Total flavonoids of Broussonetia papyrifera alleviate non-alcohol fatty liver disease via regulating Nrf2/AMPK/mTOR signaling pathways.

BACKGROUNDS: Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver diseases. The leaves of Broussonetia papyrifera contain a large number of flavonoids, which have a variety of biological functions. METHODS: In vitro experiments, free fatty acids were used to stimulate HepG2 cells. NAFLD model was established in vivo in mice fed with high fat diet (HFD) or intraperitoneally injected with Tyloxapol (Ty). At the same time, Total flavonoids of Broussonetia papyrifera (TFBP) was used to interfere with HepG2 cells or mice. RESULTS: The results showed that TFBP significantly decreased the lipid accumulation induced by oil acid (OA) with palmitic acid (PA) in HepG2 cells. TFBP decreased the total cholesterol (TC), the triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and increased high-density lipoprotein cholesterol (HDLC) in serum. TFBP could also effectively inhibit the generation of reactive oxygen species (ROS) and restrained the level of myeloperoxidase (MPO), and enhance the activity of superoxide dismutase (SOD) to alleviate the injury from oxidative stress in the liver. Additionally, TFBP activated nuclear factor erythroid-2-related factor 2 (Nrf2) pathway to increasing the phosphorylation of AMP-activated protein kinase (AMPK). Meanwhile, protein levels of mTORC signaling pathway were evidently restrained with the treatment of TFBP. CONCLUSION: Our experiments proved that TFBP has the therapeutic effect in NAFLD, and the activation of Nrf2 and AMPK signaling pathways should make sense.

The effect of auditor's cooperation with independent financial advisors on the reliability of performance commitment-Based on the moderating effect of managerial overconfidence.

Based on the sample of major asset restructuring transactions of Shanghai and Shenzhen A-share listed companies from 2009 to 2018, this paper uses Logit model to examine the impact of auditors ' cooperation experience with independent financial advisors on the reliability of performance commitments, and to examine the moderating effect of management overconfidence on the relationship between the two. The results show that the cooperation experience between auditors and independent financial advisors is significantly positively correlated with the reliability of performance commitment, and the closer the cooperation experience is, the easier the performance commitment will be realized, this has played a financial intermediary team effect. Further analysis shows that in the context of management overconfidence, the positive relationship between financial intermediaries ' cooperation experience and the reliability of performance commitment is stronger. The research results enrich the research on the influencing factors of M & A performance commitment and the economic consequences of financial intermediaries ' cooperation, and help the transaction subjects to rationally view performance commitment and regulators to improve policies and regulations.

Pterostilbene alleviated NAFLD via AMPK/mTOR signaling pathways and autophagy by promoting Nrf2.

BACKGROUND: NAFLD is a liver disease that is caused by liver damage or extreme lipid deposition but not alcohol. Nrf2 could mediate resistance to oxidative stress injury. Autophagy can degrade metabolic waste and accumulated toxic endogenous substances. Pterostilbene (PTE) is an active compound extracted from blueberry, and grape, that exhibits many biological effects, such as antiinflammation and antitumor. PURPOSE: This study provides a mechanism of PTE affecting on oxidative stress and autophagy in NAFLD mice. Tyloxapol, oil acid (OA) and palmitic acid (PA) were used to induce lipid accumulation in mice and HepG2 cells. METHODS: Western blotting, CRISPR/Cas 9 and other molecular biological approaches were applied to explore the mechanisms of PTE effected on NAFLD. RESULTS: PTE pretreatment effectively reduced the lipid accumulation in OA and PA induced HepG2 cells and tyloxapol induced mice, and significantly promoted the expression of nNrf2, PPAR-α and HO-1, and AMPK activity, but inhibited the expression of mTORC 1 and SREBP-1c. PTE activated phosphatidylinositide 3-kinase (PI3K) and proteins in the autophagy-related gene (ATG) family, and promoted the transformation of LC3Ⅰ to LC3Ⅱ which indicated the activation of autophagy, however, these effects were abolished after Nrf2 knockout. CONCLUSION: PTE effectively alleviated oxidative stress damage induced by excessive lipid accumulation in hepatocytes, thus promoting the metabolism and decomposition of fatty acids to improve NAFLD.

Corrigendum: Arachidonic acid in follicular fluid of PCOS induces oxidative stress in a human ovarian granulosa tumor cell line (KGN) and upregulates GDF15 expression as a response.

[This corrects the article DOI: 10.3389/fendo.2022.865748.].

Effect of Different Glucose Monitoring Methods on Bold Glucose Control: A Systematic Review and Meta-Analysis.

Objective: To evaluate the effectiveness of different glucose monitoring methods on blood glucose control and the incidence of adverse events among patients with type 1 diabetes mellitus. Methods: Using the method of literature review, the databases PubMed, Cochrane, and Embase were retrieved to obtain relevant research literature, and the selected studies were analyzed and evaluated. This study used Cochrane software RevMan5.4 to statistically analyze all the data. Results: A total of 15 studies were included in this study, including 10 randomized controlled trials and 5 crossover design trials, with a total of 2071 patients. Meta-analysis results showed that continuous blood glucose monitoring (CGM) could significantly reduce the HbA1c level of patients, weighted mean difference (WMD) = -2.69, 95% confidence interval (CI) (-4.25, -1.14), and P < 0.001 compared with self-monitoring of blood glucose (SMBG). Meanwhile, the incidence of severe hypoglycemia in the CGM group was significantly decreased, risk ratio (RR) = 0.52, 95% CI 0.35-0.77, and P = 0.001. However, there was no statistical difference in the probability of diabetic ketoacidosis between CGM and SMBG groups, RR = 1.34, 95% CI 0.57-3.15, and P = 0.5. Conclusion: Continuous blood glucose monitoring is associated with lower blood glucose levels than the traditional blood glucose self-test method.

Arachidonic Acid in Follicular Fluid of PCOS Induces Oxidative Stress in a Human Ovarian Granulosa Tumor Cell Line (KGN) and Upregulates GDF15 Expression as a Response.

Polycystic ovarian ovary syndrome (PCOS) is the main cause of ovulatory infertility and a common reproductive endocrine disease of women in reproductive age. In addition, nearly half of PCOS patients are associated with obesity, and their total free fatty acids tend to increase. Arachidonic acid (AA) is a polyunsaturated fatty acid. Oxidation products of AA reacting with various enzymes[cyclooxygenases (COX), lipoxygenases (LOX), cytochrome P450s (CYP)] can change cellular mitochondrial distribution and calcium ion concentration, and increase reactive oxygen species (ROS) production. In this study, we analyzed the follicular fluid fatty acids and found higher levels of C20:4n6 (AA) in PCOS patients than in normal control subjects. Also, to determine whether AA induces oxidative stress (OS) in the human ovarian granulosa tumor cell line (KGN) and affects its function, we treated KGN cells with or without reduced glutathione (GSH) and then stimulated them with AA. The results showed that AA significantly reduced the total antioxidant capacity (TAC) and activity of antioxidant enzymes and increased the malondialdehyde (MDA), ROS and superoxide anion(O2-)levels in KGN cells. In addition, AA was also found to impair the secretory and mitochondrial functions of KGN cells and induce their apoptosis. We further investigated the downstream genes affected by AA in KGN cells and its mechanism of action. We found that AA upregulated the expression of growth differentiation factor 15 (GDF15), which had a protective effect on inflammation and tissue damage. Therefore, we investigated whether AA-induced OS in KGN cells upregulates GDF15 expression as an OS response.Through silencing of GDF15 and supplementation with recombinant GDF15 (rGDF15), we found that GDF15, expressed as an OS response, protected KGN cells against AA-induced OS effects, such as impairment of secretory and mitochondrial functions and apoptosis. Therefore, this study suggested that AA might induce OS in KGN cells and upregulate the expression of GDF15 as a response to OS.

CARD9 Regulation and its Role in Cardiovascular Diseases.

Caspase recruitment domain-containing protein 9 (CARD9) is an adaptor protein expressed on myeloid cells and located downstream of pattern recognition receptors (PRRs), which transduces signals involved in innate immunity. CARD9 deficiency is associated with increased susceptibility to various fungal diseases. Increasing evidence shows that CARD9 mediates the activation of p38 MAPK, NF-κB, and NLRP3 inflammasome in various CVDs and then promotes the production of proinflammatory cytokines and chemokines, which contribute to cardiac remodeling and cardiac dysfunction in certain cardiovascular diseases (CVDs). Moreover, CARD9-mediated anti-apoptosis and autophagy are implicated in the progression of CVDs. Here, we summarize the structure and function of CARD9 in innate immunity and its various roles in inflammation, apoptosis, and autophagy in the pathogenesis of CVDs. Furthermore, we discuss the potential therapies targeting CARD9 to prevent CVDs and raise some issues for further exploring the role of CARD9 in CVDs.

Correlation of the controlling nutritional status score and the prognostic nutritional index with the prognosis of patients treated with radiotherapy for small-cell lung cancer.

BACKGROUND: We aimed to explore the associations between the controlling nutritional status (CONUT), the prognostic nutritional index (PNI), and prognostic outcomes in patients with small-cell lung cancer (SCLC) receiving radiotherapy. METHODS: A total of 93 SCLC patients who received radiotherapy at the hematology department in the First Affiliated Hospital of Hainan Medical University were retrospectively included in this analysis. Patient CONUT and PNI values were calculated. Receiver operating characteristic (ROC) curves were utilized to determine the optimal cut-off, the area under the curve (AUC), sensitivity, and specificity of CONUT and PNI in discriminating patient outcomes. Kaplan-Meier curve analysis was performed, and overall survival (OS) was compared for patients with CONUT >3 and ≤3, or those with PNI >47.7 and ≤47.7. Univariate and multivariate analysis using the Cox proportional hazard model was performed to identify the risk factors for patient death. RESULTS: The AUCs for CONUT and PNI were 0.95 and 0.82, respectively. The CONUT results indicated that patient OS decreased significantly from normal to mildly malnourished. Meanwhile, the OS for moderately malnourished patient decreased to severely malnourished (P for trend <0.001). Patients with CONUT >3 or PNI ≤47.7 had significantly shorter OS than those with CONUT ≤3 (median survival time 12 vs. 23 months; P<0.001) or with PNI >47.7 (median survival time 20 vs. 15 months; P=0.010). Multivariate analysis indicated that the TNM stage [hazard ratio (HR) =1.21; 95% confidence interval (CI): 1.03-1.66], CONUT score (HR =2.33; 95% CI: 1.76-3.91), and PNI ≤47.7 (HR =1.33; 95% CI: 1.09-1.99) were independent prognostic indicators for patient death. CONCLUSIONS: The CONUT and PNI were potential indicators for the outcome of patients with SCLC. CONUT >3 or PNI ≤47.7 indicated an unfavorable prognosis for SCLC patients.

The Role of Immune Cells in Recurrent Spontaneous Abortion.

Recurrent spontaneous abortion affects approximately 1-2% of women of childbearing, and describes a condition in which women suffer from three or more continuous spontaneous miscarriages. However, the origin of recurrent spontaneous abortion (RSA) remains unknown, preventing effective treatment and placing stress upon patients. It has been acknowledged that successful pregnancy necessitates balanced immune responses. Therefore, immunological aberrancy may be considered a root cause of poor pregnancy outcomes. Considerable published studies have investigated the relationship between various immune cells and RSA. Here, we review current knowledge on this area, and discuss the five main categories of immune cells involved in RSA; these include innate lymphocytes (ILC), macrophages, decidual dendritic cells (DCs), and T cells. Furthermore, we sought to summarize the impact of the multiple interactions of various immune cells on the emergence of RSA. A good understanding of pregnancy-induced immunological alterations could reveal new therapeutic strategies for favorable pregnancy outcomes.

Ginsenoside Rg2 alleviates myocardial fibrosis by regulating TGF-ß1/Smad signalling pathway.

CONTEXT: Panax ginseng C.A. Meyer (Araliaceae) has cardioprotective effects. Ginsenosides are responsible for most of the pharmacological activities of ginseng. OBJECTIVE: This study investigates the effect of ginsenoside Rg2 on myocardial fibrosis in myocardial ischaemia rats. MATERIALS AND METHODS: Male Wistar rats were divided into control, isoproterenol, ginsenoside Rg2 (5, 20 mg/kg) groups (n = 8). The rats were subcutaneously injected with isoproterenol (5 mg/kg) or normal saline (control group) once daily for 7 days. The animals were intragastrically treated with ginsenoside Rg2 or 0.5% CMC-Na (control and isoproterenol groups) daily for 28 days. At day 28, cardiac function, myocardial fibrosis, and TGF-ß1/Smad signalling pathway were evaluated. RESULTS: Compared with myocardial ischaemic rats, ginsenoside Rg2 at doses of 5, 20 mg/kg abated partially the augment of LVEDP (8.9 ± 1.3 vs. 7.5 ± 0.7, 7.2 ± 1.0 mmHg) and the decreases of the LVSP (96.75 ± 13.2 vs. 118.3 ± 19.4, 124.3 ± 21.3 mmHg), the + dp/dt (2142.8 ± 309.3 vs. 2598.6 ± 404.0, 2661.5 ± 445.2 mmHg/s), and the -dp/dt (1996.3 ± 306.3 vs. 2476.6 ± 289.7, 2509.6 ± 353.1 mmHg/s). Ginsenoside Rg2 (9.2 ± 0.9%, 8.5 ± 0.8%) alleviated myocardial fibrosis when compared with the isoproterenol group (10.1 ± 1.0%), which was accompanied by suppressed TGF-ß1/Smad signalling in heart tissues. CONCLUSIONS: Ginsenosides from ginseng possess the property of alleviating myocardial fibrosis, improving cardiac function after myocardial ischaemia. Ginsenosides may be promising agents for improving the outcomes of patients with myocardial ischaemia.

Three new compounds with nitric oxide inhibitory activity from Tirpitzia sinensis, an ethnomedicinal plant from Southwest China.

The medicinal plant Tirpitzia sinensis has been used by the Zhuang ethnic people in mountainous areas of Southwest China to stop bleeding, invigorate blood circulation, and treat inflammation and wounds. In order to further explore its traditional medicinal uses, the phytochemical constituents of this species were examined. Three new compounds, the lignan tirpitzin (1), the flavonoid tirpitzoside (2), and the furan-glycoside tirpitziol (3), along with five known compounds were isolated from the aerial part of T. sinensis for the first time. The structures of these compounds were elucidated by 1D and 2D NMR, LC/MS, IR spectrometric methods and compared with published data. The results of an in silico pharmacophore-based analysis showed potential targets of the new compounds, including ERBB2, IRAK4, LCK, JAK2, MAPK14, and MMP-12. These targets suggested that 1-3 may be involved with wound-healing and/or inflammation, leading to an in vitro assay of nitric oxide (NO) inhibition assays with lipopolysaccharide-induced BV-2 cells. All three new compounds displayed moderate NO inhibitory activity with the IC50 values of 14.97 ± 0.87, 26.63 ± 1.32, and 17.09 ± 2.3 µM, respectively.

An uncommon case of dual ventricular response in dual atrioventricular nodal non-reentrant tachycardia: A case report.

RATIONALE: Dual atrioventricular nodal non-reentrant tachycardia (DAVNNT) is an uncommon arrhythmia. Because of the different refractory periods of fast and slow pathways, a single atrial depolarization gives rise to 2 ventricular activationsthrough fast and slow pathways separately. PATIENT CONCERNS: A 45-year-old woman was referred to our Cardiology Center with symptoms of recurrent palpitations and fatigue persisting for the previous 3 years. On echocardiography, the ejection fraction of the left ventricle was 45%. DIAGNOSES: Electrophysiological study findings and 12-lead electrocardiogram led to a diagnosis of DAVNNT. INTERVENTIONS: Our case responded very well to the ablation of the slow pathway, and her tachycardia completely disappeared. OUTCOME: Her left ventricle ejection fraction also improved to52% after 3 months of follow-up. The patient remained asymptomatic throughout the follow-up period of 1 year, without any recurrence or complications. LESSONS: DAVNNT is a rare arrhythmia which can induce tachycardia-induced cardiomyopathy. Ablation of the slow pathway isconsidered a curative treatment.

Supra-Segmental Changes in Speech Production as a Result of Spectral Feedback Degradation: Comparison with Lombard Speech.

Perturbations to acoustic speech feedback have been typically localized to specific phonetic characteristics, for example, fundamental frequency (F0) or the first two formants (F1/F2), or affect all aspects of the speech signal equally, for example, via the addition of background noise. This paper examines the consequences of a more selective global perturbation: real-time cochlear implant (CI) simulation of acoustic speech feedback. Specifically, we examine the potential similarity between speakers' response to noise vocoding and the characteristics of Lombard speech. An acoustic analysis of supra-segmental characteristics in speaking rate, F0 production, and voice amplitude revealed changes that paralleled the Lombard effect in some domains but not others. Two studies of speech intelligibility complemented the acoustic analysis, finding that intelligibility significantly decreased as a result of CI simulation of speaker feedback. Together, the results point to differences in speakers' responses to these two superficially similar feedback manipulations. In both cases we see a complex, multi-faceted behavior on the part of talkers. We argue that more instances of global perturbation and broader response assessment are needed to determine whether such complexity is present in other feedback manipulations or if it represents a relatively rare exception to the typical compensatory feedback response.

Antioxidant and anti-inflammatory caffeoyl phenylpropanoid and secoiridoid glycosides from Jasminum nervosum stems, a Chinese folk medicine.

Eight compounds including four caffeoyl phenylpropanoid glycosides, jasnervosides A-D (1-4), one monoterpenoid glycoside, jasnervoside E (5), and three secoiridoid glycosides, jasnervosides F-H (10-12), were isolated from the stems of Jasminum nervosum Lour. (Oleaceae), along with four known compounds, poliumoside (6), verbascoside (7), α-l-rhamnopyranosyl-(1→3)-O-(α-l-rhamnopyranosyl(1→6)-1-O-E-caffeoyl-ß-d-glucopyranoside (8), and jaspolyanthoside (9). Their structures were elucidated on the basis of their physicochemical and spectroscopic properties. Compounds 1, 2, 4 and 11 displayed potent antioxidant activities in the DPPH assay, while 2 and 3 displayed good activities against LPS-induced TNF-α and IL-1ß production in BV2 cells. Compounds 1-5 and 10-12 were evaluated for their cytotoxic activities against three human cancer cell lines (A-549, Bel-7402, and HCT-8), but none displayed significant activity.

New monoterpene lactones from Actaea cimicifuga.

Three new monoterpene lactones, cimicifugolides A-C (1-3), along with a known one (4), were identified from the dried rhizome of Actaea cimicifuga L. that was used as traditional Chinese medicine for thousands of years with the Chinese common name of shengma. The structures of the new isolates were established using spectroscopic methods, including NMR, mass, UV, and IR spectra. The inhibition activity of compounds 1, 2, and 4 against pancreatic lipase was evaluated.

Regulation of contractile proteins and protein translational signaling in disused muscle.

BACKGROUND/AIMS: Muscle disuse can lead to muscle atrophy and impaired skeletal muscle function. How skeletal muscle modulates protein translational signaling in response to prolonged muscle disuse is not well understood. Using the hindlimb unloading (HU) model of muscle atrophy we examined how hindlimb unweighting affects protein translational signaling, including the activation of Akt/mTOR/p70S6K/S6 signaling and the inhibitory association of 4EBP1 with translation initiation factor eIF4E. METHODS: Male F344BN rats were randomized into baseline control, or subjected to HU for 3, 7 or 14 days. Body weight, gastrocnemius muscle, and individual myofiber cross-sectional area were measured to evaluate the degree of muscle atrophy. The amounts of myosin and related muscle contractile proteins were assessed using SDS-PAGE and immunoblotting. Microarray analysis was used to evaluate changes in the mRNA expression of muscle contractile proteins. Total and phosphorylated proteins of Akt/mTOR/p70S6K/S6 pathway were determined via immunoblotting, while the association of 4EBP1 with eIF4E was detected via co-immunoprecipitation. RESULTS: Unloading for 3 days significantly reduced cytosolic myosin content and was associated with increased binding of 4EBP1 to eIF4E, while prolonged unloading (14 days) was associated with the activation of Akt/mTOR/p70S6K/S6 signaling, decreased binding of 4EBP1 to eIF4E, increased cytosolic myosin and elevations in myofibrillar mRNA levels. CONCLUSION: Taken together, these data suggest that prolonged muscle disuse induces a biphasic translational signaling response that is associated with diminished and then increased muscle contractile protein expression.

Non-small cell lung cancer invasion and metastasis promoted by MMP-26.

Matrix metalloproteinase 26 (MMP-26) is a novel member of the matrix metalloproteinase (MMP) family and is widely expressed in cancer cells of epithelial origin. MMP-26 has been shown to contribute to tumor development and to the restoration of tissue injury. In this study, in order to identify the functions of MMP-26 that contribute to the biological phenotype and behavior of human lung carcinoma A549 cells, we established an MMP-26 low-expressing tumor cell model using RNA interference (RNAi) transfection. These cells were used to investigate the role of MMP-26 in tumor progression. The MTT, colony forming, adhere-nce and spreading, wound-healing and Transwell chamber invasion assays were performed to analyze the invasion ability of pshRNA-MMP26-transfected A549 cells. Semi-quantitative reverse transcription polymerase chain reaction, Western blotting and double immunofluorescent staining were employed to detect the relationship between MMP-26 and MMP-9. Results showed that the adhesive rate was down-regulated in pshRNA-MMP26-transfected cells, compared to the controls. Silencing of the MMP-26 gene significantly retarded the invasiveness of A549 cells in Transwell insert invasion assays. The cells proliferated in the three-dimensional (3D) culture system. A549 cells transfected with the pshRNA-MMP26-C plasmid mainly developed reticular structures in morphology, and formed few clones with clear and smooth edges as well as tight intercellular junctions. The mRNA and protein expression of MMP-9 in pshRNA-MMP26-transfected cells were significantly lower than those of the controls. Double immunofluorescence labeling and focal laser scanning microscopy showed that MMP-26 was colocalized with MMP-9 in the controls. In conclusion, we successfully established an MMP-26 low-expressing cell model and confirmed that MMP-26 contributed to A549 cell invasion and migration in vitro. We also demonstrated that MMP-26 plays an important role in local invasion at least in part through coordination with MMP-9.

Iron-induced cardiac damage: role of apoptosis and deferasirox intervention.

Excess cardiac iron levels are associated with cardiac damage and can result in increased morbidity and mortality. Here, we hypothesize that elevations in tissue iron can activate caspase-dependent signaling, which leads to increased cardiac apoptosis and fibrosis, and that these alterations can be attenuated by iron chelation. Using an iron-overloaded gerbil model, we show that increased cardiac iron is associated with reduced activation of Akt (Ser473 and Thr308), diminished phosphorylation of the proapoptotic regulator Bad (Ser136), and an increased Bax/Bcl-2 ratio. These iron-overload-induced alterations in Akt/Bad phosphorylation and Bax/Bcl-2 ratio were coupled with increased activation of the downstream caspase-9 (40/38- and 17-kDa fragments) and apoptosis executioner caspase-3 (19- and 17-kDa fragments), which were accompanied by evidence of elevated cytoskeletal α-fodrin cleavage (150- and 120-kDa fragments), discontinuity of myocardial membrane dystrophin immunoreactivity, increases in the number of terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive cells (nucleic DNA fragmentation), and cardiac fibrosis. We demonstrate that the administration of deferasirox, a tridentate iron chelator, is associated with diminished tissue iron deposition, attenuated activation of caspases, reduced α-fodrin cleavage, improved membrane integrity, decreased TUNEL reactivity, and attenuated cardiac fibrosis. These results suggest that the activation of caspase-dependent signaling may play a role in the development of iron-induced cardiac apoptosis and fibrosis, and deferasirox, via a reduction in cardiac tissue iron levels, may be useful for decreasing the extent of iron-induced cardiac damage.

Acetaminophen improves protein translational signaling in aged skeletal muscle.

BACKGROUND: Age-related muscle atrophy is characterized by increased oxidative stress, diminished Akt enzymatic function, and reduced phosphorylation of the mammalian target of rapamycin (mTOR), which can be attenuated by chronic acetaminophen ingestion. Here we hypothesize that age-related impairments in Akt/mTOR function are associated with reduced protein translational signaling, and that these changes, if present, can be attenuated by acetaminophen treatment. RESULTS: Compared to 6- and 27-month old animals, the expression of the mTOR-complex proteins raptor and GßL and the phosphorylation of tuberin/TSC2 (Thr1462) were reduced in the soleus muscles of very aged rats (33 months old). These changes in Akt/mTOR pathway signaling proteins were in turn associated with decreased phosphorylation of S6 kinase p85S6K (Thr412) and eukaryotic translation initiation factor-4E (eIF4E) binding protein-1 (4EBP1, Thr37/46), reduced phosphorylation of S6 ribosomal protein (Ser235/236), and increased inhibition of eIF4E by binding to 4EBP1. Age-associated alterations in the Akt/mTOR pathway signaling and in the phosphorylation of the stress-responsive eIF2α protein were attenuated by chronic acetaminophen treatment (30 mg/kg body weight per day). Ex vivo incubation of adult muscles with hydrogen peroxide mimicked the age-related decreases seen in eIF4E and 4EBP1 phosphorylation, whereas the inclusion of acetaminophen in the muscle bath attenuated this effect. CONCLUSION: Aging is associated with impairments in the regulation of proteins thought to be important in controlling mRNA translation, and acetaminophen may be useful for the treatment of age-related muscle atrophy by reducing oxidative stress.