Multi-omics dissection of stage-specific artemisinin tolerance mechanisms in Kelch13-mutant Plasmodium falciparum.

AIMS: We investigated the stage-specific mechanisms of partial resistance to artemisinin (ART, an antimalarial drug) in Plasmodium falciparum (P. falciparum) carrying the Kelch13 C580Y mutation. METHODS: Using fluorescence labeling and activity-based protein profiling, we systematically profile the ART activation levels in P. falciparum during the entire intra-erythrocytic developmental cycle (IDC), and determined the ART-targets profile of the ART-sensitive and -resistant strains at different stages. We retrieved and integrated datasets of single-cell transcriptomics and label-free proteomics across three IDC stages of wild-type P. falciparum. We also employed lipidomics to validate lipid metabolic reprogramming in the resistant strain. RESULTS: The activation and expression patterns of genes and proteins of ART-targets in both ART-sensitive and resistant strains varied at different stages and periods of P. falciparum development, with the late trophozoite stage harboring the largest number of ART targets. We identified and validated 36 overlapping targets, such as GAPDH, EGF-1a, and SpdSyn, during the IDC stages in both strains. We revealed the ART-insensitivity of fatty acid-associated activities in the partially resistant strain at both the early ring and early trophozoite stages. CONCLUSIONS: Our multi-omics strategies provide novel insights into the mechanisms of ART partial resistance in Kelch13 mutant P. falciparum, demonstrating the stage-specific interaction between ART and malaria parasites.

Study on chemical profiling of bailing capsule and its potential mechanism against thyroiditis based on network pharmacology with molecular docking strategy.

Bailing capsule (BLC), a drug that is clinically administered to modulate the autoimmune system, exhibits promising therapeutic potential in the treatment of thyroiditis. This study elucidates the chemical profile of BLC and its potential therapeutic mechanism in thyroiditis, leveraging network pharmacology and molecular docking techniques. Utilizing ultra-high-performance liquid chromatography coupled with linear trap-Orbitrap mass spectrometry (UHPLC-LTQ-Orbitrap MS), 58 compounds were identified, the majority of which were nucleosides and amino acids. Utilizing the ultra-high-performance liquid chromatography coupled with triple quadrupole tandem mass spectrometry (UHPLC QqQ MS/MS) strategy, 16 representative active components from six batches of BLCs were simultaneously determined. Network pharmacology analysis further revealed that the active components included 5'-adenylate, guanosine, adenosine, cordycepin, inosine, 5'-guanylic acid, and l-lysine. Targets with higher connectivity included AKT1, MAPK3, RAC1, and PIK3CA. The signaling pathways primarily focused on thyroid hormone regulation and the Ras, PI3K/AKT, and MAPK pathways, all of which were intricately linked to inflammatory immunity and hormonal regulation. Molecular docking analysis corroborated the findings from network pharmacology, revealing that adenosine, guanosine, and cordycepin exhibited strong affinity toward AKT1, MAPK3, PIK3CA, and RAC1. Overall, this study successfully elucidated the material basis and preliminary mechanism underlying BLC's intervention in thyroiditis, thus laying a solid basis for further exploration of its in-depth mechanisms.

Dissection of molecular mechanisms of liver injury induced by microcystin-leucine arginine via single-cell RNA-sequencing.

The occurrence of poisoning incidents caused by cyanobacterial blooms has aroused wide public concern. Microcystin-leucine arginine (MC-LR) is a well-established toxin produced by cyanobacterial blooms, which is widely distributed in eutrophic waters. MC-LR is not only hazardous to the water environment but also exerts multiple toxic effects including liver toxicity in both humans and animals. However, the underlying mechanisms of MC-LR-induced liver toxicity are unclear. Herein, we used advanced single-cell RNA sequencing technology to characterize MC-LR-induced liver injury in mice. We established the first single-cell atlas of mouse livers in response to MC-LR. Our results showed that the differentially expressed genes and pathways in diverse cell types of liver tissues of mice treated with MC-LR are highly heterogeneous. Deep analysis showed that MC-LR induced an increase in a subpopulation of hepatocytes that highly express Gstm3, which potentially contributed to hepatocyte apoptosis in response to MC-LR. Moreover, MC-LR increased the proportion and multiple subtypes of Kupffer cells with M1 phenotypes and highly expressed proinflammatory genes. Furthermore, the MC-LR increased several subtypes of CD8+ T cells with highly expressed multiple cytokines and chemokines. Overall, apart from directly inducing hepatocytes apoptosis, MC-LR activated proinflammatory Kupffer cell and CD8+ T cells, and their interaction may constitute a hostile microenvironment that contributes to liver injury. Our findings not only present novel insight into underlying molecular mechanisms but also provide a valuable resource and foundation for additional discovery of MC-LR-induced liver toxicity.

Imaging, Genetic, and Pathological Features of Vascular Dementia.

BACKGROUND: Over the past decades, marked progress has been made in detecting vascular dementia (VD) both through maturation of diagnostic concepts and advances in brain imaging, especially MRI. We summarized the imaging, genetic, and pathological features of VD in this review. SUMMARY: It is a challenge for the diagnosis and treatment of VD, particularly in patients where there is no evident temporal relation between cerebrovascular events and cognitive dysfunction. In patients with cognitive dysfunction with poststroke onset, the etiological classification is still complicated. KEY MESSAGES: In this review, we summarized the clinical, imaging, and genetic as well as pathological features of VD. We hope to offer a framework to translate diagnostic criteria to daily practice, address treatment, and highlight some future perspectives.

Biochemical mechanisms of tributyltin chloride-induced cell toxicity in Sertoli cells.

Tributyltin chloride (TBTCL) is a widely used fungicide and heat stabilizer in compositions of PVC. TBTCL has been detected in human bodies and potentially causes harmful effects on humans' thyroid, cardiovascular and other organs. As one of the first examples of endocrine disruptors, the toxicity effects of TBTCL on the male reproduction system have aroused concerns. However, the potential cellular mechanisms are not fully explored. In the current study, by using Sertoli cells, a critical regulator of spermatogenesis as a cell model, we showed that with 200 nM exposure for 24 h, TBTCL causes apoptosis and cell cycle arrest. RNA sequencing analyses suggested that TBTCL probably activates endoplasmic reticulum (ER) stress, and disrupts autophagy. Biochemical analysis showed that TBTCL indeed induces ER stress and the dysregulation of autophagy. Interestingly, activation of ER stress and inhibition of autophagy is responsible for TBTCL-induced apoptosis and cell cycle arrest. Our results thus uncovered a novel insight into the cellular mechanisms for TBTCL-induced toxicology in Sertoli cells.

Ginsenoside Rg1 and Acori Graminei Rhizoma Attenuates Neuron Cell Apoptosis by Promoting the Expression of miR-873-5p in Alzheimer's Disease.

Alzheimer's disease (AD) severely threatens human health in their old age, however the potential etiology underlying it is still unclear. Both Ginsenoside Rg1 (GRg1) and Acori graminei Rhizoma (AGR) are the traditional Chinese herbal drug, while their potential role in AD remains need further identification. Both SAMP1 and SAMP8 mice were employed as the control and AD mice. Morris water maze method was used to detect the cognitive function of the mice, TUNEL assay was performed to determine cell apoptosis. Real-time PCR and western blot were carried out to measure gene expression. The relationship between miR-873-5p and HMOX1 was determined using luciferase reporter assay. Comparing with SAMP1, the cognitive function was impaired and cell apoptosis was increased in SAMP8 mice. GRg1 + AGR treatment significantly attenuated the symptom of AD. The expression of miR-873-5p was decreased, while HMOX1 was increased in SAMP8 mice. GRg1 + AGR treatment significantly promoted the expression of miR-873-5p, but decreased HMOX1. MiR-873-5p targets HMOX1 to regulate its expression. Aß1-42 stimulation decreased the expression of miR-873-5p, but increased HMOX1 in PC12 cells. GRg1 + AGR treatment reversed the effect of Aß1-42, while miR-873-5p inhibitor abolished the effect of GRg1 + AGR. In vivo experiments confirmed the protect role of GRg1 + AGR in AD. GRg1 + AGR suppressed neuron cell apoptosis by regulating the expression of miR-873-5p in AD.

Amentoflavone Ameliorates Aß1-42-Induced Memory Deficits and Oxidative Stress in Cellular and Rat Model.

Alzheimer's disease (AD), a progressive neurodegenerative disease of the central nervous system, is the most common cause of senile dementia. This study aimed to investigate whether amentoflavone (AF), a biflavonoid compound, could exert neuroprotective activities against AD. The AD model was established by the intracranial injection of amyloid-beta (Aß) in rat models. The effect of AF on cognitive function was examined using the Morris water maze test. Cell survival and apoptosis in the hippocampal region in an animal model were detected using Nissl staining and a terminal deoxynucleotidyl transferased UTP nick-end labeling assay, respectively. The levels of oxidant enzymes were determined by enzyme-linked immunosorbent assay. Signaling molecule expressions were examined by western blotting. Our results showed that AF significantly attenuated Aß-induced deficits in neurological functions as well as neuronal cell death and apoptosis in the hippocampal region. Moreover, our findings revealed that AF increased nuclear factor erythroid 2-related factor 2 (Nrf2) expression and translocation and activated AMP-activated protein kinase (AMPK) signaling. In a cellular model of AD established by exposing PC12 cells to Aß, our results provided further evidence that the neuroprotective activities of AF were mediated by modulating Nrf2 through AMPK/glycogen synthase kinase 3 beta signaling. AF exerts a protective effect against Aß1-42-induced neurotoxcicity by inducing Nrf2 antioxidant pathways via AMPK signaling activation, which provided experimental evidence that AF might provide a clinical benefit to patients with AD.

Cordyceps sinensis relieves non-small cell lung cancer by inhibiting the MAPK pathway.

OBJECTIVE: To determine the pharmacodynamic mechanism underlying Cordyceps sinensis relief in a murine model of non-small cell lung cancer (NSCLC). METHODS: We created a murine model of NSCLC and studied the potential molecular mechanism by which C. sinensis relieved NSCLC using a combination of transcriptomics, proteomics, and experimental validation. RESULTS: C. sinensis markedly suppressed the fluorescence values in mice with NSCLC, improved the pathologic morphology of lung tissue, ameliorated inflammatory cytokines (tumor necrosis factor-alpha, interleukin-6, interleukin-10, and the oxidative stress indicators superoxide dismutase, malondialdehyde, and glutathione peroxidase). Transcriptomics results showed that the therapeutic effect of C. sinensis was primarily involved in the differentiation and activation of T cells. Based on the proteomic results, C. sinensis likely exerted a protective effect by recruiting immune cells and suppressing tumor cell proliferation via the MAPK pathway. Finally, the experimental validation results indicated that C. sinensis significantly decreased the VEGF and Ki67 expression, downregulated RhoA, Raf-1, and c-fos expression, which are related to cell migration and invasion, increased the serum concentration of hematopoietic factors (EPO and GM-CSF), and improved the percentage of immune cells (natural killer cells, dendritic cells, and CD4+ and CD8+ lymphocytes), which enhanced immune function. CONCLUSIONS: Based on our preclinical study, C. sinensis was shown to exert a protective effect on NSCLC, primarily by inhibiting the MAPK pathway.

Chemical Proteomics Approaches for Screening Small Molecule Inhibitors Covalently Binding to SARS-Cov-2.

Although various strategies have been used to prevent and treat SARS-CoV-2, the spread and evolution of SARS-CoV-2 is still progressing rapidly. The emerging variants Omicron and its sublineage have a greater ability to spread and escape nearly all current monoclonal antibodies treatments, highlighting an urgent need to develop therapeutics targeting current and emerging Omicron variants or recombinants with breadth and potency. Here, some small molecule drugs are rapidly identified that could covalently binding to receptor binding domain (RBD) protein of Omicron through the combined application of artificial intelligence (AI) and activity-based protein profiling (ABPP) technology. The surface plasmon resonance (SPR) and pseudo-virus neutralization experiments further reveal that an FDA-approved drug gallic acid has robust neutralization potency against Omicron pseudo-virus with the IC50 values of 23.56 × 10-6 m. Taken together, a platform combining AI intelligence, biochemical, SPR, molecular docking, and pseudo-virus-based screening for rapid identification and evaluation of potential anti-SARS-CoV-2 small molecule drugs is established and the effectiveness of the platform is validated.

Glycyrrhetinic acid inhibits non-small cell lung cancer via promotion of Prdx6- and caspase-3-mediated mitochondrial apoptosis.

Glycyrrhetinic acid (GA) shows great efficiency against non-small cell lung cancer (NSCLC), but the detailed mechanism is unclear, which has limited its clinical application. Herein, we investigated the potential targets of GA against NSCLC by activity-based protein profiling (ABPP) technology and the combination of histopathology and proteomics validation. In vitro and in vivo results indicated GA significantly inhibited NSCLC via promotion of peroxiredoxin-6 (Prdx6) and caspase-3 (Casp3)-mediated mitochondrial apoptosis. This original finding will provide theoretical and data support to improve the treatment of NSCLC with the application of GA.

Application of Shouwu Yizhi prescription in decubation of patients with ischemic stroke.

We investigate the application of Shouwu Yizhi prescription (SYP) in decubation of patients with ischemic stroke (IS). The clinical data of 106 patients recovering from IS who came to our hospital from December 2019 to December 2020 were selected for retrospective analysis, and they were separated into experimental group (n = 53, basic treatment + SYP) and control group (n = 53, basic treatment) based on the principle of random grouping. The clinical indexes such as lipid indexes and neurological disability score (NDS) after treatment were compared between both groups to comprehensively evaluate the clinical effects of different treatment regimens. Except for high-density lipoprotein cholesterol value, the lipid indexes in the experimental group after treatment were remarkably lower than those in the control group (P < 0.001). After treatment, the levels of hypersensitive C-reactive protein, homocysteine and lipoprotein-associated phospholipase A2 were remarkably lower in the experimental group than control group (P < 0.05). After treatment, the experimental group had remarkably higher mean scores of Montreal Cognitive Assessment, Fugl-Meyer Assessment in upper and lower limbs and lower NDS than control group (P < 0.001). SYP is an efficient treatment plan in decubation of IS, which can effectively improve the blood lipid indexes and neurological function of patients, and further studies will help establish a better solution for such patients.

A single-cell landscape of triptolide-associated testicular toxicity in mice.

Triptolide is a key active component of the widely used traditional Chinese herb medicine Tripterygium wilfordii Hook. F. Although triptolide exerts multiple biological activities and shows promising efficacy in treating inflammatory-related diseases, its well-known safety issues, especially reproductive toxicity has aroused concerns. However, a comprehensive dissection of triptolide-associated testicular toxicity at single cell resolution is still lacking. Here, we observed testicular toxicity after 14 days of triptolide exposure, and then constructed a single-cell transcriptome map of 59,127 cells in mouse testes upon triptolide-treatment. We identified triptolide-associated shared and cell-type specific differentially expressed genes, enriched pathways, and ligand-receptor pairs in different cell types of mouse testes. In addition to the loss of germ cells, our results revealed increased macrophages and the inflammatory response in triptolide-treated mouse testes, suggesting a critical role of inflammation in triptolide-induced testicular injury. We also found increased reactive oxygen species (ROS) signaling and downregulated pathways associated with spermatid development in somatic cells, especially Leydig and Sertoli cells, in triptolide-treated mice, indicating that dysregulation of these signaling pathways may contribute to triptolide-induced testicular toxicity. Overall, our high-resolution single-cell landscape offers comprehensive information regarding triptolide-associated gene expression profiles in major cell types of mouse testes at single cell resolution, providing an invaluable resource for understanding the underlying mechanism of triptolide-associated testicular injury and additional discoveries of therapeutic targets of triptolide-induced male reproductive toxicity.

Surface chemistry of graphene tailoring the activity of digestive enzymes by modulating interfacial molecular interactions.

As a kind of novel functional material, graphene-related nanomaterials (GRMs) have great potentials in industrial and biomedical applications. Meanwhile, the production and wide application of GRMs will increase the risk of unintended or intentional oral exposure to human beings, attracting safety concerns about their biological fates and toxicological effects. The normal enzymatic activity of digestive enzymes is essential for the proper functioning of the gastrointestinal tract system. However, whether and how orally entered GRMs and their surface groups affect digestive enzymes' activity are still scarce. In this paper, we systematically studied the effects of graphene oxide (GO), graphene modified with hydroxyl groups (OH-G), carboxyl groups (COOH-G), and amino groups (NH2-G) on enzymatic activity of three typical digestive enzymes (pepsin, trypsin, and α-pancreatic amylase). The results showed that the activity of trypsin and α-pancreatic amylase could be greatly changed after GRMs incubation in a surface chemistry dependent manner, while the activity of pepsin was not affected. To elucidate the mechanisms at the molecular level, the interactions between trypsin and GRMs were studied by spectrometry, thermophoresis, and computational simulation approaches, and the key roles of surface chemistry of GRMs in tailoring the activity of trypsin were finally figured out. GO allosterically inhibited trypsin's activity in the non-competitive manner because of the conformation transition induced by the intensive interactions. COOH-G could effectively hamper enzymatic activity of trypsin in the competitive manner by blocking the active catalytic pocket. As for NH2-G and OH-G, they had little impact on the activity of trypsin due to the weak binding affinity or limited conformational change. Our findings not only indicate surface chemistry plays an important role in tailoring the effects of GRMs on the activity of digestive enzymes but also provide new insights for understanding the oral safety of nanomaterials from daily products and the environment.

Single-nucleus RNA sequencing unveils critical regulators in various hippocampal neurons for anti-N-methyl-D-aspartate receptor encephalitis.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a neuropsychiatric disease with variable clinical manifestations caused by NMDAR autoantibody. The underlying molecular underpinnings of this disease are rarely characterized on a genomic scale. Anti-NMDAR encephalitis mainly affects the hippocampus, however, its effect on gene expression in hippocampal neurons is unclear at present. Here, we construct the active and passive immunization mouse models of anti-NMDAR encephalitis, and use single-nucleus RNA sequencing to investigate the diverse expression profile of neuronal populations isolated from different hippocampal regions. Dramatic changes in cell proportions and differentially expressed genes were observed in excitatory neurons of the dentate gyrus (DG) subregion. In addition, we found that ATP metabolism and biosynthetic regulators related genes in excitatory neurons of DG subregion were significantly affected. Kcnq1ot1 in inhibitory neurons and Meg3 in interneurons also changed. Notably, the latter two molecules exhibited opposite changes in different models. Therefore, the above genes were used as potential targets for further research on the pathological process of anti-NMDAR encephalitis. These data involve various hippocampal neurons, which delineate a framework for understanding the hippocampal neuronal circuit and the potential molecular mechanisms of anti-NMDAR encephalitis.

Tributyltin chloride (TBTCL) induces cell injury via dysregulation of endoplasmic reticulum stress and autophagy in Leydig cells.

Tributyltin chloride (TBTCL), a commonly used antiseptic substance, is commonly found in the environment. Human exposure to TBTCL through the consumption of contaminated seafood, fish, or drinking water has aroused concern. It is well-characterized that TBTCL has multiple detrimental effects on the male reproductive system. However, the potential cellular mechanisms are not fully elucidated. Here, we characterized molecular mechanisms of TBTCL-induced cell injury in Leydig cells, a critical supporter for spermatogenesis. We showed that TBTCL induces apoptosis and cell cycle arrest in TM3 mouse Leydig cells. RNA sequencing analyses revealed that endoplasmic reticulum (ER) stress and autophagy were potentially involved in TBTCL-induced cytotoxicity. We further showed that TBTCL causes ER stress and inhibited autophagy flux. Notably, the inhibition of ER stress attenuates not only TBTCL-induces autophagy flux inhibition but also apoptosis and cell cycle arrest. Meanwhile, the activation of autophagy alleviates, and inhibition of autophagy exaggerates TBTCL-induced apoptosis and cell cycle arrest flux. These results suggest that TBTCL-induced ER stress and autophagy flux inhibition contributed to apoptosis and cell cycle arrest in Leydig cells, providing novel understanding into the mechanisms of TBTCL-induced testis toxicity.

How eluents define proteomic fingerprinting of protein corona on nanoparticles.

Nanoparticles (NPs) have broad application prospects in the field of biomedicine due to their excellent physicochemical properties. When entering biological fluids, NPs inevitably encountered proteins and were subsequently surrounded by them, forming the termed protein corona (PC). As PC has been evidenced to have critical roles in deciding the biological fates of NPs, how to precisely characterize PC is vital to promote the clinical translation of nanomedicine by understanding and harnessing NPs' behaviors. During the centrifugation-based separation techniques for the PC preparation, direct elution has been most widely used to strip proteins from NPs due to its simpleness and robustness, but the roles of multifarious eluents have never been systematically declared. Herein, seven eluents composed of three denaturants, sodium dodecyl sulfate (SDS), dithiothreitol (DTT), and urea (Urea), were applied to detach PC from gold nanoparticles (AuNPs) and silica nanoparticles (SiNPs), and eluted proteins in PC have been carefully characterized by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and chromatography coupled tandem mass spectrometry (LC-MS/MS). Our results showed that SDS and DTT were the main contributors to the efficient desorption of PC on SiNPs and AuNPs, respectively. The molecular reactions between NPs and proteins were explored and verified by SDS-PAGE analysis of PC formed in the serums pretreated with protein denaturing or alkylating agents. The proteomic fingerprinting analysis indicated the difference of the eluted proteins brought by the seven eluents was the abundance rather than the species. The enrichment of some opsonins and dysopsonins in a special elution reminds us that the possibility of biased judgments on predicting NPs' biological behaviors under different elution conditions. The synergistic effects or antagonistic effects among denaturants for eluting PC were manifested in a nanoparticle-type dependent way by integrating the properties of the eluted proteins. Collectively, this study not only underlines the urgent need of choosing the appropriate eluents for identifying PC robustly and unbiasedly, but also provides an insight into the understanding of molecular interactions during PC formation.

Single-cell transcriptome analysis reveals the regulatory effects of artesunate on splenic immune cells in polymicrobial sepsis.

Sepsis is characterized by a severe and life-threatening host immune response to polymicrobial infection accompanied by organ dysfunction. Studies on the therapeutic effect and mechanism of immunomodulatory drugs on the sepsis-induced hyperinflammatory or immunosuppression states of various immune cells remain limited. This study aimed to investigate the protective effects and underlying mechanism of artesunate (ART) on the splenic microenvironment of cecal ligation and puncture-induced sepsis model mice using single-cell RNA sequencing (scRNA-seq) and experimental validations. The scRNA-seq analysis revealed that ART inhibited the activation of pro-inflammatory macrophages recruited during sepsis. ART could restore neutrophils' chemotaxis and immune function in the septic spleen. It inhibited the activation of T regulatory cells but promoted the cytotoxic function of natural killer cells during sepsis. ART also promoted the differentiation and activity of splenic B cells in mice with sepsis. These results indicated that ART could alleviate the inflammatory and/or immunosuppressive states of various immune cells involved in sepsis to balance the immune homeostasis within the host. Overall, this study provided a comprehensive investigation of the regulatory effect of ART on the splenic microenvironment in sepsis, thus contributing to the application of ART as adjunctive therapy for the clinical treatment of sepsis.

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.

Mechanistic engineering of celastrol liposomes induces ferroptosis and apoptosis by directly targeting VDAC2 in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of most common and deadliest malignancies. Celastrol (Cel), a natural product derived from the Tripterygium wilfordii plant, has been extensively researched for its potential effectiveness in fighting cancer. However, its clinical application has been hindered by the unclear mechanism of action. Here, we used chemical proteomics to identify the direct targets of Cel and enhanced its targetability and anti-tumor capacity by developing a Cel-based liposomes in HCC. We demonstrated that Cel selectively targets the voltage-dependent anion channel 2 (VDAC2). Cel directly binds to the cysteine residues of VDAC2, and induces cytochrome C release via dysregulating VDAC2-mediated mitochondrial permeability transition pore (mPTP) function. We further found that Cel induces ROS-mediated ferroptosis and apoptosis in HCC cells. Moreover, coencapsulation of Cel into alkyl glucoside-modified liposomes (AGCL) improved its antitumor efficacy and minimized its side effects. AGCL has been shown to effectively suppress the proliferation of tumor cells. In a xenograft nude mice experiment, AGCL significantly inhibited tumor growth and promoted apoptosis. Our findings reveal that Cel directly targets VDAC2 to induce mitochondria-dependent cell death, while the Cel liposomes enhance its targetability and reduces side effects. Overall, Cel shows promise as a therapeutic agent for HCC.

Oridonin acts as a novel senolytic by targeting glutathione S-transferases to activate the ROS-p38 signaling axis in senescent cells.

Most of the known senolytics are anti-cancer drugs or their derivative molecules. However, senolytics derived from the active ingredients of traditional Chinese medicine (TCM) are rarely reported. Here, we identified oridonin as a novel senolytic and further revealed that it might target a class of glutathione S-transferases to activate ROS-p38 signaling and induce apoptosis in senescent cells.