Association of Possible Sarcopenia or Sarcopenia with Body Composition, Nutritional Intakes, Serum Vitamin D Levels, and Physical Activity among Patients with Type 2 Diabetes Mellitus in Taiwan.

This study estimates the association between sarcopenia and blood biochemical parameters, nutritional intake, anthropometric measurements, physical performance, and physical activity in patients with type 2 diabetes mellitus (T2DM). Participants were recruited from a primary care clinic in Kaohsiung City. According to the diagnosis criteria of the Asian Working Group for Sarcopenia (AWGS) in 2019, 110 patients with T2DM (aged 50-80 years) were divided into three groups: non-sarcopenia (n = 38), possible sarcopenia (n = 31), and sarcopenia (n = 41). Blood samples were collected, and nutritional intake was evaluated by a registered dietitian. A food frequency questionnaire and a Godin leisure-time exercise questionnaire were used to assess their daily vitamin D intake and physical activity. There were significant differences in age, serum vitamin D levels, nutritional intake, anthropometric measurements, and physical performance between the three groups. In elderly patients with T2DM, reduced serum 25-hydroxyvitamin D [25(OH)D] levels and daily energy intake were significantly associated with possible sarcopenia. Age, lower BMI, reduced serum 25(OH)D, and reduced dietary protein and vitamin D intake were significantly associated with sarcopenia. These findings may serve as the basis for intervention trials to reduce the prevalence of sarcopenia.

Effects of bendable P3CT polymers layer on the photovoltaic performance of perovskite solar cells.

We report on the formation of bendable and edge-on poly[3-(4-carboxybutyl)thiophene-2,5-diyl] (P3CT) polymers thin layer used as a hole modification layer (HML) in the inverted perovskite solar cell. The aggregations of 2D layer-like P3CT polymers in dimethylformamide (DMF) solution can be formed via aromaticπ-πstacking interactions and/or hydrogen-bonding interactions with the different concentration from 0.01 to 0.02 wt%, which highly influences the photovoltaic performance of the inverted perovskite solar cells. The atomic-force microscopic images and water droplet contact angle images show that the P3CT polymers modify the surface properties of the transparent conductive substrate and thereby dominating the formation of perovskite crystalline thin films, which play important roles in the highly efficient and stable perovskite solar cells. It is noted that theVOC(JSC) of the encapsulated solar cells values are maintained to be higher than 1.115 V (22 mA cm-2) after 104 d when an optimizedπ-πstacked and hydrogen-bonded P3CT polymer is used as the HML. On the other hand, the solar cell showed a high long-term stability by maintaining 85% of the initial power conversion efficiency in the ambient air for 103 d.

Inositol possesses antifibrotic activity and mitigates pulmonary fibrosis.

BACKGROUND: Myo-inositol (or inositol) and its derivatives not only function as important metabolites for multiple cellular processes but also act as co-factors and second messengers in signaling pathways. Although inositol supplementation has been widely studied in various clinical trials, little is known about its effect on idiopathic pulmonary fibrosis (IPF). Recent studies have demonstrated that IPF lung fibroblasts display arginine dependency due to loss of argininosuccinate synthase 1 (ASS1). However, the metabolic mechanisms underlying ASS1 deficiency and its functional consequence in fibrogenic processes are yet to be elucidated. METHODS: Metabolites extracted from primary lung fibroblasts with different ASS1 status were subjected to untargeted metabolomics analysis. An association of ASS1 deficiency with inositol and its signaling in lung fibroblasts was assessed using molecular biology assays. The therapeutic potential of inositol supplementation in fibroblast phenotypes and lung fibrosis was evaluated in cell-based studies and a bleomycin animal model, respectively. RESULTS: Our metabolomics studies showed that ASS1-deficient lung fibroblasts derived from IPF patients had significantly altered inositol phosphate metabolism. We observed that decreased inositol-4-monophosphate abundance and increased inositol abundance were associated with ASS1 expression in fibroblasts. Furthermore, genetic knockdown of ASS1 expression in primary normal lung fibroblasts led to the activation of inositol-mediated signalosomes, including EGFR and PKC signaling. Treatment with inositol significantly downregulated ASS1 deficiency-mediated signaling pathways and reduced cell invasiveness in IPF lung fibroblasts. Notably, inositol supplementation also mitigated bleomycin-induced fibrotic lesions and collagen deposition in mice. CONCLUSION: These findings taken together demonstrate a novel function of inositol in fibrometabolism and pulmonary fibrosis. Our study provides new evidence for the antifibrotic activity of this metabolite and suggests that inositol supplementation may be a promising therapeutic strategy for IPF.

Discovery of a metastable van der Waals semiconductor via polymorphic crystallization of an amorphous film.

Here we report on the growth of thin crystalline films of the metastable phase GeTe2. Direct observation by transmission electron microscopy revealed a Te-Ge-Te stacking with van der Waals gaps. Moreover, electrical and optical measurements revealed the films exhibted semiconducting properties commensurate with electronics applications. Feasibility studies in which device structures were fabricated demonstrated the potential application of GeTe2 as an electronic material.

Dislocation characterization inc-plane GaN epitaxial layers on 6 inch Si wafer with a fast second-harmonic generation intensity mapping technique.

Second harmonic generation (SHG) intensity, Raman scattering stress, photoluminescence and reflected interference pattern are used to determine the distributions of threading dislocations (TDs) and horizontal dislocations (HDs) in thec-plane GaN epitaxial layers on 6 inch Si wafer which is a structure of high electron mobility transistor (HEMT). The Raman scattering spectra show that the TD and HD result in the tensile stress and compressive stress in the GaN epitaxial layers, respectively. Besides, the SHG intensity is confirmed that to be proportional to the stress value of GaN epitaxial layers, which explains the spatial distribution of SHG intensity for the first time. It is noted that the dislocation-mediated SHG intensity mapping image of the GaN epitaxial layers on 6 inch Si wafer can be obtained within 2 h, which can be used in the optimization of high-performance GaN based HEMTs.

Tissue Proteogenomic Landscape Reveals the Role of Uncharacterized SEL1L3 in Progression and Immunotherapy Response in Lung Adenocarcinoma.

The fundamental pursuit to complete the human proteome atlas and the unmet clinical needs in lung adenocarcinoma have prompted us to study the functional role of uncharacterized proteins and explore their implications in cancer biology. In this study, we characterized SEL1L3, a previously uncharacterized protein encoded from chromosome 4 as a dysregulated protein in lung adenocarcinoma from the large-scale tissue proteogenomics data set established using the cohort of Taiwan Cancer Moonshot. SEL1L3 was expressed in abundance in the tumor parts compared with paired adjacent normal tissues in 90% of the lung adenocarcinoma patients in our cohorts. Moreover, survival analysis revealed the association of SEL1L3 with better clinical outcomes. Intriguingly, silencing of SEL1L3 imposed a reduction in cell viability and activation of ER stress response pathways, indicating a role of SEL1L3 in the regulation of cell stress. Furthermore, the immune profiles of patients with higher SEL1L3 expression were corroborated with its active role in immunophenotype and favorable clinical outcomes in lung adenocarcinoma. Taken together, our study revealed that SEL1L3 might play a vital role in the regulation of cell stress, interaction with cancer cells and the immune microenvironment. Our research findings provide promising insights for further investigation of its molecular signaling network and also suggest SEL1L3 as a potential emerging adjuvant for immunotherapy in lung adenocarcinoma.

MTAP deficiency contributes to immune landscape remodelling and tumour evasion.

Methylthioadenosine phosphorylase (MTAP) deficiency occurs in various malignancies and is associated with poor survival in cancer patients. However, the mechanisms underlying tumour progression due to MTAP loss are yet to be elucidated. Utilizing integrated analyses of the transcriptome, proteome and secretome, we demonstrated that MTAP deficiency alters tumour-intrinsic, immune-related pathways and reprograms cytokine profiles towards a tumour-favourable environment. Additionally, MTAP-knockout cells exhibited a marked increase in the immune checkpoint protein PD-L1. Upon co-culturing primary T cells with cancer cells, MTAP loss-mediated PD-L1 upregulation inhibited T cell-mediated killing activity and induced several T cell exhaustion markers. In two xenograft tumour models, we showed a modest increase in average volume of tumours derived from MTAP-deficient cells than that of MTAP-proficient tumours. Surprisingly, a remarkable increase in tumour size was observed in humanized mice bearing MTAP-deficient tumours, as compared to their MTAP-expressing counterparts. Following immunophenotypic characterization of tumour-infiltrating leukocytes by mass cytometry analysis, MTAP-deficient tumours were found to display decreased immune infiltrates with lower proportions of both T lymphocytes and natural killer cells and higher proportions of immunosuppressive cells as compared to MTAP-expressing tumour xenografts. Taken together, our results suggest that MTAP deficiency restructures the tumour immune microenvironment, promoting tumour progression and immune evasion.

Adolescents with Atopic Dermatitis Have Lower Peak Exercise Load Capacity and Exercise Volume Compared with Unaffected Peers.

Background: Sweating and increased skin temperature caused by exercise can reduce physical activity and the willingness to exercise in adolescents with atopic dermatitis. This study was conducted to investigate the exercise load capacity of adolescents with atopic dermatitis and analyzed their exercise behavior and motivation. Methods: Adolescents with and without atopic dermatitis were assigned to the atopic dermatitis group and control group (n = 27 each). Both groups completed a cardiopulmonary exercise test and questionnaires to assess their exercise capacity, weekly exercise volume, exercise motivation, and self-efficacy, respectively. Results: The ratio of measured forced vital capacity to the predicted forced vital capacity and the peak oxygen consumption of the atopic dermatitis group were significantly lower than those of the control group. The Godin Leisure-Time Exercise Questionnaire scores of the atopic dermatitis group were significantly lower than those of the control group. As for the Behavioral Regulation in Exercise Questionnaire 2, the scores for the introjected and identified regulations of the atopic dermatitis group were significantly lower than those of the control group. Regarding the Multidimensional Self-Efficacy for Exercise Scale, the scheduling efficacy and total scores of the atopic dermatitis group were significantly lower than those of the control group. Conclusions: Adolescents with atopic dermatitis had lower peak exercise capacity and lower weekly exercise volume. Furthermore, they lacked the negative feelings toward inactivity and the self-confidence to plan regular exercise independently. The results of this study suggest that adolescents with atopic dermatitis should be encouraged to engage in regular indoor exercise.

Large-Scale 1T'-Phase Tungsten Disulfide Atomic Layers Grown by Gas-Source Chemical Vapor Deposition.

The control of crystal polymorphism and exploration of metastable, two-dimensional, 1T'-phase, transition-metal dichalcogenides (TMDs) have received considerable research attention. 1T'-phase TMDs are expected to offer various opportunities for the study of basic condensed matter physics and for its use in important applications, such as devices with topological states for quantum computing, low-resistance contact for semiconducting TMDs, energy storage devices, and as hydrogen evolution catalysts. However, due to the high energy difference and phase change barrier between 1T' and the more stable 2H-phase, there are few methods that can be used to obtain monolayer 1T'-phase TMDs. Here, we report on the chemical vapor deposition (CVD) growth of 1T'-phase WS2 atomic layers from gaseous precursors, i.e., H2S and WF6, with alkali metal assistance. The gaseous nature of the precursors, reducing properties of H2S, and presence of Na+, which acts as a countercation, provided an optimal environment for the growth of 1T'-phase WS2, resulting in the formation of high-quality submillimeter-sized crystals. The crystal structure was characterized by atomic-resolution scanning transmission electron microscopy, and the zigzag chain structure of W atoms, which is characteristic of the 1T' structure, was clearly observed. Furthermore, the grown 1T'-phase WS2 showed superconductivity with the transition temperature in the 2.8-3.4 K range and large upper critical field anisotropy. Thus, alkali metal assisted gas-source CVD growth is useful for realizing large-scale, high-quality, phase-engineered TMD atomic layers via a bottom-up synthesis.

Reduced symmetric dimethylation stabilizes vimentin and promotes metastasis in MTAP-deficient lung cancer.

The aggressive nature and poor prognosis of lung cancer led us to explore the mechanisms driving disease progression. Utilizing our invasive cell-based model, we identified methylthioadenosine phosphorylase (MTAP) and confirmed its suppressive effects on tumorigenesis and metastasis. Patients with low MTAP expression display worse overall and progression-free survival. Mechanistically, accumulation of methylthioadenosine substrate in MTAP-deficient cells reduce the level of protein arginine methyltransferase 5 (PRMT5)-mediated symmetric dimethylarginine (sDMA) modification on proteins. We identify vimentin as a dimethyl-protein whose dimethylation levels drop in response to MTAP deficiency. The sDMA modification on vimentin reduces its protein abundance but trivially affects its filamentous structure. In MTAP-deficient cells, lower sDMA modification prevents ubiquitination-mediated vimentin degradation, thereby stabilizing vimentin and contributing to cell invasion. MTAP and PRMT5 negatively correlate with vimentin in lung cancer samples. Taken together, we propose a mechanism for metastasis involving vimentin post-translational regulation.

Discrimination of Atlantic salmon origins using untargeted chemical fingerprinting.

Mislabelling the geographic origin of same-species aquaculture products is difficult to identify. This study applied untargeted small-molecule fingerprinting to discriminating between Atlantic salmon originating from Chile and Norway. The acquired liquid chromatography-high-resolution mass spectrometry data from Chilean (n = 32) and Norwegian (n = 29) salmon were chemometrically processed. The partial least squares discriminant analysis (PLS-DA) models successfully discriminated between Chilean and Norwegian salmon at both positive and negative ionisation modes (R2 > 0.96, Q2 > 0.81). Univariate analyses facilitated the selection of approximately 100 candidate markers with high statistical confidence (> 95%). Of these, 37 confirmed markers of Chilean and Norwegian salmon were primarily associated with feed formulations, including lipid derivatives and feed additives. None of the markers were residues or contaminants of potential food safety concern.

Stimuli-responsive hydrogel microcapsules for the amplified detection of microRNAs.

A method for the synthesis of DNA-based acrylamide hydrogel microcapsules loaded with quantum dots as a readout signal is introduced. The shell of DNA-acrylamide hydrogel microcapsules is encoded with microRNA-responsive functionalities, being capable of the detection of cancer-associated microRNA. The microRNA-141 (miR-141), a potential biomarker in prostate cancer, was employed as a model target in the microcapsular biosensor. The sensing principle of the microcapsular biosensor is based on the competitive sequence displacement of target miR-141 with the bridging DNA in the microcapsule's shell, leading to the unlocking of DNA-acrylamide hydrogel microcapsules and the release of the readout signal provided by fluorescent quantum dots. The readout signal is intensified as the concentration of miR-141 increases. While miR-141 was directly measured by DNA-acrylamide hydrogel microcapsules, the linear range for the detection of miR-141 is 2.5 to 50 µM and the limit of detection is 1.69 µM. To improve the sensitivity of the microcapsular biosensor for clinical needs, the isothermal strand displacement polymerization/nicking amplification machinery (SDP/NA) process was coupled to the DNA-acrylamide hydrogel microcapsule sensor for the microRNA detection. The linear range for the detection of miR-141 is improved to the range of 102 to 105 pM and the limit of detection is 44.9 pM. Compared to direct microcapsular biosensing, the detection limit for miR-141 by microcapsules coupled with strand-displacement amplification is enhanced by four orders of magnitude.

Optical study of electron and acoustic phonon confinement in ultrathin-body germanium-on-insulator nanolayers.

Nanoelectronics require semiconductor nanomaterials with high electron mobility like Ge nanolayers. Phonon and electron states in nanolayers undergo size-dependent changes induced by confinement and surface effects. Confined electrons and acoustic phonons determine layer optical, electric and thermal properties. Despite scientific and practical significance, their experimental studies in individual nanolayers are still lacking. Thanks to recent progress in the fabrication of high-quality nanolayers, here, we report the thickness dependencies of Raman spectra of acoustic phonons and optical spectra of electrons confined in germanium-on-insulator (GeOI) nanolayers with thicknesses TGeOI = 1-20 nm. We show that for TGeOI > 5 nm, both GeOI acoustic phonon Raman spectra and the E1 electron energy gap display dependencies on TGeOI which are reasonably described by the corresponding phonon and electron confinement theories. Accordingly, TGeOI can be probed using acoustic phonon Raman spectra at TGeOI > 5 nm. However, both confinement theories fail to describe GeOI thickness dependencies at TGeOI < 5 nm. We attribute this discrepancy to an increased influence of the Ge-GeO2 interface disorder with TGeOI reduction. The acoustic phonon data suggest a decrease of Ge normal-to-the-layer longitudinal sound velocity. Generation of interface-disorder-induced dispersionless phonons might contribute to this. The change in GeOI phonon properties at TGeOI < 5 nm might influence E1(TGeOI) dependence via a change in the GeOI electron-phonon interaction. We demonstrate that the Al2O3 coating improves the agreement between experimental and confinement theories, probably, via reduction of disorder at the Ge-GeOx-Al2O3-interface. Our results are important for control of nanolayer-confined electrons and phonons with benefits for modern and future nanoelectronic devices.

Targeting the AXL Receptor in Combating Smoking-related Pulmonary Fibrosis.

Tobacco smoking is a well-known risk factor for both fibrogenesis and fibrotic progression; however, the mechanisms behind these processes remain enigmatic. RTKs (receptor tyrosine kinases) have recently been reported to drive profibrotic phenotypes in fibroblasts during pulmonary fibrosis (PF). Using a phospho-RTK array screen, we identified the RTK AXL as a top upregulated RTK in response to smoke. Both expression and signaling activity of AXL were indeed elevated in lung fibroblasts exposed to tobacco smoke, whereas no significant change to the levels of a canonical AXL ligand, Gas6 (growth arrest-specific 6), was seen upon smoke treatment. Notably, we found that smoke-exposed human lung fibroblasts exhibited highly proliferative and invasive activities and were capable of inducing fibrotic lung lesions in mice. Conversely, genetic suppression of AXL in smoke-exposed fibroblasts cells led to suppression of AXL downstream pathways and aggressive phenotypes. We further demonstrated that AXL interacted with MARCKS (myristoylated alanine-rich C kinase substrate) and cooperated with MARCKS in regulating downstream signaling activity and fibroblast invasiveness. Pharmacological inhibition of AXL with AXL-specific inhibitor R428 showed selectivity for smoke-exposed fibroblasts. In all, our data suggest that AXL is a potential marker for smoke-associated PF and that targeting of the AXL pathway is a potential therapeutic strategy in treating tobacco smoking-related PF.

Bioactivities and action mechanisms of active compounds from Hottuynia cordata Thunb on human lung cancer cells.

BACKGROUND: Lung cancer is the leading cause of death in Taiwan for years. Besides the currently used chemotherapy, herbal medicine may play a role in the treatment of lung cancer. Hottuynia cordata Thunb (HC), one of the frequently used herbal medicine in Taiwan, has been widely used in various diseases. Review from literatures, HC has many effects, including anti-inflammatory, anti-viral, anti-bacterial, anti-SARS, and anti-tumor activities. However, there is no literatures describe its active compounds on lung cancer. This present study aims to evaluate the possible effect and action mechanism of active compounds from HC (aristolactam BII, aristolactam AII, and noraristolodione) on lung cancer. A549 lung cancer cell line was used to evaluate the effects of HC on the cell viability and possible anti-tumor effects. METHODS: We used A549 cells in the evaluation of anticancer activity. Cell viability, cell cycle, cell apoptosis and apoptosis related protein expression were studied. RESULTS: Active compounds from HC significantly inhibited A549 cell viability and induced accumulation of cell cycle at S or G2/M phase on A549 cells in a concentration-dependent manner, and induced A549 arrest at S or G2/M phase via increasing p21, p27, p53 and reducing cyclin-E, -A, cyclin-dependent kinase 2 (CDK2), cdc-2 (CDK1) protein expression. Additionally, HC induced A549 cell late apoptosis by up-regulating caspase-3, -8, Bax and decreasing Bcl-2 protein expression. CONCLUSIONS: The anti-tumor effects of aristolactam BII, aristolactam AII, and noraristolodione on human lung carcinoma A549 cells were via cell cycle arrest and apoptosis.

MITF functions as a tumor suppressor in non-small cell lung cancer beyond the canonically oncogenic role.

Microphthalamia-associated transcription factor (MITF) is a critical mediator in melanocyte differentiation and exerts oncogenic functions in melanoma progression. However, the role of MITF in non-small cell lung cancer (NSCLC) is still unknown. We found that MITF is dominantly expressed in the low-invasive CL1-0 lung adenocarcinoma cells and paired adjacent normal lung tissues. MITF expression is significantly associated with better overall survival and disease-free survival in NSCLC and serves as an independent prognostic marker. Silencing MITF promotes tumor cell migration, invasion and colony formation in lung adenocarcinoma cells. In xenograft mouse model, MITF knockdown enhances metastasis and tumorigenesis, but decreases angiogenesis in the Matrigel plug assay. Whole transcriptome profiling of the landscape of MITF regulation in lung adenocarcinoma indicates that MITF is involved in cell development, cell cycle, inflammation and WNT signaling pathways. Chromatin immunoprecipitation assays revealed that MITF targets the promoters of FZD7, PTGR1 and ANXA1. Moreover, silencing FZD7 reduces the invasiveness that is promoted by silencing MITF. Strikingly, MITF has significantly inverse correlations with the expression of its downstream genes in lung adenocarcinoma. In summary, we demonstrate the suppressive role of MITF in lung cancer progression, which is opposite to the canonical oncogenic function of MITF in melanoma.

Photocatalytic Properties of Graphene/Gold and Graphene Oxide/Gold Nanocomposites Synthesized by Pulsed Laser Induced Photolysis.

Graphene (Gr)/gold (Au) and graphene-oxide (GO)/Au nanocomposites (NCPs) were synthesized by performing pulsed-laser-induced photolysis (PLIP) on hydrogen peroxide and chloroauric acid (HAuCl4) that coexisted with Gr or GO in an aqueous solution. A 3-month-long aqueous solution stability was observed in the NCPs synthesized without using surfactants and additional processing. The synthesized NCPs were characterized using absorption spectroscopy, transmission electron microscopy, Raman spectroscopy, energy dispersive spectroscopy, and X-ray diffraction to prove the existence of hybrid Gr/Au or GO/Au NCPs. The synthesized NCPs were further evaluated using the photocatalytic reaction of methylene blue (MB), a synthetic dye, under UV radiation, visible light (central wavelength of 470 nm), and full spectrum of solar light. Both Gr/Au and GO/Au NCPs exhibited photocatalytic degradation of MB under solar light illumination with removal efficiencies of 92.1% and 94.5%, respectively.

Proteogenomics of Non-smoking Lung Cancer in East Asia Delineates Molecular Signatures of Pathogenesis and Progression.

Lung cancer in East Asia is characterized by a high percentage of never-smokers, early onset and predominant EGFR mutations. To illuminate the molecular phenotype of this demographically distinct disease, we performed a deep comprehensive proteogenomic study on a prospectively collected cohort in Taiwan, representing early stage, predominantly female, non-smoking lung adenocarcinoma. Integrated genomic, proteomic, and phosphoproteomic analysis delineated the demographically distinct molecular attributes and hallmarks of tumor progression. Mutational signature analysis revealed age- and gender-related mutagenesis mechanisms, characterized by high prevalence of APOBEC mutational signature in younger females and over-representation of environmental carcinogen-like mutational signatures in older females. A proteomics-informed classification distinguished the clinical characteristics of early stage patients with EGFR mutations. Furthermore, integrated protein network analysis revealed the cellular remodeling underpinning clinical trajectories and nominated candidate biomarkers for patient stratification and therapeutic intervention. This multi-omic molecular architecture may help develop strategies for management of early stage never-smoker lung adenocarcinoma.

Gas-Source CVD Growth of Atomic Layered WS2 from WF6 and H2S Precursors with High Grain Size Uniformity.

Two-dimensional (2D) transition-metal dichalcogenides have attracted a considerable amount of attention because of their potential for post-silicon device applications, as well as for exploring fundamental physics in an ideal 2D system. We tested the chemical vapour deposition (CVD) of WS2 using the gaseous precursors WF6 and H2S, augmented by the Na-assistance method. When Na was present during growth, the process created triangle-shaped WS2 crystals that were 10 µm in size and exhibited semiconducting characteristics. By contrast, the Na-free growth of WS2 resulted in a continuous film with metallic behaviour. These results clearly demonstrate that alkali-metal assistance is valid even in applications of gas-source CVD without oxygen-containing species, where intermediates comprising Na, W, and S can play an important role. We observed that the WS2 crystals grown by gas-source CVD exhibited a narrow size distribution when compared with crystals grown by conventional solid-source CVD, indicating that the crystal nucleation occurred almost simultaneously across the substrate, and that uniform lateral growth was dominant afterwards. This phenomenon was attributed to the suppression of inhomogeneous nucleation through the fast and uniform diffusion of the gas-phase precursors, supported by the Na-assisted suppression of the fast reactions between WF6 and H2S.

Alternative splicing in human cancer cells is modulated by the amiloride derivative 3,5-diamino-6-chloro-N-(N-(2,6-dichlorobenzoyl)carbamimidoyl)pyrazine-2-carboxide.

Alternative splicing (AS) is a process that enables the generation of multiple protein isoforms with different biological properties from a single mRNA. Cancer cells often use the maneuverability conferred by AS to produce proteins that contribute to growth and survival. In our previous studies, we identified that amiloride modulates AS in cancer cells. However, the effective concentration of amiloride required to modulate AS is too high for use in cancer treatment. In this study, we used computational algorithms to screen potential amiloride derivatives for their ability to regulate AS in cancer cells. We found that 3,5-diamino-6-chloro-N-(N-(2,6-dichlorobenzoyl)carbamimidoyl)pyrazine-2-carboxamide (BS008) can regulate AS of apoptotic gene transcripts, including HIPK3, SMAC, and BCL-X, at a lower concentration than amiloride. This splicing regulation involved various splicing factors, and it was accompanied by a change in the phosphorylation state of serine/arginine-rich proteins (SR proteins). RNA sequencing was performed to reveal that AS of many other apoptotic gene transcripts, such as AATF, ATM, AIFM1, NFKB1, and API5, was also modulated by BS008. In vivo experiments further indicated that treatment of tumor-bearing mice with BS008 resulted in a marked decrease in tumor size. BS008 also had inhibitory effects in vitro, either alone or in a synergistic combination with the cytotoxic chemotherapeutic agents sorafenib and nilotinib. BS008 enabled sorafenib dose reduction without compromising antitumor activity. These findings suggest that BS008 may possess therapeutic potential for cancer treatment.