Rspo

Wnt and Rspondin (RSPO) signaling drives proliferation, and bone morphogenetic protein inhibitors (BMPi) impede differentiation, of intestinal stem cells (ISCs). Here, we identify the mouse ISC niche as a complex, multi-layered structure that encompasses distinct mesenchymal and smooth muscle populations. In young and adult mice, diverse sub-cryptal cells provide redundant ISC-supportive factors; few of these are restricted to single cell types. Niche functions refine during postnatal crypt morphogenesis, in part to oppose the dense aggregation of differentiation-promoting BMP+ sub-epithelial myofibroblasts at crypt-villus junctions...

PURPOSE: To counteract early morning pathology like hypertension a time-dependent release of the drug is required. This study is focused to formulate a pulsatile and mucoadhesive drug delivery system of an ACE inhibitor Perindopril Erbumine. METHOD: Two matrix tablets were punched with Eudragit RSPO, Eudragit RLPO, and HPMC K15M using a 3-3-3 Box-Behnken Design of Response Surface Methodology. Based on the design optimized formulation P1T3 and P2T8 were coated for a lag time with compression coating of HPMC K4M and a blend of 1:1 ratio of ethylcellulose and carbopol polymer and further encapsulated in a Eudracap™ capsule to provide gastric resistance...

The transmembrane receptor LGR5 potentiates Wnt/β-catenin signaling by binding both secreted R-spondin (RSPOs) and the Wnt tumor suppressors RNF43/ZNRF3, directing clearance of RNF43/ZNRF3 from the cell surface. Besides being widely used as a stem cell marker in various tissues, LGR5 is overexpressed in many types of malignancies, including colorectal cancer. Its expression characterizes a subpopulation of cancer cells that play a crucial role in tumor initiation, progression and cancer relapse, known as cancer stem cells (CSCs)...

BACKGROUND: WNT974 is a small molecule inhibitor of Wnt signaling that specifically inhibits porcupine O-acyltransferase. This phase Ib dose--escalation study evaluated the maximum tolerated dose of WNT974 in combination with encorafenib and cetuximab in patients with BRAF V600E-mutant metastatic colorectal cancer with RNF43 mutations or RSPO fusions. PATIENTS AND METHODS: Patients received once-daily encorafenib and weekly cetuximab, in addition to once-daily WNT974, in sequential dosing cohorts...

Diacerein (DCN) is a chondroprotective agent which shows inadequate oral bioavailability along with gastrointestinal side effects. This study is intended to develop a topical novel DCN delivery system. DCN nanogel was prepared by emulsion solvent diffusion technique. The formulation was optimized by response surface methodology by taking two independent variables, concentration of carbopol 940 and eudragit RSPO and three dependent variables, particle size, % entrapment efficiency (EE) and % drug release at 24 h...

The R-spondin protein family comprises four members (RSPO1-4), which are agonists of the canonical Wnt/β-catenin pathway. Emerging evidence revealed that RSPOs should not only be viewed as agonists of the Wnt/β-catenin pathway but also as regulators for tumor development and progression. Aberrant expression of RSPOs is related to tumorigenesis and tumor development in multiple cancers and their expression of RSPOs has also been correlated with anticancer immune cell signatures. More importantly, the role of RSPOs as potential target therapies and their implication in cancer progressions has been studied in the preclinical and clinical settings...

The model of core-shell structured tablets is gaining increased interest due to its advantages in controlled-release and combinational drug delivery. Through the encapsulation of the drug by the outer shell, this model exhibits huge potential for reduced administration frequency, improved taste-masking, and personalized medication strategy. Although different types of core-shell tablets have been recently developed, most of them focused on the embedding of the solid tablets. Therefore there is still a need to investigate an optimized model in which multiple dosage forms can be loaded...

Papillary thyroid carcinoma (PTC) is the most common malignancy of the thyroid gland and early stages are curable. However, a subset of PTCs shows an unusually aggressive phenotype with extensive lymph node metastasis and higher incidence of locoregional recurrence. In this study, we investigated a large cohort of PTC cases with an unusual aggressive phenotype using a high-throughput RNA sequencing (RNA-Seq) to identify differentially regulated genes associated with metastatic PTC. All metastatic PTC with mutated BRAF (V600E) but not BRAF wild-type expressed an up-regulation of R-Spondin Protein 4 (RSPO4) concomitant with an upregulation of genes involved in focal adhesion and cell-extracellular matrix signaling...

The Rspo-Lgr4/5-Znrf3/Rnf43 module is a master regulator of hepatic Wnt/β-catenin signaling and metabolic zonation, but its impact on nonalcoholic fatty liver disease (NAFLD) remains unclear. We studied whether hepatic epithelial cell-specific loss of the Wnt/β-catenin modulators Leucine-Rich Repeat-Containing G Protein-Coupled Receptor 4/5 (Lgr4/5) promoted NAFLD. Three and 6 months-old mice with hepatic epithelial cell-specific deletion of both receptors Lgr4/5 (Lgr4/5dLKO) were compared to control mice upon feeding with normal diet (ND) or high fat diet (HFD)...

The fungal disease of the nail, onychomycosis, which is also the most prevalent nail disturbance, demands effective topical treatment options considering the possible adverse effects of systemic antifungal therapy. The current work is focused on development of an adhesive and resistant, drug-delivering and permeation-enhancing polymeric film containing econazole nitrate (ECN) for topical antifungal treatment. The development of the lacquer formulation was guided by the Quality by Design approach to achieve the critical quality attributes needed to obtain the product of desired quality...

Wnt and R-spondin (Rspo) proteins are two major types of endogenous Wnt/β-catenin signaling agonists. While Wnt/β-catenin signaling is greatly diminished in Alzheimer's disease (AD), it remains to be elucidated whether the inhibition of this pathway is associated with dysregulation of Wnt and Rspo proteins. By analyzing temporal cortex RNA-seq data of the human postmortem brain samples, we found that WNT1 and RRPO2 were significantly downregulated in human AD brains. In addition, the expression of Wnt acyltransferase porcupine (PORCN), which is essential for Wnt maturation and secretion, was greatly deceased in these human AD brains...

Oral mucositis in the oral cavity, caused by radiation therapy and chemotherapy, requires personalized care and therapy due to variations in the lesions of patients. In the present study, we fabricated a model of personalized oral film containing an ibuprofen/lidocaine ionic liquid (IL) for patients with oral mucositis using a pressure-assisted microsyringe-type 3D printer at room temperature. The film contained a Eudragit polymer (L100, EPO, or RSPO) to make the film solid, and the printer ink was composed of organo ink (organic solvent to dissolve both drugs and the Eudragit polymer)...

Three experiments (EXP) were conducted to determine the effect of feed additives on performance, intestinal integrity, gastrointestinal volatile fatty acids (VFA), and energy and nutrient digestion in non-challenged nursery pigs. In EXP 1, 480 pigs (6.36 kg body weight, BW) were placed into 96 pens with 5 pigs/pen, and allotted to 1 of 10 dietary treatments: 1) negative control containing no feed additive (NC), 2) NC + 44 mg chlortetracycline and 38.5 mg tiamulin/kg diet (CTsb), 3) NC + 5% resistant potato starch (RSpo), 4) NC + 5% soluble corn fiber (SCF), 5) NC + 5% sugar beet pulp (SBP), 6: NC + 0...

R-spondins (RSPOs) are influential signaling molecules that promote the Wnt/β-catenin pathway and self-renewal of stem cells. Currently, RSPOs are emerging as clinically relevant oncogenes, being linked to cancer development in multiple organs. Although this has instigated the rapid development and testing of therapeutic antibodies targeting RSPOs, functional evidence that RSPO causally drives cancer has focused primarily on the intestinal tract. Here, we assess the oncogenic capacity of RSPO in breast cancer in a direct fashion by generating and characterizing a novel mouse model with conditional Rspo3 expression in the mammary gland...

The nano-drug delivery system has gained greater acceptability for poorly soluble drugs. Alogliptin (ALG) is a FDA-approved oral anti-hyperglycemic drug that inhibits dipeptidyl peptidase-4. The present study is designed to prepare polymeric ALG nanoparticles (NPs) for the management of diabetes. ALG-NPs were prepared using the nanoprecipitation method and further optimized by Box-Behnken experimental design (BBD). The formulation was optimized by varying the independent variables Eudragit RSPO (A), Tween 20 (B), and sonication time (C), and the effects on the hydrodynamic diameter (Y1) and entrapment efficiency (Y2) were evaluated...

BACKGROUND: Secreted R-spondin (RSPO) proteins play a key role in reproductive organ development, epithelial stem cell renewal and cancer induction by reinforcing canonical Wnt signaling. We have previously reported that palmoplantar keratoderma (PPK), predisposition to cutaneous squamous cell carcinoma (SCC) development and sex reversal segregate as autosomal recessive trait in patients carrying RSPO1-mutations. Although our previous findings suggested that RSPO1 secreted from fibroblasts regulates keratinocyte growth or differentiation, the role of this protein in the epidermis remains largely unexplored...

Paracrine cell-cell communication is central to all developmental processes, ranging from cell diversification to patterning and morphogenesis. Precise calibration of signaling strength is essential for the fidelity of tissue formation during embryogenesis and tissue maintenance in adults. Membrane-tethered ubiquitin ligases can control the sensitivity of target cells to secreted ligands by regulating the abundance of signaling receptors at the cell surface. We discuss two examples of this emerging concept in signaling: (1) the transmembrane ubiquitin ligases ZNRF3 and RNF43 that regulate WNT and bone morphogenetic protein receptor abundance in response to R-spondin ligands and (2) the membrane-recruited ubiquitin ligase MGRN1 that controls Hedgehog and melanocortin receptor abundance...

R-spondins are critical regulators of gastric epithelial cells, with Lgr5 receptor historically considered as their main signaling transducer. Recent work by Wizenty et al (2022) now revealed distinct roles for Lgr4 and Lgr5 in directing gland reconstitution following H. pylori infection, shedding new light on the complexities of Rspo signaling during gastric regeneration and raising questions about antral stem cell hierarchy.

BACKGROUND: RSPO fusions that lead to WNT pathway activation are potential therapeutic targets in colorectal cancer (CRC), but their clinicopathological significance remains unclear. METHODS: We screened 1019 CRCs for RSPO fusions using multiplex reverse transcription-PCR. The RSPO fusion-positive tumours were subjected to whole-exome sequencing (WES). RESULTS: Our analysis identified 29 CRCs with RSPO fusions (2.8%), consisting of five with an EIF3E-RSPO2 fusion and 24 with PTPRK-RSPO3 fusions...

Bacterial small non-coding RNAs (sRNAs) play key roles as genetic regulators, mediating in the adaptability to changing environmental conditions and stress responses. In this work, we analysed putative sRNAs identified by RNA-seq experiments in different aeration conditions in the extremophile bacterium P. extremaustralis. These analyses allowed the identification of 177 putative sRNAs under aerobiosis (A), microaerobiosis (M) and microaerobiosis after H2 O2 exposure (m-OS). The size and transcription profile of eight sRNAs with differential expression were verified by Northern blot...