Rhubarb extract rebuilding the mucus homeostasis and regulating mucin-associated flora to relieve constipation.

In clinical trials, rhubarb extract (Rb) was demonstrated to efficiently alleviate constipation. We would like to find out the underlying mechanism of rhubarb relieving constipation. However, there are few studies on the effects of rhubarb on colonic mucus secretion and constipation. The aim of this study was to investigate the effects of rhubarb on colonic mucus secretion and its underlying mechanism. The mice were randomly divided into four groups. Group I was the control group and Group II was the rhubarb control group, with Rb (24 g/kg body weight [b.w.]) administered through intragastric administration for three days. Group III mice were given diphenoxylate (20 mg/kg b.w.) for five days via gavage to induce constipation. Group IV received diphenoxylate lasting five days before undergoing Rb administration for three days. The condition of the colon was evaluated using an endoscope. Particularly, the diameter of blood vessels in the colonic mucosa expanded considerably in constipation mice along with diminishing mucus output, which was in line with the observation via scanning electron microscope (SEM) and transmission electron microscope (TEM). We also performed metagenomic analysis to reveal the microbiome related to mucin gene expression level referring to mucin secretion. In conclusion, Rb relieves constipation by rebuilding mucus homeostasis and regulating the microbiome.

A Deep View of the Biological Property of Interleukin-33 and Its Dysfunction in the Gut.

Intestinal diseases have always posed a serious threat to human health, with inflammatory bowel disease (IBD) being one of them. IBD is an autoimmune disease characterized by chronic inflammation, including ulcerative colitis (UC) and Crohn's disease (CD). The "alarm" cytokine IL-33, which is intimately associated with Th2 immunity, is a highly potent inflammatory factor that is considered to have dual functions-operating as both a pro-inflammatory cytokine and a transcriptional regulator. IL-33 has been shown to play a crucial role in both the onset and development of IBD. Therefore, this review focuses on the pathogenesis of IBD, the major receptor cell types, and the activities of IL-33 in innate and adaptive immunity, as well as its underlying mechanisms and conflicting conclusions in IBD. We have also summarized different medicines targeted to IL-33-associated diseases. Furthermore, we have emphasized the role of IL-33 in gastrointestinal cancer and parasitic infections, giving novel prospective therapeutic utility in the future application of IL-33.

Limonoids from the roots of Melia azedarach and their anti-inflammatory activity.

Twelve undescribed limonoids, meliazedarines J-U (1-12), along with a known one, were isolated from the roots of Melia azedarach. Their structures were elucidated by extensive spectroscopic investigations, X-ray diffraction analyses, and ECD calculations. Compounds 1-8 were identified as ring intact limonoids, while compounds 9-12 were established as ring C-seco ones. The anti-inflammatory potential of compounds 1-4, 6, 8, 9, and 11-13 was evaluated on macrophages. Compounds 1, 3, 4, 6, and 9 significantly suppressed nitric oxide production in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages, among them compound 3 showed the best inhibitory effect with an IC50 value of 7.07 ± 0.48 µΜ. Furthermore, compound 3 effectively reduced interleukin-1ß secretion in LPS plus nigericin-induced THP-1 macrophages by inhibiting NLRP3 inflammasome activation. The results strongly suggested that limonoids from the roots of M. azedarach might be candidates for treating inflammation-related diseases.

Current perspective on biological properties of plasmacytoid dendritic cells and dysfunction in gut.

Plasmacytoid dendritic cells (pDCs), a subtype of DC, possess unique developmental, morphological, and functional traits that have sparked much debate over the years whether they should be categorized as DCs. The digestive system has the greatest mucosal tissue overall, and the pDC therein is responsible for shaping the adaptive and innate immunity of the gastrointestinal tract, resisting pathogen invasion through generating type I interferons, presenting antigens, and participating in immunological responses. Therefore, its alleged importance in the gut has received a lot of attention in recent years, and a fresh functional overview is still required. Here, we summarize the current understanding of mouse and human pDCs, ranging from their formation and different qualities compared with related cell types to their functional characteristics in intestinal disorders, including colon cancer, infections, autoimmune diseases, and intestinal graft-versus-host disease. The purpose of this review is to convey our insights, demonstrate the limits of existing research, and lay a theoretical foundation for the rational development and use of pDCs in future clinical practice.

Association of human telomerase reverse transcriptase promoter mutation with unfavorable prognosis in glioma: A systematic review and meta-analysis.

Background: Glioma is one of the most malignant and aggressive tumors, with an extremely poor prognosis. Human telomerase reverse transcriptase (hTERT) promoter mutation is regarded as a risk factor in tumor growth. Although the prevalence of hTERT promoter (pTERT) mutation in gliomas has been investigated, the results are inconsistent. This meta-analysis aims to investigate the prognostic value of hTERT in glioma patients and its interaction with other biomarkers. Materials and Methods: We searched 244 citations from four databases: PubMed (2000-2021), Web of Science (2000-2021), Embase (2010-2021), and Cochrane Library (2000-2021) with 28 articles included. Results: We calculated hazard ratios (HRs) using the random effect model and the pooled result suggested that TERT promoter mutation predicted poorer overall survival (HR: 1.53, 95% confidence interval [CI]: 1.34-1.75, P < 0.001, I2: 49.9%, pheterogeneity:0.002) and progression-free survival (HR: 1.55, 95% CI: 1.27-1.88, P < 0.001, I2: 0.0%, pheterogeneity: 0.473). For subgroup analysis, we analyzed multiple factors including iso-citrate dehydrogenase (IDH) genotype, age, diagnosis, pTERT region, so as to locate the sources of heterogeneity. Interestingly, in IDH mutant subgroup, pTERT mutation became a beneficial prognostic factor (HR: 0.73, 95% CI: 0.57-0.93, I2: 22.3%, pheterogeneity: 0.277), which is contrary to the results in pooled analysis. Conclusion: In general, pTERT mutation may result in shorter survival time in glioma patients, but longer survival time when glioma patients are combined with IDH mutation.

E2F2 modulates cell adhesion through the transcriptional regulation of PECAM1 in multiple myeloma.

Multiple myeloma (MM) is the second most common haematological malignancy. Despite the development of new drugs and treatments in recent years, the therapeutic outcomes of patients are not satisfactory. It is necessary to further investigate the molecular mechanism underlying MM progression. Herein, we found that high E2F2 expression was correlated with poor overall survival and advanced clinical stages in MM patients. Gain- and loss-of-function studies showed that E2F2 inhibited cell adhesion and consequently activated cell epithelial-to-mesenchymal transition (EMT) and migration. Further experiments revealed that E2F2 interacted with the PECAM1 promoter to suppress its transcriptional activity. The E2F2-knockdown-mediated promotion of cell adhesion was significantly reversed by the repression of PECAM1 expression. Finally, we observed that silencing E2F2 significantly inhibited viability and tumour progression in MM cell models and xenograft mouse models respectively. This study demonstrates that E2F2 plays a vital role as a tumour accelerator by inhibiting PECAM1-dependent cell adhesion and accelerating MM cell proliferation. Therefore, E2F2 may serve as a potential independent prognostic marker and therapeutic target for MM.

View from the Biological Property: Insight into the Functional Diversity and Complexity of the Gut Mucus.

Due to mucin's important protective effect on epithelial tissue, it has garnered extensive attention. The role played by mucus in the digestive tract is undeniable. On the one hand, mucus forms "biofilm" structures that insulate harmful substances from direct contact with epithelial cells. On the other hand, a variety of immune molecules in mucus play a crucial role in the immune regulation of the digestive tract. Due to the enormous number of microorganisms in the gut, the biological properties of mucus and its protective actions are more complicated. Numerous pieces of research have hinted that the aberrant expression of intestinal mucus is closely related to impaired intestinal function. Therefore, this purposeful review aims to provide the highlights of the biological characteristics and functional categorization of mucus synthesis and secretion. In addition, we highlight a variety of the regulatory factors for mucus. Most importantly, we also summarize some of the changes and possible molecular mechanisms of mucus during certain disease processes. All these are beneficial to clinical practice, diagnosis, and treatment and can provide some potential theoretical bases. Admittedly, there are still some deficiencies or contradictory results in the current research on mucus, but none of this diminishes the importance of mucus in protective impacts.

Studies on the key constituents and the related mechanisms of Clerodendranthus spicatus in the treatment of diabetes based on network pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: Clerodendranthus spicatus is a traditional Chinese medicine and has been used to treat diabetes and some kidney diseases for a long history. AIM OF THE STUDY: The research aimed to study the active constituents, the potential targets and the related mechanisms of C. spicatus in the treatment of diabetes through network pharmacology method and verify the antidiabetic activity by molecular biology experiments. MATERIALS AND METHODS: A comprehensive network pharmacology strategy was used to predict the key active constituents, the key targets and the related mechanisms and pathways of C. spicatus in the treatment of diabetes. The strategy mainly included screening and predicting potential active constituents and targets by network construction, GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analysis. Based on the predicted results, C. spicatus was extracted by ultrasonic method with 50% ethanol and enriched by using macroporous resin. The compounds with potential antidiabetic effects were separated through silica-gel column chromatography and HPLC (high performance liquid chromatography), and then identified by MS (mass spectrum) and NMR (nuclear magnetic resonance). The C. spicatus extract and isolated compounds were tested by in-vitro and cell experiments to verify their antidiabetic activities, including antioxidant activities, inhibition activities on α-glucosidase and α-amylase, the influence on glucose uptake in cell experiments and the Western blot of PI3K and Akt expression levels. RESULTS: A total of 18 active constituents and 16 key targets of C. spicatus in the treatment of diabetes were screened out through network pharmacology method. Phenolic acids might be the main target compounds for the next research. After extraction, enrichment and separation, the phenolic acids-enriched fraction of C. spicatus and four phenolic acid compounds (helisterculin C, salvianolic acid B, orthosiphoic acid E and ethyl caffeate) were obtained. Among them, salvianolic acid B was isolated from C. spicatus for the first time and orthosiphoic acid E was isolated from natural products for the first time. In experiment verification, the crude extract of C. spicatus, the phenolic acids-enriched fraction and the four compounds all showed antidiabetic potentials. The phenolic acids in C. spicatus had antioxidant activities, inhibitory activities on α-amylase and α-glucosidase and promoted glucose uptake in L6 cells through PI3K/Akt signaling pathway. CONCLUSIONS: This study showed that C. spicatus had antidiabetic activities with the mechanism of the mode of multi-compounds acting on multi-targets and multi-pathways. The main active phenolic acid compounds were also identified. It provided theoretical basis for further development and utilization of C. spicatus.

STING as an emerging therapeutic target for drug discovery: Perspectives from the global patent landscape.

BACKGROUND: The STimulator of INterferon Genes (STING) plays an essential role in the innate immune system by inducing the expression of type I interferons (IFNs) and inflammatory cytokines upon sensing cytosolic DNA. Although modulating STING has shown promise as a potential treatment for cancers and inflammatory and autoimmune diseases in substantial pre-clinical studies, current preliminary clinical results of STING agonists have demonstrated limited anti-tumor efficacy. Currently, there is ongoing R&D targeting STING and focusing on the delivery of next-generation therapeutics. Whereas no comprehensive analysis on the STING patent landscape has been conducted to fill the gap between basic research progress and drug development and commercialization. AIM OF REVIEW: This study summarized the current agents in the clinical stage and global patenting profiles to help identify the current status, development trends, and emerging technologies of the nascent field of STING modulation. KEY SCIENTIFIC CONCEPTS OF REVIEW: Rapidly increasing R&D efforts and outcomes targeting STING were indicated by the recently increasing number and pharmacologic classes of drug candidates in clinic as well as in emergent technological patenting activities. Despite the overall fragmental ownership of patents, several pioneers that have advanced the clinical evaluation of novel STING agonists have established the basis of STING-relevant inventions through their influential patents in the field. These patents also facilitated progress on novel STING modulators, relevant delivery systems, pharmaceutical compositions, and combination strategies with the potential for further enhancing therapeutic outcomes by targeting STING.

Corrigendum: Endoplasmic reticulum stress of gut enterocyte and intestinal diseases.

[This corrects the article DOI: 10.3389/fmolb.2022.817392.].

Development of nanoscale drug delivery systems of dihydroartemisinin for cancer therapy: A review.

Dihydroartemisinin (DHA), a first-line antimalarial drug, has demonstrated great anticancer effects in many types of tumors, including liver cancer, glioblastoma, and pancreatic cancer. Due to its abilities to induce programmed cell death (PCD; apoptosis, autophagy and ferroptosis), inhibit tumor metastasis and angiogenesis, and modulate the tumor microenvironment, DHA could become an antineoplastic agent in the foreseeable future. However, the therapeutic efficacy of DHA is compromised owing to its inherent disadvantages, including poor stability, low aqueous solubility, and short plasma half-life. To overcome these drawbacks, nanoscale drug delivery systems (NDDSs), such as polymeric nanoparticles (NPs), liposomes, and metal-organic frameworks (MOFs), have been introduced to maximize the therapeutic efficacy of DHA in either single-drug or multidrug therapy. Based on the beneficial properties of NDDSs, including enhanced stability and solubility of the drug, prolonged circulation time and selective accumulation in tumors, the outcomes of DHA-loaded NDDSs for cancer therapy are significantly improved compared to those of free DHA. This review first summarizes the current understanding of the anticancer mechanisms of DHA and then provides an overview of DHA-including nanomedicines, aiming to provide inspiration for further application of DHA as an anticancer drug.

Non-apoptotic cell death-based cancer therapy: Molecular mechanism, pharmacological modulators, and nanomedicine.

As an emerging cancer therapeutic target, non-apoptotic cell death such as ferroptosis, necroptosis and pyroptosis, etc., has revealed significant potential in cancer treatment for bypassing apoptosis to enhance the undermined therapeutic efficacy triggered by apoptosis resistance. A variety of anticancer drugs, synthesized compounds and natural products have been proven recently to induce non-apoptotic cell death and exhibit excellent anti-tumor effects. Moreover, the convergence of nanotechnology with functional materials and biomedicine science has provided tremendous opportunities to construct non-apoptotic cell death-based nanomedicine for innovative cancer therapy. Nanocarriers are not only employed in targeted delivery of non-apoptotic inducers, but also used as therapeutic components to induce non-apoptotic cell death to achieve efficient tumor treatment. This review first introduces the main characteristics, the mechanism and various pharmacological modulators of different non-apoptotic cell death forms, including ferroptosis, necroptosis, pyroptosis, autophagy, paraptosis, lysosomal-dependent cell death, and oncosis. Second, we comprehensively review the latest progresses of nanomedicine that induces various forms of non-apoptotic cell death and focus on the nanomedicine targeting different pathways and components. Furthermore, the combination therapies of non-apoptotic cell death with photothermal therapy, photodynamic therapy, immunotherapy and other modalities are summarized. Finally, the challenges and future perspectives in this regard are also discussed.

Insight into the Role of Psychological Factors in Oral Mucosa Diseases.

With the development of psychology and medicine, more and more diseases have found their psychological origins and associations, especially ulceration and other mucosal injuries, within the digestive system. However, the association of psychological factors with lesions of the oral mucosa, including oral squamous cell carcinoma (OSCC), burning mouth syndrome (BMS), and recurrent aphthous stomatitis (RAS), have not been fully characterized. In this review, after introducing the association between psychological and nervous factors and diseases, we provide detailed descriptions of the psychology and nerve fibers involved in the pathology of OSCC, BMS, and RAS, pointing out the underlying mechanisms and suggesting the clinical indications.

Pharmacological activities and molecular mechanisms of Pulsatilla saponins.

Saponins are found in a variety of higher plants and display a wide range of pharmacological activities, including expectorant, anti-inflammatory, vasoprotective and antimicrobial properties. Pulsatilla chinensis (P. chinensis, Bai Tou Weng, ) has been used medically in China for thousands of years for the treatment of diseases caused by bacteria, and it is rich in triterpenoid saponins. In recent decades, anemoside B4 (Pulchinenoside C) is well studied since it has been used as a quality control marker for P. chinensis. At the same time, more and more other active compounds were found in the genus of Pulsatilla. In this review, we summarize the pharmacological activities of Pulsatilla saponins (PS) and discuss the cellular or molecular mechanisms that mediate their multiple activities, such as inducing cancer cell apoptosis, inhibiting tumor angiogenesis, and protecting organs via anti-inflammatory and antioxidant measures. We aim to provide comprehensive analysis and summary of research progress and future prospects in this field to facilitate further study and drug discovery of PS.

Endoplasmic Reticulum Stress of Gut Enterocyte and Intestinal Diseases.

The endoplasmic reticulum, a vast reticular membranous network from the nuclear envelope to the plasma membrane responsible for the synthesis, maturation, and trafficking of a wide range of proteins, is considerably sensitive to changes in its luminal homeostasis. The loss of ER luminal homeostasis leads to abnormalities referred to as endoplasmic reticulum (ER) stress. Thus, the cell activates an adaptive response known as the unfolded protein response (UPR), a mechanism to stabilize ER homeostasis under severe environmental conditions. ER stress has recently been postulated as a disease research breakthrough due to its significant role in multiple vital cellular functions. This has caused numerous reports that ER stress-induced cell dysfunction has been implicated as an essential contributor to the occurrence and development of many diseases, resulting in them targeting the relief of ER stress. This review aims to outline the multiple molecular mechanisms of ER stress that can elucidate ER as an expansive, membrane-enclosed organelle playing a crucial role in numerous cellular functions with evident changes of several cells encountering ER stress. Alongside, we mainly focused on the therapeutic potential of ER stress inhibition in gastrointestinal diseases such as inflammatory bowel disease (IBD) and colorectal cancer. To conclude, we reviewed advanced research and highlighted future treatment strategies of ER stress-associated conditions.

Glytabastan B, a coumestan isolated from Glycine tabacina, alleviated synovial inflammation, osteoclastogenesis and collagen-induced arthritis through inhibiting MAPK and PI3K/AKT pathways.

The roots of Glycine tabacina are used to treat rheumatoid arthritis (RA) and joint infection in folk medicine. Glytabastan B (GlyB), a newly reported coumestan isolated from this species, was found to significantly attenuate IL-1ß-induced inflammation in SW982 human synovial cells at 3 and 6 µM, as evidenced by the decreased levels of pro-inflammatory mediators and matrix metalloproteinases (MMPs). GlyB also suppressed RANKL-induced osteoclastogenesis, decreased the expression of osteoclastogenic markers (NFATc1, CTSK, MMP-9) and osteoclast-mediated bone resorption. Further, GlyB administration (12.5 and 25 mg/kg) significantly inhibited inflammation, osteoclast formation and disease progression in collagen-induced arthritis (CIA) mice. Integration of network pharmacology, quantitative phosphoproteomic and experimental pharmacology results revealed that these beneficial actions were closely associated with the blockade of GlyB on the activation of MAPK, PI3K/AKT and their downstream signals including NF-κB and GSK3ß/NFATc1. Drug affinity responsive target stability (DARTS) assay, cellular thermal shift (CETSA) assay and molecular docking analysis confirmed that there were direct interactions between GlyB and its target proteins ERK2, JNK1 and class Ⅰ PI3K catalytic subunit p110 (α, ß, δ and γ), which significantly contributed to the inhibition of activation of MAPK and PI3K/AKT pathways. In conclusion, these results strongly suggest GlyB is a promising multiple-target candidate for the development of agents for the prevention and treatment of RA.

Spheroidization of ultrasonic degraded corn silk polysaccharide to enhance bioactivity by the anti-solvent precipitation method.

BACKGROUND: Corn silk is a very important by-product of corn production with medicinal value. Corn silk polysaccharide (CSP) is the main active ingredient. In the present study, ultrasound and spheroidization by anti-solvent were applied to improve the biological activity of CSP. RESULTS: The results showed that ultrasonic degradation improved the α-glucosidase inhibitory activity of CSP by changing its physicochemical characteristics. As the anti-solvent ratio increased, the particle size of the nanoparticles (NPs) from the spheroidization of ultrasonic-degraded corn silk polysaccharide (UCSP) gradually increased, and NP-1 exhibited the highest inhibitory effect of α-glucosidase. Isothermal titration calorimetry (ITC) results indicated that the enhanced activity might be due to more α-glucosidase binding sites with NP-1 compared with no spheroidization. Western blotting results showed that NP-1 could improve the 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-d-glucose (2-NBDG) uptake in the L6 cells by regulating the phosphatidylinositol 3-kinase (PI3K)/Akt signal pathway and the translocation of glucose transporter 4 (GLUT4). NP-1 also exhibited excellent stability in different environments. CONCLUSION: The study revealed that ultrasonic treatment and spheroidization processing showed potential applications for improving the biological activity of polysaccharides. © 2021 Society of Chemical Industry.

ROS-responsive fluorinated polyethyleneimine vector to co-deliver shMTHFD2 and shGPX4 plasmids induces ferroptosis and apoptosis for cancer therapy.

Ferroptosis is a newly discovered non-apoptotic cell death form but its therapeutic efficacy triggered by traditional iron-based nanomaterials or classic drug inducers has been far from satisfactory due to the high glutathione (GSH) level in cancer cells and insufficient lipid peroxide production. Here we reported a ferroptosis/apoptosis combinational therapy by depleting GSH and downregulating GPX4 to disrupt redox homeostasis and amplify ferroptosis-related oxidation effect. In this study, we developed reactive oxygen species (ROS)-responsive serum-resistant nanoparticles with thioketal-crosslinked fluorinated polyethyleneimine 1.8K (TKPF) as the core, which were wrapped with hyaluronic acid (HA) as the shell (TKPFH NP) to co-deliver shGPX4 and shMTHFD2 plasmids for cancer treatment. The highly efficient and tumor-selective gene carrier TKPFH NPs revealed outstanding transfection efficiency (∼100 %) and sustained the efficiency (∼50 %) even in media containing 90 % FBS. Mediated by HA, TKPFH NPs actively targeted CD44 receptors, thus enabling efficient uptake by tumor cells and experiencing surface charge conversion to induce subsequent lysosomal escape. Then the TKPF NPs were effectively disintegrated by the abundant ROS in cancer cells, which facilitated the release of plasmids and avoided the cytotoxicity of cationic polymers. shGPX4 plasmid induced ferroptosis by producing ROS and lipid peroxides via downregulating GPX4, while shMTHFD2 triggered apoptosis by modulating NADPH/NADP and depleting GSH of the cancer cells. Moreover, GSH consumption caused by shMTHFD2 indirectly suppressed GPX4 and further augmented ferroptosis, showing synergistic anticancer effect against B16-F10 cells. Taken together, the rationally designed dual-gene loaded TKPFH NPs provided a safe and high-performance platform for enhanced ferroptosis-apoptosis combined anticancer efficacy based on gene therapy. STATEMENT OF SIGNIFICANCE: The therapeutic efficacy of ferroptosis has been far from satisfactory due to high GSH level and insufficient lipid peroxide production in cancer cells. Herein, we reported a ferroptosis/apoptosis combinational therapy by depleting GSH and downregulating GPX4 to disrupt redox homeostasis and amplify ferroptosis-related oxidation effect. ROS-responsive serum-resistant nanoparticles were fabricated with thioketal-crosslinked fluorinated PEI 1.8K (TKPF) as the core and hyaluronic acid (HA) as the shell (TKPFH NP) to co-deliver shGPX4 and shMTHFD2 plasmids. The shGPX4 plasmid induced ferroptosis by producing ROS and lipid peroxides via downregulating GPX4, while shMTHFD2 triggered apoptosis by modulating NADPH/NADP and depleting GSH. The rationally designed dual-gene loaded TKPFH NPs provided a safe and high-performance platform aimed for enhanced ferroptosis-apoptosis combined anticancer efficacy.

An update on the biological characteristics and functions of tuft cells in the gut.

The intestine is a powerful digestive system and one of the most sophisticated immunological organs. Evidence shows that tuft cells (TCs), a kind of epithelial cell with distinct morphological characteristics, play a significant role in various physiological processes. TCs can be broadly categorized into different subtypes depending on different molecular criteria. In this review, we discuss its biological properties and role in maintaining homeostasis in the gastrointestinal tract. We also emphasize its relevance to the immune system and highlight its powerful influence on intestinal diseases, including inflammations and tumors. In addition, we provide fresh insights into future clinical diagnostic and therapeutic strategies related to TCs.