Replenishing decoy extracellular vesicles inhibits phenotype remodeling of tissue-resident cells in inflammation-driven arthritis.

The interleukin 6 (IL6) signaling pathway plays pleiotropic roles in regulating the inflammatory milieu that contributes to arthritis development. Here, we show that activation of IL6 trans-signaling induces phenotypic transitions in tissue-resident cells toward an inflammatory state. The establishment of arthritis increases the serum number of extracellular vesicles (EVs), while these EVs express more IL6 signal transducer (IL6ST, also known as gp130) on their surface. Transferring these EVs can block IL6 trans-signaling in vitro by acting as decoys that trap hyper IL6 and prevent inflammatory amplification in recipient arthritic mice. By genetically fusing EV-sorting domains with extracellular domains of receptors, we engineered EVs that harbor a higher quantity of signaling-incompetent decoy receptors. These exogenous decoy EVs exhibit significant potential in eliciting efficient anti-inflammatory effects in vivo. Our findings suggest an inherent resistance of decoy EVs against inflammation, highlighting the therapeutic potential of efficient decoy EVs in treating inflammatory diseases.

Acupuncture for treatment of knee osteoarthritis: A clinical practice guideline.

CLINICAL QUESTION: Is acupuncture effective in treating knee osteoarthritis (KOA)? CURRENT PRACTICE: Although increasingly used in the clinical setting, acupuncture is not mentioned or weakly recommended in guidelines for the treatment of KOA. RECOMMENDATIONS: We suggest acupuncture rather than no treatment in adult KOA (weak recommendation, moderate certainty evidence), and acupuncture combined with nonsteroidal anti-inflammatory drugs (NSAIDs) rather than acupuncture alone when KOA symptoms are severe (weak recommendation, moderate certainty evidence), with duration of acupuncture for 4-8 weeks depending on KOA severity and treatment response (weak recommendation, moderate certainty evidence), and discussing with patients in shared decision-making. HOW THIS GUIDELINE WAS CREATED: This rapid recommendation was developed following the Making GRADE the Irresistible Choice (MAGIC) methodological framework. First, the clinical specialist identified the topic of recommendation and demand for evidence. Then the independent evidence synthesis group performed a systematic review to summarize available evidence and evaluate the evidence using the GRADE approach. Finally, the clinical specialist group produced recommendations for practice through a consensus procedure. THE EVIDENCE: The linked systematic review and meta-analysis included 9422 KOA patients, 61.1% of whom were women. The median mean age was 61.8 years. Compared with no treatment, acupuncture had beneficial effect on KOA in improving the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score (moderate certainty evidence), and WOMAC pain (very low certainty evidence), WOMAC stiffness (low certainty evidence), and WOMAC function (low certainty evidence) subscale scores. Compared with usual care, acupuncture improved WOMAC stiffness subscale score (moderate certainty evidence). Subgroup analyses showed different effects in the improvement of WOMAC total scores by different durations of acupuncture and whether acupuncture combined with NSAIDs, but no difference between manual acupuncture and electroacupuncture was found. UNDERSTANDING THE RECOMMENDATIONS: Compared with no treatment, acupuncture is suggested to reduce pain, stiffness, and disfunction in KOA patients, ultimately improving the patient's health status. Acupuncture can be used as an alternative therapy when usual care is ineffective or there are adverse reactions so that patients can no longer continue the treatment. Manual acupuncture or electroacupuncture is suggested for 4-8 weeks to improve the health status of KOA. The patient's values and preferences should be considered when selecting acupuncture for KOA treatment.

Vitamin C Deficiency Causes Cell Type-Specific Epigenetic Reprogramming and Acute Tubular Necrosis in a Mouse Model.

BACKGROUND: Vitamin C deficiency is found in patients with variable kidney diseases. However, the role of vitamin C as an epigenetic regulator in renal homeostasis and pathogenesis remains largely unknown. METHODS: We showed that vitamin C deficiency leads to acute tubular necrosis (ATN) using a vitamin C-deficient mouse model (Gulo knock-out). DNA/RNA epigenetic modifications and injured S3 proximal tubule cells were identified in the vitamin C-deficient kidneys using whole-genome bisulfite sequencing, methylated RNA immunoprecipitation sequencing, and single-cell RNA sequencing. RESULTS: Integrated evidence suggested that epigenetic modifications affected the proximal tubule cells and fenestrated endothelial cells, leading to tubule injury and hypoxia through transcriptional regulation. Strikingly, loss of DNA hydroxymethylation and DNA hypermethylation in vitamin C-deficient kidneys preceded the histologic sign of tubule necrosis, indicating the causality of vitamin C-induced epigenetic modification in ATN. Consistently, prophylactic supplementation of an oxidation-resistant vitamin C derivative, ascorbyl phosphate magnesium, promoted DNA demethylation and prevented the progression of cisplatin-induced ATN. CONCLUSIONS: Vitamin C played a critical role in renal homeostasis and pathogenesis in a mouse model, suggesting vitamin supplementation may be an approach to lower the risk of kidney injury.