Intermittent fasting (IF) is a convenient dietary intervention for multiple diseases, including type 2 diabetes. However, whether it can be used as a long-term antidiabetic approach is still unknown. Here, we confirm that IF alone is beneficial for both moderate and severe diabetic mice, but its antidiabetic effects clearly diminish at later stages, especially for severe diabetic db/db mice, which have obviously impaired autophagy. We found that static magnetic fields can directly promote actin assembly and boost IF-induced autophagy. Consequently, the pancreatic islet and liver were improved, and the antidiabetic effects of IF were boosted. In fact, at later stages, combined static magnetic field and IF could reduce the blood glucose level of moderate type 2 diabetic mice by 40.5% (P < 0.001) and severe type 2 diabetes by 34.4% (P < 0.05), when IF alone no longer has significant blood glucose reduction effects. Therefore, although IF is generally beneficial for diabetes, our data reveal its insufficiency for late-stage diabetes, which can be compensated by a simple, noninvasive, long-lasting, and nonpharmacological strategy for effective long-term diabetic control.

Hydrogels have emerged as appealing prospects for wound healing due to their superior biocompatible qualities. However, the integration of antibacterial active substances into hydrogels for effective wound repair remains challenging. Here, we present a novel double-network hydrogel for nasal mucosal injury repair with antibacterial and self-healing capabilities. This hydrogel is the result of mixing aldehyde polyethylene glycol (PEG) and a carboxymethyl chitosan (CMCS)-based hydrogel with a photocured methylacrylate gelatin (GelMA) hydrogel to envelop mesenchymal stem cell exosomes (MSC-Exos). CMCS is rich in amino groups and facilitates antibacterial repair. Given the dynamically reversible Schiff base connections between the amino group of chitosan and the aldehyde group of modified PEG, the hydrogel can be easily injected into the lesion site because of its excellent injection and shear thinning properties. GelMA introduces an additional network layer for the hydrogel, which enhances its strength and extends the duration of stem cell exosomes on the wound surface. On the basis of these characteristics, we provide evidence that this compound hydrogel can substantially increase cell proliferation and regeneration, inhibit scar hyperplasia, and stimulate angiogenesis in rabbit nasal septum mucosa trauma models. These results suggest that MSC exosome-loaded hydrogels (ME-Gel) have substantial clinical potential for the repair and regeneration of nasal mucosa after surgery or trauma.

Cardiac fibrosis has emerged as the primary cause of morbidity, disability, and even mortality in numerous nations. In light of the advancements in precision medicine strategies, substantial attention has been directed toward the development of a practical and precise drug screening platform customized for individual patients. In this study, we introduce a biomimetic cardiac fibrosis-on-a-chip incorporating structural color hydrogels (SCHs) to enable optical high-throughput drug screening. By cocultivating a substantial proportion of cardiac fibroblasts (CFBs) with cardiomyocytes on the SCH, this biomimetic fibrotic microtissue successfully replicates the structural components and biomechanical properties associated with cardiac fibrosis. More importantly, the structural color shift observed in the SCH can be indicative of cardiac contraction and relaxation, making it a valuable tool for evaluating fibrosis progression. By incorporating such fibrotic microtissue into a microfluidic gradient chip, we develop a biomimetic optical cardiac fibrosis-on-a-chip platform that accurately and efficiently screens potential anti-fibrotic drugs. These characteristics suggest that this microphysiological platform possesses the capability to establish a preclinical framework for screening cardiac drugs, and may even contribute to the advancement of precision medicine.

Triple-negative breast cancer (TNBC) is currently the worst prognostic subtype of breast cancer, and there is no effective treatment other than chemotherapy. Processing of precursors 1 (POP1) is the most substantially up-regulated RNA-binding protein (RBP) in TNBC. However, the role of POP1 in TNBC remains clarified. A series of molecular biological experiments in vitro and in vivo and clinical correlation analyses were conducted to clarify the biological function and regulatory mechanism of POP1 in TNBC. Here, we identified that POP1 is significantly up-regulated in TNBC and associated with poor prognosis. We further demonstrate that POP1 promotes the cell cycle and proliferation of TNBC in vitro and vivo. Mechanistically, POP1 directly binds to the coding sequence (CDS) region of CDKN1A mRNA and degrades it. The degradation process depends on the N6-methyladenosine (m6A) modification at the 497th site of CDKN1A and the recognition of this modification by YTH N6-methyladenosine RNA binding protein 2 (YTHDF2). Moreover, the m6A inhibitor STM2457 potently impaired the proliferation of POP1-overexpressed TNBC cells and improved the sensitivity to paclitaxel. In summary, our findings reveal the pivotal role of POP1 in promoting TNBC proliferation by degrading the mRNA of CDKN1A and that inhibition of m6A with STM2457 is a promising therapeutic strategy for TNBC.

Lung ischemia–reperfusion injury (IRI) stands as the primary culprit behind primary graft dysfunction (PGD) after lung transplantation, yet viable therapeutic options are lacking. In the present study, we used a murine hilar clamp (1 h) and reperfusion (3 h) model to study IRI. The left lung tissues were harvested for metabolomics, transcriptomics, and single-cell RNA sequencing. Metabolomics of plasma from human lung transplantation recipients was also performed. Lung histology, pulmonary function, pulmonary edema, and survival analysis were measured in mice. Integrative analysis of metabolomics and transcriptomics revealed a marked up-regulation of arachidonate 12-lipoxygenase (ALOX12) and its metabolite 12-hydroxyeicosatetraenoic acid (12-HETE), which played a pivotal role in promoting ferroptosis and neutrophil extracellular trap (NET) formation during lung IRI. Additionally, single-cell RNA sequencing revealed that ferroptosis predominantly occurred in pulmonary endothelial cells. Importantly, Alox12-knockout (KO) mice exhibited a notable decrease in ferroptosis, NET formation, and tissue injury. To investigate the interplay between endothelial ferroptosis and NET formation, a hypoxia/reoxygenation (HR) cell model using 2 human endothelial cell lines was established. By incubating conditioned medium from HR cell model with neutrophils, we found that the liberation of high mobility group box 1 (HMGB1) from endothelial cells undergoing ferroptosis facilitated the formation of NETs by activating the TLR4/MYD88 pathway. Last, the administration of ML355, a targeted inhibitor of Alox12, mitigated lung IRI in both murine hilar clamp/reperfusion and rat left lung transplant models. Collectively, our study indicates ALOX12 as a promising therapeutic strategy for lung IRI.

A series of new targets containing 3 chiral elements of central, orientational, and turbo chirality have been designed and synthesized asymmetrically. The absolute configurations and conformations of these types of chirality were concurrently controlled by using chiral sulfonimine auxiliary and unambiguously determined by x-ray diffraction analysis. These targets include alpha unnatural amino acid derivatives, which may play an important role for drug design, discovery, and development. Three propellers of turbo framework are covalently connected to a chiral C(sp³) center via C(sp²)–C(sp³) bonding along with a C–N axis, while one of them is orientated away from the same carbon chiral center. The turbo or propeller chirality is characterized by 2 types of molecular arrangements of propellers, clockwise (PPP) and counterclockwise (MMM), respectively. The turbo stereogenicity was found to depend on the center chirality of sulfonimine auxiliary instead of the chiral C(sp³) center, i.e., (S)- and (R)-sulfinyl centers led to the asymmetric formation of PPP- and MMM-configurations, respectively. Computational studies were conducted on relative energies for rotational barriers of a turbo target along the C–N anchor and the transition pathway between 2 enantiomers meeting our experimental observations. This work is anticipated to have a broad impact on chemical, biomedical, and materials sciences in the future.

Background: The nasopharyngeal brush sampling can effectively collect samples from the nasopharynx. The blind brush sampling does not require the guidance of endoscopy, which is favorable for implementation and dissemination in the community. This study explored methylation markers for nasopharyngeal carcinoma (NPC) at both Epstein–Barr virus (EBV) and its host genome levels, aiming to construct a blind brushing diagnostic method. Methods: EBV DNA capture and methylation sequencing and GEO Illumina 450K methylation array data were used respectively for the discovery of EBV and host methylation markers. The diagnostic method was built in training cohort (n = 347) and validated in an independent validation cohort (n = 155). Results: A total of 1 EBV methylation marker (BILF2) and 6 host methylation markers (ITGA4, IMPA2, ITPKB, PI9, AMIGO2, and VAV3) were identified. Both EBV and host methylation markers were almost exclusively detected in NPC samples, with negligible detection in control samples. In validation cohort, the diagnostic method that included only the EBV BILF2 marker showed a sensitivity and specificity of 80.22% and 98.44%, respectively. When combining the EBV-derived marker BILF2 with the host-derived marker IMPA2, the diagnostic method’s sensitivity increased to 84.62%, while the specificity remained unchanged (IDI = 4.4%, P = 0.0419). Conclusion: Overall, the blind nasopharyngeal brushing diagnostic method, combining EBV and host methylation markers, showed great potential in NPC detection and could promote its application in nonclinical screening of NPC.

The interaction between organic and inorganic components in metal hybrid perovskites fundamentally determines the intrinsic optoelectronic performance. However, the underlying interaction sites have still remained elusive, especially for those non-hydrogen-bonded hybrid perovskites, thus largely impeding materials precise design with targeted properties. Herein, high pressure is utilized to elucidate the interaction mechanism between organic and inorganic components in the as-synthesized one-dimensional hybrid metal halide (DBU)PbBr₃ (DBU = 1,8-diazabicyclo [5.4.0] undec-7-ene). The interaction sites are identified to be the N from DBU and the Br from inorganic framework by the indicative of enhanced Raman mode under high pressure. The change in interaction strength is indeed derived from the pressure modulation on both distance and spatial arrangement of the nearest Br and N, rather than traditional hydrogen-bonding effect. Furthermore, the enhanced interaction increased charge transfer, resulting in a cyan emission with photoluminescence quantum yields (PLQYs) of 86.6%. The enhanced cyan emission is particularly important for underwater communication due to the much less attenuation in water than at other wavelength emissions. This study provides deep insights into the underlying photophysical mechanism of non-hydrogen-bonded hybrid metal halides and is expected to impart innovative construction with superior performance.

Dental, oral, and craniofacial diseases can substantially impact the quality of human life, thereby posing a serious public health concern. Although conventional therapies such as surgery have solved these problems largely, the prognosis of patients is not always satisfactory. Cell membrane-coated nanoparticles (CMCNPs) carry nanodrugs with the help of natural cell membranes, therefore utilizing their remarkable ability to interface and interact with their surrounding environment. These nanoparticles have demonstrated substantial advantages in drug targeting, prolonging blood circulation time, penetrating biofilms, and immune escape. With the assistance of CMCNPs, the therapeutic effects of dental, oral, and craniofacial diseases can reach a higher level. CMCNPs have been applied for dental, oral, and craniofacial diseases for various conditions such as head and neck cancer, periodontal disease, and oral biosignal detection. For the therapies of head and neck cancer, CMCNPs have been widely utilized as a tool of chemotherapy, phototherapy, and immunotherapy, while yet to be exploited in imaging technique. In the end, we summarized the challenges and prospectives of CMCNPs for dental, oral, and craniofacial diseases: large-scale production with uniform standards and high quantity, extensive application directions in dental, oral, and craniofacial regions (implant, endodontics), and the promotion of its clinical application.

Tinnitus is a phantom auditory sensation often accompanied by hearing loss, cognitive impairments, and psychological disturbances in various populations. Dysfunction of KCNQ2 and KCNQ3 channels—voltage-dependent potassium ion channels—in the cochlear nucleus can cause tinnitus. Despite the recognized significance of KCNQ2 and KCNQ3 channels in the auditory cortex, their precise relationship and implications in the pathogenesis of tinnitus remain areas of scientific inquiry. This study aimed to elucidate the pathological roles of KCNQ2 and KCNQ3 channels within the auditory cortex in tinnitus development and examine the therapeutic potential of mid-infrared photons for tinnitus treatment. We utilized a noise-induced tinnitus model combined with immunofluorescence, electrophysiological recording, and molecular dynamic simulation to investigate the morphological and physiological alterations after inducing tinnitus. Moreover, in vivo irradiation was administered to verify the treatment effects of infrared photons. Tinnitus was verified by deficits of the gap ratio with similar prepulse inhibition ratio and auditory brainstem response threshold. We observed an important enhancement in neuronal excitability in the auditory cortex using patch-clamp recordings, which correlated with KCNQ2 and KCNQ3 channel dysfunction. After irradiation with infrared photons, excitatory neuron firing was inhibited owing to increased KCNQ2 current resulting from structural alterations in the filter region. Meanwhile, deficits of the acoustic startle response in tinnitus animals were alleviated by infrared photons. Furthermore, infrared photons reversed the abnormal hyperexcitability of excitatory neurons in the tinnitus group. This study provided a novel method for modulating neuron excitability in the auditory cortex using KCNQ2 channels through a nonthermal effect. Infrared photons effectively mitigated tinnitus-related behaviors by suppressing abnormal neural excitability, potentially laying the groundwork for innovative therapeutic approaches for tinnitus treatment.