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Currently, chemotherapy is the main treatment for tumors, but there are still problems such as unsatisfactory chemotherapy results, susceptibility to drug resistance, and serious adverse effects. Natural compounds have numerous pharmacological activities which are important sources of drug discovery for tumor treatment. The combination of chemotherapeutic drugs and natural compounds is gradually becoming an important strategy and development direction for tumor treatment. In this paper, we described the role of natural compounds in combination with chemotherapeutic drugs in synergizing, reducing drug resistance, mitigating adverse effects and related mechanisms, and providing new insights for future oncology research. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC), the most prevalent subtype of liver cancer, is the second main reason for cancer-related deaths worldwide. In recent decades, sufficient evidence supported that immunotherapy was a safe and effective treatment option for HCC. However, tolerance and frequent recurrence and metastasis occurred in patients after immunotherapy due to the complicated crosstalk in the tumor immunosuppressive microenvironment (TIME) in HCC. Therefore, elucidating the TIME in HCC and finding novel modulators to target TIME for attenuating immune suppression is critical to optimize immunotherapy. Recently, studies have shown the potentially immunoregulatory activities of natural compounds, characterized by multiple targets and pathways and low toxicity. In this review, we concluded the unique role of TIME in HCC. Moreover, we summarized evidence that supports the hypothesis of natural compounds to target TIME to improve immunotherapy. Furthermore, we discussed the comprehensive mechanisms of these natural compounds in the immunotherapy of HCC. Accordingly, we present a well-grounded review of the naturally occurring compounds in cancer immunotherapy, expecting to shed new light on discovering novel anti-HCC immunomodulatory drugs from natural sources. [ABSTRACT FROM AUTHOR]

4-(4-Bromophenyl)-2,3-dihydro- N,3-bis(3,4,5-trimethoxyphenyl)-2-oxoidmi-dazole-1-carboxamide (MZ3) is one of the synthesized combretastatin-A-4 analogues and has been reported that it displayed a promising specific activity against leukemia cell lines. Our purpose was to investigate the mechanism of MZ3’s cytotoxicity. Cytotoxicity was measured by MTT method, apoptosis was measured by flow cytometry. DNA fragmentation was tested by agarose gel electrophoresis. Mitochondrial membrane potential (ΔΨm) was detected by JC1 staining and flow cytometry, while intracellular reactive oxygen species (ROS) was detected by 5-(and-6)-carboxy-2′-7′-dichlorofluorescin diacetate staining and flow cytometry. Protein expression was analyzed by western blotting. In vivo activity of MZ3 was assayed through severe combined immunodeficiency (SCID) mice model of human leukemia engrafts. MZ3 exhibited high anti-cancer activity in six leukemia cell lines, including two drug-resistant cell lines. MZ3 induced DNA fragmentation, and caused an elevation of ROS and a loss of ΔΨm in HL60 cells. MZ3 also induced the activation of caspase-3, influenced the expression of Bcl-2 family members, MAPKs and other proteins relative to mitochondria-induced apoptosis. In addition, N-acetylcysteine cannot inhibit HL60 cell apoptosis caused by MZ3. Furthermore, a prolonged survival time was observed after treatment with MZ3 in SCID mice model of human leukemia engrafts. MZ3 is a potent compound against leukemia cell lines both in vitro and in vivo, and the mitochondrial pathway mediated by Bcl-2 protein family and MAPKs might be involved in signaling MZ3-induced apoptosis. [ABSTRACT FROM AUTHOR]

Lenvatinib is a multi-target inhibitor that exerts anti-tumor effects by inhibiting angiogenesis and is now commonly used as a first-line treatment for hepatocellular carcinoma. However, with the widespread use of lenvatinib, the problem of serious and fatal hepatotoxicity has become increasingly prominent. Currently, the mechanism behind this toxicity is not yet understood, and as a result, there is a lack of safe and effective intervention strategies with minimal side effects. Here, we established the model of lenvatinib-induced liver injury in vivo and in vitro and found that lenvatinib caused hepatotoxicity by inducing apoptosis. Further mechanistic studies in cellular models revealed that lenvatinib upregulated death receptor signaling pathway, which activated the downstream effector Caspase-8, and ultimately led to apoptosis. Meanwhile, lenvatinib-induced apoptosis was associated with ROS generation and DNA damage. In addition, after screening marketed drugs and natural products in combination with cellular modeling, we identified a potential co-administered drug, dabrafenib, which could alleviate lenvatinib-induced hepatotoxicity. Further mechanistic studies revealed that dabrafenib attenuated lenvatinib-induced hepatotoxicity by inhibiting the activation of the death receptor signaling pathway. Subsequently, cancer cell proliferation assays confirmed that dabrafenib did not antagonize the antitumor effects of lenvatinib. In conclusion, our results validate that apoptosis caused by the death receptor signaling pathway is the key cause of lenvatinib-induced hepatotoxicity, and dabrafenib alleviates lenvatinib-induced hepatotoxicity by inhibiting this pathway. • Lenvatinib induces apoptosis by activating the death receptor pathway, causing hepatotoxicity in vivo and in vitro. • Lenvatinib upregulates the expression of Fas and TRAIL proteins, which activates the downstream effector Caspase-8. • Hepatotoxicity caused by lenvatinib is associated with ROS generation and DNA damage. • Dabrafenib alleviates lenvatinib-induced liver injury by inhibiting the death receptor signaling pathway. [ABSTRACT FROM AUTHOR]

Coronaviruses have threatened humans repeatedly, especially COVID-19 caused by SARS-CoV-2, which has posed a substantial threat to global public health. SARS-CoV-2 continuously evolves through random mutation, resulting in a significant decrease in the efficacy of existing vaccines and neutralizing antibody drugs. It is critical to assess immune escape caused by viral mutations and develop broad-spectrum vaccines and neutralizing antibodies targeting conserved epitopes. Thus, we constructed CovEpiAb, a comprehensive database and analysis resource of human coronavirus (HCoVs) immune epitopes and antibodies. CovEpiAb contains information on over 60 000 experimentally validated epitopes and over 12 000 antibodies for HCoVs and SARS-CoV-2 variants. The database is unique in (1) classifying and annotating cross-reactive epitopes from different viruses and variants; (2) providing molecular and experimental interaction profiles of antibodies, including structure-based binding sites and around 70 000 data on binding affinity and neutralizing activity; (3) providing virological characteristics of current and past circulating SARS-CoV-2 variants and in vitro activity of various therapeutics; and (4) offering site-level annotations of key functional features, including antibody binding, immunological epitopes, SARS-CoV-2 mutations and conservation across HCoVs. In addition, we developed an integrated pipeline for epitope prediction named COVEP, which is available from the webpage of CovEpiAb. CovEpiAb is freely accessible at https://pgx.zju.edu.cn/covepiab/. [ABSTRACT FROM AUTHOR]

Discovering effective anti-tumor drug combinations is crucial for advancing cancer therapy. Taking full account of intricate biological interactions is highly important in accurately predicting drug synergy. However, the extremely limited prior knowledge poses great challenges in developing current computational methods. To address this, we introduce SynergyX, a multi-modality mutual attention network to improve anti-tumor drug synergy prediction. It dynamically captures cross-modal interactions, allowing for the modeling of complex biological networks and drug interactions. A convolution-augmented attention structure is adopted to integrate multi-omic data in this framework effectively. Compared with other state-of-the-art models, SynergyX demonstrates superior predictive accuracy in both the General Test and Blind Test and cross-dataset validation. By exhaustively screening combinations of approved drugs, SynergyX reveals its ability to identify promising drug combination candidates for potential lung cancer treatment. Another notable advantage lies in its multidimensional interpretability. Taking Sorafenib and Vorinostat as an example, SynergyX serves as a powerful tool for uncovering drug-gene interactions and deciphering cell selectivity mechanisms. In summary, SynergyX provides an illuminating and interpretable framework, poised to catalyze the expedition of drug synergy discovery and deepen our comprehension of rational combination therapy. [ABSTRACT FROM AUTHOR]

The FDA Modernization Act 2.0 has brought nonclinical drug evaluation into a new era. In vitro models are widely used and play an important role in modern drug development and evaluation, including early candidate drug screening and preclinical drug efficacy and toxicity assessment. Driven by regulatory steering and facilitated by well-defined physiology, novel in vitro skin models are emerging rapidly, becoming the most advanced area in alternative testing research. The revolutionary technologies bring us many in vitro skin models, either laboratory-developed or commercially available, which were all built to emulate the structure of the natural skin to recapitulate the skin's physiological function and particular skin pathology. During the model development, how to achieve balance among complexity, accessibility, capability, and cost-effectiveness remains the core challenge for researchers. This review attempts to introduce the existing in vitro skin models, align them on different dimensions, such as structural complexity, functional maturity, and screening throughput, and provide an update on their current application in various scenarios within the scope of chemical testing and drug development, including testing in genotoxicity, phototoxicity, skin sensitization, corrosion/irritation. Overall, the review will summarize a general strategy for in vitro skin model to enhance future model invention, application, and translation in drug development and evaluation. [ABSTRACT FROM AUTHOR]

Nephrotoxicity has become prominent due to the increase in the clinical use of nilotinib, a second‐generation BCR‐ABL1 inhibitor in the first‐line treatment of Philadelphia chromosome‐positive chronic myeloid leukemia. To date, the mechanism of nilotinib nephrotoxicity is still unknown, leading to a lack of clinical intervention strategies. Here, it is found that nilotinib could induce glomerular atrophy, renal tubular degeneration, and kidney fibrosis in an animal model. Mechanistically, nilotinib induces intrinsic apoptosis by specifically reducing the level of BCL2 like 1 (Bcl‐XL) in both vascular endothelial cells and renal tubular epithelial cells, as well as in vivo. It is confirmed that chloroquine (CQ) intervenes with nilotinib‐induced apoptosis and improves mitochondrial integrity, reactive oxygen species accumulation, and DNA damage by reversing the decreased Bcl‐XL. The intervention effect is dependent on the alleviation of the nilotinib‐induced reduction in ubiquitin specific peptidase 13 (USP13) and does not rely on autophagy inhibition. Additionally, it is found that USP13 abrogates cell apoptosis by preventing excessive ubiquitin‒proteasome degradation of Bcl‐XL. In conclusion, the research reveals the molecular mechanism of nilotinib's nephrotoxicity, highlighting USP13 as an important regulator of Bcl‐XL stability in determining cell fate, and provides CQ analogs as a clinical intervention strategy for nilotinib's nephrotoxicity. [ABSTRACT FROM AUTHOR]

Predicting the biological properties of molecules is crucial in computer-aided drug development, yet it's often impeded by data scarcity and imbalance in many practical applications. Existing approaches are based on self-supervised learning or 3D data and using an increasing number of parameters to improve performance. These approaches may not take full advantage of established chemical knowledge and could inadvertently introduce noise into the respective model. In this study, we introduce a more elegant transformer-based framework with focused attention for molecular representation (TransFoxMol) to improve the understanding of artificial intelligence (AI) of molecular structure property relationships. TransFoxMol incorporates a multi-scale 2D molecular environment into a graph neural network + Transformer module and uses prior chemical maps to obtain a more focused attention landscape compared to that obtained using existing approaches. Experimental results show that TransFoxMol achieves state-of-the-art performance on MoleculeNet benchmarks and surpasses the performance of baselines that use self-supervised learning or geometry-enhanced strategies on small-scale datasets. Subsequent analyses indicate that TransFoxMol's predictions are highly interpretable and the clever use of chemical knowledge enables AI to perceive molecules in a simple but rational way, enhancing performance. [ABSTRACT FROM AUTHOR]

Aims Trastuzumab, the first humanized monoclonal antibody that targets human epidermal growth factor receptor 2 (ERBB2/HER2), is currently used as a first-line treatment for HER2 (+) tumours. However, trastuzumab increases the risk of cardiac complications without affecting myocardial structure, suggesting a distinct mechanism of cardiotoxicity. Methods and results We used medium from trastuzumab-treated human umbilical vein endothelial cells (HUVECs) to treat CCC-HEH-2 cells, the human embryonic cardiac tissue-derived cell lines, and human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) to assess the crosstalk between vascular endothelial cells (VECs) and cardiomyocytes. Protein mass spectrometry analysis was used to identify the key factors from VECs that regulate the function of cardiomyocytes. We applied RNA-sequencing to clarify the mechanism, by which PTX3 causes cardiac dysfunction. We used an anti-human/rat HER2 (neu) monoclonal antibody to generate a rat model that was used to evaluate the effects of trastuzumab on cardiac structure and function and the rescue effects of lapatinib on trastuzumab-induced cardiac side effects. Medium from trastuzumab-treated HUVECs apparently impaired the contractility of CCC-HEH-2 cells and iPSC-CMs. PTX3 from VECs caused defective cardiomyocyte contractility and cardiac dysfunction in mice, phenocopying trastuzumab treatment. PTX3 affected calcium homoeostasis in cardiomyocytes, which led to defective contractile properties. EGFR/STAT3 signalling in VECs contributed to the increased expression and release of PTX3. Notably, lapatinib, a dual inhibitor of EGFR/HER2, could rescue the cardiac complications caused by trastuzumab by blocking the release of PTX3. Conclusion We identified a distinct mode of cardiotoxicity, wherein the activation of EGFR/STAT3 signalling by trastuzumab in VECs promotes PTX3 excretion, which contributes to the impaired contractility of cardiomyocytes by inhibiting cellular calcium signalling. We confirmed that lapatinib could be a feasible preventive agent against trastuzumab-induced cardiac complications and provided the rationale for the combined application of lapatinib and trastuzumab in cancer therapy. [ABSTRACT FROM AUTHOR]

The phosphatidylinositol 3-kinase (PI3K) signalling pathway regulates cell survival, proliferation, migration, metabolism and other vital cellular life processes. In addition, activation of the PI3K signalling pathway is important for cancer development. As a result, a variety of PI3K inhibitors have been clinically developed to treat malignancies. Although several PI3K inhibitors have received approval from the Food and Drug Administration (FDA) for significant antitumour activity, frequent and severe adverse effects have greatly limited their clinical application. These toxicities are mostly on-target and immune-mediated; nevertheless, the underlying mechanisms are still unclear. Current management usually involves intervention through symptomatic treatment, with discontinuation if toxicity persists. Therefore, it is necessary to comprehensively understand these adverse events and ensure the clinical safety application of PI3K inhibitors by establishing the most effective management guidelines, appropriate intermittent dosing regimens and new combination administration. Here, the focus is on the development of PI3K inhibitors in cancer therapy, with particular emphasis on isoform-specific PI3K inhibitors. The most common adverse effects of PI3K inhibitors are also covered, as well as potential mechanisms and management approaches. [ABSTRACT FROM AUTHOR]

Dasatinib, a second-generation BCR-ABL inhibitor, is currently used as first-line treatment for patients with chronic myeloid leukemia. However, dasatinib treatment increases the risk of severe cutaneous toxicity, which limits its long-term safe use in clinic. The underlying mechanism for dasatinib-induced cutaneous toxicity has not been clarified. In this study, we tested the toxicity of dasatinib on human immortal keratinocyte line (HaCaT) and normal human epidermal keratinocytes (NHEK). We found that dasatinib directly caused cytotoxicity on keratinocytes, which could be the explanation of the clinical characteristic of pathology. Mechanistically, dasatinib impaired mitophagy by downregulating HMGB1 protein level in keratinocytes, which led to the accumulation of dysfunctional mitochondria. Mitochondria-derived ROS caused DNA damage and cell apoptosis. More importantly, we confirmed that overexpression of HMGB1 could reverse dasatinib-induced keratinocyte apoptosis, and preliminarily explored the intervention effect of saikosaponin A, which could increase HMGB1 expression, on cutaneous toxicity caused by dasatinib. Collectively, our study revealed that dasatinib induced keratinocyte apoptosis via inhibiting HMGB1-mediated mitophagy and saikosaponin A could be a viable strategy for prevention of dasatinib-induced cutaneous toxicity. [Display omitted] • Dasatinib caused mitochondria-dependent apoptosis in keratinocytes. • Dasatinib impaired mitophagy by downregulating HMGB1 protein level in keratinocytes, which led to the accumulation of damaged mitochondria. • Recovering HMGB1 expression could rescue mitophagy and reverse keratinocyte apoptosis. [ABSTRACT FROM AUTHOR]

Simple Summary: The application of IL-2 for treating cancer is limited owing to its toxicity and short half-life. Its high binding ability to IL-2 receptor α expands immunosuppressive Treg cells, which represents an undesirable toxicity in cancer immunotherapy. Moreover, its small molecular size is the reason for its short half-life. We solved these problems by using a covalent modification strategy of IL-2 variant IL-2K35C with fatty acid by maleimide chemistry, namely, IL-2K35C-moFA. The experiments performed in vitro and in vivo proved that IL-2K35C-moFA is a novel immunotherapeutic agent with the potential to selectively stimulate CD8+ T cells and NK cells. Compared to IL-2WT, IL-2K35C-moFA showed a specifically reduced potency for the stimulation of Treg cells. Our results also showed that fatty acid conjugation appears to be effective in half-life extension. The combination of selective lymphocyte expansion and its long half-life means IL-2K35C-moFA should be evaluated as a potential human immunotherapeutic in the future. Human interleukin 2 (IL-2) has shown impressive results as a therapeutic agent for cancer. However, IL-2-based cancer therapy is limited by strong Treg amplification owing to its high binding affinity to IL-2 receptor α (IL-2Rα) and its short half-life owing to its small molecular size. In this study, we solved these problems using a covalent modification strategy of the IL-2 variant, i.e., substituting cysteine (C) for lysine (K) at position 35, using octadecanedicarboxylic acid through maleimide chemistry, creating IL-2K35C-moFA. IL-2K35C-moFA was equipotent to human IL-2 wild type (IL-2WT) in activating tumor-killing CD8+ memory effector T cells (CD8+ T) and NK cells bearing the intermediate affinity IL-2 receptors, and less potent than IL-2WT on CTLL-2 cells bearing the high-affinity IL-2 receptors. Moreover, it was shown to support the preferential activation of IL-2 receptor β (IL-2Rβ) over IL-2Rα because of the mutation and fatty acid conjugation. In a B16F10 murine tumor model, IL-2K35C-moFA showed efficacy as a single dose and provided durable immunity for 1 week. Our results support the further evaluation of IL-2K35C-moFA as a novel cancer immunotherapy. [ABSTRACT FROM AUTHOR]

• Drug resistance towards chemotherapy and molecularly targeted therapies remains a great challenge in cancer treatments. • Deubiquitinating enzymes (DUBs) regulate protein stability and are extensively involved in many biological processes. • Dysregulations of DUBs frequently play important roles in drug resistance. • Therapies that combine current anti-cancer drugs and DUB inhibitors may provide new opportunities for drug resistance. Drug resistance to chemotherapy and molecularly targeted therapies is a current challenge in cancer treatments. The underlying mechanisms of resistance to cytotoxic chemotherapeutics and to drugs that target a specific molecule are not understood completely. In recent years, emerging evidence has frequently suggested that the dysregulation of deubiquitinating enzymes (DUBs) plays important roles in the development of drug resistance. We focus on the molecular mechanisms through which DUBs enable cancer cells to escape cell death and survive when exposed to a variety of anti-cancer drugs. Furthermore, this review summarizes the potential application of DUB inhibitors in combination therapies to overcome drug resistance. [ABSTRACT FROM AUTHOR]

Organoids are in vitro simplified and miniature microcosms of internal organs, which have aroused great interest in tissue development, multiple disease models, clinical diagnosis, as well as high-throughput drug screening and personalized medicine and so on. The success of physiology-related organoid culture has greatly advanced the translational medicine research in the field of cancer treatment, which was once troubled by the inconsistency between two-dimensional (2D) cell culture and in vivo studies. Especially in recent years, the success rate of establish an organoid has been greatly improved, and the types of organoids have been gradually enriched. Moreover, the utilizing of some the cutting-edge technologies, including gene editing technology such as CRISPR-Cas9, the scope of application of organoid is broadened. In this review, we discuss the latest progress and applications of organoids, and also outline the potential challenges of organoids for future improvement. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Sorafenib is the first-line treatment for advanced HCC, but the anti-cancer effects remain to be improved as indicated by its low response rates and failure to prolong the progression-free survival (PFS). Thus, it is urgent to explore approaches to improve the clinical outcome.Materials and Methods: The effect of Sorafenib in HCC was analyzed by SRB (sulforhodamine B) assay in normoxia and hypoxia, respectively. The different dose combination effect of CT707 and sorafenib was analyzed by SRB assay in hypoxia. Flow cytometry assay was used to detect the cell apoptosis rate with CT707 and sorafenib treatment in hypoxia. Western blotting was used to detect the expression levels of apoptosis -related proteins and the mechanism of CT707 overcome the resistance of sorafenib in hypoxia.Results: Our study showed that the characteristic intratumor hypoxia of advanced HCC is one of the major factors which mediated the drug resistance towards sorafenib in HCC. And CT-707, a novel multi-kinase inhibitor, could sensitize the hypoxic HCC cells towards sorafenib. Further studies showed that CT-707 abolished the nuclear translocation of Yes Associate-Protein (YAP), which has been demonstrated as one of mechanism of hypoxia-mediated sorafenib-resistance in HCC.Conclusions: Overall, this study not only favors the development of this novel multi-kinase inhibitor CT-707 as a therapeutic agent against HCC, but also provides a potential strategy to overcome the hypoxia-mediated resistance to sorafenib in HCC patients. [ABSTRACT FROM AUTHOR]

The endocytic trafficking pathway is a highly organized cellular program responsible for the regulation of membrane components and uptake of extracellular substances. Molecules internalized into the cell through endocytosis will be sorted for degradation or recycled back to membrane, which is determined by a series of sorting events. Many receptors, enzymes, and transporters on the membrane are strictly regulated by endocytic trafficking process, and thus the endocytic pathway has a profound effect on cellular homeostasis. However, the endocytic trafficking process is typically dysregulated in cancers, which leads to the aberrant retention of receptor tyrosine kinases and immunosuppressive molecules on cell membrane, the loss of adhesion protein, as well as excessive uptake of nutrients. Therefore, hijacking endocytic trafficking pathway is an important approach for tumor cells to obtain advantages of proliferation and invasion, and to evade immune attack. Here, we summarize how dysregulated endocytic trafficking process triggers tumorigenesis and progression from the perspective of several typical cancer hallmarks. The impact of endocytic trafficking pathway to cancer therapy efficacy is also discussed. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] Diminished or lost Major Histocompatibility Complex class I (MHC-I) expression is frequently observed in tumors, which obstructs the immune recognition of tumor cells by cytotoxic T cells. Restoring MHC-I expression by promoting its transcription and improving protein stability have been promising strategies for reestablishing anti-tumor immune responses. Here, through cell-based screening models, we found that cediranib significantly upregulated MHC-I expression in tumor cells. This finding was confirmed in various non-small cell lung cancer (NSCLC) cell lines and primary patient-derived lung cancer cells. Furthermore, we discovered cediranib achieved MHC-I upregulation through transcriptional regulation. interferon regulatory factor 1 (IRF-1) was required for cediranib induced MHC-I transcription and the absence of IRF-1 eliminated this effect. Continuing our research, we found cediranib triggered STAT1 phosphorylation and promoted IRF-1 transcription subsequently, thus enhancing downstream MHC-I transcription. In vivo study, we further confirmed that cediranib increased MHC-I expression, enhanced CD8+ T cell infiltration, and improved the efficacy of anti-PD-L1 therapy. Collectively, our study demonstrated that cediranib could elevate MHC-I expression and enhance responsiveness to immune therapy, thereby providing a theoretical foundation for its potential clinical trials in combination with immunotherapy. [ABSTRACT FROM AUTHOR]

Abstract: A series of 2,4-diarylchromane[4,3-d]-Δ1,9b-1,2,3-thiadiazolines have been synthesized by cyclization of corresponding 2-arylchroman-4-one-arylhydrazones with SOCl2 then treated with alcohol. All the compounds have been tested for their antiproliferative activity in vitro against six human tumor cell lines, and the highly potent derivative 11a exhibited in vivo inhibitory effect on tumor growth. Mechanism research indicated that it is due to 11a that induces DNA fragmentation. [Copyright &y& Elsevier]

Abstract: A novel series of nitrogen-containing flavonoids 5a–l, 6a,b, and 7a,b were designed and synthesized as cyclin-dependent kinases (CDKs) inhibitors. The representative compounds 5a, 5b, 5e, and 5g showed potent CDK1/Cyclin B inhibitory activities. All compounds displayed a significant growth inhibitory action in vitro against Bel-7402, PC-3, ECA-109, A-549, HL-60, and MCF-7 cancer cell lines. Flow cytometry analysis showed that 5b induced apoptosis in PC-3 cells. [Copyright &y& Elsevier]

Atomic charges play a very important role in drug-target recognition. However, computation of atomic charges with high-level quantum mechanics (QM) calculations is very time-consuming. A number of machine learning (ML)-based atomic charge prediction methods have been proposed to speed up the calculation of high-accuracy atomic charges in recent years. However, most of them used a set of predefined molecular properties, such as molecular fingerprints, for model construction, which is knowledge-dependent and may lead to biased predictions due to the representation preference of different molecular properties used for training. To solve the problem, we present a new architecture based on graph convolutional network (GCN) and develop a high-accuracy atomic charge prediction model named DeepAtomicCharge. The new GCN architecture is designed with only the atomic properties and the connection information between the atoms in molecules and can dynamically learn and convert molecules into appropriate atomic features without any prior knowledge of the molecules. Using the designed GCN architecture, substantial improvement is achieved for the prediction accuracy of atomic charges. The average root-mean-square error (RMSE) of DeepAtomicCharge is 0.0121 e, which is obviously more accurate than that (0.0180 e) reported by the previous benchmark study on the same two external test sets. Moreover, the new GCN architecture needs much lower storage space compared with other methods, and the predicted DDEC atomic charges can be efficiently used in large-scale structure-based drug design, thus opening a new avenue for high-performance atomic charge prediction and application. [ABSTRACT FROM AUTHOR]

• Macrophages contribute to gefitinib-induced pulmonary toxicity. • Macrophage-secreted MCP-1 is a key mediator of gefitinib-induced pulmonary toxicity. • MCP-1 promotes alveolar epithelial cells to undergo EMT. • MCP-1 participates in gefinitib-induced activation and antiapoptosis in fibroblasts. • Gefitinib increases Mcp-1 transcription level via the nuclear import of STAT3. Gefitinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor indicated for the first-line treatment of patients with metastatic or advanced non-small cell lung cancer (NSCLC) whose tumors have specific EGFR mutations. Pulmonary toxicity is one of the fatal adverse effects of gefitinib and the underlying mechanism remains unclear. Here we demonstrated that alveolar macrophages contributed to gefitinib-induced pulmonary toxicity through promoting alveolar epithelial cells to undergo epithelial to mesenchymal transition (EMT) and inducing activation and antiapoptotic effect in fibroblasts. Further, we found that alveolar macrophage-secreted MCP-1 worked as a key factor in the pathologic changes of these two cell types. Gefitinib increased Mcp-1 transcription level via the nuclear import of the transcription factor STAT3. In conclusion, our data uncovered the underlying mechanisms of macrophage-promoted pulmonary toxicity in the presence of gefitinib. MCP-1 antibody or inhibition of STAT3 activation may represent novel therapeutic strategies for preventing gefitinib-induced pulmonary toxicity. [ABSTRACT FROM AUTHOR]

Virtual screening (VS) based on molecular docking has emerged as one of the mainstream technologies of drug discovery due to its low cost and high efficiency. However, the scoring functions (SFs) implemented in most docking programs are not always accurate enough and how to improve their prediction accuracy is still a big challenge. Here, we propose an integrated platform called ASFP, a web server for the development of customized SFs for structure-based VS. There are three main modules in ASFP: (1) the descriptor generation module that can generate up to 3437 descriptors for the modelling of protein–ligand interactions; (2) the AI-based SF construction module that can establish target-specific SFs based on the pre-generated descriptors through three machine learning (ML) techniques; (3) the online prediction module that provides some well-constructed target-specific SFs for VS and an additional generic SF for binding affinity prediction. Our methodology has been validated on several benchmark datasets. The target-specific SFs can achieve an average ROC AUC of 0.973 towards 32 targets and the generic SF can achieve the Pearson correlation coefficient of 0.81 on the PDBbind version 2016 core set. To sum up, the ASFP server is a powerful tool for structure-based VS. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant cancer-associated fibroblasts (CAFs), early perineural invasion (PNI) and microvascular invasion (MVI). However, the differentiation trajectories and underlying molecular mechanisms of CAFs in PDAC early invasion have not been fully elucidated. In this study, we integrated and reanalysed single-cell data from the National Geoscience Data Centre (NGDC) database and confirmed that myofibroblast-like CAFs (myCAFs) mediated epithelial-mesenchymal transformation (EMT) and enhanced the invasion abilities of PDAC cells by secreting regulators of angiogenesis and metastasis. Furthermore, we constructed a differentiation trajectory of CAFs and revealed that reprogramming from iCAFs to myCAFs was associated with poor prognosis. Mechanistically, SOX4 was aberrantly activated in myCAFs, which promoted the secretion of MMP11 and eventually induced early cancer cell invasion. Together, our results provide a comprehensive transcriptomic overview of PDAC patients with early invasion and reveal the intercellular crosstalk between myCAFs and cancer cells, which suggests potential targets for early invasion PDAC therapy. [Display omitted] • myCAFs enhances metastatic capacity of PDAC cells via secreting various regulators. • The reprogramming from iCAFs to myCAFs is associated with poor prognosis. • SOX4 is aberrantly activated in myCAFs and promotes secretion of MMP11. • SOX4+ myCAFs is a potential therapeutic target of metastatic PDAC. [ABSTRACT FROM AUTHOR]

Forchlorfenuron (CPPU), a plant growth regulator, is widely used in agriculture. However, its long-term exposure effects on humans, especially neonates, remain unclear. Therefore, we investigated the developmental toxicity of prenatal and postnatal gavage administration of CPPU in rats. Pregnant Sprague-Dawley rats were administered 300 mg/kg/day CPPU by gavage from day 6 of gestation to the cessation of nursing. During weaning, rat offspring were administered 0, 30, 100, or 300 mg/kg/day CPPU for 4 weeks, followed by a 4-week CPPU-free recovery period. There were no significant differences in clinical symptoms, body weight, development indicators, serum biochemical parameters, sex hormone levels, sperm motility, relative organ weights, and histopathological changes among the 0–100 mg/kg/day CPPU groups. In the 300 mg/kg/day CPPU group, female rats exhibited decreased body weight, earlier time of vaginal opening (VO) and first estrus time (FE), elevated estradiol and blood urea nitrogen (BUN) levels, and upregulation of estrogen receptor 1 gene expression, whereas male rats only exhibited increases in serum BUN, creatinine, and glucose levels. Most changes were reversed after the recovery period. Furthermore, the endometrial epithelial height was significantly increased in female rats despite the absence of significant changes in uterine wall thickness and endometrial glands. Thus, CPPU may promote estradiol secretion, resulting in altered VO and FE and adverse effects in prepubertal female rats. These findings may be applied for risk assessment following CPPU exposure in humans. [ABSTRACT FROM AUTHOR]

In recent years, phase separation has been increasingly reported to play a pivotal role in a wide range of biological processes. Due to the close relationships between cancer and disorders in intracellular physiological function, the identification of new mechanisms involved in intracellular regulation has been regarded as a new direction for cancer therapy. Introducing the concept of phase separation into complex descriptions of disease mechanisms may provide many different insights. Here, we review the recent findings on the phase separation of cancer-related proteins, describing the possible relationships between phase separation and key proteins associated with cancer and indicate possible regulatory modalities, especially drug candidates for phase separation, which may provide more effective strategies for cancer therapy. [ABSTRACT FROM AUTHOR]

• Triple negative breast cancer (TNBC) has high degree of immune cell infiltration. • Anti-programmed death receptor-1/programmed death ligand-1 (PD-1/PD-L1) antibodies monotherapy has mild respond. • Combination immunotherapy for TNBC has received extensive attention. • Propose multiple strategies to overcome bottleneck in TNBC immunotherapy treatment. Despite extensive research into adjuvant and neoadjuvant chemotherapy, triple-negative breast cancer (TNBC) remains a common breast cancer (BC) subtype with poor prognosis. Given that it has higher immune cell infiltration, theoretically, it should be a protagonist of potential BC immunotherapies. However, only mild responses have been observed in monotherapy with anti-programmed death receptor-1/programmed death ligand-1 (PD-1/PD-L1) antibodies. In this review, we reappraise PD-1/PD-L1 inhibitor combination immunotherapy and effective experimental compounds, focusing the level of PD-L1 expression, neoantigens, abnormal signaling pathways, and tumor microenvironment signatures, to provide guidance for future clinical trials based on the molecular mechanisms involved. [ABSTRACT FROM AUTHOR]

• Transcription factors are generally dysregulated in tumors. • Most oncogenic transcription factors are considered as "undruggable" targets. • Post-translational modifications dictate diverse aspects of transcription factors. • Agents that target transcription factors PTMs exert potent anti-tumor activities. Dysregulated transcription factors (TFs) fuel aberrant gene expression networks, resulting in cell overproliferation, migration, and immunosuppression. Given that TFs are regarded to have vital roles in tumors, various approaches are exploited to modulate their activities. Nevertheless, except for some ligand-binding nuclear receptors, most TFs are still considered 'undruggable' targets. Responding to extra- or intracellular stimuli, TFs are decorated with an array of post-translational modifications (PTMs) to regulate their subcellular localizations, protein–protein/DNA interactions, and stability. These PTMs orchestrate the multiple functions of TFs, thus offering numerous potential targets. In this review, we systematically review emerging concepts and effective agents in PTMs-associated TF-targeting, which could provide paradigms for cancer treatment. [ABSTRACT FROM AUTHOR]

Yes-associated protein (YAP) is a key effector of the Hippo pathway and is frequently dysregulated in aggressive human cancers. Aberrant YAP activation has emerged as an important driver of tumorigenesis, chemoresistance and metastasis. Since posttranslational modifications (PTMs) are pivotal modifiers that determine protein activation or subcellular localization, the malfunction of YAP due to dysregulated PTMs has been linked to various cancers. Collectively, although YAP has long been considered an "undruggable" transcription cofactor, its PTMs may be its "Achilles' heel". To provide theoretical support for developing small molecule inhibitors based on PTMs, in this review article, we summarize the current understanding of the impact of PTMs in regulating the Hippo-YAP pathway and further discuss potential therapeutic intervention. In our review, we summarize the known posttranslational modifications (PTMs) of YAP that dictate its protein stability, transcriptional activity and subcellular localization at different stages. Here, we clearly summarize the specific enzymes and sites involved in YAP PTMs and place additional focus on the consequences of PTM-modulated YAP activity and translocation. PTMs of YAP play fundamental roles in controlling the protein abundance and function. Therefore, interfering with PTMs of YAP may contribute to solving the "undruggable" problem in YAP inhibition, thus providing new approaches for YAP-based cancer therapy. Future studies that target corresponding PTM-related kinases/enzymes will provide new strategies for cancer therapy, particularly in tumors with YAP dysregulation. • YAP is a transcriptional cofactor and generally dysregulated in cancers. • Posttranslational modifications dictate diverse aspects of YAP activity. • Targeting PTMs may be an effective strategy to inhibit YAP-mediated tumorigenesis. [ABSTRACT FROM AUTHOR]

Comparative biological studies typically require plenty of samples to ensure full representation of the given problem. A frequently-encountered question is how many samples are sufficient for a particular study. This question is traditionally assessed using the statistical power , but it alone may not guarantee the full and reproducible discovery of features truly discriminating biological groups. Two new types of statistical criteria have thus been introduced to assess sample sufficiency from different perspectives by considering diagnostic accuracy and robustness. Due to the complementary nature of these criteria, a comprehensive evaluation based on all criteria is necessary for achieving a more accurate assessment. However, no such tool is available yet. Herein, an online tool SSizer (https://idrblab.org/ssizer/) was developed and validated to enable the assessment of the sample sufficiency for a user-input biological dataset, and three statistical criteria were adopted to achieve comprehensive and collective assessment. A sample simulation based on a user-input dataset was performed to expand the data and then determine the sample size required by the particular study. In sum, SSizer is unique for its ability to comprehensively evaluate whether the sample size is sufficient and determine the required number of samples for the user-input dataset, which, therefore, facilitates the comparative and OMIC-based biological studies. Image 1 • A key question in the current comparative biological study is how many samples are sufficient. • A novel tool was developed to comprehensively evaluate sample sufficiency using multiple criteria. • This new tool was unique in determining the required sample size for comparative biological study. • The developed tool can facilitate the current comparative biological and OMIC-based studies. [ABSTRACT FROM AUTHOR]

• Osteosarcoma is a disease resulting from osteogenic differentiation defects. • Differentiation therapy for osteosarcoma has received extensive attention. • Various agents have been shown to induce terminal differentiation in osteosarcoma. • The exploration of new inducers and biomarkers is the way forward. Differentiation therapy involves the use of agents that can induce differentiation in cancer cells, with the irreversible loss of tumour phenotype. The application of differentiation therapy in osteosarcoma has made progress because of a better understanding of the potential links between differentiation defects and tumorigenesis. Here, we review recent studies on differentiation therapy for osteosarcoma, describing a variety of differentiation inducers. By highlighting these examples of drug-induced osteosarcoma cell differentiation, we can acquire unique insights into not only osteosarcoma treatment, but also novel approaches to transform differentiating drugs into more effective therapies for other solid tumours. [ABSTRACT FROM AUTHOR]

• Crizotinib induces apoptosis of human keratinocytes directly. • Crizotinib induces human keratinocytes apoptosis through caspase-dependent way. • The extrinsic pathway is responsible for crizotinib-induced apoptosis. • The apoptosis independent of mitochondrial dysfunction, DNA damage and related drug targets inhibition. Crizotinib is a multi-target receptor tyrosine kinase inhibitor which is of great importance for the management of ALK-rearranged non-small cell lung cancer (NSCLC) patients. Serious erythroderma and toxic epidermal necrolysis have been reported associated with crizotinib treatment. The underlying mechanisms have not been examined. In this study, we tested the toxicity of crizotinib on immortal human keratinocytes (HaCaT) and human primary keratinocytes. We found that crizotinib directly cause cytotoxic on these two cells, which could be the explanation of the clinical characteristic of pathology. Apoptosis was observed and Z-VAD-FMK, a pan-caspase inhibitor can almost totally reverse the apoptosis induction effect of crizotinib. However, mitochondrial dysfunction and DNA damage were not involved in crizotinib-induced apoptosis, indicating the intrinsic apoptosis pathway have no connection with this cutaneous toxicity. Further studies showed that crizotinib significantly increased cleaved-caspase-8, a signaling protein of extrinsic apoptosis pathway, in a concentration and time-dependent manner. Moreover, we found the targets of crizotinib were not involved in HaCaT cells apoptosis. Collectively, our findings first report keratinocytes apoptosis is the key cause of crizotinib-induced cutaneous toxicity. We also reveal crizotinib induce apoptosis through the extrinsic apoptosis pathway due to detected up-regulated cleaved-caspase-8. Meanwhile, the apoptosis is independent of mitochondrial dysfunction, DNA damage and related drug targets inhibition. [ABSTRACT FROM AUTHOR]

Stress granules (SGs) are primarily composed of mRNAs that stall at translation initiation and usually appear in the cytoplasm under unusual physiological or pathological conditions such as hypoxia, oxidative stress, and viral infection. Recent studies have indicated that several components of SGs participate in tumourigenesis and cancer metastasis through tumour-associated signalling pathways as well as other mechanisms. Furthermore, some chemotherapy drugs have been reported to induce SGs. Thus, the roles of SGs in cancer treatment have attracted considerable interest. Importantly, disturbing the recruitment of SGs components or microtubule polymerization, as well as other strategies that can abolish SGs formation, is reported to inhibit tumour progression, suggesting that targeting SGs could be a promising strategy for cancer treatment. In this review, we summarize the relationship between SGs and cancer, as well as recent advances in targeting SGs, in the interest of providing new opportunities for cancer treatment. [ABSTRACT FROM AUTHOR]

[Display omitted] Anti-programmed cell death 1/programmed cell death ligand 1 (anti-PD-1/PD-L1) antibodies have developed rapidly but exhibited modest activity in ovarian cancer (OC), achieving a clinical response rate ranging from 5.9% to 19%. Current evidence indicate that the establishment of an integrated cancer-immunity cycle is a prerequisite for anti-PD-1/PD-L1 antibodies. Any impairment in this cycle, including lack of cancer antigens release, impaired antigen-presenting, decreased T cell priming and activation, less T cells that are trafficked or infiltrated in tumor microenvironment (TME), and low tumor recognition and killings, will lead to decreased infiltrated cytotoxic T cells to tumor bed and treatment failure. Therefore, combinatorial strategies aiming to modify cancer-immunity cycle and reprogram tumor immune microenvironment are of great interest. By far, various strategies have been studied to enhance responsiveness to PD-1/PD-L1 inhibitors in OC. Platinum-based chemotherapy increases neoantigens release; poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) improve the function of antigen-presenting cells and promote the trafficking of T cells into tumors; epigenetic drugs help to complete the immune cycle by affecting multiple steps; immunotherapies like anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) antibodies reactivate T cells, and other treatment strategies like radiotherapy helps to increase the expression of tumor antigens. In this review, we will summarize the preclinical studies by analyzing their contribution in modifying the cancer immunity cycle and remodeling tumor environment, and we will also summarize recent progress in clinical trials and discuss some perspectives to improve these treatment strategies. [ABSTRACT FROM AUTHOR]

[Display omitted] Crizotinib is the first-line drug for advanced non-small cell lung cancer with the abnormal expression of anaplastic lymphoma kinase gene. Severe, life-threatening, or fatal interstitial lung disease/pneumonia has been reported in patients treated with crizotinib. The clinical benefit of crizotinib is limited by its pulmonary toxicity, but the underlying mechanisms have not been adequately studied, and protective strategies are relatively scarce. Here, we established an in vivo mouse model in which crizotinib was continuously administered to C57BL/6 at 100 mg/kg/day for 6 weeks and verified that crizotinib induced interstitial lung disease in vivo , which was consistent with the clinical observations. We further treated BEAS-2B and TC-1 cells, the alveolar epithelial cell lines, with crizotinib and found the increased apoptosis rate. We proved that crizotinib-blocked autophagic flux caused apoptosis of the alveolar epithelial cells and then promoted the recruitment of immune cells, suggesting that limited autophagy activity was the key reason for pulmonary injury and inflammation caused by crizotinib. Subsequently, we found that metformin could reduce the macrophage recruitment and pulmonary fibrosis by recovering the autophagy flux, thereby ameliorating impaired lung function caused by crizotinib. In conclusion, our study revealed the mechanism of crizotinib-induced apoptosis of alveolar epithelial cells and activation of inflammation during the onset of pulmonary toxicity and provided a promising therapeutic strategy for the treatment of crizotinib-induced pulmonary toxicity. [ABSTRACT FROM AUTHOR]

Abstract Renal fibrosis is the common final outcome of nearly all progressive chronic kidney diseases (CKD) that eventually develop into end-stage renal failure, which threatens the lives of patients. Currently, there are no effective drugs for the treatment of renal fibrosis. However, studies have shown that certain plant natural products have a fibrosis-alleviating effect. Thus, we have screened a large number of natural products for their ability to protect against renal fibrosis and found that bisdemethoxycurcumin has a good therapeutic effect in renal fibrosis according to the data obtained in a mouse model of unilateral ureteral obstruction (UUO). The results indicate that bisdemethoxycurcumin can efficiently attenuate renal fibrosis induced by UUO. Additional studies of the bisdemethoxycurcumin mechanism of action in the treatment of renal fibrosis demonstrated that the therapeutic effect of bisdemethoxycurcumin is mediated by the specific induction of fibroblast apoptosis at a concentration of 20 μM. bisdemethoxycurcumin can efficiently protect against renal fibrosis both in vitro and in vivo. This discovery will provide new ideas for renal fibrosis treatment in clinics and a new direction for the development of effective drug therapy of renal fibrosis. [ABSTRACT FROM AUTHOR]

Abstract Idiopathic pulmonary fibrosis is a pathological result of dysfunctional repair response to tissue injury, leading to chronically impaired gas exchange and death. Macrophages are believed to be critical in this disease pathogenesis; However, the exact mechanisms remain enigmatic. Here, we demonstrated that macrophages might contribute to pulmonary fibrosis at the early stage because the aggregation of macrophages appeared earlier than epithelial-mesenchymal transition and fibrosis in mouse and rat experimental models of pulmonary fibrosis. It has been found that macrophages could promote epithelial-mesenchymal transition of alveolar epithelial cells and fibroblast migration in co-culture models between macrophages and alveolar epithelial cells/fibroblasts. Importantly, we used protein micro array to analyze the cytokines that were altered after bleomycin treatment. Only thymic stromal lymphopoietin and matrix metalloproteinase 9 were significantly increased. We further confirmed that TSLP participated in the macrophage-induced epithelial-mesenchymal transition of alveolar epithelial cells using a TSLP recombinant protein. MMP9 was also involved in macrophage-induced fibroblast migration, which can be reversed by an inhibitor of MMP9. Collectively, these findings explained the underlying mechanisms of macrophage-promoted pulmonary fibrosis. Highlights • Macrophages contribute to bleomycin-induced pulmonary fibrosis • TSLP and MMP9 may be pivotal cytokines secreted by macrophages • TSLP may induce epithelial-mesenchymal transition of alveolar epithelial cells • MMP9 is involved in macrophage-induced fibroblast migration [ABSTRACT FROM AUTHOR]

Retinoids, vitamin A and its natural and synthetic analogues have various functions, including being involved in cell proliferation and differentiation and participating in the formation of vertebrate morphology. In addition, they may activate certain tumour suppressor genes that then act as tumour inhibitors. In the past decades, retinoids have been regarded as promising chemotherapeutic and chemopreventive agents; however, their mechanisms are still not fully understood. Immune cells that participate in or are associated with the immune response play vital roles in the initiation and development of many cancers. Interestingly, recent studies have demonstrated that retinoids can also exert various effects on immune cells including macrophages, T cells and dendritic cells in tumour tissues to execute anti-tumour actions, providing new insights into chemoprevention and chemotherapeutics. In this review, we focus on the effects of retinoids on immune cells in the tumour, which may provide new approaches for antineoplastic strategies. [ABSTRACT FROM AUTHOR]

Dasatinib shows remarkable activity against imatinib-refractory chronic myelogenous leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph + ALL). However, severe cardiovascular toxicity limits the clinical applications of dasatinib. Since the underlying mechanism of dasatinib-induced cardiotoxicity is still elusive, we aim to clarify this. Recent studies have shown that necroptosis and apoptosis participate in multiple toxicity development. Here, we first report that dasatinib could directly induce cardiomyocytes death, as analyzed by the Sulforhodamine B (SRB) assay. This type of cardiomyocytes death was mediated by the necrosis pathway rather than apoptosis, as determined by using flow cytometry to characterize the mode of dasatinib-induced cell death. Inhibition of receptor-interacting protein kinase 1 (RIP1)activity and knockdown of receptor-interacting protein kinase 3 (RIP3)expression can block dasatinib-evoked cardiotoxicity, which further confirmed the involvement of necroptosis. We next found that the classic substrates of RIP3, mixed lineage kinase domain-like protein (MLKL) and Ca 2+ -calmodulin-dependent protein kinase II (CaMKII) were not involved in dasatinib-induced cardiomyocytes necroptosis. What’s more, unlike the inflammation-associated necroptosis, dasatinib-triggered necroptosis was dependent on intracellular instead of secreted High-mobility group box 1 (HMGB1) protein. Collectively, our study revealed that dasatinib-induced cardiotoxicity acted via leading cardiomyocytes to HMGB1-mediated necroptosis, indicating a viable strategy for prevention of dasatinib-induced cardiotoxicity. [ABSTRACT FROM AUTHOR]

Adriamycin (ADR) is one of the most widely used and effective anthracycline antitumor agents in the treatment of certain hematological malignancies and solid tumors. However, the severe cardiotoxicity of ADR limits its clinical application. So far, the mechanism of the cardiotoxicity of ADR has not been completely clarified. In our research, cardiomyocyte autophagy and cardiac damage were observed in accompany ADR treatment, and autophagy appeared earlier than cardiac damage. Inhibition of autophagy by silencing ATG7 improved the survival rate of cardiomyocytes treated with ADR. The release of HMGB1 increased after ADR treatment, and silencing HMGB1 could reverse cardiomyocyte damage by attenuating autophagy. In addition, the expression of YAP was decreased, and overexpressing YAP down-regulated HMGB1 and alleviated cardiomyocyte damage. These results indicated that autophagy was the leading cause of ADR-induced cardiotoxicity, and HMGB1 played a vital role in the process of up-regulating autophagy. [ABSTRACT FROM AUTHOR]

With the growing importance of PROTAC-mediated protein degradation in drug discovery, robust synthetic methodologies and rapid screening assays are urgently needed. By harnessing the improved alkene hydroazidation reaction, we developed a novel strategy to introduce azido groups into the linker-E3 ligand conjugates and effectively created a range of prepacked terminal azide-labeled "preTACs" as PROTAC toolkit building blocks. Moreover, we demonstrated that preTACs are ready to conjugate to ligands targeting a protein of interest to generate libraries of chimeric degraders, which are subsequently screened for effective protein degradation directly from cultured cells with a cytoblot assay. Our study exemplifies that this practical "preTACs-cytoblot" platform allows efficient PROTAC assembly and rapid activity assessments. It may help industrial and academic investigators to accelerate their streamlined development of PROTAC-based protein degraders. [Display omitted] • A practical preTACs-Cytoblot platform is reported to streamline the PROTAC discovery. • Alkene hydroazidation is a useful method to synthesize the preTAC building blocks. • Improved methods to efficiently conjugate preTACs to the ligand of a target protein. • The Cytoblot assay was used to assess PROTAC activity directly from cells rapidly. • A potent CDK12 degrader V7 was identified with cell-selective antiproliferation activity. [ABSTRACT FROM AUTHOR]

Although M2-like tumor-associated macrophages (TAMs) have been considered as a vital therapeutic target in cancer therapy due to their role in promoting tumor progression and metastasis, very few compounds have been identified to inhibit M2-like polarization of TAMs. Here, we showed that Imatinib significantly prevented macrophage M2-like polarization induced by IL-13 or IL-4 in vitro, as illustrated by reduced expression of cell surface marker CD206 and M2-like genes, including Arg1, Mgl2, Mrc1, CDH1, and CCL2. Further, the migration of lung cancer cells promoted by the conditioned medium from M2-like macrophages could be restrained by Imatinib. Mechanistically, Imatinib inhibited STAT6 phosphorylation and nuclear translocation, resulting in the macrophage M2-like polarization arrest. Furthermore, Imatinib reduced the number of metastasis of Lewis lung cancer without affecting tumor growth. Both in tumor and lung tissues, the percentage of M2-like macrophages decreased after the administration of Imatinib for one week. Taken together, these data suggest that Imatinib is able to inhibit macrophage M2-like polarization, which plays a vital role in Imatinib suppressed metastasis of Lewis lung cancer. [ABSTRACT FROM AUTHOR]

Summary: With the use of multikinase inhibitors (MKIs) having emerged in recent years, skin toxicities such as hand–foot skin reaction (HFSR) are primary side effects, and they lack effective prediction methods. Here, we updated a previous systematic review by establishing a meta‐analysis of the risk of developing HFSR among patients receiving MKIs and antivascular endothelial growth factor antibody. Publications from PubMed and abstracts presented at the American Society of Clinical Oncology Annual Meeting up to February 5, 2015, were searched to identify relevant studies, and a total of 236 patients with metastatic tumours in nine trials were included for analysis. In the meta‐analysis, the pooled incidence rates of all‐grade and high‐grade HFSR among patients who received the combination therapy were 56.9% [95% confidence interval (CI), 45%‐71.1%] and 14.3% (95% CI, 9%‐24.2%), respectively, with significant differences observed with MKI monotherapy (P < .05). Further subgroup analysis demonstrated that increasing the dosages of bevacizumab (77.8% vs 51.1%, P = .04) and MKIs (64.3% vs 52.6%, P = .02) significantly increased HFSR incidence. Moreover, combination with chemotherapy exerted a minimal effect on HFSR risk (61% vs 55.3%, P = .5). This updated review and meta‐analysis confirm the increased risk of HFSR incidence due to the use of MKIs and antivascular endothelial growth factor antibody. Thus, using these therapies requires safety standards. [ABSTRACT FROM AUTHOR]

The purpose of this study is to prove the lipid-regulating effects of neohesperidin (NHP) and explore the potential mechanisms related to fibroblast growth factor 21 (FGF21) and AMP-activated protein kinase (AMPK). Free fatty acids (FFAs)-induced lipid-accumulated HepG 2 cells, acutely egg yolk-induced dyslipidemia and chronically diet-induced obese (DIO) model mice were treated with NHP. Biochemical analyses were carried out to determine the lipid profiles. Western blotting and real-time PCR were employed to analyze FGF21, AMPK and the related proteins or mRNA expressions. Body weight and food intake were measured in DIO mice. siRNA or inhibitors of FGF21 or AMPK were utilized in further study. NHP showed potent hypolipidemic effect in HepG 2 cells loaded with FFAs and reversed the pathological changes of lipid in the acute or chronic dyslipidemia mouse model. It obviously improved the lipid profiles in plasma, liver and gastrocnemius muscles in DIO mice, and led to a significant body weight loss. Simultaneously, FGF21 protein expression or secretion, and AMPK/sirtuin type 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) axis or related molecules, was improved by NHP in HepG 2 cells and/or DIO mice. Furthermore, the siRNA or inhibitor targeting FGF21 or AMPK rejected the triglyceridelowering effect of NHP. In conclusion, NHP regulates lipid metabolism in vivo and in vitro via FGF21 and AMPK/SIRT1/PGC-1α signaling axis. [ABSTRACT FROM AUTHOR]