NeuroMolecular Medicine最新文献

The composition of intestinal microbial communities plays a crucial role in maintaining immune homeostasis, influencing both innate and adaptive immune responses. Growing evidence indicates that bidirectional communication between gut bacteria and host immune cells contributes to the development of autoimmune diseases. Disruptions in microbial diversity, known as dysbiosis, are linked to an increased susceptibility to autoimmune disorders such as rheumatoid arthritis (RA), multiple sclerosis (MS), and lupus erythematosus. This review examines the mechanistic connections between microbial dysregulation and abnormal immune activation, focusing on key signaling pathways. Pathways such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), Janus kinase/signal transducers and activators of transcription (JAK/STAT), and Toll-like receptor (TLR) networks act as immunological gatekeepers, and their dysregulation-induced by microbial metabolites or shifts in microbial composition-can lead to chronic inflammation and the breakdown of self-tolerance. Additionally, bacterial fermentation products, including short-chain fatty acids (SCFAs), exert immunomodulatory effects by influencing T-cell differentiation and cytokine profiles. Emerging therapeutic strategies targeting microbial restoration, such as precision probiotics, microbiota transplantation, and tailored nutritional interventions, aim to restore immune balance. This review underscores the gut microbiota as a dynamic regulator of immune signaling.

Hypertension is a significant risk factor for cognitive decline and dementia, yet the underlying mechanisms linking hypertension to cognitive impairments remain poorly understood. Central acetylcholine (ACh) receptors play a crucial role in the regulation of cognitive function. This study aimed to investigate the effects of hypertension on the mRNA levels of ACh receptors in the hippocampus and medial prefrontal cortex (mPFC). We induced hypertension in mice by continuous Angiotensin II (Ang II) infusion and evaluated cardiovascular parameters as well as cognitive performance using behavioral tests, including the Y-maze, object location task, and Morris water maze. Our findings indicated a significant increase in systolic blood pressure (SBP) and heart weight in Ang II-treated mice without affecting body weight or heart rate. Behavioral assessments revealed notable cognitive deficits characterized by reduced alternation in the Y-maze, impaired object recognition, and increased escape latency in the Morris water maze. Furthermore, quantitative real-time PCR analysis demonstrated reductions in the mRNA levels of muscarinic ACh receptor (Chrm1) and nicotinic ACh receptors (Chrnα4, Chrnα7 and Chrnβ2) in the hippocampus as well as Chrm1, Chrnα5 and Chrnα7 in the mPFC. In addition, correlations were observed between SBP and mRNA levels of labile ACh receptors in mice. Our findings elucidate the critical relationship between hypertension-induced cognitive impairment and the altered mRNA levels of ACh receptors, providing a foundation for future research aimed at restoring cholinergic function and developing therapeutic strategies to mitigate cognitive decline in hypertensive patients.

Autoimmune diseases occur when the immune system mistakenly attacks the body's own tissues, affecting millions of people and often requiring long-term treatment. Current therapies, such as immunosuppressants and biologics, help manage symptoms but can cause serious side effects. A promising new approach involves engineered microbiota-a method that modifies gut bacteria to influence immune function and potentially ease autoimmune conditions. The gut microbiome is crucial in regulating immunity, and imbalances in its composition have been linked to diseases, such as rheumatoid arthritis (RA), multiple sclerosis (MS), and inflammatory bowel disease (IBD). Engineered microbiota works by altering microbial communities, either by adding new strains, genetically modifying existing bacteria, or using carefully selected groups of microbes to control inflammation and immune responses. Recent studies in both animal models and human trials suggest this approach could help restore immune tolerance, reduce inflammation, and repair the gut barrier. However, challenges remain, including ensuring safety, long-term effectiveness, and meeting regulatory standards. Despite being in its early stages, engineered microbiota holds great promise as a future treatment for autoimmune diseases, paving the way for more precise and personalized therapies that leverage the power of the microbiome to improve health.

It is now widely accepted that the development of neurodegenerative diseases depends on and affects many pathological processes, both in the brain and the periphery. Inflammatory, cardiovascular, metabolic, cerebrovascular, autoimmune, and other environmental factors have been extensively studied and shown to contribute notably to the onset, pathogenesis, and clinical outcome of Alzheimer´s disease (AD), Parkinson´s disease (PD), cerebral amyloid angiopathy (CAA), multiple sclerosis, and other neurological disorders. Likewise, AD-induced changes in other tissues outside the central nervous system, such as abnormalities observed in the liver, spleen, or lungs, have been documented and extensively studied, leading to a better understanding of brain-periphery crosstalk in neurodegenerative diseases and the development of novel diagnostic and therapeutic approaches. In this study, we documented striking differences in the periphery in two frequently used, well-established APP transgenic mouse models of AD: 3xTg-AD mice, harboring three human genes (APP, tau, and Psen1), and Tg-SwDI mice, expressing human APP with the Swedish and vasculotropic Dutch/Iowa mutations in the brain. We documented splenomegaly, immunoglobulin-associated spleen amyloidosis, and an increase in the percentage of neutrophils in the spleen and macrophages in the liver in 3xTg-AD mice but not in age-matched Tg-SwDI mice, which are commonly used as an AD/CAA model. Our data suggest that the results observed in any transgenic mouse strain should be taken into account with caution. A detailed knowledge of pathological characteristics recapitulated in a particular strain can help to determine which mice are more appropriate for studying a specific mechanism or therapeutic approach.

The recently discovered family of heat-resistant obscure (Hero) proteins represents a novel class with chaperone-like activity and unique protective properties. These proteins may contribute to cellular survival in ischemic stroke (IS) conditions. Herein, we aimed to investigate the expression dynamics of six Hero genes during the acute and subacute phases of IS. Peripheral blood samples were collected from IS patients in the acute (day 1, n = 47) and subacute (day 7, n = 41) phases, along with healthy controls (n = 42). Gene expression was assessed via quantitative PCR. Statistical analysis included group comparisons, multivariate regression modelling, and correlation analysis. In the acute phase, C9orf16 (P = 0.006), C11orf58 (P = 0.00001), and SERBP1 (P = 0.006) were significantly downregulated compared to controls. By day 7, SERBP1 expression normalized, while C9orf16 (P = 0.002) and C11orf58 (P = 0.0004) remained downregulated. Multivariate regression identified C11orf58 expression as a potential biomarker of IS. Expression levels of SERBP1 and C11orf58 negatively correlated with infarct size during both the acute (R = - 0.59, P = 0.00012; R = - 0.49, P = 0.004) and subacute phases (R = - 0.54, P = 0.0024; R = - 0.44, P = 0.032). eQTL analysis showed that SERBP1 SNPs were associated with reduced expression only in controls. Our findings underscore the potential relevance of Hero proteins as biomarkers or therapeutic targets in IS, warranting further investigation into their mechanistic involvement in neuroprotection and recovery.

Long-term hyperglycemia and insulin dysfunction deteriorate peripheral nerve functions, leading to sensory loss, spontaneous pain, and hypersensitivity (i.e., allodynia and hyperalgesia). Evidence indicates glucose-induced upregulation of the Wnt/β-catenin mechanism in diabetic peripheral neuropathy (DPN). Eriodictyol (Ed) has shown protective effects against glucotoxicity. The present study explored the bioactivity of Ed in streptozotocin (STZ) induced DPN and the role of the Wnt/β-catenin pathway. Ed or gabapentin (Gpn), or methyl vanillate (MV) was administered in Wistar rats for 4 weeks, starting 6 weeks after STZ administration. Ed ameliorated the mean body weight and mitigated polydipsia and polyphagia in DPN rats. The data indicated that Ed attenuated hyperglycemia, glycosylated hemoglobin (HbA1c) levels, and HOMA-IR, and enhanced circulating insulin levels and HOMA-β against STZ-induced DPN. MV (Wnt/β-catenin activator) caused a significant increase in STZ-induced hyperglycemia, HbA1c, HOMA-IR, and further decreased the insulin levels and HOMA-β in STZ-treated rats. Ed attenuated oxidative stress, inflammatory expression, level of advanced glycation end products, and nuclear factor kappa B in the sciatic nerve of STZ-treated neuropathic rats, and MV further potentiated these markers triggered by STZ. Interestingly, Ed and Gpn attenuated mRNA expression of Wnt1/β-catenin in the sciatic nerve of neuropathic rats. Hyperalgesia and allodynia were significantly ameliorated in Ed or Gpn-treated rats against DPN. Furthermore, Ed ameliorated the biochemical biomarkers, histopathological characteristics, and nociceptive-like responses in STZ and MV-treated rats. It is concluded that Ed can alleviate the pathogenic course of DPN. Wnt/β-catenin pathway might be involved in the eriodyctiol-triggered mitigation of nociceptive-like responses in diabetic rats.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by motor neuron degeneration, muscle weakness, paralysis, and eventual death, with TAR DNA-binding protein 43 (TDP-43) pathology observed in almost all cases. Mouse models based on TDP-43 are thus essential for studying ALS and developing therapeutic approaches. The TDP-43 rNLS8 mouse model expresses a human TDP-43 transgene with a mutated nuclear localization sequence (hTDP-43 ΔNLS), but this is normally suppressed by the presence of doxycycline (Dox). Disease is initiated by removal of Dox, which replicates key ALS features, including TDP-43 pathology, neuromuscular junction denervation, motor neuron loss, and reduced survival. However, this model has a rapid disease progression which limits its use for extended preclinical studies and investigation of early disease mechanisms. To overcome these limitations, we explored whether maintaining low Dox concentrations in the diet (10-20 mg/kg) could slow disease progression. Our findings demonstrate that this approach significantly reduced hTDP-43 ΔNLS expression (up to 4.8-fold), which delayed disease onset by four weeks. Disease progression, assessed by rotarod performance, grip strength, and neurological scores, was extended from six to 15 weeks, with a threefold increase in survival. Despite slower progression, at the end stage, mice displayed similar levels of neuroinflammation, motor neuron loss, as Dox off mice. These findings highlight slower-progressing TDP-43 rNLS8 mice as a robust model for preclinical and early disease mechanism studies.

Depression is a leading global cause of disability. Emerging evidence highlights glutamatergic dysfunction, particularly impaired NMDA receptor signaling, as a key contributor to its neurobiology. Hydrogen sulfide (H₂S), once regarded solely as toxic, is now recognized for its role in regulating synaptic plasticity, inflammation, and neuronal survival. This review synthesizes recent findings on the antidepressant effects of H₂S. In animal models, H₂S administration improves depression-like behaviors while modulating key pathways such as PI3K/AKT/mTOR, Sirt1, and the cGAS-STING pathway. These benefits extend across models of stress, neuropathic pain, diabetes, and sleep deprivation. Among H₂S donors, sodium hydrosulfide (NaHS) demonstrated the most consistent antidepressant effects in preclinical studies. Clinical studies further show that individuals with major depression exhibit lower plasma H₂S levels, with symptom severity inversely correlated to H₂S concentration. Together, these findings support a multifaceted role for H₂S in mood regulation and highlight its promise as both a therapeutic candidate and a potential biomarker in depressive disorders, though translational studies remain needed.

Excessive pro-inflammatory polarization of microglia is a critical driver of secondary inflammation following spinal cord injury (SCI). Jaceosidin, a natural flavonoid with established anti-inflammatory properties, has not been extensively studied in the context of post-SCI inflammation regulation. Given the fundamental role of glycolysis in cellular energy metabolism and its crucial involvement in inflammatory processes, this study investigated the effects of Jaceosidin. We demonstrated that Jaceosidin significantly attenuated the inflammatory response in lipopolysaccharide-stimulated microglia in vitro. Subsequent in vitro and in vivo experiments revealed that Jaceosidin shifted microglial polarization away from the inflammatory state and suppressed glycolytic flux. Mechanistically, Jaceosidin directly targeted and inhibited the activity of pyruvate kinase M2 (PKM2), a key glycolytic enzyme. Intervention with Jaceosidin in a mouse SCI model resulted in reduced microglial activation at the injury site, diminished tissue damage, and significantly improved motor and autonomic nerve function recovery. In conclusion, our findings indicate that Jaceosidin mitigates microglial inflammation and promotes functional recovery after SCI by inhibiting PKM2 activity and dampening glycolysis. As a natural phytochemical derived from traditional Chinese medicine, Jaceosidin presents a promising novel therapeutic strategy for the clinical management of spinal cord injury.

Doxorubicin (DOX) is an effective chemotherapeutic agent, but its clinical utility is limited by its neurotoxic side effects. This study investigates the neuroprotective effects of phosphocreatine (PCr) against DOX-induced neurotoxicity in Sprague-Dawley rats. Forty rats were randomly assigned to four groups: control, DOX (2 mg/kg), DOX + PCr (20 mg/kg), and DOX + PCr (50 mg/kg). Parameters assessed included body weight, oxidative stress markers (MDA, SOD, GSH), and neurofunctional indicators (nNOS, BDNF). Mitochondrial respiration was evaluated using high-resolution respirometry, measuring state 3 and state 4 respiration, the respiratory control ratio (RCR), and ADP/O ratio. Western blotting was used to analyze apoptosis-related proteins (Bax, Bcl-2, cleaved caspase-3, pro-caspase-3, pro-caspase-9, cytochrome c) and signaling molecules (NF-κB, PGC-1α). PCr treatment significantly reduced oxidative stress, as evidenced by lower MDA levels and elevated GSH and SOD. It also modulated apoptotic signaling by decreasing pro-apoptotic proteins (Bax, cleaved caspase-3) and increasing anti-apoptotic Bcl-2. Moreover, PCr enhanced mitochondrial function and biogenesis, while attenuating neuroinflammation through regulation of the NF-κB/PGC-1α pathway. These findings suggest that PCr protects against DOX-induced neurotoxicity by improving mitochondrial bioenergetics, reducing oxidative damage, and inhibiting neuronal apoptosis. PCr may represent a promising therapeutic strategy to mitigate chemotherapy-associated neurotoxicity.