Also published as: B. Zhao, BS Zhao, Baojing Zhao, Baolu Zhao, C Zhao, C. Zhao, Chong Zhao, F Zhao, F. Zhao, Fei Zhao, Feng Zhao, Fengchao Zhao, H Zhao, Hai Zhao, J Zhao, J. Zhao, JJ Zhao, Jian Zhao, Jian-Hua Zhao, Jianfu Zhao, Jianzhang Zhao, Jing Zhao, Jingyue Zhao, Juanjuan Zhao, Jumei Zhao, K Zhao, K. Zhao, Kaikai Zhao, L Zhao, L. Zhao, LP Zhao, Lei Zhao, Liping Zhao, M Zhao, M. Zhao, Max Xiaohang Zhao, N. Zhao, PY Zhao, Peng-Yue Zhao, Q Zhao, Q. Zhao, Qiang Zhao, R Zhao, R. Zhao, Ren Zhao, S Zhao, S. Zhao, Sendong Zhao, Shu-Lin Zhao, T Zhao, T. Zhao, Ting Zhao, W Zhao, W. Zhao, W.-N. Zhao, Wenhua Zhao, X Zhao, X. Zhao, Xiang Zhao, Xingmeng Zhao, Xu Zhao, Xuan-Hao Zhao, Xuanhao Zhao, Y Zhao, Y. S. Zhao, Y. Zhao, Y.D. Zhao, YY Zhao, Yan Zhao, Yao Zhao, Yaxing Zhao, Yibo Zhao, Yufen Zhao, Yunhua Zhao, Z Zhao, Z. Zhao, Zhennan Zhao, Zihan Zhao, Zizhuo Zhao
Atomically precise Au25 nanoclusters are ideal catalyst models for unraveling the nanozyme structure-activity relationship due to their well-defined structures and tunable electronic proper Show more
Atomically precise Au25 nanoclusters are ideal catalyst models for unraveling the nanozyme structure-activity relationship due to their well-defined structures and tunable electronic properties. Herein, ab initio molecular dynamics (AIMD) simulations combined with density functional theory (DFT) calculations were employed to systematically investigate the ligand removal behavior and peroxidase (POD)-like catalytic activity of Au25 nanoclusters modified with phosphine (PR), thiol (SR), alkynyl (C≡CR), and N-heterocyclic carbene (NHC) ligands. Constrained AIMD (cAIMD) simulations revealed that all clusters preferentially remove halogen ligands (Cl/Br) with free energy barriers below 0.25 eV, while NHC and phosphine ligands exhibit stronger binding stability with the Au core. The exposed low-coordination gold sites upon halogen removal display excellent POD-like activity, wherein the second *OH reduction (or the second TMB oxidation) is determined to be the rate-determining step (RDS). Among them, [Au25(NHC)10(Br)6]2+-top (removal of Br at the top coordination site) exhibits the most optimal activity with a moderate RDS barrier (0.83 eV) owing to its isolated active site and higher d-band center that balance *OH adsorption and the catalytic activity. This study clarifies the structure-activity relationship of atomically precise Au25 nanoclusters in the peroxidase-like catalysis, providing a quantitative basis for high-efficiency Au-based nanozyme design. Show less
Cell death is a basic physiological process involved in embryonic development, aging, immune responses and other life processes. In particular, ferroptosis
Cancer remains a major global health burden, with rising incidence and mortality linked to aging populations and increased exposure to genotoxic agents. Oxidative stress plays a critical role in cance Show more
Cancer remains a major global health burden, with rising incidence and mortality linked to aging populations and increased exposure to genotoxic agents. Oxidative stress plays a critical role in cancer development, progression, and resistance to therapy. The nuclear factor erythroid 2-related factor 2 (NRF2)-Kelch-like ECH-associated protein 1 (KEAP1)-antioxidant response element (ARE) signaling pathway is central to maintaining redox balance by regulating the expression of antioxidant and detoxification genes. Under physiological conditions, this pathway protects cells from oxidative damage, however, sustained activation of NRF2 in cancer, often due to mutations in KEAP1, supports tumor cell survival, drug resistance, and metabolic reprogramming. Recent studies demonstrate that NRF2 enhances glutathione (GSH) synthesis, induces detoxifying enzymes, and upregulates drug efflux transporters, collectively contributing to resistance against chemotherapy and targeted therapies. The inhibition of NRF2 using small molecules or dietary phytochemicals has shown promise in restoring drug sensitivity in preclinical cancer models. This review highlights the dual role of NRF2 in redox regulation and cancer therapy, emphasizing its potential as a therapeutic target. While targeting NRF2 offers a novel approach to overcoming treatment resistance, further research is needed to enhance specificity and facilitate clinical translation. Show less
The success of cancer immunotherapies is predicated on the targeting of highly expressed neoepitopes, which preferentially favours malignancies with high mutational burden. Here we show that early res Show more
The success of cancer immunotherapies is predicated on the targeting of highly expressed neoepitopes, which preferentially favours malignancies with high mutational burden. Here we show that early responses by type-I interferons mediate the success of immune checkpoint inhibitors as well as epitope spreading in poorly immunogenic tumours and that these interferon responses can be enhanced via systemic administration of lipid particles loaded with RNA coding for tumour-unspecific antigens. In mice, the immune responses of tumours sensitive to checkpoint inhibitors were transferable to resistant tumours and resulted in heightened immunity with antigenic spreading that protected the animals from tumour rechallenge. Our findings show that the resistance of tumours to immunotherapy is dictated by the absence of a damage response, which can be restored by boosting early type-I interferon responses to enable epitope spreading and self-amplifying responses in treatment-refractory tumours. Show less
Carnitine O-acetyltransferase (CRAT) is a key mitochondrial enzyme involved in maintaining metabolic homeostasis by mediating the reversible transfer of acetyl groups between acetyl-CoA and carnitine. Show more
Carnitine O-acetyltransferase (CRAT) is a key mitochondrial enzyme involved in maintaining metabolic homeostasis by mediating the reversible transfer of acetyl groups between acetyl-CoA and carnitine. This enzymatic activity ensures the optimal functioning of mitochondrial carbon flux by preventing acetyl-CoA accumulation, buffering metabolic flexibility, and regulating the balance between fatty acid and glucose oxidation. CRAT’s interplay with the mitochondrial carnitine shuttle, involving carnitine palmitoyltransferases (CPT1 and CPT2) and the carnitine carrier (SLC25A20), underscores its critical role in energy metabolism. Emerging evidence highlights the structural and functional diversity of CRAT and structurally related acetyltransferases across cellular compartments, illustrating their coordinated role in lipid metabolism, amino acid catabolism, and mitochondrial bioenergetics. Moreover, the structural insights into CRAT have paved the way for understanding its regulation and identifying potential modulators with therapeutic applications for diseases such as diabetes, mitochondrial disorders, and cancer. This review examines CRAT’s structural and functional aspects, its relationships with carnitine shuttle members and other carnitine acyltransferases, and its broader role in metabolic health and disease. The potential for targeting CRAT and its associated pathways offers promising avenues for therapeutic interventions aimed at restoring metabolic equilibrium and addressing metabolic dysfunction in disease states. Show less
Non-small cell lung cancer (NSCLC) is one of the most prevalent and lethal types of cancers worldwide and its high incidence and mortality rates pose a significant public health challenge. Despite sig Show more
Non-small cell lung cancer (NSCLC) is one of the most prevalent and lethal types of cancers worldwide and its high incidence and mortality rates pose a significant public health challenge. Despite significant advances in targeted therapy and immunotherapy, the overall prognosis of patients with NSCLC remains poor. Hypoxia is a critical driving factor in tumor progression, influencing the biological behavior of tumor cells through complex molecular mechanisms. The present review systematically examined the role of the hypoxic microenvironment in NSCLC, demonstrating its crucial role in promoting tumor cell growth, invasion and metastasis. Additionally, it has been previously reported that the hypoxic microenvironment enhances tumor cell resistance by activating hypoxia-inducible factor and regulating exosome secretion. The hypoxic microenvironment also enables tumor cells to adapt to low oxygen and nutrient-deficient conditions by enhancing metabolic reprogramming, such as through upregulating glycolysis. Further studies have shown that the hypoxic microenvironment facilitates immune escape by modulating tumor-associated immune cells and suppressing the antitumor response of the immune system. Moreover, the hypoxic microenvironment increases tumor resistance to radiotherapy, chemotherapy and other types of targeted therapy through various pathways, significantly reducing the therapeutic efficacy of these treatments. Therefore, it could be suggested that early detection of cellular hypoxia and targeted therapy based on hypoxia may offer new therapeutic approaches for patients with NSCLC. The present review not only deepened the current understanding of the mechanisms of action and role of the hypoxic microenvironment in NSCLC but also provided a solid theoretical basis for the future development of precision treatments for patients with NSCLC. Show less
Cancer cells often upregulate ribosome biogenesis to meet increased protein synthesis demands for rapid proliferation; therefore, targeting ribosome biogenesis has emerged as a promising cancer therap Show more
Cancer cells often upregulate ribosome biogenesis to meet increased protein synthesis demands for rapid proliferation; therefore, targeting ribosome biogenesis has emerged as a promising cancer therapeutic strategy. Herein, we introduce two Pt complexes, ataluren monosubstituted platinum(IV) (SPA, formula: c,c,t,-[Pt(NH3)2Cl2(OH)(C15H8FN2O3)], where C15H8FN2O3 = ataluren) and ataluren bisubstituted platinum(IV) complex (DPA, formula: c,c,t,-[Pt(NH3)2Cl2(C15H8FN2O3)2], where C15H8FN2O3 = ataluren), which effectively suppress ribosome biogenesis by inhibiting 47s pre-RNA expression. Furthermore, SPA and DPA induce nucleolar stress by dispersing nucleolar protein NPM1, ultimately inhibiting protein generation in tumor cells. More importantly, DPA exhibits superior cytotoxicity to various cancer cells and in vivo antitumor efficacy compared to cisplatin, with lower systemic toxicity. Notably, in clinically relevant models, including orthotopic hepatic tumor-bearing mice and patient-derived bladder cancer organoids, DPA outperforms cisplatin significantly, with the added benefit of oral administration, enhancing clinical feasibility. To our knowledge, DPA emerges as the pioneering Pt(IV) agent targeting the ribosome, providing new insights for designing next-generation metal-based therapeutics. Show less
Dihydroorotate dehydrogenase (DHODH)-mediated ferroptosis defense is a targetable vulnerability in cancer. Currently, only a few DHODH inhibitors have been utilized in clinical practice. To further en Show more
Dihydroorotate dehydrogenase (DHODH)-mediated ferroptosis defense is a targetable vulnerability in cancer. Currently, only a few DHODH inhibitors have been utilized in clinical practice. To further enhance DHODH targeting, we introduced the mitochondrial targeting group triphenylphosphine (TPP) to brequinar (BRQ), a robust DHODH inhibitor, resulting in the creation of active molecule B2. This compound exhibits heightened anticancer activity, effectively inhibiting proliferation in various cancer cells, and restraining tumor growth in melanoma xenografts in mice. B2 achieves these effects by targeting DHODH, triggering the formation of reactive oxygen species (ROS), promoting mitochondrial lipid peroxidation, and inducing ferroptosis in B16F10 and A375 cells. Surprisingly, B2 significantly downregulates PD-L1 and alleviates immune suppression. Importantly, B2 exhibits no apparent adverse effects in mice. Collectively, these findings highlight that enhancing the mitochondrial targeting capability of the DHODH inhibitor is a promising therapeutic approach for melanoma treatment. Show less
Copper plays vital roles in numerous cellular processes and its imbalance can lead to oxidative stress and dysfunction. Recent research has unveiled a unique form of copper-induced cell death, termed Show more
Copper plays vital roles in numerous cellular processes and its imbalance can lead to oxidative stress and dysfunction. Recent research has unveiled a unique form of copper-induced cell death, termed cuproptosis, which differs from known cell death mechanisms. This process involves the interaction of copper with lipoylated tricarboxylic acid cycle enzymes, causing protein aggregation and cell death. Recently, a growing number of studies have explored the link between cuproptosis and cancer development. This review comprehensively examines the systemic and cellular metabolism of copper, including tumor-related signaling pathways influenced by copper. It delves into the discovery and mechanisms of cuproptosis and its connection to various cancers. Additionally, the review suggests potential cancer treatments using copper ionophores that induce cuproptosis, in combination with small molecule drugs, for precision therapy in specific cancer types. Show less
For decades, great strides have been made in the field of immunometabolism. A plethora of evidence ranging from basic mechanisms to clinical transformation has gradually embarked on immunometabolism t Show more
For decades, great strides have been made in the field of immunometabolism. A plethora of evidence ranging from basic mechanisms to clinical transformation has gradually embarked on immunometabolism to the center stage of innate and adaptive immunomodulation. Given this, we focus on changes in immunometabolism, a converging series of biochemical events that alters immune cell function, propose the immune roles played by diversified metabolic derivatives and enzymes, emphasize the key metabolism-related checkpoints in distinct immune cell types, and discuss the ongoing and upcoming realities of clinical treatment. It is expected that future research will reduce the current limitations of immunotherapy and provide a positive hand in immune responses to exert a broader therapeutic role. Show less
Mitochondria are central actors in diverse physiological phenomena ranging from energy metabolism to stress signaling and immune modulation. Accumulating scientific evidence points to the critical inv Show more
Mitochondria are central actors in diverse physiological phenomena ranging from energy metabolism to stress signaling and immune modulation. Accumulating scientific evidence points to the critical involvement of specific mitochondrial-associated events, including mitochondrial quality control, intercellular mitochondrial transfer, and mitochondrial genetics, in potentiating the metastatic cascade of neoplastic cells. Furthermore, numerous recent studies have consistently emphasized the highly significant role mitochondria play in coordinating the regulation of tumor-infiltrating immune cells and immunotherapeutic interventions. This review provides a comprehensive and rigorous scholarly investigation of this subject matter, exploring the intricate mechanisms by which mitochondria contribute to tumor metastasis and examining the progress of mitochondria-targeted cancer therapies. Show less
We have designed cell-penetrating peptides that target the leucine zipper transcription factors ATF5, CEBPB and CEBPD and that promote apoptotic death of a wide range of cancer cell types, but not nor Show more
We have designed cell-penetrating peptides that target the leucine zipper transcription factors ATF5, CEBPB and CEBPD and that promote apoptotic death of a wide range of cancer cell types, but not normal cells, in vitro and in vivo. Though such peptides have the potential for clinical application, their mechanisms of action are not fully understood. Here, we show that one such peptide, Dpep, compromises glucose uptake and glycolysis in a cell context-dependent manner (in about two-thirds of cancer lines assessed). These actions are dependent on induction of tumor suppressor TXNIP (thioredoxin-interacting protein) mRNA and protein. Knockdown studies show that TXNIP significantly contributes to apoptotic death in those cancer cells in which it is induced by Dpep. The metabolic actions of Dpep on glycolysis led us to explore combinations of Dpep with clinically approved drugs metformin and atovaquone that inhibit oxidative phosphorylation and that are in trials for cancer treatment. Dpep showed additive to synergistic activities in all lines tested. In summary, we find that Dpep induces TXNIP in a cell context-dependent manner that in turn suppresses glucose uptake and glycolysis and contributes to apoptotic death of a range of cancer cells. Show less
Colorectal cancer (CRC) is the third most common cancer worldwide, and the second most common cause of cancer-related death. In 2020, the estimated number of deaths due to CRC was approximately 930000 Show more
Colorectal cancer (CRC) is the third most common cancer worldwide, and the second most common cause of cancer-related death. In 2020, the estimated number of deaths due to CRC was approximately 930000, accounting for 10% of all cancer deaths worldwide. Accordingly, there is a vast amount of ongoing research aiming to find new and improved treatment modalities for CRC that can potentially increase survival and decrease overall morbidity and mortality. Current management strategies for CRC include surgical procedures for resectable cases, and radiotherapy, chemotherapy, and immunotherapy, in addition to their combination, for non-resectable tumors. Despite these options, CRC remains incurable in 50% of cases. Nonetheless, significant improvements in research techniques have allowed for treatment approaches for CRC to be frequently updated, leading to the availability of new drugs and therapeutic strategies. This review summarizes the most recent therapeutic approaches for CRC, with special emphasis on new strategies that are currently being studied and have great potential to improve the prognosis and lifespan of patients with CRC. Show less
DNA structure has many potential places where endogenous compounds and xenobiotics can bind. Therefore, xenobiotics bind along the sites of the nucleic acid with the aim of changing its structure, its Show more
DNA structure has many potential places where endogenous compounds and xenobiotics can bind. Therefore, xenobiotics bind along the sites of the nucleic acid with the aim of changing its structure, its genetic message, and, implicitly, its functions. Currently, there are several mechanisms known to be involved in DNA binding. These mechanisms are covalent and non-covalent interactions. The covalent interaction or metal base coordination is an irreversible binding and it is represented by an intra-/interstrand cross-link. The non-covalent interaction is generally a reversible binding and it is represented by intercalation between DNA base pairs, insertion, major and/or minor groove binding, and electrostatic interactions with the sugar phosphate DNA backbone. In the present review, we focus on the types of DNA–metal complex interactions (including some representative examples) and on presenting the methods currently used to study them. Show less
Lung cancer is a common malignant tumor that occurs in the human body and poses a serious threat to human health and quality of life. The existing treatment methods mainly include surgical treatment, Show more
Lung cancer is a common malignant tumor that occurs in the human body and poses a serious threat to human health and quality of life. The existing treatment methods mainly include surgical treatment, chemotherapy, and radiotherapy. However, due to the strong metastatic characteristics of lung cancer and the emergence of related drug resistance and radiation resistance, the overall survival rate of lung cancer patients is not ideal. There is an urgent need to develop new treatment strategies or new effective drugs to treat lung cancer. Ferroptosis, a novel type of programmed cell death, is different from the traditional cell death pathways such as apoptosis, necrosis, pyroptosis and so on. It is caused by the increase of iron-dependent reactive oxygen species due to intracellular iron overload, which leads to the accumulation of lipid peroxides, thus inducing cell membrane oxidative damage, affecting the normal life process of cells, and finally promoting the process of ferroptosis. The regulation of ferroptosis is closely related to the normal physiological process of cells, and it involves iron metabolism, lipid metabolism, and the balance between oxygen-free radical reaction and lipid peroxidation. A large number of studies have confirmed that ferroptosis is a result of the combined action of the cellular oxidation/antioxidant system and cell membrane damage/repair, which has great potential application in tumor therapy. Therefore, this review aims to explore potential therapeutic targets for ferroptosis in lung cancer by clarifying the regulatory pathway of ferroptosis. Based on the study of ferroptosis, the regulation mechanism of ferroptosis in lung cancer was understood and the existing chemical drugs and natural compounds targeting ferroptosis in lung cancer were summarized, with the aim of providing new ideas for the treatment of lung cancer. In addition, it also provides the basis for the discovery and clinical application of chemical drugs and natural compounds targeting ferroptosis to effectively treat lung cancer. Show less
Abstract Imaging contrast agents are widely investigated in preclinical and clinical studies, among which biogenic imaging contrast agents (BICAs) are developing rapidly and playing an increasingly i Show more
Abstract Imaging contrast agents are widely investigated in preclinical and clinical studies, among which biogenic imaging contrast agents (BICAs) are developing rapidly and playing an increasingly important role in biomedical research ranging from subcellular level to individual level. The unique properties of BICAs, including expression by cells as reporters and specific genetic modification, facilitate various in vitro and in vivo studies, such as quantification of gene expression, observation of protein interactions, visualization of cellular proliferation, monitoring of metabolism, and detection of dysfunctions. Furthermore, in human body, BICAs are remarkably helpful for disease diagnosis when the dysregulation of these agents occurs and can be detected through imaging techniques. There are various BICAs matched with a set of imaging techniques, including fluorescent proteins for fluorescence imaging, gas vesicles for ultrasound imaging, and ferritin for magnetic resonance imaging. In addition, bimodal and multimodal imaging can be realized through combining the functions of different BICAs, which helps overcome the limitations of monomodal imaging. In this review, the focus is on the properties, mechanisms, applications, and future directions of BICAs. Show less
Introduction: Drugs targeting mitochondria are emerging as promising antitumor therapeutics in preclinical models. However, a few of these drugs have shown clinical toxicity. Developing mitochondria- Show more
Introduction: Drugs targeting mitochondria are emerging as promising antitumor therapeutics in preclinical models. However, a few of these drugs have shown clinical toxicity. Developing mitochondria-targeted modified natural compounds and US FDA-approved drugs with increased therapeutic index in cancer is discussed as an alternative strategy. Areas Covered: Triphenylphosphonium cation (TPP + )-based drugs selectively accumulate in the mitochondria of cancer cells due to their increased negative membrane potential, target the oxidative phosphorylation proteins, inhibit mitochondrial respiration, and inhibit tumor proliferation. TPP + -based drugs exert minimal toxic side effects in rodents and humans. These drugs can sensitize radiation and immunotherapies. Expert Opinion: TPP + -based drugs targeting the tumor mitochondrial electron transport chain are a new class of oxidative phosphorylation inhibitors with varying antiproliferative and antimetastatic potencies. Some of these TPP + -based agents, which are synthesized from naturally occurring molecules and FDA-approved drugs, have been tested in mice and did not show notable toxicity, including neurotoxicity, when used at doses under the maximally tolerated dose. Thus, more effort should be directed toward the clinical translation of TPP + -based OXPHOS-inhibiting drugs in cancer prevention and treatment. Show less
Developing novel therapeutics often follows three steps: target identification, design of strategies to suppress target activity and drug development to implement the strategies. In this review, we re Show more
Developing novel therapeutics often follows three steps: target identification, design of strategies to suppress target activity and drug development to implement the strategies. In this review, we recount the evidence identifying the basic leucine zipper transcription factors ATF5, CEBPB, and CEBPD as targets for brain and other malignancies. We describe strategies that exploit the structures of the three factors to create inhibitory dominant-negative (DN) mutant forms that selectively suppress growth and survival of cancer cells. We then discuss and compare four peptides (CP-DN-ATF5, Dpep, Bpep and ST101) in which DN sequences are joined with cell-penetrating domains to create drugs that pass through tissue barriers and into cells. The peptide drugs show both efficacy and safety in suppressing growth and in the survival of brain and other cancers in vivo, and ST101 is currently in clinical trials for solid tumors, including GBM. We further consider known mechanisms by which the peptides act and how these have been exploited in rationally designed combination therapies. We additionally discuss lacunae in our knowledge about the peptides that merit further research. Finally, we suggest both short- and long-term directions for creating new generations of drugs targeting ATF5, CEBPB, CEBPD, and other transcription factors for treating brain and other malignancies. Show less
Abstract The hallmark of tumorigenesis is the successful circumvention of cell death regulation for achieving unlimited replication and immortality. Ferroptosis is a newly identified type of cell deat Show more
Abstract The hallmark of tumorigenesis is the successful circumvention of cell death regulation for achieving unlimited replication and immortality. Ferroptosis is a newly identified type of cell death dependent on lipid peroxidation which differs from classical programmed cell death in terms of morphology, physiology and biochemistry. The broad spectrum of injury and tumor tolerance are the main reasons for radiotherapy and chemotherapy failure. The effective rate of tumor immunotherapy as a new treatment method is less than 30%. Ferroptosis can be seen in radiotherapy, chemotherapy, and tumor immunotherapy; therefore, ferroptosis activation may be a potential strategy to overcome the drug resistance mechanism of traditional cancer treatments. In this review, the characteristics and causes of cell death by lipid peroxidation in ferroptosis are briefly described. In addition, the three metabolic regulations of ferroptosis and its crosstalk with classical signaling pathways are summarized. Collectively, these findings suggest the vital role of ferroptosis in immunotherapy based on the interaction of ferroptosis with tumor immunotherapy, chemotherapy and radiotherapy, thus, indicating the remarkable potential of ferroptosis in cancer treatment. Show less
The elucidation of a compound's Mechanism of Action (MoA) is a challenging task in the drug discovery process, but it is important in order to rationalise phenotypic findings and to anticipate potenti Show more
The elucidation of a compound's Mechanism of Action (MoA) is a challenging task in the drug discovery process, but it is important in order to rationalise phenotypic findings and to anticipate potential side-effects. Bioinformatic approaches, advances in machine learning techniques and the increasing deposition of high-throughput data in public databases have significantly contributed to recent advances in the field, but it is not straightforward to decide which data and methods are most suitable to use in a given case. In this review, we focus on these methods and data and their applications in generating MoA hypotheses for subsequent experimental validation. We discuss compound-specific data such as -omics, cell morphology and bioactivity data, as well as commonly used supplementary prior knowledge such as network and pathway data, and provide information on databases where this data can be accessed. In terms of methodologies, we discuss both well-established methods (connectivity mapping, pathway enrichment) as well as more developing methods (neural networks and multi-omics integration). Finally, we review case studies where the MoA of a compound was successfully suggested from computational analysis by incorporating multiple data modalities and/or methodologies. Our aim for this review is to provide researchers with insights into the benefits and drawbacks of both the data and methods in terms of level of understanding, biases and interpretation – and to highlight future avenues of investigation which we foresee will improve the field of MoA elucidation, including greater public access to -omics data and methodologies which are capable of data integration. Show less
Background Chemotherapy, radiotherapy, targeted therapy and immunotherapy have demonstrated expected clinical efficacy, while drug resistance remains the predominant limiting factor to therapeutic fa Show more
Background Chemotherapy, radiotherapy, targeted therapy and immunotherapy have demonstrated expected clinical efficacy, while drug resistance remains the predominant limiting factor to therapeutic failure in patients with colorectal cancer (CRC). Although there have been numerous basic and clinical studies on CRC resistance in recent years, few publications utilized the bibliometric method to evaluate this field. The objective of current study was to provide a comprehensive analysis of the current state and changing trends of drug resistance in CRC over the past 20 years. Methods The Web of Science Core Collection (WOSCC) was utilized to extracted all studies regarding drug resistance in CRC during 2002-2021. CiteSpace and online platform of bibliometrics were used to evaluate the contributions of various countries/regions, institutions, authors and journals in this field. Moreover, the recent research hotspots and promising future trends were identified through keywords analysis by CiteSpace and VOSviewer. Results 1451 related publications from 2002 to 2021 in total were identified and collected. The number of global publications in this field has increased annually. China and the USA occupied the top two places with respect to the number of publications, contributing more than 60% of global publications. Sun Yat-sen University and Oncotarget were the institution and journal which published the most papers, respectively. Bardelli A from Italy was the most prolific writer and had the highest H-index. Keywords burst analysis identified that “Growth factor receptor”, “induced apoptosis” and “panitumumab” were the ones with higher burst strength in the early stage of this field. Analysis of keyword emergence time showed that “oxaliplatin resistance”, “MicroRNA” and “epithelial mesenchymal transition (EMT)” were the keywords with later average appearing year (AAY). Conclusions The number of publications and research interest on drug resistance in CRC have been increasing annually. The USA and China were the main driver and professor Bardelli A was the most outstanding researcher in this field. Previous studies have mainly concentrated on growth factor receptor and induced apoptosis. Oxaliplatin resistance, microRNA and EMT as recently appeared frontiers of research that should be closely tracked in the future. Show less
A triphenylphosphine-modified tetra-nuclear Cu(I) coordinated cluster was constructed for enhanced chemodynamic therapy (CDT) by increasing the number of metal centers. Once inside human bladd Show more
A triphenylphosphine-modified tetra-nuclear Cu(I) coordinated cluster was constructed for enhanced chemodynamic therapy (CDT) by increasing the number of metal centers. Once inside human bladder cancer (T24) cells, a larger amount of copper accumulated compared with the mono-nuclear Cu(I) complex; the additional copper could generate more •OH and then induce more obvious apoptosis via a Fenton-like reaction, thus further increasing the tumor inhibition effect and ultimately improving the CDT efficiency.
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In this work, three iridium(III) tetrazolato complexes have been designed and successfully synthesized. Beside photophysical properties, their performances in protein staining have been compre Show more
In this work, three iridium(III) tetrazolato complexes have been designed and successfully synthesized. Beside photophysical properties, their performances in protein staining have been comprehensively investigated in this work for the first time. Notably, these iridium(III) tetrazolato complexes with high quantum efficiency exhibited much better protein staining properties than the commercial agent Coomassie Brilliant Blue (CBB) under the same experimental conditions, which may pave the way to explore new efficient iridium-based protein staining agents both for commercial markets and academic research in the future.
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Oxaliplatin is a platinum analog that can interfere with DNA replication and transcription. Continuous exposure to oxaliplatin results in chemoresistance; however, this mechanism is not well known. In Show more
Oxaliplatin is a platinum analog that can interfere with DNA replication and transcription. Continuous exposure to oxaliplatin results in chemoresistance; however, this mechanism is not well known. In this study, oxaliplatin-resistant (OR) colorectal cancer (CRC) cells of HCT116, HT29, SW480 and SW620 were established by gradually increasing the drug concentration to 2.5 μM. The inhibitory concentrations of cell growth by 50% (IC 50 ) of oxaliplatin were 4.40–12.7-fold significantly higher in OR CRC cells as compared to their respective parental (PT) CRC cells. Phospho-Akt and phospho-mammalian target of rapamycin (mTOR) decreased in PT CRC cells but was overexpressed in OR CRC cells in response to oxaliplatin. In addition, an oxaliplatin-mediated decrease in phospho-AMP-activated protein kinase (AMPK) in PT CRC cells induced autophagy. Contrastingly, an increased phospho-AMPK in OR CRC cells was accompanied by a decrease in LC3B, further inducing the activity of glycolytic enzymes, such as glucose transporter 1 (GLUT1), 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) and phosphofructokinase 1 (PFK1), to mediate cell survival. Inhibition of AMPK in OR CRC cells induced autophagy through inactivation of Akt/mTOR pathway and a decrease in GLUT1, PFKFB3, and PFK1. Collectively, targeting AMPK may provide solutions to overcome chemoresistance in OR CRC cells and restore chemosensitivity to anticancer drugs. Show less
Osteoporosis is a disorder of bone metabolism that is extremely common in elderly patients as well as in postmenopausal women. The main manifestation is that the bone resorption capacity is greater th Show more
Osteoporosis is a disorder of bone metabolism that is extremely common in elderly patients as well as in postmenopausal women. The main manifestation is that the bone resorption capacity is greater than the bone formation capacity, which eventually leads to a decrease in bone mass, increasing the risk of fracture. There is growing evidence that inhibiting osteoclast formation and resorption ability can be effective in treating and preventing the occurrence of osteoporosis. Our study is the first time to explore the role of the mitochondrial calcium uniporter (MCU) and its inhibitor ruthenium red (RR) in bone metabolism, clarifying the specific mechanism by which it inhibits osteoclast formation in vitro and plays a therapeutic role in osteoporosis in vivo. We verified the suppressive effects of RR on the receptor activator of nuclear factor‐κB ligand (RANKL‐)‐induced differentiation and bone resorption function of osteoclasts in vitro. The reactive oxygen species (ROS) production stimulated by RANKL and the expression level of P38 MAPK/NFATc1 were also found to be inhibited by RR. Moreover, the promotion of RR on osteogenesis differentiation was investigated by alkaline phosphatase (ALP) and alizarin red S (ARS) staining and the detection of osteogenesis‐specific gene expression levels by quantitative polymerase chain reaction (qPCR) and western blotting. Moreover, in ovariectomy (OVX‐)‐induced osteoporosis models, RR can downregulate the expression and function of the MCU, relieving bone loss and promoting osteogenesis to present a therapeutic effect on osteoporosis. This new finding will provide an important direction for the study of RR and MCU in the study of bone metabolism therapy targets. Show less