A modified system using macrophage-conditioned medium revealed that the indirect effects of anti-inflammatory food-derived compounds improve inflammation-induced suppression of UCP-1 mRNA expression in 10T1/2 adipocytes.

Recently, it has been suggested that brown and beige adipocytes may ameliorate obesity because these adipocytes express uncoupling protein-1 (UCP-1), which generates heat by consuming lipid. However, obesity-induced inflammation suppresses the expression of UCP-1. To improve such conditions, food components with anti-inflammatory properties are attracting attention. In this study, we developed a modified system to evaluate only the indirect effects of anti-inflammatory food-derived compounds by optimizing the conventional experimental system using conditioned medium. We validated this new system using 6-shogaol and 6-gingerol, which have been reported to show the anti-inflammatory effects and to increase the basal expression of UCP-1 mRNA. In addition, we found that the acetone extract of Sarcodon aspratus, an edible mushroom, showed anti-inflammatory effects and rescued the inflammation-induced suppression of UCP-1 mRNA expression. These findings indicate that the system with conditioned medium is valuable for evaluation of food-derived compounds with anti-inflammatory effects on the inflammation-induced thermogenic adipocyte dysfunction.

Resveratrol Upregulates Senescence Marker Protein 30 by Activating AMPK/Sirt1-Foxo1 Signals and Attenuating H2O2-Induced Damage in FAO Rat Liver Cells.

Resveratrol (RSV) is a polyphenol with numerous biological functions, including anti-inflammatory, antioxidant, and anti-aging activities. The novel senescence marker protein-30 (SMP30) indicates aging, and it suppresses hepatic oxidative stress. However, the effects of RSV on SMP30 expression regulation remain unclear. We observed that RSV positively regulates SMP30 expression in rat hepatoma-derived FAO cells. However, this was abolished by Compound C and EX-527 that specifically inhibit AMP-activated protein kinase (AMPK) and Silent Information Regulator T1 (Sirt1), respectively. We predicted binding sites for AMPK, forkhead box protein O1 (Foxo1), and Sirt1 downstream molecules as possible SMP30 promoters using the JASPAR and UniProtKB databases. We identified a Foxo1 binding site in the promoter region of SMP30. Inhibiting Foxo1 with AS1842527 also decreased the RSV-induced upregulation of SMP30 expression. Moreover, RSV suppressed the substantial downregulation of SMP30 expression caused by oxidative stress and hydrogen peroxide (H2O2) and released accumulated lactate dehydrogenase. These results demonstrate that, as a novel food factor, RSV-induced upregulation of SMP30 by activating AMPK/Sirt1-Foxo1 signaling and may attenuates H2O2-induced oxidative damage. The findings of this study offer new perspectives of the anti-ageing properties of RSV.

Distribution and clinical impact of molecular subtypes with dark zone signature of DLBCL in a Japanese real-world study.

The distribution and clinical impact of cell-of-origin (COO) subtypes of diffuse large B-cell lymphoma (DLBCL) outside Western countries remain unknown. Recent literature also suggests that there is an additional COO subtype associated with the germinal center dark zone (DZ) that warrants wider validation to generalize clinical relevance. Here, we assembled a cohort of Japanese patients with untreated DLBCL and determined the refined COO subtypes, which include the DZ signature (DZsig), using the NanoString DLBCL90 assay. To compare the distribution and clinical characteristics of the molecular subtypes, we used a data set from the cohort of British Columbia Cancer (BCC) (n = 804). Through the 1050 patient samples on which DLBCL90 assay was successfully performed in our cohort, 35%, 45%, and 6% of patients were identified to have germinal center B-cell-like (GCB) DLBCL, activated B-cell-like (ABC) DLBCL, and DZsig-positive (DZsigpos) DLBCL, respectively, with the highest prevalence of ABC-DLBCL, differing significantly from the BCC result (P < .001). GCB-DLBCL, ABC-DLBCL, and DZsigpos-DLBCL were associated with 2-year overall survival rates of 88%, 75%, and 66%, respectively (P < .0001), with patients with DZsigpos-DLBCL having the poorest prognosis. In contrast, GCB-DLBCL without DZsig showed excellent outcomes after rituximab-containing immunochemotherapy. DZsigpos-DLBCL was associated with the significant enrichment of tumors with CD10 expression, concurrent MYC/BCL2 expression, and depletion of microenvironmental components (all, P < .05). These results provide evidence of the distinct distribution of clinically relevant molecular subtypes in Japanese DLBCL and that refined COO, as measured by the DLBCL90 assay, is a robust prognostic biomarker that is consistent across geographical areas.

Progressive arteriopathy with vasospasm in focal cerebral arteriopathy in childhood: a case report.

BACKGROUND: Focal cerebral arteriopathy (FCA) is a clinically important disease that often causes progressive arteriopathy. We report a case of FCA with progressive arteriopathy due to arterial shrinkage of the outer diameter found on T2-weighted three-dimensional sampling perfection with application optimized contrasts using different flip angle evolutions (3D-SPACE) imaging. CASE PRESENTATION: The patient was a 9-year-old girl who developed right hemiparesis. Acute infarction was detected in the basal ganglia. Vascular images revealed stenosis from the distal internal carotid artery (ICA) to the middle cerebral artery (MCA). Intravenous heparin was administered for 8 days, and the symptoms improved. However, 29 days after onset, right hemiparesis transiently developed again and magnetic resonance angiography (MRA) showed progressive stenosis from the ICA to MCA, while 3D-SPACE showed similar shrinkage of the outer diameter. Aspirin was started, and there was no subsequent recurrence. After 12 months, MRA and 3D-SPACE showed improvement of stenosis and arterial shrinkage. CONCLUSIONS: Given the time course, the change in the outer diameter was thought to be vasospasm. Thus, vasospasm may be one of the causes of progressive arteriopathy in FCA.

Organophosphate agent action at the fatty acid amide hydrolase enhancing anandamide-induced apoptosis in NG108-15 cells.

Organophosphate (OP) agents are continuously utilized in large amount throughout the globe for crop protection and public health, thereby creating a potential concern on human health. OP agent as an anticholinesterase also acts on the endocannabinoid (EC)-hydrolases, i.e., fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), to reveal unexpected adverse effects including ADHD-like behaviors in adolescent male rats. The present investigation examines a hypothesis that OP compound inhibiting the EC-hydrolase(s) dysregulates the EC-signaling system, triggering apoptosis in neuronal cells. Ethyl octylphosphonofluoridate (EOPF), as an OP probe, preferably acts on FAAH over MAGL in intact NG108-15 cells. Anandamide (AEA), an endogenous FAAH substrate, is cytotoxic in a concentration-dependent manner, although 2-arachidonoylglycerol, an endogenous MAGL substrate, gives no effect in the concentrations examined here. EOPF pretreatment markedly enhances AEA-induced cytotoxicity. Interestingly, the cannabinoid receptor blocker AM251 diminishes AEA-induced cell death, whereas AM251 does not prevent the cell death in the presence of EOPF. The consistent results are displayed in apoptosis markers evaluation (caspases and mitochondrial membrane potential). Accordingly, FAAH inhibition by EOPF suppresses AEA-metabolism, and accumulated excess AEA overstimulates both the cannabinoid receptor- and mitochondria-mediated apoptotic pathways.

AMPK negatively regulates RANKL-induced osteoclast differentiation by controlling oxidative stress.

AMP-activated protein kinase (AMPK) is a crucial energy sensor of cellular metabolism under various metabolic stresses, such as oxidative stress and inflammation. AMPK deficiency increases osteoclast numbers and reduces bone mass; however, the precise mechanisms remain unclear. This study aimed to clarify the mechanistic connection between AMPK and osteoclast differentiation, and the potential role of AMPK in the anti-resorptive effects of several phytochemicals. We found that receptor activator of nuclear factor-kappa B (NF-κB) ligand (RANKL)-induced osteoclast differentiation, osteoclastic gene expression, and activation of mitogen-activated protein kinase (MAPK) and NF-κB were promoted in cells transfected with AMPK siRNA. AMPK knockdown led to defective synthesis of heme oxygenase-1, an antioxidant enzyme, and the upstream mediator, nuclear factor erythroid-2-related factor 2. Furthermore, treatment with N-acetyl-l-cysteine, an antioxidant, abolished osteoclast differentiation and MAPK/NF-κB activation induced by AMPK knockdown. AMPK activators, hesperetin, gallic acid, resveratrol, and curcumin, suppressed osteoclast differentiation via the activation of AMPK. These results suggest that AMPK inhibits RANKL-induced osteoclast differentiation by enhancing antioxidant defense system and regulating oxidative stress. AMPK activation by dietary-derived phytochemicals may be effective for the treatment of bone diseases.

Release of SMP30 in Extracellular Vesicles under Conditions of Ascorbic Acid Deficiency Is Involved with Acute Phase Response in ODS Rat.

Senescence marker protein-30 (SMP30) is a senescence marker molecule that exhibits lactonase activity in the ascorbic acid (AsA) biosynthesis pathway, except in primate mammals, including humans. Although numerous studies have shown that hepatic AsA deficiency causes acute-phase responses, details of the relationship between SMP30 expression and acute-phase responses in AsA-deficient conditions remain to be elucidated. Here, we investigated the effects of AsA deficiency on the relationship between SMP30 and acute liver injury in osteogenic disorder Shionogi (ODS) rats, which have a hereditary defect in AsA biosynthesis. Male-ODS rats (4 wk old) were pair-fed an AsA-free diet with distilled or 0.1% AsA-dissolved water for 14 d. Under AsA-deficient conditions, hepatic SMP30 protein level was decreased and liver injury markers, the serum aspartate aminotransferase/alanine transaminase ratio and cytokine-induced neutrophil chemoattractant-1 (CINC-1) concentration, were elevated. In contrast, SMP30 protein level in extracellular vesicles (EVs) was significantly increased in addition to the positive acute proteins haptoglobin and asialoglycoprotein receptor 1 (ASGPR1), hepatic-derived specific markers expression under AsA-deficient conditions. AsA deficiency also activated signal transducer and activator of transcription 3 (STAT3) which is linked to EVs release in the liver. These results suggest that the release of SMP30 in EVs by AsA deficiency is involved with acute-phase responses.

Ca2+/Calmodulin induces translocation of membrane-associated TSC2 to the nucleus where it suppresses CYP24A1 expression.

Tuberous sclerosis complex 2 (TSC2) is a tumor-suppressor protein. A loss of TSC2 function induces hyperactivation of mechanistic target of rapamycin (mTOR). The C-terminal region of TSC2 contains a calmodulin (CaM) binding region and the CaM-TSC2 interaction contributes to proper mTOR activity. However, other downstream signaling pathways/effectors activated by the CaM-TSC2 complex have not been fully elucidated. In this study, we found that activation of Ca2+/CaM signaling resulted in the translocation of membrane-associated TSC2 to the nucleus and suppressed the transcriptional activity of the vitamin D receptor (VDR). TSC2 was released from the membrane in an activated CaM-dependent state in rat brain and HeLa cells. It subsequently formed a transcriptional complex to partially suppress the transcription of CYP24A1, a well-known VDR target gene. These data suggest, in part, that TSC2 attenuates VDR-associated transcriptional regulation via Ca2+/CaM signaling.

Clinicopathological and histological analysis of secondary malignant giant cell tumors of bone without radiotherapy.

Giant cell tumor of bone (GCTB) is an intermediate bone tumor that rarely undergoes malignant transformation. Secondary malignant GCTB (SMGCTB) is defined as a lesion in which high-grade sarcoma occurs at the site of previously treated GCTB. The present study retrospectively reviewed the medical records of patients with GCTB treated at Okayama University Hospital between April 1986 and April 2020. The clinicopathological and histological features of patients with SMGCTB without prior radiotherapy were investigated. A total of three patients (4%) with SMGCTB were detected, and the tumor sites were the distal ulna, distal femur and sacrum. Two of the patients had been treated with curettage and bone graft, and one had been treated with denosumab. In all cases, the lesions were made up of two components, the conventional GCTB component and the malignant component. The Ki67 labeling index was higher in the malignant components of SMGCTB and metastatic lesions compared with that in primary and recurrent conventional GCTB, or the conventional GCTB component of SMGCTB. Moreover, p53 expression was higher in these same components in patients who underwent curettage and bone grafting; however, there was no difference in the patient that received denosumab treatment. In this patient, clinical cancer genomic profiling revealed loss of CDKN2A, CDKN2B and MTAP expression. All three patients developed distant metastasis. The patients with SMGCTB in the ulna and femur died 13 and 54 months after detection of malignant transformation, respectively. The patient with SMGCTB in the sacrum received carbon-ion radiotherapy to the sacrum and pazopanib; the treatment was effective and the patient was alive at the last follow-up 3 years later. In conclusion, p53 may be associated with malignant transformation in GCTB. Future studies should investigate the association of between denosumab treatment and malignant transformation, as well as molecular targeted therapy to improve the clinical outcomes of SMGCTB.

(S)-Equol Is More Effective than (R)-Equol in Inhibiting Osteoclast Formation and Enhancing Osteoclast Apoptosis, and Reduces Estrogen Deficiency-Induced Bone Loss in Mice.

BACKGROUND: Equol, a metabolite of daidzein, binds to the estrogen receptor with greater affinity than daidzein and exhibits various biological properties. It exists as an enantiomer, either (S)-equol or (R)-equol. OBJECTIVES: We have previously shown that the inhibitory effect of (S)-equol on bone fragility is stronger than that of racemic equol in ovariectomized (OVX) mice; however, the effect of (R)-equol has not been elucidated. The aim of this study was to compare the activities of equol enantiomers on bone metabolism in vitro and in vivo. METHODS: Bone marrow cells (BMCs) and RAW 264.7 cells were treated with equol enantiomers. The number of osteoclasts and caspase-3/7 activity were measured. We examined the effect of equol enantiomers on osteoblast differentiation in MC3T3-E1 cells. In vivo, 8-wk-old female ddY mice were assigned to 4 groups: sham-operated (sham), OVX, OVX + 0.5 mg/d of (S)-equol (S-eq), and OVX + 0.5 mg/d of (R)-equol (R-eq). Four weeks after the intervention, femoral bone mineral density (BMD) and osteoclastic gene expression were analyzed, along with concentrations of equol enantiomers in the serum and tissues. RESULTS: (S)-equol and (R)-equol inhibited osteoclast differentiation in BMCs (97% and 60%, P < 0.05) and RAW 264.7 cells (83% and 68%, P < 0.05). (S)-equol promoted apoptosis of mature osteoclasts by inducing caspase-3/7 activity (29%, P < 0.05) and enhanced osteoblast differentiation (29%, P < 0.05). In OVX mice, BMD was ameliorated in (S)-equol-treated mice (11%, P < 0.05), but not in (R)-equol-treated mice. The concentrations of (S)-equol were greater than those of (R)-equol in the serum, tibia, liver, and kidney (by 148%, 80%, 22%, and 139%, respectively). CONCLUSIONS: These results suggest that (S)-equol is more effective than (R)-equol in inhibiting osteoclast formation and enhancing osteoclast apoptosis in vitro, supporting the beneficial effect of (S)-equol to reduce estrogen deficiency-induced bone loss in OVX mice.

Shotgun proteomic investigation of methyltransferase and methylation profiles in lipopolysaccharide stimulated RAW264.7 murine macrophages.

Arginine methylation is a common post-translational modification which functions as an epigenetic regulator of transcription and plays a key role in various cell signaling pathways. The methylation of arginine residues is catalyzed by protein arginine methyltransferase (PRMT). However, the expression pattern and underlying mechanism of PRMTs and protein methylation profile in lipopolysaccharide (LPS)-induced innate immune responses are poorly understood. Using a shotgun proteomic approach, we found that LPS stimulation increased arginine and proline metabolism and responses to inflammation and bacterial infections. In comparison, cysteine and methionine metabolism, the pentose phosphate pathway, purine metabolism, and protein methylation factors were also decreased in LPS stimulated murine macrophage cell lines. We revealed that LPS stimulation downregulated PRMT1, PRMT5, and protein arginine methylation profiles in RAW264.7 cells using western blot analysis. Additionally, this phenomenon occurred in parallel with nitric oxide accumulation in LPS-induced macrophages. Using inflammation models, we demonstrate for the first time that LPS stimulation decreases PRMTs, leading to the decreasing of arginine methylation in macrophages.

Erucin inhibits osteoclast formation via suppressing cell-cell fusion molecule DC-STAMP without influencing mineralization by osteoblasts.

OBJECTIVE: Erucin (ERN), an isothiocyanate, is derived from the vegetable arugula. Although ERN has antitumor and antioxidant activity, the effect of ERN on osteoclast and osteoblast differentiation is not well documented. In this study, we evaluated the effects of ERN on osteoclast and osteoblast differentiation in vitro. RESULTS: ERN significantly reduced the formation of 1α,25(OH)2D3-induced tartrate-resistant acid phosphatase (TRAP)-positive cells at non-cytotoxic concentrations. Furthermore, ERN downregulated the mRNA expression of osteoclast-associated genes, such as nuclear factor of activated T cells cytoplasmic-1, TRAP, and cathepsin K. In addition, ERN suppressed mRNA expression of dendritic cell specific transmembrane protein (DC-STAMP), which encodes cell-cell fusion. However, ERN did not affect mineralization by osteoblasts. Thus, our data suggest that ERN may attenuate osteoclastic bone resorption by inhibiting multinucleation of mononuclear pre-osteoclasts and by suppressing mRNA expression of DC-STAMP in bone marrow cells without influencing mineralization by osteoblasts.

In Vitro and in Silico Studies of Potential Coronavirus-Specific 3C-Like Protease Inhibitors.

We investigated similar compounds to ebselen and tideglusib, which exhibit strong activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), using Molecular ACCess System (MACCS) keys. Four candidate compounds were identified. One of them, phenyl-benzothiazol-3-one, showed coronavirus-specific 3C-like (3CL) protease inhibitory activity. The results indicated that a similarity score above 0.81 is a good indicator of activity for ebselen-and-tideglusib-like compounds. Subsequently, we simulated the ring-cleavage Michael reaction of ebselen at the Se center, which is responsible for its 3CL protease inhibitory activity, and determined the activation free energy of the reaction. The results showed that reaction simulation is a useful tool for estimating the activity of inhibitory compounds that undergo Michael addition reactions with the relevant cysteine S atom of 3CL proteases.

Randomized trial comparing the 25G and 22G Franseen needles in endoscopic ultrasound-guided tissue acquisition from solid pancreatic masses for adequate histological assessment.

BACKGROUND: The effects of the Franseen needle size in endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) of solid pancreatic masses remain unclear. This study aimed to compare 25G and 22G Franseen needles in terms of adequate tissue acquisition from solid pancreatic masses. METHODS: In this single-center, crossover, randomized noninferiority trial, eligible patients underwent EUS-FNB with both 25G and 22G Franseen needles in a randomized order between November 2018 and August 2020. Tissue specimens from each pass were separately evaluated based on the cellularity scoring system. The primary outcome was the proportion of acquired specimens allowing adequate histological assessment (cellularity score ≥3). A -15% noninferiority margin was assumed. RESULTS: Data from 88 patients were analyzed, which showed malignant and benign lesions in 84 (95.5%) and four (4.5%) patients, respectively. Of the 88 specimens, 62 (70.5%) and 69 (78.4%) acquired using 25G and 22G needles, respectively, allowed adequate histological assessment. The adjusted proportion difference was -6.6% (95% confidence interval -8.8% to -4.5%), indicating noninferiority of the 25G Franseen needle (P < 0.001). The diagnostic accuracies of the 25G and 22G needles were 86.4% and 89.8%, respectively, with no significant difference (P = 0.180). Adverse events occurred in one patient. CONCLUSIONS: The 25G Franseen needle showed a noninferior adequate tissue acquisition and similar diagnostic performance compared to that of the 22G Franseen needle. However, a 15% noninferiority margin was high for clinical use; thus, further consideration is needed (Clinical Trial Registry no. UMIN000034596).

Retroperitoneal leiomyosarcoma in a female patient with a germline splicing variant RAD51D c.904-2A > T: a case report.

BACKGROUND: RAD51D (RAD51 paralog D) is an intermediate cancer susceptibility gene for primary ovarian cancer, including fallopian tube and peritoneal carcinomas and breast cancer. Although gynecological non-epithelial tumors such as uterine sarcomas are associated with genomic instability, including BRCA impairment, there is no clear evidence of the relationship between RAD51D variants and the risk of sarcoma development. CASE PRESENTATION: A Japanese woman in her 50s underwent multiple surgical resections and several regimens of chemotherapy for tumors that originated in the retroperitoneum and recurred in the peritoneum over a clinical course of approximately 4 years. The peritoneal tumor was histologically diagnosed as a leiomyosarcoma and was genetically identified to show a splice variant of RAD51D c.904-2A > T [NM_002878] through tumor profiling performed as a part of cancer precision medicine. The confirmatory genetic test performed after genetic counseling revealed that the RAD51D splicing variant detected in her tumor was of germline origin. In silico analyses supported the possible pathogenicity of the detected splice variant of RAD51D with a predicted attenuation in mRNA transcription and truncated protein production due to frameshifting, which was attributed to a single-nucleotide alteration in the splicing acceptor site at the 3'-end of intron 9 of RAD51D. Considering her unfavorable clinical outcome, which showed a highly aggressive phenotype of leiomyosarcoma with altered RAD51D, this case provided novel evidence for the relationship of a RAD51D splicing variant with malignant tumor development or progression. We report the findings of this rare case with possible involvement of the germline variant of RAD51D c.904-2A > T as a potential predisposing factor for malignant tumors, including leiomyosarcoma. CONCLUSIONS: We present the findings of a case of leiomyosarcoma in the peritoneum of a female patient with a novel germline splicing variant of RAD51D as potential evidence for the pathogenicity of the variant and its involvement in the risk of sarcoma etiology and/or development. To the best of our knowledge, this is the first case report describing a leiomyosarcoma carrying a germline RAD51D splicing variant and elucidating its pathogenicity on the basis of computational prediction of the impairment of normal transcription and the presumed loss of functional protein production.

Detection of Lung Cancer Cells in Solutions Using a Terahertz Chemical Microscope.

Cancer genome analysis has recently attracted attention for personalized cancer treatment. In this treatment, evaluation of the ratio of cancer cells in a specimen tissue is essential for the precise analysis of the genome. Conventionally, the evaluation takes at least two days and depends on the skill of the pathologist. In our group, a terahertz chemical microscope (TCM) was developed to easily and quickly measure the number of cancer cells in a solution. In this study, an antibody was immobilized on a sensing plate using an avidin-biotin reaction to immobilize it for high density and to improve antibody alignment. In addition, as the detected terahertz signals vary depending on the sensitivity of the sensing plate, the sensitivity was evaluated using pH measurement. The result of the cancer cell detection was corrected using the result of pH measurement. These results indicate that a TCM is expected to be an excellent candidate for liquid biopsies in cancer diagnosis.

[Stability of Six Drugs in Total Parenteral Nutrition Solution].

Elneopa NF No. 1 and No. 2 infusions are total parenteral nutrition solutions packaged in four-chambered infusion bags. They have been used as home parenteral nutrition, with various drugs injected into the infusion bags, for treating patient symptoms. In this study, we investigated the stability of six drugs, including famotidine, scopolamine butylbromide, furosemide, bromhexine hydrochloride, betamethasone sodium phosphate, and metoclopramide hydrochloride in the infusion bags under dark conditions at 4℃ for 7 days. Additionally, we developed a high-performance liquid chromatography method to determine drug concentrations in the infusions. The concentrations of injected famotidine, scopolamine butylbromide, and betamethasone sodium phosphate remained unchanged when the four chambers of Elneopa NF No. 1 and No. 2 were opened and the infusions were mixed. Their respective concentrations in the upper and lower chambers also remained unchanged. The concentration of furosemide in the upper chamber of the No. 1 infusion bag decreased after 5 days, although no change was observed in the other chambers and the mixed infusions with the four chambers opened. The concentration of bromhexine hydrochloride slightly decreased in the upper chambers (approximately 3%) after the co-infusion but decreased significantly in the other chambers and the mixed infusions with the four chambers opened. The concentration of metoclopramide hydrochloride significantly decreased in the upper chambers after the co-infusion; however, no change in concentration was observed in the other chambers and the mixed infusion with the four chambers opened. The results of this study provide useful information on home-based parenteral nutrition.

Adrenergic signaling promotes the expansion of cancer stem-like cells of malignant peripheral nerve sheath tumors.

Malignant peripheral nerve sheath tumor (MPNST), a highly malignant tumor that arises in peripheral nerve tissues, is known to be highly resistant to radiation and chemotherapy. Although there are several reports on genetic mutations and epigenetic changes that define the pathogenesis of MPNST, there is insufficient information regarding the microenvironment that contributes to the malignancy of MPNST. In the present study, we demonstrate that adrenaline increases the cancer stem cell population in MPNST. This effect is mediated by adrenaline stimulation of beta-2 adrenergic receptor (ADRB2), which activates the Hippo transducer, YAP/TAZ. Inhibition and RNAi experiments revealed that inhibition of ADRB2 attenuated the adrenaline-triggered activity of YAP/TAZ and subsequently attenuated MPNST cells stemness. Furthermore, ADRB2-YAP/TAZ axis was confirmed in the MPNST patients' specimens. The prognosis of patients with high levels of ADRB2 was found to be significantly worse. These data show that adrenaline exacerbates MPNST prognosis and may aid the development of new treatment strategies for MPNST.