Also published as: Anmin Gao, B Gao, B. Gao, C Gao, Chuan Gao, Dong Gao, E Gao, Enjun Gao, F.X. Gao, Fangfang Gao, Feng Gao, H Gao, J. F. Gao, J. Gao, Jie Gao, Jinhao Gao, Jinmin Gao, Junjie Gao, Junning Gao, L Gao, L. Gao, LC Gao, Li Gao, Ling Gao, M Gao, Minghui Gao, P Gao, P. Gao, Pengli Gao, Ping Gao, Q Gao, Qingzhi Gao, S Gao, S. Gao, W. Gao, Wei Gao, Wen-gui Gao, Wenyuan Gao, X Gao, X. Gao, XB Gao, XL Gao, Y Gao, Y. Gao, Ya Gao, Yan Gao, Yanjun Gao, Yi Qin Gao, Yihang Gao, Yue Gao, Z Gao, Z. Gao
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. CRATâs 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 CRATâs 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
Z-DNA-binding protein 1 (ZBP1; also known as DAI or DLM-1) regulates cell death and inflammation by sensing left-handed double-helical nucleic acids, including Z-RNA and Z-DNA. However, the physiologi Show more
Z-DNA-binding protein 1 (ZBP1; also known as DAI or DLM-1) regulates cell death and inflammation by sensing left-handed double-helical nucleic acids, including Z-RNA and Z-DNA. However, the physiological conditions that generate Z-form nucleic acids (Z-NAs) and activate ZBP1-dependent signaling pathways remain largely elusive. In this study, we developed a probe, Zα-mFc, that specifically detected both Z-DNA and Z-RNA. Utilizing this probe, we discovered that inhibiting spliceosome causes nuclear accumulation of Z-RNA:DNA hybrids, which are sensed by ZBP1 via its Zα domains, triggering apoptosis and necroptosis in mammalian cells. Furthermore, we solved crystal structures of the human or mouse Zα1 domain complexed with a 6-bp RNA:DNA hybrid, revealing that the RNA:DNA hybrid adopts a left-handed conformation. Our findings demonstrate that the spliceosome acts as a checkpoint preventing accumulation of Z-RNA:DNA hybrids, which potentially function as endogenous ligands activating ZBP1-dependent cell death pathways. Show less
Macroautophagy/autophagy is a complex degradation process with a dual role in cell death that is influenced by the cell types that are involved and the stressors they are exposed to. Ferroptosis is an Show more
Macroautophagy/autophagy is a complex degradation process with a dual role in cell death that is influenced by the cell types that are involved and the stressors they are exposed to. Ferroptosis is an iron-dependent oxidative form of cell death characterized by unrestricted lipid peroxidation in the context of heterogeneous and plastic mechanisms. Recent studies have shed light on the involvement of specific types of autophagy (e.g. ferritinophagy, lipophagy, and clockophagy) in initiating or executing ferroptotic cell death through the selective degradation of anti-injury proteins or organelles. Conversely, other forms of selective autophagy (e.g. reticulophagy and lysophagy) enhance the cellular defense against ferroptotic damage. Dysregulated autophagy-dependent ferroptosis has implications for a diverse range of pathological conditions. This review aims to present an updated definition of autophagy-dependent ferroptosis, discuss influential substrates and receptors, outline experimental methods, and propose guidelines for interpreting the results.Abbreviation: 3-MA:3-methyladenine; 4HNE: 4-hydroxynonenal; ACD: accidentalcell death; ADF: autophagy-dependentferroptosis; ARE: antioxidant response element; BH2:dihydrobiopterin; BH4: tetrahydrobiopterin; BMDMs: bonemarrow-derived macrophages; CMA: chaperone-mediated autophagy; CQ:chloroquine; DAMPs: danger/damage-associated molecular patterns; EMT,epithelial-mesenchymal transition; EPR: electronparamagnetic resonance; ER, endoplasmic reticulum; FRET: Försterresonance energy transfer; GFP: green fluorescent protein;GSH: glutathione;IF: immunofluorescence; IHC: immunohistochemistry; IOP, intraocularpressure; IRI: ischemia-reperfusion injury; LAA: linoleamide alkyne;MDA: malondialdehyde; PGSK: Phen Green⹠SK;RCD: regulatedcell death; PUFAs: polyunsaturated fatty acids; RFP: red fluorescentprotein;ROS: reactive oxygen species; TBA: thiobarbituricacid; TBARS: thiobarbituric acid reactive substances; TEM:transmission electron microscopy. Show less
In the past, hydrogen sulfide (H2S) was recognized as a toxic and dangerous gas; in recent years, with increased research, we have discovered that H2S can act as an endogenous regulatory transmitter. Show more
In the past, hydrogen sulfide (H2S) was recognized as a toxic and dangerous gas; in recent years, with increased research, we have discovered that H2S can act as an endogenous regulatory transmitter. In mammals, H2S-catalyzing enzymes, such as cystathionine-ÎČ-synthase, cystathionine-Îł-lyase, and 3-mercaptopyruvate sulfurtransferase, are differentially expressed in a variety of tissues and affect a variety of biological functions, such as transcriptional and posttranslational modification of genes, activation of signaling pathways in the cell, and metabolic processes in tissues, by producing H2S. Various preclinical studies have shown that H2S affects physiological and pathological processes in the body. However, a detailed systematic summary of these roles in health and disease is lacking. Therefore, this review provides a thorough overview of the physiological roles of H2S in different systems and the diseases associated with disorders of H2S metabolism, such as ischemia-reperfusion injury, hypertension, neurodegenerative diseases, inflammatory bowel disease, and cancer. Meanwhile, this paper also introduces H2S donors and novel release modes, as well as the latest preclinical experimental results, aiming to provide researchers with new ideas to discover new diagnostic targets and therapeutic options. Show less
For a long time, hydrogen sulfide (H2S) has been considered a toxic compound, but recent studies have found that H2S is the third gaseous signaling molecule which plays a vital role in physiological a Show more
For a long time, hydrogen sulfide (H2S) has been considered a toxic compound, but recent studies have found that H2S is the third gaseous signaling molecule which plays a vital role in physiological and pathological conditions. Currently, a large number of studies have shown that H2S mediates apoptosis through multiple signaling pathways to participate in cancer occurrence and development, for example, PI3K/Akt/mTOR and MAPK signaling pathways. Therefore, the regulation of the production and metabolism of H2S to mediate the apoptotic process of cancer cells may improve the effectiveness of cancer treatment. In this review, the role and mechanism of H2S in cancer cell apoptosis in mammals are summarized. Show less
Oxaliplatin-based chemotherapy has proven to be one of the most effective treatments for advanced or metastatic colorectal cancer. However, increasing clinical resistance to oxaliplatin poses unpreced Show more
Oxaliplatin-based chemotherapy has proven to be one of the most effective treatments for advanced or metastatic colorectal cancer. However, increasing clinical resistance to oxaliplatin poses unprecedented challenges for both patients and clinicians. Despite extensive efforts to combat this issue, to date, no new molecules have been discovered that can successfully replace oxaliplatin. With the aim of developing a new generation of Pt(II)-based anticancer agents in response to the challenges of oxaliplatin-induced drug resistance, we performed a systematic screening of new Pt(II)-complexes with a quantitative structure-activity relationship (QSAR) study based on their antiresistance activity against oxaliplatin-resistant colon cancer cells. The results revealed that both the structure and chirality of the chelating ligand had a significant impact on the antiresistance properties of the Pt(II)-complexes. Our study culminated in the identification of chiral R-binaphthyldiamine-ligated Pt(II)-malonatoglycoconjugates that can completely counteract oxaliplatin resistance with excellent in vitro and in vivo potency. 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
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
Protein Arginine Methyltransferases (PRMTs) are a family of enzymes regulating protein arginine methylation, which is a post-translational modification crucial for various cellular processes. Recent s Show more
Protein Arginine Methyltransferases (PRMTs) are a family of enzymes regulating protein arginine methylation, which is a post-translational modification crucial for various cellular processes. Recent studies have highlighted the mechanistic role of PRMTs in cancer pathogenesis, immunotherapy, and drug resistance. PRMTs are involved in diverse oncogenic processes, including cell proliferation, apoptosis, and metastasis. They exert their effects by methylation of histones, transcription factors, and other regulatory proteins, resulting in altered gene expression patterns. PRMT-mediated histone methylation can lead to aberrant chromatin remodeling and epigenetic changes that drive oncogenesis. Additionally, PRMTs can directly interact with key signaling pathways involved in cancer progression, such as the PI3K/Akt and MAPK pathways, thereby modulating cell survival and proliferation. In the context of cancer immunotherapy, PRMTs have emerged as critical regulators of immune responses. They modulate immune checkpoint molecules, including programmed cell death protein 1 (PD-1), through arginine methylation. Drug resistance is a significant challenge in cancer treatment, and PRMTs have been implicated in this phenomenon. PRMTs can contribute to drug resistance through multiple mechanisms, including the epigenetic regulation of drug efflux pumps, altered DNA damage repair, and modulation of cell survival pathways. In conclusion, PRMTs play critical roles in cancer pathogenesis, immunotherapy, and drug resistance. In this overview, we have endeavored to illuminate the mechanistic intricacies of PRMT-mediated processes. Shedding light on these aspects will offer valuable insights into the fundamental biology of cancer and establish PRMTs as promising therapeutic targets. 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
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
Parthanatos is a form of regulated cell death involved in the pathogenesis of many diseases, particularly neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, Huntingtonâs di Show more
Parthanatos is a form of regulated cell death involved in the pathogenesis of many diseases, particularly neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, Huntingtonâs disease, and amyotrophic lateral sclerosis. Parthanatos is a multistep cell death pathway cascade that involves poly (ADP-ribose) polymerase 1 (PARP-1) overactivation, PAR accumulation, PAR binding to apoptosis-inducing factor (AIF), AIF release from the mitochondria, nuclear translocation of the AIF/macrophage migration inhibitory factor (MIF) complex, and MIF-mediated large-scale DNA fragmentation. All the key players in the parthanatos pathway are pleiotropic proteins with diverse functions. An in-depth understanding of the structure-based activity of the key factors, and the biochemical mechanisms of parthanatos, is crucial for the development of drugs and therapeutic strategies. In this review, we delve into the key players of the parthanatos pathway and reveal the multiple levels of therapeutic opportunities for treating parthanatos-based pathogenesis. 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 â 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
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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Metabolic rewiring and epigenetic remodeling, which are closely linked and reciprocally regulate each other, are among the well-known cancer hallmarks. Recent evidence suggests that many metabolites s Show more
Metabolic rewiring and epigenetic remodeling, which are closely linked and reciprocally regulate each other, are among the well-known cancer hallmarks. Recent evidence suggests that many metabolites serve as substrates or cofactors of chromatin-modifying enzymes as a consequence of the translocation or spatial regionalization of enzymes or metabolites. Various metabolic alterations and epigenetic modifications also reportedly drive immune escape or impede immunosurveillance within certain contexts, playing important roles in tumor progression. In this review, we focus on how metabolic reprogramming of tumor cells and immune cells reshapes epigenetic alterations, in particular the acetylation and methylation of histone proteins and DNA. We also discuss other eminent metabolic modifications such as, succinylation, hydroxybutyrylation, and lactylation, and update the current advances in metabolism- and epigenetic modification-based therapeutic prospects in cancer. Show less
AbstractDespite widespread applications for cancer treatment, chemotherapy is restricted by several limitations, including low targeting specificity, acquired drug resistance, and concomitant adverse Show more
AbstractDespite widespread applications for cancer treatment, chemotherapy is restricted by several limitations, including low targeting specificity, acquired drug resistance, and concomitant adverse side effects. It remains challenging to overcome these drawbacks. Herein, we report a new bioenergetic approach for treating cancer efficiently. As a proofâofâconcept, we construct activatable mitochondriaâtargeting organoarsenic prodrugs from organoarsenic compounds and traditional chemotherapeutics. These prodrugs could accomplish selective delivery and controlled release of both therapeutic agents to mitochondria, which synergistically promote mitochondrial ROS production and induce mitochondrial DNA damage, finally leading to mitochondriaâmediated apoptosis of cancer cells. Our in vitro and in vivo experiments reveal the excellent anticancer efficacy of these prodrugs, underscoring the encouraging outlook of this strategy for effective cancer therapy. Show less
Simple Summary The gene-regulatory factors ATF5, CEBPB and CEBPD promote survival, growth, metastasis and treatment resistance of a range of cancer cell types. Presently, no drugs target all three at Show more
Simple Summary The gene-regulatory factors ATF5, CEBPB and CEBPD promote survival, growth, metastasis and treatment resistance of a range of cancer cell types. Presently, no drugs target all three at once. Here, with the aim of treating cancers, we designed novel cell-penetrating peptides that interact with and inactivate all three. The peptides Bpep and Dpep kill a range of cancer cell types in culture and in animals. In animals with tumors, they also significantly increase survival time. In contrast, they do not affect survival of non-cancer cells and have no apparent side effects in animals. The peptides work in combination with other anti-cancer treatments. Mechanism studies of how the peptides kill cancer cells indicate a decrease in survival proteins and increase in death proteins. These studies support the potential of Bpep and Dpep as novel, safe agents for the treatment of a variety of cancer types, both as mono- and combination therapies. Abstract Transcription factors are key players underlying cancer formation, growth, survival, metastasis and treatment resistance, yet few drugs exist to directly target them. Here, we characterized the in vitro and in vivo anti-cancer efficacy of novel synthetic cell-penetrating peptides (Bpep and Dpep) designed to interfere with the formation of active leucine-zipper-based dimers by CEBPB and CEBPD, transcription factors implicated in multiple malignancies. Both peptides similarly promoted apoptosis of multiple tumor lines of varying origins, without such effects on non-transformed cells. Combined with other treatments (radiation, Taxol, chloroquine, doxorubicin), the peptides acted additively to synergistically and were fully active on Taxol-resistant cells. The peptides suppressed expression of known direct CEBPB/CEBPD targets IL6 , IL8 and asparagine synthetase ( ASNS ), supporting their inhibition of transcriptional activation. Mechanisms by which the peptides trigger apoptosis included depletion of pro-survival survivin and a required elevation of pro-apoptotic BMF. Bpep and Dpep significantly slowed tumor growth in mouse models without evident side effects. Dpep significantly prolonged survival in xenograft models. These findings indicate the efficacy and potential of Bpep and Dpep as novel agents to treat a variety of cancers as mono- or combination therapies. Show less
The task of drug-target interaction prediction holds significant importance in pharmacology and therapeutic drug design. In this paper, we present FRnet-DTI, an auto-encoder based feature manipulation Show more
The task of drug-target interaction prediction holds significant importance in pharmacology and therapeutic drug design. In this paper, we present FRnet-DTI, an auto-encoder based feature manipulation and a convolutional neural network based classifier for drug target interaction prediction. Two convolutional neural networks are proposed: FRnet-Encode and FRnet-Predict. Here, one model is used for feature manipulation and the other one for classification. Using the first method FRnet-Encode, we generate 4096 features for each of the instances in each of the datasets and use the second method, FRnet-Predict, to identify interaction probability employing those features. We have tested our method on four gold standard datasets extensively used by other researchers. Experimental results shows that our method significantly improves over the state-of-the-art method on three out of four drug-target interaction gold standard datasets on both area under curve for Receiver Operating Characteristic (auROC) and area under Precision Recall curve (auPR) metric. We also introduce twenty new potential drug-target pairs for interaction based on high prediction scores. The source codes and implementation details of our methods are available from https://github.com/farshidrayhanuiu/FRnet-DTI/ and also readily available to use as an web application from http://farshidrayhan.pythonanywhere.com/FRnet-DTI/ . Show less
Three novel complexes, namely [Nd·L1·HCOO·(H2O)4] (1), [Pr·L1·HCOO·(H2O)4] (2) and [In·L2·Cl·(H2O)2] (3) (L1 = 1,1âbis(5â(pyrazinâ2âyl)â1,2,4âtriazolâ3âyl)methane, L2 = 1,1âbis(5â(pyrazinâ2âyl)â1,2,4â Show more
Three novel complexes, namely [Nd·L1·HCOO·(H2O)4] (1), [Pr·L1·HCOO·(H2O)4] (2) and [In·L2·Cl·(H2O)2] (3) (L1 = 1,1âbis(5â(pyrazinâ2âyl)â1,2,4âtriazolâ3âyl)methane, L2 = 1,1âbis(5â(pyrazinâ2âyl)â1,2,4âtriazolâ3âyl)ketone), were synthesized and characterized. The molecular structures of 1â3 were confirmed using singleâcrystal Xâray diffraction. All three obtained complexes are zeroâdimensional and connected to each other by hydrogen bonds. In 1 and 2 the metal is surrounded by nine donors and 3 has seven coordination sites. The interaction of 1â3 with calf thymus DNA (CTâDNA) was explored using UV absorption spectra and fluorescence spectra. The intrinsic binding constants of 1â3 with CTâDNA are about 1.9 Ă 104, 1.4 Ă 104 and 1.1 Ă 104, respectively. SternâVolmer quenching plots of 1â3 have slopes of 0.1508, 0.134 and 0.1205, respectively. The ability of these complexes to cleave pBR322 plasmid DNA was demonstrated using gel electrophoresis assay. Apoptosis studies of the three novel complexes showed a significant inhibitory effect on HeLa cells. Furthermore, MTT assays were used to evaluate the anticancer activity of the three complexes. The cytotoxicity study indicated that complex 1 possesses a higher inhibitory rate of HeLa cells than the other complexes. Especially, the efficacy of 1 was shown to be the highest for cisplatin at 24 h. A further molecular docking technique was introduced to understand the binding of the complexes toward the target DNA. Show less
Tetrazole, a bioisostere of the carboxylic acid group, can replace the carboxyl group in drugs to increase the lipophilicity, bioavailability and reduce side effects. Tetrazole derivatives possess a b Show more
Tetrazole, a bioisostere of the carboxylic acid group, can replace the carboxyl group in drugs to increase the lipophilicity, bioavailability and reduce side effects. Tetrazole derivatives possess a broad-spectrum of biological properties including anti-tubercular and anti-malarial activities, and some tetrazole-based compounds have already been used in clinics for the treatment of various diseases. Therefore, tetrazole is an important pharmacophore in the development of new drugs. This review covers the recent advances of tetrazole derivatives as potential anti-tubercular and anti-malarial agents, and the structure-activity relationship is also discussed for the further rational design of tetrazole derivatives. Show less
Feng Gao, Jiaqi Xiao, Gang Huang · 2019 · European journal of medicinal chemistry · Elsevier · added 2026-04-20
The incidence of invasive bacterial infections has increased remarkably over the past two decades, which was mainly attributed to the increasing emergence of drug-resistant bacteria especially multidr Show more
The incidence of invasive bacterial infections has increased remarkably over the past two decades, which was mainly attributed to the increasing emergence of drug-resistant bacteria especially multidrug-resistant strains, intractable pathogens and newly arising pathogenic organisms. Tetrazoles, the bioisoster of carboxylic acid, possess considerable antibacterial property. Hybridization of tetrazole with other antibacterial pharmacophores has the potential to enhance the efficacy against both drug-sensitive and drug-resistant pathogens. Some tetrazole hybrids such as tetrazole-oxazolidinone hybrid Tedizolid 25 and Tedizolid phosphate 26 have already been marketed for the treatment of acute bacterial skin and skin structure infections caused by various bacteria. DA-7867 (27), the amide analog of Tedizolid, also exhibited promising activities against a panel of clinically important pathogens including drug-resistant organisms, demonstrating the possible utility of the tetrazole scaffolds in the development of new antibacterial agents. Thus, hybridization of tetrazole with other antibacterial pharmacophores represents a promising strategy to develop novel antibacterial candidates. This work is attempted to systematically review the research of tetrazole hybrids in the design and development of antibacterial agents during the past two decades. The structure-activity relationship (SAR) is also discussed to provide an insight for rational design of more effective tetrazole antibacterial candidates. Show less
Abstract TFIIH is a 10âsubunit complex that regulates RNA polymerase II (pol II) transcription but also serves other important biological roles. Although much remains unknown about TFIIH function in Show more
Abstract TFIIH is a 10âsubunit complex that regulates RNA polymerase II (pol II) transcription but also serves other important biological roles. Although much remains unknown about TFIIH function in eukaryotic cells, much progress has been made even in just the past few years, due in part to technological advances (e.g. cryoEM and single molecule methods) and the development of chemical inhibitors of TFIIH enzymes. This review focuses on the major cellular roles for TFIIH, with an emphasis on TFIIH function as a regulator of pol II transcription. We describe the structure of TFIIH and its roles in pol II initiation, promoterâproximal pausing, elongation, and termination. We also discuss cellular roles for TFIIH beyond transcription (e.g. DNA repair, cell cycle regulation) and summarize small molecule inhibitors of TFIIH and diseases associated with defects in TFIIH structure and function. Show less