Identification of Sodium- and Chloride-Sensitive Sites in the Slack Channel.

The Slack channel (KCNT1, Slo2.2) is a sodium-activated and chloride-activated potassium channel that regulates heart rate and maintains the normal excitability of the nervous system. Despite intense interest in the sodium gating mechanism, a comprehensive investigation to identify the sodium-sensitive and chloride-sensitive sites has been missing. In the present study, we identified two potential sodium-binding sites in the C-terminal domain of the rat Slack channel by conducting electrophysical recordings and systematic mutagenesis of cytosolic acidic residues in the rat Slack channel C terminus. In particular, by taking advantage of the M335A mutant, which results in the opening of the Slack channel in the absence of cytosolic sodium, we found that among the 92 screened negatively charged amino acids, E373 mutants could completely remove sodium sensitivity of the Slack channel. In contrast, several other mutants showed dramatic decreases in sodium sensitivity but did not abolish it altogether. Furthermore, molecular dynamics (MD) simulations performed at the hundreds of nanoseconds timescale revealed one or two sodium ions at the E373 position or an acidic pocket composed of several negatively charged residues. Moreover, the MD simulations predicted possible chloride interaction sites. By screening predicted positively charged residues, we identified R379 as a chloride interaction site. Thus, we conclude that the E373 site and the D863/E865 pocket are two potential sodium-sensitive sites, while R379 is a chloride interaction site in the Slack channel.SIGNIFICANCE STATEMENT The research presented here identified two distinct sodium and one chloride interaction sites located in the intracellular C-terminal domain of the Slack (Slo2.2, KCNT1) channel. Identification of the sites responsible for the sodium and chloride activation of the Slack channel sets its gating property apart from other potassium channels in the BK channel family. This finding sets the stage for future functional and pharmacological studies of this channel.

Study of the mechanism by which Xiaoyan decoction combined with E7449 regulates tumorigenesis in lung adenocarcinoma.

TNKS is a new target for the treatment of lung adenocarcinoma, the synergistic effects of the TCM compound Xiaoyan decoction and the TNKS inhibitor E7449 in the intervention on TNKS were investigated, and the possible underlying mechanisms involved were clarified. Immunohistochemistry was used to analyse TNKS expression in tumour tissues. The impact of targeting TNKS on cell growth, invasion, apoptosis, key genes and signalling pathways was investigated in tumour cells by Western blotting, rescue experiments, colony formation assays, flow cytometry and label-free experiments. Tumour xenografts with A549 cells were then transplanted for in vivo study. We found that TNKS high expression was closely related to the advanced tumour stage and tumour size in lung adenocarcinom. After TNKS was knocked down in vitro, the growth, proliferation, migration and invasion were markedly reduced in A549 and H1975 cells. We subsequently applied the Xiaoyan decoction and TNKS inhibitors to intervene in lung adenocarcinoma. Xiaoyan decoction and E7449 suppressed TNKS expression and inhibited adenocarcinoma cell proliferation, migration, invasion and apoptosis in vitro. Proteomic analysis revealed that E7449 treatment may be most closely associated with the classic Wnt/ß-catenin pathway, whereas Xiaoyan decoction treatment may be related to the WNT/PLAN pathway. Xenograft studies confirmed that E7449 or Xiaoyan decoction inhibited lung tumour growth in vivo and attenuated the Wnt signalling pathway in adenocarcinoma. These findings suggest that TNKS is a novel therapeutic target. TCM preparations and small molecule inhibitors are expected to constitute an effective combination strategy.

Long non-coding RNA NORAD regulates megakaryocyte differentiation and proplatelet formation via the DUSP6/ERK signaling pathway.

Megakaryopoiesis and platelet production is a complex process that is underpotential regulation at multiple stages. Many long non-coding RNAs (lncRNAs) are distributed in hematopoietic stem cells and platelets. lncRNAs may play important roles as key epigenetic regulators in megakaryocyte differentiation and proplatelet formation. lncRNA NORAD can affect cell ploidy by sequestering PUMILIO proteins, although its direct effect on megakaryocyte differentiation and thrombopoiesis is still unknown. In this study, we demonstrate NORAD RNA is highly expressed in the cytoplasm during megakaryocyte differentiation. Interestingly, we identified for the first time that NORAD has a strong inhibitory effect on megakaryocyte differentiation and proplatelet formation from cultured megakaryocytes. DUSP6/ERK1/2 pathway is activated in response to NORAD knockdown during megakaryocytopoiesis, which is achieved by sequestering PUM2 proteins. Finally, compared with the wild-type control mice, NORAD knockout mice show a faster platelet recovery after severe thrombocytopenia induced by 6 Gy total body irradiation. These findings demonstrate lncRNA NORAD has a key role in regulating megakaryocyte differentiation and thrombopoiesis, which provides a promising molecular target for the treatment of platelet-related diseases such as severe thrombocytopenia.

Fabrication of Zn-Air Battery with High Output Capacity Under Ultra-Large Current.

Zn-air battery (ZAB) is advocated as a more viable option in the new-energy technology. However, the limited-output capacity at a high current density impedes the driving range in power batteries substantially. Here, a novel heterojunction-based graphdiyne (GDY) and Ag29Cu7 alloy quantum dots (Ag29Cu7 QDs/GDY) for constructing a high-performance aqueous ZAB are fabricated. The as-fabricated ZAB achieves discharge at up to 100 mA cm-2 (the highest value ever reported) along with a remarkable output specific capacity of 786.2 mAh g-1 Zn, which is mainly benefitted from the binary-synergistic effect toward a stable triple-phase interface for air electrode induced by the Ag29Cu7 QDs and GDY in harsh base, together with the decreasing reaction energy barrier and polarization. The results outperform the superior reports discharging at low current and will bring breakthrough progress toward the practical applications of ZAB on large power supply facilities.

Deep Reconstruction of Ruthenate Perovskite Oxide Enables Efficient pH-Universal Hydrogen Evolution Reaction.

Designing highly efficient, stable, and pH-universal perovskites for hydrogen evolution reaction (HER) is urgently needed yet remains a grand challenge. Herein, a titanium-containing strontium ruthenate (SrTi0.5Ru0.5O3, STRO) is developed as an excellent HER electrocatalyst in a wide pH range. The introduction of Ti into SrRuO3 significantly reduces the size of STRO, endowing with a high reactivity that facilitates a deep surface-reconstruction during HER. Furthermore, Sr2+ leaching triggered reconstruction leads to STRO breaking into tiny nanoparticles accompanied by high-valence ruthenium (Ru) species reducing to metallic Ru. The generated active species, increased accessible sites, and improved electrical conductivity greatly boost HER. The reconstructed STRO displays remarkable HER activities with exceptional low overpotentials of 18, 24, and 55 mV at 10 mA cm-2 in 1 m KOH, 0.5 m H2SO4, and 1 m PBS, respectively, surpassing most perovskites reported previously and comparable to or even outperforming that of commercial Pt/C. Moreover, the STRO exhibits excellent stabilities over 200 h in alkaline and acidic media, superior to that of Pt/C. This work not only provides insights into structure reconstruction of perovskites during HER, but also opens new perspectives for developing high-efficiency and pH-universal electrocatalysts for future energy applications.

Association between different insulin resistance surrogates and all-cause mortality in patients with coronary heart disease and hypertension: NHANES longitudinal cohort study.

BACKGROUND: Studies on the relationship between insulin resistance (IR) surrogates and long-term all-cause mortality in patients with coronary heart disease (CHD) and hypertension are lacking. This study aimed to explore the relationship between different IR surrogates and all-cause mortality and identify valuable predictors of survival status in this population. METHODS: The data came from the National Health and Nutrition Examination Survey (NHANES 2001-2018) and National Death Index (NDI). Multivariate Cox regression and restricted cubic splines (RCS) were performed to evaluate the relationship between homeostatic model assessment of IR (HOMA-IR), triglyceride glucose index (TyG index), triglyceride glucose-body mass index (TyG-BMI index) and all-cause mortality. The recursive algorithm was conducted to calculate inflection points when segmenting effects were found. Then, segmented Kaplan-Meier analysis, LogRank tests, and multivariable Cox regression were carried out. Receiver operating characteristic (ROC) and calibration curves were drawn to evaluate the differentiation and accuracy of IR surrogates in predicting the all-cause mortality. Stratified analysis and interaction tests were conducted according to age, gender, diabetes, cancer, hypoglycemic and lipid-lowering drug use. RESULTS: 1126 participants were included in the study. During the median follow-up of 76 months, 455 participants died. RCS showed that HOMA-IR had a segmented effect on all-cause mortality. 3.59 was a statistically significant inflection point. When the HOMA-IR was less than 3.59, it was negatively associated with all-cause mortality [HR = 0.87,95%CI (0.78, 0.97)]. Conversely, when the HOMA-IR was greater than 3.59, it was positively associated with all-cause mortality [HR = 1.03,95%CI (1.00, 1.05)]. ROC and calibration curves indicated that HOMA-IR was a reliable predictor of survival status (area under curve = 0,812). No interactions between HOMA-IR and stratified variables were found. CONCLUSION: The relationship between HOMA-IR and all-cause mortality was U-shaped in patients with CHD and hypertension. HOMA-IR was a reliable predictor of all-cause mortality in this population.

Differential alterations of CXCR3, CXCR5 and CX3CR1 in patients with immune thrombocytopenia.

As a versatile element for maintaining homeostasis, the chemokine system has been reported to be implicated in the pathogenesis of immune thrombocytopenia (ITP). However, research pertaining to chemokine receptors and related ligands in adult ITP is still limited. The states of several typical chemokine receptors and cognate ligands in the circulation were comparatively assessed through various methodologies. Multiple variable analyses of correlation matrixes were conducted to characterize the correlation signatures of various chemokine receptors or candidate ligands with platelet counts. Our data illustrated a significant decrease in relative CXCR3 expression and elevated plasma levels of CXCL4, 9-11, 13, and CCL3 chemokines in ITP patients with varied platelet counts. Flow cytometry assays revealed eminently diminished CXCR3 levels on T and B lymphocytes and increased CXCR5 on cytotoxic T cell (Tc) subsets in ITP patients with certain platelet counts. Meanwhile, circulating CX3CR1 levels were markedly higher on T cells with a concomitant increase in plasma CX3CL1 level in ITP patients, highlighting the importance of aberrant alterations of the CX3CR1-CX3CL1 axis in ITP pathogenesis. Spearman's correlation analyses revealed a strong positive association of peripheral CXCL4 mRNA level, and negative correlations of plasma CXCL4 concentration and certain chemokine receptors with platelet counts, which might serve as a potential biomarker of platelet destruction in ITP development. Overall, these results indicate that the differential expression patterns and distinct activation states of peripheral chemokine network, and the subsequent expansion of circulating CXCR5+ Tc cells and CX3CR1+ T cells, may be a hallmark during ITP progression, which ultimately contributes to thrombocytopenia in ITP patients.

Tunable Optical Anisotropy in Rare-Earth Borates with Flexible [BO3] Clusters.

Borates have garnered a lot of attention in the realm of solid-state chemistry due to their remarkable characteristics, in which the synthesis of borates with isolated [BO3] by adding rare-earth elements is one of the main areas of structural design study. Five new mixed-metal Y-based rare-earth borates, Ba2ZnY2(BO3)4, KNa2Y(BO3)2, Li2CsY4(BO3)5, LiRb2Y(BO3)2, and RbCaY(BO3)2, have been discovered using the high-temperature solution approach. Isolated [BO3] clusters arranged in various configurations comprise their entire anionic framework, allowing for optical anisotropy tuning between 0.024 and 0.081 under 1064 nm. In this study, we characterize the relative placements of their [BO3] groups and examine how their structure affects their characteristics. The origin of their considerable optical anisotropy has been proven theoretically. This study unequivocally demonstrates that even a slight alteration to borates' anionic structure can result in a significant improvement in performance.

New Phenanthro[9,10-d]oxazole-Based Fluorophores with Hybridized Local and Charge-Transfer Characteristics for Highly Efficient Blue Non-Doped OLEDs with Negligible Efficiency Roll-Off.

It is vital to develop highly efficient non-doped blue organic light-emitting diodes (OLEDs) with high color purity and low-efficiency roll-off for applications in display and lighting. Herein, two blue D-A fluorophores TPA-PO and TPA-DPO are designed and synthesized, in which phenanthro[9,10-d]oxazole (PO) acts as the acceptor and triphenylamine as the donor. TPA-PO and TPA-DPO display good thermal stability and efficient luminescence efficiency in neat film. Results based on photophysical property and theoretical calculation demonstrate that TPA-PO and TPA-DPO possess the hybridized local and charge-transfer (HLCT) feature, which can utilize the triplet exciton to achieve highly efficient electroluminance (EL). The non-doped OLEDs with TPA-PO/TPA-DPO as pure emissive layer show the uniform EL emission peak at 468 nm, corresponding to CIE coordinates of (0.168, 0.187) and (0.167, 0.167), respectively. The TPA-DPO-based non-doped OLEDs provide the maximum external quantum efficiency (EQE) of 7.99 % and high exciton utility efficiency of 48.4 %~72.6 %. Moreover, the TPA-DPO-based device exhibits low-efficiency roll-off, still maintaining the EQE of 6.03 % at the high luminance of 5000 cd m-2. Those findings state clearly that PO is a promising building block of blue fluorophore with a potential HLCT feature to be applied in non-doped OLEDs.

Advances in pH Sensing: From Traditional Approaches to Next-Generation Sensors in Biological Contexts.

pH has been considered one of the paramount factors in bodily functions because most cellular tasks exclusively rely on precise pH values. In this context, the current techniques for pH sensing provide us with the futuristic insight to further design therapeutic and diagnostic tools. Thus, pH-sensing (electrochemically and optically) is rapidly evolving toward exciting new applications and expanding researchers' interests in many chemical contexts, especially in biomedical applications. The adaptation of cutting-edge technology is subsequently producing the modest form of these biosensors as wearable devices, which are providing us the opportunity to target the real-time collection of vital parameters, including pH for improved healthcare systems. The motif of this review is to provide insight into trending tech-based systems employed in real-time or in-vivo pH-responsive monitoring. Herein, we briefly go through the pH regulation in the human body to help the beginners and scientific community with quick background knowledge, recent advances in the field, and pH detection in real-time biological applications. In the end, we summarize our review by providing an outlook; challenges that need to be addressed, and prospective integration of various pH in vivo platforms with modern electronics that can open new avenues of cutting-edge techniques for disease diagnostics and prevention.

A novel model for predicting prognosis in patients with idiopathic pulmonary fibrosis based on endoplasmic reticulum stress-related genes.

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic disease of unknown pathogenic origin. Endoplasmic reticulum (ER) stress refers to the process by which cells take measures to ER function when the morphology and function of the reticulum are changed. Recent studies have demonstrated that the ER was involved in the evolution and progression of IPF. In this study, we obtained transcriptome data and relevant clinical information from the Gene Expression Omnibus database and conducted bioinformatics analysis. Among the 544 ER stress-related genes (ERSRGs), 78 were identified as differentially expressed genes (DEGs). These DEGs were primarily enriched in response to ER stress, protein binding, and protein processing. Two genes (HTRA2 and KTN1) were included for constructing an accurate molecular signature. The overall survival of patients was remarkably worse in the high-risk group than in the low-risk group. We further analyzed the difference in immune cells between high-risk and low-risk groups. M0 and M2 macrophages were significantly increased in the high-risk group. Our results suggested that ERSRGs might play a critical role in the development of IPF by regulating the immune microenvironment in the lungs, which provide new insights on predicting the prognosis of patients with IPF.

Immunological platelet transfusion refractoriness: current insights from mechanisms to therapeutics.

Although there have been tremendous improvements in the production and storage of platelets, platelet transfusion refractoriness (PTR) remains a serious clinical issue that may lead to various severe adverse events. The burden of supplying platelets is worsened by rising market demand and limited donor pools of compatible platelets. Antibodies against platelet antigens are known to activate platelets through FcγR-dependent or complement-activated channels, thereby rapidly eliminating foreign platelets. Recently, other mechanisms of platelet clearance have been reported. The current treatment strategy for PTR is to select appropriate and compatible platelets; however, this necessitates a sizable donor pool and technical assistance for costly testing. Consolidation of these mechanisms should be of critical significance in providing insight to establish novel therapeutics to target immunological platelet refractoriness. Therefore, the purposes of this review were to explore the modulation of the immune system over the activation and elimination of allogeneic platelets and to summarize the development of alternative approaches for treating and avoiding alloimmunization to human leukocyte antigen or human platelet antigen in PTR.

Platelet transfusion is a critical treatment for patients with a severely reduced platelet count and significant bleeding symptoms. However, some patients do not respond to transfused platelets, especially those with repeated transfusions and malignant hematologic disorders, which may increase the burden of disease. In this review article, the authors outline how immunological factors contribute to the failure of platelet transfusions and conventional therapies. Although antibody-mediated platelet removal is often considered the predominant immunological mechanism, studies have shown that CD8⁺ T cells also play a unique role in platelet clearance. The authors also cover the prospects and challenges of alternative treatment strategies in clinical practice.

Vertical Distribution Mapping for Methane Fugitive Emissions Using Laser Path-Integral Sensing in Non-Cooperative Open Paths.

Observing the vertical diffusion distribution of methane fugitive emissions from oil/gas facilities is significant for predicting the pollutant's spatiotemporal transport and quantifying the random emission sources. A method is proposed for methane's vertical distribution mapping by combining the laser path-integral sensing in non-non-cooperative open paths and the computer-assisted tomography (CAT) techniques. It uses a vertical-plume-mapping optical path configuration and adapts the developed dynamic relaxation and simultaneous algebraic reconstruction technique (DR-SART) into methane-emission-distribution reconstruction. A self-made miniaturized TDLAS telemetry sensor provides a reliable path to integral concentration information in non-non-cooperative open paths, with Allan variance analysis yielding a 3.59 ppm·m sensitivity. We employed a six-indexes system for the reconstruction performance analysis of four potential optical path-projection configurations and conducted the corresponding validation experiment. The results have shown that that of multiple fan-beams combined with parallel-beam modes (MFPM) is better than the other optical path-projection configurations, and its reconstruction similarity coefficient (ε) is at least 22.4% higher. For the different methane gas bag-layout schemes, the reconstruction errors of maximum concentration (γm) are consistently around 0.05, with the positional errors of maximum concentration (δ) falling within the range of 0.01 to 0.025. Moreover, considering the trade-off between scanning duration and reconstruction accuracy, it is recommended to appropriately extend the sensor measurement time on a single optical path to mitigate the impact of mechanical vibrations induced by scanning motion.

Evolution and Function of the Notch Signaling Pathway: An Invertebrate Perspective.

The highly conserved Notch signaling pathway affects embryonic development, neurogenesis, homeostasis, tissue repair, immunity, and numerous other essential processes. Although previous studies have demonstrated the location and function of the core components of Notch signaling in various animal phyla, a more comprehensive summary of the Notch core components in lower organisms is still required. In this review, we objectively summarize the molecular features of the Notch signaling pathway constituents, their current expression profiles, and their functions in invertebrates, with emphasis on their effects on neurogenesis and regeneration. We also analyze the evolution and other facets of Notch signaling and hope that the contents of this review will be useful to interested researchers.

Increased ecological land and atmospheric CO2 dominate the growth of ecosystem carbon sinks under the regulation of environmental conditions in national key ecological function zones in China.

Increased ecological land (IEL) such as forests and grasslands can greatly enhance ecosystem carbon sinks. Understanding the mechanisms for the magnitude of IEL-induced ecosystem carbon sinks is crucial for achieving carbon neutrality. We estimated the impact of IEL, specifically the increase in forests and grasslands, as well as global changes including atmospheric CO2 concentration, nitrogen deposition, and climate change on net ecosystem productivity (NEP) in National Key Ecological Function Zones (NKEFZs) in China using a calibrated ecological process model. The NEP in NKEFZs in China was calculated to be 119.4 Tg C yr-1, showing an increase of 42.6 Tg C yr-1 from 2001 to 2021. Compared to the slight contributions of climate change (-8.0%), nitrogen deposition (11.5%), and reduction in ecological land (-3.5%), the increase in NEP was primarily attributed to CO2 (66.5%) and IEL (33.5%). Moreover, the effect of IEL (14.8 Tg C yr-1) surpassed that of global change (13.1 Tg C yr-1) in the land use change zone. The IEL-induced NEP is significantly associated with CO2 fertilization, regulated by precipitation and nitrogen deposition. The high values of IEL-induced NEP occurred in areas with precipitation exceeding 800 mm and nitrogen deposition exceeding 25 kg N ha-1 yr-1. We recommend prioritizing the expansion of ecological land in areas with sufficient water and nutrients to enhance CO2 fertilization, while avoiding increasing ecological land in regions facing unfavorable climate change conditions. This study serves as a foundation for comprehending the NEP response to ecological restoration and global change.

Preparation and Support Effect of Graphdiyne Nanotubes with Abundant Cu Quantum Dots.

Graphdiyne (GDY) is considered a very attractive support for metal nanocatalysts due to its unique structure and superior properties. The metal-GDY interaction can significantly affect the performance of catalysts. Herein, GDY nanotubes abundant in in situ formed Cu quantum dots (QDs) (Cu-GDYNT) are prepared using the electrospun polyacrylonitrile nanofibers collected on the surface of electrolytic Cu foil as templates. The diameter of the Cu-GDYNT is controllable and the uniform size of the embedded Cu QDs is about 2.2 nm. And then, the uniformly dispersed and highly active supported catalysts of ruthenium nanoparticles (Rux/Cu-GDYNT) are produced using the Cu-GDYNT as the support. Among them, the Ru3/Cu-GDYNT exhibit outstanding HER performance at all pH levels. Only 17, 67 and 83 mV overpotential is required to reach a current density of 10 mA cm-2 in 1.0 M KOH, 0.5 M H2SO4 and 1.0 M neutral PBS solutions, respectively. The sample exhibits 3000 CV cycle stability and 20 h continuous electrolysis without performance degradation in an alkaline medium. This work provides a new idea for constructing the GDY-supported metal nanocatalysts.

Cascade DNA Circuits Mediated CRISPR-Cas12a Fluorescent Aptasensor based on Multifunctional Fe3 O4 @hollow-TiO2 @MoS2 Nanochains for Tetracycline Determination.

Herein, for the first time, the CRISPR-Cas12a system is combined with aptamer, cascaded dynamic DNA network circuits, and Fe3 O4 @hollow-TiO2 @MoS2 nanochains (Fe3 O4 @h-TiO2 @MoS2 NCs) to construct an efficient sensing platform for tetracycline (TC) analysis. In this strategy, specific recognition of the target is transduced and amplified into H1-H2 duplexes containing the specific sequence of Cas12a-crRNA through an aptamer recognition module and the dual amplification dynamic DNA network. Subsequently, the obtained activated Cas12a protein non-specifically cleaves the adjacent reporter gene ssDNA-FAM to dissociate the FAM molecule from the quencher Fe3 O4 @h-TiO2 @MoS2 NCs, resulting in the recovery of the fluorescence signal and further signal amplification. Particularly, the synthesized multifunctional Fe3 O4 @h-TiO2 @MoS2 NCs composites also exhibit superb magnetic separability and photocatalytic degradation ability. Under optimal conditions, the aptasensor displays a distinct linear relationship with the logarithm of TC concentration, and the limit of detection is as low as 0.384 pg mL-1 . Furthermore, the results of spiked recovery confirm the viability of the proposed aptasensor for TC quantification in real samples. This study extends the application of the CRISPR-Cas12a system in the field of analytical sensing and contributes new insights into the exploration of reliable tools for monitoring and treating hazards in food and environment.

Plant lipid phosphate phosphatases: current advances and future outlooks.

Lipids are widely distributed in various tissues of an organism, mainly in plant storage organs (e.g., fruits, seeds, etc.). Lipids are vital biological substances that are involved in: signal transduction, membrane biogenesis, energy storage, and the formation of transmembrane fat-soluble substances. Some lipids and related lipid derivatives could be changed in their: content, location, or physiological activity by the external environment, such as biotic or abiotic stresses. Lipid phosphate phosphatases (LPPs) play important roles in regulating intermediary lipid metabolism and cellular signal response. LPPs can dephosphorylate lipid phosphates containing phosphate monolipid bonds such as: phosphatidic acid, lysophosphatidic acid (LPA), and diacylglycerol pyrophosphate, etc. These processes can change the contents of some important lipid signal mediation such as diacylglycerol and LPA, affecting lipid signal transmission. Here, we summarize the research progress of LPPs in plants, emphasizing the structural and biochemical characteristics of LPPs and their role in spatio-temporal regulation. In the future, more in-depth studies are required to boost our understanding of the key role of plant LPPs and lipid metabolism in: signal regulation, stress tolerance pathway, and plant growth and development.

Exosomal ACADM sensitizes gemcitabine-resistance through modulating fatty acid metabolism and ferroptosis in pancreatic cancer.

This study aimed to evaluate the potential of exosomes from cancer cells to predict chemoresistance in pancreatic cancer (PC) and explore the molecular mechanisms through RNA-sequencing and mass spectrometry. We sought to understand the connection between the exosomal Medium-chain acyl-CoA dehydrogenase (ACADM) level and the reaction to gemcitabine in vivo and in patients with PC. We employed loss-of-function, gain-of-function, metabolome mass spectrometry, and xenograft models to investigate the effect of exosomal ACADM in chemoresistance in PC. Our results showed that the molecules involved in lipid metabolism in exosomes vary between PC cells with different gemcitabine sensitivity. Exosomal ACADM (Exo-ACADM) was strongly correlated with gemcitabine sensitivity in vivo, which can be used as a predictor for postoperative gemcitabine chemosensitivity in pancreatic patients. Moreover, ACADM was found to regulate the gemcitabine response by affecting ferroptosis through Glutathione peroxidase 4 (GPX4) and mevalonate pathways. It was also observed that ACADM increased the consumption of unsaturated fatty acids and decreased intracellular lipid peroxides and reactive oxygen species (ROS) levels. In conclusion, this research suggests that Exo-ACADM may be a viable biomarker for predicting the responsiveness of patients to chemotherapy.

The FACT-targeted drug CBL0137 enhances the effects of rituximab to inhibit B-cell non-Hodgkin's lymphoma tumor growth by promoting apoptosis and autophagy.

BACKGROUND: Aggressive B-cell non-Hodgkin's lymphoma (B-NHL) patients often develop drug resistance and tumor recurrence after conventional immunochemotherapy, for which new treatments are needed. METHODS: We investigated the antitumor effects of CBL0137. In vitro, cell proliferation was assessed by CCK-8 and colony formation assay. Flow cytometry was performed to analyze cell cycle progression, apoptosis, mitochondrial depolarization, and reactive oxygen species (ROS) production. Autophagy was detected by transmission electron microscopy and mGFP-RFP-LC3 assay, while western blotting was employed to detect proteins involved in apoptosis and autophagy. RNA-sequencing was conducted to analyze the transcription perturbation after CBL0137 treatment in B-NHL cell lines. Finally, the efficacy and safety of CBL0137, rituximab, and their combination were tested in vivo. RESULTS: CBL0137, a small molecule anticancer agent that has significant antitumor effects in B-NHL. CBL0137 sequesters the FACT (facilitates chromatin transcription) complex from chromatin to produce cytotoxic effects in B-NHL cells. In addition, we discovered novel anticancer mechanisms of CBL0137. CBL0137 inhibited human B-NHL cell proliferation by inducing cell cycle arrest in S phase via the c-MYC/p53/p21 pathway. Furthermore, CBL0137 triggers ROS generation and induces apoptosis and autophagy in B-NHL cells through the ROS-mediated PI3K/Akt/mTOR and MAPK signaling pathways. Notably, a combination of CBL0137 and rituximab significantly suppressed B-NHL tumor growth in subcutaneous models, consistent with results at the cellular level in vitro. CONCLUSIONS: CBL0137 has potential as a novel approach for aggressive B-NHL, and its combination with rituximab can provide new therapeutic options for patients with aggressive B-NHL. Video Abstract.