Microenvironmental effects on growth response of Pinus massoniana to climate at its northern boundary in the Tongbai Mountains,Central China

The Tongbai Mountains is an ecologically sensi-tive region and the northern boundary of Pinus massoniana Lamb.To analyze the effect of different microenvironments on tree growth response to climate factors,we developed standard chronologies for earlywood width(EWW),late-wood width(LWW),and total ring width(TRW)of P.massoniana at two sampling sites on slopes with different orientations,then analyzed characteristics of the chronolo-gies and their correlations with climate variables from five stations in the region and with a regional normalized differ-ence vegetation index(NDVI).Statistical results showed that the TRW/EWW/LWW chronology consistency and charac-teristics(mean sensitivity,signal to noise ratio,expressed population signal)for trees growing on the southeastern slope were much higher than for trees on the northeastern slope.Correlations indicated that temperature in current March and August has a significant positive effect on TRW/EWW/LWW formation,and the effect on the northeastern slope was weaker than on the southeastern slope.Compared to temperature,precipitation has more complicated effects on tree growth,but the effect on the northeastern slope was also generally weaker than on the southeastern slope.Step-wise linear regression analyses showed that temperature in August was the main limiting factor at the two sampling sites.Similarly,the response of tree growth on the southeast-ern slope as determined by the NDVI is better than on the northeastern slope,and the TRW/EWW/LWW chronologies for the southeastern slope explained over 50%of the total NDVI variances in June.Overall,the results indicate that the difference in the climate response of P.massoniana at two sampling sites is clearly caused by differences in the microenvironment,and such differences should be properly considered in future studies of forest dynamics and climate reconstructions.

Construction of microenvironmental biointerfaces

Biomaterial acts as artificial extracellular matrix for providing a provisional three-dimensional (3D) microenvironments to interact biophysically and/or biochemically with cells to regulate cell behaviors,such as cell adhesion,migration,prolifera-

Microenvironmental biomaterials

Biomaterials play essential role in regenerative medicine and tissue engineering,which providing a provisional three-dimensional(3D) microenvironments to interact biophysically and/or biochemically with cells to guide cellular performance[1].It thus spatially and

Stem cell-based bone and dental regeneration: a view of microenvironmental modulation

In modern medicine,bone and dental loss and defects are common and widespread morbidities,for which regenerative therapy has shown great promise.Mesenchymal stem cells,obtained from various sources and playing an essential role in organ development and postnatal repair,have exhibited enormous potential for regenerating bone and dental tissue.Currently,mesenchymal stem cells (MSCs)-based bone and dental regeneration mainly includes two strategies: the rescue or mobilization of endogenous MSCs and the application of exogenous MSCs in cytotherapy or tissue engineering.Nevertheless,the efficacy of MSCbased regeneration is not always fulfilled,especially in diseased microenvironments.Specifically,the diseased microenvironment not only impairs the regenerative potential of resident MSCs but also controls the therapeutic efficacy of exogenous MSCs,both as donors and recipients.Accordingly,approaches targeting a diseased microenvironment have been established,including improving the diseased niche to restore endogenous MSCs,enhancing MSC resistance to a diseased microenvironment and renormalizing the microenvironment to guarantee MSC-mediated therapies.Moreover,the application of extracellular vesicles (EVs) as cell-free therapy has emerged as a promising therapeutic strategy.In this review,we summarize current knowledge regarding the tactics of MSC-based bone and dental regeneration and the decisive role of the microenvironment,emphasizing the therapeutic potential of microenvironment-targeting strategies in bone and dental regenerative medicine.

Input of microenvironmental regulation on colorectal cancer: Role of the CCN family

Colorectal cancer(CRC)is a major health problem causing significant morbidity and mortality.Previous results from various studies indicate that CRC tumorigenicity encompasses tumor microenvironment,emphasizing the complex interacting network between cancer cells and nearby host cells,which triggers diverse signaling pathways to promote the growth and spread ofcancer cells.The CCN family proteins share a uniform modular structure,mediating a variety of physiological functions,including proliferation,apoptosis,migration,adhesion,differentiation,and survival.Furthermore,CCN proteins are also involved in CRC initiation and development.Many studies have shown that CCN members,such as CCN1,CCN2,CCN3,Wnt-induced secreted protein(WISP)-1,WISP-2,and WISP-3,are dysregulated in CRC,which implies potential diagnostic markers or therapeutic targets clinically.In this review,we summarize the research findings on the role of CCN family proteins in CRC initiation,development,and progression,highlighting their potential for diagnosis,prognosis,and therapeutic application.

Effect of microenvironmental quantitative regulation on growth of Korean pine trees planted under secondary forest

Korean pine（Pinus koraiensis） and broadleaved mixed forest in Northeast China has been changed regressively into secondary forest with almost no conifers.Planting Korean pine trees under the canopy of secondary forest is a feasible approach for recovering Korean pine and broadleaved mixed forest.For establishing an effective growth promotion method for under-canopy planted young Korean pine trees,two stands were selected as the experiment plots,Stand A（planted in 1989） and Stand B（planted in 1982）,and an experiment of microenvironment regulation was conducted relying mainly on Opening degree（K=1,K=1.5,K=2,CK） in 2004.The results were shown that the adjustment had promoted growth of diameter and height of Korean pine planted in Stand A and Stand B,and had a significant influence on the growth rate of basal diameter,diameter at breast height and height in the two growth stands.The four years periodic increment of mean diameter and height of Korean pine planted in 1989 and in 1982 after regulation in K=1 level were 63.4%（D0） and 82.7%（H）,64.8%（D1.3） and 69.7%（H） higher than that of control respectively.Quantitative regulation had significant influence on specific leaf area of Korean pine planted in 1989,and the current year specific leaf area（SLA） was lager than perennial year SLA.Quality indexes of natural pruning capacity,normal form quotient and crown size was not significantly changed but shown a positive tendency.The regulation scheme of Opening degree K=1 might be proper for adjusting the microenvironment of Korean pine trees planted under the canopy of secondary forest when the Korean pine trees were in the growth period of 15 to 26 years old in the experiment region.

Microenvironmental engineering:An effective strategy for tailoring enzymatic activities

Rationally,engineering a favorable physicochemical microenvironment for enzymes has recently emerged as an effective strategy to improve their catalytic performance.In this review,we discuss four microenvironmental effects according to the mechanism of action:localizing and excluding reactants and regulators,regulating microenvironmental pH,creating a water-like microenvironment,and increasing the local temperature.These mechanisms are enzyme-independent and can in principle be used in combination to tailor enzyme behaviors,offering new approaches to enabling,enhancing,and regulating enzyme catalysis in diverse applications without the need for genetic engineering.

New targeted therapies for breast cancer: A focus on tumor microenvironmental signals and chemoresistant breast cancers

Breast cancer is the most frequent female malignancy worldwide. Current strategies in breast cancer therapy,including classical chemotherapy, hormone therapy, and targeted therapies, are usually associated with chemoresistance and serious adverse effects. Advances in our understanding of changes affecting the interactome in advanced and chemoresistant breast tumors have provided novel therapeutic targets, including, cyclin dependent kinases, mammalian target of rapamycin,Notch, Wnt and Shh. Inhibitors of these molecules recently entered clinical trials in mono- and combination therapy in metastatic and chemo-resistant breast cancers. Anticancer epigenetic drugs, mainly histone deacetylase inhibitors and DNA methyltransferase inhibitors, also entered clinical trials. Because of the complexity and heterogeneity of breast cancer, the future in therapy lies in the application of individualized tailored regimens. Emerging therapeutic targets and the implications for personalized-based therapy development in breast cancer are herein discussed.

Role of Immune Microenvironmental Factors for Improving the IPI-related Risk Stratification of Aggressive B Cell Lymphoma

Objective To investigate the risk stratification of aggressive B cell lymphoma using the immune microenvironment and clinical factors. Methods A total of 127 patients with aggressive B cell lymphoma between 2014 and 2015 were enrolled in this study. CD4, Foxp3, CDS, CD68, CD163, PD-1, and PD-L1 expression levels were evaluated in paraffin-embedded lymphoma tissues to identify their roles in the risk stratification. Eleven factors were identified for further evaluation using analysis of variance, chi-square, and multinomial logistic regression analysis. Results Significant differences in 11 factors （age, Ann Arbor stage, B symptom, ECOG performance status, infiltrating CD8＋ T cells, PD-L1 expression, absolute blood monocyte count, serum lactate dehydrogenase, serum iron, serum albumin, and serum l^2-microglobulin） were observed among patient groups stratified by at least two risk stratification methods [International Prognostic Index （IPI）, revised IPI, and NCCN-IPI models] （P 〈 0.05）. Concordance rates were high （81.4%-100.0%） when these factors were used for the risk stratification. No difference in the risk stratification results was observed with or without the Ann Arbor stage data. Conclusion We developed a convenient and inexpensive tool for use in risk stratification of aggressive B cell lymphomas, although further studies on the role of immune microenvironmental factors are needed.

Microenvironmental regulation of stem cells injected in the area at risk of neurodegenerative diseases

The complex mechanism of degenerative diseases and the non-specific modulation of regenerative targets aretopics that need to be elucidated in order to advance the use of stem cells in improvement of neurodegenerative diseases.From pre-transplantation through post-transplantation, there are many changes in the conditions, both inside andoutside of the stem cells that have not been carefully considered. This has hindered development in the field of celltherapy and regeneration. This viewpoint highlights the potential implications of intracellular and extracellularalterations of stem cells in transplanted areas at risk of neurodegenerative disease.

Centrosome and vascular microenvironmental homeostasis

The homeostasis of vascular microenvironment is essential to maintain the normal vascular structure and function,while its disorder leads to vascular dysfunction,and cardiovascular and cerebrovascular diseases.Centrosome is an important organelle existing in mammalian cells as well as the microtubule organizing center,playing an important role in maintaining vascular structure and homeostasis.This study reviewed the role of centrosome in the regulation of vascular microenvironmental homeostasis.Centrosomal proteins intricately regulate microtubule dynamics and stabilization,and diverse microtubule-relatived cellular activities,including the division,polarization and directional migration of vascular endothelial cells,smooth muscle cells and other types of cells.In addition,primary cilia formed by centrosome are essential in vascular microenvironment.Tumor endothelial cells usually acquire excess centrosomes,and excess centrosomes are regulated by several angiogenic factors.Therefore,uncovering the detailed molecular mechanisms underlying centrosome affecting vascular microenvironmental homeostasis are needed for the treatment of cardiovascular and cerebrovascular diseases.

Understanding endometriosis from an immunomicroenvironmental perspective

Endometriosis,a heterogeneous,inflammatory,and estrogen-dependent gynecological disease defined by the presence and growth of endometrial tissues outside the lining of the uterus,affects approximately 5-10%of reproductive-age women,causing chronic pelvic pain and reduced fertility.Although the etiology of endometriosis is still elusive,emerging evidence supports the idea that immune dysregulation can promote the survival and growth of retrograde endometrial debris.Peritoneal macrophages and natural killer(NK)cells exhibit deficient cytotoxicity in the endometriotic microenvironment,leading to inefficient eradication of refluxed endometrial fragments.In addition,the imbalance of T-cell subtypes results in aberrant cytokine production and chronic inflammation,which contribute to endometriosis development.Although it remains uncertain whether immune dysregulation represents an initial cause or merely a secondary enhancer of endometriosis,therapies targeting altered immune pathways exhibit satisfactory effects in preventing disease onset and progression.Here,we summarize the phenotypic and functional alterations of immune cells in the endometriotic microenvironment,focusing on their interactions with microbiota and endocrine and nervous systems,and how these interactions contribute to the etiology and symptomology of endometriosis.

Microbiome changes in esophageal cancer:implications for pathogenesis and prognosis

Esophageal cancer(EC)is an aggressive malignancy with a poor prognosis.Various factors,including dietary habits,and antacid and antibiotic use,have been shown to influence the esophageal microbiome.Conversely,enrichment and diversity of the esophageal microbiome can also impact its function.Recent studies have revealed prevalent changes in the esophageal microbiome among patients with EC,thus suggesting the potential contribution of the esophageal microbiome to EC development.Additionally,distinct microbiome compositions have been observed in patients with different responses to radiotherapy and chemotherapy,indicating the role of the esophageal microbiome in modulating treatment outcomes.In this review,we have examined previous studies on the esophageal microbiome in healthy individuals and patients with EC or other esophageal diseases,with a focus on identifying microbial communities associated with EC pathogenesis and prognosis.Understanding the role of the microbiome in EC may aid in early detection and optimized treatment strategies,ultimately leading to better outcomes for patients.

Estimation of cancer cell migration in biomimetic random/oriented collagen fiber microenvironments

Increasing data indicate that cancer cell migration is regulated by extracellular matrixes and their surrounding biochemical microenvironment,playing a crucial role in pathological processes such as tumor invasion and metastasis.However,conventional two-dimensional cell culture and animal models have limitations in studying the influence of tumor microenvironment on cancer cell migration.Fortunately,the further development of microfluidic technology has provided solutions for the study of such questions.We utilize microfluidic chip to build a random collagen fiber microenvironment(RFM)model and an oriented collagen fiber microenvironment(OFM)model that resemble early stage and late stage breast cancer microenvironments,respectively.By combining cell culture,biochemical concentration gradient construction,and microscopic imaging techniques,we investigate the impact of different collagen fiber biochemical microenvironments on the migration of breast cancer MDA-MB-231-RFP cells.The results show that MDA-MB-231-RFP cells migrate further in the OFM model compared to the RFM model,with significant differences observed.Furthermore,we establish concentration gradients of the anticancer drug paclitaxel in both the RFM and OFM models and find that paclitaxel significantly inhibits the migration of MDA-MB-231-RFP cells in the RFM model,with stronger inhibition on the high concentration side compared to the low concentration side.However,the inhibitory effect of paclitaxel on the migration of MDA-MB-231-RFP cells in the OFM model is weak.These findings suggest that the oriented collagen fiber microenvironment resembling the late-stage tumor microenvironment is more favorable for cancer cell migration and that the effectiveness of anticancer drugs is diminished.The RFM and OFM models constructed in this study not only provide a platform for studying the mechanism of cancer development,but also serve as a tool for the initial measurement of drug screening.

New roles of tumor-derived exosomes in tumor microenvironment

Throughout tumorigenesis, the co-evolution of tumor cells and their surrounding microenvironment leads to the development of malignant phenotypes. Cellular communication within the tumor microenvironment(TME) plays a critical role in influencing various aspects of tumor progression, including invasion and metastasis. The release of exosomes, a type of extracellular vesicle, by most cell types in the body, is an essential mediator of intercellular communication. A growing body of research indicates that tumor-derived exosomes(TDEs) significantly expedite tumor progression through multiple mechanisms, inducing epithelial-mesenchymal transition and macrophage polarization, enhancing angiogenesis, and aiding in the immune evasion of tumor cells. Herein, we describe the formation and characteristics of the TME, and summarize the contents of TDEs and their diverse functions in modulating tumor development. Furthermore, we explore potential applications of TDEs in tumor diagnosis and treatment.

Spatial transcriptomics reveals that metabolic characteristics define the tumor immunosuppression microenvironment via iCAF transformation in oral squamous cell carcinoma

Tumor progression is closely related to tumor tissue metabolism and reshaping of the microenvironment. Oral squamous cell carcinoma (OSCC), a representative hypoxic tumor, has a heterogeneous internal metabolic environment. To clarify the relationship between different metabolic regions and the tumor immune microenvironment (TME) in OSCC, Single cell (SC) and spatial transcriptomics (ST) sequencing of OSCC tissues were performed. The proportion of TME in the ST data was obtained through SPOTlight deconvolution using SC and GSE103322 data. The metabolic activity of each spot was calculated using scMetabolism,and k-means clustering was used to classify all spots into hyper-, normal-, or hypometabolic regions. CD4T cell infiltration and TGF-βexpression is higher in the hypermetabolic regions than in the others. Through CellPhoneDB and NicheNet cell-cell communication analysis, it was found that in the hypermetabolic region, fibroblasts can utilize the lactate produced by glycolysis of epithelial cells to transform into inflammatory cancer-associated fibroblasts (iCAFs), and the increased expression of HIF1A in iCAFs promotes the transcriptional expression of CXCL12. The secretion of CXCL12 recruits regulatory T cells (Tregs), leading to Treg infiltration and increased TGF-β secretion in the microenvironment and promotes the formation of a tumor immunosuppressive microenvironment. This study delineates the coordinate work axis of epithelial cells-iCAFs-Tregs in OSCC using SC, ST and TCGA bulk data, and highlights potential targets for therapy.

Transplantation of fibrin-thrombin encapsulated human induced neural stem cells promotes functional recovery of spinal cord injury rats through modulation of the microenvironment

Recent studies have mostly focused on engraftment of cells at the lesioned spinal cord,with the expectation that differentiated neurons facilitate recovery.Only a few studies have attempted to use transplanted cells and/or biomaterials as major modulators of the spinal cord injury microenvironment.Here,we aimed to investigate the role of microenvironment modulation by cell graft on functional recovery after spinal cord injury.Induced neural stem cells reprogrammed from human peripheral blood mononuclear cells,and/or thrombin plus fibrinogen,were transplanted into the lesion site of an immunosuppressed rat spinal cord injury model.Basso,Beattie and Bresnahan score,electrophysiological function,and immunofluorescence/histological analyses showed that transplantation facilitates motor and electrophysiological function,reduces lesion volume,and promotes axonal neurofilament expression at the lesion core.Examination of the graft and niche components revealed that although the graft only survived for a relatively short period(up to 15 days),it still had a crucial impact on the microenvironment.Altogether,induced neural stem cells and human fibrin reduced the number of infiltrated immune cells,biased microglia towards a regenerative M2 phenotype,and changed the cytokine expression profile at the lesion site.Graft-induced changes of the microenvironment during the acute and subacute stages might have disrupted the inflammatory cascade chain reactions,which may have exerted a long-term impact on the functional recovery of spinal cord injury rats.

Hypoxic tumor microenvironment:Destroyer of natural killer cell function

In recent years, immunotherapy has made remarkable progress in treating certain tumors and hematological malignancies. However, the efficacy of natural killer(NK) cells, which are an important subset of innate lymphocytes used in anticancer immunotherapy, remains limited. Hypoxia, a critical characteristic of the tumor microenvironment(TME), is involved in tumor development and resistance to radiotherapy, chemotherapy, and immunotherapy. Moreover, hypoxia contributes to the impairment of NK cell function and may be a significant factor that limits their therapeutic effects. Targeted hypoxia therapy has emerged as a promising research area for enhancing the efficacy of NK cell therapy. Therefore, understanding how the hypoxic TME influences NK cell function is crucial for improving antitumor treatment outcomes.

NAD+associated genes as potential biomarkers for predicting the prognosis of gastric cancer

Nicotinamide adenine dinucleotide(NAD+)plays an essential role in cellular metabolism,mitochondrial homeostasis,inflammation,and senescence.However,the role of NAD+-regulated genes,including coding and long non-coding genes in cancer development is poorly understood.We constructed a prediction model based on the expression level of NAD+metabolism-related genes(NMRGs).Furthermore,we validated the expression of NMRGs in gastric cancer(GC)tissues and cell lines;additionally,β-nicotinamide mononucleotide(NMN),a precursor of NAD+,was used to treat the GC cell lines to analyze its effects on the expression level of NMRGs lncRNAs and cellular proliferation,cell cycle,apoptosis,and senescence-associated secretory phenotype(SASP).A total of 13 NMRGs-related lncRNAs were selected to construct prognostic risk signatures,and patients with high-risk scores had a poor prognosis.Some immune checkpoint genes were upregulated in the high-risk group.In addition,cell cycle,epigenetics,and senescence were significantly downregulated in the high-risk group.Notably,we found that the levels of immune cell infiltration,including CD8 T cells,CD4 naïve T cells,CD4 memory-activated T cells,B memory cells,and naïve B cells,were significantly associated with risk scores.Furthermore,the treatment of NMN showed increased proliferation of AGS and MKN45 cells.In addition,the expression of SASP factors(IL6,IL8,IL10,TGF-β,and TNF-α)was significantly decreased after NMN treatment.We conclude that the lncRNAs associated with NAD+metabolism can potentially be used as biomarkers for predicting clinical outcomes of GC patients.

Novel lactylation-related signature to predict prognosis for pancreatic adenocarcinoma

BACKGROUND Lactate,previously considered a metabolic byproduct,is pivotal in cancer progression and maintaining the immunosuppressive tumor microenvironment.Further investigations confirmed that lactate is a primary regulator,introducing recently described post-translational modifications of histone and non-histone proteins,termed lysine lactylation.Pancreatic adenocarcinomas are characterized by increased glycolysis and lactate accumulation.However,our understanding of lactylation-related genes in pancreatic adenocarcinomas remains limited.AIM To construct a novel lactylation-related gene signature to predict the survival of patients with pancreatic cancer.METHODS RNA-seq and clinical data of pancreatic adenocarcinoma(PDAC)were obtained from the GTEx(Genotype-Tissue Expression)and TCGA(The Cancer Genome Atlas)databases via Xena Explorer,and GSE62452 datasets from GEO.Data on lactylation-related genes were obtained from publicly available sources.Differential expressed genes(DEGs)were acquired by using R package“DESeq2”in R.Univariate COX regression analysis,LASSO Cox and multivariate Cox regressions were produced to construct the lactylation-related prognostic model.Further analyses,including functional enrichment,ESTIMATE,and CIBERSORT,were performed to analyze immune status and treatment responses in patients with pancreatic cancer.PDAC and normal human cell lines were subjected to western blot analysis under lactic acid intervention;two PDAC cell lines with the most pronounced lactylation were selected.Subsequently,RT-PCR was employed to assess the expression of LRGs genes;SLC16A1,which showed the highest expression,was selected for further investigation.SLC16A1-mediated lactylation was analyzed by immunofluorescence,lactate production analysis,colony formation,transwell,and wound healing assays to investigate its role in promoting the proliferation and migration of PDAC cells.In vivo validation was performed using an established tumor model.RESULTS In this study,we successfully identified 10 differentially expressed lactylation-related genes(LRGs)with prognostic value.Subsequently,a lactylation-related signature was developed based on five OS-related lactylationrelated genes(SLC16A1,HLA-DRB1,KCNN4,KIF23,and HPDL)using Lasso Cox hazard regression analysis.Subsequently,we evaluated the clinical significance of the lactylation-related genes in pancreatic adenocarcinoma.A comprehensive examination of infiltrating immune cells and tumor mutation burden was conducted across different subgroups.Furthermore,we demonstrated that SLC16A1 modulates lactylation in pancreatic cancer cells through lactate transport.Both in vivo and in vitro experiments showed that decreasing SLC16A1 Level and its lactylation significantly inhibited tumor progression,indicating the potential of targeting the SLC16A1/Lactylation-associated signaling pathway as a therapeutic strategy against pancreatic adenocarcinoma.CONCLUSION We constructed a novel lactylation-related prognostic signature to predict OS,immune status,and treatment response of patients with pancreatic adenocarcinoma,providing new strategic directions and antitumor immunotherapies.