Exploration (Beijing, China)最新文献

Young migrants, particularly those at high altitudes, are predisposed to heart health abnormalities, including high-altitude heart disease. Despite the profound impact of hypobaric hypoxia on the gut microbial community, the understanding of the roles played by gut microbiota and gut microbiota-associated serum metabolites in high-altitude heart diseases remains limited. Therefore, we conducted a comprehensive multi-omics analysis involving 230 graduates from the same university, with 163 Tibetan Plateau migrants and 67 Chengdu Plain residents, and identified 206 differential metabolites (82 in serum and 124 in feces) and 369 species that differed between migrants and residents. Among these, 27 microbial species and four metabolites (Ketoglutaric acid, L-Aspartic acid, 3-Guanidinopropionic acid, betaine) detected in both serum and feces were found to be associated with migrants exhibiting compromised heart health, as diagnosed through clinical examinations. Notably, the abundances of Veillonella rogosae and Streptococcus rubneri were correlated with serum levels of L-Aspartic acid, betaine, and Ketoglutaric acid in heart health-abnormal individuals. Validation of these microbiome biomarkers and gut microbiota-associated serum metabolites in an independent cohort demonstrated their excellent predictive ability for indicating heart health abnormalities in migrants (AUC = 0.7857). Furthermore, supplementation with these identified species or gut microbiota-associated serum metabolites effectively mitigated hypobaric hypoxia-induced increases in serum lactate, glycolysis, myocardial damage, and cardiac hypertrophy. Integrated analysis revealed that the alterations in the gut microbiome negatively regulated key metabolic pathways such as the malate-aspartate shuttle, tricarboxylic acid cycle, and oxidative phosphorylation in heart health-abnormal individuals. The migration to high-altitude plateaus significantly reshaped the gut microbiome and metabolome signatures. Lower abundances of Veillonella rogosae, Streptococcus rubneri, and gut microbiota-associated serum metabolites promoted the remodeling of metabolic processes, thereby increasing susceptibility to high-altitude heart health abnormalities. Overall, our findings elucidate the microbial mechanisms underlying high-altitude heart disease and provide valuable insights for potential early intervention strategies in this context.

Asymmetrical pleated textile with unidirectional water transport plays a vital role in maintaining personal moisture and thermal comfort. Inspired by the cactus branch, in this work, an asymmetrical pleated structure textile embedded with a unidirectional water transport channel was proposed by seamless weft knitting technology. This innovative textile with differential capillary effect can swiftly transport water within 1 s, with an accumulative one-way transport index (AOTI) of 499.57%. This textile also exhibits excellent external water repellency with a stable contact angle exceeding 120°. Most importantly, water repellency, water collection, and directional water transport ability are integrated into one unified system by means of the asymmetrical pleated structure, thereby ensuring both safety and comfort for the wearer. The advanced fabrics meet high transmission indexes and fast transport rates, which are expected to provide a fresh avenue for the development and creation of more efficient and adaptive personal moisture and thermal management fabrics.

The role of CD8⁺ T cells in the pathogenesis of ulcerative colitis (UC) remains unclear. Similarly, the posttranscriptional regulation of the highly heterogenic CD8⁺ T cell populations and their effector function in IBD also remains poorly understood. Here, we find that miR-29a and -29b (miR-29a/b) regulate T cell fate, and their expression is higher near damaged colon tissue in patients with IBD compared to controls. In mice, we find that miR-29a/b suppresses the differentiation of CD8⁺ T cells and the secretion of pro-inflammatory and chemotactic factors during severe colitis by inhibiting transcriptional pathways, including those involving the T cell receptor and JAK-STAT signaling. Furthermore, we identify Ifng, an inflammatory factor that drives immune response and the reshaping of CD8⁺ T cell fate, as a potential target of the miRNAs. Finally, we show that delivery of miR-29 mimics to the colon of mice is sufficient to alleviate DSS-induced inflammation. Together, these data show that miR-29 plays an important role in suppressing T cell overactivation during inflammatory diseases.

Sepsis and their sequelae are the leading causes of death in intensive care units, with limited therapeutic options. Immunoparalysis plays a vital role in the pathophysiological progression of sepsis, leading to intracellular persistent infections and high mortality of septic patients. Eradicating intracellular infections and rescuing immunoparalysis are critical for sepsis management, yet effective tactics remain elusive. Here, we report immunomodulatory nanozymes (named PdIr@OMVs) that enable intracellular bacteria elimination and reinvigorate systemic innate-adaptive immune response during immunoparalysis to tackle multidrug-resistant (MDR) bacterial sepsis. The PdIr@OMVs are designed by encapsulating plasmonic PdIr nanocatalysts with immunostimulants of biocompatible bacterial outer membrane vesicles (OMVs). PdIr@OMVs exhibit unique localized surface plasmon response-enhanced peroxidase-like catalytic activity, and inherit the remarkable immunocyte-targeting capability and adjuvanticity of OMVs. We demonstrate that PdIr@OMVs not only potentiate the phagolysosomal killing effect of impaired macrophages via in situ catalysis to eradicate intracellular MDR bacteria and burst antigen release, but also allow rapid activation/maturation of dendritic cells to boost the presentation of bacterial antigen and orchestrate innate-adaptive immunity for rescuing immunoparalysis. In two immunocompromised mouse models of MDR bacterial sepsis, PdIr@OMVs collaboratively reduce bacterial burden and restore immune homeostasis, thereby circumventing organ damage and enabling the recovery of septic mice. Our work offers a promising therapeutic modality for sepsis and septic shock.

Photodynamic therapy (PDT) triggers immunogenic cell death (ICD) within the tumor microenvironment, consequently enhancing tumor immunotherapy. However, the maximum absorption wavelengths of first and second-generation PDT photosensitizers limit the penetration depth of therapeutics, resulting in insufficient anti-tumor outcomes. This study reports a custom-designed polymer, PTSQ, which exhibits significant absorption in the near-infrared region (NIR) window and fluorescence emission spectra within the NIR II range, demonstrating excellent PDT efficiency. Additionally, PTSQ self-assembles into nanomicelles, exhibiting outstanding siRNA delivery. To further enhance tumor immunotherapy, we introduce an immune checkpoint blockade strategy and prepared PTSQ/siPD-L1 complexes. We present a novel approach to tumor treatment by combining NIR light-activated PDT and ICD to enhance siPD-L1 therapy. At the cellular level, PTSQ/siPD-L1 complexes exhibit potent induction of ICD while concurrently suppressing PD-L1 gene expression. In vivo, these complexes significantly impede the growth of CT26, 4T1, and patient-derived xenograft (PDX) tumors. This effect is achieved by promoting in situ ICD, which reverses tumor environment and activates immune cells in tumors and spleens, including T cells, dendritic cells (DCs), and macrophages. Overall, this study offers insights for the development of NIR II-guided cancer immunotherapy and underscores the efficacy of PDT in conjunction with checkpoint blockade for cancer treatment.

Glucose metabolism reprogramming has emerged as a hallmark of cancer. We have reported that high temperature food or drink (>65°C) is the key etiological factors contributing to esophageal squamous cell carcinoma (ESCC) progression. Intriguingly, we observed that heat stimulation (42°C) alters glycolytic pathways in esophagus cells, but the underlying mechanisms remain poorly understood. Our findings revealed that stress-induced phosphoprotein 1 (STIP1) exhibits elevated expression in esophageal tissues exposed to heat stimulation (>65°C) compared to unexposed tissues, and its overexpression correlated with clinical grade and predict poor prognosis in ESCC patients. Mechanistically, STIP1 interacts with and activates adenosylhomocysteinase (AHCY; also termed SAHH) and change the conformation of AHCY. STIP1 also facilitates AHCY binding to lactate dehydrogenase A (LDHA), stimulating glycolysis. Notably, AHCY recruits protein arginine methyltransferase 3 (PRMT3) to methylate LDHA at R106, inhibiting ubiquitination-mediated AHCY degradation. In vivo, STIP1 knockout in mice dramatically inhibits 4-nitrochinoline-oxide (4NQO) induced esophageal tumorigenesis. Through virtual screening and functional validation, we identified licochalcone A (LCA) as a potent inhibitor of STIP1-driven ESCC proliferation in vitro and in vivo. In summary, these findings delineate a pro-tumorigenic signaling pathway whereby heat-induced STIP1 upregulation promotes ESCC glycolysis and growth via moonlighting functions that coordinate AHCY activity and LDHA methylation.

The immune characteristics and pathological mechanisms of COVID-19 and tuberculosis coinfection are not well understood. Single-cell RNA sequencing has emerged as a powerful tool for dissecting complex immune responses and cellular interactions in infectious diseases. Here, we employed scRNA-seq, combined with laboratory examinations and clinical observations, to elucidate potential mechanisms of immunopathology and protective immunity in coinfected patients. Substantial alterations in immune cell populations in patients with severe coinfection were observed, characterized by severe lymphopenia and massive expansion of myeloid cells. Lymphocytopenia may have resulted from lymphocyte apoptosis and migration. Systemic upregulation of S100 family proteins, mainly released by classical monocytes, might contribute to inflammatory cytokine storm via S100-TLR4-MyD88 signaling pathway in severely coinfected patients. Myeloid cells may contribute to immune paralysis in severe cases through expansion of myeloid-derived suppressor cells and dysregulated dendritic cell function. The immune landscape of T cells in severe patients were featured by dysregulated Th1 response, widespread exhaustion and increased cytotoxic, apoptosis, migration and inflammatory states. We observed increased plasma cells and overexpression of B-cell-activation-related pathways in severe patients. Together, we provide a comprehensive atlas illustrating the immune response to coinfected patients at the single-cell resolution and highlight mechanisms of pathogenesis in severe patients.

Radiotherapy (RT) resistance remains a substantial challenge in cancer therapy. Although physical factors are optimizing, the biological mechanisms for RT resistance are still elusive. Herein, we explored potential reasons for this difficult problem by generating RT-resistant models for in vitro and in vivo experiments. We found that abnormal spindle-like microcephaly-associated protein (ASPM) was highly expressed in RT-resistant samples and significantly correlated with disease advance in lung adenocarcinoma. Mechanistically, ASPM helps RT-resistant cells to evade spindle checkpoint surveillance and complete cell division after irradiation through destruction of microtubule stability, with subsequent increases in chromosome mis-segregation and deteriorating chromosomal stability during mitosis. Depletion of ASPM stabilized microtubules and significantly decreased chromosome mis-segregation, restoring the sensitivity of RT-resistant cells to radiation. We further found, with bioinformatics analysis, amino acid sequence 963–1263 of ASPM as a potential new drug target for overcoming RT resistance and identified 9 drug pockets within this domain for clinical translation. Our findings suggest that ASPM is a key regulator with an important role in promoting RT resistance in non-small cell lung cancer, and that suppressing or blocking its expression could be worth exploring as therapy for a variety of RT-resistant cancers.

Metal surface coating modification is an effective method to solve the problem of corrosion and inflammation in biometal clinical applications. Hydrogel is currently a commonly used biometal surface coating material. Because of its hydrophilicity, biocompatibility, and good biomechanical properties, hydrogel is widely used in clinical applications. Functionalized hydrogel coatings on biometal surfaces can effectively ameliorate problems such as corrosion, late thrombosis, inflammation, and other complications of implanted metals. Therefore, realizing a strong bond between biometal and hydrogel is a hot issue. This article centers on the bonding of hydrogel to biometal, focusing on a review of (i) biometal surface pretreatment methods, (ii) biometal-hydrogel bonding methods, and (iii) application of hydrogel coatings on biometal surfaces.

Cancer cells are characterized by the Warburg effect, which hijacks glycolysis and hinders OXPHOS. Pyruvate dehydrogenase kinase 1 (PDK1) is a key modulator in the Warburg effect and is highly expressed in tumor cells. We utilize PROTAC technology to design compounds that could achieve long-lasting degradation on PDK1. After screening anti-tumor activity in vitro, we selected a top compound A04, among 22 chemical candidates in various structures. Compared to a conventional PDK1 inhibitor, A04 dramatically improves over 1000-fold proliferation inhibition efficacy. Besides, A04 reverses Warburg effect and causes tumor apoptosis. In vivo, A04 achieves potent therapeutic efficacy in tumor-bearing mice and dramatically prolongs their lifetime after surgery resection. For the mechanism, A04 induces immunogenic cell death and reverses immunosuppression in the TME to enhance antitumor immunoreactivity. Further, transcriptome analysis verifies the mechanisms and uncovers fluctuation in cancer related pathways. Combination with αPD-L1 improves therapeutic efficacy and promotes multiple immunocytes infiltration. In conclusion, we first utilize PROTAC technology on modulating aberrant expressed metabolic enzyme PDK1 in cancer cells and achieve a great pharmacological effect, rendering it promising for energy-aberrant cancer therapy.