Artificial intelligence-driven prediction of multiple drug interactions.

When a drug is administered to exert its efficacy, it will encounter multiple barriers and go through multiple interactions. Predicting the drug-related multiple interactions is critical for drug development and safety monitoring because it provides foundations for practical, safe compatibility and rational use of multiple drugs. With the progress of artificial intelligence (AI) technology, a variety of novel prediction methods for single interaction have emerged and shown great advantages compared to the traditional, expensive and time-consuming laboratory research. To promote the comprehensive and simultaneous predictions of multiple interactions, we systematically reviewed the application of AI in drug-drug, drug-food (excipients) and drug-microbiome interactions. We began by outlining the model methods, evaluation indicators, algorithms and databases commonly used to build models for three types of drug interactions. The models based on the metabolic enzyme P450, drug similarity and drug targets have empathized among the machine learning models of drug-drug interactions. In particular, we discussed the limitations of current approaches and identified potential areas for future research. It is anticipated the in-depth review will be helpful for the development of the next-generation of systematic prediction models for simultaneous multiple interactions.

DrugSK: A Stacked Ensemble Learning Framework for Predicting Drug Combinations of Multiple Diseases.

Combination therapy is an important direction of continuous exploration in the field of medicine, with the core goals of improving treatment efficacy, reducing adverse reactions, and optimizing clinical outcomes. Machine learning technology holds great promise in improving the prediction of drug synergy combinations. However, most studies focus on single disease-oriented collaborative predictive models or involve excessive feature categories, making it challenging to predict the majority of new drugs. To address these challenges, the DrugSK comprehensive model was developed, which utilizes SMILES-BERT to extract structural information from 3492 drugs and trains on reactions from 48,756 drug combinations. DrugSK is an integrated learning model capable of predicting interactions among various drug categories. First, the primary learner is trained from the initial data set. Random forest, support vector machine, and XGboost model are selected as primary learners and logistic regression as secondary learners. A new data set is then "generated" to train level 2 learners, which can be thought of as a prediction for each model. Finally, the results are filtered using logistic regression. Furthermore, the combination of the new antibacterial drug Drafloxacin with other antibacterial agents was tested. The synergistic effect of Drafloxacin and Isavuconazonium in the fight against Candida albicans has been confirmed, providing enlightenment for the clinical treatment of skin infection. DrugSK's prediction is accurate in practical application and can also predict the probability of the outcome. In addition, the tendency of Drafloxacin and antifungal drugs to be synergistic was found. The development of DrugSK will provide a new blueprint for predicting drug combination synergies.

Tunable metal-organic frameworks assist in catalyzing DNAzymes with amplification platforms for biomedical applications.

Various binding modes of tunable metal organic frameworks (MOFs) and functional DNAzymes (Dzs) synergistically catalyze the emergence of abundant functional nanoplatforms. Given their serial variability in formation, structural designability, and functional controllability, Dzs@MOFs tend to be excellent building blocks for the precise "intelligent" manufacture of functional materials. To present a clear outline of this new field, this review systematically summarizes the progress of Dz integration into MOFs (MOFs@Dzs) through different methods, including various surface infiltration, pore encapsulation, covalent binding, and biomimetic mineralization methods. Atomic-level and time-resolved catalytic mechanisms for biosensing and imaging are made possible by the complex interplay of the distinct molecular structure of Dzs@MOF, conformational flexibility, and dynamic regulation of metal ions. Exploiting the precision of DNAzymes, MOFs@Dzs constructed a combined nanotherapy platform to guide intracellular drug synthesis, photodynamic therapy, catalytic therapy, and immunotherapy to enhance gene therapy in different ways, solving the problems of intracellular delivery inefficiency and insufficient supply of cofactors. MOFs@Dzs nanostructures have become excellent candidates for biosensing, bioimaging, amplification delivery, and targeted cancer gene therapy while emphasizing major advancements and seminal endeavors in the fields of biosensing (nucleic acid, protein, enzyme activity, small molecules, and cancer cells), biological imaging, and targeted cancer gene delivery and gene therapy. Overall, based on the results demonstrated to date, we discuss the challenges that the emerging MOFs@Dzs might encounter in practical future applications and briefly look forward to their bright prospects in other fields.

Ensemble learning-based gene signature and risk model for predicting prognosis of triple-negative breast cancer.

Although medical science has been fully developed, due to the high heterogeneity of triple-negative breast cancer (TNBC), it is still difficult to use reasonable and precise treatment. In this study, based on local optimization-feature screening and genomics screening strategy, we screened 25 feature genes. In multiple machine learning algorithms, feature genes have excellent discriminative diagnostic performance among samples composed of multiple large datasets. After screening at the single-cell level, we identified genes expressed substantially in myeloid cells (MCGs) that have a potential association with TNBC. Based on MCGs, we distinguished two types of TNBC patients who showed considerable differences in survival status and immune-related characteristics. Immune-related gene risk scores (IRGRS) were established, and their validity was verified using validation cohorts. A total of 25 feature genes were obtained, among which CXCL9, CXCL10, CCL7, SPHK1, and TREM1 were identified as the result after single-cell level analysis and screening. According to these entries, the cohort was divided into MCA and MCB subtypes, and the two subtypes had significant differences in survival status and tumor-immune microenvironment. After Lasso-Cox screening, IDO1, GNLY, IRF1, CTLA4, and CXCR6 were selected for constructing IRGRS. There were significant differences in drug sensitivity and immunotherapy sensitivity among high-IRGRS and low-IRGRS groups. We revealed the dynamic relationship between TNBC and TIME, identified a potential biomarker called Granulysin (GNLY) related to immunity, and developed a multi-process machine learning package called "MPMLearning 1.0" in Python.

A bibliometric and visualized analysis of liver fibrosis from 2002 to 2022.

Fibrosis of the liver is a degenerative alteration that occurs in the majority of chronic liver disorders. Further progression can lead to cirrhosis, liver failure, and hepatocellular carcinoma, which can seriously affect the health and lives of patients. The field of liver fibrosis research has flourished in the last 20 years, with approximately 9000 articles retrieved from the Web of Science Core Collection database alone. In order to identify future research hotspots and potential paths in a thorough and scientifically reliable manner, it is important to organize and visualize the research on this topic from a holistic and very general perspective. This study used bibliometric analysis with CiteSpace and VOSviewer software to provide a quantitative analysis, hotspot mining, and commentary of articles published in the field of liver fibrosis over the last 20 years. This bibliometric analysis contains a total of 8994 articles with 45667 authors from 6872 institutions in 97 countries, published in 1371 journals and citing 156 309 references. The literature volume has steadily increased over the last 20 years. Research has focused on gastroenterology and hepatology, pharmacology and pharmacy, and medicine, research, and experimental areas. We found that the pathological mechanisms, diagnostic and quantitative methods, etiology, and antifibrotic strategies constitute the knowledge structure of liver fibrosis. Finding mechanisms for liver fibrosis regression, identifying precise noninvasive diagnostic and prognostic biomarkers, and creating efficient liver fibrosis patient treatments are the main goals of current research.

Application of curcumin nanoformulations in Alzheimer's disease: prevention, diagnosis and treatment.

Objectives: Alzheimer's disease (AD) is a serious neurodegenerative disease. Although many therapeutic strategies have been studied, their clinical applications are immature. Moreover, these methods can only alleviate symptoms rather than cure it, posing a challenge to brain health in older adults worldwide. Curcumin (CUR) is a very promising natural compound for nerve protection and treatment. It can prevent and treat AD, and on the other hand, its fluorescence properties can be used in the diagnosis of AD. However, CUR is characterized by very low water solubility, fluid instability, rapid metabolism, low bioavailability and difficulty in penetrating the biological barriers, which limit its application. Nanocarriers are a potential material to improve the biocompatibility of CUR and its ability to cross biological barriers. Therefore, delivering CUR by nanocarriers is an effective method to achieve better efficacy. Methods: In this review, the preventive, therapeutic and diagnostic effects of CUR nanoformulations on AD, as well as various patents, clinical trials and experimental research progress in this field are discussed. The aim is to provide detailed reference and practical suggestions for future research. Results: CUR has a variety of pharmacological activities in the prevention and treatment of AD, and its nanoformulation can effectively improve solubility, bioavailability and the ability to penetrate the blood-brain barrier. Significant benefits have been observed in the current study. Discussion: CUR formulations have a good prospect in the prevention, diagnosis and treatment of AD, but the safety and principle of its administration need more detailed study in the future.

Biomimetic platelet-camouflaged drug-loaded polypyrrole for the precise targeted antithrombotic therapy.

Lower extremity deep venous thrombosis (LEDVT) affects patient's quality of life for a long time, and even causes pulmonary embolism, which threatens human health. Current anticoagulant drugs in clinical treatment are hampered by the risk of bleeding due to poor targeting and low drug penetration. Here, we used platelet (PLT)-like biological targeting to enhance the delivery and accumulation of nanomedicines in thrombus and reduce the risk of bleeding. Meanwhile, the parallel strategy of "thrombus thermal ablation and anticoagulation" was applied to increase the permeability of drugs in thrombus and achieve the optimal antithrombotic effect. Polypyrrole (PPy) and rivaroxban (Riv, an anticoagulant drug) were co-assembled into platelet membrane-coated nanoparticles (NPs), PLT-PPy/Riv NPs, which actively targeted the thrombotic lesion at multiple targets in the platelet membrane and were thermally and drug-specific thrombolysed by 808 nm laser irradiation. The combination therapy resulted in up to 90% thrombolysis in a femoral vein thrombosis model compared to single phototherapy or drug therapy. The results showed that the nanoformulation provided a new direction for remote precise and controlled sustained thrombolysis, which was in line with the trend of nanomedicine towards clinical translation.

Potential therapies and diagnosis based on Golgi-targeted nano drug delivery systems.

With the rapid development of nanotechnology, organelle-targeted nano drug delivery systems (NDDSs) have emerged as a potential method which can transport drugs specifically to the subcellular compartments like nucleus, mitochondrion, lysosome, endoplasmic reticulum (ER) and Golgi apparatus (GA). GA not only plays a key role in receiving, modifying, packaging and transporting proteins and lipids, but also contributes to a set of cellular processes. Golgi-targeted NDDSs can alter the morphology of GA and will become a promising strategy with high specificity, low-dose administration and decreased occurrence of side effects. In this review, Golgi-targeted NDDSs and their applications in disease therapies and diagnosis such as cancer, metastasis, fibrosis and neurological diseases are introduced. Meanwhile, modifications of NDDSs to achieve targeting strategies, Golgi-disturbing agents to change the morphology of GA, special endocytosis to achieve endosomal/lysosomal escape strategies are also involved.

Swellable PVA/PVP hydrogel microneedle patches for the extraction of interstitial skin fluid toward minimally invasive monitoring of blood glucose level.

Interstitial skin fluid (ISF) is an emerging alternative source of blood samples that has attracted great interest from researchers. It is a very promising way to use microneedle patches for extracting ISF. However, the recovery of ISF still faces great challenges, such as long extraction time and low extraction volume, which may affect the analysis of biomarkers. Traditional centrifugation methods cannot completely recover ISF, which leads to inaccuracy in ISF detection. In this paper, the prepared polyvinyl alcohol/polyvinylpyrrolidone (PVA/PVP) microneedle patches had the ability to insert into the skin in a dry state; at the same time, the microneedle patches had good swelling properties and could extract ISF in a short time without any additional devices. Due to the thermal degradation of PVA, the way of gentle heating was used to recover ISF, which could greatly improve the accuracy of detection. By comparing the D-glucose content assay kit with the blood glucose concentration of rats detected using a commercial glucometer, the detection accuracy of the microneedle patches was verified. The microneedle patches can be used to sample ISF and analyze the level of biomarkers in ISF, and are expected to provide a basis for the prevention and diagnosis of clinical diseases in the future.

Application of Fe3O4@CNFs combined with deep eutectic solvent-based dual microextraction: a novel and green strategy for rapid determination of pesticides in edible oil samples.

A novel, green, and effective strategy employing Fe3O4-modified carbon nanofibers (CNFs) combined with deep eutectic solvent (DES) is proposed as an extraction agent to extract five pesticides in edible oil samples via dual microextraction modes, followed by high-performance liquid chromatography for determination. The Fe3O4@CNFs nanomaterial and a sequence of hydrophilic DES were prepared at first and then characterized by multiple techniques. Subsequently, the extraction performance of DES and Fe3O4@CNFs-DES was compared and Fe3O4@CNFs-DES exhibited better extraction ability. After that, several influencing parameters such as the composition of DES, the amount of Fe3O4@CNFs-DES, the dispersion methods, and the extraction time were investigated and optimized. Eventually, Fe3O4@CNFs as the solid adsorbent combined with tetrabutylammonium chloride-lactic acid-based DES as the extraction solvent were selected to extract target pesticides from oil samples. The established method received good linearity in the range 25-1000 ng·g-1. The limits of detection for all analytes were in the range 2.25-7.50 ng·mL-1. Satisfactory recoveries of target pesticides were obtained (ranging from 82 to 117%) with a relative standard deviation of 0.26-9.46%. The proposed method has been successfully applied to the rapid detection of target pesticides in oil samples, demonstrating its great potential for quick screening and analysis.

Transdermal Adhesive Patches Loaded with Ketoprofen Evaluated by Dynamic Detection of Percutaneous Absorption.

Topical delivery has many benefits toward NSAIDs administration, and the best-selling transdermal preparation in 2015 was the NSAID patch MOHRUS®. Herein, we report a ketoprofen adhesive patch (KAP) and evaluate the penetration and absorption compared to MOHRUS®. Microdialysis sampling technique was applied to determine drug penetration in the dermis and subcutaneous tissue. Simultaneously, blood samples were withdrawn over time to obtain the drug absorption in plasma. The ketoprofen concentrations in the dermis, subcutaneous tissue, and plasma were compared with the commercially available patch (MOHRUS®). Based on the detection, pharmacokinetic parameters including Cmax, Tmax, and AUC0-8h were determined for both the formulations. No significant differences were found in the dermis, subcutaneous tissue, and plasma in rats according to the bioequivalence assessment. The KAP demonstrated multiple therapeutic advantages including the controlled drug release and the sustained drug concentration in the skin as well as in plasma. The pharmacokinetic study coupled with microdialysis sampling provided an effective strategy to evaluate transdermal delivery.

Nanostructured lipid-carrageenan hybrid carriers (NLCCs) for controlled delivery of mitoxantrone hydrochloride to enhance anticancer activity bypassing the BCRP-mediated efflux.

Novel nanostructured lipid-carrageenan hybrid carriers (NLCCs) were exploited for controlled delivery of water soluble chemotherapeutic agent mitoxantrone hydrochloride (MTO) with high loading capacity, sustained release property, and potential for improving oral bioavailability and antitumor efficacy. By introducing the negative polymer of carrageenan, MTO was highly incorporated into NLCCs with encapsulation efficiency of 95.8% by electrostatic interaction. In vivo pharmacokinetics of MTO solution (MTO-Sol) and MTO-NLCCs in rats demonstrated that the apparent bioavailability of MTO-NLCCs was increased to approximate 3.5-fold compared to that of MTO-Sol. The cytotoxicity investigations by MTT method indicated that NLCCs could significantly enhanced the antitumor efficacy against resistant MCF-7/MX cells. The relative cellular association of MTO-NLCCs was 9.2-fold higher than that of MTO-Sol in breast cancer resistance protein (BCRP) over-expressing MCF-7/MX cells, implying that BCRP-mediated drug efflux was diminished by the introduction of NLCCs. The endocytosis inhibition study implied that the NLCCs entered the MCF-7/MX cells by clathrin-mediated endocytosis process, which can bypass the efflux of MTO mediated by BCRP. The new developed NLCCs provide an effective strategy for oral delivery of water-soluble MTO with improved encapsulation efficiency, oral bioavailability, and cytotoxicity against resistant breast cancer cells.

A swellable hydrogel microneedle based on cerium-metal organic frame composite nanozyme for detection of biomarkers.

Skin interstitial fluid (ISF) has been an alternative source in the field of biomarkers analysis. This work developed swellable hydrogel microneedles (MNs) composed of polyvinyl alcohol and sodium alginate by chemical crosslinking (PVA/SA). Here, PVA/SA was firstly used to fabricate hydrogel MNs, achieving a swellable ratio of 150 % and a rapid extraction of 6.4 mg ISF in 15 min. To replace expensive and non-reusable test kits, hydrogel MNs based on composite nanozyme with high oxidase-like activity were successfully developed to recover and detect biomarkers. The nanozyme was composed of MnO2-modified mixed valence cerium-metal organic frame (MCM). MCM was characterized by multiple techniques to further confirm its composition and structure. MCM combined with the reduction reaction of glutathione (GSH) with oxidized substrate to achieve a colorimetric GSH detection, which had a detection limit (LOD, 0.36 µM) of GSH. The hydrogel MNs based on MCM (MCM-MNs) were firstly applied to the rapid detection of GSH in ISF. All in all, this method combines the advantages of nanozyme and hydrogel MNs to achieve a timely and minimally invasive analysis, which provides a new dimension for the in vivo detection of GSH by skin ISF and holds great implications in biomedical and bioanalysis fields.

Nanotechnology of inhalable vaccines for enhancing mucosal immunity.

Vaccines are the cornerstone of world health. The majority of vaccines are formulated as injectable products, facing the drawbacks of cold chain transportation, needle-stick injuries, and primary systemic immunity. Inhalable vaccines exhibited unique advantages due to their small dose, easy to use, quick effect, and simultaneous induction of mucosal and systemic responses. Facing global pandemics, especially the coronavirus disease 2019 (COVID-19), a majority of inhalable vaccines are in preclinical or clinical trials. A better understanding of advanced delivery technologies of inhalable vaccines may provide new scientific insights for developing inhalable vaccines. In this review article, detailed immune mechanisms involving mucosal, cellular, and humoral immunity were described. The preparation methods of inhalable vaccines were then introduced. Advanced nanotechnologies of inhalable vaccines containing inhalable nucleic acid vaccines, inhalable adenovirus vector vaccines, novel adjuvant-assisted inhalable vaccines, and biomaterials for inhalable vaccine delivery were emphatically discussed. Meanwhile, the latest clinical progress in inhalable vaccines for COVID-19 and tuberculosis was discussed.

Metal organic framework-based variable-size nanoparticles for tumor microenvironment-responsive drug delivery.

Nanoparticles (NPs) have been designed for the treatment of tumors increasingly. However, the drawbacks of single-size NPs are still worth noting, as their circulation and metabolism in the blood are negatively correlated with their accumulation at the tumor site. If the size of single-size NPs is too small, it will be quickly cleared in the blood circulation, while, the size is too large, the distribution of NPs in the tumor site will be reduced, and the widespread distribution of NPs throughout the body will cause systemic toxicity. Therefore, a class of variable-size NPs with metal organic frameworks (MOFs) as the main carrier, and size conversion in compliance with the characteristics of the tumor microenvironment (TME), was designed. MOF-based variable-size NPs can simultaneously extend the time of blood circulation and metabolism, then enhance the targeting ability of the tumor site. In this review, MOF NPs are categorized and exemplified from a new perspective of NP size variation; the advantages, mechanisms, and significance of MOF-based variable-size NPs were summarized, and the potential and challenges in delivering anti-tumor drugs and multimodal combination therapy were discussed.

Porous reticular Co@Fe metal-organic gel: dual-function simulated peroxidase nanozyme for both colorimetric sensing and antibacterial applications.

Constructing metal-organic gels (MOGs) with enzyme-catalyzed activity and studying their catalytic mechanism are crucial for the development of novel nanozyme materials. In this study, a Co@Fe MOG with excellent peroxidase activity was developed by a simple and mild one-pot process. The results showed that the material exhibited almost a single peroxidase activity under optimal pH conditions, which allowed it to attract and oxidize the chromogenic substrate 3,3',5,5'-tetramethylbenzidine (TMB). Based on the active electron transfer between the metal centers and the organic ligand in the synthetic material, the Co@Fe MOG-H2O2-TMB system was verified to be able to detect H2O2 and citric acid (CA). The catalytic microenvironment formed by the adsorption and the catalytic center accelerated the electron-transfer rate, which expedited the generation of hydroxyl radicals (˙OH, a kind of reactive oxygen species (ROS)) in the presence of H2O2. The persistence and high intensity of ˙OH generation were proven, which would endow Co@Fe MOG with a certain antibacterial ability, promoting the healing of bacteria-infected wounds. In conclusion, this study contributes to the development efforts toward the application systems of nanozymes for marker detection and antibacterial activity.

Two-mode sensing strategies based on tunable cobalt metal organic framework active sites to detect Hg2.

Heavy metal pollution poses a major threat to human health, and developing a user-deliverable heavy metal detection strategy remains a major challenge. In this work, two-mode Hg2+ sensing platforms based on the tunable cobalt metal-organic framework (Co-MOF) active site strategy are constructed, including a colorimetric, and an electrochemical assay using a personal glucose meter (PGM) as the terminal device. Specifically, thymine (T), a single, adaptable nucleotide, is chosen to replace typical T-rich DNA aptamers. The catalytic sites of Co-MOF are tuned competitively by the specific binding of T-Hg2+-T, and different signal output platforms are developed based on the different enzyme-like activities of Co-MOF. DFT calculations are utilized to analyze the interaction mechanism between T and Co-MOF with defect structure. Notably, the two-mode sensing platforms exhibit outstanding detection performance, with LOD values as low as 0.5 nM (colorimetric) and 3.69 nM (PGM), respectively, superior to recently reported nanozyme-based Hg2+ sensors. In real samples of tap water and lake water, this approach demonstrates an effective recovery rate and outstanding selectivity. Surprisingly, the method is potentially versatile and, by exchanging out T-Hg2+-T, can also detect Ag+. This simple, portable, and user-friendly Hg2+ detection approach shows plenty of promise for application in the future.

Glucose detection: In-situ colorimetric analysis with double-layer hydrogel microneedle patch based on polyvinyl alcohol and carboxymethyl chitosan.

Skin interstitial fluid (ISF) has emerged as a significant reservoir of biomarkers for disease diagnosis and prevention. Microneedle (MN) patches are regarded as an optimal platform for ISF extraction from the skin due to their non-invasive nature. However, challenges such as prolonged sampling durations and complex detection procedures impede timely metabolic analysis. In this investigation, we amalgamated MN technology with immobilized enzyme technology to fabricate a dual-layer MN patch integrating sampling and detection functionalities, thereby enabling in-situ colorimetric detection of hyperglycemia. The tip layer of the patch, comprising polyvinyl alcohol/carboxymethyl chitosan (PVA/CMCS) MN, was synthesized utilizing a chemical crosslinking approach for the first time, with glucose oxidase (GOx) being incorporated. The hydrophilicity of CMCS expedited the extraction process, facilitating the retrieval of approximately 10 mg of ISF within 10 min. The backing layer consisted of an immobilized polyvinyl alcohol-chitosan-horseradish peroxidase (PVA-CS-HRP) hydrogel film loaded with 3,3', 5,5'-tetramethylbenzidine (TMB). Incorporating macromolecular polymer PVA and CS for HRP immobilization addressed the issue of poor stability associated with traditional natural enzymes, thereby enhancing the sensitivity of the reaction system. The in-situ colorimetric sensor facilitated minimally invasive ISF extraction and swift conversion of glucose levels into detectable color changes.

Nanozymes-Mediated Cascade Reaction System for Tumor-Specific Diagnosis and Targeted Therapy.

Cascade reactions are described as efficient and versatile tools, and organized catalytic cascades can significantly improve the efficiency of chemical interworking between nanozymes. They have attracted great interest in many fields such as chromogenic detection, biosensing, tumor diagnosis, and therapy. However, how to selectively kill tumor cells by enzymatic reactions without harming normal cells, as well as exploring two or more enzyme-engineered nanoreactors for cascading catalytic reactions, remain great challenges in the field of targeted and specific cancer diagnostics and therapy. The latest research advances in nanozyme-catalyzed cascade processes for cancer diagnosis and therapy are described in this article. Here, various sensing strategies are summarized, for tumor-specific diagnostics. Targeting mechanisms for tumor treatment using cascade nanozymes are classified and analyzed, "elements" and "dimensions" of cascade nanozymes, types, designs of structure, and assembly modes of highly active and specific cascade nanozymes, as well as a variety of new strategies of tumor targeting based on the cascade reaction of nanozymes. Finally, the integrated application of the cascade nanozymes systems in tumor-targeted and specific diagnostic therapy is summarized, which will lay the foundation for the design of more rational, efficient, and specific tumor diagnostic and therapeutic modalities in the future.