Biology subjects

Weinberg, E.

Publications and source records attributed to Weinberg, E..

5 recordsLinked to original sources

bioRxiv2024

Anti-fungal recombinant psoriasin effectively inhibits Candida albicans growth on denture base

Oral candidiasis leading to denture stomatitis is a fungal infection resulting from unregulated growth and adhesion mainly of Candida albicans onto acrylic denture base. Once the biofilm is formed, it is immune resistant and mainstay treatments involve toxic chemical antifungal agents or mechanical cleaning techniques, both offer limited efficacy. Consequently, there is an urgent need for more effective and safer therapeutic approaches. While biological modalities are expanding in general medicine, the exploration of protein-based therapeutics in dental medicine remains limited. This research evaluates the inhibitory effect of recombinantly expressed psoriasin on the growth of Candida albicans on polymethyl methacrylate denture bases. Psoriasin, also known as S100-A7, has shown promise in treating microbial skin infections, and its natural presence in saliva makes it a promising candidate for treating oral microbial infections. Our findings indicate that psoriasin exhibits a strong, dose-dependent inhibition of Candida albicans growth. Further, we incubated a polymethyl methacrylate denture base within the psoriasin solution. Notably, immersing the denture base in the solution completely eradicated fungal growth. Our research utilizes natural antifungal proteins within biomedical devices like denture bases, suggesting psoriasin as a safe alternative to chemical antifungals in dental medicine.

biochemistry↗

bioRxiv2023

Nature-Inspired Peptide of MtDef4 C-terminus Tail Enables Protein Delivery in Mammalian Cells

Cell-penetrating peptides hold great promise as versatile tools for the intracellular delivery of therapeutic agents. Various peptides have originated from natural proteins with antimicrobial activity. In this study, we investigated the mammalian cell-penetrating properties of a 16-residue peptide derived from the C-terminus tail of the Medicago truncatula defensin protein, with the sequence GRCRHGFRRRCFCTTHC. We evaluated the ability of this peptide to penetrate multiple types of cells. Our results demonstrate that the peptide efficiently penetrates mammalian cells within minutes and at a sub-micromolar concentration. Moreover, upon N-terminal fusion to the fluorescent protein GFP, the peptide efficiently delivers the GFP into the cells. Despite its remarkable cellular penetration, the peptide has only a minor effect on cellular viability, making it a promising candidate for the development of a cell-penetrating peptide, with potential therapeutic applications.

cell biology↗

bioRxiv2023

Immunorecognition of Streptococcus mutans secreted proteins protects against caries by limiting tooth adhesion

Childhood caries, a chronic disease affecting 60-90% of children in industrialized countries, results in lesions in primary and permanent dentition, leading to hospitalizations, emergency room visits, high treatment costs, and loss of school days. It diminishes the childs ability to learn and increases the risk of caries in adulthood. Despite multiple risk factors for caries, significant interpersonal variability unaccounted for by these factors exists. The immune system generates a personal antibody repertoire that helps maintain a balanced and healthy oral microbiome. Streptococcus mutans is a key bacterium in caries development. Utilizing mass-spectrometry, we examined which S. mutans proteins are identified by antibodies of children with and without caries and identified a core set of proteins recognizable by the immune system of most individuals. This set was enriched with proteins enabling bacterial adhesion. To study the physiological relevance of these findings, we tested the ability of saliva to prevent S. mutans adherence to tooth surfaces. Saliva from caries-free individuals, but not children with caries, was found to hinder the binding of S. mutans to teeth. These findings delineate the S. mutans proteome targeted by the immune system and suggest that the inhibition of bacterial adherence to teeth is a primary mechanism employed by the immune system to maintain oral balance and prevent caries formation. These discoveries offer fresh insights into the immune systems role in preserving oral health and preventing caries development. Targeting S. mutans proteins implicated in bacterial adhesion could be a promising strategy for preventing childhood caries.

microbiology↗

bioRxiv2020

RBMS1 suppresses colon cancer metastasis through targeted stabilization of its mRNA regulon

Broad dysregulation of gene expression control is a hallmark of cancer progression. Identifying the underlying master regulators that drive pathological gene expression is a key challenge in precision oncology. Here, we have developed a network analytical framework, named PRADA, that identifies oncogenic RNA-binding proteins through the systematic detection of coordinated changes in their target regulons. Application of this approach to data collected from clinical samples, patient-derived xenografts, and cell line models of colon cancer metastasis revealed the RNA-binding protein RBMS1 as a suppressor of colon cancer progression. We observed that silencing RBMS1 results in increased metastatic capacity in xenograft mouse models, and that restoring its expression blunts metastatic liver colonization. We have found that RBMS1 functions as a post-transcriptional regulator of RNA stability by directly binding and stabilizing ~80 target mRNAs. Measurements in more than 180 clinical samples as well as survival analyses in publicly available datasets, have shown that RBMS1 silencing and the subsequent downregulation of its targets are strongly associated with disease progression and poor survival in colon cancer patients. Together, our findings establish a role for RBMS1 as a previously unknown regulator of RNA stability and as a suppressor of colon cancer metastasis with clinical utility for risk stratification of patients. SignificanceBy applying a new analytical approach to transcriptomic data from clinical samples and models of colon cancer progression, we have uncovered RBMS1 as a suppressor of metastasis and as a post-transcriptional regulator of RNA stability. Notably, RBMS1 silencing and downregulation of its targets are negatively associated with patient survival.

systems biology↗

bioRxiv2019

PCK1 and DHODH drive colorectal cancer liver metastatic colonization and hypoxic pyrimidine nucleotide anabolic biosynthesis

Colorectal cancer (CRC) is a major cause of human death. Mortality is primarily due to metastatic organ colonization, with liver being the primary organ affected. We modeled metastatic CRC (mCRC) liver colonization using patient-derived primary and metastatic tumor xenografts (PDX). Such PDX modeling predicted patient survival outcomes. In vivo selection of multiple PDXs for enhanced metastatic capacity upregulated the gluconeogenic enzyme PCK1, which enhanced metastatic hypoxic survival by driving anabolic pyrimidine nucleotide biosynthesis. Consistently, highly metastatic tumors upregulated multiple pyrimidine biosynthesis intermediary metabolites. Therapeutic inhibition of the pyrimidine biosynthetic enzyme DHODH with oral leflunomide substantially impaired CRC liver metastatic colonization and hypoxic survival. Our findings provide a potential mechanistic basis for the epidemiologic association of anti-gluconeogenic drugs with improved CRC metastasis outcomes, reveal the exploitation of a gluconeogenesis enzyme for pyrimidine biosynthesis during hypoxia, and implicate DHODH and PCK1 as metabolic therapeutic targets in colorectal cancer metastasis.

cancer biology↗