Integrative Chinese-Western medicine strategy to overcome docetaxel resistance in prostate cancer.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese Medicines (TCMs) have emerged as a promising complementary therapy in the management of prostate cancer (PCa), particularly in addressing resistance to Docetaxel (DTX) chemotherapy. AIM OF THE REVIEW: This review aims to elucidate the mechanisms underlying the development of resistance to DTX in PCa and explore the innovative approach of integrating TCMs in PCa treatment to overcome this resistance. Key areas of investigation include alterations in microtubule proteins, androgen receptor and androgen receptor splice variant 7, ERG rearrangement, drug efflux mechanisms, cancer stem cells, centrosome clustering, upregulation of the PI3K/AKT signaling pathway, enhanced DNA damage repair capability, and the involvement of neurotrophin receptor 1/protein kinase C. MATERIALS AND METHODS: With "Prostate cancer", "Docetaxel", "Docetaxel resistance", "Natural compounds", "Traditional Chinese medicine", "Traditional Chinese medicine compound", "Medicinal plants" as the main keywords, PubMed, Web of Science and other online search engines were used for literature retrieval. RESULTS: Our findings underscore the intricate interplay of molecular alterations that collectively contribute to the resistance of PCa cells to DTX. Moreover, we highlight the potential of TCMs as a promising complementary therapy, showcasing their ability to counteract DTX resistance and enhance therapeutic efficacy. CONCLUSION: The integration of TCMs in PCa treatment emerges as an innovative approach with significant potential to overcome DTX resistance. This review not only provides insights into the mechanisms of resistance but also presents new prospects for improving the clinical outcomes of patients with PCa undergoing DTX therapy. The comprehensive understanding of these mechanisms lays the foundation for future research and the development of more effective therapeutic interventions.

The molecular subtyping and precision medicine in triple-negative breast cancer---based on Fudan TNBC classification.

Triple-negative breast cancer (TNBC) is widely recognized as the most aggressive form of breast cancer, occurring more frequently in younger patients and characterized by high heterogeneity, early distant metastases and poor prognosis. Multiple treatment options have failed to achieve the expected therapeutic effects due to the lack of clear molecular targets. Based on genomics, transcriptomics and metabolomics, the multi-omics analysis further clarifies TNBC subtyping, which provides a greater understanding of tumour heterogeneity and targeted therapy sensitivity. For instance, the luminal androgen receptor subtype (LAR) exhibits responsiveness to anti-AR therapy, and the basal-like immune-suppressed subtype (BLIS) tends to benefit from poly (ADP-ribose) polymerase inhibitors (PARPis) and anti-angiogenic therapy. The efficacy of multi-dimensional combination therapy holds immense importance in guiding personalized and precision medicine for TNBC. This review offers a systematic overview of recent FuDan TNBC molecular subtyping and its role in the instruction of clinical precision therapy.

HTRA1-driven detachment of type I collagen from endoplasmic reticulum contributes to myocardial fibrosis in dilated cardiomyopathy.

BACKGROUND: The aberrant secretion and excessive deposition of type I collagen (Col1) are important factors in the pathogenesis of myocardial fibrosis in dilated cardiomyopathy (DCM). However, the precise molecular mechanisms underlying the synthesis and secretion of Col1 remain unclear. METHODS AND RESULTS: RNA-sequencing analysis revealed an increased HtrA serine peptidase 1 (HTRA1) expression in patients with DCM, which is strongly correlated with myocardial fibrosis. Consistent findings were observed in both human and mouse tissues by immunoblotting, quantitative reverse transcription polymerase chain reaction (qRT-PCR), immunohistochemistry, and immunofluorescence analyses. Pearson's analysis showed a markedly positive correlation between HTRA1 level and myocardial fibrosis indicators, including extracellular volume fraction (ECV), native T1, and late gadolinium enhancement (LGE), in patients with DCM. In vitro experiments showed that the suppression of HTRA1 inhibited the conversion of cardiac fibroblasts into myofibroblasts and decreased Col1 secretion. Further investigations identified the role of HTRA1 in promoting the formation of endoplasmic reticulum (ER) exit sites, which facilitated the transportation of Col1 from the ER to the Golgi apparatus, thereby increasing its secretion. Conversely, HTRA1 knockdown impeded the retention of Col1 in the ER, triggering ER stress and subsequent induction of ER autophagy to degrade misfolded Col1 and maintain ER homeostasis. In vivo experiments using adeno-associated virus-serotype 9-shHTRA1-green fluorescent protein (AAV9-shHTRA1-GFP) showed that HTRA1 knockdown effectively suppressed myocardial fibrosis and improved left ventricular function in mice with DCM. CONCLUSIONS: The findings of this study provide valuable insights regarding the treatment of DCM-associated myocardial fibrosis and highlight the therapeutic potential of targeting HTRA1-mediated collagen secretion.

Unveiling macrophage diversity in myocardial ischemia-reperfusion injury: identification of a distinct lipid-associated macrophage subset.

Background and objective: Macrophages play a crucial and dichotomous role cardiac repair following myocardial ischemia-reperfusion, as they can both facilitate tissue healing and contribute to injury. This duality is intricately linked to environmental factors, and the identification of macrophage subtypes within the context of myocardial ischemia-reperfusion injury (MIRI) may offer insights for the development of more precise intervention strategies. Methods: Specific marker genes were used to identify macrophage subtypes in GSE227088 (mouse single-cell RNA sequencing dataset). Genome Set Enrichment Analysis (GSEA) was further employed to validate the identified LAM subtypes. Trajectory analysis and single-cell regulatory network inference were executed using the R packages Monocle2 and SCENIC, respectively. The conservation of LAM was verified using human ischemic cardiomyopathy heart failure samples from the GSE145154 (human single-cell RNA sequencing dataset). Fluorescent homologous double-labeling experiments were performed to determine the spatial localization of LAM-tagged gene expression in the MIRI mouse model. Results: In this study, single-cell RNA sequencing (scRNA-seq) was employed to investigate the cellular landscape in ischemia-reperfusion injury (IRI). Macrophage subtypes, including a novel Lipid-Associated Macrophage (LAM) subtype characterized by high expression of Spp1, Trem2, and other genes, were identified. Enrichment and Progeny pathway analyses highlighted the distinctive functional role of the SPP1+ LAM subtype, particularly in lipid metabolism and the regulation of the MAPK pathway. Pseudotime analysis revealed the dynamic differentiation of macrophage subtypes during IRI, with the activation of pro-inflammatory pathways in specific clusters. Transcription factor analysis using SCENIC identified key regulators associated with macrophage differentiation. Furthermore, validation in human samples confirmed the presence of SPP1+ LAM. Co-staining experiments provided definitive evidence of LAM marker expression in the infarct zone. These findings shed light on the role of LAM in IRI and its potential as a therapeutic target. Conclusion: In conclusion, the study identifies SPP1+ LAM macrophages in ischemia-reperfusion injury and highlights their potential in cardiac remodeling.

Exploring personalized treatment for cardiac graft rejection based on a four-archetype analysis model and bioinformatics analysis.

Heart transplantation is the gold standard for treating patients with advanced heart failure. Although improvements in immunosuppressive therapies have significantly reduced the frequency of cardiac graft rejection, the incidences of T cell-mediated rejection (TCMR) and antibody-mediated rejection remain almost unchanged. A four-archetype analysis (4AA) model, developed by Philip F. Halloran, illustrated this problem well. It provided a new dimension to improve the accuracy of diagnoses and an independent system for recalibrating the histology guidelines. However, this model was based on the invasive method of endocardial biopsy, which undoubtedly increased the postoperative risk of heart transplant patients. Currently, little is known regarding the associated genes and specific functions of the different phenotypes. We performed bioinformatics analysis (using machine-learning methods and the WGCNA algorithm) to screen for hub-specific genes related to different phenotypes, based Gene Expression Omnibus accession number GSE124897. More immune cell infiltration was observed with the ABMR, TCMR, and injury phenotypes than with the stable phenotype. Hub-specific genes for each of the four archetypes were verified successfully using an external test set (accession number GSE2596). Logistic-regression models based on TCMR-specific hub genes and common hub genes were constructed with accurate diagnostic utility (area under the curve > 0.95). RELA, NFKB1, and SOX14 were identified as transcription factors important for TCMR/injury phenotypes and common genes, respectively. Additionally, 11 Food and Drug Administration-approved drugs were chosen from the DrugBank Database for each four-archetype model. Tyrosine kinase inhibitors may be a promising new option for transplant rejection treatment. KRAS signaling in cardiac transplant rejection is worth further investigation. Our results showed that heart transplant rejection subtypes can be accurately diagnosed by detecting expression of the corresponding specific genes, thereby enabling precise treatment or medication.

Development of target-based cell membrane affinity ultrafiltration technology for a simplified approach to discovering potential bioactive compounds in natural products.

Target-based drug discovery technology based on cell membrane targets has gained significant traction and has been steadily advancing. However, current methods still face certain limitations that need to be addressed. One of the challenges is the laborious preparation process of screening materials, which can be time-consuming and resource-intensive. Additionally, there is a potential issue of non-specific adsorption caused by carrier materials, which can result in false-positive results and compromise the accuracy of the screening process. To address these challenges, this paper proposes a target-based cell membrane affinity ultrafiltration technology for active ingredient discovery in natural products. In this technique, the cell membranes of human lung adenocarcinoma epithelial cells (A549) with a high expression of epidermal growth factor receptor (EGFR) were incubated with candidate drugs and then transferred to an ultrafiltration tube. Through centrifugation, components that interacted with EGFR were retained in the ultrafiltration tube as "EGFR-ligand" complex, while the components that did not interact with EGFR were separated. After thorough washing and eluting, the components interacting with EGFR were dissociated and further identified using LC-MS, enabling the discovery of bioactive compounds. Moreover, the target-based cell membrane affinity ultrafiltration technology exhibited commendable binding capacity and selectivity. Ultimately, this technology successfully screened and identified two major components from the Curcumae Rhizoma-Sparganii Rhizoma (CS) herb pair extracts, which were further validated for their potential anti-tumor activity through pharmacological experiments. By eliminating the need for laborious preparation of screening materials and the potential non-specific adsorption caused by carriers, the development of target-based cell membrane affinity ultrafiltration technology provides a simplified approach and method for bioactive compounds discovery in natural sources.

Metal-Phenolic Nanocapsules with Photothermal Antibacterial and Ros Scavenging Ability for Diabetic Wound Healing.

The presence of bacteria in diabetic wounds not only leads to the formation of biofilms but also triggers oxidative stress and inflammatory responses, which hinder the wound-healing process. Therefore, it is imperative to formulate a comprehensive strategy that can proficiently eliminate bacteria and enhance the wound microenvironment. Herein, this work develops multifunctional metal-phenolic nanozymes (TA-Fe/Cu nanocapsules), wherein the one-pot coordination of tannic acid (TA)and Fe3+/Cu2+ using a self-sacrificial template afforded hollow nanoparticles (NPs) with exceptional photothermal and reactive oxygen species scavenging capabilities. After photothermal disruption of the biofilms, TA-Fe/Cu NPs autonomously capture bacteria through hydrogen bonding interactions with peptidoglycans (the bacterial cell wall component), ultimately bolstering the bactericidal efficacy. Furthermore, these NPs exhibit peroxidase-like enzymatic activity, efficiently eliminating surplus hydrogen peroxide in the vicinity of the wound and mitigating inflammatory responses. As the wound transitions into the remodeling phase, the presence of Cu2+ stimulates vascular migration and regeneration, expediting the wound-healing process. This study innovatively devises a minimalist approach to synthesize multifunctional metal-phenolic nanozymes integrating potent photothermal antibacterial activity, bacterial capture, anti-inflammatory, and angiogenesis properties, showcasing their great potential for diabetic wound treatment.

Porous phenolic resin regulated by alcohol-based deep eutectic solvent for selective extraction and separation of tanshinones from Salvia miltiorrhiza.

Deep eutectic solvents (DES), regarded as promising green solvents, have gained attention due to their distinctive properties, particularly in analytical chemistry. While the use of DES in solvent extraction and separation has been extensively studied, its application in the synthesis of adsorbents has just begun. Phenolic resin, with its polyhydroxy structure and stable spherical morphology, could serve as an effective as adsorbents for enrichment of active ingredients in herbal medicine. Designing adsorbents with high selectivity and adsorption capacity presents a critical challenge in the enrichment of active ingredients in herbal medicine. In this study, alcohol-based DESs were employed as regulators of morphology and structure instead of organic solvents, facilitating the creation of polyhydroxy structure, adjustable pores and high specific surface areas. The resulting DES-regulated porous phenolic resin demonstrated enhanced extraction and separation capacity for active ingredients compared to conventional spherical phenolic resin owing to the alcohol-based DES offering more interaction modes with the analytes.

Magnesium Ion-Doped Mesoporous Bioactive Glasses Loaded with Gallic Acid Against Myocardial Ischemia/Reperfusion Injury by Affecting the Biological Functions of Multiple Cells.

Introduction: Excessive generation of reactive oxygen species (ROS) following myocardial ischemia-reperfusion (I/R) can result in additional death of myocardial cells. The rapid clearance of ROS after reperfusion injury and intervention during subsequent cardiac repair stages are crucial for the ultimate recovery of cardiac function. Methods: Magnesium-doped mesoporous bioactive glasses were prepared and loaded with the antioxidant drug gallic acid into MgNPs by sol-gel method. The antioxidant effects of MgNPs/GA were tested for their pro-angiogenic and anti-inflammatory effects based on the release characteristics of GA and Mg2+ from MgNPs/GA. Later, we confirmed in our in vivo tests through immunofluorescence staining of tissue sections at various time points that MgNPs/GA exhibited initial antioxidant effects and had both pro-angiogenic and anti-inflammatory effects during the cardiac repair phase. Finally, we evaluated the cardiac function in mice treated with MgNPs/GA. Results: We provide evidence that GA released by MgNPs/GA can effectively eliminate ROS in the early stage, decreasing myocardial cell apoptosis. During the subsequent cardiac repair phase, the gradual release of Mg2+ from MgNPs/GA stimulated angiogenesis and promoted M2 macrophage polarization, thereby reducing the release of inflammatory factors. Conclusion: MgNPs/GA acting on multiple cell types is an integrated solution for comprehensive attenuation of myocardial ischaemia-reperfusion injury and cardiac function protection.

Targeted metabolomics reveals PFKFB3 as a key target for elemene-mediated inhibition of glycolysis in prostate cancer cells.

BACKGROUND: Elemene, an active anticancer extract derived from Curcuma wenyujin, has well-documented anticarcinogenic properties. Nevertheless, the role of elemene in prostate cancer (PCa) and its underlying molecular mechanism remain elusive. PURPOSE: This study focuses on investigating the anti-PCa effects of elemene and its underlying mechanisms. METHODS: Cell-based assays, including CCK-8, scratch, colony formation, cell cycle, and apoptosis experiments, to comprehensively assess the impact of elemene on PCa cells (LNCaP and PC3) in vitro. Additionally, we used a xenograft model with PC3 cells in nude mice to evaluate elemene in vivo efficacy. Targeted metabolomics analysis via HILIC-MS/MS was performed to investigate elemene potential target pathways, validated through molecular biology experiments, including western blotting and gene manipulation studies. RESULTS: In this study, we discovered that elemene has remarkable anti-PCa activity in both in vitro and in vivo settings, comparable to clinical chemotherapeutic drugs but with fewer side effects. Using our established targeted metabolomics approach, we demonstrated that ß-elemene, elemene's primary component, effectively inhibits glycolysis in PCa cells by downregulating 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) expression. Furthermore, we found that ß-elemene accomplishes this downregulation by upregulating p53 and FZR1. Knockdown and overexpression experiments conclusively confirmed the pivotal role of PFKFB3 in mediating ß-elemene's anti-PCa activity. CONCLUSION: This finding presents compelling evidence that elemene exerts its anti-PCa effect by suppressing glycolysis through the downregulation of PFKFB3. This study not only improves our understanding of elemene in PCa treatment but also provides valuable insights for developing more effective and safer therapies for PCa.

Bidirectional causal relationship between hypercholesterolemia and ischemic heart disease: a Mendelian randomization study.

Background: Ischemic Heart Disease (IHD) is a leading cause of morbidity and mortality worldwide. Hypercholesterolaemia, a metabolic syndrome distinguished by elevated cholesterol levels, is positively correlated with IHD, yet the precise causal relationship between these two health conditions remains to be clearly defined. Methods: We conducted a two-sample MR analysis using genetic variants associated with hypercholesterolemia and IHD. Various statistical techniques including MR-Egger, Weighted Median, Inverse Variance Weighted (IVW), Simple Mode, and Weighted Mode were employed. We also performed sensitivity analyses to assess pleiotropy, heterogeneity, and influence of individual SNPs. Furthermore, genetic co-localization analysis was performed to identify shared genes between hypercholesterolemia and IHD. Results: Our MR study illuminated a bidirectional causal relationship between hypercholesterolaemia and ischaemic heart disease. Utilising the IVW with multiplicative random effects, upon considering IHD as the outcome, we identified an OR of 2.27 (95% CI: 1.91-2.70, p = 1.68 × 10-20). Conversely, when hypercholesterolaemia was viewed as the outcome, the OR detected was 1.80 (95% CI: 1.58-2.05, p = 2.79 × 10-19). These findings remained consistent across various MR methods and sensitivity analyses. Additionally, our research pinpointed four co-localised genes CELSR2, PCSK9, LPA, and APOE as integral candidates implicated in the pathogenesis of both conditions, thereby suggesting shared common genetic causal variants and offering potential targets for innovative therapeutic strategies. Conclusion: bidirectional MR studies reveal genetic evidence of a potential causal link between hypercholesterolaemia and IHD. Notably, these findings also lend credence to the less traditional hypothesis that IHD may instigate hypercholesterolaemia episodes. Moreover, co-localisation analyses intimate the presence of shared genetic causal variants, paving the way for the development of new therapeutic strategies.

Lipid metabolism, amino acid metabolism, and prostate cancer: a crucial metabolic journey.

Prostate cancer (PCa) is one of the most common malignancies in males worldwide, and its development and progression involve the regulation of multiple metabolic pathways. Alterations in lipid metabolism affect the proliferation and metastatic capabilities of PCa cells. Cancer cells increase lipid synthesis and regulate fatty acid oxidation to meet their growth and energy demands. Similarly, changes occur in amino acid metabolism in PCa. Cancer cells exhibit an increased demand for specific amino acids, and they regulate amino acid transport and metabolic pathways to fulfill their proliferation and survival requirements. These changes are closely associated with disease progression and treatment response in PCa cells. Therefore, a comprehensive investigation of the metabolic characteristics of PCa is expected to offer novel insights and approaches for the early diagnosis and treatment of this disease.

Elevated circulating PCSK9 level is associated with 28-day mortality in patients with sepsis: a prospective cohort study.

OBJECTIVES: Pro-protein convertase subtilisin/kexin 9 (PCSK9) decreases the clearance of the pathogenic lipids, supporting the potential role of PCSK9 in the prognosis of sepsis. METHODS: In this prospective cohort study, patients with sepsis were consecutively recruited from 1 to 2020 to 30 September 2021 at the First People's Hospital of Huaihua, China. All the eligible patients were categorized into low-PCSK9 and high-PCSK9 groups, based on their PCSK9 levels at admission. Time-dependent receiver operating characteristic curves and Cox proportional hazards regression were used to evaluate the association between PCSK9 level and 28-day mortality of sepsis. RESULTS: Of the 203 enrolled patients, 56 (27.59%) died during the 28-day follow-up. The PCSK9 level was positively related to the C-reactive protein level. The cut-off point of PCSK9 levels for 28-day mortality risk was 370 ng/ml. Through comparison between high-PCSK9 (> 370 ng/ml) with low-PCSK9 (≤ 370 ng/ml) groups, the adjusted HR for mortality was 2.56 (95% CI: 1.25-5.23, p = 0.01). CONCLUSIONS: The 28-day mortality of sepsis increased significantly as the baseline circulating PCSK9 level exceeded 370 ng/ml, indicating circulating PCSK9 levels may be a potential biomarker to predict the prognosis of sepsis.

Screening of anti-cancer compounds from Vaccariae Semen by lung cancer A549 cell fishing and UHPLC-LTQ Orbitrap MS.

Vaccariae Semen, derived from the dried ripe seed of Vaccaria segetalis (Neck.) Garcke, has various therapeutic characteristics in traditional Chinese medicine (TCM), containing promoting blood circulation and unblocking meridians. It exhibits significant anti-cancer activity and is therapeutically utilized to treat and reduce chemotherapy adverse effects in cancer patients, notably those with lung cancer. However, the active ingredients responsible for its anti-lung cancer efficacy remain unknown. In this study, we used A549 cell fishing in conjunction with UHPLC-LTQ Orbitrap MS to screen for anti-lung cancer active components in Vaccariae Semen. The cell counting Kit-8 (CCK-8) assay revealed that the n-butanol extract substantially reduced A549 cell growth. Through the cell fishing assay, we found 14 A549 cell-binding compounds in the n-butanol extract, all of which were identified as triterpenoid saponins. The total saponins of Vaccariae Semen were subsequently purified using macroporous adsorption resin (MAR), and they showed a significant inhibitory effect on the proliferation of A549 lung cancer cells, as well as alterations in cell morphology, apoptosis, and fragmentation. In conclusion, saponins were discovered as the key active components responsible for the anti-lung cancer activity of Vaccariae Semen.

Biofunctionalized Decellularized Tissue-Engineered Heart Valve with Mesoporous Silica Nanoparticles for Controlled Release of VEGF and RunX2-siRNA against Calcification.

The goal of tissue-engineered heart valves (TEHV) is to replace normal heart valves and overcome the shortcomings of heart valve replacement commonly used in clinical practice. However, calcification of TEHV is the major bottleneck to break for both clinical workers and researchers. Endothelialization of TEHV plays a crucial role in delaying valve calcification by reducing platelet adhesion and covering the calcified spots. In the present study, we loaded RunX2-siRNA and VEGF into mesoporous silica nanoparticles and investigated the properties of anti-calcification and endothelialization in vitro. Then, the mesoporous silica nanoparticle was immobilized on the decellularized porcine aortic valve (DPAV) by layer self-assembly and investigated the anti-calcification and endothelialization. Our results demonstrated that the mesoporous silica nanoparticles delivery vehicle demonstrated good biocompatibility, and a stable release of RunX2-siRNA and VEGF. The hybrid decellularized valve exhibited a low hemolysis rate and promoted endothelial cell proliferation and adhesion while silencing RunX2 gene expression in valve interstitial cells, and the hybrid decellularized valve showed good mechanical properties. Finally, the in vivo experiment showed that the mesoporous silica nanoparticles delivery vehicle could enhance the endothelialization of the hybrid valve. In summary, we constructed a delivery system based on mesoporous silica to biofunctionalized TEHV scaffold for endothelialization and anti-calcification.

Advancements in Analyzing Tumor Metabolites through Chemical Derivatization-Based Chromatography.

Understanding the metabolic abnormalities of tumors is crucial for early diagnosis, prognosis, and treatment. Accurate identification and quantification of metabolites in biological samples are essential to investigate the relationship between metabolite variations and tumor development. Common techniques like LC-MS and GC-MS face challenges in measuring aberrant metabolites in tumors due to their strong polarity, isomerism, or low ionization efficiency during MS detection. Chemical derivatization of metabolites offers an effective solution to overcome these challenges. This review focuses on the difficulties encountered in analyzing aberrant metabolites in tumors, the principles behind chemical derivatization methods, and the advancements in analyzing tumor metabolites using derivatization-based chromatography. It serves as a comprehensive reference for understanding the analysis and detection of tumor metabolites, particularly those that are highly polar and exhibit low ionization efficiency.

Financial inclusion and low-carbon architectural design strategies: solutions for architectural climate conditions and architectural temperature on new buildings.

The objective of this research is to explore the potential of financial inclusion and low-carbon architectural design strategies as solutions to improve the thermal comfort and energy efficiency of new buildings in different architectural climate conditions. The manufacture sector, which accounts for about 40% of all yearly greenhouse gas releases, has been stimulating with trying to reduce the amount of energy it consumes and the detrimental effects it has on the climate, in accordance with the standards outlined in the 2016 Paris Agreement. In this study, panel data analysis is used to examine the connection between green property financing and carbon dioxide emissions from the building sector in one hundred and five developed and developing countries. Although this analysis finds a negative correlation among the development of environmentally friendly real estate financing and firms' worldwide carbon dioxide emissions, it finds that this correlation is most robust in developing nations. A number of these countries are experiencing an unregulated and rapid population explosion, which has boosted their demand for oil, making this discovery essential for them. The difficulty in securing green funding during this crisis is slowing and even reversing gains made in past years, making it all the more important to keep this momentum going during the COVID-19 outbreak. It's critical to keep the momentum going by doing something.

Potentiated effects of lactate receptor GPR81 on immune microenvironment in breast cancer.

G protein-coupled receptor (GPR81), as lactate receptor, is an upstart in immune regulation, however, its mechanisms involved in tumor escape have not been fully elucidated. In this study, we explored the effects of GPR81 activation on triple-negative breast cancer (TNBC) cells and macrophages. The expression and relationship with immune infiltration of GPR81 were analyzed with TCGA database. Checkpoints and cytokines were evaluated with flow cytometry or ELISA. The TCGA-based data showed a marked decrease of GPR81 in breast cancer (BRCA) compared with normal breast, especially in the basal-like subtype. In normal mammary tissues, GPR81 had negative correlation with various immune checkpoints, nevertheless, this trend weakened accompanied with the reduction of GPR81. GPR81 stimulation had a significantly inhibitory influence on PD-L1 exposure in BT-549 and MDA-MB-231 cell lines, but not in MDA-MB-453 cell line. The pretreatment of siGPR81 to knockdown GPR81 expression resulted in a remitting of PD-L1 reduction when MDA-MB-231 cells were treated with GPR81 agonist 1. However, little effect of GPR81 activation was observed on the expression of PD-L1 on phorbol-12-myristate-13-acetate (PMA)-induced THP-1 cells. Furthermore, GPR81 agonist 1 exerted no significant impact on the secretion of cytokines in THP-1 cells. In general, it is suggested that GPR81 may facilitate immune monitoring via the reduction of PD-L1 in TNBC with glycolytic phenotype. Our results not only provide a novel insight into the effects of GPR81 on immune evasion but a potential therapy targeting GPR81 in BRCA.

Elemene induces cell apoptosis via inhibiting glutathione synthesis in lung adenocarcinoma.

ETHNOPHARMACOLOGICAL RELEVANCE: The rhizome of Curcuma wenyujin Y.H. Chen & C. Ling, also known as Wen-E-Zhu, has been used for cancer treatment since ancient times, with roots dating back to the Song Dynasty. Elemene (EE), a sesquiterpene extract with potent anticancer properties, is extracted from Wen-E-Zhu, with ß-elemene (BE) being its main active compound, along with trace amounts of ß-caryophyllene (BC), γ-elemene and δ-elemene isomers. EE has demonstrated broad-spectrum anti-cancer effects and is commonly used in clinical treatments for various types of malignant cancers, including lung cancer. Studies have shown that EE can arrest the cell cycle, inhibit cancer cell proliferation, and induce apoptosis and autophagy. However, the exact mechanism of its anti-lung cancer activity remains unclear and requires further research and investigation. AIM OF THE STUDY: In this study, the possible mechanism of EE and its main active components, BE and BC, against lung adenocarcinoma was investigated by using A549 and PC9 cell lines. MATERIALS AND METHODS: The subcutaneous tumor model of nude mice was constructed to evaluate the efficacy of EE in vivo, then the in vitro half-inhibitory concentration (IC50) of EE and its main active components, BE and BC, on A549 and PC9 cells at different concentrations were determined by CCK-8. Flow cytometry was used to detect the apoptosis and cycle of A549 and PC9 cells treated with different concentrations of BE and BC for 24 h. Non-targeted metabolomics analysis was performed on A549 cells to explore potential target pathways, which were subsequently verified through kit detection and western blot analysis. RESULTS: Injection of EE in A549 tumor-bearing mice effectively suppressed cancer growth in vivo. The IC50 of EE and its main active components, BE and BC, was around 60 µg/mL. Flow cytometry analysis showed that BE and BC blocked the G2/M and S phases of lung adenocarcinoma cells and induced apoptosis, leading to a significant reduction in mitochondrial membrane potential (MMP). Results from non-targeted metabolomics analysis indicated that the glutathione metabolism pathway in A549 cells was altered after treatment with the active components. Kit detection revealed a decrease in glutathione (GSH) levels and an increase in the levels of oxidized glutathione (GSSG) and reactive oxygen (ROS). Supplementation of GSH reduced the inhibitory activity of the active components on lung cancer and also decreased the ROS content of cells. Analysis of glutathione synthesis-related proteins showed a decrease in the expression of glutaminase, cystine/glutamate reverse transporter (SLC7A11), and glutathione synthase (GS), while the expression of glutamate cysteine ligase modified subunit (GCLM) was increased. In the apoptosis-related pathway, Bax protein and cleaved caspase-9/caspase-9 ratio were up-regulated and Bcl-2 protein was down-regulated. CONCLUSIONS: EE, BE, and BC showed significant inhibitory effects on the growth of lung adenocarcinoma cells, and the mechanism of action was linked to the glutathione system. By down-regulating the expression of proteins related to GSH synthesis, EE and its main active components BE and BC disrupted the cellular redox system and thereby promoted cell apoptosis.