Role In Metabolism Research Articles

Ras-dependent activation of BMAL2 regulates hypoxic metabolism in pancreatic cancer.

To identify drivers of malignancy in human pancreatic ductal adenocarcinoma (PDAC), we performed regulatory network analysis on a large collection of expression profiles from laser capture microdissected samples of PDAC and benign precursors. We discovered that BMAL2 plays a role in the initiation, progression, post resection survival, and KRAS activity in PDAC. Functional analysis of BMAL2 target genes led us to hypothesize that it plays a role in regulating the response to hypoxia, a critical but poorly understood feature of PDAC physiology. Knockout of BMAL2 in multiple human PDAC cell lines revealed effects on viability and invasion, particularly under hypoxic conditions. Loss of BMAL2 also affected glycolysis and other metabolic processes. We found that BMAL2 directly regulates hypoxia-responsive target genes. We also found that BMAL2 is necessary for the stabilization of HIF1A upon exposure to hypoxia, but destabilizes HIF2A under hypoxia. These data demonstrate that BMAL2 is a master transcriptional regulator of hypoxia responses in PDAC and may serve as a long-sought molecular switch that distinguishes HIF1A- and HIF2A-dependent modes of hypoxic metabolism.

Identification and Characterization of Polyamine Metabolism in Citrus in Response to 'Candidatus Liberibacter asiaticus' Infection.

Citrus Huanglongbing, one of the most devastating citrus diseases, is caused by 'Candidatus Liberibacter asiaticus' (CLas). Polyamines are aliphatic nitrogen-containing compounds that play important roles in disease resistance and are synthesized primarily by two pathways: an arginine decarboxylation pathway and an ornithine decarboxylation pathway. However, it is unclear whether polyamines play a role in the tolerance of citrus to infection by CLas and, if so, whether one or both of the core polyamine metabolic pathways are important. We used high-performance liquid chromatography and ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry to detect the contents of nine polyamine metabolism-related compounds in six citrus cultivars with varying levels of tolerance to CLas. We also systematically detected the changes in polyamine metabolism-related compounds and H2O2 contents and compared the gene expression levels and the activities of enzymes involved in the polyamine metabolic pathway among healthy, asymptomatic, and symptomatic leaves of Newhall navel oranges infected with CLas. The tolerant and moderately tolerant varieties showed higher polyamine metabolism-related compound levels than those of susceptible varieties. Compared with the healthy group, the symptomatic group showed significantly increased contents of arginine, ornithine, γ-aminobutyric acid, and putrescine by approximately 180, 19, 1.5, and 0.2 times, respectively, and upregulated expression of biosynthetic genes. Arginase and ornithine decarboxylase enzyme activities were the highest in the symptomatic group, whereas arginine decarboxylase and agmatine deiminase enzyme activities were the highest in the asymptomatic group. The two polyamine biosynthetic pathways showed different trends with the increase of the CLas titer, indicating that polyamines were mainly synthesized through the arginine decarboxylase pathway in the asymptomatic leaves and were synthesized via the ornithine decarboxylase pathway in symptomatic leaves. These findings provide new insight into the changes in polyamine metabolism in citrus infected with CLas.

Lamprey--an excellent model for iron metabolism.

After 500 million years of evolution, lamprey is in a natural environment characterized by low temperature and high iron content, and its unique adaptive evolution mode has developed its organizational structure and life mechanism in the process of metamorphosis, which provides a new direction for people to further study the origin and evolution of life. Iron is one of the essential nutrients for the human body and plays an important role in metabolic processes, but when exceeded, it can lead to iron toxicity. For example, the serum iron concentration of pre-metamorphosis larvae is 149 times that of normal males, and the iron content in the liver of juveniles is about 2-3 times that of normal humans. Lamprey has a complete biochemical system to tolerate high concentrations of free iron in the body, and high expression of important genes for iron homeostasis, such as transferrin, ferritin heavy chain, superoxide dismutase, etc., improves iron transport, iron storage and antioxidant capacity. Lamprey has an IRE/IRP regulatory system, which is an important protection mechanism for lamprey to adapt to the high iron content environment in the organization. In addition, lampreys gradually form oral glands during metamorphosis and development, which become the unique iron metabolism organs of lampreys. In this review, we mainly summarize the distribution of iron in various tissues of lamprey and the potential mechanism of adapting to the content of iron in the body, so as to provide a theoretical basis for the subsequent search for the molecular mechanism of iron metabolism.

Exploring unconventional targets in myofibroblast transdifferentiation outside classical TGF- signaling in renal fibrosis.

We propose that the key initiators of renal fibrosis are myofibroblasts which originate from four predominant sources-fibroblasts, pericytes, endothelial cells and macrophages. Increased accumulation of renal interstitial myofibroblasts correlates with an increase in collagen, fibrillar proteins, and fibrosis severity. The canonical TGF- pathway, signaling via Smad proteins, is the central molecular hub that initiates these cellular transformations. However, directly targeting these classical pathway molecules has proven challenging due their integral roles in metabolic process, and/or non-sustainable effects involving compensatory cross-talk with TGF-β. This review explores recently discovered alternative molecular targets that drive transdifferentiation into myofibroblasts. Discovering targets outside of the classical TGF-β/Smad pathway is crucial for advancing antifibrotic therapies, and strategically targeting the development of myofibroblasts offers a promising approach to control excessive extracellular matrix deposition and impede fibrosis progression.

Analysis of Lysine Metabolism in a Rat Model of Type 2 Diabetes Reveals Modulation of Endocytosis and Glucose Metabolism

Lysine is an essential amino acid that serves as a building block for proteins and plays a role in metabolic processes. While a recent study provided evidence that lysine is beneficial for hypertension-associated kidney disease, possibly through inhibiting renal tubular reabsorption and forming new lysine conjugates, knowledge about the role of lysine in diabetic nephropathy (DN) is rudimentary. Therefore, the aim of the study was to investigate the role of lysine in kidney function in the setting of DN and its underlying mechanisms. We hypothesized that lysine may impact the kidneys in the following ways: 1) by mediating protein endocytosis in proximal tubules; 2) by altering protein abundance in the kidneys and other organs; and 3) by disrupting metabolic pathways through the formation of conjugates or degradation products. We investigated the effects of lysine on proximal tubule endocytosis and other organs using proteomic approaches and studied changes in lysine conjugates and metabolic products using targeted metabolomics. The results of urinary proteomics suggested that lysine’s impact on endocytosis may be associated with the inhibition of megalin and cubilin. Furthermore, lysine affected proteins related to glucose metabolism. Subsequently, we proceeded to investigate the influence of lysine on various organs in Type 2 Diabetic Nephropathy (T2DN) rats. Gene Ontology (GO) enrichment revealed that lysine exerts tissue-specific effects on different organs, with pathways enriched in the kidney including phagocytosis and enzyme inhibitor activity. Additionally, within the kidney, the lysine-treated group showed downregulation of glycolysis-related enzymes. The metabolomics results showed that lysine leads to a decrease in glucose and an increase in fructose 1,6-bisphosphate, while also resulting in an upregulation of related metabolites in the tricarboxylic acid cycle (TCA cycle). Our findings showed changes in the protein composition involved in lysine-mediated endocytosis and the impact of lysine on glucose metabolism enzymes and metabolites. The specific molecular mechanisms are still under investigation. R01 DK135644 and I01 BX004024 (to AS). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Development of technology for obtaining juice from persimmon fruit (Diospyros kaki L.)

Development of technology for obtaining juice from persimmon fruit (Diospyros kaki L.)

Computational models as catalysts for investigating redoxin systems.

Thioredoxin, glutaredoxin and peroxiredoxin systems play central roles in redox regulation, signaling and metabolism in cells. In these systems, reducing equivalents from NAD(P)H are transferred by coupled thiol-disulfide exchange reactions to redoxins which then reduce a wide array of targets. However, the characterization of redoxin activity has been unclear, with redoxins regarded as enzymes in some studies and redox metabolites in others. Consequently, redoxin activities have been quantified by enzyme kinetic parameters in vitro, and redox potentials or redox ratios within cells. By analyzing all the reactions within these systems, computational models showed that many kinetic properties attributed to redoxins were due to system-level effects. Models of cellular redoxin networks have also been used to estimate intracellular hydrogen peroxide levels, analyze redox signaling and couple omic and kinetic data to understand the regulation of these networks in disease. Computational modeling has emerged as a powerful complementary tool to traditional redoxin enzyme kinetic and cellular assays that integrates data from a number of sources into a single quantitative framework to accelerate the analysis of redoxin systems.

The mTOR Signaling Pathway and mTOR Inhibitors in Cancer: Next-generation Inhibitors and Approaches.

mTOR is a serine/threonine kinase that plays various roles in cell growth, proliferation, and metabolism. mTOR signaling in cancer becomes irregular. Therefore, drugs targeting mTOR have been developed. Although mTOR inhibitors rapamycin and rapamycin rapalogs (everolimus, rapamycin, temsirolimus, deforolimus, etc.) and new generation mTOR inhibitors (Rapalink, Dual PI3K/mTOR inhibitors, etc.) are used in cancer treatments, mTOR resistance mechanisms may inhibit the efficacy of these drugs. Therefore, new inhibition approaches are developed. Although these new inhibition approaches have not been widely investigated in cancer treatment, the use of nanoparticles has been evaluated as a new treatment option in a few types of cancer. This review outlines the functions of mTOR in the cancer process, its resistance mechanisms, and the efficiency of mTOR inhibitors in cancer treatment. Furthermore, it discusses the next-generation mTOR inhibitors and inhibition strategies created using nanoparticles. Since mTOR resistance mechanisms prevent the effects of mTOR inhibitors used in cancer treatments, new inhibition strategies should be developed. Inhibition approaches are created using nanoparticles, and one of them offers a promising treatment option with evidence supporting its effectiveness.

BIOEXTRACTION OF IRON THROUGH Bacillus sp. SP10 FROM MINERAL OXIDE AND ITS APPLICATION AS PLANT MICRONUTRIENT

Iron is an essential micronutrient for all living organisms because of its critical 
 role in metabolic processes. In plants it plays a key role in the synthesis of 
 chlorophyll, some vital enzymatic and metabolic processese. However, most of 
 the iron in nature is present as precipitates or in insoluble forms. Therefore, 
 biological mechanism has been employed to mineralize Fe(III) oxides into 
 Fe(II) through microbial action to increase the availability of soluble iron. An 
 iron reducing bacterial strain was isolated based on its tolerant limits and iron 
 mineralizing ability. The strain Bacillus sp. SP10 effectively mineralized iron 
 in synthetic medium possessing 1% starch and pH 7. In a 25 day’s column 
 study, the soluble Fe(II) as micronutrient showed a gradual increase in each 
 seepage collected from different treatment columns. Similarly, the plants 
 grown on soil obtained from treatment D (i.e. 1% starch + 1% Bacillus sp. 
 SP10 inoculum + 0.25% anthraquinone-2,6-disulphonate) column displayed 
 good growth and maximum shoot length, mainly due to the increased 
 accessibility of iron through microbial mineralization. The mineralization of 
 Fe in soil was established through SEM and EDX analysis.

Abstract 1811: Efficient identification of new small molecules targeting succinate dehydrogenase in non-small cell lung cancer

Abstract Efficient lung cancer treatment remains challenging due to the lack of therapeutic targets. The succinate dehydrogenase (SDH) enzyme plays a critical metabolic role as an intermediate between the citric acid cycle and the electron transport chain associated with the cancer disease state. Although several existing compounds have been applied to target metabolic diseases in vitro, modulating SDH for lung cancer treatment is still elusive. By integrating the AtomNet® technology for compound identification with mitochondria- and cell-based enzyme activity assays, we identified four new small molecules from 96 predicted candidates. Cellular thermal shift assay confirmed that these small molecules bind directly to SDH subunits in lung cancer cells. Mechanistically, treatment with these small molecules increased cellular and mitochondrial reactive oxygen species, accumulated succinate, and DNA damage-induced apoptosis in lung cancer cell lines. Functionally, these small molecules reduced the growth, migration, and formation of 3D organoids in vitro in lung cancer cell lines, both in the short and long term. Our study sheds light on the function of SDH in metabolic dysfunction related to cancer and highlights the potential of modulating SDH as a viable therapeutic strategy for targeting lung cancer and other cancer types. LS, NS, and WCZ contributed equally to this work. Citation Format: Luis Silva, Nicholas Skiados, Nikitha Murugavel, Nastassja Luna, Karen Cover, Manish K. Gupta, Stephanie C. Contreras, Terrence E. O'Brien, Wen Cai Zhang. Efficient identification of new small molecules targeting succinate dehydrogenase in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1811.

Maternal nutrient metabolism in the liver during pregnancy.

The liver plays pivotal roles in nutrient metabolism, and correct hepatic adaptations are required in maternal nutrient metabolism during pregnancy. In this review, hepatic nutrient metabolism, including glucose metabolism, lipid and cholesterol metabolism, and protein and amino acid metabolism, is first addressed. In addition, recent progress on maternal hepatic adaptations in nutrient metabolism during pregnancy is discussed. Finally, the factors that regulate hepatic nutrient metabolism during pregnancy are highlighted, and the factors include follicle-stimulating hormone, estrogen, progesterone, insulin-like growth factor 1, prostaglandins fibroblast growth factor 21, serotonin, growth hormone, adrenocorticotropic hormone, prolactin, thyroid stimulating hormone, melatonin, adrenal hormone, leptin, glucagon-like peptide-1, insulin glucagon and thyroid hormone. Our vision is that more attention should be paid to liver nutrient metabolism during pregnancy, which will be helpful for utilizing nutrient appropriately and efficiently, and avoiding liver diseases during pregnancy.

Oxidized-LDL Induces Metabolic Dysfunction in Retinal Pigment Epithelial Cells.

Recently, mitochondrial dysfunction has gained attention as a causative factor in the pathogenesis and progression of age-related macular degeneration (AMD). Mitochondrial damage plays a key role in metabolism and disrupts the balance of intracellular metabolic pathways, such as oxidative phosphorylation (OXPHOS) and glycolysis. In this study, we focused on oxidized low-density lipoprotein (ox-LDL), a major constituent of drusen that accumulates in the retina of patients with AMD, and investigated whether it could be a causative factor for metabolic alterations in retinal pigment epithelial (RPE) cells. We found that prolonged exposure to ox-LDL induced changes in fatty acid β-oxidation (FAO), OXPHOS, and glycolytic activity and increased the mitochondrial reactive oxygen species production in RPE cells. Notably, the effects on metabolic alterations varied with the concentration and duration of ox-LDL treatment. In addition, we addressed the limitations of using ARPE-19 cells for retinal disease research by highlighting their lower barrier function and FAO activity compared to those of induced pluripotent stem cell-derived RPE cells. Our findings can aid in the elucidation of mechanisms underlying the metabolic alterations in AMD.

First trimester maternal tryptophan metabolism and embryonic and fetal growth: the Rotterdam Periconceptional Cohort (Predict Study).

What is the association between first trimester maternal tryptophan (TRP) metabolites and embryonic and fetal growth? Higher 5-hydroxytryptophan (5-HTP) concentrations are associated with reduced embryonic growth and fetal growth and with an increased risk of small-for-gestational age (SGA), while higher kynurenine (KYN) concentrations are associated with a reduced risk of SGA. The maternal TRP metabolism is involved in many critical processes for embryonic and fetal growth, including immune modulation and regulation of vascular tone. Disturbances in TRP metabolism are associated with adverse maternal and fetal outcomes. This study was embedded within the Rotterdam Periconceptional Cohort (Predict Study), an ongoing prospective observational cohort conducted at a tertiary hospital from November 2010 onwards. A total of 1115 women were included before 11 weeks of gestation between November 2010 and December 2020. Maternal serum samples were collected between 7 and 11 weeks of gestation, and TRP metabolites (TRP, KYN, 5-HTP, 5-hydroxytryptamine, and 5-hydroxyindoleacetic acid) were determined using a validated liquid chromatography (tandem) mass spectrometry method. Serial 3D ultrasound scans were performed at 7, 9, and 11 weeks of gestation to accurately assess features of embryonic growth, including crown-rump length (CRL) and embryonic volume (EV) offline using virtual reality systems. Fetal growth parameters were retrieved from medical records and standardized according to Dutch reference curves. Mixed models were used to assess associations between maternal TRP metabolites and CRL and EV trajectories. Linear and logistic regression models were utilized to investigate associations with estimated fetal weight (EFW) and birthweight, and with SGA, respectively. All analyses were adjusted for potential confounders. Maternal 5-HTP concentrations and the maternal 5-HTP/TRP ratio were inversely associated with embryonic growth (5-HTP, √CRL: β = -0.015, 95% CI = -0.028 to -0.001; 5-HTP 3√EV: β = -0.009, 95% CI = -0.016 to -0.003). An increased maternal 5-HTP/TRP ratio was also associated with lower EFW and birthweight, and with an increased risk of SGA (odds ratio (OR) = 1.006, 95% CI = 1.00-1.013). In contrast, higher maternal KYN concentrations were associated with a reduced risk of SGA in the unadjusted models (OR = 0.548, 95% CI = 0.320-0.921). Residual confounding cannot be ruled out because of the observational design of this study. Moreover, this study was conducted in a single tertiary hospital, which assures high internal validity but may limit external validity. The novel finding that maternal 5-HTP concentrations are associated with a smaller embryo and fetus implies that disturbances of the maternal serotonin pathway in the first trimester of pregnancy are potentially involved in the pathophysiology of fetal growth restriction. The association between higher maternal KYN concentrations and a reduced risk of SGA substantiate the evidence that the KYN pathway has an important role in fetal growth. More research is needed to delve deeper into the potential role of the maternal TRP metabolism during the periconception period and pregnancy outcome for mother and offspring. This study was funded by the Department of Obstetrics and Gynecology and the Department of Clinical Chemistry of the Erasmus MC, University Medical Center, Rotterdam, the Netherlands. The authors have no competing interests to disclose. N/A.

Metabolism, digestion, and horizontal transfer: potential roles and interaction of symbiotic bacteria in the ladybird beetle Novius pumilus and their prey Icerya aegyptiaca.

In this study, we first time sequenced and analyzed the 16S rRNA gene data of predator ladybird beetles Novius pumilus and globally distributed invasive pest Icerya aegyptiaca at different stages, and combined data with bacterial genome sequences in N. pumilus to explored the taxonomic distribution, alpha and beta diversity, differentially abundant bacteria, co-occurrence network, and putative functions of their microbial community. Our finding revealed that Candidatus Walczuchella, which exhibited a higher abundance in I. aegyptiaca, possessed several genes in essential amino acid biosynthesis and seemed to perform roles in providing nutrients to the host, similar to other obligate symbionts in scale insects. Lactococcus, Serratia, and Pseudomonas, more abundant in N. pumilus, were predicted to have genes related to hydrocarbon, fatty acids, and chitin degradation, which may assist their hosts in digesting the wax shell covering the scale insects. Notably, our result showed that Lactococcus had relatively higher abundances in adults and eggs compared to other stages in N. pumilus, indicating potential vertical transmission. Additionally, we found that Arsenophonus, known to influence sex ratios in whitefly and wasp, may also function in I. aegyptiaca, probably by influencing nutrient metabolism as it similarly had many genes corresponding to vitamin B and essential amino acid biosynthesis. Also, we observed a potential horizontal transfer of Arsenophonus between the scale insect and its predator, with a relatively high abundance in the ladybirds compared to other bacteria from the scale insects.IMPORTANCEThe composition and dynamic changes of microbiome in different developmental stages of ladybird beetles Novius pumilus with its prey Icerya aegyptiaca were detected. We found that Candidatus Walczuchella, abundant in I. aegyptiaca, probably provide nutrients to their host based on their amino acid biosynthesis-related genes. Abundant symbionts in N. pumilus, including Lactococcus, Serratia, and Pseudophonus, may help the host digest the scale insects with their hydrocarbon, fatty acid, and chitin degrading-related genes. A key endosymbiont Arsenophonus may play potential roles in the nutrient metabolisms and sex determination in I. aegyptiaca, and is possibly transferred from the scale insect to the predator.

Enhancing Leukemia Treatment: The Role of Combined Therapies Based on Amino Acid Starvation.

Cancer cells demand amino acids beyond their usage as "building blocks" for protein synthesis. As a result, targeting amino acid acquisition and utilization has emerged as a pivotal strategy in cancer treatment. In the setting of leukemia therapy, compelling examples of targeting amino acid metabolism exist at both pre-clinical and clinical stages. This review focuses on summarizing novel insights into the metabolism of glutamine, asparagine, arginine, and tryptophan in leukemias, and providing a comprehensive discussion of perturbing their metabolism to improve the therapeutic outcomes. Certain amino acids, such as glutamine, play a vital role in the energy metabolism of cancer cells and the maintenance of redox balance, while others, such as arginine and tryptophan, contribute significantly to the immune microenvironment. Therefore, assessing the efficacy of targeting amino acid metabolism requires comprehensive strategies. Combining traditional chemotherapeutics with novel strategies to perturb amino acid metabolism is another way to improve the outcome in leukemia patients via overcoming chemo-resistance or promoting immunotherapy. In this review, we also discuss several ongoing or complete clinical trials, in which targeting amino acid metabolism is combined with other chemotherapeutics in treating leukemia.

Juvenil İdiyopatik Artrit Tanılı Çocuklarda 25 Hidroksivitamin D Düzey Takibinin Önemi

Objective: In patients with juvenile idiopathic arthritis (JIA), bone metabolism may be negatively affected due to both the activity of the disease and the medications used. Our study aimed to investigate the necessity of evaluating 25 hydroxyvitamin D (25 (OH) Vit D), calcium (Ca), phosphorus (P), alkaline phosphatase (ALP) levels and possible related factors in the follow-up of patients diagnosed with JIA.
 Method: The records of 68 patients with JIA were retrospectively evaluated. Disease subtypes, medications used, and whether they were in remission or active disease were reviewed.
 Results: 25 OH Vit D levels were low in 14.7% of patients with JIA compared to the control group. 66.6% of the patients with systemic arthritis had high ALP levels. 25 OH Vit D level was low in 16.6% of steroid users, and Vitamin D level was low in 55.5% of the patients in the active disease group. It was determined that patients in the active disease group had the highest ALP and lowest vitamin D levels compared to patients in remission with and without medication.
 Conclusion: Bone metabolism in patients with JIA is negatively affected. Since vitamin D plays a crucial role in bone metabolism, it was emphasized that vitamin D levels should be evaluated especially during active disease and supplements should be provided for patients with low vitamin D levels.

Polyphosphate Nanoparticles: Balancing Energy Requirements in Tissue Regeneration Processes.

Nanoparticles of a particular, evolutionarily old inorganic polymer found across the biological kingdoms have attracted increasing interest in recent years not only because of their crucial role in metabolism but also their potential medical applicability: it is inorganic polyphosphate (polyP). This ubiquitous linear polymer is composed of 10-1000 phosphate residues linked by high-energy anhydride bonds. PolyP causes induction of gene activity, provides phosphate for bone mineralization, and serves as an energy supplier through enzymatic cleavage of its acid anhydride bonds and subsequent ATP formation. The biomedical breakthrough of polyP came with the development of a successful fabrication process, in depot form, as Ca- or Mg-polyP nanoparticles, or as the directly effective polymer, as soluble Na-polyP, for regenerative repair and healing processes, especially in tissue areas with insufficient blood supply. Physiologically, the platelets are the main vehicles for polyP nanoparticles in the circulating blood. To be biomedically active, these particles undergo coacervation. This review provides an overview of the properties of polyP and polyP nanoparticles for applications in the regeneration and repair of bone, cartilage, and skin. In addition to studies on animal models, the first successful proof-of-concept studies on humans for the healing of chronic wounds are outlined.

CYP14 family in Caenorhabditis elegans: Mitochondrial function, detoxification, and lifespan.

CYP-14 members of the Caenorhabditis elegans (C. elegans) Cytochrome P450 (CYP) enzyme family, plays important roles in mitochondrial dysfunction, detoxification, lipid metabolism, defense and lifespan regulation. The review identifies CYP-14 members: cyp-14A1, cyp-14A2, cyp-14A3, cyp-14A4, cyp-14A5 and their homology with human CYP families. Despite limited studies on C. elegans cyp-14 members, the findings unraveled their complex crosstalk between mitochondrial stress, detoxification mechanisms, and lifespan regulation, emphasizing the complexity of these interconnected pathways as well as how their regulation depends on environmental cues changes including pH, nutrients, ROS and chemical stressors. The review underscores the translational relevance to human health, shedding light on potential human homologues and their implications in age-related, metabolic and respiratory diseases. Among other genes, cyp-14A2 and cyp-14A4 predominate the mitochondrial function, heat resistance, lipid metabolism, detoxification and lifespan pathways. In conclusion, these insights pave the way for future research, offering promising avenues for therapeutic interventions targeting CYP-14 activity to address age-related diseases and promote healthy aging.

ROP GTPases with a geranylgeranylation motif modulate alkaloid biosynthesis in Catharanthus roseus.

Rho of Plant (ROP) GTPases function as molecular switches that control signaling processes essential for growth, development, and defense. However, their role in specialized metabolism is poorly understood. Previously, we demonstrated that inhibition of protein geranylgeranyl transferase (PGGT-I) negatively impacts the biosynthesis of monoterpenoid indole alkaloids (MIA) in Madagascar periwinkle (Catharanthus roseus), indicating the involvement of prenylated proteins in signaling. Here, we show through biochemical, molecular, and in planta approaches that specific geranylgeranylated ROPs modulate C. roseus MIA biosynthesis. Among the six C. roseus ROP GTPases (CrROPs), only CrROP3 and CrROP5, having a C-terminal CSIL motif, were specifically prenylated by PGGT-I. Additionally, their transcripts showed higher expression in most parts than other CrROPs. Protein-protein interaction studies revealed that CrROP3 and CrROP5, but not ΔCrROP3, ΔCrROP5, and CrROP2 lacking the CSIL motif, interacted with CrPGGT-I. Further, CrROP3 and CrROP5 exhibited nuclear localization, whereas CrROP2 was localized to the plasma membrane. In planta functional studies revealed that silencing of CrROP3 and CrROP5 negatively affected MIA biosynthesis, while their overexpression upregulated MIA formation. In contrast, silencing and overexpression of CrROP2 had no effect on MIA biosynthesis. Moreover, overexpression of ΔCrROP3 and ΔCrROP5 mutants devoid of sequence coding for the CSIL motif failed to enhance MIA biosynthesis. These results implicate that CrROP3 and CrROP5 have a positive regulatory role on MIA biosynthesis and thus shed light on how geranylgeranylated ROP GTPases mediate the modulation of specialized metabolism in C. roseus.

The relation between plasma apelin 36 and insulin resistance in obese type 2 diabetic Egyptian population

ABSTRACT Background Obesity causes changes in the production of adipose tissue secreted factors, which are responsible for metabolism modulation. One of these factors is Apelin, a small peptide that interacts with a specific cell-surface receptor to modulate various cells signaling processes. Apelin is regarded as a new player because of its powerful role in energy metabolism and improvement of insulin sensitivity. Aim of the Work This study investigates the plasma apelin 36 role and to what extent it can impact the insulin resistance in obese Egyptians diagnosed with type 2 diabetes (T2DM). Subjects and Methods The study involved 90 participants, with 30 assigned to each of the three study involved categories: obese individuals with diabetes, obese individuals without diabetes, and healthy controls (n = 30 for each group). Measurements of skin fold thickness, body mass index (BMI), waist/hip ratio, and body fat % were obtained along with a comprehensive clinical examination and history. The following were investigated: plasma insulin, Hb A1c, lipid profile, plasma apelin (ELISA), plasma leptin (ELISA), and plasma adiponectin (ELISA). Results The median value of serum leptin in obese subjects (groups I and II) was higher significantly than healthy control group (group III) (p = <0.001). A significant decrease in serum adiponectin could be detected in obese subjects (groups I and II) compared to control subjects (Group III) (p = 0.004). When compared to the healthy control group (group III), the mean serum apelin level was significantly higher in the obese participants (groups I and II) and much higher among obese diabetic group (p = <0.001). A statistically significant correlation (p = 0.001) was observed between fasting serum insulin and both HOMA-IR and serum apelin among the non-diabetic obese participants involved in the study. Conclusions Obese people have raised serum apelin levels; those with T2DM have significantly greater serum apelin levels. While it showed a positive correlation with insulin level and HOMA-IR among the obese non-diabetic individuals.