Background: Spinal cord injury (SCI) favors a persistent pro-inflammatory macrophages/microglia-mediated response with only a transient appearance of anti-inflammatory phenotype of immune cells. However, the mechanisms controlling this special sterile inflammation after SCI are still not fully elucidated. It is known that damage-associated molecular patterns (DAMPs) released from necrotic cells after injury can trigger severe inflammation. High mobility group box 1(HMGB1), a ubiquitously expressed DNA binding protein, is an identified DAMP, and our previous study demonstrated that reactive astrocytes could undergo necroptosis and release HMGB1 after SCI in mice. The present study aimed to explore the effects and the possible mechanism of HMGB1on macrophages/microglia polarization, as well as the neuroprotective effects by HMGB1 inhibition after SCI. Methods: In this study, the expression and the concentration of HMGB1 was determined by qRT-PCR, ELISA, and immunohistochemistry. Glycyrrhizin was applied to inhibit HMGB1, while FPS-ZM1 to suppress receptor for advanced glycation end products (RAGE). The polarization of macrophages/microglia in vitro and in vivo was detected by qRT-PCR, immunostaining, and western blot. The lesion area was detected by GFAP staining, while neuronal survival was examined by Nissl staining. Luxol fast blue (LFB) staining, DAB staining, and western blot were adopted to evaluate the myelin loss. Basso-Beattie-Bresnahan (BBB) scoring and rump-height Index (RHI) assay was applied to evaluate locomotor functional recovery. Results: Our data showed that HMGB1 can be elevated and released from necroptotic astrocytes and HMGB1 could induce pro-inflammatory microglia through the RAGE-nuclear factor-kappa B (NF-κB) pathway. We further demonstrated that inhibiting HMGB1 or RAGE effectively decreased the numbers of detrimental pro-inflammatory macrophages/microglia while increased anti-inflammatory cells after SCI. Furthermore, our data showed that inhibiting HMGB1 or RAGE significantly decreased neuronal loss and demyelination, and improved functional recovery after SCI. Conclusions: The data implicated that HMGB1-RAGE axis contributed to the dominant pro-inflammatory macrophages/microglia-mediated pro-inflammatory response, and inhibiting this pathway afforded neuroprotection for SCI. Thus, therapies designed to modulate immune microenvironment based on this cascade might be a prospective treatment for SCI.

Ischemic stroke is a neurological disorder caused by vascular stenosis or occlusion, accounting for approximately 87% of strokes. Clinically, the most effective therapy for ischemic stroke is vascular recanalization, which aims to rescue neurons undergoing ischemic insults. Although reperfusion therapy is the most effective treatment for ischemic stroke, it still has limited benefits for many patients, and ischemia-reperfusion (I/R) injury is a widely recognized cause of poor prognosis. Here, we aim to investigate the mechanism of protein phosphatase Mg²⁺/Mn²⁺ dependent 1 K (PPM1K) mediates metabolic disorder of branched-chain amino acids (BCAA) by promoting fatty acid oxidation led to ferroptosis after cerebral I/R injury. We established the I/R model in mice and used BT2, a highly specific BCAA dehydrogenase (BCKD) kinase inhibitor to promote BCAA metabolism. It was further verified by lentivirus knocking down PPM1K in neurons. We found that BCAA levels were elevated after I/R injury due to dysfunctional oxidative degradation caused by phosphorylated BCKD E1α subunit (BCKDHA). Additionally, the level of phosphorylated BCKDHA was determined by decreased PPM1K in neurons. We next demonstrated that BCAA could induce oxidative stress, lipid peroxidation, and ferroptosis in primary cultured cortical neurons in vitro. Our results further showed that BT2 could reduce neuronal ferroptosis by enhancing BCAA oxidation through inhibition of BCKDHA phosphorylation. We further found that defective BCAA catabolism could induce neuronal ferroptosis by PPM1K knockdown. Furthermore, BT2 was found to alleviate neurological behavior disorders after I/R injury in mice, and the effect was similar to ferroptosis inhibitor ferrostatin-1. Our findings reveal a novel role of BCAA in neuronal ferroptosis after cerebral ischemia and provide a new potential target for the treatment of ischemic stroke.

Background: Recently, increasing evidence has implicated methylenetetrahydrofolate reductase (MTHFR) gene mutation as a risk factor for ischemic stroke (IS) in the general population. However, studies have been inconclusive and lack evidence on specific populations. We aim to determine whether the rs1801133 (NC_000001.11 (MTHFR):g. 677C>T (p.Ala222Val) variant, we termed as MTHFR rs1801133 (677 C>T), is linked to an increased risk of IS in different age groups and ancestry groups.Methods: The literature relevant to our study was found by searching the PubMed, Cochrane Library, Web of Science, EMBASE, and CNKI databases. A random effect model analysis was used to calculate the pooled odds ratio (OR) and 95% confidence interval (CI) to evaluate any possible association. We conducted a subgroup analysis based on the age and ancestry groups of the included populations.Results: As of March 2022, 1,925 citations had been identified in electronic databases, of which 96 studies involving 34,814 subjects met our eligibility criteria. A strong link was found between IS and the MTHFR gene rs1801133 (677C>T) polymorphism in all genetic models [dominant genetic model (OR = 1.47; 95%CI = 1.33–1.61; p < 0.001), recessive genetic model (OR = 1.52; 95%CI = 1.36–1.71; p < 0.001), heterozygous model (OR = 1.36; 95%CI = 1.24–1.48; p < 0.001), homozygous model (OR = 1.82; 95%CI = 1.58–2.11; p < 0.001), and T allelic genetic model (OR = 1.37; 95%CI = 1.27–1.48; p < 0.001)]. Further subgroup analyses indicated that the MTHFR rs1801133 (677C>T) variant may increase the risk of IS in Asian, Hispanic, or Latin population, middle-aged, and elderly populations (p < 0.001).Conclusion: Our results implied that mutation of the T allele of MTHFR rs1801133 (677C>T) could be a risk factor for IS. A significant association was found among Asian, Hispanic, or Latin population, middle-aged, and elderly people.

Iodide mumps is an uncommon condition induced by iodide-containing contrast. We present the first reported case of iodide mumps in mainland China, which occurred after carotid artery intervention.The patient, a 65-year-old Chinese male, had a history of dizziness, hypertension, diabetes, and right arm weakness. He had no history of allergies and had never previously received iodide-containing contrast. The patient's kidney function and other laboratory findings were normal. He underwent stenting of the left internal carotid artery (LICA) opening and received approximately 250 mL of a nonionic contrast agent (ioversol). Approximately 5 hours after angioplasty, bilateral local swellings were noted near the mandible; the masses were moderately firm and nontender.Iodide mumps was diagnosed in the patient. Intravenous dexamethasone (10 mg) was administered. The submandibular glands had shrunk by 11 hours after angioplasty, and they gradually became softer. The mandibular salivary glands had completely recovered by 5 days after surgery.Iodide mumps represents a rare late reaction to iodine-containing contrast media. This condition can occur in any patient receiving any iodinated contrast agent and may recur upon repeated exposure, but self-resolution can be expected within 2 weeks. All clinicians who use contrast media or iodide should be aware of this condition.

The time window from stroke onset is critical for the treatment decision. However, in unknown onset stroke, it is often difficult to determine the exact onset time because of the lack of assessment methods, which can result in controversial and random treatment decisions. Previous studies have shown that serum biomarkers, in addition to imaging assessment, are useful for determining the stroke onset time. However, as yet there are no specific biomarkers or corresponding methodologies that are accurate and effective for determining the onset time of unknown onset stroke. Herein, we describe our novel advanced metabolites-based machine learning method (termed extreme gradient boost [XGBoost]) combined with recursive feature elimination, which accurately screened five metabolites from 1124 metabolites detected in serum. These metabolites were capable of both detecting acute ischemic stroke and backtracking the acute ischemic stroke onset time. To further investigate the pathological mechanisms of acute ischemic stroke, we also examined characteristic metabolites in different brain regions, and found two metabolites that could distinguish the core infarct area from the ischemic penumbra. Although this study is based on animal experiments, our machine learning framework and selected metabolites may provide a basis for clinical stroke evaluation and treatment.