Explore the vast range of titles available.

Paclitaxel (PTX) is a commonly used chemotherapeutic agent for treating various solid tumors; however, it often leads to a severe side effect known as paclitaxel‐induced peripheral neuropathy (PIPN), for which effective treatments are limited. Although mRNA therapies have shown promise in addressing central nervous system (CNS) disorders, the successful delivery of mRNA therapeutics to the nervous system is still hindered by many biological barriers. In this study, it is demonstrated that, compared with commercial MC3 lipid nanoparticles (MC3 LNPs), mRNA‐loaded P6CIT‐derived lipopolymer nanoparticles (P6CIT LPNPs), which are delivered via intrathecal injection, achieve effective penetration through the pia mater. More importantly, this P6CIT LPNP demonstrates the ability to achieve highly targeted mRNA transfection in gliocytes within the spinal cord and dorsal root ganglia (DRG), which is essential for the regulation of neuroinflammation. Furthermore, two intrathecal injections of P6CIT LPNPs encapsulating mIL‐10 (P6CIT/mIL‐10) significantly alleviate PIPN by reducing proinflammatory cytokine production, gliocyte activation, and presynaptic NMDA receptor hyperactivity in both male and female mice. This study presents a promising and clinically translatable platform for using mRNA‐loaded LPNPs to treat PIPN. The P6CIT lipopolymer demonstrates superior transfection efficacy in the spinal cord and DRG, as well as enhanced penetration of the pia mater compared to the MC3 ionizable lipid. Intrathecal delivery of P6CIT LPNPs enables effective transfection in the gliocytes in the spinal cord and DRG. Notably, intrathecal administration of P6CIT/mIL‐10 significantly alleviates allodynia in paclitaxel‐induced peripheral neuropathy mice.

Chronic alcohol consumption can lead to disruption of the blood-brain barrier. The gut-brain axis may be involved in this pathological process. We investigated the gut microbiota of 30 healthy individuals and 30 alcohol use disorder (AUD) patients and found that at the genus level, AUD patients had decreased Faecalibacterium and increased Streptococcus . Liquid chromatography mass spectrometer (LC-MS/MS) revealed that 604 metabolites were upregulated and 606 were downregulated in AUD patients with cognitive impairment, compared to healthy controls. Chronic alcohol consumption led to cognitive decline in mice, with increased 20 kDa FITC-dextran leakage in the prefrontal cortex (PFC) and hippocampus, and decreased expression of ZO-1, occludin, and claudin-5. Transplantation of feces from AUD patients into germ-free mice resulted in increased 20 kDa FITC-dextran leakage in PFC and hippocampus, and decreased expression of ZO-1, occludin, and claudin-5, compared to mice receiving feces from healthy individuals. Administration of Faecalibacterium prausnitzii to chronically alcohol-fed mice improved cognitive function, reduced 20 kDa FITC-dextran leakage in PFC and hippocampus, and increased the expression of ZO-1, occludin, and claudin-5. Chronic alcohol consumption can disrupt the blood-brain barrier through the gut-brain axis. Faecalibacterium prausnitzii can improve alcohol-induced blood-brain barrier disruption and cognitive impairment. By fecal microbiota transplantation from alcohol use disorder patients and healthy individuals into germ-free mice, it was proved that chronic alcohol consumption affects blood-brain barrier integrity through the gut-brain axis.

Aims Chronic alcohol exposure leads to persistent neurological disorders, which are mainly attributed to neuroinflammation and apoptosis. Stimulator of IFN genes (STING) is essential in the cytosolic DNA sensing pathway and is involved in inflammation and cellular death processes. This study was to examine the expression pattern and biological functions of STING signaling in alcohol use disorder (AUD). Methods Cell‐free DNA was extracted from human and mouse plasma. C57BL/6J mice were given alcohol by gavage for 28 days, and behavior tests were used to determine their mood and cognition. Cultured cells were treated with ethanol for 24 hours. The STING agonist DMXAA, STING inhibitor C‐176, and STING‐siRNA were used to intervene the STING. qPCR, western blot, and immunofluorescence staining were used to assess STING signaling, inflammation, and apoptosis. Results Circulating cell‐free mitochondrial DNA (mtDNA) was increased in individuals with AUD and mice chronically exposed to alcohol. Upregulation of STING signaling under alcohol exposure led to inflammatory responses in BV2 cells and mitochondrial apoptosis in PC12 cells. DMXAA exacerbated alcohol‐induced cognitive impairment and increased the activation of microglia, neuroinflammation, and apoptosis in the medial prefrontal cortex (mPFC), while C‐176 exerted neuroprotection. Conclusion Activation of STING signaling played an essential role in alcohol‐induced inflammation and mitochondrial apoptosis in the mPFC. This study identifies STING as a promising therapeutic target for AUD. Compared to healthy controls, individuals with alcohol use disorder (AUD) and mice chronically exposed to alcohol had increased circulating cell‐free mtDNA, which could be a potential biomarker for AUD. Activation of the STING caused inflammation in microglia and mitochondrial apoptosis in neurons. The STING agonist DMXAA aggravated alcohol‐induced cognitive impairment with upregulation of microglial activation, neuroinflammation, and apoptosis, while the STING inhibitor C‐176 exerted neuroprotection.

Background: Long-term heavy drinking is a major risk factor for cerebral microbleeds(CMBs), which are increasingly gaining attention as a pathological phenotype of cerebral small vessel diseases(CSVD). Under pathological conditions, remodeling of the extracellular matrix(ECM) on small vessels walls causes disarray in the structure and function of these vessels, leading to cerebral small vessel sclerosis and consequent rupture and bleeding. This can result in cognitive and emotional disorders, abnormal gait and increased risk of falling. However, the mechanisms underlying how long-term alcohol consumption leads to CMBs and decline in motor function remain unknown. Methods: We constructed a chronic alcohol exposure mouse model and measured the deposition of ECMs on the small vessels in motor-related brain regions. The presence of microbleeds was confirmed through Prussian blue staining and Magnetic Resonance Imaging. We also extracted primary cerebral microvascular smooth muscle cells (CMVSMCs) from the newborn mice and explored the effects of alcohol on the phenotypic transformation and substance synthesis function. Additionally, we conducted interventional experiments on the cell and animal models with an anti-fibrotic drugs Pirfenidone(PFD). Results: We found that mice with long-term alcohol exposure showed decreased motor function. In their motor-related brain regions, such as the motor cortex(MC), thalamus/basal ganglia(Tha/BG), and cerebellum(CB), we observed microbleeds. On the small vessels in these areas, we detected excessive deposited ECM proteins. In vitro experiments with primary CMVSMCs revealed that after alcohol treatment, the cells underwent a transformation into fibroblast-like phenotypes, and excessive production of the aforementioned ECM proteins, which is regulated by upstream TGFβ1/Smad signaling pathway. Additionally, PFD applied on cell and animal models could reverse the above processes to some extent. Conclusions: Our study found that the remodeling of ECM accompanied by activation of TGF-β1/Smad signaling pathway may be involved in alcohol-induced CMBs. It could be a potential therapeutic target for CMBs or CSVD.Competing Interest StatementThe authors have declared no competing interest.

Doxorubicin (DOX) is a key chemotherapeutic agent but is also a leading cause of DOX-induced cardiotoxicity (DIC), limiting its clinical use. Akkermansia muciniphila ( A. muciniphila ), known for its benefits as a probiotic in treating metabolic syndrome, has uncertain effects in the context of DIC. Here, 16S rRNA sequencing of fecal samples from anthracycline-treated patients and DIC mice revealed marked depletion of A. muciniphila . Cardiac transcriptomics, supported by in vitro experiments, showed that A. muciniphila colonization improved mitochondrial function and alleviated DIC by activating the PPARα/PGC1α signaling pathway in both normal and antibiotic-treated C57BL/6 mice. Further analysis uncovered a restructured microbiome–metabolome network following A. muciniphila administration, which contributed to DIC protection. Notably, A. muciniphila supplementation increased serum levels of the tryptophan metabolite indole-3-propionic acid (IPA), which binds to the cardiac aryl hydrocarbon receptor (AhR), leading to the activation of the PPARα/PGC1α signaling pathway. In conclusion, our study sheds light on the potential of A. muciniphila as a probiotic in mitigating DIC.

Diabetic cardiomyopathy (DCM), a prevalent cardiovascular complication and the principal driver of mortality among patients with diabetes, represents a significant clinical challenge. The gut microbiota, which reside a complex ecosystem within the human intestinal tract, play a fundamental role in host metabolism and systemic physiology. Mounting evidence underscores a critical link between gut microbial dysbiosis, microbial-derived metabolites, and DCM pathogenesis mediated through the gut-heart axis. This comprehensive review systematically synthesizes the current research elucidating the multifaceted interplay between the gut microbiota, their bioactive metabolites (e.g., short-chain fatty acids, bile acids, and branched-chain amino acids), and the development and progression of DCM. By critically evaluating the mechanisms underlying the gut-heart crosstalk, we provide novel insights into the etiopathogenesis of DCM. Furthermore, we evaluated emerging therapeutic strategies aimed at mitigating DCM by targeted modulation of the gut microbiota and their metabolic output, highlighting promising avenues for future research and clinical translation.