Plant mucus-derived microgels: Blood-triggered gelation and strong hemostatic adhesion.

Arrest of bleeding usually applies clotting agents to trigger coagulation procedures or adhesives to interrupt blood flow through sealing the vessel; however, the efficiency is compromised. Here, we propose a concept of integration of hemostasis and adhesion via yam mucus's microgels. The mucus microgels exhibit attractive attributes of hydrogel with uniform size and shape. Their shear-thinning, self-healing and strong adhesion make them feasible as injectable bioadhesion. Exceptionally, the blood can trigger the microgels' gelation with the outcome of super extensibility, which leads to the microgels a strong hemostatic agent. We also found a tight gel adhesive layer formed upon microgels' contacting the blood on the tissue, where there is the coagulation factor XIII triggered to form a dense three-dimensional fibrin meshwork. The generated structures show that the microgels look like hard balls in the dispersed phase into the blood-produced fibrin mesh of a soft net phase. Both phases work together for a super-extension gel. We demonstrated the microgels' fast adhesion and hemostasis in the livers and hearts of rabbits and mini pigs. The microgels also promoted wound healing with good biocompatibility and biodegradability.

Comprehensive profiling of cell subsets of gastric cancer and liver metastasis based on single cell RNA-sequencing analysis.

Background: Liver metastasis (Li) is one of the most common distant metastatic sites for gastric cancer. A deeper understanding of its mechanism of action from a bioinformatics perspective may provide new insights. Therefore, the aim of this study was to use single cell RNA sequencing (scRNA-seq) to evaluate cell subtypes and understand the molecular mechanism of gastric cancer Li. Methods: The scRNA-seq data GSE163558 of gastric cancer and Li were downloaded from Gene Expression Omnibus (GEO). Single cell data were analyzed by various R packages such as Seurat, CellChat, gene set variation analysis (GSVA), monocle, gene set enrichment analysis (GSEA), and survival analysis and the results were plotted by ggplot2, R4.1.1. Protein expression was confirmed by immunohistochemistry in an additional patient cohort. Results: The genes APOD, CXCL5, and JUN are involved in epithelial cell metastasis. The infiltration of cytotoxic CD8 T cells was more frequent in gastric primary tumors (PTs) than in Lis. IL7R high natural killer (NK) cells that had high TXNIP and RIPOR2 expression were located at the site of Li and corresponded to a favorable prognosis. NK cells with high TNFAIP3 expression were located at the PT site and corresponded to a poor prognosis. Furthermore, the gene expression of myeloid cells was different depending on their localization in the PT site or Li. MHC-I signaling pathway was found to be activated in the PT compared to MHC-II at the site of Li, as revealed by cell-cell interaction, and HLA-E-CD94/NKG2A of NK cells was only activated in the PT and not in the Li. Conclusions: The present study revealed the difference between Li and gastric PT by scRNA-seq, demonstrating the impact of partial gene expression on patient prognosis. Our study provides new insights into gastric cancer and Li.

Plasma and urine proteomics and gut microbiota analysis reveal potential factors affecting COVID-19 vaccination response.

The efficacy of COVID-19 vaccination relies on the induction of neutralizing antibodies, which can vary among vaccine recipients. In this study, we investigated the potential factors affecting the neutralizing antibody response by combining plasma and urine proteomics and gut microbiota analysis. We found that activation of the LXR/FXR pathway in plasma was associated with the production of ACE2-RBD-inhibiting antibodies, while urine proteins related to complement system, acute phase response signaling, LXR/FXR, and STAT3 pathways were correlated with neutralizing antibody production. Moreover, we observed a correlation between the gut microbiota and plasma and urine proteins, as well as the vaccination response. Based on the above data, we built a predictive model for vaccination response (AUC = 0.85). Our study provides insights into characteristic plasma and urine proteins and gut microbiota associated with the ACE2-RBD-inhibiting antibodies, which could benefit our understanding of the host response to COVID-19 vaccination.

The translational potential of miR-26 in atherosclerosis and development of agents for its target genes ACC1/2, COL1A1, CPT1A, FBP1, DGAT2, and SMAD7.

Atherosclerosis is one of the leading causes of death worldwide. miR-26 is a potential biomarker of atherosclerosis. Standardized diagnostic tests for miR-26 (MIR26-DX) have been developed, but the fastest progress has been in predicting the efficacy of IFN-α therapy for hepatocellular carcinoma (HCC, phase 3). MiR-26 slows atherosclerosis development by suppressing ACC1/2, ACLY, ACSL3/4, ALDH3A2, ALPL, BMP2, CD36, COL1A1, CPT1A, CTGF, DGAT2, EHHADH, FAS, FBP1, GATA4, GSK3ß, G6PC, Gys2, HMGA1, HMGB1, LDLR, LIPC, IL-1ß, IL-6, JAG2, KCNJ2, MALT1, ß-MHC, NF-κB, PCK1, PLCß1, PYGL, RUNX2, SCD1, SMAD1/4/5/7, SREBF1, TAB3, TAK1, TCF7L2, and TNF-α expression. Many agents targeting these genes, such as the ACC1/2 inhibitors GS-0976, PF-05221304, and MK-4074; the DGAT2 inhibitors IONIS-DGAT2Rx, PF-06427878, PF-0685571, and PF-07202954; the COL1A1 inhibitor HT-100; the stimulants 68Ga-CBP8 and RCT-01; the CPT1A inhibitors etomoxir, perhexiline, and teglicar; the FBP1 inhibitors CS-917 and MB07803; and the SMAD7 inhibitor mongersen, have been investigated in clinical trials. Interestingly, miR-26 better reduced intima-media thickness (IMT) than PCSK9 or CT-1 knockout. Many PCSK9 inhibitors, including alirocumab, evolocumab, inclisiran, AZD8233, Civi-007, MK-0616, and LIB003, have been investigated in clinical trials. Recombinant CT-1 was also investigated in clinical trials. Therefore, miR-26 is a promising target for agent development. miR-26 promotes foam cell formation by reducing ABCA1 and ARL4C expression. Multiple materials can be used to deliver miR-26, but it is unclear which material is most suitable for mass production and clinical applications. This review focuses on the potential use of miR-26 in treating atherosclerosis to support the development of agents targeting it.

RNF112-mediated FOXM1 ubiquitination suppresses the proliferation and invasion of gastric cancer.

Forkhead box M1 (FOXM1) plays a critical role in development physiologically and tumorigenesis pathologically. However, insufficient efforts have been dedicated to exploring the regulation, in particular the degradation of FOXM1. Here, the ON-TARGETplus siRNA library targeting E3 ligases was used to screen potential candidates to repress FOXM1. Of note, mechanism study revealed that RNF112 directly ubiquitinates FOXM1 in gastric cancer, resulting in a decreased FOXM1 transcriptional network and suppressing the proliferation and invasion of gastric cancer. Interestingly, the well-established small-molecule compound RCM-1 significantly enhanced the interaction between RNF112 and FOXM1, which further promoted FOXM1 ubiquitination and subsequently exerted promising anticancer effects in vitro and in vivo. Altogether, we demonstrate that RNF112 suppresses gastric cancer progression by ubiquitinating FOXM1 and highlight the RNF112/FOXM1 axis serves as both prognosis biomarker and therapeutic target in gastric cancer.

TIGD1 Is an Independent Prognostic Factor that Promotes the Progression of Colon Cancer.

Background: Trigger transposable element-derived 1 (TIGD1) is a human-specific gene, but no studies have been conducted to determine its mechanism of action. Our aim is to ascertain the function and mode of action of TIGD1 in the development of colon cancer. Materials and Methods: We used bioinformatics to analyze the relationship between TIGD1 and the clinical characteristics of colon cancer, as well as its prognosis. A series of cell assays were conducted to assess the function of TIGD1 in the proliferation and migration of colon cancer, and flow cytometry was used to explore its effects on apoptosis and the cell cycle. Results: We discovered that the expression of TIGD1 was remarkably elevated in colon cancer. Clinical correlation analysis demonstrated that TIGD1 expression was elevated in the tissues of advanced-stage patients, and it was remarkably elevated in individuals with both lymph node and distant metastasis. Further, we found that individuals showing elevated TIGD1 expression levels had a shortened survival time. Univariate and multivariate Cox regression analyses revealed that TIGD1 was an independent prognostic factor. Overexpression of the TIGD1 gene remarkedly enhances the proliferation and metastasis of colon cancer cells and suppresses apoptosis. In addition, the overexpression of TIGD1 can enhance the transition of tumor cells from the G1 toward the S phase. Western blot results suggested that TIGD1 may promote the malignant activity of colon cancer cells via the Wnt/ß-catenin signaling pathway, Bcl-2, N-cadherin, BAX, E-cadherin, CDK6, and CyclinD1. Conclusions: TIGD1 may be an independent prognostic factor in the advancement of colon cancer, and therefore function as a therapeutic target.

Helicobacter pylori and unignorable extragastric diseases: Mechanism and implications.

Considered as the most popular pathogen worldwide, Helicobacter pylori is intensively associated with diverse gastric diseases, including gastric ulcers, chronic progressive gastritis, and gastric cancer. Aside from its pathogenic effect on gastric diseases, growing evidences reveal that H. pylori may be related to numerous extragastric diseases. In this article, we reviewed recent studies and systematically elucidated that H. pylori may interfere with many biological processes outside the stomach and influence the occurrence of various extragastric diseases. Many epidemiological studies have indicated that H. pylori plays a pathogenic role in COVID-19, atherosclerosis, hyperemesis gravidarum and several other extragastric diseases, while the effect of H. pylori is currently under investigation in gastroesophageal reflux disease, asthma, and inflammatory bowel disease. Moreover, we also summarized the possible pathogenic mechanisms of H. pylori that may be related to chronic systemic inflammation and molecular mimicker. Taken together, this review provides a new perspective on the role of H. pylori in extragastric diseases and explores the possible mechanisms, which may help guide clinical treatment.

Nature-Derived Okra Gel as Strong Hemostatic Bioadhesive in Human Blood, Liver, and Heart Trauma of Rabbits and Dogs.

Bioadhesive performance can be compromised due to bleeding. Bleeding increases mortality. Adhesives with hemostatic function are of great significance. A sustainable and robust hemostatic bioadhesive from okra is reported. The adhesive strength reaches around three and six-fold higher than commercial fibrin on pigskin and glass, respectively. The okra gel presents high-pressure resistance and great underwater adhesive strength. In human blood experiments, the okra gel can activate platelets, enhance the adhesion of activated platelets, and release coagulation factors XI and XII. By forming a fast gel layer and closely adhering to the wound, it can quickly stop bleeding in the liver and heart of rabbits and dogs. Meanwhile, okra gel can cause platelet activation at the wound site and further strengthen its hemostatic performance. It is biocompatible, biodegradable, and can promote wound healing and shows potential as a sustainable bioadhesive, especially in the scenario of significant hemorrhage.

Helicobacter pylori infection induces stem cell-like properties in Correa cascade of gastric cancer.

Gastric cancer (GC) is the fourth leading cause of cancer-related death. Its poor prognosis is attributed to unclear pathogenesis. Currently, the most widely accepted model for elucidating the mechanism of GC is the Correa cascade, which covers several histological lesions of the gastric mucosa. GC stem cells (CSCs) are crucial for oncogenesis in the Correa cascade and GC progression. As Helicobacter pylori (H. pylori) is the etiological factor in the Correa cascade, growing evidence suggests that enhancement of gastric stem cell-like properties and increase in CSCs correlate with H. pylori infection. In this paper, we review recent studies that present pathogenic mechanisms by which H. pylori induces gastric stem cell-like properties and CSCs, which may supplement the existing Correa model of GC. First, the dysfunction of developmental signaling pathways associated with H. pylori infection leads to the enhancement of gastric stemness. Second, H. pylori infection promotes alteration of the gastric mucosal microenvironment. In addition, epithelial-mesenchymal transition (EMT) may contribute to H. pylori-induced gastric stemness. Taken together, understanding these pathogeneses will provide potential therapeutic targets for the treatment of CSCs and malignant GC in H. pylori induced-Correa cascade of GC.

Proteolysis-targeting chimeras: A promising technique in cancer therapy for gaining insights into tumor development.

Proteolysis-targeting chimeras (PROTACs) are small molecules that specifically link E3 ubiquitin ligases to proteins of interest to mediate targeted ubiquitination and degradation. PROTACs are advantageous since they can target undruggable proteins with multiple domains, particularly those with smooth surfaces that lack a common binding domain for small-molecule inhibitors (SMIs). This review provides an overview of PROTAC technology and third-generation PROTAC development. We focused on designing and executing the most recent clinical trials involving PROTACs in cancer therapy. Additionally, we summarized novel findings regarding the mechanisms and signaling pathways involved in cancer development, such as the scaffolding function of certain proteins ignored by traditional SMIs and several recognized oncoproteins that participate in novel signaling pathways. We also discussed strategies for enhancing PROTAC antitumor activity and specificity.

An acidic polysaccharide from Oxalis corniculata L. and the preliminary study on its antioxidant activity.

It has been reported that the aqueous extract from Oxalis corniculate has excellent pharmacological effects, but its polysaccharide as the major ingredient in the aqueous extract has not been reported. When the temperature of 50°C, ultrasonic power of 270 W, time of 25 min, solid to liquid ratio of 30 ml·g-1 , the optimal O. corniculate polysaccharide (OCP) yield was 9.45%. The physicochemical properties indicated that OCP-3, as the major fraction of OCP, was an acidic polysaccharide with 31.5 kDa, and it mainly consisted of arabinose (47.83%), galacturonic acid (17.81%), and galactose (14.25%). In addition, OCP-3 displayed an excellent antioxidant activity in vitro, including scavenging free radical, anti-lipid peroxidation, and protecting plasmid DNA from oxidative damage. Meanwhile, OCP-3 significantly reduced the levels of malondialdehyde and protein carbonyl by significantly increasing the activity of superoxide dismutase, catalase, and glutathione peroxidase, which protected the HEK 293 cell and Caenorhabditis elegans from oxidative damage. All the results suggested that OCP-3 might be the major active ingredient of the aqueous extract from O. corniculate, and OCP-3 might be a potent antioxidant supplement in the food, cosmetics, and medical industries. PRACTICAL APPLICATIONS: Oxalis corniculate is a kind of wild vegetable and ethnomedicine, and it is widely distributed in temperate zones. Unfortunately, its utilization rate is low compared to its yield. Our research suggested that the polysaccharide of OCP-3 from O corniculate might be used as a potent antioxidant supplement in the food, cosmetics, and medical industries.

Corrigendum to "Viscosity and degradation controlled injectable hydrogel for esophagealendoscopic submucosal dissection" [Bioact. Mater. 6 (2021) 1150-1162].

[This corrects the article DOI: 10.1016/j.bioactmat.2020.09.028.].

Different Effects of Leucine Supplementation and/or Exercise on Systemic Insulin Sensitivity in Mice.

Objective: Obesity-related diseases such as diabetes, hypertension, dyslipidemia, and cardiovascular diseases have increased due to the obesity epidemic. Early intervention for obesity through lifestyle and nutrition plays an important role in preventing obesity-related diseases. Therefore, the purpose of this study is to explore the role of leucine and exercise in adiposity, systemic insulin resistance, and inflammation to provide theoretical and guiding basis for the early prevention and treatment of obesity. Methods: C57BL/6J male mice were randomly divided into HFD or LFD-fed mice group. After 9 weeks, glucose tolerance test (GTT) was performed to detect their systemic insulin sensitivity. Starting from week 10, mice were divided into eight groups and treated with moderate exercise or/and 1.5% leucine. At week 13, systemic insulin sensitivity was detected by GTT. At week 14, mice were dissected to analyze adiposity and inflammation. Results: In LFD mice, exercise significantly increased systemic insulin sensitivity by increasing GLUT4 expression in the muscle and decreasing adiposity through increasing AMPK phosphorylation in adipose tissue. In HFD mice, the simultaneous intervention of exercise and leucine increases systemic insulin sensitivity by reducing liver and adipose tissue inflammation via decreasing NF-κB p65 phosphorylation, and increasing the expression of adiponectin in adipose tissue. Conclusion: There are different mechanisms underlying the effects of exercise and leucine on insulin resistance and inflammation in LFD-fed mice or HFD-fed mice.

Viscosity and degradation controlled injectable hydrogel for esophageal endoscopic submucosal dissection.

Endoscopic submucosal dissection (ESD) is a common procedure to treat early and precancerous gastrointestinal lesions. Via submucosal injection, a liquid cushion is created to lift and separate the lesion and malignant part from the muscular layer where the formed indispensable space is convenient for endoscopic incision. Saline is a most common submucosal injection liquid, but the formed liquid pad lasts only a short time, and thus repeated injections increase the potential risk of adverse events. Hydrogels with high osmotic pressure and high viscosity are used as an alternate; however, with some drawbacks such as tissue damage, excessive injection resistance, and high cost. Here, we reported a nature derived hydrogel of gelatin-oxidized alginate (G-OALG). Based on the rheological analysis and compare to commercial endoscopic mucosal resection (EMR) solution (0.25% hyaluronic acid, HA), a designed G-OALG hydrogel of desired concentration and composition showed higher performances in controllable gelation and injectability, higher viscosity and more stable structures. The G-OALG gel also showed lower propulsion resistance than 0.25% HA in the injection force assessment under standard endoscopic instruments, which eased the surgical operation. In addition, the G-OALG hydrogel showed good in vivo degradability biocompatibility. By comparing the results acquired via ESD to normal saline, the G-OALG shows great histocompatibility and excellent endoscopic injectability, and enables create a longer-lasting submucosal cushion. All the features have been confirmed in the living both pig and rat models. The G-OALG could be a promising submucosal injection agent for esophageal ESD.

Microwave-assisted extraction, physicochemical characterization and bioactivity of polysaccharides from Camptotheca acuminata fruits.

Microwave-assisted extraction of polysaccharides from Camptotheca acuminate (CAPs) was optimized by response surface methodology. The optimal parameters were as follows: microwave power, 600 W; liquid-solid ratio, 40:1 g/mL; extraction time, 14 min; and extraction temperature, 70 °C. Under these conditions, the yield of CAPs reached up to 8.61%. CAP-3, an acidic polysaccharide with a molecular weight of 121.34 kDa, was separated and purified from CAPs, which was only composed of glucose and mannose. CAP-3 exhibited strong antioxidant activity against DPPH (IC50: 0.78 mg/mL), hydroxyl radicals (IC50: 0.84 mg/mL) and also showed synergistic antioxidative effect with ascorbic acid in vitro. Meanwhile, CAP-3 could protect plasmid DNA from oxidative damage. Moreover, CAP-3 could improve immunomodulatory activity of RAW264.7 cells through promoting the phagocytosis and nitric oxide release. Therefore, CAP-3 had a strong potential in functional food, pharmaceuticals and cosmetics industries.

Antioxidant and immunomodulatory activities of polysaccharides from the rhizome of Dryopteris crassirhizoma Nakai.

Rhizome of the fern Dryopteris crassirhizoma Nakai is used as an antiviral drug in China. The objective was to characterize physicochemical properties, structural features and antioxidant and immunological activities of D. crassirhizoma polysaccharides. An acidic polysaccharide fraction (DCP-3) was obtained from Dryopteris crassirhizoma Nakai by purification with DEAE-52 and Sephadex G-100. DCP-3 was a novel triple-helical polysaccharide with an average MW of 273.2 kDa. This fraction was mainly composed of galactose (36.65%), xylose (34.75%), arabinose (17.07%) and mannose (9.22%). DCP-3 had strong activity for scavenging DPPH radical (IC50: 2.04 mg/mL), hydroxyl radical (IC50: 1.70 mg/mL), and superoxide anions (IC50: 4.20 mg/mL) and also was capable of reducing ferric ions. In addition, nitric oxide production was enhanced in RAW264.7 macrophages stimulated by DCP-3. Based on these bioactivities, we inferred that DCP-3 was a functional component of D. crassirhizoma and may confer antivirus activity, with potential applications in functional food and drug industries.