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关键词： cerebellum   obesity   Purkinje cell   TNF-alpha   topiramate   volume  

摘要： The rising incidence of obesity underscores the necessity for alternative obesity treatments. Patients commonly prefer medication aiding in weight reduction. Topiramate, an antiepileptic drug, is gaining popularity among obese patients for its weight loss benefits. This study aims to explore Topiramate's impact on the cerebella of obese female rats. In the experiment, 24 female rats (200-250 g) were divided into four groups: non-obese control (NOC), obese control (OC), non-obese topiramate (NOT) and obese topiramate (OT). The non-obese rats were given a standard diet, while the obese rats received a high-fat diet (40% fat). After 9 weeks, topiramate was administered intraperitoneally daily for 6 weeks. Following this, the rats were euthanised, and their cerebella were removed. The volume of the cerebellum and mean numerical density of the molecular neurons, granular neurons and Purkinje cells were estimated using stereological methods, and the link between obesity-caused cerebellum damage and TNF-alpha was assessed through immunohistochemical and bioinformatic techniques. Additionally, histopathological evaluations of the tissues were conducted. The cerebellar volume in the OC group was decreased compared to the NOC group. The topiramate groups exhibited a decrease in molecular or/and granular neuron numbers in the NOT and OT groups. Notably, neurons with dark cytoplasm were observed in the topiramate-treated groups, alongside neuronal degeneration was seen in the obese groups. The connection between TNF-alpha and obesity or obesity-caused cerebellum damage was confirmed through both immunohistochemical and bioinformatics analyses. These findings suggest that topiramate might have a degenerative effect on the cerebellum, especially following obesity.

关键词： xerostomia   mesenchymal stromal cell   interferon gamma  

摘要： Background & AimThe Phase I Dose-Escalation Trial of Mesenchymal Stromal Cells in Patients with Xerostomia After Radiation Therapy for Head and Neck Cancer (NCT05820711) is a first-in-human clinical trial manufactured by the University of Wisconsin Program for Advanced Cell Therapy (UW PACT) in partnership with UW Health hospital. Xerostomia, dry mouth, is a common side effect of radiation for head and neck cancer when cells necessary for saliva production are destroyed. Patients suffering from xerostomia experience decreased quality of life including difficulty eating and drinking. Current treatment options are generally palliative in nature. We have demonstrated the tolerability of bone marrow aspiration, feasibility of MSC expansion, safety and tolerability of injection into the submandibular glands and maximum tolerated dose of IFNγ-stimulated MSCs. MethodologyA total of 9 subjects were enrolled in a dose escalation cohort. Patients on Dose Level 0 received one injection of 10 × 10 6 MSCs in each submandibular gland and patients on Dose Level 1 received 20 × 10 6 MSCs. The expansion cohort is currently enrolling up to 12 patients. MSCs are isolated from bone marrow by Ficoll method in a GMP cleanroom facility. Cells are cultured in platelet lysate-based media and incubated at 37°C with 5% CO 2. After approximately two weeks, expanded cells are stimulated with IFNγ and cryopreserved. Prior to administration, MSCs are thawed and culture-rescued overnight. MSC harvest, drug product formulation, and release testing are performed on the day of administration. ResultsDue to insufficient quality of starting material, one manufacturing batch was terminated prior to completion. The 10 other successful manufacturing runs were analyzed by flow cytometry to determine the following potency markers: MHC I, PD-L1, MHC II, ICAM and IDO (Figure 1). Results were calculated by comparison of median fluorescent intensity (MFI) between IFNγ-stimulated and unstimulated MSCs and report

关键词： L. plantarum BX62   Rheumatoid arthritis   Oxidative stress   Methotrexate   Bone damage  

摘要： This study explored the effect of antioxidant Lactiplantibacillus plantarum BX62 (2x109CFU/ml) on RA and elucidated its underlying mechanisms using a collagen induced arthritis rat model. Results showed L. plantarum BX62 reduced oxidative stress, decreased the levels of inflammatory cytokines in the serum, and increased antiinflammatory interleukin-10 levels. Bone damage mitigation was confirmed via histology and micro-computed tomography analyses. Furthermore, L. plantarum BX62 restored immune balance and CD4+/CD8+ T cell ratio in the spleen. Downregulations of NLRP3, Cleaved Caspased-1, Cleaved IL-1R, RANKL, p-AKT, p-mTOR, and p62, and upregulations of OPG and Beclin-1 proteins were also observed in L. plantarum BX62 group. Meanwhile, The stable organ coefficients of L. plantarum BX62 demonstrated its safety for oral administration. Overall, L. plantarum BX62 demonstrated preventive effects against RA progression by reducing oxidative stress, modulating NLRP3/Caspase-1/IL-1R, AKT/mTOR pathways, balancing autophagy, and enhancing bone protection;thus, making it a formidable probiotic strain for curing RA.