Insulin Signaling Pathway Research Articles

Effects of exogenous insulin supplementation on lipid metabolism in peripartum obese dairy cows

Cows with high body condition scores experience more severe negative energy balance (NEB) and undergo mobilization of more body fat during the peripartum period, leading to more production of nonesterified fatty acids (NEFA) and β-hydroxybutyric acid (BHBA). Postpartum insulin secretion is lower, and insulin resistance is stronger in obese cows. Exogenous insulin supplementation has been hypothesized as a key approach for regulating NEFA in these cows. In this study, we assessed the effects of exogenous insulin supplementation on lipid metabolism, key genes regulated by insulin, and the underlying regulatory mechanism. We selected 181 periparturient multiparous obese dairy cows for the study. Cows in the insulin group (n = 96) received subcutaneous injections of 200 IU insulin (5 mL) on postpartum days 1 and 7, while cows in the control group (n = 85) received subcutaneous injections of 5 mL physiological saline on the same days. The incidence of ketosis was recorded and compared between the two groups. The results demonstrated that postpartum insulin injections significantly reduced the incidence of type II ketosis and delayed the onset time. Meanwhile, a cohort experiment was conducted on 20 cows selected from 181 field trial cows, with 10 cows in the insulin group and 10 cows in the control group. Blood samples were collected for biochemical indicators and subcutaneous adipose tissue was collected for paraffin-embedding and sectioning and RNA sequencing analysis. The results showed that insulin supplementation postpartum reduced concentrations of NEFA and BHBA as well as BCS loss, but did not affect glucose. Additionally, the expression of SREBF1 in insulin signaling pathway and the downstream-regulated lipogenesis network genes were successfully upregulated in insulin-treated healthy group. High expression of SREBF1 may be a key for postpartum insulin supplementation to improve insulin resistance, significantly reduce NEFA concentrations, and prevent or treat ketosis and fatty liver in obese cows. Postpartum administration of insulin could effectively decrease alterations of adipocytes size, which also fully validates that postpartum insulin supplementation promotes lipogenesis and reduces NEFA release.

The Effect of the 14:10-Hour Time-Restricted Feeding (TRF) Regimen on Selected Markers of Glucose Homeostasis in Diet-Induced Prediabetic Male Sprague Dawley Rats

Background: Prediabetes is a condition that often precedes the onset of type 2 diabetes mellitus (T2DM). Literature evidence indicates that prediabetes is reversible, making it an important therapeutic target for preventing the progression to T2DM. Several studies have investigated intermittent fasting as a possible method to manage or treat prediabetes. Objectives: This study evaluated the impact of a 14:10-hour time-restricted feeding (TRF) regimen on leptin concentration, insulin sensitivity and selected markers associated with the insulin signalling pathway and glucose homeostasis in diet-induced prediabetic rats. Methods: Twenty-four male Sprague Dawley rats were obtained and randomly divided into two dietary groups: group 1 (n = 6) received a standard diet and water, while group 2 (n = 18) was provided a high-fat, high-carbohydrate (HFHC) diet supplemented with 15% fructose for a period of 20 weeks to induce prediabetes. After confirming prediabetes, an intermittent fasting (IF) regimen was assigned to the rats while also having untreated and metformin-treated prediabetic rats serving as controls. Results: Both IF and HFHC-Met groups yield significantly lower blood glucose, leptin and BMI results compared to the prediabetic group. The IF group yielded significantly lower insulin, HOMA-IR and HbA1C than both controls. Conclusions: The study showed the potential of IF in alleviating prediabetes-induced dysregulation of glucose homeostasis and therefore warrants further investigations into its use in the management of prediabetes.

Integrated transcriptome and metabolome analysis of liver reveals unsynchronized growth mechanisms in blunt-snout bream (Megalobrama amblycephala)

BackgroundMegalobrama amblycephala presents unsynchronized growth, which affects its productivity and profitability. The liver is essential for substance exchange and energy metabolism, significantly influencing the growth of fish.ResultsTo investigate the differential metabolites and genes governing growth, and understand the mechanism underlying their unsynchronized growth, we conducted comprehensive transcriptomic and metabolomic analyses of liver from fast-growing (FG) and slow-growing (SG) M. amblycephala individuals. A total of 2,097 differentially expressed genes (DEGs) were identified between FG and SG, with 830 genes exhibiting significantly higher expression level in FG. KEGG and GO enrichment analysis indicated that the DEGs with higher expression level were significantly correlated with insulin signaling pathway, steroid hormone and lipid metabolism related pathway (PPAR signaling pathway and fatty acid degradation). In the metabolomic analysis, 224 differentially expressed metabolites (DEMs) were detected, of which 128 were significantly more abundant in FG. These more abundant DEMs were prominently enriched in pathways associated with cell proliferation and energy metabolism (Oxidative phosphorylation, mTOR signaling pathway and FoxO signaling pathway). In addition, DEGs and DEMs in adenosine diphosphate (ATP) hydrolysis activity and associate with fatty acid metabolism, glucose metabolism, and amino acid metabolism pathways were both found in the transcriptomic and metabolomic integrated data. These findings suggest that the large amounts of energy generated by fatty acid, glucose metabolism and other energy metabolism pathway promote the rapid growth of FG.ConclusionsThis research is the first to integrate metabolomic and transcriptomic analyses of liver to identify key genes, metabolites, and pathways to uncover the molecular and metabolic mechanisms of unsynchronized growth in M. amblycephala. The identified metabolic and genes can be potential targets for selective breeding programs to improve growth performance in aquaculture.

The microenvironment cell index is a novel indicator for the prognosis and therapeutic regimen selection of cancers

BackgroundIt is worthwhile to establish a prognostic prediction model based on microenvironment cells (MCs) infiltration and explore new treatment strategies for triple-negative breast cancer (TNBC).MethodsThe xCell algorithm was used to quantify the cellular components of the TNBC microenvironment based on bulk RNA sequencing (bulk RNA-seq) data. The MCs index (MCI) was constructed using the least absolute shrinkage and selection operator Cox (LASSO-Cox) regression analysis. Single-cell RNA sequencing (scRNA-seq), spatially resolved transcriptomics (SRT), and multiplex immunofluorescence (mIF) staining analyses verified MCI. The mechanism of action of the MCI was investigated in tumor-bearing mice.ResultsMCI consists of the six types of MCs, which can precisely predict the prognosis of the TNBC patients. scRNA-seq, SRT, and mIF analyses verified the existence and proportions of these cells. Furthermore, combined with the spatial distribution characteristics of the six types of MCs, an MCI-enhanced (MCI-e) model was constructed, which could predict the prognosis of the TNBC patients more accurately. More importantly, inhibition of the insulin signaling pathway activated in the cancer cells of the MCIhigh the TNBC patients significantly prolonged the survival time of tumor-bearing mice.ConclusionsOverall, our results demonstrate that MCs infiltration can be exploited as a novel indicator for the prognosis and therapeutic regimen selection of the TNBC patients.

Glucose-Sensing Carbohydrate Response Element-Binding Protein in the Pathogenesis of Diabetic Retinopathy

Glucose-sensing ChREBP and MondoA are transcriptional factors involved in the lipogenic, inflammatory, and insulin signaling pathways implicated in metabolic disorders; however, limited ocular studies have been conducted on these proteins. We aimed to investigate the potential role of ChREBP in the pathogenesis of diabetic retinopathy (DR). We used diabetic human and mouse retinal cryosections analyzed by immunohistochemistry. qRT-PCR was performed to quantify gene expression. To explore the role of ChREBP in rods, we generated caChREBPRP mice with constitutively active (ca) ChREBP. These mice underwent retinal functional testing, which was followed by proteomic analysis using LC-MS. Furthermore, ARPE-19 cells were infected with lentiviral particles expressing human ChREBP (ARPE-19ChREBP) and subjected to global proteomics. Our results demonstrate that both proteins were expressed across the retina, although with distinct distribution patterns: MondoA was more prominently expressed in cones, while ChREBP was broadly expressed throughout the retina. Elevated expression of both proteins was observed in DR. This may have contributed to rod photoreceptor degeneration, as we observed diminished scotopic ERG amplitudes in caChREBPRP mice at P35. The retinal proteomic landscape revealed a decline in the KEGG pathways associated with phototransduction, amino acid metabolism, and cell adhesion. Furthermore, rod-specific caChREBP induced TXNIP expression. Consistent with altered retinal proteomics, ARPE-19ChREBP cells exhibit a metabolic shift toward increased glyoxylate signaling, sugar metabolism, and lysosomal activation. Our study demonstrates that ChREBP overexpression causes significant metabolic reprogramming triggering retinal functional loss in mice.

Activation of the De Novo Serine Synthesis Pathway and Disruption of Insulin Signaling Induced by Supplemental SeMet in Vitro.

Selenium (Se) intake or selenoprotein overexpression can cause abnormal glucose metabolism and increase the risk of type 2 diabetes (T2D). The purpose of this study is to observe whether glycolysis bypass in the de novo serine synthesis pathway (SSP) is activated under high-Se stress in vitro. Initially, HCT-116, L02, HepG2, and differentiated C2C12 cells were exposed to five selenomethionine (SeMet) concentrations (0.001 to 10µmol/L) for 48h. The expressions of glutathione peroxidase 1 (GPX1), selenoprotein P (SELENOP), 3-phosphoglycerate dehydrogenase (PHGDH), and serine hydroxy-methyltransferases 1 (SHMT1) were assessed by western blotting (WB). Then, corresponding to the peak expressions of GPX1, SELENOP, and PHGDH, 0.1µmol/L SeMet was identified as the highest intervention concentration. With more detailed levels of SeMet (0.001 to 0.1µmol/L) given, the differentiated C2C12 cells were treated for 48h to analyze the expressions of selenoproteins, enzymes related with serine metabolism and insulin signaling pathway. Among the four cell lines, the expressions of selenoproteins and metabolic enzymes of serine in C2C12 cells were more sensitive to changes in Se concentrations, which was similar to that in L02 cells. In C2C12 cells, the expressions of GPX1, SELENOP, selenoprotein N (SELENON), PHGDH, and SHMT1 exhibited a parabolic inflection point at SeMet concentrations of 0.05µmol/L or 0.075µmol/L, while 5,10-methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MS) showed no such trend. After 15min of insulin stimulation, glucose retained more in the culture medium due to the decreased uptake by C2C12 cells. The expressions of key enzymes (AKT, AKT (Ser-473), AKT (Thr-308), mTOR, and PI3K) in the PI3K-AKT-mTOR signaling pathway decreased with the increased level of SeMet. This study demonstrated that excessive Se intake could induce abnormal glucose metabolism via SSP and impair the normal signaling of insulin in the differentiated C2C12 cells.

Insulin signaling and oxidative stress: Bridging the gap between type 2 diabetes mellitus and Alzheimer's disease.

Type 2 diabetes mellitus (T2D) and Alzheimer's disease (AD) are two prevalent chronic diseases that pose significant global health challenges. Increasing evidence suggests a complex bidirectional relationship between these conditions, where T2D elevates the risk of AD, and AD exacerbates glucose metabolism abnormalities in T2D. This review explores the molecular mechanisms linking T2D and AD, focusing on the role of insulin signaling pathways and oxidative stress. A comprehensive literature search from PubMed, Web of Science, and other relevant databases was conducted and analyzed. Insulin resistance in T2D leads to impaired insulin signaling in the brain, contributing to cognitive decline and the development of AD. Hyperglycemia-induced oxidative stress exacerbates neuronal damage, promoting the formation of amyloid-β plaques and neurofibrillary tangles characteristic of AD. Clinically antidiabetic drugs such as metformin show potential against AD in preclinical studies; Many natural products such as Dendrobium nobile Lindl. have anti-T2D efficacy and are also effective against AD in various in vivo and in vitro models. Improving insulin resistance and reducing oxidative stress are important strategies in the treatment of T2D and AD. To understand the bridging role of insulin singling and oxidative stress in T2D and AD will provide insights and broader applications in alleviating T2D and AD.

In silico evaluation via the docking of selected antidiabetic phytochemicals on proteins in the insulin signalling pathway: PTP1B, IRS1 and PP2A

In silico evaluation via the docking of selected antidiabetic phytochemicals on proteins in the insulin signalling pathway: PTP1B, IRS1 and PP2A

NLRP3 inflammasome activation and disruption of IRS-1/PI3K/AKT signaling: Potential mechanisms of arsenic-induced pancreatic beta cells dysfunction in rats.

Environmental exposure to arsenic is associated with significant health risks, including diabetogenic effects linked to pancreatic dysfunction. The NOD-like receptor protein 3 (NLRP3) inflammasome has been implicated in various metabolic abnormalities; however, its specific role in arsenic-induced pancreatic dysfunction remains insufficiently understood. This study aimed to elucidate the involvement and underlying mechanisms of the NLRP3 inflammasome in arsenic-induced pancreatic beta cells dysfunction through in vivo and in vitro models. In rat models, arsenic exposure was found to activate the NLRP3 inflammasome, as evidenced by pathomorphological changes and the expression of inflammasome activation markers. These pathological changes were accompanied by disruptions in the insulin signaling pathway, characterized by increased phosphorylation of insulin receptor substrate 1 (IRS-1) at Ser616, reduced expression of phosphatidylinositol 3-kinase (PI3K) and phosphorylated protein kinase B (AKT) at Ser473, and significant decreases in downstream targets, including the nuclear translocation of PDX-1, membrane translocation of glucose transporter 2 (GLUT2), and glucokinase (GCK) expression. In vitro, NaAsO2-treated INS-1 cells exhibited a dose-dependent reduction in glucose-stimulated insulin secretion. Furthermore, arsenic exposure in these cells activated the NLRP3 inflammasome, suppressed the IRS-1/PI3K/AKT signaling pathway, and downregulated insulin secretion regulatory molecules (PDX-1, GLUT2, and GCK). Notably, these arsenic-induced effects were reversed by MCC950, an NLRP3 inflammasome inhibitor, and Extendin-4, an agonist of the IRS-1/PI3K/AKT signaling pathway. Collectively, these findings demonstrate that NLRP3 inflammasome activation disrupts the IRS-1/PI3K/AKT signaling pathway, contributing to arsenic-induced pancreatic beta cells dysfunction in rats.

<i>In silico</i> evaluation via the docking of selected antidiabetic phytochemicals on proteins in the insulin signalling pathway: PTP1B, IRS1 and PP2A

<i>In silico</i> evaluation via the docking of selected antidiabetic phytochemicals on proteins in the insulin signalling pathway: PTP1B, IRS1 and PP2A

Effect of Acetyl tributyl citrate on bone metabolism based on network toxicology and molecular docking technology

This study aims to elucidate the intricate effects of Acetyl tributyl citrate (ATBC) on bone metabolism, disentangling the underlying molecular mechanisms that govern the impact of environmental contaminants on disease processes. Leveraging the exhaustive exploration of databases such as ChEMBL, STITCH, GeneCards, and OMIM, we have identified a comprehensive list of 164 potential targets intimately associated with both ATBC and bone metabolism. Following rigorous refinement using the STRING platform and Cytoscape software, we pinpointed ten core targets, encompassing KDM1A, EP300, HDAC2, EHMT2, DNMT1, and several others. In-depth Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, conducted within the Metascape database, revealed that the core targets of ATBC’s influence on bone metabolism are predominantly concentrated within vital signaling cascades, including thyroid hormone signaling, FOXO signaling, glucagon signaling, AMPK signaling, insulin signaling, adipocytokine signaling, and Notch signaling pathways. Additionally, molecular docking simulations performed with AutoDock software confirmed the robust binding interactions between ATBC and these core targets, reinforcing our understanding of their interactions. To explore the cellular impact of ATBC, we performed in vitro experiments using osteoblasts (MC3T3-E1) exposed to relevant concentrations. Our findings revealed that low-dose ATBC (100μM) significantly impaired cell proliferation and migration. Concurrently, we observed a downregulation in the transcriptional expression of key epigenetic regulators (KDM1A, EP300, HDAC2), suggesting that ATBC can disrupt bone metabolism at the cellular level. Collectively, our findings provide a theoretical scaffold for comprehending the intricate molecular mechanisms mediating ATBC’s effects on bone metabolism, and paves the way for the development of preventive and therapeutic strategies against orthopedic disorders that may arise from exposure to plastic products containing ATBC or excessive ATBC environments.

Fermented rhubarb alleviates metabolic dysfunction-associated steatotic liver disease symptoms by modulating gut microbiota and activating the hepatic insulin signaling pathway

Fermented rhubarb alleviates metabolic dysfunction-associated steatotic liver disease symptoms by modulating gut microbiota and activating the hepatic insulin signaling pathway

Gut Microbiota and Insulin Resistance: Understanding the Mechanism of Better Treatment of Type 2 Diabetes Mellitus.

Gut microbiota refers to the population of trillions of microorganisms present in the human intestine. The gut microbiota in the gastrointestinal system is important for an individual's good health and well-being. The possibility of an intrauterine colonization of the placenta further suggests that the fetal environment before birth may also affect early microbiome development. Various factors influence the gut microbiota. Dysbiosis of microbiota may be associated with various diseases. Insulin regulates blood glucose levels, and disruption of the insulin signaling pathway results in insulin resistance. Insulin resistance or hyperinsulinemia is a pathological state in which the insulin-responsive cells have a diminished response to the hormone compared to normal physiological responses, resulting in reduced glucose uptake by the tissue cells. Insulin resistance is an important cause of type 2 diabetes mellitus. While there are various factors responsible for the etiology of insulin resistance, dysbiosis of gut microbiota may be an important contributing cause for metabolic disturbances. We discuss the mechanisms in skeletal muscles, adipose tissue, liver, and intestine by which insulin resistance can occur due to gut microbiota's metabolites. A better understanding of gut microbiota may help in the effective treatment of type 2 diabetes mellitus and metabolic syndrome.

Development, biological evaluation, and molecular modelling of some benzene-sulfonamide derivatives as protein tyrosine phosphatase-1B inhibitors for managing diabetes mellitus and associated metabolic disorders.

Exploring new inhibitors with good bioavailability and high selectivity for managing type 2 diabetes mellitus (T2DM) and its associated complications is a major challenge for research, academia, and the pharmaceutical industry. Protein tyrosine phosphatase-1B (PTP1B) arose as an important negative regulator in insulin signaling pathways associated with metabolic disorders, including T2DM and obesity. Novel neutral compounds with a benzene-sulfonamide scaffold were designed and synthesized based on structural- and ligand-based drug design strategies for fragment growth. Promising hits against PTP1B were identified through in vitro enzymology inhibition assay. Mechanistic aspects of the compound's different inhibition activities were rigorously investigated through molecular docking coupled with explicit dynamics simulations. Four identified hits, 3c, 8, 10a, and 11, with sub-micromolar PTP-1B IC50 and significant predicted pharmacokinetic and pharmacodynamic parameters, were further biologically evaluated for their anti-diabetic, anti-obesity, anti-inflammatory, and anti-oxidant effects in a high-fat diet (HFD) + streptozotocin (STZ)-induced T2DM rat model. All these hit compounds exhibited a significant anti-diabetic and anti-obesity effect and a significant efficacy in reducing oxidative stress and increasing anti-oxidant enzymes while reducing inflammatory markers. Improving compound potency was further highlighted by improving the pharmacokinetic profile of the most active compound, 10a, through nano formulation. Compound 10a nano formulation showed the most promising anti-diabetic and anti-obesity effects and a remarkable histopathological improvement in all organs studied.

Insulin-Sensitizing Properties of Decoctions from Leaves, Stems, and Roots of Cucumis prophetarum L.

Type 2 diabetes mellitus (T2DM) is a chronic disease characterized by insulin resistance and impaired beta-cell secretory function. Since existing treatments often present side effects based on different mechanisms, alternative therapeutic options are needed. In this scenario, the present study first evaluates the cytotoxicity of decoctions from the leaves, stems, and roots of Cucumis prophetarum L. on HepG2 and L6C5 cells. The extracts were chemically investigated by UV-Vis and ATR-FTIR spectroscopic techniques and by ultra high-performance chromatographic techniques, coupled with high-resolution mass spectrometry. Briefly, decoctions from the leaves and stems were mainly composed of apigenin C-glycosides, while the root decoction was rich in raffinose and cucumegastigmane II. To evaluate the insulin-sensitizing properties of the extracts in insulin-resistant L6 myoblasts, an evaluation by Western blot analysis of the proteins in the insulin signaling pathway was then performed. Particularly, key proteins of insulin signaling were investigated, i.e., insulin receptor substrate (IRS-1), protein kinase B (PKB/AKT), and glycogen synthase kinase-3 (GSK-3β), which have gained considerable attention from scientists for the treatment of diabetes. Under all conditions tested, the three decoctions showed low cytotoxicity. The stem and root decoction (300 μg/mL) resulted in a significant increase in the levels of p-IRS-1 (Tyr612), GSK3β (Ser9), and p-AMPK (Thr172) compared to those of the palmitic acid-treated group, and the leaf decoction resulted an increase in the level of p-IRS-1 (Tyr612) and p-AMPK (Thr172) and a decrease in p-GSK3β (Ser9) compared to the levels for the palmitic acid-treated group. The root decoction also reduced the level of p-mToR (Ser2448). Overall, the acquired data demonstrate the effect of reducing insulin resistance induced by the investigated decoctions, opening new scenarios for the evaluation of these effects aimed at counteracting diabetes and related diseases in animal models.

Interplay between elevated RAB5B gene expression and insulin resistance among women with PCOS-insights from a case-control study.

Polycystic ovary syndrome (PCOS) represents a multifaceted endocrine, reproductive, and metabolic disorder characterized by hyperandrogenism and hyperinsulinemia-induced insulin resistance (IR). Recent studies reported that the etiology of PCOS is likely correlated with genes involved in steriodogenesis, IR and glucose metabolism. Among the candidate genes in insulin signaling pathways, RAB5B, a small GTPase involved in vesicle trafficking, significantly impacts cellular pathways in ovarian follicular cells, leading to clinical and endocrine changes among women with PCOS. Additionally, RAB5B is crucial for insulin-mediated glucose uptake and is involved in PI3K, AKT, and MAPK/ERK pathways, affecting LHCGR-stimulated steroidogenesis. Despite extensive research, the precise molecular mechanisms underlying RAB5B mediated IR in PCOS remained elusive. The study aimed to explore the potential link between RAB5B gene expression and IR among women with PCOS. A total of age matched 270 subjects were enrolled in this study including 135 PCOS women and 135 apparently healthy controls. These study participants were subjected to detailed medical history, clinical and physical examination. All subjects were further evaluated for biochemical, hormonal and RAB5B gene expression estimation. Expression levels of RAB5B gene were analyzed using gene-specific primers and the SYBR® Green PCR Kit (Qiagen, Germany) and their qPCR reaction mix, according to the manufacturer's guidelines. Student t-test and ANOVA were used to evaluate the differences in the means of various parameters. The HOMA-IR (2.28 ± 1.4 vs. 1.36 ± 0.73) was significantly elevated among women with PCOS than controls (p < 0.05). We also found that the QUICKI (0.35 ± 0.04 vs. 0.37 ± 0.04), MATSUDA (12.59 ± 4.71 vs. 15.47 ± 4.33) and FGIR (11.56 ± 7.06 vs. 14.32 ± 8.66) were higher in controls than women with PCOS (p < 0.05). We also observed that women with PCOS had elevated levels of RAB5B mRNA levels when compared with apparently healthy controls. Bivariate correlation analysis among HOMA-IR stratified PCOS and control subjects revealed strong negative correlation between IR+ PCOS and IR- PCOS (r = -0.61, P < 0.05) and IR- control (r = -0.37, p < 0.05) subjects respectively. Our study demonstrated that there is potential link between RAB5B gene expression and IR specifically in the context of IR indices among women with PCOS.

Non-autonomous insulin signaling delays mitotic progression in C. elegans germline stem and progenitor cells.

Stem and progenitor cell mitosis is essential for tissue development and homeostasis. How these cells ensure proper chromosome segregation, and thereby maintain mitotic fidelity, in the complex physiological environment of a living animal is poorly understood. Here we use in situ live-cell imaging of C. elegans germline stem and progenitor cells (GSPCs) to ask how the signaling environment influences stem and progenitor cell mitosis in vivo. Through a candidate screen we identify a new role for the insulin/IGF receptor (IGFR), daf-2, during GSPC mitosis. Mitosis is delayed in daf-2/IGFR mutants, and these delays require canonical, DAF-2/IGFR to DAF-16/FoxO insulin signaling, here acting cell non-autonomously from the soma. Interestingly, mitotic delays in daf-2/IGFR mutants depend on the spindle assembly checkpoint but are not accompanied by a loss of mitotic fidelity. Correspondingly, we show that caloric restriction, which delays GSPC mitosis and compromises mitotic fidelity, does not act via the canonical insulin signaling pathway, and instead requires AMP-activated kinase (AMPK). Together this work demonstrates that GSPC mitosis is influenced by at least two genetically separable signaling pathways and highlights the importance of signaling networks for proper stem and progenitor cell mitosis in vivo.

Prognostic and Immunologic Significance of SH2B2 in Colon Adenocarcinoma and its Relationship to Proliferation, Migration, and Invasion.

SH2B adaptor protein 2 (SH2B2, also named APS) is an adaptor protein implicated in the modulation of insulin signaling pathways and glucose metabolism. Its role in colon adenocarcinoma (COAD) is unknown. Data from The Cancer Genome Atlas and Gene Expression Omnibus database were utilized to assess SH2B2 expression and its clinical significance in COAD. We investigated the associations between SH2B2 expression with genomic instability, tumor mutational burden (TMB), DNA methylation, alternative splicing, immune infiltration, and drug sensitivity. A SH2B2 knockdown model was developed to examine its impact on COAD cellular functions. Highly expressed SH2B2 is associated with a poorer prognosis in COAD. SH2B2 expression in COAD is associated with copy number variations, microsatellite instability, methylation patterns, and alternative 5' splicing events, but not with TMB. SH2B2 is positively correlated with mostly immune cells and the expression of PD-1 and CTLA4. The IC50 values of ten drugs were significantly correlated with SH2B2 expression. BI-2536_1086 had a strong binding affinity with SH2B2. Furthermore, the knockdown of SH2B2 reduced the proliferation, migration, and invasion of COAD cells. SH2B2 appears to act as an oncogene in COAD and may serve as a pivotal prognostic and therapeutic target, deserving further exploration.

Juvenile hormone induces phosphorylation of insulin/insulin-like growth factor signaling proteins in previtellogenic Aedes aegypti mosquitoes.

Juvenile hormone (JH) plays a pivotal role in regulating post-emergence development and metabolism in previtellogenic female Aedes aegypti mosquitoes. In contrast, yolk protein precursor production and egg maturation after a blood meal are regulated by the steroid hormone 20-hydroxyecdysone, the insulin-like growth factor (IGF)/insulin signaling (IIS) pathway, and the mammalian target of rapamycin (mTOR) pathway. The role of IIS/mTOR signaling in female adults prior to blood feeding has not been thoroughly investigated. In this study, we identified a significant increase in the phosphorylation of key effector proteins in the IIS/mTOR signaling pathway, including eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), ribosomal protein S6 kinase (S6K) and forkhead box protein O1 (FoxO1), in previtellogenic females. In vitro fat body culture experiments suggest that JH induces these phosphorylations through rapid nongenomic signaling mediated by the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mTOR network. RNA interference experiments demonstrated that activation of IIS/mTOR signaling in previtellogenic females modulate metabolic gene expression, promoting the accumulation of energy reserves (glycogen and triglycerides), which influence mosquito fecundity. Additionally, depletion of either the insulin receptor (InR) or the JH receptor Methoprene-tolerant (Met) in adult mosquitoes abolished the phosphorylation of these proteins, indicating that both receptors are involved in JH-induced membrane-initiated signal transduction. Although the precise mechanisms remain unclear, this study uncovers a novel function of the IIS/mTOR pathway in adult mosquitoes before blood feeding, as well as a new mode of JH action through its crosstalk with the IIS pathway.

Transcriptome and Metabolome Insights into Key Genes Regulating Fat Deposition and Meat Quality in Pig Breeds.

Meat quality is a complex trait that exhibits significant variation across pig breeds, and the regulatory mechanisms governing pork meat quality are not fully elucidated. We compared the transcriptomics and metabolomics of the longissimus dorsi (LD) muscle between the Songliao Black Pig (SBP) and Large White × Landrace Pig (LWLDP) to investigate breed-specific differences in meat quality and underlying regulatory pathways. The results showed that SBP meat had a higher marbling score and backfat thickness, a richer color, a lower shear force, and reduced drip loss. Fatty acid (FA) analysis identified 15 significant FAs in the LWLDP, with docosahexaenoic acid (DHA) in the SBP, while amino acid (AA) analysis revealed no breed-based differences. Transcriptome analysis identified 134 upregulated and 362 downregulated genes in the SBP. Protein-protein interaction (PPI) network analysis found 25 key genes, which are associated with muscle development, fat deposition, and overall meat quality, while genes in the insulin signaling pathway, such as PPP1R3B, PPARGC1A, SOCS1, EIF4E, PRKAR2A, PRKAG2, and FASN, play a crucial role in balancing fat metabolism and catabolism. Metabolomic analysis identified 89 upregulated and 10 downregulated metabolites in the SBP, primarily involved in fructose and mannose metabolism, amino acid biosynthesis, nucleotide sugar metabolism, and glucagon signaling pathways. Gene-metabolite association analysis found that the PPP1R3B gene had a strong association with Thr-Leu, Maltol, D-myo-Inositol-4-phosphate, and Fructose-6-phosphate, while MYOG correlated with Mannose-6-phosphate, Fructose-1-phosphate, Mannose-1-phosphate, and Glucose-6-phosphate. In contrast, NR4A3 and PPARGC1A showed a strong negative correlation with most upregulated metabolites. In conclusion, this study identified functional genes, elucidated the mechanisms associated with meat quality traits, and identified gene-metabolite associations involved in energy metabolism, muscle development, and fat deposition, providing valuable insights into the molecular mechanisms that regulate meat quality between pig breeds.