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The relationship between serum 25-hydroxyvitamin D (25(OH)D) levels, genomic response to vitamin D (Vit.D), and positivity to SARS-CoV-2 remains understudied. In this pilot study, during the follow-up of patients with Inflammatory Bowel Disease (IBD) and COVID-19, we investigated this issue by analyzing the molecular contents of serum extracellular vesicles (EVs) from six groups of IBD patients (n = 32), classified according to anti-SARS-CoV-2 status, 25(OH)D level, and Vit.D supplementation, by small RNA-seq. This analysis revealed differentially expressed miRNAs, PIWI-RNA, transfer RNA, small nucleolar RNAs, and protein-coding RNAs in the EVs obtained from these cohorts of IBD patients. Experimental validation evidenced a statistically significant increase in miR30d-5p, miR150-5p, Let-7f-5p, and Let-7a-5p in the anti-SARS-CoV-2-positive and low 25(OH)D and Vit.D supplemented groups with respect to the non-Vit.D supplemented group, indicating their responsiveness to Vit.D treatment. Bioinformatics analysis highlighted the regulation of these validated miRNAs by oxidative stress and inflammation, hallmarks of IBD and COVID-19. Our study reports an unprecedented panel of circulating EV-enclosed inflammation- and oxidative stress-related miRNAs, the potentiality of which, as biomarkers for Vit.D responsivity in IBD patients, needs to be explored in future studies on larger cohorts in order to allow clinicians to optimize current treatment strategies upon viral infection. [ABSTRACT FROM AUTHOR]

In recent years, EVs have emerged as promising vehicles for coding and non-coding RNAs (ncRNAs), which have demonstrated remarkable potential as biomarkers for various diseases, including chronic liver diseases (CLDs). EVs are small, membrane-bound particles released by cells, carrying an arsenal of ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and other ncRNA species, such as piRNAs, circRNAs, and tsRNAs. These ncRNAs act as key regulators of gene expression, splicing, and translation, providing a comprehensive molecular snapshot of the cells of origin. The non-invasive nature of EV sampling, typically via blood or serum collection, makes them highly attractive candidates for clinical biomarker applications. Moreover, EV-encapsulated ncRNAs offer unique advantages over traditional cell-free ncRNAs due to their enhanced stability within the EVs, hence allowing for their detection in circulation for extended periods and enabling more sensitive and reliable biomarker measurements. Numerous studies have investigated the potential of EV-enclosed ncRNAs as biomarkers for CLD. MiRNAs, in particular, have gained significant attention due to their ability to rapidly respond to changes in cellular stress and inflammation, hallmarks of CLD pathogenesis. Elevated levels of specific miRNAs have been consistently associated with various CLD subtypes, including metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction-associated steatohepatitis (MASH), and chronic hepatitis B and C. LncRNAs have also emerged as promising biomarkers for CLD. These transcripts are involved in a wide range of cellular processes, including liver regeneration, fibrosis, and cancer progression. Studies have shown that lncRNA expression profiles can distinguish between different CLD subtypes, providing valuable insights into disease progression and therapeutic response. Promising EV-enclosed ncRNA biomarkers for CLD included miR-122 (elevated levels of miR-122 are associated with MASLD progression and liver fibrosis), miR-21 (increased expression of miR-21 is linked to liver inflammation and fibrosis in CLD patients), miR-192 (elevated levels of miR-192 are associated with more advanced stages of CLD, including cirrhosis and HCC), LncRNA HOTAIR (increased HOTAIR expression is associated with MASLD progression and MASH development), and LncRNA H19 (dysregulation of H19 expression is linked to liver fibrosis and HCC progression). In the present review, we focus on the EV-enclosed ncRNAs as promising tools for the diagnosis and monitoring of CLD of various etiologies. [ABSTRACT FROM AUTHOR]

This article discusses the increasing incidence of early-onset colorectal cancer (EO-CRC) and the importance of timely screening. While mortality rates from colorectal cancer are expected to decline in Europe and the UK, the prevalence of EO-CRC is on the rise, particularly among young adults. The article highlights the need for earlier screening and explores different screening methods and potential therapeutic combinations to improve treatment outcomes. [Extracted from the article]

Diabetes mellitus (DM) is an excessively widespread condition resulting as a consequence of either autoimmune-mediated dysfunction of the pancreatic P-cells and abolishment of insulin production (Type I DM; T1DM), or deficient insulin production and irresponsiveness of cells to it (type II DM; T2DM). Either ways, the result is elevated blood glucose levels or hyperglycemia, the characteristic feature of DM. Tremendous efforts and resources have been spent in deciphering effective therapies/treatments against DM. In spite of hard-earned successes, the problems associated with DM still persist, warranting the need for exploration, development and application of novel dimensions in our quest for controlling this serious problem. Recent years have seen the emergence of promising genetic manipulation technologies, the clustered regularly interspaced short palindromic repeat (CRIsPR) associated nucleases Cas being one of them. CRIsPR-Cas9 technology has the potential to revolutionize and accelerate the gene editing-based therapies in the clinical practice. It can be fine-tuned for direct modification of specific genome sites in target cells, opening up the possibility for rectifying cellular and metabolic defects associated with diseases such as DM. For instance, genes (e.g., octamer-binding transcription factor 4; OCT 4 and pancreatic duodenal homeobox 1; PDX 1) involved in the differentiation pathway of human P-cells can be identified and amended in transplantable pluripotent stem cells. The present perspective review summarizes the recent experimental successes in cellular and animal models for the utilization of the CRIsPR-Cas9 technology in DM research. Further, we conclude with a discussion regarding the critical shortcomings of this technology and suggest means to circumvent these, with the expectation that this review will serve as a relevant and timely research platform aiding global research for further identification of novel and efficient CRISPR-Cas9- based anti-DM treatment strategies. [ABSTRACT FROM AUTHOR]

Cancer is one of the leading causes of death worldwide. Serious side effects, drug resistance and a narrow therapeutic window of chemotherapy drugs have led to the exploration and discovery of new natural anticancer agents. Alvaradoins are the secondary metabolites of the Alvaradoa Liebm. plant species, from the Picramniaceae family, belonging to the class of anthracenone C-glycosides. Among them, alvaradoin E, isolated from A. haitiensis Urb., is characterized by the most powerful anticancer properties as demonstrated by in-vitro and in-vivo assays. This updated review aims to provide new insights into the anticancer efficacy of alvaradoin E and analyses molecular pharmacological evidence to contribute to researchers' efforts to discover new adjunctive therapies in the pharmacotherapeutic management of cancer. To achieve this goal, relevant recent data on the anticancer pharmacological mechanisms of alvaradoin E were searched in specialized databases such as PubMed/ MedLine, Scopus, TRIP database, Web of Science, and Google Scholar. Most of the studies investigated the cytotoxic effects of alvaradoins and the extracts of the Alvaradoa species. Alvaradoin E excelled in its tumor-modulating activity in vitro in several human carcinomas (epidermoid, prostate, colon, lung), promyelocytic leukemia, and cells expressing telomerase reverse transcriptase. The cytotoxic effects of alvaradoin E were associated with its capacity to induce cell apoptosis. Further detailed studies are necessary to explain the precise mechanisms of actions, the effects on living organisms and possible adverse effects. Although data on its anticancer activity in vivo are scarce, Alvaradoin E can develop into a promising agent in fighting carcinoma. [ABSTRACT FROM AUTHOR]

Metastatic melanoma has less frequency, but considered as the most dreaded cancer. The combination of nivolumab & ipilimumab is proving their mettle in treating metastatic melanoma. The patients when administered with the combination of nivolumab & ipilimumab have shown improved median progression free survival, objective response rate and overall survival rate compared with nivolumab and ipilimumab monotherapy. The combination shrinks the tumor cells by attacking different checkpoints viz. CTLA-4 and PD-L1, respectively. The combination treatment reveals reduced disease progression and suggests nivolumab's non-cross resistant nature. The median progression free survival in "nivolumab plus ipilimumab" group has shown an increase of 66.7% and 296.6% in comparison to nivolumab and ipilimumab monotherapy. The other parameter viz. objective response rate improvement is equivalent to almost 14% and 38.6% when compared to nivolumab and ipilimumab monotherapy, respectively. [ABSTRACT FROM AUTHOR]