Age-dependent loss of Crls1 causes myopathy and skeletal muscle regeneration failure.

Skeletal muscle aging results in the gradual suppression of myogenesis, leading to muscle mass loss. However, the specific role of cardiolipin in myogenesis has not been determined. This study investigated the crucial role of mitochondrial cardiolipin and cardiolipin synthase 1 (Crls1) in age-related muscle deterioration and myogenesis. Our findings demonstrated that cardiolipin and Crls1 are downregulated in aged skeletal muscle. Moreover, the knockdown of Crls1 in myoblasts reduced mitochondrial mass, activity, and OXPHOS complex IV expression and disrupted the structure of the mitochondrial cristae. AAV9-shCrls1-mediated downregulation of Crls1 impaired muscle regeneration in a mouse model of cardiotoxin (CTX)-induced muscle damage, whereas AAV9-mCrls1-mediated Crls1 overexpression improved regeneration. Overall, our results highlight that the age-dependent decrease in CRLS1 expression contributes to muscle loss by diminishing mitochondrial quality in skeletal muscle myoblasts. Hence, modulating CRLS1 expression is a promising therapeutic strategy for mitigating muscle deterioration associated with aging, suggesting potential avenues for developing interventions to improve overall muscle health and quality of life in elderly individuals.

Androgen deprivation induces double-null prostate cancer via aberrant nuclear export and ribosomal biogenesis through HGF and Wnt activation.

Androgen deprivation therapy (ADT) targeting androgen/androgen receptor (AR)- signaling pathways is the main therapy for advanced prostate cancer (PCa). However, ADT eventually fails in most patients who consequently develop castration-resistant prostate cancer (CRPC). While more potent AR antagonists and blockers for androgen synthesis were developed to improve clinical outcomes, they also show to induce more diverse CRPC phenotypes. Specifically, the AR- and neuroendocrine-null PCa, DNPC, occurs in abiraterone and enzalutamide-treated patients. Here, we uncover that current ADT induces aberrant HGF/MET signaling activation that further elevates Wnt/ß-catenin signaling in human DNPC samples. Co-activation of HGF/MET and Wnt/ß-catenin axes in mouse prostates induces DNPC-like lesions. Single-cell RNA sequencing analyses identify increased expression and activity of XPO1 and ribosomal proteins in mouse DNPC-like cells. Elevated expression of XPO1 and ribosomal proteins is also identified in clinical DNPC specimens. Inhibition of XPO1 and ribosomal pathways represses DNPC growth in both in vivo and ex vivo conditions, evidencing future therapeutic targets.

An induced annual modulation signature in COSINE-100 data by DAMA/LIBRA's analysis method.

The DAMA/LIBRA collaboration has reported the observation of an annual modulation in the event rate that has been attributed to dark matter interactions over the last two decades. However, even though tremendous efforts to detect similar dark matter interactions were pursued, no definitive evidence has been observed to corroborate the DAMA/LIBRA signal. Many studies assuming various dark matter models have attempted to reconcile DAMA/LIBRA's modulation signals and null results from other experiments, however no clear conclusion can be drawn. Apart from the dark matter hypothesis, several studies have examined the possibility that the modulation is induced by variations in detector's environment or their specific analysis methods. In particular, a recent study presents a possible cause of the annual modulation from an analysis method adopted by the DAMA/LIBRA experiment in which the observed annual modulation could be reproduced by a slowly varying time-dependent background. Here, we study the COSINE-100 data using an analysis method similar to the one adopted by the DAMA/LIBRA experiment and observe a significant annual modulation, however the modulation phase is almost opposite to that of the DAMA/LIBRA data. Assuming the same background composition for COSINE-100 and DAMA/LIBRA, simulated experiments for the DAMA/LIBRA without dark matter signals also provide significant annual modulation with an amplitude similar to DAMA/LIBRA with opposite phase. Even though this observation does not directly explain the DAMA/LIBRA results directly, this interesting phenomenon motivates more profound studies of the time-dependent DAMA/LIBRA background data.

Effects of the administration of Shinbaro 2 in a rat lumbar disk herniation model.

The current standard for the pharmacological management of lumbar disk herniation (LDH), involving non-steroidal anti-inflammatory drugs, muscle relaxants, and opioid analgesics, often carries a risk of adverse events. The search for alternative therapeutic options remains a vital objective, given the high prevalence of LDH and the critical impact on the quality of life. Shinbaro 2 is a clinically effective herbal acupuncture against inflammation and various musculoskeletal disorders. Therefore, we explored whether Shinbaro 2 exerts protective effects in an LDH rat model. The results showed that Shinbaro 2 suppressed pro-inflammatory cytokines, interleukin-1 beta, tumor necrosis factor-alpha, disk degeneration-related factors, matrix metalloproteinase-1,-3,-9, and ADAMTS-5 in LDH rats. Shinbaro 2 administration reinstated a behavioral activity to a normal level in the windmill test. The results indicated that Shinbaro 2 administration restored spinal cord morphology and functions in the LDH model. Therefore, Shinbaro 2 exerted a protective effect in LDH via actions on inflammatory responses and disk degeneration, indicating that future research is warranted to assess the action mechanisms further and validate its effects.

Periplocin exerts antitumor activity by regulating Nrf2-mediated signaling pathway in gemcitabine-resistant pancreatic cancer cells.

Although gemcitabine-based chemotherapy is common and effective for pancreatic cancer (PC), acquired drug resistance is one of the major reasons for treatment failure. Therefore, a novel therapeutic approach for gemcitabine-resistant PC is required. Nuclear factor erythroid 2-related factor 2 (Nrf2) is an oxidative stress-responsive transcription factor regulating antioxidant responses and plays a crucial role in chemoresistance. In the present study, the antitumor activity of periplocin, a natural cardiac glycoside, was evaluated in an established gemcitabine-resistant PC cell line (PANC-GR). Nrf2 was overexpressed in gemcitabine-resistant cells, and Nrf2 knockdown recovered gemcitabine sensitivity in PANC-GR cells. The antiproliferative activity of periplocin was highly associated with Nrf2 downregulation and Nrf2-mediated signaling pathways in PANC-GR cells. Periplocin also increased reactive oxygen species production inducing G0/G1 cell cycle arrest and apoptosis in PANC-GR cells. Periplocin and gemcitabine combined significantly inhibited tumor growth in a PANC-GR cells-implanted xenograft mouse model via Nrf2 downregulation. Overall, these findings suggest that periplocin might be a novel therapeutic agent against gemcitabine resistance, as it could recover sensitivity to gemcitabine by regulating Nrf2-mediated signaling pathways in gemcitabine-resistant PC cells.

Stromal androgen signaling acts as tumor niches to drive prostatic basal epithelial progenitor-initiated oncogenesis.

The androgen receptor (AR)-signaling pathways are essential for prostate tumorigenesis. Although significant effort has been devoted to directly targeting AR-expressing tumor cells, these therapies failed in most prostate cancer patients. Here, we demonstrate that loss of AR in stromal sonic-hedgehog Gli1-lineage cells diminishes prostate epithelial oncogenesis and tumor development using in vivo assays and mouse models. Single-cell RNA sequencing and other analyses identified a robust increase of insulin-like growth factor (IGF) binding protein 3 expression in AR-deficient stroma through attenuation of AR suppression on Sp1-regulated transcription, which further inhibits IGF1-induced Wnt/ß-catenin activation in adjacent basal epithelial cells and represses their oncogenic growth and tumor development. Epithelial organoids from stromal AR-deficient mice can regain IGF1-induced oncogenic growth. Loss of human prostate tumor basal cell signatures reveals in basal cells of stromal AR-deficient mice. These data demonstrate a distinct mechanism for prostate tumorigenesis and implicate co-targeting stromal and epithelial AR-signaling for prostate cancer.

Aberrant androgen action in prostatic progenitor cells induces oncogenesis and tumor development through IGF1 and Wnt axes.

Androgen/androgen receptor (AR) signaling pathways are essential for prostate tumorigenesis. However, the fundamental mechanisms underlying the AR functioning as a tumor promoter in inducing prostatic oncogenesis still remain elusive. Here, we demonstrate that a subpopulation of prostatic Osr1 (odd skipped-related 1)-lineage cells functions as tumor progenitors in prostate tumorigenesis. Single cell transcriptomic analyses reveal that aberrant AR activation in these cells elevates insulin-like growth factor 1 (IGF1) signaling pathways and initiates oncogenic transformation. Elevating IGF1 signaling further cumulates Wnt/ß-catenin pathways in transformed cells to promote prostate tumor development. Correlations between altered androgen, IGF1, and Wnt/ß-catenin signaling are also identified in human prostate cancer samples, uncovering a dynamic regulatory loop initiated by the AR through prostate cancer development. Co-inhibition of androgen and Wnt-signaling pathways significantly represses the growth of AR-positive tumor cells in both ex-vivo and in-vivo, implicating co-targeting therapeutic strategies for these pathways to treat advanced prostate cancer.

Antitumor Activity of Rutaecarpine in Human Colorectal Cancer Cells by Suppression of Wnt/ß-Catenin Signaling.

Alkaloids derived from natural products have been traditionally used to treat various diseases, including cancers. Rutaecarpine (1), a ß-carboline-type alkaloid obtained from Evodia rutaecarpa, has been previously reported as an anti-inflammatory agent. Nonetheless, its anticancer activity and the underlying molecular mechanisms remain to be explored. In the procurement of Wnt/ß-catenin inhibitors from natural alkaloids, 1 was found to exhibit activity against the Wnt/ß-catenin-response reporter gene. Since the abnormal activation of Wnt/ß-catenin signaling is highly involved in colon carcinogenesis, the antitumor activity and molecular mechanisms of 1 were investigated in colorectal cancer (CRC) cells. The antiproliferative activity of 1 was associated with the suppression of the Wnt/ß-catenin-mediated signaling pathway and its target gene expression in human CRC cells. 1 also induced G0/G1 cell cycle arrest and apoptotic cell death, and the antimigration and anti-invasion potential of 1 was confirmed through epithelial-mesenchymal transition biomarker inhibition by the regulation of Wnt signaling. The antitumor activity of 1 was supported in an Ls174T-implanted xenograft mouse model via Wnt target gene regulation. Overall, these findings suggest that targeting the Wnt/ß-catenin signaling pathway by 1 is a promising therapeutic option for the treatment of human CRC harboring ß-catenin mutation.

Strong constraints from COSINE-100 on the DAMA dark matter results using the same sodium iodide target.

We present new constraints on dark matter interactions using 1.7 years of COSINE-100 data. The COSINE-100 experiment, consisting of 106 kg of tallium-doped sodium iodide [NaI(Tl)] target material, is aimed to test DAMA's claim of dark matter observation using the same NaI(Tl) detectors. Improved event selection requirements, a more precise understanding of the detector background, and the use of a larger dataset considerably enhance the COSINE-100 sensitivity for dark matter detection. No signal consistent with the dark matter interaction is identified and rules out model-dependent dark matter interpretations of the DAMA signals in the specific context of standard halo model with the same NaI(Tl) target for various interaction hypotheses.

Identification of stemness and differentially expressed genes in human cementum-derived cells.

PURPOSE: Periodontal treatment aims at complete regeneration of the periodontium, and developing strategies for periodontal regeneration requires a deep understanding of the tissues composing the periodontium. In the present study, the stemness characteristics and gene expression profiles of cementum-derived cells (CDCs) were investigated and compared with previously established human stem cells. Candidate marker proteins for CDCs were also explored. METHODS: Periodontal ligament stem cells (PDLSCs), pulp stem cells (PULPSCs), and CDCs were isolated and cultured from extracted human mandibular third molars. Human bone marrow stem cells (BMSCs) were used as a positive control. To identify the stemness of CDCs, cell differentiation (osteogenic, adipogenic, and chondrogenic) and surface antigens were evaluated through flow cytometry. The expression of cementum protein 1 (CEMP1) and cementum attachment protein (CAP) was investigated to explore marker proteins for CDCs through reverse-transcription polymerase chain reaction. To compare the gene expression profiles of the 4 cell types, mRNA and miRNA microarray analysis of 10 samples of BMSCs (n=1), PDLSCs (n=3), PULPSCs (n=3), and CDCs (n=3) were performed. RESULTS: The expression of mesenchymal stem cell markers with a concomitant absence of hematopoietic markers was observed in PDLSCs, PULPSCs, CDCs and BMSCs. All 4 cell populations also showed differentiation into osteogenic, adipogenic, and chondrogenic lineages. CEMP1 was strongly expressed in CDCs, while it was weakly detected in the other 3 cell populations. Meanwhile, CAP was not found in any of the 4 cell populations. The mRNA and miRNA microarray analysis showed that 14 mRNA genes and 4 miRNA genes were differentially expressed in CDCs vs. PDLSCs and PULPSCs. CONCLUSIONS: Within the limitations of the study, CDCs seem to have stemness and preferentially express CEMP1. Moreover, there were several up- or down-regulated genes in CDCs vs. PDLSCs, PULPSCs, and BMSCs and these genes could be candidate marker proteins of CDCs.

Stromal androgen and hedgehog signaling regulates stem cell niches in pubertal prostate development.

Stromal androgen-receptor (AR) action is essential for prostate development, morphogenesis and regeneration. However, mechanisms underlying how stromal AR maintains the cell niche in support of pubertal prostatic epithelial growth are unknown. Here, using advanced mouse genetic tools, we demonstrate that selective deletion of stromal AR expression in prepubescent Shh-responsive Gli1-expressing cells significantly impedes pubertal prostate epithelial growth and development. Single-cell transcriptomic analyses showed that AR loss in these prepubescent Gli1-expressing cells dysregulates androgen signaling-initiated stromal-epithelial paracrine interactions, leading to growth retardation of pubertal prostate epithelia and significant development defects. Specifically, AR loss elevates Shh-signaling activation in both prostatic stromal and adjacent epithelial cells, directly inhibiting prostatic epithelial growth. Single-cell trajectory analyses further identified aberrant differentiation fates of prostatic epithelial cells directly altered by stromal AR deletion. In vivo recombination of AR-deficient stromal Gli1-lineage cells with wild-type prostatic epithelial cells failed to develop normal prostatic epithelia. These data demonstrate previously unidentified mechanisms underlying how stromal AR-signaling facilitates Shh-mediated cell niches in pubertal prostatic epithelial growth and development.

Mechanical Strength and Hydration Characteristics of Cement Mixture with Highly Concentrated Hydrogen Nanobubble Water.

In this study, highly concentrated hydrogen nanobubble water was utilized as the blending water for cement mortar to improve its compressive and flexural strengths. Highly concentrated nanobubbles can be obtained through osmosis. This concentration was maintained by sustaining the osmotic time. The mortar specimens were cured for 28 days, in which the nanobubble concentration was increased. This improved their flexural strength by 2.25-13.48% and compressive strength by 6.41-11.22%, as compared to those afforded by plain water. The nanobubbles were densified at high concentrations, which caused a decrease in their diameter. This increased the probability of collisions with the cement particles and accelerated the hydration and pozzolanic reactions, which facilitated an increase in the strength of cement. Thermogravimetric analysis and scanning electron microscopy were used to confirm the development of calcium silicate hydrate (C-S-H) and hydration products with an increase in the nanobubble concentration. Quantitative analysis of the hydration products and the degree of hydration were calculated by mineralogical analysis.

Effect of Hydrogen Nanobubbles on the Mechanical Strength and Watertightness of Cement Mixtures.

This study analyzed the effects of applying highly concentrated hydrogen nanobubble water (HNBW) on the workability, durability, watertightness, and microstructure of cement mixtures. The number of hydrogen nanobubbles was concentrated twofold to a more stable state using osmosis. The compressive strength of the cement mortar for each curing day was improved by about 3.7-15.79%, compared to the specimen that used general water, when two concentrations of HNBW were used as the mixing water. The results of mercury intrusion porosimetry and a scanning electron microscope analysis of the cement paste showed that the pore volume of the specimen decreased by about 4.38-10.26%, thereby improving the watertightness when high-concentration HNBW was used. The improvement in strength and watertightness is a result of the reduction of the microbubbles' particle size, and the increase in the zeta potential and surface tension, which activated the hydration reaction of the cement and accelerated the pozzolanic reaction.

HbA1c changes in patients with diabetes following periodontal therapy.

PURPOSE: This retrospective cohort study aimed to assess the effect of nonsurgical periodontal therapy on glycated hemoglobin (HbA1c) levels in patients with both type 2 diabetes and chronic periodontitis. METHODS: The intervention cohort (IC) comprised 133 patients with type 2 diabetes who received nonsurgical periodontal treatment, while the matching cohort (MC) included 4787 patients with type 2 diabetes who visited the Department of Endocrinology and Metabolism of Asan Medical Center. The patients in each cohort were divided into 3 groups according to their baseline HbA1c level: subgroup 1, HbA1c <7%; subgroup 2, 7%≤ HbA1c <9%; and subgroup 3, HbA1c ≥9%. Changes in HbA1c levels from baseline to 6 and 12 months were analyzed. In addition, the association between changes in HbA1c levels and the number of periodontal maintenance visits was investigated. RESULTS: There were no statistically significant changes in HbA1c levels in the IC and MC or their subgroups when evaluated with repeated-measures analysis of variance. However, the IC showed maintenance of baseline HbA1c levels, while the MC had a trend for HbA1c levels to steadily increase as shown by pairwise comparisons (baseline to 6 months and baseline to 12 months). IC subgroup 1 also maintained steady HbA1c levels from 6 months to 12 months, whereas MC subgroup 1 presented a steady increase during the same period. The number of periodontal maintenance visits had no association with changes in HbA1c levels during the 1-year study duration. CONCLUSIONS: For patients with both type 2 diabetes and periodontitis, nonsurgical periodontal treatment and periodontal maintenance may help to control HbA1c levels.

Characterization of early postzygotic somatic mutations through multi-organ analysis.

Mosaicisms caused by postzygotic mutational events are of increasing interest because of their potential association with various human diseases. Postzygotic somatic mutations have not been well characterized however in terms of their developmental lineage in humans. We conducted whole-genome sequencing (WGS) and targeted deep sequencing in 15 organs across three developmental lineages from a single male fetus with polycystic kidney disease (PKD) of 21 weeks gestational age. This fetus had no detectable neurological abnormalities at autopsy but germline mutations in the PKHD1 gene were identified that may have been associated with the PKD. Eight early embryonic mosaic variants with no alteration of protein function were detected. These variants were thought to have occurred at the two or four cell stages after fertilization with a mutational pattern involving frequent C>T and T>C transitions. In our current analyses, no tendency toward organ-specific mutation occurrences was found as the eight variants were detected in all 15 organs. However different allele fractions of these variants were found in different organs, suggesting a tissue-specific asymmetric growth of cells that reflected the developmental germ layer of each organ. This indicated that somatic mutation occurrences, even in early embryogenesis, can affect specific organ development or disease. Our current analyses demonstrate that multi-organ analysis is helpful for understanding genomic mosaicism. Our results also provide insights into the biological role of mosaicism in embryonic development and disease.

Accuracy of periodontal probe visibility in the assessment of gingival thickness.

PURPOSE: The present study was undertaken to examine whether periodontal probe visibility (PV) accurately reflects gingival thickness (GT) and to identify factors affecting PV using cluster and multivariate analyses. METHODS: The clinical characteristics of the maxillary central incisors (n=90 subjects) were examined. Clinical photographs, sex, PV, probing depth, gingival width, papilla height, GT as measured with an ultrasonic device, and the ratio of crown width to crown length were recorded. Multivariate analysis, using multinomial baseline-category logistic regression, was used to identify factors predictive of PV. Cluster analysis was used to identify gingival biotypes. RESULTS: In the multivariate analysis, sex was the only significant predictor of PV (odds ratio, 6.48). Two clusters of subjects were created based on morphometric parameters. The mean GT among cluster A subjects was significantly lower than that among cluster B subjects (P=0.015). No significant difference was found between cluster A and B subjects in terms of PV score (P=0.583). CONCLUSIONS: Periodontal PV was not associated with GT as measured directly using an ultrasonic device. Sex was a highly significant predictor of periodontal PV. GT was found to be correlated with morphological characteristics of the periodontium.

Antitumor Activity of Asperphenin B by Induction of Apoptosis and Regulation of Glyceraldehyde-3-phosphate Dehydrogenase in Human Colorectal Cancer Cells.

Colorectal cancer (CRC) is a common and intractable malignancy with a high mortality risk. Conventional chemotherapeutics are effective for patients with early stage CRC, but the majority of deaths of CRC patients are linked to acquired drug resistance or metastasis occurrence. Asperphenin B (1), a lipopeptidyl benzophenone isolated from a marine-derived Aspergillus sp. fungus, reportedly possesses antiproliferative activity against cancer cells. However, its antitumor activity and the underlying molecular mechanisms remain unexplored. In this study, 1 induced G2/M phase cell cycle arrest and subsequent apoptotic cell death and inhibited tumor growth in a xenograft model. The 1-induced G2/M phase arrest was associated with the regulation of checkpoint proteins, including Chk1/2 and Cdc25c. The 1-induced apoptosis was correlated with an upregulation of p53 and cleaved caspases and a downregulation of survivin. Further experiments revealed that 1-mediated suppression of migration and invasion of metastatic HCT116 cells was partially associated with the downregulation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression. The antimetastatic potential of 1 was also confirmed by E-cadherin upregulation and N-cadherin and Snail downregulation, which were in turn associated with the GAPDH regulation. These findings highlight the potential use of 1 as a novel candidate for treating metastatic CRC with the modulation of GAPDH function.

Androgen action in cell fate and communication during prostate development at single-cell resolution.

Androgens/androgen receptor (AR)-mediated signaling pathways are essential for prostate development, morphogenesis and regeneration. Specifically, stromal AR signaling has been shown to be essential for prostatic initiation. However, the molecular mechanisms underlying AR-initiated mesenchymal-epithelial interactions in prostate development remain unclear. Here, using a newly generated mouse model, we have directly addressed the fate and role of genetically marked AR-expressing cells during embryonic prostate development. Androgen signaling-initiated signaling pathways were identified in mesenchymal niche populations at single-cell transcriptomic resolution. The dynamic cell-signaling networks regulated by stromal AR were additionally characterized in relation to prostatic epithelial bud formation. Pseudotime analyses further revealed the differentiation trajectory and fate of AR-expressing cells in both prostatic mesenchymal and epithelial cell populations. Specifically, the cellular properties of Zeb1-expressing progenitors were assessed. Selective deletion of AR signaling in a subpopulation of mesenchymal rather than epithelial cells dysregulated the expression of the master regulators and significantly impaired prostatic bud formation. These data provide novel, high-resolution evidence demonstrating the important role of mesenchymal androgen signaling in the cellular niche controlling prostate early development by initiating dynamic mesenchyme-epithelia cell interactions.