CCDC92 promotes podocyte injury by regulating PA28α/ABCA1/cholesterol efflux axis in type 2 diabetic mice.

Podocyte lipotoxicity mediated by impaired cellular cholesterol efflux plays a crucial role in the development of diabetic kidney disease (DKD), and the identification of potential therapeutic targets that regulate podocyte cholesterol homeostasis has clinical significance. Coiled-coil domain containing 92 (CCDC92) is a novel molecule related to metabolic disorders and insulin resistance. However, whether the expression level of CCDC92 is changed in kidney parenchymal cells and the role of CCDC92 in podocytes remain unclear. In this study, we found that Ccdc92 was significantly induced in glomeruli from type 2 diabetic mice, especially in podocytes. Importantly, upregulation of Ccdc92 in glomeruli was positively correlated with an increased urine albumin-to-creatinine ratio (UACR) and podocyte loss. Functionally, podocyte-specific deletion of Ccdc92 attenuated proteinuria, glomerular expansion and podocyte injury in mice with DKD. We further demonstrated that Ccdc92 contributed to lipid accumulation by inhibiting cholesterol efflux, finally promoting podocyte injury. Mechanistically, Ccdc92 promoted the degradation of ABCA1 by regulating PA28α-mediated proteasome activity and then reduced cholesterol efflux. Thus, our studies indicate that Ccdc92 contributes to podocyte injury by regulating the PA28α/ABCA1/cholesterol efflux axis in DKD.

JAML promotes acute kidney injury mainly through a macrophage-dependent mechanism.

Although macrophages are undoubtedly attractive therapeutic targets for acute kidney injury (AKI) because of their critical roles in renal inflammation and repair, the underlying mechanisms of macrophage phenotype switching and efferocytosis in the regulation of inflammatory responses during AKI are still largely unclear. The present study elucidated the role of junctional adhesion molecule-like protein (JAML) in the pathogenesis of AKI. We found that JAML was significantly upregulated in kidneys from 2 different murine AKI models including renal ischemia/reperfusion injury (IRI) and cisplatin-induced AKI. By generation of bone marrow chimeric mice, macrophage-specific and tubular cell-specific Jaml conditional knockout mice, we demonstrated JAML promoted AKI mainly via a macrophage-dependent mechanism and found that JAML-mediated macrophage phenotype polarization and efferocytosis is one of the critical signal transduction pathways linking inflammatory responses to AKI. Mechanistically, the effects of JAML on the regulation of macrophages were, at least in part, associated with a macrophage-inducible C-type lectin-dependent mechanism. Collectively, our studies explore for the first time to our knowledge new biological functions of JAML in macrophages and conclude that JAML is an important mediator and biomarker of AKI. Pharmacological targeting of JAML-mediated signaling pathways at multiple levels may provide a novel therapeutic strategy for patients with AKI.

[Effect of liposome on permeability and drug retention of sodium fluorescein in rat skin: an experimental study].

OBJECTIVE: To investigate the effect of liposome on the permeability and drug retention of sodium fluorescein(NaFl) in rat skin. METHODS: With an improved Franz diffusion cell and 0.125% NaFl liposome suspension as the model drug, in vitro measurement of percutaneous absorption and skin reservoir capacity for NaF1 was conducted using a fluorescence spectrophotometry at 4 and 12 h respectively after the diffusion experiment had started, and distribution of the fluorescence in rat skin was observed under fluorescence microscope at 4 h penetration experiment. NaFl solution of the same concentration as the model drugs served as the control for this experiment. RESULTS: In comparison with NaFl solution, liposomal NaFl suspension resulted in larger amount of NaFl retention in rat skin but smaller amount in the receiver cell in a four-hour Franz diffusion test, with also higher fluorescence intensity in the skin, especially the skin around the hair follicles. CONCLUSION: Local high drug concentrations can be achieved in the skin by liposomal suspension of water soluble drug for more effective treatment of skin diseases.

Experimental study of podophyllotoxin dipalmitoylphosphatidylcholine liposome for topical skin application.

OBJECTIVE: To observe the drug release of podophyllotoxin liposome and the drug retention in the skin. METHODS: Two liposome suspensions containing respectively podophyllotoxin dipalmitoylphosphatidylcholine (DPPC) and soya bean lecithin were prepared ultrasonically. Podophyllotoxin anhydride and the liposome suspensions were applied onto the skin of young pigs to observe the drug retention in the skin at different time points in the following 2 days, with exclusive liposome or anhydride serving as control. RESULTS: One hour after application of podophyllotoxin anhydride, a peak of the drug concentration in the skin occurred followed by immediate declination, a process not observed after the application of bean lecithin liposome due to gradual drug release that produced drug concentration constantly much higher than that of podophyllotoxin anhydride. A peak concentration was also observed 4 h after application of podophyllotoxin DPPC liposome, which then declined slowly to and stabilized at a higher level than that of bean lecithin liposome of anhydride within 48 h. CONCLUSION: DPPC liposome-embedded podophyllotoxin better targets the drug to the skin after application, and is a suitable preparation for topical skin application.

Clinical analysis of 12 cases of pyoderma gangrenosum.

Twelve cases of pyoderma gangrenosum is reported in light of the clinical data including the patients' gender, age, complications, laboratory examinations, treatment and outcome, in an attempt to explore the pathogenesis, treatment and prognosis of the disease.

[Changes in serum concentration of podophyllotoxin after its topical application with liposome on rat skin].

OBJECTIVE: To investigate the changes of serum concentration of podophyllotoxin after topical application of liposome podophyllotoxin suspension on rat skin. METHODS: SD rats were used in this study, which were divided into test group (n=48) to receive application of liposome podophyllotoxin (0.5 % ) suspension and control group (n=48) treated with 0.5 % podophyllotoxin alcohol solution. Blood samples were obtained from the heart at 1, 2, 4, 6, 8, 10, 12 and 24 h respectively after drug application, and the serum concentration of podophyllotoxin was determined by spectrofluorometry. RESULTS: The area under the curve of plasma drug concentration of the control group was 2.3-fold greater than that of the test group. Eight hours after drug application, the serum concentration of podophyllotoxin reached the peak in the test group, while in the control group, only two hours was needed to reach the peak. The peak serum level of podophyllotoxin in the test group were significantly lower than that of the control group (166.395 +/- 14.634 ng/ml vs 378.603 +/- 26.105 ng/ml, P<0.001). CONCLUSION: The systemic absorption of podophyllotoxin in rats after its topical application in liposome suspension is significantly lower than that after application of 0.5 % podophyllotoxin alcohol solution, therefore the systemic toxicity may be reduced.