Berbamine ameliorates DSS-induced colitis by inhibiting peptidyl-arginine deiminase 4-dependent neutrophil extracellular traps formation.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease with immune dysregulation affecting colon inflammatory response. Recent studies have highlighted that neutrophil extracellular traps (NETs) play an important role in the pathogenesis of UC. Berbamine (BBM), one of the bioactive ingredients extracted from Chinese herbal medicine Berberis vulgaris L, has attracted intensive attentions due to its significant anti-inflammatory activity and a marketing drug for treating leukemia in China. However, the exact role and potential molecular mechanism of BBM against UC remains elusive. In the present study, our results showed that BBM could markedly improve the pathological phenotype and the colon inflammation in mice with dextran sulfate sodium (DSS)-induced colitis. Then, comprehensive approaches combining network pharmacology and molecular docking analyses were employed to predict the therapeutic potential of BBM in treating UC by peptidyl-arginine deiminase 4 (PAD4), a crucial molecule involved in NETs formation. The molecular docking results showed BBM had a high affinity for PAD4 with a binding energy of -9.3 kcal/mol Moreover, PAD4 expression and NETs productions, including citrullination of histone H3 (Cit-H3), neutrophil elastase (NE), myeloperoxidase (MPO) in both neutrophils and colonic tissue were reduced after BBM administration. However, in the mice with DSS-induced colitis pretreated with GSK484, a PAD4-specific inhibitor, BBM could not further reduce disease related indexes, expression of PAD4 and NETs productions. Above all, the identification of PAD4 as a potential target for BBM to inhibit NETs formation in colitis provides novel insights into the development of BBM-derived drugs for the clinical management of UC.

LDL receptor-related protein 5 selectively transports unesterified polyunsaturated fatty acids to intracellular compartments.

Polyunsaturated fatty acids (PUFAs), which cannot be synthesized by animals and must be supplied from the diet, have been strongly associated with human health. However, the mechanisms for their accretion remain poorly understood. Here, we show that LDL receptor-related protein 5 (LRP5), but not its homolog LRP6, selectively transports unesterified PUFAs into a number of cell types. The LDLa ligand-binding repeats of LRP5 directly bind to PUFAs and are required and sufficient for PUFA transport. In contrast to the known PUFA transporters Mfsd2a, CD36 and FATP2, LRP5 transports unesterified PUFAs via internalization to intracellular compartments including lysosomes, and n-3 PUFAs depend on this transport mechanism to inhibit mTORC1. This LRP5-mediated PUFA transport mechanism suppresses extracellular trap formation in neutrophils and protects mice from myocardial injury during ischemia-reperfusion. Thus, this study reveals a biologically important mechanism for unesterified PUFA transport to intracellular compartments.

Wnt5 controls splenic myelopoiesis and neutrophil functional ambivalency during DSS-induced colitis.

Neutrophils are important innate immune cells with plasticity, heterogenicity, and functional ambivalency. While bone marrow is often regarded as the primary source of neutrophil production, the roles of extramedullary production in regulating neutrophil plasticity and heterogenicity in autoimmune diseases remain poorly understood. Here, we report that the lack of wingless-type MMTV integration site family member 5 (WNT5) unleashes anti-inflammatory protection against colitis in mice, accompanied by reduced colonic CD8+ T cell activation and enhanced splenic extramedullary myelopoiesis. In addition, colitis upregulates WNT5 expression in splenic stromal cells. The ablation of WNT5 leads to increased splenic production of hematopoietic niche factors, as well as elevated numbers of splenic neutrophils with heightened CD8+ T cell suppressive capability, in part due to elevated CD101 expression and attenuated pro-inflammatory activities. Thus, our study reveals a mechanism by which neutrophil plasticity and heterogenicity are regulated in colitis through WNT5 and highlights the role of splenic neutrophil production in shaping inflammatory outcomes.

PITPNC1 Suppress CD8+ T cell immune function and promote radioresistance in rectal cancer by modulating FASN/CD155.

BACKGROUND: Radioresistance is a primary factor contributing to the failure of rectal cancer treatment. Immune suppression plays a significant role in the development of radioresistance. We have investigated the potential role of phosphatidylinositol transfer protein cytoplasmic 1 (PITPNC1) in regulating immune suppression associated with radioresistance. METHODS: To elucidate the mechanisms by which PITPNC1 influences radioresistance, we established HT29, SW480, and MC38 radioresistant cell lines. The relationship between radioresistance and changes in the proportion of immune cells was verified through subcutaneous tumor models and flow cytometry. Changes in the expression levels of PITPNC1, FASN, and CD155 were determined using immunohistochemistry and western blotting techniques. The interplay between these proteins was investigated using immunofluorescence co-localization and immunoprecipitation assays. Additionally, siRNA and lentivirus-mediated gene knockdown or overexpression, as well as co-culture of tumor cells with PBMCs or CD8+ T cells and establishment of stable transgenic cell lines in vivo, were employed to validate the impact of the PITPNC1/FASN/CD155 pathway on CD8+ T cell immune function. RESULTS: Under irradiation, the apoptosis rate and expression of apoptosis-related proteins in radioresistant colorectal cancer cell lines were significantly decreased, while the cell proliferation rate increased. In radioresistant tumor-bearing mice, the proportion of CD8+ T cells and IFN-γ production within immune cells decreased. Immunohistochemical analysis of human and animal tissue specimens resistant to radiotherapy showed a significant increase in the expression levels of PITPNC1, FASN, and CD155. Gene knockdown and rescue experiments demonstrated that PITPNC1 can regulate the expression of CD155 on the surface of tumor cells through FASN. In addition, co-culture experiments and in vivo tumor-bearing experiments have shown that silencing PITPNC1 can inhibit FASN/CD155, enhance CD8+ T cell immune function, promote colorectal cancer cell death, and ultimately reduce radioresistance in tumor-bearing models. CONCLUSIONS: PITPNC1 regulates the expression of CD155 through FASN, inhibits CD8+ T cell immune function, and promotes radioresistance in rectal cancer.

Cell surface RNAs control neutrophil recruitment.

RNAs localizing to the outer cell surface have been recently identified in mammalian cells, including RNAs with glycan modifications known as glycoRNAs. However, the functional significance of cell surface RNAs and their production are poorly known. We report that cell surface RNAs are critical for neutrophil recruitment and that the mammalian homologs of the sid-1 RNA transporter are required for glycoRNA expression. Cell surface RNAs can be readily detected in murine neutrophils, the elimination of which substantially impairs neutrophil recruitment to inflammatory sites in vivo and reduces neutrophils' adhesion to and migration through endothelial cells. Neutrophil glycoRNAs are predominantly on cell surface, important for neutrophil-endothelial interactions, and can be recognized by P-selectin (Selp). Knockdown of the murine Sidt genes abolishes neutrophil glycoRNAs and functionally mimics the loss of cell surface RNAs. Our data demonstrate the biological importance of cell surface glycoRNAs and highlight a noncanonical dimension of RNA-mediated cellular functions.

The CUL5 E3 ligase complex negatively regulates central signaling pathways in CD8+ T cells.

CD8+ T cells play an important role in anti-tumor immunity. Better understanding of their regulation could advance cancer immunotherapies. Here we identify, via stepwise CRISPR-based screening, that CUL5 is a negative regulator of the core signaling pathways of CD8+ T cells. Knocking out CUL5 in mouse CD8+ T cells significantly improves their tumor growth inhibiting ability, with significant proteomic alterations that broadly enhance TCR and cytokine signaling and their effector functions. Chemical inhibition of neddylation required by CUL5 activation, also enhances CD8 effector activities with CUL5 validated as a major target. Mechanistically, CUL5, which is upregulated by TCR stimulation, interacts with the SOCS-box-containing protein PCMTD2 and inhibits TCR and IL2 signaling. Additionally, CTLA4 is markedly upregulated by CUL5 knockout, and its inactivation further enhances the anti-tumor effect of CUL5 KO. These results together reveal a negative regulatory mechanism for CD8+ T cells and have strong translational implications in cancer immunotherapy.

Predicting colorectal cancer prognosis based on long noncoding RNAs of disulfidptosis genes.

BACKGROUND: A recently hypothesized cause of cell death called disulfidptosis has been linked to the expansion, emigration, and vascular rebuilding of cancer cells. Cancer can be treated by targeting the pathways that trigger cell death. AIM: To discover the long non-coding RNA of the disulfidaptosis-related lncRNAs (DRLs), prognosis clinical survival, and treat patients with colorectal cancer with medications. METHODS: Initially, we queried the Cancer Genome Atlas database to collect transcriptome, clinical, and genetic mutation data for colorectal cancer (CRC). Training and testing sets for CRC patient transcriptome data were generated randomly. Key long non-coding RNAs (lncRNAs) related to DRLs were then identified and evaluated using a least absolute shrinkage and selection operator procedure, as well as univariate and multivariate Cox regression models. A prognostic model was then created after risk scoring. Also, Immune infiltration analysis, immune checkpoint analysis, and medication susceptibility analysis were used to investigate the causes of the different prognoses between high and low risk groups. Finally, we validated the differential expression and biomarker potential of risk-predictive lncRNAs through induction using both NCM460 and HT-29 cell lines, as well as a disulfidptosis model. RESULTS: In this work, eight significant lncRNAs linked to disulfidptosis were found. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses of differentially expressed genes between high- and low-risk groups from the prognostic model showed a close relationship with the immune response as well as significant enrichment in neutrophil extracellular trap formation and the IL-17 signaling pathway. Furthermore, significant immune cell variations between the high-risk and low-risk groups were seen, as well as a higher incidence of immunological escape risk in the high-risk group. Finally, Epirubicin, bortezomib, teniposide, and BMS-754807 were shown to have the lowest sensitivity among the four immunotherapy drugs. CONCLUSION: Our findings emphasizes the role of disulfidptosis in regulating tumor development, therapeutic response, and patient survival in CRC patients. For the clinical treatment of CRC, these important LncRNAs could serve as viable therapeutic targets.

Clinical activity and safety of sintilimab, bevacizumab, and TMZ in patients with recurrent glioblastoma.

PURPOSE: There are limited and no standard therapies for recurrent glioblastoma. We herein report the antitumour activity and safety of sintilimab, bevacizumab and temozolomide (TMZ) in recurrent glioblastoma. METHODS: We retrospectively analysed eight patients with recurrent glioblastoma treated with sintilimab (200 mg) every three weeks + bevacizumab (10 mg/kg) every three weeks + TMZ (200 mg/m²orally) (5 days orally every 28 days for a total of four weeks). The primary objective was investigator-assessed median progression-free survival(mPFS). Secondary objectives were to assess the 6-month PFS, objective response rate (ORR) and duration of response (DOR) accroding to RANO criteria. RESULTS: The mPFS time for 8 patients was 3.340 months (95% CI: 2.217-4.463), The longest PFS was close to 9 months. Five patients were assessed to have achieved partial response (PR), with an overall remission rate of 62.5%, Four patients experienced a change in tumour volume at the best response time of greater than 60% shrinkage from baseline, and one patient remained progression free upon review, with a DOR of more than 6.57 months. The 6-month PFS was 25% (95% CI: 5.0-55.0%). Three patients had a treatment-related adverse events, though no grade 4 or 5 adverse events occurred. CONCLUSION: In this small retrospective study, the combination regimen of sintilimab, bevacizumab and TMZ showed promising antitumour activity in treatment of recurrent glioblastoma, with a good objective remission rate.

Advances in the study of antisense long­stranded non­coding RNAs in tumors (Review).

Long­stranded non­coding RNAs (lncRNAs) are RNAs that consist of >200 nucleotides. The majority of lncRNAs do not encode proteins but have been revealed to mediate a variety of important physiological functions. Antisense­lncRNAs (AS­lncRNAs) are transcribed from the opposite strand of a protein or non­protein coding gene as part of the antisense strand of the coding gene. AS­lncRNAs can serve an important role in the tumorigenesis, prognosis, metastasis and drug resistance of a number of malignancies. This has been reported to be exerted through various mechanisms, such as endogenous competition, promoter interactions, direct interactions with mRNAs, acting as 'scaffolds' to regulate mRNA half­life, interactions with 5­untranslated regions and regulation of sense mRNAs. AS­lncRNAs have been found to either inhibit or promote tumor aggressiveness by regulating cell proliferation, energy metabolism, inflammation, inflammatory­carcinoma transformation, invasion, migration and angiogenesis. In addition, accumulating evidence has documented that AS­lncRNAs can regulate tumor therapy resistance. Therefore, targeting aberrantly expressed AS­lncRNAs for cancer treatment may prove to be a promising approach to reverse therapy resistance. In the present review, research advances on the role of AS­lncRNAs in tumor occurrence and development were summarized, with the aim of providing novel ideas for further research in this field.

Effects of topping on rhizome, and analysis of chemical composition, antioxidant activity and α-amylase and α-glucosidase inhibition of the aerial parts in Polygonatum cyrtonema.

Polygonatum cyrtonema is a perennial plant, and it has long been used in traditional Chinese medicine for food and medicine. The medicinal part of P.cyrtonema is the rhizome; however, the aerial part has not been studied. To understand the effect of the topping of aerial parts on the yield and chemical components of rhizomes, as well as the chemical constituents, antioxidant, and in vitro hypoglycemic activities of the aerial stem, leave, and flower parts of P.cyrtonema, the present study was conducted. The results showed that compared to the control (CK) treatment, the topping of the aerial part increased rhizome weight gain coefficient (3.43) and the total saponin content (37.60 mg/g) significantly (P<0.01) than the CK treatment. The contents of total phenols and total flavonoids in PCL and PCF were significantly (P<0.01) higher than those in rhizomes; however, the polysaccharide content (10.47%) in PCR (whole rhizome) was higher than that in PCS (3.65%), PCL (5.99%), and PCF (4.76%) content. The protein and amino acid contents in PCS, PCL, and PCF were higher than those in rhizomes. The protein and amino acid contents in PCS, PCL, and PCF were higher than those in rhizomes. PCS, PCL, and PCF showed strong antioxidant activity (DPPH, ·OH, ABTS, and FRAP), which were better than traditional medicinal parts (the rhizome).In vitro hypoglycemic results showed that PCS, PCL, and PCF had certain inhibitory activities on α-amylase and α-glucosidase (66.25% and 52.81%), which were close to the hypoglycemic activity of rhizomes (67.96% and 52.22%). The leaf extracts also showed better inhibitory activity. To sum up, the topping measures can improve yield and total saponin content of the rhizomes from P.cyrtonema, which can be applied to improve production. The stems, leaves, and flowers had a much stronger antioxidant and hypoglycemic activities and higher the total polyphenols, flavonoids, proteins, and amino acid content. Therefore, stems, leaves, and flowers of Polygonatum can be fully developed according to different needs. they are typically used in animal feed, food storage and cosmetics.

Sfxn5 Regulation of Actin Polymerization for Neutrophil Spreading Depends on a Citrate-Cholesterol-PI(4,5)P2 Pathway.

Cell spreading is an initial and critical step in neutrophil adhesion and migration, leading to neutrophil recruitment to inflammatory tissues. Sideroflexin (Sfxn) family proteins are metabolite transporters located in the mitochondrial membrane. Recombinant SFXN5 protein is a citrate transporter in vitro; however, whether Sfxn5 regulates any cellular behavior or function remains unknown. In this study, we found that small interfering RNA transfection or morpholino injection achieving Sfxn5 deficiency in neutrophils significantly decreased neutrophil recruitment in mice and zebrafish, respectively. Sfxn5 deficiency impaired neutrophil spreading and spreading-associated cellular phenotypes, such as cell adhesion, chemotaxis, and ROS production. Actin polymerization is critical for neutrophil spreading, and we found that actin polymerization in spreading neutrophils was partially inhibited by Sfxn5 deficiency. Mechanistically, we observed that the levels of cytosolic citrate and its downstream metabolic products, acetyl-CoA and cholesterol, were decreased in Sfxn5-deficient neutrophils. The levels of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), a mediator for the regulation of actin polymerization by cholesterol, were reduced in the plasma membrane of Sfxn5-deficient neutrophils. Exogenous supplementation with citrate or cholesterol partially reversed the reduction in PI(4,5)P2 levels, defective neutrophil actin polymerization, and cell spreading. Altogether, we demonstrated that Sfxn5 maintains cytosolic citrate levels and ensures the synthesis of sufficient cholesterol to promote actin polymerization in a PI(4,5)P2-dependent manner during neutrophil spreading, which is essential for the eventual inflammatory recruitment of neutrophils. Our study revealed the importance of Sfxn5 in neutrophil spreading and migration, thus identifying, to our knowledge, for the first time, the physiological cellular functions of the Sfxn5 gene.

Clinical effect of wumei bolus on ulcerative colitis: A meta-analysis.

Wumei Bolus is a traditional Chinese medicine prescription, first appeared in Shennong Bencao Jing. Modern pharmacology believes that Wumei Bolus has antibacterial, antitussive, sedative, antiviral and anti-tumor effects, and plays a therapeutic role by acting on multi-target/multi-pathway. Moreover, it has great advantages in digestive system diseases, such as repairing the damaged gastrointestinal mucosa and improving the inflammatory environment. Aim of the study: This review aimed to evaluate the efficacy and safety of prescriptions based on the Wumei Bolus treating ulcerative colitis (UC). Materials and methods: In this meta-analysis, we searched CNKI, Wanfang Database, VIP, Pubmed, Web of Science (WOS) with language restrictions of Chinese and English for articles published from the establishment of the database to Dec 2022. This meta-analysis controlled randomized controlled trials (RCTs) assessing the efficacy and safety of Wumei Bolus against ulcerative colitis and using RevMan 5.4 and Stata 15.0to analyze information from the compliant studies. Results: The search incorporated 3145 results (1617 cases assigned into Wumei Bolus group and 1528 cases assigned into control group), from which 37 studies fulfilled our inclusion criteria and were included. The outcomes of this meta-analysis showed that compared to the control group, the Experiment group was significantly more effective (RR = 1.24，95%CI [1.20，1.28])and lower adverse reactions (RR = 0.32, 95%CI [0.20, 0.53]). According to the subgroup analysis, The results showed that the RR = 1.23 and 95%CI [1.16, 1.30] in the group treated with Wumei Bolus alone and the group treated with Western medicine with RR = 1.25 and 95%CI [1.20, 1.30], indicating that the efficacy of Wumei Bolus in the treatment of UC was better and the difference was statistically significant (P < 0.00001). The results showed that compared with the control group, the experimental group had more advantages in reducing inflammatory factors whether TNF-α or IL-8 (TNF-α:SMD = -4.44, 95%CI [-5.75, -3.14]; IL-8: SMD = -3.02, 95%CI [-4.06, -1.97]) and improving TCM symptoms and reduced TCM syndrome points (SMD = -3.82, 95%CI [-4.30, -3.34]). There was significant association of the basic treatment of Wumei Bolus improving clinical efficacy, reducing serum pro-inflammatory factors, improving symptoms, and reducing adverse reactions in UC patients. These results were statistically significant (P < 0.00001). Conclusions: The prescriptions based on the Wumei Bolus is greatly related to reducing serum pro-inflammatory factors, improving symptoms, improving clinical efficacy and reducing adverse reactions in the treatment of UC compared to conventional western medicine and improve the total clinical effective rate.

Comparative Analysis of Roots from Vicatia thibetica de Boiss and Angelica sinensis Based on Chemical Composition, Antioxidant, Nitrite-Scavenging and Enzyme Inhibition Activities.

Radix Vicatia thibetica de Boiss (RVT) is locally known as "Xigui" or "Dujiao-danggui" in Tibetan medicine and is often used as a substitute for Radix Angelica sinensis (RAS) in daily nourishing diets and clinical applications. In this study, we determined and compared the contents of polysaccharides, total coumarins, ferulic acid, total phenols, total flavonoids, chlorogenic acid, protein, and amino acids, and the composition of volatile oil in RVT and RAS. Biological activities, including antioxidants, scavenging of nitrite, inhibition of tyrosinase, thrombin, and coagulation FXa, were comparatively evaluated. Results showed that RVT contains more polysaccharides, phenols, flavonoids, proteins, glutamic acid, and lysine as compared to RAS. Among volatile compounds, 14 species are similar, and 20 species are different in RVT and RAS. Overall, among volatile compounds, the content of 3-N-Butylphthalide was higher, whereas the content of ligustilide was lower in RVT volatile oil. A significant difference was reported in the bioactivity of RVT and RAS. The biological activity of RVT had higher antioxidant, nitrite scavenging, and tyrosinase inhibitory activities, whereas it showed much lower thrombin and FXa inhibitory activities. Correlation analysis showed that the antioxidant, nitrite scavenging, and tyrosinase inhibitory activities were related to the phenol and flavonoid content, whereas the thrombin and FXa inhibitory activities were related to ferulic acid and volatile oil content. This study presents a comparative analysis of RAS and RVT's chemical compositions of antioxidant, nitrite-scavenging, inhibition of tyrosinase, thrombin, and coagulation FXa activities. It was found that both RVT and RAS have their unique advantages, and RVT has the potential to be utilized as functional foods, cosmetics, and medical products.

Pazopanib Is a Potential Treatment for Coronavirus-Induced Lung Injuries.

Severe acute respiratory syndrome coronavirus 2, responsible for the severe acute respiratory syndrome known as COVID-19, has rapidly spread in almost every country and devastated the global economy and health care system. Lung injury is an early disease manifestation believed to be a major contributor to short- and long-term pathological consequences of COVID-19, and thus drug discovery aiming to ameliorate lung injury could be a potential strategy to treat COVID-19 patients. By inducing a severe acute respiratory syndrome-like pulmonary disease model through infecting A/J mice with murine hepatitis virus strain 1 (MHV-1), we show that i.v. administration of pazopanib ameliorates acute lung injuries without affecting MHV-1 replication. Pazopanib reduces cell apoptosis in MHV-1-infected lungs. Furthermore, we also identified that pazopanib has to be given no later than 48 h after the virus infection without compromising the therapeutic effect. Our study provides a potential treatment for coronavirus-induced lung injuries and support for further evaluation of pazopanib in COVID-19 patients.

SARS-CoV-2 Continuous Genetic Divergence and Changes in Multiplex RT-PCR Detection Pattern on Positive Retesting Median 150 Days after Initial Infection.

Being in the epicenter of the COVID-19 pandemic, our lab tested 193,054 specimens for SARS-CoV-2 RNA by diagnostic multiplex reverse transcription polymerase chain reaction (mRT-PCR) starting in March 2020, of which 17,196 specimens resulted positive. To investigate the dynamics of virus molecular evolution and epidemiology, whole genome amplification (WGA) and Next Generation Sequencing (NGS) were performed on 9516 isolates. 7586 isolates with a high quality were further analyzed for the mutation frequency and spectrum. Lastly, we evaluated the utility of the mRT-PCR detection pattern among 26 reinfected patients with repeat positive testing three months after testing negative from the initial infection. Our results show a continuation of the genetic divergence in viral genomes. Furthermore, our results indicate that independent mutations in the primer and probe regions of the nucleocapsid gene amplicon and envelope gene amplicon accumulate over time. Some of these mutations correlate with the changes of detection pattern of viral targets of mRT-PCR. Our data highlight the significance of a continuous genetic divergence on a gene amplification-based assay, the value of the mRT-PCR detection pattern for complementing the clinical diagnosis of reinfection, and the potential for WGA and NGS to identify mutation hotspots throughout the entire viral genome to optimize the design of the PCR-based gene amplification assay.

Probenecid-Blocked Pannexin-1 Channel Protects Against Early Brain Injury via Inhibiting Neuronal AIM2 Inflammasome Activation After Subarachnoid Hemorrhage.

Aim: Previous studies have proved that inhibiting inflammasome activation provides neuroprotection against early brain injury (EBI) after subarachnoid hemorrhage (SAH), which is mainly focused on the microglial inflammatory response, but the potential role of neuronal inflammasome activation in EBI has not been clearly identified. This study examined whether the pannexin-1 channel inhibitor probenecid could reduce EBI after SAH by inhibiting neuronal AIM2 inflammasome activation. Methods: There are in vivo and in vitro parts in this study. First, adult male SD rats were subjected to the endovascular perforation mode of SAH. The time course of pannexin-1 and AIM2 expressions were determined after SAH in 72 h. Brain water content, neurological function, AIM2 inflammasome activation, and inflammatory response were evaluated at 24 h after SAH in sham, SAH, and SAH + probenecid groups. In the in vitro part, HT22 cell treated with hemin was applied to mimic SAH. The expression of AIM2 inflammasome was detected by immunofluorescence staining. Neuronal death and mitochondrial dysfunction were determined by the LDH assay kit and JC-1 staining. Results: The pannexin-1 and AIM2 protein levels were upregulated after SAH. Pannexin-1 channel inhibitor probenecid attenuated brain edema and improved neurological dysfunction by reducing AIM2 inflammasome activation and reactive oxygen species (ROS) generation after SAH in rats. Treating HT22 cells with hemin for 12 h resulted in AIM2 and caspase-1 upregulation and increased mitochondrial dysfunction and neuronal cell death. Probenecid significantly attenuated the hemin-induced AIM2 inflammasome activation and neuronal death. Conclusions: AIM2 inflammasome is activated in neurons after SAH. Pharmacological inhibition of the pannexin-1 channel by probenecid attenuated SAH-induced AIM2 inflammasome activation and EBI in vivo and hemin-induced AIM2 inflammasome activation and neuronal death in vitro.

Decontamination performance of a bioretention system using a simple sand-based filler proportioning method.

This study investigated the decontamination performance of a bioretention system using a sand-based filler constructed using sand and peat soil. The filler was constructed according to a simple proportioning method that considers water turnover time and organic content. Different inorganic constituents were added to the filler including zeolite, volcanic rock, coal slag, vermiculite and perlite to further improve the decontamination effect. Total suspended solids (TSS), total phosphorus (TP), ammonium nitrogen (NH4+-N), total nitrogen (TN) and chemical oxygen demand (COD) were measured in the influent and effluent. The results showed that: (1) the overall removal effect of the sand-based filler was satisfactory, indicating a certain feasibility and practicality of the method; (2) bioretention based on the sand-based filler had a better performance in removing TSS and TP with the removal rate both over 95%, and the addition of inorganic constituents to the filler was beneficial to TSS removal due to the effect of cumulative filtration capabilities of multiple materials, while phosphate was easily adsorbed by the positively charged particles of the peat soil; (3) the high removal rate of NH4+-N was due to adsorption and it could reach more than 80% by adding inorganic constituents with good adsorption such as zeolite vermiculite and perlite. Similarly, the addition of vermiculite and coal slag could increase the removal rate of COD by 15-25%. This research offers a novel alternative for guiding the selection and proportion of fillers in bioretention systems.

Towards high performance room temperature sodium-sulfur batteries: Strategies to avoid shuttle effect.

Room temperature sodium-sulfur battery has high theoretical specific energy and low cost, so it has good application prospect. However, due to the disadvantageous reaction between soluble intermediate polysulfides and sodium anode, the capacity drops sharply, which greatly limits its practical application. In recent years, various strategies have been formulated to address the problem of polysulfides dissolution. This perspective article provides an overview of the research progress on research progress of novel cathode materials, multifunctional host, new electrolyte systems and modified separator/interlayer/anode. The challenge and prospect of the advanced strategies to suppress the polysulfides shuttle for long-life and high-efficiency room temperature sodium-sulfur batteries are proposed.

The Crosstalk Between Long Non-Coding RNAs and Various Types of Death in Cancer Cells.

With the increasing aging population, cancer has become one of the leading causes of death worldwide, and the number of cancer cases and deaths is only anticipated to grow further. Long non-coding RNAs (lncRNAs), which are closely associated with the expression level of downstream genes and various types of bioactivity, are regarded as one of the key regulators of cancer cell proliferation and death. Cell death, including apoptosis, necrosis, autophagy, pyroptosis, and ferroptosis, plays a vital role in the progression of cancer. A better understanding of the regulatory relationships between lncRNAs and these various types of cancer cell death is therefore urgently required. The occurrence and development of tumors can be controlled by increasing or decreasing the expression of lncRNAs, a method which confers broad prospects for cancer treatment. Therefore, it is urgent for us to understand the influence of lncRNAs on the development of different modes of tumor death, and to evaluate whether lncRNAs have the potential to be used as biological targets for inducing cell death and predicting prognosis and recurrence of chemotherapy. The purpose of this review is to provide an overview of the various forms of cancer cell death, including apoptosis, necrosis, autophagy, pyroptosis, and ferroptosis, and to describe the mechanisms of different types of cancer cell death that are regulated by lncRNAs in order to explore potential targets for cancer therapy.

Dickkopf-2 regulates the stem cell marker LGR5 in colorectal cancer via HNF4α1.

Enhanced stemness in colorectal cancer has been reported and it contributes to aggressive progression, but the underlying mechanisms remain unclear. Here we report a Wnt ligand, Dickkopf-2 (DKK2) is essential for developing colorectal cancer stemness. Genetic depletion of DKK2 in intestinal epithelial or stem cells reduced tumorigenesis and expression of the stem cell marker genes including LGR5 in a model of colitis-associated cancer. Sequential mutations in APC, KRAS, TP53, and SMAD4 genes in colonic organoids revealed a significant increase of DKK2 expression by APC knockout and further increased by additional KRAS and TP53 mutations. Moreover, DKK2 activates proto-oncogene tyrosine-protein kinse Src followed by increased LGR5 expressing cells in colorectal cancer through degradation of HNF4α1 protein. These findings suggest that DKK2 is required for colonic epithelial cells to enhance LGR5 expression during the progression of colorectal cancer.