Fuelling the Fight from the Gut: Short-Chain Fatty Acids and Dexamethasone Synergise to Suppress Gastric Cancer Cells
Ontology highlight
ABSTRACT:
INSTRUMENT(S):
ORGANISM(S): Homo Sapiens (human)
TISSUE(S): Cell Culture
DISEASE(S): Stomach Cancer
SUBMITTER: 
Muhammad Alsherbiny
LAB HEAD: Deep Bhuyan
PROVIDER: PXD061822 | Pride | 2025-07-30
REPOSITORIES: Pride
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Project description:We tested the hypothesis that a panel of placental mammal-specific miRNAs and their targets play important to establish receptivity to implantation and their dysregulated expression may be a feature in women with early pregnancy loss. Relative expression levels of miR-340-5p, −542-3p, and −671-5p all increased following treatment of Ishikawa cells with progesterone (10 μg/ml) for 24 hrs (p < 0.05). RNA sequencing of these P4-treated cells identified co-ordinate changes to 6,367 transcripts of which 1713 were predicted targets of miR-340-5p, 670 of miR-542-3p, and 618 of miR-671-5p. Quantitative proteomic analysis of Ishikawa cells transfected with mimic or inhibitor (48 hrs: n=3 biological replicates) for each of the P4-regulated miRNAs was carried out to identify targets of these miRNAs. Excluding off target effects, mir-340-5p mimic altered 1,369 proteins while inhibition changed expression of 376 proteins (p < 0.05) of which, 72 were common to both treatments. A total of 280 proteins were identified between predicted (mirDB) and confirmed (in vitro) targets. In total, 171 proteins predicted to be targets by mirDB were altered in vitro by treatment with miR-340-5p mimic or inhibitor and were also altered by treatment of endometrial epithelial cells with P4. In vitro targets of miR-542-3p identified 1,378 proteins altered by mimic while inhibition altered 975 a core of 200 proteins were changed by both. 100 protein targets were predicted and only 46 proteins were P4 regulated. miR-671-mimic altered 1,252 proteins with inhibition changing 492 proteins of which 97 were common to both, 95 were miDB predicted targets and 46 were also P4-regulated. All miRNAs were detected in endometrial biopsies taken from patients during the luteal phase of their cycle, irrespective of prior or future pregnancy outcomes Expression of mir-340-5p showed an overall increase in patients who had previously suffered a miscarriage and had a subsequent miscarriage, as compared to those who had infertility or previous miscarriage and subsequently went on to have a life birth outcome. The regulation of these miRNAs and their protein targets regulate the function of transport and secretion, and adhesion of the endometrial epithelia required for successful implantation in humans. Dysfunction of these miRNAs (and therefore the targets they regulate) may contribute to endometrial-derived recurrent pregnancy loss in women.
2023-05-10 | PXD036109 | Pride
Project description:Background and Aims: Many inflammatory diseases are associated with microbial dysbiosis, which may considerably alter the production of short-chain fatty acids (SCFAs). SCFAs are produced in the large bowel through bacterial fermentation of dietary fiber and play an important role in maintaining gut homeostasis. SCFAs, particularly acetate and butyrate, show beneficial immunomodulatory effects contributing to the prevention of inflammatory and allergic reactions. Thus, reduced production of SCFAs may impact on the mucosal immune responses critical to fighting pathogens. This study aims to determine the influence of SCFAs on a murine model of colonic bacterial infection. Methods: In the present study, we used acetate- (HAMSA) or butyrate- (HAMSB) yielding diets to deliver high concentrations of individual SCFAs to the large bowel of mice infected with C. rodentium. We assessed the effects of these SCFAs on clinical burden and gut pathogenicity in correlation with changes in bacteria growth, fecal microbiota composition, function and changes in the immunological profile. Results: Here we show in vitro that acetate and butyrate directly inhibited growth of the attaching and effacing (A/E) pathogen C. rodentium in a bacteriostatic manner. This correlated with reduced expression of Tir, a gene responsible for bacterial adherence and pathogenicity. Interestingly, HAMSA-fed mice presented reduced clinical scores during C. rodentium infection associated with high concentrations of fecal acetate. This was linked with compositional and functional changes in the microbiota when examining 16s sequencing and proteomics analysis. The HAMSA mediated is protection involved increased expression IL-22 and Muc-2 in the colon and increased numbers of CD8αα+ TCRγδ T cells in the colonic epithelium. These effects were dependent on GPR43, a metabolite-sensing GPCR that binds acetate. Conclusions: We established a promising new approach to moderate bacterial gut infections by manipulating the gut microbiota and mucosal immune tolerance through diets that yield the SCFA acetate.
2022-02-15 | PXD008149 | Pride
Project description:Sodium appetite is an instinct that involves avid specific intention. It is elicited by sodium deficiency, stress-evoked ACTH and by reproduction. Genome-wide microarrays in sodium deficient mice, or following ACTH infusion, showed upregulation of hypothalamic genes, including DARPP-32, dopamine receptors-1 and -2, alpha-2C-adrenoceptor, and STEP. Both DARPP-32 and neural plasticity regulator, ARC were upregulated in lateral hypothalamic orexinergic neurons by sodium deficiency. Administration of dopamine D1- (SCH23390) and D2-receptor (raclopride) antagonists reduced gratification of sodium appetite triggered by sodium deficiency. SCH23390 was specific, having no effect on osmotic-induced water drinking, whereas raclopride also reduced water intake. D1-receptor knockout mice had normal sodium appetite, indicating compensatory regulation. It was insensitive to SCH23390, confirming the absence of off-target effects. Bilateral microinjection of SCH23390 (100nM in 200nL) into rats? lateral hypothalamus greatly reduced sodium appetite. Gene Set Enrichment Analysis in hypothalami of mice with sodium appetite showed significant enrichment of gene sets previously linked to addiction (opiates, cocaine). This finding of concerted gene regulation was attenuated upon gratification with perplexingly rapid kinetics of only 10 minutes, anteceding significant absorption of salt from the gut. Salt appetite and hedonic liking of salt taste have evolved over more than a hundred million years e.g. being present in Metatheria. Drugs causing pleasure and addiction are comparatively recent and likely reflect usurping of evolutionary ancient systems with high survival value by the gratification of contemporary hedonic indulgences. Our findings outline a novel molecular logic for instinctive behavior encoded by the brain with possible important translational-medical implications. Transcripts were profiled in the hypothalamus and whole brain of control and salt craving animals to determine the gene expression profile corresponding to that behavioral state. We show an over-representation of addiction-related genes in the set that is common to different methods of salt craving. Mouse hypothalamus and whole brain under three conditions: control, furosemide treated, and ACTH treated. 4 or 5 biological replicated per group. Two channels - experimental and reference are used.
2011-07-04 | E-GEOD-29451 | biostudies-arrayexpress
Project description:The human gut microbiota plays a vital role in host health by acting as a barrier against pathogens, boosting the immune system, and metabolizing complex carbon sources into beneficial compounds such as short-chain fatty acids (SCFAs). However, external factors like diet and xenobiotics, including food colorants, can impact this microbial community. Brilliant blue FCF (E-133), a common food dye that is not absorbed or metabolized by the body, thus, leading to significant exposure of the gut microbiota, and its effects on it are not well-documented. This study investigated the impact of brilliant blue on the simplified human gut microbiota model (SIHUMIx) over a seven-day exposure period, followed by a four-day recovery phase. Using continuous culture bioreactors along with metaproteomic and metabolomic analyses, the research uncovered substantial structural and functional changes in the microbiota. Our findings showed alterations in the species abundance such as B. thetaiotaomicron, B. longum, and C. butyricum, reductions in energy metabolism by-products, particularly lactate and butyrate, and disruptions in metabolic pathways involved in the metabolism of xenobiotics and amino acids. The results indicate that brilliant blue exposure compromises microbiota stability and functionality, highlighting the need for further research on its long-term effects and recovery mechanisms. This study underscores the importance of assessing the impacts of food additives on gut microbiota as part of comprehensive health risk evaluations.
2025-05-07 | PXD055767 | Pride
Project description:Equine odontoclastic tooth resorption and hypercementosis (EOTRH) is a relatively recently described dental disorder, commonly found in horses above the age of 15 years old (Carsten Staszyk et al. 2008). The disease was first categorised as EOTRH in 2008, following the identification of clinical cases involving severe resorptive lesions and cementomas forming on the lower portion of equine incisors (Kreutzer et al. 2007) (Baratt 2007). The two main disease indicators are resorptive lesions caused by odontoclasts and hypercementosis, characterised by reparative/irregular cementum deposition, forming bulbous-like features (Schätzle, Tanner, and Bosshardt 2005). Horses with severe EOTRH often present dysphagia, pain whilst eating and behavioral changes, which may lead to further unrelated complications (Earley and Rawlinson 2013). Some suggested that Warmbloods and Thoroughbreds are more commonly diagnosed (Sykora et al, 2014; Smedley et al, 2015; Lorello et al, 2016; Earley et al, 2017), although others state there are no appar¬ent breed associations (James, 2022; Tretow et al, 2023). Furthermore, in a limited group of Icelandic horses, a diagnosis was established in 72.2% of cases (Tretow, Hain, and Bienert-Zeit 2023). While radiography is the primary diagnostic method for EOTRH after clinical examination, recent studies have indicated that this approach may lack sensitivity for early disease detection, potentially impeding treatment if the condition has advanced significantly (Albers, Bienert-Zeit, and Staszyk 2022). A comparable ailment observed in cats is Feline Odontoclastic Resorptive Lesions (FORL). In this species there was a prevalence of 29% , and similar to EOTRH, it exhibited an elevated risk associated with age (Gorrel 2014). The underlying causes of EOTRH are not yet fully understood with many potential factors considered, including age, sex, breed, diet and environment (Pearson et al. 2013). One of the first theories suggest a sequence of events beginning with periodontal inflammation leading to resorptive lesions and subsequent cementum production (Carsten Staszyk et al. 2008). Other studies found gram-negative bacteria (Treponema, Tannerella) were more commonly identified in the gingival crevicular fluid of diseased horses, highlighting the potential importance of the oral microbiome in disease aetiology (Sykora et al. 2013). Current treatment involves extraction of affected teeth. However there is an increased likelihood of neighboring teeth developing EOTRH (Rahmani et al. 2019). Presently there are no reported disease modifying treatments available to treat EOTRH and symptom management and pain reduction are the current gold standard approaches (Foster 2013). Whilst the cementum of teeth is the most effected dental tissue other types of dental tissues include dentine, enamel, pulp and the periodontium. The latter consists of cementum, periodontal ligament and alveolar bone. Compositionally cementum is similar to bone with 55% organic material and 45% inorganic hydroxyapatite (Tziafas 2005). It covers the entire length of equine teeth, potentially explaining the hyperactivity of cementum-producing cells (cementoblasts) in EOTRH [C. Staszyk, Suske, and Pöschke (2015)](Bosshardt 2005). Coronal cementum acts as a support to enamel, whilst cementum nearer to the roots is primarily an interface between tooth and the periodontal ligament (PDL). Finally a third type of cementum is present within the infundibulum near the coronal surface of the tooth. Irregular cementum has been shown to be deposited during EOTRH at both resorbed and non-resorbed surfaces along the tooth-PDL interface. Proteomic tools have been utilised to analyse clinical samples in both normal and disease-specific states. Specifically in dental tissues proteomics has been used to map proteomes of enamel, dentin, cementum and pulp in human teeth [Green et al. (2019)](Widbiller et al. 2019)[Giovani et al. (2020)](Eckhardt et al. 2014). As well as this human dental diseases, such as gingivitis, caries and periodontal disease have all been investigated with a similar approach [Gonçalves et al. (2011)](Wang et al. 2018)(Hartenbach et al. 2020). There have been no studies performed to identify potential pathological distinctions between the cementum tissues from healthy horses and those with EOTRH. We hypothesised that global protein changes in horses with and without EOTRH would increase the understanding of underlying pathways and disease mechanisms enabling insight into aetiologies. In addition, by understanding the pathophysiological mechanisms related to EOTRH this could provide treatment targets to delay or prevent disease progression. To investigate protein profiles we used unbiased label-free mass spectrometry-based proteomics.
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