Biology subjects

Kauppinen, S.

Publications and source records attributed to Kauppinen, S..

5 recordsLinked to original sources

bioRxiv2026

A positively selected microRNA controls a reversible aging program in striated muscle

Aging is the primary risk factor for most chronic diseases and is characterized in striated muscle by progressive functional decline, mitochondrial dysfunction, and chronic inflammation. The miR-128-1 locus resides within a positively selected haplotype on chromosome 2q21.3 associated with variation in grip strength, pulmonary function, and cardiometabolic traits in humans. Here, we show that antisense oligonucleotide-mediated inhibition of miR-128-3p restores muscle mass and function in aged mice, improves cardiac function while limiting adverse remodeling following myocardial infarction, and ameliorates skeletal and cardiac muscle pathology in mouse and pig models of Duchenne muscular dystrophy. Across these contexts, miR-128-3p inhibition induces a conserved transcriptional response characterized by activation of mitochondrial programs and suppression of inflammatory and fibrotic signaling, resembling the effects of established longevity interventions. These findings identify miR-128-3p as a regulator of a conserved aging-associated program and establish its inhibition as a strategy to restore tissue function across aging-related muscle pathologies.

molecular biology↗

bioRxiv2025

Evaluation of Iodine-Based Contrast Agents for Micro-Computed Tomography Imaging of Porcine Cardiac Conduction System

PurposeThis study compares two iodine-based contrast agents: iodine in ethanol (I2E) and aqueous solution of potassium triiodide (I2KI) in optimizing high-resolution, contrast-enhanced micro computed tomography imaging (micro-CT) of the cardiac conduction system (CCS) in porcine hearts. The study evaluates their relative efficacy in enhancing tissue contrast and anatomical delineation, aiming to improve CCS visualization for advanced cardiac research. MethodsDissected porcine hearts were stained with I2E or I2KI for contrast enhancement and scanned with micro-computed tomography. Signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and volumetric shrinkage were evaluated. Additionally, qualitative visualization of CCS-related anatomical landmarks, such as the sinoatrial node (SAN), atrioventricular node (AVN), and Purkinje fibres, was performed, along with assessment of artefact occurrence and sample integrity. The efficacy of the contrast agents was also determined by segmenting the regions of interest corresponding to the CCS from micro-CT images. These were then further validated against histology. ResultsI2E provided superior CNR, fewer artefacts, and preserved sample integrity, enabling smooth post-processing and histological sectioning. I2KI staining produced higher soft-tissue signal intensity and faster stain saturation (day 2) than I2E (day 3). However, I2KI exhibited leaching and introduced substantial staining artefacts. I2KI also exhibited structural disintegration, which, in turn, compromised downstream processing. ConclusionThese results suggest that I2E is a viable alternative to I2KI for CCS micro-CT imaging when sample preservation and downstream analyses are essential, whereas I2KI may be preferred for rapid, high-intensity staining where tissue integrity is less critical.

bioengineering↗

bioRxiv2024

circPCMTD1: A protein-coding circular RNA that regulates DNA damage response in BCR/ABL-positive leukemias

Circular RNAs are a novel class of RNA transcripts, which regulate important cellular functions in health and disease. Herein, we report on the functional relevance of the circPCMTD1 transcript in acute leukemias. In screening experiments, we found that circPCMTD1 depletion strongly inhibited the proliferative capacity of leukemic cells with BCR-ABL translocations. Mass cytometry experiments identified the aberrant activation of the DNA damage response as an early downstream event of circPCMTD1 depletion. In in vivo experiments, circPCMTD1 targeting prolonged the survival of mice engrafted with leukemic blasts harboring the Philadelphia chromosome. Mechanistically, we found that circPCMTD1 was enriched in the cytoplasm and associated with the ribosomes of the leukemic cells. We detected a cryptic open reading frame within the circPCMTD1 sequence and found that circPCMTD1 could generate a peptide product. The circPCMTD1-derived peptide interacted with proteins of the BTR complex and enhanced BTR complex formation, thereby increasing tolerance to genotoxic stress.

cancer biology↗

bioRxiv2021

An intranasal ASO therapeutic targeting SARS-CoV-2

The COVID-19 pandemic is exacting an increasing toll worldwide, with new SARS-CoV-2 variants emerging that exhibit higher infectivity rates and that may partially evade vaccine and antibody immunity1. Rapid deployment of non-invasive therapeutic avenues capable of preventing infection by all SARS-CoV-2 variants could complement current vaccination efforts and help turn the tide on the COVID-19 pandemic2. Here, we describe a novel therapeutic strategy targeting the SARS-CoV-2 RNA using locked nucleic acid antisense oligonucleotides (LNA ASOs). We identified an LNA ASO binding to the 5 leader sequence of SARS-CoV-2 ORF1a/b that disrupts a highly conserved stem-loop structure with nanomolar efficacy in preventing viral replication in human cells. Daily intranasal administration of this LNA ASO in the K18-hACE2 humanized COVID-19 mouse model potently (98-99%) suppressed viral replication in the lungs of infected mice, revealing strong prophylactic and treatment effects. We found that the LNA ASO also represses viral infection in golden Syrian hamsters, and is highly efficacious in countering all SARS-CoV-2 "variants of concern" tested in vitro and in vivo, including B.1.427, B.1.1.7, and B.1.351 variants3. Hence, inhaled LNA ASOs targeting SARS-CoV-2 represents a promising therapeutic approach to reduce transmission of variants partially resistant to vaccines and monoclonal antibodies, and could be deployed intranasally for prophylaxis or via lung delivery by nebulizer to decrease severity of COVID-19 in infected individuals. LNA ASOs are chemically stable and can be flexibly modified to target different viral RNA sequences4, and they may have particular impact in areas where vaccine distribution is a challenge, and could be stockpiled for future coronavirus pandemics.

microbiology↗

bioRxiv2020

PTENP1-AS contributes to BRAF inhibitor resistance and is associated with adverse clinical outcome in stage III melanoma

Approximately 50% of human cutaneous melanomas carry activating mutations in the serine/threonine protein kinase BRAF. BRAF inhibitors (BRAFi) selectively target the oncogenic BRAFV600E/K and are effective in approximately 80% of patients carrying the mutation. However, resistance to BRAFi is common and emerges within a median time of 6-7 months of treatment and is prolonged to 11 months when combined with MEK inhibitors. Better characterization of the underlying molecular processes is therefore needed to further improve treatments. Inactivation of the tumor suppressor gene PTEN has been suggested to occur during melanomagenesis and drug resistance development. We recently demonstrated that transcription of PTEN is negatively regulated by an antisense RNA from the PTEN pseudogene (PTENP1-AS) and here set out to investigate the impact of this molecular pathway on the resistance to BRAFi and clinical outcome. We used a panel of BRAFi resistant A375 sublines, and observed increased levels of PTENP1-AS associated with reduced expression of PTEN. Furthermore, this loss of PTEN expression was correlated to increased recruitment of Enhancer of zeste homolog 2 (EZH2) and formation of the transcriptional repression mark H3K27me3 at the PTEN promoter in the resistant cells. We demonstrated that targeting of PTENP1-AS was able to re-activate the expression of PTEN and sensitize resistant melanoma cells to BRAFi. Finally, we showed that PTENP1-AS is a promising prognostic marker for clinical outcome in melanoma patients as high expression of PTENP1-AS in regional lymph node metastases from stage III melanoma patients correlated with poor survival.

cancer biology↗