The tricarboxylic acid (TCA) cycle is capable of providing sufficient energy for the physiological activities under aerobic conditions. Although tumor metabolic reprogramming places aerobic glycolysis in a dominant position, the TCA cycle remains indispensable for tumor cells as a hub for the metabolic linkage and interconversion of glucose, lipids, and certain amino acids. TCA intermediates such as citrate, α-ketoglutarate, succinate, and fumarate are altered in tumors, and they regulate the tumor metabolism, signal transduction, and immune environment to affect tumorigenesis and tumor progression. This article provides a comprehensive review of the modifications occurring in tumor cells in relation to the intermediates of the TCA cycle, which affects tumor pathogenesis and current therapeutic strategy for therapy through targeting TCA cycle in cancer cells.

Messenger RNA (mRNA) has emerged as an innovative therapeutic modality, offering promising avenues for the prevention and treatment of a variety of diseases. The tremendous success of mRNA vaccines in effectively combatting coronavirus disease 2019 (COVID-19) evidences the unlimited medical and therapeutic potential of mRNA technology. Overcoming challenges related to mRNA stability, immunogenicity, and precision targeting has been made possible by recent advancements in lipid nanoparticles (LNPs). This review summarizes state-of-the-art LNP-mRNA-based therapeutics, including their structure, material compositions, design guidelines, and screening principles. Additionally, we highlight current preclinical and clinical trends in LNP-mRNA therapeutics in a broad range of treatments in ophthalmological conditions, cancer immunotherapy, gene editing, and rare-disease medicine. Particular attention is given to the translation and evolution of LNP-mRNA vaccines into a broader spectrum of therapeutics. We explore concerns in the aspects of inadequate extrahepatic targeting efficacy, elevated doses, safety concerns, and challenges of large-scale production procedures. This discussion may offer insights and perspectives on near- and long-term clinical development prospects for LNP-mRNA therapeutics.

Platelet activation contributes to sepsis development, leading to microthrombosis and increased inflammation, which results in disseminated intravascular coagulation and multiple organ dysfunction. Although Cathelicidin can alleviate sepsis, its role in sepsis regulation remains largely unexplored. In this study, we identified Cath-HG, a novel Cathelicidin from Hylarana guentheri skin, and analyzed its structure using nuclear magnetic resonance spectroscopy. The modulatory effect of Cath-HG on the symptoms of mice with sepsis induced by cecal ligation and puncture was evaluated in vivo, and the platelet count, degree of organ damage, and microthrombosis were measured. The antiplatelet aggregation activity of Cath-HG was studied in vitro, and its target was verified. Finally, we further investigated whether Cath-HG could regulate thrombosis in vivo in a FeCl₃ injury-induced carotid artery model. The results showed that Cath-HG exhibited an α-helical structure in sodium dodecyl sulfate solution and effectively reduced organ inflammation and damage, improving survival in septic mice. It alleviated sepsis-induced thrombocytopenia and microthrombosis. In vitro, Cath-HG specifically inhibited collagen-induced platelet aggregation and modulated glycoprotein VI (GPVI) signaling pathways. Dot blotting, enzyme-linked immunosorbent assay, and pull-down experiments confirmed GPVI as the target of Cath-HG. Molecular docking and amino acid residue truncations/mutations identified crucial sites of Cath-HG. These findings suggest that GPVI represents a promising therapeutic target for sepsis, and Cath-HG may serve as a potential treatment for sepsis-related thrombocytopenia and thrombotic events. Additionally, identifying Cath-HG as a GPVI inhibitor provides insights for developing novel antithrombotic therapies targeting platelet activation mediated by GPVI.

Hepatocellular carcinoma (HCC) was characterized as being hypervascular. In the present study, we generated a single-cell spatial transcriptomic landscape of the vasculogenic etiology of HCC and illustrated overexpressed Golgi phosphoprotein 73 (GP73) HCC cells exerting cellular communication with vascular endothelial cells with high pro-angiogenesis potential via multiple receptor–ligand interactions in the process of tumor vascular development. Specifically, we uncovered an interactive GP73-mediated regulatory network coordinated with c-Myc, lactate, Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway, and endoplasmic reticulum stress (ERS) signals in HCC cells and elucidated its pro-angiogenic roles in vitro and in vivo. Mechanistically, we found that GP73, the pivotal hub gene, was activated by histone lactylation and c-Myc, which stimulated the phosphorylation of downstream STAT3 by directly binding STAT3 and simultaneously enhancing glucose-regulated protein 78 (GRP78)-induced ERS. STAT3 potentiates GP73-mediated pro-angiogenic functions. Clinically, serum GP73 levels were positively correlated with HCC response to anti-angiogenic regimens and were essential for a prognostic nomogram showing good predictive performance for determining 6-month and 1-year survival in patients with HCC treated with anti-angiogenic therapy. Taken together, the aforementioned data characterized the pro-angiogenic roles and mechanisms of a GP73-mediated network and proved that GP73 is a crucial tumor angiogenesis niche gene with favorable anti-angiogenic potential in the treatment of HCC.

Dipeptidyl peptidase-IV (DPP-4) enzyme inhibitors are a promising category of diabetes medications. Bioactive peptides, particularly those derived from bovine milk proteins, play crucial roles in inhibiting the DPP-4 enzyme. This study describes a comprehensive strategy for DPP-4 inhibitory peptide discovery and validation that combines machine learning and virtual proteolysis techniques. Five machine learning models, including GBDT, XGBoost, LightGBM, CatBoost, and RF, were trained. Notably, LightGBM demonstrated superior performance with an AUC value of 0.92 ± 0.01. Subsequently, LightGBM was employed to forecast the DPP-4 inhibitory potential of peptides generated through virtual proteolysis of milk proteins. Through a series of in silico screening process and in vitro experiments, GPVRGPF and HPHPHL were found to exhibit good DPP-4 inhibitory activity. Molecular docking and molecular dynamics simulations further confirmed the inhibitory mechanisms of these peptides. Through retracing the virtual proteolysis steps, it was found that GPVRGPF can be obtained from β-casein through enzymatic hydrolysis by chymotrypsin, while HPHPHL can be obtained from κ-casein through enzymatic hydrolysis by stem bromelain or papain. In summary, the integration of machine learning and virtual proteolysis techniques can aid in the preliminary determination of key hydrolysis parameters and facilitate the efficient screening of bioactive peptides.

Photochromic polymer is defined as a series of materials based on photochromic units in polymer chains, which produces reversible color changes under irradiation with a particular wavelength. Currently, as the research progresses, it shows increasing potential applications in various fields, such as anti-counterfeiting, information storage, super-resolution imaging, and logic gates. However, there is a paucity of published reviews on the topic of photochromic polymers. Herein, this review discusses and summarizes the research progress and prospects of such materials, mainly summarizing the basic mechanisms, classification, and applications of azobenzene, spiropyran, and diarylethene photochromic polymers. Moreover, 3-dimensional (3D) printable photochromic polymers are worthy to be summarized specifically because of its innovative approach for practical application; meanwhile, the developing 3D printing technology has shown increasing potential opportunities for better applications. Finally, the current challenges and future directions of photochromic polymer materials are summarized.

Vehicle skin is the key component in maintaining the aerodynamic shape of the vehicle. A deformable high-speed vehicle needs to adjust its shape in real time to realize optimum aerodynamic efficiency and to withstand extreme heat flow induced by high-speed flight, which requires the skin to possess large strain and high-temperature resistance. Traditional vehicle skin cannot satisfy both of the requirements. Biomimetic flexible skin for deformable high-speed vehicles (DHSV-bio-FS) combines flexible material fabrication with transpiration cooling technology, which can simulate human skin sweat cooling, and has the characteristics of large strain and high-temperature resistance. The thermal protection performance of the prepared prototype of DHSV-bio-FS was evaluated by simulation and wind tunnel experiments at 40% tensile strain with liquid water as coolant. Simulation results suggest that the surface temperature of the DHSV-bio-FS at 40% tensile strain is consistent with the temperature of the coolant (350 K) in a 3,000 K high-temperature gas environment. In addition, the prepared prototype DHSV-bio-FS survived for 1,200 s in a high-temperature gas environment of 200 kW/m² in wind tunnel experiments. This paper verifies the reliability of DHSV-bio-FS in a high-temperature gas environment and can be deployed in applications of flexible skin for deformable high-speed vehicles (DHSV-FS).

Short-chain fatty acids (SCFAs) have been increasingly evidenced to be important bioactive metabolites of the gut microbiota and transducers in controlling diverse psychiatric or neurological disorders via the microbiota–gut–brain axis. However, the precise mechanism by which brain SCFAs extert multiple beneficial effects is not completely understood. Our previous research has demonstrated that the acetyl-coenzyme A synthetase short-chain family member 2 (ACSS2) is a novel target of the rapid and long-lasting antidepressant responses. Here, we show that micromolar SCFAs significantly augment both total cellular and nuclear ACSS2 to trigger tryptophan hydroxylase 2 (TPH2) promoter histone acetylation and its transcription in SH-SY5Y cells. In chronic-restraint-stress-induced depression mice, neuronal ACSS2 knockdown by stereotaxic injection of adeno-associated virus in the hippocampus abolished SCFA-mediated improvements in depressive-like behaviors of mice, supporting that ACSS2 is required for SCFA-mediated antidepressant responses. Mechanistically, the peroxisome-proliferator-activated receptor gamma (PPARγ) is identified as a novel partner of ACSS2 to activate TPH2 transcription. Importantly, PPARγ is also responsible for SCFA-mediated antidepressant-like effects via ACSS2–TPH2 axis. To further support brain SCFAs as a therapeutic target for antidepressant effects, d-mannose, which is a naturally present hexose, can significantly reverse the dysbiosis of gut microbiota in the chronic-restraint-stress-exposure mice and augment brain SCFAs to protect against the depressive-like behaviors via ACSS2–PPARγ–TPH2 axis. In summary, brain SCFAs can activate ACSS2–PPARγ–TPH2 axis to play the antidepressive-like effects, and d-mannose is suggested to be an inducer of brain SCFAs in resisting depression.