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Cellular and Molecular Gastroenterology... May 2024Type 2 innate lymphoid cells (ILC2s) and interleukin-13 (IL-13) promote the onset of spasmolytic polypeptide-expressing metaplasia (SPEM) cells. However, little is known...
BACKGROUND & AIMS
Type 2 innate lymphoid cells (ILC2s) and interleukin-13 (IL-13) promote the onset of spasmolytic polypeptide-expressing metaplasia (SPEM) cells. However, little is known about molecular effects of IL-13 in SPEM cells. We now sought to establish a reliable organoid model, Meta1 gastroids, to model SPEM cells in vitro. We evaluated cellular and molecular effects of ILC2s and IL-13 on maturation and proliferation of SPEM cells.
METHODS
We performed single-cell RNA sequencing to characterize Meta1 gastroids, which were derived from stomachs of Mist1-Kras transgenic mice that displayed pyloric metaplasia. Cell sorting was used to isolate activated ILC2s from stomachs of IL-13-tdTomato reporter mice treated with L635. Three-dimensional co-culture was used to determine the effects of ILC2s on Meta1 gastroids. Mouse normal or metaplastic (Meta1) and human metaplastic gastroids were cultured with IL-13 to evaluate cell responses. Air-Liquid Interface culture was performed to test long-term culture effects of IL-13. In silico analysis determined possible STAT6-binding sites in gene promoter regions. STAT6 inhibition was performed to corroborate STAT6 role in SPEM cells maturation.
RESULTS
Meta1 gastroids showed the characteristics of SPEM cell lineages in vitro even after several passages. We demonstrated that co-culture with ILC2s or IL-13 treatment can induce phosphorylation of STAT6 in Meta1 and normal gastroids and promote the maturation and proliferation of SPEM cell lineages. IL-13 upregulated expression of mucin-related proteins in human metaplastic gastroids. Inhibition of STAT6 blocked SPEM-related gene expression in Meta1 gastroids and maturation of SPEM in both normal and Meta1 gastroids.
CONCLUSIONS
IL-13 promotes the maturation and proliferation of SPEM cells consistent with gastric mucosal regeneration.
PubMed: 38815928
DOI: 10.1016/j.jcmgh.2024.101366 -
Frontiers in Bioscience (Landmark... May 2024It has been demonstrated that exosomes derived from HPV-16 E7-over-expressiong non-small cell lung cancer (NSCLC) cells (E7 Exo) trigger increased levels of epidermal...
BACKGROUND
It has been demonstrated that exosomes derived from HPV-16 E7-over-expressiong non-small cell lung cancer (NSCLC) cells (E7 Exo) trigger increased levels of epidermal growth factor receptor (EGFR) and miR-381-3p. The purpose of this investigation was to examine the role of E7 Exo in NSCLC angiogenesis, and to analyze the contribution of exosomal EGFR and miR-381-3p to it.
METHODS
The influence of E7 Exo on the proliferation and migration of human umbilical vein endothelial cells (HUVECs) was assessed using colony formation and transwell migration assays. Experiments on both cells and animal models were conducted to evaluate the angiogenic effect of E7 Exo treatment. The involvement of exosomal EGFR and miR-381-3p in NSCLC angiogenesis was further investigated through suppressing exosome release or EGFR activation, or by over-expressing miR-381-3p.
RESULTS
Treatment with E7 Exo increased the proliferation, migration, and tube formation capacities of HUVECs, as well as angiogenesis in animal models. The suppression of exosome release or EGFR activation in NSCLC cells decreased the E7-induced enhancements in HUVEC migration and tube formation, and notably reduced vascular endothelial growth factor A (VEGFA) and Ang-1 levels. HUVECs that combined miR-381-3p mimic transfection and E7 Exo treatment exhibited a more significant tube-forming capacity than E7 Exo-treated HUVECs alone, but were reversed by the miR-381-3p inhibitor.
CONCLUSION
The angiogenesis induced by HPV-16 E7 in NSCLC is mediated through exosomal EGFR and miR-381-3p.
Topics: MicroRNAs; Humans; Carcinoma, Non-Small-Cell Lung; Exosomes; ErbB Receptors; Lung Neoplasms; Papillomavirus E7 Proteins; Neovascularization, Pathologic; Human Umbilical Vein Endothelial Cells; Animals; Cell Proliferation; Cell Movement; Cell Line, Tumor; Mice; Mice, Nude; Human papillomavirus 16; Angiogenesis
PubMed: 38812317
DOI: 10.31083/j.fbl2905189 -
Frontiers in Bioscience (Landmark... May 2024Gastric cancer (GC) is frequently diagnosed at advanced stages, when cancer cells have already metastasized. Therefore, patients with GC have a low survival rate and...
BACKGROUND
Gastric cancer (GC) is frequently diagnosed at advanced stages, when cancer cells have already metastasized. Therefore, patients with GC have a low survival rate and poor prognosis even after treatment.
METHODS
We downloaded GC-related RNA sequencing (RNA-Seq) data, copy number variation (CNV) data, and clinical data for bioinformatics analysis to screen prognostic genes of GC. Single-sample gene set enrichment analysis and survival analyses were performed on the RNA-Seq data, and differential and correlation analyses were conducted on the CNV data to obtain CNV-driven differentially expressed genes (DEGs). Prognostic genes were identified through univariate Cox analyses of the CNV-driven DEGs, combined with the clinical data. () was finally selected for verification after functional and survival analyses of the prognostic genes.
RESULTS
expression was lower in paracancer tissue than in GC tissue, and lower in GES-1 gastric epithelial cells than in GC cells. The cell culture supernatants from -knockdown GC cells were collected and used to culture human umbilical vein endothelial cells (HUVECs). It was observed that enhanced the activity, metastasis, invasion, and angiogenesis of GC cells; promoted the epithelial-mesenchymal transition (EMT) of GC cells; and impacted the Ras-associated protein 1 (Rap1)/mitogen-activated protein kinase (MAPK) pathway. To further explore the involvement of the Rap1/MAPK pathway in GC development, a pathway activator was added to GC cells with knockdown of expression. This pathway activator not only enhanced the activity, invasion, and migration of GC cells but also promoted the EMT and blood vessel formation.
CONCLUSIONS
regulates the angiogenesis and EMT of GC cells through the Rap1/MAPK pathway, thus influencing the onset and progression of GC.
Topics: Stomach Neoplasms; Humans; Epithelial-Mesenchymal Transition; Neovascularization, Pathologic; Cell Line, Tumor; Prognosis; Gene Expression Regulation, Neoplastic; MAP Kinase Signaling System; Human Umbilical Vein Endothelial Cells; Shelterin Complex; Male; Female; Telomere-Binding Proteins; DNA Copy Number Variations; Cell Movement; rap1 GTP-Binding Proteins; Angiogenesis
PubMed: 38812308
DOI: 10.31083/j.fbl2905177 -
Cell Communication and Signaling : CCS May 2024Eph receptors constitute the largest family of receptor tyrosine kinases, comprising 14 distinct members classified into two subgroups: EphAs and EphBs.. Despite their... (Review)
Review
Eph receptors constitute the largest family of receptor tyrosine kinases, comprising 14 distinct members classified into two subgroups: EphAs and EphBs.. Despite their essential functions in normal physiological processes, accumulating evidence suggests that the involvement of the Eph family in cancer is characterized by a dual and often contradictory nature. Research indicates that Eph/ephrin bidirectional signaling influences cell-cell communication, subsequently regulating cell migration, adhesion, differentiation and proliferation. The contradictory functionalities may arise from the diversity of Eph signaling pathways and the heterogeneity of different cancer microenvironment. In this review, we aim to discuss the dual role of the Eph receptors in tumor development, attempting to elucidate the paradoxical functionality through an exploration of Eph receptor signaling pathways, angiogenesis, immune responses, and more. Our objective is to provide a comprehensive understanding of the molecular mechanisms underlying tumor development. Additionally, we will explore the evolving landscape of utilizing Eph receptors as potential targets for tumor therapy and diagnostic tools.
Topics: Humans; Neoplasms; Neovascularization, Pathologic; Signal Transduction; Receptors, Eph Family; Animals; Disease Progression; Immunity; Angiogenesis
PubMed: 38811954
DOI: 10.1186/s12964-024-01580-3 -
World Journal of Clinical Cases May 2024The Correa sequence, initiated by (), commonly progresses to gastric cancer through the stage of chronic atrophic gastritis (CAG). Although eradication of only reduces... (Clinical Trial)
Clinical Trial
BACKGROUND
The Correa sequence, initiated by (), commonly progresses to gastric cancer through the stage of chronic atrophic gastritis (CAG). Although eradication of only reduces the risk of gastric cancer, it does not eliminate the risk for neoplastic progression. Yiwei Xiaoyu granules (YWXY) are a commonly used composite preparation in Chinese clinics. However, the pursuit of excellence in clinical trials and the establishment of standardized animal experiments are still needed to contribute to full understanding and application of traditional Chinese medicine in the treatment of CAG.
AIM
To demonstrate the effectiveness of YWXY in patients with CAG and spleen-stomach deficiency syndrome (DSSS), by alleviating histological scores, improving response rates for pathological lesions, and achieving clinical efficacy in relieving DSSS symptoms.
METHODS
We designed a double-blind, randomized, controlled trial. The study enrolled seventy-two -negative patients (mean age, 52.3 years; 38 men) who were randomly allocated to either the treatment group or control group in a 1:1 ratio, and treated with 15 g YWXY or 0.36 g Weifuchun (WFC) tablet combined with the respective dummy for 24 wk. The pre-randomization phase resulted in the exclusion of 72 patients: 50 participants did not meet the inclusion criteria, 12 participants declined to participate, and 10 participants were excluded for various other reasons. Seven visits were conducted during the study, and histopathological examination with target endoscopic biopsy of narrow-band imaging was requested before the first and seventh visits. We also evaluated endoscopic performance scores, total symptom scores, serum pepsinogen and gastrin-17.
RESULTS
Six patients did not complete the trial procedures. Treatment with YWXY improved the Operative Link on Gastric Intestinal Metaplasia Assessment (OLGIM) stage, compared with WFC ( < 0.05). YWXY provided better relief from symptoms of DSSS and better improvement in serum gastric function, compared with WFC ( < 0.05).
CONCLUSION
YWXY compared with WFC significantly reduced the risk of mild or moderate atrophic disease, according to OLGIM stage, significantly relieved symptoms of DSSS, and improved serum gastric function.
PubMed: 38808353
DOI: 10.12998/wjcc.v12.i13.2201 -
Frontiers in Immunology 2024Asthma is a common obstructive airway disease with an inflammatory etiology. The main unmet need in the management of asthma is inadequate adherence to pharmacotherapy,...
Bronchom assuages airway hyperresponsiveness in house dust mite-induced mouse model of allergic asthma and moderates goblet cell metaplasia, sub-epithelial fibrosis along with changes in Th2 cytokines and chemokines.
BACKGROUND
Asthma is a common obstructive airway disease with an inflammatory etiology. The main unmet need in the management of asthma is inadequate adherence to pharmacotherapy, leading to a poorly-controlled disease state, necessitating the development of novel therapies. Bronchom is a calcio-herbal formulation, which is purported to treat chronic asthma. The objective of the current study was to examine the in-vivo efficacy of Bronchom in mouse model of allergic asthma.
METHODS
Ultra high performance liquid chromatography was utilized to analyze the phytocompounds in Bronchom. Further, the in-vivo efficacy of Bronchom was evaluated in House dust mite (HDM)-induced allergic asthma in mice. Mice were challenged with aerosolized methacholine to assess airway hyperresponsiveness. Subsequently, inflammatory cell influx was evaluated in bronchoalveolar lavage fluid (BALF) followed by lung histology, wherein airway remodeling features were studied. Simultaneously, the levels of Th2 cytokines and chemokines in the BALF was also evaluated. Additionally, the mRNA expression of pro-inflammatory and Th2 cytokines was also assessed in the lung along with the oxidative stress markers.
RESULTS
Phytocompounds present in Bronchom included, gallic acid, protocatechuic acid, methyl gallate, rosmarinic acid, glycyrrhizin, eugenol, 6-gingerol and piperine. Bronchom effectively suppressed HDM-induced airway hyperresponsiveness along with the influx of leukocytes in the BALF. Additionally, Bronchom reduced the infiltration of inflammatory cells in the lung and it also ameliorated goblet cell metaplasia, sub-epithelial fibrosis and increase in α-smooth muscle actin. Bronchom decreased Th2 cytokines (IL-4 and IL-5) and chemokines (Eotaxin and IP-10) in the BALF. Likewise, it could also suppress the mRNA expression of pro-inflammatory cytokines (TNF-α, IFN-γ, IL-6 and IL-33), and IL-13. Moreover, Bronchom restored the HDM-induced diminution of endogenous anti-oxidants (GSH and SOD) and the increase in pro-oxidants (GSSG and MDA). Furthermore, Bronchom could also decrease the nitrosative stress by lowering the observed increase in nitrite levels.
CONCLUSION
Taken together, the results of the present study data convincingly demonstrate that Bronchom exhibits pharmacological effects in an animal model of allergic asthma. Bronchom mitigated airway hyperresponsiveness, inflammation and airway remodeling evoked by a clinically relevant allergen and accordingly it possesses therapeutic potential for the treatment of asthma.
Topics: Animals; Asthma; Mice; Disease Models, Animal; Cytokines; Goblet Cells; Metaplasia; Pyroglyphidae; Th2 Cells; Chemokines; Fibrosis; Mice, Inbred BALB C; Airway Remodeling; Female; Plant Extracts; Lung
PubMed: 38807596
DOI: 10.3389/fimmu.2024.1384697 -
BMC Ophthalmology May 2024Macular retinoschisis (MRS) and myopic macular neovascularization (mMNV) are both potentially blinding complications of high myopia. In this case report, we highlight... (Review)
Review
BACKGROUND
Macular retinoschisis (MRS) and myopic macular neovascularization (mMNV) are both potentially blinding complications of high myopia. In this case report, we highlight the progression of MRS after intravitreal anti-vascular endothelial growth factor (anti-VEGF) treatment for mMNV, as well as an extensive review of the literature on this topic.
CASE DESCRIPTION
A 49-year-old woman presented with two weeks of recent onset blurring and metamorphopsia in her right eye. She had high myopia in both eyes (right eye - 20/60 with - 16D, left eye - 20/20 with - 13D). Slit-lamp ophthalmoscopy found a normal anterior segment in both eyes. On fundus examination, features of pathological myopia with posterior staphyloma and peripapillary atrophy were observed in both eyes. An active mMNV, as well as intraretinal fluid, minimal perifoveal inner and outer MRS, and focal posterior vitreous traction along the inferotemporal retinal arcade, were detected on optical coherence tomography (OCT) of the right eye. The patient received an intravitreal injection of Aflibercept (2 mg/0.05 ml).
RESULTS
OCT scans at two- and four-month follow-up visits revealed regressed mMNV with a taut epiretinal membrane, progressive worsening of outer MRS, and the development of multiple perifoveal retinal detachment inferior to the fovea. Pars plana vitrectomy surgery was performed for the progressive MRS with good anatomical (resolved MRS) and functional outcome (maintained visual acuity at 20/60) at the last one-month post-surgery visit.
CONCLUSION
Intravitreal anti-VEGF injections for mMNV can cause vitreoretinal interface changes, exacerbating MRS and causing visual deterioration. Vitrectomy for MRS could be one of several treatment options.
Topics: Humans; Receptors, Vascular Endothelial Growth Factor; Female; Intravitreal Injections; Middle Aged; Retinoschisis; Recombinant Fusion Proteins; Myopia, Degenerative; Tomography, Optical Coherence; Visual Acuity; Angiogenesis Inhibitors; Disease Progression; Retinal Neovascularization; Fluorescein Angiography
PubMed: 38807066
DOI: 10.1186/s12886-024-03497-4 -
Clinics and Practice May 2024Previous studies demonstrate an association between metabolic factors and -related gastric cancer. However, the association of gastric atrophy or intestinal metaplasia...
BACKGROUND
Previous studies demonstrate an association between metabolic factors and -related gastric cancer. However, the association of gastric atrophy or intestinal metaplasia (IM) with these factors remains unknown.
METHODS
Data on 1603 -positive patients who underwent esophagogastroduodenoscopy between 2001 and 2021 were evaluated. The outcome measures were endoscopic atrophy, IM grade, and the incidence of endoscopically diagnosed and pathologically confirmed gastric neoplasms. Clinical factors associated with these findings were also determined.
RESULTS
Advanced age; successful eradication; and comorbidities including diabetes mellitus (DM), hypertension, dyslipidemia, and fib4 index were significantly associated with endoscopic gastric atrophy grade. Male sex; advanced age; and comorbidities including DM, hypertension, dyslipidemia, hyperuricemia, fatty liver, aortic calcification, and fib4 index were also significantly associated with endoscopic IM grade, whereas advanced age, successful eradication, DM, fatty liver, and fib4 index were significantly associated with the incidence of gastric neoplasms.
CONCLUSION
Several metabolic disorders, including DM, hypertension, dyslipidemia, hyperuricemia, and fatty liver disease, are risk factors for advanced-grade gastric atrophy, intestinal metaplasia, and gastric neoplasms. Risk stratification according to these factors, particularly those with metabolic disorders, would affect EGD surveillance for -positive patients.
PubMed: 38804394
DOI: 10.3390/clinpract14030062 -
Epigenomes May 2024We consider the newly developed multinomial mixed-link models for a high-risk intestinal metaplasia (IM) study with DNA methylation data. Different from the traditional...
We consider the newly developed multinomial mixed-link models for a high-risk intestinal metaplasia (IM) study with DNA methylation data. Different from the traditional multinomial logistic models commonly used for categorical responses, the mixed-link models allow us to select the most appropriate link function for each category. We show that the selected multinomial mixed-link model (Model 1) using the total number of stem cell divisions (TNSC) based on DNA methylation data outperforms the traditional logistic models in terms of cross-entropy loss from ten-fold cross-validations with significant -values 8.12×10-4 and 6.94×10-5. Based on our selected model, the significance of TNSC's effect in predicting the risk of IM is justified with a -value less than 10-6. We also select the most appropriate mixed-link models (Models 2 and 3) when an additional covariate, the status of gastric atrophy, is available. When the status is negative, mild, or moderate, we recommend Model 2; otherwise, we prefer Model 3. Both Models 2 and 3 can predict the risk of IM significantly better than Model 1, which justifies that the status of gastric atrophy is informative in predicting the risk of IM.
PubMed: 38804368
DOI: 10.3390/epigenomes8020019 -
Journal of Nanobiotechnology May 2024Corneal neovascularization (CNV) is one of the common blinding factors worldwide, leading to reduced vision or even blindness. However, current treatments such as...
Corneal neovascularization (CNV) is one of the common blinding factors worldwide, leading to reduced vision or even blindness. However, current treatments such as surgical intervention and anti-VEGF agent therapy still have some shortcomings or evoke some adverse effects. Recently, SU6668, an inhibitor targeting angiogenic tyrosine kinases, has demonstrated growth inhibition of neovascularization. But the hydrophobicity and low ocular bioavailability limit its application in cornea. Hereby, we proposed the preparation of SU6668 pure nanoparticles (NanoSU6668; size ~135 nm) using a super-stable pure-nanomedicine formulation technology (SPFT), which possessed uniform particle size and excellent aqueous dispersion at 1 mg/mL. Furthermore, mesenchymal stem cell membrane vesicle (MSCm) was coated on the surface of NanoSU6668, and then conjugated with TAT cell penetrating peptide, preparing multifunctional TAT-MSCm@NanoSU6668 (T-MNS). The T-MNS at a concentration of 200 µg/mL was treated for CNV via eye drops, and accumulated in blood vessels with a high targeting performance, resulting in elimination of blood vessels and recovery of cornea transparency after 4 days of treatment. Meanwhile, drug safety test confirmed that T-MNS did not cause any damage to cornea, retina and other eye tissues. In conclusion, the T-MNS eye drop had the potential to treat CNV effectively and safely in a low dosing frequency, which broke new ground for CNV theranostics.
Topics: Corneal Neovascularization; Animals; Nanoparticles; Ophthalmic Solutions; Cornea; Mice; Angiogenesis Inhibitors; Particle Size; Humans; Male; Mice, Inbred C57BL; Rabbits
PubMed: 38802884
DOI: 10.1186/s12951-024-02510-8