摘要：Reliable molecular biomarkers to predict fertility remain scarce.The current study investigated the potential of testis-specific circBOULE RNAs as biomarkers for male infertility and sperm quality.Using reverse transcription-PCR and real-time reverse transcription-PCR assays,we identified seven circular RNAs from the human BOULE gene in human sperm.We observed that the expression level of circEx3-6 was significantly reduced in asthenozoospermia,while the expression levels of both circEx2-6 and circEx2-7 were decreased in terato-zoospermia,compared with the controls.Furthermore,we demonstrated that the expression level of circEx2-6 was negatively correlated with the sperm DNA fragmentation index,and the expression level of circEx2-7 was correlated with both fertilization and cleavage rates in those treated with the assisted reproductive technologies.Further functional analyses in a transgenic fly model supported the roles of circBOULE RNAs in sperm development and human male fertility.Collectively,our findings support that sperm circBOULE RNAs may serve as diagnostic biomarkers for assessing sperm motility and DNA quality.Therefore,clinical application and significance of sperm circBOULE RNAs in the assisted reproductive technologies warrant further investigation.

摘要：Long noncoding RNA(lncRNA)IDH1 antisense RNA 1(IDH1-AS1)is involved in the progression of multiple cancers,but its role in epithelial ovarian cancer(EOC)is unknown.Therefore,we investigated the expression levels of IDH1-AS1 in EOC cells and normal ovarian epithelial cells by quantitative real-time PCR(qPCR).We first evaluated the effects of IDH1-AS1 on the proliferation,migration,and invasion of EOC cells through cell counting kit-8,colony formation,EdU,transwell,wound-healing,and xenograft assays.We then explored the downstream targets of IDH1-AS1 and verified the results by a dual-luciferase reporter,qPCR,rescue experiments,and Western blotting.We found that the expression levels of IDH1-AS1 were lower in EOC cells than in normal ovarian epithelial cells.High IDH1-AS1 expression of EOC patients from the Gene Expression Profiling Interactive Analysis database indicated a favorable prognosis,because IDH1-AS1 inhibited cell proliferation and xenograft tumor growth of EOC.IDH1-AS1 sponged miR-518c-5p whose overexpression promoted EOC cell proliferation.The miR-518c-5p mimic also reversed the proliferation-inhibiting effect induced by IDH1-AS1 overexpression.Furthermore,we found that RNA binding motif protein 47(RBM47)was the downstream target of miR-518c-5p,that upregulation of RBM47 inhibited EOC cell proliferation,and that RBM47 overexpressing plasmid counteracted the proliferation-promoting effect caused by the IDH1-AS1 knockdown.Taken together,IDH1-AS1 may suppress EOC cell proliferation and tumor growth via the miR-518c-5p/RBM47 axis.

摘要：The retinal pigment epithelium(RPE)is fundamental to sustaining retinal homeostasis.RPE abnormality leads to visual defects and blindness,including age-related macular degeneration(AMD).Although breakthroughs have been made in the treatment of neovascular AMD,effective intervention for atrophic AMD is largely absent.The adequate knowledge of RPE pathology is hindered by a lack of the patients'RPE datasets,especially at the single-cell resolution.In the current study,we delved into a large-scale single-cell resource of AMD donors,in which RPE cells were occupied in a substantial proportion.Bulk RNA-seq datasets of atrophic AMD were integrated to extract molecular characteristics of RPE in the pathogenesis of atrophic AMD.Both in vivo and in vitro models revealed that carboxypeptidase X,M14 family member 2(CPXM2),was specifically expressed in the RPE cells of atrophic AMD,which might be induced by oxidative stress and involved in the epithelial-mesenchymal transition of RPE cells.Additionally,silencing of CPXM2 inhibited the mesenchymal phenotype of RPE cells in an oxidative stress cell model.Thus,our results demonstrated that CPXM2 played a crucial role in regulating atrophic AMD and might serve as a potential therapeutic target for atrophic AMD.

摘要：The current study used multivariable logistic regression analysis to investigate associations between the intake frequencies of 13 food groups(or four diet groups)and infectious diseases.The analysis included 487 849 participants from the UK Biobank,with 75 209 participants diagnosed with infectious diseases.Participants reporting the highest intake frequency of processed meat(odds ratio[OR]=1.096 4,95%confidence interval[CI]:1.062 2-1.131 8)and red meat(OR=1.089 5,95%CI:1.056 3-1.123 9)had a higher risk of infectious diseases,compared with those with the lowest intake frequency.Consuming fish 2.0-2.9 times(OR=0.822 1,95%CI:0.795 5-0.849 6),cheese≥5.0 times(OR=0.882 2,95%CI:0.855 9-0.909 2),fruit 3.0-3.9 servings(OR=0.886 7,95%CI:0.866 1-0.907 8),and vegetables 2.0-2.9 servings(OR=0.937 2,95%CI:0.918 9-0.955 9)per week were associated with a lower risk of infection.Low meat-eaters(OR=0.940 4,95%CI:0.924 3-0.956 7),fish-eaters(OR=0.839 1,95%CI:0.788 7-0.891 9),and vegetarians(OR=0.915 4,95%CI:0.856 1-0.977 8)had a lower risk of infectious diseases,compared with regular meat-eaters.The mediation analysis revealed that glycosylated hemoglobin,white blood cell count,and body mass index served as the mediators in the associations between diet and infectious diseases.The current study indicates that the intake frequency of food groups is a risk factor for infectious diseases,and fish-eaters have a lower risk of infection.

摘要：Studies have shown that differentiated embryo-chondrocyte expressed gene 1(DEC1)promotes osteoblast osteogenesis.To investigate the role of DEC1 in postmenopausal osteoporosis,we used the two genotypes of mice(Dec1+/+and Dec1-/-)to establish an ovariectomy model and found that the bone loss was significantly lower in Dec1-/-ovariectomy mice than in Dec1+/+ovariectomy mice.The expression levels of RUNX2 and OSX were significantly increased in Dec1-/-ovariectomy mice,compared with Dec1+/+ovariectomy mice;however,the expression levels of NFATc1,c-Fos,CTSK,and RANKL/OPG ratio were significantly decreased in Dec1-/-ovariectomy mice,compared with those in Dec1+/+ovariectomy mice.Likewise,DEC1 deficiency also suppressed the expression levels of IL-6 and IL-1β.Further results showed that the mRNA expression levels of Runx2,Osx,and Alp were significantly increased in bone marrow mesenchymal stem cells of Dec1-/-ovariectomy mice,compared with those of Dec1+/+ovariectomy mice.Moreover,the mRNA levels of Il1b,Il6,Tnfa,and Ifng were significantly increased in bone marrow-derived macrophages(BMMs)of Dec1+/+ovariectomy mice,compared with those of Dec1+/+sham mice,but not in Dec1-/-ovariectomy BMMs,when compared with those in Dec1-/-sham BMMs.Additionally,the expression levels of p-IκBα and p-P65 were significantly increased in Dec1+/+ovariectomy BMMs,compared with those in Dec1+/+sham BMMs,but did not increase in Dec1-/-ovariectomy BMMs,compared with those in Dec1-/-sham BMMs.Taken together,DEC1 deficiency inhibited the NF-κB pathway induced by ovariectomy,thereby decreasing cytokines and subsequently inhibiting the decrease of osteo-genesis and the increase of osteoclastogenesis caused by ovariectomy.The findings may provide a novel under-standing of postmenopausal osteoporosis development,and offer potential avenues for the disease intervention.

摘要：Islet beta cells(β-cells)produce insulin in response to high blood glucose levels,which is essential for preserving glucose homeostasis.Voltage-gated ion channels in β-cells,including Na+,K+,and Ca2+channels,aid in the release of insulin.The epithelial sodium channel alpha subunit(α-ENaC),a voltage-independent sodium ion channel,is also expressed in human pancreatic endocrine cells.However,there is no reported study on the function of ENaC in the β-cells.In the current study,we found that α-ENaC was expressed in human pancreatic glandule and pancreatic islet β-cells.In the pancreas of db/db mice and high-fat diet-induced mice,and in mouse islet β-cells(MIN6 cells)treated with palmitate,α-ENaC expression was increased.When α-ENaC was overexpressed in MIN6 cells,insulin content and glucose-induced insulin secretion were significantly reduced.On the other hand,palmitate injured islet β-cells and suppressed insulin synthesis and secretion,but increased α-ENaC expression in MIN6 cells.However,α-ENaC knockout(Scnn1a-/-)in MIN6 cells attenuated β-cell disorder induced by palmitate.Furthermore,α-ENaC regulated the ubiquitylation and degradation of sirtuin 2 in β-cells.α-ENaC also modulated β-cell function in correlation with the inositol-requiring enzyme 1 alpha/X-box binding protein 1(IRE1α/XBP1)and protein kinase RNA-like endoplasmic reticulum kinase/C/EBP homologous protein(PERK/CHOP)endoplasmic reticulum stress pathways.These results suggest that α-ENaC may play a novel role in insulin synthesis and secretion in the β-cells,and the upregulation of α-ENaC promotes islet β-cell dysfunction.In conclusion,α-ENaC may be a key regulator involved in islet β-cell damage and a potential therapeutic target for type 2 diabetes mellitus.

摘要：The intestinal mucosal barrier serves as a vital guardian of the gut health,maintaining a delicate equilibrium between gut microbiota and host immune homeostasis.Gasdermin D(GSDMD),a key executioner of pyroptosis downstream of the inflammasome,has been found to play intricate roles in modulating colitis by influencing intestinal macrophages and regulating mucus secretion from goblet cells.However,the exact nature of the regulatory function of GSDMD in maintaining intestinal immune homeostasis and defending against pathogens remains to be elucidated.In the current study,by using the Citrobacter rodentium infection model,we found that GSDMD played a key role in the defense against intestinal Citrobacter rodentium infection,with high expression levels in intestinal epithelial and lamina propria myeloid cells.Our results showed that GSDMD acted specifically in intestinal epithelial cells to combat the infection,independently of its effects on antimicrobial peptides or mucin secretion.Instead,the resistance was mediated by the N-terminal fragment of GSDMD,highlighting its importance in intestinal immunity.However,the specific mechanism underlying the N-terminal activity of GSDMD in protecting against intestinal bacterial infections requires future investigation.

摘要：The interplay between DNA replication stress and immune microenvironment alterations is known to play a crucial role in colorectal tumorigenesis,but a comprehensive understanding of their association with and relevant biomarkers involved in colorectal tumorigenesis is lacking.To address this gap,we conducted a study aiming to investigate this association and identify relevant biomarkers.We analyzed transcriptomic and proteomic profiles of 904 colorectal tumor tissues and 342 normal tissues to examine pathway enrichment,biological activity,and the immune microenvironment.Additionally,we evaluated genetic effects of single variants and genes on colorectal cancer susceptibility using data from genome-wide association studies(GWASs)involving both East Asian(7 062 cases and 195 745 controls)and European(24 476 cases and 23 073 controls)populations.We employed mediation analysis to infer the causal pathway,and applied multiplex immunofluorescence to visualize colocalized biomarkers in colorectal tumors and immune cells.Our findings revealed that both DNA replication activity and the flap structure-specific endonuclease 1(FEN1)gene were significantly enriched in colorectal tumor tissues,compared with normal tissues.Moreover,a genetic variant rs4246215 G>T in FEN1 was associated with a decreased risk of colorectal cancer(odds ratio=0.94,95%confidence interval:0.90-0.97,Pmeta=4.70×10-9).Importantly,we identified basophils and eosinophils that both exhibited a significantly decreased infiltration in colorectal tumors,and were regulated by rs4246215 through causal pathways involving both FEN1 and DNA replication.In conclusion,this trans-omics incorporating GWAS data provides insights into a plausible pathway connecting DNA replication and immunity,expanding biological knowledge of colorectal tumorigenesis and therapeutic targets.

摘要：Parasitic helminths,taxonomically comprising trematodes,cestodes,and nematodes,are multicellular invertebrates widely disseminated in nature and have afflicted humans continuously for a long time.Helminths play potent roles in the host by generating a variety of novel molecules,including some excretory/secretory products and others that are involved in intracellular material exchange and information transfer as well as the initiation or stimulation of immune and metabolic activation.The helminth-derived molecules have developed powerful and diverse immunosuppressive effects to achieve immune evasion for parasite survival and establish chronic infections.However,they also improve autoimmune and allergic inflammatory responses and promote metabolic homeostasis by promoting metabolic reprogramming of various immune functions,and then inducing alternatively activated macrophages,T helper 2 cells,and regulatory T cell-mediated immune responses.Therefore,a deeper exploration of the immunopathogenic mechanism and immune regulatory mechanisms of helminth-derived molecules exerted in the host is crucial for understanding host-helminth interactions,as well as the development of therapeutic drugs for infectious or non-infectious diseases.In this review,we focus on the properties of helminth-derived molecules to give an overview of the most recent scientific knowledge about their pathogenic and pharmacopeial roles in immune-metabolic homeostasis.

摘要：Menopause is characterized by various physical,mental and emotional symptoms.ERr 731® is a standardized extract from Rheum rhaponticum root and has been clinically studied for its role in reducing menopausal symptoms.The current systematic review and meta-analysis aimed to evaluate the efficacy of ERr 731® supplementation in alleviating the severity of menopausal symptoms.In this review,we searched across three online databases up to March 2023,evaluated the quality of the included studies by the Physiotherapy Evidence Database scale,and assessed the risk of bias by the Cochrane Risk of Bias tool.We then performed a meta-analysis using RevMan software to estimate the pooled mean difference(MD).The study protocol was registered in the Prospective Register of Systematic Reviews(CRD42023416808).After screening and evaluation,we included four high-quality studies(a total of 390 participants;the ERr 731® group:193 participants;the control group:197 participants)in the meta-analysis.The results showed that ERr 731® supplementation significantly reduced the Menopause Rating Scale score(MD:-15.12;P<0.001),compared with control therapy.Sensitivity analysis revealed no effect of individual studies on the overall pooled estimate or overall observed heterogeneity.The current review provides evidence that ERr 731® supplementation is effective in reducing menopause symptoms.Potential bias and high heterogeneity in the results warrant further clinical studies.

摘要：Numerous studies in immunology focus on areas such as cancer immunotherapy,autoimmune disease therapy,neuroimmunoregulation,immune metabolism,and the discovery of novel immune cell subsets. In endocrinology,there is a focus on the prevention and treatment of diabetes,the management of obesity,thyroid disease,kidney disease,metabolic syndrome,osteoporosis,and the application of artificial intelligence in the management of endocrine diseases,etc. In the current special issue,we selected nine papers covering diverse topics,including ocular vascular diseases,systemic lupus erythematosus(SLE),pathogenic and pharmacopeial roles of helminth-derived molecules,sepsis-induced acute lung injury (ALI),intestinal immune homeostasis,diet and infectious diseases,postmenopausal osteoporosis,per-and polyfluoroalkyl substance (PFAS) exposure and liver damage,and targeted therapies for acrodermatitis continua of Hallopeau (ACH).

摘要：The receptor for activated C kinase 1(RACK1)is a protein that plays a crucial role in various signaling pathways and is involved in the pathogenesis of Alzheimer's disease(AD),a prevalent neurodegenerative disease.RACK1 is highly expressed in neuronal cells of the central nervous system and regulates the pathogenesis of AD.Specifically,RACK1 is involved in regulation of the amyloid-β precursor protein processing through α-or β-secretase by binding to different protein kinase C isoforms.Additionally,RACK1 promotes synaptogenesis and synaptic plasticity by inhibiting N-methyl-D-aspartate receptors and activating gamma-aminobutyric acid A receptors,thereby preventing neuronal excitotoxicity.RACK1 also assembles inflammasomes that are involved in various neuroinflammatory pathways,such as nuclear factor-kappa B,tumor necrosis factor-alpha,and NOD-like receptor family pyrin domain-containing 3 pathways.The potential to design therapeutics that block amyloid-β accumulation and inflammation or precisely regulate synaptic plasticity represents an attractive therapeutic strategy,in which RACK1 is a potential target.In this review,we summarize the contribution of RACK1 to the pathogenesis of AD and its potential as a therapeutic target.

摘要：The present study aimed to dynamically observe the segmental and global myocardial movements of the left ventricle during coronary artery bypass grafting by transesophageal speckle-tracking echocardiography,and to assess the effect of sevoflurane on cardiac function.Sixty-four patients scheduled for the off-pump coronary artery bypass grafting were randomly divided into a sevoflurane-based anesthesia(AS)group and a propofol-based total intravenous anesthesia(AA)group.The AS group demonstrated a higher absolute value of left ventricular global longitudinal strain than that of the AA group at both T1(after harvesting all grafts and before coronary anastomosis)and T2(30 min after completing all coronary anastomoses)(P<0.05).Moreover,strain improvement in the segment with the highest preoperative strain was significantly reduced in the AS group,compared with the AA group at both T1 and T2(P<0.01).The flow of the left internal mammary artery-left anterior descending artery graft was superior,and the postoperative concentration of troponin T decreased rapidly in the AS group,compared with the AA group(P<0.05).Compared with total intravenous anesthesia,sevoflurane resulted in a significantly higher global longitudinal strain,stroke volume,and cardiac output.Sevoflurane also led to an amelioration in the condition of the arterial graft.Furthermore,sevoflurane significantly reduced strain improvement in the segmental myocardium with a high preoperative strain value.The findings need to be replicated in larger studies.

摘要：We have developed a protein array system,named"Phospho-Totum",which reproduces the phosphorylation state of a sample on the array.The protein array contains 1 471 proteins from 273 known signaling pathways.According to the activation degrees of tyrosine kinases in the sample,the corresponding groups of substrate proteins on the array are phosphorylated under the same conditions.In addition to measuring the phosphorylation levels of the 1 471 substrates,we have developed and performed the artificial intelligence-assisted tools to further characterize the phosphorylation state and estimate pathway activation,tyrosine kinase activation,and a list of kinase inhibitors that produce phosphorylation states similar to that of the sample.The Phospho-Totum system,which seamlessly links and interrogates the measurements and analyses,has the potential to not only elucidate pathophysiological mechanisms in diseases by reproducing the phosphorylation state of samples,but also be useful for drug discovery,particularly for screening targeted kinases for potential drug kinase inhibitors.

摘要：cis-Diamminedichloroplatinum(CDDP)is widely used for the treatment of various solid cancers.Here we reported that CDDP increased the expression and enzymatic activities of carboxylesterase 1(CES1)and carboxylesterase 2(CES2),along with the upregulation of pregnane X receptor(PXR)and the downregulation of differentiated embryonic chondrocyte-expressed gene 1(DEC1)in human hepatoma cells,primary mouse hepatocytes,mouse liver and intestine.The overexpression or knockdown of PXR alone upregulated or downregulated the CES1 and CES2 expression,respectively.The increases in CES1 and CES2 expression levels induced by CDDP abolished or enhanced by PXR knockdown or overexpression,implying that CDDP induces carboxylesterases through the activation of PXR.Likewise,the overexpression or knockdown of DEC1 alone significantly decreased or increased PXR and its targets.Moreover,the increases of PXR and its targets induced by CDDP were abolished or alleviated by the overexpression or knockdown of DEC1.The overexpression or knockdown of DEC1 affected the response of PXR to CDDP,but not vice versa,suggesting that CDDP increases carboxylesterases by upregulating PXR mediated by the decrease of DEC1.In addition,CDDP did not increase DEC1 mRNA degradation but suppressed DEC1 promoter reporter activity,indicating that it suppresses DEC1 transcriptionally.The combined use of CDDP and irinotecan had a synergistic effect on two cell lines,especially when CDDP was used first.

摘要：Pericytes are located in the stromal membrane of the capillary outer wall and contain endothelial cells.They are pivotal in regulating blood flow,enhancing vascular stability,and maintaining the integrity of the blood-retina barrier/blood-brain barrier.The pluripotency of pericytes allows them to differentiate into various cell types,highlighting their significance in vascular disease pathogenesis,as demonstrated by previous studies.This capability enables pericytes to be a potential biomarker for the diagnosis and a target for the treatment of vascular disorders.The retina,an essential part of the eyeball,is an extension of cerebral tissue with a transparent refractive medium.It offers a unique window for assessing systemic microvascular lesions.Routine fundus examination is necessary for patients with diabetes and hypertension.Manifestations,such as retinal artery tortuosity,dilation,stenosis,and abnormal arteriovenous anastomosis,serve as typical hallmarks of retinal vasculopathy.Therefore,studies of ocular vascular diseases significantly facilitate the exploration of systemic vascular diseases.

摘要：Most papillary thyroid carcinoma(PTC)patients have a good prognosis.However,lymph node metastasis(LNM),the most common manifestation of disease progression,is frequently associated with a poor prognosis.Nevertheless,few studies have focused on the underlying mechanisms of LNM.In the current study,we aimed to investigate the potential role of exosomal circRNAs that contribute to LNM in PTC.We identified 9 000 differentially expressed exosomal circRNAs in PTC patients with LNM,including 684 upregulated and 2 193 downregulated circRNAs.Functional enrichment analysis revealed that these differentially expressed circRNAs were primarily involved in a variety of molecular and signaling pathways correlated with PTC progression and LNM.Through bioinformatics analysis,we identified 14 circRNA-miRNA-mRNA networks related to LNM-associated signaling pathways in PTC.Moreover,both circTACC2-miR-7-EGFR and circBIRC6-miR-24-3p-BCL2L11 axes were verified for their potential involvement in PTC with LNM.Additionally,we identified four upregulated circRNA-related hub genes and eight hub genes correlated with downregulated circRNAs,some of which were validated as being potentially involved in LNM in PTC.Collectively,our findings provide a novel framework for an in-depth investigation of the function of dysregulated exosomal circRNAs and their potential as biomarkers in PTC patients with LNM.

摘要：Dear Editor, Treating psoriatic arthritis (PsA) is always difficult.Systemic treatments can be administered either orally or through intramuscular and intra-articular injection,including conventional synthetics,biologics and targeted synthetic disease-modifying antirheumatic drugs[1]. The alternatives,topical external therapies,are not effective on joint lesions due to drug permeability issues. Drugs injected into the articular cavity are also unsuitable for small peripheral joint lesions,the most common manifestations of PsA. The limited treatment options for PsA present a challenge.

摘要：Dear Editor, Acrodermatitis continua of Hallopeau (ACH),a rare and chronic variant of pustular psoriasis,is characterized by atrophic skin changes,sterile pustules,onychodystrophy,and osteolysis of the distal phalanges of the fingers and toes. Given the absence of international consensus guidelines and comprehensive clinical studies of high methodological rigor,the management of ACH primarily relies on antipsoriatic therapeutic approaches and empirical evidence derived from scattered case reports.

摘要：In mammals,the timing of physiological,biochemical and behavioral processes over a 24-h period is controlled by circadian rhythms.To entrain the master clock located in the suprachiasmatic nucleus of the hypothalamus to a precise 24-h rhythm,environmental zeitgebers are used by the circadian system.This is done primarily by signals from the retina via the retinohypothalamic tract,but other cues like exercise,feeding,temperature,anxiety,and social events have also been shown to act as non-photic zeitgebers.The recently identified myokine irisin is proposed to serve as an entraining non-photic signal of exercise.Irisin is a product of cleavage and modification from its precursor membrane fibronectin type Ⅲ domain-containing protein 5(FNDC5)in response to exercise.Apart from well-known peripheral effects,such as inducing the"browning"of white adipocytes,irisin can penetrate the blood-brain barrier and display the effects on the brain.Experimental data suggest that FNDC5/irisin mediates the positive effects of physical activity on brain functions.In several brain areas,irisin induces the production of brain-derived neurotrophic factor(BDNF).In the master clock,a significant role in gating photic stimuli in the retinohypothalamic synapse for BDNF is suggested.However,the brain receptor for irisin remains unknown.In the current review,the interactions of physical activity and the irisin/BDNF axis with the circadian system are reconceptualized.