Search

Low fertility is a critical social problem worldwide, and infertility has a prevalence of 15%. This cross-sectional study aimed to understand the factors affecting the usage and satisfaction of Korean medicine (KM) in subfertile women. An online survey was conducted from 3 November to 8 November 2021. The survey collected basic information, KM treatment experience, and satisfaction from women who experienced poor pregnancy. The t-test and chi-square test (χ2-test) were used to determine the overall characteristics of the subjects and factors affecting the utilization and satisfaction of KM treatment. Of the total of 29,465 people, 4922 read the survey email, and 601 responded. After excluding 51 respondents with questionable response patterns, 550 respondents were included in the final analysis. Of these, 43.1% (n = 237) had experience with conventional treatment, and 16.5% (n = 91) had received KM treatment. The group that received both KM treatment and CM treatment (n = 59, 24.9%) was significantly more prevalent than the group that received KM treatment alone (n = 32, 10.2%) (p = 0.00). Women who had given birth more than once or held a master's degree were significantly more willing to participate in the 'KM Support Project for Subfertility' program. Our findings suggest that subfertile patients prefer integrated treatment that combines KM and CM treatments. Further studies are needed to assess the status of integrative medicine treatment, satisfaction with each KM intervention, factors for low satisfaction, and patient requirements. [ABSTRACT FROM AUTHOR]

Although abnormal increases in the level or activity of cyclin-dependent kinase 4 (CDK4) occur frequently in cancer, the underlying mechanism is not fully understood. Here, we show that methionyl-tRNA synthetase (MRS) specifically stabilizes CDK4 by enhancing the formation of the complex between CDK4 and a chaperone protein. Knockdown of MRS reduced the CDK4 level, resulting in G0/G1 cell cycle arrest. The effects of MRS on CDK4 stability were more prominent in the tumor suppressor p16INK4a-negative cancer cells because of the competitive relationship of the two proteins for binding to CDK4. Suppression of MRS reduced cell transformation and the tumorigenic ability of a p16INK4a-negative breast cancer cell line in vivo. Further, the MRS levels showed a positive correlation with those of CDK4 and the downstream signals at high frequency in p16INK4a-negative human breast cancer tissues. This work revealed an unexpected functional connection between the two enzymes involving protein synthesis and the cell cycle.

A protein synthesis enzyme, leucyl-tRNA synthetase (LRS), serves as a leucine sensor for the mechanistic target of rapamycin complex 1 (mTORC1), which is a central effector for protein synthesis, metabolism, autophagy, and cell growth. However, its significance in mTORC1 signaling and cancer growth and its functional relationship with other suggested leucine signal mediators are not well-understood. Here we show the kinetics of the Rag GTPase cycle during leucine signaling and that LRS serves as an initiating "ON" switch via GTP hydrolysis of RagD that drives the entire Rag GTPase cycle, whereas Sestrin2 functions as an "OFF" switch by controlling GTP hydrolysis of RagB in the Rag GTPase-mTORC1 axis. The LRS-RagD axis showed a positive correlation with mTORC1 activity in cancer tissues and cells. The GTP-GDP cycle of the RagD-RagB pair, rather than the RagC-RagA pair, is critical for leucine-induced mTORC1 activation. The active RagD-RagB pair can overcome the absence of the RagC-RagA pair, but the opposite is not the case. This work suggests that the GTPase cycle of RagD-RagB coordinated by LRS and Sestrin2 is critical for controlling mTORC1 activation, and thus will extend the current understanding of the amino acid-sensing mechanism.

Mucin1 (MUC1), a heterodimeric oncoprotein, containing tandem repeat structures with a high proportion of threonine, is aberrantly overexpressed in many human cancers including pancreatic cancer. Since the overall survival rate of pancreatic cancer patients has remained low for several decades, novel therapeutic approaches are highly needed. Intestinal mucin has been known to be affected by dietary threonine supply since de novo synthesis of mucin proteins is sensitive to luminal threonine concentration. However, it is unknown whether biosynthesis of MUC1 is regulated by threonine in human cancers. In this study, data provided suggests that threonine starvation reduces the level of MUC1 and inhibits the migration of MUC1-expressing pancreatic cancer cells. Interestingly, knockdown of threonyl-tRNA synthetase (TRS), an enzyme that catalyzes the ligation of threonine to its cognate tRNA, also suppresses MUC1 levels but not mRNA levels. The inhibitors of TRS decrease the level of MUC1 protein and prohibit the migration of MUC1-expressing pancreatic cancer cells. In addition, a positive correlation between TRS and MUC1 levels is observed in human pancreatic cancer cells. Concurrent with these results, the bioinformatics data indicate that co-expression of both TRS and MUC1 is correlated with the poor survival of pancreatic cancer patients. Taken together, these findings suggest a role for TRS in controlling MUC1-mediated cancer cell migration and provide insight into targeting TRS as a novel therapeutic approach to pancreatic cancer treatment.

Idiopathic pulmonary fibrosis (IPF), a chronic disease of unknown cause, is characterized by abnormal accumulation of extracellular matrix (ECM) in fibrotic foci in the lung. Previous studies have shown that the transforming growth factor β1 (TGFβ1) and signal transducers and activators of transcription (STAT) pathways play roles in IPF pathogenesis. Glutamyl-prolyl-tRNA-synthetase (EPRS) has been identified as a target for anti-fibrosis therapy, but the link between EPRS and TGFβ1-mediated IPF pathogenesis remains unknown. Here, we studied the role of EPRS in the development of fibrotic phenotypes in A549 alveolar epithelial cells and bleomycin-treated animal models. We found that EPRS knockdown inhibited the TGFβ1-mediated upregulation of fibronectin and collagen I and the mesenchymal proteins α-smooth muscle actin (α-SMA) and snail 1. TGFβ1-mediated transcription of collagen I-α1 and laminin γ2 in A549 cells was also down-regulated by EPRS suppression, indicating that EPRS is required for ECM protein transcriptions. Activation of STAT signaling in TGFβ1-induced ECM expression was dependent on EPRS. TGFβ1 treatment resulted in EPRS-dependent in vitro formation of a multi-protein complex consisting of the TGFβ1 receptor, EPRS, Janus tyrosine kinases (JAKs), and STATs. In vivo lung tissue from bleomycin-treated mice showed EPRS-dependent STAT6 phosphorylation and ECM production. Our results suggest that epithelial EPRS regulates the expression of mesenchymal markers and ECM proteins via the TGFβ1/STAT signaling pathway. Therefore, epithelial EPRS can be used as a potential target to develop anti-IPF treatments.

Leucyl-tRNA synthetase (LRS) is known to function as leucine sensor in the mammalian target of rapamycin complex 1 (mTORC1) pathway. However, the pathophysiological significance of its activity is not well understood. Here, we demonstrate that the leucine sensor function for mTORC1 activation of LRS can be decoupled from its catalytic activity. We identified compounds that inhibit the leucine-dependent mTORC1 pathway by specifically inhibiting the GTPase activating function of LRS, while not affecting the catalytic activity. For further analysis, we selected one compound, BC-LI-0186, which binds to the RagD interacting site of LRS, thereby inhibiting lysosomal localization of LRS and mTORC1 activity. It also effectively suppressed the activity of cancer-associated MTOR mutants and the growth of rapamycin-resistant cancer cells. These findings suggest new strategies for controlling tumor growth that avoid the resistance to existing mTOR inhibitors resulting from cancer-associated MTOR mutations.Leucyl-tRNA synthetase (LRS) is a leucine sensor of the mTORC1 pathway. Here, the authors identify inhibitors of the GTPase activating function of LRS, not affecting its catalytic activity, and demonstrate that the leucine sensor function of LRS can be a new target for mTORC1 inhibition.

Although many patients with mild traumatic brain injury (mTBI) suffer from postconcussional syndrome (PCS) including abnormal emotional responses, most conventional imaging studies fail to detect any causative brain lesion. We hypothesized that event-related electroencephalography (EEG) recordings with time-frequency analysis would show a distinguishable pattern in patients with mTBI with PCS compared with normal healthy controls. EEG signals were collected from a total of 18 subjects: eight patients with mTBI with PCS and 10 healthy control subjects. The signals were recorded while the subjects were presented with affective visual stimuli, including neutral, pleasant, and unpleasant emotional cues. Event-related spectral perturbation analysis was performed to calculate frontal midline theta activity and posterior midline gamma activity, followed by statistical analysis to identify whether patients with mTBI with PCS have distinct patterns of theta or gamma oscillations in response to affective stimuli. Compared with the healthy control group, patients with mTBI with PCS did not show a significant increase in the power of frontal theta activity in response to the pleasant stimuli, indicating less susceptibility toward pleasant cues. Moreover, the patient group showed attenuated gamma oscillatory activity, with no clear alteration in gamma oscillations in response to either pleasant or unpleasant cues. This study demonstrates that patients with mTBI with PCS exhibited altered patterns of oscillatory activities in the theta and gamma bands in response to affective visual stimuli compared with the normal control group. The current finding implicates that these distinguishable patterns of brain oscillation may represent the mechanism behind various psychiatric symptoms in patients with mTBI. NEW & NOTEWORTHY: Patients with mild traumatic brain injury (mTBI) with postconcussional syndrome (PCS) exhibited altered patterns of changes in oscillatory activities in the theta and gamma bands in response to visual affective stimuli. Distinguishable patterns of brain oscillation may represent the mechanism behind various psychiatric symptoms in patients with mTBI. [ABSTRACT FROM AUTHOR]