WTAP-induced N6-methyladenosine of PD-L1 blocked T-cell-mediated antitumor activity under hypoxia in colorectal cancer.

N6-Methyladenosine (m6A) is a important process regulating gene expression post-transcriptionally. Programmed death ligand 1 (PD-L1) is a major immune inhibitive checkpoint that facilitates immune evasion and is expressed in tumor cells. In this research we discovered that Wilms' tumor 1-associated protein (WTAP) degradation caused by ubiquitin-mediated cleavage in cancer cells (colorectal cancer, CRC) under hypoxia was inhibited by Pumilio homolog 1 (PUM1) directly bound to WTAP. WTAP enhanced PD-L1 expression in a way that was m6A-dependent. m6A "reader," Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) identified methylated PD-L1 transcripts and subsequently fixed its mRNA. Additionally, we found that T-cell proliferation and its cancer cell-killing effects were prevented by overexpression of WTAP in vitro and in vivo. Overexpression prevented T cells from proliferating and killing CRC by maintaining the expression of PD-L1. Further evidence supporting the WTAP-PD-L1 regulatory axis was found in human CRC and organoid tissues. Tumors with high WTAP levels appeared more responsive to anti-PD1 immunotherapy, when analyzing samples from patients undergoing treatment. Overall, our findings demonstrated a novel PD-L1 regulatory mechanism by WTAP-induced mRNA epigenetic regulation and the possible application of targeting WTAP as immunotherapy for tumor hypoxia.

Photonic control of image-guided ferroptosis cancer nanomedicine.

Photonic nanomaterials, characterized by their remarkable photonic tunability, empower a diverse range of applications, including cutting-edge advances in cancer nanomedicine. Recently, ferroptosis has emerged as a promising alternative strategy for effectively killing cancer cells with minimizing therapeutic resistance. Novel design of photonic nanomaterials that can integrate photoresponsive-ferroptosis inducers, -diagnostic imaging, and -synergistic components provide significant benefits to effectively trigger local ferroptosis. This review provides a comprehensive overview of recent advancements in photonic nanomaterials for image-guided ferroptosis cancer nanomedicine, offering insights into their strengths, constraints, and their potential as a future paradigm in cancer treatment.

DNA Origami Incorporated into Solid-State Nanopores Enables Enhanced Sensitivity for Precise Analysis of Protein Translocations.

The rapidly advancing field of nanotechnology is driving the development of precise sensing methods at the nanoscale, with solid-state nanopores emerging as promising tools for biomolecular sensing. This study investigates the increased sensitivity of solid-state nanopores achieved by integrating DNA origami structures, leading to the improved analysis of protein translocations. Using holo human serum transferrin (holo-hSTf) as a model protein, we compared hybrid nanopores incorporating DNA origami with open solid-state nanopores. Results show a significant enhancement in holo-hSTf detection sensitivity with DNA origami integration, suggesting a unique role of DNA interactions beyond confinement. This approach holds potential for ultrasensitive protein detection in biosensing applications, offering advancements in biomedical research and diagnostic tool development for diseases with low-abundance protein biomarkers. Further exploration of origami designs and nanopore configurations promises even greater sensitivity and versatility in the detection of a wider range of proteins, paving the way for advanced biosensing technologies.

Wearable functional near-infrared spectroscopy for measuring dissociable activation dynamics of prefrontal cortex subregions during working memory.

The prefrontal cortex (PFC) has been extensively studied in relation to various cognitive abilities, including executive function, attention, and memory. Nevertheless, there is a gap in our scientific knowledge regarding the functionally dissociable neural dynamics across the PFC during a cognitive task and their individual differences in performance. Here, we explored this possibility using a delayed match-to-sample (DMTS) working memory (WM) task using NIRSIT, a high-density, wireless, wearable functional near-infrared spectroscopy (fNIRS) system. First, upon presentation of the sample stimulus, we observed an immediate signal increase in the ventral (orbitofrontal) region of the anterior PFC, followed by activity in the dorsolateral PFC. After the DMTS test stimulus appeared, the orbitofrontal cortex activated once again, while the rest of the PFC showed overall disengagement. Individuals with higher accuracy showed earlier and sustained activation of the PFC across the trial. Furthermore, higher network efficiency and functional connectivity in the PFC were correlated with individual WM performance. Our study sheds new light on the dynamics of PFC subregional activity during a cognitive task and its potential applicability in explaining individual differences in experimental, educational, or clinical populations. PRACTITIONER POINTS: Wearable functional near-infrared spectroscopy (fNIRS) captured dissociable temporal dynamics across prefrontal subregions during a delayed match-to-sample task. Anterior regions of the orbitofrontal cortex (OFC) activated first during the delay period, followed by the dorsolateral prefrontal cortex (PFC). PFC disengaged overall after the delay, but the OFC reactivated to the test stimulus. Earlier and sustained activation of PFC was associated with better accuracy. Functional connectivity and network efficiency also varied with task performance.

Surveillance for Distant Metastasis in Breast Cancer Patients Who Underwent Contemporary Management: A Report from the Korean Breast Cancer Society Survivor Research Group.

BACKGROUND: Current guidelines recommend against the use of routine imaging tests to detect distant metastasis in asymptomatic breast cancer patients. However, recent advancements in effective therapeutics and diagnostic accuracy have raised the need to reassess the clinical efficacy of intensive metastasis surveillance. We report the results of a multicenter retrospective study to investigate the association between intensive imaging studies and survival outcomes. PATIENTS AND METHODS: We retrospectively reviewed the data of 4130 patients who underwent surgery from 11 hospitals in Korea between January 2010 and December 2011. Patients were divided into two groups on the basis of the intensity of metastasis imaging studies during their disease-free period. The types and intervals of the imaging studies were based on each physician's decisions. RESULTS: High-intensive screening showed a shorter distant metastasis-free survival [p < 0.001, hazard ratio (HR) 1.62; 95% confidence interval (CI) 1.29-2.04], especially for patients in whom bone or lung was the first site of metastasis. With a median follow-up period of 110.0 months, the 5-year breast cancer-specific survival (BCSS) rate was 96.5%. The high-intensity screening group showed significantly poorer BCSS compared with the low-intensity screening group (p < 0.001, HR 3.13; 95% CI 2.32-4.21). However, both multivariable analysis and propensity score matching analysis showed no significant association between the screening intensity and BCSS. CONCLUSIONS: Frequent imaging studies to detect distant metastasis were associated with earlier detection of distant metastasis, especially for lung and bone metastasis. However, intensive surveillance showed no apparent association with BCSS despite the use of currently available treatments.

Relocation of lower pole renal stones helps improve the stone-free rate during flexible ureteroscopy with a low complication rate.

OBJECTIVE: To compare the efficacy and safety of relocating the lower pole stones to a favorable pole during flexible ureteroscopy with in situ lithotripsy for the treatment of 10-20 mm lower pole stone (LPS). METHODS: This study was a prospective analysis of patient outcomes who underwent an FURS procedure for the treatment of 10-20 mm lower pole renal stones from January 2020 to November 2022. The patients were randomized into a relocation group or in situ group. The LPSs were relocated into a calyx, during lithotripsy in the relocation group was performed, whereas the in situ group underwent FURS without relocation. All the procedures were performed by the same surgeon. The patients' demographic data, stone characteristics, perioperative parameters and outcomes, stone-free rate (SFR), complications, and overall costs were assessed retrospectively. RESULTS: A total of 90 patients were enrolled and analyzed in this study (45 per group) with no significant differences between the two groups in terms of age, gender, BMI, diabetes, hypertension, stone size, number, laterality, composition, and density. The mean operation time, total energy consumption, postoperative stay, and complications were similar between the groups. Both groups had similar SFR at 1 day postoperative follow-up (p = 0.091), while the relocation group achieved significantly higher SFR 3 months later (97.8% vs 84.4%, p = 0.026). The relocation group also had a significantly higher WisQol score than the in situ group (126.98 vs 110.18, p < 0.001). CONCLUSION: A satisfactory SFR with a relatively low complication rate was achieved by the relocation technique during the FURS procedure.

Communicative competence of generative artificial intelligence in responding to patient queries about colorectal cancer surgery.

PURPOSE: To examine the ability of generative artificial intelligence (GAI) to answer patients' questions regarding colorectal cancer (CRC). METHODS: Ten clinically relevant questions about CRC were selected from top-rated hospitals' websites and patient surveys and presented to three GAI tools (Chatbot Generative Pre-Trained Transformer [GPT-4], Google Bard, and CLOVA X). Their responses were compared with answers from the CRC information book. Response evaluation was performed by two groups, each consisting of five healthcare professionals (HCP) and patients. Each question was scored on a 1-5 Likert scale based on four evaluation criteria (maximum score, 20 points/question). RESULTS: In an analysis including only HCPs, the information book scored 11.8 ± 1.2, GPT-4 scored 13.5 ± 1.1, Google Bard scored 11.5 ± 0.7, and CLOVA X scored 12.2 ± 1.4 (P = 0.001). The score of GPT-4 was significantly higher than those of the information book (P = 0.020) and Google Bard (P = 0.001). In an analysis including only patients, the information book scored 14.1 ± 1.4, GPT-4 scored 15.2 ± 1.8, Google Bard scored 15.5 ± 1.8, and CLOVA X scored 14.4 ± 1.8, without significant differences (P = 0.234). When both groups of evaluators were included, the information book scored 13.0 ± 0.9, GPT-4 scored 14.4 ± 1.2, Google Bard scored 13.5 ± 1.0, and CLOVA X scored 13.3 ± 1.5 (P = 0.070). CONCLUSION: The three GAIs demonstrated similar or better communicative competence than the information book regarding questions related to CRC surgery in Korean. If high-quality medical information provided by GAI is supervised properly by HCPs and published as an information book, it could be helpful for patients to obtain accurate information and make informed decisions.

Real-time monitoring of Ti(IV) metal ion binding of transferrin using a solid-state nanopore.

Transferrin, a central player in iron transport, has been recognized not only for its role in binding iron but also for its interaction with other metals, including titanium. This study employs solid-state nanopores to investigate the binding of titanium ions [Ti(IV)] to transferrin in a single-molecule and label-free manner. We demonstrate the novel application of solid-state nanopores for single-molecule discrimination between apo-transferrin (metal-free) and Ti(IV)-transferrin. Despite their similar sizes, Ti(IV)-transferrin exhibits a reduced current drop, attributed to differences in translocation times and filter characteristics. Single-molecule analysis reveals Ti(IV)-transferrin's enhanced stability and faster translocations due to its distinct conformational flexibility compared to apo-transferrin. Furthermore, our study showcases solid-state nanopores as real-time monitors of biochemical reactions, tracking the gradual conversion of apo-transferrin to Ti(IV)-transferrin upon the addition of titanium citrate. This work offers insights into Ti(IV) binding to transferrin, promising applications for single-molecule analysis and expanding our comprehension of metal-protein interactions at the molecular level.

Characterization of Phytoplankton-Derived Amino Acids and Tracing the Source of Organic Carbon Using Stable Isotopes in the Amundsen Sea.

We utilized amino acid (AA) and carbon stable isotope analyses to characterize phytoplankton-derived organic matter (OM) and trace the sources of organic carbon in the Amundsen Sea. Carbon isotope ratios of particulate organic carbon (δ13C-POC) range from -28.7‱ to -23.1‱, indicating that particulate organic matter originated primarily from phytoplankton. The dissolved organic carbon isotope (δ13C-DOC) signature (-27.1 to -21.0‱) observed in the sea-ice melting system suggests that meltwater contributes to the DOC supply of the Amundsen Sea together with OM produced by phytoplankton. A negative correlation between the degradation index and δ13C-POC indicates that the quality of OM significantly influences isotopic fractionation (r2 = 0.59, p < 0.001). The AA distribution in the Amundsen Sea (5.43 ± 3.19 µM) was significantly larger than previously reported in the Southern Ocean and was associated with phytoplankton biomass (r2 = 0.49, p < 0.01). Under conditions dominated by P. antarctica (DI = 2.29 ± 2.30), OM exhibited greater lability compared to conditions co-dominated by diatoms and D. speculum (DI = 0.04 ± 3.64). These results highlight the important role of P. antarctica in influencing the properties of OM, suggesting potential impacts on carbon cycling and microbial metabolic activity in the Amundsen Sea.

Optical neuromodulation at all scales: from nanomaterials to wireless optoelectronics and integrated systems.

Light-based neuromodulation systems offer exceptional spatiotemporal resolution combined with the elimination of physical tether to communicate with neurons. Currently, optical neuromodulation systems ranging from the nano to the centimeter scale enable neural activity control from the single cell to the organ level in retina, heart, spinal cord, and brain, facilitating a wide range of experiments in intact and freely moving animals in different contexts, such as during social interactions and behavioral tasks. Nanotransducers (e.g., metallic nanoparticles, silicon nanowires, and polymeric nanoparticles) and microfabricated photodiodes convert light to electrical, thermal, and mechanical stimuli that can allow remote and non-contact stimulation of neurons. Moreover, integrated devices composed of nano and microscale optoelectronic components comprise fully implantable and wirelessly powered smart optoelectronic systems that exhibit multimodal and closed-loop operation. In this review, we first discuss the material platforms, stimulation mechanisms, and applications of passive systems, i.e., nanotransducers and microphotodiodes. Then, we review the use of organic and inorganic light-emitting diodes for optogenetics and implantable wireless optoelectronic systems that enable closed-loop optogenetic neuromodulation through the use of light-emitting diodes, wireless power transfer circuits, and feedback loops. Exploration of materials and mechanisms together with the presented applications from both research and clinical perspectives in this review provides a comprehensive understanding of the optical neuromodulation field with its advantages and challenges to build superior systems in the future.

Efficient Combination Chemo-Sonodynamic Cancer Therapy Using Mitochondria-Targeting Sonosensitizer-Loaded Polysorbate-Based Micelles.

Sonodynamic therapy (SDT), utilizing ultrasound (US) and sonosensitizers, holds immense potential as a noninvasive and targeted treatment for a variety of deep-seated tumors. However, the clinical translation of SDT is hampered by several key limitations in sonosensitizers, especially their low aqueous stability and poor cellular uptake. In this study, non-ionic polysorbate (Tween 80, T80) was adopted to formulate effective nanocarriers for the safe and efficient delivery of sonosensitizers to cancer cells. Mitochondria-targeting triphenylphosphonium (TPP)-conjugated chlorin e6 (Ce6) sonosensitizer was loaded into T80-based micelles for efficient SDT. Pro-oxidant piperlongumine (PL) was co-encapsulated with TPP-conjugated Ce6 (T-Ce6) in T80 micelles to enable combination chemo-SDT. T80 micelles substantially enhanced the cellular internalization of T-Ce6. As a result, T80 micelles loaded with T-Ce6 and PL [T80(T-Ce6/PL)] significantly elevated intracellular reactive oxygen species (ROS) generation in MCF-7 human breast cancer cells upon US exposure. Moreover, T-Ce6 exhibited selective accumulation within the mitochondria, leading to efficient cell death under US irradiation. Importantly, T80(T-Ce6/PL) micelles caused cancer-specific cell death by selectively triggering apoptosis in cancer cells through PL. This study demonstrated the feasibility of using T80(T-Ce6/PL) micelles for efficient and cancer-specific combination chemo-SDT.

Korean Black Goat Extract Exerts Estrogen-like Osteoprotective Effects by Stimulating Osteoblast Differentiation in MC3T3-E1 Cells and Suppressing Osteoclastogenesis in RAW 264.7 Cells.

Postmenopausal osteoporosis, characterized by an imbalance between osteoclast-mediated bone resorption and osteoblast-driven bone formation, presents substantial health implications. In this study, we investigated the role of black goat extract (BGE), derived from a domesticated native Korean goat, estrogen-like activity, and osteoprotective effects in vitro. BGE's mineral and fatty acid compositions were analyzed via the ICP-AES method and gas chromatography-mass spectrometry, respectively. In vitro experiments were conducted using MCF-7 breast cancer cells, MC3T3-E1 osteoblasts, and RAW264.7 osteoclasts. BGE exhibits a favorable amount of mineral and fatty acid content. It displayed antimenopausal activity by stimulating MCF-7 cell proliferation and augmenting estrogen-related gene expression (ERα, ERß, and pS2). Moreover, BGE positively impacted osteogenesis and mineralization in MC3T3-E1 cells through Wnt/ß-catenin pathway modulation, leading to heightened expression of Runt-related transcription factor 2, osteoprotegerin, and collagen type 1. Significantly, BGE effectively suppressed osteoclastogenesis by curtailing osteoclast formation and activity in RAW264.7 cells, concurrently downregulating pivotal signaling molecules, including receptor activator of nuclear factor κ B and tumor necrosis factor receptor-associated factor 6. This study offers a shred of preliminary evidence for the prospective use of BGE as an effective postmenopausal osteoporosis treatment.

Constituents of Chimaphila japonica and Their Diuretic Activity.

Three new phenols (1-3), one new cyclohexanol (4), two known phenols (5-6), and six known flavonoids (7-12) were isolated from the n-butanol of the 75% ethanol extract of all plants of Chimaphila japonica Miq. Among them, compound 5 was named and described in its entirety for the first time, and compounds 9 and 10 were reported in C. japonica for the first time. The structures of all compounds were confirmed using a comprehensive analysis of 1D and 2D NMR and HRESIMS data. Biological results show that compounds 4, 7, and 11 exhibited potent diuretic activity. The modes of interaction between the selected compounds and the target diuretic-related WNK1 kinase were investigated in a preliminary molecular docking study. These results provided insight into the chemodiversity and potential diuretic activities of metabolites in C. japonica.

Effects of Rhythm Step Training on Foot and Lower Limb Balance in Children and Adolescents with Flat Feet: A Radiographic Analysis.

Background and Objectives: Owing to the recent reports regarding the efficacy of rhythm step training (RST) in lower limb muscle development and motor skill enhancement, this study aimed to evaluate the effects of RST on foot and lower limb balance in children and adolescents diagnosed with flat feet using radiographic analysis. Materials and Methods: A total of 160 children and adolescents diagnosed with flat feet from a hospital in Seoul were randomly assigned to the general flat feet training (GFFT) (n = 80) or RST (n = 80) group. Patients in both groups exercised for 50 min once a week for 12 weeks. Key variables, such as quadriceps angle (Q-angle), calcaneal pitch angle (CPA), calcaneal-first metatarsal angle (CFMA), and navicular-cuboid overlap ratio (OR) were measured before and after the intervention. Results: Significant improvements in Q-angle (p < 0.001), CPA (p < 0.001), CFMA (p < 0.001), and navicular-cuboid OR (p < 0.001) were observed in the RST group compared to the GFFT group. RST was found to be more effective in normalizing the biomechanical function of the calcaneus and improving lower limb function. Conclusions: RST significantly enhances foot and lower limb balance in children and adolescents with flat feet, suggesting its potential use as an effective intervention for this population. The study did not specifically analyze the effects of various components of rhythm training, such as music, exercise intensity, and frequency, on the outcomes. Further research is needed to determine how each of these elements individually influences the results.

Arenicolide Family Macrolides Provide a New Therapeutic Lead Combating Multidrug-resistant Tuberculosis.

The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis (Mtb) poses a significant threat to health globally. During searching for new chemical entities regulating MDR- and XDR-Mtb, chemical investigation of the black oil beetle gut bacterium Micromonospora sp. GR10 led to the discovery of eight new members of arenicolides along with the identification of arenicolide A (Ar-A, 1), which was a previously reported macrolide with incomplete configuration. Genomic analysis of the bacterial strain GR10 revealed their putative biosynthetic pathway. Quantum mechanics-based computation, chemical derivatizations, and bioinformatic analysis established the absolute stereochemistry of Ar-A and arenicolides D-K (Ar-D-K, 2-9) completely for the first time. Biological studies of 1-9 revealed their antimicrobial activity against MDR and XDR strains of Mtb. Ar-A had the most potent in vitro antimicrobial efficacy against MDR- and XDR-Mtb. Mechanistically, Ar-A induced ATP depletion and destabilized Mtb cell wall, thereby inhibiting growth. Notably, Ar-A exerted a significant antimicrobial effect against Mtb in macrophages, was effective in the treatment of Mtb infections, and showed a synergistic effect with amikacin (AMK) in a mouse model of MDR-Mtb lung infection. Collectively, our findings indicate Ar-A to be a promising drug lead for drug-resistant tuberculosis.

Over One Million DNA and Protein Events Through Ultra-Stable Chemically-Tuned Solid-State Nanopores.

Stability, long lifetime, resilience against clogging, low noise, and low cost are five critical cornerstones of solid-state nanopore technology. Here, a fabrication protocol is described wherein >1 million events are obtained from a single solid-state nanopore with both DNA and protein at the highest available lowpass filter (LPF, 100 kHz) of the Axopatch 200B-the highest event count mentioned in literature. Moreover, a total of ≈8.1 million events are reported in this work encompassing the two analyte classes. With the 100 kHz LPF, the temporally attenuated population is negligible while with the more ubiquitous 10 kHz, ≈91% of the events are attenuated. With DNA experiments, the pores are operational for hours (typically >7 h) while the average pore growth is merely ≈0.16 ± 0.1 nm h-1 . The current noise is exceptionally stable with traces typically showing <10 pA h-1 increase in noise. Furthermore, a real-time method to clean and revive pores clogged with analyte with the added benefit of minimal pore growth during cleaning (< 5% of the original diameter) is showcased. The enormity of the data collected herein presents a significant advancement to solid-state pore performance and will be useful for future ventures such as machine learning where large amounts of pristine data are a prerequisite.

Use of a solid-state nanopore for profiling the transferrin receptor protein and distinguishing between transferrin receptor and its ligand protein.

A nanopore device is capable of providing single-molecule level information of an analyte as they translocate through the sensing aperture-a nanometer-sized through-hole-under the influence of an applied electric field. In this study, a silicon nitride (Six Ny )-based nanopore was used to characterize the human serum transferrin receptor protein (TfR) under various applied voltages. The presence of dimeric forms of TfR was found to decrease exponentially as the applied electric field increased. Further analysis of monomeric TfR also revealed that its unfolding behaviors were positively dependent on the applied voltage. Furthermore, a comparison between the data of monomeric TfR and its ligand protein, human serum transferrin (hSTf), showed that these two protein populations, despite their nearly identical molecular weights, could be distinguished from each other by means of a solid-state nanopore (SSN). Lastly, the excluded volumes of TfR were experimentally determined at each voltage and were found to be within error of their theoretical values. The results herein demonstrate the successful application of an SSN for accurately classifying monomeric and dimeric molecules while the two populations coexist in a heterogeneous mixture.

Yin Yang 1 suppresses apoptosis and oxidative stress injury in SH-SY5Y cells by facilitating NR4A1 expression.

Oxidative stress plays a significant role in the development of Parkinson's disease (PD). Previous studies implicate nuclear receptor subfamily 4 group A member 1 (NR4A1) in oxidative stress associated with PD. However, the molecular mechanism underlying the regulation of NR4A1 expression remains incompletely understood. In the present study, a PD cell model was established by using 1-methyl-4-phenylpyridinium (MPP+) in SH-SY5Y cells. Cell viability and apoptosis were assessed by using CCK-8 assay and flow cytometry, respectively. The activities of LDH and SOD, and ROS generation were used as an indicators of oxidative stress. ChIP-PCR was performed to detect the interaction between Yin Yang 1 (YY1) and the NR4A1 promoter. MPP+ treatment inhibited SH-SY5Y cell viability in a dose- and time-dependent manner. NR4A1 and YY1 expression were decreased in MPP+-treated SH-SY5Y cells. Increasing NR4A1 or YY1 alleviated MPP+-induced apoptosis and oxidative stress in SH-SY5Y cells, whereas reduction of NR4A1 aggravated MPP+-induced cell injury. Transcription factor YY1 facilitated NR4A1 expression by binding with NR4A1 promoter. In addition, in MPP+-treated SH-SY5Y cells, the inhibition of NR4A1 to apoptosis and oxidative stress was further enhanced by overexpression of YY1. The reduction of NR4A1 led to an elevation of apoptosis and oxidative stress in MPP+-induced SH-SY5Y cells, and this effect was partially reversed by the overexpression of YY1. In conclusion, YY1 suppresses MPP+-induced apoptosis and oxidative stress in SH-SY5Y cells by binding with NR4A1 promoter and boosting NR4A1 expression. Our findings suggest that NR4A1 may be a candidate target for PD treatment.HIGHLIGHTSNR4A1 and YY1 are decreased in MPP+-treated SH-SY5Y cells.NR4A1 prevents oxidative stress and apoptosis in MPP+-treated SH-SY5Y cells.YY1 binds with NR4A1 promoter and increases NR4A1 expression.YY1 enhances the inhibition of NR4A1 to SH-SY5Y cell apoptosis and oxidative stress.

Small heterodimer partner interacting leucine zipper protein (SMILE) ameliorates autoimmune arthritis via AMPK signaling pathway and the regulation of B cell activation.

Rheumatoid arthritis (RA) is an autoimmune disease that causes joint swelling and inflammation and can involve the entire body. RA is characterized by the increase of pro-inflammatory cytokines such as interleukin (IL) and tumor necrosis factor, and the over-activation of T lymphocytes and B lymphocytes, which may lead to severe chronic inflammation of joints. However, despite numerous studies the pathogenesis and treatment of RA remain unresolved. This study investigated the use of small heterodimer partner-interacting leucine zipper protein (SMILE) overexpression to treat a mouse model of RA. SMILE is an insulin-inducible corepressor through adenosine monophosphate-activated kinase (AMPK) signaling pathway. The injection of a SMILE overexpression vector to mice with collagen induced-arthritis resulted in a milder clinical pathology and a reduced incidence of arthritis, less joint tissue damage, and lower levels of Th17 cells and plasma B cells in the spleen. Immunohistochemistry of the joint tissue showed that SMILE decreased B-cell activating factor (BAFF) receptor (BAFF-R), mTOR, and STAT3 expression but increased AMPK expression. In SMILE-overexpressing transgenic mice with collagen antibody-induced arthritis (CAIA), a decrease in the arthritis score and reductions in tissue damage, the number of B cells, and antibody production were observed. The treatment of immune cells in vitro with curcumin, a known SMILE-inducing agent, led to decreases in plasma B cells, germinal center B cells, IL-17-producing B cells, and BAFF-R-positive B cells. Taken together, our findings demonstrate the therapeutic potential of SMILE in RA, based on its inhibition of B cell activation mediated by the AMPK/mTOR and STAT3 signaling pathway and BAFF-R expression. Video abstract.

A duplex-specific nuclease (DSN) and catalytic hairpin assembly (CHA)-mediated dual amplification method for miR-146b detection.

A novel method for detecting miRNA has been developed using a combination of duplex-specific nuclease signal amplification (DSNSA) and a catalytic hairpin assembly (CHA). In this work, a biotinylated trigger release (BTR) probe with a biotin group at the 3'-end and a CHA reaction sequence trigger as an initiator (catalyst I) at the 5'-end was designed to hybridize target miRNA. The DSN enzyme was introduced to initiate the DSNSA. The miRNA was released to consume more BTR probes and amplify the signals. Subsequently, streptavidin-coated magnetic beads (SA-MBs) were added to the DSNSA reaction solution to remove excess BTR probes that did not hybridize with miRNA, which would then separate BTR probes and catalyst-I, to ensure detection with high selectivity and sensitivity. The catalyst-I remaining in the solution could trigger the CHA reaction to enable signal amplification in the second step. The developed method exhibits a sensitive detection limit and excellent selectivity in identifying a high sequence homology among family members.