number of inputs and produce different outputs leading to the consolidation and integration of memory. Synaptic plasticity is the set of experience-dependent changes in neuronal pathways that support acquired habits. It is the ability of the nervous system to reshape connectivity between neurons, changing the functional and structural organization of neuronal circuits that allows us to adapt to the multiple and continuous changes in the environment and leading to processes such as cognitive development and the ability to learn. Synaptic plasticity is mainly due to short- and long-term mechanisms. Short-term synaptic plasticity refers to changes in synaptic strength that occurs very quickly (from one-thousandth of a second to 5 minutes) and are temporary and decay over minutes (maximum 30 minutes). Long-term synaptic plasticity is defined by a long-lasting, activity-dependent change in synaptic efficacy, last from hours up to a lifetime (from 30 minutes to weeks, months, and years) and is thought to constitute the basis of learning and memory. A significant difference occurs in the nature of the change; short-term plasticity adds only a functional change, whereas long-term plasticity causes not only functional but also structural changes. Aside from genetic factors and metabolic processes, brain development is mediated also by environmental factors. Interaction with the environment plays a key role in the development and growth of neural networks and neuroplasticity. Environmental interactions that can modify and increase the development of neural networks and intelligence in children are several and are herein discussed.

Prebiotics and Probiotics their Sources and Actions Combined Effects of Pro and Pre Biotics and their Challenges and Regulation

The gut microbiota, comprising a diverse array of bacteria, viruses, fungi, and archaea, inhabits the gastrointestinal tract of humans and other animals, exerting a profound influence on various physiological functions. This intricate ecosystem, characterized by its heterogeneity and resilience, plays a pivotal role in maintaining overall health. Through a mutualistic relationship with the host, the gut microbiota contributes to the production of short-chain fatty acids and participates in carbohydrate metabolism, thus influencing energy metabolism and inflammatory processes. Moreover, it actively modulates the immune system, promoting a balanced and well-functioning immune response while providing defense against invading pathogens. Importantly, disruptions in the composition and diversity of the gut microbiota have been implicated in the pathogenesis of numerous chronic diseases, including inflammatory bowel disease, obesity, diabetes, and neurological disorders. Understanding and harnessing the potential of the gut flora hold promise for developing preventive and therapeutic strategies for these conditions. This abstract highlights the multifaceted roles of gut microbiota in human health and underscores the importance of further research in this field for advancing public health initiatives.

Preservation of conjugated primary bile acids by oxygenation of the small intestinal microbiota in vitro.

Conjugated primary bile acids are produced by the liver and exist at high concentrations in the proximal small intestine, where they are critical for proper digestion. Deconjugation of these bile acids with subsequent transformation via dehydroxylation into secondary bile acids is regulated by the colonic gut microbiota and reduces their digestive function. Using an in vitro platform modeling the small intestinal microbiota, we analyzed the ability of this community to transform primary bile acids and studied the effect of physiological levels of oxygen normally found in the proximal small intestine (5%) on this metabolic process. We found that oxygenation of the small intestinal microbiota inhibited the deconjugation of primary bile acids in vitro. These findings suggest that luminal oxygen levels normally found in the small intestine may maintain the optimal role of bile acids in the digestive process by regulating bile acid conversion by the gut microbiota.

Genetic determinants of obesity in adolescent girls

Significant progress in understanding the genetic contribution in obesity and its prevalence at all ages has been achieved since existing methods of treatment and preventive measures aimed at combating obesity are not effective enough.Purpose. To study the prevalence of pathologic single nucleotide polymorphisms rs6265 of the brain neutrophic factor gene BDNF; rs1137101 of the leptin receptor gene LEPR; rs9939609 of the gene, associated with fat mass, FTO; rs4762 and rs699 of angiotensinogen AGT gene; rs1799883 of fatty acid transporter gene FABP2; rs1801282 of PPARG2 gene in obese adolescent girls.Material and methods. 72 teenage girls aged 12–17 years were examined. Group 1 consisted of 36 obese children (standard deviation coefficient SDS BMI ≥ 2.0), group 2 — 36 non-obese children (SDS BMI &lt;1.0). Anthropometric, molecular genetic, and statistical methods were used.Results. In obese adolescent girls, an association was detected with only one gene — PPARG2, a polymorphic locus (Pro/Pro). The prevalence rate of the C allele in group 1 was 80%, in group 2 — 3% (p&lt;0.05). No statistically significant differences in the frequencies of genotypes and alleles of other genes in children with obesity and normal body weight were established.Conclusion. Further large-scale studies, including biochemical and hormonal parameters, are needed to establish the influence of specific polymorphic loci of various genes contributing in obesity and metabolic processes.

Apicoplast-Resident Processes: Exploiting the Chink in the Armour of Plasmodium falciparum Parasites

The discovery of a relict plastid, also known as an apicoplast (apicomplexan plastid), that houses housekeeping processes and metabolic pathways critical to Plasmodium parasites’ survival has prompted increased research on identifying potent inhibitors that can impinge on apicoplast-localised processes. The apicoplast is absent in humans, yet it is proposed to originate from the eukaryote’s secondary endosymbiosis of a primary symbiont. This symbiotic relationship provides a favourable microenvironment for metabolic processes such as haem biosynthesis, Fe-S cluster synthesis, isoprenoid biosynthesis, fatty acid synthesis, and housekeeping processes such as DNA replication, transcription, and translation, distinct from analogous mammalian processes. Recent advancements in comprehending the biology of the apicoplast reveal it as a vulnerable organelle for malaria parasites, offering numerous potential targets for effective antimalarial therapies. We provide an overview of the metabolic processes occurring in the apicoplast and discuss the organelle as a viable antimalarial target in light of current advances in drug discovery. We further highlighted the relevance of these metabolic processes to Plasmodium falciparum during the different stages of the lifecycle.

СВЯЗЬ ЦИРКУЛИРУЮЩИХ УРОВНЕЙ АМИНОКИСЛОТ С РАЗВЕТВЛЕННОЙ ЦЕПЬЮ У ПАЦИЕНТОВ С ХРОНИЧЕСКОЙ СЕРДЕЧНОЙ НЕДОСТАТОЧНОСТЬЮ С НАЛИЧИЕМ НАРУШЕНИЙ УГЛЕВОДНОГО ОБМЕНА

The importance of the problem of chronic heart failure (CHF) is hard to overestimate: this syndrome is diagnosed in millions of patients around the world and its prevalence continues to grow. The proportion of patients suffering from carbohydrate metabolism disorders (CMD) is also steadily increasing. The close connection between carbohydrate metabolism disorders and the progression of CHF allowed such patients to be classified into a separate phenotype cluster - the “metabolic phenotype of CHF”. The pathophysiology of the “metabolic phenotype of CHF” is based on significant metabolic disorders, which determines the characteristic features of the metabolome of this cohort of patients. Therefore, the purpose of this work is to compare and evaluate the relationship between metabolites that occupy one of the most important places in the metabolic processes of the body - the levels of branched chain amino acids (BCAA) and the phenotypic characteristics of patients with CHF. The study included 218 patients: 133 patients of the main group suffering from CHF and having CMD; comparison group - 85 patients with CHF without CMD. The groups were comparable by gender (p=0,324) and age (p=0,936). The levels of BCAAs - leucine, isoleucine, valine - in the blood plasma of patients were assessed by high-performance liquid chromatography combined with mass spectrometry (HPLC-MS). Based on the results of the analysis, the following data were obtained: plasma levels of valine and leucine in patients with CHF and CMD were higher (p=0,022 and p&lt;0,001, respectively) than in patients with CHF and normal carbohydrate metabolism. A direct relationship between the level of leucine + isoleucine and the concentration of glucose (r=0,3, p&lt;0,001) and an inverse relationship between the plasma concentration of valine and the level of N-terminal propeptide of natriuretic hormone (NTproBNP) (r=-0,388, p&lt;0,001) were found. It has been established that a high level of tissue insulin resistance in patients is associated with increased concentrations of BCAA. The results indicate the important role of BCAA in the pathogenesis of the “metabolic phenotype of CHF,” which requires further research in this direction.