Pyroptosis,ferroptosis,and autophagy in spinal cord injury:regulatory mechanisms and therapeutic targets

Regulated cell death is a form of cell death that is actively controlled by biomolecules.Several studies have shown that regulated cell death plays a key role after spinal cord injury.Pyroptosis and ferroptosis are newly discovered types of regulated cell deaths that have been shown to exacerbate inflammation and lead to cell death in damaged spinal cords.Autophagy,a complex form of cell death that is interconnected with various regulated cell death mechanisms,has garnered significant attention in the study of spinal cord injury.This injury triggers not only cell death but also cellular survival responses.Multiple signaling pathways play pivotal roles in influencing the processes of both deterioration and repair in spinal cord injury by regulating pyroptosis,ferroptosis,and autophagy.Therefore,this review aims to comprehensively examine the mechanisms underlying regulated cell deaths,the signaling pathways that modulate these mechanisms,and the potential therapeutic targets for spinal cord injury.Our analysis suggests that targeting the common regulatory signaling pathways of different regulated cell deaths could be a promising strategy to promote cell survival and enhance the repair of spinal cord injury.Moreover,a holistic approach that incorporates multiple regulated cell deaths and their regulatory pathways presents a promising multi-target therapeutic strategy for the management of spinal cord injury.

G protein coupled receptors signaling pathways implicate in inflammatory and immune response of rheumatoid arthritis

G protein coupled receptors(GPCRs)are transmembrane receptor proteins,which allow signals to transfer across membrane.GPCRs include a large number of receptors,different receptors mediated different signaling pathways of GPCRs-adenylyl cyclase(AC)-cyclic adenosine 3',5'-monophosphate(c AMP),including β2 adrenergic receptors(β2-ARs)-AC-c AMP signaling pathways,E-prostanoid2/4(EP2/4)-AC-cA MP signaling pathways.Regulatory proteins,such as G protein coupled receptor kinases(GRKs)andβ-arrestins,play important modulatory roles in GPCRs signaling pathway.GPCRs signaling pathway and regulatory proteins implicate the pathogenesis process of inflammatory and immune response.Rheumatoid arthritis(RA)is an autoimmune disease characterized by synovitis and accompanied with inflammatory and abnormal immune response.This article review the advances on GPCRs signaling pathway implicating in the inflammatory and immune response of RA.

MicroRNA regulatory pattern in spinal cord ischemia-reperfusion injury

After spinal cord injury, dysregulated miRNAs appear and can participate in inflammatory responses, as well as the inhibition of apoptosis and axon regeneration through multiple pathways. However, the functions of miRNAs in spinal cord ischemia-reperfusion injury progression remain unclear. miRCURY LNATM Arrays were used to analyze miRNA expression profiles of rats after 90 minutes of ischemia followed by reperfusion for 24 and 48 hours. Furthermore, subsequent construction of aberrantly expressed miRNA regulatory patterns involved cell survival, proliferation, and apoptosis. Remarkably, the mitogen-activated protein kinase(MAPK) signaling pathway was the most significantly enriched pathway among 24-and 48-hour groups. Bioinformatics analysis and quantitative reverse transcription polymerase chain reaction confirmed the persistent overexpression of miR-22-3 p in both groups. These results suggest that the aberrant miRNA regulatory network is possibly regulated MAPK signaling and continuously affects the physiological and biochemical status of cells, thus participating in the regulation of spinal cord ischemia-reperfusion injury. As such, miR-22-3 p may play sustained regulatory roles in spinal cord ischemia-reperfusion injury. All experimental procedures were approved by the Animal Ethics Committee of Jilin University, China [approval No. 2020(Research) 01].

Research status of E3 ubiquitin ligase Smurf2 and related signaling pathways in glioma

Glioma is the tumor with the highest incidence in the brain,and it is eager to seek new and efiective treatment.The interaction of ubiquitination and deubiquitination regulates many cell activities in organisms,and participates in tumor occurrence,development,migration,invasion and other processes.This article summarized the progress of E3 ubiquitination ligase smad ubiquitination regulatory factor 2(Smurf2)and glioma-related signaling pathways to assist clinical diagnosis and treatment of glioma.

Long noncoding RNAs:new insights in modulating mammalian spermatogenesis

Spermatogenesis is a complex differentiating developmental process in which undifferentiated spermatogonial germ cells differentiate into spermatocytes,spermatids,and finally,to mature spermatozoa.This multistage developmental process of spermatogenesis involves the expression of many male germ cell-specific long noncoding RNAs(lncRNAs)and highly regulated and specific gene expression.LncRNAs are a recently discovered large class of noncoding cellular transcripts that are still relatively unexplored.Only a few of them have postmeiotic;however,lncRNAs are involved in many cellular biological processes.The expression of lncRNAs is biologically relevant in the highly dynamic and complex program of spermatogenesis and has become a research focus in recent genome studies.This review considers the important roles and novel regulatory functions whereby lncRNAs modulate mammalian spermatogenesis.

Grain Shape Genes:Shaping the Future of Rice Breeding

The main goals of rice breeding nowadays include increasing yield,improving grain quality,and promoting complete mechanized production to save labor costs.Rice grain shape,specified by three dimensions,including grain length,width and thickness,has a more precise meaning than grain size,contributing to grain appearance quality as well as grain weight and thus yield.Furthermore,the divergence of grain shape characters could be utilized in mechanical seed sorting in hybrid rice breeding systems,which has been succeeded in utilizing heterosis to achieve substantial increase in rice yield in the past decades.Several signaling pathways that regulate rice grain shape have been elucidated,including G protein signaling,ubiquitination-related pathway,mitogen-activated protein kinase signaling,phytohormone biosynthesis and signaling,micro RNA process,and some other transcriptional regulatory pathways and regulators.This review summarized the recent progress on molecular mechanisms underlying rice grain shape determination and the potential of major genes in future breeding applications.

Expressions of the Cell Cycle Relative Proteins in Esophageal Cancer Tissues

The aim of the research is to investigate the expression of the cell cycle relative proteins (P53, P16, Cyclin D1, and Ki67) in Esophageal Cancer (EC) patients of the Chaoshan area, China. In China, Chaoshan has the high incidence of EC. Different areas have shown different rate for expression of these proteins in EC. We investigated the expression of p53, p16, cyclinD1, and ki67 for the first time in Chaoshan. In this research, DNA was extracted from formalin fixed and paraffin embedded tissues of esophageal cancer (EC) patients. The expression level of proteins cycle was detected by using immunohistochemistry (IHC). And the data was checked by χ2 test or Fisher’s exact test of SPSS17.0. The positive immunohistochemical staining of p53, p16, cyclinD1, and ki67 were observed in 65.7% 39.2%, 69.1%, and 83.5% specimens respectively. There was a positive correlation between p53 positive staining and p16, cyclinD1, ki67 staining at p < 0.05. CyclinD1 has the high correlation with ki67 at p < 0.05. A significant inverse correlation was considered between the expression of p16 and cyclinD1 and there was no correlation observed between p16 and ki67. In Conclusion, this study demonstrated the high expression of p53, Cyclin D1 and Ki67 and low expression of P16 and the association of these cell cycle relative proteins in esophageal cancer are new data in Chaoshan area of China. Geographical distribution of EC on the molecular basis is revealed in this research.

A pH-responsive polymersome depleting regulatory T cells and blocking A2A receptor for cancer immunotherapy

The immunosuppressive tumor microenvironment(ITM)and low immunogenicity of tumors greatly limit cancer immunotherapy efficacy.The approach of solely depleting regulatory T cells(Tregs)cannot ameliorate ITM,but possibly worsen it since the produced apoptotic Tregs will activate the A2A signaling pathway and cause more severe immune suppression.To address it,in this work a pH-responsive polymersome(CY/ZM@CS-BPA)based on chondroitin sulfate(CS)-poly(β-amino ester)is rationally developed.In the acidic tumor microenvironment,the tertiary amine groups in the polymersome will reverse from hydrophobic to hydrophilic due to protonation,which leads to the disintegration of nanostructures and the release of cyclophosphamide(CY)and A2A receptor(A2AR)antagonist ZM241385(ZM).CY can selectively deplete Tregs.Additionally,CY can induce immunogenic cell death(ICD)of tumor cells,which results in the proapoptotic translocation of calreticulin to the cell surface,further initiating the antitumor immune responses.ZM can inhibit the activation of the adenosine A2A pathway,subsequently preventing the differentiation of CD4^(+)T cells into Tregs and enhancing the cytotoxicity of CD8+T cells.As a result,the combination of depleting regulatory T cells and blocking the A2A receptor can enhance cancer immunotherapy efficacy.

Transcription factor EHF interacting with coactivator AJUBA aggravates malignancy and acts as a therapeutic target for gastroesophageal adenocarcinoma

Transcriptional dysregulation of genes is a hallmark of tumors and can serve as targets for cancer drug development.However,it is extremely challenging to develop small-molecule inhibitors to target abnormally expressed transcription factors(TFs)except for the nuclear receptor family of TFs.Little is known about the interaction between TFs and transcription cofactors in gastroesophageal adenocarcinoma(GEA)or the therapeutic effects of targeting TF and transcription cofactor complexes.In this study,we found that ETS homologous factor(EHF)expression is promoted by a core transcriptional regulatory circuitry(CRC),specifically ELF3-KLF5-GATA6,and interference with its expression suppressed the malignant biological behavior of GEA cells.Importantly,we identified Ajuba LIM protein(AJUBA)as a new coactivator of EHF that cooperatively orchestrates transcriptional network activity in GEA.Furthermore,we identified KRAS signaling as a common pathway downstream of EHF and AJUBA.Applicably,dual targeting of EHF and AJUBA by lipid nanoparticles cooperatively attenuated the malignant biological behaviors of GEA in vitro and in vivo.In conclusion,EHF is upregulated by the CRC and promotes GEA malignancy by interacting with AJUBA through the KRAS pathway.Targeting of both EHF and its coactivator AJUBA through lipid nanoparticles is a novel potential therapeutic strategy.

An Uncanonical CCCH-Tandem Zinc-Finger Protein Represses Secondary Wall Synthesis and Controls Mechanical Strength in Rice

Secondary walls, which represent the bulk of biomass, have a large impact on plant growth and adaptation to environments. Secondary wall synthesis is switched and regulated by a sophisticated signaling transduction network. However, there is limited understanding of these regulatory pathways. Here, we report that ILAl-interacting protein 4 （lIP4） can repress secondary wall synthesis, lIP4 is a phosphorylation sub- strate of an Raf-like MAPKKK, but its function is unknown. By generating lip4 mutants and relevant transgenic plants, we found that lesions in lIP4 enhance secondary wall formation. Gene expression and transactivation activity assays revealed that lIP4 negatively regulates the expression of MYB61 and CESAs but does not bind their promoters, lIP4 interacts with NAC29/NAC31, the upstream regulators of secondary wall synthesis, and suppresses the downstream regulatory pathways in plants. Mutagenesis analyses showed that phosphomimic UP4 proteins translocate from the nucleus to the cytoplasm, which releases interacting NACs and attenuates its repression function. Moreover, we revealed that liPs are evolutionarily conserved and share unreported CCCH motifs, referred to as uncanonical CCCH-tandem zinc-finger proteins. Collectively, our study provides mechanistic insights into the control of secondary wall synthesis and presents an opportunity for improving relevant agronomic traits in crops.

Osteoporosis:A Silent Disease with Complex Genetic Contribution

Osteoporosis is the most common multifactorial metabolic bone disorder worldwide with a strong genetic component. In this review, the evidence for a genetic contribution to osteoporosis and related phenotypes is summarized alongside with methods used to identify osteoporosis susceptibility genes. The key biological pathways involved in the skeleton and bone development are discussed with a particular focus on master genes clustered in these pathways and their mode of action. Furthermore, the most studied single nucleotide polymorphisms （SNPs） analyzed for their importance as genetic markers of the disease are presented. New data generated by next- generation sequencing in conjunction with extensive meta-analyses should contribute to a better understanding of the genetic basis of osteoporosis and related phenotype variability. These data could be ultimately used for identifying at-risk patients for disease prevention by both controlling environmental factors and providing possible therapeutic targets.

Long noncoding RNA(lncRNA)HOTAIR:Pathogenic roles and therapeutic opportunities in gastric cancer

Gastric cancer is one of the first malignant cancers in the world and a large number of people die every year due to this disease.Many genetic and epigenetic risk factors have been identified that play a major role in gastric cancer.HOTAIR is an effective epigenetic agent known as long noncoding RNA(lncRNA).HOTAIR has been described to have biological functions in biochemical and cellular processes through interactions with many factors,leading to genomic stability,proliferation,survival,invasion,migration,metastasis,and drug resistance.In the present article,we reviewed the prognostic value of the molecular mechanisms underlying the HOTAIR regulation and its function in the development of Gastric Cancer,whereas elucidation of HOTAIR–protein and HOTAIR–DNA interactions can be helpful in the identification of cancer processes,leading to the development of potential therapeutic strategies.

Systematic identification and functional analysis of long noncoding RNAs involved in indoxacarb resistance in Spodoptera litura

Long noncoding RNAs(lncRNAs)are noncoding transcripts that are more than 200 nucleotides long.They play essential roles in regulating a variety of biological processes in many species,including insects,and some lncRNAs have been found to be associated with insecticide resistance.However,the characteristics and biological func-tions of lncRNAs involved in indoxacarb resistance are unknown in Spodoptera litura.We performed RNA sequencing in the SS,InRS,and FInRS of S.litura and identified 11978 lncRNAs,including 3136 intergenic lncRNAs,7393 intronic lncRNAs,and 1449 anti-sense lncRNAs.Compared with the SS,51 lncRNAs were upregulated and 134 lncRNAs were downregulated in the two resistant strains,and 908 differentially expressed mRNAs were predicted as the target genes of the 185 differentially expressed lncRNAs.Further analysis showed that 112 of differentially expressed lncRNAs may be associated with in-doxacarb resistance by regulating the expression of 14 P450s,seven CCEs,one GST,six UGTs,five ABC transporters,and 24 cuticle protein genes,and 79 of differentially ex-pressed lncRNAs may regulate the expression of 14 detoxification genes and 19 cuticle protein genes to participate in indoxacarb resistance by sponging 10 microRNAs.Interest-ingly,47 of differentially expressed lncRNAs may mediate indoxacarb resistance through both lncRNA-mRNA and lncRNA-miRNA-mRNA regulatory pathways.Furthermore,quantitative PCR,RNA interference,and indoxacarb bioassay analyses indicated that over-expressed LNC_004867 and LNC_006576 were involved in indoxacarb resistance.This study provides comprehensive information for lncRNAs of S.litura,and presents evidence that lncRNAs havekey roles in conferring insecticide resistance in S.litura.

Integrated analysis of miRNA and mRNA expression profiles in response to gut microbiota depletion in the abdomens of female Bactrocera dorsalis

Insect gut microbiota has been reported to participate in regulating host multiple biological processes including metabolism and reproduction.However,the corresponding molecular mechanisms remain largely unknown.Recent studies suggest that microRNAs(miRNAs)are involved in complex interactions between the gut microbiota and the host.Here,we used next-generation sequencing technology to characterize miRNA and mRNA expression profiles and construct the miRNA–gene regulatory network in response to gut microbiota depletion in the abdomens of female Bactrocera dorsalis.A total of 3016 differentially expressed genes(DEGs)and 18 differentially expressed miRNAs(DEMs)were identified.Based on the integrated analysis of miRNA and mRNA sequencing data,229 negatively correlated miRNA-gene pairs were identified from the miRNA-mRNA network.Gene ontology enrichment analysis indicated that DEMs could target several genes involved in the metabolic process,oxidation-reduction process,oogenesis,and insulin signaling pathway.Finally,real-time quantitative polymerase chain reaction further verified the accuracy of RNA sequencing results.In conclusion,our study provides the profiles of miRNA and mRNA expressions under antibiotics treatment and provides an insight into the roles of miRNAs and their target genes in the interaction between the gut microbiota and its host.

Temperature-mediated regulation of flowering time in Arabidopsis thaliana

Throughout a plant's life cyde,temperature plays a major role in development.Regulatory modules use temperature cues to control gene expression,facilitating physiological change from germination to flowering.These regulatory modules control morphological and molecular responses to temperature changes caused by seasonal changes or by temporary fluctuations,providing a versatile plasticity of plants.In this review,we outline how temperature changes affect the regu latory modules that induce and repress flowering,in addition to general temperature regulation.Recent studies have identified several regulatory modules by which floral transition and growth responses are controlled in a tem-perature-dependent manner.This review will report on recent studies related to floral transition and ambient temperature response.