Maternal hyperhomocysteinemia compromises female offspring fertility through overactivation of primordial follicles.

miR-302 protects the liver from glucolipotoxicity-induced lipid accumulation through activating AMPK and suppressing Elovl6 in HepG2 cells and also in mice.

Insulin resistance is a hallmark of type 2 diabetes (T2DM) and can increase the risk of cognitive impairment, including Alzheimer's disease. Nuciferine, an alkaloid derived from lotus leaves, shows neuroprotective effects. This study investigated nuciferine's protective role in T2DM-induced cognitive impairment (T2DM-CI) and its mechanisms. Mouse models were created using high-fat diets and streptozotocin, along with high glucose-induced HT-22 cells. Nuciferine reduced blood glucose, improved cognitive function, and mitigated glial cell activation, neuron and synapse loss in T2DM mice. It enhanced insulin signaling by increasing protein levels of IR, IRS1, and IGF-1R, reversing PI3K and AKT phosphorylation, inhibiting GSK3β activity, and reducing hyperphosphorylated Tau in HT-22 cells and T2DM mice. mRNA levels of these molecules matched their protein levels. Further studies revealed that nuciferine directly interacts with IR, knocking out IR abolished its effects on the PI3K/AKT pathway. Thus, nuciferine activates the PI3K/AKT pathway via IR, improving insulin resistance and slowing T2DM-CI progression.

Ethyl caffeate reprograms macrophage immunometabolism via the SIRT3-FOXO3A-AKT axis to enhance host defense against Candida auris.

Zerumbone from Zingiber zerumbet (L.) Roscoe ex Sm. ameliorates atopic dermatitis by regulating the MAP kinase/NF-κB, Akt, and STAT pathways.

Novel methoxyquinazoline sulfonamide derivatives as angiogenesis inhibitors and radiosensitizers.

MIP-8, a Morchella importuna-derived peptide, protects against 6-OHDA-induced neurotoxicity via AKT signaling modulation.

Arecoline, the primary alkaloid in areca nut, is a major risk factor for metastasis-associated progression in esophageal squamous cell carcinoma (ESCC). Epigallocatechin gallate (EGCG), a major polyphenol in green tea, has exhibited anti-cancer and anti-metastatic activity in multiple tumor models. However, the effects of EGCG on arecoline-induced metastatic behavior in ESCC have not been directly examined. In this study, we examined the effects of EGCG on arecoline-induced migration and invasion in human ESCC cells. Parental CE81T/VGH cells and a highly invasive subline, CE81T-M4, were treated with arecoline, EGCG, or their combination. Cell migration and invasion were assessed using the wound-healing and transwell assays, while changes in EGFR-related signaling and epithelial-mesenchymal transition (EMT)-associated markers were analyzed by western blotting and immunofluorescence. Arecoline increased ESCC cell motility and invasion and activated EGFR-dependent signaling, including AKT and P38 phosphorylation, accompanied by increased expression of EMT-associated markers. EGCG suppressed these effects in both parental and invasive ESCC cells. Genetic knockdown of AKT reduced P38 activation and VIMENTIN expression, supporting a role for AKT upstream of P38 in regulating EMT-related responses. The attenuation of arecoline-driven metastatic behavior in ESCC cells by EGCG is associated with alterations in EGFR-AKT-P38 signaling, supporting its potential role as a dietary or adjunctive agent in areca-associated esophageal cancer.

Branched-chain amino acids alleviate Parkinson's neurodegeneration via microbial propionate-dependent restoration of the PI3K/Akt/mTORC1 axis.

Lycorine protects against inflammatory hemorrhagic skin injury via suppression of neutrophil-driven NADPH oxidase activation.

Knockdown of FGL2 ameliorates retinal microvascular endothelial cell injury and oxidative stress in diabetic retinopathy.

Lycorine suppresses cell growth and attenuates stemness through PI3K/AKT pathway in ovarian cancer.

Loureirin A, a bioactive monomer derived from Sanguis Draconis flavones, is a traditional Chinese medicine extract recognized for its potent antioxidant properties. Although pharmacological therapies for colorectal cancer (CRC) continue to advance, the overall prognosis of CRC patients remains dismal. Therefore, alternative treatment strategies, such as complementary and alternative medicine, should be considered to aid in the management of this malignancy. In this study, we aimed to investigate the anti-cancer effects and mechanisms of Loureirin A treatment in CRC. We performed various in vitro experiments, including cell proliferation, colony formation, and apoptosis assays, following treatment of two CRC cell lines (HCT116 and HT29) with increasing concentrations of Loureirin A. Loureirin A exerts anti-cancer effects in CRC by significantly inhibiting cell proliferation, reducing colony formation, and enhancing apoptotic activity compared with the control group. These effects occurred in a dose-dependent manner. Moreover, Loureirin A treatment could significantly reduce the levels of phosphorylated protein kinase B (AKT) in both CRC cell lines by western blot analysis. Loureirin A exhibits anti-cancer effects in CRC cells and may serve as a potential adjunctive treatment option for this disease.

Esculetin inhibits PRV replication by suppressing activation of the PI3K-AKT/NF-κB pathway.

SIK1 drives lipid-induced insulin resistance in skeletal muscle by linking TGFβ1-Smad2/3 activation to PDE4-cAMP dysregulation.

BEZ235 inhibits Cryptosporidium parvum infection in mice by targeting the PI3K-NF-κB-c-MYB/BCL2A1 axis to restore host cell apoptosis.

Invariant natural killer T (iNKT) cells serve as a crucial bridge between innate and adaptive immunity, yet the molecular mechanisms that sustain their subset homeostasis remain incompletely defined. Here, we identify CD23 (FcεRII) as a previously unrecognized intrinsic regulator of NKT17 cell homeostasis. CD23 deficiency selectively diminished NKT17 frequency and IL-17 production in the thymus and spleen, while leaving NKT1 and NKT2 subsets largely unaffected. Loss of CD23 led to decreased IL-7Rα expression and impaired mTORC2-dependent phosphorylation of AKT (Ser473), accompanied by reduced Bcl-2 expression and increased apoptosis of NKT17 cells. Administration of exogenous IL-7 restored NKT17 abundance and IL-17 secretion in CD23-deficient mice without normalizing PLZF or RORγt expression, indicating that CD23 primarily supports metabolic and survival signaling rather than transcriptional programming. Collectively, these findings define CD23 as an upstream checkpoint of the IL-7Rα-mTORC2 axis that preserves NKT17 viability. By delineating a previously unrecognized link between cytokine and metabolic pathways, this study expands the molecular framework governing iNKT cell development and subset maintenance.

Spinal Cord Injury (SCI) is a severe central nervous system disorder with limited effective treatments. Mesenchymal stem cell (MSC)-derived exosomes have emerged as important mediators of intercellular communication and carry microRNAs with potential neuroprotective properties. This study aimed to explore the role and underlying mechanism of human umbilical cord MSC (hUMSC)-derived exosomal miR-486-5p in experimental SCI. Exosomes were isolated from hUMSCs and characterized by transmission electron microscopy, nanoparticle tracking analysis, and exosomal marker expression. A rat SCI model and an LPS-induced PC12 cell inflammatory injury model were established. Histological injury and apoptosis were assessed by HE staining and TUNEL assay. Inflammatory cytokine levels were measured by ELISA. Cell viability, apoptosis, and gene and protein expression were evaluated using CCK-8 assay, flow cytometry, qPCR, and western blotting. A dual-luciferase reporter assay was performed to validate the interaction between miR-486-5p and PTEN. hUMSC-derived exosomes attenuated spinal cord tissue damage, reduced neuronal apoptosis, and suppressed inflammatory cytokine production in vivo and in vitro. Inhibition of exosomal miR-486-5p partially reversed these protective effects. Mechanistically, miR-486-5p directly targeted the 3'-UTR of PTEN, leading to reduced PTEN expression and enhanced phosphorylation of AKT and mTOR. These findings indicate that exosomal miR-486-5p contributes to the regulation of apoptosis- and inflammation-associated molecular events following SCI, primarily through modulation of the PTEN/AKT/mTOR signaling pathway. Given the experimental design, these results should be interpreted as mechanistic insights rather than evidence of functional recovery. hUMSC-derived exosomal miR-486-5p alleviates apoptosis and inflammation following SCI by targeting PTEN and activating the AKT/mTOR pathway. These findings provide mechanistic support for the potential application of exosome-based miRNA therapy in SCI.

Many bacterial immunotherapies, because of their intracellular lifestyle, have the potential to overcome the limitations that reduce the efficacy of immune checkpoint inhibitors. One reason this approach is not completely curative is the innate immune suppression of the bacteria. After cell invasion, Salmonella injects effector proteins that inhibit host cell signaling and suppress subsequent immune responses. To increase the efficacy of bacterial therapies we designed a CRISPRi (clustered regularly interspaced short palindromic repeats─interference) system to repress the expression of two Salmonella effectors, SopB and SteE. We hypothesized that repressing SopB decreases AKT phosphorylation and repressing SteE decreases STAT3 phosphorylation. For each effector, we optimized the response by creating multiple guide RNAs and evaluating their ability to repress expression of fluorescent fusion proteins. To characterize their biological effects, we administered these engineered bacteria to cancer cells and macrophages. In cancer cells, CRISPRi repression of SopB reduced activation of AKT and increased cellular apoptosis. In both cancer cells and macrophages, repression of SteE reduced activation of STAT3, reduced the secretion of immunosuppressive IL-10 and increased the secretion of pro-inflammatory TNF-α. Promotion of apoptosis and secretion of IL-10 are biological functions downstream of AKT and STAT3, respectively. The increased production of TNF-α was most likely mediated by the reduced levels of IL-10. These experiments show, for the first time, that CRISPRi modulation of effector expression in therapeutic Salmonella can control the physiology of mammalian cells and shift their phenotype to one that is less immunosuppressive and more favorable for cancer therapy.

Obesity that develops at different life stages may have distinct metabolic consequences, and the mechanisms distinguishing juvenile from adult-onset obesity remain incompletely defined. Thus, we examined how the timing of exposure to a high-fat diet (HFD) affects expansion, lipid metabolism, and insulin signaling in epididymal visceral adipose tissue (eVAT). Male C57BL/6J mice were fed either a control diet or a 60% HFD, initiated immediately after weaning during the juvenile period (3 weeks of age) or at young adulthood (9 weeks of age), and continued until 17 weeks of age. HFD increased both total VAT and subcutaneous adipose tissue (SAT) mass regardless of exposure timing. However, when introduced during adulthood, it led to a higher total VAT to SAT ratio, greater total VAT mass, more severe hyperglycemia, and more pronounced eVAT adipocyte hypertrophy and reduction in PPARγ protein levels. Only adult mice exposed to HFD exhibited impaired eVAT insulin signaling, characterized by increased inhibitory IRS1 phosphorylation, reduced Akt phosphorylation, and lower GLUT4 protein levels. This was associated with increased fatty acid influx, indicated by higher lipoprotein lipase and Cd36 expression, reduced SREBP-1c protein levels, and a shift toward a pro-lipolytic profile with increased Hsl expression. These findings indicate that adult exposure to HFD leads to more adverse effects on eVAT expansion, lipid metabolism, and insulin signaling than juvenile exposure, further supporting the concept that the developmental stage at which caloric overload is initiated shapes adipose tissue plasticity and influences the severity of obesity-related metabolic disturbances.