Biology subjects

Kang, B.-Y.

Publications and source records attributed to Kang, B.-Y..

4 recordsLinked to original sources

bioRxiv2022

Circular RNA ROR B; regulates TGFBR1 by decoying miR-140 in alcohol-exposed lungs and fibroblasts

Alcohol ingestion exaggerates transforming growth factor-beta 1 (TGF{beta}1) expression and signaling leading to fibroproliferation. Inhibition of TGF{beta} receptor type 1 (TGF{beta}R1) mitigates the effect of TGF{beta}1 signaling. We showed that alcohol can modulate microRNA (miRNA) expressions. The mechanism by which alcohol modulates microRNA and how it ties to TGF{beta}1 signaling has not been well elucidated. Circular RNA (circRNAs or circ) emerges as a potential therapeutic target based on its stability, tissue specificity, and its ability to modify miRNAs. In this study, we showed that alcohol upregulates TGF{beta}R1 and circRNA form of retinoic acid receptor-related orphan receptor beta (circ-ROR{beta}) in lung fibroblasts (LF) and the lung. We identified miR-140 to have binding sites for both TGF{beta}R1 3 UTR and circ-ROR{beta} and alcohol attenuated miR-140 expression in LF and the lung. We demonstrated that inhibition of circ-ROR{beta} upregulated miR-140 and completely abrogated alcohol-induced miR-140 suppression. We further showed that inhibition of circ-ROR{beta} attenuated alcohol-induced TGF{beta}R1, fibronectin (FN1), and -smooth muscle actin (SMA) expressions and myofibroblast development as seen by an attenuation of SMA stress fiber formation in LF. Taken together, these findings identify circ-ROR{beta}-miR-140-TGF{beta}R1 axis as a novel mechanism by which alcohol induces TGF{beta}1 signaling and promotes FMD. HighlightsAlcohol induces circ-ROR{beta} expression in lung fibroblasts Circ-ROR{beta} regulates TGF{beta}R1 by decoying miR-140 in lung fibroblasts Inhibition of Circ-ROR{beta} restores miR-140 expression Inhibition of Circ-ROR{beta} mitigates alcohol-mediated myofibroblast differentiation This is the first description of circ-ROR{beta} functional significance in lung fibroblast

physiology↗

bioRxiv2022

USP11 promotes endothelial apoptosis-resistance in pulmonary hypertension by deubiquitinating HINT3

IntroductionPulmonary arterial hypertension (PAH) is a progressive, lethal, and incurable disease of the pulmonary vasculature. Evolving evidence indicates that the ubiquitin-specific proteases (USPs), play an important role in the pathogenesis of PAH by deubiquitinating key proteins involved in cell proliferation, migration, and apoptosis. Our genome-wide association study (GWAS) analysis-paired with transcriptomic profiling indicated that deubiquitinase USP11 and histidine triad nucleotide binding protein 3 (HINT3) are positively correlated and that their expression increased in lungs of PAH patients compared to control (fail donor) group, and inversely correlated with survival. However, mechanisms and function of the USP11/HNT3 axis have not been explored in PAH. Therefore, we aimed to investigate that HINT3 stabilized by USP11 activation links to endothelial apoptosis-resistance in PAH. Methods and ResultsExpression of USP11 and HINT3 was increased in the lungs of idiopathic PAH (IPAH) patients and Hypoxia/Sugen-treated mice using qRT-PCR and Western blot analyses. USP11 and HINT3 interacted physically as shown by co-immunoprecipitation (co-IP) assay in human pulmonary artery endothelial cells (HPAECs). HINT3 levels were decreased upon transfection of HA-tagged Ubi plasmid into HPAECs. Pretreatment with the potent proteasome inhibitor MG132 prolonged the half-life of HINT3 protein, indicating that HINT3 is degraded by polyubiquitination. HINT3 was stabilized and destabilized by forced overexpression or siRNA knockdown of USP11 respectively. Similarly, treatment with mitoxantrone, a USP11 antagonist, reduced HPAEC HINT3 expression. HINT3 interacted with the antiapoptotic mediator, BCL2. Overexpression of USP11 increased BCL2 content, congruent to elevated lung tissue levels seen in IPAH patients and Hypoxia/Sugen-treated mice. Conversely, knockdown of HINT3 function led to depletion of BCL2. ConclusionsThe HINT3-USP11 axis contributes to apoptosis-resistance in pulmonary artery endothelial cells, as is potentially a novel and attractive therapeutic target for ubiquitination modulators.

physiology↗

bioRxiv2022

PPARγ/ETV2 Axis Regulates Endothelial-to-Mesenchymal Transition in Pulmonary Hypertension

Endothelial-to-mesenchymal transition (EndoMT) plays an important role in pulmonary hypertension (PH). Also, the molecular mechanisms regulating EndoMT in PH remain to be defined. In this study, we first showed that reduced expression of the transcription factors ETV2 (ETS variant 2) and PPAR{gamma} (Peroxisome Proliferator-Activated Receptor gamma) along with reduced endothelial markers and increased EndoMT markers were consistently observed in lungs and pulmonary artery endothelial cells (PAECs) of idiopathic pulmonary arterial hypertension (IPAH) patients, in hypoxia-exposed mouse lungs, human PAECs, and in induced EndoMT cells. Base on this observation, we aimed to investigate the function of ETV2 and PPAR{gamma} in EndoMT. We have explored the function of ETV2 and PPAR{gamma} and its mechanism in PH using in Etv2+/- mice or PPAR{gamma} KO mice. Etv2+/- mice spontaneously developed PH and right ventricular hypertrophy, associated with increased EndoMT markers and decreased EC markers. PPAR{gamma} transcriptionally activated the ETV2 promoter. Endothelial PPAR{gamma} expression in mice is positively correlated with ETV2 expression, but inversely with EndoMT markers. Overexpression of ETV2 in hypoxia-exposed rat pulmonary artery led to vascular relaxation. We conclude that PPAR{gamma}-ETV2 signaling can function as a novel pathway in PH pathogenesis by attenuating EndoMT.

physiology↗

bioRxiv2021

A computational study on the optimization of transcranial temporal interfering stimulation with high-definition electrode using unsupervised neural network

Transcranial temporal interfering stimulation (tTIS) can focally stimulate deep parts of the brain, which are related to specific functions, by using beats at two high AC frequencies that do not affect the human brain. However, it has limitations in terms of calculation time and precision for optimization because of its complexity and non-linearity. We aimed to propose a method using an unsupervised neural network (USNN) for tTIS to optimize quickly the interfering current value of high-definition electrodes, which can finely stimulate the deep part of the brain, and analyze the performance and characteristics of tTIS. A computational study was conducted using 16 realistic head models. This method generated the strongest stimulation on the target, even when targeting deep areas or multi-target stimulation. The tTIS was robust with target depth compared with transcranial alternating current stimulation, and mis-stimulation could be reduced compared with the case of using two-pair inferential stimulation. Optimization of a target could be performed in 3 min. By proposing the USNN for tTIS, we showed that the electrode currents of tTIS can be optimized quickly and accurately, and the possibility of stimulating the deep part of the brain precisely with transcranial electrical stimulation was confirmed.

bioengineering↗