Comparative analysis of primate and pig cells reveals primate-specific PINK1 expression and phosphorylation

PTEN-induced putative kinase 1(PINK1),a mitochondrial kinase that phosphorylates Parkin and other proteins,plays a crucial role in mitophagy and protection against neurodegeneration.Mutations in PINK1 and Parkin can lead to loss of function and early onset Parkinson's disease.However,there is a lack of strong in vivo evidence in rodent models to support the theory that loss of PINK1 affects mitophagy and induces neurodegeneration.Additionally,PINK1 knockout pigs(Sus scrofa)do not appear to exhibit neurodegeneration.In our recent work involving non-human primates,we found that PINK1 is selectively expressed in primate brains,while absent in rodent brains.To extend this to other species,we used multiple antibodies to examine the expression of PINK1 in pig tissues.In contrast to tissues from cynomolgus monkeys(Macaca fascicularis),our data did not convincingly demonstrate detectable PINK1expression in pig tissues.Knockdown of PINK1 in cultured pig cells did not result in altered Parkin and BAD phosphorylation,as observed in cultured monkey cells.A comparison of monkey and pig striatum revealed more PINK1-phosphorylated substrates in the monkey brain.Consistently,PINK1 knockout in pigs did not lead to obvious changes in the phosphorylation of Parkin and BAD.These findings provide new evidence that PINK1expression is specific to primates,underscoring the importance of non-human primates in investigating PINK1function and pathology related to PINK1 deficiency.

Genetically modified non-human primate models for research on neurodegenerative diseases

Neurodegenerative diseases(NDs)are a group of debilitating neurological disorders that primarily affect elderly populations and include Alzheimer's disease(AD),Parkinson's disease(PD),Huntington's disease(HD),and amyotrophic lateral sclerosis(ALS).Currently,there are no therapies available that can delay,stop,or reverse the pathological progression of NDs in clinical settings.As the population ages,NDs are imposing a huge burden on public health systems and affected families.Animal models are important tools for preclinical investigations to understand disease pathogenesis and test potential treatments.While numerous rodent models of NDs have been developed to enhance our understanding of disease mechanisms,the limited success of translating findings from animal models to clinical practice suggests that there is still a need to bridge this translation gap.Old World nonhuman primates(NHPs),such as rhesus,cynomolgus,and vervet monkeys,are phylogenetically,physiologically,biochemically,and behaviorally most relevant to humans.This is particularly evident in the similarity of the structure and function of their central nervous systems,rendering such species uniquely valuable for neuroscience research.Recently,the development of several genetically modified NHP models of NDs has successfully recapitulated key pathologies and revealed novel mechanisms.This review focuses on the efficacy of NHPs in modeling NDs and the novel pathological insights gained,as well as the challenges associated with the generation of such models and the complexities involved in their subsequent analysis.

Large animal models for Huntington's disease research

Huntington'sdisease(HD)isahereditary neurodegenerative disorder for which there is currently no effectivetreatmentavailable.Consequently,the development of appropriate disease models is critical to thoroughly investigate disease progression.The genetic basis of HD involves the abnormal expansion of CAG repeats in the huntingtin(HTT)gene,leading to the expansion of a polyglutamine repeat in the HTT protein.Mutant HTT carrying the expanded polyglutamine repeat undergoes misfolding and forms aggregates in the brain,which precipitate selective neuronal loss in specific brain regions.Animal models play an important role in elucidating the pathogenesis of neurodegenerative disorders such as HD and in identifying potential therapeutic targets.Due to the marked species differences between rodents and larger animals,substantial efforts have been directed toward establishing large animal models for HD research.These models are pivotal for advancing the discovery of novel therapeutic targets,enhancing effective drug delivery methods,and improving treatment outcomes.We have explored the advantages of utilizing large animal models,particularly pigs,in previous reviews.Since then,however,significant progress has been made in developing more sophisticated animal models that faithfully replicate the typical pathology of HD.In the current review,we provide a comprehensive overview of large animal models of HD,incorporating recent findings regarding the establishment of HD knock-in(KI)pigs and their genetic therapy.We also explore the utilization of large animal models in HD research,with a focus on sheep,non-human primates(NHPs),and pigs.Our objective is to provide valuable insights into the application of these large animal models for the investigation and treatment of neurodegenerative disorders.

A booming field of large animal model research

Animal models are integral to the study of fundamental biological processes and the etiology of human diseases.Small animal models,especially those involving mice,have yielded abundant and significant insights,greatly enhancing our understanding of biological phenomena and disease mechanisms.

Advances in anti-tumor mechanism and clinical application of Astragalus polysaccharides

Astragalus polysaccharide has the beneficial effect of Qi-deficiency,and it also has several anti-tumor mechanisms,including pharmacological actions and clinical functions.Through literature review,this work concluded anti-tumor mechanism and clinical application of astragalus polysaccharide,which was of considerable significance to expand and optimize its anti-tumor function and clinical application.

Clinical significance of serum TK1 and PNI in the prognosis of geriatric patients with advanced non-small cell lung cancer:a retrospective study

Objective:This study was designed to evaluate the clinical significance of the serum thymidine kinase 1(TK1)and prognosis nutrition index(PNI)in the prognosis of elderly patients with advanced non-small cell lung cancer(NSCLC).Methods:A total of 126 elderly patients with advanced non-small cell lung cancer from Jan.2015 to Apr.2016 were enrolled.The clinical,pathological and survival information were collected.The serum TK1 level was measured as well as PNI was calculated when the patient was admitted to our hospital for the first time.The relationship between serum TK1,PNI,and clinical prognostic characteristics was analyzed.The clinical significance of serum TK1 and PNI in the prognosis of elderly patients with advanced non-small cell lung cancer was investigated.Results:The results showed that the survival time of the patients was related to TK1 and PNI.The further Kaplan-Meier method and log-rank tests showed that the long-term outcome of the high-TK1 group was significantly worse than low-TK1 group(mOS,27 m vs.15 m,P=0.047).Besides,the Kaplan-Meier method and log-rank tests also showed that the long-term outcome of high-PNI group was significantly better than low-PNI group(mOS,31.5 m vs.16 m,P=0.015).However,the Spearman’s correlation analysis showed there was no correlation between PNI and TK1.The univariate and multivariate analysis showed that TK1,PNI and the number of metastatic sites were independent prognostic factors.Conclusions:The study confirmed the TK1 and PNI were independent prognostic factors of advanced NSCLC in the elderly.More attention worth is paid in routine clinical practice for patients cell proliferation and nutritional status.

Research progress on the regulation of androgen receptor signaling pathway in the treatment of prostate cancer by traditional Chinese medicine monomers

The prevalence of prostate cancer in males worldwide is increasing every year.Androgen and androgen receptor drive the development of prostate cancer and are important targets for the treatment of prostate cancer.A growing number of reports indicate that the traditional Chinese medicine has a clear advantage in the prevention and treatment of prostate cancer.This article provides an overview of the in vitro and in vivo studies of different traditional Chinese medicine monomers acting on the androgen receptor-signaling pathway in prostate cancer.

Prognostic implication and oncogenic role of RHCG in lung adenocarcinoma

Background:Previous studies have shown that the interaction of tumor cells and the microenvironment is critical for immunotherapy response.However,predicting clinical response to immunotherapy remains a challenging problem for clinicians.Therefore,this study aimed to investigate the relationship between the expression of Rh family,C glycoprotein(RHCG)in lung adenocarcinoma(LUAD)and prognosis and tumor-infiltrating immune cells.Methods:First,the expression of RHCG in LUAD tissues was detected by biological database.Chi-square test,Kaplan-Meier,univariate and multivariate Cox regression analysis were used to analyze the clinical significance of RHCG expression.To investigate the correlation between RHCG expression and the level of tumor-infiltrating immune cells in LUAD tissues.Receiver operating characteristic analysis was used to compare the predictive power of RHCG with other common immune-related markers.Results:In a TCGA cohort,we found that RHCG was upregulated in LUAD and increased with tumor grade.High RHCG expression was significantly associated with poor clinicopathological features and poor survival,which was further confirmed by clinical correlation analysis and survival analysis results.Furthermore,multivariate analysis indicated that RHCG was an independent prognostic biomarker for LUAD.Significantly,RHCG overexpression was associated with higher infiltration levels of CD4+T cells,CD8+T cells,B cells,macrophages and neutrophils in LUAD.Conclusions:We found that RHCG is upregulated as a biomarker of poor prognosis in LUAD.Importantly,RHCG overexpression correlated with the immune infiltration level of B cells,CD4+T cells,CD8+T cells,macrophages,neutrophils and other immune cells,and was closely related to the overall immune infiltration level of LUAD.These results suggest that RHCG may be a potential biomarker for assessing prognosis and immune infiltration in LUAD.

Clinical research progress of first-line immunotherapy for extensive-stage small cell lung cancer

Small cell lung cancer(SCLC)has a high degree of malignancy and rapid progression,and most of the patients are in the extensive stage when they are diagnosed.The traditional treatment of SCLC is mainly systematic chemotherapy combined with radiotherapy,but there has been no significant progress for many years.The emergence of immunotherapy represented by immune checkpoint inhibitors(ICIs)has changed the treatment pattern of SCLC.Some studies have confirmed the effect of ICIs monotherapy.However,the disadvantages of ICIs monotherapy such as low responsiveness,drug resistance,and adverse reactions limited the clinical application.The combined treatment of immune checkpoint inhibitors was newly developing treatment models.Clinical studies have found that ICIs combined with standard chemotherapy can significantly improve the survival of patients with extensive small cell lung cancer without increasing adverse reactions.Based on the synergistic effect of immunotherapy combined with chemotherapy,this paper reviews the current progress,deficiency and future exploration direction of first-line immunotherapy for extensive small cell lung cancer.

lncRNA NNT-AS1调控miR-518a-3p抑制IL-17诱导胃癌细胞增殖、迁移和侵袭的分子机制

背景白细胞介素17(interleukin 17,IL-17)是多细胞分泌因子,与肿瘤细胞发展有关,lncRNA NNT-AS1胃癌组织中lncRNA NNT-AS1表达上调,lncRNA NNT-AS1可能通过降低miR-363的表达抑制胃癌细胞增殖和侵袭,并阻滞细胞周期的发展.关于lncRNA NNT-AS1与IL-17调控作用对胃癌细胞研究尚不明确.目的探究长链非编码RNA烟酰胺核苷酸转氢酶反义RNA1(lncRNA NNT-AS1)调控miR-518a-3p抑制IL-17诱导胃癌细胞增殖、迁移和侵袭的分子机制.方法使用IL-17处理胃癌细胞AGS,将细胞分为对照(Con)组、IL-17组、IL-17+si-NC组、IL-17+si-lncRNA NNT-AS1组、IL-17+si-lncRNA NNT-AS1+anti-miR-NC组、IL-17+si-lncRNA NNT-AS1+anti-miR-518a-3p组.实时荧光定量PCR(RT-qPCR)检测miR-518a-3p和lncRNA NNT-AS1表达水平;克隆实验、Transwell检测AGS细胞增殖、迁移、侵袭;蛋白印迹法(Western blot)检测增殖、转移蛋白表达;双荧光素酶实验检测miR-518a-3p和lncRNA NNT-AS1关系.结果与Con组相比,IL-17组克隆细胞数、迁移细胞数、侵袭细胞数增多,lncRNA NNT-AS1表达水平、细胞核增殖抗原标记物(Ki-67)、基质金属蛋白酶2(matrix metalloproteinase 2,MMP2)、神经钙黏蛋白(N-cadherin)蛋白表达升高,miR-518a-3p表达水平、上皮钙黏蛋白(E-cadherin)蛋白表达降低.下调lncRNA NNT-AS1降低IL-17处理胃癌细胞克隆细胞数、迁移细胞数、侵袭细胞数,下调Ki-67、N-cadherin、MMP2蛋白表达,上调E-cadherin蛋白表达增加.lncRNA NNT-AS1靶向调控miR-518a-3p的表达,抑制miR-518a-3p可以逆转下调NNT-AS1对IL-17诱导胃癌细胞增殖、迁移和侵袭的影响.结论lncRNA NNT-AS1靶向调控miR-518a-3p抑制IL-17诱导胃癌细胞增殖、迁移和侵袭.

不同煤阶热解半焦的FT-Raman光谱研究(英文)

在热天平上采用慢速升温制备了褐煤、高挥发分烟煤和低挥发分烟煤的半焦。采用FTRaman光谱对半焦进行了分析。半焦800cm-1至1800cm-1的Raman光谱可分解为10个谱带,以表征高度无序炭材料中的典型结构。光谱和谱带的强度比都可用来描述半焦的结构特征。在600℃低温热解时,三种煤半焦的结构差异明显。随热解温度升至800℃或900℃,这种差别消失。褐煤中可交换的钠离子影响热解过程中的成焦反应。

The effect of strain rate on compressive behavior and failure mechanism of CMDB propellant

The compressive mechanical behavior of composite modified double base(CMDB)propellant was investigated across a wide scope of strain rates ranging from 10^(-3) s^(-1) to 4210 s^(-1) at room temperature,by applying a conventional universal testing machine and a split Hopkinson tension bar(SHPB),respectively.The derived stress-strain curves at different strain rates show a strong rate dependence,indicated that yield stress,ultimate stress and strain energy density of CMDB propellant all increase with strain rate by following a power law function,while the amplification of increase are different.The deformation and damage modes of CMDB propellant has changed from a typical ductile manner(cracking along the axial direction)to a brittle manner(maximum shear failure)with increasing of strain rate.Scanning electron microscopy(SEM)was employed to explore the microscopic failure characteristics of CMDB propellant.Under quasi-static loading,the nearly parallel micro-cracks propagating along the axial direction and the debonding of RDX particle without particle crushing can be observed.While under dynamic loading,the micro-crack is 45 angle to the axial direction,and multiple cracking modes of RDX particles appeared.Finally,the correlation between strain energy density and failure mechanisms of CMDB propellant was revealed by developing four characteristic failure modes.The findings of this study is very important to evaluate the structural integrity of CMDB propellant.

Xiaoyan decoction inhibits tumor growth and improves the immunity of mouse with A549 lung carcinoma xenograft

Background:Previously,Xiaoyan decoction(XYD)has been found to have a potential anti-tumor effect in vitro.The aim of this study was to explore the effect of XYD in A549 lung carcinoma xenograft mouse model.Method:The A549 lung carcinoma xenograft mouse model were established and divided into control and experiment group.The dynamic growth of the xenograft tumors was observed and the immune cells such as T cell,regulatory T cell(Treg)were explored by Fluorescence-activated cell sorter(FACS)analysis.In this study,network pharmacology was used to screen the anti-cancer monomers in XYD,and their effect targets were also predicted.Result:The result showed that the tumor growth was inhibited and the percent of Treg was down-regulated(P<0.05).Ten drug monomers were screened to inhibit lung cancer cell proliferation and promote cell apoptosis through PI3K/Akt pathway.Conclusion:Our results suggested that XYD inhibited tumor growth and improved the immunity of A549 lung carcinoma xenograft mouse model.

Traditional Chinese Medicine for Treatment of Apatinib-induced Hand and Foot Skin Reaction:A case report

Squamous cell carcinoma arising at maxillary sinus is a rare neoplasm, characterized by aggressive growth pattern and glooming prognosis. A 78-year-old woman presented with left maxillary sinus carcinoma. The patient received four courses of chemotherapy after surgery in our center. Eight months after treatment, the patient experienced local progress, severe gastrointestinal reactions and asthenia. Then apatinib was used as third-line treatment. Good curative effect was achieved with 250 mg apatinib per day, while adverse reaction such as hand and foot skin reaction affected the quality of her life. Traditional Chinese medicine exhibits good results and no obvious side effects in relieving hand and foot skin reaction. Traditional Chinese medicine is Chinese treasure, it remains challenging, and further investigations are needed.

Differential development and electrophysiological activity in cultured cortical neurons from the mouse and cynomolgus monkey

In vitro cultures of primary cortical neurons are widely used to investigate neuronal function.However,it has yet to be fully investigated whether there are significant differences in development and function between cultured rodent and primate cortical neurons,and whether these differences influence the utilization of cultured cortical neurons to model pathological conditions.Using in vitro culture techniques combined with immunofluorescence and electrophysiological methods,our study found that the development and maturation of primary cerebral cortical neurons from cynomolgus monkeys were slower than those from mice.We used a microelectrode array technique to compare the electrophysiological differences in cortical neurons,and found that primary cortical neurons from the mouse brain began to show electrical activity earlier than those from the cynomolgus monkey.Although cultured monkey cortical neurons developed slowly in vitro,they exhibited typical pathological features-revealed by immunofluorescent staining-when infected with adeno-associated viral vectors expressing mutant huntingtin(HTT),the Huntington’s disease protein.A quantitative analysis of the cultured monkey cortical neurons also confirmed that mutant HTT significantly reduced the length of neurites.Therefore,compared with the primary cortical neurons of mice,cultured monkey cortical neurons have longer developmental and survival times and greater sustained physiological activity,such as electrophysiological activity.Our findings also suggest that primary cynomolgus monkey neurons cultured in vitro can simulate a cell model of human neurodegenerative disease,and may be useful for investigating time-dependent neuronal death as well as treatment via neuronal regeneration.All mouse experiments and protocols were approved by the Animal Care and Use Committee of Jinan University of China(IACUC Approval No.20200512-04)on May 12,2020.All monkey experiments were approved by the IACUC protocol(IACUC Approval No.LDACU 20190820-01)on August 23,2019 for animal management and use.

Androgen receptor mediated resistance in the progression of castration-resistant prostate cancer

The incidence of prostate cancer has increased year by year in the world.Despite improvements in diagnosis,surgical techniques,and drugs,survival rates of prostate cancer have improved little,and most prostate cancer-related deaths are as a result of castration resistant prostate cancer(CRPC),which progresses and metastasizes after surgical or medical castration.The pathogenesis of CRPC is still unclear.It has been found that the majority of CRPC patients have overexpression of androgen receptors(ARs),and there are many forms of changes in the signaling pathways that intersect with them during he process to CRPC.Micro ribonucleic acid(miRNA)plays an important role in regulating the expression and translation of prostate cancer target genes,and in the life cycle of cell cycle distribution and apoptosis.Relatedly,active changes in miRNA expression are also closely related to androgen.Therefore,the study of AR-related signaling pathways and AR and miRNA-related signaling pathways is of great significance in the treatment of CRPC.

Bioinformatics analysis of Astragalus membranaceus on the treatment of prostate cancer

Objective:Prostate cancer(PCa)is the second most common male malignancy tumor in the world,and the occurrence rate and the mortality of PCa keeps increasing nowadays,exploration of accurate biomarker and predict clinical outcome of PCa is of great significance.Traditional Chinese medicine Huangqi(Astragalus membranaceus,AM)has been widely used for PCa treatment in China,while the pharmacological mechanisms are still unclear.The current paper intend to perform a network pharmacology analysis to reveal the mechanism of the effects of AM in PCa.Methods:Traditional Chinese Medicine Systems Pharmacology Database(TCMSP)was used to obtain chemical constituents of AM.PCa-related target genes were collected via OMIM and GeneCards databases.PCa-AM common target protein interaction network was established by the STRING database.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analyses were performed to further explore the PCa mechanism and therapeutic effect of AM.The network diagrams of the active component-action target and protein-protein interaction(PPI)networks were constructed using Cytoscape software.Results:A total of 20 active ingredients contained and 462 putative identified target genes were screened from AM,of which 46 overlapped with the targets of PCa and were considered potential therapeutic targets.The analysis of the network results showed that the AM activity components quercetin,kaempferol,isorhamnetin,3,9-di-O-methylnissolin and 7-O-methylisomucronulatol have a good binding activity with top ten screened targets,such as MYC,AKT1,CCND1,MAPK1,CASP3,EGFR,ESR1,VEGFA,ERBB2 and IL-6.GO and KEGG analyses revealed that these targets were associated with proteoglycans in cancer,virus infection,microRNAs in cancer,PI3K-Akt signaling pathway,and other biological process.Conclusion:This study demonstrated the multicomponent,multitarget,and multichannel characteristics of AM,which provided a novel approach for further research of the mechanism of AM in the treatment of PCa.

Evaluation of autophagy-related genes and lncRNAs signature for prognositic prediction in thyroid carcinoma via bioinformatics analysis

Autophagy plays a significant role in the pathogenesis and prognosis of thyroid carcinoma.The role of autophagy-related genes and long non-coding RNAs,as well as the risk model of thyroid carcinoma patients were investigated to predict clinical outcome of thyroid carcinoma.Different expression of autophagy-related genes and long non-coding RNAs in thyroid carcinoma patients was identified in The Cancer Genome Atlas database.Functional enrichment analysis and gene set enrichment analysis was used to hint the mechanism that autophagy might act in thyroid carcinoma.Univariate and multivariate Cox regression analyses were performed for screening the prognostic autophagy-related genes and long non-coding RNAs to construct prognostic related risk model.thyroid carcinoma patients were divided into the low-risk and high-risk groups.The overall survival time was both shorter in the high-risk groups than that in the low-risk groups.As for autophagy-related genes prognostic risk model,age and autophagy-related genes risk score are independent prognostic factors that affect the survival of thyroid carcinoma.ATIC and CDKN2A expression was closely related to pathological stage and T status,DNAJB1 expression was closely related to M status,age and gender.While autophagy-associated long non-coding RNA related prognostic risk model consequently demonstrated that the long non-coding RNA risk score could significantly predict the survival rate of thyroid carcinoma patients with areas under the curve of 0.972.gene set enrichment analysis presented that a total of 16 gene sets including 10 up-regulated and 6 down-regulated gene sets were significantly enriched.The autophagy-related genes and long non-coding RNAs based prognostic risk models are a reliable forecasting tool for thyroid carcinoma patients.

Interaction between LCSCs and lung cancer microenvironment and TCM intervention

Lung cancer has become a leading cause of cancer-related death because of its high morbidity and mortality.Although some progress has been made in the diagnosis,surgery,chemoradiotherapy,and other aspects of lung cancer in the last decade,actually there is no substantial breakthrough for the 5-year survival rate of patients has no significant improvement and is still below 15%.Plenty of evidence suggests that malignant tumors including lung cancer have a unique subgroup of cells featured with self-renewal and multidirectional differentiation potential.Cancer stem cells(CSCs)are the root of tumor growth and metastasis,and the characteristic changes of malignant phenotype(such as recurrence,invasion and metastasis,and drug resistance)are closely linked with CSCs.This paper explored the possible correlated mechanism of the complex interaction between lung cancer stem cells(LCSCs)and lung cancer microenvironment,to provide ideas for the R&D of relevant treatment technologies,the promotion of the progress in traditional medical technology,and the breakthrough of the bottleneck of long-term effect of lung cancer.