PIK3CA is a frequently mutated gene in cancer, including about ~15 to 20% of colorectal cancers (CRC). PIK3CA mutations lead to activation of the PI3K/AKT/mTOR signaling pathway, which plays pivotal ...roles in tumorigenesis. Here, we investigated the mechanism of resistance of PIK3CA‐mutant CRC cell lines to gedatolisib, a dual PI3K/mTOR inhibitor. Out of a panel of 29 CRC cell lines, we identified 7 harboring one or more PIK3CA mutations; of these, 5 and 2 were found to be sensitive and resistant to gedatolisib, respectively. Both of the gedatolisib‐resistant cell lines expressed high levels of active glycogen synthase kinase 3‐beta (GSK3β) and harbored the same frameshift mutation (c.465_466insC; H155fs*) in TCF7, which encodes a positive transcriptional regulator of the WNT/β‐catenin signaling pathway. Inhibition of GSK3β activity in gedatolisib‐resistant cells by siRNA‐mediated knockdown or treatment with a GSK3β‐specific inhibitor effectively reduced the activity of molecules downstream of mTOR and also decreased signaling through the WNT/β‐catenin pathway. Notably, GSK3β inhibition rendered the resistant cell lines sensitive to gedatolisib cytotoxicity, both in vitro and in a mouse xenograft model. Taken together, these data demonstrate that aberrant regulation of WNT/β‐catenin signaling and active GSK3β induced by the TCF7 frameshift mutation cause resistance to the dual PI3K/mTOR inhibitor gedatolisib. Cotreatment with GSK3β inhibitors may be a strategy to overcome the resistance of PIK3CA‐ and TCF7‐mutant CRC to PI3K/mTOR‐targeted therapies.
What's new?
Mutations in the PI3K/mTOR and WNT/β‐catenin pathways are common in colorectal cancer. Here, in colorectal cancer cells, the authors show that the frameshift mutation H155fs* in transcription factor TCF7 serves a critical role in mediating resistance to the PI3K/mTOR dual inhibitor gedatolisib. TCF7 H155fs* maintained mTOR signaling by inducing the active form of glycogen synthase kinase 3‐beta (GSK3β) and aberrant WNT/β‐catenin signaling. The latter conferred resistance to gedatolisib. Co‐treatment with a GSK3β inhibitor increased sensitivity to gedatolisib, a combination that synergistically inhibited colorectal tumor growth in mice. The findings shed light on gedatolisib resistance mechanisms and potential resistance biomarkers.
Spinal cord injury (SCI) is a life-threatening condition that leads to permanent disability with partial or complete loss of motor, sensory, and autonomic functions. SCI is usually caused by initial ...mechanical insult, followed by a cascade of several neuroinflammation and structural changes. For ameliorating the neuroinflammatory cascades, MSC has been regarded as a therapeutic agent. The animal SCI research has demonstrated that MSC can be a valuable therapeutic agent with several growth factors and cytokines that may induce anti-inflammatory and regenerative effects. However, the therapeutic efficacy of MSCs in animal SCI models is inconsistent, and the optimal method of MSCs remains debatable. Moreover, there are several limitations to developing these therapeutic agents for humans. Therefore, identifying novel agents for regenerative medicine is necessary. Extracellular vesicles are a novel source for regenerative medicine; they possess nucleic acids, functional proteins, and bioactive lipids and perform various functions, including damaged tissue repair, immune response regulation, and reduction of inflammation. MSC-derived exosomes have advantages over MSCs, including small dimensions, low immunogenicity, and no need for additional procedures for culture expansion or delivery. Certain studies have demonstrated that MSC-derived extracellular vesicles (EVs), including exosomes, exhibit outstanding chondroprotective and anti-inflammatory effects. Therefore, we reviewed the principles and patho-mechanisms and summarized the research outcomes of MSCs and MSC-derived EVs for SCI, reported to date.
The aim of this study was to investigate the effect of a senior-friendly diet based on the dietary inflammatory index (DII) on the nutritional status and health indicators of older people. A total of ...256 participants were classified into tertiles based on their DII values and split into intervention
= 201) and control (
= 55) groups. The intervention group was provided with a senior-friendly diet, and the control group was allowed to eat their usual diet. Before and after the trial, anthropometric measurements, blood analyses, and questionnaires were completed for both groups. The mean age of the participants was 82.49 years, and 66.4% were female. On average, participants had 2.5 medical conditions, with a notable prevalence of cardiovascular disease. Following the intervention, the energy, carbohydrate, protein, and fat intakes significantly increased in the intervention group compared to pre-intervention levels. Tertile 3 exhibited substantial improvements in total nutrition score, NQ-E balance, and DII total score, as well as in triglycerides and blood glucose, attributed to this dietary intervention compared to other groups. In comparison with Tertile 1, nutrient intake and nutritional status in Tertile 3 were closely associated with significant influencing factors of the dietary intervention. For the group with the worst DII (Tertile 3), this dietary intervention greatly improved nutritional status, nutrient intake, and clinical indicators; thus, this senior-friendly diet appears to be beneficial for elderly people with nutritional vulnerabilities.
Vitamin D plays an important role in the immune system, and its deficiency has been implicated in various skin diseases, including atopic dermatitis and psoriasis. Acne is a common inflammatory skin ...disease; however, the association with vitamin D remains unclear.
We evaluated vitamin D levels in patients with acne to determine the effect of vitamin D supplementation.
This study included 80 patients with acne and 80 healthy controls. Serum 25-hydroxyvitamin D (25(OH)D) levels were measured, and demographic data were collected. Vitamin D-deficient patients were treated with oral cholecalciferol at 1000 IU/day for 2 months.
Deficiency in 25(OH)D was detected in 48.8% of patients with acne, but in only 22.5% of the healthy controls. The level of 25(OH)D was inversely associated with the severity of acne, and there was a significant negative correlation with inflammatory lesions. In a subsequent trial, improvement in inflammatory lesions was noted after supplementation with vitamin D in 39 acne patients with 25(OH)D deficiency.
Limitations of the study include the small number of patients in the supplementation study and the natural fluctuation of acne.
Vitamin D deficiency was more frequent in patients with acne, and serum 25(OH)D levels were inversely correlated with acne severity, especially in patients with inflammatory lesions.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Lichens are a life form in which algae and fungi have a symbiotic relationship and have various biological activities, including anti-inflammatory and antiproliferative activities. This is the first ...study to investigate the anti-inflammatory activity of a Phlebia sp. fungal extract (PSE) isolated from Peltigera neopolydactyla in lipopolysaccharide- (LPS-) stimulated RAW 264.7 macrophage. PSE reduced the production of the proinflammatory cytokine (tumor necrosis factor-α, interleukin-6, and interleukin-1β), chemokine (granulocyte-macrophage colony-stimulating factor), nitric oxide, and prostaglandin E2 in the LPS-stimulated RAW264.7 macrophages. Especially, PSE inhibits the phosphorylation of activator protein-1 (AP-1) signaling (c-Fos and c-Jun) and their upstream mitogen-activated protein kinase kinases/mitogen-activated protein kinases (MKK/MAPKs: MKK4, MKK7, and JNK) and finally reduced the production of the inflammatory cytokines. The inhibitory effects mainly act via suppressing JNK-mediated AP-1 rather than the NF-κB pathway. Furthermore, PSE inhibited the production of final inflammatory effector molecules involved in AP-1 signaling, including nitric oxide (NO) and prostaglandin E2 (PGE2). Here, we report that PSE has the potential to be developed as an anti-inflammatory agent.
Pancreatic cancer (PC; pancreatic ductal adenocarcinoma) is characterized by significant morbidity and mortality worldwide. Although carbohydrate antigen (CA) 19-9 has been known as a PC biomarker, ...it is not commonly used for general screening because of its low sensitivity and specificity. Therefore, there is an urgent need to develop a new biomarker for PC diagnosis in the earlier stage of cancer. To search for a novel serologic PC biomarker, we carried out an integrated proteomic analysis for a total of 185 pooled or individual plasma from healthy donors and patients with five disease groups including chronic pancreatitis (CP), PC, and other cancers (e.g., hepatocellular carcinoma, cholangiocarcinoma, and gastric cancer) and identified complement factor b (CFB) as a candidate serologic biomarker for PC diagnosis. Immunoblot analysis of CFB revealed more than two times higher expression in plasma samples from PC patients compared with plasma from individuals without PC. Immunoprecipitation coupled to mass spectrometry analysis confirmed both molecular identity and higher expression of CFB in PC samples. CFB showed distinctly higher specificity than CA 19-9 for PC against other types of digestive cancers and in discriminating PC patients from non-PC patients (p < 0.0001). In receiver operator characteristic curve analysis, CFB showed an area under curve of 0.958 (95% CI: 0.956 to 0.959) compared with 0.833 (95% CI: 0.829 to 0.837) for CA 19-9. Furthermore, the Y-index of CFB was much higher than that of CA 19-9 (71.0 vs 50.4), suggesting that CFB outperforms CA 19-9 in discriminating PC from CP and other gastrointestinal cancers. This was further supported by immunoprecipitation and qRT-PCR assays showing higher expression of CFB in PC cell lines than in normal cell lines. A combination of CFB and CA 19-9 showed markedly improved sensitivity (90.1 vs 73.1%) over that of CFB alone in the diagnosis of PC against non-PC, with similar specificity (97.2 vs 97.9%). Thus, our results identify CFB as a novel serologic PC biomarker candidate and warrant further investigation into a large-scale validation and its role in molecular mechanism of pancreatic carcinogenesis.
Small humanin-like peptide 2 (SHLP2) is a mitochondrial-derived peptide implicated in several biological processes such as aging and oxidative stress. However, its functional role in the regulation ...of energy homeostasis remains unclear, and its corresponding receptor is not identified. Hereby, we demonstrate that both systemic and intracerebroventricular (ICV) administrations of SHLP2 protected the male mice from high-fat diet (HFD)-induced obesity and improved insulin sensitivity. In addition, the activation of pro-opiomelanocortin (POMC) neurons by SHLP2 in the arcuate nucleus of the hypothalamus (ARC) is involved in the suppression of food intake and the promotion of thermogenesis. Through high-throughput structural complementation screening, we discovered that SHLP2 binds to and activates chemokine receptor 7 (CXCR7). Taken together, our study not only reveals the therapeutic potential of SHLP2 in metabolic disorders but also provides important mechanistic insights into how it exerts its effects on energy homeostasis.
Extracellular vesicles (EVs) are generated and secreted by cells into the circulatory system. Stem cell-derived EVs have a therapeutic effect similar to that of stem cells and are considered an ...alternative method for cell therapy. Accordingly, research on the characteristics of EVs is emerging. EVs were isolated from human epidural fat-derived mesenchymal stem cells (MSCs) and human fibroblast culture media by ultracentrifugation. The characterization of EVs involved the typical evaluation of cluster of differentiation (CD antigens) marker expression by fluorescence-activated cell sorting, size analysis with dynamic laser scattering, and morphology analysis with transmission electron microscopy. Lastly, the secreted levels of cytokines and chemokines in EVs were determined by a cytokine assay. The isolated EVs had a typical size of approximately 30-200 nm, and the surface proteins CD9 and CD81 were expressed on human epidural fat MSCs and human fibroblast cells. The secreted levels of cytokines and chemokines were compared between human epidural fat MSC-derived EVs and human fibroblast-derived EVs. Human epidural fat MSC-derived EVs showed anti-inflammatory effects and promoted macrophage polarization. In this study, we demonstrated for the first time that human epidural fat MSC-derived EVs exhibit inflammatory suppressive potency relative to human fibroblast-derived EVs, which may be useful for the treatment of inflammation-related diseases.
•The pathophysiological role of CARM1 in high-glucose-induced RPE cell apoptosis.•The epigenetic modification of histone 3 arginine 17 in RPE cell apoptosis.•Signaling of CARM1 and H3R17 in diabetic ...retinopathy.
Hyperglycemia-induced apoptosis of retinal pigment epithelial (RPE) cells is considered to be involved in the progression of diabetic retinopathy. Histone arginine methylation catalyzed by protein arginine methyltransferases (PRMTs) has emerged as an important histone modification involved in gene regulation. However, the role of PRMTs in diabetic retinopathy has not been elucidated. Here, we found that expression of coactivator-associated arginine methyltransferase 1 (CARM1; also known as PRMT4) was increased in the high-glucose treated human RPE cell line ARPE-19 and in the RPE layer of streptozotocin-treated rats. In addition, high-glucose induced apoptosis in ARPE-19 cells. To determine the function of CARM1 on RPE cell apoptosis, we performed gain- and loss-of-function studies. CARM1 overexpression increased apoptosis of RPE cells. In contrast, silencing of CARM1 expression by siRNA and pharmacological inhibition of CARM1 activity abolished high-glucose-induced RPE cell apoptosis. Furthermore, we found that inhibition of histone 3 arginine 17 (H3R17) asymmetric dimethylation attenuates both CARM1- and high-glucose-induced apoptosis in RPE cells. Together, these results show that high-glucose-induced CARM1 expression increases RPE cell apoptosis via H3R17 asymmetric dimethylation. Strategies to reduce CARM1 expression or enzymatic activity could be used to prevent apoptosis of RPE cells in the progression of diabetic retinopathy.
Although MEK blockade has been highlighted as a promising antitumor drug, it has poor clinical efficacy in KRAS mutant colorectal cancer (CRC). Several feedback systems have been described in which ...inhibition of one intracellular pathway leads to activation of a parallel signaling pathway, thereby decreasing the effectiveness of single‐MEK targeted therapies. Here, we investigated a bypass mechanism of resistance to MEK inhibition in KRAS CRC. We found that KRAS mutant CRC cells with refametinib, MEK inhibitor, induced MIF secretion and resulted in activation of STAT3 and MAPK. MIF knockdown by siRNA restored sensitivity to refametinib in KRAS mutant cells. In addition, combination with refametinib and 4‐IPP, a MIF inhibitor, effectively reduced the activity of STAT3 and MAPK, more than single‐agent treatment. As a result, combined therapy was found to exhibit a synergistic growth inhibitory effect against refametinib‐resistant cells by inhibition of MIF activation. These results reveal that MIF‐induced STAT3 and MAPK activation evoked an intrinsic resistance to refametinib. Our results provide the basis for a rational combination strategy against KRAS mutant colorectal cancers, predicated on the understanding of cross talk between the MEK and MIF pathways.
Although drug resistance to MEK inhibitor has been researched, the mechanism of resistance remains unclear. We found that macrophage inhibitory factor (MIF) was associated with drug resistance in KRAS mutant colorectal cancer cell lines. The results suggest suppression of MIF and MEK as a promising combination strategy against KRAS mutant colorectal cancers.
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