UNASSIGNED: Ovarian cancer is an aggressive malignancy with high mortality known for its considerable metastatic potential. This study aimed to explore the expression and functional role of Unc-51 like autophagy activating kinase 2 (ULK2) in the progression of ovarian cancer.
UNASSIGNED: ULK2 expression patterns in ovarian cancer tissues as well as benign tumor control samples obtained from our institution were evaluated using immunohistochemistry. Cell counting kit 8 and Transwell assays were applied to assess the effects of ULK2 overexpression on cell proliferation, migration and invasion, respectively. RNA sequencing was performed to explore potential mechanisms of action of ULK2 beyond its classical autophagy modulation.
UNASSIGNED: Our experiments showed significant downregulation of ULK2 in ovarian cancer tissues. Importantly, low expression of ULK2 was markedly correlated with decreased overall survival. In vitro functional studies further demonstrated that overexpression of ULK2 significantly suppressed tumor cell proliferation, migration, and invasion. RNA sequencing analysis revealed a potential regulatory role of ULK2 in the insulin signaling pathway through upregulation of insulin-like growth factor binding protein-3 (IGFBP3) in ovarian cancer cells.
UNASSIGNED: In summary, the collective data indicated that ULK2 acted as a tumor suppressor in ovarian cancer by upregulating the expression of IGFBP3. Our study underscores the potential utility of ULK2 as a valuable prognostic marker for ovarian cancer.

The therapeutic potential of targeting the β-catenin/CBP interaction has been demonstrated in a variety of preclinical tumor models with a small molecule inhibitor, ICG-001, characterized as a β-catenin/CBP antagonist. Despite the high binding specificity of ICG-001 for the N-terminus of CBP, this β-catenin/CBP antagonist exhibits pleiotropic effects. Our recent studies found global changes in three-dimensional (3D) chromatin architecture in response to disruption of the β-catenin/CBP interaction in pancreatic cancer cells. However, an understanding of how the functional crosstalk between the antagonist and the β-catenin/CBP interaction affects changes in 3D chromatin architecture and, thereby, gene expression and downstream effects remains to be elucidated. Here, we perform Hi-C analyses on canonical and patient-derived pancreatic cancer cells before and after treatment with ICG-001. In addition to global alteration of 3D chromatin domains, we unexpectedly identify insulin signaling genes enriched in the altered chromatin domains. We further demonstrate that the chromatin loops associated with insulin signaling genes are significantly weakened after ICG-001 treatment. We finally elicit the deletion of a looping of IRS1-a key insulin signaling gene-significantly impeding pancreatic cancer cell growth, indicating that looping-mediated insulin signaling might act as an oncogenic pathway to promote pancreatic cancer progression. Our work shows that targeting aberrant insulin chromatin looping in pancreatic cancer might provide a therapeutic benefit.

The insulin signaling (IIS) pathway plays a key role in the regulation of various physiological functions in animals. However, the involvement of IIS pathway in the reproduction of natural enemy insects remains enigmatic. Here, 3 key genes (named ClInR, ClPI3K, and ClAKT) related to IIS pathway were cloned from Cyrtorhinus lividipennis (Reuter) (Hemiptera: Miridae), an important natural enemy in the rice ecosystem. These 3 proteins had the typical features of corresponding protein families and shared high similarity with their respective homologs from the Hemipteran species. The ClInR, ClPI3K, and ClAKT were highly expressed in the adult stage. Tissue distribution analysis revealed that ClInR, ClPI3K, and ClAKT were highly expressed in the midgut and ovary of adults. Silencing of ClInR, ClPI3K, and ClAKT caused 92.1%, 72.1%, and 57.8% reduction in the expression of ClVg, respectively. Depletion of these 3 genes impaired vitellogenin synthesis and ovary development. Moreover, the fecundity in the dsInR, dsPI3K, and dsAKT injected females were 53.9%, 50.8%, and 48.5% lower than the control treatment, respectively. These results indicated that ClInR, ClPI3K, and ClAKT are of great importance for the reproduction of C. lividipennis. Our results advance the knowledge about the molecular mechanism of reproduction regulation in natural enemy insects.

Polycystic ovary syndrome (PCOS) is a prevalent endocrinologic and gynecologic disorder that affects women of reproductive age; besides, insulin resistance (IR) occurs in 50-70 % of PCOS cases. Metformin (Met) is commonly prescribed for IR management; however, it does not affect IR with some gastrointestinal symptoms. Spirulina platensis (SP) is a blue-green alga that may increase insulin sensitivity. Therefore, our study aims to evaluate SP as an alternative treatment to Met for improving glucose homeostasis by assessing the expression of 11 crucial genes involved in the insulin signaling pathway. After induction of the PCOS model using dehydroepiandrosterone (DHEA) (60 mg/kg bwt) for 30 consecutive days, rats were allocated into six groups. Relative liver weight, glutamic pyruvic transaminase (GPT) serum levels, glutamic-oxaloacetic transaminase (GOT), and insulin were determined. Furthermore, the gene expression of Ins1, Irs1, Pik3ca, Prkcz, Foxo1, Srebf1, Ppargc1a, Pklr, Gk, G6pc, and Pepck in the rat\'s liver tissue was determined using qRT-PCR. Treatment of the PCOS control group with Met or SP revealed a decrease in all these parameters compared with the PCOS model. Additionally, we found a statistically significant difference in the expression of both the Gk and Prkcz genes. To summarize our study results, SP or Met supplementation to PCOS rats had almost the same effect on assessed relative liver weight, GOT, GPT, and insulin levels compared with PCOS control rats. If further studies confirm and detect more impact of SP on IR in PCOS, SP could be used instead of Met since the latter causes many side effects.

Impairment of the insulin signaling pathway is a key contributor to insulin resistance under arsenic exposure. Specifically, O-GlcNAcylation, an important post-translational modification, plays a crucial role in insulin resistance. Nevertheless, the concrete effect and mechanism of O-GlcNAcylation in arsenic-induced impairment of the insulin signaling pathway remain elusive. Herein, C57BL/6 mice were continuously fed arsenic-containing food, with a total arsenic concentration of 30 mg/kg. We observed that the IRS/Akt/GSK-3β insulin signaling pathway was impaired, and autophagy was activated in mouse livers and HepG2 cells exposed to arsenic. Additionally, O-GlcNAcylation expression in mouse livers and HepG2 cells was elevated, and the key O-GlcNAcylation homeostasis enzyme, O-GlcNAc transferase (OGT), was upregulated. In vitro, non-targeted metabolomic analysis showed that metabolic disorder was induced, and inhibition of O-GlcNAcylation restored the metabolic profile of HepG2 cells exposed to arsenic. In addition, we found that the compromised insulin signaling pathway was dependent on AMPK activation. Inhibition of AMPK mitigated autophagy activation and impairment of insulin signaling pathway under arsenic exposure. Furthermore, down-regulation of O-GlcNAcylation inhibited AMPK activation, thereby suppressing autophagy activation, and improving the impaired insulin signaling pathway. Collectively, our findings indicate that arsenic can impair the insulin signaling pathway by regulating O-GlcNAcylation homeostasis. Importantly, O-GlcNAcylation inhibition alleviated the impaired insulin signaling pathway by suppressing the AMPK/mTOR-autophagy pathway. This indicates that regulating O-GlcNAcylation may be a potential intervention for the impaired insulin signaling pathway induced by arsenic.

BACKGROUND: 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.
METHODS: 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 in vitro and in vivo.
RESULTS: 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.
CONCLUSIONS: 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.

As one of the most abundant plant polyphenols in the human diet, (-)-epicatechin (EC) can improve insulin sensitivity and regulate glucose homeostasis. However, the primary mechanisms involved in EC anti-T2DM benefits remain unclear. The present study explored the effects of EC on the gut microbiota and liver transcriptome in type 2 diabetes mellitus (T2DM) Goto-Kakizaki rats for the first time. The findings showed that EC protected glucose homeostasis, alleviated systemic oxidative stress, relieved liver damage, and increased serum insulin. Further investigation showed that EC reshaped gut microbiota structure, including inhibiting the proliferation of lipopolysaccharide (LPS)-producing bacteria and reducing serum LPS. In addition, transcriptome analysis revealed that the insulin signaling pathway may be the core pathway of the EC anti-T2DM effect. Therefore, EC may modulate the gut microbiota and liver insulin signaling pathways by the gut-liver axis to alleviate T2DM. As a diet supplement, EC has promising potential in T2DM prevention and treatment.

BACKGROUND: Liver fibrosis (LF) is a common reversible consequence of chronic liver damage with limited therapeutic options. Yinchen Gongying decoction (YGD) composed of two homologous plants: (Artemisia capillaris Thunb, Taraxacum monochlamydeum Hand.-Mazz.), has a traditionally application as a medicinal diet for acute icteric hepatitis. However, its impact on LF and underlying mechanisms remain unclear.
OBJECTIVE: This study aims to assess the impact of YGD on a carbon tetrachloride (CCl4) induced liver fibrosis and elucidate its possible mechanisms. The study seeks to establish an experimental foundation for YGD as a candidate drug for hepatic fibrosis.
METHODS: LC-MS/MS identified 11 blood-entry components in YGD, and network pharmacology predicted their involvement in the FoxO signaling pathway, insulin resistance, and PI3K-AKT signaling pathway. Using a CCl4-induced LF mouse model, YGD\'s protective effects were evaluated in comparison to a positive control and a normal group. The underlying mechanisms were explored through the assessments of hepatic stellate cells (HSCs) activation, fibrotic signaling, and inflammation.
RESULTS: YGD treatment significantly improved liver function, enhanced liver morphology, and reduced liver collagen deposition in CCl4-induced LF mice. Mechanistically, YGD inhibited HSC activation, elevated MMPs/TIMP1 ratios, suppressed the FoxO1/TGF-β1/Smad2/3 and YAP pathways, and exhibited anti-inflammatory and antioxidant effects. Notably, YGD improved the insulin signaling pathway.
CONCLUSIONS: YGD mitigates LF in mice by modulating fibrotic and inflammatory pathways, enhancing antioxidant responses, and specifically inhibiting FoxO1/TGF-β1/Smad2/3 and YAP signal pathways.

BACKGROUND: Psoriasis is an autoimmune disease characterized by dysfunctional T cells and dysregulated immune responses. Smilax glabra Roxb. (SGR) is a formulation used in Traditional Chinese Medicine for the treatment of inflammatory skin disorders, including psoriasis. This study explores the scientific basis for its use by examining the effects of SGR on T cell differentiation and insulin receptor signaling, relevant pathways implicated in the pathophysiology of psoriasis.
OBJECTIVE: This study investigates the therapeutic potential of SGR (a Chinese medicine) in psoriasis and its impact on T cell differentiation.
METHODS: An integrated network pharmacology and bioinformatics approach was employed to elucidate the mechanisms of SGR in regulating T cell differentiation. A psoriasis mouse model was utilized to evaluate the effects of SGR on T cell subsets. Immunohistochemistry and gene expression analyses were conducted to investigate the modulation of insulin receptor signaling pathways by SGR.
RESULTS: SGR treatment effectively reset the expression of various T cell subsets in the psoriasis mouse model, suggesting its ability to regulate T cell differentiation and immune function. Furthermore, SGR treatment inhibited insulin receptor signaling and downstream pathways, including PI3K/AKT and ERK, in psoriatic skin lesions. This indicates that SGR may exert its therapeutic effects through modulation of the insulin receptor signaling pathway.
CONCLUSIONS: This study provides novel insights into the therapeutic potential of SGR in psoriasis. By modulating T cell differentiation and targeting the insulin receptor signaling pathway, SGR holds promise as a potential treatment option for psoriasis.

BACKGROUND: While several antidepressants have been identified as potential geroprotectors, the effect and mechanism of sertraline on healthspan remain to be elucidated. Here, we explored the role of sertraline in the lifespan and healthspan of Caenorhabditis elegans.
METHODS: The optimal effect concentration of sertraline was first screened in wild-type N2 worms under heat stress conditions. Then, we examined the effects of sertraline on lifespan, reproduction, lipofuscin accumulation, mobility, and stress resistance. Finally, the expression of serotonin signaling and aging-related genes was investigated to explore the underlying mechanism, and the lifespan assays were performed in ser-7 RNAi strain, daf-2, daf-16, and aak-2 mutants.
RESULTS: Sertraline extended the lifespan in C. elegans with concomitant extension of healthspan as indicated by increasing mobility and reducing fertility and lipofuscin accumulation, as well as enhanced resistance to different abiotic stresses. Mechanistically, ser-7 orchestrated sertraline-induced longevity via the regulation of insulin and AMPK pathways, and sertraline-induced lifespan extension in nematodes was abolished in ser-7 RNAi strain, daf-2, daf-16, and aak-2 mutants.
CONCLUSIONS: Sertraline promotes health and longevity in C. elegans through ser-7-insulin/AMPK pathways.