GSDMD in regulated cell death: A novel therapeutic target for sepsis.

Sepsis is a life-threatening multi-organ dysfunction syndrome caused by an abnormal host response to infection. Regulated cell death is essential for maintaining tissue homeostasis and eliminating damaged, infected, or aging cells in multicellular organisms. Gasdermin D, as a member of the gasdermin family, plays a crucial role in the formation of cytoplasmic membrane pores. Research has found that GSDMD plays important roles in various forms of regulated cell death such as pyroptosis, NETosis, and necroptosis. Therefore, through mediating regulated cell death, GSDMD regulates different stages of disease pathophysiology. This article mainly summarizes the concept of GSDMD, its role in regulated cell death, its involvement in organ damage associated with sepsis-related injuries mediated by regulated cell death via GSDMD activation and introduces potential drugs targeting GSDMD that may provide more effective treatment options for sepsis patients through drug modification.

A near-complete genome assembly of Thalia dealbata Fraser (Marantaceae).

This study presents a chromosome-level, near-complete genome assembly of Thalia dealbata (Marantaceae), a typical emergent wetland plant with high ornamental and environmental value. Based on 36.99 Gb PacBio HiFi reads and 39.44 Gb Hi-C reads, we obtained a 255.05 Mb assembly, of which 251.92 Mb (98.77%) were anchored into eight pseudo-chromosomes. Five pseudo-chromosomes were completely assembled, and the other three had one to two gaps. The final assembly had a high contig N50 value (29.80 Mb) and benchmarking universal single-copy orthologs (BUSCO) recovery score (97.52%). The T. dealbata genome had 100.35 Mb repeat sequences, 24,780 protein-coding genes, and 13,679 non-coding RNAs. Phylogenetic analysis revealed that T. dealbata was closest to Zingiber officinale, whose divergence time was approximately 55.41 million years ago. In addition, 48 and 52 significantly expanded and contracted gene families were identified within the T. dealbata genome. Moreover, 309 gene families were specific to T. dealbata, and 1,017 genes were positively selected. The T. dealbata genome reported in this study provides a valuable genomic resource for further research on wetland plant adaptation and the genome evolution dynamics. This genome is also beneficial for the comparative genomics of Zingiberales species and flowering plants.

EZH2 targeting to improve the sensitivity of acquired radio-resistance bladder cancer cells.

Among the many treatments for Bladder cancer (BCa) patients, radiotherapy is an effective way to preserve the bladder. However, as the frequency of irradiation increases, the tumor cells appear "acquired radio-resistance" (ARR) and loss the sensitivity to radiotherapy. To explore the molecular mechanism of ARR, two BCa cell lines, 5637 and T24, were enrolled here and their ARR counterparts, 5637R and T24R, were obtained by exposure to γ-ray of 2 Gy for 30 times. Compared to parental cells, ARR cells have significantly enhanced stem cell-like phenotype, robust DNA damage repair capabilities and elevated expression of zeste homolog 2 (EZH2). Decreasing EZH2 expression, both parental and ARR cells exhibited reduced abilities of forming microsphere and repairing DNA damage, but enhanced cells radio-sensitivity and intracellular autophagy compared to untreated cells. Down-regulation the expression of EZH2 induced an increasing of both LC3 and P62 in parental cells, while in ARR cells, only LC3 increased upon EZH2 reduction. On the other hand, UNC1999 treatment caused the increasing of LC3B and P62 in all cells, suggested that siEZH2 and UNC1999 affect ARR cells autophagy through different mechanisms. In vivo study showed that pre-treated with UNC1999 greatly enhanced T24R cells sensitivity to IR, and knocking down the expression of EZH2 significantly suppressed the tumor growth. Combined with bioinformatics data analysis, we speculate that EZH2 is an important biomolecule linking the diagnosis, radiotherapy and prognosis of BCa. EZH2 targeted therapy may be an effective way to overcome ARR of BCa, and is worthy of in-depth study.

[Research progress in mechanism of necroptosis in acute pancreatitis].

Acute pancreatitis (AP) is a common and potentially threatening disease of the pancreas, and some patients eventually develop to severe acute pancreatitis (SAP). Symptomatic support therapies such as rehydration therapy and anti-infection are still the main treatments. Lacking specific therapies is the main reason for the high mortality of AP patients, especially those with SAP. Premature trypsinogen activation is the most important pathologic cellular event in the pathogenesis of AP. The release of trypsin can cause self-digestion inside and outside of acinar cells, especially the release of cathepsin B can also cause a caspase-unrelated regulatory cell death (RCD) known as necroptosis, which is closely related to the development and prognosis of AP. Therefore, it is necessary to further study the mechanism of necroptosis in the occurrence and development of AP. This article reviews the mechanism of necroptosis and the research progress related to AP, in an attempt to provide a new understanding of the pathogenesis and treatment of AP, and promote the better target drug development.

Root exudates contribute to belowground ecosystem hotspots: A review.

Root exudates are an essential carrier for material cycling, energy exchange, and information transfer between the belowground parts of plants and the soil. We synthesize current properties and regulators of root exudates and their role in the belowground ecosystem as substances cycle and signal regulation. We discussed the composition and amount of root exudates and their production mechanism, indicating that plant species, growth stage, environmental factors, and microorganisms are primary influence factors. The specific mechanisms by which root secretions mobilize the soil nutrients were summarized. First, plants improve the nutrient status of the soil by releasing organic acids for acidification and chelation. Then, root exudates accelerated the SOC turnover due to their dual impacts, forming and destabilizing aggregates and MASOC. Eventually, root exudates mediate the plant-plant interaction and plant-microbe interaction. Additionally, a summary of the current collection methods of root exudates is presented.

PD-1 Inhibitor Enhanced Radiosensitivity by Reactivating T Cells and Inducing G2/M Phase Arrest in Esophageal Squamous Cell Carcinoma.

Radiotherapy is a main treatment for esophageal squamous cell carcinoma (ESCC), but radioresistance leads to treatment failure ultimately. The combination of radiotherapy and PD-1 inhibitors showed significant antitumor effects. Our study showed that high-immune score, IFNG and CD8A level were associated with a low-radiosensitivity index (RSI) in the TCGA-ESCC cohort. And blocking PD-1 promoted exhausted T cells proliferation and IFN-γ expression. PD-1 inhibitor-reactivated T cells promoted G2/M-phase arrest, apoptosis and impaired DNA damage in radioresistant cells in an IFN-γ-dependent manner. Our study showed PD-1 inhibitors promote radiosensitivity though enhancing exhausted T cells expansion and IFN-γ expression, and highlights that neoadjuvant anti-PD-1 therapy and radiotherapy could offer an optimum strategy for improving cancer patients' outcome.

STAT3 enhances radiation-induced tumor migration, invasion and stem-like properties of bladder cancer.

Bladder cancer (BCa) is the most common cancer of the human urinary system, and is associated with poor patient prognosis and a high recurrence rate. Cancer stem cells (CSCs) are the primary cause of tumor recurrence and metastasis, possessing self­renewal properties and resistance to radiation therapy. Our previous studies indicated that phosphorylated signal transduction and transcription activator 3 (STAT3) may be a potential biomarker to predict radiation tolerance and tumor recurrence in patients with BCa, following conventional radiotherapy. The aim of the present study was to investigate the underlying mechanism of STAT3 in the radio­resistance of BCa cells. It was found that fractionated irradiation promoted the activation of two STAT3­associated CSCs signaling pathways in BCa cells, namely suppressor of variegation 3­9 homolog 1/GATA binding protein 3/STAT3 and Janus kinase 2/STAT3. Surviving cells exhibited elevated migratory and invasive abilities, enhanced CSC­like characteristics and radio­resistance. Furthermore, knockdown of STAT3 expression or inhibition of STAT3 activation markedly decreased the self­renewal ability and tumorigenicity of radiation­resistant BCa cells. Kaplan­Meier analysis revealed that decreased STAT3 mRNA levels were associated with increased overall survival times in patients with BCa. Taken together, these data indicated that STAT3 may be an effective therapeutic target for inhibiting the progression, metastasis and recurrence of BCa in patients receiving radiotherapy.

Down-regulation of autophagy-associated protein increased acquired radio-resistance bladder cancer cells sensitivity to taxol.

BACKGROUND: As a bladder-preserving therapy, radiation therapy (RT) has been widely used in the treatment of bladder cancer (BCa) and made great progress in the past few decades. However, some BCa patients have low RT responsiveness and local recurrence rate after RT could reach 50%. Acquired radio-resistance (ARR) is one of the important reasons for the failure of RT. Unfortunately, these ARR cells also lack sensitivity to chemotherapy and cause tumor recurrence and metastasis. PURPOSE: To build ARR-phenotype BCa cell model, discuss the possible molecular mechanism of ARR and find effective target molecules to overcome ARR. MATERIALS AND METHODS: Five thousand six hundred and thirty-seven cells were subjected 30 times to 2 Gy of γ-rays and the surviving cells were called 5637R. Colony formation and MTT assay were applied to evaluate cells sensitivity to ionizing radiation (IR) and anti-neoplastic agents, respectively. Cells abilities of migration and invasion were determined using transwell method. Quantitative real-time polymerase chain reaction (RT-qPCR) and western blot (WB) were respectively utilized to compare the difference of gene and protein expression between 5637 and 5637R cells. Molecule inhibitors and small interfering RNA (siRNA) systems were employed to decrease the expression of target proteins, respectively. RESULTS: BCa cells survived from fractionated irradiation (FI) exhibited tolerance to both IR and chemotherapy drugs. These ARR cells (5637R) had elevated migration and invasion abilities, accompanied by increased expression of epithelial mesenchymal transition (EMT)-related transcription factors (ZEB1/Snail/Twist). Moreover, 5637R cells showed enhanced cancer stem cell (CSC)-like characteristics with activated KMT1A-GATA3-STAT3 circuit, a newly reported self-renewal pathway of human bladder cancer stem cell (BCSC). Combined with Kaplan-Meier's analysis, we speculated that GATA3/MMP9/STAT3 could be an effective molecular panel predicting poor prognosis of BCa. In order to enhance the sensitivity of resistant cells to radiation, we introduced ERK inhibitor (FR 180204) and STAT3 inhibitor (S3I-201). However, both of them could not enhance ARR cells response to IR. On the other hand, siRNAs were respectively implemented to inhibit the expression of endogenous Beclin1 and Atg5, two important autophagy-related genes, in BCa cells, which significantly increased 5637R cells death upon taxol exposing. Similarly, chloroquine (CQ), a classic autophagy inhibitor, enhanced the cytotoxicity of taxol only on 5637R cells. CONCLUSIONS: Long-term FI treatment is an effective method to establish the ARR-phenotype BCa cell model, by enriching BCSCs and enhancing cells migration and invasion. Both inhibiting the expression of autophagy-related proteins and using autophagy inhibitor can increase the sensitivity of ARR cells to taxol, suggesting that autophagy may play an important role in ARR cells chemical tolerance.