JMJD3 ablation in myeloid cells confers renoprotection in mice with DOCA/salt-induced hypertension.

Hypertension-induced renal injury is characterized by robust inflammation and tubulointerstitial fibrosis. Jumonji domain containing-3 (JMJD3) is closely linked with inflammatory response and fibrogenesis. Here we examined the effect of myeloid JMJD3 ablation on kidney inflammation and fibrosis in deoxycorticosterone acetate (DOCA)/salt hypertension. Our results showed that JMJD3 is notably induced in the kidneys with hypertensive injury. DOCA/salt stress causes an elevation in blood pressure that was no difference between myeloid specific JMJD3-deficient mice and wild-type control mice. Compared with wild-type control mice, myeloid JMJD3 ablation ameliorated kidney function and injury of mice in response to DOCA/salt challenge. Myeloid JMJD3 ablation attenuated collagen deposition, extracellular matrix proteins expression, and fibroblasts activation in injured kidneys following DOCA/salt treatment. Furthermore, myeloid JMJD3 ablation blunts inflammatory response in injured kidneys after DOCA/salt stress. Finally, myeloid JMJD3 ablation precluded myeloid myofibroblasts activation and protected against macrophages to myofibroblasts transition in injured kidneys. These beneficial effects were accompanied by reduced expression of interferon regulator factor 4. In summary, JMJD3 ablation in myeloid cells reduces kidney inflammation and fibrosis in DOCA salt-induced hypertension. Inhibition of myeloid JMJD3 may be a novel potential therapeutic target for hypertensive nephropathy. Myeloid JMJD3 deficiency reduces inflammatory response, myeloid fibroblasts activation, macrophages to myofibroblasts transition, and delays kidney fibrosis progression.

Status of N-of-1 Trials in Chronic Pain Management: A Narrative Review.

N-of-1 trials are randomized controlled clinical trials conducted exclusively on a single patient. The ultimate aim of N-of-1 trials is to optimize a strategy in a particular individual. Chronic pain is a common but refractory clinical problem. Its diverse etiologies and broad variations among patients often lead to the requirement of individualizing medicine. Thus, chronic pain represents a classical condition for N-of-1 clinical trials. Studies have indicated that N-of-1 benefits patients with chronic pain, multiple comorbidities, and uncertain variations during therapies; however, this approach it is not yet adopted as the first choice in pain clinics. To dissect the current status of N-of-1 in chronic pain management, as well as the limitations for its implementation, we herein studied all N-of-1 studies related to chronic pain by searching three major databases (PubMed, ClinicalTrial.gov, Cochrane Library) for publications between 1985 and 2020. Of 35 eligibility papers, 19 were selected for analysis. Results confirmed that N-of-1 trials have solved the refractory cases including osteoarthritis, chronic musculoskeletal pain, and neuropathic pain; however, none of the trials dealt with cancer pain. Longer time and more efforts are needed from investigators when carrying out N-of-1 trials, which inevitably result in implementation difficulties. Of note, all recruited trials were conducted in developed countries. As mobile devices have been introduced and protocols improve, renewed interest in the implementation of N-of-1 trials will occur. Collectively, a previously underestimated conflict between "precision medicine" and "poor implementation" has put N-of-1 in a challenging position for chronic pain management.