Determinants of circulating microRNA‐125b, a risk predictor of vascular calcification, among community‐dwelling older adults<sup>*</sup>

Oxidative Medicine and Cellular Longevity

Tsai

Lee

et al. 2022

Self Cite

Background. Vascular calcification (VC) constitutes subclinical vascular burden and increases cardiovascular mortality. Effective therapeutics for VC remains to be procured. We aimed to use a deep learning-based strategy to screen and uncover plant compounds that potentially can be repurposed for managing VC. Methods. We integrated drugome, interactome, and diseasome information from Comparative Toxicogenomic Database (CTD), DrugBank, PubChem, Gene Ontology (GO), and BioGrid to analyze drug-disease associations. A deep representation learning was done using a high-level description of the local network architecture and features of the entities, followed by learning the global embeddings of nodes derived from a heterogeneous network using the graph neural network architecture and a random forest classifier established for prediction. Predicted results were tested in an in vitro VC model for validity based on the probability scores. Results. We collected 6,790 compounds with available Simplified Molecular-Input Line-Entry System (SMILES) data, 11,958 GO terms, 7,238 diseases, and 25,482 proteins, followed by local embedding vectors using an end-to-end transformer network and a node2vec algorithm and global embedding vectors learned from heterogeneous network via the graph neural network. Our algorithm conferred a good distinction between potential compounds, presenting as higher prediction scores for the compound categories with a higher potential but lower scores for other categories. Probability score-dependent selection revealed that antioxidants such as sulforaphane and daidzein were potentially effective compounds against VC, while catechin had low probability. All three compounds were validated in vitro. Conclusions. Our findings exemplify the utility of deep learning in identifying promising VC-treating plant compounds. Our model can be a quick and comprehensive computational screening tool to assist in the early drug discovery process.

Section: Discussionmentioning

confidence: 99%

Deep Learning-Assisted Repurposing of Plant Compounds for Treating Vascular Calcification: An In Silico Study with Experimental Validation

Oxidative Medicine and Cellular Longevity

Tsai

Lee

et al. 2022

Self Cite

“…The study protocol has been published previously ( 10 ). In brief, community-dwelling older adults (age ≥65) were prospectively recruited from health examination programs and clinics of National Taiwan University Hospital BeiHu Branch as well as Taipei municipal long-term care service centers during 2017.…”

Section: Methodsmentioning

confidence: 99%

“…Results based on this approach reportedly reduce fluctuations in data and permit cross-study comparisons. Data were then averaged with miR-125b levels calculated using the ΔΔCt method ( 10 ). If the participants' miR-125b expression levels were undetectable upon PCR cycling despite the presence of measurable Caenorhabditis elegans miR-39, we substituted their miR-125b cycle number with 40, which was the lowest detectable value specified by the cycler, followed by calculation.…”

Section: Methodsmentioning

confidence: 99%

Circulating microRNA-125b Levels Are Associated With the Risk of Vascular Calcification in Healthy Community-Dwelling Older Adults

Front. Cardiovasc. Med.

Han

Huang

2021

Background: Vascular calcification (VC) is a subclinical manifestation of vascular disease burden among older adults, conferring an elevated mortality risk. Biomarkers capable of detecting and risk-stratifying VC associated with advanced age remains unavailable, impeding our effort to provide optimal care to geriatric patients.Objectives: In this study, we aimed to investigate whether circulating miR-125b served as a potential indicator for VC in relatively healthy older adults.Methods: Community-dwelling older adults (age ≥65) were prospectively recruited during 2017, followed by clinical features documentation and VC rating based on aortic arch calcification (AAC) and abdominal aortic calcification (AbAC). Multiple logistic regression was done to evaluate the relationship between circulating miR-125b levels, VC presence and severity, followed by selecting the optimal cutoff point for VC diagnosis.Results: A total of 343 relatively healthy older adults (median age, 73.8 years; 40% male; 59.8% having AAC) were enrolled, with a median circulating miR-125b level of 0.012 (interquartile range, 0.003–0.037). Those with more severe AAC had progressively decreasing miR-125b levels (p<0.001). Multiple regression analyses showed that having higher miR-125b levels based on the median value were associated with a substantially lower risk of AAC [odds ratio (OR) 0.022, 95% confidence interval (CI) 0.011–0.044] compared to those having lower ones. An optimal cutoff of miR-125b for identifying AAC in older adults was 0.008, with a sensitivity and specificity of 0.86 and 0.80, respectively. Similar findings were obtained when using AbAC as the endpoint.Conclusions: We found that miR-125b serves as an independent indicator for VC in relatively healthy older adults, and may potentially be linked with VC pathophysiology.

“…Results from several studies may provide us with encouraging hints. In a prior attempt, we showed that in older adults, circulating miR-125b predicted the risk of VC, an important risk factor for frailty, in community-dwelling older adults [106,107]. A recent study showed that 2 weeks of metformin, a potential MAPK inhibitor, administration could improve myoblast functions in older adults through histone and chromatin remodeling [108].…”

Section: Mediators Of Organ Degeneration and Frailty As Emerging Diag...mentioning

confidence: 98%

Uremic Toxins and Frailty in Patients with Chronic Kidney Disease: A Molecular Insight

Lin

2021

IJMS

Self Cite

The accumulation of uremic toxins (UTs) is a prototypical manifestation of uremic milieu that follows renal function decline (chronic kidney disease, CKD). Frailty as a potential outcome-relevant indicator is also prevalent in CKD. The intertwined relationship between uremic toxins, including small/large solutes (phosphate, asymmetric dimethylarginine) and protein-bound ones like indoxyl sulfate (IS) and p-cresyl sulfate (pCS), and frailty pathogenesis has been documented recently. Uremic toxins were shown in vitro and in vivo to induce noxious effects on many organ systems and likely influenced frailty development through their effects on multiple preceding events and companions of frailty, such as sarcopenia/muscle wasting, cognitive impairment/cognitive frailty, osteoporosis/osteodystrophy, vascular calcification, and cardiopulmonary deconditioning. These organ-specific effects may be mediated through different molecular mechanisms or signal pathways such as peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α), mitogen-activated protein kinase (MAPK) signaling, aryl hydrocarbon receptor (AhR)/nuclear factor-κB (NF-κB), nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), Runt-related transcription factor 2 (RUNX2), bone morphogenic protein 2 (BMP2), osterix, Notch signaling, autophagy effectors, microRNAs, and reactive oxygen species induction. Anecdotal clinical studies also suggest that frailty may further accelerate renal function decline, thereby augmenting the accumulation of UTs in affected individuals. Judging from these threads of evidence, management strategies aiming for uremic toxin reduction may be a promising approach for frailty amelioration in patients with CKD. Uremic toxin lowering strategies may bear the potential of improving patients’ outcomes and restoring their quality of life, through frailty attenuation. Pathogenic molecule-targeted therapeutics potentially disconnect the association between uremic toxins and frailty, additionally serving as an outcome-modifying approach in the future.