Pharmacology Progresses and Applications of Chloroquine in Cancer Therapy.

Chloroquine is a common antimalarial drug and is listed in the World Health Organization Standard List of Essential Medicines because of its safety, low cost and ease of use. Besides its antimalarial property, chloroquine also was used in anti-inflammatory and antivirus, especially in antitumor therapy. A mount of data showed that chloroquine mainly relied on autophagy inhibition to exert its antitumor effects. However, recently, more and more researches have revealed that chloroquine acts through other mechanisms that are autophagy-independent. Nevertheless, the current reviews lacked a comprehensive summary of the antitumor mechanism and combined pharmacotherapy of chloroquine. So here we focused on the antitumor properties of chloroquine, summarized the pharmacological mechanisms of antitumor progression of chloroquine dependent or independent of autophagy inhibition. Moreover, we also discussed the side effects and possible application developments of chloroquine. This review provided a more systematic and cutting-edge knowledge involved in the anti-tumor mechanisms and combined pharmacotherapy of chloroquine in hope of carrying out more in-depth exploration of chloroquine and obtaining more clinical applications.

Hybrid-index-based array configuration optimization for Michelson interferometric imaging.

Array configuration design is a critical issue for a high quality of the snapshot point spread function (PSF) and restored image in Michelson imaging interferometer. In classic design, the optimized configurations usually address the few specifications and single objective, which is unable to balance the requirements of both non-redundancy and sampling distribution. In this paper, we formalize mathematically the composite metric to trade-off the multiple demands of observation, and propose the hybrid-index-based array layout optimization strategy. The simulation results demonstrate that, in comparison with the typical distribution, the optimized array using the proposed optimization framework enables the acquisition of more comprehensive spectrum information while utilizing an equal number of apertures, providing superior imaging quality in different observation situations. Furthermore, the designed optimized array masks and the compared conventional array masks were fabricated and used for our experimental validation, further verifying the feasibility of this strategy. This array configuration optimization framework may not only find applications to Michelson interferometric imaging, but also provide a positive impact on all u-v sampling-based imaging modes, including radio interferometry, magnetic resonance imaging, and photonic integrated interferometric imaging.

The consistent fuzzy suitability assessment of forest land resources with multi-source heterogeneous data.

In view of the suitability assessment of forest land resources, a consistent fuzzy assessment method with heterogeneous information is proposed. Firstly, some formulas for transforming large-scale real data and interval data into fuzzy numbers are provided. To derive the unified representation of multi-granularity linguistic assessment information, a fuzzy quantitative transformation for multi-granularity uncertain linguistic information is proposed. The proofs of the desirable properties and some normalized formulas for the trapezoidal fuzzy numbers are presented simultaneously. Next, the objective weight of each assessment indicator is further determined by calculating the Jaccard-Cosine similarity between the trapezoidal fuzzy numbers. Moreover, the trapezoidal fuzzy numbers corresponding to the comprehensive assessment values of each alternative are obtained. The alternatives are effectively ranked according to the distance from the centroid of the trapezoidal fuzzy number to the origin. Finally, based on the proposed consistent fuzzy assessment method, the suitability assessment of forest land resources is achieved under a multi-source heterogeneous data setting.

Photoaffinity probe-based antimalarial target identification of artemisinin in the intraerythrocytic developmental cycle of Plasmodium falciparum.

Malaria continues to pose a serious global health threat, and artemisinin remains the core drug for global malaria control. However, the situation of malaria resistance has become increasingly severe due to the emergence and spread of artemisinin resistance. In recent years, significant progress has been made in understanding the mechanism of action (MoA) of artemisinin. Prior research on the MoA of artemisinin mainly focused on covalently bound targets that are alkylated by artemisinin-free radicals. However, less attention has been given to the reversible noncovalent binding targets, and there is a paucity of information regarding artemisinin targets at different life cycle stages of the parasite. In this study, we identified the protein targets of artemisinin at different stages of the parasite's intraerythrocytic developmental cycle using a photoaffinity probe. Our findings demonstrate that artemisinin interacts with parasite proteins in vivo through both covalent and noncovalent modes. Extensive mechanistic studies were then conducted by integrating target validation, phenotypic studies, and untargeted metabolomics. The results suggest that protein synthesis, glycolysis, and oxidative homeostasis are critically involved in the antimalarial activities of artemisinin. In summary, this study provides fresh insights into the mechanisms underlying artemisinin's antimalarial effects and its protein targets.

Comparative time-dependent proteomics reveal the tolerance of cancer cells to magnetic iron oxide nanoparticles.

Cancer is one of the most challenging diseases in the world. Recently, iron oxide nanoparticles (IONPs) are emerging materials with rapid development and high application value, and have shown great potential on tumor therapy due to their unique magnetic and biocompatible properties. However, some data hint us that IONPs were toxic to normal cells and vital organs. Thus, more data on biosafety evaluation is urgently needed. In this study, we compared the effects of silicon-coated IONPs (Si-IONPs) on two cell types: the tumor cells (Hela) and the normal cells (HEK293T, as 293 T for short), compared differences of protein composition, allocation and physical characteristics between these two cells. The major findings of our study pointed out that 293 T cells death occurred more significant than that of Hela cells after Si-IONPs treatment, and the rate and content of endocytosis of Si-IONPs in 293 T cells was more prominent than in Hela cells. Our results also showed Si-IONPs significant promoted the production of reactive oxygen species and disturbed pathways related to oxidative stress, iron homeostasis, apoptosis and ferroptosis in both two types of cells, however, Hela cells recovered from these disturbances more easily than 293 T. In conclusion, compared with Hela cells, IONPs are more likely to induce 293 T cells death and Hela cells have their own unique mechanisms to defense invaders, reminding scientists that future in vivo and in vitro studies of nanoparticles need to be cautious, and more safety data are needed for further clinical treatment.

Double reverse traction repositor assisted closed reduction and internal fixation versus open reduction and internal fixation for treatment of lateral tibial plateau fractures among the elderly.

BACKGROUND: In elderly tibial plateau fractures (TPFs), the lateral condyles are involved frequently. This study aimed to compare the outcomes of open reduction and internal fixation (ORIF) and double reverse traction repositor (DRTR) assisted closed reduction and internal fixation (CRIF) in elderly patients with lateral TPFs. METHODS: From January 2015 to July 2020, we retrospectively reviewed 68 patients treated surgically at our trauma center for lateral TPFs (Schatzker type I-III). 31 patients were eventually assigned to the DRTR assisted CRIF group, whereas 37 patients were assigned to the ORIF group. The primary outcomes included surgical details, radiological assessment, follow-up knee function, and complications. RESULTS: The DRTR assisted CRIF group experienced a 43.6 mL decrease in intraoperative blood loss (161.3 ml vs 204.9 ml, p = 0.033), and the operation duration was 32.1 min shorter than the ORIF group (83.8 min vs 115.9 min, p < 0.001). There was no statistically significant difference in terms of widening of the tibia plateau (WTP), depth of articular depression (DAD), medial proximal tibial angle (MPTA) and posterior tibial slope angle (PTSA) immediately after surgery and at the last follow-up. No differences in malreduction (p = 0.566) or reduction loss (p = 0.623) were observed between the groups, and Lysholm and HSS scores were similar between the two groups (83.6 ± 15.8 vs 83.4 ± 5.1, p = 0.934; 89.3 ± 7.8 vs 86.9 ± 6.2, p = 0.172; respectively). However, ORIF was associated with a greater increase in postoperative complications than DRTR assisted CRIF (3.2% vs 27%, p = 0.008). CONCLUSION: Both types of internal fixation provide good radiological outcomes and knee function in the treatment of lateral TPFs in the elderly. However, DRTR assisted CRIF has the advantage of a shorter duration of surgery, less blood loss, and fewer postoperative complications, and appears to be a better treatment option for elderly patients with lateral TPFs.

Gambogic acid exhibits promising anticancer activity by inhibiting the pentose phosphate pathway in lung cancer mouse model.

BACKGROUND: The pentose phosphate pathway (PPP) plays a crucial role in the material and energy metabolism in cancer cells. Targeting 6-phosphogluconate dehydrogenase (6PGD), the rate-limiting enzyme in the PPP metabolic process, to inhibit cellular metabolism is an effective anticancer strategy. In our previous study, we have preliminarily demonstrated that gambogic acid (GA) induced cancer cell death by inhibiting 6PGD and suppressing PPP at the cellular level. However, it is unclear whether GA could suppress cancer cell growth by inhibiting PPP pathway in mouse model. PURPOSE: This study aimed to confirm that GA as a covalent inhibitor of 6PGD protein and to validate that GA suppresses cancer cell growth by inhibiting the PPP pathway in a mouse model. METHODS: Cell viability was detected by CCK-8 assays as well as flow cytometry. The protein targets of GA were identified using a chemical probe and activity-based protein profiling (ABPP) technology. The target validation was performed by in-gel fluorescence assay, the Cellular Thermal Shift Assay (CETSA). A lung cancer mouse model was constructed to test the anticancer activity of GA. RNA sequencing was performed to analyze the global effect of GA on gene expression. RESULTS: The chemical probe of GA exhibited high biological activity in vitro. 6PGD was identified as one of the binding proteins of GA by ABPP. Our findings revealed a direct interaction between GA and 6PGD. We also found that the anti-cancer activity of GA depended on reactive oxygen species (ROS), as evidenced by experiments on cells with 6PGD knocked down. More importantly, GA could effectively reduce the production of the two major metabolites of the PPP in lung tissue and inhibit cancer cell growth in the mouse model. Finally, RNA sequencing data suggested that GA treatment significantly regulated apoptosis and hypoxia-related physiological processes. CONCLUSION: These results demonstrated that GA was a covalent inhibitor of 6PGD protein. GA effectively suppressed cancer cell growth by inhibiting the PPP pathway without causing significant side effects in the mouse model. Our study provides in vivo evidence that elucidates the anticancer mechanism of GA, which involves the inhibition of 6PGD and modulation of cellular metabolic processes.

Unveiling the molecular mechanisms of size-dependent effect of polystyrene micro/nano-plastics on Chlamydomonas reinhardtii through proteomic profiling.

Microplastics have become a prevalent environmental pollutant due to widespread release and production. Algae, as primary producers, play a crucial role in maintaining the ecological balance of freshwater environments. Despite reports on the inhibition of microalgae by microplastics, the size-dependent effects on microalgae and associated molecular mechanism remain poorly understood. This study investigates the impacts of three polystyrene micro/nano-plastics (PS-MNPs) with different sizes (100 nm, 350 nm, and 6 µm) and concentrations (25-200 mg/L) on Chlamydomonas reinhardtii (C. reinhardtii) throughout its growth period. Results reveal size- and concentration-dependent growth inhibition and induction of oxidative stress by PS-MNPs, with microalgae exhibiting increased vulnerability to smaller-sized and higher-concentration PS-MNPs. Proteomics analysis elucidates the size-dependent suppression of proteins involved in the photosynthesis process by PS-MNPs. Photosynthetic activity assays demonstrate that smaller PS-MNPs more significantly reduce chlorophyll content and the maximal photochemical efficiency of photosystem II. Finally, electron microscope and Western blot assays collectively confirm the size effect of PS-MNPs on microalgae growth is attributable to suppressed protein expression rather than shading effects. This study contributes to advancing our understanding of the intricate interactions between micro/nano-plastics and algae at the molecular level, emphasizing the efficacy of proteomics in dissecting the mechanistic aspects of microplastics-induced biological effects on environmental indicator organisms.

The biomedical application of inorganic metal nanoparticles in aging and aging-associated diseases.

Aging and aging-associated diseases (AAD), including neurodegenerative disease, cancer, cardiovascular diseases, and diabetes, are inevitable process. With the gradual improvement of life style, life expectancy is gradually extended. However, the extended lifespan has not reduced the incidence of disease, and most elderly people are in ill-health state in their later years. Hence, understanding aging and AAD are significant for reducing the burden of the elderly. Inorganic metal nanoparticles (IMNPs) predominantly include gold, silver, iron, zinc, titanium, thallium, platinum, cerium, copper NPs, which has been widely used to prevent and treat aging and AAD due to their superior properties (essential metal ions for human body, easily synthesis and modification, magnetism). Therefore, a systematic review of common morphological alternations of senescent cells, altered genes and signal pathways in aging and AAD, and biomedical applications of IMNPs in aging and AAD is crucial for the further research and development of IMNPs in aging and AAD. This review focus on the existing research on cellular senescence, aging and AAD, as well as the applications of IMNPs in aging and AAD in the past decade. This review aims to provide cutting-edge knowledge involved with aging and AAD, the application of IMNPs in aging and AAD to promote the biomedical application of IMNPs in aging and AAD.

Alginate oligosaccharide assimilation by gut microorganisms and the potential role in gut inflammation alleviation.

Dietary fiber metabolism by gut microorganisms plays important roles in host physiology and health. Alginate, the major dietary fiber of daily diet seaweeds, is drawing more attention because of multiple biological activities. To advance the understanding of alginate assimilation mechanism in the gut, we show the presence of unsaturated alginate oligosaccharides (uAOS)-specific alginate utilization loci (AUL) in human gut microbiome. As a representative example, a working model of the AUL from the gut microorganism Bacteroides clarus was reconstructed from biochemistry and transcriptome data. The fermentation of resulting monosaccharides through Entner-Doudoroff pathway tunes the metabolism of short-chain fatty acids and amino acids. Furthermore, we show that uAOS feeding protects the mice against dextran sulfate sodium-induced acute colitis probably by remodeling gut microbiota and metabolome. IMPORTANCE: Alginate has been included in traditional Chinese medicine and daily diet for centuries. Recently discovered biological activities suggested that alginate-derived alginate oligosaccharides (AOS) might be an active ingredient in traditional Chinese medicine, but how these AOS are metabolized in the gut and how it affects health need more information. The study on the working mechanism of alginate utilization loci (AUL) by the gut microorganism uncovers the role of unsaturated alginate oligosaccharides (uAOS) assimilation in tuning short-chain fatty acids and amino acids metabolism and demonstrates that uAOS metabolism by gut microorganisms results in a variation of cell metabolites, which potentially contributes to the physiology and health of gut.

Treatment for Resistant Hypertension Under the Guidance of Pharmacogenomics: A Randomised Controlled Open-Label Trial.

OBJECTIVE: To evaluate the efficacy and safety of pharmacogenomics (PGx)-guided treatment in individuals with resistant hypertension (RH). STUDY DESIGN: Randomised controlled open-label study. Place and Duration of the Study: Department of Cardiology, The First Hospital of China Medical University, Shenyang, Liaoning Province, China, from June 2019 to November 2021. METHODOLOGY: The study assigned RH patients to two groups. The intervention group (IG) received 12 weeks of PGx-guided treatment, while the control group (CG) followed a consensus-based approach. Examining 10 genes and their alleles with 31 antihypertensive drugs in the IG, the study provided specific medication advice. The primary outcome measured the difference in office systolic blood pressure (SBP) change from baseline at 12 weeks. Secondary outcomes included changes in diastolic blood pressure (DBP), hepatic and renal function, and major adverse cardiovascular events. RESULTS: Fifty-nine patients from the First Hospital of China Medical University participated, with 29 in the IG and 30 in the CG. Significant differences were noted in SBP reduction (IG: 31.26 ± 18.64 mmHg; CG: 14.61 ± 17.74 mmHg; p=0.001) and DBP reduction (IG: 19.61 ± 17.32 mmHg; CG: 7.81 ± 11.23 mmHg; p = 0.003) after 12 weeks. One IG patient had a heart attack, and one CG subject developed heart failure. At week 12, hepatic insufficiency was observed in one IG patient and six CG patients, while renal insufficiency occurred in five patients of both groups. CONCLUSION: Treatment guided by PGx demonstrated significant reductions in both SBP and DBP compared to consensus-based treatment. KEY WORDS: Resistant hypertension, Treatment, Pharmacogenomics, Clinical study.

Learning to Restore Compressed Point Cloud Attribute: A Fully Data-Driven Approach and A Rules-Unrolling-Based Optimization.

The emergence of holographic media drives the standardization of Geometry-based Point Cloud Compression (G-PCC) to sustain networked service provisioning. However, G-PCC inevitably introduces visually annoying artifacts, degrading the quality of experience (QoE). This work focuses on restoring G-PCC compressed point cloud attributes, e.g., RGB colors, to which fully data-driven and rules-unrolling-based post-processing filters are studied. At first, as compressed attributes exhibit nested blockiness, we develop a learning-based sample adaptive offset (NeuralSAO), which leverages a neural model using multiscale feature aggregation and embedding to characterize local correlations for quantization error compensation. Later, given statistically Gaussian distributed quantization noise, we suggest the utilization of a bilateral filter with Gaussian kernels to weigh neighbors by jointly considering their geometric and photometric contributions for restoration. Since local signals often present varying distributions, we propose estimating the smoothing parameters of the bilateral filter using an ultra-lightweight neural model. Such a bilateral filter with learnable parameters is called NeuralBF. The proposed NeuralSAO demonstrates the state-of-art restoration quality improvement, e.g., >20% BD-BR (Bjøntegaard delta rate) reduction over G-PCC on solid points clouds. However, NeuralSAO is computationally intensive and may suffer from poor generalization. On the other hand, although NeuralBF only achieves half of the gains of NeuralSAO, it is lightweight and exhibits impressive generalization across various samples. This comparative study between the data-driven large-scale NeuralSAO and the rules-unrolling-based small-scale NeuralBF helps to understand the capacity (i.e., performance, complexity, generalization) of underlying filters in terms of the quality restoration for compressed point cloud attribute.

13-oxyingenol dodecanoate derivatives induce mitophagy and ferroptosis through targeting TMBIM6 as potential anti-NSCLC agents.

Ingenol diterpenoids continue to attract the attention for their extensive biological activity and novel structural features. To further explore this type of compound as anti-tumor agent, 13-oxyingenol dodecanoate (13-OD) was prepared by a standard chemical transformation from an Euphorbia kansui extract, and 29 derivatives were synthesized through parent 13-OD. Their inhibition activities against different types of cancer were screened and some derivatives showed superior anti-non-small cell lung cancer (NSCLC) cells cytotoxic potencies than oxaliplatin. In addition, TMBIM6 was identified as a crucial cellular target of 13-OD using ABPP target angling technique, and subsequently was verified by pull down, siRNA interference, BLI and CETSA assays. With modulating the function of TMBIM6 protein by 13-OD and its derivatives, Ca2+ release function was affected, causing mitochondrial Ca2+ overload, depolarisation of membrane potential. Remarkably, 13-OD, B6, A2, and A10-2 induced mitophagy and ferroptosis. In summary, our results reveal that 13-OD, B6, A2, and A10-2 holds great potential in developing anti-tumor agents for targeting TMBIM6.

Polystyrene microplastics induce anxiety via HRAS derived PERK-NF-κB pathway.

Exposure to environmentally hazardous substances is recognized as a significant risk factor for neurological associated disorders. Among these substances, polystyrene microplastics (PS-MPs), widely utilized in various consumer products, have been reported to exhibit neurotoxicity. However, the potential association of PS-MPs with abnormal anxiety behaviors, along with the underlying molecular mechanisms and key proteins involved, remains insufficiently explored. Here, we delineated the potential mechanisms of PS-MPs-induced anxiety through proteomics and molecular investigations. We characterized the PS-MPs, observed their accumulation in the brain, leading to anxiety-like behavior in mice, which is correlated with microglia activation and pro-inflammatory response. Consistent with these findings, our studies on BV2 microglia cells showed that PS-MPs activated NF-κB-mediated inflammation resulting in the upregulation of pro-inflammatory cytokines such as TNFα and IL-1ß. Of particular significance, HRAS was identified as a key factor in the PS-MPs induced pro-inflammatory response through whole proteomics analysis, and knockdown of H-ras effectively inhibited PS-MPs induced PERK-NF-κB activation and associated pro-inflammatory response in microglia cells. Collectively, our findings highlight that PS-MPs induce anxiety of mice via the activation of the HRAS-derived PERK-NF-κB pathway in microlglia. Our results contribute valuable insights into the molecular mechanisms of PS-MPs-induced anxiety, and may offer implications for addressing neurotoxicity and prevention the adverse effects of environmentally hazardous substances, including microplastics.

Chemoproteomics-based profiling reveals potential antimalarial mechanism of Celastrol by disrupting spermidine and protein synthesis.

BACKGROUND: Malaria remains a global health burden, and the emergence and increasing spread of drug resistance to current antimalarials poses a major challenge to malaria control. There is an urgent need to find new drugs or strategies to alleviate this predicament. Celastrol (Cel) is an extensively studied natural bioactive compound that has shown potentially promising antimalarial activity, but its antimalarial mechanism remains largely elusive. METHODS: We first established the Plasmodium berghei ANKA-infected C57BL/6 mouse model and systematically evaluated the antimalarial effects of Cel in conjunction with in vitro culture of Plasmodium falciparum. The potential antimalarial targets of Cel were then identified using a Cel activity probe based on the activity-based protein profiling (ABPP) technology. Subsequently, the antimalarial mechanism was analyzed by integrating with proteomics and transcriptomics. The binding of Cel to the identified key target proteins was verified by a series of biochemical experiments and functional assays. RESULTS: The results of the pharmacodynamic assay showed that Cel has favorable antimalarial activity both in vivo and in vitro. The ABPP-based target profiling showed that Cel can bind to a number of proteins in the parasite. Among the 31 identified potential target proteins of Cel, PfSpdsyn and PfEGF1-α were verified to be two critical target proteins, suggesting the role of Cel in interfering with the de novo synthesis of spermidine and proteins of the parasite, thus exerting its antimalarial effects. CONCLUSIONS: In conclusion, this study reports for the first time the potential antimalarial targets and mechanism of action of Cel using the ABPP strategy. Our work not only support the expansion of Cel as a potential antimalarial agent or adjuvant, but also establishes the necessary theoretical basis for the development of potential antimalarial drugs with pentacyclic triterpenoid structures, as represented by Cel. Video Abstract.

Transcriptome and proteomic analysis of mpox virus F3L-expressing cells.

Background: Monkeypox or mpox virus (mpox) is a double-stranded DNA virus that poses a significant threat to global public health security. The F3 protein, encoded by mpox, is an apoenzyme believed to possess a double-stranded RNA-binding domain (dsRBD). However, limited research has been conducted on its function. In this study, we present data on the transcriptomics and proteomics of F3L-transfected HEK293T cells, aiming to enhance our comprehension of F3L. Methods: The gene expression profiles of pCAGGS-HA-F3L transfected HEK293T cells were analyzed using RNA-seq. Proteomics was used to identify and study proteins that interact with F3L. Real-time PCR was used to detect mRNA levels of several differentially expressed genes (DEGs) in HEK293T cells (or Vero cells) after the expression of F3 protein. Results: A total of 14,822 genes were obtained in cells by RNA-Seq and 1,672 DEGs were identified, including 1,156 up-regulated genes and 516 down-regulated genes. A total of 27 cellular proteins interacting with F3 proteins were identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and 19 cellular proteins with large differences in abundance ratios were considered to be candidate cellular proteins. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses showed that the DEGs were significantly enriched in immune-related pathways, including type I interferon signaling pathway, response to virus, RIG-I-like receptor signaling pathway, NOD-like receptor signaling pathway, etc. Moreover, some selected DEGs were further confirmed by real-time PCR and the results were consistent with the transcriptome data. Proteomics data show that cellular proteins interacting with F3 proteins are mainly related to RNA splicing and protein translation. Conclusions: Our analysis of transcriptomic and proteomic data showed that (1) F3L up-regulates the transcript levels of key genes in the innate immune signaling pathway, such as RIGI, MDA5, IRF5, IRF7, IRF9, ISG15, IFNA14, and elicits a broad spectrum of antiviral immune responses in the host. F3L also increases the expression of the FOS and JNK genes while decreasing the expression of TNFR2, these factors may ultimately induce apoptosis. (2) F3 protein interacts with host proteins involved in RNA splicing and protein translation, such as SNRNP70, POLR2H, HNRNPA1, DDX17, etc. The findings of this study shed light on the function of the F3 protein.

Insights into the time-course cellular effects triggered by iron oxide nanoparticles by combining proteomics with the traditional pharmacology strategy.

In recent years, a number of initially approved magnetic iron oxide nanoparticle (IONP)-based nano-medicines have been withdrawn due to the obscure nano-bio effects. Therefore, there is an urgent need to study the cellular effects triggered by IONPs on cells. In this study, we investigate the time-course cellular effects on the response of RAW 264.7 cells caused by Si-IONPs via pharmacological and mass spectrometry-based proteomics techniques. Our results revealed that Si-IONPs were internalized by clathrin-mediated endocytosis within 1 hour, and gradually degraded in endolysosomes over time, which might influence autophagy, oxidative stress, innate immune response, and inflammatory response after 12 hours. Our research provides a necessary assessment of Si-IONPs for further clinical treatment.

Systematic thermal analysis of the Arabidopsis proteome: Thermal tolerance, organization, and evolution.

Understanding the thermal stability of the plant proteome in the context of the native cellular environment would aid the design of crops with high thermal tolerance, but only limited such data are available. Here, we applied quantitative mass spectrometry to profile the thermal stability of the Arabidopsis proteome and identify thermo-sensitive and thermo-resilient protein networks in Arabidopsis, providing a basis for understanding heat-induced damage. We also show that the similarities of the protein-melting curves can be used as a proxy to evaluate system-wide protein-protein interactions in non-engineered plants and enable the identification of transient interactions exhibited by metabolons in the context of the cellular environment. Finally, we report a systematic comparison of the thermal stability of paralogs in Arabidopsis to aid the investigation and understanding of gene duplication and protein evolution. Taken together, our results could have broad implications for the fields of plant thermal tolerance, plant protein assemblies, and evolution.

Single-cell transcriptome analysis uncovers underlying mechanisms of acute liver injury induced by tripterygium glycosides tablet in mice.

Tripterygium glycosides tablet (TGT), the classical commercial drug of Tripterygium wilfordii Hook. F. has been effectively used in the treatment of rheumatoid arthritis, nephrotic syndrome, leprosy, Behcet's syndrome, leprosy reaction and autoimmune hepatitis. However, due to its narrow and limited treatment window, TGT-induced organ toxicity (among which liver injury accounts for about 40% of clinical reports) has gained increasing attention. The present study aimed to clarify the cellular and molecular events underlying TGT-induced acute liver injury using single-cell RNA sequencing (scRNA-seq) technology. The TGT-induced acute liver injury mouse model was constructed through short-term TGT exposure and further verified by hematoxylin-eosin staining and liver function-related serum indicators, including alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and total bilirubin. Using the mouse model, we identified 15 specific subtypes of cells in the liver tissue, including endothelial cells, hepatocytes, cholangiocytes, and hepatic stellate cells. Further analysis indicated that TGT caused a significant inflammatory response in liver endothelial cells at different spatial locations; led to marked inflammatory response, apoptosis and fatty acid metabolism dysfunction in hepatocytes; activated hepatic stellate cells; brought about the activation, inflammation, and phagocytosis of liver capsular macrophages cells; resulted in immune dysfunction of liver lymphocytes; disturbed the intercellular crosstalk in liver microenvironment by regulating various signaling pathways. Thus, these findings elaborate the mechanism underlying TGT-induced acute liver injury, provide new insights into the safe and rational applications in the clinic, and complement the identification of new biomarkers and therapeutic targets for liver protection.

Cholesterol modulates the physiological response to nanoparticles by changing the composition of protein corona.

Nanoparticles (NPs) in biological fluids form a layer of biomolecules known as the protein corona. The protein corona has been shown to determine the biological identity and in vivo fate of NPs, but whether and how metabolites, especially disease-related small molecules, regulate the protein corona and subsequently impact NP fate in vivo is relatively poorly understood. Here we report on the effects of cholesterol on the generation of protein corona and subsequent effects. We find that high levels of cholesterol, as in hypercholesterolemia, result in a protein corona with enriched apolipoproteins and reduced complement proteins by altering the binding affinity of the proteins to the NPs. The cholesterol-mediated protein corona can induce stronger inflammatory responses to NPs in macrophages and promote the cellular uptake of NPs in hepatocytes by enhancing the recognition of lipoprotein receptors when compared with normal protein corona. The result of in vivo biodistribution assays shows that, compared with healthy mice, NPs in hypercholesterolemic mice were more likely to be delivered to the liver, spleen and brain, and less likely to be delivered to the lungs. Our findings reveal that the metabolome profile is an unexploited factor impacting the target efficacy and safety of nanomedicines, providing a way to develop personalized nanomedicines by harnessing disease-related metabolites.