The arginine methyltransferase PRMT5 promotes mucosal defense in the intestine.

PRMT5 is a type II arginine methyltransferase abundantly expressed in the colonic epithelium. It is up-regulated in inflammatory bowel disease and colorectal cancer. However, its role in mucosal defense against enteric infection has not been studied. Here, we report that Prmt5 in the murine colon is up-regulated in response to Citrobacter rodentium infection. Pathogen clearance in mice with haploinsufficient expression of Prmt5 is significantly delayed compared with wildtype littermate controls. Transcriptomic analyses further reveal that PRMT5 regulates the expression of canonical crypt goblet cell genes involved in mucus production, assembly, and anti-microbial responses via methyltransferase activity-dependent and -independent mechanisms. Together, these findings uncover PRMT5 as a novel regulator of mucosal defense and a potential therapeutic target for treating intestinal diseases.

The long non-coding RNA MALAT1 regulates intestine host-microbe interactions and polyposis.

The long non-coding RNA (lncRNA) Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) maintains the integrity of the intestinal epithelial barrier and regulates local inflammation. However, its influences on intestinal microbial communities and tissue susceptibility to cancer development remain unexplored. Here, we report that MALAT1 regulates host anti-microbial response gene expression and the composition of mucosal-associated microbial communities in a region-specific manner. In the APC mutant mouse model of intestine tumorigenesis, knocking out MALAT1 results in higher polyp counts in the small intestine and colon. Interestingly, intestine polyps that developed in the absence of MALAT1 were smaller in size. These findings highlight the unexpected bivalent role of MALAT1 in restricting and promoting cancer progression at different disease stages. Among the 30 MALAT1-targets shared by both the small intestine and colon, ZNF638 and SENP8 levels are predictive of colon adenoma patient overall survival and disease-free survival. Genomic assays further revealed that MALAT1 modulates intestinal target expression and splicing through both direct and indirect mechanisms. This study expands the role of lncRNAs in regulating intestine homeostasis, microbial communities, and cancer pathogenesis.

Protocol to assess cell-intrinsic regulatory mechanisms using an ex vivo murine T cell polarization and co-culture system.

This protocol describes an ex vivo cell culture system for simultaneously generating a mixture of CD4+ T helper lineages, including T helper 17 (Th17), RORγt+ Treg, and conventional Treg (cTreg), in proportions representative of those found in mucosal tissues in vivo. When combined with a co-culture approach, this system allows a more rapid assessment of a candidate molecule's T cell-intrinsic and -extrinsic functions over the traditional bone marrow chimera and co-transfer approaches. For complete details on the use and execution of this protocol, please refer to Ma et al. (2022).

RNA binding protein DDX5 directs tuft cell specification and function to regulate microbial repertoire and disease susceptibility in the intestine.

OBJECTIVE: Tuft cells residing in the intestinal epithelium have diverse functions. In the small intestine, they provide protection against inflammation, combat against helminth and protist infections, and serve as entry portals for enteroviruses. In the colon, they had been implicated in tumourigenesis. Commitment of intestinal progenitor cells to the tuft cell lineage requires Rho GTPase Cell Division Cycle 42 (CDC42), a Rho GTPase that acts downstream of the epidermal growth factor receptor and wingless-related integration site signalling cascades, and the master transcription factor POU class 2 homeobox 3 (POU2F3). This study investigates how this pathway is regulated by the DEAD box containing RNA binding protein DDX5 in vivo. DESIGN: We assessed the role of DDX5 in tuft cell specification and function in control and epithelial cell-specific Ddx5 knockout mice (DDX5ΔIEC) using transcriptomic approaches. RESULTS: DDX5ΔIEC mice harboured a loss of intestinal tuft cell populations, modified microbial repertoire, and altered susceptibilities to ileal inflammation and colonic tumourigenesis. Mechanistically, DDX5 promotes CDC42 protein synthesis through a post-transcriptional mechanism to license tuft cell specification. Importantly, the DDX5-CDC42 axis is parallel but distinct from the known interleukin-13 circuit implicated in tuft cell hyperplasia, and both pathways augment Pou2f3 expression in secretory lineage progenitors. In mature tuft cells, DDX5 not only promotes integrin signalling and microbial responses, it also represses gene programmes involved in membrane transport and lipid metabolism. CONCLUSION: RNA binding protein DDX5 directs tuft cell specification and function to regulate microbial repertoire and disease susceptibility in the intestine.

DDX5 promotes oncogene C3 and FABP1 expressions and drives intestinal inflammation and tumorigenesis.

Tumorigenesis in different segments of the intestinal tract involves tissue-specific oncogenic drivers. In the colon, complement component 3 (C3) activation is a major contributor to inflammation and malignancies. By contrast, tumorigenesis in the small intestine involves fatty acid-binding protein 1 (FABP1). However, little is known of the upstream mechanisms driving their expressions in different segments of the intestinal tract. Here, we report that the RNA-binding protein DDX5 binds to the mRNA transcripts of C3 and Fabp1 to augment their expressions posttranscriptionally. Knocking out DDX5 in epithelial cells protected mice from intestinal tumorigenesis and dextran sodium sulfate (DSS)-induced colitis. Identification of DDX5 as a common upstream regulator of tissue-specific oncogenic molecules provides an excellent therapeutic target for intestinal diseases.

Effects of distance from a heavily transited avenue on asthma and atopy in a periurban shantytown in Lima, Peru.

BACKGROUND: Proximity to roadways increases the risk of asthma in developed countries; however, relatively little is known about this relationship in developing countries, where rapid and uncontrolled growth of cities has resulted in urban sprawl and heavy traffic volumes. OBJECTIVE: We sought to determine the effect of distance from a heavily transited avenue on asthma symptoms and quantitative respiratory outcome measures in a periurban shantytown in Lima, Peru. METHODS: We enrolled 725 adolescents aged 13 to 15 years who were administered a survey on asthma symptoms and measured spirometry, response to allergy skin testing, and exhaled nitric oxide (eNO). We calculated distances from the main avenue for all households and measured indoor particulate matter in 100 households. We used multivariable regression to model the risk of asthma symptoms, risk of atopy, eNO levels, and FEV(1)/forced vital capacity ratio as a function of distance. RESULTS: Compared against 384 meters, the odds of current asthma symptoms in households living within 100 meters increased by a factor of 2 (P < .05). The odds of atopy increased by a factor of 1.07 for every 100-meter difference in the distance from the avenue (P = .03). We found an inverse relationship in prebronchodilator FEV(1)/forced vital capacity and distance to the avenue in female subjects (P = .01) but not in male subjects. We did not find an association between eNO or household particulate matter levels and distance. CONCLUSION: Living in close proximity to a high-traffic-density avenue in a periurban community in Peru was associated with a greater risk of asthma symptoms and atopy. Regulation of mobile-source pollutants in periurban areas of developing countries might help reduce the burden of asthma symptoms and atopy.

Toxicidad a dosis repetidas de Azadirachta indica A Juss (árbol del Nim) / Repeated dose toxicity in Azadichfa indica A Juss (Neem tree)

Azadirachta indica A Juss, conocida como árbol del Nim, tiene múltiples aplicaciones para la agricultura, la medicina veterinaria y la salud, es una especie vegetal de importancia relevante por su uso como antimicrobiano, antiparasitario e inmunoestimulante. OBJETIVO: detectar signos de toxicidad tras la administración diaria durante 28 d de la decocción de A. indica. MÉTODOS: se realizó un ensayo de toxicidad a dosis repetidas a una decocción de esta planta administrando una dosis de 1 000 mg/kg por vía oral a ratas Sprague Dawley durante 28 d. Se evaluaron los signos clínicos y el peso corporal de los animales en estudio y se realizaron exámenes de hematología, bioquímica sanguínea, análisis anatomopatológico e histopatológico. RESULTADOS: la decocción de la planta no produjo alteraciones significativas en el peso corporal, ni hubo signos clínicos indicadores de toxicidad. No se observaron alteraciones en los indicadores hematológicos y bioquímicos atribuibles a la sustancia de ensayo. Los resultados anatomopatológicos no mostraron alteraciones sobre sistemas, órganos y tejidos. CONCLUSIONES: el estudio no demostró efectos tóxicos en el modelo animal utilizado, que pudieran estar asociados a la administración repetida de la decocción de la planta A indica en las condiciones empleadas(AU)

Azadirachta indica A Juss, known as Neem tree, has various applications in agriculture, veterinary medicine and health care, thus it is a relevant vegetable species due to its antimicrobial, antiparasitic and immunostimulating properties. OBJECTIVE: to detect any signal of toxicity after daily oral administration of decoction for 28 days. METHODS: a repeated dose toxicity assay using a A. indica decoction at a dose of 1000 mg/kg, orally administered to Sprague Dawley rats for 28 days. Clinical signs and body weight of the study animals were evaluated together with hamatological, blood chemistry, anatomopathological and histopathological analyses. RESULTS: this decoction brought about neither significant change in the body weight nor clinical signs indicating toxicity. There were not altered hematological and biochemical indicators that may be attributed to the substance under testing. The anatomopathological results did not show any alteration upon systems, organs and tissues. CONCLUSIONS: the study did not reveal toxic effects in the animal model that might be connected with the repeated oral administration of A indica decoction under the study conditions(AU)

Toxicidad a dosis repetidas de Azadirachta indica A Juss (árbol del Nim) / Repeated dose toxicity in Azadichfa indica A Juss (Neem tree)

Azadirachta indica A Juss, conocida como árbol del Nim, tiene múltiples aplicaciones para la agricultura, la medicina veterinaria y la salud, es una especie vegetal de importancia relevante por su uso como antimicrobiano, antiparasitario e inmunoestimulante. OBJETIVO: detectar signos de toxicidad tras la administración diaria durante 28 d de la decocción de A. indica. MÉTODOS: se realizó un ensayo de toxicidad a dosis repetidas a una decocción de esta planta administrando una dosis de 1 000 mg/kg por vía oral a ratas Sprague Dawley durante 28 d. Se evaluaron los signos clínicos y el peso corporal de los animales en estudio y se realizaron exámenes de hematología, bioquímica sanguínea, análisis anatomopatológico e histopatológico. RESULTADOS: la decocción de la planta no produjo alteraciones significativas en el peso corporal, ni hubo signos clínicos indicadores de toxicidad. No se observaron alteraciones en los indicadores hematológicos y bioquímicos atribuibles a la sustancia de ensayo. Los resultados anatomopatológicos no mostraron alteraciones sobre sistemas, órganos y tejidos. CONCLUSIONES: el estudio no demostró efectos tóxicos en el modelo animal utilizado, que pudieran estar asociados a la administración repetida de la decocción de la planta A indica en las condiciones empleadas

Azadirachta indica A Juss, known as Neem tree, has various applications in agriculture, veterinary medicine and health care, thus it is a relevant vegetable species due to its antimicrobial, antiparasitic and immunostimulating properties. OBJECTIVE: to detect any signal of toxicity after daily oral administration of decoction for 28 days. METHODS: a repeated dose toxicity assay using a A. indica decoction at a dose of 1000 mg/kg, orally administered to Sprague Dawley rats for 28 days. Clinical signs and body weight of the study animals were evaluated together with hamatological, blood chemistry, anatomopathological and histopathological analyses. RESULTS: this decoction brought about neither significant change in the body weight nor clinical signs indicating toxicity. There were not altered hematological and biochemical indicators that may be attributed to the substance under testing. The anatomopathological results did not show any alteration upon systems, organs and tissues. CONCLUSIONS: the study did not reveal toxic effects in the animal model that might be connected with the repeated oral administration of A indica decoction under the study conditions