Hepatic stellate cells (HSCs) are the primary fibrogenic cells in the liver, and their activation plays a crucial role in the development and progression of hepatic fibrosis. Here, we report that retinoid X receptor-alpha (RXRα), a unique member of the nuclear receptor superfamily, is a key modulator of HSC activation and liver fibrosis. RXRα exerts its effects by modulating calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ)-mediated activation of AMP-activated protein kinase-alpha (AMPKα). In addition, we demonstrate that K-80003, which binds RXRα by a unique mechanism, effectively suppresses HSC activation, proliferation, and migration, thereby inhibiting liver fibrosis in the CCl₄ and amylin liver NASH (AMLN) diet animal models. The effect is mediated by AMPKα activation, promoting mitophagy in HSCs. Mechanistically, K-80003 activates AMPKα by inducing RXRα to form condensates with CaMKKβ and AMPKα via a two-phase process. The formation of RXRα condensates is driven by its N-terminal intrinsic disorder region and requires phosphorylation by CaMKKβ. Our results reveal a crucial role of RXRα in liver fibrosis regulation through modulating mitochondrial activities in HSCs. Furthermore, they suggest that K-80003 and related RXRα modulators hold promise as therapeutic agents for fibrosis-related diseases.

Objective:To analyze the efficacy and safety of daratumumab plus dexamethasone in the treatment of renal injury patients with light chain amyloidosis, and to provide clinical reference.Methods:It was a single center retrospective observational study. The clinical data before and after daratumumab treatment of renal injury patients with light chain amyloidosis treated with daratumumab plus dexamethasone from December 2021 to August 2022 were retrospectively collected. The hematologic response, kidney response, prognosis, and adverse events were analyzed. The treatment regimen was 16 mg/kg intravenous infusion of daratumumab on day 1 + 20 mg intravenous push of dexamethasone on day 1-2, once every 2 weeks. The follow-up was up to February 28, 2023.Results:The study included 18 patients, with age of (58.4±7.7) years old, and a male to female ratio of 11∶7. Eleven patients were newly diagnosed and 7 patients were retreated. There were 7, 5, 5 and 1 patients, respectively at the stage Ⅰ, Ⅱ, Ⅲ and Ⅳ of light chain amyloidosis according to 2012 Mayo stage criteria. The median course of disease before onset was 2.5 (1.0, 8.0) months and the follow-up time was (8.7±2.8) months. The patients received (10±3) times of treatment. The overall hematologic response rates were 9/13, 11/13 and 13/13 at 1 month, 3 months, and 6 months respectively after treatment, meanwhile 8/13, 10/13 and 12/13 achieved at least very good partial response at 1 month, 3 months, and 6 months respectively (the other 5 patients did not undergo detailed evaluation due to baseline difference of serum free κ and λ light chain <20 mg/L). The median duration of hematologic response was 16 (13, 40) days. At 3 months, 6 months and the end of follow-up, 10, 13 and 13 of 18 patients respectively achieved renal response, and the median duration of response was 66 (26, 182) days. During follow-up, the median difference of serum free κ and λ light chain decreased by 93% (72%, 97%). Until the last follow-up, one patient died of organ hemorrhage. Other infusion reactions, leukopenia, neutropenia and infection all improved after symptomatic treatments.Conclusion:Daratumumab plus dexamethasone treatment is effective for light chain amyloidosis nephropathy in inducing hematologic remission and kidney remission, with good safety.

Objective:To retrospectively evaluate the clinical effect of mitral valve repair for rheumatic mitral stenosis.Methods:We retropectively analyze the clinical datd of 50 rheumatic mitral disease patients undergoing mitral valve repair from January 2016 to March 2019, the clinical outcome was compaired with those of patients undergoing mitral valve replacement. The operation time, cardiopulmonary bypass time, blood loss, ICU time, hospital stay, and postoperative cardiac function were analyzed, and followed up for 2 years to assess mitral regurgitation, cardiac function, and complication rates.Results:The time of cardiopulmonary bypass and ascending aorta occlusion in the valve repair group were longer than those in the valve replacement group ( P<0.05), and the postoperative ventilator assistance time, ICU stay time, and hospital stay were shorter than those in the valve replacement group ( P<0.05). After 2 years of follow-up, no patients died in the two groups. The rehospitalization rate in the valve repair group was lower than that in the replacement group ( P<0.05), and there was no significant difference in the reoperation rate between the groups ( P>0.05); There was 1 case (2%) of moderate mitral valve regurgitation in the mitral valve repair group, no moderate or severe mitral valve stenosis, no paravalvular leakage in the mitral valve replacement group, and no significant difference between the two groups ( P>0.05). The left ventricular end-diastolic diameter and left ventricular ejection fraction in the mitral valve repair group were significantly better than those in the mitral valve replacement group ( P<0.05). Conclusion:Mitral valve repair is effective in treating rheumatic mitral stenosis. It is beneficial to protect heart function, reduce postoperative anticoagulation complications, and does not increase the rate of reoperation. It is a safe, effective and feasible treatment.

Objective: To observe the clinical efficacy and safety of Q-modulated laser combined with compound repair of oligosaccharides in the treatment of melasma. Methods: From January 2017 to December 2018, 90 patients with chloasma were divided into Q-switched laser treatment group (control group) and Q-switched laser combined repair oligopeptide treatment group (experimental group) according to random number table method. In the experimental group, the interval between microneedle introduction of oligopeptide and Q-switched laser therapy was 2 weeks, and the treatment was carried out alternately. Each treatment lasted for 4 months, with a total of 8 treatments completed. The control group was treated with Q-switched laser only. Each patient was treated four times, once a month for four months. All patients were evaluated before treatment and 1 month after treatment. Evaluation indicators: (1) Macular severity index (MASI), calculating its decline rate, analyzing the improvement of chloasma; (2) Applying Visia skin analyzer to evaluate the characteristic count of brown spots, calculating its decline rate; (3) Doctors Subjectively Evaluate Patient Pigmentation Legacy; (4) Patient self-evaluation. Measuring data were tested by t-test and counting data by Chi square test. Results: All subjects completed the treatment. Most of the chloasma in the two groups improved significantly after treatment. In the control group, the MASI decreased by 75.61%, 1 case of inefficiency, 13 cases of improvement, 28 cases of marked improvement and 3 cases of recovery. In the experimental group, the MASI decreased by 85.25%, 0 cases of inefficiency, 6 cases of improvement, 27 cases of significant improvement and 12 cases of recovery. Comparing the improvement of the two groups, the experimental group was better than the control group, the difference was statistically significant (χ²=9.00, P=0.03). After treatment, the number of chloasma brown spots in the two groups improved significantly. In the control group, the decrease rate of chloasma brown spots was (1.59 ± 1.33)% and in the trial experiment was (3.45± 1.54)%. The experimental group was better than the control group, and the difference between the two groups was statistically significant (P=0.01). The overall evaluation of therapeutic effect by doctors showed that 95.56% (43/45) of the patients in the experimental group had clearance rate greater than 75%, which was better than 86.67% (39/45) of the control group. There was a significant difference between the two groups (P<0.05). The self-evaluation result showed that the improvement rate of the experimental group was 66.67% (30/45) which was more than 75%, which was better than 37.78% (17/45) of the control group. The difference was statistically significant (P=0.04). Conclusions Q-switched laser combined with compound repair oligopeptide can effectively treat chloasma with less adverse reactions.