Combining QSAR techniques, molecular docking, and molecular dynamics simulations to explore anti-tumor inhibitors targeting Focal Adhesion Kinase.

Focal Adhesion Kinase (FAK) is an important target for tumor therapy and is closely related to tumor cell genesis and progression. In this paper, we selected 46 FAK inhibitors with anticancer activity in the pyrrolo pyrimidine backbone to establish 3D/2D-QSAR models to explore the relationship between inhibitory activity and molecular structure. We have established two ideal models, namely, the Topomer CoMFA model (q2= 0.715, r2= 0.984) and the Holographic Quantitative Structure-Activity Relationship (HQSAR) model (q2= 0.707, r2= 0.899). Both models demonstrate excellent external prediction capabilities.Based on the QSAR results, we designed 20 structurally modified novel compounds, which were subjected to molecular docking and molecular dynamics studies, and the results showed that the new compounds formed many robust interactions with residues within the active pocket and could maintain stable binding to the receptor proteins. This study not only provides a powerful screening tool for designing novel FAK inhibitors, but also presents a series of novel FAK inhibitors with high micromolar activity that can be used for further characterization. It provides a reference for addressing the shortcomings of drug metabolism and drug resistance of traditional FAK inhibitors, as well as the development of novel clinically applicable FAK inhibitors.Communicated by Ramaswamy H. Sarma.

Edge sulfur vacancies riched MoS2 nanosheets assist PEDOT:PSS flexible film ammonia sensing enhancement for wireless greenhouse vegetables monitoring.

Poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) is a promising NH3 sensing material owing to its super high electrical conductivity, excellent environmental stability, and reversible doping/dedoping nature. However, the low sensitivity and sluggish recovery rate limit its further application in gas sensors. Herein, exfoliated layered MoS2 nanosheets with large-specific surface area and abundant edge sulfur (S) vacancies are utilized to assist PEDOT:PSS and achieve ideal improvement in NH3 sensing performance at room temperature (RT), including high response values, fast response/recovery ability, and excellent sensing stability in complex environment. MoS2 nanosheets are combined with PEDOT:PSS to construct p-n heterojunction, the S vacancies can improve carrier transfer rate and serve as conductive bridge, effective active sites for NH3 adsorption, this series of performance improvement strategies is the significance of this work. Meanwhile, the density-functional theory (DFT), current-voltage (I-V), and in-situ FITR are firstly employed to discuss the sensing mechanisms in detail. Furthermore, integrating MoS2/PEDOT:PSS flexible sensor into a designed printed circuit board to intelligent, visual, and wireless real-time monitoring the NH3 resistance information in a simulated greenhouse vegetables equipment through the smartphone APP has also been successfully implemented.

Cerebral venous congestion alters brain metabolite profiles, impairing cognitive function.

Vascular cognitive impairment (VCI) represents the second most common cause of dementia after Alzheimer's disease, and pathological changes in cerebral vascular structure and function are pivotal causes of VCI. Cognitive impairment caused by arterial ischemia has been extensively studied the whole time; the influence of cerebral venous congestion on cognitive impairment draws doctors' attention in recent clinical practice, but the underlying neuropathophysiological alterations are not completely understood. This study elucidated the specific pathogenetic role of cerebral venous congestion in cognitive-behavioral deterioration and possible electrophysiological mechanisms. Using cerebral venous congestion rat models, we found these rats exhibited decreased long-term potentiation (LTP) in the hippocampal dentate gyrus and impaired spatial learning and memory. Based on untargeted metabolomics, N-acetyl-L-cysteine (NAC) deficiency was detected in cerebral venous congestion rats; supplementation with NAC appeared to ameliorate synaptic deficits, rescue impaired LTP, and mitigate cognitive impairment. In a cohort of cerebral venous congestion patients, NAC levels were decreased; NAC concentration was negatively correlated with subjective cognitive decline (SCD) score but positively correlated with mini-mental state examination (MMSE) score. These findings provide a new perspective on cognitive impairment and support further exploration of NAC as a therapeutic target for the prevention and treatment of VCI.

USP51/PD-L1/ITGB1-deployed juxtacrine interaction plays a cell-intrinsic role in promoting chemoresistant phenotypes in non-small cell lung cancer.

BACKGROUND: Programmed death ligand 1 (PD-L1) has been demonstrated to facilitate tumor progression and therapeutic resistance in an immune-independent manner. Nevertheless, the function and underlying signaling network(s) of cancer cell-intrinsic PD-L1 action remain largely unknown. Herein, we sought to better understand how ubiquitin-specific peptidase 51 (USP51)/PD-L1/integrin beta-1 (ITGB1) signaling performs a cell-intrinsic role in mediating chemotherapeutic resistance in non-small cell lung cancer (NSCLC). METHODS: Western blotting and flow cytometry were employed for PD-L1 detection in NSCLC cell lines. Coimmunoprecipitation and pulldown analyses, protein deubiquitination assay, tissue microarray, bioinformatic analysis and molecular biology methods were then used to determine the significance of PD-L1 in NSCLC chemoresistance and associated signaling pathways in several different cell lines, mouse models and patient tissue samples. Ubiquitin-7-amido-4-methylcoumarin (Ub-AMC)-based deubiquitinase activity, cellular thermal shift and surface plasmon resonance (SPR) analyses were performed to investigate the activity of USP51 inhibitors. RESULTS: We provided evidence that cancer cell-intrinsic PD-L1 conferred the development of chemoresistance by directly binding to its membrane-bound receptor ITGB1 in NSCLC. At the molecular level, PD-L1/ITGB1 interaction subsequently activated the nuclear factor-kappa B (NF-κB) axis to elicit poor response to chemotherapy. We further determined USP51 as a bona fide deubiquitinase that targeted the deubiquitination and stabilization of the PD-L1 protein in chemoresistant NSCLC cells. Clinically, we found a significant direct relationship between the USP51, PD-L1 and ITGB1 contents in NSCLC patients with chemoresistant potency. The elevated USP51, PD-L1 and ITGB1 levels were strongly associated with worse patient prognosis. Of note, we identified that a flavonoid compound dihydromyricetin (DHM) acted as a potential USP51 inhibitor and rendered NSCLC cells more sensitive to chemotherapy by targeting USP51-dependent PD-L1 ubiquitination and degradation in vitro and in vivo. CONCLUSIONS: Together, our results demonstrated that the USP51/PD-L1/ITGB1 network potentially contributes to the malignant progression and therapeutic resistance in NSCLC. This knowledge is beneficial to the future design of advanced cancer therapy.

Cerebral venous thrombosis in patients with autoimmune disease, hematonosis or coronavirus disease 2019: Many familiar faces and some strangers.

BACKGROUND: Cerebral venous thrombosis, a rare stroke, is characterized by neurological dysfunction caused by bleeding and/or infarction resulting from venous sinus thrombosis, the so-called venous stroke. Current guidelines recommend anticoagulants as first-line therapy in the treatment of venous stroke. With complicated causes of cerebral venous thrombosis, treatment is difficult, especially when combined with autoimmune diseases, blood diseases, and even COVID-19. AIMS: This review summarizes the pathophysiological mechanisms, epidemiology, diagnosis, treatment, and clinical prognosis of cerebral venous thrombosis combined with autoimmune diseases, blood diseases, or infectious diseases such as COVID-19. CONCLUSION: A systematic understanding of particular risk factors that should not be neglected when unconventional cerebral venous thrombosis occurs and for a scientific understanding of pathophysiological mechanisms, clinical diagnosis, and treatment, thus contributing to knowledge on special types of venous stroke.

A Highly Selective Electrochemical Sensor Based on Molecularly Imprinted Copolymer Functionalized with Arginine for the Detection of Chloramphenicol in Honey.

Developing an efficient method for chloramphenicol (CAP) detection is of great significance for food safety. Arginine (Arg) was selected as a functional monomer. Benefiting from its excellent electrochemical performance, which is different from traditional functional monomers, it can be combined with CAP to form a highly selective molecularly imprinted polymer (MIP) material. It overcomes the shortcoming of poor MIP sensitivity faced by traditional functional monomers, and achieves high sensitivity detection without compounding other nanomaterials, greatly reducing the preparation difficulty and cost investment of the sensor. The possible binding sites between CAP and Arg molecules were calculated by molecular electrostatic potential (MEP). A low-cost, non-modified MIP electrochemical sensor was developed for the high-performance detection of CAP. The prepared sensor has a wide linear range from 1 × 10-12 mol L-1 to 5 × 10-4 mol L-1, achieves a very low concentration CAP detection, and the detection limit is 1.36 × 10-13 mol L-1. It also exhibits excellent selectivity, anti-interference, repeatability, and reproducibility. The detection of CAP in actual honey samples was achieved, which has important practical value in food safety.

Endothelial Senescence in Neurological Diseases.

Endothelial cells, which are highly dynamic cells essential to the vascular network, play an indispensable role in maintaining the normal function of the body. Several lines of evidence indicate that the phenotype associated with senescent endothelial cells causes or promotes some neurological disorders. In this review, we first discuss the phenotypic changes associated with endothelial cell senescence; subsequently, we provide an overview of the molecular mechanisms of endothelial cell senescence and its relationship with neurological disorders. For refractory neurological diseases such as stroke and atherosclerosis, we intend to provide some valid clues and new directions for clinical treatment options.

Recent Advances in Carbon Nitride-Based S-scheme Photocatalysts for Solar Energy Conversion.

Energy shortages are a major challenge to the sustainable development of human society, and photocatalytic solar energy conversion is a potential way to alleviate energy problems. As a two-dimensional organic polymer semiconductor, carbon nitride is considered to be the most promising photocatalyst due to its stable properties, low cost, and suitable band structure. Unfortunately, pristine carbon nitride has low spectral utilization, easy recombination of electron holes, and insufficient hole oxidation ability. The S-scheme strategy has developed in recent years, providing a new perspective for effectively solving the above problems of carbon nitride. Therefore, this review summarizes the latest progress in enhancing the photocatalytic performance of carbon nitride via the S-scheme strategy, including the design principles, preparation methods, characterization techniques, and photocatalytic mechanisms of the carbon nitride-based S-scheme photocatalyst. In addition, the latest research progress of the S-scheme strategy based on carbon nitride in photocatalytic H2 evolution and CO2 reduction is also reviewed. Finally, some concluding remarks and perspectives on the challenges and opportunities for exploring advanced nitride-based S-scheme photocatalysts are presented. This review brings the research of carbon nitride-based S-scheme strategy to the forefront and is expected to guide the development of the next-generation carbon nitride-based S-scheme photocatalysts for efficient energy conversion.

Potential role of plasma branched-chain amino acids in the differential diagnosis of acute cerebral venous thrombosis.

Cerebral venous thrombosis (CVT) is a special and easily misdiagnosed or undiagnosed subtype of stroke. To identify specific biomarkers with a high predictive ability for the diagnosis of acute CVT, we performed metabolomic analysis in plasma samples from acute CVT patients and healthy controls and confirmed the results in validation cohorts. In the discovery stage, there were 343 differential metabolites, and the caffeine metabolism pathway and the biosynthesis pathway for the branched chain amino acids (BCAAs) valine, leucine, and isoleucine were two significant pathways between the CVT and healthy cohorts. The area under the curve (AUC) for metabolites associated with valine, leucine, and isoleucine biosynthesis was 0.934. In the validation stage, the BCAA concentrations demonstrated an AUC of 0.935 to differentiate patients with acute CVT from the control cohort. In addition, BCAAs combined with D-dimer levels were used to establish a diagnostic model for CVT, and the AUC was 0.951, showing good diagnostic efficacy of separating CVT patients from the control cohort. BCAAs as plasma biomarkers deserve to be further studied and even developed in clinical CVT management.

Discovery of novel BRD4-BD2 inhibitors via in silico approaches: QSAR techniques, molecular docking, and molecular dynamics simulations.

Bromodomain-containing protein 4(BRD4) plays an important role in the occurrence and development of various malignant tumors, which has attracted the attention of scientific research institutions and pharmaceutical companies. The structural modification of most currently available BRD4 inhibitors is relatively simple, but the drug effectiveness is limited. Research has found that the inhibition of BD1 may promote the differentiation of oligodendrocyte progenitor cell; however, the inhibition of BD2 will not cause this outcome. Therefore, newly potential drugs which target BRD4-BD2 need further research. Herein, we initially built QSAR models out of 49 compounds using HQSAR, CoMFA, CoMSIA, and Topomer CoMFA technology. All of the models have shown suitable reliabilities (q2 = 0.778, 0.533, 0.640, 0.702, respectively) and predictive abilities (r2pred = 0.716, 0.6289, 0.6153, 0.7968, respectively) for BRD4-BD2 inhibitors. On the basis of QSAR results and the search of the R-group in the topomer search module, we designed 20 new compounds with high activity that showed appropriate docking score and suitable ADMET. Docking studies and MD simulation were carried out to reveal the amino acid residues (Asn351, Cys347, Tyr350, Pro293, and Asp299) at the active site of BRD4-BD2. Free energy calculations and free energy landscapes verified the stable binding results and indicated stable conformations of the complexes. These theoretical studies provide guidance and theoretical basis for designing and developing novel BRD4-BD2 inhibitors.

Pt/MoS2/Polyaniline Nanocomposite as a Highly Effective Room Temperature Flexible Gas Sensor for Ammonia Detection.

A Pt/MoS2/polyaniline (Pt/MoS2/PANI) nanocomposite is successfully synthesized by the hydrothermal process combined with the in situ polymerization method, and then Pt particles are decorated on its surface. The Pt/MoS2/PANI nanocomposite is deposited on a flexible Au-interdigitated electrode of a polyimide (PI) film. The flexible sensor exhibits a higher response value and fast response/recovery time to NH3 at room temperature (RT). It results in 2.32-fold and 1.13-fold improvement in the gas-sensing response toward 50 ppm NH3 compared to those of PANI and MoS2/PANI-based gas sensors. The detection limit is 250 ppb. The enhancement sensing mechanisms are attributed to the p-n heterojunction and the Schottky barrier between the three components, which has been confirmed by the current-voltage (I-V) curves. A satisfactory selectivity to NH3 against trimethylamine (TMA) and triethylamine (TEA) is obtained according to density functional theory (DFT), Bader's analysis, and differential charge density to illustrate the adsorption behavior and charge transfer of gas molecules on the surface of the sensing materials. The sensor retains the excellent sensing response value even under high relative humidity and sensing stability at higher bending angle/numbers to NH3 gas. Hence, Pt/MoS2/PANI can be regarded as a promising sensing material for high-performance NH3 detection at room temperature applied in flexible wearable electronics.

High sensitivity electrochemical detection of ultra-trace imidacloprid in fruits and vegetables using a Fe-rich FeCoNi-MOF.

High sensitivity and ultra-trace detection of imidacloprid are important and challenging in the field of food. In this study, we prepared a Fe-rich FeCoNi-MOF in-situ modified nickel foam working electrode by one-step hydrothermal method, and achieved a highly sensitive detection of the imidacloprid. The characterization techniques confirmed that Fe-rich FeCoNi-MOF had excellent crystallinity, tighter structure, and exposed rich active sites. The detection results showed that Fe-rich FeCoNi-MOF electrochemical sensor had a minimum detection limit of 0.04 pmol/L (100 times lower than that of the bioelectrochemical sensors), a wide response range (1 pmol/L-120 µmol/L), and high sensitivity (124 µA pmol/L-1 cm-2). These advantages of the electrochemical sensor were revealed theoretically by the valence change of active metal and the first principle calculation. Lastly, the Fe-rich FeCoNi-MOF electrochemical sensor was applied to detect imidacloprid in apple, fresh tea leaves, tomato, cucumber, and had an excellent recovery of 98-102.8 %.

Vascular endothelial cells: a fundamental approach for brain waste clearance.

Accumulation of neurotoxic protein aggregates is the pathological hallmark of neurodegenerative disease. Proper clearance of these waste metabolites is an essential process for maintaining brain microenvironment homeostasis and may delay or even halt the onset and progression of neurodegeneration. Vascular endothelial cells regulate the molecular exchange between the circulation and brain parenchyma, thereby protecting the brain against the entry of xenobiotics and decreasing the accumulation of neurotoxic proteins. In this review, we provide an overview of cerebrovascular endothelial cell characteristics and their impact on waste metabolite clearance. Lastly, we speculate that molecular changes in cerebrovascular endothelial cells are the drivers of neurodegenerative diseases.

Overview of the meningeal lymphatic vessels in aging and central nervous system disorders.

In the aging process and central nervous system (CNS) diseases, the functions of the meningeal lymphatic vessels (MLVs) are impaired. Alterations in MLVs have been observed in aging-related neurodegenerative diseases, brain tumors, and even cerebrovascular disease. These findings reveal a new perspective on aging and CNS disorders and provide a promising therapeutic target. Additionally, recent neuropathological studies have shown that MLVs exchange soluble components between the cerebrospinal fluid (CSF) and interstitial fluid (ISF) and drain metabolites, cellular debris, misfolded proteins, and immune cells from the CSF into the deep cervical lymph nodes (dCLNs), directly connecting the brain with the peripheral circulation. Impairment and dysfunction of meningeal lymphatics can lead to the accumulation of toxic proteins in the brain, exacerbating the progression of neurological disorders. However, for many CNS diseases, the causal relationship between MLVs and neuropathological changes is not fully clear. Here, after a brief historical retrospection, we review recent discoveries about the hallmarks of MLVs and their roles in the aging and CNS diseases, as well as potential therapeutic targets for the treatment of neurologic diseases.

Biochanin A inhibits lung adenocarcinoma progression by targeting ZEB1.

Lung adenocarcinoma is the major subtype of lung cancer, accounting for approximately 40% of lung cancers. During clinical treatment, the emergence of chemotherapy resistance seriously affects the effectiveness of treatment. Thus, finding new chemotherapeutic sensitizers is considered to be one of the effective solutions. Biochanin A, as a naturally occurring isoflavone, has been demonstrated to exhibit anticancer effects in various tumors. However, the potential mechanisms of Biochanin A to inhibit tumor development have not been clarified. In the present study, we found that the combinational treatment of cisplatin and Biochanin A exhibited strong synergistic repression on lung adenocarcinoma growth and progression in vitro and in vivo. Considering that epithelial-mesenchymal transition (EMT) is recognized to be associated with both chemoresistance and metastasis, we examined the EMT-related markers and found that Biochanin A could specifically inhibit the expression of ZEB1. Importantly, Biochanin A chemosensitizes lung adenocarcinoma and inhibits cancer cell metastasis by suppressing ZEB1. At the molecular level, Biochanin A affects the stability of ZEB1 protein through the deubiquitination pathway and thereby influences the progression of lung adenocarcinoma. In conclusion, our finding elucidates the potential efficacy of Bichanin A as a chemosensitizer and provides new strategy for the chemotherapy of advanced lung adenocarcinoma.

Plasma Ag-Modified α-Fe2O3/g-C3N4 Self-Assembled S-Scheme Heterojunctions with Enhanced Photothermal-Photocatalytic-Fenton Performances.

Low spectral utilization and charge carrier compounding limit the application of photocatalysis in energy conversion and environmental purification, and the rational construction of heterojunction is a promising strategy to break this bottleneck. Herein, we prepared surface-engineered plasma Ag-modified α-Fe2O3/g-C3N4 S-Scheme heterojunction photothermal catalysts by electrostatic self-assembly and light deposition strategy. The local surface plasmon resonance effect induced by Ag nanoparticles broadens the spectral response region and produces significant photothermal effects. The temperature of Ag/α-Fe2O3/g-C3N4 powder is increased to 173 °C with irradiation for 90 s, ~3.2 times higher than that of the original g-C3N4. The formation of 2D/2D structured S-Scheme heterojunction promotes rapid electron-hole transfer and spatial separation. Ternary heterojunction construction leads to significant enhancement of photocatalytic performance of Ag/α-Fe2O3/g-C3N4, the H2 photocatalytic generation rate up to 3125.62 µmol g-1 h-1, which is eight times higher than original g-C3N4, and the photocatalytic degradation rate of tetracycline to reach 93.6%. This thermally assisted photocatalysis strategy improves the spectral utilization of conventional photocatalytic processes and provides new ideas for the practical application of photocatalysis in energy conversion and environmental purification.

Hypoxia inducible factor 1α promotes interleukin-1 receptor antagonist expression during hepatic ischemia-reperfusion injury.

BACKGROUND: Ischemia-reperfusion injury (IRI) is a major risk associated with liver surgery and transplantation, and its pathological mechanism is complex. Interleukin-1 receptor antagonist (IL-1ra) can protect the liver from IRI. However, the regulatory mechanism of IL-1ra expression is still unclear. AIM: To identify the mechanism that could protect the liver in the early stage of IRI. METHODS: To screen the key genes in hepatic IRI, we performed RNA sequencing and gene enrichment analysis on liver tissue from mice with hepatic IRI. Subsequently, we verified the expression and effect of IL-1ra in hepatic IRI. We also used promoter mutagenesis and chromatin immunoprecipitation assay to search for the transcriptional regulatory sites of hypoxia-inducible factor (HIF)-1α. Finally, to explore the protective mechanism of ischemic preconditioning (IP), we examined the expression of HIF-1α and IL-1ra after IP. RESULTS: We identified IL-1ra as a key regulator in hepatic IRI. The expression of IL-1ra was significantly upregulated after hepatic IRI both in vivo and in vitro. Furthermore, we found that HIF-1α regulated Il-1ra transcription in response to hypoxia. Increased HIF-1α accumulation promoted IL-1ra expression, whereas inhibition of HIF-1α exhibited the opposite effect. We also confirmed a predominant role for hypoxia response element in the regulation of Il1ra transcription by HIF-1α activation. Of note, we demonstrated that IP protects against hepatic IRI by inducing IL-1ra expression, which is mediated through HIF-1α. CONCLUSION: We demonstrated that ischemia or hypoxia leads to increased expression of IL-1ra through HIF-1α. Importantly, IP protects the liver from IRI via the HIF-1α-IL-1ra pathway.

Effect of Dietary Lactose Supplementation on Growth Performance and Intestinal Epithelium Functions in Weaned Pigs Challenged by Rotavirus.

The purpose of this study was to investigate whether dietary lactose supplementation relieves rotavirus (RV)-induced diarrhea and gut dysfunction. Thirty-six crossbred weaned piglets were randomly allocated into three groups and fed diets containing 0, 4%, and 6% lactose for 20 days. On Day 15, half of the piglets in each group were orally infused with RV. RV infection impaired growth performance; induced severe diarrhea; decreased serum D-xylose concentration and morphology and sIgA level of jejunal mucosa; downregulated MUC1, MUC2, occludin, Bcl-2, IL-4, pBD3, pBD2, and pBD1 mRNA expression of jejunal mucosa and/or mesenteric lymph nodes; upregulated Bax, caspase-3, IL-2, IFN-γ, and IFN-ß mRNA expression of jejunal mucosa and/or mesenteric lymph nodes; and damaged microbiota and metabolites of cecal digesta in weaned piglets (p < 0.05). Dietary lactose supplementation improved nutrient digestibility and growth performance and relieved the negative influence of RV challenge on intestinal barrier function, mRNA expression of cytokines, and host defense peptides of jejunal mucosa and/or mesenteric lymph nodes in weaned piglets (p < 0.05). Dietary administration of 6% lactose tended to relieve diarrhea (p = 0.07). These results suggest that lactose in feed increases growth performance and has a tendency to alleviate RV-induced diarrhea, derived from the improvement of nutrient utilization, gut barrier function, and immunity.

Porous MCo2O4(M = Zn, Cu, Fe, Mn) as high efficient bi-functional catalysts for oxygen reduction and oxygen evolution reaction.

High-efficiency bi-functional electrocatalysts with long-term stability are critical to the development of many kinds of fuel cells, because that the performance of battery is limited by the slow kinetics of oxygen reduction reaction (ORR) and oxygen evolution reaction (OER). In this work, porous MCo2O4(M = Zn, Cu, Fe, Mn) were prepared by hydrothermal method with NH4F and urea as surfactants. FeCo2O4with porous structure has more oxygen defects and the larger specific surface area than other MCo2O4(M = Zn, Cu, Mn), and it not onlysupplies more active sites but also avails the transmission of electrolyte and O2in the process of ORR and OER in 0.1 M KOH aqueous solution. Porous FeCo2O4electrode material produces less intermediate H2O2, and its ORR is mainly controlled by a 4e-reaction path. Compared with commercial Pt/C, the prepared FeCo2O4has comparable ORR activity and excellent OER activity. At the same time, the stability of FeCo2O4to ORR is significantly higher than that of commercial Pt/C. The porous FeCo2O4was prepared by facile synthesis procedure could be a potential promising bi-functional catalyst due to its high electrocatalytic activities and long-term stability for both the ORR and OER.

Zeb1-induced metabolic reprogramming of glycolysis is essential for macrophage polarization in breast cancer.

Aerobic glycolysis (the Warburg effect) has been demonstrated to facilitate tumor progression by producing lactate, which has important roles as a proinflammatory and immunosuppressive mediator. However, how aerobic glycolysis is directly regulated is largely unknown. Here, we show that ectopic Zeb1 directly increases the transcriptional expression of HK2, PFKP, and PKM2, which are glycolytic rate-determining enzymes, thus promoting the Warburg effect and breast cancer proliferation, migration, and chemoresistance in vitro and in vivo. In addition, Zeb1 exerts its biological effects to induce glycolytic activity in response to hypoxia via the PI3K/Akt/HIF-1α signaling axis, which contributes to fostering an immunosuppressive tumor microenvironment (TME). Mechanistically, breast cancer cells with ectopic Zeb1 expression produce lactate in the acidic tumor milieu to induce the alternatively activated (M2) macrophage phenotype through stimulation of the PKA/CREB signaling pathway. Clinically, the expression of Zeb1 is positively correlated with dysregulation of aerobic glycolysis, accumulation of M2-like tumor-associated macrophages (TAMs) and a poor prognosis in breast cancer patients. In conclusion, these findings identify a Zeb1-dependent mechanism as a driver of breast cancer progression that acts by stimulating tumor-macrophage interplay, which could be a viable therapeutic target for the treatment of advanced human cancers.