Poor healthy lifestyle and life's essential 8 are associated with higher risk of new-onset migraine: a prospective cohort study.

BACKGROUND: Lifestyle are closely related to migraine. However, there is a lack of studies investigating the association between Healthy lifestyle or Life's Essential 8 (LE8) and the risk of migraine. The objective of this research was to investigate the relationship between Healthy lifestyle scores and Life's essential 8 scores, and migraine. METHODS: 332,895 UK Biobank participants without migraine were included. Healthy lifestyle were assessed using seven lifestyle factors, and categorized as poor, intermediate, or ideal. LE8, based on the American Heart Association (AHA) Guidelines for Cardiovascular Health (CVH), consist of eight indicators classified as low, moderate, or high CVH. The Cox proportional hazard model was employed to examine the association between Healthy lifestyle scores, LE8 scores, and migraine, with calculations for population-attributable fraction (PAF) and cumulative incidence. RESULTS: During a median follow-up of 13.58 years, participants in intermediate (HR: 0.91; 95% CI: 0.85, 0.99) or ideal category of Healthy lifestyle (HR: 0.81; 95% CI: 0.73, 0.91) significantly reduced migraine risk compared to the poor category. Similarly, high CVH (HR: 0.73; 95% CI: 0.58, 0.92) also lowered migraine risk, while moderate CVH (HR: 0.93; 95% CI: 0.85, 1.02) did not show a difference compared to low CVH. If all individuals adhered to higher categories of Healthy lifestyle and LE8, approximately 11.38% and 22.05% of migraine cases could be prevented. Among individual lifestyle factors, maintaining an ideal body mass index (BMI), physical activity, sleep duration, sleep pattern, and sedentary time were associated with substantial reductions in migraine risk, by 5.65%, 0.81%, 10.16%, 16.39%, and 6.57%, respectively. CONCLUSION: Our study provides evidence that poor Healthy lifestyle and Life's Essential 8 are associated with higher risk of new-onset migraine.

Inhibiting PAC1 receptor internalization and endosomal ERK pathway activation may ameliorate hyperalgesia in a chronic migraine rat model.

BACKGROUND: Pituitary adenylate cyclase-activating polypeptide (PACAP) is a multipotent neuropeptide widely distributed in the trigeminovascular system (TVS) and higher brain regions. At present, the underlying mechanism of PACAP/PACAP type1 (PAC1) receptor in migraine generation remains unclear. METHODS: The rat model of chronic migraine (CM) was established by repeated intraperitoneal injection of nitroglycerin (NTG). Von Frey filaments and hot plate tests were used to measure the mechanical and thermal thresholds. The expression levels of c-Fos, calcitonin gene-related peptide (CGRP), PACAP, PAC1, protein kinase A (PKA) and phosphorylated extracellular signal-regulated kinase (ERK) were assessed by western blotting or immunofluorescence staining. The internalization of PAC1 receptor was visualized by fluorescence microscope and laser scanning confocal microscope. RESULTS: The results showed that c-Fos and CGRP expression significantly increased after repeated administrations of NTG or PACAP. Pitstop2 notably improved hyperalgesia in CM rats, while PACAP6-38 offered no benefit. In addition, PACAP-induced PAC1 receptor internalization, PKA and ERK pathways activation were blocked by Pitstop2 instead of PACAP6-38. CONCLUSIONS: Our results demonstrate that inhibition of PAC1 receptor internalization could effectively improve allodynia in CM rats by restraining ERK signaling pathway activation in a chronic migraine rat model. Modulation of receptor internalization may be a novel perspective to explore specific mechanisms of PACAP signaling activation in the trigeminal vascular system.

SS-31 alleviated nociceptive responses and restored mitochondrial function in a headache mouse model via Sirt3/Pgc-1α positive feedback loop.

Migraine is the second highest cause of disability worldwide, bringing a huge socioeconomic burden. Improving mitochondrial function has promise as an effective treatment strategy for migraine. Szeto-Schiller peptide (SS-31) is a new mitochondria-targeted tetrapeptide molecule that has been shown to suppress the progression of diseases by restoring mitochondrial function, including renal disease, cardiac disease, and neurodegenerative disease. However, whether SS-31 has a therapeutic effect on migraine remains unclear. The aim of this study is to clarify the treatment of SS-31 for headache and its potential mechanisms. Here we used a mouse model induced by repeated dural infusion of inflammatory soup (IS), and examined roles of Sirt3/Pgc-1α positive feedback loop in headache pathogenesis and mitochondrial function. Our results showed that repeated IS infusion impaired mitochondrial function, mitochondrial ultrastructure and mitochondrial homeostasis in the trigeminal nucleus caudalis (TNC). These IS-induced damages in TNC were reversed by SS-31. In addition, IS-induced nociceptive responses were simultaneously alleviated. The effects of SS-31 on mitochondrial function and mitochondrial homeostasis (mainly mitochondrial biogenesis) were attenuated partially by the inhibitor of Sirt3/Pgc-1α. Overexpression of Sirt3/Pgc-1α increased the protein level of each other. These results indicated that SS-31 alleviated nociceptive responses and restored mitochondrial function in an IS-induced headache mouse model via Sirt3/Pgc-1α positive feedback loop. SS-31 has the potential to be an effective drug candidate for headache treatment.

P2X7R/NLRP3 signaling pathway-mediated pyroptosis and neuroinflammation contributed to cognitive impairment in a mouse model of migraine.

Migraine is the second most common form of headache disorder and the second leading cause of disability worldwide. Cognitive symptoms ranked second resulting in migraine-related disability, after pain. P2X7 receptor (P2X7R) was recently shown to be involved in hyperalgesia in migraine. However, the role of P2X7R in migraine-related cognitive impairment is still ill-defined. The aim of this study was to explore the molecular mechanisms underlying migraine-related cognitive impairment and the role of P2X7R in it. Here we used a well-established mouse model of migraine that triggered migraine attacks by application of inflammatory soup (IS) to the dura. Our results showed that repeated dural IS stimulation triggered upregulation of P2X7R, activation of NLRP3 inflammasome, release of proinflammatory cytokines (IL-1ß and IL-18) and activation of pyroptotic cell death pathway. Gliosis (microgliosis and astrogliosis), neuronal loss and cognitive impairment also occurred in the IS-induced migraine model. No significant apoptosis or whiter matter damage was observed following IS-induced migraine attacks. These pathological changes occurred mainly in the cerebral cortex and to a less extent in the hippocampus, all of which can be prevented by pretreatment with a specific P2X7R antagonist Brilliant Blue G (BBG). Moreover, BBG can alleviate cognitive impairment following dural IS stimulation. These results identified P2X7R as a key contributor to migraine-related cognitive impairment and may represent a potential therapeutic target for mitigating cognitive impairment in migraine.

Interferon Regulatory Factor 4 (IRF4) Plays a Key Role in Osteoblast Differentiation of Postmenopausal Osteoporosis.

BACKGROUND: Postmenopausal osteoporosis (PMOP) is a prevalent disease, which features decreased bone mass, bone weakness and deteriorated bone microstructure in postmenopausal women. Although many factors have been revealed to contribute to the occurrence of PMOP, its mechanism remains undefined. This work aimed to identify significant changes in gene expression during PMOP formation and to examine the most valuable differential genes in postmenopausal osteoporosis versus the control group. METHODS: The GSE68303 dataset that contains 12 ovariectomize (OVX) experimental and 11 sham groups was downloaded and analyzed. The results indicated that interferon regulatory factor 4 (IRF4) might be a hub gene in the development of postmenopausal osteoporosis. Western blot and immunohistochemistry were carried out to evaluate IRF4 levels in thoracic vertebra extracts from OVX and Sham mice. To assess IRF4's impact on osteogenic differentiation in postmenopausal bone marrow mesenchymal stem cells (BM-MSCs), IRF4 overexpression (OV-IRF4) and knockdown (Sh-IRF4) plasmids were constructed. RESULTS: The results showed that comparing with the sham group, bone samples from the OVX group showed higher IRF4 expression. Alkaline phosphatase (ALP) staining revealed that IRF4 overexpression significantly inhibited ALP activity, while IRF4 knockdown promoted ALP activity in BM-MSCs. Simvastatin-treated OVX mice showed increased total bone volume/total tissue volume (BV/TV) and elevated Runx2 expression by immunohistochemical staining compared with the OVX group. CONCLUSIONS: This study demonstrated that IRF4 is associated with OVX induced osteoporosis, it can regulate bone stability by inhibiting the osteogenic differentiation BM-MSCs. This study may help enhance our understanding of the molecular mechanism of PMOP formation, providing new insights into estrogen defiance induced osteoporosis.

A new experimental rat model of nocebo-related nausea involving double mechanisms of observational learning and conditioning.

AIM: The nocebo effect, such as nausea and vomiting, is one of the major reasons patients discontinue therapy. The underlying mechanisms remain unknown due to a lack of reliable experimental models. The goal of this study was to develop a new animal model of nocebo-related nausea by combining observational learning and Pavlovian conditioning paradigms. METHODS: Male Sprague-Dawley rats with nitroglycerin-induced migraine were given 0.9% saline (a placebo) or LiCl (a nausea inducer) following headache relief, according to different paradigms. RESULTS: Both strategies provoked nocebo nausea responses, with the conditioning paradigm having a greater induction impact. The superposition of two mechanisms led to a further increase in nausea responses. A preliminary investigation of the underlying mechanism revealed clearly raised peripheral and central cholecystokinin (CCK) levels, as well as specific changes in the 5-hydroxytryptamine and cannabinoid systems. Brain networks related to emotion, cognition, and visceral sense expressed higher c-Fos-positive neurons, including the anterior cingulate cortex (ACC), insula, basolateral amygdala (BLA), thalamic paraventricular nucleus (PVT), hypothalamic paraventricular nucleus (PVN), nucleus tractus solitarius (NTS), periaqueductal gray (PAG), and dorsal raphe nucleus-dorsal part (DRD). We also found that nausea expectances in the model could last for at least 12 days. CONCLUSION: The present study provides a useful experimental model of nocebo nausea that might be used to develop potential molecular pathways and therapeutic strategies for nocebo.

New management strategies for primary headache disorders: Insights from P4 medicine.

Primary headache disorder is the main cause of headache attacks, leading to significant disability and impaired quality of life. This disorder is increasingly recognized as a heterogeneous condition with a complex network of genetic, environmental, and lifestyle factors. However, the timely diagnosis and effective treatment of these headaches remain challenging. Precision medicine is a potential strategy based on P4 (predictive, preventive, personalized, and participatory) medicine that may bring new insights for headache care. Recent machine learning advances and widely available molecular biology and imaging data have increased the usefulness of this medical strategy. Precision medicine emphasizes classifying headaches according to their risk factors, clinical presentation, and therapy responsiveness to provide individualized headache management. Furthermore, early preventive strategies, mainly utilizing predictive tools, are critical in reducing headache attacks and improving the quality of life of individuals with headaches. The current review comprehensively discusses the potential application value of P4 medicine in headache management.

2-Deoxyglucose alleviates migraine-related behaviors by modulating microglial inflammatory factors in experimental model of migraine.

Background: Targeting metabolic pathways has emerged as a new migraine treatment strategy as researchers realize the critical role metabolism plays in migraine. Activated inflammatory cells undergo metabolic reprogramming and rely on glycolysis to function. The objective of this study was to investigate the glycolysis changes in the experimental model of migraine and the effect of glycolysis inhibitor 2-Deoxy-D-glucose (2-DG) in the pathophysiology of migraine. Methods: We used a rat model of migraine that triggered migraine attacks by applying inflammatory soup (IS) to the dura and examined changes in glycolysis. 2-DG was used to inhibit glycolysis, and the effects of 2-DG on mechanical ectopic pain, microglial cell activation, calcitonin gene-related peptides (CGRP), c-Fos, and inflammatory factors induced by inflammatory soup were observed. LPS stimulated BV2 cells to establish a model in vitro to observe the effects of 2-DG on brain-derived neurotrophic factor (BDNF) after microglia activation. Results: In the experimental model of migraine, key enzymes involved in glycolysis such as phosphofructokinase platelet (PFKP), hexokinase (HK2), hypoxia inducible factor-1α (HIF-1α), lactate dehydrogenase (LDH) and pyruvate kinase (PKM2) were expressed in the medullary dorsal horn. While the expression of electronic respiratory transport chain complex IV (COXIV) decreased. There were no significant changes in glucose 6-phosphate dehydrogenase (G6PD), a key enzyme in the pentose phosphate pathway. The glycolysis inhibitor 2-DG alleviated migraine-like symptoms in an experimental model of migraine, reduced the release of proinflammatory cytokines caused by microglia activation, and decreased the expression of CGRP and c-Fos. Further experiments in vitro demonstrated that glycolysis inhibition can reduce the release of Iba-1/proBDNF/BDNF and inhibit the activation of microglia. Conclusion: The migraine rat model showed enhanced glycolysis. This study suggests that glycolytic inhibitor 2-DG is an effective strategy for alleviating migraine-like symptoms. Glycolysis inhibition may be a new target for migraine treatment.

Machine Learning Prediction Model and Risk Factor Analysis of Reoperation in Recurrent Lumbar Disc Herniation Patients After Percutaneous Endoscopic Lumbar Discectomy.

OBJECTIVE: To investigate the risk factors of reoperation after percutaneous endoscopic lumbar discectomy (PELD) due to recurrent lumbar disc herniation (rLDH) and to establish a set of individualized prediction models. METHODS: Patients who underwent PELD successfully from January 2016 to February 2022 in a single institution were enrolled in this study. Six methods of machine learning (ML) were used to establish an individualized prediction model for reoperation in rLDH patients after PELD, and these models were compared with logistics regression model to select optimal model. RESULTS: A total of 2603 patients were enrolled in this study. 57 patients had repeated operation due to rLDH and 114 patients were selected from the remaining 2546 nonrecurrent patients as matched controls. Multivariate logistic regression analysis showed that disc herniation type (P < .001), Modic changes (type II) (P = .003), sagittal range of motion (sROM) (P = .022), facet orientation (FO) (P = .028) and fat infiltration (FI) (P = .001) were independent risk factors for reoperation in rLDH patients after PELD. The XGBoost AUC was of 90.71%, accuracy was approximately 88.87%, sensitivity was 70.81%, specificity was 97.19%. The traditional logistic regression AUC was 77.4%, accuracy was about 77.73%, sensitivity was 47.15%, specificity was 92.12%. CONCLUSION: This study showed that disc herniation type (extrusion, sequestration), Modic changes (type II), a large sROM, a large FO and high FI were independent risk factors for reoperation in LDH patients after PELD. The prediction efficiency of XGBoost model was higher than traditional Logistic regression analysis model.

The Role of Circadian Rhythm in Neurological Diseases: A Translational Perspective.

Intrinsic biological clocks drive the circadian rhythm, which coordinates the physiological and pathophysiological processes in the body. Recently, a bidirectional relationship between circadian rhythms and several neurological diseases has been reported. Neurological diseases can lead to the disruption of circadian homeostasis, thereby increasing disease severity. Therefore, optimizing the current treatments through circadian-based approaches, including adjusted dosing, changing lifestyle, and targeted interventions, offer a promising opportunity for better clinical outcomes and precision medicine. In this review, we provide detailed implications of the circadian rhythm in neurological diseases through bench-to-bedside approaches. Furthermore, based on the unsatisfactory clinical outcomes, we critically discuss the potential of circadian-based interventions, which may encourage more studies in this discipline, with the hope of improving treatment efficacy in neurological diseases.

Development of degradable magnesium-based metal implants and their function in promoting bone metabolism (A review).

Background: Use of degradable magnesium (Mg)-based metal implants in orthopaedic surgeries can avoid drawbacks associated with subsequent removal of the non-degradable metallic implants, reducing cost and trauma of patients. Although Mg has been applied in the clinic for orthopaedic treatment, the use of Mg-based metal implants is largely in the research phase. But its application is potentially beneficial in this context as it has been shown that Mg can promote osteogenesis and inhibit osteoclast activity. Methods: A systematic literature search about "degradable magnesium (Mg)-based metal implants" was performed in PubMed and Web of Science. Meanwhile, relevant findings have been reviewed and quoted. Results: In this review, we summarize the latest developments in Mg-based metal implants and their role in bone regeneration. We also review the various molecular mechanisms by which Mg ions regulate bone metabolic processes, including osteogenesis, osteoclast activity, angiogenesis, immunity, and neurology. Finally, we discuss the remaining research challenges and opportunities for Mg-based implants and their applications. Conclusion: Currently, establishment of the in vitro and in vivo biological evaluation systems and phenotypic modification improvement of Mg-based implants are still needed. Clarifying the functions of Mg-based metal implants in promoting bone metabolism is beneficial for their clinical application. The Translational potential of this article: All current reviews on Mg-based implants are mainly concerned with the improvement of Mg alloy properties or the progress of applications. However, there are few reviews that provides a systematic narrative on the effect of Mg on bone metabolism. This review summarized the latest developments in Mg-based metal implants and various molecular mechanisms of Mg ions regulating bone metabolism, which is beneficial to further promote the translation of Mg based implants in the clinic and is able to provide a strong basis for the clinical application of Mg based implants.

Lumbosacral Transitional Vertebrae in Adolescents: Effects on the Short-Term Outcomes of Percutaneous Endoscopic Lumbar Discectomy.

OBJECTIVE: To investigate whether lumbosacral transitional vertebrae (LSTV) affects the clinical outcomes of percutaneous endoscopic lumbar discectomy (PELD) in adolescent patients with lumbar disc herniation (LDH). METHODS: This was a retrospective study with two groups. Group A was made up of 22 adolescent LDH patients with LSTV (18 males and 4 females). Group B was made up of 44 adolescent LDH patients without LSTV (36 males and 4 females), who were matched to group A for age, sex, and body mass index. All patients underwent PELD at the L4/5 or L5/S1 single level and were followed up at 18 months after surgery. We identified LSTV on radiographs and computed tomography and assessed the imaging characteristics of all patients. Outcomes were evaluated through a numerical rating scale (NRS), the Oswestry Disability Index (ODI), the modified MacNab grading system, and the incidence of additional lumbar surgery. RESULTS: At 18 months after PELD, both groups had significant improvements in the mean NRS scores of low back pain (LBP) or leg pain and the ODI scores. In terms of the MacNab criteria, 90.9% in group A and 93.2% in group B showed excellent or good outcomes. The mean NRS scores of LBP or leg pain, ODI score, and MacNab grade after surgery were not significantly different between the 2 groups. Two patients (one patient had a recurrence; one patient had a new lumbar disc herniation) in group A and 3 patients (one patient had a recurrence; two patients had new lumbar disc herniations) in group B underwent additional lumbar surgery. CONCLUSIONS: Our study suggests that in terms of pain relief, life function improvement, and the incidence of additional lumbar surgery, LSTV has no effect on the short-term clinical outcomes of PELD in adolescents. A new lumbar disc herniation is an important reason for additional surgery in adolescents, regardless of the LSTV status.