Protein aggregation in plant mitochondria lacking Lon1 inhibits translation and induces unfolded protein responses.

Loss of Lon1 led to stunted plant growth and accumulation of nuclear-encoded mitochondrial proteins including Lon1 substrates. However, an in-depth label-free proteomics quantification of mitochondrial proteins in lon1 revealed that the majority of mitochondrial-encoded proteins decreased in abundance. Additionally, we found that lon1 mutants contained protein aggregates in the mitochondrial that were enriched in metabolic enzymes, ribosomal subunits and PPR-containing proteins of the translation apparatus. These mutants exhibited reduced general mitochondrial translation as well as deficiencies in RNA splicing and editing. These findings support the role of Lon1 in maintaining a functional translational apparatus for mitochondrial-encoded gene translation. Transcriptome analysis of lon1 revealed a mitochondrial unfolded protein response reminiscent of the mitochondrial retrograde signalling dependent on the transcription factor ANAC017. Notably, lon1 mutants exhibited transiently elevated ethylene production, and the shortened hypocotyl observed in lon1 mutants during skotomorphogenesis was partially alleviated by ethylene inhibitors. Furthermore, the short root phenotype was partially ameliorated by introducing a mutation in the ethylene receptor ETR1. Interestingly, the upregulation of only a select few target genes was linked to ETR1-mediated ethylene signalling. Together this provides multiple steps in the link between loss of Lon1 and signalling responses to restore mitochondrial protein homoeostasis in plants.

SETMAR Facilitates the Differentiation of Thyroid Cancer by Regulating SMARCA2-Mediated Chromatin Remodeling.

Thyroid cancer is the most common type of endocrine cancer, and most patients have a good prognosis. However, the thyroid cancer differentiation status strongly affects patient response to conventional treatment and prognosis. Therefore, exploring the molecular mechanisms that influence the differentiation of thyroid cancer is very important for understanding the progression of this disease and improving therapeutic options. In this study, SETMAR as a key gene that affects thyroid cancer differentiation is identified. SETMAR significantly regulates the proliferation, epithelial-mesenchymal transformation (EMT), thyroid differentiation-related gene expression, radioactive iodine uptake, and sensitivity to MAPK inhibitor-based redifferentiation therapies of thyroid cancer cells. Mechanistically, SETMAR methylates dimethylated H3K36 in the SMARCA2 promoter region to promote SMARCA2 transcription. SMARCA2 can bind to enhancers of the thyroid differentiation transcription factors (TTFs) PAX8, and FOXE1 to promote their expression by enhancing chromatin accessibility. Moreover, METTL3-mediated m6A methylation of SETAMR mRNA is observed and showed that this medication can affect SETMAR expression in an IGF2BP3-dependent manner. Finally, the METTL3-14-WTAP activator effectively facilitates the redifferentiation of thyroid cancer cells via the SETMAR-SMARCA2-TTF axis utilized. The research provides novel insights into the molecular mechanisms underlying thyroid cancer dedifferentiation and provides a new approach for therapeutically promoting redifferentiation.

A Dual-Channel Ca2+ Nanomodulator Induces Intracellular Ca2+ Disorders via Endogenous Ca2+ Redistribution for Tumor Radiosensitization.

Tumor cells harness Ca2+ to maintain cellular homeostasis and withstand external stresses from various treatments. Here, a dual-channel Ca2+ nanomodulator (CAP-P-NO) is constructed that can induce irreversible intracellular Ca2+ disorders via the redistribution of tumor-inherent Ca2+ for disrupting cellular homeostasis and thus improving tumor radiosensitivity. Stimulated by tumor-overexpressed acid and glutathione, capsaicin and nitric oxide are successively escaped from CAP-P-NO to activate the transient receptor potential cation channel subfamily V member 1 and the ryanodine receptor for the influx of extracellular Ca2+ and the release of Ca2+ in the endoplasmic reticulum, respectively. The overwhelming level of Ca2+ in tumor cells not only impairs the function of organelles but also induces widespread changes in the gene transcriptome, including the downregulation of a set of radioresistance-associated genes. Combining CAP-P-NO treatment with radiotherapy achieves a significant suppression against both pancreatic and patient-derived hepatic tumors with negligible side effects. Together, the study provides a feasible approach for inducing tumor-specific intracellular Ca2+ overload via endogenous Ca2+ redistribution and demonstrates the great potential of Ca2+ disorder therapy in enhancing the sensitivity for tumor radiotherapy.

Heme-Mimetic Photosensitizer with Iron-Targeting and Internalizing Properties for Enhancing PDT Activity and Promoting Infected Diabetic Wound Healing.

The management of multibacterial infections remains clinically challenging in the care and treatment of chronic diabetic wounds. Photodynamic therapy (PDT) offers a promising approach to addressing bacterial infections. However, the limited target specificity and internalization properties of traditional photosensitizers (PSs) toward Gram-negative bacteria pose significant challenges to their antibacterial efficacy. In this study, we designed an iron heme-mimetic PS (MnO2@Fe-TCPP(Zn)) based on the iron dependence of bacteria that can be assimilated by bacteria and retained in different bacteria strains (Escherichia coli, Staphylococcus aureus, and methicillin-resistant Staphylococcus aureus) and which shows high PDT antibacterial efficacy. For accelerated wound healing after antibacterial treatment, MnO2@Fe-TCPP(Zn) was loaded into a zwitterionic hydrogel with biocompatibility and antifouling properties to form a nanocomposite antibacterial hydrogel (PSB-MnO2@Fe-TCPP(Zn)). In the multibacterial infectious diabetic mouse wound model, the PSB-MnO2@Fe-TCPP(Zn) hydrogel dressing rapidly promoted skin regeneration by effectively inhibiting bacterial infections, eliminating inflammation, and promoting angiogenesis. This study provides an avenue for developing broad-spectrum antibacterial nanomaterials for combating the antibiotic resistance crisis and promoting the healing of complex bacterially infected wounds.

Engineering biomimetic nanosystem targeting multiple tumor radioresistance hallmarks for enhanced radiotherapy.

Tumor cells establish a robust self-defense system characterized by hypoxia, antioxidant overexpression, DNA damage repair, and so forth to resist radiotherapy. Targeting one of these features is insufficient to overcome radioresistance due to the feedback mechanisms initiated by tumor cells under radiotherapy. Therefore, we herein developed an engineering biomimetic nanosystem (M@HHPt) masked with tumor cell membranes and loaded with a hybridized protein-based nanoparticle carrying oxygens (O2) and cisplatin prodrugs (Pt(IV)) to target multiple tumor radioresistance hallmarks for enhanced radiotherapy. After administration, M@HHPt actively targeted and smoothly accumulated in tumor cells by virtue of its innate homing abilities to realize efficient co-delivery of O2 and Pt(IV). O2 introduction induced hypoxia alleviation cooperated with Pt(IV) reduction caused glutathione consumption greatly amplified radiotherapy-ignited cellular oxidative stress. Moreover, the released cisplatin effectively hindered DNA damage repair by crosslinking with radiotherapy-produced DNA fragments. Consequently, M@HHPt-sensitized radiotherapy significantly suppressed the proliferation of lung cancer H1975 cells with an extremely high sensitizer enhancement ratio of 1.91 and the progression of H1975 tumor models with an excellent tumor inhibition rate of 94.7%. Overall, this work provided a feasible strategy for tumor radiosensitization by overcoming multiple radioresistance mechanisms.

Co-Catalyzed Hydrofluorination of Alkenes: Photocatalytic Method Development and Electroanalytical Mechanistic Investigation.

The hydrofluorination of alkenes represents an attractive strategy for the synthesis of aliphatic fluorides. This approach provides a direct means to form C(sp3)-F bonds selectively from readily available alkenes. Nonetheless, conducting hydrofluorination using nucleophilic fluorine sources poses significant challenges due to the low acidity and high toxicity associated with HF and the poor nucleophilicity of fluoride. In this study, we present a new Co(salen)-catalyzed hydrofluorination of simple alkenes utilizing Et3N·3HF as the sole source of both hydrogen and fluorine. This process operates via a photoredox-mediated polar-radical-polar crossover mechanism. We also demonstrated the versatility of this method by effectively converting a diverse array of simple and activated alkenes with varying degrees of substitution into hydrofluorinated products. Furthermore, we successfully applied this methodology to 18F-hydrofluorination reactions, enabling the introduction of 18F into potential radiopharmaceuticals. Our mechanistic investigations, conducted using rotating disk electrode voltammetry and DFT calculations, unveiled the involvement of both carbocation and CoIV-alkyl species as viable intermediates during the fluorination step, and the contribution of each pathway depends on the structure of the starting alkene.

Mitochondrial Localized In Situ Self-Assembly Reprogramming Tumor Immune and Metabolic Microenvironment for Enhanced Cancer Therapy.

The inherent immune and metabolic tumor microenvironment (TME) of most solid tumors adversely affect the antitumor efficacy of various treatments, which is an urgent issue to be solved in clinical cancer therapy. In this study, a mitochondrial localized in situ self-assembly system is constructed to remodel the TME by improving immunogenicity and disrupting the metabolic plasticity of cancer cells. The peptide-based drug delivery system can be pre-assembled into nanomicelles in vitro and form functional nanofibers on mitochondria through a cascade-responsive process involving reductive release, targeted enrichment, and in situ self-assembly. The organelle-specific in situ self-assemblyeffectively switches the role of mitophagy from pro-survival to pro-death, which finally induces intense endoplasmic reticulum stress and atypical type II immunogenic cell death. Disintegration of the mitochondrial ultrastructure also impedes the metabolic plasticity of tumor cells, which greatly promotes the immunosuppresive TME remodeling into an immunostimulatory TME. Ultimately, the mitochondrial localized in situ self-assembly system effectively suppresses tumor metastases, and converts cold tumors into hot tumors with enhanced sensitivity to radiotherapy and immune checkpoint blockade therapy. This study offers a universal strategy for spatiotemporally controlling supramolecular self-assembly on sub-organelles to determine cancer cell fate and enhance cancer therapy.

Influence of restorative materials on the mechanical properties of maxillary first molars with different degrees of cryptic fractures and defects: A finite element analysis.

This study aimed to apply finite element analysis to evaluate the effects of pile materials with different elastic moduli and cement materials on the stress distribution between the remaining tooth tissue and cryptic fracture defects. A three-dimensional finite element model was established for 20 maxillary first molars with hidden fissures and mesial tongue-tip defects. Two levels of hidden cracks and three types of pile and adhesive materials were used in the design. The stress distribution and maximum stress peak in the remaining tooth tissue and crack defects were determined by simulating the normal bite, maximum bite, and lateral movement forces. When titanium posts, zinc phosphate binders, and porcelain crowns were used to repair the two types of deep cracked teeth, the maximum principal stress at the crack and dentin was the smallest. As the crack depth increased, the maximum principal stress of the residual dentin and crack defects increased.

VIP interneurons in sensory cortex encode sensory and action signals but not direct reward signals.

Vasoactive intestinal peptide (VIP) interneurons in sensory cortex modulate sensory responses based on global exploratory behavior and arousal state, but their function during non-exploratory, goal-directed behavior is not well understood. In particular, whether VIP cells are activated by sensory cues, reward-seeking actions, or directly by reinforcement is unclear. We trained mice on a Go/NoGo whisker touch detection task that included a delay period and other features designed to separate sensory-evoked, action-related, and reward-related neural activity. Mice had to lick in response to a whisker stimulus to receive a variable-sized reward. Using two-photon calcium imaging, we measured ΔF/F responses of L2/3 VIP neurons in whisker somatosensory cortex (S1) during behavior. In both expert and novice mice, VIP cells were strongly activated by whisker stimuli and goal-directed actions (licking), but not by reinforcement. VIP cells showed somatotopic whisker tuning that was spatially organized relative to anatomical columns in S1, unlike lick-related signals which were spatially widespread. In expert mice, lick-related VIP responses were suppressed, not enhanced, when a reward was delivered, and the amount of suppression increased with reward size. This reward-related suppression was not seen in novice mice, where reward delivery was not yoked to licking. These results indicate that besides arousal and global state variables, VIP cells are activated by local sensory features and goal-directed actions, but not directly by reinforcement. Instead, our results are consistent with a role for VIP cells in encoding the expectation of reward associated with motor actions.

Biomodified Extracellular Vesicles Remodel the Intestinal Microenvironment to Overcome Radiation Enteritis.

Ionizing radiation (IR) is associated with the occurrence of enteritis, and protecting the whole intestine from radiation-induced gut injury remains an unmet clinical need. Circulating extracellular vesicles (EVs) are proven to be vital factors in the establishment of tissue and cell microenvironments. In this study, we aimed to investigate a radioprotective strategy mediated by small EVs (exosomes) in the context of irradiation-induced intestinal injury. We found that exosomes derived from donor mice exposed to total body irradiation (TBI) could protect recipient mice against TBI-induced lethality and alleviate radiation-induced gastrointestinal (GI) tract toxicity. To enhance the protective effect of EVs, profilings of mouse and human exosomal microRNAs (miRNAs) were performed to identify the functional molecule in exosomes. We found that miRNA-142-5p was highly expressed in exosomes from both donor mice exposed to TBI and patients after radiotherapy (RT). Moreover, miR-142 protected intestinal epithelial cells from irradiation-induced apoptosis and death and mediated EV protection against radiation enteritis by ameliorating the intestinal microenvironment. Then, biomodification of EVs was accomplished via enhancing miR-142 expression and intestinal specificity of exosomes, and thus improved EV-mediated protection from radiation enteritis. Our findings provide an effective approach for protecting against GI syndrome in people exposed to irradiation.

Cancer Stem-Like Cells-Oriented Surface Self-Assembly to Conquer Radioresistance.

Cancer stem-like cells (CSCs), capable of indefinite self-renewal and differentiation, are considered to be the root cause of tumor radiotherapy (RT) resistance. However, the CSCs-targeted therapy still remains to be a great challenge because they are commonly located in the deep tumor making drugs hard to approach, and their hypoxic and acidic niche can further aggravate radioresistance. Herein, based on the finding that hypoxic CSCs highly express carbonic anhydrase IX (CAIX) on the cell membrane, a CAIX-targeted induced in situ self-assembly system on the surface of CSC is reported to overcome hypoxic CSC-mediated radioresistance. Via the sequential processes of "monomer release-target accumulation-surface self-assembly", the constructed peptide-based drug delivery system (CA-Pt) exhibits the advantages of deep penetration, amplified CAIX inhibition, and enhanced cellular uptake, which greatly relieves the hypoxic and acidic microenvironment to promote the hypoxic CSC differentiation and combines with platinum to boost the RT-inducing DNA damage. In both lung cancer tumor mouse and zebrafish embryo models, CA-Pt treatment can effectively assist RT in suppressing tumor growth and preventing tumor invasion and metastasis. This study uses a surface-induced self-assembly strategy to differentiate hypoxic CSCs, which may provide a universal treatment strategy for overcoming tumor radioresistance.

EISA in Tandem with ICD to Form In Situ Nanofiber Vaccine for Enhanced Tumor Radioimmunotherapy.

Radiotherapy (RT) can produce a vaccine effect and remodel a tumor microenvironment (TME) by inducing immunogenic cell death (ICD) and inflammation in tumors. However, RT alone is insufficient to elicit a systemic antitumor immune response owing to limited antigen presentation, immunosuppressive microenvironment, and chronic inflammation within the tumor. Here, a novel strategy is reported for the generation of in situ peptide-based nanovaccines via enzyme-induced self-assembly (EISA) in tandem with ICD. As ICD progresses, the peptide Fbp-GD FD FD pY (Fbp-pY), dephosphorylated by alkaline phosphatase (ALP) forms a fibrous nanostructure around the tumor cells, resulting in the capture and encapsulation of the autologous antigens produced by radiation. Utilizing the adjuvant and controlled-release advantages of self-assembling peptides, this nanofiber vaccine effectively increases antigen accumulation in the lymph nodes and cross-presentation by antigen-presenting cells (APCs). In addition, the inhibition of cyclooxygenase 2 (COX-2) expression by the nanofibers promotes the repolarization of M2-macrophages into M1 and reduces the number of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) required for TME remodeling. As a result, the combination of nanovaccines and RT significantly enhances the therapeutic effect on 4T1 tumors compared with RT alone, suggesting a promising treatment strategy for tumor radioimmunotherapy.

Tumor-Specific Peroxynitrite Overproduction Disrupts Metabolic Homeostasis for Sensitizing Melanoma Immunotherapy.

Tumor cells elicit metabolic reprogramming to establish an immunosuppressive tumor microenvironment (TME) for escaping from immunosurveillance. Therefore, interrupting the metabolic adaptation of tumor cells may be a promising strategy for TME immunomodulation, favoring immunotherapy. In this work, a tumor-specific peroxynitrite nanogenerator APAP-P-NO is constructed that can selectively disrupt metabolic homeostasis in melanoma cells. Stimulated by melanoma-characteristic acid, glutathione, and tyrosinase, APAP-P-NO can efficiently generate peroxynitrite through the in situ coupling of the produced superoxide anion and released nitric oxide. Metabolomics profiling reveals that the accumulated peroxynitrite induces a great decrease in metabolites in the tricarboxylic acid cycle. Meanwhile, the glycolysis-produced lactate drops sharply both intracellularly and extracellularly under peroxynitrite stress. Mechanistically, peroxynitrite impairs the activity of glyceraldehyde-3-phosphate dehydrogenase in glucose metabolism through S-nitrosylation. The metabolic alterations effectively reverse the immunosuppressive TME to evoke potent antitumor immune responses, including polarization of M2-like macrophages to M1phenotype, reduction of myeloid-derived suppressor cells and regulatory T cells, and restoration of CD8+ T cell infiltration. Combining APAP-P-NO with anti-PD-L1 achieves a significant inhibition against both primary and metastatic melanomas without systemic toxicities. Collectively, a tumor-specific peroxynitrite overproduction approach is developed and the possible mechanism of peroxynitrite-mediated TME immunomodulation is explored, providing a new strategy for facilitating immunotherapy sensitivity.

Learning from human metabolism for nanomedicine: a convertible bismuth-agent for tumour-selective theranostics.

Tumour-selective theranostic agents have attracted considerable interest over the past decade in oncology owing to their extraordinary anticancer efficacy. However, it still remains a challenge to develop theranostic agents balancing biocompatibility, multidimensional theranostics, tumour-selectivity, and simple components. Inspired by the metabolic pathways of exogenous sodium selenite against selenium-deficient diseases, reported here is the first convertible bismuth-based agent for tumour-selective theranostic functionalities. The specifically overexpressed substances in tumour tissue enable it to act as a natural reactor for the conversion from bismuth selenite to bismuth selenide, activating the theranostic functionalities specifically in tumour tissues. The converted product exhibits excellent multidimensional imaging-guided therapy. This study not only demonstrates a simple agent with both biocompatibility and sophisticated tumour-selective theranostic functionalities, but also pioneers a new approach from emulating nature towards oncological theranostic applications.

Bio-Inspired Antioxidant Heparin-Mimetic Peptide Hydrogel for Radiation-Induced Skin Injury Repair.

Radiotherapy is one of the most important means of cancer treatment, however, radiation can also cause adverse reactions and even serious injuries to the skin. Radiation-induced excess reactive oxygen species (ROS) production and inflammatory infiltration make skin wounds difficult to heal compared to normal skin injuries. Herein, an antioxidant heparin-mimetic peptide hydrogel (K16, KYKYEYEYAGEGDSS-4Sa) is designed for radiation-induced skin injury (RISI) repair. First, the K16 peptide can self-assemble into a hydrogel with a 3D mesh-like porous nanofiber structure, which can provide certain physical support for skin repair like extracellular matrix (ECM). Then, K16 hydrogel not only scavenges ROS and prevents radiation damage to cellular DNA, but also promotes cell proliferation, migration, and angiogenesis. Meanwhile, 4-sulfobenzoic acid (4Sa) modified at the N-terminal end of the K16 peptide can adsorb inflammatory cytokines, thus acting to eliminate inflammation at the wound site. In vivo experiments showed that K16 hydrogel can inhibit early wound degradation, reduce inflammatory infiltration, and promote angiogenesis and collagen deposition, thus promoting wound healing. Therefore, the K16 hydrogel designed in this study has good potential for application in the field of radiation-induced skin injury repair.