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Z-RNA is a higher-energy, left-handed conformation of RNA, whose function has remained elusive. A growing body of work alludes to regulatory roles for Z-RNA in the immune response. Here, we review how Z-RNA features present in cellular RNAs-especially containing retroelements-could be recognized by a family of winged helix proteins, with an impact on host defense. We also discuss how mutations to specific Z-contacting amino acids disrupt their ability to stabilize Z-RNA, resulting in functional losses. We end by highlighting knowledge gaps in the field, which, if addressed, would significantly advance this active area of research. Show less

Kelch-like ECH-associated protein 1 (Keap1) is a drug target for diseases involving oxidative stress and inflammation. There are three covalent Keap1-binding drugs on the market, but noncovalent compounds that inhibit the interaction between Keap1 and nuclear factor erythroid 2-related factor 2 (Nrf2) represent an attractive alternative. Both compound types prevent degradation of Nrf2, leading to the expression of antioxidant and antiinflammatory proteins. However, their off-target profiles differ as do their exact pharmacodynamic effects. Here, we discuss the opportunities and challenges of targeting Keap1 with covalent versus noncovalent inhibitors. We then provide a comprehensive overview of current noncovalent Keap1-Nrf2 inhibitors, with a focus on their pharmacological effects, to examine the therapeutic potential for this compound class. Show less

The immune system is coordinated by an intricate network of stimulatory and inhibitory circuits that regulate host responses against endogenous and exogenous insults. Disruption of these safeguard and homeostatic mechanisms can lead to unpredictable inflammatory and autoimmune responses, whereas deficiency of immune stimulatory pathways may orchestrate immunosuppressive programs that contribute to perpetuate chronic infections, but also influence cancer development and progression. Glycans have emerged as essential components of homeostatic circuits, acting as fine-tuners of immunological responses and potential molecular targets for manipulation of immune tolerance and activation in a wide range of pathologic settings. Cell surface glycans, present in cells, tissues and the extracellular matrix, have been proposed to serve as “self-associated molecular patterns” that store structurally relevant biological data. The responsibility of deciphering this information relies on different families of glycan-binding proteins (including galectins, siglecs and C-type lectins) which, upon recognition of specific carbohydrate structures, can recalibrate the magnitude, nature and fate of immune responses. This process is tightly regulated by the diversity of glycan structures and the establishment of multivalent interactions on cell surface receptors and the extracellular matrix. Here we review the spatiotemporal regulation of selected glycan-modifying processes including mannosylation, complex N-glycan branching, core 2 O-glycan elongation, LacNAc extension, as well as terminal sialylation and fucosylation. Moreover, we illustrate examples that highlight the contribution of these processes to the control of immune responses and their integration with canonical tolerogenic pathways. Finally, we discuss the power of glycans and glycan-binding proteins as a source of immunomodulatory signals that could be leveraged for the treatment of autoimmune inflammation and chronic infection. Show less

Cancer is a leading cause of death worldwide and involves an oxidative stress mechanism. The transcription factor Nrf2 has a crucial role in cytoprotective response against oxidative stress, including cancer growth and progression and therapy resistance. For this reason, inhibitors of Nrf2 are new targets to be studied. Traditional plant-based remedies rich in phytochemicals have been used against human cancers and phenolic compounds are known for their chemopreventive properties. This comprehensive review offers an updated review of the role of phenolic compounds as anticancer agents due to their action on Nrf2 inhibition. In addition, the role of naturally-occurring bioactive anticancer agents are covered in the clinical applications of polyphenols as Nrf2 inhibitors. Video Abstract Show less

Reactive sulfur species (RSS) entail a diverse family of sulfur derivatives that have emerged as important effector molecules in H2S-mediated biological events. RSS (including H2S) can exert their biological roles via widespread interactions with metalloproteins. Metalloproteins are essential components along the metabolic route of oxygen in the body, from the transport and storage of O2, through cellular respiration, to the maintenance of redox homeostasis by elimination of reactive oxygen species (ROS). Moreover, heme peroxidases contribute to immune defense by killing pathogens using oxygen-derived H2O2 as a precursor for stronger oxidants. Coordination and redox reactions with metal centers are primary means of RSS to alter fundamental cellular functions. In addition to RSS-mediated metalloprotein functions, the reduction of high-valent metal centers by RSS results in radical formation and opens the way for subsequent per- and polysulfide formation, which may have implications in cellular protection against oxidative stress and in redox signaling. Furthermore, recent findings pointed out the potential role of RSS as substrates for mitochondrial energy production and their cytoprotective capacity, with the involvement of metalloproteins. The current review summarizes the interactions of RSS with protein metal centers and their biological implications with special emphasis on mechanistic aspects, sulfide-mediated signaling, and pathophysiological consequences. A deeper understanding of the biological actions of reactive sulfur species on a molecular level is primordial in H2S-related drug development and the advancement of redox medicine. Show less

The article presents overview of modern concepts about application of artificial intelligence (AI) in pharmacotherapy to decrease risk of developing undesirable side effects of medications. The possibilities of applying AI in selection of optimal medicine or combination of medicines and prediction of treatment results are considered. The choice of the best medicine for patient usually requires integration of data of results of comprehensive examination of patient considering success of genetics and/or proteomics as well as data about chemical descriptors of compounds of medications. The prognosis of medication interactions is often based on indicators of similarity assuming that medications with analogous structures or targets will have comparable behavior or may impede each other. The optimization of scheme of dosage of medicines is implemented applying mathematical models to interpret pharmacokinetic and pharmacodynamic data. Show less

Mitochondria play an important role in energy conversion as well as in intracellular calcium (Ca2+) storage. Ca2+ uptake from the cytosol to the mitochondria is mediated by the calcium uniporter, which functions as a Ca2+ ion channel. However, the molecular composition of this uniporter has remained unclear until recently. The Ca2+ ion channel consists of seven subunits. The yeast reconstitution technique revealed that the mitochondrial calcium uniporter (MCU) and essential MCU regulatory element (EMRE) are the core subunits of the complex. Furthermore, detailed structure-function analyses of the core subunits (MCU and EMRE) were performed. In this review, the regulatory mechanism of mitochondrial Ca2+ uptake is discussed. Show less

Ca2+ ions serve as pleiotropic second messengers in the cell, regulating several cellular processes. Mitochondria play a fundamental role in Ca2+ homeostasis since mitochondrial Ca2+ (mitCa2+) is a key regulator of oxidative metabolism and cell death. MitCa2+ uptake is mediated by the mitochondrial Ca2+ uniporter complex (MCUc) localized in the inner mitochondrial membrane (IMM). MitCa2+ uptake stimulates the activity of three key enzymes of the Krebs cycle, thereby modulating ATP production and promoting oxidative metabolism. As Paracelsus stated, "Dosis sola facit venenum,"in pathological conditions, mitCa2+ overload triggers the opening of the mitochondrial permeability transition pore (mPTP), enabling the release of apoptotic factors and ultimately leading to cell death. Excessive mitCa2+ accumulation is also associated with a pathological increase of reactive oxygen species (ROS). In this article, we review the precise regulation and the effectors of mitCa2+ in physiopathological processes. Show less

In recent years, protein arginine methyltransferases (PRMTs) have emerged as new members of a gene expression regulator family in eukaryotes, and are associated with cancer pathogenesis and progression. Cancer immunotherapy has significantly improved cancer treatment in terms of overall survival and quality of life. Protein arginine methylation is an epigenetic modification function not only in transcription, RNA processing, and signal transduction cascades, but also in many cancer-immunity cycle processes. Arginine methylation is involved in the activation of anti-cancer immunity and the regulation of immunotherapy efficacy. In this review, we summarize the most up-to-date information on regulatory molecular mechanisms and different underlying arginine methylation signaling pathways in innate and adaptive immune responses during cancer. We also outline the potential of PRMT-inhibitors as effective combinatorial treatments with immunotherapy. Show less

Medicinal inorganic chemistry is a burgeoning subfield of medicinal chemistry that focuses on the development of metal-based diagnostic and therapeutic agents. This tutorial review aims to provide an introductory primer, present a timely overview of recent discoveries and identify current challenges and opportunities of the field. Three specific areas of discovery are highlighted herein. The first part focuses on metal-based radiopharmaceuticals for diagnostic and therapeutic purposes and specific design criteria for the development of radiopharmaceuticals that combine fundamental aqueous coordination chemistry with elucidation of pharmacokinetics. The second part describes approaches to photodynamic therapy with metal complexes. Here, photophysical characterization, combined with the challenge of careful control of the chemical behavior and selective biological deposition of transition metals with significant off-target toxicity, is discussed. In the third part, we summarize emerging strategies to modulate enzyme inhibition with coordination chemistry, while also highlighting the utility of the unique properties of metal ions for the characterization of mechanisms of action of these emerging diagnostic and therapeutic agents. Show less

Carcinoma, characterized by abnormal growth of cells and tissue, is a ubiquitously leading cause of mortality across the globe due to some carcinogenic factors. Currently, several anticancer agents are commercially available in the global market. However, due to their resistance and cost, researchers are gaining more interest in developing newer novel potential anticancer agents. In the search for new drugs for clinical use, the tetrazole ring system has emerged as an exciting prospect in the optimization studies of promising lead molecules. Among the various heterocyclic agents, tetrazole-containing compounds have shown significant promise in the treatment of a wide range of diseases, particularly cancer. Here, in this review, we focused on several synthetic approaches for the synthesis of tetrazole analogs, their targets for treating cancer along with the biological activity of some of the recently reported tetrazole-containing anticancer agents. Show less

Artificial intelligence (AI) and machine learning (ML) are expanding in popularity for broad applications to challenging tasks in chemistry and materials science. Examples include the prediction of properties, the discovery of new reaction pathways, or the design of new molecules. The machine needs to read and write fluently in a chemical language for each of these tasks. Strings are a common tool to represent molecular graphs, and the most popular molecular string representation, Smiles, has powered cheminformatics since the late 1980s. However, in the context of AI and ML in chemistry, Smiles has several shortcomings-most pertinently, most combinations of symbols lead to invalid results with no valid chemical interpretation. To overcome this issue, a new language for molecules was introduced in 2020 that guarantees 100% robustness: SELF-referencing embedded string (Selfies). Selfies has since simplified and enabled numerous new applications in chemistry. In this perspective, we look to the future and discuss molecular string representations, along with their respective opportunities and challenges. We propose 16 concrete future projects for robust molecular representations. These involve the extension toward new chemical domains, exciting questions at the interface of AI and robust languages, and interpretability for both humans and machines. We hope that these proposals will inspire several follow-up works exploiting the full potential of molecular string representations for the future of AI in chemistry and materials science. Show less

Abstract Apoptosis is the most thoroughly studied type of regulated cell death. Certain events, such as externalization of phosphatidylserine (PS) into the outer leaflet of plasma membrane, mitochondrial outer membrane permeabilization, caspase cascade activation, DNA fragmentation and blebbing, are widely considered to be hallmarks of apoptosis as well as being traditionally viewed as irreversible. This review shows that under particular circumstances these events can also participate in physiological processes not associated with initiation of apoptosis, such as cell differentiation, division, and motility, as well as non-apoptotic types of cell death. Moreover, these events may often be reversible. This review focuses on three processes: phosphatidylserine externalization, blebbing, and activation of apoptotic caspases. Mitochondrial outer membrane permeabilization and DNA fragmentation are not discussed. Show less

Since the discovery of cell apoptosis, other gene-regulated cell deaths are gradually appreciated, including pyroptosis, ferroptosis, and necroptosis. Necroptosis is, so far, one of the best-characterized regulated necrosis. In response to diverse stimuli (death receptor or toll-like receptor stimulation, pathogenic infection, or other factors), necroptosis is initiated and precisely regulated by the receptor-interacting protein kinase 3 (RIPK3) with the involvement of its partners (RIPK1, TRIF, DAI, or others), ultimately leading to the activation of its downstream substrate, mixed lineage kinase domain-like (MLKL). Necroptosis plays a significant role in the host’s defense against pathogenic infections. Although much has been recognized regarding modulatory mechanisms of necroptosis during pathogenic infection, the exact role of necroptosis at different stages of infectious diseases is still being unveiled, e.g., how and when pathogens utilize or evade necroptosis to facilitate their invasion and how hosts manipulate necroptosis to counteract these detrimental effects brought by pathogenic infections and further eliminate the encroaching pathogens. In this review, we summarize and discuss the recent progress in the role of necroptosis during a series of viral, bacterial, and parasitic infections with zoonotic potentials, aiming to provide references and directions for the prevention and control of infectious diseases of both human and animals. 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, Huntington’s 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

Gases like H2, N2, CO2, and CO are increasingly recognized as critical feedstock in "green" energy conversion and as sources of nitrogen and carbon for the agricultural and chemical sectors. However, the industrial transformation of N2, CO2, and CO and the production of H2 require significant energy input, which renders processes like steam reforming and the Haber-Bosch reaction economically and environmentally unviable. Nature, on the other hand, performs similar tasks efficiently at ambient temperature and pressure, exploiting gas-processing metalloenzymes (GPMs) that bind low-valent metal cofactors based on iron, nickel, molybdenum, tungsten, and sulfur. Such systems are studied to understand the biocatalytic principles of gas conversion including N2 fixation by nitrogenase and H2 production by hydrogenase as well as CO2 and CO conversion by formate dehydrogenase, carbon monoxide dehydrogenase, and nitrogenase. In this review, we emphasize the importance of the cofactor/protein interface, discussing how second and outer coordination sphere effects determine, modulate, and optimize the catalytic activity of GPMs. These may comprise ionic interactions in the second coordination sphere that shape the electron density distribution across the cofactor, hydrogen bonding changes, and allosteric effects. In the outer coordination sphere, proton transfer and electron transfer are discussed, alongside the role of hydrophobic substrate channels and protein structural changes. Combining the information gained from structural biology, enzyme kinetics, and various spectroscopic techniques, we aim toward a comprehensive understanding of catalysis beyond the first coordination sphere. Show less

Tetra-coordinated boron compounds offer a plethora of luminescent materials. Different chelation around the boron center (O,O-, N,C-, N,O-, and N,N-) has been explored to tune the electronic and photophysical properties of tetra-coordinated boron compounds. A number of fascinating molecules with interesting properties such as aggregation induced emission, mechanochromism and tunable emission by changing the solvent polarity were realised. Owing to their rich and unique properties, some of the molecules have shown applications in making optoelectronic devices, probes and so on. This perspective provides an overview of the recent developments of tetra-coordinated boron compounds and their potential applications. Show less

Metal complexes have demonstrated significant antitumor activities and platinum complexes are well established in the clinical application of cancer chemotherapy. However, the platinum-based treatment of different types of cancers is massively hampered by severe side effects and resistance development. Consequently, the development of novel metal-based drugs with different mechanism of action and pharmaceutical profile attracts modern medicinal chemists to design and synthesize novel metal-based agents. Among non-platinum anticancer drugs, gold complexes have gained considerable attention due to their significant antiproliferative potency and efficacy. In most situations, the gold complexes exhibit anticancer activities by targeting thioredoxin reductase (TrxR) or other thiol-rich proteins and enzymes and trigger cell death via reactive oxygen species (ROS). Interestingly, gold complexes were recently reported to elicit biochemical hallmarks of immunogenic cell death (ICD) as an ICD inducer. In this review, the recent progress of gold(I) and gold(III) complexes is comprehensively summarized, and their activities and mechanism of action are documented. Show less

Several PI3K pathway inhibitors are currently approved as cancer treatments; however, finding an acceptable therapeutic window to target this key signalling cascade linking cancer growth with metabolism has proven challenging and the clinical results to date have arguably been disappointing. In this Review, Vasan and Cantley discuss the effects of PI3K pathway alterations on signalling and metabolism in solid tumours as well as past and present efforts to improve the somewhat limited clinical efficacy of PI3K pathway inhibitors, with a particular focus on PI3Kα in breast cancers. 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 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 field of oxygen free radicals, antioxidants and reactive oxygen species (ROS) has exploded in the past few decades, and BBRC has published several seminal papers. ROS can cause oxidative damage, but also play fundamental roles in living organisms, in such processes as signal transduction and defence against pathogens. ROS underpin every aspect of human biology. Indeed, an endless stream of published papers refers to the biological roles of "ROS". Sadly, much of this work is mechanistically meaningless. To make progress, the detailed molecular mechanisms of action of ROS must be elucidated and appropriate methodology must be used to measure them and the oxidative damage that they can cause, as emphasized in a recent review by Murphy et al. Attention must also switch from clinical studies involving administration of high-dose supplements of vitamins E, C and β-carotene for the treatment or prevention of human disease into other promising diet-derived cytoprotective agents. One of them may be ergothioneine. Show less

Dimethyl fumarate (DMF) is an antioxidative and anti-inflammatory drug approved for treatment of multiple sclerosis and psoriasis; however, beneficial effects of DMF have also been found in other inflammatory diseases and cancers. DMF is a prodrug that is immediately hydrolysed to monomethyl fumarate (MMF) in vivo. Both fumarates activate the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway, and Nrf2 is a key transcription factor of the antioxidant response. The immunosuppressive and anti-inflammatory actions of DMF occur through several mechanisms: via inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway and by downregulation of aerobic glycolysis and pyroptosis in activated myeloid and lymphoid cells. MMF is also an agonist of hydroxycarboxylic acid receptor 2 (HCAR2). Differences in the strength of effects and mechanisms of action of both fumarates are discussed. The aim of this review was to analyse and compare the neuroprotective, antioxidative and anti-inflammatory effects of DMF and its active metabolite, MMF, in cellular (in vitro) and animal models of neurodegenerative diseases (NDs), other than multiple sclerosis. There are more than twenty studies that currently represent this field. Most of the studies are concerned with cellular or animal models of Alzheimer's disease (AD) and Parkinson's disease (PD), one utilized a mouse model of Huntington's disease (HD) and one clinical trial was carried out with amyotrophic lateral sclerosis (ALS) patients. The discrepancies in the results of the various studies are discussed, and issues requiring further research have been identified. Show less

Cancer is the deadliest disease in the world behind heart disease. Sadly, this remains true even as we suffer the ravages of the Covid-19 pandemic. Whilst current chemo- and radiotherapeutic treatment strategies have significantly improved the patient survival rate, disease reoccurrence continues to pose a deadly risk for all too many patients. Incomplete removal of tumour cells from the body increases the chances of metastasis and developing resistance against current treatments. Immunotherapy represents a therapeutic modality that has helped to overcome these limitations in recent decades. However, further progress is needed. So-called immunogenic cell death (ICD) is a recently discovered and unique mode of cell death that could trigger this necessary further progress. ICD involves stimulation of a tumour-specific immune response as a downstream effect. Facilitated by certain treatment modalities, cells undergoing ICD can trigger the IFN-γ mediated immune response involving cytotoxic T cells (CTLs) and γδ T cells that eradicate residual tumour cells. In recent years, there has been a significant increase in the number of small-molecules being tested as potential ICD inducers. A large number of these ICD inducers are metal-based complexes. In fact, anticancer metal drugs based on Pt, Ru, Ir, Cu, and Au are now known to give rise to an immune response against tumour cells as the result of ICD. Advances have also been made in terms of exploiting combinatorial and delivery strategies. In favourable cases, these approaches have been shown to increase the efficacy of otherwise ICD "silent" metal complexes. Taken in concert, rationally designed novel anticancer metal complexes that can act as ICD inducers show promise as potential new immunotherapies for neoplastic disease. This Tutorial Review will allow the readers to assess the progress in this fast-evolving field thus setting the stage for future advances. Show less

Mitochondria are key regulators of many important cellular processes and their dysfunction has been implicated in a large number of human disorders. Importantly, mitochondrial function is tightly linked to their ultrastructure, which possesses an intricate membrane architecture defining specific submitochondrial compartments. In particular, the mitochondrial inner membrane is highly folded into membrane invaginations that are essential for oxidative phosphorylation. Furthermore, mitochondrial membranes are highly dynamic and undergo constant membrane remodeling during mitochondrial fusion and fission. It has remained enigmatic how these membrane curvatures are generated and maintained, and specific factors involved in these processes are largely unknown. This review focuses on the current understanding of the molecular mechanism of mitochondrial membrane architectural organization and factors critical for mitochondrial morphogenesis, as well as their functional link to human diseases. Show less

Cancer is frequently caused by microRNAs, which control post-transcriptional levels of gene expression by binding to target mRNAs. MiR-29a-3p has recently been shown to play a twofold function in the majority of malignancies, including colorectal cancer (CRC), according to mounting evidence. Here, we not only briefly summarize such connection between miR-29a-3p and cancers, but aslo primarily evaluate the miR-29a-3p expression pattern, clinical applicability, and molecular mechanisms in CRC to provide a guide for future studies. This review established the diagnostic and prognostic value of miR-29a-3p abnormalty in a variety of clinical samples for CRC. Furthermore, current molecular mechanisms of miR-29a-3p for regulating cancerous biological processes such growth, invasion, metastasis, the epithelial-mesenchymal transformation process, and immunomodulation through its upstream regulatory factors and downstream targeted genes were briefly explored. More specifically, miR-29a-3p has been linked to a few medications that have been shown to have anticancer benefits. To sum up, miR-29a-3p is a promising biomarker and prospective therapeutic target for the diagnosis and prognosis of CRC, but further research is still needed to establish a theoretical basis for more practical applications. Show less

Cellular DNA is continuously transcribed into RNA by multisubunit RNA polymerases (RNAPs). The continuity of transcription can be disrupted by DNA lesions that arise from the activities of cellular enzymes, reactions with endogenous and exogenous chemicals or irradiation. Here, we review available data on translesion RNA synthesis by multisubunit RNAPs from various domains of life, define common principles and variations in DNA damage sensing by RNAP, and consider existing controversies in the field of translesion transcription. Depending on the type of DNA lesion, it may be correctly bypassed by RNAP, or lead to transcriptional mutagenesis, or result in transcription stalling. Various lesions can affect the loading of the templating base into the active site of RNAP, or interfere with nucleotide binding and incorporation into RNA, or impair RNAP translocation. Stalled RNAP acts as a sensor of DNA damage during transcription-coupled repair. The outcome of DNA lesion recognition by RNAP depends on the interplay between multiple transcription and repair factors, which can stimulate RNAP bypass or increase RNAP stalling, and plays the central role in maintaining the DNA integrity. Unveiling the mechanisms of translesion transcription in various systems is thus instrumental for understanding molecular pathways underlying gene regulation and genome stability. Show less

Cancer is characterized by abnormal cell differentiation in or on the part of the body. The most commonly used chemotherapeutic drugs are developed to target rapidly dividing cells, such as cancer cells, but they also damage healthy epithelial cells. This has serious consequences for normal cells and become responsible for the development of various disorders. Several strategies for delivering the cytotoxic drugs to cancerous sites that limit systemic toxicity and other adverse effects have recently been evolved. Among them, biomolecule-conjugated metal complexes-based cancer targeting strategies have shown tremendous advantages in cancer therapy. This review focuses on several chemoselective biomolecules-bound metal complexes as prospective cancer therapy-targeted agents. In this review, we presented the details of the various extra- and intracellular targeting mechanisms in cancer therapy. We also addressed the current clinical issues and recent therapeutic strategies in targeted cancer therapy that may pave a way for the future direction of metal complexes-based targeted cancer therapy. Show less

G-quadruplexes turned out to be important targets for the development of novel targeted anticancer/antiviral therapies. More than 3000 G-quadruplex small-molecule ligands have been described, with most of them exerting anticancer/antiviral activity by inducing telomeric damage and/or altering oncogene or viral gene expression in cancer cells and viruses, respectively. For some ligands, in-depth NMR and/or crystallographic studies were performed, providing detailed knowledge on their interactions with diverse G-quadruplex targets. Here, the PDB-deposited NMR and crystal structures of the complexes between telomeric, oncogenic or viral G-quadruplexes and small-molecule ligands, of both organic and metal-organic nature, have been summarized and described based on the G-quadruplex target, from telomeric DNA and RNA G-quadruplexes to DNA oncogenic G-quadruplexes, and finally to RNA viral G-quadruplexes. An overview of the structural details of these complexes is here provided to guide the design of novel ligands targeting more efficiently and selectively cancer- and virus-related G-quadruplex structures. Show less

The silent information regulator sirtuin 1 (SIRT1) protein, a highly conserved NAD+-dependent deacetylase belonging to the sirtuin family, is a post-translational regulator that plays a role in modulating inflammation. SIRT1 affects multiple biological processes by deacetylating a variety of proteins including histones and non-histone proteins. Recent studies have revealed intimate links between SIRT1 and inflammation, while alterations to SIRT1 expression and activity have been linked to inflammatory diseases. In this review, we summarize the mechanisms that regulate SIRT1 expression, including upstream activators and suppressors that operate on the transcriptional, post-transcriptional, and post-translational levels. We also summarize factors that influence SIRT1 activity including the NAD+/NADH ratio, SIRT1 binding partners, and post-translational modifications. Furthermore, we underscore the role of SIRT1 in the development of inflammation by commenting on the proteins that are targeted for deacetylation by SIRT1. Finally, we highlight the potential for SIRT1-based therapeutics for inflammatory diseases. Show less

In the analysis of gene expression data, network approaches take a system perspective and have played an irreplaceably important role. Gaussian graphical models (GGMs) have been popular in the network analysis of gene expression data. They investigate the conditional dependence between genes and "transform" the problem of estimating network structures into a sparse estimation of precision matrices. When there is a moderate to large number of genes, the number of parameters to be estimated may overwhelm the limited sample size, leading to unreliable estimation and selection. In this article, we propose incorporating information from previous studies (for example, those deposited at PubMed) to assist estimating the network structure in the present data. It is recognized that such information can be partial, biased, or even wrong. A penalization-based estimation approach is developed, shown to have consistency properties, and realized using an effective computational algorithm. Simulation demonstrates its competitive performance under various information accuracy scenarios. The analysis of TCGA lung cancer prognostic genes leads to network structures different from the alternatives. Show less