Strategic disruption of cancer's powerhouse: precise nanomedicine targeting of mitochondrial metabolism.

Mitochondria occupy a central role in the biology of most eukaryotic cells, functioning as the hub of oxidative metabolism where sugars, fats, and amino acids are ultimately oxidized to release energy. This crucial function fuels a variety of cellular activities. Disruption in mitochondrial metabolism is a common feature in many diseases, including cancer, neurodegenerative conditions and cardiovascular diseases. Targeting tumor cell mitochondrial metabolism with multifunctional nanosystems emerges as a promising strategy for enhancing therapeutic efficacy against cancer. This review comprehensively outlines the pathways of mitochondrial metabolism, emphasizing their critical roles in cellular energy production and metabolic regulation. The associations between aberrant mitochondrial metabolism and the initiation and progression of cancer are highlighted, illustrating how these metabolic disruptions contribute to oncogenesis and tumor sustainability. More importantly, innovative strategies employing nanomedicines to precisely target mitochondrial metabolic pathways in cancer therapy are fully explored. Furthermore, key challenges and future directions in this field are identified and discussed. Collectively, this review provides a comprehensive understanding of the current state and future potential of nanomedicine in targeting mitochondrial metabolism, offering insights for developing more effective cancer therapies.

Modulating extracellular matrix stiffness: a strategic approach to boost cancer immunotherapy.

The interplay between extracellular matrix (ECM) stiffness and the tumor microenvironment is increasingly recognized as a critical factor in cancer progression and the efficacy of immunotherapy. This review comprehensively discusses the key factors regulating ECM remodeling, including the activation of cancer-associated fibroblasts and the accumulation and crosslinking of ECM proteins. Furthermore, it provides a detailed exploration of how ECM stiffness influences the behaviors of both tumor and immune cells. Significantly, the impact of ECM stiffness on the response to various immunotherapy strategies, such as immune checkpoint blockade, adoptive cell therapy, oncolytic virus therapy, and therapeutic cancer vaccines, is thoroughly examined. The review also addresses the challenges in translating research findings into clinical practice, highlighting the need for more precise biomaterials that accurately mimic the ECM and the development of novel therapeutic strategies. The insights offered aim to guide future research, with the potential to enhance the effectiveness of cancer immunotherapy modalities.

Decoding the ribosome's hidden language: rRNA modifications as key players in cancer dynamics and targeted therapies.

Ribosomal RNA (rRNA) modifications, essential components of ribosome structure and function, significantly impact cellular proteomics and cancer biology. These chemical modifications transcend structural roles, critically shaping ribosome functionality and influencing cellular protein profiles. In this review, the mechanisms by which rRNA modifications regulate both rRNA functions and broader cellular physiological processes are critically discussed. Importantly, by altering the translational output, rRNA modifications can shift the cellular equilibrium towards oncogenesis, thus playing a key role in cancer development and progression. Moreover, a special focus is placed on the functions of mitochondrial rRNA modifications and their aberrant expression in cancer, an area with profound implications yet largely uncharted. Dysregulation in these modifications can lead to metabolic dysfunction and apoptosis resistance, hallmark traits of cancer cells. Furthermore, the current challenges and future perspectives in targeting rRNA modifications are highlighted as a therapeutic approach for cancer treatment. In conclusion, rRNA modifications represent a frontier in cancer research, offering novel insights and therapeutic possibilities. Understanding and harnessing these modifications can pave the way for breakthroughs in cancer treatment, potentially transforming the approach to combating this complex disease.

New frontiers in salivary extracellular vesicles: transforming diagnostics, monitoring, and therapeutics in oral and systemic diseases.

Salivary extracellular vesicles (EVs) have emerged as key tools for non-invasive diagnostics, playing a crucial role in the early detection and monitoring of diseases. These EVs surpass whole saliva in biomarker detection due to their enhanced stability, which minimizes contamination and enzymatic degradation. The review comprehensively discusses methods for isolating, enriching, quantifying, and characterizing salivary EVs. It highlights their importance as biomarkers in oral diseases like periodontitis and oral cancer, and underscores their potential in monitoring systemic conditions. Furthermore, the review explores the therapeutic possibilities of salivary EVs, particularly in personalized medicine through engineered EVs for targeted drug delivery. The discussion also covers the current challenges and future prospects in the field, emphasizing the potential of salivary EVs in advancing clinical practice and disease management.

[Retrospective cross-sectional survey of clinical characteristics and syndrome elements distribution at different stages of coronary heart disease].

The clinical data of coronary heart disease(CHD) patients treated in the First Affiliated Hospital of Guangzhou University of Chinese Medicine and Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine from January 2022 to March 2023 were retrospectively collected. This study involved the descriptive analysis of demographic characteristics, clinical symptoms, and tongue and pulse features. The χ~2 test was conducted to analyze the distribution of syndrome elements and their combinations at diffe-rent stages of CHD, so as to reveal the clinical characteristics and syndrome patterns at various pathological stages of CHD. This study extracted 28 symptom entries, 10 tongue manifestation entries, and 7 pulse manifestation entries, summarized the 5 main disease locations of the heart, lung, liver, spleen, and kidney, and the 8 main disease natures of blood stasis, phlegm turbidity, Qi stagnation, heat(fire), fluid retention, Qi deficiency, Yin deficiency, and Yang deficiency and 8 combinations of disease natures. The χ~2 test showed significant differences in the distribution of syndrome elements including the lung, liver, spleen, kidney, blood stasis, heat(fire), Qi stagnation, heat syndrome, water retention, Qi deficiency, Yin deficiency, and Yang deficiency between different disease stages. Specifically, the liver, blood stasis, heat(fire), and Qi stagnation accounted for the highest proportion during unstable stage, and the lung, spleen, kidney, water retention, Qi deficiency, Yin deficiency, and Yang deficiency accounted for the highest proportion at the end stage. The distribution of Qi deficiency varied in the different time periods after percutaneous coronary intervention(PCI). As shown by the χ~2 test of the syndrome elements combination, the distribution of single disease location, multiple disease locations, single disease nature, double disease natures, multiple natures, excess syndrome, and mixture of deficiency and excess varied significantly at different stages of CHD. Specifically, single disease location, single disease nature, and excess syndrome accounted for the highest proportion during the stable stage, and double disease natures accounted for the highest proportion during the unstable stage. Multiple disease locations, multiple disease natures, and mixture of deficiency and excess accounted for the highest proportion during the end stage. In conclusion, phlegm turbidity and blood stasis were equally serious during the stable stage, and a pathological mechanism caused by blood stasis and toxin existed during the unstable stage. The overall Qi deficiency worsened after PCI, and the end stage was accompanied by the Yin and Yang damage and the aggravation of water retention. There were significant differences in the distribution of clinical characteristics and syndrome elements at different stages of CHD. The pathological process of CHD witnessed the growth and decline of deficiency and excess and the combination of phlegm turbidity and blood stasis, which constituted the basic pathogenesis.

Alternative pre-mRNA splicing in stem cell function and therapeutic potential: A critical review of current evidence.

Alternative splicing is a crucial regulator in stem cell biology, intricately influencing the functions of various biological macromolecules, particularly pre-mRNAs and the resultant protein isoforms. This regulatory mechanism is vital in determining stem cell pluripotency, differentiation, and proliferation. Alternative splicing's role in allowing single genes to produce multiple protein isoforms facilitates the proteomic diversity that is essential for stem cells' functional complexity. This review delves into the critical impact of alternative splicing on cellular functions, focusing on its interaction with key macromolecules and how this affects cellular behavior. We critically examine how alternative splicing modulates the function and stability of pre-mRNAs, leading to diverse protein expressions that govern stem cell characteristics, including pluripotency, self-renewal, survival, proliferation, differentiation, aging, migration, somatic reprogramming, and genomic stability. Furthermore, the review discusses the therapeutic potential of targeting alternative splicing-related pathways in disease treatment, particularly focusing on the modulation of RNA and protein interactions. We address the challenges and future prospects in this field, underscoring the need for further exploration to unravel the complex interplay between alternative splicing, RNA, proteins, and stem cell behaviors, which is crucial for advancing our understanding and therapeutic approaches in regenerative medicine and disease treatment.

Emerging Roles of B56 Phosphorylation and Binding Motif in PP2A-B56 Holoenzyme Biological Function.

Protein serine/threonine phosphatase 2A (PP2A) regulates diverse cellular processes via the formation of ~100 heterotrimeric holoenzymes. However, a scarcity of knowledge on substrate recognition by various PP2A holoenzymes has greatly prevented the deciphering of PP2A function in phosphorylation-mediated signaling in eukaryotes. The review summarized the contribution of B56 phosphorylation to PP2A-B56 function and proposed strategies for intervening B56 phosphorylation to treat diseases associated with PP2A-B56 dysfunction; it especially analyzed recent advancements in LxxIxEx B56-binding motifs that provide the molecular details of PP2A-B56 binding specificity and, on this basis, explored the emerging role of PP2A-B56 in the mitosis process, virus attack, and cancer development through LxxIxE motif-mediated PP2A-B56 targeting. This review provides theoretical support for discriminatingly targeting specific PP2A holoenzymes to guide PP2A activity against specific pathogenic drivers.

Mix proportion and microscopic characterization of coal-based solid waste backfill material based on response surface methodology and multi-objective decision-making.

The mix proportion of multi-source coal-based solid waste (CSW) for underground backfilling affects transportation and support performance of backfill materials, and even the backfilling cost. In this study, the optimal mix proportion of desulfurization gypsum (DG), furnace bottom slag (FBS) and gasification fine slag (GFS) is determined by the Response Surface Methodology-Box Behnken Design (RSM-BBD). Then the fluidity, bleeding rate, 3-day strength, 7-day strength and preparation cost are evaluation indicators, the optimal mix proportion of backfill materials is determined by the multi-objective decision-making method (MDM). Finally, the microstructure of the backfill material with optimal mix proportion was studied by TGA, MIP, SEM-EDS and XRD. The results show that the mix proportion of CSW with the optimal comprehensive index is coal gangue (CG): coal fly ash (CFA): DG: FBS: GFS = 1:1.5:0.2:0.1:0.1, the mass concentration is 78%, and ordinary Portland cement (OPC)/CSW = 7.5%. The weight loss phenomenon of the backfill material with the optimal mix proportion occurs continuously during the heating process, mainly due to the evaporation of crystal water, structural water and hydroxyl water. There are dense narrow-necked pores in the backfill material, and the pore connectivity is poor. There is no hydration reaction occurs between CSW particles, and the strength increase of the backfill material mainly depends on the hydration reaction of cement. In ettringite, part of Al2O3 is replaced by SiO2, and part of CaSO4 is replaced by CaCO3. This study provides a reference for the engineering application of underground backfilling with multi-source CSW.

Research status of comprehensive utilization of coal-based solid waste (CSW) and key technologies of filling mining in China: A review.

Coal-based solid waste (CSW) is the solid waste generated in the process of coal mining, washing and pyrolysis, which is an important industrial solid waste. The comprehensive utilization of CSW is a key link in the process of clean and efficient utilization of coal, and the use of CSW for coal mine filling mining is an important means of "harmless, resourceful and large-scale" utilization. In order to study the research status of comprehensive utilization of CSW and key technologies of filling mining in China, this paper combs and analyzes the current situation of comprehensive utilization of CSW from three parts, namely, physical and chemical properties of CSW, Industry-related policies, and ways and means of comprehensive utilization. It is found that coal mine filling mining is a green disposal method with relatively reliable technical means, low supervision cost and large-scale disposal of CSW in the comprehensive utilization of CSW in China. Furthermore, an analysis was conducted on the current research status of key technologies in the CSW filling and mining process, including the integration of "mining, selection and filling", adsorption and complexation passivation of heavy metals in CSW, the preparation of CSW collaborative filling materials, and monitoring and control of the whole filling process, etc. Based on the above analysis and research, it was pointed out that there were some problems, namely: (1) large output of CSW and low level of comprehensive utilization; (2) high investment and high cost of CSW filling and mining; and (3) imperfect CSW waste filling mining theory and technology. In response to these issues, prospects have been made from the aspects of policy incentive mechanisms, collaborative utilization of CSW with multi-industry links, and the theory and technology of CSW filling mining. This study provided reference and inspiration for the comprehensive utilization of CSW in the world, and provides guidance for the large-scale promotion and application of CSW filling mining methods.

Structures and activation mechanism of the Gabija anti-phage system.

Prokaryotes have evolved intricate innate immune systems against phage infection1-7. Gabija is a highly widespread prokaryotic defence system that consists of two components, GajA and GajB8. GajA functions as a DNA endonuclease that is inactive in the presence of ATP9. Here, to explore how the Gabija system is activated for anti-phage defence, we report its cryo-electron microscopy structures in five states, including apo GajA, GajA in complex with DNA, GajA bound by ATP, apo GajA-GajB, and GajA-GajB in complex with ATP and Mg2+. GajA is a rhombus-shaped tetramer with its ATPase domain clustered at the centre and the topoisomerase-primase (Toprim) domain located peripherally. ATP binding at the ATPase domain stabilizes the insertion region within the ATPase domain, keeping the Toprim domain in a closed state. Upon ATP depletion by phages, the Toprim domain opens to bind and cleave the DNA substrate. GajB, which docks on GajA, is activated by the cleaved DNA, ultimately leading to prokaryotic cell death. Our study presents a mechanistic landscape of Gabija activation.

The role and regulation of SIRT1 in pulmonary fibrosis.

Pulmonary fibrosis (PF) is a progressive and fatal lung disease with high incidence and a lack of effective treatment, which is a severe public health problem. PF has caused a huge socio-economic burden, and its pathogenesis has become a research hotspot. SIRT1 is a nicotinamide adenosine dinucleotide (NAD)-dependent sirtuin essential in tumours, Epithelial mesenchymal transition (EMT), and anti-aging. Numerous studies have demonstrated after extensive research that it is crucial in preventing the progression of pulmonary fibrosis. This article reviews the biological roles and mechanisms of SIRT1 in regulating the progression of pulmonary fibrosis in terms of EMT, oxidative stress, inflammation, aging, autophagy, and discusses the potential of SIRT1 as a therapeutic target for pulmonary fibrosis, and provides a new perspective on therapeutic drugs and prognosis prospects.

Portably and Visually Sensing Cytisine through Smartphone Scanning Based on a Post-Modified Luminescence Center Strategy in Zinc-Organic Frameworks.

Cytisine (CTS) is a useful medicine for treating nervous disorders and smoking addiction, and exploring a convenient method to detect CTS is of great significance for long-term/home medication to avoid the risk of poisoning, but it is full of challenges. Here, a modified metal-organic framework sensor Tb@Zn-TDA-80 with dual emission centers was prepared using a post-modified luminescence center strategy. The obtained Tb@Zn-TDA-80 can serve as a CTS sensor with high sensitivity and selectivity. To achieve portable detection, Tb@Zn-TDA-80 was further fabricated as a membrane sensor, M-Tb@Zn-TDA-80, which displayed an obvious CTS-responsive color change by simply dropping a CTS solution onto its surface. Benefiting from this unique functionality, M-Tb@Zn-TDA-80 successfully realized the visual detection and quantitative monitoring of CTS in the range of 5.26-52.6 mM by simply scanning the color with a smartphone. The results of nuclear magnetic resonance spectroscopy and theoretical computation illustrated that the high sensing efficiency of Tb@Zn-TDA-80 for CTS was attributed to the N-H⋅⋅⋅π and π⋅⋅⋅π interactions between the ligand and CTS. And luminescence quenching may result from the intramolecular charge transfer. This study provides a convenient method for ensuring long-term medication safety at home.

Glutamine enhances sucrose taste through a gut microbiota-gut-brain axis in Drosophila.

AIMS: Amino acids (AAs) are known to play important roles in various physiological functions. However, their effect on sweet taste perception remains largely unknown. MAIN METHODS: We used Drosophila to evaluate the effect of each AA on sucrose taste perception. Individual AA was supplemented into diets and male flies were fed on these diets for 6 days. The proboscis extension response (PER) assay was applied to assess the sucrose taste sensitivity of treated flies. We further utilized the RNA-seq and germ-free (GF) flies to reveal the underlying mechanisms of sucrose taste sensitization induced by glutamine (Gln). KEY FINDINGS: We found that supplementation of Gln into diets significantly enhances sucrose taste sensitivity. This sucrose taste sensitization is dependent on gut microbiota and requires a specific gut bacterium Acetobacter tropicalis (A. tropicalis). We further found that CNMamide (CNMa) in the gut and CNMa receptor (CNMaR) in dopaminergic neurons are required for increased sucrose taste sensitivity by Gln diet. Finally, we demonstrated that a gut microbiota-gut-brain axis is required for Gln-induced sucrose taste sensitization. SIGNIFICANCE: These findings can advance understanding of the complex interplay between host physiology, dietary factors, and gut microbiota.

Hypoxia-driven TNS4 fosters HNSCC tumorigenesis by stabilizing integrin α5ß1 complex and triggering FAK-mediated Akt and TGFß signaling pathways.

Head and neck squamous cell carcinoma (HNSCC) remains a formidable clinical challenge due to its high recurrence rate and limited targeted therapeutic options. This study aims to elucidate the role of tensin 4 (TNS4) in the pathogenesis of HNSCC across clinical, cellular, and animal levels. We found a significant upregulation of TNS4 expression in HNSCC tissues compared to normal controls. Elevated levels of TNS4 were associated with adverse clinical outcomes, including diminished overall survival. Functional assays revealed that TNS4 knockdown attenuated, and its overexpression augmented, the oncogenic capabilities of HNSCC cells both in vitro and in vivo. Mechanistic studies revealed that TNS4 overexpression promotes the interaction between integrin α5 and integrin ß1, thereby activating focal adhesion kinase (FAK). This TNS4-mediated FAK activation simultaneously enhanced the PI3K/Akt signaling pathway and facilitated the interaction between TGFßRI and TGFßRII, leading to the activation of the TGFß signaling pathway. Both of these activated pathways contributed to HNSCC tumorigenesis. Additionally, we found that hypoxia-inducible factor 1α (HIF-1α) transcriptionally regulated TNS4 expression. In conclusion, our findings provide the basis for innovative TNS4-targeted therapeutic strategies, which could potentially improve prognosis and survival rates for patients with HNSCC.

Identification of Core-Fucosylated Glycoproteins by Single-Step Truncation of N-Glycans.

Alpha-1,6 core fucosylation (CF) is a unique glycoform of N-glycans, and studies showed that CF modifications are involved in the occurrence and progression of various diseases and may provide potential disease biomarkers. Current strategies for the CF glycoproteome are often based on multistep enrichment of glycoproteins or glycopeptides and sequential cleavage with different glycosidases to truncate the N-glycans. Although the detection ability of low-abundance glycoproteins is improved, sample loss, high cost, and the time-consuming multistep operation also affect the reproducibility of results and the practicality of the method. Here we developed a single-step truncation (SST) strategy and evaluated its potential for the CF glycoproteome of human serum. The SST strategy has the advantages of fewer operational steps, lower cost, higher number of identifications, and better quantitative stability compared with previous approaches and provides an efficient solution for large-scale quantitative analysis of the CF glycoproteome. © 2024 Wiley Periodicals LLC. Basic Protocol 1: Single-step truncation strategy for core fucosylation glycoproteome analysis in human serum Basic Protocol 2: Liquid chromatography-tandem mass spectrometry quantification of site-specific core fucosylation glycopeptides Alternate Protocol: Pretreatment of cellular samples of core fucosylation glycoproteome with single-step truncation strategy.

Single-cell RNA sequencing analysis to evaluate antimony exposure effects on cell-lineage communications within the Drosophila testicular niche.

The increasing production and prevalence of antimony (Sb)-related products raise concerns regarding its potential hazards to reproductive health. Upon environmental exposure, Sb reportedly induces testicular toxicity during spermatogenesis; moreover, it is known to affect various testicular cell populations, particularly germline stem cell populations. However, the cell-cell communication resulting from Sb exposure within the testicular niche remains poorly understood. To address this gap, herein we analyzed testicular single-cell RNA sequencing data from Sb-exposed Drosophila. Our findings revealed that the epidermal growth factor receptor (EGFR) and WNT signaling pathways were associated with the stem cell niche in Drosophila testes, which may disrupt the homeostasis of the testicular niche in Drosophila. Furthermore, we identified several ligand-receptor pairs, facilitating the elucidation of intercellular crosstalk involved in Sb-mediated reproductive toxicology. We employed scRNA-seq analysis and conducted functional verification to investigate the expression patterns of core downstream factors associated with EGFR and WNT signatures in the testes under the influence of Sb exposure. Altogether, our results shed light on the potential mechanisms of Sb exposure-mediated testicular cell-lineage communications.

Epitranscriptomic modifications in mesenchymal stem cell differentiation: advances, mechanistic insights, and beyond.

RNA modifications, known as the "epitranscriptome", represent a key layer of regulation that influences a wide array of biological processes in mesenchymal stem cells (MSCs). These modifications, catalyzed by specific enzymes, often termed "writers", "readers", and "erasers", can dynamically alter the MSCs' transcriptomic landscape, thereby modulating cell differentiation, proliferation, and responses to environmental cues. These enzymes include members of the classes METTL, IGF2BP, WTAP, YTHD, FTO, NAT, and others. Many of these RNA-modifying agents are active during MSC lineage differentiation. This review provides a comprehensive overview of the current understanding of different RNA modifications in MSCs, their roles in regulating stem cell behavior, and their implications in MSC-based therapies. It delves into how RNA modifications impact MSC biology, the functional significance of individual modifications, and the complex interplay among these modifications. We further discuss how these intricate regulatory mechanisms contribute to the functional diversity of MSCs, and how they might be harnessed for therapeutic applications. The review also highlights current challenges and potential future directions in the study of RNA modifications in MSCs, emphasizing the need for innovative tools to precisely map these modifications and decipher their context-specific effects. Collectively, this work paves the way for a deeper understanding of the role of the epitranscriptome in MSC biology, potentially advancing therapeutic strategies in regenerative medicine and MSC-based therapies.

Natural compounds as obesity pharmacotherapies.

Obesity has become a serious global public health problem, affecting over 988 million people worldwide. Nevertheless, current pharmacotherapies have proven inadequate. Natural compounds have garnered significant attention due to their potential antiobesity effects. Over the past three decades, ca. 50 natural compounds have been evaluated for the preventive and/or therapeutic effects on obesity in animals and humans. However, variations in the antiobesity efficacies among these natural compounds have been substantial, owing to differences in experimental designs, including variations in animal models, dosages, treatment durations, and administration methods. The feasibility of employing these natural compounds as pharmacotherapies for obesity remained uncertain. In this review, we systematically summarized the antiobesity efficacy and mechanisms of action of each natural compound in animal models. This comprehensive review furnishes valuable insights for the development of antiobesity medications based on natural compounds.

Biotoxicity of Halide Perovskites in Mice.

Halide perovskites are crystalline semiconductors with exceptional optoelectronic properties, rapidly developing toward large-scale applications. Lead (II) (Pb2+ ) is the core element used to prepare halide perovskites. Pb2+ can displace key 2+ elements, including calcium, zinc and iron, that regulate vital physiological functions. Sn2+ can replace Pb2+ within the perovskite structure and, if accidentally dispersed in the environment, it readily oxidizes to Sn4+ , which is compatible with physiological functions and thus potentially safe. The 3+ salt bismuth (III) (Bi3+ ) is also potentially safe for the same reason and useful to prepare double perovskites. Here, this work studies the biotoxicity of Pb, Sn, and Bi perovskites in mice for the first time. This work analyses histopathology and growth of mice directly exposed to perovskites and investigate the development of their offspring generation. This study provides the screening of organs and key physiological functions targeted by perovskite exposure to design specific studies in mammalians.