Integrated analysis of gut metabolome, microbiome, and brain function reveal the role of gut-brain axis in longevity.

The role of microbiota-gut-brain axis in modulating longevity remains undetermined. Here, we performed a multiomics analysis of gut metagenomics, gut metabolomics, and brain functional near-infrared spectroscopy (fNIRS) in a cohort of 164 participants, including 83 nonagenarians (NAs) and 81 non-nonagenarians (NNAs) matched with their spouses and offspring. We found that 438 metabolites were significantly different between the two groups; among them, neuroactive compounds and anti-inflammatory substances were enriched in NAs. In addition, increased levels of neuroactive metabolites in NAs were significantly associated with NA-enriched species that had three corresponding biosynthetic potentials: Enterocloster asparagiformis, Hungatella hathewayi and Oxalobacter formigenes. Further analysis showed that the altered gut microbes and metabolites were linked to the enhanced brain connectivity in NAs, including the left dorsolateral prefrontal cortex (DLPFC)-left premotor cortex (PMC), left DLPFC-right primary motor area (M1), and right inferior frontal gyrus (IFG)-right M1. Finally, we found that neuroactive metabolites, altered microbe and enhanced brain connectivity contributed to the cognitive preservation in NAs. Our findings provide a comprehensive understanding of the microbiota-gut-brain axis in a long-lived population and insights into the establishment of a microbiome and metabolite homeostasis that can benefit human longevity and cognition by enhancing functional brain connectivity.

Granulomatous rosacea in Chinese patients: Clinical-histopathological analysis and pathogenesis exploration.

The pathogenesis of granulomatous rosacea (GR), the only variant of rosacea, is unclear. To investigate the differences between GR and non-granulomatous rosacea (NGR) in clinical characteristics, histopathological changes and gene expression for the purpose of providing new ideas on the pathogenesis of rosacea. A total of 30 GR and 60 NGR patients were included. Their clinical and histopathological information was collected retrospectively, and the characteristics of immune cell infiltration were investigated by multiple immunohistochemical staining. RNA sequencing and transcriptome analysis were performed on three pairs of skin samples from GR and NGR patients, respectively. Then, the expressions of candidate genes that were potentially associated with granuloma formation were verified by immunohistochemical staining. It was found that GR patients were more prone to the occurrence of rosacea in the forehead, periocular and perioral skin (p = 0.001, p < 0.001, p = 0.001), and presented more severe papules and pustules when compared with NGR patients (p = 0.032). For histopathological features, the inflammatory cells primarily infiltrated around hair follicles in the GR group and around blood vessels in the NGR group. In addition, the neutrophils were richer (p = 0.036) and the expression levels of CD4+ , CD8+ and CD68+ cells were higher (p = 0.047, p < 0.001, p < 0.001) in the GR group than in the NGR group. In addition, the GR group had apparent collagen hyperplasia (p = 0.026). A total of 420 differentially expressed genes (DEGs) were detected, and bioinformatics analysis showed that the DEGs were enriched in neutrophil activation, adaptive immune response and other biological processes. Lastly, the candidate genes related to neutrophil activation and collagen hyperplasia, i.e., Cathepsin S (CTSS), Cathepsin Z (CTSZ) and matrix metalloproteinases 9 (MMP9), were confirmed to be highly expressed in the GR group. The clinical and histopathological features of GR exhibited a very diverse pattern compared with NGR, and the underlying mechanisms may be related to neutrophil activation and collagen hyperplasia.

Catalytically Active Metal-Organic Frameworks Elicit Robust Immune Response to Combination Chemodynamic and Checkpoint Blockade Immunotherapy.

Chemodynamic therapy (CDT) strategies rely on the generation of reactive oxygen species (ROS) to kill tumor cells, with hydroxyl radicals (•OH) serving as the key mediators of cytotoxicity in this setting. However, the efficacy of CDT approaches is often hampered by the properties of the tumor microenvironment (TME) and associated limitations to the Fenton reaction that constrains ROS generation. As such, there is a pressing need for the design of new nanoplatforms capable of improving CDT outcomes. In this study, an Fc-based metal-organic framework (MOF) vitamin k3 (Vk3)-loaded cascade catalytic nanoplatform (Vk3@Co-Fc) was developed. This platform was capable of undergoing TME-responsive degradation without impacting normal cells. After its release, Vk3 was processed by nicotinamide adenine dinucleotide hydrogen phosphate (NAD(P)H) quinone oxidoreductase-1 (NQO1), which is highly expressed in tumor cells, thereby yielding large quantities of H2O2 that in turn interact with Fe ions via the Fenton reaction to facilitate in situ cytotoxic •OH production. This process leads to immunogenic cell death (ICD) of the tumor, which then promotes dendritic cell maturation and ultimately increases T cell infiltration into the tumor site. When this nanoplatform was combined with programmed death 1 (PD-1) checkpoint blockade approaches, it was sufficient to enhance tumor-associated immune responses in breast cancer as evidenced by increases in the frequencies of CD45+ leukocytes and CD8+ cytotoxic T lymphocytes, thereby inhibiting tumor metastasis to the lungs and improving murine survival outcomes. Together, this Vk3@Co-Fc cascading catalytic nanoplatform enables potent cancer immunotherapy for breast cancer regression and metastasis prevention.

Collagenase-Loaded H-TiO2 Nanoparticles Enhance Ultrasound Imaging-Guided Sonodynamic Therapy in a Pancreatic Carcinoma Xenograft Model via Digesting Stromal Barriers.

Sonodynamic therapy (SDT), a noninvasive therapy that relies on sonosensitizers and generates reactive oxygen species (ROS), has attracted considerable attention in the treatment of pancreatic cancer. However, being surrounded by dense stromal barriers, pancreatic cancer exhibits high interstitial fluid pressure (IFP) and hypoxia in the tumor microenvironment (TME), resulting in poor SDT efficacy. Collagenase-loaded hollow TiO2 (Col-H-TiO2) nanoparticles (NPs) capable of degrading stromal barriers and producing sufficient ROS production were synthesized in this study. After administration of NPs in the patient-derived xenograft (PDX) model, ultrasonic irradiation-released collagenase degraded tumor matrix fibers, decreased intratumoral IFP, and enhanced the penetration and retention of NPs within tumor tissues. Moreover, the NPs accumulated within the tumor not only generate abundant ROS under the influence of ultrasound irradiation but also improve intratumoral ultrasound signal, providing ultrasonic imaging-guided highly effective SDT for pancreatic cancer. In conclusion, this research improves the SDT technique and enhances the visualization of pancreatic cancer by remodeling the TME and is a promising strategy for further clinical applications.