Dual-enzyme inhibiting nanomedicines for enhanced cancer chemodynamic therapy by inducing intratumoral acidosis.

Deficiency of endogenous hydrogen peroxide and insufficient intracellular acidity are usually two important factors limiting chemodynamic therapy (CDT). Here we report a glutathione-responsive nanomedicine that can provide a suitable environment for CDT by inhibiting dual-enzymes simultaneously. The nanomedicine is constructed by encapsulation of a novel hydrogen sulfide donor in nanomicelle assembled by glutathione-responsive amphiphilic polymer. In response to intracellular glutathione, the nanomedicine can efficiently release the active ingredients hydrogen sulfide, carbonic anhydrase inhibitor and ferrocene. The hydrogen sulfide can increase the concentrations of hydrogen peroxide and lactic acid by inhibiting catalase and enhancing glycolysis. The carbonic anhydrase inhibitor can further induce intratumoral acidosis by inhibiting the function of carbonic anhydrase IX. Therefore, the nanomedicine can provide more efficient reaction conditions for the ferrocene-mediated Fenton reaction to generate abundant toxic hydroxyl radicals. In vivo results show that the combination of enhanced CDT and acidosis can effectively inhibit tumor growth. This design of nanomedicine provides a promising dual-enzyme inhibiting strategy to enhance antitumor efficacy of CDT.

Glutathione-depleting polyprodrug nanoparticle for enhanced photodynamic therapy and cascaded locoregional chemotherapy.

Nanomedicines that combine reactive oxygen species (ROS)-responsive polyprodrug and photodynamic therapy have shown great potential for improving treatment efficacy. However, the consumption of ROS by overexpressed glutathione in tumor cells is a major obstacle for achieving effective ROS amplification and prodrug activation. Herein, we report a polyprodrug-based nanoparticle that can realize ROS amplification and cascaded drug release. The nanoparticle can respond to the high level of hydrogen peroxide in tumor microenvironment, achieving self-destruction and release of quinone methide. The quinone methide depletes intracellular glutathione and thus decreases the antioxidant capacity of cancer cells. Under laser irradiation, a large amount of ROS will be generated to induce cell damage and prodrug activation. Therefore, the glutathione-depleting polyprodrug nanoparticles can efficiently inhibit tumor growth by enhanced photodynamic therapy and cascaded locoregional chemotherapy.

Novel Isoalantolactone-Based Derivatives as Potent NLRP3 Inflammasome Inhibitors: Design, Synthesis, and Biological Characterization.

The NLRP3 inflammasome has been recognized as a promising therapeutic target in drug discovery for inflammatory diseases. Our initial research identified a natural sesquiterpene isoalantolactone (IAL) as the active scaffold targeting NLRP3 inflammasome. To improve its activity and metabolic stability, a total of 64 IAL derivatives were designed and synthesized. Among them, compound 49 emerged as the optimal lead, displaying the most potent inhibitory efficacy on nigericin-induced IL-1ß release in THP-1 cells, with an IC50 value of 0.29 µM, approximately 27-fold more potent than that of IAL (IC50: 7.86 µM), and exhibiting higher metabolic stability. Importantly, 49 remarkably improved DSS-induced ulcerative colitis in vivo. Mechanistically, we demonstrated that 49 covalently bound to cysteine 279 in the NACHT domain of NLRP3, thereby inhibiting the assembly and activation of NLRP3 inflammasome. These results provided compelling evidence to further advance the development of more potent NLRP3 inhibitors based on this scaffold.

NQO1-activated multifunctional theranostic probe for imaging-guided mitochondria-targeted photodynamic therapy and boosting immunogenic cell death.

NAD(P)H: quinine oxidoreductase (NQO1) is overexpressed in many types of cancer cells, and have been used as a biomarker for cancer diagnosis and targeted therapy. The development of activatable theranostic agents is highly desirable for precise cancer diagnosis and therapy. Herein, a NQO1-activated near-infrared multifunctional theranostic probe I-HCy-Q is successfully developed for imaging guided photodynamic therapy. The NIR fluorescence (λex/em = 685/703 nm) and capacity of reactive oxygen species generation are sensitive controllable by the level of NQO1, the linear detection range of NQO1 and limit of detection are 0.05-1.5 µg/mL and 5.66 ng/mL, respectively. On the one hand, I-HCy-Q can monitor the activity of NQO1 and distinguish the NQO1 positive cancer cells; on the other hand, the capacity of mitochondria-targeted photodynamic therapy makes I-HCy-Q an effective inducer of apoptosis and immunogenic cell death. Attribute to its complementary advantages, I-HCy-Q holds potential for the imaging and treatment of tumors in complex organisms.

NU6300 covalently reacts with cysteine-191 of gasdermin D to block its cleavage and palmitoylation.

Gasdermin D (GSDMD) serves as a vital mediator of inflammasome-driven pyroptosis. In our study, we have identified NU6300 as a specific GSDMD inhibitor that covalently interacts with cysteine-191 of GSDMD, effectively blocking its cleavage while not affecting earlier steps such as ASC oligomerization and caspase-1 processing in AIM2- and NLRC4-mediated inflammation. On the contrary, NU6300 robustly inhibits these earlier steps in NLRP3 inflammasome, confirming a unique feedback inhibition effect in the NLRP3-GSDMD pathway upon GSDMD targeting. Our study reveals a previously undefined mechanism of GSDMD inhibitors: NU6300 impairs the palmitoylation of both full-length and N-terminal GSDMD, impeding the membrane localization and oligomerization of N-terminal GSDMD. In vivo studies further demonstrate the efficacy of NU6300 in ameliorating dextran sodium sulfate-induced colitis and improving survival in lipopolysaccharide-induced sepsis. Overall, these findings highlight the potential of NU6300 as a promising lead compound for the treatment of inflammatory diseases.

Recent Progress and Prospects of Small Molecules for NLRP3 Inflammasome Inhibition.

NLRP3 inflammasome is a multiprotein complex involved in host immune response─which exerts various biological effects by mediating the maturation and secretion of IL-1ß and IL-18─and pyroptosis. However, its aberrant activation could cause amplification of inflammatory effects, thereby triggering a range of ailments, including Alzheimer's disease, Parkinson's disease, rheumatoid arthritis, gout, type 2 diabetes mellitus, and cancer. For the past few years, as an attractive anti-inflammatory target, NLRP3-targeting small-molecule inhibitors have been widely reported by both the academic and the industrial communities. In order to deeply understand the advancement of NLRP3 inflammasome inhibitors, we provide comprehensive insights and commentary on drugs currently under clinical investigation, as well as other NLRP3 inflammasome inhibitors from a chemical structure point of view, with an aim to provide new insights for the further development of clinical drugs for NLRP3 inflammasome-mediated diseases.

A Photo-Activated Continuous Reactive Oxygen Species Nanoamplifier for Dual-Dynamic Cascade Cancer Therapy.

The special redox homeostasis of tumor cells makes reactive oxygen species (ROS)-based approaches a promising cancer therapeutic strategy. Among these approaches, photodynamic therapy is the most widely studied ROS-based treatment due to its ability to achieve targeted therapy by local light irradiation. However, achieving efficient and continuous ROS generation without prolonged laser exposure is still challenging. In this work, a photo-activated continuous ROS nanoamplifier is proposed for photodynamic-chemodynamic cascade therapy. Upon local laser irradiation, the nanoamplifier can continuously amplify cellular oxidative stress through a positive feedback loop of "light-triggered ROS generation, ROS-responsive prodrug activation, and Fenton reaction-mediated ROS cyclic regenerative amplification", avoiding tissue damage caused by excessive laser exposure. This strategy provides a potential pathway to overcome the limitations of ROS-based therapeutic approaches.

Gas-assisted phototherapy for cancer treatment.

Phototherapies, mainly including photodynamic and photothermal therapy, have made considerable strides in the field of cancer treatment. With the aid of phototherapeutic agents, reactive oxygen species (ROS) or heat are generated under light irradiation to selectively damage cancer cells. However, sole-modality phototherapy faces certain drawbacks, such as limited penetration of phototherapeutic agents into tumor tissues, inefficient ROS generation due to hypoxia, treatment-induced inflammation and resistance of tumor to treatment (e.g., high levels of antioxidants, expression of heat shock protein). Gas therapy, an emerging therapy approach that damages cancer cells by improving the level of certain gas at the tumor site, shows potential to overcome the challenges associated with phototherapies. In addition, with the rapid development of nanotechnology, gas-assisted phototherapy based on nanomedicines has emerged as a promising strategy to enhance the treatment efficacy. This review summarizes recent advances in gas-assisted phototherapy and discusses the prospects and challenges of this strategy in cancer phototherapy.

LRP1B suppresses HCC progression through the NCSTN/PI3K/AKT signaling axis and affects doxorubicin resistance.

Accumulating evidence supports the association of somatic mutations with tumor occurrence and development. We aimed to identify somatic mutations with important implications in hepatocellular carcinoma (HCC) and explore their possible mechanisms. The gene mutation profiles of HCC patients were assessed, and the tumor mutation burden was calculated. Gene mutations closely associated with tumor mutation burden and patient overall survival were identified. In vivo and in vitro experiments were performed to verify the effects of putative genes on proliferation, invasion, drug resistance, and other malignant biological behaviors of tumor cells. Fourteen genes with a high mutation frequency were identified. The mutation status of 12 of these genes was closely related to the mutation burden. Among these 12 genes, LRP1B mutation was closely associated with patient prognosis. Nine genes were associated with immune cell infiltration. The results of in vivo and in vitro experiments showed that the knockdown of LRP1B promotes tumor cell proliferation and migration and enhances the resistance of tumor cells to liposomal doxorubicin. LRP1B could directly bind to NCSTN and affect its protein expression level, thereby regulating the PI3K/AKT pathway. Our mutational analysis revealed complex and orchestrated liposomal alterations linked to doxorubicin resistance that may also render cancers less susceptible to immunotherapy and also provides new treatment alternatives.

From lead to clinic: A review of the structural design of P2X7R antagonists.

P2X7R, which is a member of the purinergic P2 receptor family, is widely expressed in many immune cells, such as macrophages, lymphocytes, monocytes, and neutrophils. P2X7R is upregulated in response to proinflammatory stimulation, which is closely related to a variety of inflammatory diseases. The inhibition of P2X7 receptors has resulted in the elimination or reduction of symptoms in animal models of arthritis, depression, neuropathic pain, multiple sclerosis, and Alzheimer's disease. Therefore, the development of P2X7R antagonists is of great significance for the treatment of various inflammatory diseases. This review classifies the reported P2X7R antagonists according to their different cores, focuses on the structure-activity relationship (SAR) of the compounds, and analyzes some common substituents and strategies in the design of lead compounds, with the hope of providing valuable information for the development of new and efficient P2X7R antagonists.

SPRDA: a link prediction approach based on the structural perturbation to infer disease-associated Piwi-interacting RNAs.

piRNA and PIWI proteins have been confirmed for disease diagnosis and treatment as novel biomarkers due to its abnormal expression in various cancers. However, the current research is not strong enough to further clarify the functions of piRNA in cancer and its underlying mechanism. Therefore, how to provide large-scale and serious piRNA candidates for biological research has grown up to be a pressing issue. In this study, a novel computational model based on the structural perturbation method is proposed to predict potential disease-associated piRNAs, called SPRDA. Notably, SPRDA belongs to positive-unlabeled learning, which is unaffected by negative examples in contrast to previous approaches. In the 5-fold cross-validation, SPRDA shows high performance on the benchmark dataset piRDisease, with an AUC of 0.9529. Furthermore, the predictive performance of SPRDA for 10 diseases shows the robustness of the proposed method. Overall, the proposed approach can provide unique insights into the pathogenesis of the disease and will advance the field of oncology diagnosis and treatment.

Dual-prodrug cascade activation for chemo/chemodynamic mutually beneficial combination cancer therapy.

The combination of chemodynamic therapy (CDT) and chemotherapy has shown promise for achieving improved cancer treatment outcomes. However, due to the lack of synergy rationale, a simple one-plus-one combination therapy remains suboptimal in overcoming the obstacles of each treatment approach. Herein, we report a nanoplatform consisting of a pH-sensitive ferrocene- and cinnamaldehyde-based polyprodrug and a hydrogen peroxide-responsive doxorubicin (DOX) prodrug. Under an acidic tumor environment, the cinnamaldehyde polyprodrug will be activated to release free cinnamaldehyde, which can increase the intracellular hydrogen peroxide level and enhance the Fenton reaction. Subsequently, due to the collapse of nanoparticle structures, the DOX prodrug will be released and activated under a hydrogen peroxide stimulus. Meanwhile, the quinone methide produced during DOX prodrug activation can consume glutathione, an important antioxidant, and thus in turn enhance the efficacy of CDT. This design of a nanoplatform with dual-prodrug cascade activation provides a promising mutually beneficial cooperation mode between chemotherapy and CDT for enhancing antitumor efficacy.

The mechanisms and cross-protection of trained innate immunity.

In recent years, the traditional cognition of immunological memory being specific to adaptive immunity has been challenged. Innate immunity can mount enhanced responsiveness upon secondary stimulation, and a phenomenon is termed trained innate immunity. Trained innate immunity is orchestrated by distinct metabolic and epigenetic reprogramming in both circulating myeloid cells and myeloid progenitor cells in bone marrow, leading to long-term resistance to related and non-related pathogens infections. The induction of trained innate immunity can also polarize innate immune cells towards a hyperresponsive phenotype in the tumor microenvironment to exert antitumor effects. This review will discuss the current understanding of innate immune memory and the mechanisms during the induction of innate immunity, including signaling pathways, metabolic changes, and epigenetic rewriting. We also provide an overview of cross-protection against infectious diseases and cancers based on trained innate immunity.

Worldwide cancer statistics of adults over 75 years old in 2019: a systematic analysis of the global burden of disease study 2019.

BACKGROUND AND PURPOSE: Cancer has become one of the major killers of humanity due to the number of people over the age of 75 increasing with population ageing. The aim of this study was to analyse the incidence and mortality rates in people over 75 of 29 cancer types in 204 countries and regions, as well as the trends from 1990 to 2019. METHODS: Twenty-nine cancer types were collected from the Global Burden of Disease (GBD) 2019 database( https://vizhub.healthdata.org/gbd-results/ ). We collected global cancer data for 2019 in terms of sex, age, sociodemographic index (SDI), region, etc. The estimated annual percentage change (EAPC) was calculated to assess the trend of the cancer incidence and mortality rate from 1990 to 2019. RESULTS: In 2019, the number of new cancer cases and deaths among people 75 and older was almost 3 and 4.5 times that of 1990, respectively. From 1990 to 2019, there was a slow rise in incidence and a slight decline in mortality. There were significant differences in the cancer burden based on sex, age, region, and SDI. The cancer burden in men was higher than in women. In addition, the cancer burden varied from region to region. The highest cancer burden occurred in high-income North America. In addition, the higher the SDI was, the greater the burden of cancer. The incidence of cancer in high SDI was approximately seven times that of low SDI, and the trend of increase in high SDI was obvious. However, the trend of mortality in high SDI was decreasing, while it was increasing in low SDI. CONCLUSIONS: The present study focused on the cancer burden in adults over 75 years old. The findings in the study could serve as the basis for an analysis of the types of cancers that are most prevalent in different regions. This is beneficial for strategies of prevention and treatment according to the characteristics of different countries and regions to reduce the burden of cancer in older adults.

Line graph attention networks for predicting disease-associated Piwi-interacting RNAs.

PIWI proteins and Piwi-Interacting RNAs (piRNAs) are commonly detected in human cancers, especially in germline and somatic tissues, and correlate with poorer clinical outcomes, suggesting that they play a functional role in cancer. As the problem of combinatorial explosions between ncRNA and disease exposes gradually, new bioinformatics methods for large-scale identification and prioritization of potential associations are therefore of interest. However, in the real world, the network of interactions between molecules is enormously intricate and noisy, which poses a problem for efficient graph mining. Line graphs can extend many heterogeneous networks to replace dichotomous networks. In this study, we present a new graph neural network framework, line graph attention networks (LGAT). And we apply it to predict PiRNA disease association (GAPDA). In the experiment, GAPDA performs excellently in 5-fold cross-validation with an AUC of 0.9038. Not only that, it still has superior performance compared with methods based on collaborative filtering and attribute features. The experimental results show that GAPDA ensures the prospect of the graph neural network on such problems and can be an excellent supplement for future biomedical research.

CKMT1A is a novel potential prognostic biomarker in patients with endometrial cancer.

PURPOSE: The International Federation of Gynecology and Obstetrics (FIGO) stage remains the standard staging system for the assessment of endometrial cancer (EC) prognosis. Thus, we aim to identify the significant genes or biomarkers associated with the stage of endometrial cancer, which may also help reveal the mechanism of EC progression and assess the prognosis of patients with EC. MATERIALS AND METHODS: We compared the mRNA expression levels of EC patients with stages I and II as well as stages III and IV in the Cancer Genome Atlas (TCGA) database. The differentially expressed genes (DEGs) of EC patients at different stages were selected by volcano plot and Venn analysis. Gene Ontology (GO) and Pathways were applied to analyze the identified genes. Protein protein interaction (PPI) network was employed to identify the correlation. The survival analyses based on TCGA database were conducted for further screening. The Human Protein Atlas, quantitative PCR and immunohistochemistry were utilized to confirm the differences in expression of DEGs in endometrial cancer samples at different FIGO stages. RESULTS: CKMT1A was identified as a candidate gene. Through survival analyses, we found that CKMT1A may be a poor prognostic factor in the overall survival of endometrial cancer patients. GO and Pathways revealed that CKMT1A is closely associated with the metabolic process. More importantly, Human Protein Atlas and quantitative PCR confirmed the differences in expression of CKMT1A in endometrial cancer samples at different FIGO stages. CONCLUSION: In summary, this study shows that CKMT1A is a newly identified essential tumor progression regulator of endometrial cancer, which may give rise to novel therapeutic strategies in the management of endometrial cancer patients to prolong its prognosis and prevent tumor progression.

Multiparametric magnetic resonance imaging-derived radiomics for the prediction of disease-free survival in early-stage squamous cervical cancer.

OBJECTIVE: To conduct multiparametric magnetic resonance imaging (MRI)-derived radiomics based on multi-scale tumor region for predicting disease-free survival (DFS) in early-stage squamous cervical cancer (ESSCC). METHODS: A total of 191 ESSCC patients (training cohort, n = 135; validation cohort, n = 56) from March 2016 to September 2019 were retrospectively recruited. Radiomics features were derived from the T2-weighted imaging (T2WI), contrast-enhanced T1-weighted imaging (CET1WI), diffusion-weighted imaging (DWI), and apparent diffusion coefficient (ADC) map for each patient. DFS-related radiomics features were selected in 3 target tumor volumes (VOIentire, VOI+5 mm, and VOI-5 mm) to build 3 rad-scores using the least absolute shrinkage and selection operator (LASSO) Cox regression analysis. Logistic regression was applied to build combined model incorporating rad-scores with clinical risk factors and compared with clinical model alone. Kaplan-Meier analysis was used to further validate prognostic value of selected clinical and radiomics characteristics. RESULTS: Three radiomics scores all showed favorable performances in DFS prediction. Rad-score (VOI+5 mm) performed best with a C-index of 0.750 in the training set and 0.839 in the validation set. Combined model was constructed by incorporating age categorized by 55, Federation of Gynecology and Obstetrics (Figo) stage, and lymphovascular space invasion with rad-score (VOI+5 mm). Combined model performed better than clinical model in DFS prediction in both the training set (C-index 0.815 vs 0.709; p = 0.024) and the validation set (C-index 0.866 vs 0.719; p = 0.001). CONCLUSION: Multiparametric MRI-derived radiomics based on multi-scale tumor region can aid in the prediction of DFS for ESSCC patients, thereby facilitating clinical decision-making. KEY POINTS: • Three radiomics scores based on multi-scale tumor region all showed favorable performances in DFS prediction. Rad-score (VOI+5 mm) performed best with favorable C-index values. • Combined model incorporating multiparametric MRI-based radiomics with clinical risk factors performed significantly better in DFS prediction than the clinical model. • Combined model presented as a nomogram can be easily used to predict survival, thereby facilitating clinical decision-making.

Low expression of developing brain homeobox 2 (Dbx2) may serve as a biomarker to predict poor prognosis in endometrial cancer.

OBJECTIVE: For investigating Dbx2's expression in endometrial cancer (EC) and its effect on prognosis of patients with EC. METHODS: A comparison was performed in the Cancer Genome Atlas (TCGA) database in terms of the expression profiling of EC and the survival data. To obtain differential expression genes (DEGs), Volcano plot and Venn analysis were adopted. DEGs function was performed by carrying out the GO annotation analysis (GO) and gene set enrichment analysis (GSEA). In clinical EC samples, PCR was applied to the verification of Dbx2's expression. RESULTS: Dbx2 was a downregulated expression in tumor tissues. Dbx2 can have a poor prognosis role in EC by regulating the apoptotic signaling pathway and the immune pathway. Lower expression of Dbx2 was related to lymph node metastasis and FIGO stage. CONCLUSION: Dbx2 is downregulated in endometrial cancer, which serves as a biomarker to predict poor prognosis.

Programmed Size-Changeable Nanotheranostic Agents for Enhanced Imaging-Guided Chemo/Photodynamic Combination Therapy and Fast Elimination.

An ideal nanotheranostic agent should be able to achieve efficient tumor accumulation, retention, and fast elimination after its theranostic functions exhausts. However, there is an irreconcilable contradiction on optimum sizes for effective tumor retention and fast elimination. Herein, a programmed size-changeable nanotheranostic agent based on polyprodrug-modified iron oxide nanoparticles (IONPs) and aggregation-induced emission photosensitizer is developed for enhanced magnetic resonance imaging (MRI)-guided chemo/photodynamic combination therapy. The nano-sized theranostic agents with an initial diameter of about 90 nm can accumulate in tumor tissue through passive targeting. In the acidic tumor microenvironment, large aggregates of IONPs are formed, realizing enhanced tumor retention and MR signal enhancement. Under the guidance of MRI, light irradiation is applied to the tumor site for triggering the generation of reactive oxygen species and drug release. Moreover, after chemo/photodynamic combination therapy, the large-sized aggregates are re-dispersed into small-sized IONPs for fast elimination, reducing the risk of toxicity caused by long-term retention. Therefore, this study provides a promising size-changeable strategy for the development of nanotheranostic agents.

Identification of Transcriptional Variation in Aortic Remodeling Using a Murine Transverse Aortic Constriction (TAC) Model.

Arterial remodeling is a major pathological consequence of hypertension, which is recognized as the most common chronic non-communicable disease. However, the detailed mechanism of how arterial remodeling is induced by hypertension has not yet been fully elucidated. Evaluating the transcriptional changes in arterial tissue in response to elevated blood pressure at an early stage may provide new insights and identify novel therapeutic candidates in preventing arterial remodeling. Here, we used the ascending aorta of the transverse aortic constriction (TAC) model to induce arterial remodeling in C57BL/6 male mice. Age-matched mice were subjected to sham surgery as controls. The TAC model was only considered successful if the mice conformed to the criteria (RC/LC blood flow velocity with 5-10-fold change) 1 week after the surgery. Two weeks after surgery, the ascending aorta developed severe remodeling in TAC mice as compared to the sham group. High throughput sequencing was then applied to identify differentially expressed (DE) transcripts. In silicon analysis were then performed to systematically network transcriptional changes. A total of 1,019 mRNAs were significantly changed between TAC and the sham group at the transcriptional level. GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis revealed that stress/stimulus/immune-related biological processes played a crucial role during arterial remodeling. Our data provide a comprehensive understanding of global gene expression changes in the TAC model, which suggests that targeting inflammation and vascular smooth cell transformation are potential therapeutic strategies to interfere with the aortic remodeling at an early stage in the development of hypertension.