Effect of Mnk1 on lipopolysaccharide-induced inflammatory responses in macrophages

Objective:To investigate the effect of mitogen-activated protein kinase interaction serine kinase 1(Mnk1)gene deletion on lipopolysaccharide(LPS)-induced inflammatory response in mouse macrophages(Mφ)and the possible mechanism.Methods:Healthy male wildtype C57BL/6J(WT)and Mnk1 knockout(KO)mice were selected at 8-10 weeks of age and divided into WT+PBS,KO+PBS,WT+LPS and KO+LPS groups,and the serum levels of IL-1βwere measured by ELISA after 24 h intraperitoneal injection of PBS or LPS.The mRNA expression levels of IL-1βand Sprouty2(Spry2)in the spleen Mφwere measured by qRTPCR.Mφwas also extracted from the peritoneal cavity of two strains of mice for in vitro experiments to detect macrophage adhesion function and stimulated with equal volumes of LPS or PBS solution for 24 h,divided into WT+PBS group,KO+PBS group,WT+LPS group and KO+LPS group,and transfected with adenovirus expressing Spry2.qRT-PCR was used to detect the mRNA expression levels of LFA-1α,IL-1β,iNOS,CD206,Arg1 and Spry2 in Mφ.Mnk1,ERK1/2,P-ERK1/2,P-p38,P-JNK and Spry2 protein levels in Mφwere detected by western blot.Results:In the in vivo experiments,the concentration of IL-1βin the serum of the KO+LPS group was more significantly elevated than that of the WT+LPS group in mice injected intraperitoneally with LPS.The expression level of splenic MφIL-1βwas higher and the mRNA expression level of Spry2 was decreased in the KO+LPS group compared to the WT+LPS group.In the in vitro experiments,the mRNA expression levels of IL-1βand iNOS were elevated and those of CD206,Arg1 and Spry2 were decreased in the KO+LPS group compared with the WT+LPS group;the expression of LFA-1αwas not significantly different in the WT+PBS and WT+LPS groups,while the expression level of LFA-1αwas significantly increased in the KO+LPS group compared with the WT+LPS group.The results of the macrophage adhesion function assay showed that the adhesion rate of Mφin the KO group was increased at several time points compared to the WT group.After LPS stimulation,the expression of MφSpry2 decreased in Mnk1 KO group compared to WT group,while the expression of P-ERK1/2 increased compared to WT group.After Mφwas transfected with adenovirus overexpressing Spry2 and stimulated with LPS,MφSpry2 expression increased in the KO+AdSpry2 group and P-ERK1/2 expression decreased significantly compared to KO+AdGFP.Conclusion:Mnk1 knockdown enhances LPS-induced inflammatory responses in macrophages,and the mechanism may be related to the involvement of Spry2,a substrate of Mnk1,in regulating macrophage function.

Potential preventive effects of time-restricted eating on cancer

Intermittent fasting is a novel dietary intervention that has been demonstrated to improve the efficacy of cancer therapy and reduce complications.Time-restricted eating is a specific form of intermittent fasting.It usually restricts only the daily eating window and not the amount of calories consumed.In addition to providing a means for weight management and improving metabolism like other intermittent fasting methods,time-restricted eating also synchronizes circadian rhythms and affects autophagy levels,which has potential antiaging effects.Some studies have shown that time-restricted eating can prevent tumorigenesis and slow tumor progression.Moreover,because of its simplicity and mild adverse effects,time-restricted eating is safe and has a high rate of compliance.It may be used an adjuvant therapy and may be part of a healthy lifestyle suitable for long term by cancer patients or those at high risk of developing specific cancers.This article expounds on the potential impact of time-restricted eating on the prevention and treatment of cancer,as well as the potential mechanism(s)of action.There are 3 main aspects considered to be impacted by time-restricted eating:improving obesity and metabolic disorders,synchronizing the circadian rhythm,and upregulating autophagy.We herein present the current research progress related to the effects of time-restricted eating on malignant tumors.The purpose of this review is to provide a theoretical basis and direction for future research to explore the potential of time-restricted eating as a nutritional intervention to prevent the occurrence of cancer and as a treatment or adjuvant therapy for cancer.We believe that this approach may be conducive to improving the nutritional status of cancer patients and improving their prognosis and quality of life.

Metabolic landscape in cardiac aging:insights into molecular biology and therapeutic implications

Cardiac aging is evident by a reduction in function which subsequently contributes to heart failure.The metabolic microenvironment has been identified as a hallmark of malignancy,but recent studies have shed light on its role in cardiovascular diseases(CVDs).Various metabolic pathways in cardiomyocytes and noncardiomyocytes determine cellular senescence in the aging heart.Metabolic alteration is a common process throughout cardiac degeneration.Importantly,the involvement of cellular senescence in cardiac injuries,including heart failure and myocardial ischemia and infarction,has been reported.However,metabolic complexity among human aging hearts hinders the development of strategies that targets metabolic susceptibility.Advances over the past decade have linked cellular senescence and function with their metabolic reprogramming pathway in cardiac aging,including autophagy,oxidative stress,epigenetic modifications,chronic inflammation,and myocyte systolic phenotype regulation.In addition,metabolic status is involved in crucial aspects of myocardial biology,from fibrosis to hypertrophy and chronic inflammation.However,further elucidation of the metabolism involvement in cardiac degeneration is still needed.Thus,deciphering the mechanisms underlying how metabolic reprogramming impacts cardiac aging is thought to contribute to the novel interventions to protect or even restore cardiac function in aging hearts.Here,we summarize emerging concepts about metabolic landscapes of cardiac aging,with specific focuses on why metabolic profile alters during cardiac degeneration and how we could utilize the current knowledge to improve the management of cardiac aging.

Idebenone alleviates doxorubicin-induced cardiotoxicity by stabilizing FSP1 to inhibit ferroptosis

Doxorubicin(DOX)-mediated cardiotoxicity can exacerbate mortality in oncology patients,but related pharmacotherapeutic measures are relatively limited.Ferroptosis was recently identified as a major mechanism of DOX-induced cardiotoxicity.Idebenone,a novel ferroptosis inhibitor,is a well-described clinical drug widely used.However,its role and pathological mechanism in DOX-induced cardiotoxicity are still unclear.In this study,we demonstrated the effects of idebenone on DOX-induced cardiotoxicity and elucidated its underlying mechanism.A single intraperitoneal injection of DOX(15 mg/kg)was administrated to establish DOX-induced cardiotoxicity.The results showed that idebenone significantly attenuated DOX-induced cardiac dysfunction due to its ability to regulate acute DOX-induced Fe^(2+)and ROS overload,which resulted in ferroptosis.CESTA and BLI further revealed that idebenone's anti-ferroptosis effect was mediated by FSP1.Interestingly,idebenone increased FSP1 protein levels but did not affect Fsp1 mRNA levels in the presence of DOX.Idebenone could form stable hydrogen bonds with FSP1 protein at K355,which may influence its association with ubiquitin.The results confirmed that idebenone stabilized FSP1 protein levels by inhibiting its ubiquitination degradation.In conclusion,this study demonstrates idebenone attenuated DOX-induced cardiotoxicity by inhibiting ferroptosis via regulation of FSP1,making it a potential clinical drug for patients receiving DOX treatment.

Significant reduction of humoral response to SARS-CoV-2 4 months after the diagnosis of COVID-19

Editor’s note A commentary on“Humoral immune response to SARS-CoV-2 in Iceland”.Humoral response to COVID-19 disease,including IgM and IgG antibodies against SARS-CoV-2 virus,is well documented.1,2 Neutralizing activities against SARS-CoV-2 virus have also been confirmed in patients who have recovered from COVID-19.2 These observations form the basis for the assumption that SARS-CoV-2 vaccines can be developed through stimulation of the host immune system to generate neutralizing antibodies to SARS-CoV-2 virus.

Cardiac fibroblast heat shock protein 47 aggravates cardiac fibrosis post myocardial ischemia-reperfusion injury by encouraging ubiquitin specific peptidase 10 dependent Smad4 deubiquitination

Despite complications were significantly reduced due to the popularity of percutaneous coronary intervention(PCI) in clinical trials, reperfusion injury and chronic cardiac remodeling significantly contribute to poor prognosis and rehabilitation in AMI patients. We revealed the effects of HSP47 on myocardial ischemia-reperfusion injury(IRI) and shed light on the underlying molecular mechanism.We generated adult mice with lentivirus-mediated or miRNA(mi1/133TS)-aided cardiac fibroblastselective HSP47 overexpression. Myocardial IRI was induced by 45-min occlusion of the left anterior descending(LAD) artery followed by 24 h reperfusion in mice, while ischemia-mediated cardiac remodeling was induced by four weeks of reperfusion. Also, the role of HSP47 in fibrogenesis was evaluated in cardiac fibroblasts following hypoxia-reoxygenation(HR). Extensive HSP47 was observed in murine infarcted hearts, human ischemic hearts, and cardiac fibroblasts and accelerated oxidative stress and apoptosis after myocardial IRI. Cardiac fibroblast-selective HSP47 overexpression exacerbated cardiac dysfunction caused by chronic myocardial IRI and presented deteriorative fibrosis and cell proliferation.HSP47 upregulation in cardiac fibroblasts promoted TGFβ1-Smad4 pathway activation and Smad4 deubiquitination by recruiting ubiquitin-specific peptidase 10(USP10) in fibroblasts. However, cardiac fibroblast specific USP10 deficiency abolished HSP47-mediated fibrogenesis in hearts. Moreover, blockage of HSP47 with Col003 disturbed fibrogenesis in fibroblasts following HR. Altogether, cardiac fibroblast HSP47 aggravates fibrosis post-myocardial IRI by enhancing USP10-dependent Smad4 deubiquitination,which provided a potential strategy for myocardial IRI and cardiac remodeling.