The opportunities and challenges of using PD-1/PD-L1 inhibitors for leukemia treatment.

Leukemia poses a significant clinical challenge due to its swift onset, rapid progression, and treatment-related complications. Tumor immune evasion, facilitated by immune checkpoints like programmed death receptor 1/programmed death receptor ligand 1 (PD-1/PD-L1), plays a critical role in leukemia pathogenesis and progression. In this review, we summarized the research progress and therapeutic potential of PD-L1 in leukemia, focusing on targeted therapy and immunotherapy. Recent clinical trials have demonstrated promising outcomes with PD-L1 inhibitors, highlighting their role in enhancing treatment efficacy. This review discusses the implications of PD-L1 expression levels on treatment response and long-term survival rates in leukemia patients. Furthermore, we address the challenges and opportunities in immunotherapy, emphasizing the need for personalized approaches and combination therapies to optimize PD-L1 inhibition in leukemia management. Future research prospects include exploring novel treatment strategies and addressing immune-related adverse events to improve clinical outcomes in leukemia. Overall, this review provides valuable insights into the role of PD-L1 in leukemia and its potential as a therapeutic target in the evolving landscape of leukemia treatment.

Deciphering the Genomic Characterization of the GGP Gene Family and Expression Verification of CmGGP1 Modulating Ascorbic Acid Biosynthesis in Melon Plants.

Ascorbic acid (AsA), also known as vitamin C, is a well-known antioxidant found in living entities that plays an essential role in growth and development, as well as in defensive mechanisms. GDP-L-galactose phosphorylase (GGP) is a candidate gene regulating AsA biosynthesis at the translational and transcriptional levels in plants. In the current study, we conducted genome-wide bioinformatic analysis and pinpointed a single AsA synthesis rate-limiting enzyme gene in melon (CmGGP1). The protein prediction analysis depicted that the CmGGP1 protein does not have a signaling peptide or transmembrane structure and mainly functions in the chloroplast or nucleus. The constructed phylogenetic tree analysis in multispecies showed that the CmGGP1 protein has a highly conserved motif in cucurbit crops. The structural variation analysis of the CmGGP1 gene in different domesticated melon germplasms showed a single non-synonymous type-base mutation and indicated that this gene was selected by domestication during evolution. Wild-type (WT) and landrace (LDR) germplasms of melon depicted close relationships to each other, and improved-type (IMP) varieties showed modern domestication selection. The endogenous quantification of AsA content in both the young and old leaves of nine melon varieties exhibited the major differentiations for AsA synthesis and metabolism. The real-time quantitative polymerase chain reaction (qRT-PCR) analysis of gene co-expression showed that AsA biosynthesis in leaves was greater than AsA metabolic consumption, and four putative interactive genes (MELO3C025552.2, MELO3C007440.2, MELO3C023324.2, and MELO3C018576.2) associated with the CmGGP1 gene were revealed. Meanwhile, the CmGGP1 gene expression pattern was noticed to be up-regulated to varying degrees in different acclimated melons. We believe that the obtained results would provide useful insights for an in-depth genetic understanding of the AsA biosynthesis mechanism, aimed at the development of improving crop plants for melon.

Association between urinary phthalates and phthalate metabolites and cancer risk: A systematic review and meta-analysis.

Phthalates, widely utilized in industrial products, are classified as endocrine-disrupting chemicals (EDCs). Although certain phthalate and their metabolites have been implicated in cancer development, the reported findings have exhibited inconsistencies. Therefore, we conducted the comprehensive literature search to assess the association between phthalate and their metabolites and cancer risk by identifying original studies measuring phthalates or their metabolites and reporting their correlation with cancer until July 4, 2023. The Odds Ratios (ORs) and corresponding 95% confidence intervals (CIs) were extracted and analyzed to estimate the risk. Pooled data from eleven studies, including 3101 cancer patients and 6858 controls, were analyzed using a fixed- or random-effects model based on heterogeneity tests. When comparing extreme categories of different phthalates and their metabolites, we observed a significant association between urinary phthalates and phthalate metabolites (MEHHP, MECPP, DBP and MBzP) and cancer risk. The findings of our meta-analysis reinforce the existing evidence that urinary phthalates and phthalate metabolites is strongly associated with cancer development. Further investigations are warranted to elucidate the underlying mechanisms of this association. These results may offer novel insights into cancer development.

CHL1 inhibits cell proliferation, migration and invasion by regulating the NF­κB signaling pathway in colorectal cancer.

Cell adhesion molecule close homolog of L1 (CHL1) is implicated in tumorigenesis of various malignancies. However, its role and underlying molecular mechanisms in colorectal cancer (CRC) remain unclear. The present study aimed to evaluate the specific biological functions and mechanisms of CHL1, in order to provide a theoretical basis for the use of CHL1 as a biological target in CRC. CHL1 expression was originally determined in CRC cell lines. Subsequently, CHL1 overexpression was induced by plasmid transfection in HT29 and SW480 cells, and cell proliferation, migration and invasion were evaluated using the Cell Counting Kit-8, clone formation, organoids formation and Transwell assays. Immunofluorescence and western blotting were performed to assess the protein expression of E-cadherin or N-cadherin. Differentially expressed genes (DEGs) were further evaluated using RNA-sequencing (RNA-seq) in HT29 and SW480 cells following CHL1 overexpression and functional enrichment analysis. Western blotting was performed to validate the expression of proteins related to the nuclear factor κB (NF-κB) signaling pathway. The TNMplot online database revealed the significant downregulation of CHL1 in CRC tissues. The results indicated that exogenous CHL1 overexpression significantly inhibited the proliferative, organoid-forming, migratory and invasive abilities of HT29 and SW480 cells, and increased E-cadherin protein expression. Additionally, CHL1 overexpression reduced xenograft tumor growth in vivo. RNA-seq and functional analysis revealed that DEGs in CHL1 overexpressing cells were mainly enriched in the NF-κB signaling pathway. The expression of p-p65 and p-p65/p65 ratio were significantly reduced in HT29 and SW480 cells, following CHL1 overexpression. Additionally, the inhibitory effects of CHL1 overexpression on CRC cell proliferation, organoid formation, migration and invasion were partially counteracted following the overexpression of p65 expression. Overall, the present study demonstrates that CHL1 inhibits CRC cell growth, migration and invasion through the inactivation of the NF-κB signaling pathway.

Synthetic steroid of 5α-Androst-3ß,5α,6ß-Triol alleviates acute lung injury via inhibiting inflammation and oxidative stress.

Acute lung injury (ALI) is a severe and potentially fatal respiratory condition with limited treatment options. The pathological evolution of ALI is driven by persistent inflammation, destruction of the pulmonary vascular barrier and oxidative stress. Evidence from prior investigations has identified 5α-androst-3ß,5α,6ß-Triol (TRIOL), a synthetic analogue of the naturally occurring neuroprotective compound cholestane-3ß,5α,6ß-triol, possesses notable anti-inflammatory and antioxidative properties. However, the precise effects of TRIOL on alleviating lung injury along with the mechanisms, have remained largely unexplored. Here, TRIOL exhibited pronounced inhibitory actions on lipopolysaccharide (LPS)-induced inflammation and oxidative stress damage in both lung epithelial and endothelial cells. This protective effect is achieved by its ability to mitigate oxidative stress and restrain the inflammatory cascade orchestrated by nuclear factor-kappa B (NF-κB), thereby preserving the integrity of the pulmonary epithelial barrier. We further validated that TRIOL can attenuate LPS-induced lung injury in rats and mice by reducing inflammatory cell infiltration and improving pulmonary edema. Furthermore, TRIOL decreased the pro-inflammatory factors and increased of anti-inflammatory factors induced by LPS. In conclusion, our study presents TRIOL as a promising novel candidate for the treatment of ALI.

Exosomal circRNAs: Novel biomarkers and therapeutic targets for urinary tumors.

Exosomal circRNAs have emerged as promising biomarkers and therapeutic targets for urinary tumors. In this review, we explored the intricate role of exosomal circRNAs in urological cancers, focusing on their biological functions, dysregulation in tumors, and potential clinical applications. The review delves into the mechanisms by which exosomal circRNAs contribute to tumor progression and highlights their diagnostic and therapeutic implications. By synthesizing current research findings, we present a compelling case for the significance of exosomal circRNAs in the context of urinary tumors. Furthermore, the review discusses the challenges and opportunities associated with utilizing exosomal circRNAs as diagnostic tools and targeted therapeutic agents. There is a need for further research to elucidate the specific mechanisms of exosomal circRNA secretion and delivery, as well as to enhance the detection methods for clinical translational applications. Overall, this comprehensive review underscores the pivotal role of exosomal circRNAs in urinary tumors and underscores their potential as valuable biomarkers and therapeutic tools in the management of urological cancers.

Targeting tumor and bone microenvironment: Novel therapeutic opportunities for castration-resistant prostate cancer patients with bone metastasis.

Despite standard hormonal therapy that targets the androgen receptor (AR) attenuates prostate cancer (PCa) effectively in the initial stage, the tumor ultimately converts to castration-resistant prostate cancer (CRPC), and the acquired resistance is still a great challenge for the management of advanced prostate cancer patients. The tumor microenvironment (TME) consists of multiple cellular and noncellular agents is well known as a vital role during the development and progression of CRPC by establishing communication between TME and tumor cells. Additionally, as primary prostate cancer progresses towards metastasis, and CRPC always experiences bone metastasis, the TME is conducive to the spread of tumors to the distant sits, particularly in bone. In addition, the bone microenvironment (BME) is also closely related to the survival, growth and colonization of metastatic tumor cells. The present review summarized the recent studies which mainly focused on the role of TME or BME in the CRPC patients with bone metastasis, and discussed the underlying mechanisms, as well as the potential therapeutic values of targeting TME and BME in the management of metastatic CRPC patients.

The Effects of the Al and Zr Contents on the Microstructure Evolution of Light-Weight AlxNbTiVZry High Entropy Alloy.

To investigate the comprehensive effects of the Al and Zr element contents on the microstructure evolution of the AlNbTiVZr series light-weight refractory high entropy alloys (HEAs), five samples were studied. Samples with different compositions were designated Al1.5NbTiVZr, Al1.5NbTiVZr0.5, AlNbTiVZr, AlNbTiVZr0.5, and Al0.5NbTiVZr0.5. The results demonstrated that the actual density of the studied HEA samples ranged from 5.291 to 5.826 g·cm-3. The microstructure of these HEAs contains a solid solution phase with a BCC structure and a Laves phase. The Laves phase was further identified as the ZrAlV intermetallic compound by TEM observations. The microstructure of the AlNbTiVZr series HEAs was affected by both the Al and Zr element contents, whereas the Zr element showed a more dominant effect due to Zr atoms occupying the core position of the ZrAlV Laves phase (C14 structure). Therefore, the as-cast Al0.5NbTiVZr0.5 sample exhibits the best room temperature compression property with a compression strength (σp) of 1783 MPa and an engineering strain of 28.8% due to having the lowest ZrAlV intermetallic compound area fraction (0.7%), as characterized by the EBSD technique.

Molecular Mapping of Putative Genomic Regions Controlling Fruit and Seed Morphology of Watermelon.

The genetic regulatory basis of qualitative and quantitative phenotypes of watermelon is being investigated in different types of molecular and genetic breeding studies around the world. In this study, biparental F2 mapping populations were developed over two experimental years, and the collected datasets of fruit and seed traits exhibited highly significant correlations. Whole-genome resequencing of comparative parental lines was performed and detected single nucleotide polymorphism (SNP) loci were converted into cleaved amplified polymorphic sequence (CAPS) markers. The screened polymorphic markers were genotyped in segregating populations and two genetic linkage maps were constructed, which covered a total of 2834.28 and 2721.45 centimorgan (cM) genetic lengths, respectively. A total of 22 quantitative trait loci (QTLs) for seven phenotypic traits were mapped; among them, five stable and major-effect QTLs (PC-8-1, SL-9-1, SWi-9-1, SSi-9-1, and SW-6-1) and four minor-effect QTLs (PC-2-1 and PC-2-2; PT-2-1 and PT-2-2; SL-6-1 and SSi-6-2; and SWi-6-1 and SWi-6-2) were observed with 3.77-38.98% PVE. The adjacent QTL markers showed a good fit marker-trait association, and a significant allele-specific contribution was also noticed for genetic inheritance of traits. Further, a total of four candidate genes (Cla97C09G179150, Cla97C09G179350, Cla97C09G180040, and Cla97C09G180100) were spotted in the stable colocalized QTLs of seed size linked traits (SL-9-1 and SWi-9-1) that showed non-synonymous type mutations. The gene expression trends indicated that the seed morphology had been formed in the early developmental stage and showed the genetic regulation of seed shape formation. Hence, we think that our identified QTLs and genes would provide powerful genetic insights for marker-assisted breeding aimed at improving the quality traits of watermelon.

Clorf Encodes Carotenoid Isomerase and Regulates Orange Flesh Color in Watermelon (Citrullus lanatus L.).

Flesh color is a significant characteristic of watermelon. Although various flesh-color genes have been identified, the inheritance and molecular basis of the orange flesh trait remain relatively unexplored. In the present study, the genetic analysis of six generations derived from W1-1 (red flesh) and W1-61 (orange flesh) revealed that the orange flesh color trait was regulated by a single recessive gene, Clorf (orange flesh). Bulk segregant analysis (BSA) locked the range to ∼4.66 Mb, and initial mapping situated the Clorf locus within a 688.35-kb region of watermelon chromosome 10. Another 1,026 F2 plants narrowed the Clorf locus to a 304.62-kb region containing 32 candidate genes. Subsequently, genome sequence variations in this 304.62-kb region were extracted for in silico BSA strategy among 11 resequenced lines (one orange flesh and ten nonorange flesh) and finally narrowed the Clorf locus into an 82.51-kb region containing nine candidate genes. Sequence variation analysis of coding regions and gene expression levels supports Cla97C10G200950 as the most possible candidate for Clorf, which encodes carotenoid isomerase (Crtiso). This study provides a genetic resource for investigating the orange flesh color of watermelon, with Clorf malfunction resulting in low lycopene accumulation and, thus, orange flesh.

Effectiveness and Safety of Apatinib Plus Programmed Cell Death Protein 1 Blockades for Patients with Treatment-refractory Metastatic Colorectal Cancer: A Retrospective Exploratory Study.

This study aimed to investigate the efficacy and safety of apatinib plus programmed cell death protein 1 (PD-1) blockades for patients with metastatic colorectal cancer (CRC) who were refractory to the standard regimens. In this retrospective study, patients with metastatic CRC who received apatinib plus PD-1 blockades in clinical practice were included. The initial dosage of apatinib was 250 mg or 500 mg, and PD-1 blockades were comprised of camrelizumab, sintilimab and pembrolizumab. Efficacy and safety data were collected through the hospital's electronic medical record system. From October 2018 to March 2022, a total of 43 patients with metastatic CRC were evaluated for efficacy and safety. The results showed an objective response rate of 25.6% (95% CI, 13.5%-41.2%) and a disease control rate of 72.1% (95% CI, 56.3%-84.7%). The median progression-free survival (PFS) of the cohort was 5.8 months (95% CI, 3.81-7.79), and the median overall survival (OS) was 10.3 months (95% CI, 5.75-14.85). The most common adverse reactions were fatigue (76.7%), hypertension (72.1%), diarrhea (62.8%), and hand-foot syndrome (51.2%). Multivariate Cox regression analysis revealed that Eastern Cooperative Oncology Group (ECOG) performance status and location of CRC (left or right-side) were independent factors to predict PFS of patients with metastatic CRC treated with the combination regimen. Consequently, the combination of apatinib and PD-1 blockades demonstrated potential efficacy and acceptable safety for patients with treatment-refractory metastatic CRC. This conclusion should be confirmed in prospective clinical trials subsequently.

Nano-drug delivery system targeting tumor microenvironment: A prospective strategy for melanoma treatment.

Melanoma, the most aggressive form of cutaneous malignancy arising from melanocytes, is frequently characterized by metastasis. Despite considerable progress in melanoma therapies, patients with advanced-stage disease often have a poor prognosis due to the limited efficacy, off-target effects, and toxicity associated with conventional drugs. Nanotechnology has emerged as a promising approach to address these challenges with nanoparticles capable of delivering therapeutic agents specifically to the tumor microenvironment (TME). However, the clinical approval of nanomedicines for melanoma treatment remains limited, necessitating further research to develop nanoparticles with improved biocompatibility and precise targeting capabilities. This comprehensive review provides an overview of the current research on nano-drug delivery systems for melanoma treatment, focusing on liposomes, polymeric nanoparticles, and inorganic nanoparticles. It discusses the potential of these nanoparticles for targeted drug delivery, as well as their ability to enhance the efficacy of conventional drugs while minimizing toxicity. Furthermore, this review emphasizes the significance of interdisciplinary collaboration between researchers from various fields to advance the development of nanomedicines. Overall, this review serves as a valuable resource for researchers and clinicians interested in the potential of nano-drug delivery systems for melanoma treatment and offers insights into future directions for research in this field.

Four Ounces Can Move a Thousand Pounds: The Enormous Value of Nanomaterials in Tumor Immunotherapy.

The application of nanomaterials in healthcare has emerged as a promising strategy due to their unique structural diversity, surface properties, and compositional diversity. In particular, nanomaterials have found a significant role in improving drug delivery and inhibiting the growth and metastasis of tumor cells. Moreover, recent studies have highlighted their potential in modulating the tumor microenvironment (TME) and enhancing the activity of immune cells to improve tumor therapy efficacy. Various types of nanomaterials are currently utilized as drug carriers, immunosuppressants, immune activators, immunoassay reagents, and more for tumor immunotherapy. Necessarily, nanomaterials used for tumor immunotherapy can be grouped into two categories: organic and inorganic nanomaterials. Though both have shown the ability to achieve the purpose of tumor immunotherapy, their composition and structural properties result in differences in their mechanisms and modes of action. Organic nanomaterials can be further divided into organic polymers, cell membranes, nanoemulsion-modified, and hydrogel forms. At the same time, inorganic nanomaterials can be broadly classified as nonmetallic and metallic nanomaterials. The current work aims to explore the mechanisms of action of these different types of nanomaterials and their prospects for promoting tumor immunotherapy.

Ferroptosis, Necroptosis, and Pyroptosis in Gastrointestinal Cancers: The Chief Culprits of Tumor Progression and Drug Resistance.

In recent years, the incidence of gastrointestinal cancers is increasing, particularly in the younger population. Effective treatment is crucial for improving patients' survival outcomes. Programmed cell death, regulated by various genes, plays a fundamental role in the growth and development of organisms. It is also critical for maintaining tissue and organ homeostasis and takes part in multiple pathological processes. In addition to apoptosis, there are other types of programmed cell death, such as ferroptosis, necroptosis, and pyroptosis, which can induce severe inflammatory responses. Notably, besides apoptosis, ferroptosis, necroptosis, and pyroptosis also contribute to the occurrence and development of gastrointestinal cancers. This review aims to provide a comprehensive summary on the biological roles and molecular mechanisms of ferroptosis, necroptosis, and pyroptosis, as well as their regulators in gastrointestinal cancers and hope to open up new paths for tumor targeted therapy in the near future.

Nanomaterials in tumor immunotherapy: new strategies and challenges.

Tumor immunotherapy exerts its anti-tumor effects by stimulating and enhancing immune responses of the body. It has become another important modality of anti-tumor therapy with significant clinical efficacy and advantages compared to chemotherapy, radiotherapy and targeted therapy. Although various kinds of tumor immunotherapeutic drugs have emerged, the challenges faced in the delivery of these drugs, such as poor tumor permeability and low tumor cell uptake rate, had prevented their widespread application. Recently, nanomaterials had emerged as a means for treatment of different diseases due to their targeting properties, biocompatibility and functionalities. Moreover, nanomaterials possess various characteristics that overcome the defects of traditional tumor immunotherapy, such as large drug loading capacity, precise tumor targeting and easy modification, thus leading to their wide application in tumor immunotherapy. There are two main classes of novel nanoparticles mentioned in this review: organic (polymeric nanomaterials, liposomes and lipid nanoparticles) and inorganic (non-metallic nanomaterials and metallic nanomaterials). Besides, the fabrication method for nanoparticles, Nanoemulsions, was also introduced. In summary, this review article mainly discussed the research progress of tumor immunotherapy based on nanomaterials in the past few years and offers a theoretical basis for exploring novel tumor immunotherapy strategies in the future.

Exosomal circular RNAs: A chief culprit in cancer chemotherapy resistance.

Chemotherapy is one of the primary treatments for malignant tumors. However, the acquired drug resistance hinders clinical efficacy and leads to treatment failure in most patients. Exosomes are cell-derived vesicles with a diameter of 30-150 nm carrying and delivering substances such as DNAs, RNAs, lipids, and proteins for cellular communication in tumor development. Circular RNAs (circRNAs) present covalently closed-loop RNA structures, which regulate tumor cell proliferation, apoptosis, and metastasis by controlling different genes and signaling pathways. CircRNAs are abundant and stably expressed in exosomes. Recent studies have shown that they play critical roles in chemotherapy resistance in various cancers. In this review, we summarized the origin of exosomes and discussed the regulation mechanism of exosomal circRNAs in cancer drug resistance.

SCGN deficiency is a risk factor for autism spectrum disorder.

Autism spectrum disorder (ASD) affects 1-2% of all children and poses a great social and economic challenge for the globe. As a highly heterogeneous neurodevelopmental disorder, the development of its treatment is extremely challenging. Multiple pathways have been linked to the pathogenesis of ASD, including signaling involved in synaptic function, oxytocinergic activities, immune homeostasis, chromatin modifications, and mitochondrial functions. Here, we identify secretagogin (SCGN), a regulator of synaptic transmission, as a new risk gene for ASD. Two heterozygous loss-of-function mutations in SCGN are presented in ASD probands. Deletion of Scgn in zebrafish or mice leads to autism-like behaviors and impairs brain development. Mechanistically, Scgn deficiency disrupts the oxytocin signaling and abnormally activates inflammation in both animal models. Both ASD probands carrying Scgn mutations also show reduced oxytocin levels. Importantly, we demonstrate that the administration of oxytocin and anti-inflammatory drugs can attenuate ASD-associated defects caused by SCGN deficiency. Altogether, we identify a convergence between a potential autism genetic risk factor SCGN, and the pathological deregulation in oxytocinergic signaling and immune responses, providing potential treatment for ASD patients suffering from SCGN deficiency. Our study also indicates that it is critical to identify and stratify ASD patient populations based on their disease mechanisms, which could greatly enhance therapeutic success.

Nanomaterials: Breaking through the bottleneck of tumor immunotherapy.

Immunotherapy exerts its excellent anti-tumor effects by stimulating and enhancing the immune response of the body, and has become another important class of anti-tumor therapy besides chemotherapy, targeted therapy and radiotherapy. Various types of immunotherapeutic drugs have gained their clinical values, but the in vivo delivery of drugs still faces many challenges, such as poor tumor permeability and low tumor cell uptake rate. In recent years, owing to highly targeting properties, better biocompatibility, and easy functionalization, nanomaterials have been widely applicated in tumor treatment, especially in tumor immunotherapy. Furthermore, nanomaterials have large drug loading capacity, strong tumor targeting and easy modification, which can effectively overcome the drawbacks of traditional immunotherapy. This paper reviews the progress of nanomaterial-based tumor immunotherapy in recent years and provides a theoretical basis for exploring new nanomaterial-based tumor immunotherapy strategies.

Directly targeting ASC by lonidamine alleviates inflammasome-driven diseases.

BACKGROUND: Dysregulated activation of the inflammasome is involved in various human diseases including acute cerebral ischemia, multiple sclerosis and sepsis. Though many inflammasome inhibitors targeting NOD-like receptor protein 3 (NLRP3) have been designed and developed, none of the inhibitors are clinically available. Growing evidence suggests that targeting apoptosis-associated speck-like protein containing a CARD (ASC), the oligomerization of which is the key event for the assembly of inflammasome, may be another promising therapeutic strategy. Lonidamine (LND), a small-molecule inhibitor of glycolysis used as an antineoplastic drug, has been evidenced to have anti-inflammation effects. However, its anti-inflammatory mechanism is still largely unknown. METHODS: Middle cerebral artery occlusion (MCAO), experimental autoimmune encephalomyelitis (EAE) and LPS-induced sepsis mice models were constructed to investigate the therapeutic and anti-inflammasome effects of LND. The inhibition of inflammasome activation and ASC oligomerization by LND was evaluated using western blot (WB), immunofluorescence (IF), quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA) in murine bone marrow-derived macrophages (BMDMs). Direct binding of LND with ASC was assessed using molecular mock docking, surface plasmon resonance (SPR), and drug affinity responsive target stability (DARTS). RESULTS: Here, we find that LND strongly attenuates the inflammatory injury in experimental models of inflammasome-associated diseases including autoimmune disease-multiple sclerosis (MS), ischemic stroke and sepsis. Moreover, LND blocks diverse types of inflammasome activation independent of its known targets including hexokinase 2 (HK2). We further reveal that LND directly binds to the inflammasome ligand ASC and inhibits its oligomerization. CONCLUSIONS: Taken together, our results identify LND as a broad-spectrum inflammasome inhibitor by directly targeting ASC, providing a novel candidate drug for the treatment of inflammasome-driven diseases in clinic.

Asymptomatic Hyperuricemia Is Associated with Achilles Tendon Rupture through Disrupting the Normal Functions of Tendon Stem/Progenitor Cells.

Hyperuricemia is a metabolic disorder that is essential to the development of inflammatory gout, with increasing prevalence over recent years. Emerging clinical findings has evidenced remarkable tendon damage in individuals with longstanding asymptomatic hyperuricemia, yet the impact of hyperuricemia on tendon homeostasis and associated repercussions is largely unknown. Here, we investigated whether asymptomatic hyperuricemia was associated with spontaneous ruptures in the Achilles tendon and the pathological effect of hyperuricemia on the tendon stem/progenitor cells (TSPCs). Significantly higher serum uric acid (SUA) levels were found in 648 closed Achilles tendon rupture (ATR) patients comparing to those in 12559 healthy volunteers. In vitro study demonstrated that uric acid (UA) dose dependently reduced rat Achilles TSPC viability, decreased the expressions of tendon collagens, and deformed their structural organization while significantly increased the transcript levels of matrix degradative enzymes and proinflammatory factors. Consistently, marked disruptions in Achilles tendon tissue structural and functional integrity were found in a rat model of hyperuricemia, together with enhanced immune cell infiltration. Transcriptome analysis revealed a significant elevation in genes involved in metabolic stress and tissue degeneration in TSPCs challenged by hyperuricemia. Specifically, reduced activity of the AKT-mTOR pathway with enhanced autophagic signaling was confirmed. Our findings indicate that asymptomatic hyperuricemia may be a predisposition of ATR by impeding the normal functions of TSPCs. This information may provide theoretical and experimental basis for exploring the early prevention and care of ATR.