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Journal of Pharmacy & Bioallied Sciences 2023Gastroesophageal reflux disease (GERD) is a chronic, relapsing disorder. In this era of modern and fast-track lifestyle and food habits, the incidence of GERD is rapidly...
BACKGROUND
Gastroesophageal reflux disease (GERD) is a chronic, relapsing disorder. In this era of modern and fast-track lifestyle and food habits, the incidence of GERD is rapidly increasing. Currently, proton pump inhibitors (PPIs) are the primary choice of treatment. However, the associated side effects and a high relapse rate give rise to the need to explore alternative therapies.
OBJECTIVE
The study aimed to evaluate HAGE-101912, an herbal combination, in different experimental models of GERD.
METHODS
Antacid activity was assessed based on H/KATPase inhibitory activity of parietal cells using artificial gastric juice. Tonic contraction of the lower esophageal sphincter (LES) was evaluated using an AD Instrument. A GERD model of the pylorus and fundus ligation (preventive and curative models) in rats was selected to assess the efficacy of HAGE-101912 at a dose of 250 mg/kg body weight, and various parameters such as the gastric pH, gastric volume, total acidity, gross esophageal ulcer index, and histopathological changes were evaluated. The prokinetic activity was assessed using the phenol red method.
RESULTS
HAGE-101912 increased the acid-neutralizing capacity ( < 0.001), decreased H/KATPase activity ( < 0.01), and increased the contraction of the LES. In the preventive model, HAGE-101912 significantly reduced the gastric acid volume ( < 0.01), total acidity ( < 0.001), and gross esophageal ulcer index ( < 0.01); increased the gastric acid pH ( < 0.01); and protected the esophageal epithelium. In addition, HAGE-101912 increased gastric emptying and gastrointestinal transit through its prokinetic activity ( < 0.05).
CONCLUSION
HAGE-101912 has a beneficial effect in GERD as it effectively inhibits the H/KATPase, increases the gastric pH, restores the LES function, protects the esophageal epithelium, and increases gastric emptying and transit.
PubMed: 38235047
DOI: 10.4103/jpbs.jpbs_860_21 -
Indian Journal of Pathology &... Nov 2023Inverted papillomas are predominantly seen in the sinonasal region. Extra-sinonasal lesions are considered to be heterotopic. We present a case of primary laryngeal...
Inverted papillomas are predominantly seen in the sinonasal region. Extra-sinonasal lesions are considered to be heterotopic. We present a case of primary laryngeal inverted papilloma with an unusual subglottic localization. An 84-year-old female patient presented with dyspnea on exertion. In the endoscopic examination, a subglottic vegetative lesion was observed. Radiological examination revealed a well-circumscribed, solid mass involving the anterior commissure and extending to the subglottic region. Total excision of the mass was performed with the CO2 laser surgery. Histopathologic examination revealed endophytic growth of round-oval nests of transitional hyperplastic epithelium. The patient was diagnosed with primary laryngeal inverted papilloma. Primary laryngeal inverted papillomas are extremely rare. This is the fifth case and the only the second with a subglottic localization. Due to its rarity, it is difficult to predict the underlying cause and clinical course. However, cases with an atypical localization must be followed up like those in the sinonasal region.
PubMed: 38394419
DOI: 10.4103/ijpm.ijpm_332_23 -
Cancer Prevention Research... Aug 2023Glutathione S-transferase pi 1 (GSTP1) is lowly expressed in normal prostate luminal cells and becomes induced in most proliferative inflammatory atrophy (PIA) lesions....
UNLABELLED
Glutathione S-transferase pi 1 (GSTP1) is lowly expressed in normal prostate luminal cells and becomes induced in most proliferative inflammatory atrophy (PIA) lesions. GSTP1 becomes silenced in prostatic intraepithelial neoplasia (PIN) and prostate adenocarcinoma (CaP) via cytosine-phospho-guanine (CpG) island promoter hypermethylation. However, GSTP1 methylation patterns in PIA and PIN, and their relationship to patterns in CaP are poorly understood. We used bisulfite genomic sequencing to examine patterns of GSTP1 promoter CpG island methylation in laser capture microdissected benign, PIA, PIN, and CaP regions from 32 subjects that underwent radical prostatectomy. We analyzed 908 sequence clones across 24 normal epithelium, 37 PIA, 18 PIN, and 23 CaP regions, allowing assessment of 34,863 CpG sites with allelic phasing. Normal and PIA lesions were mostly unmethylated with 0.52 and 1.3% of total CpG sites methylated, respectively. PIN and CaP lesions had greater methylation with 24% and 51% of total CpG sites methylated, respectively. The degree of GSTP1 methylation showed progression from PIA << PIN < CaP. PIN lesions showed more partial methylation compared with CaP lesions. Partially methylated lesions were enriched for methylation changes at AP1 and SP1 transcription factor binding sites. These results demonstrate that methylation density in the GSTP1 CpG island in PIN was intermediate relative to that in normal prostate epithelium/PIA and CaP lesions. These results are consistent with gradual spreading of DNA methylation centered at the SP1/AP1 transcription factor binding sites in precursor lesions, with subsequent spreading of methylation across the entire CpG island in transition to CaP.
PREVENTION RELEVANCE
DNA hypermethylation at the GSTP1 promoter progressively spreads from being unmethylated in normal prostate to intermediate levels in precursor lesions to extensive methylation in cancer. This molecular progression of GSTP1 promoter methylation patterns in early prostate carcinogenesis could be useful for identification and interception of prostate cancer precursors.
Topics: Male; Humans; Glutathione S-Transferase pi; DNA Methylation; CpG Islands; Glutathione Transferase; Prostatic Neoplasms; Prostatic Intraepithelial Neoplasia
PubMed: 37347938
DOI: 10.1158/1940-6207.CAPR-22-0485 -
Kindlin-2 in myoepithelium controls luminal progenitor commitment to alveoli in mouse mammary gland.Cell Death & Disease Oct 2023Myoepithelium plays an important role in mammary gland development, but less is known about the molecular mechanism underlying how myoepithelium controls acinus...
Myoepithelium plays an important role in mammary gland development, but less is known about the molecular mechanism underlying how myoepithelium controls acinus differentiation during gestation. Herein, we found that loss of Kindlin-2 in myoepithelial cells impaired mammary morphogenesis, alveologenesis, and lactation. Using five genetically modified mouse lines combined with single-cell RNA sequencing, we found a Kindlin-2-Stat3-Dll1 signaling cascade in myoepithelial cells that inactivates Notch signaling in luminal cells and consequently drives luminal progenitor commitment to alveolar cells identity. Single-cell profiling revealed that Kindlin-2 loss significantly reduces the proportion of matured alveolar cells. Mechanistically, Kindlin-2 depletion in myoepithelial cells promotes Stat3 activation and upregulates Dll1, which activates the Notch pathway in luminal cells and inhibits luminal progenitor differentiation and maturation during gestation. Inhibition of Notch1 with tangeretin allowed luminal progenitors to regain commitment ability in the pregnant mice with Kindlin-2 depletion in myoepithelium. Taken together, we demonstrated that Kindlin-2 is essential to myoepithelium-controlled luminal progenitors to alveoli transition during gestation.
Topics: Animals; Female; Mice; Pregnancy; Cell Differentiation; Epithelial Cells; Epithelium; Lactation; Mammary Glands, Animal
PubMed: 37833248
DOI: 10.1038/s41419-023-06184-2 -
Respiratory Research Jun 2024Airway epithelium is an important component of airway structure and the initiator of airway remodeling in asthma. The changes of extracellular matrix (ECM), such as...
BACKGROUND
Airway epithelium is an important component of airway structure and the initiator of airway remodeling in asthma. The changes of extracellular matrix (ECM), such as collagen deposition and structural disturbance, are typical pathological features of airway remodeling. Thus, identifying key mediators that derived from airway epithelium and capable of modulating ECM may provide valuable insights for targeted therapy of asthma.
METHODS
The datasets from Gene Expression Omnibus database were analyzed to screen differentially expressed genes in airway epithelium of asthma. We collected bronchoscopic biopsies and serum samples from asthmatic and healthy subjects to assess lysyl oxidase like 2 (LOXL2) expression. RNA sequencing and various experiments were performed to determine the influences of LOXL2 knockdown in ovalbumin (OVA)-induced mouse models. The roles and mechanisms of LOXL2 in bronchial epithelial cells were explored using LOXL2 small interfering RNA, overexpression plasmid and AKT inhibitor.
RESULTS
Both bioinformatics analysis and further experiments revealed that LOXL2 is highly expressed in airway epithelium of asthmatics. In vivo, LOXL2 knockdown significantly inhibited OVA-induced ECM deposition and epithelial-mesenchymal transition (EMT) in mice. In vitro, the transfection experiments on 16HBE cells demonstrated that LOXL2 overexpression increases the expression of N-cadherin and fibronectin and reduces the expression of E-cadherin. Conversely, after silencing LOXL2, the expression of E-cadherin is up-regulated. In addition, the remodeling and EMT process that induced by transforming growth factor-β1 could be enhanced and weakened after LOXL2 overexpression and silencing in 16HBE cells. Combining the RNA sequencing of mouse lung tissues and experiments in vitro, LOXL2 was involved in the regulation of AKT signaling pathway. Moreover, the treatment with AKT inhibitor in vitro partially alleviated the consequences associated with LOXL2 overexpression.
CONCLUSIONS
Taken together, the results demonstrated that epithelial LOXL2 plays a role in asthmatic airway remodeling partly via the AKT signaling pathway and highlighted the potential of LOXL2 as a therapeutic target for airway remodeling in asthma.
Topics: Animals; Amino Acid Oxidoreductases; Ovalbumin; Airway Remodeling; Proto-Oncogene Proteins c-akt; Mice; Humans; Asthma; Signal Transduction; Female; Mice, Inbred BALB C; Male; Epithelial-Mesenchymal Transition
PubMed: 38824593
DOI: 10.1186/s12931-024-02811-4 -
Cellular Signalling Oct 2023Portal hypertension is a group of clinical syndromes induced by increased portal system pressure due to various etiologies including cirrhosis. When portal hypertension...
Portal hypertension is a group of clinical syndromes induced by increased portal system pressure due to various etiologies including cirrhosis. When portal hypertension develops, the portal vein dilates and endothelial cells (ECs) in the portal vein are subjected to mechanical stretch. In this study, elastic silicone chambers were used to simulate the effects of mechanical stretch on ECs under portal hypertension. We found that mechanical stretch decreased PPARγ expression in ECs by blocking the PI3K/AKT/CREB signaling pathway or increasing NEDD4-mediated ubiquitination and degradation of PPARγ. Moreover, PPARγ downregulation triggered Endothelial-to-mesenchymal transition (EndoMT) in ECs under stretch by promoting Smad3 phosphorylation. The PPARγ agonist rosiglitazone mitigated stretch-induced EndoMT in vitro and alleviated EndoMT of the portal vein endothelium in cirrhotic rats.
Topics: Animals; Rats; Down-Regulation; Endothelial Cells; Endothelium, Vascular; Hypertension, Portal; Phosphatidylinositol 3-Kinases; PPAR gamma; Stress, Mechanical; Cell Transdifferentiation
PubMed: 37468053
DOI: 10.1016/j.cellsig.2023.110812 -
European Urology Jul 2024Quantity and the spatial relationship of specific immune cell types can provide prognostic information in bladder cancer. The objective of the study was to characterize...
BACKGROUND AND OBJECTIVE
Quantity and the spatial relationship of specific immune cell types can provide prognostic information in bladder cancer. The objective of the study was to characterize the spatial interplay and prognostic role of different immune cell subpopulations in bladder cancer.
METHODS
A total of 2463 urothelial bladder carcinomas were immunostained with 21 antibodies using BLEACH&STAIN multiplex fluorescence immunohistochemistry in a tissue microarray format and analyzed using a framework of neuronal networks for an image analysis. Spatial immune parameters were compared with histopathological parameters and overall survival data.
KEY FINDINGS AND LIMITATIONS
The identification of > 300 different immune cell subpopulations and the characterization of their spatial relationship resulted in numerous spatial interaction patterns. Thirty-nine immune parameters showed prognostic significance in univariate analyses, of which 16 were independent from pT, pN, and histological grade in muscle-invasive bladder cancer. Among all these parameters, the strongest association with prolonged overall survival was identified for intraepithelial CD8 cytotoxic T cells (time-dependent area under receiver operating characteristic curve [AUC]: 0.70), while stromal CD8 T cells were less relevant (AUC: 0.65). A favorable prognosis of inflamed cancers with high levels of "exhaustion markers" suggests that TIM3, PD-L1, PD-1, and CTLA-4 on immune cells do not hinder antitumoral immune response in tumors rich of tumor infiltrating immune cells.
CONCLUSIONS AND CLINICAL IMPLICATIONS
The density of intraepithelial CD8 T cells was the strongest prognostic feature in muscle-invasive bladder cancer. Given that tumor cell killing by CD8 cytotoxic T lymphocytes through direct cell-to-cell-contacts represents the "terminal end route" of antitumor immunity, the quantity of "tumor cell adjacent CD8 T cells" may constitute a surrogate for the efficiency of cancer recognition by the immune system that can be measured straightaway in routine pathology as the CD8 labeling index.
PATIENT SUMMARY
Quantification of intraepithelial CD8 T cells, the strongest prognosticfeature identified in muscle-invasive bladder cancer, can easily be assessed by brightfield immunohistochemistry and is therefore "ready to use" for routine pathology.
Topics: Humans; Urinary Bladder Neoplasms; Prognosis; Lymphocytes, Tumor-Infiltrating; CD8-Positive T-Lymphocytes; Immunohistochemistry; Male; Female; Tissue Array Analysis; Urothelium; Carcinoma, Transitional Cell; Aged; Tumor Microenvironment; Biomarkers, Tumor; Middle Aged
PubMed: 38383257
DOI: 10.1016/j.eururo.2024.01.023 -
Neurochemistry International Jun 2024Maintaining an optimum microbial community within the gastrointestinal tract is intricately linked to human metabolic, immune and brain health. Disturbance to these... (Review)
Review
Maintaining an optimum microbial community within the gastrointestinal tract is intricately linked to human metabolic, immune and brain health. Disturbance to these microbial populations perturbs the production of vital bioactive compounds synthesised by the gut microbiome, such as short-chain fatty acids (SCFAs). Of the SCFAs, butyrate is known to be a major source of energy for colonocytes and has valuable effects on the maintenance of intestinal epithelium and blood brain barrier integrity, gut motility and transit, anti-inflammatory effects, and autophagy induction. Inducing endogenous butyrate production is likely to be beneficial for gut-brain homeostasis and for optimal neuronal function. For these reasons, butyrate has gained interest as a potential therapy for not only metabolic and immunological disorders, but also conditions related to the brain, including neurodegenerative diseases. While direct and indirect sources of butyrate, including prebiotics, probiotics, butyrate pro-drugs and glucosidase inhibitors, offer a promising therapeutic avenue, their efficacy and dosage in neurodegenerative conditions remain largely unknown. Here, we review current literature on effects of butyrate relevant to neuronal function, the impact of butyrate in a range of neurodegenerative diseases and related treatments that may have potential for the treatment of neurodegenerative diseases.
Topics: Humans; Butyrates; Gastrointestinal Microbiome; Neurodegenerative Diseases; Probiotics
PubMed: 38641025
DOI: 10.1016/j.neuint.2024.105745 -
Nutrients Jun 2024Celiac disease (CeD) is an autoimmune disease with a strong association with human leukocyte antigen (HLA), characterized by the production of specific autoantibodies... (Review)
Review
Celiac disease (CeD) is an autoimmune disease with a strong association with human leukocyte antigen (HLA), characterized by the production of specific autoantibodies and immune-mediated enterocyte killing. CeD is a unique autoimmune condition, as it is the only one in which the environmental trigger is known: gluten, a storage protein present in wheat, barley, and rye. How and when the loss of tolerance of the intestinal mucosa to gluten occurs is still unknown. This event, through the activation of adaptive immune responses, enhances epithelial cell death, increases the permeability of the epithelial barrier, and induces secretion of pro-inflammatory cytokines, resulting in the transition from genetic predisposition to the actual onset of the disease. While the role of gastrointestinal infections as a possible trigger has been considered on the basis of a possible mechanism of antigen mimicry, a more likely alternative mechanism appears to involve a complex disruption of the gastrointestinal microbiota ecosystem triggered by infections, rather than the specific effect of a single pathogen on intestinal mucosal homeostasis. Several lines of evidence show the existence of intestinal dysbiosis that precedes the onset of CeD in genetically at-risk subjects, characterized by the loss of protective bacterial elements that both epigenetically and functionally can influence the response of the intestinal epithelium leading to the loss of gluten tolerance. We have conducted a literature review in order to summarize the current knowledge about the complex and in part still unraveled dysbiosis that precedes and accompanies CeD and present some exciting new data on how this dysbiosis might be prevented and/or counteracted. The literature search was conducted on PubMed.gov in the time frame 2010 to March 2024 utilizing the terms "celiac disease and microbiota", "celiac disease and microbiome", and "celiac disease and probiotics" and restricting the search to the following article types: Clinical Trials, Meta-Analysis, Review, and Systematic Review. A total of 364 papers were identified and reviewed. The main conclusions of this review can be outlined as follows: (1) quantitative and qualitative changes in gut microbiota have been clearly documented in CeD patients; (2) intestinal microbiota's extensive and variable interactions with enterocytes, viral and bacterial pathogens and even gluten combine to impact the inflammatory immune response to gluten and the loss of gluten tolerance, ultimately affecting the pathogenesis, progression, and clinical expression of CeD; (3) gluten-free diet fails to restore the eubiosis of the digestive tract in CeD patients, and also negatively affects microbial homeostasis; (4) new tools allowing targeted microbiota therapy, such as the use of probiotics (a good example being precision probiotics like the novel strain of (20220303-A2) begin to show exciting potential applications.
Topics: Celiac Disease; Humans; Gastrointestinal Microbiome; Glutens; Dysbiosis; Intestinal Mucosa
PubMed: 38931237
DOI: 10.3390/nu16121882 -
Biomedicine & Pharmacotherapy =... Apr 2024Gastric cancer (GC) is a malignant tumor that originates from the epithelium of the gastric mucosa. The latest global cancer statistics show that GC ranks fifth in... (Review)
Review
Gastric cancer (GC) is a malignant tumor that originates from the epithelium of the gastric mucosa. The latest global cancer statistics show that GC ranks fifth in incidence and fourth in mortality among all cancers, posing a serious threat to public health. While early-stage GC is primarily treated through surgery, chemotherapy is the frontline option for advanced cases. Currently, commonly used chemotherapy regimens include FOLFOX (oxaliplatin + leucovorin + 5-fluorouracil) and XELOX (oxaliplatin + capecitabine). However, with the widespread use of chemotherapy, an increasing number of cases of drug resistance have emerged. This article primarily explores the potential mechanisms of chemotherapy resistance in GC patients from five perspectives: cell death, tumor microenvironment, non-coding RNA, epigenetics, and epithelial-mesenchymal transition. Additionally, it proposes feasibility strategies to overcome drug resistance from four angles: cancer stem cells, tumor microenvironment, natural products, and combined therapy. The hope is that this article will provide guidance for researchers in the field and bring hope to more GC patients.
Topics: Humans; Stomach Neoplasms; Oxaliplatin; Deoxycytidine; Capecitabine; Fluorouracil; Antineoplastic Combined Chemotherapy Protocols; Leucovorin; Drug Resistance; Tumor Microenvironment
PubMed: 38394851
DOI: 10.1016/j.biopha.2024.116310