Insulin Signaling Pathway Research Articles

Crithmum maritimum Extract Restores Lipid Homeostasis and Metabolic Profile of Liver Cancer Cells to a Normal Phenotype.

Hepatocellular carcinoma (HCC) is an alarming epidemiological clinical problem worldwide. Pharmacological approaches currently available do not provide adequate responses due to poor effectiveness, high toxicity, and serious side effects. Our previous studies have shown that the wild edible plant Crithmum maritimum L. inhibits the growth of liver cancer cells and promotes liver cell differentiation by reducing lactic acid fermentation (Warburg effect). Here, we aimed to further characterise the effects of C. maritimum on lipid metabolism and markers of cellular metabolic health, such as AMP-activated protein kinase (AMPK), Sirtuin 1 (SIRT1), and Sirtuin 3 (SIRT3), as well as the insulin signalling pathway. To better mimic the biological spectrum of HCC, we employed four HCC cell lines with different degrees of tumorigenicity and lactic acid fermentation/Warburg phenotype. Lipid accumulation was assessed by Oil Red O (ORO) staining, while gene expression was measured by real-time quantitative PCR (RT-qPCR). The activation of AMPK and insulin signalling pathways was determined by Western blotting. Results indicate that C. maritimum prevents lipid accumulation, downregulates lipid and cholesterol biosynthesis, and modulates markers of metabolic health, such as AMPK, SIRT1 and SIRT3. This modulation is different amongst HCC cell lines, revealing an important functional versatility of C. maritimum. Taken together, our findings corroborate the importance of C. maritimum as a valuable nutraceutical, reinforcing its role for the improvement of metabolic health.

Regulation of placental amino acid transport in health and disease.

Abnormal fetal growth, i.e., intrauterine growth restriction (IUGR) or fetal growth restriction (FGR) and fetal overgrowth, is associated with increased perinatal morbidity and mortality and is strongly linked to the development of metabolic and cardiovascular disease in childhood and later in life. Emerging evidence suggests that changes in placental amino acid transport may contribute to abnormal fetal growth. This review is focused on amino acid transport in the human placenta, however, relevant animal models will be discussed to add mechanistic insights. At least 25 distinct amino acid transporters with different characteristics and substrate preferences have been identified in the human placenta. Of these, System A, transporting neutral nonessential amino acids, and System L, mediating the transport of essential amino acids, have been studied in some detail. Importantly, decreased placental Systems A and L transporter activity is strongly associated with IUGR and increased placental activity of these two amino acid transporters has been linked to fetal overgrowth in human pregnancy. An array of factors in the maternal circulation, including insulin, IGF-1, and adiponectin, and placental signaling pathways such as mTOR, have been identified as key regulators of placental Systems A and L. Studies using trophoblast-specific gene targeting in mice have provided compelling evidence that changes in placental Systems A and L are mechanistically linked to altered fetal growth. It is possible that targeting specific placental amino acid transporters or their upstream regulators represents a novel intervention to alleviate the short- and long-term consequences of abnormal fetal growth in the future.

Berberine attenuates obesity-induced insulin resistance by inhibiting miR-27a secretion.

Berberine (BBR) is an alkaloid found in plants. It has neuroprotective, anti-inflammatory and lipid-lowering activity. However, the efficacy of treatment with BBR and the mechanisms through which it acts need further study. This study investigated the therapeutic effects and the mechanism of action of BBR on obesity-induced insulin resistance in peripheral tissues. High-fat-fed C57BL/6J mice and low-fat-fed C57BL/6J mice with miR-27a overexpression were given BBR intervention (100 mg/kg, po), and the oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) were performed. Palmitic acid-stimulated hypertrophic adipocyte models were treated with BBR (10 μM). Related indicators and protein expression levels were examined. The AUCs of the OGTT and the ITT in the BBR intervention group were reduced significantly (p < 0.01) (p < 0.05), and the serum biochemical parameters, including FBG, TC, TG and LDL-C were significantly reduced after BBR intervention. In the invitro experiments, the triglyceride level and volume of lipid droplets decreased significantly after BBR intervention (p < 0.01) (p < 0.05). Likewise, BBR ameliorates skeletal muscle and pancreas insulin signalling pathways invivo and invitro. The results showed that BBR significantly ameliorated insulin resistance, reduced body weight and percent body fat and improved serum biochemical parameters in mice. Likewise, BBR reduced triglyceride level and lipid droplet volume in hypertrophic adipocytes, BBR improved obesity effectively. Meanwhile, BBR ameliorated the histomorphology of the pancreas, and skeletal muscle and pancreas insulin related signalling pathways of islets in invitro and invivo experiments. The results further demonstrated that BBR inhibited miR-27a levels in serum from obese mice and supernatant of hypertrophic adipocytes. miR-27a overexpression in low-fat fed mice indicated that miR-27a caused insulin resistance, and BBR intervention significantly improved the miR-27a induced insulin resistance status. This study demonstrates the important role of BBR in obesity-induced peripheral insulin resistance and suggest that the mechanism of its effect may be inhibition of miR-27a secretion.

Abstract PO3-02-03: Ketogenic diet and letrozole to inhibit PI3K signaling in ER+ breast cancer

Abstract Obesity is associated with an increased risk of breast cancer recurrence, similar in magnitude to the reduction in risk seen with the use of adjuvant chemotherapy. However, whether and how obesity causes that increased risk of recurrence remains unknown. Plausible mechanisms include obesity-mediated increases in estrogen signaling, inflammatory conditions resulting from obesity, or effects on insulin or other growth factor signaling pathways resulting from the insulin-resistant state that often accompanies obesity. While phosphatidyl inositol 3-kinase (PI3K) signaling is the normal, biological effector of insulin signaling, abnormal activation of PI3K is of particular concern in breast cancer, where it is associated with resistance to endocrine therapies and HER2-targeted therapies. We hypothesize that at least part of the adverse outcome associated with obesity results from aberrant activation of PI3K signaling in tumors. This may confer resistance to established therapies, or directly stimulate tumor growth (particularly in tumors with existing PI3K pathway mutations), or both. We tested a dietary intervention designed to alter insulin resistance pathophysiology coupled with endocrine therapy in the well-established neoadjuvant treatment paradigm in breast cancer. This will allow us to study the effects of the dietary intervention directly on tumor biology. The primary objective of this neoadjuvant study was to assess feasibility and tolerability of 2 weeks of a very low-carbohydrate ketogenic diet in combination with letrozole for patients with early stage operable ER+ disease. Up to 36 patients will be enrolled for this pilot and feasibility study (24 in the treatment group and 12 controls). Baseline metabolic parameters will be measured and the treatment group will begin a dietitian-supervised 2-week diet to induce a ketogenic state, along with letrozole 2.5 mg daily. The control group will receive only letrozole. At the end of 2 weeks, patients will proceed with surgical treatment of their breast cancer. We will report the primary outcome measure of feasibility, assessed by determining 1) the proportion of patients in the diet group achieving ketosis, 2) adherence to the diet and 3) participant-reported measures of stress, fatigue, and emotional health. For both groups, cell proliferation will be measured in a tumor biopsy obtained from the surgical specimen and compared with the pre-treatment diagnostic biopsy. Correlative studies will evaluate tumor markers of insulin/PI3K signaling before and after the intervention and between diet and control. Citation Format: Brent Rexer, Vandana Abramson, Sara Nunnery, Sonya Reid, Laura Kennedy, Melinda Sanders, Jessica Bennett, Paula Gonzalez-Ericsson, Violeta Sanchez. Ketogenic diet and letrozole to inhibit PI3K signaling in ER+ breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-02-03.

Dietary starch level regulates the growth and glycolipid metabolism through the insulin-PI3K-AKT signaling pathway of juvenile mud crab (Scylla paramamosain)

A six-week feeding trial was conducted to investigate the effects of dietary starch levels on growth performance, glucose and lipid metabolism and insulin signaling pathway of juvenile Scylla paramamosain. Three isonitrogenous (41.51% ± 0.31%) and isolipidic (8.68% ± 0.53%) experimental diets were formulated to contain 10%, 20% and 30% starch levels, respectively. A total 96 crabs were divided into 3 treatment groups. There were 4 replicates per treatment group and 8 crabs per replicate (initial weight 5.12 ± 0.05 g). The crabs fed the diet with 20% starch showed the best growth performance, with higher weight gain rate (WGR), specific growth rate (SGR), protein efficiency ratio (PER), and feed efficiency (FE) compared to the other diets. Increasing starch levels in the diet resulted in higher levels of glycogen and lipid in the muscles and hepatopancreas. The levels of glucose (GLU), triglyceride (TG), and free fatty acid (FFA) displayed a significant increase in both hemolymph and hepatopancreas with the escalating dietary starch concentrations. In contrast, as the dietary starch levels increased, the concentrations of crustacean hyperglycemic hormone (CHH) and insulin-like peptides (ILPs) in hemolymph and hepatopancreas demonstrated a notable decline. The glycolysis and pentose phosphorylation pathways were significantly promoted, while the gluconeogenic pathway was significantly inhibited, with dietary starch levels increasing from 10% to 30%. Additionally, increasing dietary starch levels led to a significant down-regulation of genes related to the lipid synthesis, lipolysis and insulin signaling pathway. Histological results showed that hepatopancreas fat accumulation increased with the increase of dietary starch level. Overall, the findings of this study suggest that adding 20% starch to the diet can promote growth and improve nutrient utilization. In addition, the level of dietary starch had significant effects on the glucose and lipid metabolism and insulin signaling pathway of mud crabs, thus affecting the deposition of lipid reserves in hepatopancreas.

Depression and Type 2 Diabetes: Dissecting the Causal Mechanisms

Depression and Type 2 Diabetes (T2D) are two prevalent and debilitating chronic conditions that often coexist and exhibit a bidirectional relationship. This review paper aims to dissect the causal mechanisms underlying the association between depression and T2D, shedding light on the complex interplay between these two disorders. Epidemiological evidence suggests a robust association between depression and an increased risk of developing T2D, as well as a reciprocal relationship where T2D serves as a risk factor for depression onset. Various biological, psychological, and behavioral mechanisms have been proposed to underlie this bidirectional relationship. Depression is thought to contribute to the development of T2D through dysregulation of neuroendocrine pathways, increased inflammation, alterations in lifestyle behaviors, and poor treatment adherence. Conversely, T2D may exacerbate or precipitate depression through mechanisms involving insulin resistance, hyperglycemia-induced neuronal damage, inflammation, and the impact of chronic illness on psychological well-being. Shared pathophysiological mechanisms between depression and T2D, including dysregulation of the hypothalamic-pituitary-adrenal axis, insulin signaling pathways, and inflammatory processes, further contribute to their co-occurrence. Psychosocial factors such as socioeconomic status, social support, and access to healthcare also play significant roles in shaping the depression-T2D relationship. Integrated care models that address both physical and mental health needs, along with targeted interventions addressing lifestyle modifications and psychosocial support, are essential for managing these comorbid conditions effectively. Future research directions include longitudinal studies to elucidate temporal associations, intervention trials targeting shared mechanisms, and precision medicine approaches to identify subgroups at heightened risk. Understanding the causal mechanisms underlying the depression-T2D relationship is crucial for informing clinical practice, public health strategies, and the development of personalized interventions aimed at mitigating the burden of these interconnected disorders.

Unveiling Diabetes: Categories, Genetics, Diagnostics, Treatments, and Future Horizons.

Diabetes mellitus is a global epidemic affecting millions of individuals worldwide. This comprehensive review aims to provide a thorough understanding of the categorization, disease identity, genetic architecture, diagnosis, and treatment of diabetes. The categorization of diabetes is discussed, with a focus on type 1 and type 2 diabetes, as well as the lesser-known types, type 3 and type 4 diabetes. The geographical variation, age, gender, and ethnic differences in the prevalence of type 1 and type 2 diabetes are explored. The impact of disease identity on disease management and the role of autoimmunity in diabetes are examined. The genetic architecture of diabetes, including the interplay between genotype and phenotype, is discussed to enhance our understanding of the underlying mechanisms. The importance of insulin injection sites and the insulin signalling pathway in diabetes management are highlighted. The diagnostic techniques for diabetes are reviewed, along with advancements for improved differentiation between types. Treatment and management approaches, including medications used in diabetes management are presented. Finally, future perspectives are discussed, emphasizing the need for further research and interventions to address the global burden of diabetes. This review serves as a valuable resource for healthcare professionals, researchers, and policymakers, providing insights to develop targeted strategies for the prevention, diagnosis, and management of this complex disease.

Differential Expression Profiles and Bioinformatics Analysis of tRNA-derived Small RNAs in Epicardial fat of Patients with Atrial Fibrillation

The exact processes underlying atrial fibrillation (AF) are still unclear. It has been suggested that epicardial adipose tissue (EAT) may contribute to arrhythmias and can release various bioactive molecules, including exosomes containing tRNA-derived small RNAs (tsRNAs). Numerous studies have indicated that these tsRNAs can significantly affect key cellular functions. However, there is currently no research investigating the relationship between tsRNAs from EAT and AF. In order to explore the regulatory mechanisms of tsRNAs from EAT associated with AF, we conducted RNA-sequencing analysis on EAT samples collected from 6 AF patients and 6 control subjects with sinus rhythm. Our analysis revealed an upregulation of 146 tsRNAs and a downregulation of 126 tsRNAs in AF. Furthermore, we randomly selected four tsRNAs (tRF-SeC-TCA-001, tiRNA-Gly-CCC-003, tRF-Gly-GCC-002, and tRF-Tyr-GTA-007) for validation using quantitative reverse transcription-polymerase chain reaction. Following this, bioinformatic analyses revealed that the target genes of these tsRNAs were prominently involved in the regulation of cell adhesion and various cellular processes mediated by plasma membrane adhesion molecules. Additionally, based on KEGG analysis, it was suggested that the majority of these target genes might contribute to the pathogenesis of AF through processes such as glycosaminoglycan biosynthesis, AMP-activated protein kinase activity, and the insulin signaling pathway. Our results elucidate changes in the expression profiles of tsRNAs within EAT samples obtained from AF patients, and they forecast potential target genes and interactions between tsRNAs and mRNA within EAT that could contribute to the pathogenesis of AF.

Identification of Novel Peptides in Distillers’ Grains as Antioxidants, α-Glucosidase Inhibitors, and Insulin Sensitizers: In Silico and In Vitro Evaluation

Distillers’ grains are rich in protein and constitute a high-quality source of various bioactive peptides. The purpose of this study is to identify novel bioactive peptides with α-glucosidase inhibitory, antioxidant, and insulin resistance-ameliorating effects from distiller’s grains protein hydrolysate. Three novel peptides (YPLPR, AFEPLR, and NDPF) showed good potential bioactivities, and the YPLPR peptide had the strongest bioactivities, whose IC50 values towards α-glucosidase inhibition, radical scavenging rates of 2,2′-azino-bis (3-ethylbenzothiazoline-6- sulfonic acid) (ABTS) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) were about 5.31 mmol/L, 6.05 mmol/L, and 7.94 mmol/L, respectively. The glucose consumption of HepG2 cells treated with YPLPR increased significantly under insulin resistance condition. Moreover, the YPLPR peptide also had a good scavenging effect on intracellular reactive oxygen species (ROS) induced by H2O2 (the relative contents: 102.35% vs. 100%). Molecular docking results showed that these peptides could stably combine with α-glucosidase, ABTS, and DPPH free radicals, as well as related targets of the insulin signaling pathway through hydrogen bonding and van der Waals forces. This research presents a potentially valuable natural resource for reducing oxidative stress damage and regulating blood glucose in diabetes, thereby increasing the usage of distillers’ grains peptides and boosting their economic worth.

Melatonin as a promising agent alleviating endocrine deregulation and concurrent cardiovascular dysfunction: a review and future prospect

Endocrine modulation of various growth and survival mechanisms is at the helm of cellular homeostasis and impaired endocrine balance may potentially galvanize cardiovascular health to go haywire. Melatonin, an effective antioxidant and multipotent hormone has preponderant influence on the activities of several endocrine factors including growth hormones, thyroid hormones, gastro-intestinal hormones, and those controlling reproductive and metabolic functions. Many of these hormones tightly regulate cardiovascular functions while the mammalian heart has its own endocrine machinery. Endocrine disruptions severely affect cardiovascular integrity and hormonal therapies may instigate adverse cardiac events. Therefore, this review focuses on the cardioprotective potential of melatonin concerning endocrine instability-mediated cardiovascular dysfunction. Melatonin has been reported to effectively counteract sympathetic overstimulation and also reduce the cardiotoxic attributes of catecholamines and their derivatives. Melatonin suppresses the pernicious cardiovascular manifestation of thyrotoxicosis and autoimmune thyroiditis, which is possibly attributed to its antioxidant property and regulation of iodothyronine-deiodinase activity. Interestingly, being a circadian synchronizer melatonin potentially preserves the diurnal pattern of insulin secretion and thereby improves glucose tolerance and cardiac GLUT-4 expression. Besides, melatonin modulates insulin signaling pathway by enhancing the activation of insulin receptor-associated tyrosine kinase, thus protecting the heart against diabetogenic outcomes. Further, melatonin has demonstrated its beneficial action against non-dipper hypertension by regulating the RAAS function. However, there is a plethora of unresolved research question that necessitates additional investigation into the potential therapeutic effect of melatonin in endocrine dysfunctions that emanates during various physiological and pathological states and may have potentially harmful cardiovascular implications.

Impacts of superfine grinding on structural characteristics and lipid‐lowering effect of bitter melon polysaccharides

SummaryIn this study, the effects of superfine grinding on the structural and physicochemical properties of bitter melon polysaccharides (BPS) were investigated, and Caenorhabditis elegans model was used to evaluate fat‐lowering bioactivities of BPS. Results illustrated that superfine grinding resulted in high extraction of BPSs yielding with altered microstructure, different monosaccharide compositions and molecular weights. In addition, improved water/oil‐holding capacity, solubility and swelling capacity of polysaccharides were observed following superfine grinding. Furthermore, C. elegans study revealed that BPSs exhibited strong inhibitory effects on lipid accumulation, especially BPS‐25 (extracted from bitter melon treated with superfine grinding) reducing the triglyceride content from 9.49 to 1.85 mg g−1.prot. Mechanistic study showed that the lipid‐lowering effects of BPSs largely dependent on the insulin signalling pathway, fatty acid oxidation or lipolysis pathways. In all, our study underscore that superfine grinding can effectively improve the lipid‐lowing effects of bitter melon polysaccharides.

Conjugated Linoleic Acid Ameliorates High Fat-Induced Insulin Resistance via Regulating Gut Microbiota-Host Metabolic and Immunomodulatory Interactions.

Interaction between gut microbiota, host immunity and metabolism has been suggested to crucially affect the development of insulin resistance (IR). This study aims to investigate how gut microbiota, inflammatory responses and metabolism in individuals with IR are affected by the supplementation of conjugated linoleic acid (CLA) and how this subsequently affects the pathophysiology of IR by using a high-fat diet-induced IR mouse model. Serum biochemical indices showed that 400 mg/kg body weight of CLA effectively attenuated hyperglycemia, hyperlipidemia, glucose intolerance and IR, while also promoting antioxidant capacities. Histomorphology, gene and protein expression analysis revealed that CLA reduced fat deposition and inflammation, and enhanced fatty acid oxidation, insulin signaling and glucose transport in adipose tissue or liver. Hepatic transcriptome analysis confirmed that CLA inhibited inflammatory signaling pathways and promoted insulin, PI3K-Akt and AMPK signaling pathways, as well as linoleic acid, arachidonic acid, arginine and proline metabolism. Gut microbiome analysis further revealed that these effects were highly associated with the enriched bacteria that showed positive correlation with the production of short-chain fatty acids (SCFAs), as well as the improved SCFAs production simultaneously. This study highlights the therapeutic actions of CLA on ameliorating IR via regulating microbiota-host metabolic and immunomodulatory interactions, which have important implications for IR control.

LRP1 facilitates hepatic glycogenesis by improving the insulin signaling pathway in HFD-fed mice.

LDL receptor-related protein-1 (LRP1) is a cell-surface receptor that functions in diverse physiological pathways. We previously demonstrated that hepatocyte-specific LRP1 deficiency (hLRP1KO) promotes diet-induced insulin resistance and increases hepatic gluconeogenesis in mice. However, it remains unclear whether LRP1 regulates hepatic glycogenesis. Insulin signaling, glycogenic gene expression, and glycogen content were assessed in mice and HepG2 cells. The pcDNA 3.1 plasmid and adeno-associated virus serotype 8 vector (AAV8) were used to overexpress the truncated β-chain (β∆) of LRP1 both invitro and invivo. On a normal chow diet, hLRP1KO mice exhibited impaired insulin signaling and decreased glycogen content. Moreover, LRP1 expression in HepG2 cells was significantly repressed by palmitate in a dose- and time-dependent manner. Both LRP1 knockdown and palmitate treatment led to reduced phosphorylation of Akt and GSK3β, increased levels of phosphorylated glycogen synthase (GYS), and diminished glycogen synthesis in insulin-stimulated HepG2 cells, which was restored by exogenous expression of the β∆-chain. By contrast, AAV8-mediated hepatic β∆-chain overexpression significantly improved the insulin signaling pathway, thus activating glycogenesis and enhancing glycogen storage in the livers of high-fat diet (HFD)-fed mice. Our data revealed that LRP1, especially its β-chain, facilitates hepatic glycogenesis by improving the insulin signaling pathway, suggesting a new therapeutic strategy for hepatic insulin resistance-related diseases.

Exploring the mechanism of nonylphenol-induced ovarian developmental delay of manila clams, Ruditapes philippinarum: Applying RNAi to toxicological analysis

Nonylphenol (NP) contamination in the coastal environment of China poses ecological risks to aquatic organisms. However, the endocrine disruptive impacts of NP on bivalves, particularly on ovarian development, remain poorly understood. In this study, Manila clams Ruditapes philippinarum at the developing stage of gonad were exposed to 1.0 μg/L NP for 21 days. Utilizing RNA interference (RNAi) to suppress ER gene expression, we observed a delay in ovarian development as evidenced by histological observations under both NP and NPRi (NP with ER-RNAi) treatment, with Vtg elevation exclusive to the NP group. Comprehensive analyses encompassing transcriptomics, real-time quantitative PCR, and steroid hormone measurement revealed significant alterations in aldosterone synthesis, estrogen signaling, and thyroid hormone synthesis. These pathways showed similar perturbations in both NP and NPRi groups compared to controls. Notably, the NPRi group exhibited distinct enrichment in PPAR and insulin signaling pathways, may implicating these in ER function suppression. Steroid hormone biosynthesis was notably reduced in both treatments, pointing to a profound impact on hormone synthesis. The contrast between in vivo and in vitro findings suggests that NP's detrimental effects on ovarian development may primarily involve neuroendocrine regulation of steroidogenesis. This investigation highlights the complex dynamics of NP-induced endocrine disruption in bivalves, emphasizing the pivotal role of ER and associated pathways.

Transcriptomic changes in the microsporidia proliferation and host responses in congenitally infected embryos and larvae

Congenital infection caused by vertical transmission of microsporidia N. bombycis can result in severe economic losses in the silkworm-rearing industry. Whole-transcriptome analyses have revealed non-coding RNAs and their regulatory networks in N. bombycis infected embryos and larvae. However, transcriptomic changes in the microsporidia proliferation and host responses in congenitally infected embryos and larvae remains unclear. Here, we simultaneously compared the transcriptomes of N. bombycis and its host B. mori embryos of 5-day and larvae of 1-, 5- and 10-day during congenital infection. For the transcriptome of N. bombycis, a comparison of parasite expression patterns between congenital-infected embryos and larva showed most genes related to parasite central carbon metabolism were down-regulated in larvae during infection, whereas the majority of genes involved in parasite proliferation and growth were up-regulated. Interestingly, a large number of distinct or shared differentially expressed genes (DEGs) were revealed by the Venn diagram and heat map, many of them were connected to infection related factors such as Ricin B lectin, spore wall protein, polar tube protein, and polysaccharide deacetylase. For the transcriptome of B. mori infected with N. bombycis, beyond numerous DEGs related to DNA replication and repair, mRNA surveillance pathway, RNA transport, protein biosynthesis, and proteolysis, with the progression of infection, a large number of DEGs related to immune and infection pathways, including phagocytosis, apoptosis, TNF, Toll-like receptor, NF-kappa B, Fc epsilon RI, and some diseases, were successively identified. In contrast, most genes associated with the insulin signaling pathway, 2-oxacarboxylic acid metabolism, amino acid biosynthesis, and lipid metabolisms were up-regulated in larvae compared to those in embryos. Furthermore, dozens of distinct and three shared DEGs that were involved in the epigenetic regulations, such as polycomb, histone-lysine-specific demethylases, and histone-lysine-N-methyltransferases, were identified via the Venn diagram and heat maps. Notably, many DEGs of host and parasite associated with lipid-related metabolisms were verified by RT-qPCR. Taken together, simultaneous transcriptomic analyses of both host and parasite genes lead to a better understanding of changes in the microsporidia proliferation and host responses in embryos and larvae in N. bombycis congenital infection.

A fast and efficient method for screening and evaluation of hypoglycemic ingredients of Traditional Chinese Medicine acting on PTP1B by capillary electrophoresis

As a pivotal enzyme that regulates dephosphorylation in cell activities and participates in the insulin signaling pathway, protein tyrosine phosphatase 1B (PTP1B) is considered to be an important target for the therapy of diabetes. In this work, a rapid and efficient inhibitor screening method of PTP1B was established based on capillary electrophoresis (CE), and used for screening and evaluating the inhibition effect of Traditional Chinese Medicine on PTP1B. Response Surface Methodology was used for optimizing the conditions of analysis. After method validation, the enzyme kinetic study and inhibition test were performed. As a result, the IC50 of PTP1B inhibitors Ⅳ and ⅩⅧ were consistent with reported values measured by a conventional method. It was found that the extracts of Astragalus membranaceus (Fisch) Bunge and Morus alba L. showed prominent inhibition on the activity of PTP1B, which were stronger than the positive controls. Meanwhile, on top of the excellent advantages of CE, the whole analysis time is less than 2 min. Thus, the results demonstrated that a fast and efficient screening method was successfully developed. This method could be a powerful tool for screening inhibitors from complex systems. It can also provide an effective basis for lead compound development in drug discovery.

Network Pharmacology and Molecular Docking Technology-based Strategy to Explore the Potential Mechanism of Diabecon Formulation Botanicals

This study presents network pharmacology and a molecular docking-centered approach to elucidate the possible mechanism of action underlying the therapeutic effects of diabecon, a formulation containing Gymnema sylvestre, Pterocarpus marsupium, and Asphaltum punjabinum botanicals. Through comprehensive bioinformatics analysis, a collection of bioactive compounds present in these botanicals was identified, and their potential targets were forecasted using Swiss Target Prediction and STITCH. Disease-related genes were retrieved from Genecards and OMIM, and common genes between potential targets and disease-related genes were determined. Pathway analysis using the DAVID database revealed significant enrichment in pathways related to metabolic processes, xenobiotic metabolism, and signaling pathways, such as the insulin signaling pathway and pathways in cancer. Network construction using cytoscape highlighted interactions among identified genes, providing insights into the molecular pathways modulated by diabecon. Molecular docking analysis further elucidated the possible connections amongst biologically active compounds and target proteins, with (2S)-7-hydroxyflavanone exhibiting strong binding affinity with DPP-IV enzyme. Overall, this integrated approach offers valuable insights into the potential mechanisms of action of diabecon, contributing to our understanding of its therapeutic effects in the management of diabetes mellitus

Melatonin increases AKT and SOD gene and protein expressions in diabetic rats

Diabetes mellitus (DM) is a chronic metabolic disease marked by hyperglycemia due to insulin deficiency or insulin resistance leading to many chronic complications. It is thus important to manage diabetes effectively in order to prevent and or delay these complications. Melatonin is produced by the pineal gland and regulates the wake-sleep circadian rhythm. Existing evidence suggests that melatonin may be effective in the management of DM. However, the evidence on the mechanism of the beneficial effect melatonin as a treatment for DM is limited. In this study, we investigated the effect of melatonin treatment on blood glucose, insulin (INS), AKT and superoxide dismutase (SOD) gene levels in diabetic rats. Non-diabetic and diabetic rats were treated orally for 4 weeks with either 25 mg or 50 mg/kg body weight of melatonin. At the end of the study, pancreatic and liver tissues morphology, glucose homeostasis, serum insulin and SOD levels, hepatic gene and protein expression of SOD as protecting antioxidant enzyme and AKT as central element involved in PI3K/AKT insulin signaling pathway were estimated. Melatonin treated diabetic rats showed reduced hyperglycemia, and increased serum insulin and SOD levels. In addition, melatonin induced an increased gene and protein expression of SOD and AKT. In conclusion, melatonin may play a role in treating diabetic rats via stimulation of insulin secretion, insulin signaling and reduction in oxidative stress.

Glucose dependent resistance associated with intestinal microbiota facilitate teleost to survive bacterial infection

Host microbiota interaction affects the metabolism and immune regulation in the host. To explore the disease resistance mechanism and the host-microbiota interaction details, the intestinal transcriptome and microbiome of moribund and surviving fish infected with Aerompnas hydrophila as well as healthy controls were cross-analyzed. Survivors presented an intestinal microbiome with slight change and more intensive interspecies cooperation, while a distinct gene expression profile related to glycometabolism and immunomodulation was observed, resulting in lower-level inflammation in intestinal tissue. Genes related to FoxO, Insulin, and Glucagon signaling pathways, such as g6pc, socs2, and foxg1, correlated positively with intestinal Eubacterium_coprostanoligenes_Group, Mannheimia, Leptotrichia, and Shewanella, corresponding to a higher serum glucose level and IgM titer in surviving fish. Besides, Pseudomonas and Shewanella, with higher abundance in surviving fish, showed antagonism towards the pathogen in vitro, and a positive correlation with serum glucose level and IgM titer, respectively. Co-cultures promoted these antagonism effects and these effects connected with glucose concentration. Glucose supplementation to fish raised the survival rate significantly. In general, glycometabolism homeostasis is critical for fish to survive A. hydrophila infection. Metabolism modulation would be a potential approach to facilitate bacterial infection resistance.

Transcriptomic profile in carbendazim-induced developmental defects in zebrafish (Danio rerio) embryos/larvae

Carbendazim is a widely used fungicide to protect agricultural and horticultural crops against a wide array of fungal species. Published reports have shown that the wide usage of carbendazim resulted in reprotoxicity, carcinogenicity, immunotoxicity, and developmental toxicity in mammalian models. However, studies related to the developmental toxicity of carbendazim in aquatic organisms are not clear. To address this gap, an attempt was made by exposing zebrafish embryos to carbendazim (800 μg/L) and assessing the phenotypic and transcriptomic profile at different developmental stages [24 hour post fertilization (hpf), 48 hpf, 72 hpf and 96 hpf). At 48 hpf, phenotypic abnormalities such as delay in hatching rate, deformed spinal axial curvature, and pericardial edema were observed in zebrafish larvae over its respective controls. At 72 hpf, exposure of zebrafish embryos exposed to carbendazim resulted in scoliosis; however, unexposed larvae did not exhibit signs of scoliosis. Interestingly, the transcriptomic analysis revealed a total of 1253 DEGs were observed at selected time points, while unique genes at 24 hpf, 48 hpf, 72 hpf and 96 hpf was found to be 76.54 %, 61.14 %, 92.98 %, and 68.28 %, respectively. Functional profiling of downregulated genes revealed altered transcriptomic markers associated with phototransduction (24 hpf and 72 hpf), immune system (48 hpf), and SNARE interactions in the vesicular pathway (96 hpf). Whereas functional profiling of upregulated genes revealed altered transcriptomic markers associated with riboflavin metabolism (24 hpf), basal transcription factors (48 hpf), insulin signaling pathway (72 hpf), and primary bile acid biosynthesis (96 hpf). Taken together, carbendazim-induced developmental toxicity could be ascribed to pleiotropic responses at the molecular level, which in turn might reflect phenotypic abnormalities.