Accepted

Gelsemiumelegans(Gardner. & Chapm.) Benth. has long been considered a traditional Chinese medicine effective against rheumatoid pain, cancer, cirrhosis, and skin diseases. Koumine (KM), the most abundant alkaloid in G.elegans Benth., demonstrates a variety of biological effects, including antitumor, analgesic, anxiolytic, anti-inflammatory, antidepressant, antioxidant, immunoregulatory, and hepatoprotective effects. Furthermore, the relatively low toxicity of KM makes it a promising drug candidate. This study aimed to investigate the protective effects of KM and its possible mechanisms using a concanavalin A (Con A)-induced autoimmune hepatitis (AIH) model in mice. Mice were orally administered different doses of KM for 14 d before Con A tail vein injections. The effects of KM on serum biochemical markers and liver histopathology were then evaluated 12 h after Con A exposure. The Nrf2 and NF-κB signaling pathways and alterations in gut microbiota were determined using western blotting, immunohistochemistry, and 16S rRNA sequencing to explore the underlying mechanisms of KM exposure. KM pretreatment dose-dependently decreased serum liver injury markers (Alanine aminotransferase, and aspartate aminotransferase) and cytokine levels (Tumor necrosis factor-α and interleukin-6), as well as the liver pathological damage triggered by Con A. Furthermore, the results of the multi-technique analysis indicated that KM activated the Nrf2 pathway, upregulated the expression of anti-oxidation factors HO-1 and Nrf2, and downregulated the expression of Keap1. Moreover, the NF-κB signaling pathway was inhibited. Interestingly, pre-treatment with KM also significantly improved the composition of the gut microbiota probably because it increases the richness of probiotics. Our findings suggest that KM pretreatment could attenuate Con A-induced AIH, the Nrf2 and NF-κB signaling pathways, and that gut microbiota are involved in the process of the hepatoprotective effect. This study provides a theoretical basis for the development of KM as an effective agent against AIH.

Migraine and stroke are highly prevalent diseases with a high impact on quality of life, with multiple epidemiological, pathophysiological, clinical, and prognostic areas of overlap. Migraine is a risk factor for stroke. This risk is explained by common risk factors, migraine-specific mechanisms, and non-migraine-specific mechanisms that have a relevant role in patients with migraine with aura (e.g., atrial fibrillation, paradoxical embolism through a patent foramen ovale). Another important link between migraine aura and ischemic stroke is cardiac embolism. Cardioembolism is the most frequent cause of ischemic stroke and increasing evidence suggests that microembolism, predominantly but not exclusively originating in the heart, is a contributing mechanism to the development of migraine aura. In this review, we discuss epidemiological aspects of the association between migraine and ischemic stroke, the clinical presentation of ischemic strokes in patients with migraine, and the differentiation between migrainous and non-migrainous infarctions. After that, we review migraine-specific and non-migraine-specific stroke mechanisms. We then review updated preclinical and clinical data on microembolism as a cause of migraine aura. In the last section, we summarize knowledge gaps and important areas to explore in future research. The review includes a clinical vignette with a discussion of the most relevant topics addressed.

Neuronal N-type (CaV2.2) voltage-gated calcium channels are essential for neurotransmission from primary afferent terminals in the dorsal horn. In this study we have utilized a knock-in mouse expressing CaV2.2 with an inserted extracellular hemagglutinin-tag (CaV2.2_HA), to visualise the distribution of endogenous CaV2.2 in dorsal root ganglion (DRG) neurons and their primary afferents in the dorsal horn. We examined the effect of partial sciatic nerve ligation (PSNL) and found an increase in CaV2.2_HA only in large and medium dorsal root ganglion neurons, and also in deep dorsal-horn synaptic terminals. Furthermore, there is a parallel increase in co-expression with GFRα1, present in a population of low threshold mechanoreceptors, both in large DRG neurons and in their terminals. The increased expression of CaV2.2_HA in these DRG neurons and their terminals is dependent on the presence of the auxiliary subunit α2δ-1, which is required for channel trafficking to the cell surface and to synaptic terminals, and likely contributes to enhanced synaptic transmission at these synapses following PSNL. In contrast the increase of GFRα1 is not altered in α2δ-1 knockout mice. We also found following PSNL there is patchy loss of glomerular synapses immunoreactive for CaV2.2_HA and CGRP or IB4, restricted to the superficial layers of the dorsal horn. This reduction is not dependent on α2δ-1, and likely reflects partial deafferentation of C-nociceptor presynaptic terminals. Therefore, we can distinguish in this pain model two different events affecting specific DRG terminals, with opposite consequences for CaV2.2_HA expression and function in the dorsal horn.

To develop a patient-centered text message-based platform that promotes self-management of symptoms of interstitial cystitis/bladder pain syndrome (IC/BPS).

Quantitative sensory testing (QST) has been one of the neurophysiological tools used for follow-up and disease progression assessment in ATTRv amyloidosis. We aimed to detect the utility of QST in identifying subclinical neuropathic involvement in ATTRV30M amyloidosis carriers.