Dickkopf-1 exerts protective effects by inhibiting PANoptosis and retinal neovascularization in diabetic retinopathy.

Diabetic retinopathy (DR) is a key reason for legal blindness worldwide. Currently, it is urgently necessary to determine the etiology and pathological molecular mechanism of DR to search for resultful therapies. Dickkopf-1 (DKK1) is inhibitive for canonical Wnt signaling via negative feedback, and has been reported as a biomarker for DR. However, the related mechanisms are still unclear. In this work, our data showed that DKK1 was decreased in the vitreous tissues at an early stage of diabetes triggered by streptozotocin (STZ) injection in rats. We subsequently found that DKK1 intravitreal injection significantly ameliorated the physiological function of retina in STZ-challenged rats, accompanied by improved retinal structure. Surprisingly, our results indicated that DKK1 injection remarkably suppressed PANoptosis in retinal tissues of STZ-challenged rats with DR, as proved by ameliorated pyroptosis, apoptosis and necroptosis, which were mainly through the blockage of cleaved Gasdermin-D (GSDMD), Caspase-3 and receptor-interacting protein kinase-3 (RIPK3). Additionally, Wnt signaling including the expression of Wnt, ß-catenin and LDL receptor-related protein 5/6 (LRP5/6) was also highly prohibited in retina of DKK1-injected rats with DR. Furthermore, retinal neovascularization and acellular vessel in DR rats were also considerably abolished after DKK1 injection, accompanied by reduced expression levels of retinal vascular endothelial growth factor (VEGF), matrix metalloproteinase-2 (MMP2) and matrix metalloproteinase-9 (MMP9). More in vitro experiments showed that DKK1 treatment markedly repressed the proliferative and migratory ability of endothelial cells via inhibiting angiogenesis-related molecules. Together, all our results broaden the knowledge of the correlation between DKK1 and DR, and then provide a novel therapeutic strategy for the suppression of management of DR.

The Association of Axial Length with Macular Microvascular Changes in Chinese Diabetic Retinopathy Patients.

Objective: To use optical coherence tomography angiography (OCTA) to compare macular blood flow density, subfoveal choroidal thickness (SFCT) and outer retina thickness (ORT) in non-proliferative diabetic retinopathy (NPDR) patients with different axial length (AL). Methods: Total 42 patients with NPDR with different eye axis were divided into three groups: group A: 22 mm≤AL<24 mm; group B: 24 mm≤AL<26 mm; group C: AL≥26 mm. Superficial capillary plexus (SCP) in the macular area, vascular length density (VLD) and vascular perfusion density (VPD) in the foveal region, the parafoveal region, the perifoveal region and whole macular region were analyzed. The correlations among axial length, macular microvascular density, SFCT and outer retinal thickness (ORT) were analyzed. Results: Compared with group A and B, VLD and VPD in group C were significantly lower except the foveal region, and VLD and VPD were negatively correlated with AL. The difference in SFCT among group A, B and C was significant, and SFCT was negatively correlated with AL. Compared with group A, parafoveal ORT in group C was significantly lower than that in group A, and parafoveal ORT was negatively correlated with AL. Conclusion: In NPDR patients with different AL, macular microvascular density, SFCT, and parafoveal ORT decreased with the increase of AL.

Effect of wrist-ankle acupuncture therapy combined with auricular acupuncture on cancer pain: A four-parallel arm randomized controlled trial.

BACKGROUND: Cancer pain affects the quality of life of cancer patients; therefore, various methods exist for alleviating the adverse effects caused by cancer pain. Nonpharmacological intervention is regarded as an important means of auxiliary therapy for drug treatment, with acupuncture receiving the most attention; However, there are numerous types of acupuncture therapies, including acupuncture, wrist-ankle acupuncture (WAA) and auricular acupuncture (AA). Previous studies have demonstrated that all types of acupuncture therapy can alleviate cancer pain. However, the effects and pathways of different acupuncture treatments are not similar, and it is unknown whether single therapy or combination therapy has better analgesic effects. This study aimed to examine the effect of WAA therapy combined with AA on cancer pain. DESIGN: A randomized controlled trial. METHOD: A total of 160 patients were selected and randomly divided into groups A, B, C and D, with 40 patients in each group. Group A received conventional analgesia alone, with opioids administered based on the World Health Organization (WHO) 3-tiered "cancer pain ladder". Group B received WAA, in addition to the treatment received by group A. Group C received AA, in addition to the treatment received by group A. Group D received WAA combined with AA, in addition to the treatment received by group A. Analgesic effects and analgesic drug use before and 3, 5 and 7 days after treatment were observed in each group. RESULT: A total of 159 patients were included in the analysis. The verbal rating scale (VRS) and numeric rating scale (NRS) scores for patients who received mono-acupuncture therapy and combination therapy for 1 week were significantly different from those of the control group. Combination therapy had a stronger effect on the VRS score and a faster onset time, based on the NRS score, and the patients who received combination therapy had reduced analgesic drug use. CONCLUSION: WAA combined with AA can more quickly reduce pain symptoms with more lasting analgesic effects and can effectively reduce analgesic drug use.

MEF2C/miR-133a-3p.1 circuit-stabilized AQP1 expression maintains endothelial water homeostasis.

Aquaporin 1 (AQP1) plays an important role in endothelial functions and is regulated by MEF2C. However, how AQP1 level is stabilized to maintain endothelial water homeostasis is still not clear. Here, we show that AQP1 expression is significantly upregulated by MEF2C transcriptionally and inhibited by miR-133a-3p.1 post-transcriptionally. Meanwhile, MEF2C activates the expression of miR-133a1. Simultaneous overexpression of MEF2C and miR-133a-3p.1 suppresses the aptitude of changes in AQP1 expression caused by either MEF2C or miR-133a-3p.1. Accordingly, the changes in migration and tube formation of human umbilical vein endothelial cells (HUVECs) caused by MEF2C or miR133a-3p.1 are blunted by coexpression of both of them. These data demonstrate that the homeostasis and physiological function of AQP1 in endothelial health are maintained by the MEF2C and miR-133a-3p.1 regulatory circuit.