Glycolytic enzyme PFKL governs lipolysis by promoting lipid droplet-mitochondria tethering to enhance ß-oxidation and tumor cell proliferation.

Lipid droplet tethering with mitochondria for fatty acid oxidation is critical for tumor cells to counteract energy stress. However, the underlying mechanism remains unclear. Here, we demonstrate that glucose deprivation induces phosphorylation of the glycolytic enzyme phosphofructokinase, liver type (PFKL), reducing its activity and favoring its interaction with perilipin 2 (PLIN2). On lipid droplets, PFKL acts as a protein kinase and phosphorylates PLIN2 to promote the binding of PLIN2 to carnitine palmitoyltransferase 1A (CPT1A). This results in the tethering of lipid droplets and mitochondria and the recruitment of adipose triglyceride lipase to the lipid droplet-mitochondria tethering regions to engage lipid mobilization. Interfering with this cascade inhibits tumor cell proliferation, promotes apoptosis and blunts liver tumor growth in male mice. These results reveal that energy stress confers a moonlight function to PFKL as a protein kinase to tether lipid droplets with mitochondria and highlight the crucial role of PFKL in the integrated regulation of glycolysis, lipid metabolism and mitochondrial oxidation.

Supramolecular 3 in 1: A Lubrication and Co-Delivery System for Synergistic Advanced Osteoarthritis Therapy.

The complexity, heterogeneity, and drug resistance of diseases necessitate a shift in therapeutic paradigms from monotherapy to combination therapy, which could augment treatment efficiency. Effective treatment of advanced osteoarthritis (OA) requires addressing three key factors contributing to its deterioration: chronic joint inflammation, lubrication dysfunction, and cartilage-tissue degradation. Herein, we present a supramolecular nanomedicine of multifunctionality via molecular recognition and self-assembly. The employed macrocyclic carrier, zwitterion-modified cavitand (CV-2), not only accurately loads various drugs but also functions as a therapeutic agent with lubricating properties for the treatment of OA. Kartogenin (KGN), a drug for articular cartilage regeneration and protection, and flurbiprofen (FP), an anti-inflammatory agent, were coloaded onto CV-2 assembly, forming a supramolecular nanomedicine KGN&FP@CV-2. The three-in-one combination therapy of KGN&FP@CV-2 addresses the three pathological features for treating OA collectively, and thus provides long-term therapeutic benefits for OA through sustained drug release and intrinsic lubrication in vivo. The multifunctional integration of macrocyclic delivery and therapeutics provides a simple, flexible, and universal platform for the synergistic treatment of diseases involving multiple drugs.

LncRNAs as nodes for the cross-talk between autophagy and Wnt signaling in pancreatic cancer drug resistance.

Pancreatic cancer is a malignancy with high mortality. In addition to the few symptoms until the disease reaches an advanced stage, the high fatality rate is attributed to its rapid development, drug resistance and lack of appropriate treatment. In the selection and research of therapeutic drugs, gemcitabine is the first-line drug for pancreatic cancer. Solving the problem of gemcitabine resistance in pancreatic cancer will contribute to the progress of pancreatic cancer treatment. Long non coding RNAs (lncRNAs), which are RNA transcripts longer than 200 nucleotides, play vital roles in cellular physiological metabolic activities. Currently, our group and others have found that some lncRNAs are aberrantly expressed in pancreatic cancer cells, which can regulate the process of cancer through autophagy and Wnt/ß-catenin pathways simultaneously and affect the sensitivity of cancer cells to therapeutic drugs. This review presents an overview of the recent evidence concerning the node of lncRNA for the cross-talk between autophagy and Wnt/ß-catenin signaling in pancreatic cancer, together with the practicability of lncRNAs and the core regulatory factors as targets in therapeutic resistance.

Acetate reprogrammes tumour metabolism and promotes PD-L1 expression and immune evasion by upregulating c-Myc.

Acetate, a precursor of acetyl-CoA, is instrumental in energy production, lipid synthesis and protein acetylation. However, whether acetate reprogrammes tumour metabolism and plays a role in tumour immune evasion remains unclear. Here, we show that acetate is the most abundant short-chain fatty acid in human non-small cell lung cancer tissues, with increased tumour-enriched acetate uptake. Acetate-derived acetyl-CoA induces c-Myc acetylation, which is mediated by the moonlighting function of the metabolic enzyme dihydrolipoamide S-acetyltransferase. Acetylated c-Myc increases its stability and subsequent transcription of the genes encoding programmed death-ligand 1, glycolytic enzymes, monocarboxylate transporter 1 and cell cycle accelerators. Dietary acetate supplementation promotes tumour growth and inhibits CD8+ T cell infiltration, whereas disruption of acetate uptake inhibits immune evasion, which increases the efficacy of anti-PD-1-based therapy. These findings highlight a critical role of acetate promoting tumour growth beyond its metabolic role as a carbon source by reprogramming tumour metabolism and immune evasion, and underscore the potential of controlling acetate metabolism to curb tumour growth and improve the response to immune checkpoint blockade therapy.

Shexiang Tongxin Dropping Pill Promotes Angiogenesis through VEGF/eNOS Signaling Pathway on Diabetic Coronary Microcirculation Dysfunction.

OBJECTIVE: To study the effect of Shexiang Tongxin Dropping Pill (STDP) on angiogenesis in diabetic cardiomyopathy mice with coronary microcirculation dysfunction (CMD). METHODS: According to a random number table, 6 of 36 SPF male C57BL/6 mice were randomly selected as the control group, and the remaining 30 mice were injected with streptozotocin intraperitoneally to replicate the type 1 diabetes model. Mice successfully copied the diabetes model were randomly divided into the model group, STDP low-dose group [15 mg/(kg·d)], medium-dose group [30 mg/(kg·d)], high-dose group [60 mg/(kg·d)], and nicorandil group [15 mg/(kg·d)], 6 in each group. The drug was given by continuous gavage for 12 weeks. The cardiac function of mice in each group was detected at the end of the experiment, and coronary flow reserve (CFR) was detected by chest Doppler technique. Pathological changes of myocardium were observed by hematoxylin-eosin staining, collagen fiber deposition was detected by masson staining, the number of myocardial capillaries was detected by platelet endothelial cell adhesion molecule-1 staining, and the degree of myocardial hypertrophy was detected by wheat germ agglutinin staining. The expression of the vascular endothlial growth factor (VEGF)/endothelial nitric oxide synthase (eNOS) signaling pathway-related proteins in myocardial tissue was detected by Western blot. RESULTS: Compared with the model group, medium- and high-dose STDP significantly increased the left ventricular ejection fraction and left ventricular fraction shortening (P<0.01), obviously repaired the disordered cardiac muscle structure, reduced myocardial fibrosis, reduced myocardial cell area, increased capillary density, and increased CFR level (all P<0.01). Western blot showed that high-dose STDP could significantly increase the expression of VEGF and promote the phosphorylation of vascular endothelial growth factor receptor 2, phosphoinositide 3-kinase, protein kinase B, and eNOS (P<0.05 or P<0.01). CONCLUSION: STDP has a definite therapeutic effect on diabetic CMD, and its mechanism may be related to promoting angiogenesis through the VEGF/eNOS signaling pathway.

Enhanced quantum secret sharing protocol for anonymous secure communication utilizing W states.

Quantum secret sharing (QSS) represents the fusion of quantum mechanics principles with secret information sharing, allowing a sender to distribute a secret among receivers for collective recovery. This paper introduces the concept of quantum anonymous secret sharing (QASS) to enhance the practicality of such protocols. We propose a QASS protocol leveraging W states, ensuring both recover-security and anonymity of shared secrets. Our protocol undergoes rigorous evaluation verifying their accuracy and fortifying their security against scenarios involving the active adversary. Additionally, acknowledging the imperfections inherent in real-world communication channels, we conduct a comprehensive analysis of protocol security and efficacy in noisy quantum networks. Our investigations reveal that W states exhibit good performance in mitigating noise interference, making them apt for practical applications.

Single Molecular Nanomedicines Based on Macrocyclic Carrier-Drug Conjugates for Concentration-Independent Encapsulation and Precise Activation of Drugs.

Nanomedicines often rely on noncovalent self-assembly and encapsulation for drug loading and delivery. However, challenges such as reproducibility issues due to the multicomponent nature, off-target activation caused by premature drug release, and complex pharmacokinetics arising from assembly dissociation have hindered their clinical translation. In this study, we introduce an innovative design concept termed single molecular nanomedicine (SMNM) based on macrocyclic carrier-drug conjugates. Through the covalent linkage of two chemotherapy drugs to a hypoxia-cleavable macrocyclic carrier, azocalix[4]arene, we obtained two self-included complexes to serve as SMNMs. The intramolecular inclusion feature of the SMNMs has not only demonstrated comprehensive shielding and protection for the drugs but also effectively prevented off-target drug leakage, thereby significantly reducing their side effects and enhancing their antitumor therapeutic efficacy. Additionally, the attributes of being a single component and molecularly dispersed confer advantages such as ease of preparation and good reproducibility for SMNMs, which is desirable for clinical applications.

HDAC inhibitors as a potential therapy for chemotherapy-induced neuropathic pain.

Cancer, a chronic disease characterized by uncontrolled cell development, kills millions of people globally. The WHO reported over 10 million cancer deaths in 2020. Anticancer medications destroy healthy and malignant cells. Cancer treatment induces neuropathy. Anticancer drugs cause harm to spinal cord, brain, and peripheral nerve somatosensory neurons, causing chemotherapy-induced neuropathic pain. The chemotherapy-induced mechanisms underlying neuropathic pain are not fully understood. However, neuroinflammation has been identified as one of the various pathways associated with the onset of chemotherapy-induced neuropathic pain. The neuroinflammatory processes may exhibit varying characteristics based on the specific type of anticancer treatment delivered. Neuroinflammatory characteristics have been observed in the spinal cord, where microglia and astrocytes have a significant impact on the development of chemotherapy-induced peripheral neuropathy. The patient's quality of life might be affected by sensory deprivation, loss of consciousness, paralysis, and severe disability. High cancer rates and ineffective treatments are associated with this disease. Recently, histone deacetylases have become a novel treatment target for chemotherapy-induced neuropathic pain. Chemotherapy-induced neuropathic pain may be treated with histone deacetylase inhibitors. Histone deacetylase inhibitors may be a promising therapeutic treatment for chemotherapy-induced neuropathic pain. Common chemotherapeutic drugs, mechanisms, therapeutic treatments for neuropathic pain, and histone deacetylase and its inhibitors in chemotherapy-induced neuropathic pain are covered in this paper. We propose that histone deacetylase inhibitors may treat several aspects of chemotherapy-induced neuropathic pain, and identifying these inhibitors as potentially unique treatments is crucial to the development of various chemotherapeutic combination treatments.

scMNMF: a novel method for single-cell multi-omics clustering based on matrix factorization.

MOTIVATION: The technology for analyzing single-cell multi-omics data has advanced rapidly and has provided comprehensive and accurate cellular information by exploring cell heterogeneity in genomics, transcriptomics, epigenomics, metabolomics and proteomics data. However, because of the high-dimensional and sparse characteristics of single-cell multi-omics data, as well as the limitations of various analysis algorithms, the clustering performance is generally poor. Matrix factorization is an unsupervised, dimensionality reduction-based method that can cluster individuals and discover related omics variables from different blocks. Here, we present a novel algorithm that performs joint dimensionality reduction learning and cell clustering analysis on single-cell multi-omics data using non-negative matrix factorization that we named scMNMF. We formulate the objective function of joint learning as a constrained optimization problem and derive the corresponding iterative formulas through alternating iterative algorithms. The major advantage of the scMNMF algorithm remains its capability to explore hidden related features among omics data. Additionally, the feature selection for dimensionality reduction and cell clustering mutually influence each other iteratively, leading to a more effective discovery of cell types. We validated the performance of the scMNMF algorithm using two simulated and five real datasets. The results show that scMNMF outperformed seven other state-of-the-art algorithms in various measurements. AVAILABILITY AND IMPLEMENTATION: scMNMF code can be found at https://github.com/yushanqiu/scMNMF.

Association of dietary nutrient intake with type 2 diabetes: A Mendelian randomization study.

Observational research suggests that the evidence linking dietary nutrient intake (encompassing minerals, vitamins, amino acids, and unsaturated fatty acids) to type 2 diabetes (T2D) is both inconsistent and limited. This study aims to explore the potential causal relationship between dietary nutrients and T2D. Causal estimation utilized Mendelian randomization techniques. Single nucleotide polymorphisms linked to dietary nutrients were identified from existing genome-wide association studies and used as instrumental variables. Genome-wide association studies data pertinent to T2D were sourced from the DIMANTE consortium and the FinnGen database. Techniques including inverse variance weighting (IVW), weighted mode, weighted median, and Mendelian randomization-Egger were employed for causal inference, complemented by sensitivity analysis. Genetically predicted higher phenylalanine (IVW: odds ratio = 1.10 95% confidence interval 1.04-1.17, P = 1.5 × 10-3, q_pval = 3.4 × 10-2) and dihomo-gamma-linolenic acid (IVW: odds ratio = 1.001 95% confidence interval 1.0006-1.003, P = 3.7 × 10-3, q_pval = 4.1 × 10-2) levels were directly associated with T2D risk. Conversely, no causal relationships between other nutrients and T2D were established. We hypothesize that phenylalanine and dihomo-gamma-linolenic acid contribute to the pathogenesis of T2D. Clinically, the use of foods with high phenylalanine content may pose potential risks for patients with a heightened risk of T2D. Our study provides evidence supporting a causal link between dietary nutrient intake and the development of T2D.

Discovery of Sovleplenib, a Selective Inhibitor of Syk in Clinical Development for Autoimmune Diseases and Cancers.

Herein we describe the medicinal chemistry efforts that led to the discovery of the clinical-staged Syk inhibitor sovleplenib (41) via a structure-activity relationship investigation and pharmacokinetics (PK) optimization of a pyrido[3,4-b]pyrazine scaffold. Sovleplenib is a potent and selective Syk inhibitor with favorable preclinical PK profiles and robust anti-inflammation efficacy in a preclinical collagen-induced arthritis model. Sovleplenib is now being developed for treating autoimmune diseases such as immune thrombocytopenic purpura and warm antibody hemolytic anemia as well as hematological malignancies.

Recent advances in mesenchymal stem cell therapy for myocardial infarction.

Myocardial infarction refers to the ischemic necrosis of myocardium, characterized by a sharp reduction or interruption of blood flow in the coronary arteries due to the coronary artery occlusion, resulting in severe and prolonged ischemia in the corresponding myocardium and ultimately leading to ischemic necrosis of the myocardium. Given its high risk, it is considered as one of the most serious health threats today. In current clinical practice, multiple approaches have been explored to diminish myocardial oxygen consumption and alleviate symptoms, but notable success remains elusive. Accumulated clinical evidence has showed that the implantation of mesenchymal stem cell for treating myocardial infarction is both effective and safe. Nevertheless, there persists controversy and variability regarding the standardizing MSC transplantation protocols, optimizing dosage, and determining the most effective routes of administration. Addressing these remaining issues will pave the way of integration of MSCs as a feasible mainstream cardiac treatment.

A long non-coding RNA functions as a competitive endogenous RNA to modulate TaNAC018 by acting as a decoy for tae-miR6206.

Increasing evidence indicates a strong correlation between the deposition of cuticular waxes and drought tolerance. However, the precise regulatory mechanism remains elusive. Here, we conducted a comprehensive transcriptome analysis of two wheat (Triticum aestivum) near-isogenic lines, the glaucous line G-JM38 rich in cuticular waxes and the non-glaucous line NG-JM31. We identified 85,143 protein-coding mRNAs, 4,485 lncRNAs, and 1,130 miRNAs. Using the lncRNA-miRNA-mRNA network and endogenous target mimic (eTM) prediction, we discovered that lncRNA35557 acted as an eTM for the miRNA tae-miR6206, effectively preventing tae-miR6206 from cleaving the NAC transcription factor gene TaNAC018. This lncRNA-miRNA interaction led to higher transcript abundance for TaNAC018 and enhanced drought-stress tolerance. Additionally, treatment with mannitol and abscisic acid (ABA) each influenced the levels of tae-miR6206, lncRNA35557, and TaNAC018 transcript. The ectopic expression of TaNAC018 in Arabidopsis also improved tolerance toward mannitol and ABA treatment, whereas knocking down TaNAC018 transcript levels via virus-induced gene silencing in wheat rendered seedlings more sensitive to mannitol stress. Our results indicate that lncRNA35557 functions as a competing endogenous RNA to modulate TaNAC018 expression by acting as a decoy target for tae-miR6206 in glaucous wheat, suggesting that non-coding RNA has important roles in the regulatory mechanisms responsible for wheat stress tolerance.

Turning waste into treasure: A new direction for low-cost production of lipid chemicals from Thraustochytrids.

Thraustochytrids are marine microorganisms known for their fast growth and ability to store lipids, making them useful for producing polyunsaturated fatty acids (PUFAs), biodiesel, squalene, and carotenoids. However, the high cost of production, mainly due to expensive fermentation components, limits their wider use. A significant challenge in this context is the need to balance production costs with the value of the end products. This review focuses on integrating the efficient utilization of waste with Thraustochytrids fermentation, including the economic substitution of carbon sources, nitrogen sources, and fermentation water. This approach aligns with the 3Rs principles (reduction, recycling, and reuse). Furthermore, it emphasizes the role of Thraustochytrids in converting waste into lipid chemicals and promoting sustainable circular production models. The aim of this review is to emphasize the value of Thraustochytrids in converting waste into treasure, providing precise cost reduction strategies for future commercial production.

FPL+: Filtered Pseudo Label-based Unsupervised Cross-Modality Adaptation for 3D Medical Image Segmentation.

Adapting a medical image segmentation model to a new domain is important for improving its cross-domain transferability, and due to the expensive annotation process, Unsupervised Domain Adaptation (UDA) is appealing where only unlabeled images are needed for the adaptation. Existing UDA methods are mainly based on image or feature alignment with adversarial training for regularization, and they are limited by insufficient supervision in the target domain. In this paper, we propose an enhanced Filtered Pseudo Label (FPL+)-based UDA method for 3D medical image segmentation. It first uses cross-domain data augmentation to translate labeled images in the source domain to a dual-domain training set consisting of a pseudo source-domain set and a pseudo target-domain set. To leverage the dual-domain augmented images to train a pseudo label generator, domain-specific batch normalization layers are used to deal with the domain shift while learn the domain-invariant structure features, generating high-quality pseudo labels for target-domain images. We then combine labeled source-domain images and target-domain images with pseudo labels to train a final segmentor, where image-level weighting based on uncertainty estimation and pixel-level weighting based on dual-domain consensus are proposed to mitigate the adverse effect of noisy pseudo labels. Experiments on three public multi-modal datasets for Vestibular Schwannoma, brain tumor and whole heart segmentation show that our method surpassed ten state-of-the-art UDA methods, and it even achieved better results than fully supervised learning in the target domain in some cases.

Essential role of lattice oxygen in hydrogen sensing reaction.

Understanding the sensing mechanism of metal oxide semiconductors is imperative to the development of high-performance sensors. The traditional sensing mechanism only recognizes the effect of surface chemisorbed oxygen from the air but ignores surface lattice oxygen. Herein, using in-situ characterizations, we provide direct experimental evidence that the surface chemisorbed oxygen participated in the sensing process can come from lattice oxygen of the oxides. Further density functional theory (DFT) calculations prove that the p-band center of O serves as a state of art for regulating the participation of lattice oxygen in gas-sensing reactions. Based on our experimental data and theoretical calculations, we discuss mechanisms that are fundamentally different from the conventional mechanism and show that the easily participation of lattice oxygen is helpful for the high response value of the materials.

Laccase-induced decontamination and humification mechanisms of estrogen in water-crop matrices.

Enzymatic humification plays a crucial biogeochemical role in eliminating steroidal estrogens and expanding organic carbon stocks. Estrogenic contaminants in agroecosystems can be taken up and acropetally translocated by crops, but the roles of laccase-triggered rhizospheric humification (L-TRH) in pollutant dissipation and plant uptake remain poorly understood. In this study, the laccase-induced decontamination and humification mechanisms of 17ß-estradiol (E2) in water-crop media were investigated by performing greenhouse pot experiments with maize seedlings (Zea mays L.). The results demonstrated that L-TRH effectively dissipated E2 in the rhizosphere solution and achieved the kinetic constants of E2 dissipation at 10 and 50 µM by 8.05 and 2.75 times as much as the treatments without laccase addition, respectively. The copolymerization of E2 and root exudates (i.e. phenols and amino acids) consolidated by L-TRH produced a larger amount of humified precipitates with the richly functional carbon architectures. The growth parameters and photosynthetic pigment levels of maize seedlings were greatly impeded after a 120-h exposure to 50 µM E2, but L-TRH motivated the detoxication process and thus mitigated the phytotoxicity and bioavailability of E2. The tested E2 contents in the maize tissues initially increased sharply with the cultivation time but decreased steadily. Compared with the treatment without laccase addition, the uptake and accumulation of E2 in the maize tissues were obviously diminished by L-TRH. E2 oligomers such as dimer, trimer, and tetramer recognized in the rhizosphere solution were also detected in the root tissues but not in the shoots, demonstrating that the acropetal translocation of E2 oligomers was interrupted. These results highlight a promising strategy for decontaminating estrogenic pollutants, boosting rhizospheric humification, and realizing low-carbon emissions, which would be beneficial for agroenvironmental bioremediation and sustainability.

MS/MS-based molecular networking discovery of sesquiterpenes from Carpesium abrotanoides L. with their cytotoxic and acetylcholinesterase inhibitory activity.

Employing an MS/MS-based molecular networking-guided strategy, three new eudesmane-type sesquiterpenes (1-3) and one undescribed pseudoguaianolide sesquiterpene (8), along with four known eudesmane-type sesquiterpene lactones (4-7) were extracted and purified from the herbs of Carpesium abrotanoides L. Structural elucidation encompassed comprehensive spectroscopic analysis, NMR calculations, DP4+ analysis, and ECD calculations. The cytotoxicity activity of all isolates was evaluated against two human hepatoma carcinoma cells (HepG2 and Hep3B) in vitro. It was demonstrated that compounds 2 and 4 showed moderate cytotoxic against HepG2 and Hep3B cells. Furthermore, all compounds were evaluated for their acetylcholinesterase (AChE) inhibitory activity. Particularly noteworthy is that, in comparison to the positive control, compound 1 demonstrated significant AChE inhibition with an inhibition rate of 77.86%. In addition, the inhibitory mechanism of compound 1 were investigated by in silico docking analyze and molecular dynamic simulation.

13-Oxyingenol-dodecanoate inhibits the growth of non-small cell lung cancer cells by targeting ULK1.

Lung cancer is the leading cause of cancer deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for 80-85% of all lung cancers. Euphorbia kansui yielded 13-oxyingenol-dodecanoate (13OD), an ingenane-type diterpenoid, which had a strong cytotoxic effect on NSCLC cells. The underlying mechanism and potential target, however, remained unknown. The study found that 13OD effectively inhibited the cell proliferation and colony formation of NSCLC cells (A549 and H460 cells), with less toxicity in normal human lung epithelial BEAS-2B cells. Moreover, 13OD can cause mitochondrial dysfunction, and apoptosis in NSCLC cells. Mechanistically, the transcriptomics results showed that differential genes were mainly enriched in the mTOR and AMPK signaling pathways, which are closely related to cellular autophagy, the related indicators were subsequently validated. Additionally, bafilomycin A1 (Baf A1), an autophagy inhibitor, reversed the mitochondrial damage caused by 13OD. Furthermore, the Omics and Text-based Target Enrichment and Ranking (OTTER) method predicted ULK1 as a potential target of 13OD against NSCLC cells. This hypothesis was further confirmed using molecular docking, the cellular thermal shift assay (CETSA), and Western blot analysis. Remarkably, ULK1 siRNA inhibited 13OD's toxic activity in NSCLC cells. In line with these findings, 13OD was potent and non-toxic in the tumor xenograft model. Our findings suggested a possible mechanism for 13OD's role as a tumor suppressor and laid the groundwork for identifying targets for ingenane-type diterpenoids.