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Accurate diagnosis of minor cartilage injuries with delayed contrast-enhanced computed tomography (CECT) is challenging as poor diffusion and toxicity issues limit the usage of common CT contrast agents. Hence, the design of safe contrast agents with physiochemical properties suitable for fast, deep cartilage imaging is imminent. Herein, a novel cationic bismuth contrast agent (Bi-DOTAPXD) based on dodecane tetraacetic acid (DOTA) was synthesized and examined for CECT of cartilage. The complex was designed to improve diagnosis by utilising a net-positive charge for enhanced permeability through cartilage, inherent low-toxicity and high X-ray attenuation of bismuth. Osteochondral plugs (n = 12), excised from visually intact porcine articular cartilage were immersed in Bi-DOTAPXD (8 mg/mL) and Gd-DOTAPXD (10 mg/mL) contrast agents and scanned with a high-resolution microcomputed tomography scanner at multiple time-points. The mean Bi-DOTAPXD and Gd-DOTAPXD partitions at 45-min time-point were 85.7 ± 35.1 and 69.8 ± 30.2%, and the partitions correlated with the histopathological analysis of cartilage proteoglycan (PG) content (r) at 0.657 and 0.632, respectively. The time diffusion constants (τ) for Bi-DOTAPXD and Gd-DOTA were 121 and 159 min, respectively. Diffusion Bi-DOTAPXD and Gd-DOTAPXD reflected inter-sample variation in cartilage PG content. Cationic Bi-DOTAPXD may have the potential as a CT agent for the diagnosis of cartilage.

Metals are essential components in life processes and participate in many important biological processes. Dysregulation of metal homeostasis is correlated with many diseases. Metals are also frequently incorporated into diagnosis and therapeutics. Understanding of metal homeostasis under (patho)physiological conditions and the molecular mechanisms of action of metallodrugs in biological systems has positive impacts on human health. As an emerging interdisciplinary area of research, metalloproteomics involves investigating metal-protein interactions in biological systems at a proteome-wide scale, has received growing attention, and has been implemented into metal-related research. In this review, we summarize the recent advances in metalloproteomics methodologies and applications. We also highlight emerging single-cell metalloproteomics, including time-resolved inductively coupled plasma mass spectrometry, mass cytometry, and secondary ion mass spectrometry. Finally, we discuss future perspectives in metalloproteomics, aiming to attract more original research to develop more advanced methodologies, which could be utilized rapidly by biochemists or biologists to expand our knowledge of how metal functions in biology and medicine.

S-dimethylarsino-glutathione (ZIO-101, darinaparsin®) exhibits broader antitumor activity and less toxicity than arsenic trioxide (ATO), a clinically used drug for acute promyelocytic leukemia (APL...

A cocktail therapy comprising bismuth drugs and N-acetyl-l-cysteine is reported to suppress the replication of SARS-CoV-2 via the oral route. The broad-spectrum inhibitory activities of the combination upon key viral cysteine enzymes are verified.

The emerging COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has claimed over six million lives globally to date. Despite the availability of vaccines, the pandemic still cannot be fully controlled owing to rapid mutation of the virus that renders enhanced transmissibility and antibody evasion. This is thus an unmet need to develop safe and effective therapeutic options for COVID-19, in particular, remedies that can be used at home. Considering the great success of multi-targeted cocktail therapy for the treatment of viral infections, metal-based drugs might represent a unique and new source of antivirals that resemble a cocktail therapy in terms of their mode of actions. In this review, we first summarize the role that metal ions played in SARS-CoV-2 viral replication and pathogenesis, then highlight the chemistry of metal-based strategies in the fight against SARS-CoV-2 infection, including both metal displacement and chelation based approaches. Finally, we outline a perspective and direction on how to design and develop metal-based antivirals for the fight against the current or future coronavirus pandemic.

The COVID-19 pandemic is the third outbreak this century of a zoonotic disease caused by a coronavirus, following the emergence of severe acute respiratory syndrome (SARS) in 20031 and Middle East respiratory syndrome (MERS) in 20122. Treatment options for coronaviruses are limited. Here we show that clofazimine-an anti-leprosy drug with a favourable safety profile3-possesses inhibitory activity against several coronaviruses, and can antagonize the replication of SARS-CoV-2 and MERS-CoV in a range of in vitro systems. We found that this molecule, which has been approved by the US Food and Drug Administration, inhibits cell fusion mediated by the viral spike glycoprotein, as well as activity of the viral helicase. Prophylactic or therapeutic administration of clofazimine in a hamster model of SARS-CoV-2 pathogenesis led to reduced viral loads in the lung and viral shedding in faeces, and also alleviated the inflammation associated with viral infection. Combinations of clofazimine and remdesivir exhibited antiviral synergy in vitro and in vivo, and restricted viral shedding from the upper respiratory tract. Clofazimine, which is orally bioavailable and comparatively cheap to manufacture, is an attractive clinical candidate for the treatment of outpatients and-when combined with remdesivir-in therapy for hospitalized patients with COVID-19, particularly in contexts in which costs are an important factor or specialized medical facilities are limited. Our data provide evidence that clofazimine may have a role in the control of the current pandemic of COVID-19 and-possibly more importantly-in dealing with coronavirus diseases that may emerge in the future.

Bismuth as a relatively non-toxic and inexpensive metal with exceptional properties has numerous biomedical applications. Bismuth-based compounds are used extensively as medicines for the treatment of gastrointestinal disorders including dyspepsia, gastric ulcers and H. pylori infections. Recently, its medicinal application was further extended to potential treatments of viral infection, multidrug resistant microbial infections, cancer and also imaging, drug delivery and biosensing. In this review we have highlighted the unique chemistry and biological chemistry of bismuth-209 as a prelude to sections covering the unique antibacterial activity of bismuth including a description of research undertaken to date to elucidate key molecular mechanisms of action against H. pylori, the development of novel compounds to treat infection from microbes beyond H. pylori and the significant role bismuth compounds can play as resistance breakers. Furthermore we have provided an account of the potential therapeutic application of bismuth-213 in targeted alpha therapy as well as a summary of the biomedical applications of bismuth-based nanoparticles and composites. Ultimately this review aims to provide the state of the art, highlight the untapped biomedical potential of bismuth and encourage original contributions to this exciting and important field.

Significance Superbugs carrying a mobile colistin resistance gene ( mcr ) are jeopardizing the clinical efficacy of the last-line antibiotic colistin. The development of MCR inhibitors is urgently required to cope with antibiotic-resistance emergencies. Here, we show that silver (Ag + ) fully restores the susceptibility of mcr-1 –carrying superbugs against colistin both in vitro and in vivo. We found an unprecedented tetra-silver center in the active-site pocket of MCR-1 through the substitution of the essential Zn 2+ ions in the intact enzyme, leading to the prevention of substrate binding (i.e. the dysfunction of MCR-1 in transferring phosphorylethanolamine to lipid A). Importantly, the ability of Ag + to suppress resistance evolution extends the lifespan of currently used antibiotics, providing a strategy to treat infections by mcr -positive bacteria.

Colistin is considered the last-line antimicrobial for the treatment of multidrug-resistant gram-negative bacterial infections. The emergence and spread of superbugs carrying the mobile colistin resistance gene (

In our current work, hierarchically porous carbon-coated nickel oxide nanoplates were successfully synthesized through Ni(OH)2 cladding with resorcinol and formaldehyde resin after subsequent carbonization process. The as-prepared NiO-coated carbon nanomaterials were examined, using TEM, XRD, Raman, XPS, TG and BET measurements. The optimized electrode (NiO/Ni@C-450 nanoplates) has regular hexagonal core–shell structure, uniform diameter and thickness. Owing to its porous core–shell structure, high specific surface area (457.03 m2 g−1) and high contents of Ni (6.43 at.%) and O (19.35 at.%) elements, NiO/Ni@C-450 electrode possesses the specific capacitance of 276.1 F/g at 0.5 A/g and good coulombic efficiency. Because the coated carbon layer enables to protect NiO structure and extends the cyclic life of electrode materials, the capacitance retention of NiO/Ni@C-450 electrode is 88.7% after 1000 cycles, which is much higher than that of NiO electrode. All these measured results demonstrate that the as-prepared NiO/Ni@C-450 nanoplate is supposed to be a promising material with easy preparation, high specific capacitance and good cyclic stability properties for potential applications in energy storage devices.

Staphylococcus aureus produces staphyloxanthin, a C30 carotenoid with golden color, as an antioxidant to promote bacterial resistance to reactive oxygen species. The biosynthesis pathway of staphyl...

Understanding how metallodrugs interact with their protein targets is of vital importance for uncovering their molecular mode of actions as well as overall pharmacological/toxicological profiles, which in turn facilitates the development of novel metallodrugs. Silver has been used as an antimicrobial agent since antiquity, yet there is limited knowledge about silver-binding proteins. Given the multiple dispersed cysteine residues and histidine–methionine pairs, Escherichia coli malate dehydrogenase (EcMDH) represents an excellent model to investigate silver coordination chemistry as well as its targeting sites in enzymes. We show by systematic biochemical characterizations that silver ions (Ag+) bind EcMDH at multiple sites including three cysteine-containing sites. By X-ray crystallography, we unravel the binding preference of Ag+ to multiple binding sites in EcMDH, i.e., Cys113 > Cys251 > Cys109 > Met227. Silver exhibits preferences to the donor atoms and residues in the order of S > N > O and Cys > Met > His > Lys > Val, respectively, in EcMDH. For the first time, we report the coordination of silver to a lysine in proteins. Besides, we also observed argentophilic interactions (Ag⋯Ag, 2.7 to 3.3 Å) between two silver ions coordinating to one thiolate. Combined with site-directed mutagenesis and an enzymatic activity test, we unveil that the binding of Ag+ to the site IV (His177-Ag-Met227 site) plays a vital role in Ag+-mediated MDH inactivation. This work stands as the first unusual and explicit study of silver binding preference to multiple binding sites in its authentic protein target at the atomic resolution. These findings enrich our knowledge on the biocoordination chemistry of silver(i), which in turn facilitates the prediction of the unknown silver-binding proteins and extends the pharmaceutical potentials of metal-based drugs., Silver-binding preference in its authentic protein targets with MDH as a paradigm was uncovered.

Metal/metalloid complexes have been commonly used in medicine as either therapeutic or diagnostic agents. Understanding the molecular mechanisms of action of metallodrugs is crucial for the develop...

Metalloproteins play important roles in many biological processes. Mutations at the metal-binding sites may functionally disrupt metalloproteins, initiating severe diseases; however, there seemed to be no effective approach to predict such mutations until now. Here we develop a deep learning approach to successfully predict disease-associated mutations that occur at the metal-binding sites of metalloproteins. We generate energy-based affinity grid maps and physiochemical features of the metal-binding pockets (obtained from different databases as spatial and sequential features) and subsequently implement these features into a multichannel convolutional neural network. After training the model, the multichannel convolutional neural network can successfully predict disease-associated mutations that occur at the first and second coordination spheres of zinc-binding sites with an area under the curve of 0.90 and an accuracy of 0.82. Our approach stands for the first deep learning approach for the prediction of disease-associated metal-relevant site mutations in metalloproteins, providing a new platform to tackle human diseases. Metals can bind to proteins to fulfil important biological functions. Predicting the features of mutated binding sites can thus help us understand the connection between specific mutations and their role in diseases.

To resolve the problems of low prediction accuracy and slow convergence speed of traditional extreme learning machines in network security situation prediction methods, we combine a meta-heuristic search algorithm with neural networks and propose a prediction method based on the improved sparrow search algorithm optimization of an extreme learning machine. Firstly, the initial population is initialized by cat-mapping chaotic sequences to enhance the randomness and ergodicity of the initial population and improve the global search ability of the algorithm. Secondly, the Cauchy mutation and tent chaos disturbance are introduced to expand the local search ability, so that the individuals caught in the local extremum can jump out of the limit and continue the search. Finally, the explorer-follower number adaptive adjustment strategy is proposed to enhance the global search ability in the early stage and the local depth mining ability in the later stage of the algorithm by using the change of the explorer and follower numbers in each stage to improve the optimization-seeking accuracy of the algorithm. The improvement not only guarantees the diversity of the population, but also makes up for the defect that the sparrow search algorithm is easily trapped in the local optima in later iterations, and greatly improves the accuracy of the network security situation prediction.

Earlier detection of biomarkers responsible for cancer relapse facilitates more rational cancer treatment regimens to be designed. Herein, we develop a mass cytometry-based strategy for unbiased mining of cell subsets that potentially contribute to cancer recurrence through panoramic examination of the immunophenotypic features and multidrug resistance characteristics. The incorporation of metal tags enables multiplexed information of single cells to be interrogated based on metal fingerprint. Using acute lymphoblastic leukemia (B-ALL) as a showcase, we show overexpressed multidrug resistance biomarkers, i. e., BCRP, Bcl-2, MRP1, and P-gp in B-ALL cells compared with healthy control, and a positive correlation among different multidrug resistance biomarkers. Different cell subsets with multidrug resistance are well-defined, featured with CD34+ CD38+ CD10- and CD34+ CD38+/int CD10+ . Importantly, we uncovered that CD34 expression level is positively correlated to multidrug resistance, indicative of a higher potential of immature cells to induce B-ALL relapse. In addition, the cell subsets positively expressing CD73 and CD304 (CD34+ CD10+ CD304+ ; CD34+ CD38+/int CD10+ CD73+ ) also overexpress multidrug resistance biomarkers, suggesting that they may serve as additional new biomarkers for B-ALL stratification and prognosis. Our data provide the first evidence that highly expressed multidrug resistance biomarkers in certain cell subpopulations with specific immunophenotypes may potentially induce B-ALL recurrence. The incorporation of multidrug resistance features with cell phenotypes using mass cytometry proposed in this study provides a general strategy for risk assessment and the prediction of recurrence of different types of cancers.

The ongoing COVID-19 pandemic caused by SARS-CoV-2 highlights the urgent need to develop sensitive methods for diagnosis and prognosis. To achieve this, multidimensional detection of SARS-CoV-2 related parameters including virus loads, immune response, and inflammation factors is crucial. Herein, by using metal-tagged antibodies as reporting probes, we developed a multiplex metal-detection based assay (MMDA) method as a general multiplex assay strategy for biofluids. This strategy provides extremely high multiplexing capability (theoretically over 100) compared with other reported biofluid assay methods. As a proof-of-concept, MMDA was used for serologic profiling of anti-SARS-CoV-2 antibodies. The MMDA exhibits significantly higher sensitivity and specificity than ELISA for the detection of anti-SARS-CoV-2 antibodies. By integrating the high dimensional data exploration/visualization tool (tSNE) and machine learning algorithms with in-depth analysis of multiplex data, we classified COVID-19 patients into different subgroups based on their distinct antibody landscape. We unbiasedly identified anti-SARS-CoV-2-nucleocapsid IgG and IgA as the most potently induced types of antibodies for COVID-19 diagnosis, and anti-SARS-CoV-2-spike IgA as a biomarker for disease severity stratification. MMDA represents a more accurate method for the diagnosis and disease severity stratification of the ongoing COVID-19 pandemic, as well as for biomarker discovery of other diseases.

Microbial persisters enable the development of certain intrinsic strategies for survival with extreme tolerance to multiple antimicrobials. Porphyromonas gingivalis is considered to be the “keystone” periodontopathogen. Indeed, periodontitis, as a highly common inflammatory disease, is the major cause of severe tooth loss and edentulism in adults globally, and yet it is crucially involved in various systemic comorbidities like diabetes. We have recently revealed P. gingivalis persisters-induced perturbation of immuno-inflammatory responses and effective suppression of this key pathogen by bismuth drugs. This study further explored novel approaches to eradicating P. gingivalis persisters through synergistic combination of colloidal bismuth subcitrate (CBS) with traditional antibiotics. P. gingivalis (ATCC 33277) cells in planktonic and biofilm states were cultured to stationary phase, and then treated with metronidazole (100 mg/L), amoxicillin (100 mg/L), CBS, (100 μM) and combinations of these medications, respectively. Persister survival rate was calculated by colony-forming unit. Cell viability and cytotoxicity of CBS were assessed in human gingival epithelial cells (HGECs). Notably, CBS combined with metronidazole enabled the effective eradication of P. gingivalis persisters in planktonic mode, and nearly eliminated their existence in biofilm mode. Importantly, CBS exhibited no effects on the viability of HGECs, along with minimal cytotoxicity (P. gingivalis persisters could be well eliminated via the synergistic combination of CBS with metronidazole. Our findings may contribute to developing novel approaches to tackling periodontitis and inflammatory systemic comorbidities.

The COVID-19 pandemic has led to severe threat globally. As a result, scientists are increasing their efforts in developing testing methods, antiviral drugs, and vaccines, to diagnose, treat, and defend against COVID-19 respectively. Although RT-PCR and antigen tests are used for the screening of COVID-19, there are many disadvantages including high cost, long processing time, and false-negative results. With the exception of supportive care, no specific treatment for COVID-19 has been established. Metallomics focuses on the systematic study of the interactions and functional connections of metallic/metalloid ions and their species with genes, proteins, metabolites, and other biomolecules within organisms and ecosystems. It has been applied in the screening of various cancers, neurodegenerative diseases, and viral infections and metallodrug development with the advantages of high throughput, low risk of cross-infection, low cost, and ready availability. Therefore, we proposed the use of metallomics for the screening and metallodrug development of COVID-19. An operational work scheme is also presented.

The emergence of SARS-CoV-2 variants of concern compromises vaccine efficacy and emphasizes the need for further development of anti-SARS-CoV-2 therapeutics, in particular orally administered take-home therapies. Cocktail therapy has shown great promise in the treatment of viral infection. Herein, we reported the potent preclinical anti-SARS-CoV-2 efficacy of a cocktail therapy consisting of clinically used drugs

Being identified with less toxic and generally showing selective effects for solid tumor metastases, ruthenium and osmium compounds are promising drug candidates for clinical uses. Human serum proteins, such as albumin and transferrin, play vital roles in the transportation and accumulation of ruthenium and osmium agents into target tissues. However, the molecular mechanism of how transferrin transport ruthenium and their osmium analogues at atomic level remains obscure. In this study, we uncovered that the cellular uptake of Os

Microbial persisters enable the development of certain intrinsic strategies for survival with extreme tolerance to multiple antimicrobials. Porphyromonas gingivalis is considered to be the “keystone” periodontopathogen. Indeed, periodontitis, as a highly common inflammatory disease, is the major cause of severe tooth loss and edentulism in adults globally, and yet it is crucially involved in various systemic comorbidities like diabetes. We have recently revealed P. gingivalis persisters-induced perturbation of immuno-inflammatory responses and effective suppression of this key pathogen by bismuth drugs. This study further explored novel approaches to eradicating P. gingivalis persisters through synergistic combination of colloidal bismuth subcitrate (CBS) with traditional antibiotics. P. gingivalis (ATCC 33277) cells in planktonic and biofilm states were cultured to stationary phase, and then treated with metronidazole (100 mg/L), amoxicillin (100 mg/L), CBS, (100 μM) and combinations of these medications, respectively. Persister survival rate was calculated by colony-forming unit. Cell viability and cytotoxicity of CBS were assessed in human gingival epithelial cells (HGECs). Notably, CBS combined with metronidazole enabled the effective eradication of P. gingivalis persisters in planktonic mode, and nearly eliminated their existence in biofilm mode. Importantly, CBS exhibited no effects on the viability of HGECs, along with minimal cytotoxicity (