Celastrol augments sensitivity of NLRP3 to CP-456773 by modulating HSP-90 and inducing autophagy in dextran sodium sulphate-induced colitis in rats.

NLRP3, one of the HSP-90 clients, has been defined as a critical component of IBD. In a rat model of DSS-induced colitis, we investigated the anti-inflammatory potential of the combined therapy with CP-456773 (CP), an NLRP3 inhibitor, and celastrol (CSR), an NF-κB inhibitor. Our results revealed that the CSR/CP combined therapy (CCCT) attenuated colon shortening, DAI and MDI in addition to improvement of the colonic histological picture. Moreover, the CCCT increased the antioxidant defense machinery of the colonic tissue and decreased MPO activity. Furthermore, the inflammation markers such as TNF-α and IL-6 were downregulated. These effects might be attributed to the inhibitory effect of CSR on the priming step of the NLRP3 inflammasome activation by interrupting NF-κB signalling and inhibition of HSP-90 (at the protein and mRNA levels) along with inhibitory effect of CP on the expression of the NLRP3. These latter effects resulted in decreased tissue expression and activity of the caspase-1 and repressing the subsequent release of the active forms of IL-1ß and IL-18, hence, the pyroptosis process is restrained. Additionally, the CCCT resulted in inducing autophagy by AMPK/mTOR-dependent mechanisms leading to the accumulation of BECN1 protein and a significant decrease in the levels of p62 SQSTM1. The inhibitory effect on HSP-90 in conjunction with induction of autophagy suggest increased autophagic degradation of NLRP3. This novel approach provides a basis for the clinical application of this combination in IBD treatment and might also be promising for the pharmacological intervention of other NLRP3 inflammasome-dependent inflammatory conditions.

Empty waiting rooms: the New Zealand general practice experience with telehealth during the COVID-19 pandemic.

AIM: The primary care response to the coronavirus disease 2019 (COVID-19) pandemic in early 2020 required significant changes to the delivery of healthcare by general practices. This study explores the experiences of New Zealand general practice teams in their use of telehealth during the early stages of the COVID-19 pandemic in New Zealand. METHOD: We qualitatively analysed a subtheme on telehealth of the General Practice Pandemic Experience New Zealand (GPPENZ) study, where general practice team members across the country were invited to participate in five surveys between 8 May 2020 to 27 August 2020. RESULTS: 164 participants enrolled in the study during survey one, with 78 (48%) completing all surveys. Five telehealth themes were identified: benefits, limitations, paying for consults, changes over time and plans for future use. Benefits included rapid triage, convenience and efficiency, and limitations included financial and technical barriers for practices and patients and concerns about clinical risk. Respondents rapidly returned to in-person consultations and wanted clarification of conditions suited to telehealth, better infrastructure and funding. CONCLUSION: To equitably sustain telehealth use, the following are required: adequate funding, training, processes communicated to patients, improved patient access to technology and technological literacy, virtual physical examination methods and integration with existing primary health care services.