Insulin Signaling Pathway Research Articles

Contribution of differential alteration in oxidative stress and anti-oxidation related molecular signals to toxicity difference between atrazine and its main metabolites in nematodes

As a widely used herbicide, atrazine and its two main metabolites of deethylatrazine (DEA) and deisopropylatrazine (DIA) pose an exposure risk for both human beings and animals in the environment. In this study, Caenorhabditis elegans was selected as an in vivo model to compare the toxicity between atrazine and its main metabolites. Upon exposure from the larval stage L1 to adult day 3, both DEA and DIA showed less toxicity on locomotion and reproduction compared with atrazine at concentration of 0.001, 0.01 0.1 and 1 mg/L for parental generation. In addition, exposure to DEA and DIA at concentration of 0.1 mg/L also induced less transgenerational toxicity on locomotion than exposure to atrazine for both parental generation and offspring of F1–F4. Accordingly, exposure to DEA and DIA caused less ROS production and alteration in the expression of some genes (mev-1, gas-1, and clk-1) governing oxidative stress compared to atrazine. Meanwhile, DEA and DIA lead to less increase in expression of superoxide dismutase genes (sod-2 and sod-3) and SOD-3::GFP than atrazine. Moreover, atrazine and its two main metabolites differentially activated the daf-16 encoding FOXO transcriptional factor in insulin signaling pathway during the control of downstream target of SOD-3. Overall, our results highlighted the important role of oxidative stress and anti-oxidation related molecular signals in mediating toxicity of atrazine, DEA and DIA, which provided a novel explanation for the different toxicity between atrazine and its main metabolites.

The PCOS-NAFLD Multidisease Phenotype Occurred in Medaka Fish Four Generations after the Removal of Bisphenol A Exposure.

As a heterogeneous reproductive disorder, polycystic ovary syndrome (PCOS) can be caused by genetic, diet, and environmental factors. Bisphenol A (BPA) can induce PCOS and nonalcoholic fatty liver disease (NAFLD) due to direct exposure; however, whether these phenotypes persist in future unexposed generations is not currently understood. In a previous study, we observed that transgenerational NAFLD persisted in female medaka for five generations (F4) after exposure to an environmentally relevant concentration (10 μg/L) of BPA. Here, we demonstrate PCOS in the same F4 generation female medaka that developed NAFLD. The ovaries contained immature follicles, restricted follicular progression, and degenerated follicles, which are characteristics of PCOS. Untargeted metabolomic analysis revealed 17 biomarkers in the ovary of BPA lineage fish, whereas transcriptomic analysis revealed 292 genes abnormally expressed, which were similar to human patients with PCOS. Metabolomic-transcriptomic joint pathway analysis revealed activation of the cancerous pathway, arginine-proline metabolism, insulin signaling, AMPK, and HOTAIR regulatory pathways, as well as upstream regulators esr1 and tgf signaling in the ovary. The present results suggest that ancestral BPA exposure can lead to PCOS phenotypes in the subsequent unexposed generations and warrant further investigations into potential health risks in future generations caused by initial exposure to EDCs.

Mechanisms underlying large-leaf yellow tea mediated inhibition of cognitive impairment in the 5xFAD model of Alzheimer's disease

BackgroundAlzheimer's disease (AD) is the most common cause of dementia and is characterized by amyloid-β (Aβ) peptides and hyperphosphorylated Tau proteins. Evidence indicates that AD and type 2 diabetes mellitus (T2DM) share pathophysiological characteristics, including impaired insulin sensitivity. Large-leaf yellow tea (LYT) has been widely recognized for its health benefits, and we previously found that LYT can improve peripheral insulin resistance. PurposeThis study aimed to investigate the protective effects and underlying mechanisms of LYT in the 5xFAD mouse model of AD. MethodsHPLC and spectrophotometric methods determined the chemical composition of the LYT extract. 5xFAD mice were treated with LYT supplementation (2 and 4 mg/ml) in drinking water for six months. Barnes and Y mazes were used to evaluate cognitive function, and the open field test assessed anxiety-like behavior. Immunofluorescence, silver, and Nissl staining were used to evaluate the pathological effects of LYT extract. A FRET-based assay assessed β-site APP cleavage enzyme 1 (BACE1) activity, ELISA measured Aβ levels in the brain, and Western blot analyses explored protein expression levels. ResultsOur results revealed that LYT significantly attenuated memory impairment and anxiety levels and alleviated cerebral neural damage. A reduction of senile plaques was also observed in both the cortex and hippocampus. LYT significantly inhibited the activity of BACE1, which resulted in a lower Aβ protein level. In addition, LYT enhanced insulin receptor substrate 1 (IRS-1)-mediated phosphorylation of phosphoinositide 3-kinase (PI3K) and protein kinase B (AKT), further suppressed glycogen synthase kinase-3β (GSK3β), and ultimately inhibited hyperphosphorylation of the protein Tau. The inhibitory effect of the LYT extract on the phosphorylation of Tau and BACE1 activity was dose-dependent. ConclusionLYT improves cognitive ability and reduces Aβ production by inhibiting BACE1 activity. Decreases of Tau protein hyperphosphorylation upon LYT treatment appear to be associated with the regulation of the IRS-1/PI3K/AKT/GSK3β axis. Thus, the findings of this study also provide new evidence that LYT regulates insulin signaling pathways within the central nervous system.

Akebia saponin D from Dipsacus asper wall. Ex C.B. Clarke ameliorates skeletal muscle insulin resistance through activation of IGF1R/AMPK signaling pathway

Ethnopharmacological relevanceDipsacus asper Wall. Ex C.B. Clarke (DA), a perennial herb, is one of the most commonly used herbs in Traditional Chinese Medicine for strengthening muscles and bones and regulating blood vessels. Akebia saponin D (ASD/AVI) is a triterpenoid saponin extracted from the root of DA, which has favorable pharmacological properties such as anti-osteoporosis, anti-apoptosis, liver protection and hypolipidemic. Aim of the studyTo explore the underlying mechanisms and regulatory role of Akebia saponin D (ASD/AVI) on high-fat diet-induced insulin resistance in skeletal muscle. Materials and methodsC2C12 cells were used to explore the best concentration in the skeletal muscle insulin resistance model in an in vitro experiment. The protective effect of AVI on insulin resistance and the corresponding signaling pathway were detected by glucose content measurement, quantitative PCR, and Western blot. A high-fat diet STZ-induced insulin resistance mice model was used to evaluate the protective function of AVI in vivo. After four weeks of treatment, ITT, OGTT, and treadmill tests were applied to examine insulin sensitivity and their serum and skeletal muscle tissues were collected for further analysis. ResultsAVI effectively reduced body weight, blood glucose levels and calorie intake in insulin-resistant mice, and reduced lipid accumulation and in their muscle tissue. AVI also improved glucose uptake and insulin sensitivity in both in vivo and in vitro experiments. Following AVI administration, there was an increase in the expression of the AMPK signaling pathway. Our experiments further confirmed that AVI specifically targets the IGF1R, thereby more effectively regulating the insulin signaling pathway. ConclusionAVI improves type 2 diabetes-induced insulin resistance in skeletal muscle by activating the IGF1R-AMPK signaling pathway, promoting glucose uptake and energy metabolism in IR.

Sleep-associated insulin resistance promotes neurodegeneration.

Lifestyle modification can lead to numerous health issues closely associated with sleep. Sleep deprivation and disturbances significantly affect inflammation, immunity, neurodegeneration, cognitive depletion, memory impairment, neuroplasticity, and insulin resistance. Sleep significantly impacts brain and memory formation, toxin excretion, hormonal function, metabolism, and motor and cognitive functions. Sleep restriction associated with insulin resistance affects these functions by interfering with the insulin signalling pathway, neurotransmission, inflammatory pathways, and plasticity of neurons. So, in this review, We discuss the evidence that suggests that neurodegeneration occurs via sleep and is associated with insulin resistance, along with the insulin signalling pathways involved in neurodegeneration and neuroplasticity, while exploring the role of hormones in these conditions.

What Are the Implications of Cr(III) Serving as an Inhibitor of the Beta Subunit of Mitochondrial ATP Synthase?

A recent report has shown the active site of the beta subunit of mitochondrial ATP synthase is probably the site of action of Cr(III) action, independent of the insulin signaling pathway. This works appears to answer an important question about the mode of action of Cr(III) at a molecular level when supplied in supra-nutritional levels to rodents. However, as with any good research, the research also raises several questions. The relationship between this study and the results of rodent studies of chromium supplementation and between this study and the current understanding the chromium(III) transport and detoxification system are put into perspective.

The efficacy and mechanism of Angelica sinensis (Oliv.) Diels root aqueous extract based on RNA sequencing and 16S rDNA sequencing in alleviating polycystic ovary syndrome

BackgroundPolycystic ovary syndrome (PCOS) leads to persistent anovulation, hyperandrogenism, insulin resistance, and polycystic ovary, and is mainly characterized by menstrual disorders, and reproductive dysfunction. Angelica sinensis (Oliv.) Diels root has been used in many classical formulas of traditional Chinese medicine, and is commonly used to treat various gynecological diseases. PurposeTo investigate the protective effect of water extract of A. sinensis root (WEA) on PCOS rats, and the mechanism by RNA sequencing, and 16S rDNA sequencing. MethodsThe PCOS rat model was established by letrozole combined with high-fat diet (gavage; 2 months), and treated with WEA (gavage; 2 g/kg, 4 g/kg or 8 g/kg; 1 month). To evaluate the therapeutic effect of WEA on PCOS rats, vaginal smear, hematoxylin-eosin staining, and biochemical indicators detection were performed. The rat ovarian tissue was analyzed by RNA sequencing, and the results were verified by qRT-PCR, and Western blot. 16S rDNA sequencing was used to analyze the gut microbiota of rats. ResultsThe results of the vaginal smear, and hematoxylin-eosin staining showed that WEA improved estrous cycle disorder, and ovarian tissue lesions. WEA (4 g/kg or 8 g/kg; 1 months) alleviated hormone disorders, insulin resistance, and dyslipidemia. RNA sequencing showed that WEA intervention significantly changed the expressions of 2756 genes, which were enriched in phosphatidylinositol3-kinase/phosphorylated protein kinase B (PI3K/AKT), peroxisome proliferator-activated receptor (PPAR), mitogen-activated protein kinase (MAPK), AMP-activated protein kinase (AMPK), and insulin signaling pathways. 16S rDNA sequencing found that WEA increased the species diversity of gut microbiota, and regulated the abundance of some microbiota (genus level: Dubosiella, Bifidobacterium, Coriobacteriaceae (UCG-002), and Treponema; species level: Bifidobacterium animalis, Lactobacillus murinus, and Lactobacillus johnsonii). ConclusionWEA regulated hormone, and glycolipid metabolism disorders, thereby relieving the PCOS induced by letrozole combined with high-fat diet. The mechanism was related to the regulation of PI3K/AKT, PPAR, MAPK, AMPK, and insulin signaling pathways in ovarian tissues, and the maintenance of gut microbiota homeostasis. Clarifying the efficacy and mechanism of WEA in alleviating PCOS based on RNA sequencing and 16S rDNA sequencing will guide the more reasonable clinical use of WEA.

Integrated analysis of mRNAs and lncRNAs reveals candidate marker genes and potential hub lncRNAs associated with growth regulation of the Pacific Oyster, Crassostrea gigas

BackgroundThe Pacific oyster, Crassostrea gigas, is an economically important shellfish around the world. Great efforts have been made to improve its growth rate through genetic breeding. However, the candidate marker genes, pathways, and potential lncRNAs involved in oyster growth regulation remain largely unknown. To identify genes, lncRNAs, and pathways involved in growth regulation, C. gigas spat was cultured at a low temperature (15 ℃) to yield a growth-inhibited model, which was used to conduct comparative transcriptome analysis with spat cultured at normal temperature (25 ℃).ResultsIn total, 8627 differentially expressed genes (DEGs) and 1072 differentially expressed lncRNAs (DELs) were identified between the normal-growth oysters (cultured at 25 ℃, hereinafter referred to as NG) and slow-growth oysters (cultured at 15 ℃, hereinafter referred to as SG). Functional enrichment analysis showed that these DEGs were mostly enriched in the AMPK signaling pathway, MAPK signaling pathway, insulin signaling pathway, autophagy, apoptosis, calcium signaling pathway, and endocytosis process. LncRNAs analysis identified 265 cis-acting pairs and 618 trans-acting pairs that might participate in oyster growth regulation. The expression levels of LNC_001270, LNC_003322, LNC_011563, LNC_006260, and LNC_012905 were inducible to the culture temperature and food abundance. These lncRNAs were located at the antisense, upstream, or downstream of the SREBP1/p62, CDC42, CaM, FAS, and PIK3CA genes, respectively. Furthermore, the expression of the trans-acting lncRNAs, including XR_9000022.2, LNC_008019, LNC_015817, LNC_000838, LNC_00839, LNC_011859, LNC_007294, LNC_006429, XR_002198885.1, and XR_902224.2 was also significantly associated with the expression of genes enriched in AMPK signaling pathway, insulin signaling pathway, autophagy, apoptosis, calcium signaling pathway, and endocytosis process.ConclusionsIn this study, we identified the critical growth-related genes and lncRNAs that could be utilized as candidate markers to illustrate the molecular mechanisms underlying the growth regulation of Pacific oysters.

Molecular insights into the lipid-carbohydrates metabolism switch under the endurance effort in Arabian horses.

Recent studies have shown that in Arabian horse muscle, long-term exercise-induced expression of genes related to fatty acid degradation and the downregulation of genes belonging to the glycolysis/gluconeogenesis and insulin signalling pathways. Long-lasting physical exertion may trigger the metabolism to switch the main energy source from carbohydrates to lipids due to higher caloric content. To describe the metabolism adaptation at the whole transcriptome of blood to endurance effort in Arabian horses. In vivo experiment. Venous blood samples from 10 Arabian horses were taken before and after a 120 km long endurance ride to isolate the RNA and perform the high-throughput NGS transcriptome sequencing. The results, including KEGG (Kyoto Encyclopaedia of Genes and Genomes) and GO (Gene Ontology) analyses, allowed us to describe the most significantly upregulated-ARV1, DGAT2, LIPE, APOA2, MOGAT1, MOGAT2, GYS1, GYS2 and downregulated-ACACA, ACACB, FADS1, FADS2 genes involved in carbohydrate and lipid metabolism. Also, the increased expression of RAF1, KRAS and NRAS genes involved in the Insulin pathway and PI3K-Akt was shown. Limited sample size, Arabians used for endurance racing were not compared to Arabians from other equestrian disciplines. This general insight into the processes described supports the thesis of the lipid-carbohydrates metabolism switch in endurance Arabian horses and provides the basis for further research.

Toxic effects of tire wear particles and the leachate on the Chinese mitten crab (Eriocheir sinensis)

Tire wear particles (TWPs) were considered as an important component of microplastic pollution in the aquatic environment. To understand the ecotoxicity of TWPs to crustacean, this study investigated toxic effects of TWPs and the leachate on the mitten crab Eriocheir sinensis and the accumulation of TWPs in the crabs. Although TWPs could be accumulated in various tissues (i.e., liver, gills and gut) of the crabs, exposure to TWPs or the leachate had no lethal effect on the crabs in this study. Lower concentrations of TWPs and the leachate exposure could stimulate the antioxidant defense system of the crabs, while higher concentrations could disrupt the stress defense system. In addition, the energy supply and metabolism of the crabs could also be affected by TWPs or the leachate. The transcriptomic profiles showed that the toxic mechanisms of TWPs and the leachate were not exactly the same. Similar to the results of biochemical analysis, several Gene Ontology (GO) terms and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways related to oxidative stress and energy metabolism were significantly regulated by both TWPs and the leachate. However, TWPs could affect the expression of genes enriched in immune-related pathways, while the leachate regulated the enrichment of some other signaling pathways including FoxO signaling pathway, insulin signaling pathway, RIG-I-like receptor signaling pathway, NOD-like receptor signaling pathway, PPAR signaling pathway and neuroactive ligand-receptor interaction. Overall, our study could provide basic biological information for assessing the ecological risk of the TWP pollution in the aquatic environment and was useful to understand the potential toxic mechanisms of the TWPs and the leachate to crustaceans.

Alteration of the N6-methyladenosine methylation landscape in a mouse model of polycystic ovary syndrome

ObjectiveTo explore the N6-methyladenosine (m6A) methylation abnormality of mRNAs and its potential roles in the mouse model of polycystic ovary syndrome (PCOS).MethodsThe mouse model of PCOS were induced by injecting dehydroepiandrosterone (DHEA), and confirmed by observing the morphological structures of ovarian follicles. Subsequently, m6A-tagged mRNAs were identified via m6A epitranscriptomic microarray and its potential functional pathways were predicted in KEGG database. The expression and modification levels of key mRNAs in the most enriched pathway were evaluated and compared using western blot and methylated RNA immunoprecipitation-quantitative PCR (MeRIP-qPCR).ResultsCompared with the control group, 415 hypermethylated and downregulated mRNAs, 8 hypomethylated and upregulated mRNAs, and 14 hypermethylated and upregulated mRNAs were identified in the PCOS group (Fold change ≥ 1.5). Those mRNAs were mainly involved in insulin signaling pathway, type II diabetes mellitus, Fc epsilon RI signaling pathway, inositol phosphate metabolism, and GnRH secretion. In insulin signaling pathway, the expression levels of phosphorylated protein kinase B (p-AKT) were decreased, whereas that of upstream phosphorylated phosphatidylinositol 3-kinase (p-PI3K) were increased in PCOS group. Moreover, skeletal muscle and kidney-enriched inositol polyphosphate 5-phosphatease (SKIP), one of PIP3 phosphatases, was verified to be overexpressed, and Skip mRNAs were hypermethylated in PCOS group.ConclusionThe altered m6A modification of mRNAs might play a critical role in PCOS process. The PI3K/AKT pathway is inhibited in the mouse model of PCOS. Whether it is caused by the m6A modification of Skip mRNAs is worthy of further exploration.

IGF/mTORC1/S6 Signaling Is Potentiated and Prolonged by Acute Loading of Subtoxicological Manganese Ion.

The insulin-like growth factor (IGF)/insulin signaling (IIS) pathway is involved in cellular responses against intracellular divalent manganese ion (Mn2+) accumulation. As a pathway where multiple nodes utilize Mn2+ as a metallic co-factor, how the IIS signaling patterns are affected by Mn2+ overload is unresolved. In our prior studies, acute Mn2+ exposure potentiated IIS kinase activity upon physiological-level stimulation, indicated by elevated phosphorylation of protein kinase B (PKB, also known as AKT). AKT phosphorylation is associated with IIS activity; and provides direct signaling transduction input for the mammalian target of rapamycin complex 1 (mTORC1) and its downstream target ribosomal protein S6 (S6). Here, to better define the impact of Mn2+ exposure on IIS function, Mn2+-induced IIS activation was evaluated with serial concentrations and temporal endpoints. In the wild-type murine striatal neuronal line STHdh, the acute treatment of Mn2+ with IGF induced a Mn2+ concentration-sensitive phosphorylation of S6 at Ser235/236 to as low as 5 μM extracellular Mn2+. This effect required both the essential amino acids and insulin receptor (IR)/IGF receptor (IGFR) signaling input. Similar to simultaneous stimulation of Mn2+ and IGF, when a steady-state elevation of Mn2+ was established via a 24-h pre-exposure, phosphorylation of S6 also displayed higher sensitivity to sub-cytotoxic Mn2+ when compared to AKT phosphorylation at Ser473. This indicates a synergistic effect of sub-cytotoxic Mn2+ on IIS and mTORC1 signaling. Furthermore, elevated intracellular Mn2+, with both durations, led to a prolonged activation in AKT and S6 upon stimulation. Our data demonstrate that the downstream regulator S6 is a highly sensitive target of elevated Mn2+ and is well below the established acute cytotoxicity thresholds (<50 μM). These findings indicate that the IIS/mTORC1 pathways, in which Mn2+ normally serves as an essential co-factor, are dually responsible for the cellular changes in exposures to real-world Mn2+ concentrations.

Correlation and enlightenment between type 2 diabetes and aging from the perspective of oxidative stress

Type 2 diabetes is a very common type in diabetes, which is also called noninsulin-dependent diabetes. This paper focuses on the correlation between type 2 diabetes (T2D) and aging from the perspective of oxidative stress (OS), including the pathway that T2D produces oxidative stress and the effect that oxidative stress imposes on T2D. This paper also mentioned some specific mechanisms, like a glycolytic pathway, enhanced formation of advanced glycation end products (AGE), activation of protein kinase C (PKC), and deactivation of the insulin signaling pathway. In addition, this paper also talks about the important influence of OS in the process of aging. And, the attention was focused on the excessive ROS produced by mitochondria. On this basis, this paper sorts out the correlation between aging and T2D in OS and finds some experimental evidence, through which this paper also offers some enlightenment from the way of anti-aging to anti-diabetes.

The Marine Factor 3,5-Dihydroxy-4-methoxybenzyl Alcohol Represses Adipogenesis in Mouse 3T3-L1 Adipocytes In Vitro: Regulating Diverse Signaling Pathways

The augmentation of adipocytes in the adipose tissues brings disordered pathophysiological conditions, including type 2 diabetes, hyperlipidemia, hypertension, cardiovascular disease, and cancer. The phenolic antioxidant 3,5-dihydroxy-4-methoxybenzyl alcohol (DHMBA) prevents oxidative stress as radical scavenging in cells. However, the role of the disorder as a pharmacologic factor has been poorly understood. This study elucidates the regulatory effects of DHMBA on adipogenesis in mouse 3T3-L1 adipocytes in vitro. The 3T3-L1 preadipocytes were cultured in DMEM containing 10% calf fetal serum in the presence of DHMBA. Culturing with DHMBA repressed the growth of 3T3-L1 preadipocytes cultured in a medium without differentiation factors. Interestingly, when 3T3-L1 preadipocytes were cultured in a medium including differentiation factors containing insulin, DHMBA did not affect the number of cells with the differentiation process of adipogenesis. Culturing with DHMBA (1, 10, or 100 μM) inhibited lipid accumulation in adipocytes and repressed adipogenesis in 3T3-L1 cells. The potent inhibitory effects of DHMBA on adipogenesis were seen at the later stage of culture. Adipogenesis was inhibited by the presence of wortmannin, PD98059, or Bay 11-7082, which are inhibitors of pathways related to insulin signaling pathway. Notably, the suppressive effects of DHMBA on adipogenesis were expressed by the presence of these inhibitors. DHMBA treatment declined the levels of PPARy and C/EBPα related to preadipocyte differentiation and PI3 kinase 100α, Akt, MAPK, phosphor-MAPK, and mTOR implicated in the insulin signaling pathway, leading to adipogenesis promotion. Thus, DHMBA may inhibit adipogenesis via regulating diverse signaling pathways, providing a new strategy for the therapy of obesity.

Exploration of the molecular mechanism of insulin resistance in adipose tissue of patients with type 2 diabetes mellitus through a bioinformatic analysis.

We aimed to determine the cis-expression Quantitative Trait Loci (cis-eQTL) and trans-eQTL of differentially expressed genes (DEGs) in insulin resistance (IR) related pathways. The expression profile data for insulin sensitivity (IS) and IR in the adipose tissue of patients with type 2 diabetes mellitus (T2DM) were acquired from the Gene Expression Omnibus databases. Then, the Gene set enrichment analysis (GSEA) and Gene set variation analysis (GSVA) methods were performed to identify the significant enrichment of potential Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways between IS and IR groups, and the Wilcoxon rank sum test was carried out to identify the DEGs related to KEGG pathways. Finally, the cis-eQTLs and trans-eQTLs that can affect the expression of DEGs were screened from the eQTLGen database. The GSEA and GSVA analysis indicated that the mTOR signaling pathway, insulin signaling pathway and T2DM had a strong correlation with the pathological process of T2DM. Furthermore, six genes (ACACA, GYS2, PCK1, PRKAR1A, SLC2A4, and VEGFA) were found to be significantly differentially expressed in IR-related pathways. Finally, we have identified a total of 1073 cis-eQTLs and 24 trans-eQTLs. We screened out six genes that were significantly differentially expressed in IR-related pathways, including ACACA, GYS2, PCK1, PRKAR1A, SLC2A4, and VEGFA. Moreover, we discovered that these six genes were affected by 1073 cis-eQTLs and 24 trans-eQTLs.

The impact of dietary fructose on gut permeability, microbiota, abdominal adiposity, insulin signaling and reproductive function

The excessive intake of fructose in the regular human diet could be related to global increases in metabolic disorders. Sugar-sweetened soft drinks, mostly consumed by children, adolescents, and young adults, are the main source of added fructose. Dietary high-fructose can increase intestinal permeability and circulatory endotoxin by changing the gut barrier function and microbial composition. Excess fructose transports to the liver and then triggers inflammation as well as de novo lipogenesis leading to hepatic steatosis. Fructose also induces fat deposition in adipose tissue by stimulating the expression of lipogenic genes, thus causing abdominal adiposity. Activation of the inflammatory pathway by fructose in target tissues is thought to contribute to the suppression of the insulin signaling pathway producing systemic insulin resistance. Moreover, there is some evidence that high intake of fructose negatively affects both male and female reproductive systems and may lead to infertility. This review addresses dietary high-fructose-induced deteriorations that are obvious, especially in gut permeability, microbiota, abdominal fat accumulation, insulin signaling, and reproductive function. The recognition of the detrimental effects of fructose and the development of relevant new public health policies are necessary in order to prevent diet-related metabolic disorders.

Manual annotation of Drosophila genes: a Genomics Education Partnership protocol

Annotating the genomes of multiple species allows us to analyze the evolution of their genes. While many eukaryotic genome assemblies already include computational gene predictions, these predictions can benefit from review and refinement through manual gene annotation. The Genomics Education Partnership (GEP; https://thegep.org/) developed a structural annotation protocol for protein-coding genes that enables undergraduate student and faculty researchers to create high-quality gene annotations that can be utilized in subsequent scientific investigations. For example, this protocol has been utilized by the GEP faculty to engage undergraduate students in the comparative annotation of genes involved in the insulin signaling pathway in 27 Drosophila species, using D. melanogaster as the reference genome. Students construct gene models using multiple lines of computational and empirical evidence including expression data (e.g., RNA-Seq), sequence similarity (e.g., BLAST and multiple sequence alignment), and computational gene predictions. Quality control measures require each gene be annotated by at least two students working independently, followed by reconciliation of the submitted gene models by a more experienced student. This article provides an overview of the annotation protocol and describes how discrepancies in student submitted gene models are resolved to produce a final, high-quality gene set suitable for subsequent analyses. The protocol can be adapted to other scientific questions (e.g., expansion of the Drosophila Muller F element) and species (e.g., parasitoid wasps) to provide additional opportunities for undergraduate students to participate in genomics research. These student annotation efforts can substantially improve the quality of gene annotations in publicly available genomic databases.

Fast drosophila enterocyte regrowth after infection involves a reverse metabolic flux driven by an amino acid transporter

Upon exposure to a bacterial pore-forming toxin, enterocytes rapidly purge their apical cytoplasm into the gut lumen, resulting in a thin intestinal epithelium. The enterocytes regain their original shape and thickness within 16h after the ingestion of the bacteria. Here, we show that the regrowth of Drosophila enterocytes entails an inversion of metabolic fluxes from the organism back toward the intestine. We identify a proton-assisted transporter, Arcus, that is required for the reverse absorption of amino acids and the timely recovery of the intestinal epithelium. Arcus is required for a peak of amino acids appearing in the hemolymph shortly after infection. The regrowth of enterocytes involves the insulin signaling pathway and Myc. The purge decreases Myc mRNA levels, which subsequently remain at low levels in the arcus mutant. Interestingly, the action of arcus and Myc in the intestinal epithelium is not cell-autonomous, suggesting amino acid fluxes within the intestinal epithelium.

Repurposing Drugs for Diabetes Mellitus as Potential Pharmacological Treatments for Sarcopenia - A Narrative Review.

Sarcopenia, the age-related loss of muscle strength and mass or quality, is a common condition with major adverse consequences. Although the pathophysiology is incompletely understood, there are common mechanisms between sarcopenia and the phenomenon of accelerated ageing seen in diabetes mellitus. Drugs currently used to treat type 2 diabetes mellitus may have mechanisms of action that are relevant to the prevention and treatment of sarcopenia, for those with type 2 diabetes and those without diabetes. This review summarises shared pathophysiology between sarcopenia and diabetes mellitus, including the effects of advanced glycation end products, mitochondrial dysfunction, chronic inflammation and changes to the insulin signalling pathway. Cellular and animal models have generated intriguing, albeit mixed, evidence that supports possible beneficial effects on skeletal muscle function for some classes of drugs used to treat diabetes, including metformin and SGLT2 inhibitors. Most human observational and intervention evidence for the effects of these drugs has been derived from populations with type 2 diabetes mellitus, and there is a need for intervention studies for older people with, and at risk of, sarcopenia to further investigate the balance of benefit and risk in these target populations. Not all diabetes treatments will be safe to use in those without diabetes because of variable side effects across classes. However, some agents [including glucagon-like peptide (GLP)-1 receptor agonists and SGLT2 inhibitors] have already demonstrated benefits in populations without diabetes, and it is these agents, along with metformin, that hold out the most promise for further investigation in sarcopenia.

Single-cell multi-omics profiling reveals key regulatory mechanisms that poise germinal vesicle oocytes for maturation in pigs.

The molecular mechanisms controlling the transition from meiotic arrest to meiotic resumption in mammalian oocytes have not been fully elucidated. Single-cell omics technology provides a new opportunity to decipher the early molecular events of oocyte growth in mammals. Here we focused on analyzing oocytes that were collected from antral follicles in different diameters of porcine pubertal ovaries, and used single-cell M&T-seq technology to analyze the nuclear DNA methylome and cytoplasmic transcriptome in parallel for 62 oocytes. 10× Genomics single-cell transcriptomic analyses were also performed to explore the bi-directional cell-cell communications within antral follicles. A new pipeline, methyConcerto, was developed to specifically and comprehensively characterize the methylation profile and allele-specific methylation events for a single-cell methylome. We characterized the gene expressions and DNA methylations of individual oocyte in porcine antral follicle, and both active and inactive gene's bodies displayed high methylation levels, thereby enabled defining two distinct types of oocytes. Although the methylation levels of Type II were higher than that of Type I, Type II contained nearly two times more of cytoplasmic transcripts than Type I. Moreover, the imprinting methylation patterns of Type II were more dramatically divergent than Type I, and the gene expressions and DNA methylations of Type II were more similar with that of MII oocytes. The crosstalk between granulosa cells and Type II oocytes was active, and these observations revealed that Type II was more poised for maturation. We further confirmed Insulin Receptor Substrate-1 in insulin signaling pathway is a key regulator on maturation by in vitro maturation experiments. Our study provides new insights into the regulatory mechanisms between meiotic arrest and meiotic resumption in mammalian oocytes. We also provide a new analytical package for future single-cell methylomics study.