ARG2 knockdown promotes G0/G1 cell cycle arrest and mitochondrial dysfunction in adenomyosis via regulation NF-κB and Wnt/Β-catenin signaling cascades.

BACKGROUND: Adenomyosis is a common gynecological disease, characterized by overgrowth of endometrial glands and stroma in the myometrium, however its exact pathophysiology still remains uncertain. Emerging evidence has demonstrated the elevated level of arginase 2 (ARG2) in endometriosis and adenomyosis. This study aimed to determine whether ARG2 involved in mitochondrial function and epithelial to mesenchymal transition (EMT) in adenomyosis and its potential underlying mechanisms. MATERIALS AND METHODS: RNA interference was used to inhibit ARG2 gene, and then Cell Counting Kit (CCK-8) assay and flow cytometery were performed to detect the cell proliferation capacity, cell cycle, and apoptosis progression, respectively. The mouse adenomyosis model was established and RT-PCR, Western blot analysis, mitochondrial membrane potential (Δψm) detection and mPTP opening evaluation were conducted. RESULTS: Silencing ARG2 effectively down-regulated its expression at the mRNA and protein levels in endometrial cells, leading to decreased enzyme activity and inhibition of cell viability. Additionally, ARG2 knockdown induced G0/G1 cell cycle arrest, promoted apoptosis, and modulated the expression of cell cycle- and apoptosis-related regulators. Notably, the interference with ARG2 induces apoptosis by mitochondrial dysfunction, ROS production, ATP depletion, decreasing the Bcl-2/Bax ratio, releasing Cytochrome c, and increasing the expression of Caspase-9/-3 and PARP. In vivo study in a mouse model of adenomyosis demonstrated also elevated levels of ARG2 and EMT markers, while siARG2 treatment reversed EMT and modulated inflammatory cytokines. Furthermore, ARG2 knockdown was found to modulate the NF-κB and Wnt/ß-catenin signaling pathways in mouse adenomyosis. CONCLUSION: Consequently, ARG2 silencing could induce apoptosis through a mitochondria-dependent pathway mediated by ROS, and G0/G1 cell cycle arrest via suppressing NF-κB and Wnt/ß-catenin signaling pathways in Ishikawa cells. These findings collectively suggest that ARG2 plays a crucial role in the pathogenesis of adenomyosis and may serve as a potential target for therapeutic intervention.

Predicting gastric cancer response to anti-HER2 therapy or anti-HER2 combined immunotherapy based on multi-modal data.

The sole use of single modality data often fails to capture the complex heterogeneity among patients, including the variability in resistance to anti-HER2 therapy and outcomes of combined treatment regimens, for the treatment of HER2-positive gastric cancer (GC). This modality deficit has not been fully considered in many studies. Furthermore, the application of artificial intelligence in predicting the treatment response, particularly in complex diseases such as GC, is still in its infancy. Therefore, this study aimed to use a comprehensive analytic approach to accurately predict treatment responses to anti-HER2 therapy or anti-HER2 combined immunotherapy in patients with HER2-positive GC. We collected multi-modal data, comprising radiology, pathology, and clinical information from a cohort of 429 patients: 310 treated with anti-HER2 therapy and 119 treated with a combination of anti-HER2 and anti-PD-1/PD-L1 inhibitors immunotherapy. We introduced a deep learning model, called the Multi-Modal model (MuMo), that integrates these data to make precise treatment response predictions. MuMo achieved an area under the curve score of 0.821 for anti-HER2 therapy and 0.914 for combined immunotherapy. Moreover, patients classified as low-risk by MuMo exhibited significantly prolonged progression-free survival and overall survival (log-rank test, P < 0.05). These findings not only highlight the significance of multi-modal data analysis in enhancing treatment evaluation and personalized medicine for HER2-positive gastric cancer, but also the potential and clinical value of our model.

Metastable FeSe2 nanosheets as a one-for-all platform for stepwise synergistic tumor therapy.

The urgent need to curb the rampant rise in cancer has impelled the rapid development of nanomedicine. Under the above issue, transition metal compounds have received special attention considering their physicochemical and biochemical properties. However, how to take full advantage of the valuable characteristics of nanomaterials based on their spatial structures and chemical components for synergistic tumor therapy is a worthwhile exploration. In this work, a tailored two-dimensional (2D) FeSe2 nanosheet (NS) platform is proposed, which integrates enzyme activity and drug efficacy through the regulation of itsstability. Specifically, metastable FeSe2 NSs can serve as dual nanozymes in an intact state, depleting GSH and increasing ROS to induce oxidative stress in the tumor microenvironment (TME). With the gradual degradation of the FeSe2 in TME, its degraded products can amplify the Fenton reaction and GSH consumption, enhance the expression of inflammatory factors, and achieve effective near-infrared (NIR)-light irradiation-enhanced synergistic photothermal therapy (PTT) and chemodynamic therapy (CDT). Our exploration further confirmed such a strategy that may integrate carrier activity and drug action into a metastable nanoplatform for tumor synergistic therapy. These results prompt the consideration of the rational design of a one-for-all carrier that can exhibit multifunctional properties and nanomedicine efficacy for versatile therapeutic applications in the future.

Root growth characteristics and antioxidant system of Suaeda salsa in response to the short-term nitrogen and phosphorus addition in the Yellow River Delta.

Human activities have increased nitrogen (N) and phosphorus (P) inputs to the Yellow River Delta and the supply level of N and P affects plant growth as well as ecosystem structure and function directly. However, the root growth, stoichiometry, and antioxidant system of plants in response to N and P additions, especially for herbaceous halophyte in the Yellow River Delta (YRD), remain unknown. A field experiment with N addition (0, 5, 15, and 45 g N m-2 yr-1, respectively) as the main plot, and P addition (0 and 1 g N m-2 yr-1, respectively) as the subplot, was carried out with a split-plot design to investigate the effects on the root morphology, stoichiometry, and antioxidant system of Suaeda salsa. The results showed that N addition significantly increased the above-ground and root biomass as well as shoot-root ratio of S. salsa, which had a significant interaction with P addition. The highest biomass was found in the treatment with 45 g N m-2 yr-1 combined with P addition. N addition significantly increased TN content and decreased C:N ratio of root, while P addition significantly increased TP content and decreased C:P ratio. The main root length (MRL), total root length (TRL), specific root length (SRL), and root tissue density (RTD) of S. salsa root were significantly affected by N addition and P addition, as well as their interaction. The treatments with or without P addition at the 45 g N m-2 yr-1 of N addition significantly increased the superoxide dismutase (SOD), peroxidase (POD), catalase (CAT) activities and soluble protein content of roots, decreased malondialdehyde (MDA) content. And there was a significant interaction between the N and P addition on SOD activity. Therefore, N and P additions could improve the growth of S. salsa by altering the root morphology, increasing the root nutrient content, and stimulating antioxidant system.

Erratum: Multi-Gene Single Nucleotide Polymorphism Detection in Gastric Cancer Based on Ion Semiconductor Sequencing Platform.

This corrects the article 10.3791/66058.

Multi-Gene Single Nucleotide Polymorphism Detection in Gastric Cancer Based on Ion Semiconductor Sequencing Platform.

Gastric cancer is a common heterogeneous tumor. Most patients have advanced gastric cancer at the time of diagnosis and often need chemotherapy. Although 5-fluorouracil (5-FU) is widely used for treatment, its therapeutic sensitivity and drug tolerance still need to be determined, which emphasizes the importance of individualized administration. Pharmacogenetics can guide the clinical implementation of individualized treatment. Single nucleotide polymorphisms (SNPs), as a genetic marker, contribute to the selection of appropriate chemotherapy regimens and dosages. Some SNPs are associated with folate metabolism, the therapeutic target of 5-FU. Methylenetetrahydrofolate reductase (MTHFR) rs1801131 and rs1801133, dihydrofolate reductase (DHFR) rs1650697 and rs442767, methionine synthase (MTR) rs1805087, gamma-glutamyl hydrolase (GGH) rs11545078 and solute carrier family 19 member 1 (SLC19A1) rs1051298 have been investigated in different kinds of cancers and antifolate antitumor drugs, which have potential forecasting and guiding significance for application of 5-FU. The ion torrent next-generation semiconductor sequencing technology can rapidly detect gastric cancer-related SNPs. Each time a base is extended in a DNA chain, an H+ will be released, causing local pH changes. The ionic sensor detects pH changes and converts chemical signals into digital signals, achieving sequencing by synthesis. This technique has low sample requirement, simple operation, low cost, and fast sequencing speed, which is beneficial for guiding individualized chemotherapy by SNPs.

Effects of positive end-expiratory pressure on regional cerebral oxygen saturation in elderly patients undergoing thoracic surgery during one-lung ventilation: a randomized crossover-controlled trial.

BACKGROUND: A significant reduction in regional cerebral oxygen saturation (rSO2) is commonly observed during one-lung ventilation (OLV), while positive end-expiratory pressure (PEEP) can improve oxygenation. We compared the effects of three different PEEP levels on rSO2, pulmonary oxygenation, and hemodynamics during OLV. METHODS: Forty-three elderly patients who underwent thoracoscopic lobectomy were randomly assigned to one of six PEEP combinations which used a crossover design of 3 levels of PEEP-0 cmH2O, 5 cmH2O, and 10 cmH2O. The primary endpoint was rSO2 in patients receiving OLV 20 min after adjusting the PEEP. The secondary outcomes included hemodynamic and respiratory variables. RESULTS: After exclusion, thirty-six patients (36.11% female; age range: 60-76 year) were assigned to six groups (n = 6 in each group). The rSO2 was highest at OLV(0) than at OLV(10) (difference, 2.889%; [95% CI, 0.573 to 5.204%]; p = 0.008). Arterial oxygen partial pressure (PaO2) was lowest at OLV(0) compared with OLV(5) (difference, -62.639 mmHg; [95% CI, -106.170 to -19.108 mmHg]; p = 0.005) or OLV(10) (difference, -73.389 mmHg; [95% CI, -117.852 to -28.925 mmHg]; p = 0.001), while peak airway pressure (Ppeak) was lower at OLV(0) (difference, -4.222 mmHg; [95% CI, -5.140 to -3.304 mmHg]; p < 0.001) and OLV(5) (difference, -3.139 mmHg; [95% CI, -4.110 to -2.167 mmHg]; p < 0.001) than at OLV(10). CONCLUSIONS: PEEP with 10 cmH2O makes rSO2 decrease compared with 0 cmH2O. Applying PEEP with 5 cmH2O during OLV in elderly patients can improve oxygenation and maintain high rSO2 levels, without significantly increasing peak airway pressure compared to not using PEEP. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2200060112 on 19 May 2022.

Riboflavin Attenuates Fluoride-Induced Testicular Injury via Interleukin 17A-Mediated Classical Pyroptosis.

Male reproductive toxicity of fluoride is of great concern worldwide, yet the underlying mechanism is unclear. Pyroptosis is a novel mode of inflammatory cell death, and riboflavin with anti-inflammatory properties has the potential to protect against fluoride damage. However, it is unknown whether pyroptosis is involved in fluoride-induced testicular injury and riboflavin intervention. Here, we first found that riboflavin could alleviate fluoride-caused lower sperm quality and damaged testicular morphology by reducing pyroptosis based on a model of ICR mice treated with NaF (100 mg/L) and/or riboflavin supplementation (40 mg/L) via drinking water for 13 weeks. And then, together with the results of in vitro Leydig cell modelsm it was confirmed that the pyroptosis occurs predominantly through classical NLRP3/Caspase-1/GSDMD pathway. Furthermore, our results reveal that interleukin-17A mediates the process of pyroptosis in testes induced by fluoride and riboflavin attenuation according to the results of our established models of riboflavin- and/or fluoride-treated IL-17A knockout mice. The results not only declare a new mechanism by which fluoride induces testicular injury via interleukin 17A-mediated classical pyroptosis but also provide evidence for the potential clinical application of riboflavin as an effective therapy for fluoride toxicity.

Helicobacter pylori CagA-mediated ether lipid biosynthesis promotes ferroptosis susceptibility in gastric cancer.

Helicobacter pylori, particularly cytotoxin-associated gene A (CagA)-positive strains, plays a key role in the progression of gastric cancer (GC). Ferroptosis, associated with lethal lipid peroxidation, has emerged to play an important role in malignant and infectious diseases, but the role of CagA in ferroptosis in cancer cells has not been determined. Here, we report that CagA confers GC cells sensitivity to ferroptosis both in vitro and in vivo. Mechanistically, CagA promotes the synthesis of polyunsaturated ether phospholipids (PUFA-ePLs), which is mediated by increased expression of alkylglycerone phosphate synthase (AGPS) and 1-acylglycerol-3-phosphate O-acyltransferase 3 (AGPAT3), leading to susceptibility to ferroptosis. This susceptibility is mediated by activation of the MEK/ERK/SRF pathway. SRF is a crucial transcription factor that increases AGPS transcription by binding to the AGPS promoter region. Moreover, the results demonstrated that CagA-positive cells are more sensitive to apatinib than are CagA-negative cells, suggesting that detecting the H. pylori CagA status may aid patient stratification for treatment with apatinib.

Bacillus subtilis improves antioxidant capacity and optimizes inflammatory state in broilers.

OBJECTIVE: Bacillus subtilis, a kind of probiotic with broad-spectrum antibacterial function, was commonly used in livestock and poultry production. Recent research suggested that Bacillus subtilis may have antioxidant properties and improve immune response. This study aimed to verify the probiotic function of Bacillus subtilis in the production of broiler chickens. METHODS: A total of 324 (1-day-old) Arbor Acres broilers were selected and randomly divided into three groups: basal diet group (Ctr Group), basal diet + antibiotic growth promoter group (Ctr + AGP) and basal diet + 0.5% Bacillus subtilis preparation group (Ctr + Bac). The experiment lasted for 42 days. Muscle, serum and liver samples were collected at 42 days for determination. RESULTS: The results showed that Bacillus subtilis could decrease malondialdehyde content in the serum and liver (p<0.05) and increase superoxide dismutase 1 mRNA expression (p<0.01) and total superoxide dismutase (p<0.05) in the liver. In addition, compared with AGP supplementation, Bacillus subtilis supplementation increased interleukin-10 (IL-10) and decreased tumor necrosis factor-α and IL-1ß level in the serum (p<0.05). At 45 minutes after slaughter Ctr + Bac presented a higher a* value of breast muscle than Ctr Group (p<0.05), while significant change in leg muscle was not identified. Moreover, there was no difference in weight, shear force, cooking loss and drip loss of breast and leg muscle between treatments. CONCLUSION: Our results demonstrate that Bacillus subtilis in diet can enhance antioxidant capacity and optimize immune response of broilers.

Hollow CoZnSe@CN nanocage with enzymatic activity for determination of tetracycline using smartphone platforms and virtual reality revealing.

Antibiotic residues in the environment pose a serious threat to ecosystems and human health. Therefore, it is important to develop sensitive and rapid in situ detection methods. In this work, the designed nanozymes, with excellent four enzyme activities, were proved to be constituted of unique hollow nanocage structures (CoZnSe@CN HCs). Based on the peroxidase-like enzymes, a portable colorimetric sensor was constructed for the on-site determination of tetracycline (TC) in real samples. The linear range of TC detection was 0.1-100 µM, and the detection limit was 0.02 µM. At the same time, colorimetric detection and smartphones have also been combined for on-site colorimetric detection of TC. In-depth exploration of the detection mechanism showed that TC could be bound with the material, inhibiting the production of oxidized 3,3',5,5'-tetramethylbenzidine. The sensor was also used for the detection of TC in environmental soil and water samples. This study can provide an intelligent detection method for environmental monitoring.

Novel Synthesis of Phytosterol Ferulate Using Acidic Ionic Liquids as a Catalyst and Its Hypolipidemic Activity.

Phytosterol ferulate (PF) is quantitively low in rice, corn, wheat, oats, barley, and millet, but it is potentially effective in reducing plasma lipids. In this study, PF was synthesized for the first time using acidic ionic liquids as a catalyst. The product was purified, characterized using Fourier transform infrared, mass spectroscopy, and nuclear magnetic resonance, and ultimately confirmed as the desired PF compound. The conversion of phytosterol surpassed an impressive 99% within just 2 h, with a selectivity for PF exceeding 83%. Plasma lipid-lowering activity of PF was further investigated by using C57BL/6J mice fed a high-fat diet as a model. Supplementation of 0.5% PF into diet resulted in significant reductions in plasma total cholesterol, triacylglycerols, and nonhigh-density lipoprotein cholesterol by 13.7, 16.9, and 46.3%, respectively. This was accompanied by 55.8 and 36.3% reductions in hepatic cholesterol and total lipids, respectively, and a 22.9% increase in fecal cholesterol excretion. Interestingly, PF demonstrated a higher lipid-lowering activity than that of its substrates, a physical mixture of phytosterols and ferulic acid. In conclusion, an efficient synthesis of PF was achieved for the first time, and PF had the great potential to be developed as a lipid-lowering dietary supplement.

Repurposing an Antioxidant to Kill Mycobacterium tuberculosis by Targeting the 50S Subunit of the Ribosome.

Tuberculosis and drug-resistant TB remain serious threats to global public health. It is urgent to develop novel anti-TB drugs in order to control it. In addition to redesigning and developing new anti-TB drugs, drug repurposing is also an innovative way to develop antibacterial drugs. Based on this method, we discovered SKQ-1 in the FDA-approved drug library and evaluated its anti-TB activity. In vitro, we demonstrated that SKQ-1 engaged in bactericidal activity against drug-sensitive and -resistant Mtb and confirmed the synergistic effects of SKQ1 with RIF and INH. Moreover, SKQ-1 showed a significant Mtb-killing effect in macrophages. In vivo, both the SKQ-1 treatment alone and the treatment in combination with RIF were able to significantly reduce the bacterial load and improve the survival rate of G. mellonella infected with Mtb. We performed whole-genome sequencing on screened SKQ-1-resistant strains and found that the SNP sites were concentrated in the 50S ribosomal subunit of Mtb. Furthermore, we proved that SKQ-1 can inhibit protein translation. In summary, from the perspective of drug repurposing, we discovered and determined the anti-tuberculosis effect of SKQ-1, revealed its synergistic effects with RIF and INH, and demonstrated its mechanism of action through targeting ribosomes and disrupting protein synthesis, thus making it a potential treatment option for DR-TB.

Nutritional composition, health-promoting effects, bioavailability, and encapsulation of tree peony seed oil: a review.

Tree peony is cultivated worldwide in large quantities due to its exceptional ornamental and medicinal value. In recent years, the edible value of tree peony seed oil (TPSO) has garnered significant attention for its high content of alpha-linolenic acid (ALA, >40%) and other beneficial minor components, including phytosterols, tocopherols, squalene, and phenolics. This review provides a systematic summary of the nutritional composition and health-promoting effects of TPSO, with a specific focus on its digestion, absorption, bioavailability, and encapsulation status. Additionally, information on techniques for extracting and identifying adulteration of TPSO, as well as its commercial applications and regulated policies, is included. Thanks to its unique nutrients, TPSO offers a wide range of health benefits, such as hypolipidemic, anti-obesity, cholesterol-lowering, antioxidant and hypoglycemic activities, and regulation of the intestinal microbiota. Consequently, TPSO shows promising potential in the food and cosmetic industries and should be cultivated in more countries. However, the application of TPSO is hindered by its low bioavailability, poor stability, and limited water dispersibility. Therefore, it is crucial to develop effective delivery strategies, such as microencapsulation and emulsion, to overcome these limitations. In conclusion, this review provides a comprehensive understanding of the nutritional value of TPSO and emphasizes the need for further research on its nutrition and product development.

Construction of CuO/Fe2O3 Nanozymes for Intelligent Detection of Glufosinate and Chlortetracycline Hydrochloride.

In this work, CuO/Fe2O3 nanozymes with high peroxidase-like activity were synthesized by using hydrothermal and calcination methods. The high-resolution transmission electron microscopy (HRTEM) proved that the heterogeneous interface of CuO/Fe2O3 was the main reason for the high enzyme-like activity. Strong interactions of CuO and Fe2O3 were successfully verified by X-ray absorption near-edge structure (XANES) characterization. Experiments and density functional theory (DFT) calculations were also used to explain the increased enzyme activity. The heterogeneous interface acted as the main active center, facilitating the electron transfer from CuO to Fe2O3. A colorimetric and intelligent sensing system was constructed based on deep learning. Using the peroxidase-like activity of CuO/Fe2O3, a platform for glufosinate pesticides and chlortetracycline hydrochloride (CTC) with the signal "on-off-on" changes were established. The limit of detection (LOD) of glufosinate and CTC was 28 and 0.69 µM, respectively. It was successfully applied in the detection of environmental water and soil. This study can provide an intelligent detection method for environmental monitoring.

Clinical outcomes of conversion surgery following immune checkpoint inhibitors and chemotherapy in stage IV gastric cancer.

BACKGROUND: The clinical benefit of conversion surgery following immunochemotherapy in patients with stage IV gastric cancer (GC) remains uncertain. This study aims to clarify the clinical outcomes of conversion surgery for such patients. METHODS: This retrospective cohort study enroled consecutive patients with stage IV GC treated with a combination of immune checkpoint inhibitors and chemotherapy and/or anti-human epidermal growth factor receptor-2 targeted therapy as first-line therapy. Cumulative survival curves were estimated using Kaplan-Meier method. Logistic regression and Cox regression analyses were conducted to identify factors associated with conversion surgery and survival, respectively. RESULTS: Among the 136 patients included in the study. The disease control rate was 72.1% (98/136), with objective response rate in 58.8% (80/136) and complete response rate in 5.9% (8/136). Among 98 patients with disease control, 56 patients underwent palliative immunochemotherapy with median progression-free survival (PFS) and overall survival at 9.2 and 16.2 months, respectively; the remaining 42 patients underwent conversion surgery, yielding an unreached median PFS over a 19.0-month median follow-up, accompanied by 1-year overall survival and PFS rates of 96.6% and 89.1%, respectively. The R0 resection rate reached 90.5% (38/42). 7 out of 42 patients achieved pathological complete response, of whom three patients demonstrated human epidermal growth factor receptor-2 positivity. No serious complications leading to death were observed during the perioperative period. Multivariate analysis indicated that programmed death ligand 1 combined positive score greater than or equal to 5 (odds ratio, 0.22; 95% CI, 0.08-0.57; P =0.002) favored successful conversion surgery, while signet ring cell carcinoma (hazard ratio, 6.29; 95% CI, 1.56-25.36; P =0.010) was the poor prognostic factor associated with survival in patients who underwent conversion surgery. CONCLUSIONS: Conversion surgery holds the potential for significant survival benefits in stage IV GC patients who have achieved a favourable clinical response to immunochemotherapy. Individuals with signet ring cell carcinoma may experience increased post-conversion surgery recurrence.

Impact of preoperative therapy on surgical outcomes of laparoscopic total gastrectomy for gastric/gastroesophageal junction cancer.

Objective: As laparoscopic surgery is widely applied for primarily treated gastric cancer (GC)/gastroesophageal junction cancer (GEJC) and gains many advantages, the feasibility of laparoscopic total gastrectomy (LTG) for GC/GEJC patients who have received preoperative therapy (PT) has come to the fore. This study aims to analyze the safety and feasibility of LTG after PT for GC/GEJC patients. Methods: We retrospectively analyzed the data of 511 patients with GC/GEJC undergoing LTG, of which 405 received LTG (LTG group) and 106 received PT+LTG (PT-LTG group) at Nanfang Hospital between June 2018 and September 2022. The surgical outcomes were compared between the two groups. Results: The surgical duration was significantly longer in the PT-LTG group (P<0.001), while the incidence of intraoperative complications (P=1.000), postoperative complications (LTG group vs. PT-LTG group: 26.2% vs. 23.6%, P=0.587), the classification of complication severity (P=0.271), and postoperative recovery was similar between two groups. Notably, the incidence of anastomotic complications of esophagojejunostomy was also comparable between the two groups (LTG group vs. PT-LTG group: 5.9% vs. 5.7%, P=0.918). The univariate and multivariate analysis confirmed that positive proximal margin [positive vs. negative: odds ratio (OR)=14.094, 95% confidence interval (95% CI): 2.639-75.260, P=0.002], rather than PT, has an impact on anastomotic complications after LTG (OR=0.945, 95% CI: 0.371-2.408, P=0.905). Conclusions: PT did not increase the surgical risk of LTG for GC/GEJC. Therefore, considering the positive effect of PT on long-term survival, the broader application of PT and LTG for GC/GEJC is supported by our findings.

Corrigendum: Relationship between programmed death ligand 1 expression and other clinicopathological features in a large cohort of gastric cancer patients.

[This corrects the article DOI: 10.3389/fimmu.2022.783695.].

N4-Acetylcytidine Drives Glycolysis Addiction in Gastric Cancer via NAT10/SEPT9/HIF-1α Positive Feedback Loop.

Anti-angiogenic therapy has long been considered a promising strategy for solid cancers. Intrinsic resistance to hypoxia is a major cause for the failure of anti-angiogenic therapy, but the underlying mechanism remains unclear. Here, it is revealed that N4-acetylcytidine (ac4C), a newly identified mRNA modification, enhances hypoxia tolerance in gastric cancer (GC) cells by promoting glycolysis addiction. Specifically, acetyltransferase NAT10 transcription is regulated by HIF-1α, a key transcription factor of the cellular response to hypoxia. Further, acRIP-sequencing, Ribosome profiling sequencing, RNA-sequencing, and functional studies confirm that NAT10 in turn activates the HIF-1 pathway and subsequent glucose metabolism reprogramming by mediating SEPT9 mRNA ac4C modification. The formation of the NAT10/SEPT9/HIF-1α positive feedback loop leads to excessive activation of the HIF-1 pathway and induces glycolysis addiction. Combined anti-angiogenesis and ac4C inhibition attenuate hypoxia tolerance and inhibit tumor progression in vivo. This study highlights the critical roles of ac4C in the regulation of glycolysis addiction and proposes a promising strategy to overcome resistance to anti-angiogenic therapy by combining apatinib with ac4C inhibition.

SARS-Cov-2 Spike-S1 Antigen Test Strip with High Sensitivity Endowed by High-Affinity Antibodies and Brightly Fluorescent QDs/Silica Nanospheres.

The extensive research into developing novel strategies for detecting respiratory syndrome coronavirus 2 (SARS-CoV-2) antigens in clinical specimens, especially the sensitive point-of-care testing method, is still urgently needed to reach rapid screening of viral infections. Herein, a new lateral flow immunoassay (LFIA) platform was reported for the detection of SARS-CoV-2 spike-S1 protein antigens, in which four sensitive and specific SARS-CoV-2 mouse monoclonal antibodies (MmAbs) were tailored by using quantum dot (QD)-loaded dendritic mesoporous silica nanoparticles modified further for achieving the -COOH group surface coating (named Q/S-COOH nanospheres). Importantly, compact QD adsorption was achieved in mesoporous channels of silica nanoparticles on account of highly accessible central-radial pores and electrostatic interactions, leading to significant signal amplification. As such, a limit of detection for SARS-CoV-2 spike-S1 testing was found to be 0.03 ng/mL, which is lower compared with those of AuNPs-LFIA (traditional colloidal gold nanoparticles, Au NPs) and enzyme-linked immunosorbent assay methods. These results show that optimizing the affinity of antibody and the intensity of fluorescent nanospheres simultaneously is of great significance to improve the sensitivity of LFIA.