Insulin-like Signaling Pathway Research Articles

Heat-killed probiotic Levilactobacillus brevis MKAK9 and its exopolysaccharide promote longevity by modulating aging hallmarks and enhancing immune responses in Caenorhabditis elegans

BackgroundProteostasis is a critical aging hallmark responsible for removing damaged or misfolded proteins and their aggregates by improving proteasomal degradation through the autophagy-lysosome pathway (ALP) and the ubiquitin–proteasome system (UPS). Research on the impact of heat-killed probiotic bacteria and their structural components on aging hallmarks and innate immune responses is scarce, yet enhancing these effects could potentially delay age-related diseases.ResultsThis study introduces a novel heat-killed Levilactobacillus brevis strain MKAK9 (HK MKAK9), along with its exopolysaccharide (EPS), demonstrating their ability to extend longevity by improving proteostasis and immune responses in wild-type Caenorhabditis elegans. We elucidate the underlying mechanisms through a comprehensive approach involving mRNA- and small RNA sequencing, proteomic analysis, lifespan assays on loss-of-function mutants, and quantitative RT-PCR. Mechanistically, HK MKAK9 and its EPS resulted in downregulation of the insulin-like signaling pathway in a DAF-16-dependent manner, enhancing protein ubiquitination and subsequent proteasomal degradation through activation of the ALP pathway, which is partially mediated by microRNA mir-243. Importantly, autophagosomes engulf ubiquitinylated proteins, as evidenced by increased expression of the autophagy receptor sqst-3, and subsequently fuse with lysosomes, facilitated by increased levels of the lysosome-associated membrane protein (LAMP) lmp-1, suggesting the formation of autolysosomes for degradation of the selected cargo. Moreover, HK MKAK9 and its EPS activated the p38 MAPK pathway and its downstream SKN-1 transcription factor, which are known to regulate genes involved in innate immune response (thn-1, ilys-1, cnc-2, spp-9, spp-21, clec-47, and clec-266) and antioxidation (sod-3 and gst-44), thereby reducing the accumulation of reactive oxygen species (ROS) at both cellular and mitochondrial levels. Notably, SOD-3 emerged as a transcriptional target of both DAF-16 and SKN-1 transcription factors.ConclusionOur research sets a benchmark for future investigations by demonstrating that heat-killed probiotic and its specific cellular component, EPS, can downregulate the insulin-signaling pathway, potentially improving the autophagy-lysosome pathway (ALP) for degrading ubiquitinylated proteins and promoting organismal longevity. Additionally, we discovered that increased expression of microRNA mir-243 regulates insulin-like signaling and its downstream ALP pathway. Our findings also indicate that postbiotic treatment may bolster antioxidative and innate immune responses, offering a promising avenue for interventions in aging-related diseases.

An insulin-like signalling pathway model for Fasciola gigantica

BackgroundThe insulin/insulin-like signalling (IIS) pathway is common in mammals and invertebrates, and the IIS pathway is unknown in Fasciola gigantica. In the present study, the IIS pathway was reconstructed in F. gigantica. We defined the components involved in the IIS pathway and investigated the transcription profiles of these genes for all developmental stages of F. gigantica. In addition, the presence of these components in excretory and secretory products (ESPs) was predicted via signal peptide annotation.ResultsThe core components of the IIS pathway were detected in F. gigantica. Among these proteins, one ligand (FgILP) and one insulin-like molecule binding protein (FgIGFBP) were analysed. Interestingly, three receptors (FgIR-1/FgIR-2/FgIR-3) were detected, and a novel receptor, FgIR-3, was screened, suggesting novel functions. Fg14-3-3ζ, Fgirs, and Fgpp2a exhibited increased transcription in 42-day-old juveniles and 70-day-old juveniles, while Fgilp, Fgigfb, Fgsgk-1, Fgakt-1, Fgir-3, Fgpten, and Fgaap-1 exhibited increased transcription in metacercariae. FgILP, FgIGFBP, FgIR-2, FgIR-3, and two transcription factors (FgHSF-1 and FgSKN-1) were predicted to be present in FgESPs, indicating their exogenous roles.ConclusionsThis study helps to elucidate the signal transduction pathway of IIS in F. gigantica, which will aid in understanding the interaction between flukes and hosts, as well as in understanding fluke developmental regulation, and will also lay a foundation for further characterisation of the IIS pathways of trematodes.

Molecular characterization and functional identification of the insulin-like peptides receptor gene in the oriental river prawn Macrobrachium nipponense

The insulin-like signaling pathway plays diverse biological roles in regulating metabolism, immune responses, growth, and development in invertebrates. The insulin-like peptides (ILP) receptor (ILPR) is the pivotal protein in any insulin-like signaling pathway. In our previous study, we cloned the Mn-ILP gene from the oriental river prawn Macrobrachium nipponense and elucidated its function. However, the ILPR has not yet been described in M. nipponense. In the present study, we further examined the function of Mn-ILPR in M. nipponense. The full length of the Mn-ILPR mRNA was 4790 bp, encoding 1412 amino acids. Mn-ILPR was a transmembrane receptor under a subfamily of receptor tyrosine kinases. The Mn-ILPR mRNA was predominantly expressed in muscle and hepatopancreas. To elucidate the function of Mn-ILPR, we investigated its expression in different growth stages of prawns of both sexes, in prawns of different sizes at the same time, and in prawns of the same size at different stages of the molt cycle using qRT-PCR. The expression of Mn-ILPR was markedly higher: (1) in the rapid growth stage than in other stages of male individuals; (2) in the normal growth stage than in the gonad development stage of female individuals; (3) in large male individuals than in small male individuals; and (4) in the intermolt stage than in other stages of the molt cycle. Furthermore, the long-term knockdown of Mn-ILPR by RNAi effectively delayed the growth speed of M. nipponense. Meanwhile, the short-term knockdown of Mn-ILPR revealed that the ILP-ILPR signal pathway played a part in the process of growth of M. nipponense. These findings provide a greater understanding of the molecular mechanisms underlying growth and development in crustaceans.

#411 Magnesium deficiency abrogates the activation of Insulin-like growth factor-1 signaling pathway in the kidney induced by DPP4 inhibitor

Abstract Background and Aims Dipeptidyl peptidase-4 (DPP-4) inhibitor could attenuate cisplatin nephrotoxicity dependent on the glucagon-like peptide-1 (GLP-1) signaling pathway [1]. We had previously reported that the use of a DPP-4 inhibitor might also attenuate cisplatin nephrotoxicity in diabetic cancer patients [2], and its renoprotective effect was lost under magnesium (Mg) deficiency [3]. However, it remains to be investigated how the GLP-1 signaling pathway changes after the treatment of a DPP-4 inhibitor under Mg deficiency. The purpose of this study was to examine the changes in the downstream pathway of the GLP-1 signaling pathway after the treatment of DPP-4 inhibitor under Mg deficiency. Method Sprague Dawley rats received a Mg-deficient diet for 7 days to induce Mg deficiency (low Mg group). Control diet was given to the normal Mg group. Oral administration of a DPP-4 inhibitor was injected 1 day before sacrifice. The changes in serum active GLP-1, insulin, insulin-like growth factor (IGF-1), and the expression of their receptor in the kidney were examined. In addition, the phosphorylation of insulin/IGF-1 receptors in the kidney were investigated. Results Serum active GLP-1 increased equally in both groups with DPP-4 inhibitor administration. Renal GLP-1 receptor expression was not observed in the renal tubules. Serum IGF-1 did not change with DPP-4 inhibitor administration in the normal Mg group but increased in the low Mg group. In normal Mg group, renal IGF-1 receptor expression tended to increase with DPP-4 inhibitor administration, and its phosphorylation increased significantly. In contrast, the expression and phosphorylation of the IGF-1 receptor did not change with DPP-4 inhibitor administration in the low Mg group. The increase in serum insulin with the DPP-4 inhibitor was enhanced in the low Mg group, compared to the normal Mg group. The expression and phosphorylation of the insulin receptor did not change with DPP-4 inhibitor administration in both groups. Conclusion DPP-4 inhibitor activated the renal IGF-1 signaling pathway, but this effect disappeared under Mg deficiency. Further investigation is needed to determine whether the renal protective effect of DPP-4 inhibitor is dependent on the IGF-1 signaling pathway.

Network visualization of genes involved in skeletal muscle myogenesis in livestock animals

BackgroundMuscle growth post-birth relies on muscle fiber number and size. Myofibre number, metabolic and contractile capacities are established pre-birth during prenatal myogenesis. The aim of this study was to identify genes involved in skeletal muscle development in cattle, sheep, and pigs - livestock.ResultsThe cattle analysis showed significant differences in 5043 genes during the 135–280 dpc period. In sheep, 444 genes differed significantly during the 70–120 dpc period. Pigs had 905 significantly different genes for the 63–91 dpc period.The biological processes and KEGG pathway enrichment results in each species individually indicated that DEGs in cattle were significantly enriched in regulation of cell proliferation, cell division, focal adhesion, ECM-receptor interaction, and signaling pathways (PI3K-Akt, PPAR, MAPK, AMPK, Ras, Rap1); in sheep - positive regulation of fibroblast proliferation, negative regulation of endothelial cell proliferation, focal adhesion, ECM-receptor interaction, insulin resistance, and signaling pathways (PI3K-Akt, HIF-1, prolactin, Rap1, PPAR); in pigs - regulation of striated muscle tissue development, collagen fibril organization, positive regulation of insulin secretion, focal adhesion, ECM-receptor interaction, and signaling pathways (PPAR, FoxO, HIF-1, AMPK). Among the DEGs common for studied animal species, 45 common genes were identified. Based on these, a protein-protein interaction network was created and three significant modules critical for skeletal muscle myogenesis were found, with the most significant module A containing four recognized hub genes - EGFR, VEGFA, CDH1, and CAV1. Using the miRWALK and TF2DNA databases, miRNAs (bta-miR-2374 and bta-miR-744) and transcription factors (CEBPB, KLF15, RELA, ZNF143, ZBTB48, and REST) associated with hub genes were detected. Analysis of GO term and KEGG pathways showed that such processes are related to myogenesis and associated with module A: positive regulation of MAP kinase activity, vascular endothelial growth factor receptor, insulin-like growth factor binding, focal adhesion, and signaling pathways (PI3K-Akt, HIF-1, Rap1, Ras, MAPK).ConclusionsThe identified genes, common to the prenatal developmental period of skeletal muscle in livestock, are critical for later muscle development, including its growth by hypertrophy. They regulate valuable economic characteristics. Enhancing and breeding animals according to the recognized genes seems essential for breeders to achieve superior gains in high-quality muscle mass.

C. elegans insulin-like peptides

Insulin-like peptides are a group of hormones crucial for regulating metabolism, growth, and development in animals. Invertebrates, such as C. elegans, have been instrumental in understanding the molecular mechanisms of insulin-like peptides. Here, we review the 40 insulin-like peptide genes encoded in the C. elegans genome. Despite the large number, there is only one C. elegans insulin-like peptide receptor, called DAF-2. The insulin and insulin-like growth factor signaling (IIS) pathway is evolutionarily conserved from worms to humans. Thus C. elegans provides an excellent model to understand how these insulin-like peptides function. C. elegans is unique in that it possesses insulin-like peptides that have antagonistic properties, unlike all human insulin-like peptides, which are agonists. This review provides an overview of the current literature on C. elegans insulin-like peptide structures, processing, tissue localization, and regulation. We will also provide examples of insulin-like peptide signaling in C. elegans during growth, development, germline development, learning/memory, and longevity.

Investigating the clinical role and prognostic value of genes related to insulin-like growth factor signaling pathway in thyroid cancer.

Thyroid cancer (THCA) is the most common endocrine malignancy having a female predominance. The insulin-like growth factor (IGF) pathway contributed to the unregulated cell proliferation in multiple malignancies. We aimed to explore the IGF-related signature for THCA prognosis. The TCGA-THCA dataset was collected from the Cancer Genome Atlas (TCGA) for screening of key prognostic genes. The limma R package was applied for differentially expressed genes (DEGs) and the clusterProfiler R package was used for the Gene Ontology (GO) and KEGG analysis of DEGs. Then, the un/multivariate and least absolute shrinkage and selection operator (Lasso) Cox regression analysis was used for the establishment of RiskScore model. Receiver Operating Characteristic (ROC) analysis was used to verify the model's predictive performance. CIBERSORT and MCP-counter algorithms were applied for immune infiltration analysis. Finally, we analyzed the mutation features and the correlation between the RiskScore and cancer hallmark pathway by using the GSEA. We obtained 5 key RiskScore model genes for patient's risk stratification from the 721 DEGs. ROC analysis indicated that our model is an ideal classifier, the high-risk patients are associated with the poor prognosis, immune infiltration, high tumor mutation burden (TMB), stronger cancer stemness and stronger correlation with the typical cancer-activation pathways. A nomogram combined with multiple clinical features was developed and exhibited excellent performance upon long-term survival quantitative prediction. We constructed an excellent prognostic model RiskScore based on IGF-related signature and concluded that the IGF signal pathway may become a reliable prognostic phenotype in THCA intervention.

Lactococcus kimchii extends lifespan and alleviates motility decline in Caenorhabditis elegans through ins-20, an insulin-like peptide gene.

Lactococcus kimchii is isolated from commercial kimchi, which is a traditional Korean fermented food. This study was conducted to evaluate the probiotic effects of L. kimchii. Caenorhabditis elegans was fed L. kimchii, and its longevity, motility, and gene expression were examined. When fed a 1:1 mixture of Escherichia coli OP50 and L. kimchii (OP+LK), C. elegans had a significantly longer lifespan and increased locomotion than when it was fed OP alone. There was no significant difference in brood size between the OP+LK and OP groups, suggesting that these effects occurred in a dietary restriction-independent manner. RNA sequencing and Gene Ontology analysis showed that the expression of ins-20, an insulin-like peptide and agonist of the insulin receptor, was significantly upregulated in the OP+LK group. The ins-20 mutation annulled the effects of OP+LK on lifespan extension and motility. In addition, OP+LK failed to extend the lifespan of C. elegans deficient in daf-2, a receptor for the insulin-like signaling pathway. These results suggest that L. kimchii extends the lifespan and alleviates motility decline in C. elegans through the insulin signaling pathway, highlighting the potential of using L. kimchii as a beneficial bacterium for probiotics and postbiotics.

Combined analysis of the proteome and metabolome provides insight into microRNA-1174 function in Aedes aegypti mosquitoes

BackgroundPathogenic viruses can be transmitted by female Aedes aegypti (Ae. aegypti) mosquitoes during blood-meal acquisition from vertebrates. Silencing of mosquito- and midgut-specific microRNA (miRNA) 1174 (miR-1174) impairs blood intake and increases mortality. Determining the identity of the proteins and metabolites that respond to miR-1174 depletion will increase our understanding of the molecular mechanisms of this miRNA in controlling blood-feeding and nutrient metabolism of mosquitoes.MethodsAntisense oligonucleotides (antagomirs [Ant]) Ant-1174 and Ant-Ct were injected into female Ae. aegypti mosquitoes at 12–20 h posteclosion, and depletion of miR-1174 was confirmed by reverse transcription quantitative real-time PCR (RT-qPCR). Ant-1174-injected and control mosquitoes were collected before the blood meal at 72 h post-injection for tandem mass tag-based proteomic analysis and liquid chromatography-tandom mass spectrometry non-target metabolomic analysis to identify differentially expressed proteins and metabolites, respectively. RNA interference (RNAi) using double-stranded RNA (dsRNA) injection was applied to investigate the biological roles of these differentially expressed genes. The RNAi effect was verified by RT-qPCR and western blotting assays. Triglyceride content and ATP levels were measured using the appropriate assay kits, following the manufacturers’ instructions. Statistical analyses were conducted with GraphPad7 software using the Student’s t-test.ResultsUpon depletion of mosquito- and midgut-specific miR-1174, a total of 383 differentially expressed proteins (DEPs) were identified, among which 258 were upregulated and 125 were downregulated. Functional analysis of these DEPs using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment suggested that miR-1174 plays important regulatory roles in amino acid metabolism, nucleotide metabolism, fatty acid metabolism and sugar metabolism pathways. A total of 292 differential metabolites were identified, of which 141 were upregulated and 151 were downregulated. Integrative analysis showed that the associated differential proteins and metabolites were mainly enriched in a variety of metabolic pathways, including glycolysis, citrate cycle, oxidative phosphorylation and amino acid metabolism. Specifically, the gene of one upregulated protein in miR-1174-depleted mosquitoes, purine nucleoside phosphorylase (PNP; AAEL002269), was associated with the purine, pyrimidine and niacin-nicotinamide metabolism pathways. PNP knockdown seriously inhibited blood digestion and ovary development and increased adult mortality. Mechanically, PNP depletion led to a significant downregulation of the vitellogenin gene (Vg); in addition, some important genes in the ecdysone signaling and insulin-like peptide signaling pathways related to ovary development were affected.ConclusionsThis study demonstrates differential accumulation of proteins and metabolites in miR-1174-depleted Ae. aegypti mosquitoes using proteomic and metabolomic techniques. The results provide functional evidence for the role of the upregulated gene PNP in gut physiological activities. Our findings highlight key molecular changes in miR-1174-depleted Ae. aegypti mosquitoes and thus provide a basis and novel insights for increased understanding of the molecular mechanism involved in a lineage-specific miRNA in mosquito vectors.Graphical

Structural and expression analysis of the dopamine receptors reveals their crucial roles in regulating the insulin signaling pathway in oysters

Dopamine performs its critical role upon binding to receptors. Since dopamine receptors are numerous and versatile, understanding their protein structures and evolution status, and identifying the key receptors involved in the modulation of insulin signaling will provide essential clues to investigate the molecular mechanism of neuroendocrine regulating the growth in invertebrates. In this study, seven dopamine receptors were identified in the Pacific oysters (Crassostrea gigas) and were classified into four subtypes according to their protein secondary and tertiary structures, and ligand-binding activities. Of which, DR2 (dopamine receptor 2) and D(2)RA-like (D(2) dopamine receptor A-like) were considered the invertebrate-specific type 1 and type 2 dopamine receptors, respectively. Expression analysis indicated that the DR2 and D(2)RA-like were highly expressed in the fast-growing oyster “Haida No.1”. After in vitro incubation of ganglia and adductor muscle with exogenous dopamine and dopamine receptor antagonists, the expression of these two dopamine receptors and ILPs (insulin-like peptides) was also significantly affected. Dual-fluorescence in situ hybridization results showed that D(2)RA-like and DR2 were co-localized with MIRP3 (molluscan insulin-related peptide 3) and MIRP3-like (molluscan insulin-related peptide 3-like) in the visceral ganglia, and were co-localized with ILP (insulin-like peptide) in the adductor muscle. Furthermore, the downstream components of dopamine signaling, including PKA, ERK, CREB, CaMKK1, AKT, and GSK3β were also significantly affected by the exogenous dopamine and dopamine receptor antagonists. These findings confirmed that dopamine might affect the secretion of ILPs through the invertebrate-specific dopamine receptors D(2)RA-like and DR2, and thus played crucial roles in the growth regulation of the Pacific oysters. Our study establishes the potential regulatory relationship between the dopaminergic system and insulin-like signaling pathway in marine invertebrates.

Eurycomanone (EN) Activates Transcription Factor FoxO by Inhibiting the Insulin Signaling Pathway to Suppress the Development of Spodoptera frugiperda.

The insulin-like signaling (IIS) pathway is essential for insect growth and development. In this study, we showed that eurycomanone (EN) is an active compound with growth inhibitory activity against Spodoptera frugiperda larvae. Experiments in cells and RNA-seq analysis in the midgut showed that EN targeted the IIS pathway in S. frugiperda to activate the transcription factor SfFoxO (S. frugiperda forkhead boxO) to regulate mRNA levels associated with nutrient catabolism. Additionally, mass spectrometry imaging revealed that EN was distributed in the larval gut and enriched in the inner membrane of the gut. Immunofluorescence, western blotting, and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) results showed that EN induced program cell death (PCD) in the larvae midgut. Thus, EN targeted the insulin receptor to inhibit the IIS signaling pathway, exerting inhibitory activity on the growth and development of S. frugiperda larvae. Our results suggest that EN has great potential as a botanical pesticide, and the IIS signaling pathway may be an effective target for botanical pesticides.

Study of insulin-like growth factors and their association with clinic pathological features and survival in colon cancer

The present study aimed to elucidate the clinicopathological relationship of insulin-like growth factor signaling pathway in patients with advanced colon adenocarcinoma. The relationship of protein expression in this pathway is controversial

Angelica keiskei Impacts the Lifespan and Healthspan of Drosophila melanogaster in a Sex and Strain-Dependent Manner.

Angelica keiskei is a perennial plant, belonging to the Apiaceae family and originating from Japan. This plant has been reported to act as a diuretic, analeptic, antidiabetic, hypertensive, tumor, galactagogue, and laxative. The mechanism of action of A. keiskei is not known, but previous studies have suggested that it may act as an antioxidant. In this work, we used Drosophila melanogaster to evaluate the impact of A. keiskei on lifespan and healthspan and its potential anti-aging mechanism by conducting multiple assays on three fly strains: w1118, chico, and JIV. We observed that the extract extended lifespan and improved healthspan in a sex- and strain-dependent manner. A. keiskei extended lifespan and improved reproductive fitness in female flies and either had no effect or decreased survival and physical performance in males. The extract protected against the superoxide generator paraquat in both sexes. These sex-specific effects suggest that A. keiskei may act through age-specific pathways such as the insulin and insulin-like growth factor signaling (IIS) pathways. Upon examination, we found that the increased survival of A. keiskei-fed females was dependent on the presence of the insulin receptor substrate chico, supporting the role of IIS in the action of A. keiskei.

The lipidomes of C. elegans with mutations in asm-3/acid sphingomyelinase and hyl-2/ceramide synthase show distinct lipid profiles during aging.

Lipid metabolism affects cell and physiological functions that mediate animal healthspan and lifespan. Lipidomics approaches in model organisms have allowed us to better understand changes in lipid composition related to age and lifespan. Here, using the model C. elegans, we examine the lipidomes of mutants lacking enzymes critical for sphingolipid metabolism; specifically, we examine acid sphingomyelinase (asm-3), which breaks down sphingomyelin to ceramide, and ceramide synthase (hyl-2), which synthesizes ceramide from sphingosine. Worm asm-3 and hyl-2 mutants have been previously found to be long- and short-lived, respectively. We analyzed longitudinal lipid changes in wild type animals compared to mutants at 1-, 5-, and 10-days of age. We detected over 700 different lipids in several lipid classes. Results indicate that wildtype animals exhibit increased triacylglycerols (TAG) at 10-days compared to 1-day, and decreased lysophoshatidylcholines (LPC). We find that 10-day hyl-2 mutants have elevated total polyunsaturated fatty acids (PUFA) and increased LPCs compared to 10-day wildtype animals. These changes mirror another short-lived model, the daf-16/FOXO transcription factor that is downstream of the insulin-like signaling pathway. In addition, we find that hyl-2 mutants have poor oxidative stress response, supporting a model where mutants with elevated PUFAs may accumulate more oxidative damage. On the other hand, 10-day asm-3 mutants have fewer TAGs. Intriguingly, asm-3 mutants have a similar lipid composition as the long-lived, caloric restriction model eat-2/mAChR mutant. Together, these analyses highlight the utility of lipidomic analyses to characterize metabolic changes during aging in C. elegans.

Luteolin promotes pathogen resistance in Caenorhabditis elegans via DAF-2/DAF-16 insulin-like signaling pathway.

The DAF-2/DAF-16 insulin-like signaling pathway was an evolutionarily conserved pathway, which regulated many aspects of organismal physiology, such as pathogen resistance, metabolism, stress response, longevity. Luteolin, a flavone contained in many medical plants and in vegetables, had been shown to exhibit activities such as anti-tumor, anti-oxidant and neuroprotective effects. However, whether the Luteolin influenced the immune response and the underlying molecular mechanisms remained obscure. We found that Luteolin increased resistance to not only the Gram-negative pathogens Pseudomonas aeruginosa and Salmonella enterica but also the Gram-positive pathogens Enterococcus faecalis and Staphylococcus aureus in dose dependent manner. Meanwhile, Luteolin promoted host immune response via inhibiting the growth of pathogenic bacteria. Through the genetic screening in C. elegans, we found that Luteolin promoted innate immunity via DAF-2/DAF-16 insulin-like signaling pathway rather than p38 MAPK pathway and SKN-1. Furthermore, Luteolin activated the DAF-16/FOXO transcription factor for innate immune response. Our work suggested that Luteolin had the potential of improving the patients with pathogen infection.

Multi-Omics Reveals the Effect of Population Density on the Phenotype, Transcriptome and Metabolome of Mythimna separata.

Population-density-dependent polymorphism is important in the biology of some agricultural pests. The oriental armyworm (Mythimna separata) is a lepidopteran pest (family Noctuidae). As the population density increases, its body color becomes darker, and the insect eats more and causes greater damage to crops. The molecular mechanisms underlying this phase change are not fully clear. Here, we used transcriptomic and metabolomic methods to study the effect of population density on the differentiation of second-day sixth instar M. separata larvae. The transcriptomic analysis identified 1148 differentially expressed genes (DEGs) in gregarious-type (i.e., high-population-density) armyworms compared with solitary-type (low-population-density) armyworms; 481 and 667 genes were up- and downregulated, respectively. The metabolomic analysis identified 137 differentially accumulated metabolites (DAMs), including 59 upregulated and 78 downregulated. The analysis of DEGs and DAMs showed that activation of the insulin-like signaling pathway promotes the melanization of gregarious armyworms and accelerates the decomposition of saccharides, which promotes the gregarious type to take in more food. The gregarious type is more capable of digesting and absorbing proteins and decreases energy consumption by inhibiting transcription and translation processes. The phase change traits of the armyworm are thus attributable to plasticity of its energy metabolism. These data broaden our understanding of the molecular mechanisms of insect-density-dependent polymorphism.

In vivo investigation of Lcr35® anti-candidiasis properties in Caenorhabditis elegans reveals the involvement of highly conserved immune pathways.

Lactic acid bacteria, including the microorganisms formerly designated as Lactobacillus, are the major representatives of Live Biotherapeutic Microorganisms (LBM) when used for therapeutic purposes. However, in most cases, the mechanisms of action remain unknown. The antifungal potential of LBM has already been demonstrated using preclinical models (cell cultures, laboratory animals). Understanding their mechanisms of action is strategic for the development of new therapeutics for humans. Here, Caenorhabditis elegans was used as an in vivo model to analyze pro-longevity, anti-aging and anti-candidiasis effects of the LBM Lacticaseibacillus rhamnosus (formerly Lactobacillus rhamnosus) Lcr35®. A high-throughput transcriptomic analysis revealed a specific response of C. elegans depending on whether it is in the presence of the LBM L. rhamnosus Lcr35® (structural response), the yeast Candida albicans (metabolic response) or both (structural and metabolic responses) in a preventive and a curative conditions. Studies on C. elegans mutants demonstrated that the p38 MAPK (sek-1, skn-1) and the insulin-like (daf-2, daf-16) signaling pathways were involved in the extended lifespan provided by L. rhamnosus Lcr35® strain whereas the JNK pathway was not involved (jnk-1). In addition, the anti C. albicans effect of the bacterium requires the daf-16 and sek-1 genes while it is independent of daf-2 and skn-1. Moreover, the anti-aging effect of Lcr35®, linked to the extension of longevity, is not due to protection against oxidative stress (H2O2). Taken together, these results formally show the involvement of the p38 MAP kinase and insulin-like signaling pathways for the longevity extension and anti-Candida albicans properties of Lcr35® with, however, differences in the genes involved. Overall, these findings provide new insight for understanding the mechanisms of action of a probiotic strain with antimicrobial potential.

The Insulin-like Growth Factor Signaling Pathway in Breast Cancer: An Elusive Therapeutic Target.

In this review, we provide an overview of the role of the insulin-like growth factor (IGF) signaling pathway in breast cancer and discuss its potential as a therapeutic target. The IGF pathway ligands, IGF-1 and IGF-2, and their receptors, primarily IGF-1R, are important for normal mammary gland biology, and dysregulation of their expression and function drives breast cancer risk and progression through activation of downstream signaling effectors, often in a subtype-dependent manner. The IGF signaling pathway has also been implicated in resistance to current therapeutic strategies, including ER and HER2 targeting drugs. Unfortunately, efforts to target IGF signaling for the treatment of breast cancer have been unsuccessful, due to a number of factors, most significantly the adverse effects of disrupting IGF signaling on normal glucose metabolism. We highlight here the recent discoveries that provide enthusiasm for continuing efforts to target IGF signaling for the treatment of breast cancer patients.

Comparative analysis of microsatellites in coding regions provides insights into the adaptability of the giant panda, polar bear and brown bear.

Short Tandem repeats (STRs) often occur within coding regions and adaptive selection could play a vital role in shaping the landscape of coding STRs. Here, we identified 849, 1282 and 1501 genes that contained 966, 1565 and 1921 STRs in the coding regions of the giant panda, polar bear and brown bear genomes, respectively. The results showed that coding STRs were subject to strong selection on STR type, motif, repetition and mode of evolution. Coding STRs were primarily found in regulatory genes. Of the three ursids studied, we found 585 differential genes in the giant panda. Gene Ontology analysis showed that the significant enrichment term (insulin-like growth factor receptor signaling pathway) exerted direct carbohydrate metabolic effects in vivo in this species. The enrichment of this pathway suggested that the giant panda's ability to absorb carbohydrates (starch) and adapt to a bamboo diet might be enhanced by variable coding STRs. We also identified 377 conserved coding STRs located in 377 genes across the three species. Kyoto Encyclopedia of Genes and Genomesenrichment analysis showed that these genes were significantly enriched in two pathway involved in key physiological processes, including cardiovascular function and energy metabolism regulation. This study provides an important resource for future studies on the regulation of rapid diet and environmental adaptation of species by coding STRs.

Nutrition regulates the expression of storage proteins in Bombyx mori via insulin-like/FoxO signaling pathway

Insect serum proteins, also termed storage proteins (SPs), are hexamer proteins that form amino acid reservoirs important for the development of pupae and embryos in most insects. In this study, we investigated the SP genes expression and regulation pathways in silkworms (Bombyx mori). We observed that B. mori SPs (BmSPs) in the fat body of larvae were strongly decreased by starvation, suggesting they respond to nutrition deprivation. Further, we examined the relationship between BmSP expression and the insulin-like signaling pathway (ILS) to study the regulation of BmSPs expression. The results showed that insulin up-regulated the expression of BmSPs, but an inhibitor of the ILS pathway protein PI3K downregulated the expression of BmSPs in B. mori larvae. Similar results were observed in cultured fat body in vitro and BmE cells. We then over-expressed FoxO, an ILS transcriptional factor, in BmE cells and B. mori larvae to further verify the regulatory role of ILS on expression of BmSPs and found BmFoxO negatively regulates the expression of BmSPs in both BmE cells and larvae. Moreover, BmFoxO was dephosphorylated and translocated from the cytoplasm to the nucleus under starvation treatment. Finally, an element on −2627–2644 bp upstream of the transcription start site of BmSP1 was identified as the binding site of BmFoxO by electrophoretic mobility shift assay and verified by chromatin immunoprecipitation. In summary, our results indicate that nutrient uptake triggers the expression of BmSPs via the ILS/FoxO signaling pathway. This study provides a reference for further study on the expression and regulation of insect SP genes.