MUC1 Levels Research Articles

Salivary Transmembrane Mucins of the MUC1 Family (CA 15-3, CA 27.29, MCA) in Breast Cancer: The Effect of Human Epidermal Growth Factor Receptor 2 (HER2)

The MUC1 family of transmembrane glycoproteins (CA 15-3, CA 27.29, MCA) is aberrantly expressed among patients with breast cancer. Objectives: to measure the level of degradation products of MUC1, including CA 15-3, CA 27.29, and MCA, in the saliva of breast cancer patients and to describe the biochemical processes that influence their expression and the regulation of their biological functions. Methods: The case–control study included three groups (breast cancer, fibroadenomas, and healthy controls). All study participants provided saliva samples strictly before starting treatment. The levels of MUC1, including CA 15-3, CA 27.29, and MCA, free progesterone and estradiol, cytokines (MCP-1, VEGF, TNF-α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-18), and amino acids (Asp, Gln, Gly, His, Leu + Ile, Orn, Phe, Pro, Tyr) were determined. Results: It was shown that the levels of the MUC1 family in the saliva of patients with HER2-positive breast cancer were significantly lower compared to the control group. The level of pro-inflammatory cytokines and the level of free estradiol affected the expression of MUC1. We obtained a reliable relationship between the aggressive nature of tumor growth, an increased level of pro-inflammatory cytokines, a low level of free estradiol, and the suppressed expression of salivary MUC1. Conclusions: Among patients with aggressive breast cancer, a high level of pro-inflammatory cytokines, and a low level of free estradiol, there was an inhibition of the expression of pathologically unchanged glycoprotein MUC1 in saliva.

Relationship between pathogenic E.coli O78-induced intestinal epithelial barrier damage and Zonulin expression levels in yaks.

The Zonulin gene overexpression and knockout cell lines were successfully constructed, the TEER value of the barrier of Zonulin overexpression cell lines began to decrease at 1 h after the addition of E.coli O78 and reached the lowest value at 4 h, and the TEER value of Zonulin interference cell lines decreased within 1-4 h after the addition of E.coli O78. At 4 h, the FD4 passing capacity of Zonulin overexpression cell lines was significantly higher than that of interfering cell lines, reaching twice as much as siRNA-1. The amount of bacterial translocation in overexpressed cell lines increased rapidly within 1-4 h, and the concentration of E.coli in the lower chamber was significantly higher than that in the siRNA-1 group at 4 h, but there was no significant change in the siRNA-1 group in the 1-4 h. There was no significant change in the mRNA level of MUC1 in Zonulin overexpression and interference cell lines after the addition of E.coli O78. In the overexpression group, the mRNA levels of MUC2, Occludin, and ZO-1 were significantly decreased, and the mRNA level of FABP2 was increased considerably. These results suggest stimulate epithelial cells to secrete Zonulin protein. Many Zonulin proteins regulate the opening of tight junction structures, reduce the transmembrane resistance of the cell barrier, and improve the permeability of the cell barrier and the amount of bacterial translocation.

Study on the alleviative effect of Lactobacillus plantarum on Eimeria falciformis infection.

Coccidia of the genus Eimeria are specialized intracellular parasitic protozoa that cause severe coccidiosis when they infect their hosts. Animals infected with Eimeria develop clinical symptoms, such as anorexia, diarrhea, and hematochezia, which can even cause death. Although the current preferred regimen for the treatment of coccidiosis is antibiotics, this treatment strategy is limited by the ban on antibiotics and the growing problem of drug resistance. Therefore, the exploration of alternative methods for controlling coccidiosis has attracted much attention. Lactobacillus plantarum has been shown to have many beneficial effects. In this study, L. plantarum M2 was used as a research object to investigate the effect of L. plantarum on intestinal inflammation induced by infection with Eimeria falciformis in mice by detecting indicators, such as oocyst output, serum cytokines, and the intestinal microbiota. Compared with that in the infection group, the percent weight loss of the mice that were administered with L. plantarum M2 was significantly reduced (P < 0.05). Supplemented L. plantarum M2 and probiotics combined with diclazuril can reduce the total oocyst output significantly (P < 0.05, P < 0.001). L. plantarum M2 had outstanding performance in maintaining intestinal barrier function, and the levels of the mucin MUC1 and the tight junction protein E-cadherin were significantly elevated (P < 0.01, P < 0.05). Studies have shown that probiotic supplementation can alleviate adverse reactions after infection and significantly improve intestinal barrier function. In addition, probiotics combined with diclazuril could optimize the partial efficacy of diclazuril, which not only enhanced the effect of antibiotics but also alleviated their adverse effects. This study expands the application of probiotics, provides new ideas for alternative strategies for coccidia control, and suggests a basis for related research on lactobacilli antagonizing intracellular pathogen infection.IMPORTANCECoccidia of the genus Eimeria are specialized intracellular parasitic protozoa, and the current preferred regimen for the treatment of coccidiosis is antibiotics. However, due to antibiotic bans and drug resistance, the exploration of alternative methods for controlling coccidiosis has attracted much attention. In this work, we focused on Lactobacillus plantarum M2 and found that probiotic supplementation can alleviate adverse reactions after infection and improve intestinal barrier function. This study proposes the possibility of using lactic acid bacteria to control coccidiosis, and its potential mechanism needs further exploration.

Modified Sanliangsan Improved Sjogren's Syndrome Complicated with Interstitial Lung Disease by Suppressing Serum MUC1 Levels.

To clarify if the mechanism of Sanliangsan in improving Sjogren's syndrome complicated with interstitial lung disease (SS-ILD) involves MUC1 suppression, which is involved in SS-ILD pathogenesis. Fifty-six patients were randomly divided into two groups receiving Sanliangsan prescription (SP) therapy and conventional therapy (western medicine). In-depth transcriptome profiles from a large database of SS-ILD patients were collected and analyzed to identify candidate genes involved in SS pathogenesis. Clinical symptom scores, metabolic compositions, lung HRCT (high-resolution computed tomography) scores, and serum MUC1 levels were compared between the two groups before and after treatment. Network pharmacology, molecular docking, and ITC assays were performed to identify bioactive compounds of SP in improving SS. Metabolome analyzed the metabolic composition of serum associated with SS-ILD before and after SP treatment. Transcriptome results identified the involvement of abnormal expression of genes relevant to the immune system, inflammatory responses, and signaling pathways. Numerous genes, including CD58, CD86, CTLA4, CXCL8, STAT1, and especially MUC1, were involved in SS pathogenesis and could be used to diagnose SS-ILD early. Both treatments improved the lung HRCT scores and clinical symptoms of SS-ILD. The SP therapy improved SS-ILD more effectively than conventional therapy. Moreover, Sanliangsan prescription therapy reduced serum MUC1 levels and restored the abnormal metabolisms, improving the abnormal inflammatory and immune responses of patients. Eugenol directly interacted with MUC1, suppressed related genes, and was the bioactive compound of SP. SP could partially restore the abnormal metabolisms associated with SS-ILD pathogenesis. Based on conventional Western medicine treatment, modified Sanliangsan can significantly improve the clinical symptoms, signs, and lung function of patients; the mechanism may be due to eugenol and related to MUC1 regulation.

Plasma extracellular vesicles proteomics in meningioma patients

Tumor derived Extracellular vesicles (EVs) in circulating system may contain tumor-specific markers, and EV detection in body fluids could become an important tool for early tumor diagnosis, prognosis assessment. Meningiomas are the most common benign intracranial tumors, few studies have revealed specific protein markers for meningiomas from patients’ body fluids. In this study, using proximity labeling technology and non-tumor patient plasma as a control, we detected protein levels of EVs in plasma samples from meningioma patients before and after surgery. Through bioinformatics analysis, we discovered that the levels of EV count and protein count in meningioma patients were significantly higher than those in healthy controls, and were significantly decreased postoperatively. Among EV proteins in meningioma patients, the levels of MUC1, SIGLEC11, E-Cadherin, KIT, and TASCTD2 were found not only significantly elevated than those in healthy controls, but also significantly decreased after tumor resection. Moreover, using publicly available GEO databases, we verified that the mRNA level of MUC1, SIGLEC11, and CDH1 in meningiomas were significantly higher in comparison with normal dura mater tissues. Additionally, by analyzing human meningioma specimens collected in this study, we validated the protein levels of MUC1 and SIGLEC11 were significantly increased in WHO grade 2 meningiomas and were positively correlated with tumor proliferation levels. This study indicates that meningiomas secret EV proteins into circulating system, which may serve as specific markers for diagnosis, malignancy predicting and tumor recurrent assessment.

First-in-human autologous CAR-T for metastatic breast cancers to target growth factor receptor MUC1*.

TPS2683 Background: MUC1 has been one of the most important therapeutic targets for solid tumor cancers for the past 20+ years. However, no MUC1 targeted therapeutic has yet succeeded or has been granted FDA approval. Although MUC1 is overexpressed on cancer cells, it is also widely expressed on normal epithelial cells. We previously reported that a MUC1 transmembrane cleavage product, MUC1* (muk 1 star), is a Class I growth factor receptor activated by ligand-induced dimerization of its truncated extra cellular domain. We generated monoclonal antibodies that recognize the specific conformation that is created when MUC1 is cleaved by specific enzymes expressed in the tumor microenvironment. 93% of human breast cancer tissues are recognized by one of these antibodies, huMNC2, which importantly does not bind to normal MUC1. We have incorporated this antibody into two CARs, wherein one bears the “1XX” mutations in CD3z that greatly increase CAR-T cell persistence, inhibit exhaustion and enable the killing of low antigen expressing cancer cells. Methods: Phase I for huMNC2-CAR44, an autologous frozen product, opened January, 2020, but as a 1st-in-human trial was paused during COVID. All patients receive 300 mg/m2 cyclophosphamide and 30 mg/m2 fludarabine for 3 days prior to CAR-T treatment. Dose escalation from 3.3x105 – 1x107 CAR+ cells/kg follows a standard 3 + 3 design. In addition to standard organ function inclusion criteria, the trial was first open to breast cancer patients whose cancer had progressed after at least 2 or 3 prior therapies while metastatic, yet there was no limit on the number of prior therapies. A recent patient biopsy had to be at least 30% positive for MUC1* in a CLIA validated IHC assay. Importantly, there were no limits on the vein-to-vein time. Dose levels 1 and 2 for huMNC2-CAR44 were completed without DLTs. Phase I for huMNC2-CAR22, which bore the 1XX mutations in CD3z to increase persistence and increase the killing of low antigen expressing cells opened September, 2023. Based on responses of initial huMNC2-CAR44 patients, inclusion criteria were amended to an Enrichment Trial Design. The number of prior therapies was limited to less than or equal to 10. Anticipated survival at the time of product infusion should be at least 3 months. Vein-to-vein time, which historically had been 15-16 days at one site and as high as 83 days at another site, would be targeted to 16- 22 days. The tumors of eligible patients need to have a MUC1* membrane positive H-score equal to or greater than 120 out of a possible 300, defined as high MUC1* positivity. Based on IHC analysis of human breast cancer TMAs, the H-score restriction would include roughly 40% of breast cancers. The increased ability of huMNC2-CAR22 to kill low antigen expressing cancer cells may support future studies of patients expressing low levels of MUC1*. Clinical trial information: NCT04020575 .

Clinical Significance of MUC4 and Associated Proteins in Pancreatic and Periampullary Cancers.

This study primarily aimed to assess the expression of MUC4 in patients with pancreatic ductal adenocarcinoma (PDAC) as compared with controls and assess its clinical relevance. Serum MUC4 levels and MUC4 gene expression in snap-frozen tissue were analyzed through surface plasmon resonance and quantitative polymerase chain reaction, respectively. Tumor tissues and control tissues were analyzed for MUC4 and other mucins through immunohistochemistry. MUC4 expression in tumor tissue was found to be significantly elevated in PDAC patients as compared with chronic pancreatitis tissues and normal pancreatic tissues. Periampullary carcinoma and cholangiocarcinoma tissue also showed increased expression of MUC4 and other mucins. Differential expression of MUC4 in pancreatic tumor tissues can help to differentiate PDAC from benign conditions.

Establishment of a cholangiocarcinoma risk evaluation model based on mucin expression levels.

Cholangiocarcinoma (CCA) is a highly malignant cancer, characterized by frequent mucin overexpression. MUC1 has been identified as a critical oncogene in the progression of CCA. However, the comprehensive understanding of how the mucin family influences CCA progression and prognosis is still incomplete. To investigate the functions of mucins on the progression of CCA and to establish a risk evaluation formula for stratifying CCA patients. Single-cell RNA sequencing data from 14 CCA samples were employed for elucidating the roles of mucins, complemented by bioinformatic analyses. Subsequent validations were conducted through spatial transcriptomics and immunohistochemistry. The construction of a risk evaluation model utilized the least absolute shrinkage and selection operator regression algorithm, which was further confirmed by independent cohorts and diverse data types. CCA tumor cells with elevated levels of MUC1 and MUC4 showed activated nucleotide metabolic pathways and increased invasiveness. MUC5AC-high cells were found to promote CCA progression through WNT signaling. MUC5B-high cells exhibited robust cellular oxidation activities, leading to resistance against antitumoral treatments. MUC13-high cells were observed to secret chemokines, recruiting and transforming macrophages into the M2-polarized state, thereby suppressing antitumor immunity. MUC16-high cells were found to promote tumor progression through interleukin-1/nuclear factor kappa-light-chain-enhancer of activated B cells signaling upon interaction with neutrophils. Utilizing the expression levels of these mucins, a risk factor evaluation formula for CCA was developed and validated across multiple cohorts. CCA samples with higher risk factors exhibited stronger metastatic potential, chemotherapy resistance, and poorer prognosis. Our study elucidates the functional mechanisms through which mucins contribute to CCA development, and provides tools for risk stratification in CCA.

INDICATORS OF MUC 5AC AND MUC 1 MUCOPOLYSACCHARIDE EXPRESSION IN THE NASAL MUCOSA OF PATIENTS WITH POSTNASAL DRIP SYNDROME AND NASAL SEPTUM DEVIATION

Introduction. Determining the cause of postnasal drip syndrome can be quite challenging. Nasal septum deformation has been recognized as one possible factor. Understanding the fundamental processes of postnasal drip syndrome is crucial for developing targeted therapeutic strategies for treating this pathology. In our study, we examined the clinical and histological features of postnasal drip syndrome in individuals with nasal septum deformation and investigated the expression of mucopolysaccharides, specifically the indicators of MUC 5AC and MUC 1.&#x0D; The aim. This study aims to investigate the clinical and histological aspects of postnasal drip syndrome (PNDS) in patients with nasal septum deformation. Specifically, the study aims to explore the expression levels of MUC5AC and MUC1 in biopsies of the nasal turbinate mucosa.&#x0D; Materials and methods. A total of 29 samples of nasal mucosa from the lower nasal turbinates were collected. These samples were divided into two groups: patients with nasal septum deviation with and without postnasal drip syndrome. Levels of MUC5AC and MUC1 were determined using Western blot analysis.&#x0D; Results. Upon analysis of histological sections, we identified a significant increase in tissue metaplasia and lymphoid infiltration in the nasal mucosa of patients with postnasal drip syndrome compared to the control group. The levels of mucopolysaccharides, MUC5AC and MUC1, were higher in the nasal mucosa of the research group compared to the control group.&#x0D; Conclusions. The obtained data suggest that anatomical changes in the nasal cavity may play a role in the development of postnasal drip syndrome through alterations in mucin secretion.

Mucin 1 and venous thrombosis in tumor-bearing mice and patients with cancer

IntroductionMucins released from epithelial tumors have been proposed to play a role in cancer-associated thrombosis. Mucin1 (MUC1) is a transmembrane mucin that is overexpressed in a variety of human malignancies, including breast and pancreatic cancer. We analyzed the association of MUC1 and venous thrombosis in a mouse tumor model and in patients with cancer. Materials and methodsWe used a human pancreatic cancer cell line HPAF-II that expresses a high level of MUC1. We grew HPAF-II tumors in the pancreas of Crl:NU-Foxn1nu male mice. MUC1 in plasma and extracellular vesicles (EVs) isolated from plasma was measured using an enzyme-linked immunosorbent assay. MUC1 in EVs and venous thrombi from tumor-bearing mice was assessed by western blotting. We measured MUC1 in plasma from healthy controls and patients with stomach, colorectal or pancreatic cancer with or without venous thromboembolism. Results and discussionMUC1 was detected in the plasma of mice bearing HPAF-II tumors and was associated with EVs. MUC1 was present in venous thrombi from mice bearing HFAP-II tumors. Recombinant MUC1 did not induce platelet aggregation. Levels of MUC1 were higher in patients with pancreatic cancer compared with healthy controls. In contrast to the mouse model, MUC1 was present in EV-free plasma in samples from healthy controls and patients with cancer. There was no significant difference in the levels of MUC1 in cancer patients with or without VTE. Our data did not find any evidence that MUC1 contributed to VTE in patients with cancer.

Rhodomyrtus tomentosa as a new anticancer molecular strategy in breast histology via Her2, IL33, EGFR, and MUC1.

The prevalence of breast cancer among patients in Indonesia is significant. Indonesian individuals maintain the belief that cancer cannot be cured alone by pharmaceuticals and treatment; herbal remedies must be used in conjunction. Rhodomyrtus tomentosa, also known as Haramonting, is an indigenous Indonesian medicinal plant renowned for its copious antioxidant properties. The objective of study was to assess the impact of haramonting on breast cancer by examining the expression of various biomarker proteins associated with breast cancer. Haramonting was administered to breast cancer model mice at different doses over a period of 30days. Subsequently, blood and breast samples were obtained for immunohistochemistry and enzyme-linked immunosorbent assays (ELISA). Authors have discovered that there has been a notable rise in the proliferation of epithelial cells in the duct lobes, resulting in the formation of ducts and lobules. Additionally, the researchers discovered that the breasts exhibited distinct clinical and histological alterations. Haramonting possesses the capacity to restore the concentrations of malondialdehyde (MDA) and superoxide dismutase (SOD) to normal levels in the blood serum of rats afflicted with cancer. The histopathological analysis of the breast tissue revealed elevated levels of Her2, IL33, EGFR, and MUC1. The authors also discovered a notable increase in the growth of epithelial cells, with two or more layers of cells reaching towards the centre of the duct. The size of the epithelial cells exhibits variability; however, this state ameliorates with the administration of a dosage of 300mg/kgBW of this botanical specimen. This study proposes that Haramonting may be effective in treating breast cancer.

Diagnostic efficacy of combining diffusion-weighted magnetic resonance imaging with serum Mucin 1, Mucin 13, and Mucin 16 in distinguishing borderline from malignant epithelial ovarian tumors.

To enhance ovarian tumor diagnosis beyond conventional methods, this study explored combining diffusion-weighted magnetic resonance imaging (DWI-MRI) and serum biomarkers (Mucin 1 [MUC1], MUC13, and MUC16) for distinguishing borderline from malignant epithelial ovarian tumors. A total of 126 patients, including 71 diagnosed with borderline (BEOTs) and 55 with malignant epithelial ovarian tumors (MEOTs), underwent preoperative DWI-MRI. Region of interest (ROI) was manually drawn along the solid component's boundary of the largest tumor, focusing on areas with potentially the lowest apparent diffusion coefficient (ADC). For entirely cystic tumors, a free-form ROI enclosed the maximum number of septa while targeting the lowest ADC. Serum biomarkers were determined using enzyme-linked immunosorbent assay. Basic morphological traits proved inadequate for malignancy diagnosis, warranting this investigation. BEOTs had an ADC mean of (1.670±0.250) × 103 mm2 /s, while MEOTs had a lower ADC mean of (1.332±0.481) × 103 mm2 /s, with a sensitivity of 63.6% and specificity of 90.1%. Median MUC1 (167.0 U/mL vs. 87.3 U/mL), MUC13 (12.44ng/mL vs. 7.77ng/mL), and MUC16 (180.6 U/mL vs. 36.1 U/mL) levels were higher in MEOTs patients. The biomarker performance was: MUC1, sensitivity 50.9%, specificity 100%; MUC13, sensitivity 56.4%, specificity 78.9%; MUC16, sensitivity 83.64%, specificity 100%. Combining serum biomarkers and ADC mean resulted in a sensitivity of 96.4% and specificity of 100%. The integration of DWI-MRI with serum biomarkers (MUC1, MUC13, and MUC16) achieves exceptional diagnostic accuracy, offering a powerful tool for the precise differentiation between borderline and malignant epithelial ovarian tumors.

Knockdown of MUC1 by RNA Interference (siRNA) Influenced Vascular Endothelial Growth Factor Receptor (VEGFR2) and Suppression of Growth of Pancreatic Cancer Cells (PANC1)

MUC1 is overexpressed approximately in most of pancreatic adenocarcinomas and has been revealed to be linked with a worse prognosis, beside effectiveness, MUC1 hold for regulating cellular and developmental pathways. The objective of the current study is to downregulate the overexpression of MUC1 by small interfering RNA (siRNA) on PANC1 and to investigate its effect on vascular endothelial growth factor (VEGFR-2) expression. Besides MUC1, the expression levels of VEGFR2 were investigated in PANC1. Then the expression level of MUC1 was downregulated by using MUC1 specific siRNA approach to identify whether MUC1 is involved in the regulation of VEGFR-2 mRNA and protein, which were determined by QRT-PCR and Western blot, respectively. Interestingly, siRNA is considered an emerging approach in cancer cell therapy. Furthermore, the impact of MUC1 silencing in pancreatic adenocarcinoma cell lines was investigated. Transwell and Matrigel assays were performed to study the functional significance of MUC1 activity on cell migration and invasion, respectively. The present study indicates that targeting MUC1 by siRNA in pancreatic adenocarcinoma cells is associated with silencing of VEGFR-2 expression in both mRNA and protein levels, demonstrating that MUC1 regulates the main driver of angiogenesis and metastasis. The current study showed that targeting MUC1 with siRNA decreases pancreatic cancer cell proliferation, migration, and invasion, by significantly decreasing the expression of the potent angiogenic receptor VEGFR-2. Therefore, targeting MUC1 with siRNA can be exploited as a therapeutic option for pancreatic cancer treatment.

Human vaginal microbiota colonization is regulated by female sex hormones in a mouse model.

Clinically, a Lactobacillus rich vaginal microbiota (VMB) is considered optimal for reproductive outcomes, while a VMB populated by anaerobes is associated with dysbiosis and the clinical condition bacterial vaginosis (BV), which is linked to increased susceptibility to sexually transmitted infections and adverse reproductive outcomes. Mouse models that mimic eubiotic and dysbiotic VMB are currently lacking but could play a critical role in improving protective interventions. In this study, probiotic, eubiotic, and dysbiotic models were developed in C57BL/6 mice, using probiotic strains Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14, eubiotic Lactobacillus crispatus, or dysbiotic Gardnerella vaginalis strains. Endogenous sex hormones were manipulated by either ovariectomizing (OVX) mice or administering 17β-estradiol or progesterone pellets in OVX mice. Hormone-altered mice were inoculated with probiotic Lactobacillus species, L. crispatus, or G. vaginalis, and colonization was tracked using quantitative plating assays. Glycogen and MUC-1 levels in hormone-treated mice were determined with ELISA and MUC-1 staining. Following a single administration, L. rhamnosus and L. reuteri persisted in the mouse vaginal tract for up to eight days, L. crispatus persisted for up to three days, and G. vaginalis persisted for up to two days, as measured by quantitative plating assays and qPCR. Colonization of G. vaginalis was facilitated by the presence of mucin. The lack of endogenous hormones in OVX mice dramatically decreased VMB bacterial load compared to normal mice. None of the exogenous bacteria including Lactobacilli could colonize OVX mice for more than 24 hours. Treatment with 17β-estradiol but not progesterone restored the endogenous VMB and colonization with Lactobacilli and G. vaginalis. Interestingly, 17β-estradiol treated mice had significantly increased levels of glycogen compared to OVX and progesterone-treated mice. Based on the results, we have shown that estrogen played a significant role in the ability for human VMB species to colonize in our mouse models, potentially through a glycogen mediated mechanism. These results suggest there is a dynamic interaction between sex hormones and the VMB, which can affect bacterial diversity and the ability for a VMB to colonize.

Lower myostatin and higher MUC1 levels are associated with better response to mepolizumab and omalizumab in asthma: a protein–protein interaction analyses

IntroductionBiomarkers are needed to inform the choice of biologic therapy in patients with asthma given the increasing number of biologics. We aimed to identify proteins associated with response to omalizumab and mepolizumab.MethodsAptamer-based proteomic profiling (SomaScan) was used to assess 1437 proteins from 51 patients with moderate to severe asthma who received omalizumab (n = 29) or mepolizumab (n = 22). Response was defined as the change in asthma-related exacerbations in the 12 months following therapy initiation. All models were adjusted for age, sex, and pre-treatment exacerbation rate. Additionally, body mass index was included in the omalizumab model and eosinophil count in the mepolizumab model. We evaluated the association between molecular signatures and response using negative binomial regression correcting for the false discovery rate (FDR) and gene set enrichment analyses (GSEA) to identify associated pathways.ResultsOver two-thirds of patients were female. The average age for omalizumab patients was 42 years and 57 years for mepolizumab. At baseline, the average exacerbation rate was 1.5/year for omalizumab and 2.4/year for mepolizumab. Lower levels of LOXL2 (unadjusted p: 1.93 × 10E−05, FDR-corrected: 0.028) and myostatin (unadjusted: 3.87 × 10E−05, FDR-corrected: 0.028) were associated with better response to mepolizumab. Higher levels of CD9 antigen (unadjusted: 5.30 × 10E−07, FDR-corrected: 0.0006) and MUC1 (unadjusted: 1.15 × 10E−06, FDR-corrected: 0.0006) were associated with better response to omalizumab, and LTB4R (unadjusted: 1.12 × 10E−06, FDR-corrected: 0.0006) with worse response. Protein–protein interaction network modeling showed an enrichment of the TNF- and NF-kB signaling pathways for patients treated with mepolizumab and multiple pathways involving MAPK, including the FcER1 pathway, for patients treated with omalizumab.ConclusionsThis study provides novel fundamental data on proteins associated with response to mepolizumab or omalizumab in severe asthma and warrants further validation as potential biomarkers for therapy selection.

Role of the cAMP-PKA-NF-κB pathway in Mucin1 over-expression in A549 cells during Respiratory syncytial virus infection

Respiratory syncytial virus (RSV) is the most common pathogen associated with acute lower respiratory tract infections in infants and young children worldwide. RSV commonly presents as bronchiolitis in young children; however, it can sometimes progress to pneumonia, respiratory failure, apnoea and even death. Although mucin1 (MUC1), a type of transmembrane glycoprotein present on airway epithelial surfaces, plays a crucial anti-inflammatory role in airway infections; however, its roles in RSV-associated acute lower respiratory tract infections have rarely been explored. In this study, we first revealed very high MUC1 protein levels in the exacerbation phase in sputum samples from children with RSV bronchiolitis. Because MUC1 is the downstream target of tumour necrosis factor-alpha (TNF-α) in RSV-infected A549 cells, we observed the inhibition of NF-κB activity, main downstream signalling of TNF-α and remarkably reduced levels of MUC1 in RSV-infected and TNF-α treated A549 cells. Furthermore, the cyclic adenosine monophosphate (cAMP) analogue (dbcAMP) downregulated the protein levels of p-IκBα and MUC1 in TNF-α-treated A549 cells. By contrast, a protein kinase A inhibitor (KT5720) up-regulated the levels of those proteins. dbcAMP and KT5720 had the same effects on MUC1 protein levels in RSV-infected A549 cells. In conclusion, we found that the cAMP-PKA-NF-κB pathway may play a role in the regulation of MUC-1 over-expression during RSV infection.

Assessment of toxicological effects of favipiravir (T-705) on the lung tissue of rats: An experimental study.

This study aimed to present new data on the side effects of favipiravir on healthy lung tissue and the respiratory system. In the study, two different durations (5 and 10 days) were preferred to determine the effect of favipiravir treatment due to clinical improvement rates of approximately 5 and 10 days during the use of favipiravir in COVID-19 patients. In addition, after 10 days of favipiravir treatment, animals were kept for 5 days without any treatment to determine the regeneration of lung tissues. Favipiravir was administered to rats by oral gavage at a daily dose of 200 mg/kg for 5 and 10 days, as in previous studies. At the end of the experiment, the histopathological and biochemical effects of favipiravir in the lung tissue were investigated. The data obtained from the study showed that favipiravir increased oxidative stress parameters, expression of apoptotic markers, and pro-inflammatory markers in lung tissue. Since malondialdehydes is an oxidant parameter, it increased in favipiravir-administered groups; It was determined that the antioxidant parameters glutathione, superoxide dismutase, glutathione peroxidase, and catalase decreased. Other markers used in the analysis are Bcl-2, Bax, NF-κB, interleukin (IL)-6, Muc1, iNOS, P2X7R, IL-6 and caspase-3. The levels of Bax, caspase-3, NF-κB, IL-6, Muc1, and P2X7R were increased in the Fav-treated groups compared with the control. However, the levels of Bcl-2 decreased in the Fav-treated groups. The present study proves that favipiravir, widely used today, causes side effects in lung tissue.

Mucin1 induced trophoblast dysfunction in gestational diabetes mellitus via Wnt/β-catenin pathway

BackgroundTo elucidate the role of Mucin1 (MUC1) in the trophoblast function (glucose uptake and apoptosis) of gestational diabetes mellitus (GDM) women through the Wnt/β-catenin pathway.MethodsGlucose uptake was analyzed by plasma GLUT1 and GLUT4 levels with ELISA and measured by the expression of GLUT4 and INSR with immunofluorescence and Western blotting. Apoptosis was measured by the expression of Bcl-2 and Caspase3 by Western blotting and flow cytometry. Wnt/β-catenin signaling measured by Western blotting. In vitro studies were performed using HTR-8/SVneo cells that were cultured and treated with high glucose (HG), sh-MUC1 and FH535 (inhibitor of Wnt/β-catenin signaling).ResultsMUC1 was highly expressed in the placental trophoblasts of GDM, and the Wnt/β-catenin pathway was activated, along with dysfunction of glucose uptake and apoptosis. MUC1 knockdown resulted in increased invasiveness and decreased apoptosis in trophoblast cells. The initial linkage between MUC1, the Wnt/β-catenin pathway, and glucose uptake was confirmed by using an HG-exposed HTR-8/SVneo cell model with MUC1 knockdown. MUC1 knockdown inhibited the Wnt/β-catenin signaling pathway and reversed glucose uptake dysfunction and apoptosis in HG-induced HTR-8/SVneo cells. Meanwhile, inhibition of Wnt/β-catenin signaling could also reverse the dysfunction of glucose uptake and apoptosis.ConclusionsIn summary, the increased level of MUC1 in GDM could abnormally activate the Wnt/β-catenin signaling pathway, leading to trophoblast dysfunction, which may impair glucose uptake and induce apoptosis in placental tissues of GDM women.

Effect of fermented rapeseed meal on growth performance, nutrient digestibility, and intestinal health in growing pigs

To explore the effects of fermented rapeseed meal (FRSM) on growth performance and intestinal health, a total of 30 growing pigs were randomly allotted to three treatments consisting of corn-soybean meal diet (CSD), rapeseed meal diet (RSD), and fermented rapeseed meal diet (FRSD). Results showed that compared with RSD, FRSD feeding increased the average daily gain and final body weight in pigs (P < 0.01). Compared with RSD feeding, FRSD feeding elevated the apparent digestibility of crude protein, acid detergent fiber, and ether extract in pigs (P < 0.01). Moreover, the FRSD group exhibited greater apparent ileal digestibility of His, Thr, Lys, and Ser than the RSD group (P < 0.01). The digestible energy, metabolic energy, and nitrogen utilization were higher in the FRSD and CSD groups than in the RSD group (P < 0.01). As compared to the RSD, FRSD feeding decreased the serum concentration of leptin but significantly increased the concentrations of immunoglobulin (Ig) A, IgG, ghrelin, and enzyme activities of amylase, lipase, and trypsin in the pancreas (P < 0.05). Interestingly, the villus height, the ratio of villus height to crypt depth, and the activities of brush border enzymes (e.g., maltase and sucrase) in the small intestine were higher in the CSD and FRSD groups than in the RSD group (P < 0.05). As compared to the RSD, the FRSD feeding not only increased the expression level of the occludin in the small intestinal epithelium (P < 0.05) but also elevated the expression levels of claudin-1, MUC1, and PepT1 genes in the duodenum, and elevated the expression levels of SGLT1 and CAT1 genes in the jejunum (P < 0.05). Importantly, FRSD feeding significantly decreased the abundance of Escherichia coli, but increased the abundance of Lactobacillus and the content of butyrate in the cecum and colon (P < 0.05). These results indicated that compared with rapeseed meal, fermented rapeseed meal exhibited a positive effect on improving the growth performance and intestinal health in growing pigs, and the results may also help develop novel protein sources for animal nutrition and the feed industry.

Hypoxia controls expression of kidney-pathogenic MUC1 variants.

The interplay between genetic and environmental factors influences the course of chronic kidney disease (CKD). In this context, genetic alterations in the kidney disease gene MUC1 (Mucin1) predispose to the development of CKD. These variations comprise the polymorphism rs4072037, which alters splicing of MUC1 mRNA, the length of a region with variable number of tandem repeats (VNTR), and rare autosomal-dominant inherited dominant-negative mutations in or 5' to the VNTR that causes autosomal dominant tubulointerstitial kidney disease (ADTKD-MUC1). As hypoxia plays a pivotal role in states of acute and chronic kidney injury, we explored the effects of hypoxia-inducible transcription factors (HIF) on the expression of MUC1 and its pathogenic variants in isolated primary human renal tubular cells. We defined a HIF-binding DNA regulatory element in the promoter-proximal region of MUC1 from which hypoxia or treatment with HIF stabilizers, which were recently approved for an anti-anemic therapy in CKD patients, increased levels of wild-type MUC1 and the disease-associated variants. Thus, application of these compounds might exert unfavorable effects in patients carrying MUC1 risk variants.