Objectives Fibromyalgia is commonly considered a stress-related chronic pain disorder, and daily stressors are known triggers. However, the relation between stress and pain development remains poorly defined by clinical approaches. Also, the aetiology remains largely unknown. Methods We used a newly developed mouse model and lipidomic approaches to probe the causation and explore the biological plausibility for how perceived stress translates into chronic non-inflammatory pain. Clinical and lipidomic investigations of fibromyalgia were conducted for human validation. Results Using non-painful sound stimuli as psychological stressors, we demonstrated that mice developed long-lasting non-inflammatory hyperalgesia after repeated and intermittent sound stress exposure. Elevated serum malondialdehyde level in stressed mice indicated excessive oxidative stress and lipid oxidative damage. Lipidomics revealed upregulation of lysophosphatidylcholine 16:0 (LPC16:0), a product of lipid oxidisation, in stressed mice. Intramuscular LPC16:0 injection triggered nociceptive responses and a hyperalgesic priming-like effect that caused long-lasting hypersensitivity. Pharmacological or genetic inhibition of acid-sensing ion channel 3 impeded the development of LPC16:0-induced chronic hyperalgesia. Darapladib and antioxidants could effectively alleviate the stress-induced hyperalgesia by inhibiting LPC16:0 synthesis. Clinical investigations showed that excessive oxidative stress and LPC16:0 expression also exist in patients with fibromyalgia. Moreover, LPC16:0 expression was correlated with pain symptoms in patients with high oxidative stress and disease severity. Conclusions Our study provides experimental evidence for the causal effect of psychological stressors on chronic pain development. The findings identify a possible pathophysiological mechanism of stress-induced chronic non-inflammatory pain at molecular, behavioural and clinical levels that might indicate a new therapeutic approach for fibromyalgia.

Purpose: Music therapy (MT) reviews have found beneficial effects on behaviors and social interaction in Alzheimer’s disease (AD) but inconsistent effects on cognition. The purpose of the study was to evaluate the adjunct effect of long-term and home-based MT in AD patients under pharmacological treatment. Patients and methods: Mild AD cases (clinical dementia rating =0.5~1) were consecutively recruited and voluntarily separated into an MT group or control group (CG) for 6 months. Outcome assessments included Cognitive Abilities Screening Instrument (CASI), CASI-estimated mini-mental state examination, clinical dementia rating with sum of box scores, and neuropsychiatric inventory. The MT interventions were Mozart’s Sonata (KV 448) and Pachelbel’s Canon, listening with headphones for 30 minutes daily in the morning and before sleep, respectively. Results: Forty-one cases (MT versus CG number =20 versus 21) were analyzed. Adjusted differences of CASI-estimated mini-mental state examination and CASI after 6 months in the MT group were slightly less decreased than the CG without statistical significance. In further analysis of cognitive domains of CASI, the adjusted difference of abstraction domain in the MT group was significantly better than the CG. Conclusion: Although there were no apparent additional benefits of this MT on the global cognition and daily functioning in mild AD patients, it confirms the adjunct cognition effect on the abstraction. This MT contributes to the supplementary treatment of AD.

Recanalization therapy is the most effective treatment for eligible patients with acute ischemic stroke (AIS). Gut microbiota are involved in the pathological mechanisms and outcomes of AIS. However, the association of gut microbiota features with adverse recanalization therapy outcomes remains unclear. Herein, we investigated gut microbiota features associated with neurological deficits in patients with AIS after recanalization therapy and whether they predict the patients’ functional outcomes. We collected fecal samples from 51 patients with AIS who received recanalization therapy and performed 16S rRNA gene sequencing (V3–V4). We compared the gut microbiota diversity and community composition between mild to moderate and severe disability groups. Next, the characteristic gut microbiota was compared between groups, and we noted that the characteristic gut microbiota in patients with mild to moderate disability included Bilophila, Butyricimonas, Oscillospiraceae_UCG-003, and Megamonas. Moreover, the relative abundance of Bacteroides fragilis, Fusobacterium sp., and Parabacteroides gordonii was high in patients with severe disability. The characteristic gut microbiota was correlated with neurological deficits, and areas under the receiver operating characteristic curves confirmed that the characteristic microbiota predicted adverse recanalization therapy outcomes. In conclusion, gut microbiota characteristics are correlated with recanalization therapy outcomes in patients with AIS. Gut microbiota may thus be a promising biomarker associated with early neurological deficits and predict recanalization therapy outcomes.

Bidirectional communication of the microbiota–gut–brain axis is crucial in stroke. Recanalization therapy, namely intravenous thrombolysis (IVT) and endovascular thrombectomy (EVT), are recommended for eligible patients with acute ischemic stroke (AIS). It remains unclear whether gut microbiota metabolites, namely trimethylamine N-oxide (TMAO) and short-chain fatty acids (SCFAs), can predict the prognosis after recanalization therapy. This prospective study recruited patients with AIS receiving IVT, EVT, or both. The National Institutes of Health Stroke Scale (NIHSS) and modified Rankin scale (mRS) scores were used to assess the severity and functional outcomes of AIS, respectively. A functional outcome of mild-to-moderate disability was defined as a mRS score of 0–3 at discharge. Plasma TMAO and SCFA levels were measured through liquid chromatography with triple-quadrupole mass spectrometry. Fifty-six adults undergoing recanalization therapy for AIS were enrolled. Results showed that TMAO levels were not associated with stroke severity and functional outcomes, while isovalerate levels (one of the SCFAs) were negatively correlated with NIHSS scores at admission and discharge. In addition, high isovalerate levels were independently associated with a decreased likelihood of severe disability. The study concluded that an elevated plasma isovalerate level was correlated with mild stroke severity and disability after recanalization therapy for AIS.

There have been striking associations of cardiovascular diseases (e.g., atherosclerosis) and hypercholesterolemia with increased risk of neurodegeneration including Alzheimer’s disease (AD). Low-density lipoprotein (LDL), a cardiovascular risk factor, plays a crucial role in AD pathogenesis; further, L5, a human plasma LDL fraction with high electronegativity, may be a factor contributing to AD-type dementia. Although L5 contributing to atherosclerosis progression has been studied, its role in inducing neurodegeneration remains unclear. Here, PC12 cell culture was used for treatments with human LDLs (L1, L5, or oxLDL), and subsequently cell viability and nerve growth factor (NGF)-induced neuronal differentiation were assessed. We identified L5 as a neurotoxic LDL, as demonstrated by decreased cell viability in a time- and concentration-dependent manner. Contrarily, L1 had no such effect. L5 caused cell damage by inducing ATM/H2AX-associated DNA breakage as well as by activating apoptosis via lectin-like oxidized LDL receptor-1 (LOX-1) signaling to p53 and ensuring cleavage of caspase-3. Additionally, sublethal L5 long-termly inhibited neurite outgrowth in NGF-treated PC12 cells, as evidenced by downregulation of early growth response factor-1 and neurofilament-M. This inhibitory effect was mediated via an interaction between L5 and LOX-1 to suppress NGF-induced activation of PI3k/Akt cascade, but not NGF receptor TrkA and downstream MAPK pathways. Together, our data suggest that L5 creates a neurotoxic stress via LOX-1 in PC12 cells, thereby leading to impairment of viability and NGF-induced differentiation. Atherogenic L5 likely contributes to neurodegenerative disorders.