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As a bioisosteric strategy to overcome the poor metabolic stability of lead compound KYS05090S, a series of new fluoro-substituted 3,4-dihydroquinazoline derivatives was prepared and evaluated for T-type calcium channel (Ca v 3.2) block, cytotoxic effects and liver microsomal stability. Among them, compound 8h (KCP10068F) containing 4-fluorobenzyl amide and 4-cyclohexylphenyl ring potently blocked Ca v 3.2 currents (>90% inhibition) at 10 μM concentration and exhibited cytotoxic effect (IC 50 = 5.9 μM) in A549 non-small cell lung cancer cells that was comparable to KYS05090S. Furthermore, 8h showed approximately a 2-fold increase in liver metabolic stability in rat and human species compared to KYS05090S. Based on these overall results, 8h (KCP10068F) may therefore represent a good backup compound for KYS05090S for further biological investigations as novel cytotoxic agent. In addition, compound 8g (KCP10067F) was found to partially protect from inflammatory pain via a blockade of Ca v 3.2 channels. [ABSTRACT FROM AUTHOR]

Skeletal muscle atrophy is a feature of aging (termed sarcopenia) and various diseases, such as cancer and kidney failure. Effective drug treatment options for muscle atrophy are lacking. The tapeworm medication, niclosamide is being assessed for repurposing to treat numerous diseases, including end-stage cancer metastasis and hepatic steatosis. In this study, we investigated the potential of niclosamide as a repurposing drug for muscle atrophy. In a myotube atrophy model using the glucocorticoid, dexamethasone, niclosamide did not prevent the reduction in myotube diameter or the decreased expression of phosphorylated FOXO3a, which upregulates the ubiquitin-proteasome pathway of muscle catabolism. Treatment of normal myotubes with niclosamide did not activate mTOR, a major regulator of muscle protein synthesis, and increased the expression of atrogin-1, which is induced in catabolic states. Niclosamide treatment also inhibited myogenesis in muscle precursor cells, enhanced the expression of myoblast markers Pax7 and Myf5, and downregulated the expression of differentiation markers MyoD, MyoG and Myh2. In an animal model of muscle atrophy, niclosamide did not improve muscle mass, grip strength or muscle fiber cross-sectional area. Muscle atrophy is also feature of cancer cachexia. IC50 analyses indicated that niclosamide was more cytotoxic for myoblasts than cancer cells. In addition, niclosamide did not suppress the induction of iNOS, a key mediator of atrophy, in an in vitro model of cancer cachexia and did not rescue myotube diameter. Overall, these results suggest that niclosamide may not be a suitable repurposing drug for glucocorticoid-induced skeletal muscle atrophy or cancer cachexia. Nevertheless, niclosamide may be employed as a compound to study mechanisms regulating myogenesis and catabolic pathways in skeletal muscle. [ABSTRACT FROM AUTHOR]

Aging is associated with increased prevalence of skeletal and cardiac muscle disorders, such as sarcopenia and cardiac infarction. In this study, we constructed a compendium of purified ginsenoside compounds from Panax ginseng C.A. Meyer, which is a traditional Korean medicinal plant used to treat for muscle weakness. Skeletal muscle progenitor cell-based screening identified three compounds that enhance cell viability, of which 20(R)-ginsenoside Rh2 showed the most robust response. 20(R)-ginsenoside Rh2 increased viability in myoblasts and cardiomyocytes, but not fibroblasts or disease-related cells. The cellular mechanism was identified as downregulation of cyclin-dependent kinase inhibitor 1B (p27Kip1) via upregulation of Akt1/PKB phosphorylation at serine 473, with the orientation of the 20 carbon epimer being crucially important for biological activity. In zebrafish and mammalian models, 20(R)-ginsenoside Rh2 enhanced muscle cell proliferation and accelerated recovery from degeneration. Thus, we have identified 20(R)-ginsenoside Rh2 as a p27Kip1 inhibitor that may be developed as a natural therapeutic for muscle degeneration. [ABSTRACT FROM AUTHOR]

The presence of veterinary drug residues in foods and the environment could potentially cause adverse effects on humans and wildlife. Several veterinary drugs were reported to exhibit endocrine disrupting effects via binding affinities to sexual hormone receptors such as estrogen and androgen receptors. Therefore, we confirmed the human estrogen receptor (ER) agonistic/antagonistic effects of 135 chemicals that were used as veterinary drugs in Korea by the official Organization for Economic Cooperation and Development (OECD) in vitro ER transcriptional activation (TA) assay using the VM7Luc4E2 cell line. In the case of ER agonist screening, 7 veterinary drugs (cefuroxime, cymiazole, trenbolone, zeranol, phoxim, altrenogest and nandrolone) were determined to be ER agonists. In addition, only zeranol was found to exhibit weak ER antagonistic activity. These 7 veterinary drugs, which were determined as ER agonists and/or antagonists by an OECD in vitro assay, were also found to have binding affinity to ERs. These results indicate that various veterinary drugs possess potential (anti-)estrogenic effects. However, further study is needed to determine the precise endocrine-disrupting effects of these compounds. • ER agonistic/antagonistic effects of 135 veterinary drugs, used in Korea, are assessed. • OECD in vitro stably transfected transcriptional activation assays using the VM7Luc4E2 cell line are applied. • Cefuroxime, cymiazole, trenbolone, zeranol, phoxim, altrenogest and nandrolone) are determined to be ER agonists. • Zenarol also exhibited a weak ER antagonistic effect. • This report provides valuable evidences about potential endocrine disrupting effects of various veterinary drugs. [ABSTRACT FROM AUTHOR]

Indirubin-based compounds affect diverse biological processes, such as inflammation and angiogenesis. In this study, we tested a novel indirubin derivative, LDD-1819 (2-((((2Z,3E)-5-hydroxy-5′-nitro-2′-oxo-[2,3′-biindolinylidene]-3-ylidene)amino)oxy)ethan-1-aminium chloride) for two major biological activities: cell plasticity and anti-cancer activity. Biological assays indicated that LDD-1819 induced somatic cell plasticity. LDD-1819 potentiated myoblast reprogramming into osteogenic cells and fibroblast reprogramming into adipogenic cells. Interestingly, in an assay of skeletal muscle dedifferentiation, LDD-1819 induced human muscle cellularization and blocked residual proliferative activity to produce a population of mononuclear refractory cells, which is also observed in the early stages of limb regeneration in urodele amphibians. In cancer cell lines, LDD-1819 treatment inhibited cell invasion and selectively induced apoptosis compared to normal cells. In an animal tumor xenograft model, LDD-1819 reduced human cancer cell metastasis in vivo at doses that did not produce toxicity. Biochemical assays showed that LDD-1819 possessed inhibitory activity against glycogen synthase kinase-3β, which is linked to cell plasticity, and aurora kinase, which regulates carcinogenesis. These results indicate that novel indirubin derivative LDD-1819 is a dual inhibitor of glycogen synthase kinase-3β and aurora A kinase, and has potential for development as an anti-cancer drug or as a reprogramming agent for cell-therapy based approaches to treat degenerative diseases. [ABSTRACT FROM AUTHOR]

For the next generation display devices, dry etching technique for indium tin oxide (ITO) used as a transparent electrode is required to obtain a highly anisotropic etch profile, and to decrease the dimensional loss after the etching. For the dry etching of ITO, the easy dry cleaning of etch byproducts attached to the chamber wall during the dry etching is also important. In this study, by using novel hydrocarbon gases mixed with Ar, such as ethane (C 2 H 6) and propane (C 3 H 8), the dry etch characteristics and the etch residue cleaning process have been investigated using an inductively coupled plasma etcher, and the results were compared with the conventionally investigated methane (CH 4)-based gases, such as CH 4 and CH 4 /H 2 mixed with Ar. The result showed that the hydrogen in CH 4 /H 2 both decreased the ITO etch rate, and decreased the etch selectivity over photoresist (PR). By using hydrogen-less hydrocarbon gas having the alkane structure, such as C x H 2x+2 (x = 2, 3), both the ITO etch rate and the etch selectivity were increased with the increase of carbon in the alkane structure; therefore, the highest etch rate was observed for C 3 H 8. In addition, with the increase of x in the carbon of C x H 2x+2 , less dimensional loss, more anisotropic etch profile, and lower surface roughness could be observed. During the etching, etch residues containing C, In, Sn, O, and H were accumulated on the chamber wall due to the low volatility of the etch byproducts; however, the etch residues formed by all three hydrocarbon gases could be successfully dry cleaned using H 2 /Ar plasmas through the formation of InC x H y (x < y), CO x , and S n H x. • Etching of ITO with H 2 /CH 4 showed damage on the photoresist surface due to the redeposition of etch byproduct on the photoresist (PR) surface while etching the PR with hydrogen. • In C x H 2x+2 (x = 1,2,3)/Ar, the etch rate of ITO and the etch selectivity over PR increased as x is increased in the order of CH 4 , C 2 H 6 , and C 3 H 8 while showing no damage to the PR surface. • Due to the increase of etch selectivity, more anisotropic etch profile angle was observed in the order of CH 4 , C 2 H 6 , and C 3 H 8. • The residue was deposited on the chamber wall during the etching of ITO using C x H 2x+2 (x = 1,2,3)/Ar, however, the residue on the chamber wall could be completely cleaned by a H 2 /Ar plasma generated by the ICP source power. [ABSTRACT FROM AUTHOR]

Abstract: Our study investigated the histogenesis and biological significance of spindle cell carcinoma (SpCC) by comparing with moderately-well-differentiated squamous cell carcinoma (SCC) cell lines. Snail mRNA expression was readily detectable in the SpCC cell line, while E-cadherin was undetectable. SpCC cells showed lower proliferative and invasive activities than two other SCC cell lines. Culturing under air–liquid interface conditions promoted squamous cell differentiation, whereas fibroblastic differentiation after submerged culture with collagen, suggesting that the microenvironment may be a regulating factor of spindle cell differentiation as well as Snail expression and spindle cell change may not always entail the invasive behavior. [Copyright &y& Elsevier]

• In-vitro biotransformation of levothyroxine is conducted by S9 fraction. • The biotransformants are predicted by in-silico prediction and validated by LC-MS/MS. • Reporter gene assay is applied to link the activity changes with metabolite profiles. Thyroid-disrupting compounds (TDCs) are chemicals that modify thyroid gland function and disrupt hormonal homeostasis. Like other endocrine-disrupting chemicals (EDCs), TDCs often show altered activities following post-metabolic modification via endogenous enzymatic reaction. Hence, we developed evaluation system consisting of (1) in vitro metabolic reaction module, (2) high-resolution mass-spectrometry, and (3) human cell-based reporter gene assay. We developed the reaction module using rat S9 fraction where levothyroxine (T4) as a model compound, was subjected to phase-I or phase-I+II biotransformation. The metabolic profiles of the biotransformants were systematically configured based on in-silico prediction of potential products and experimental validation using liquid-chromatography Orbitrap mass-spectrometry. Thyroid agonistic activities of the biotransformants were evaluated by thyroid receptor-mediated stably transfected transcriptional activation assay using hTRE_HeLa cells. Indeed, we detected the increased activities following metabolic conversion of T4 in a dose-dependent manner. Note that the activity by phase-I+II reaction was much greater than by phase-I reaction (3.8-fold increase). Subsequently, we explored metabolic signatures, which potentially contributed to the hyperactivity by phase-I+II reaction. A total of 77 metabolic features were annotated based on the in-silico prediction, which included biotransformants with deiodination and conjugation. The glucuronide-conjugated form was found at the highest fold-increase (970-fold increase) whereas marginal increases were determined in the deiodinized forms (1.6-fold increase in T3 and 2.0-fold increase in rT3). Further, the systematic approach was evaluated and comparably analyzed by the metabolic profiles of bithionol, which is structurally related to T4. Our current result suggested the potential application of in vitro evaluation system to risk assessment of thyroid-disrupting activity. [ABSTRACT FROM AUTHOR]

Simple Summary: Few studies have employed expression data of normal tissues to explore the survival of cancer patients. Hence, we identified aging-related genes and microRNAs in normal tissues from patients with various types of cancer and investigated their effects on survival. We built statistical models to predict the survival of cancer patients using the expression levels of aging-related genes and microRNAs. We found that five aging-related genes (DUSP22, MAPK14, MAPKAPK3, STAT1, and VCP) from kidney cancer patients were significantly related to patient survival. We experimentally showed that there is an increase in the five aging-related genes in the macrophages of aged mice and, among these five genes, the invasion of cancer cells is inhibited by downregulating DUSP22. Using the zebrafish model of tumor cell dissemination, it was also confirmed that in vivo treatment with a small molecule inhibitor of DUSP22 blocked the metastasis of cancer cells in the early stage. The relationship between expression of aging-related genes in normal tissues and cancer patient survival has not been assessed. We developed a genome-wide transcriptomic analysis approach for normal tissues adjacent to the tumor to identify aging-related transcripts associated with survival outcome, and applied it to 12 cancer types. As a result, five aging-related genes (DUSP22, MAPK14, MAPKAPK3, STAT1, and VCP) in normal tissues were found to be significantly associated with a worse survival outcome in patients with renal cell carcinoma (RCC). This computational approach was investigated using nontumorigenic immune cells purified from young and aged mice. Aged immune cells showed upregulated expression of all five aging-related genes and promoted RCC invasion compared to young immune cells. Further studies revealed DUSP22 as a regulator and druggable target of metastasis. DUSP22 gene knockdown reduced RCC invasion and the small molecule inhibitor BML-260 prevented RCC dissemination in a tumor/immune cell xenograft model. Overall, these results demonstrate that deciphering the relationship between aging-related gene expression in normal tissues and cancer patient survival can provide new prognostic markers, regulators of tumorigenesis and novel targets for drug development. [ABSTRACT FROM AUTHOR]

Inflammation-mediated skeletal muscle wasting occurs in patients with sepsis and cancer cachexia. Both conditions severely affect patient morbidity and mortality. Lithium chloride has previously been shown to enhance myogenesis and prevent certain forms of muscular dystrophy. However, to our knowledge, the effect of lithium chloride treatment on sepsis-induced muscle atrophy and cancer cachexia has not yet been investigated. In this study, we aimed to examine the effects of lithium chloride using in vitro and in vivo models of cancer cachexia and sepsis. Lithium chloride prevented wasting in myotubes cultured with cancer cell-conditioned media, maintained the expression of the muscle fiber contractile protein, myosin heavy chain 2, and inhibited the upregulation of the E3 ubiquitin ligase, Atrogin-1. In addition, it inhibited the upregulation of inflammation-associated cytokines in macrophages treated with lipopolysaccharide. In the animal model of sepsis, lithium chloride treatment improved body weight, increased muscle mass, preserved the survival of larger fibers, and decreased the expression of muscle-wasting effector genes. In a model of cancer cachexia, lithium chloride increased muscle mass, enhanced muscle strength, and increased fiber cross-sectional area, with no significant effect on tumor mass. These results indicate that lithium chloride exerts therapeutic effects on inflammation-mediated skeletal muscle wasting, such as sepsis-induced muscle atrophy and cancer cachexia. [ABSTRACT FROM AUTHOR]

Alternative splicing (AS) is an important posttranscriptional regulatory process. Damaged or unnecessary cells need to be removed though apoptosis to maintain physiological processes. Caspase-2 pre-mRNA produces pro-apoptotic long mRNA and anti-apoptotic short mRNA isoforms through AS. How AS of Caspase-2 is regulated remains unclear. In the present study, we identified a novel regulatory protein SRSF9 for AS of Caspase-2 cassette exon 9. Knock-down (KD) of SRSF9 increased inclusion of cassette exon and on the other hand, overexpression of SRSF9 decreased inclusion of this exon. Deletion mutagenesis demonstrated that exon 9, parts of intron 9, exon 8 and exon 10 were not required for the role of SRSF9 in Caspase-2 AS. However, deletion and substitution mutation analysis revealed that AGGAG sequence located at exon 10 provided functional target for SRSF9. In addition, RNA-pulldown mediated immunoblotting analysis showed that SRSF9 interacted with this sequence. Gene ontology analysis of RNA-seq from SRSF9 KD cells demonstrates that SRSF9 could regulate AS of a subset of apoptosis related genes. Collectively, our results reveal a basis for regulation of Caspase-2 AS. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cell (MSC) transplantation is promising for repairing heart tissues post myocardial infarction (MI). In particular, paracrine effects of the transplanted MSCs have been highlighted to play major roles in heart regeneration by secreting multiple growth factors and immune-modulatory cytokines. Nevertheless, its therapeutic efficacy still remains low, which is strongly associated with low viability and activity of the transplanted stem cells, because the transplanted MSCs are exposed to high shear stress during injection and harsh environments (e.g., high oxidative stress and host immune reactions) post injection. In this study, we aimed to develop novel injectable MSC-delivery microgel systems possessing high anti-oxidant activities. Specifically, we encapsulated MSCs in graphene oxide (GO)/alginate composite microgels by electrospraying. To further enhance the anti-oxidizing activities of the gels, we developed reduced MSC-embedded GO/alginate microgels (i.e., r(GO/alginate)), which have the potential to protect MSCs from the abovementioned harsh environments within MI tissues. Our in vitro studies demonstrated that the MSCs encapsulated in the r(GO/alginate) microgels showed increased viability under oxidative stress conditions with H 2 O 2. Furthermore, cardiomyocytes (CMs), co-cultured with the encapsulated MSCs in transwells with H 2 O 2 treatment, showed higher cell viability and cardiac maturation compared to monolayer cultured CMs, likely due to ROS scavenging by the gels and positive paracrine signals from the encapsulated MSCs. In vivo experiments with acute MI models demonstrated improved therapeutic efficacy of MSC delivery in r(GO/alginate) microgels, exhibiting significant decreases in the infarction area and the improvement of cardiac function. We believe that our novel MSC encapsulation system with GO, alginate, and mild reduction, which exhibits high cell protection capacity (e.g., anti-oxidant activity), will serve as an effective platform for the delivery of stem cells and other therapeutic cell types to treat various injuries and diseases, including MI. Image 1 [ABSTRACT FROM AUTHOR]

The aging population is growing rapidly around the world and there is also an increase in sarcopenia, which is characterized by decreased muscle mass, strength and function in the elderly population. AMP-activated protein kinase (AMPK) is an essential sensor and regulator of glucose, lipid and energy metabolism throughout the body. Previous studies have shown that AMPK pathway activation by regular exercise and appropriate dietary control have beneficial effects on skeletal muscle. In the process of searching for new AMPK activators from medicinal plants, we isolated and characterized eight new 12,23-dione dammarane triterpenoids (1-3 and 5-9), as well as one known gypentonoside A from Gynostemma longipes. When all isolates were tested for their AMPK activation activities, seven compounds (1 and 3-8) were significantly activated AMPK phosphorylation in mouse C2C12 skeletal muscle cell lines. Since G. longipes contained a significant amount of active compound 1 (over 2.08% per dried raw plant), it suggested the potential of this plant to be developed as a functional food or botanical drug that enhances muscle proliferation by activating AMPK signaling pathways. [ABSTRACT FROM AUTHOR]

A metabolic conversion study on microbes is known as one of the most useful tools to predict the xenobiotic metabolism of organic compounds in mammalian systems. The microbial biotransformation of isoxanthohumol (1), a major hop prenylflavanone in beer, has resulted in the production of three diastereomeric pairs of oxygenated metabolites (2–7). The microbial metabolites of 1 were formed by epoxidation or hydroxylation of the prenyl group, and HPLC, NMR, and CD analyses revealed that all of the products were diastereomeric pairs composed of (2S)- and (2R)- isomers. The structures of these metabolic compounds were elucidated to be (2S,2″S)- and (2R,2″S)-4′-hydroxy-5-methoxy-7,8-(2,2-dimethyl-3-hydroxy-2,3-dihydro-4H-pyrano)-flavanones (2 and 3), (2S)- and (2R)-7,4′-dihydroxy-5-methoxy-8-(2,3-dihydroxy-3-methylbutyl)-flavanones (4 and 5) which were new oxygenated derivatives, along with (2R)- and (2S)-4′-hydroxy-5-methoxy-2″-(1-hydroxy-1-methylethyl)dihydrofuro[2,3-h]flavanones (6 and 7) on the basis of spectroscopic data. These results could contribute to understanding the metabolic fates of the major beer prenylflavanone isoxanthohumol that occur in mammalian system. [ABSTRACT FROM AUTHOR]

Obesity is a medical condition that impacts on all levels of society and causes numerous comorbidities, such as diabetes, cardiovascular disease, and cancer. We assessed the suitability of targeting enolase, a glycolysis pathway enzyme with multiple, secondary functions in cells, to treat obesity. Treating adipocytes with ENOblock, a novel modulator of these secondary 'moonlighting' functions of enolase, suppressed the adipogenic program and induced mitochondrial uncoupling. Obese animals treated with ENOblock showed a reduction in body weight and increased core body temperature. Metabolic and inflammatory parameters were improved in the liver, adipose tissue and hippocampus. The mechanism of ENOblock was identified as transcriptional repression of master regulators of lipid homeostasis (Srebp-1a and Srebp-1c), gluconeogenesis (Pck-1) and inflammation (Tnf-α and Il-6). ENOblock treatment also reduced body weight gain, lowered cumulative food intake and increased fecal lipid content in mice fed a high fat diet. Our results support the further drug development of ENOblock as a therapeutic for obesity and suggest enolase as a new target for this disorder. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) significantly impacts on human health and patient numbers are predicted to rise. Discovering novel drugs and targets for treating T2DM is a research priority. In this study, we investigated targeting of the glycolysis enzyme, enolase, using the small molecule ENOblock, which binds enolase and modulates its non-glycolytic 'moonlighting' functions. In insulin-responsive cells ENOblock induced enolase nuclear translocation, where this enzyme acts as a transcriptional repressor. In a mammalian model of T2DM, ENOblock treatment reduced hyperglycemia and hyperlipidemia. Liver and kidney tissue of ENOblock-treated mice showed down-regulation of known enolase target genes and reduced enolase enzyme activity. Indicators of secondary diabetic complications, such as tissue apoptosis, inflammatory markers and fibrosis were inhibited by ENOblock treatment. Compared to the well-characterized anti-diabetes drug, rosiglitazone, ENOblock produced greater beneficial effects on lipid homeostasis, fibrosis, inflammatory markers, nephrotoxicity and cardiac hypertrophy. ENOblock treatment was associated with the down-regulation of phosphoenolpyruvate carboxykinase and sterol regulatory element-binding protein-1, which are known to produce anti-diabetic effects. In summary, these findings indicate that ENOblock has potential for therapeutic development to treat T2DM. Previously considered as a 'boring' housekeeping gene, these results also implicate enolase as a novel drug target for T2DM. [ABSTRACT FROM AUTHOR]

In this study, we focused on confirming the steroid hormone receptor-mediated endocrine-disrupting potential of the pyrethroid insecticide fenvalerate and unraveling the underlying mechanisms. Therefore, we assessed estrogen receptor-α (ERα)- and androgen receptor (AR)-mediated responses in vitro using a hormone response element-dependent transcription activation assay with a luciferase reporter following the Organization for Economic Cooperation and Development (OECD) test guidelines. We observed that fenvalerate acted as estrogen by inducing the translocation of cytosolic ERα to the nucleus via ERα dimerization, whereas it exhibited no AR-mediated androgen response element-dependent luciferase activity. Furthermore, we confirmed that fenvalerate-induced activation of ERα caused lipid accumulation, promoted in a fenvalerate-dependent manner in 3 T3-L1 adipocytes. Moreover, fenvalerate-induced lipid accumulation was inhibited in the presence of an ERα-selective antagonist, whereas it remained unaffected in the presence of a glucocorticoid receptor (GR)-specific inhibitor. In addition, fenvalerate was found to stimulate the expression of transcription factors that promote lipid accumulation in 3 T1-L1 adipocytes, and co-treatment with an ERα-selective antagonist suppressed adipogenic/ lipogenic transcription factors at both mRNA and protein levels. These findings suggest that fenvalerate exposure may lead to lipid accumulation by interfering with ERα activation-dependent processes, thus causing an ERα-mediated endocrine-disrupting effect., Competing Interests: Declaration of competing interest The authors declare that they have no competing financial interests or personal relationships that may have influenced the work reported in this study., (Copyright © 2024. Published by Elsevier Inc.)

Bisphenol A (BPA) and its various forms used as BPA alternatives in industries are recognized toxic compounds and antiandrogenic endocrine disruptors. These chemicals are widespread in the environment and frequently detected in biological samples. Concerns exist about their impact on hormones, disrupting natural biological processes in humans, together with their negative impacts on the environment and biotic life. This study aims to characterize the interaction between BPA analogs and the androgen receptor (AR) and the effect on the receptor's normal activity. To achieve this goal, molecular docking was conducted with BPA and its analogs and dihydrotestosterone (DHT) as a reference ligand. Four BPA analogs exhibited higher affinity (-10.2 to -8.7 kcal/mol) for AR compared to BPA (-8.6 kcal/mol), displaying distinct interaction patterns. Interestingly, DHT (-11.0 kcal/mol) shared a binding pattern with BPA. ADMET analysis of the top 10 compounds, followed by molecular dynamics simulations, revealed toxicity and dynamic behavior. Experimental studies demonstrated that only BPA disrupts DHT-induced AR dimerization, thereby affecting AR's function due to its binding nature. This similarity to DHT was observed during computational analysis. These findings emphasize the importance of targeted strategies to mitigate BPA toxicity, offering crucial insights for interventions in human health and environmental well-being., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Beauvericin (BEA) is a cyclic depsipeptide secondary metabolite of Fusarium species. It causes chemical hazards in food products and exists in an environment containing soil and various food types. On the other hand, the purified BEA has various biological activities and is regarded as a potential candidate for pharmaceutical research. This study was performed to assess the anti-proliferation activity of BEA against human breast cancer cells by regulating the estrogen receptor-alpha (ERα)/p38 pathway. TA and BA assays verified that BEA is a completed ER antagonist. Additionally, BEA suppressed cell proliferation in the anti-proliferation assay involving ER-positive human breast cancer cells co-treated with BPA and BEA. In respect to an anti-proliferation activity, the BPA-induced phosphorylation of p38 protein was inhibited in the presence of BEA. These results suggested that BEA exerts inhibitory potentials on endocrine disrupting effect and possibly acts as a natural therapeutic material for human estrogen hormonal health., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

In current study, Fusarium mycotoxin, beauvericin (BEA), has endocrine disrupting potential through suppressing the exogenous androgen receptor (AR)-mediated transcriptional activation. BEA was classified as an AR antagonist, with IC 30 and IC 50 values indicating that it suppressed AR dimerization in the cytosol. BEA suppress the translocation of cytosolic activated ARs to the nucleus via exogenous androgens. Furthermore, we investigated the impact of environmental conditions for BEA production on rice cereal using response surface methodology. The environmental factors affecting the production of BEA, namely temperature, initial moisture content, and growth time were optimized at 20.28 °C, 42.79 % (w/w), and 17.31 days, respectively. To the best of our knowledge, this is the first report showing that BEA has endocrine disrupting potential through suppressing translocation of cytosolic ARs to nucleus, and temperature, initial moisture content, and growth time are important influencing environmental factors for its biosynthesis in Fusarium strains on cereal., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Fenhexamid are fungicides that act against plant pathogens by inhibiting sterol biosynthesis. Nonetheless, it can trigger endocrine disruption and promote breast cancer cell growth. In a recent study, we investigated the mechanism underlying the lipid accumulation induced by fenhexamid hydroxyanilide fungicides in 3 T3-L1 adipocytes. To examine the estrogen receptor alpha (ERα)-agonistic effect, ER transactivation assay using the ERα-HeLa-9903 cell line was applied, and fenhexamid-induced ERα agonist effect was confirmed. Further confirmation that ERα-dependent lipid accumulation occurred was provided by treating 3 T3-L1 adipocytes with Methyl-piperidino-pyrazole hydrate (MPP), an ERα-selective antagonist. Fenhexamid mimicked the actions of ERα agonists and impacted lipid metabolism, and its mechanism involves upregulation of the expression of transcription factors that facilitate adipogenesis and lipogenesis. Additionally, it stimulated the expression of peroxisome proliferator-activated receptor (PPARγ), CCAAT/enhancer-binding protein α (C/EBPα), fatty acid synthase (FAS), and sterol regulatory element-binding protein 1 (SREBP1) and significantly elevated the expression of fatty acid-binding protein 4 (FABP4). In contrast, in combination with an ERα-selective antagonist, fenhexamid suppressed the expression of adipogenic/lipogenic transcription factors. These results suggest that fenhexamid affects the endocrine system and leads to lipid accumulation by interfering with processes influenced by ERα activation., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing financial interests or personal relationships that may have influenced the work reported in the present study., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Targeted therapies for inhibiting the growth of cancer cells or inducing apoptosis are urgently needed for effective rhabdomyosarcoma (RMS) treatment. However, identifying cancer-targeting compounds with few side effects, among the many potential compounds, is expensive and time-consuming. A computational approach to reduce the number of potential candidate drugs can facilitate the discovery of attractive lead compounds. To address this and obtain reliable predictions of novel cell-line-specific drugs, we apply prediction models that have the potential to improve drug discovery approaches for RMS treatment. The results of two prediction models were ensemble and validated via in vitro experiments. The computational models were trained using data extracted from the Genomics of Drug Sensitivity in Cancer database and tested on two RMS cell lines to select potential RMS drug candidates. Among 235 candidate drugs, 22 were selected following the result of the computational approach, and three candidate drugs were identified (NSC207895, vorinostat, and belinostat) that showed selective effectiveness in RMS cell lines in vitro via the induction of apoptosis. Our in vitro experiments have demonstrated that our proposed methods can effectively identify and repurpose drugs for treating RMS., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Baek et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Sarcopenia is a disease characterized by the progressive loss of skeletal muscle mass and function that occurs with aging. The progression of sarcopenia is correlated with the onset of physical disability, the inability to live independently, and increased mortality. Due to global increases in lifespan and demographic aging in developed countries, sarcopenia has become a major socioeconomic burden. Clinical therapies for sarcopenia are based on physical therapy and nutritional support, although these may suffer from low adherence and variable outcomes. There are currently no clinically approved drugs for sarcopenia. Consequently, there is a large amount of pre-clinical research focusing on discovering new candidate drugs and novel targets. In this review, recent progress in this research will be discussed, along with the challenges that may preclude successful translational research in the clinic. The types of drugs examined include mitochondria-targeting compounds, anti-diabetes agents, small molecules that target non-coding RNAs, protein therapeutics, natural products, and repositioning candidates. In light of the large number of drugs and targets being reported, it can be envisioned that clinically approved pharmaceuticals to prevent the progression or even mitigate sarcopenia may be within reach.

We assessed the mechanism of human androgen receptor-mediated endocrine-disrupting effect by a triazole fungicide, metconazole in this study. The internationally validated stably transfected transactivation (STTA) in vitro assay, which was established for determination of a human androgen receptor (AR) agonist/antagonist by using 22Rv1/MMTV&#95;GR-KO cell line, alongside an in vitro reporter-gene assay to confirm AR homodimerization was used. The STTA in vitro assay results showed that metconazole is a true AR antagonist. Furthermore, the results from the in vitro reporter-gene assay and western blotting showed that metconazole blocks the nuclear transfer of cytoplasmic AR proteins by suppressing the homodimerization of AR. These results suggest that metconazole can be considered to have an AR-mediated endocrine-disrupting effect. Additionally, the evidence from this study might help identify the endocrine-disrupting mechanism of triazole fungicides containing a phenyl ring., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

This study was carried out to provide the evidence with respect to the adverse potential of chlorpropham, a representative carbamate ester herbicide product, on the endocrine system by using in vitro testing methods in accordance with the Organization for Economic Cooperation and Development Test Guideline No. 458 (22Rv1/MMTV&#95;GR-KO human androgen receptor [AR] transcriptional activation assay) and a bioluminescence resonance energy transfer-based AR homodimerization assay. Results revealed that chlorpropham had no AR agonistic effects, but it was determined to be a true AR antagonist without intrinsic toxicity against the applied cell lines. In the mechanism of chlorpropham-induced AR-mediated adverse effects, chlorpropham suppressed cytoplasmic AR translocation to the nucleus by inhibiting the homodimerization of the activated ARs. This suggests that chlorpropham exposure caused endocrine-disrupting effects through its interactions with human AR. Additionally, this study might help identify the genomic pathway of the AR-mediated endocrine-disrupting potential of N-phenyl carbamate herbicides., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

We selected azole pesticides products that are managed by setting maximum residue limits (MRLs) in the Republic of Korea and describe the estrogen receptor (ER) α-related negative effect to endocrine system using in vitro Organization for Economic Cooperation and Development performance-based test guideline. No azoles were found to be an ERα agonist. Conversely, three azoles (bitertanol, cafenstrole, and tebufenpyrad) were determined to be ERα antagonists. In addition, the ERα antagonistic activities of bitertanol, cafenstrole, and tebufenpyrad were not significantly perturbed in the existence of phase I (hydroxylation, dealkylation, oxidation or reduction) and phase II (conjugation). Regarding the mechanism underlying their ERα-mediated endocrine disrupting potentials, ERα proteins cannot be translocated to the nucleus by suppressing the dimerization of ERα in the cytoplasm by bitertanol, cafenstrole, and tebufenpyrad. These data indicated that azole pesticide products show the capability to interfere the ERα-related human endocrine system. Furthermore, we identified the mechanism of ERα-mediated endocrine disrupting by azole insecticide products through this study., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Several pesticides widely used in agriculture have been considered to be endocrine disrupting chemicals through their binding affinities to estrogen or androgen receptors. This study was conducted to clarify the human androgen receptor (hAR)-mediated genomic endocrine disrupting mechanism of eight selected pesticide products by in vitro assay providing the Organization for Economic Co-operation and Development Test Guideline No. 458, 22Rv1/MMTV&#95;GR-KO AR transcriptional activation assay and a homo-dimerization confirmation assay. None of the tested pesticide products showed an AR agonistic effect, whereas they were all determined to be AR antagonists at non-toxic concentrations. Also, the eight pesticide products were verified as true AR antagonists through a specificity control test. In the Bioluminescence Resonance Energy Transfer-based AR homo-dimerization confirmation assay, the eight pesticide products did not induce AR homo-dimerization. Additionally, western blotting revealed that none of the eight pesticide products induced AR translocation from the cytoplasm to the nucleus. In conclusion, we found for the first-time evidence to understand the AR-mediated endocrine disrupting mechanisms induced by selected azole and organophosphorus pesticide products., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Inc.)

Background: Skeletal muscle atrophy can occur in response to numerous factors, such as ageing and certain medications, and produces a major socio-economic burden. At present, there are no approved drugs for treating skeletal muscle atrophy. Arachidonate 5-lipoxygenase (Alox5) is a drug target for a number of diseases. However, pharmacological targeting of Alox5, and its role in skeletal muscle atrophy, is unclear., Methods: The potential effects of gene knockdown and pharmacological targeting of Alox5 on skeletal muscle atrophy were investigated using cell-based models, animal models and human skeletal muscle primary cells. Malotilate, a clinically safe drug developed for enhancing liver regeneration and Alox5 inhibitor, was investigated as a repurposing candidate. Mechanism(s) of action in skeletal muscle atrophy was assessed by measuring the expression level or activation status of key regulatory pathways and validated using gene knockdown and RNA sequencing., Results: Myotubes treated with the atrophy-inducing glucocorticoid, dexamethasone, were protected from catabolic responses by treatment with malotilate (+41.29%, P < 0.01). Similar anti-atrophy effects were achieved by gene knockdown of Alox5 (+30.4%, P < 0.05). Malotilate produced anti-atrophy effects without affecting the myogenic differentiation programme. In an in vivo model of skeletal muscle atrophy, malotilate treatment preserved muscle force/strength (grip strength: +35.72%, latency to fall: +553.1%, P < 0.05), increased mass and fibre cross-sectional area (quadriceps: +23.72%, soleus: +33.3%, P < 0.01) and down-regulated atrogene expression (Atrogin-1: -61.58%, Murf-1: -66.06%, P < 0.01). Similar, beneficial effects of malotilate treatment were observed in an ageing muscle model, which also showed the preservation of fast-twitch fibres (Type 2a: +56.48%, Type 2b: +37.32%, P < 0.01). Leukotriene B4, a product of Alox5 activity with inflammatory and catabolic functions, was found to be elevated in skeletal muscle undergoing atrophy (quadriceps: +224.4%, P < 0.001). Cellular transcriptome analysis showed that targeting Alox5 up-regulated biological processes regulating organogenesis and increased the expression of insulin-like growth factor-1, a key anti-atrophy hormone (+226.5%, P < 0.05). Interestingly, these effects were restricted to the atrophy condition and not observed in normal skeletal muscle cultures with Alox5 inhibition. Human myotubes were also protected from atrophy by pharmacological targeting of Alox5 (+23.68%, P < 0.05)., Conclusions: These results shed new light on novel drug targets and mechanisms underpinning skeletal muscle atrophy. Alox5 is a regulator and drug target for muscle atrophy, and malotilate is an attractive compound for repurposing studies to treat this disease., (© 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)

Objectives: Nasal obstruction is common in patients with obstructive sleep apnea (OSA). Nonetheless, the effectiveness of isolated nasal surgery in treatment of OSA remains controversial. This study is to evaluate the subjective and objective outcome after isolated nasal surgery in patients with OSA and to determine the associated factors related to the success rate of isolated nasal surgery., Methods: The study population consisted of 35 patients with nasal obstruction who had been diagnosed with OSA and were undergoing septoplasty and inferior turbinate reduction to correct nasal pathologies. Preoperative drug-induced sleep endoscopy was performed to evaluate the obstruction site. Patients were assessed before and after nasal surgery using subjective outcomes measures, including the Visual Analog Scale and Epworth Sleepiness Scale, as well as by overnight polysomnography., Results: All patients experienced improved nasal breathing postoperatively. At 6 months postoperatively, patients exhibited significant symptomatic improvement in snoring, sleep apnea, morning headache, tiredness, and daytime sleepiness. Postoperative polysomnography revealed significant improvement in the apnea-hypopnea index, respiratory disturbance index, and percentage of time with oxygen saturation < 90%. Although the overall success rate of nasal surgery alone was 14.3%, the criteria for success were met in 50% of patients with allergic rhinitis. Furthermore, the success rate was significantly higher in patients with moderate to severe nasal obstruction than in patients with mild nasal obstruction., Conclusion: Among patients with OSA, those with allergic rhinitis and severe nasal obstruction are likely to have a better surgical outcome following isolated nasal surgery., (Copyright © 2021 Elsevier Inc. All rights reserved.)

We describe the characterisation and validation of an androgen receptor (AR) transactivation assay for detection of AR agonists and antagonists using a stably transfected human prostate cancer cell line. This 22Rv1/mouse mammary tumour virus glucocorticoid knock-out cell line based AR transactivation assay was validated by criteria in Organisation for Economic Cooperation and Development Guidance Document 34 to determine if the assay performed equally well to the AR EcoScreen Assay included in Test Guideline for AR Transactivation (OECD TG 458). There was no Glucocorticoid Receptor (GR) crosstalk, and no changes in the AR DNA sequence in cells after the successful knock out of GR. Subsequently, the concordance of classifications of the 22 test chemicals was 100% in all laboratories. The AR agonistic and antagonistic inter-laboratory coefficients of variation based on log[10% effect for 10 nM DHT, PC 10 ] and log[inhibitory response of 800 pM DHT by at 30%, IC 30 ] from comprehensive tests were 2.75% and 2.44%, respectively. The AR agonist/antagonist test chemical classifications were consistent across AR EcoScreen ARTA assay data for 82/89%, and the balanced accuracy, sensitivity, and specificity were 83/90%, 88/100% and 78/80%, respectively. This assay was successfully validated and was approved for inclusion in TG 458 in 2020., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Endothelial cells appear to emerge from diverse progenitors. However, to which extent their developmental origin contributes to define their cellular and molecular characteristics remains largely unknown. Here, we report that a subset of endothelial cells that emerge from the tailbud possess unique molecular characteristics that set them apart from stereotypical lateral plate mesoderm (LPM)-derived endothelial cells. Lineage tracing shows that these tailbud-derived endothelial cells arise at mid-somitogenesis stages, and surprisingly do not require Npas4l or Etsrp function, indicating that they have distinct spatiotemporal origins and are regulated by distinct molecular mechanisms. Microarray and single cell RNA-seq analyses reveal that somitogenesis- and neurogenesis-associated transcripts are over-represented in these tailbud-derived endothelial cells, suggesting that they possess a unique transcriptomic signature. Taken together, our results further reveal the diversity of endothelial cells with respect to their developmental origin and molecular properties, and provide compelling evidence that the molecular characteristics of endothelial cells may reflect their distinct developmental history., (Copyright © 2020 Pak, Schmitt, Choi, Kim, Han, Alsiö, Jung, Williams, Coppieters, Stainier and Jin.)

This article contains chemical characterization and biological activity data for a novel indirubin derivative, termed LDD-1819. The detailed synthesis procedure and associated NMR data are presented. The concentration-dependent inhibition data of two biological targets, glycogen synthase kinase-3 β and aurora kinase A are described. The following biological data are also contained in this article: 1) the cellularization of skeletal muscle myotubes by LDD-1819 or two small molecule inhibitors of glycogen synthase kinase-3 β and aurora kinase A (BIO and reversine) and gene expression data for the myoblast markers Pax-7 and Myf5, 2) Cell viability of hTERT human immortalized fibroblasts, colon cancer cells and breast cancer cells, and 3) Western blotting analysis of full length and cleaved caspse-7, and cleaved poly (ADP-ribose) polymerase (PARP) in hTERT fibroblasts treated with LDD-1819. A schematic diagram of the biological activities of LDD-1819 is also presented. Further interpretation and discussion of these data are provided in the associated research article 'A novel indirubin derivative that increases somatic cell plasticity and inhibits tumorigenicity' (Kim et al., 2019).

Cancer-associated fibroblasts(CAFs) participate in carcinogenesis through interaction with cancer cells. This study aimed to investigate the mechanism of cytoskeletal alteration of CAFs and its role in invasion of oral squamous cell carcinoma(OSCC).Immortalized normal fibroblasts(hTERT-hNOFs) co-cultured with OSCC cells showed myofibroblastic and senescent phenotypes like CAFs. Thus, this study substituted hTERT-hNOFs for CAFs. Next, the cytoskeletal alteration and its molecular mechanism were investigated in hTERT-hNOFs co-cultured with OSCC. As results, we found that RhoA regulated cytoskeletal organization in fibroblasts surrounding OSCC cells. Furthermore, as a downstream transcriptional factor of RhoA, YAP was mainly localized in the nucleus of hTERT-hNOFs co-cultured with OSCC. Consequently, we examined whether nuclear YAP localization of fibroblasts could influence cancer progression. YAPS127A fibroblasts manifesting nuclear localization of YAP induced cytoskeletal alteration and increased gel contractility and matrix stiffness, and thereby enhances the invasiveness of OSCC cells. In conclusion, the modification of tumor microenvironment, such as cytoskeletal change and matrix remodeling via RhoA-YAP in CAFs, modulates OSCC invasion. These understandings will provide the development of novel approaches for CAFs-based cancer therapy., Competing Interests: The authors have declared that no competing interests exist.

Purpose: M2-type TAMs are increasingly implicated as a crucial factor promoting metastasis. Numerous cell types dictate monocyte differentiation into M2 TAMs via a complex network of cytokine-based communication. Elucidating critical pathways in this network can provide new targets for inhibiting metastasis. In this study, we focused on cancer cells, CAFs, and monocytes as a major node in this network. Experimental Design: Monocyte cocultures with cancer-stimulated CAFs were used to investigate differentiation into M2-like TAMs. Cytokine array analyses were employed to discover the CAF-derived regulators of differentiation. These regulators were validated in primary CAFs and bone marrow-derived monocytes. Orthotopic, syngeneic colon carcinoma models using cotransplanted CAFs were established to observe effects on tumor growth and metastasis. To confirm a correlation with clinical evidence, meta-analyses were employed using the Oncomine database. Results: Our coculture studies identify IL6 and GM-CSF as the pivotal signals released from cancer cell-activated CAFs that cooperate to induce monocyte differentiation into M2-like TAMs. In orthotopic, syngeneic colon carcinoma mouse models, cotransplanted CAFs elevated IL6 and GM-CSF levels, TAM infiltration, and metastasis. These pathologic effects were dramatically reversed by joint IL6 and GM-CSF blockade. A positive correlation between GM-CSF and IL6 expression and disease course was observed by meta-analyses of the clinical data. Conclusions: Our studies indicate a significant reappraisal of the role of IL6 and GM-CSF in metastasis and implicate CAFs as the "henchmen" for cancer cells in producing an immunosuppressive tumor ecological niche. Dual targeting of GM-CSF and IL6 is a promising new approach for inhibiting metastasis. Clin Cancer Res; 24(21); 5407-21. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Fillers are products that fill the space in soft tissues of the human body and actively used in the various medical fields. Unfortunately, most of the cost-effective commercially available fillers are synthetic and have limitations in terms of their biocompatibility. Here, we evaluated the possible application of decellularized xenogenic cartilage as a long-lasting material for soft tissue augmentation and compared it with two commercially available fillers Artesense (polymethylmethacrylate microspheres) and Radiesse (calcium hydroxyapatite [CaHa]). To do so, porcine auricular cartilage was harvested, followed by freezing and grinding of the tissue into flakes. Then, we used 1% Triton X-100 to decellularize the flakes. We then, respectively, injected 0.1 cc of each material (decellularized xenogenic cartilage, Radiesse, and Artesense) into the subcutaneous layer at three different sites per subject in 12 Sprague-Dawley rats, and evaluated the inflammatory cell infiltration and foreign body reactions of each. Our data indicate that the infiltration of giant cells in the injection area was significantly lower in the decellularized xenogenic cartilage injection group than that in the Radiesse and Artesense injection groups. Further, we observed some neutrophil infiltration in the xenogenic cartilage and Artesense injection groups at 1 month, but these levels were much lower at 3 months (comparable to the Radiesse injection group). Thus, decellularized xenogenic cartilage may have a distinct advantage in terms of biocompatibility compared with other commercial injectable long-lasting fillers, making it one of the most feasible, natural, and cost effective materials in the market. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2708-2715, 2018., (© 2018 Wiley Periodicals, Inc.)

Trenbolone acetate (TBA) is a synthetic anabolic steroidal growth factor that is used for rapid muscle development in cattle. The absorbed TBA is hydrolyzed to the active form, 17β-trenbolone (17 TB; 17β-hydroxy-estra-4,9,11-trien-3-one) in meat and milk products, which can cause adverse health effects in humans. Similar to 5α-dihydrotestosterone (DHT), 17 TB was reported to exhibit endocrine disrupting effects on animals and humans due to its androgenic effect via binding to the androgen receptor. The purpose of this study is to investigate the molecular mechanism of cell proliferation in prostate cancer (PCa) cells treated with 17 TB. We found that 17 TB induces AR-dependent cell proliferation in the human prostate cancer cell line, 22Rv1 in a concentration dependent manner. Treatment with 17 TB increased the expression of cell cycle regulatory proteins, cyclin D2/CDK-4 and cyclin E/CDK-2, whereas the expression of p27 was down-regulated. Furthermore, phosphorylation of Rb and activation of E2F were also induced, which suggests the activation of cyclin D2/CDK-4 and cyclin E/CDK-2 in the cells. When 22Rv1 cells were exposed to 30 pM of 17 TB, which is the effective concentration (EC 50 ) value required to observe proliferative effects on 22Rv1 cells, the expression levels of the phosphorylated forms of Akt and GSK3β were increased. This study demonstrates that 17 TB induces AR-dependent proliferation through the modulation of cell cycle-related proteins in the Akt signaling pathway. The present study provides an effective methodology for identifying cell proliferation signaling of veterinary drugs that exert AR agonistic effects., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: Degenerative diseases, such as Alzheimer's disease, heart disease and arthritis cause great suffering and are major socioeconomic burdens. An attractive treatment approach is stem cell transplantation to regenerate damaged or destroyed tissues. However, this can be problematic. For example, donor cells may not functionally integrate into the host tissue. An alternative methodology is to deliver bioactive agents, such as small molecules, directly into the diseased tissue to enhance the regenerative potential of endogenous stem cells. Areas covered: In this review, the authors discuss the necessity of developing these small molecules to treat degenerative diseases and survey progress in their application as therapeutics. They describe both the successes and caveats of developing small molecules that target endogenous stem cells to induce tissue regeneration. This article is based on literature searches which encompass databases for biomedical research and clinical trials. These small molecules are also categorized per their target disease and mechanism of action. Expert opinion: The development of small molecules targeting endogenous stem cells is a high-profile research area. Some compounds have made the successful transition to the clinic. Novel approaches, such as modulating the stem cell niche or targeted delivery to disease sites, should increase the likelihood of future successes in this field.

Objective: Nocturnal pulse oximetry has been proposed as a simpler alternative to polysomnography in diagnosing sleep apnea. However, existing techniques are limited in terms of inability to provide time information on sleep apnea occurrence. This study aimed to propose a new strategy for near real-time automatic detection of apneic events and reliable estimation of apnea-hypopnea index using nocturnal pulse oximetry., Methods: Among 230 polysomnographic recordings with apnea-hypopnea index values ranging from 0 to 86.5 events/h, 138 (60%) and the remaining 92 recordings (40%) were categorized as training and test sets, respectively. By extracting the quantitative characteristics caused by the apneic event for the amount and duration of the change in blood oxygen saturation value, we established the criteria to determine the occurrence of apneic event. Regression modeling was used to estimate the apnea-hypopnea index from the apneic event detection results., Results: The minute-by-minute apneic segment detection exhibited an average accuracy of 91.0% and an average Cohen's kappa coefficient of 0.71. Between the apnea-hypopnea index estimations and reference values, the mean absolute error was 2.30 events/h. The average accuracy of our diagnosis of sleep apnea was 96.7% for apnea-hypopnea index cutoff values of ≥5, 10, 15, and 30 events/h., Conclusion: We developed an effective strategy to detect apneic events by using morphometric characteristics in the fluctuation of blood oxygen saturation values., Significance: Our study could be potentially useful in home-based multinight apneic event monitoring for purposes of therapeutic intervention and follow-up study on sleep apnea.

We developed a simple attachable endoscopic nerve stimulator that can be connected to monopolar cauterization surgical instruments. This study on porcine models aimed to investigate the feasibility and efficacy of an attachable endoscopic nerve stimulator for intraoperative neuromonitoring (IONM) before application in humans. We evaluated the electromyography (EMG) amplitudes of 8 recurrent laryngeal nerves in 4 pigs with a conventional nerve probe and the attachable endoscopic nerve stimulator. The attachable endoscopic nerve stimulator was feasible and safe in all cases. There was no significant difference in the EMG amplitude of the recurrent laryngeal nerve among instruments ( P = .429). The application of stimulating dissection with an attachable endoscopic nerve stimulator during endoscopic or robotic thyroidectomy with IONM is simple, convenient, and effective. It provides surgeons with real-time feedback of the EMG response during intermittent IONM. We believe that this novel device could be an essential guide and functional navigator for most surgeons, especially for less experienced ones.

As tissue engineering and regenerative medicine have evolved recently, stem cell therapy has been investigated in the field of impaired wound healing. Several studies have reported that mesenchymal stem cells derived from various tissues including bone marrow and adipose tissue can exert the regenerative efficacy in the wound healing. Previously, we have demonstrated the isolation and characterization of tonsil-derived mesenchymal stem cells (TMSCs) with excellent proliferative property. In the present study, we aimed to evaluate the regenerative efficacy of TMSCs in the wound healing process. Two distinct cutaneous surgical defects were generated in the dorsum of mice. Each wound was treated with TMSCs or phosphate-buffered saline (PBS), respectively. After sacrifice, the skin and subcutaneous tissues around the surgical defect were harvested and assessed for inflammation, re-epithelialization, dermal regeneration, and granulation tissue formation. The administration of TMSCs into wound beds significantly promoted the repair of surgical defects in mice. Especially, TMSCs efficiently contributed to the attenuation of excessive inflammation in the surgical lesion, as well as the augmentation of epidermal and dermal regeneration. To elucidate the underlying mechanisms, TMSCs were analyzed for their potency in immunomodulatory ability on immune cells, stimulatory effect on the proliferation of keratinocytes, and fibroblasts, as well as the regulation of fibroblast differentiation. TMSCs inhibited the non-specific or T-cell-specific proliferation of peripheral blood mononuclear cells, as well as the M1 polarization of macrophage-like cells. Moreover, TMSCs augmented the proliferation of skin-constituting fibroblasts and keratinocytes while they suppressed the differentiation of fibroblasts into myofibroblasts. Taken together, our findings demonstrate the regenerative potential of TMSCs in wound healing process through the regulation on inflammation, proliferation, and remodeling of various skin cells, implying that TMSCs can be a promising alternative for wound repair.

Background: Fluorine-18 fluorodeoxyglucose positron emission tomography/CT ( 18 F-FDG PET/CT) has been widely accepted as an effective method for detecting recurrent papillary thyroid cancer (PTC) in patients with increased serum thyroglobulin (Tg) or Tg antibody (TgAb) levels and negative whole-body scintigraphy (WBS) results. The role of WBS as a diagnostic tool in detecting recurrence has relatively decreased recently. However, only a few studies have examined the usefulness of 18 F-FDG PET/CT for evaluating patients with recurrent PTC, regardless of the WBS results. The purpose of this analysis was to evaluate the diagnostic value and prognostic role of 18 F-FDG PET/CT for patients with recurrent PTC, irrespective of their WBS results., Methods: Sixty-six patients with locoregional recurrent PTC who underwent 18 F-FDG PET/CT and neck CT within 6 months before surgical treatment were included in this retrospective analysis. Imaging findings were compared with postoperative histopathologic results. The diagnostic values of 18 F-FDG PET/CT and neck CT were compared according to the serum Tg and TgAb levels and cervical levels. Each patient's status at the last follow-up was also reviewed, and survival probabilities were estimated using the Kaplan-Meier plot., Results: The sensitivity, specificity, and diagnostic accuracy of 18 F-FDG PET/CT for the entire patient group were 38.5%, 90.2%, and 58.3%, respectively. The corresponding neck CT values were 55.0%, 85.7%, and 66.7%, respectively. According to the serum Tg and TgAb levels, except for the specificity, most diagnostic values of 18 F-FDG PET/CT were worse than those of the neck CTs, with or without statistical significance. For the high maximum standardized uptake value (SUVmax) group (SUVmax >10) and the low SUVmax group, the median locoregional disease-free survival times were 33.3 months and 81.8 months, respectively (P < .001)., Conclusion: The diagnostic value of 18 F-FDG PET/CT for localizing recurrent lesions was worse than that of the neck CT, irrespective of the WBS results. However, patients with a higher SUVmax showed a significantly worse prognosis than did those with a lower SUVmax. Therefore, we suggest that, in patients with recurrent PTC, 18 F-FDG PET/CT should be considered for prognostication rather than diagnosis., (© 2017 Wiley Periodicals, Inc.)

Background: Recently, several energy-based devices (EBDs) have been developed and applied in the context of thyroid surgery. EBDs can reduce operation time, blood loss, and postoperative pain. Compared to conventional electrocautery, EBDs operate at a relatively lower temperature and produce minimal lateral tissue damage. Yet, during device operation, the tip of the EBD is hot enough to cause thermal nerve damage, increasing the need for surgeons to be cautious about EBD application. To increase the safety of EBDs, we attached nerve stimulators to the tips of two EBDs and compared them to conventional monopolar nerve stimulation using a porcine model., Methods: Three piglets (30-40 kg) underwent total thyroidectomy after orotracheal intubation with a nerve integrity monitor (NIM) electromyography (EMG) endotracheal tube. Nerve stimulators were attached to two EBDs (Harmonic Focus ® + and LigaSure™). After dissection and identification of six recurrent laryngeal nerves in the three piglets, both of the EBDs with attached nerve stimulators and a conventional monopolar nerve stimulator were applied near the nerve and EMG parameters were recorded using the NIM 3.0 system. The stimulus intensity was varied from 5 mA to 1 mA and the maximum distance and amplitude at which nerve detection was achieved were measured., Results: There were no statistically significant differences between the maximum distance or mean amplitude obtained from nerve stimulators attached to EBDs and those obtained from the conventional nerve stimulator. Additionally, there were no adverse EMG events related to the use of nerve stimulators attached to EBDs., Conclusions: Attachment of a nerve stimulator to an EBD for nerve detection during thyroidectomy was as safe and effective as attachment of a conventional nerve stimulator. Use of a nerve stimulator attachment may reduce the likelihood of EBD-associated nerve damage during thyroid surgery., (Copyright © 2017. Published by Elsevier Ltd.)

Background: With the increasing demand for general anesthesia for endoscopic esophageal procedures, anesthesiologists should understand the clinical characteristics of post-procedural complications (PPCs)., Methods: We retrospectively investigated the incidence of and risk factors associated with PPCs of endoscopic esophageal procedures performed under general anesthesia from July 2013 to November 2016. The final analysis included 129 patients; 114 who underwent esophageal endoscopic dissection for esophageal tumors and 15 cases of peroral endoscopic myotomy for achalasia. Frank perforation during the procedure was defined as an endoscopically recognizable or clinically detected perforation during the procedures. A multivariable logistic regression analysis was conducted to identify independent risk factors for PPCs., Results: The overall incidence of PPCs was 19.4% (25/129). All of the PPCs were managed successfully with conservative measures. The most common PPC was symptomatic, radiologically documented atelectasis (11/25, 44.0%), followed by esophageal perforation-related PPCs (symptomatic pneumomediastinum or pneumoperitoneum; 9/25, 36.0%). In the multivariable analysis, frank perforation during the procedure was the only independent risk factor for PPCs (odds ratio, 8.470, 95% CI, 2.051-34.974, P = 0.003). Although frank perforation during the procedure occurred in 13 patients, 38.5% (5/13) of them did not develop any clinical sequelae after their procedures. Compared with patients without PPCs, patients who developed PPCs took longer to their first oral intake and had prolonged hospital stays (P = 0.047 and 0.026, respectively)., Conclusions: Iatrogenic perforation during endoscopic esophageal procedures under general anesthesia was the only independent risk factor for PPCs; therefore, proactive measures and close follow-up are necessary.

Cyclooxygenase-2 (COX-2) triggers pro-inflammatory processes that can aggravate neuronal degeneration and functional impairments in many neurological conditions, mainly via producing prostaglandin E2 (PGE 2 ) that activates four membrane receptors, EP1-EP4. However, which EP receptor is the culprit of COX-2/PGE 2 -mediated neuronal inflammation and degeneration remains largely unclear and presumably depends on the insult types and responding components. Herein, we demonstrated that COX-2 was induced and showed nuclear translocation in two neuronal cell lines - mouse Neuro-2a and human SH-SY5Y - after treatment with neurotoxin 6-hydroxydopamine (6-OHDA), leading to the biosynthesis of PGE 2 and upregulation of pro-inflammatory cytokine interleukin-1β. Inhibiting COX-2 or microsomal prostaglandin E synthase-1 suppressed the 6-OHDA-triggered PGE 2 production in these cells. Treatment with PGE 2 or EP2 selective agonist butaprost, but not EP4 agonist CAY10598, increased cAMP response in both cell lines. PGE 2 -initiated cAMP production in these cells was blocked by our recently developed novel selective EP2 antagonists - TG4-155 and TG6-10-1, but not by EP4 selective antagonist GW627368X. The 6-OHDA-promoted cytotoxicity was largely blocked by TG4-155, TG6-10-1 or COX-2 selective inhibitor celecoxib, but not by GW627368X. Our results suggest that PGE 2 receptor EP2 is a key mediator of COX-2 activity-initiated cAMP signaling in Neuro-2a and SH-SY5Y cells following 6-OHDA treatment, and contributes to oxidopamine-mediated neurotoxicity.

Background: The active involvement of anesthesiologists in chronic pain management has been associated with an increase in the number of related medical dispute cases., Methods: Using the Korean Society of Anesthesiologists Legislation Committee database covering case files from July 2009 to June 2016, we explored injuries and liability characteristics in a subset of cases involving chronic pain management., Results: During the study period, 58 cases were eligible for final analysis. There were 27 cases related to complex regional pain syndrome (CRPS), many of them involving problems with financial compensation (24/27, 88.9%). The CRPS cases showed male dominance (22 males, 5 females). In a disproportionately large number of these cases, the causative injury occurred during military training (n = 5). Two cases were associated with noninvasive pain managements, and 29 cases with invasive procedures. Of the latter group, procedures involving the spine (both neuraxial and non-neuraxial procedures) resulted in more severe complications than other procedures (P = 0.007). Seven of the patients who underwent invasive procedures died. The most common type of invasive procedures were lumbosacral procedures (16/29, 55.2%). More specifically, the most common damaging events were inadvertent intravascular or intrathecal injection of local anesthetics (n = 6)., Conclusions: Several characteristics of medical disputes related to chronic pain management were identified: the prevalence of injury benefit claims in CRPS patients, higher severity of complications in procedures performed at the spine or cervical region, and the preventability of inadvertent intravascular or intrathecal injection of local anesthetics.