Search Results (68)

Colorectal cancer remains a leading malignancy. As the aberrant activation of Wnt/β-catenin signaling causes colorectal cancer, Wnt/β-catenin signaling inhibitors are potential candidates for colorectal cancer treatment. Our drug screening platform identified ursolic acid (UA), a triterpenoid with various biological activities, as a potential anticancer drug because it inhibits the T-cell factor (TCF)/β-catenin-mediated transcriptional activity. Here, we discovered that UA inhibited Wnt signaling by reducing the Wnt reporter activity and Wnt target gene expression, leading to a delay in cell cycle progression and the suppression of cell proliferation. Stepwise epistatic analyses suggested that UA functions on β-catenin protein stability in Wnt signaling. Further studies revealed that UA reduced β-catenin protein levels by Western blotting and immunofluorescent staining and induced autophagy by microtubule-associated protein 1 light chain 3 beta (LC3B) punctate staining. The cotreatment with UA and the autophagy inhibitors chloroquine and wortmannin recovered the β-catenin protein levels. Therefore, UA was confirmed to induce β-catenin degradation by the autophagy–lysosomal degradation system through inhibition in the phosphatidylinositol 3-kinase (PI3K)/Ak strain transforming (protein kinase B; AKT)/mammalian target of rapamycin (mTOR) signaling pathway. Our results not only highlight the potential of UA in Wnt-driven colorectal cancer therapy but also provide a workable Wnt signaling termination approach for the treatment of other Wnt-related diseases. Full article

Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (MTOR) pathway hyperactivation is seen in a multitude of malignancies. Due to the importance of this pathway in numerous critical cellular functions, preclinical and clinical investigations have aimed to target this pathway as an anti-cancer therapeutic strategy. This has led to the development of PI3K, AKT, and MTOR inhibitors for use in cancer patients, leading to multiple FDA approvals over the past decade. In this review, we outline therapeutic targets in PI3K/AKT/MTOR signaling in solid tumors, the current state of using inhibitors of this pathway to treat patients whose cancers possess activating mutations in PIK3CA, AKT1/2, or MTOR, and exciting new inhibitors that are entering clinical trials. Full article

OP, a systemic bone disorder marked by reduced bone mass and heightened fracture risk, poses a significant global health burden, particularly among aging populations. Current treatments, including bisphosphonates and calcium supplementation, are limited by adverse effects and incomplete efficacy. Emerging research highlights ferroptosis—an iron-dependent cell death driven by lipid peroxidation—as a critical contributor to OP pathogenesis, characterized by dysregulated iron metabolism, oxidative stress, and lipid peroxide accumulation, which disrupt bone remodeling by impairing osteoblast function and enhancing osteoclast activity. This review elucidates the mechanistic interplay between ferroptosis and OP subtypes (diabetic osteoporosis (DOP), glucocorticoid-induced (GIOP), and postmenopausal osteoporosis (PMOP)) and evaluates the efficacy of Chinese herbal interventions in mitigating ferroptosis-driven bone loss. Key findings reveal that excess iron exacerbates lipid peroxidation via the Fenton reaction, while glutathione peroxidase 4 (GPX4) inactivation and system Xc- inhibition amplify oxidative damage. In DIOP, hyperglycemia-induced ROS and advanced glycation end products suppress osteogenesis, countered by melatonin and naringenin via nuclear factor -related factor 2 (Nrf2)/GPX4 activation. GIOP involves dexamethasone-mediated GPX4 downregulation, mitigated by exosomes and melatonin through phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling. PMOP driven by estrogen deficiency-induced iron overload is alleviated by aconitine and icariin (ICA) via nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and signal transducer and activator of transcription 3 (STAT3) pathways. Chinese herbs, including active compounds (quercetin, gastrodin, ICA, etc.) and formulations (Bugu Shengsui Capsule, Erxian Decoction (EXD), etc.), regulate iron metabolism, enhance antioxidant defenses (Nrf2/heme oxygenase 1(HO-1)), and inhibit lipid peroxidation, effectively restoring bone homeostasis. These findings underscore ferroptosis as a pivotal mechanism in OP progression and highlight the therapeutic promise of Chinese herbs in bridging traditional medicine with modern mechanistic insights. Future research should prioritize elucidating precise molecular targets, optimizing formulations, and validating clinical efficacy to address current therapeutic gaps. Full article

The objective of this study was to examine whether fucosterol, a phytosterol of marine algae, could ameliorate skeletal muscle atrophy in tumor necrosis factor-alpha (TNF-α)-treated C2C12 myotubes and in immobilization-induced C57BL/6J mice. Male C57BL6J mice were immobilized for 1 week to induce skeletal muscle atrophy. Following immobilization, the mice were administrated orally with saline or fucosterol (10 or 30 mg/kg/day) for 1 week. Fucosterol significantly attenuated immobilization-induced muscle atrophy by enhancing muscle strength, with a concomitant increase in muscle volume, mass, and myofiber cross-sectional area in the tibialis anterior (TA) muscle in mice. In both the TNF-α-treated C2C12 myotubes and the TA muscle of immobilized mice, fucosterol significantly prevented muscle protein degradation, which was attributed to a reduction in atrogin-1 and muscle ring finger 1 gene expression through an increase in forkhead box O3α (FoxO3α) phosphorylation. Continuously, fucosterol stimulated muscle protein synthesis by increasing the phosphorylation of the mammalian target of the rapamycin (mTOR), 70 kDa ribosomal protein S6 kinase, and 4E binding protein 1, which was mediated through the stimulation of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Thus, fucosterol alleviated skeletal muscle atrophy in TNF-α-treated C2C12 myotubes and immobilized C57BL/6J mice through the regulation of the Akt/mTOR/FoxO3α signaling pathway. Full article

The mammalian target of rapamycin (mTOR), a serine/threonine kinase, promotes cell growth and inhibits autophagy. The following two complexes contain mTOR: mTORC1 with the regulatory associated protein of mTOR (RAPTOR) and mTORC2 with the rapamycin-insensitive companion of mTOR (RICTOR). The phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR signaling pathway is important in the intervertebral disk, which is the largest avascular, hypoxic, low-nutrient organ in the body. To examine gene-silencing therapeutic approaches targeting PI3K/Akt/mTOR signaling in degenerative disk cells, an in vitro comparative study was designed between small interfering RNA (siRNA)-mediated RNA interference (RNAi) and clustered regularly interspaced short palindromic repeat (CRISPR)–CRISPR-associated protein 9 (Cas9) gene editing. Surgically obtained human disk nucleus pulposus cells were transfected with a siRNA or CRISPR–Cas9 plasmid targeting mTOR, RAPTOR, or RICTOR. Both of the approaches specifically suppressed target protein expression; however, the 24-h transfection efficiency differed by 53.8–60.3% for RNAi and 88.1–89.3% for CRISPR–Cas9 (p < 0.0001). Targeting mTOR, RAPTOR, and RICTOR all induced autophagy and inhibited apoptosis, senescence, pyroptosis, and matrix catabolism, with the most prominent effects observed with RAPTOR CRISPR–Cas9. In the time-course analysis, the 168-h suppression ratio of RAPTOR protein expression was 83.2% by CRISPR–Cas9 but only 8.8% by RNAi. While RNAi facilitates transient gene knockdown, CRISPR–Cas9 provides extensive gene knockout. Our findings suggest that RAPTOR/mTORC1 is a potential therapeutic target for degenerative disk disease. Full article

Colorectal cancer (CRC) is the third most prevalent cancer to be diagnosed, and it has a substantial mortality rate. Despite numerous studies being conducted on CRC, it remains a significant health concern. The disease-free survival rates notably decrease as CRC progresses, emphasizing the urgency for effective diagnostic and therapeutic approaches. CRC development is caused by environmental factors, which mostly lead to the disruption of signaling pathways. Among these pathways, the Wingless/Integrated (Wnt) signaling pathway, Phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway, Mitogen-Activated Protein Kinase (MAPK) signaling pathway, Transforming Growth Factor-β (TGF-β) signaling pathway, and p53 signaling pathway are considered to be important. These signaling pathways are also regulated by non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). They have emerged as crucial regulators of gene expression in CRC by changing their expression levels. The altered expression patterns of these ncRNAs have been implicated in CRC progression and development, suggesting their potential as diagnostic and therapeutic targets. This review provides an overview of the five key signaling pathways and regulation of ncRNAs involved in CRC pathogenesis that are studied to identify promising avenues for diagnosis and treatment strategies. Full article

In the last decade, pathway-specific targeted therapy has revolutionized colorectal cancer (CRC) treatment strategies. This type of therapy targets a tumor-vulnerable spot formed primarily due to an alteration in an oncogene and/or a tumor suppressor gene. However, tumor heterogeneity in CRC frequently results in treatment resistance, underscoring the need to understand the molecular mechanisms involved in CRC for the development of novel targeted therapies. The phosphatidylinositol 3-kinase/protein kinase B/mammalian target of the rapamycin (PI3K/Akt/mTOR) signaling pathway axis is a major pathway altered in CRC. The aberrant activation of this pathway is associated with CRC initiation, progression, and metastasis and is critical for the development of drug resistance in CRC. Several drugs target PI3K/Akt/mTOR in clinical trials, alone or in combination, for the treatment of CRC. This review aims to provide an overview of the role of the PI3K/Akt/mTOR signaling pathway axis in driving CRC, existing PI3K/Akt/mTOR-targeted agents against CRC, their limitations, and future trends. Full article

Gastric cancer (GC) is the fourth leading cause of death worldwide, with more than 1 million cases diagnosed every year. Helicobacter pylori represents the main risk factor, being responsible for 78% of the cases. Increased amounts of salt, pickled food, red meat, alcohol, smoked food, and refined sugars negatively affect the stomach wall, contributing to GC development. Several gene mutations, including PIK3CA, TP53, ARID1A, CDH1, Ras, Raf, and ERBB3 are encountered in GC pathogenesis, leading to phosphatidylinositol 3-kinase (PI3K) protein kinase B (AKT)/mammalian target of rapamycin (mTOR)—PI3K/AKT/mTOR—and mitogen-activated protein kinase (MAPK) signaling pathway activation and promoting tumoral activity. Helicobacter pylori, growth factors, cytokines, hormones, and oxidative stress also activate both pathways, enhancing GC development. In clinical trials, promising results have come from monoclonal antibodies such as trastuzumab and ramucirumab. Dual inhibitors targeting the PI3K/AKT/mTOR and MAPK signaling pathways were used in vitro studies, also with promising results. The main aim of this review is to present GC incidence and risk factors and the dysregulations of the two protein kinase complexes together with their specific inhibitors. Full article

It has been confirmed that improving the energy level of the diet contributed to the greater reproductive performance and birth weight of calves in periparturient dairy cows. To investigate the effect of glucose on nutrient transport during fetal development, the bovine placental trophoblast cells (BPTCs) were cultured in media with different glucose concentrations (1, 2, 4, 8, or 16 mg/mL). Subsequently, the BPTCs were cultured in media with 1, 8 mg/mL glucose and 8 mg/mL glucose plus 100 nmol/L rapamycin (the inhibitor of mTOR pathway). Compared with the 1 mg/mL glucose, the addition of 8 mg/mL glucose stimulated cell proliferation, upregulated the mRNA abundance of the glucose transporter GLUT1 and GLUT4, and increased the activity of glucose metabolism-related enzyme glucose-6-phosphate dehydrogenease (G6PD), lactate dehydrogenase (LDHA) and phosphoglycerate kinase 1 (PGK1), as well as adenosine-triphosphate (ATP) content (p < 0.05).Furthermore, compared with the treatment of 1 mg/mL glucose, adding 8 mg/mL of glucose-upregulated gene expression in the mTOR signaling pathway, including phosphatidylinositol3-kinase (PI3K), protein kinase B (Akt), mammalian target of rapamycin (mTOR) and 70 kDa ribosomal protein S6 kinase 2 (P70S6K) (p < 0.05).The supplementation of rapamycin downregulated the gene and protein expression of the mTOR signaling pathway, including mTOR, P70S6K, EIF4E-binding protein 1 (4EBP1), hypoxia-inducible factor 1-alpha (HIF-1α) and gene expression of glucose transporter upregulated by 8 mg/mL glucose (p < 0.05). Thus, these results indicated that the addition of 8 mg/mL glucose regulated the glucose transport and metabolism in BPTCs through the mTOR signaling pathway, thereby promoting the supply of nutrients to fetus. Full article

Due to its intricate heterogeneity, high invasiveness, and poor prognosis, triple-negative breast cancer (TNBC) stands out as the most formidable subtype of breast cancer. At present, chemotherapy remains the prevailing treatment modality for TNBC, primarily due to its lack of estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth receptor 2 (HER2). However, clinical chemotherapy for TNBC is marked by its limited efficacy and a pronounced incidence of adverse effects. Consequently, there is a pressing need for novel drugs to treat TNBC. Given the rich repository of diverse natural compounds in traditional Chinese medicine, identifying potential anti-TNBC agents is a viable strategy. This study investigated lasiokaurin (LAS), a natural diterpenoid abundantly present in Isodon plants, revealing its significant anti-TNBC activity both in vitro and in vivo. Notably, LAS treatment induced cell cycle arrest, apoptosis, and DNA damage in TNBC cells, while concurrently inhibiting cell metastasis. In addition, LAS effectively inhibited the activation of the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway and signal transducer and activator of transcription 3 (STAT3), thus establishing its potential for multitarget therapy against TNBC. Furthermore, LAS demonstrated its ability to reduce tumor growth in a xenograft mouse model without exerting detrimental effects on the body weight or vital organs, confirming its safe applicability for TNBC treatment. Overall, this study shows that LAS is a potent candidate for treating TNBC. Full article

Blood malignancies remain a therapeutic challenge despite the development of numerous treatment strategies. The phosphatidylinositol-3 kinase (PI3K)/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway plays a central role in regulating many cellular functions, including cell cycle, proliferation, quiescence, and longevity. Therefore, dysregulation of this pathway is a characteristic feature of carcinogenesis. Increased activation of PI3K/Akt/mTOR signaling enhances proliferation, growth, and resistance to chemo- and immunotherapy in cancer cells. Overactivation of the pathway has been found in various types of cancer, including acute and chronic leukemia. Inhibitors of the PI3K/Akt/mTOR pathway have been used in leukemia treatment since 2014, and some of them have improved treatment outcomes in clinical trials. Recently, new inhibitors of PI3K/Akt/mTOR signaling have been developed and tested both in preclinical and clinical models. In this review, we outline the role of the PI3K/Akt/mTOR signaling pathway in blood malignancies’ cells and gather information on the inhibitors of this pathway that might provide a novel therapeutic opportunity against leukemia. Full article

The hypothalamus is an important regulator of autonomic and endocrine functions also involved in aging regulation. The aging process in the hypothalamus is accompanied by disturbed intracellular signaling including insulin/insulin-like growth factor-1 (IGF-1)/growth hormone (GH), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (AKT)/the mammalian target of rapamycin (mTOR), mitogen activated protein kinase (MAPK), janus kinase (JAK)/signal transducer and activator of transcription (STAT), AMP-activated protein kinase (AMPK), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ĸB), and nitric oxide (NO). In the current review, I have summarized the current understanding of the changes in the above-mentioned pathways in aging with a focus on hypothalamic alterations. Full article

This experiment aims to investigate the effects of partial replacement of fish meal (FM) by soybean meal (SBM) and/or fermented soybean meal (FSBM) on the growth, serum biochemistry, digestion, antioxidation, immunity, and mTOR signaling pathway of juvenile coho salmon (Oncorhynchus kisutch). Four iso-nitrogen and iso-lipid diets were designed and fed to four groups of juvenile coho salmon (152.25 ± 2.96 g) in triplicate for 10 weeks. The four diets were the G0 diet (control group, containing 28% FM protein), the G1 diet (containing 10% SBM protein and 18% FM protein), the G2 diet (containing 5% SBM protein, 5% FSBM protein, and 18% FM protein), and the G3 diet (containing 10% FSBM protein and 18% FM protein). It was found that compared with the G0 diet (control group), the activities of catalase (CAT), superoxide dismutase (SOD), pepsin, trypsin, α-amylase, and lipase, and the expression levels of mammalian target of rapamycin (mtor), protein kinase B (akt), phosphatidylinositol 3-kinase (pi3k), plant ribosome S6K protein kinase (s6ks), and lysozyme (lyz) genes, of juvenile coho salmon fed the G3 diet increased significantly (p < 0.05), and the expression levels of tumor necrosis factor (tnf-α), interleukin-1β (il-1β), and interleukin-6 (il-6) genes of juvenile coho salmon fed the G3 diet decreased significantly (p < 0.05). However, there were no significant differences in growth, muscle composition, and serum biochemistry of juvenile coho salmon fed the G3 diet compared with the G0 diet (p > 0.05). In conclusion, replacing 10% FM protein with FSBM protein could improve the digestion, antioxidation, immunity, and mTOR signaling pathway of juvenile coho salmon. Full article

Ovarian clear cell (OCCC) and endometrioid (EnOC) carcinomas are often subsumed under the umbrella term “endometriosis-associated ovarian cancer” (EAOC), since they frequently arise from ectopic endometrium settled in the ovaries. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is known to be aberrantly activated both in endometriosis and EAOC; however, its role in the progression of endometriosis to ovarian cancer remains unclear. In fact, cancer-associated alterations in the mTOR pathway may be found in normal uterine epithelium, likely acting as a first step towards ovarian cancer, through the intermediary stage of endometriosis. This review aims to summarize the current knowledge regarding mTOR signaling dysregulation in the uterine endometrium, endometriosis, and EAOC while focusing on the interconnections between the PI3K/AKT/mTOR pathway and other signaling molecules that give rise to synergistic molecular mechanisms triggering ovarian cancer development in the presence of endometriosis. Full article

The dysregulated phosphatidylinositol-3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) signaling pathway has been implicated in various immune-mediated inflammatory and hyperproliferative dermatoses such as acne, atopic dermatitis, alopecia, psoriasis, wounds, and vitiligo, and is associated with poor treatment outcomes. Improved comprehension of the consequences of the dysregulated PI3K/Akt/mTOR pathway in patients with inflammatory dermatoses has resulted in the development of novel therapeutic approaches. Nonetheless, more studies are necessary to validate the regulatory role of this pathway and to create more effective preventive and treatment methods for a wide range of inflammatory skin diseases. Several studies have revealed that certain natural products and synthetic compounds can obstruct the expression/activity of PI3K/Akt/mTOR, underscoring their potential in managing common and persistent skin inflammatory disorders. This review summarizes recent advances in understanding the role of the activated PI3K/Akt/mTOR pathway and associated components in immune-mediated inflammatory dermatoses and discusses the potential of bioactive natural products, synthetic scaffolds, and biologic agents in their prevention and treatment. However, further research is necessary to validate the regulatory role of this pathway and develop more effective therapies for inflammatory skin disorders. Full article