Biology subjects

Shigemori, K.

Publications and source records attributed to Shigemori, K..

3 recordsLinked to original sources

bioRxiv2024

Simply crushed Zizyphi spinosi semen prevents neurodegenerative diseases and reverses age-related cognitive decline in mice

Neurodegenerative diseases are age-related disorders characterized by the cerebral accumulation of amyloidogenic proteins, and cellular senescence underlies their pathogenesis. Thus, it is necessary for preventing these diseases to remove toxic proteins, repair damaged neurons, and suppress cellular senescence. As a source for such prophylactic agents, we selected Zizyphi spinosi semen (ZSS), a medicinal herb used in traditional Chinese medicine. ZSS hot water extract ameliorated A{beta} and tau pathology and cognitive impairment in mouse models of Alzheimers disease and frontotemporal dementia. Non-extracted ZSS simple crush powder showed stronger effects than the extract and improved -synuclein pathology and cognitive/motor function in Parkinsons disease model mice. Furthermore, when administered to normal aged mice, the ZSS powder suppressed cellular senescence, reduced DNA oxidation, promoted brain-derived neurotrophic factor expression and neurogenesis, and enhanced cognition to levels similar to those in young mice. The quantity of known active ingredients of ZSS, jujuboside A, jujuboside B, and spinosin, was not proportional to the nootropic activity of ZSS. These results suggest that ZSS simple crush powder is a promising dietary material for the prevention of neurodegenerative diseases and brain aging. Impact statement Non-extracted simple crush powder of Zizyphi spinosi semen has not only disease-preventing effects but also brain-rejuvenating effects in mice.

neuroscience↗

bioRxiv2024

Mutation and cell state compatibility is required and targetable in Ph+ acute lymphoblastic leukemia minimal residual disease

Efforts to cure BCR::ABL1 B cell acute lymphoblastic leukemia (Ph+ ALL) solely through inhibition of ABL1 kinase activity have thus far been insufficient despite the availability of tyrosine kinase inhibitors (TKIs) with broad activity against resistance mutants. The mechanisms that drive persistence within minimal residual disease (MRD) remain poorly understood and therefore untargeted. Utilizing 13 patient-derived xenograft (PDX) models and clinical trial specimens of Ph+ ALL, we examined how genetic and transcriptional features co-evolve to drive progression during prolonged TKI response. Our work reveals a landscape of cooperative mutational and transcriptional escape mechanisms that differ from those causing resistance to first generation TKIs. By analyzing MRD during remission, we show that the same resistance mutation can either increase or decrease cellular fitness depending on transcriptional state. We further demonstrate that directly targeting transcriptional state-associated vulnerabilities at MRD can overcome BCR::ABL1 independence, suggesting a new paradigm for rationally eradicating MRD prior to relapse. Finally, we illustrate how cell mass measurements of leukemia cells can be used to rapidly monitor dominant transcriptional features of Ph+ ALL to help rationally guide therapeutic selection from low-input samples. HIGHLIGHTSO_LIRelapse after remission on TKI can harbor mutations in ABL1, RAS, or neither C_LIO_LIMutations and development-like cell state dictate fitness in residual disease C_LIO_LICo-targeting cell state and ABL1 markedly reduces MRD C_LIO_LIBiophysical measurements provide an integrative, rapid measurement of cell state C_LI

cancer biology↗

bioRxiv2023

Radiation-induced persistent DNA damage response and late toxicity in cardiac tissue

BackgroundRadiotherapy treatment is a mainstay of cancer treatments including for thoracic malignancies such as lung or breast cancer. Cardiac toxicity is a recognised long-term complication of thoracic radiotherapy which persists despite improvements in therapeutic modalities. The mechanisms and potential therapeutic targets that could provide cardiac protection in the context of radiation therapy remain incompletely understood. Here we investigated early and late cardiac toxicity following irradiation using the A/J mouse model to identify potential molecular drivers. MethodsSingle doses of irradiation of either 13 or 15 Gy were delivered to female A/J mice aged 6 - 8 weeks using a SmART-PLAN system. ECG traces and analysis were performed on anaesthetised mice. Cardiac tissue was harvested up to 32 weeks following irradiation for histological analysis and second-harmonic imaging microscopy. ResultsCardiac RT resulted in cardiac conductivity abnormalities including prolonged QTc interval. Additionally, an increase in pericardial and perivascular fibrosis was noted with a marked increase in pericardial fibrosis at 15 Gy compared to 13 Gy. Persistent DNA damage response was identified in cardiomyocytes at 7 days post irradiation and polarisation of cardiac-infiltrating macrophages towards a CD206+ M2-like phenotype at the same timepoint. ConclusionsOur data introduce the A/J mouse as a novel model for the study of physiologically relevant early and late cardiac toxicities following irradiation. Early events that could contribute to long term toxicities include persistent DNA damage response and repolarisation of macrophages, further investigation of which could identify potential future cardioprotective therapeutic strategies.

cancer biology↗