📋 Browse Articles

Mono or bis(tetrazole–thiolato) Pd(II) or Pt(II) complexes were obtained from the reactions of dialkyl Pd(II) or Pt(II) complexes with organic tetrazole–thiones (1-aryl- or 1-alkyl-1H-tetrazole-5-thiones) via deprotonation. In contrast, equimolar reactions of zerovalent Pt(0) or Pd(0) complexes with organic tetrazole–thiones afforded hydrido or bis(tetrazole–thiolato) Pt(II) and Pd(II) complexes, and cyclometallated Pt(II) or Pd(II) complexes bearing a tetrazole–thiolato moiety via oxidative addition, depending on the organic substituents on the tetrazole–thiones. In particular, variable (time and temperature)-dependent 1H-NMR spectra of the hydrido Pt(II) tetrazole–thiolates reveal an upfield shift of the hydride signal, suggesting N,S-coordination behavior of the tetrazole–thiolato ligand. Additionally, the N-CH2 signal corresponds to the six-membered ring of platinacycle or palladacycle exhibiting geminal coupling with multiple protons and PR3 ligands; these coupling values were further determined using 1H{31P} experiments. Finally, treatment of the alkyl Pd(II) tetrazole–thiolate or Pd(II) bis(tetrazole–thiolates) with organic tert-butyl isocyanide, thiophenol, and organic halides caused the selective insertion of the isocyanide into the Pd–C bond or deprotonation to afford a Pd(II) disulfide complex and substitution to afford new organic tetrazolyl sulfides. Show less

Recent advancements have illuminated the critical role of RNA modifications in post-transcriptional regulation, shaping the landscape of gene expression. This review explores how tRNA modifications emerge as critical players, fine-tuning functionalities that not only maintain the fidelity of protein synthesis but also dictate gene expression and translation profiles. Highlighting their dysregulation as a common denominator in various cancers, we systematically investigate the intersection of both cytosolic and mitochondrial tRNA modifications with cancer biology. These modifications impact key processes such as cell proliferation, tumorigenesis, migration, metastasis, bioenergetics and the modulation of the tumor immune microenvironment. The recurrence of altered tRNA modification patterns across different cancer types underscores their significance in cancer development, proposing them as potential biomarkers and as actionable targets to disrupt tumorigenic processes, offering new avenues for precision medicine in the battle against cancer. Show less

Title: Quinoline- and coumarin-based ligands and their rhenium(I) tricarbonyl complexes: synthesis, spectral characterization and antiproliferative activity on T-cell lymphoma. Abstract: Novel 6-substituted 2-(trifluoromethyl)quinoline 5a-5e and coumarin 6a-6d ligands with aldoxime ether linked pyridine moiety were synthesized by O-alkylation of quinoline and coumarin with (E)-picolinaldehyde oxime and subsequently with [Re(CO)5Cl] gave rhenium(I) tricarbonyl complexes 5aRe-5eRe and 6aRe-6dRe that were fully characterized by NMR, single-crystal X-ray diffraction, IR and UV-Vis spectroscopy. The results of antiproliferative evaluation of quinoline and coumarin ligands and their rhenium(I) tricarbonyl complexes on various human tumor cell lines, including acute lymphoblastic leukemia (CCRF-CEM), acute monocytic leukemia (THP1), cervical adenocarcinoma (HeLa), colon adenocarcinoma (CaCo-2), T-cell lymphoma (HuT78), and non-tumor human fibroblasts (BJ) showed that the quinoline complexes 5aRe-5eRe had higher inhibitory activity than coumarin complexes 6aRe-6dRe, particularly against T-cell lymphoma (HuT78) cells. 6-Methoxy-2-(trifluoromethyl)quinoline 5e and 6-methylcoumarin 6d, and their rhenium(I) tricarbonyl complexes 5eRe and 6dRe were found to arrest the cell cycle of HuT78 cells by causing a significant accumulation of cells in the G0/G1 phase and a marked decrease in the number of cells in the G2/M phase. These rhenium(I) tricarbonyl complexes also slightly increased ROS production and significantly decreased the mitochondrial membrane potential by 50 % (5eRe) and 45 % (6dRe) compared to untreated cells and cells treated with 5e and 6d. These results suggest that the cytotoxic effects of these compounds are mediated by their effects on mitochondrial membrane potential and the subsequent increase in ROS production. Show less

Title: The impact of biomolecule interactions on the cytotoxic effects of rhenium(I) tricarbonyl complexes. Abstract: Rhenium complexes show great promise as anticancer drug candidates. Specifically, compounds with a Re(CO)3(NN)(py)+ core in their architecture have shown cytotoxicity equal to or greater than that of well-established anticancer drugs based on platinum or organic molecules. This study aimed to evaluate how the strength of the interaction between rhenium(I) tricarbonyl complexes fac-[Re(CO)3(NN)(py)]+, NN = 1,10-phenanthroline (phen), dipyrido[3,2-f:2',3'-h]quinoxaline (dpq) or dipyrido[3,2-a:2'3'-c]phenazine (dppz) and biomolecules (protein, lipid and DNA) impacted the corresponding cytotoxic effect in cells. Results showed that fac-[Re(CO)3(dppz)(py)]+ has higher Log Po/w and binding constant (Kb) with biomolecules (protein, lipid and DNA) compared to complexes of fac-[Re(CO)3(phen)(py)]+ and fac-[Re(CO)3(dpq)(py)]+. As consequence, fac-[Re(CO)3(dppz)(py)]+ exhibited the highest cytotoxicity (IC50 = 8.5 μM for HeLa cells) for fac-[Re(CO)3(dppz)(py)]+ among the studied compounds (IC50 > 15 μM). This highest cytotoxicity of fac-[Re(CO)3(dppz)(py)]+ are probably related to its lipophilicity, higher permeation of the lipid bilayers of cells, and a more potent interaction of the dppz ligand with biomolecules (protein and DNA). Our findings open novel avenues for rational drug design and highlight the importance of considering the chemical structures of rhenium complexes that strongly interact with biomolecules (proteins, lipids, and DNA). Show less

pH-sensitive fluorescent proteins have revolutionized the field of cellular imaging and physiology, offering insight into the dynamic pH changes that underlie fundamental cellular processes. This comprehensive review explores the diverse applications and recent advances in the use of pH-sensitive fluorescent proteins. These remarkable tools enable researchers to visualize and monitor pH variations within subcellular compartments, especially mitochondria, shedding light on organelle-specific pH regulation. They play pivotal roles in visualizing exocytosis and endocytosis events in synaptic transmission, monitoring cell death and apoptosis, and understanding drug effects and disease progression. Recent advancements have led to improved photostability, pH specificity, and subcellular targeting, enhancing their utility. Techniques for multiplexed imaging, three-dimensional visualization, and super-resolution microscopy are expanding the horizon of pH-sensitive protein applications. The future holds promise for their integration into optogenetics and drug discovery. With their ever-evolving capabilities, pH-sensitive fluorescent proteins remain indispensable tools for unravelling cellular dynamics and driving breakthroughs in biological research. This review serves as a comprehensive resource for researchers seeking to harness the potential of pH-sensitive fluorescent proteins. 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 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. Citation: Greene, L.A.; Zhou, Q.; Siegelin, M.D.; Angelastro, J.M. Targeting Transcription Factors ATF5, Show less

Transition-metal acyclic carbene complexes have received increasing attention in recent years. As acyclic carbene ligands show strong σ-donating properties comparable to N-heterocyclic carbene (NHC) ligands, transition-metal complexes with acyclic carbene ligands also demonstrate outstanding performance and functional properties similar to their NHC counterparts. Therefore, transition-metal acyclic carbene complexes are considered viable alternatives to NHC complexes in the development of metal-based functional materials. As transition-metal acyclic carbene complexes can be prepared from metal isocyanide synthetic precursors, substituents of different electronic and steric natures as well as functional moieties can be readily introduced into acyclic carbene ligands by changing the isocyanide ligand. Moreover, the open structure of acyclic carbene ligands has made their structure and the electronic properties strongly dependent on the substituents as well as the micro-environment. As a result, the functional properties of acyclic complexes can be drastically varied by rational molecular design of the ligands. The environmental sensitivity of the properties of these complexes also made them ideal for the development of stimuli-responsive materials and chemical sensors. In this article, the preparation, electronic properties and design of metal acyclic carbene complexes with different functional properties for the development of advanced materials are described. Show less

The tumor microenvironment (TME) is made up of cells and extracellular matrix (non-cellular component), and cellular components include cancer cells and non-malignant cells such as immune cells and stromal cells. These three types of cells establish complex signals in the body and further influence tumor genesis, development, metastasis and participate in resistance to anti-tumor therapy. It has attracted scholars to study immune cells in TME due to the significant efficacy of immune checkpoint inhibitors (ICI) and chimeric antigen receptor T (CAR-T) in solid tumors and hematologic tumors. After more than 10 years of efforts, the role of immune cells in TME and the strategy of treating tumors based on immune cells have developed rapidly. Moreover, ICI have been recommended by guidelines as first- or second-line treatment strategies in a variety of tumors. At the same time, stromal cells is another major class of cellular components in TME, which also play a very important role in tumor metabolism, growth, metastasis, immune evasion and treatment resistance. Stromal cells can be recruited from neighboring non-cancerous host stromal cells and can also be formed by transdifferentiation from stromal cells to stromal cells or from tumor cells to stromal cells. Moreover, they participate in tumor genesis, development and drug resistance by secreting various factors and exosomes, participating in tumor angiogenesis and tumor metabolism, regulating the immune response in TME and extracellular matrix. However, with the deepening understanding of stromal cells, people found that stromal cells not only have the effect of promoting tumor but also can inhibit tumor in some cases. In this review, we will introduce the origin of stromal cells in TME as well as the role and specific mechanism of stromal cells in tumorigenesis and tumor development and strategies for treatment of tumors based on stromal cells. We will focus on tumor-associated fibroblasts (CAFs), mesenchymal stem cells (MSCs), tumor-associated adipocytes (CAAs), tumor endothelial cells (TECs) and pericytes (PCs) in stromal cells. Show less

Colorectal cancer is among the most common cancers worldwide and a frequent cause of cancer related deaths. Oxaliplatin is the first line chemotherapeutics for treatment, but the development of resistance leads to recurrence of oxaliplatin insensitive tumors. To understand possible mechanisms of drug tolerance we developed oxaliplatin resistant derivatives (OR-LoVo) of the established LoVo cell line originally isolated from a metastatic colon adenocarcinoma. We compared the microRNA (miRNA) expression profile of the cell pair and found expression of miR-29a-3p significantly increased in OR-LoVo cells compared to parent cells. In addition, miR-29a-3p was significantly elevated in tumor tissue when compared to matched surrounding tissue in human, suggesting potential clinical importance. Ectopic miR-29-a-3p expression induced chemoresistance in a number of different cancer cell lines as well as colorectal tumors in mice. We further demonstrated that miR-29-a-3p downregulates expression of the ubiquitin ligase component FEM1B and that reduction of Fem1b levels is sufficient to confer oxaliplatin resistance. FEM1B targets the glioma associated oncogene Gli1 for degradation, suggesting that increased Gli1 levels could contribute to oxaliplatin tolerance. Accordingly, knockdown of GLI1 reverted chemoresistance of OR-LoVo cells. Mechanistically, resistant cells experienced significantly lower DNA damage upon oxaliplatin treatment, which can be partially explained by reduced oxaliplatin uptake and enhanced repair. These results suggest that miR-29-a-3p overexpression induces oxaliplatin resistance through misregulation of Fem1B and Gli1 levels. TCGA analyses provides strong evidence that the reported findings regarding induced drug tolerance by the miR-29a/Fem1B axis is clinically relevant. The reported findings can help to predict oxaliplatin sensitivity and resistance of colorectal tumors. Show less

Z-DNA refers to the left-handed double-helix DNA that has attracted much attention because of its association with some specific biological functions. However, because of its low content and unstable conformation, Z-DNA is normally difficult to observe or identify. Up to now, there has been a lack of unified or standard analytical methods among diverse techniques for probing Z-DNA and its transformation conveniently. In this work, NaCl, MgCl2, and ethanol were utilized to induce d(GC)8 from B-DNA to Z-DNA in vitro, and Fourier transform infrared (FTIR) spectroscopy was employed to monitor the transformation of Z-DNA under different induction conditions. The structural changes during the transformation process were carefully examined, and the DNA chirality alterations were validated by the circular dichroism (CD) measurements. The Z-DNA characteristic signals in the 1450 cm-1-900 cm-1 region of the d(GC)8 infrared (IR) spectrum were observed, which include the peaks at 1320 cm-1, 1125 cm-1 and 925 cm-1, respectively. The intensity ratios of A1320/A970, A1125/A970, and A925/A970 increased with Z-DNA content in the transition process. Furthermore, compared with the CD spectra, the IR spectra showed higher sensitivity to Z-DNA, providing more information about the molecular structure change of DNA. Therefore, this study has established a more reliable FTIR analytical approach to assess BZ DNA conformational changes in solutions, which may help the understanding of the Z-DNA transition mechanism and promote the study of Z-DNA functions in biological systems. Show less

Abstract Hydrogen bonding is a complex phenomenon that is a resultant of many energy components like the electrostatic, dispersive, covalent, charge cloud overlap repulsion etc, nature of hydrogen bond (H-bond) depends on which of these components play a dominant role. Low barrier hydrogen bond (LBHB) constitutes a special category of hydrogen bonds characterized by near delocalization of proton between donor and acceptor groups of the H- bond unlike an ordinary hydrogen bond (OHB) having proton clearly localized near the donor group. The significance of LBHBs in macromolecular interactions has been highly controversial, despite may attempts the existence and potential importance of protein LBHBs remains debatable. In order to answer questions like whether or not a distinct class of LBHBs exists and if they do exist under what conditions they are formed and how do they behave differently from OHBs, a detailed study of H-bonding in Diglycine Perchlorate (DGPCl) crystal containing five unique hydrogen bonded glycinium-glycine pairs is undertaken. All O-H–O bonds of DGPCl are between the carboxyl (-COOH) and carboxylate (-COO−) groups with slightly different electron distributions resulting in observable variations in the H-bond geometries, this is an indication of varying strength of these short strong H-bonds. It is found that LBHB nature of the five O-H—O bonds between glycinium-glycine pairs (P1-P5) varies as P1 < P4 < P2 < P3 < P5. This study gives an experimental evidence of the existence of LBHBs and demonstrates that the behaviour of LBHBs is very different from that of strong OHBs. Show less

AbstractThe mitochondrial calcium uniporter (MCU) is a transmembrane protein that is responsible for mediating mitochondrial calcium (mCa2+) uptake. Given this critical function, the MCU has been implicated as an important target for addressing various human diseases. As such, there has a been growing interest in developing small molecules that can inhibit this protein. To date, metal coordination complexes, particularly multinuclear ruthenium complexes, are the most widely investigated MCU inhibitors due to both their potent inhibitory activities as well as their longstanding use for this application. Recent efforts have expanded the metal‐based toolkit for MCU inhibition. This concept paper summarizes the development of new metal‐based inhibitors of the MCU and their structure‐activity relationships in the context of improving their potential for therapeutic use in managing human diseases related to mCa2+ dysregulation. Show less

The Zα domain has a compact α/β architecture containing a three-helix bundle flanked on one side by a twisted antiparallel β sheet. This domain displays a specific affinity for double-stranded nucleic acids that adopt a left-handed helical conformation. Currently, only three Zα-domain proteins have been identified in eukaryotes, specifically ADAR1, ZBP1, and PKZ. ADAR1 is a double-stranded RNA (dsRNA) binding protein that catalyzes the conversion of adenosine residues to inosine, resulting in changes in RNA structure, function, and expression. In addition to its editing function, ADAR1 has been shown to play a role in antiviral defense, gene regulation, and cellular differentiation. Dysregulation of ADAR1 expression and activity has been associated with various disease states, including cancer, autoimmune disorders, and neurological disorders. As a sensing molecule, ZBP1 exhibits the ability to recognize nucleic acids with a left-handed conformation. ZBP1 harbors a RIP homotypic interaction motif (RHIM), composed of a highly charged surface region and a leucine-rich hydrophobic core, enabling the formation of homotypic interactions between proteins with similar structure. Upon activation, ZBP1 initiates a downstream signaling cascade leading to programmed cell death, a process mediated by RIPK3 via the RHIM motif. PKZ was identified in fish, and contains two Zα domains at the N-terminus. PKZ is essential for normal growth and development and may contribute to the regulation of immune system function in fish. Interestingly, some pathogenic microorganisms also encode Zα domain proteins, such as, Vaccinia virus and Cyprinid Herpesvirus. Zα domain proteins derived from pathogenic microorganisms have been demonstrated to be pivotal contributors in impeding the host immune response and promoting virus replication and spread. This review focuses on the mammalian Zα domain proteins: ADAR1 and ZBP1, and thoroughly elucidates their functions in the immune response. Show less

Despite structural differences between the right-handed conformations of A-RNA and B-DNA, both nucleic acids adopt very similar, left-handed Z-conformations. In contrast to their structural similarities and sequence preferences, RNA and DNA exhibit differences in their ability to adopt the Z-conformation regarding their hydration shells, the chemical modifications that promote the Z-conformation, and the structure of junctions connecting them to right-handed segments. In this review, we highlight the structural and chemical properties of both Z-DNA and Z-RNA and delve into the potential factors that contribute to both their similarities and differences. While Z-DNA has been extensively studied, there is a gap of knowledge when it comes to Z-RNA. Where such information is lacking, we try and extend the principles of Z-DNA stability and formation to Z-RNA, considering the inherent differences of the nucleic acids. Show less

A new bis-benzoxazolylhydrazone of 2,6-diacetylpyridine and mononuclear Cu(ii) complexes based on it have been synthesized. An in vitro study showed that all Cu(ii) complexes exhibit high cytotoxic activity against the HepG2 cancer cell line. Show less

Pt(II) chemotherapeutic complexes have been used as predominant anticancer drugs for nearly fifty years. Currently there are three FDA-approved chemotherapeutic Pt(II) complexes: cisplatin, carboplatin, and oxaliplatin. Until recently, it was believed that all three complexes induced cellular apoptosis through the DNA damage response pathway. Studies within the last decade, however, suggest that oxaliplatin may instead induce cell death through a unique nucleolar stress pathway. Pt(II)-induced nucleolar stress is not well understood and further investigation of this pathway may provide both basic knowledge about nucleolar stress as well as insight for more tunable Pt(II) chemotherapeutics. Through a previous structure-function analysis, it was determined that nucleolar stress induction is highly sensitive to modifications at the 4-position of the 1,2-diaminocyclohexane (DACH) ring of oxaliplatin. Specifically, more flexible and less rigid substituents (methyl, ethyl, propyl) induce nucleolar stress, while more rigid and bulkier substituents (isopropyl, acetamide) do not. These findings suggest that a click-capable functional group can be installed at the 4-position of the DACH ring while still inducing nucleolar stress. Herein, we report novel click-capable azide-modified oxaliplatin mimics that cause nucleolar stress. Through NPM1 relocalization, fibrillarin redistribution, and γH2AX studies, key differences have been identified between previously studied click-capable cisplatin mimics and these novel click-capable oxaliplatin mimics. These complexes provide new tools to identify cellular targets and localization through post-treatment Cu-catalyzed azide–alkyne cycloaddition and may help to better understand Pt(II)-induced nucleolar stress. To our knowledge, these are the first reported oxaliplatin mimics to include an azide handle, and cis-[(1R,2R,4S) 4-methylazido-1,2-cyclohexanediamine]dichlorido platinum(II) is the first azide-functionalized oxaliplatin derivative to induce nucleolar stress. Show less

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

Life is based on a highly specific combination of atoms, metabolism, and genetics which eventually reflects the chemistry of the Universe which is composed of hydrogen, oxygen, nitrogen, sulfur, phosphorus, and carbon. The interaction of atomic, metabolic, and genetic cycles results in the organization and de-organization of chemical information of that which we consider as living entities, including cancer cells. In order to approach the problem of the origin of cancer it is therefore reasonable to start from the assumption that the sub-molecular level, the atomic structure, should be the considered starting point on which metabolism, genetics, and external insults eventually emanate. Second, it is crucial to characterize which of the entities and parts composing human cells may live a separate life; certainly, this theoretical standpoint would consider mitochondria, an organelle of "bacteria" origin embedded in conditions favorable for the onset of both. This organelle has not only been tolerated by immunity but has also been placed as a central regulator of cell defense. Virus, bacteria, and mitochondria are also similar in the light of genetic and metabolic elements; they share not only equivalent DNA and RNA features but also many basic biological activities. Thus, it is important to finalize that once the cellular integrity has been constantly broken down, the mitochondria like any other virus or bacteria return to their original autonomy to simply survive. The Warburg's law that states the ability of cancers to ferment glucose in the presence of oxygen, indicates mitochondria respiration abnormalities may be the underlying cause of this transformation towards super cancer cells. Though genetic events play a key part in altering biochemical metabolism, inducing aerobic glycolysis, this is not enough to impair mitochondrial function since mitochondrial biogenesis and quality control are constantly upregulated in cancers. While some cancers have mutations in the nuclear-encoded mitochondrial tricarboxylic acid (TCA) cycle, enzymes that produce oncogenic metabolites, there is also a bio-physic pathway for pathogenic mitochondrial genome mutations. The atomic level of all biological activities can be considered the very beginning, marked by the electron abnormal behavior that consequently affects DNA of both cells and mitochondria. Whilst the cell's nucleus DNA after a certain number of errors and defection tends to gradually switch off, the mitochondria DNA starts adopting several escape strategies, switching-on a few important genes that belong back at their original roots as independent beings. The ability to adopt this survival trick, by becoming completely immune to current life-threatening events, is probably the beginning of a differentiation process towards a "super-power cell", the cancer cells that remind many pathogens, including virus, bacteria, and fungi. Thus, here, we present a hypothesis regarding those changes that first begin at the mitochondria atomic level to steadily involve molecular, tissue and organ levels in response to the virus or bacteria constant insults that drive a mitochondria itself to become an "immortal cancer cell". Improved insights into this interplay between these pathogens and mitochondria progression may disclose newly epistemological paradigms as well as innovative procedures in targeting cancer cell progressive invasion. Show less

Durable response to cancer therapies relies on the stimulation of cancer immunosurveillance. Reinstating antitumor immunity can be achieved by the administration of cytotoxic treatments able to induce a nontolerogenic type of cell death. This so-called immunogenic... Show less

Z-form nucleic acid-binding protein 1 (ZBP1) detects viral Z-form RNAs (Z-RNAs), activates receptor-interacting protein kinase 3, and triggers cell death during both RNA and DNA virus infections. Such cell death promotes virus clearance by eliminating infected cells and galvanizing antiviral immunity, and is thus often targeted for evasion by virus-encoded suppressors. Recent evidence demonstrates that ZBP1 can also be activated by cellular Z-RNAs transcribed from endogenous retroelements within mammalian genomes. These cellular Z-RNAs, if not edited and neutralized by adenosine deaminase RNA-specific 1, trigger ZBP1-dependent cell death and inflammation, which may drive disease in Aicardi-Goutière's syndrome and related interferonopathies. Thus, while well-controlled activation of ZBP1 by viral Z-RNAs during infections is beneficial, the same pathway can have harmful consequences when inappropriately triggered by cellular Z-RNAs in other disease settings. Show less

Mechanisms of nucleic acid accumulation were likely critical to life's emergence in the ferruginous oceans of the early Earth. How exactly prebiotic geological settings accumulated nucleic acids from dilute aqueous solutions, is poorly understood. As a possible solution to this concentration problem, we simulated the conditions of prebiotic low-temperature alkaline hydrothermal vents in co-precipitation experiments to investigate the potential of ferruginous chemical gardens to accumulate nucleic acids via sorption. The injection of an alkaline solution into an artificial ferruginous solution under anoxic conditions (O2 < 0.01% of present atmospheric levels) and at ambient temperatures, caused the precipitation of amakinite ("white rust"), which quickly converted to chloride-containing fougerite ("green rust"). RNA was only extractable from the ferruginous solution in the presence of a phosphate buffer, suggesting RNA in solution was bound to Fe2+ ions. During chimney formation, this iron-bound RNA rapidly accumulated in the white and green rust chimney structure from the surrounding ferruginous solution at the fastest rates in the initial white rust phase and correspondingly slower rates in the following green rust phase. This represents a new mechanism for nucleic acid accumulation in the ferruginous oceans of the early Earth, in addition to wet-dry cycles and may have helped to concentrate RNA in a dilute prebiotic ocean. Show less

Expansion of a single repetitive DNA sequence, termed a tandem repeat (TR), is known to cause more than 50 diseases1,2. However, repeat expansions are often not explored beyond neurological and neurodegenerative disorders. In some cancers, mutations accumulate in short tracts of TRs, a phenomenon termed microsatellite instability; however, larger repeat expansions have not been systematically analysed in cancer3-8. Here we identified TR expansions in 2,622 cancer genomes spanning 29 cancer types. In seven cancer types, we found 160 recurrent repeat expansions (rREs), most of which (155/160) were subtype specific. We found that rREs were non-uniformly distributed in the genome with enrichment near candidate cis-regulatory elements, suggesting a potential role in gene regulation. One rRE, a GAAA-repeat expansion, located near a regulatory element in the first intron of UGT2B7 was detected in 34% of renal cell carcinoma samples and was validated by long-read DNA sequencing. Moreover, in preliminary experiments, treating cells that harbour this rRE with a GAAA-targeting molecule led to a dose-dependent decrease in cell proliferation. Overall, our results suggest that rREs may be an important but unexplored source of genetic variation in human cancer, and we provide a comprehensive catalogue for further study. Show less

Colorectal cancer is among the most common cancers worldwide and a frequent cause of cancer related deaths. Oxaliplatin is the first line chemotherapeutics for treatment, but the development of resistance leads to recurrence of oxaliplatin insensitive tumors. To understand possible mechanisms of drug tolerance we developed oxaliplatin resistant derivatives (OR-LoVo) of the established LoVo cell line originally isolated from a metastatic colon adenocarcinoma. We compared the microRNA (miRNA) expression profile of the cell pair and found expression of miR-29a-3p significantly increased in OR-LoVo cells compared to parent cells. In addition, miR-29a-3p was significantly elevated in tumor tissue when compared to matched surrounding tissue in human, suggesting potential clinical importance. Ectopic miR-29-a-3p expression induced chemoresistance in a number of different cancer cell lines as well as colorectal tumors in mice. We further demonstrated that miR-29-a-3p downregulates expression of the ubiquitin ligase component FEM1B and that reduction of Fem1b levels is sufficient to confer oxaliplatin resistance. FEM1B targets the glioma associated oncogene Gli1 for degradation, suggesting that increased Gli1 levels could contribute to oxaliplatin tolerance. Accordingly, knockdown of GLI1 reverted chemoresistance of OR-LoVo cells. Mechanistically, resistant cells experienced significantly lower DNA damage upon oxaliplatin treatment, which can be partially explained by reduced oxaliplatin uptake and enhanced repair. These results suggest that miR-29-a-3p overexpression induces oxaliplatin resistance through misregulation of Fem1B and Gli1 levels. TCGA analyses provides strong evidence that the reported findings regarding induced drug tolerance by the miR-29a/Fem1B axis is clinically relevant. The reported findings can help to predict oxaliplatin sensitivity and resistance of colorectal tumors. Show less

The Caco-2 cell line derived from human colon carcinoma is commonly used to assess the permeability of compounds in in vitro conditions. Due to the significant increase in permeability studies using the Caco-2 cell line in recent years, the need to standardize this biological model seems necessary. The pharmaceutical requirements define only the acceptance criteria for the validation of the Caco-2 cell line and do not specify the protocol for its implementation. Therefore, the aim of this study is to review the conditions for permeability studies across the Caco-2 monolayer reported in the available literature concerning validation guidelines. We summarized the main aspects affecting the validation process of the Caco-2 cell line, including the culture conditions, cytotoxicity, cell differentiation process, and monolayer transport conditions, and the main conclusions may be useful in developing individual methods for preparing the cell line for validation purposes and further permeability research. Show less

Title: Iridium(III)-Based Infrared Two-Photon Photosensitizers: Systematic Regulation of Their Photodynamic Therapy Efficacy. Abstract: Cyclometalated iridium(III) complexes are of significant importance in the field of antitumor photodynamic therapy (PDT), whether they exist as single molecules or are incorporated into nanomaterials. Nevertheless, a comprehensive examination of the relationship between their molecular structure and PDT effectiveness remains awaited. The influencing factors of two-photon excited PDT can be anticipated to be further multiplied, particularly in relation to intricate nonlinear optical properties. At present, a comprehensive body of research on this topic is lacking, and few discernible patterns have been identified. In this study, through systematic structure regulation, the nitro-substituted styryl group and 1-phenylisoquinoline ligand containing YQ2 was found to be the most potent infrared two-photon excitable photosensitizer in a 4 × 3 combination library of cyclometalated Ir(III) complexes. YQ2 could enter cells via an energy-dependent and caveolae-mediated pathway, bind specifically to mitochondria, produce 1O2 in response to 808 nm LPL irradiation, activate caspases, and induce apoptosis. In vitro, YQ2 displayed a remarkable phototherapy index for both malignant melanoma (>885) and non-small-cell lung cancer (>1234) based on these functions and was minimally deleterious to human normal liver and kidney cells. In in vivo antitumor phototherapy, YQ2 inhibited tumor growth by an impressive 85% and could be eliminated from the bodies of mice with a half-life as short as 43 h. This study has the potential to contribute significantly to the development of phototherapeutic drugs that are extremely effective in treating large, profoundly located solid tumors as well as the understanding of the structure-activity relationship of Ir(III)-based PSs in PDT. Show less