Benign Paroxysmal Positional Vertigo Is Associated with an Increased Risk for Migraine Diagnosis: A Nationwide Population-Based Cohort Study.

Previous studies reported an increased risk of benign paroxysmal positional vertigo (BPPV) in patients with migraine. Hence, we aimed to assess the risk of migraine in patients with BPPV. This cohort study was conducted using the Taiwan National Health Insurance Research Database. The BPPV cohort consisted of patients aged <45 years with a diagnosis of BPPV between 2000 and 2009. An age- and sex-matched comparison group free from a history of BPPV or migraine was selected. All cases were followed up from 1 January 2000 to 31 December 2010 or until death or a diagnosis of migraine. The baseline demographic characteristics in both groups were compared using Student's t-test and the chi-square test. Cox proportional hazards regression analysis was used to estimate the hazard ratio for migraine in the BPPV cohort compared with the comparison group after adjustment for age, sex, and comorbidities. Notably, 117 of the 1386 participants with BPPV and 146 of the 5544 participants without BPPV developed migraine. After adjustment for age, sex, and comorbidities, BPPV showed an adjusted hazard ratio indicating a 2.96-fold increased risk of migraine (95% confidence interval: 2.30-3.80, p < 0.001). We found that BPPV is associated with an increased risk of a migraine diagnosis.

FT895 Impairs Mitochondrial Function in Malignant Peripheral Nerve Sheath Tumor Cells.

Neurofibromatosis type 1 (NF1) stands as a prevalent neurocutaneous disorder. Approximately a quarter of NF1 patients experience the development of plexiform neurofibromas, potentially progressing into malignant peripheral nerve sheath tumors (MPNST). FT895, an HDAC11 inhibitor, exhibits potent anti-tumor effects on MPNST cells and enhances the cytotoxicity of cordycepin against MPNST. The study aims to investigate the molecular mechanism underlying FT895's efficacy against MPNST cells. Initially, our study unveiled that FT895 disrupts mitochondrial biogenesis and function. Post-FT895 treatment, reactive oxygen species (ROS) in MPNST notably increased, while mitochondrial DNA copy numbers decreased significantly. Seahorse analysis indicated a considerable decrease in basal, maximal, and ATP-production-coupled respiration following FT895 treatment. Immunostaining highlighted FT895's role in promoting mitochondrial aggregation without triggering mitophagy, possibly due to reduced levels of XBP1, Parkin, and PINK1 proteins. Moreover, the study using CHIP-qPCR analysis revealed a significant reduction in the copy numbers of promoters of the MPV17L2, POLG, TFAM, PINK1, and Parkin genes. The RNA-seq analysis underscored the prominent role of the HIF-1α signaling pathway post-FT895 treatment, aligning with the observed impairment in mitochondrial respiration. In summary, the study pioneers the revelation that FT895 induces mitochondrial respiratory damage in MPNST cells.

A novel HDAC11 inhibitor potentiates the tumoricidal effects of cordycepin against malignant peripheral nerve sheath tumor through the Hippo signaling pathway.

Neurofibromatosis type 1 (NF1) is an autosomal dominant neurocutaneous disorder. Clinically, the hallmarks of NF1 include skin pigmentation and cutaneous neurofibroma. Some NF1 patients develop plexiform neurofibroma (PN) since early childhood. Pathologically, PN contains abundant Schwann cells, blood vessels and connective tissues, which may transform into a malignant peripheral nerve sheath tumor (MPNST). MPNST is a highly invasive sarcoma without any effective therapy. Recently, both in vitro and in vivo studies showed that cordycepin can inhibit the growth of MPNST cells. Cordycepin causes cell cycle arrest at G2/M phase and downregulates the protein levels of α-tubulin, p53 and Sp1. Herein, the present study revealed that the HDAC11 inhibitor, FT895, can synergistically enhance the tumoricidal effect of cordycepin against MPNST cells in vitro. Treatment with the combination of cordycepin and FT895 reduced the size of MPNST in the xenograft mouse model. The combined treatment decreased the protein levels of α-tubulin and KIF18A, which may disrupt the microtubule organization leading to the mis-segregation of chromosomes and aneuploidy. Moreover, the expression levels of TEAD1 and its co-activator TAZ, the candidate proteins in hippo signaling pathway, were suppressed after combined treatment. Sequence analysis found a few binding sites for the transcription factor, TEAD1 in the promoter regions of TUBA1B, KIF18A, TEAD1, TAZ, YAP, TP53 and SP1 genes. ChIP-qPCR assay showed that the combined treatment decreases the binding of TEAD1 to the promoters of TUBA1B, KIF18A, TEAD1, TAZ and YAP genes in STS26T cells. The reduced binding to TP53 and SP1 promoters was also found in S462TY cells, which was further confirmed by immunoblotting. The down-regulation of these important transcriptional factors may contribute to the vulnerability of MPNST. In summary, HDAC11 inhibitor, FT895 can potentiate the tumoricidal effect of cordycepin to suppress the MPNST cell growth, which was probably mediated by the dysfunction of hippo-signaling pathway.

Cordycepin inhibits the proliferation of malignant peripheral nerve sheath tumor cells through the p53/Sp1/tubulin pathway.

Neurofibromatosis type 1 (NF1) is one of the most common hereditary neurocutaneous disorders. In addition to skin pigmentation and cutaneous neurofibroma, some patients developed the plexiform neurofibroma since birth. Plexiform neurofibroma has abundant Schwann cells, fibroblasts, mast cells, blood vessels, and connective tissues, which increases the risk of developing a malignant peripheral nerve sheath tumor (MPNST). MPNST is a highly invasive cancer with no effective therapeutic agent. Cordycepin or 3'-deoxyadenosine is an extract from cordyceps militaris, which has been reported as an anti-inflammation and anti-tumor agent. Herein, we evaluated cordycepin's anti-proliferative effect on MPNST cell lines both in vitro and in vivo. Cordycepin inhibited the MPNST cell growth with an arrest of cell cycle at G2/M and S phases. The administration of naringin and pentostatin, inhibitors for adenosine deaminase (ADA), enzyme responsible for cordycepin degradation, did not show a synergistic effect in MPNST cells treated with cordycepin. However, the combined treatment enhanced the decrease of tumors in xenograft mouse model. Immunoblotting showed a decreased level of p53 protein in all MPNST cell lines, but S462TY cells. After cordycepin treatment, the levels of ERK, survivin, pAKT, and Sp1 proteins also decreased. The level of tubulin, but not actin or GAPDH, decreased in a dose-dependent manner. The microtubule network which is composed of tubulins was markedly decomposed in those treated MPNST cells. To elucidate the epigenetic control of transcription, ChIP-qPCR assay of the Sp1 and tubulin promoter regions revealed decreased Sp1 binding. The incorporation of 3'-doexyadenosine is detrimental for the process of poly(A) tail elongation. The poly(A) tail length assay showed the tail length in Sp1 and tubulin transcripts decreased in the treated cells. Nevertheless, the administration of SP1 protein to the treated cells could not rescue them completely. Furthermore, the p53-knocked-down cells (S462TY) where the expression of both p53 and Sp1 was suppressed, were vulnerable to cordycepin. The p53 protein could ameliorate the effect. In summary, cordycepin is effective to inhibit the growth of MPNST, probably through the pathway of p53/Sp1/tubulin.