Regulation Of Microenvironment Research Articles

Prognostic significance and response to immune checkpoint inhibitors of RIPK3, MLKL and necroptosis in non-small cell lung cancer

Lung cancer remains the leading cause of cancer death. Treatment with immune checkpoint inhibitor (ICI) alone or combination with chemotherapy served as first-line therapy in non-small cell lung cancer (NSCLC). However, only 20–50% of NSCLC patients respond to ICI. Necroptosis, an inflammatory form of cell death plays an important role in the regulation of tumor immune microenvironment which may affect prognosis and ICI response but its clinical significance in NSCLC patients has remained largely unknown. Therefore, we aimed to analyze the correlation between key necroptotic proteins and necroptosis and clinical outcomes, the status of tumor-infiltrating immune cells, and response to ICI in NSCLC patients. The expression of receptor-interacting protein kinase 3 (RIPK3), mixed lineage kinase domain-like protein (MLKL) and phosphorylated MLKL (pMLKL) were immunolocalized in 125 surgically resected NSCLC patients and 23 NSCLC patients administered with ICI therapy. CD8 + and FOXp3 + T cells and CD163 + M2 macrophages were also immunolocalized. High RIPK3 status was positively correlated with survival of the patients and RIPK3 turned out an independent favorable prognostic factor of the patients. RIPK3 was negatively correlated with CD8 + T cells, while MLKL positively correlated with CD163 + M2 macrophages, suggesting the possible involvement of RIPK3 and MLKL in formulating immunosuppressive microenvironment. In addition, high RIPK3 status tended to be associated with clinical resistance to ICI therapy (P-value = 0.057). Furthermore, NSCLC cells-expressing RIPK3 suppressed T cells response to ICI therapy in vitro. Therefore, RIPK3 and MLKL could induce an immunosuppressive microenvironment, resulting in low response to ICI therapy in NSCLC.

Abstract PR-02: Uncovering molecular differences in pancreatic ductal adenocarcinoma tissues from Black and White patients in the US

Abstract Background: Pancreatic cancer (PC) is among the leading causes of cancer-related deaths in the United States, with a 5-year survival rate of approximately 13%. Previous studies reported higher PC incidence and mortality rates among Black or African American (BAA) patients in comparison to White patients. Disadvantaged socioeconomic status (SES) and environmental exposure to chemicals are factors contributing to racial disparities in pancreatic cancer. Whether and how biological pathways play roles in disparities in pancreatic cancer is unclear. The understanding of molecular features associated racial backgrounds in pancreatic cancer will have significant impacts on both scientific inquiry on cancer biology and clinical management of pancreatic malignancy. In this study, we examined oncogene alterations and PD-L1 expression in pancreatic cancer patients of diverse racial backgrounds. Methods: We conducted our study by analyzing clinical test results of patients through a collaboration with Tempus Labs. In total, 4,249 pancreatic cancer patients’ (White: 3797 and BAA: 452) information were included in this study. DNA target panel sequencing was performed to identify genomic mutations. Genomic microsatellite instability (MSI) and tumor mutational burdens (TMB) were assessed. We also evaluated PD-L1 expression by immunohistochemistry. Results: DNA sequencing analysis revealed differential gene mutation profiles between White and BAA patients. We observed higher rates of KRAS (79.2% vs. 74.2%, q=0.14), TP53 (69.9% vs. 61.9%, q=0.014), KMT2C (6.9% vs. 2.3%, q=0.001), RNF43 (6% vs. 3.7%, q=0.14), and KMT2D (4.4% vs. 2.8%, q=0.3) mutations among BAA patients compared to White patients whereas fewer GNAS (0.2% vs 1.6%, q=0.14) mutation occur in the BAA group. Importantly, the KRAS mutant allele KRASG12R was significantly enriched in BAA compared to White patients (14.4% vs. 10.1%). Next, we compared the TMB levels and found that BAA patients showed higher average TMB levels when compared to White patients. Further, we determined the expression of PD-L1 between the two racial groups and observed BAA patients had more frequent PD-L1 overexpression than White patients (13.2% vs. 8.6%, p<0.05). Interestingly, the race associated difference in PD-L1 expression was even more remarkable in female groups (14.1% vs. 8%, p<0.05). Conclusion: We observed differences in mutation profiles of oncogenes between BAA and White patients, suggesting that such molecular-level changes may contribute to the higher incidence among BAA patients. Additionally, higher frequencies of PD-L1 upregulation in BAA patients implicate racial backgrounds influence tumor microenvironment regulation in pancreatic cancer patients. It is imperative to improve racial diversity in translational and clinical studies. Citation Format: Saurabh Mandal, Emily A Teslow, Minxuan Huang, Swathi Sridhar, Howard Crawford, Melissa C Stoppler, Albert Levin, Ling Huang. Uncovering molecular differences in pancreatic ductal adenocarcinoma tissues from Black and White patients in the US [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr PR-02.

Colorectal Cancer-Derived Exosomes Impair CD4+ T Cell Function and Accelerate Cancer Progression via Macrophage Activation.

Background: Exosomal programmed death ligand 1 (PD-L1), an exosomal membrane protein found in many tumor types, is reckoned to help regulate the immune microenvironment. However, the functions and the mechanisms underlying the exosome-mediated regulation of the immune microenvironment in colorectal cancer (CRC) remain unknown. Methods: Western blotting was used to investigate the levels of exosomal PD-L1 in the peripheral blood of patients with CRC and healthy controls. A CRC mouse model was constructed by administering 10 mg/kg azoxymethane (AOM) and dextrane sodium sulfate (DSS) intraperitoneally. The mice were then administered the control or CRC-derived exosomes to examine the regulatory effect of the exosomes on macrophage infiltration and CRC development. In vitro studies, using a coculture system, and flow cytometry analysis were conducted to examine the relationship between the regulatory effect of CRC-derived exosomes on CD4+ T cells and tumor-associated macrophages. RNA-seq and reverse transcription-quantitative polymerase chain reaction assays were used to investigate the mechanisms underlying the regulatory effect of the CRC-derived exosomes on macrophage proliferation and the regulation of the immune microenvironment during CRC development. Results: In patients with CRC, higher levels of exosomal PD-L1 were associated with a more severe form of disease. The treatment of mice with AOM/DSS-induced CRC with CRC-derived exosomes resulted in high levels of macrophage proliferation, increased PD-L1 levels in macrophages, and accelerated CRC progression. Importantly, analysis of an in vitro coculture system and flow cytometry analysis showed that the CRC-derived exosomes transported PD-L1 into macrophages and impaired CD4+ T cell function. Preliminary data suggest that the NF-κb signaling pathway regulates the function of CRC-derived exosomal PD-L1-dependent macrophages. Conclusion: CRC-derived exosomes induce the proliferation of macrophages and increase their PD-L1 levels. They also impair CD4+ T cell function and promote CRC progression. Our findings reveal a novel exosomal PD-L1-mediated crosstalk between the CRC cells and immune cells in the CRC microenvironment.

Enhancing CO2 electroreduction to ethylene via microenvironment regulation in boron-imidazolate frameworks.

Using the structure-induced effect of KBH(mim)3 ligand, four 2-dimensional (2D) boron imidazolate frameworks with identical body framework and different dangling monocarboxylate ligands, have been synthesized. Electrocatalytic results indicate that the surrounding microenvironment regulation could effectively affect the activity and selectivity towards C2H4. BIF-151 showed the highest electrocatalytic performances with the Faraday efficiency (FE) of 25.94% for C2H4 at -1.4 V vs. RHE.

Screening, identification and targeted intervention of necroptotic biomarkers of asthma

BackgroundAs a pivotal pathway of programmed cell death, necroptosis significantly contributes to the pathogenesis of respiratory disorders. However, its role in asthma is not yet fully elucidated. Therefore, this study aimed to identify markers associated with necroptosis, evaluate their functions in asthma, and explore potential therapeutic agents targeting necroptosis for the management of asthma. MethodsFirstly, machine learning algorithms, including Least Absolute Shrinkage and Selection Operator (LASSO), Random Forest, and Support Vector Machine-Recursive Feature Elimination (SVM-RFE), were utilized to identify necroptosis-related differentially expressed genes (NRDEGs) in asthma patients compared to healthy controls. Concurrently, the expression of NRDEGs was validated using external datasets, Western blot, and quantitative real-time polymerase chain reaction (qPCR). Secondly, the clinical relevance of NRDEGs was assessed through Receiver Operating Characteristic (ROC) curve analysis and correlation with clinical indicators. Thirdly, the relationship between NRDEGs and pulmonary immune cell infiltration, as well as the signaling interactions between different cells types, were analyzed through immune infiltration and single-cell analysis. Fourthly, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA), were conducted to elucidate the functional roles of NRDEGs. Finally, compounds targeting NRDEGs were screened, and their binding affinities were evaluated using molecular docking studies. ResultsIn asthma, necroptosis is activated, leading to the identification of four NRDEGs: NLRP3, PYCARD, ALOX15, and VDAC3. Among these, NLRP3, PYCARD, and ALOX15 are upregulated, whereas VDAC3 is downregulated in asthma. Comprehensive clinical evaluations indicated that NRDEGs hold diagnostic value for asthma. Specifically, NLRP3 was inversely correlated with forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC), while VDAC3 showed an inverse correlation with sputum neutrophils. Conversely, ALOX15 expression was positively correlated with fractional exhaled nitric oxide (FeNO) levels, as well as sputum eosinophils, blood eosinophils, and blood IgE levels. Subsequent immune infiltration analysis revealed associations between NRDEGs and activated dendritic cells, mast cells, and eosinophils. Single-cell RNA sequencing (scRNA-seq) further confirmed the communication signals between myeloid dendritic cells, fibroblasts, neutrophils, and helper T cells, predominantly related to fibrosis and immune-inflammatory responses. Pathway enrichment analysis demonstrated that NRDEGs are involved in ribosomal function, oxidative phosphorylation, and fatty acid metabolism. Finally, resveratrol and triptonide were identified as potential therapeutic agents targeting the proteins encoded by NRDEGs for asthma treatment. ConclusionsThe necroptosis pathway is activated in asthma, with NRDEGs—namely PYCARD, NLRP3, ALOX15, and VDAC3—correlated with declines in lung function and airway inflammation. These genes serve as reliable predictors of asthma risk and are involved in the regulation of the immune-inflammatory microenvironment. Resveratrol and triptolide have been identified as promising therapeutic candidates due to their potential to target the proteins encoded by these genes.

Electrocatalytic micro-environment regulation of ZIF-67 with broadened pore structure and unsaturated coordination sites for oxygen evolution reaction

The atomically precise mental nanoclusters have been widely explored in catalysis. However, the easy aggregation of clusters limits their application. The porous structure of metal-organic framework can prevent the aggregation and growth of clusters. In this work, a copper-phosphine complex: Cu2(dppm)2(PF6)2 (Cu2) was synthesized by one-pot method and then reacted with hydrogen sulfide to obtain a tetranuclear copper cluster: Cu4(S)(dppm)4(PF6)2 (Cu4). The two copper clusters were successfully introduced into Zeolitic imidazole frameworks-67 (ZIF-67) to form Cu2-ZIF-67 and Cu4-ZIF-67. It found that after the introduction of Cu cluster, the pore size of ZIF-67 was increased leading to more exposed Co2+ and more unsaturated coordination mental sites, which is beneficial for electrochemical oxygen evolution reaction (OER). The OER ability of pure ZIF-67 was enhanced after the introduction of Cu2 and Cu4 clusters, in which Cu4-ZIF-67 displayed the best electrochemical performance. At 10 mA cm−2, it requires an overpotential of 340 mV. The lower Tafel slope and smaller charge transfer resistance reflect its faster dynamic process. This work provides a new idea for the development of OER electrocatalysts.

Unraveling the role of lactate-related genes in myocardial infarction

BackgroundLactate is a crucial intermediary, facilitating communication between myocardial energy metabolism and microenvironmental regulation. The present study aimed to investigate the relationship between lactate-related genes (LRGs) and myocardial infarction (MI). MethodsA total of 23 LRGs exhibited differential expression between individuals with MI and healthy controls. Lasso regression analysis and validation with the GSE61144 dataset identified three hub genes: COX20, AGK, and PDHX. Single-gene GSEA of these genes revealed strong enrichment in pathways related to amino acid metabolism, cell cycle, and immune functions. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was utilized to validate the expression levels of the hub genes. ResultsImmune infiltration analysis revealed differences in CD4+ T and CD8+ T cells between the MI and control groups. Additionally, 67 candidate drugs targeting the three hub LRGs were identified, and a ceRNA network was constructed to explore the intricate interactions among these genes. ConclusionsThese findings enhance the understanding of MI and have potential therapeutic implications.

Effect of α7 nAChR-autophagy axis of deciduous tooth pulp stem cells in regulating IL-1β in the process of physiological root resorption of deciduous teeth.

Physiological root resorption of deciduous teeth is a normal phenomenon occurring during the developmental stages of children. Previous research has indicated the pivotal role of the inflammatory microenvironment in this process, although the specific mechanisms remain unclear. This study is aimed at elucidating the involvement of the alpha7 nicotinic acetylcholine receptors (α7 nAChR)-autophagy axis in the regulation of the inflammatory microenvironment during physiological root resorption in deciduous teeth. Samples were collected from deciduous teeth at various stages of physiological root resorption, and deciduous dental pulp stem cells (DDPSCs) were isolated and cultured during the mid-phase of root resorption. The findings revealed a substantial infiltration of the pulp of deciduous teeth at the mid-phase of root resorption, characterized by elevated expression levels of α7 nAChR and IL-1β. Significantly increased IL-1β and α7 nAChR expressions were observed in DDPSCs during the mid-phase of root resorption, with α7 nAChR demonstrating a regulatory effect on IL-1β. Moreover, evidence suggested that mechanical stress may act as a trigger, regulating autophagy and IL-1 expression via α7 nAChR. In conclusion, mechanical stress was identified as a regulator of autophagy in DDPSCs through α7 nAChR, influencing the expression of IL-1β and contributing to the formation of the inflammatory microenvironment. This mechanism plays a crucial role in the physiological root resorption of deciduous teeth. KEY MESSAGES: The pulp of deciduous teeth at mid-phase of root resorption was heavily infiltrated with high expression of α7nAChR and IL-1β. α7 nAChR acts as an initiating factor to regulate IL-1β through autophagy in DDPSCs. Mechanical stress can regulate autophagy of DDPSCs through α7 nAChR and thus affect IL-1β expression and inflammatory microenvironment formation in physiological root resorption in deciduous teeth.

Endothelial cells and fibroblasts mediate the microenvironmental regulatory network of carotid body paraganglioma

Objective:To explore the gene expression characteristics of endothelial cells and fibroblasts in the microenvironment of SDHD-mutated carotid body tumors（SDHD-CBT）, to fine the functional enrichment of each subcluster, and to further explore the network of cell-cell interactions in the microenvironment of SDHD-CBT. Methods:The bioinformatics analysis was used to download and reanalyze the single-nuclear RNA sequencing data of SDHD-CBT, SDHB mutated thoracic and abdominal paraganglioma（SDHB-ATPGL）, SDHB-CBT, and normal adrenal medulla（NAM）, to clarify the information of cell populations of the samples. We focused on exploring the gene expression profiles of endothelial cells and fibroblasts subclusters, and performed functional enrichment analysis based on Gene Ontology（GO） resources. CellChat was used to compare the cell-cell interactions networks of different clinical samples and predict significant signaling pathways in SDHD-CBT. Results:A total of 7 cell populations were profiled. The main subtypes of endothelial cells in SDHD-CBT are arterial and venous endothelial cells, and the main subtypes of fibroblasts are myofibroblasts and pericytes. Compared to NAM, SDHB-CBT and SDHB-ATPGL, cell communication involving endothelial cells and fibroblasts in SDHD-CBT is more abundant, with significant enrichment in pathways such as FGF, PTN, WNT, PROS, PERIOSTIN, and TGFb. Conclusion:Endothelial cells and fibroblasts in SDHD-CBT are heterogeneous and involved in important cellular interactionprocesses, in which the discovery of FGF，PTN，WNT，PROS，PERIOSTIN and TGFb signals may play an important role in the regulation of microenvironment of SDHD-CBT.

Synthesis, structural characterization, molecular docking analysis and Carbonic Anhydrase IX inhibitory evaluations of novel Cerium(III)-based MOF constructed from 1,10-phenanthroline and fumaric acid.

In this study, a novel Cerium-based MOFs with 1,10-phenanthroline (phen) and fumaric acid (H2fum) has been hydrothermally synthesized as single crystal structurally characterized by X-ray diffraction, IR spectroscopy and ATG measurements. This compound corresponds to the formula: [Ce2(phen)2(fum)3(H2O)2]n(I), it crystallizes in the triclinic system with space group P1¯, with the following parameters: a = 9.062(1) Å, b = 10.0608(5) Å, c = 10.603(1) Å, α = 72.545(6) °, β = 77.57(1) °, γ = 69.959(6) °, V = 859.49(14) Å3, Z = 2.The structure revealed 2D bridged polymeric chains where the adjacent Ce(III) atoms are bridged by fumarate linkers with a mean intermetallic distance of about 9.36 Å. H···O bonds link the 2D sheets leading to a pseudo 3D network, while the stability of the structure is assured by a weak π-π stacking between parallel and opposed phen ligands.The Ce3+ cation is nona-coordinated and it is in a distorted tricapped trigonal prism geometry.Hirshfeld surface analysis was used to investigate the non-covalent intermolecular interactions and the dominant H···O, H···C and H···H contacts were quantified. The thermal properties of the considered coordination polymer (I) are also discussed and disclose that (I) is stable up to 300°C. Besides, this study explores the potential of (I) as an inhibitor of the carbonic anhydrase IX enzyme (CA IX), a critical player in tumor microenvironment regulation. Through molecular docking simulations, we elucidate the binding interactions between (I) and CA IX, the results suggest the efficiency of (I) as a CA IX inhibitor. Moreover, we assessed the drug-likeness properties and ADMET characteristics of (I), providing valuable insights for its potential as a therapeutic agent.

Targeting delivery of mifepristone to endometrial dysfunctional macrophages for endometriosis therapy

Endometriosis seriously affects 6–10 % of reproductive women globally and poses significant clinical challenges. The process of ectopic endometrial cell colonization shares similarities with cancer, and a dysfunctional immune microenvironment, characterized by non-classically polarized macrophages, plays a critical role in the progression of endometriosis. In this study, a targeted nano delivery system (BSA@Mif NPs) was developed using bovine serum albumin (BSA) as the carrier of mifepristone. The BSA@Mif NPs were utilized to selectively target M2 macrophages highly enriched in ectopic endometrial tissue via the SPARC receptor. This targeting strategy increases drug concentration at ectopic lesions while minimizing its distribution to normal tissue, thereby reducing side effects. In vitro studies demonstrated that BSA@Mif NPs not only enhanced the cellular uptake of M2-type macrophages and ectopic endometrial cells but also improved the cytotoxic effect of mifepristone on ectopic endometrial cells. Furthermore, the BSA@Mif NPs effectively induced immunogenic cell death (ICD) in ectopic endometrial cells and repolarized M2-type macrophages toward the M1 phenotype, resulting in a synergistic inhibition of ectopic endometrial cell growth. In vivo experiments revealed that BSA@Mif NPs exhibited significant therapeutic efficacy in endometriosis-bearing mice by increasing drug accumulation in the endometriotic tissues and modulating the immune microenvironment. This targeted biomimetic delivery strategy presents a promising approach for the development of endometriosis-specific therapies based on existing drugs. Statement of significanceMacrophages play an essential role in immune dysfunctional microenvironment promoting the occurrence and progression of endometriosis and can be a crucial target for developing immune microenvironment regulation strategies for the unmet long-term management of endometriosis. The albumin nanoparticles constructed based on SPARC overexpression in macrophages and endometrial cells and albumin biosafety can achieve the targeted therapy of endometriosis by increasing the passive- and active-mediated drug accumulation in ectopic endometrium and remodeling the immune microenvironment based on macrophage regulation. This study has the following implications: i) overcoming the inherent shortcomings of clinical drugs by nanotechnology is an alternative way of developing medication; ii) developing microenvironment modulation strategies based on macrophage regulation for endometriosis management is feasible.

In Situ Triggered Self-Contraction Bioactive Microgel Assembly Accelerates Diabetic Skin Wound Healing by Activating Mechanotransduction and Biochemical Pathway.

Chronic nonhealing skin wounds, characterized by reduced tissue contractility and inhibited wound cell survival under hyperglycemia and hypoxia, present a significant challenge in diabetic care. Here, an advanced self-contraction bioactive core-shell microgel assembly with robust tissue-adhesion (SMART-EXO) is introduced to expedite diabetic wound healing. The SMART-EXO dressing exhibits strong, reversible adhesion to damaged tissue due to abundant hydrogen and dynamic coordination bonds. Additionally, the core-shell microgel components and dynamic coordination bonds provide moderate rigidity, customizable self-contraction, and an interlinked porous architecture. The triggered in situ self-contraction of the SMART-EXO dressing enables active, tunable wound contraction, activating mechanotransduction in the skin and promoting the optimal fibroblast-to-myofibroblast conversion, collagen synthesis, and angiogenesis. Concurrently, the triggered contraction of SMART-EXO facilitates efficient loading and on-demand release of bioactive exosomes, contributing to re-epithelialization and wound microenvironment regulation in diabetic mice. RNA-seq results reveal the activation of critical signaling pathways associated with mechanosensing and exosome regulation, highlighting the combined biomechanical and biochemical mechanisms. These findings underscore SMART-EXO as a versatile, adaptable solution to the complex challenges of diabetic wound care.

Improving treatment for Parkinson's disease: Harnessing photothermal and phagocytosis-driven delivery of levodopa nanocarriers across the blood-brain barrier

Parkinson's disease (PD) poses a significant therapeutic challenge, mainly due to the limited ability of drugs to cross the blood-brain barrier (BBB) without undergoing metabolic transformations. Levodopa, a key component of dopamine replacement therapy, effectively enhances dopaminergic activity. However, it encounters obstacles from peripheral decarboxylase, hindering its passage through the BBB. Furthermore, levodopa metabolism generates reactive oxygen species (ROS), exacerbating neuronal damage. Systemic pulsatile dosing further disrupts natural physiological buffering mechanisms. In this investigation, we devised a ROS-responsive levodopa prodrug system capable of releasing the drug and reducing ROS levels in the central nervous system. The prodrug was incorporated within second near-infrared region (NIR-II) gold nanorods (AuNRs) and utilized angiopep-2 (ANG) for targeted delivery across the BBB. The processes of tight junction opening and endocytosis facilitated improved levodopa transport. ROS scavenging helped alleviate neuronal oxidative stress, leading to enhanced behavioral outcomes and reduced oxidative stress levels in a mouse model of PD. Following treatment, the PD mouse model exhibited enhanced flexibility, balance, and spontaneous exploratory activity. This approach successfully alleviated the motor impairments associated with the disease model. Consequently, our strategy, utilizing NIR-Ⅱ AuNRs and ANG-mediated BBB penetration, coupled with the responsive release of levodopa, offers a promising approach for dopamine supplementation and microenvironmental regulation. This system holds substantial potential as an efficient platform for delivering neuroprotective drugs and advancing PD therapy.

Regulation of Tumor Microenvironment through YAP/TAZ under Tumor Hypoxia.

In solid tumors such as hepatocellular carcinoma (HCC), hypoxia is one of the important mechanisms of cancer development that closely influences cancer development, survival, and metastasis. The development of treatments for cancer was temporarily revolutionized by immunotherapy but continues to be constrained by limited response rates and the resistance and high costs required for the development of new and innovative strategies. In particular, solid tumors, including HCC, a multi-vascular tumor type, are sensitive to hypoxia and generate many blood vessels for metastasis and development, making it difficult to treat HCC, not only with immunotherapy but also with drugs targeting blood vessels. Therefore, in order to develop a treatment strategy for hypoxic tumors, various mechanisms must be explored and analyzed to treat these impregnable solid tumors. To date, tumor growth mechanisms linked to hypoxia are known to be complex and coexist with various signal pathways, but recently, mechanisms related to the Hippo signal pathway are emerging. Interestingly, Hippo YAP/TAZ, which appear during early tumor and normal tumor growth, and YAP/TAZ, which appear during hypoxia, help tumor growth and proliferation in different directions. Peculiarly, YAP/TAZ, which have different phosphorylation directions in the hypoxic environment of tumors, are involved in cancer proliferation and metastasis in various carcinomas, including HCC. Analyzing the mechanisms that regulate the function and expression of YAP in addition to HIF in the complex hypoxic environment of tumors may lead to a variety of anti-cancer strategies and combining HIF and YAP/TAZ may develop the potential to change the landscape of cancer treatment.

AMPK, a hub for the microenvironmental regulation of bone homeostasis and diseases.

AMP-activated protein kinase (AMPK), a crucial regulatory kinase, monitors energy levels, conserving ATP and boosting synthesis in low-nutrition, low-energy states. Its sensitivity links microenvironmental changes to cellular responses. As the primary support structure and endocrine organ, the maintenance, and repair of bones are closely associated with the microenvironment. While a series of studies have explored the effects of specific microenvironments on bone, there is lack of angles to comprehensively evaluate the interactions between microenvironment and bone cells, especially for bone marrow mesenchymal stem cells (BMMSCs) which mediate the differentiation of osteogenic lineage. It is noteworthy that accumulating evidence has indicated that AMPK may serve as a hub between BMMSCs and microenvironment factors, thus providing a new perspective for us to understand the biology and pathophysiology of stem cells and bone. In this review, we emphasize AMPK's pivotal role in bone microenvironment modulation via ATP, inflammation, reactive oxygen species (ROS), calcium, and glucose, particularly in BMMSCs. We further explore the use of AMPK-activating drugs in the context of osteoarthritis and osteoporosis. Moreover, building upon the foundation of AMPK, we elucidate a viewpoint that facilitates a comprehensive understanding of the dynamic relationship between the microenvironment and bone homeostasis, offering valuable insights for prospective investigations into stem cell biology and the treatment of bone diseases.

A Fe-NC electrocatalyst boosted by trace bromide ions with high performance in proton exchange membrane fuel cells

Replacement of expensive and rare platinum with metal–nitrogen–carbon catalysts for oxygen reduction reactions in proton exchange membrane fuel cells is hindered by their inferior activity. Herein, we report a highly active iron-nitrogen-carbon catalyst by optimizing the carbon structure and coordination environments of Fe-N4 sites. A critical high-temperature treatment with ammonium chloride and ammonium bromide not only enhances the intrinsic activity and density of Fe-N4 sites, but also introduces numerous defects, trace Br ions and creates mesopores in the carbon framework. Notably, surface Br ions significantly improve the interaction between the ionomer and catalyst particles, promoting ionomer infiltration and optimizing the O2 transport and charge transfer at triple-phase boundary. This catalyst delivers a high peak power density of 1.86 W cm−2 and 54 mA cm−2 at 0.9 ViR-free in a H2-O2 fuel cells at 80 °C. Our findings highlight the critical role of interface microenvironment regulation.

Recent Treatment Strategies and Molecular Pathways in Resistance Mechanisms of Antiangiogenic Therapies in Glioblastoma.

Malignant gliomas present great difficulties in treatment, with little change over the past 30 years in the median survival time of 15 months. Current treatment options include surgery, radiotherapy (RT), and chemotherapy. New therapies aimed at suppressing the formation of new vasculature (antiangiogenic treatments) or destroying formed tumor vasculature (vascular disrupting agents) show promise. This study summarizes the existing knowledge regarding the processes by which glioblastoma (GBM) tumors acquire resistance to antiangiogenic treatments. The discussion encompasses the activation of redundant proangiogenic pathways, heightened tumor cell invasion and metastasis, resistance induced by hypoxia, creation of vascular mimicry channels, and regulation of the tumor immune microenvironment. Subsequently, we explore potential strategies to overcome this resistance, such as combining antiangiogenic therapies with other treatment methods, personalizing treatments for each patient, focusing on new therapeutic targets, incorporating immunotherapy, and utilizing drug delivery systems based on nanoparticles. Additionally, we would like to discuss the limitations of existing methods and potential future directions to enhance the beneficial effects of antiangiogenic treatments for patients with GBM. Therefore, this review aims to enhance the research outcome for GBM and provide a more promising opportunity by thoroughly exploring the mechanisms of resistance and investigating novel therapeutic strategies.

Targeting MELK in tumor cells and tumor microenvironment: from function and mechanism to therapeutic application.

Maternal embryonic leucine zipper kinase (MELK), a member of the adenosine monophosphate-activated protein kinase (AMPK) protein family, has been reported to be involved in the regulation of many cellular events. The aberrant expression of MELK is associated with tumorigenesis and malignant progression of various tumors. Moreover, MELK plays an essential role in the regulation of tumor microenvironment (TME), which affects the function of immune cells and the responsiveness to immunotherapy. Currently, small molecule inhibitors targeting MELK have been developed and evaluated in clinical trials. A comprehensive understanding of MELK may provide clues and confidence for subsequent basic research and scientific transformation. In this review, we provide a comprehensive overview of the structural features, molecular biological functions, and critical roles of MELK in tumors and TME, as well as the targeted agents under development for the treatment of tumors and discuss the perspective for MELK-targeted therapies for tumors.

Characteristics of two different immune infiltrating pyroptosis subtypes in ischemic stroke

BackgroundIschemic stroke (IS) is a serious health hazard and identified as the second leading cause of mortality around the world. However, the role of pyroptosis in the immune microenvironment regulation in IS is still unclear. Here, our study aims to elucidate the effect of pyroptosis on immune microenvironment in IS. MethodsThe regulation mode of pyroptosis in IS was systematically evaluated, and its effects on immune microenvironment were explored, including infiltration of immune cells, immune response gene sets, and human leukocyte antigen (HLA) gene. The genes and drugs related to pyroptosis phenotype were also identified. An MCAO rat model was constructed, and the mRNA expression levels in the classifier model were validated by qRT-PCR. ResultsThe separator is composed of 11 pyroptosis genes, out of which 10 genes could distinguish between ischemic stroke and control samples. CHMP2A, CHMP4A, and NAIP genes are significantly related to immune infiltrating cells, immune response gene sets, and HLA. However, two different pyroptosis subtypes mediated by 10 pyroptosis genes were identified, which were different in immune cell abundance, HLA genes, and immune response gene sets. Furthermore, 199 genes associated with pyroptosis phenotype was identified along with the analysis of biological functions. ConclusionThese findings reveal the potential mechanism of pyroptosis in the immune microenvironment of IS, indicating that pyroptosis functions as a vital component in the complexity and diversity of the immune microenvironment in patients with IS.

Analysis of prognosis and drug sensitivity in lung cancer patients based on the integration of 18 programmed cell death modes and single-cell sequencing data

Objective: Programmed cell death (PCD) has therapeutic potential for a variety of malignant tumors, including lung cancer. In this study, we used PCD and bioinformatics to construct a prognostic model for lung cancer and explore new therapeutic strategies. Methods: Multiple bioinformatics algorithms (co-expression analysis, univariate Cox’s analysis, multivariate Cox’s analysis, and cross-validation) were used to screen PCD-related genes and construct a risk model. Lung cancer patients were divided into training and testing groups in a ratio of 7:3. The prognostic model was validated by comparing the risk scores of the high-risk and low-risk groups using receiver operating characteristic (ROC) curves, nomograms, and independent prognostic analyses. In addition, PCD patterns were classified and compared in terms of survival time, immune microenvironment and pathway regulation using consensus clustering methods with the validation of principal component analysis (PCA). Single-cell RNA sequencing (scRNA-seq) analysis was applied to validate screened PCD-related genes in this risk model. Results: Twelve risk genes were identified, including BIK, CDCP1, CHEK2, FADD, GLS2, IL33, ITPRIP, KRT8, MELK, MMP9, PTGIS and TRIB3, to construct prognostic risk model. In the process of lung cancer, the most significantly up-regulated gene was TRIML2, and the most down-regulated gene was GLS2. ROC curves, nomograms, and independent prognostic analyses confirmed the accuracy of risk model to predict the prognosis of lung cancer, indicating that it can be regarded as an independent prognostic model. In the immune cell infiltration, we found that patients with an increased M0 macrophage had a poorer prognosis. Drug sensitivity testing after reliable risk modeling identified three molecularly targeted drugs for lung cancer patients in the high-risk group, namely, Staurosporine, Luminespib and Docetaxel. scRNA-seq results further analyzed the reliability of ITPRIP and KRT8 as prognostic targets. Conclusion: This study identified twelve PCD-related genes and constructed an accurate risk model based on bioinformatics analysis, which can be used for prognostic prediction and design of clinical treatment strategies.