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Prion disease represents a group of fatal neurogenerative diseases in humans and animals that are associated with energy loss, axonal degeneration, and mitochondrial dysfunction. Axonal degeneration is an early hallmark of neurodegeneration and is triggered by SARM1. We found that depletion or dysfunctional mutation of SARM1 protected against NAD+ loss, axonal degeneration, and mitochondrial functional disorder induced by the neurotoxic peptide PrP106–126. NAD+ supplementation rescued prion-triggered axonal degeneration and mitochondrial dysfunction and SARM1 overexpression suppressed this protective effect. NAD+ supplementation in PrP106–126-incubated N2a cells, SARM1 depletion, and SARM1 dysfunctional mutation each blocked neuronal apoptosis and increased cell survival. Our results indicate that the axonal degeneration and mitochondrial dysfunction triggered by PrP106–126 are partially dependent on SARM1 NADase activity. This pathway has potential as a therapeutic target in the early stages of prion disease.

Cisplatin is the first-line chemotherapy agent for head and neck cancer (HNC), but its therapeutic effects are hampered by its resistance. In this study, we employed systemic strategies to overcome cisplatin resistance (CR) in HNC. CR cells derived from isogenic HNC cell lines were generated. The CR related hub genes, functional mechanisms, and the sensitizing candidates were globally investigated by transcriptomic and bioinformatic analyses. Clinically, the prognostic significance was assessed by the Kaplan–Meier method. Cellular and molecular techniques, including cell viability assay, tumorsphere formation assay, RT-qPCR, and immunoblot, were used. Results showed that these CR cells possessed highly invasive and stem-like properties. A total of 647 molecules was identified, and the mitotic division exhibited a novel functional mechanism significantly related to CR. A panel of signature molecules, MSRB3, RHEB, ULBP1, and spindle pole body component 25 (SPC25), was found to correlate with poor prognosis in HNC patients. SPC25 was further shown as a prominent molecule, which markedly suppressed cancer stemness and attenuated CR after silencing. Celastrol, a nature extract compound, was demonstrated to effectively inhibit SPC25 expression and reverse CR phenotype. In conclusion, the development of SPC25 inhibitors, such as the application of celastrol, maybe a novel strategy to sensitize cisplatin for the treatment of refractory HNC.

Context: Although diabetic peripheral neuropathy (DPN) is predominantly considered a disorder of the peripheral nerves, some evidence for central nervous system involvement has recently emerged. However, whether or to what extent the microstructure of central somatosensory tracts may be injured remains unknown.Objective: This work aimed to detect the microstructure of central somatosensory tracts in type 2 diabetic patients and to correlate it with the severity of DPN.Methods: A case-control study at a tertiary referral hospital took place with 57 individuals with type 2 diabetes (25 with DPN, 32 without DPN) and 33 nondiabetic controls. The fractional anisotropy (FA) values of 2 major somatosensory tracts (the spinothalamic tract and its thalamocortical [spino-thalamo-cortical, STC] pathway, the medial lemniscus and its thalamocortical [medial lemnisco-thalamo-cortical, MLTC] pathway) were assessed based on diffusion tensor tractography. Regression models were further applied to detect the association of FA values with the severity of DPN in diabetic patients.Results: The mean FA values of left STC and left MLTC pathways were significantly lower in patients with DPN than those without DPN and controls. Moreover, FA values of left STC and left MLTC pathways were significantly associated with the severity of DPN (expressed as Toronto Clinical Scoring System values) in patients after adjusting for multiple confounders.Conclusion: Our findings demonstrated the axonal degeneration of central somatosensory tracts in type 2 diabetic patients with DPN. The parallel disease progression of the intracranial and extracranial somatosensory system merits further attention to the central nerves in diabetic patients with DPN. [ABSTRACT FROM AUTHOR]

Antibodies have been developed as therapeutic agents for the treatment of cancer, infection, and inflammation. In addition to binding activity toward the target, antibodies also exhibit effector-mediated activities through the interaction of the Fc glycan and the Fc receptors on immune cells. To identify the optimal glycan structures for individual antibodies with desired activity, we have developed an effective method to modify the Fc-glycan structures to a homogeneous glycoform. In this study, it was found that the biantennary N-glycan structure with two terminal alpha-2,6-linked sialic acids is a common and optimized structure for the enhancement of antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, and antiinflammatory activities. [ABSTRACT FROM AUTHOR]