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Corrinoids are cobalt-containing tetrapyrroles. They include adenosylcobalamin (vitamin B12) and cobamides that function as cofactors and coenzymes for methyl transfer, radical-dependent and redox reactions. Though cobamides are the most complex cofactors in nature, they are essential in the acetyl-CoA pathway, thought to be the most ancient CO2-fixation pathway, where they perform a pterin-to-cobalt-to-nickel methyl transfer reaction catalyzed by the corrinoid iron-sulphur protein (CoFeS). CoFeS occurs in H2-dependent archaeal methanogens, the oldest microbial lineage by measure of physiology and carbon isotope data, dating corrinoids to ca. 3.5 billion years. However, CoFeS and cobamides are also essential in the acetyl-CoA pathway of H2-dependent bacterial acetogens. To determine whether corrin biosynthesis was established before archaea and bacteria diverged, whether the pathways arose independently or whether cobamide biosynthesis was transferred from the archaeal to the bacterial lineage (or vice versa) during evolution, we investigated phylogenies and structural data for 26 enzymes of corrin ring and lower ligand biosynthesis. The data trace cobamide synthesis to the common ancestor of bacteria and archaea, placing it in the last universal common ancestor of all lifeforms (LUCA), while pterin-dependent methyl synthesis pathways likely arose independently post-LUCA in the lineages leading to bacteria and archaea. Enzymes of corrin biosynthesis were recruited from preexisting ancient pathways. Evolutionary forerunners of CoFeS function were likely Fe-, Ni- and Co-containing solid-state surfaces, which, in the laboratory, catalyze the reactions of the acetyl-CoA pathway from CO2 to pyruvate under serpentinizing hydrothermal conditions. The data suggest that enzymatic corrin biosynthesis replaced insoluble solid-state catalysts that tethered primordial CO2 assimilation to the Earth's crust, suggesting a role for corrin synthesis in the origin of free-living cells. Show less

The direct and atom economic synthesis of azulenyl-substituted gold(i) carbene complexes, based on the modular template synthesis using gold(i) isonitrile complexes and amine nucleophiles, is presented. First, two azulenyl-substituted isonitriles as ligands were synthesized from a functionalizable azulene derivative, the latter stemming from a gold-catalyzed dimerization of internal alkynes. These azulene-bound gold(i) isonitrile complexes allow the smooth nucleophilic attack by both aliphatic and aromatic amines. The newly synthesized azulene-substituted gold(i) carbene complexes were evaluated for in vitro anticancer activity against multiple human cancer cell lines. Six lead compounds demonstrated potent and selective cytotoxicity, exceeding that of cisplatin by at least an order of magnitude in resistant and aggressive cancer models. Structure-activity relationship analysis revealed that specific ligand modifications, such as the position of the azulene moiety tethered to the carbene unit or nitrogen-bound ethyl or cyclic groups, are critical for enhancing the anticancer activity. Show less

Abstract Transition metal complexes have been widely utilized as cellular imaging tools. To impart organelle specificity, ligand architecture is usually modified to modulate properties like overall charge and lipophilicity. In many such designs, the metal identity and its intrinsic properties are often ignored. To address this gap, in this study, we explored the effects of changing the metal center on the localization patterns of isostructural complexes. To this end, we employed the thiosemicarbazone Dp44mT to synthesize coumarin‐conjugated complexes of Au(III), Pt(II), and Pd(II). Although the metal centers in these compounds share a formal d 8 configuration, they differ in properties such as ionic radius, charge density, and ligand exchange rates, which can affect their subcellular localization patterns. In addition, we synthesized a second set of analogous complexes using BODIPY as the conjugating fluorophore to assess the influence of using a different dye on the cellular distribution. Confocal imaging revealed that the complexes exhibited distinct intracellular distributions. For instance, while the coumarin‐conjugated Pt(II) complex localized specifically in lysosomes, the corresponding lipophilic Pd(II) complex lacked this specificity and instead followed a diffusely cytosolic distribution. Similarly, the more lipophilic BODIPY conjugated complexes were non‐specific in their cellular distribution as well. Overall, the findings of this study highlight the interplay of metal identity and lipophilicity in determining the localization patterns of Dp44mT‐based metal complexes, offering fresh insights into the design of new metal‐based imaging tools. Show less

Three cytotoxic copper(ii) complexes – [Cu2(bipy)2L4] (1), [Cu2(phen)2L4] (2) and [Cu2(dmphen)2L4]·2H2O (3) – were synthesized based on 5-methyltetrazole (HL) and 2,2′-bipyridine/1,10-phenanthroline derivatives. Show less

Although immunogenic cell death (ICD) has garnered significant attention in the realm of “cold” tumor therapies, effectively stimulating strong immune responses with minimal side effects, their real-time monitoring in deep-seated tumors remains challenging. There is no available drug that covers these two bases with one swing. Herein, we report a proof-of-concept for the rational design and synthesis of a novel class of five redox-active iron(III) complexes, ([FeIII(L1–L5)2]), based on sirtinol analogs bearing adamantane moieties. These complexes show potential as modest stimulators of ICD, as indicated by the expression of key ICD markers. The lead compound, Fe(L1)2, exhibits promiscuous nanoscale aggregation in RPMI-1640 cell culture media, characterized by a stable hydrodynamic effective diameter ranging from 50 nm to 70 nm over 48 hours. Fe(L1)2 nanoaggregates with enhanced efficacy against MCF-7 cells undergo an energy-dependent endocytic cellular-uptake pathway. In our proposed two-for-one approach, the DAMP marker indicates that our Fe(L1)2 nanoaggregates are iron-based complexes that warm up the tumor environment by maximizing the antitumor immune response, and Fe(L1–L3)2 display well-defined photoacoustic NIR-II spectra that underscore their suitability in future for high-resolution imaging applications. Show less

We hypothesize that predictable variations in environmental conditions caused by night/day cycles created opportunities and hazards that initiated information dynamics central to life's origin. Increased daytime temperatures accelerated key chemical reactions but also caused the separation of double-stranded polynucleotides, leading to hydrolysis, particularly of single-stranded RNA. Daytime solar UV radiation promoted the synthesis of organic molecules but caused broad damage to protocell macromolecules. We hypothesize that inter-related simultaneous adaptations to these hazards produced molecular dynamics necessary to store and use information. Self-replicating RNA heritably reduced the hydrolysis of single strands after separation during warmer daytime periods by promoting sequences that formed hairpin loops, generating precursors to transfer RNA (tRNA), and initiating tRNA-directed evolutionary dynamics. Protocell survival during daytime promoted sequences in self-replicating RNA within protocells that formed RNA-peptide hybrids capable of scavenging UV-induced free radicals or catalyzing melanin synthesis from tyrosine. The RNA-peptide hybrids are precursors to ribosomes and the triplet codes for RNA-directed protein synthesis. The protective effects of melanin production persist as melanosomes are found throughout the tree of life. Similarly, adaptations mitigating UV damage led to the replacement of Na+ by K+ as the dominant mobile cytoplasmic cation to promote diel vertical migration and selected for homochirality. We conclude that information dynamics emerged in early life through adaptations to predictably fluctuating opportunities and hazards during night/day cycles, and its legacy remains observable in extant life. Show less

Abstract Cancer cells rely heavily on de novo pyrimidine synthesis. Inhibiting pyrimidine metabolism directly suppresses tumor growth and fosters immune activation within the tumor microenvironment. Dihydroorotate dehydrogenase (DHODH) is a key enzyme in the de novo pyrimidine synthesis pathway. Inhibiting DHODH can reverse immune suppression and trigger a mild innate immune response. However, the impact of DHODH inhibition on natural killer (NK) cells remains to be explored. In this study, we found that DHODH inhibition promoted NK cell infiltration into tumors efficiently. Mechanistically, DHODH suppression induced mitochondrial oxidative stress, leading to mitochondrial DNA (mtDNA) release into the cytoplasm through voltage-dependent anion channel (VDAC) oligomerization and caspase-3 activation. This subsequently activated the stimulator of interferon gene (STING) pathway, triggered ferroptosis, and induced gasdermin E (GSDME) mediated pyroptosis in cancer cells. These changes collectively facilitated NK cell recruitment. Furthermore, infiltrated NK cells enhanced GSDME-dependent pyroptosis in tumor cells through granzyme release, establishing a positive feedback loop that amplified anti-tumor immunity. Additionally, we developed EA6, a novel DHODH inhibitor that is more effective at promoting NK cell infiltration. In summary, this study reveals that targeting pyrimidine metabolism activates a novel mechanism involving pyroptosis-ferroptosis crosstalk and STING pathway activation to enhance NK cell-mediated immunity. These finding opens new avenues for enhancing the efficacy of targeted nucleotide metabolism in cancer therapy. Show less

Submarine hydrothermal vents harbor diverse microbial communities and have long intrigued researchers studying the origin of life. Transition metals in these environments can be reduced by serpentinization, potentially forming zeolite-supported transition metal nanoparticles capable of driving prebiotic chemistry. This inorganic structure could catalyze biochemical reactions, including converting metabolically crucial pyruvate before the emergence of biological processes. This study explores the catalytic interconversion of pyruvate and lactate, mediated by lactate dehydrogenase in biochemical systems, using inorganic zeolite Y-supported Ni nanoparticles (Ni/Y) under mild hydrothermal vent conditions. Our results demonstrate that Ni/Y effectively catalyzes the hydrogenation of pyruvate in an inert environment, facilitated by the in situ generation of H₂ through an autocatalytic reaction between Ni/Y and H₂O. Post-reaction analysis by X-ray absorption spectroscopy (XAS) revealed structural transformations in the catalyst, including the formation of unique nickel oxide and hydroxide species, along with extra-framework aluminum from zeolite dealumination, resulting in a thin amorphous nickel oxide/hydroxide layer. Notably, Ni/Y also enables the oxidative reconversion of lactate to pyruvate under atmospheric conditions-an essential reaction catalyzed by lactate dehydrogenase in biological systems. These findings underscore the potential prebiotic role of Ni/Y, suggesting they may have catalyzed the synthesis of key metabolic intermediates. Show less

Platinum-based drugs are a mainstay in chemotherapy, with traditional forms exerting their work directly on DNA. In recent years, it has been observed that platinum complexes had the potential to induce immunogenic cell death (ICD) and effectively trigger antitumor immune responses. Herein, to obtain novel platinum complexes with chemo-immunological properties, a series of Pt(ΙΙ)-N-heterocyclic carbene (Pt(ΙΙ)-NHC) complexes derived from 4,5-diarylimidazoles were synthesized. Among them, the dominant complex 3f was proved to exhibit better anti-liver cancer capacity compared to cisplatin and oxaliplatin. Complex 3f showed the ability to cause DNA damage by binding to DNA. In addition, it triggered intracellular reactive oxygen species (ROS) generation, affected the function of mitochondria, and blocked cells in G0/G1 phase, ultimately induced apoptosis in liver cancer cells. Furthermore, complex 3f activated endoplasmic reticulum stress (ERS) which promoted the release of damage-associated molecular patterns (DAMPs), induced ICD and dendritic cells (DCs) maturation. Interestingly, complex 3f also upregulated PD-L1, consequently converted "cold tumors" into "hot tumors". Overall, complex 3f had the potential to be regarded as a promising chemoimmunotherapy for the treatment of liver cancer. Show less

Tetrazoles are nitrogen-rich heterocycles that have attracted interest because of their numerous applications in pharmaceutical and medicinal chemistry. Four nitrogen atoms and one carbon atom make up these five-membered rings, which have special physicochemical and electrical characteristics, including acidity, resonance stabilization, and aromaticity. This article highlights the structure, spectroscopic characteristics, and physical and chemical characteristics of tetrazoles. It also describes how overlapping mechanisms, such as DNA replication inhibition, protein synthesis disruption, and oxidative stress induction, as well as similar therapeutic targets, enable inhibitors to serve as both antibacterial and anticancer agents. Tetrazole moieties have been fused with a range of pharmacophores, such as indoles, pyrazoles, quinolines, and pyrimidines, yielding fused derivatives that display substantial inhibitory activity against bacterial, fungal, and cancer cell lines, with certain compounds exhibiting efficacy comparable to or exceeding that of established therapeutic agents. The rational design of more efficacious tetrazole-based therapies is facilitated by structure-activity relationship analysis, which further highlights significant functional groups and scaffolds that contribute to increasing activity. We investigate the relationship between microbial inhibition and anticancer efficacy, opening up new avenues for the creation of multifunctional therapeutic agents. We hope that this study will offer significant guidance and serve as a valued resource for medicinal and organic researchers working on drug development and discovery in multifunctional therapeutics. The review involves a thorough investigation of tetrazole in recent years. Show less

Glycolysis stops where gluconeogenesis starts-at pyruvate, the central metabolite of biosynthesis. The early history of carbon metabolism is preserved in archaeal and bacterial enzymes for glucose synthesis and breakdown. Here, we summarize the distribution and phylogeny of enzymes involved in glycolysis, gluconeogenesis, and glycogen metabolism from genomes of cultured prokaryotes. The presence of glycolytic pathways in H2-dependent chemolithoautotrophs, including methanogens, which cannot grow on exogenous glucose, correlates with their use of glycogen for intracellular carbon storage. Glycogen synthesis and gluconeogenesis are universal among prokaryotes, but glycolysis is not, indicating that the enzymatic conversions of glycolysis arose in the gluconeogenic direction encompassing three phases: (1) an autotrophic origin from H2 and CO2 to pyruvate and triosephosphate (trunk glycolysis) fulfilling basic amino acid and cofactor synthesis in the last universal common ancestor, (2) from triosephosphate to glucose supplying cell wall (murein and pseudomurein) and nucleic acid biosynthetic requirements in the first free-living autotrophs, also giving rise to intracellular carbon reserves (glycogen), followed by (3) diversification and transfer of enzymes for glycogen-mobilizing glycolytic routes. An autotrophic origin of trunk glycolysis followed by glycogen-dependent origin of glucose utilization account for conservation, distribution, and diversity of enzymes observed in microbial sugar phosphate pathways. Show less

Background/Objectives: The origin of genes and genetics is the story of the coevolution of translation systems and the genetic code. Remarkably, the history of the origin of life on Earth was inscribed and preserved in the sequences of tRNAs. Methods: Sequence logos demonstrate the patterning of pre-life tRNA sequences. Results: The pre-life type I and type II tRNA sequences are known to the last nucleotide with only a few ambiguities. Type I and type II tRNAs evolved from ligation of three 31 nt minihelices of highly patterned and known sequence followed by closely related 9 nt internal deletion(s) within ligated acceptor stems. The D loop 17 nt core was a truncated UAGCC repeat. The anticodon and T 17 nt stem-loop-stems are homologous sequences with 5 nt stems and 7 nt U-turn loops that were selected in pre-life to resist ribozyme nucleases and to present a 3 nt anticodon with a single wobble position. The 7 nt T loop in tRNA was selected to interact with the D loop at the "elbow". The 5'-acceptor stem was based on a 7 nt truncated GCG repeat. The 3'-acceptor stem was based on a complementary 7 nt CGC repeat. In pre-life, ACCA-Gly was a primitive adapter molecule ligated to many RNAs, including tRNAs, to synthesize polyglycine. Conclusions: Analysis of sequence logos of tRNAs from an ancient Archaeon substantiates how the pre-life to life transition occurred on Earth. Polyglycine is posited to have aggregated complex molecular assemblies, including minihelices, tRNAs, cooperating molecules, and protocells, leading to the first life on Earth. Show less

Serpentinizing hydrothermal vents are likely sites for the origin of metabolism because they produce H2 as a source of electrons for CO2 reduction while depositing zero-valent iron, cobalt, and nickel as catalysts for organic reactions. Recent work has shown that solid-state nickel can catalyze the H2-dependent reduction of CO2 to various organic acids and their reductive amination with H2 and NH3 to biological amino acids under the conditions of H2-producing hydrothermal vents and that amino acid synthesis from NH3, H2, and 2-oxoacids is facile in the presence of Ni0. Such reactions suggest a metallic origin of metabolism during early biochemical evolution because single metals replace the function of over 130 enzymatic reactions at the core of metabolism in microbes that use the acetyl-CoA pathway of CO2 fixation. Yet solid-state catalysts tether primordial amino synthesis to a mineral surface. Many studies have shown that pyridoxal catalyzes transamination reactions without enzymes. Here we show that pyridoxamine, the NH2-transferring intermediate in pyridoxal-dependent transamination reactions, is generated from pyridoxal by reaction with NH3 (as little as 5 mm) and H2 (5 bar) on Ni0 as catalyst at pH 11 and 80 °C within hours. These conditions correspond to those in hydrothermal vents undergoing active serpentinization. The results indicate that at the origin of metabolism, pyridoxamine provided a soluble, organic amino donor for aqueous amino acid synthesis, mediating an evolutionary transition from NH3-dependent amino acid synthesis on inorganic surfaces to pyridoxamine-dependent organic reactions in the aqueous phase. Show less

Cancer remains a major global health burden, with rising incidence and mortality linked to aging populations and increased exposure to genotoxic agents. Oxidative stress plays a critical role in cancer development, progression, and resistance to therapy. The nuclear factor erythroid 2-related factor 2 (NRF2)-Kelch-like ECH-associated protein 1 (KEAP1)-antioxidant response element (ARE) signaling pathway is central to maintaining redox balance by regulating the expression of antioxidant and detoxification genes. Under physiological conditions, this pathway protects cells from oxidative damage, however, sustained activation of NRF2 in cancer, often due to mutations in KEAP1, supports tumor cell survival, drug resistance, and metabolic reprogramming. Recent studies demonstrate that NRF2 enhances glutathione (GSH) synthesis, induces detoxifying enzymes, and upregulates drug efflux transporters, collectively contributing to resistance against chemotherapy and targeted therapies. The inhibition of NRF2 using small molecules or dietary phytochemicals has shown promise in restoring drug sensitivity in preclinical cancer models. This review highlights the dual role of NRF2 in redox regulation and cancer therapy, emphasizing its potential as a therapeutic target. While targeting NRF2 offers a novel approach to overcoming treatment resistance, further research is needed to enhance specificity and facilitate clinical translation. Show less

It is well established that oxaliplatin, one of the three Pt(II) anticancer drugs approved worldwide, and phenanthriplatin, an important preclinical monofunctional Pt(II) anticancer drug, possess a different mode of action from that of cisplatin and carboplatin, namely, the induction of nucleolar stress. The exact mechanisms that lead to Pt-induced nucleolar stress are, however, still poorly understood. As such, studies aimed at better understanding the biological targets of both oxaliplatin and phenanthriplatin are urgently needed to expand our understanding of Pt-induced nucleolar stress and guide the future design of Pt chemotherapeutics. One approach that has seen great success in the past is the use of Pt-click complexes to study the biological targets of Pt drugs. Herein, we report the synthesis and characterization of the first examples of click-capable phenanthriplatin complexes. Furthermore, through monitoring the relocalization of nucleolar proteins, RNA transcription levels, and DNA damage repair biomarker γH2AX, and by investigating their in vitro cytotoxicity, we show that these complexes successfully mimic the cellular responses observed for phenanthriplatin treatment in the same experiments. The click-capable phenanthriplatin derivatives described here expand the existing library of Pt-click complexes. Significantly they are suitable for studying nucleolar stress mechanisms and further elucidating the biological targets of Pt complexes. Show less

Rhenium(I) tricarbonyl complexes are widely studied for their cell imaging properties and anti-cancer and anti-microbial activities, but the complexes with S-donor ligands remain relatively unexplored. A series of six fac-[Re(NN)(CO)3(SR)] complexes, where (NN) is 2,2′-bipyridyl (bipy) or 1,10-phenanthroline (phen), and RSH is a series of thiocarboxylic acid methyl esters, have been synthesized and characterized. Cellular uptake and anti-proliferative activities of these complexes in human breast cancer cell lines (MDA-MB-231 and MCF-7) were generally lower than those of the previously described fac-[Re(NN)(CO)3(OH2)]+ complexes; however, one of the complexes, fac-[Re(CO)3(phen)(SC(Ph)CH2C(O)OMe)] (3b), was active (IC50 ∼ 10 μM at 72 h treatment) in thiol-depleted MDA-MB-231 cells. Moreover, unlike fac-[Re(CO)3(phen)(OH2)]+, this complex did not lose activity in the presence of extracellular glutathione. Taken together these properties show promise for further development of 3b and its analogues as potential anti-cancer drugs for co-treatment with thiol-depleting agents. Conversely, the stable and non-toxic complex, fac-[Re(bipy)(CO)3(SC(Me)C(O)OMe)] (1a), predominantly localized in the lysosomes of MDA-MB-231 cells, as shown by live cell confocal microscopy (λex = 405 nm, λem = 470–570 nm). It is strongly localized in a subset of lysosomes (25 μM Re, 4 h treatment), as shown by co-localization with a Lysotracker dye. Longer treatment times with 1a (25 μM Re for 48 h) resulted in partial migration of the probe into the mitochondria, as shown by co-localization with a Mitotracker dye. These properties make complex 1a an attractive target for further development as an organelle probe for multimodal imaging, including phosphorescence, carbonyl tag for vibrational spectroscopy, and Re tag for X-ray fluorescence microscopy. Show less

Morpholine motifs have been used extensively as targeting moieties for lysosomes, primarily in fluorescence imaging agents. Traditionally these imaging agents are based on organic molecules which have several shortcomings including small Stokes shifts, short emission lifetimes, and susceptibility to photobleaching. To explore alternative lysosome targeting imaging agents we have used a rhenium based phosphorescent platform which has been previously demonstrated to have an improved Stokes shift, a long lifetime emission, and is highly photostable. Rhenium complexes containing morpholine substituted ligands were designed to accumulate in acidic compartments. Two of the three complexes prepared exhibited bright emission in cells, when incubated at low concentrations (20 μM) and were non-toxic at concentrations as high as 100 μM, making them suitable for live cell imaging. We show that the rhenium complexes are amenable to chemical modification and that the morpholine targeted derivatives can be used for live cell confocal fluorescence imaging of endosomes–lysosomes. Show less

Iridium(III) complexes nowadays became rising stars in various health-related applications. Thus, there is a necessity to assess cytotoxicity of the synthesized molecules against cancer/normal cell lines. In this report, we present a dataset of 2694 experimental cytotoxicity values of 803 iridium complexes against 127 different cell lines. We specify the experimental conditions and provide representation of the complexes molecules in machine-readable format. The dataset provides a starting point for exploration of new iridium-based cellular probes and opens new possibilities for predictions of toxicities and data-driven generation of new organometallic anticancer agents. Show less

Cardiolipin (CL) is a mitochondria-exclusive phospholipid synthesized in the inner mitochondrial membrane. CL plays a key role in mitochondrial membranes, impacting a plethora of functions this organelle performs. Consequently, it is conceivable that abnormalities in the CL content, composition, and level of oxidation may negatively impact mitochondrial function and dynamics, with important implications in a variety of diseases. This review concentrates on papers published in recent years, combined with basic and underexplored research in CL. We capture new findings on its biological functions in the mitochondria, as well as its association with neurodegenerative diseases such as Alzheimer's disease or Parkinson's disease. Lastly, we explore the potential applications of CL as a biomarker and pharmacological target to mitigate mitochondrial dysfunction. Show less

An unresolved question in the origin and evolution of life is whether a continuous path from geochemical precursors to the majority of molecules in the biosphere can be reconstructed from modern-day biochemistry. Here we identified a feasible path by simulating the evolution of biosphere-scale metabolism, using only known biochemical reactions and models of primitive coenzymes. We find that purine synthesis constitutes a bottleneck for metabolic expansion, which can be alleviated by non-autocatalytic phosphoryl coupling agents. Early phases of the expansion are enriched with enzymes that are metal dependent and structurally symmetric, supporting models of early biochemical evolution. This expansion trajectory suggests distinct hypotheses regarding the tempo, mode and timing of metabolic pathway evolution, including a late appearance of methane metabolisms and oxygenic photosynthesis consistent with the geochemical record. The concordance between biological and geological analyses suggests that this trajectory provides a plausible evolutionary history for the vast majority of core biochemistry. Show less

Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating condition affecting an increasing number of cancer survivors worldwide. However, insights into its pathophysiology and availability of effective therapies remain lacking. Dorsal root ganglia (DRG) have been studied as a key component of chemotherapeutic drug toxicity and a potential therapeutic target for CIPN treatment. This comprehensive review aims to synthesize, summarize, and correlate the results of both preclinical and clinical studies relevant to the pathophysiology and management of CIPN in relation to the DRG. Design: Review. A thorough literature search was conducted using the terms 'dorsal root ganglion' and 'chemotherapy-induced peripheral neuropathy', along with appropriate variations. Searched databases included PubMed, EMBASE, Medline, Cochrane Library, Wiley Library, and Web of Science. Inclusion criteria targeted all English language, peer-reviewed original research from the inception of these databases to the present year. Review articles, book chapters, and other nonoriginal publications were excluded. Of 134 relevant studies identified, the majority were preclinical studies elucidating how various chemotherapeutic agents, especially taxanes, disrupt neurotransmission, inflammatory processes, and apoptotic pathways within sensory neurons of DRG. Not only do these effects correlate with the presentation of CIPN, but their disruption has also been shown to reduce CIPN symptoms in preclinical models. However, clinical studies addressing DRG interventions are very limited in number and scope at this time. These results reveal various pathways within DRG that may be effective targets for CIPN treatment. While limited, clinical studies do offer promise in the utility of DRG neuromodulation in managing painful CIPN. In the future, clinical trials are needed to assess interventions aimed at these neuronal and nonneuronal pathological targets to better treat this complex condition. Show less

Ferroptosis, a form of regulated cell death that is driven by iron-dependent phospholipid peroxidation, has been implicated in multiple diseases, including cancer1-3, degenerative disorders4 and organ ischaemia-reperfusion injury (IRI)5,6. Here, using genome-wide CRISPR-Cas9 screening, we identified that the enzymes involved in distal cholesterol biosynthesis have pivotal yet opposing roles in regulating ferroptosis through dictating the level of 7-dehydrocholesterol (7-DHC)-an intermediate metabolite of distal cholesterol biosynthesis that is synthesized by sterol C5-desaturase (SC5D) and metabolized by 7-DHC reductase (DHCR7) for cholesterol synthesis. We found that the pathway components, including MSMO1, CYP51A1, EBP and SC5D, function as potential suppressors of ferroptosis, whereas DHCR7 functions as a pro-ferroptotic gene. Mechanistically, 7-DHC dictates ferroptosis surveillance by using the conjugated diene to exert its anti-phospholipid autoxidation function and shields plasma and mitochondria membranes from phospholipid autoxidation. Importantly, blocking the biosynthesis of endogenous 7-DHC by pharmacological targeting of EBP induces ferroptosis and inhibits tumour growth, whereas increasing the 7-DHC level by inhibiting DHCR7 effectively promotes cancer metastasis and attenuates the progression of kidney IRI, supporting a critical function of this axis in vivo. In conclusion, our data reveal a role of 7-DHC as a natural anti-ferroptotic metabolite and suggest that pharmacological manipulation of 7-DHC levels is a promising therapeutic strategy for cancer and IRI. Show less

The path from life's origin to the emergence of the eukaryotic cell was long and complex, and as such it is rarely treated in one publication. Here, we offer a sketch of this path, recognizing that there are points of disagreement and that many transitions are still shrouded in mystery. We assume life developed within microchambers of an alkaline hydrothermal vent system. Initial simple reactions were built into more sophisticated reflexively autocatalytic food-generated networks (RAFs), laying the foundation for life's anastomosing metabolism, and eventually for the origin of RNA, which functioned as a genetic repository and as a catalyst (ribozymes). Eventually, protein synthesis developed, leading to life's biology becoming dominated by enzymes and not ribozymes. Subsequent enzymatic innovation included ATP synthase, which generates ATP, fueled by the proton gradient between the alkaline vent flux and the acidic sea. This gradient was later internalized via the evolution of the electron transport chain, a preadaptation for the subsequent emergence of the vent creatures from their microchamber cradles. Differences between bacteria and archaea suggests cellularization evolved at least twice. Later, the bacterial development of oxidative phosphorylation and the archaeal development of proteins to stabilize its DNA laid the foundation for the merger that led to the formation of eukaryotic cells. Show less

We hypothesize that the first ancestral "protocell" molecular structures, i.e., the first RNAs and peptides that gradually transformed into real cells once the Earth had cooled sufficiently for organic molecules to appear, have left traces in the RNAs and the genes in present cells. We propose a circular RNA that could have been one of these ancestral structures whose vestigial pentameric subsequences would mark the evolution from this key moment when the protocells began to join with living organisms. In particular, we propose that, in present RNAs (ribosomal or messenger), which play an important role in the metabolism of current cells, we look for traces of the proposed primitive structure in the form of pentamers (or longer fragments) that belong to their nucleotide sequence. The result obtained can be summarized in the existence of a gradient of occurrence of such pentamers, with a high frequency for the most vital functions (protein synthesis, nucleic synthesis, cell respiration, etc.). This gradient is also visible between organisms, from the oldest (Archaea) to the most recent (Eukaryotes) in the evolution of species. Show less

Neurological disorders are the leading cause of a large number of mortalities and morbidities. Nitrogen heterocyclic compounds have been pivotal in exhibiting wide array of therapeutic applications. Among them, tetrazole is a ubiquitous class of organic heterocyclic compounds that have attracted much attention because of its unique structural and chemical properties, and a wide range of pharmacological activities comprising anti-convulsant effect, antibiotic, anti-allergic, anti-hypertensive to name a few. Owing to significant chemical and biological properties, the present review aimed at highlighting the recent advances in tetrazole derivatives with special emphasis on their role in the management of neurological diseases. Besides, in-depth structure-activity relationships, molecular docking studies, and associated modes of action of tetrazole derivatives evident in in vitro, in vivo preclinical, and clinical studies have been discussed. Show less

AbstractMitochondria, recognized as the cellular powerhouses, are indispensable organelles responsible for crucial cellular processes, such as energy metabolism, material synthesis, and signaling transduction. Their intricate involvement in a broad spectrum of diseases, particularly cancer, has propelled the exploration of mitochondria‐targeting treatment as a promising strategy for cancer therapy. Since the groundbreaking discovery of cisplatin, the trajectory of research on the development of metal complexes have been marked by continuous advancement, giving rise to a diverse array of metallodrugs characterized by variations in ligand types, metal center properties, and oxidation states. By specifically targeting mitochondria, these metallodrugs exhibit the remarkable ability to elicit various programmed cell death pathways, encompassing apoptosis, autophagy, and ferroptosis. This review primarily focuses on recent developments in transition metal‐based mitochondria‐targeting agents, offering a comprehensive exploration of their capacity to induce distinct cell death modes. The aim is not only to disseminate knowledge but also to stimulate an active field of research toward new clinical applications and novel anticancer mechanisms. Show less

Developing a new generation of increased energy, stability, and easily applicable N-rich energetic materials to replace RDX and HMX has posed significant challenges over the past decade. This work presents the design and synthesis of a series of novel N-rich energetic materials (N1 to N3 series) based on the triazole–tetrazole system. Among these, the N3 series demonstrates exceptional detonation performance and stability. It is noteworthy that the N3-3 molecule has achieved the best overall performance among N-rich energetic materials, with an onset decomposition temperature of 302 °C and a detonation velocity of 9341 m s−1, which significantly surpasses that of HMX. Additionally, structural studies of the N1 molecule reveal that the positioning effect of the nitro group and steric hindrance within the molecule disrupt the planar characteristics of the triazole–tetrazole system. In contrast, the amino group in the N3 series enhances molecular planarity, facilitating the formation of large conjugated systems and extensive hydrogen bond networks in N-rich energetic materials. This approach effectively enhances the stability of energetic material molecules and offers valuable insights for the development and design of stable N-rich energetic compounds. Show less