Aspects Of Metabolism Research Articles

Effects of Copper Toxicity on Seed Germination and Seedling Growth of Brassica napus L. var. oleífera

Objective: The objective of this study was to evaluate the effects of different copper concentrations on the germination and seedling development of canola. Theoretical Framework: Soil contamination by copper can impact the production and quality of canola, making it essential to understand these aspects to ensure sustainable crop management. Method: The experiment was conducted as a randomized complete block design with crossed classification and plots subdivided in time. Each treatment was replicated four times. The main factor (plot) consisted of 4 levels (0, 200, 400, and 800 mg L⁻¹) of copper contamination, and the secondary factor (subplot) consisted of 3 evaluation days (fifth, sixth, and seventh). The seeds corresponding to each treatment were maintained in a germinator at a temperature of 25±2 ºC and a 24-hour photoperiod. Evaluations regarding seed germination, shoot/root length, and the dry weight of seedlings were conducted between the fifth and seventh days after sowing. Analysis of variance was used to evaluate the variables and, when means were significantly different, multiple comparison test (Tukey's HSD) or regression analysis were used, both at a 95% confidence level. Results and Discussion: Different copper concentrations negatively affected the germination rate, root development, shoot growth, and seedling dry mass, leading to an increase in the rate of abnormal seedlings at intermediate copper concentrations. Research Implications: The results raise the importance of understanding the type of agricultural fertilizer being used in an area so as to prevent toxic copper levels to be built up in soils. Originality/Value: Despite a considerable number of studies on the cytotoxic effects and stress mechanisms induced by heavy metals in biological systems, data regarding the effects of this metal on the germination of cultivated plants remain scarce and unclear. There is still a need to clarify many metabolic aspects, justifying the use of canola and copper for furthering the current knowledge on this subject.

Feature Review Papers in Microbial Metabolism, Physiology and Genetics

This inaugural Special Issue of Fermentation (MDPI) features review articles spanning various aspects of microbial metabolism, physiology, and genetics [...]

Transcription Factor Blimp-1: A Central Regulator of Oxidative Stress and Metabolic Reprogramming in Chronic Inflammatory Diseases

B-lymphocyte-induced maturation protein 1 (Blimp-1) is a transcription factor that, among other functions, modulates metabolism and helps to regulate antioxidant pathways, which is important in the context of chronic inflammatory diseases like diabetes, cardiovascular disease, and autoimmune disease. In immune cell function, Blimp-1 has a modulatory role in the orchestration of metabolic reprogramming and as a promoter of anti-inflammatory cytokines, including IL-10, responsible for modulating oxidative stress and immune homeostasis. Moreover, Blimp-1 also modulates key metabolic aspects, such as glycolysis and fatty acid oxidation, which regulate reactive oxygen species levels, as well as tissue protection. This review depicts Blimp-1 as an important regulator of antioxidant defenses and anti-inflammation and suggests that the protein could serve as a therapeutic target in chronic inflammatory and metabolic dysregulation conditions. The modulation of Blimp-1 in diseases such as diabetic coronary heart disease and atherosclerosis could alleviate oxidative stress, augment the protection of tissues, and improve disease outcomes. The therapeutic potential for the development of new treatments for these chronic conditions lies in the synergy between the regulation of Blimp-1 and antioxidant therapies, which are future directions that may be pursued. This review emphasizes Blimp-1’s emerging importance as a novel regulator in the pathogenesis of inflammatory diseases, providing new opportunities for therapeutic intervention.

The metabolic basis of cancer-related fatigue.

Although we are all familiar with the sensation of fatigue, there are still profound divergences on what it represents and its mechanisms. Fatigue can take various forms depending on the condition in which it develops. Cancer-related fatigue is considered a symptom of exhaustion that is often present at the time of diagnosis, increases in intensity during cancer therapy, and does not always recede after completion of treatment. It is usually attributed to the inflammation induced by damage-associated molecular patterns released by tumor cells during cancer progression and in response to its treatment. In this review, we argue that it is necessary to go beyond the symptoms of fatigue to understand its nature and mechanisms. We propose to consider fatigue as a psychobiological process that regulates the behavioral activities an organism engages in to satisfy its needs, according to its physical ability to do so and to the capacity of its intermediary metabolism to exploit the resources procured by these activities. This last aspect is critical as it implies that these metabolic aspects need to be considered to understand fatigue. Based on the findings we have accumulated over several years of studying fatigue in diverse murine models of cancer, we show that energy metabolism plays a key role in the development and persistence of this condition. Cancer-related fatigue is dependent on the energy requirements of the tumor and the negative impact of cancer therapy on the mitochondrial function of the host. When inflammation is present, it adds to the organism's energy expenses. The organism needs to adjust its metabolism to the different forms of cellular stress it experiences thanks to specialized communication factors known as mitokines that act locally and at a distance from the cells in which they are produced. They induce the subjective, behavioral, and metabolic components of fatigue by acting in the brain. Therefore, the targeting of mitokines and their brain receptors offers a window of opportunity to treat fatigue when it is no longer adaptive but an obstacle to the quality of life of cancer survivors.

Pathophysiology and diagnostic criteria of PCOS.

Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine-metabolic syndrome mainly characterized by ovarian dysfunction, which is only one manifestation of a more complex syndrome with a significant systemic impact. We review scientific literature on the pathophysiology and diagnosis of PCOS evaluating the most relevant data from original articles, reviews and meta-analyses published until June 2024. From a pathophysiological point of view, the concurrence of both metabolic aspects, such as insulin resistance and obesity, and hormonal alterations, such as hyperandrogenemia, might produce the most relevant clinical signs and/symptoms of this syndrome, for instance menstrual irregularities, hair loss, acne and hirsutism. In the latest years, many pieces of evidence highlighted the importance of family history and genetics in the development of the syndrome during adolescence and adult life. According to the available data, hypovitaminosis D could play a detrimental role in the pathogenesis and clinical manifestations of PCOS. PCOS is a challenging endocrine and metabolic dysfunction, due to its different expression among women and to the difficulty in obtaining an accurate diagnosis. The most appropriate approach to women affected by PCOS should involve a multi-step strategy, taking into account the characteristics of each patient, in order to identify the best non-pharmacologic and pharmacologic approach to manage both short- and medium-, and long-term sequelae.

A mitochondria-to-nucleus regulation mediated by the nuclear-translocated mitochondrial lncRNAs.

A bidirectional nucleus-mitochondria communication is essential for homeostasis and stress. By acting as critical molecules, the nuclear-encoded lncRNAs (nulncRNAs) have been implicated in the nucleus-to-mitochondria anterograde regulation. However, role of mitochondrial-derived lncRNAs (mtlncRNAs) in the mitochondria-to-nucleus retrograde regulation remains elusive. Here, we identify functional implication of the mtlncRNAs MDL1AS, lncND5 and lncCyt b in retrograde regulation. Mediated by HuR and PNPT1 proteins, the mtlncRNAs undergo a mitochondria-to-nucleus traveling and then regulate a network of nuclear genes. Moreover, as an example of the functional consequence, we showed that the nuclear-translocated lncCyt b cooperates with the splicing factor hnRNPA2B1 to influence several aspects of cell metabolism including glycolysis, possibly through their regulatory effect on the post-transcriptional processing of related nuclear genes. This study advances our knowledge in mitochondrial biology and provides new insights into the role of mtlncRNAs in mitochondria-nucleus communications.

Nocturnin promotes NADH and ATP production for juvenile hormone biosynthesis in adult insects.

Juvenile hormone (JH) is a key endocrine governing insect development, metamorphosis and reproduction. JH analogs have offered great potential for insect pest control. In adulthood, JH titer rapidly increases in the previtellogenic period and reaches a peak in the vitellogenic phase. However, the regulatory mechanisms of JH biosynthesis in corpora allata (CA) of adult insects remain largely unknown. We observed that the mitochondrial abundance, as well as the levels of NADH (nicotinamide adenine dinucleotide, reduced form) and adenosine triphosphate (ATP), increased in the CA of previtellogenic adults, peaking during the vitellogenic stage. The transcripts of Nocturnin (Noct), which converts nicotinamide adenine dinucleotide phosphate (NADPH) to NADH for ATP production, were more abundant in the CA compared to those of other enzymes involved in conventional NADH-producing metabolic pathways. The developmental expression pattern of Noct was like that of ATP and NADH level. RNA interference-mediated knockdown of Noct caused a significant decrease of NADH and ATP contents, along with markedly reduced expression levels of 12 genes involved in JH biosynthesis pathway. Loss of Noct function resulted in remarkably reduced expression of vitellogenin, accompanied by arrested ovarian growth and oocyte maturation. Our results demonstrated that Noct plays a crucial role in high levels of JH biosynthesis in adult insects via regulating NADH and ATP production. The findings reveal a previously unknown aspect of mitochondrial metabolism in JH biosynthesis and provide valuable information for developing pest control strategies targeting hormone pathways. © 2025 Society of Chemical Industry.

Folate metabolism in myelofibrosis: a missing key?

Folates serve as key enzyme cofactors in several biological processes. Folic acid supplementation is a cornerstone practice but may have a "dark side". Indeed, the accumulation of circulating unmetabolized folic acid (UMFA) has been associated with various chronic inflammatory conditions, including cancer. Additionally, by engaging specific folate receptors, folates can directly stimulate cancer cells and modulate the expression of genes coding for pro-inflammatory and pro-fibrotic cytokines.This evidence could be extremely relevant for myelofibrosis (MF), a chronic myeloproliferative neoplasm typified by the unique combination of clonal proliferation, chronic inflammation, and progressive bone marrow fibrosis. Folate supplementation is frequently associated with conventional or investigational drugs in the treatment of MF-related anemia to tackle ineffective erythropoiesis. In this review, we cover the different aspects of folate metabolism entailed in the behavior and function of normal and malignant hematopoietic cells and discuss the potential implications on the biology of myelofibrosis.

P0096 Impaired fatty acid oxidation is a hallmark of Ulcerative Colitis: evidence from multi-cohort transcriptomics analysis

Abstract Background Ulcerative colitis (UC) is characterized by persistent colonic mucosal inflammation. Despite available treatments, most patients experience only temporary remission. The lack of universally effective treatments results from our incomplete understanding of UC pathophysiology. While many gene expression studies have provided valuable insights into UC mechanisms, the growing availability of transcriptomics datasets offers a unique opportunity for large-scale, cross-validating analyses. Here, we used multiple independent datasets to identify the most consistently dysregulated pathways in UC mucosal biopsies. Methods We performed an integrative analysis of 10 open transcriptomics datasets from human UC and healthy mucosal biopsies (n=710 samples after selection). Each dataset underwent a separate differential expression analysis followed by gene set enrichment. We used 6 different gene set databases to make the analysis as broad as possible (9962 pathways). The results were aggregated across all datasets to identify consistently altered genes and pathways. Since each dataset has a different number of samples and a different sample distribution between the groups, the aggregation was done purely on the ranking level. The complete workflow of the experiment is in Figure 1. Results Mitochondrial fatty acid oxidation emerged as the most significantly dysregulated pathway with a mean rank 4 (median 2.5) across 6 datasets. The analysis revealed a coordinated pattern of metabolic rewiring: systematic downregulation of the entire mitochondrial transport machinery (CPT1A, SLC25A20, CPT2) and the carnitine transporter SLC22A5, accompanied by decreased expression of β-oxidation enzymes (ACADS, ACADM, ACADVL, HADHA, HADHB, HADH, EHHADH) and consistent downregulation of the medium-chain fatty acid activating enzyme ACSF2. In contrast, ACSL4, which specifically activates polyunsaturated fatty acids, showed consistent upregulation. This metabolic disruption was coupled with coordinated changes in membrane remodeling enzymes, with upregulation of LPCAT1 and downregulation of LPCAT3, suggesting systematic alterations in membrane phospholipid composition. Conclusion Our multi-cohort analysis reveals a specific pattern of metabolic disruption in UC that extends beyond pathway inhibition. The coordinated upregulation of the ferroptosis mediator ACSL4 together with systematic changes in membrane remodeling enzymes suggests active metabolic rewiring that could promote ferroptotic cell death through altered membrane phospholipid composition and increased susceptibility to lipid peroxidation. These findings highlight potential new therapeutic targets in UC focused on specific aspects of lipid metabolism and ferroptosis regulation.

Central Serous Chorioretinopathy in Endometriosis Treatment with Progestogen: A Metabolic Understanding

Endometriosis afflicts 10% of women in their reproductive years and nearly half of women with infertility, and its etiology is not yet clear. Pharmacological therapy is generally based on progestins like progestogen. This drug binds to progesterone receptors with many known side effects. Here, we describe the case of a 33-year-old woman surgically treated for endometriosis who continued with drug therapy based on estradiol valerate and dienogest. Approximately 21 months after treatment, she reported ocular symptoms with vision alteration, diplopia, and metamorphopsia related to central serous chorioretinopathy (CSC). After the discontinuation of combined progestin-based treatment, the CSC fully subsided. Semeiological, clinical, and laboratory approaches were adopted, and urinary steroids were measured. A slight increase in prolactinemia in the absence of macro-prolactinemia was reported. The steroidal profile appeared without abnormalities, although a slight alteration of estrogen balance was noted. Considering the pharmacodynamics of dienogest versus selective progesterone receptor modulators, it can be assumed that patients’ clinical events are related to specific site response to steroids that bind the progesterone receptor. Dienogest may have induced the CSC as a not yet characterized side effect of the drug. Undoubtedly, further specific studies are needed concerning the metabolic and pharmacodynamic aspects that cannot be exhaustively covered here.

Triterpenoids from Chios Mastiha Resin Against MASLD-A Molecular Docking Survey.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease without an approved pharmacological approach for its prevention/treatment. Based on the modified Delphi process, NAFLD was redefined as metabolic dysfunction-associated steatotic liver disease (MASLD) to highlight the metabolic aspect of liver pathogenesis. Chios mastiha (Pistacia lentiscus var. Chia, Anacardiaceae) resin demonstrated promising results in MASLD treatment. In this paper, molecular docking was applied to test 16 compounds from Chios mastiha as potential ligands for the receptors GR, LXRα, LXRβ, PPARα PPARγ, MC4R, AMPK, and VEGFR2, whose up- and down-regulation interfere with MASLD development and progression. The observed compounds had moderate and high affinity for LXR, GR, MC4R, and PPARγ in comparison to proven ligands, while their affinity for PPARα, AMPK, and VEGFR was less pronounced. The combination of active compounds from Chios mastiha rather than a single molecule may have a superior ability to control the intertwined MASLD metabolic pathways.

Heterogeneous nuclear ribonucleoprotein C promotes non-small cell lung cancer progression by enhancing XB130 mRNA stability and translation

BackgroundXB130, a classical adaptor protein, exerts a critical role in diverse cellular processes. Aberrant expression of XB130 is closely associated with tumorigenesis and aggressiveness. However, the mechanisms governing its expression regulation remain poorly understood. Heterogeneous nuclear ribonucleoprotein C (hnRNPC), as an RNA-binding protein, is known to modulate multiple aspects of RNA metabolism and has been implicated in the pathogenesis of various cancers. We have previously discovered that hnRNPC is one of the candidate proteins that interact with the 3’ untranslated region (3’UTR) of XB130 in non-small cell lung cancer (NSCLC). Therefore, this study aims to comprehensively elucidate how hnRNPC regulates the expression of XB130 in NSCLC.Materials and methodsWe evaluated the expression of hnRNPC in cancer and assessed the correlation between hnRNPC expression and prognosis in cancer patients using public databases. Subsequently, several stable cell lines were constructed. The proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of these cells were detected through Real-time cellular analysis, adherent colony formation, wound healing assay, invasion assay, and Western blotting. The specific regulatory manner between hnRNPC and XB130 was investigated by Real-time quantitative PCR, Western blotting, RNA pull‑down assay, dual‑luciferase reporter assay, RNA immunoprecipitation, and Co-Immunoprecipitation.ResultsWe identified that hnRNPC expression is significantly elevated in NSCLC and correlates with poor prognosis in patients with lung adenocarcinoma. HnRNPC overexpression in NSCLC cells increased the expression of XB130, subsequently activating the PI3K/Akt signaling pathway and ultimately promoting cell proliferation and EMT. Additionally, overexpressing XB130 in hnRNPC-silenced cells partially restored cell proliferation and EMT. Mechanistically, hnRNPC specifically bound to the 3’UTR segments of XB130 mRNA, enhancing mRNA stability by inhibiting the recruitment of nucleases 5’-3’ exoribonuclease 1 (XRN1) and DIS3-like 3’-5’ exoribonuclease 2 (DIS3L2). Furthermore, hnRNPC simultaneously interacted with the eukaryotic initiation factor 4E (eIF4E), a component of the eIF4F complex, facilitating the circularization of XB130 mRNA and thereby increasing its translation efficiency.ConclusionsHnRNPC overexpression promotes NSCLC progression by enhancing XB130 mRNA stability and translation, suggesting that hnRNPC might be a potential therapeutic and prognostic target for NSCLC.

Single-molecule analysis of PARP1-G-quadruplex interaction.

The human genome contains numerous repetitive nucleotide sequences that display a propensity to fold into non-canonical DNA structures including G-quadruplexes (G4s). G4s have both positive and negative impacts on various aspects of nucleic acid metabolism including DNA replication, DNA repair and RNA transcription. Poly (ADP-ribose) polymerase (PARP1), an important anticancer drug target, has been recently shown to bind a subset of G4s, and to undergo auto-PARylation. The mechanism of this interaction, however, is poorly understood. Utilizing Mass Photometry (MP) and single-molecule total internal reflection fluorescence microscopy (smTIRFM), we demonstrate that PARP1 dynamically interacts with G4s with a 1:1 stoichiometry. Interaction of a single PARP1 molecule with nicked DNA or DNA containing G4 and a primer-template junction is sufficient to activate robust auto-PARylation resulting in the addition of poly (ADP-ribose) chains with molecular weight of several hundred kDa. Pharmacological PARP inhibitors EB-47, Olaparib and Veliparib differently affect PARP1 retention on G4-containing DNA compared to nicked DNA.

Unraveling the potential contribution of DHHC2 in cancer biology via untargeted metabolomics.

DHHC-mediated protein-S-palmitoylation is recognized as a distinct and reversible lipid modification, playing a pivotal role in the progression and prevention of multiple diseases, including cancer and neurodegenerative disorders. Over the past decade, growing evidence indicates the crucial role of DHHC2 in preventing tumorigenesis by palmitoylation of various protein substrates. However, a comprehensive understanding of the specific impact of DHHC2 on cancer cell metabolic regulation remains unclear. To investigate the metabolites change by DHHC2, we conducted untargeted metabolomic profiling on the HEK-293 T cell line with DHHC2- Knockdown (DHHC2-KD), DHHC2-Overexpression (DHHC2-OE) and empty vector control (Ctrl) conditions via LC-MS/MS-based analysis. Our dataset revealed the identification of a total of 73 metabolites encompassing all the conditions, with only 22 showing significant differences in univariate analysis. Furthermore, we performed pathway analysis with metabolites having VIP ≥ 0.7, P value ≤0.05, and fold change (FC) > 2 in DHHC2-OE (upregulated) and FC < 0.5 in DHHC2-OE or FC > 2 in DHHC2-KD condition (downregulated). We unveiled significant expression of the pyrimidine metabolism, urea cycle, and aspartate metabolism due to the abundance of onco-metabolites such as glutamine, uridine, and glutamic acid in the DHHC2-KD condition. However, DHHC2 overexpression resulted in a higher expression of metabolites previously reported to be associated with anti-cancer activity, such as betaine and 5'-methylthioadenosine (5'-MTA). Overall, this study sheds light on the changes mediated by DHHC2 in a cancer cell metabolome and suggests avenues for further investigation into other DHHC isoforms and their metabolic aspects.

Lactylation in health and disease: physiological or pathological?

Lactate is an indispensable substance in various cellular physiological functions and plays regulatory roles in different aspects of energy metabolism and signal transduction. Lactylation (Kla), a key pathway through which lactate exerts its functions, has been identified as a novel posttranslational modification (PTM). Research indicates that Kla is an essential balancing mechanism in a variety of organisms and is involved in many key cellular biological processes through different pathways. Kla is closely related to disease development and represents a potential and important new drug target. In line with existing reports, we searched for newly discovered Kla sites on histone and nonhistone proteins; reviewed the regulatory mechanisms of Kla (particularly focusing on the enzymes directly involved in the reversible regulation of Kla, including "writers" (modifying enzymes), "readers" (modification-binding enzymes), and "erasers" (demodifying enzymes); and summarized the crosstalk between different PTMs to help researchers better understand the widespread distribution of Kla and its diverse functions. Furthermore, considering the "double-edged sword" role of Kla in both physiological and pathological contexts, this review highlights the "beneficial" biological functions of Kla in physiological states (energy metabolism, inflammatory responses, cell fate determination, development, etc.) and its "detrimental" pathogenic or inducive effects on pathological processes, particularly malignant tumors and complex nontumor diseases. We also clarify the molecular mechanisms of Kla in health and disease, and discuss its feasibility as a therapeutic target. Finally, we describe the detection technologies for Kla and their potential applications in diagnosis and clinical settings, aiming to provide new insights for the treatment of various diseases and to accelerate translation from laboratory research to clinical practice.

In vivo itaconate tracing reveals degradation pathway and turnover kinetics.

Itaconate is an immunomodulatory metabolite that alters mitochondrial metabolism and immune cell function. This organic acid is endogenously synthesized via tricarboxylic acid (TCA) metabolism downstream of TLR signaling. Itaconate-based treatment strategies are being explored to mitigate numerous inflammatory conditions. However, little is known about the turnover rate of itaconate in circulation, the kinetics of its degradation, and the broader consequences on metabolism. By combining mass spectrometry and in vivo 13 C itaconate tracing, we demonstrate that itaconate is rapidly eliminated from plasma, excreted via urine, and fuels TCA cycle metabolism specifically in the liver and kidneys. These studies further revealed that itaconate is converted into acetyl-CoA, mesaconate, and citramalate in mitochondria. Itaconate administration also influenced branched-chain amino acid metabolism and succinate levels, indicating a functional impact on succinate dehydrogenase (SDH) and methylmalonyl-CoA mutase (MUT) activity. Our findings uncovered a previously unknown aspect of the itaconate metabolism, highlighting its rapid catabolism in vivo that contrasts findings in cultured cells.

Reprogramming of Fatty Acid Metabolism in Acute Leukemia.

Fatty acids are essential biomolecules that support several cellular processes, such as membrane structures, energy storage and production, as well as signal transduction. Accordingly, changes in fatty acid metabolism can have a significant impact on cell behavior, such as growth, survival, proliferation, differentiation, and motility. Therefore, it is not surprising that many aspects of fatty acid metabolism are frequently dysregulated in human cancer, including in highly aggressive blood cancers such as acute leukemia. The aims of this review are to summarize the aspects of fatty acid metabolism that are specifically coopted in acute leukemia as well as current preclinical strategies for targeting fatty acid metabolism in these cancers.

Stress Parameters of Horse Riders in Kök-Börü Games by Winning and Losing Situations

ABSTRACT Introduction This study examined the effects of winning or losing situations on the stress, metabolic, and physiological aspects of horse riders in Kök-Börü, a traditional equestrian team game. Methods Blood samples were collected from the riders of four different teams participating in two separate Kök-Börü games, both before and after gameplay. The samples were examined for levels of cortisol, adrenocorticotropic hormone (ACTH), beta-endorphin, adrenaline, noradrenaline, triiodothyronine (T3), and thyroxine (T4) using species-specific commercial enzyme-linked immunosorbent assay kits. The same samples were tested for biochemical and hematological parameters with an autoanalyzer. Results Post-game, the riders from the winning teams showed an increase in the serum levels of white blood count, granulocytes (GRA), percent GRA, mean corpuscular volume, platelet count, plateletcrit, creatine kinase, albumine, aspartate transferase, creatine, cortisol, and ACTH compared to their levels before the game. In contrast, the post-game serum levels of lymphocytes, adrenaline, noradrenaline, and T3 of the winning team were lower. When the pre-game samples of winning and losing teams were compared, it was observed that sodium and T4 levels were higher in the winners. Conclusions The data suggest that winning team riders put in more effort and experienced more stress. Conversely, those on losing teams exerted less effort and experienced less stress, as indicated by the parameter changes.

RNA Metabolism and the Role of Small RNAs in Regulating Multiple Aspects of RNA Metabolism.

RNA metabolism is focused on RNA molecules and encompasses all the crucial processes an RNA molecule may or will undergo throughout its life cycle. It is an essential cellular process that allows all cells to function effectively. The transcriptomic landscape of a cell is shaped by the processes such as RNA biosynthesis, maturation (RNA processing, folding, and modification), intra- and inter-cellular transport, transcriptional and post-transcriptional regulation, modification, catabolic decay, and retrograde signaling, all of which are interconnected and are essential for cellular RNA homeostasis. In eukaryotes, sRNAs, typically 20-31 nucleotides in length, are a class of ncRNAs found to function as nodes in various gene regulatory networks. sRNAs are known to play significant roles in regulating RNA population at the transcriptional, post-transcriptional, and translational levels. Along with sRNAs, such as miRNAs, siRNAs, and piRNAs, new categories of ncRNAs, i.e., lncRNAs and circRNAs, also contribute to RNA metabolism regulation in eukaryotes. In plants, various genetic screens have demonstrated that sRNA biogenesis mutants, as well as RNA metabolism pathway mutants, exhibit similar growth and development defects, misregulated primary and secondary metabolism, as well as impaired stress response. In addition, sRNAs are both the "products" and the "regulators" in broad RNA metabolism networks; gene regulatory networks involving sRNAs form autoregulatory loops that affect the expression of both sRNA and the respective target. This review examines the interconnected aspects of RNA metabolism with sRNA regulatory pathways in plants. It also explores the potential conservation of these pathways across different kingdoms, particularly in plants and animals. Additionally, the review highlights how cellular RNA homeostasis directly impacts adaptive responses to environmental changes as well as different developmental aspects in plants.

Impact of Hedgehog modulators on signaling pathways in primary murine and human hepatocytes in vitro: insights into liver metabolism.

The Hedgehog (Hh) signaling pathway is essential for maintaining homeostasis during embryogenesis and in adult tissues. In the liver, dysregulation of this pathway often leads to liver cancer development. Recent studies also suggest that disturbances in the Hh pathway can affect liver metabolism in healthy livers through interactions with other signaling pathways, such as the Wnt/β-catenin pathway. As a result, the Hh pathway has emerged as a promising target for therapeutic intervention. However, little is known about the effects of Hh modulators on healthy hepatocytes. In our study, we investigated the effects of the Hh agonists SAG (300nM) and triamcinolone acetonide (40µM), as well as the antagonists RU-SKI43 (100nM), cyclopamine (5µM), budesonide (25µM), GANT61 (0.5µM), and vismodegib (1µM) on healthy mouse and human primary hepatocytes in vitro. We employed toxicological, transcriptomic, proteomic, and functional assays, including proliferation and Seahorse assays. Our results show that these compounds significantly impact metabolic pathways such as lipid and glucose metabolism at both transcriptional and protein levels. Mechanistically, our data suggest the involvement of both canonical and non-canonical Hedgehog pathways, a phenomenon not previously described in hepatocytes. These findings highlight the diverse effects of these compounds on signaling and key metabolic functions in the liver, which emphasizes the need to investigate the hepatic Hh cascade and its metabolic control in depth. As the compounds regulate different aspects of metabolism, they need to be carefully studied in appropriate model systems for specific therapeutic use.