Oral isotretinoin is the most effective anti‐acne drug with the strongest sebum‐suppressive effect caused by sebocyte apoptosis. It has been hypothesized that upregulation of nuclear FoxO transcription factors and p53 mediate isotretinoin‐induced sebocyte apoptosis in vivo. It is the aim of our study to analyse the distribution of the pro‐apoptotic transcription factors FoxO1 and FoxO3 in the nuclear and cytoplasmic compartments of human sebocytes in vivo before and during isotretinoin treatment of acne patients. Immunohistochemical analysis of skin biopsies with antibodies distinguishing phosphorylated and non‐phosphorylated human FoxO1 and FoxO3 proteins was performed before isotretinoin treatment, six weeks after initiation of isotretinoin therapy, and in acne‐free control patients not treated with isotretinoin. Our in vivo study demonstrates a significant increase in the nucleo‐cytoplasmic ratio of non‐phosphorylated FoxO1 and FoxO3 during isotretinoin treatment of acne patients. Translational and presented experimental evidence indicates that upregulation of nuclear FoxO1 and FoxO3 proteins is involved in isotretinoin‐induced pro‐apoptotic signalling in sebocytes confirming the scientific hypothesis of isotretinoin‐mediated upregulation of FoxO expression.
Purpose
Apatinib (Apa) is a novel anti-vascular endothelial growth factor with the potential to treat diabetic retinopathy (DR); a serious condition leading to visual impairment and blindness. DR treatment relies on invasive techniques associated with various complications. Investigating topical routes for Apa delivery to the posterior eye segment is thus promising but also challenging due to ocular barriers. Hence, the study objective was to develop Apa-loaded bovine serum albumin nanoparticles (Apa-BSA-NPs) coated with hyaluronic acid (HA); a natural polymer possessing unique mucoadhesive and viscoelastic features with the capacity to actively target CD44 positive retinal cells, for topical administration in DR.
Methods
Apa-BSA-NPs were prepared by desolvation using glutaraldehyde for cross-linking. HA-coated BSA-NPs were also prepared and HA: NPs ratio optimized. Nanoparticles were characterized for colloidal properties, entrapment efficiency (EE%), in vitro drug release and mucoadhesive potential. In vitro cytotoxicity on rabbit corneal epithelial cells (RCE) was assessed using MTT assay, while efficacy was evaluated in vivo in a diabetic rat model by histopathological examination of the retina by light and transmission electron microscopy. Retinal accumulation of fluorescently labeled BSA-NP and HA-BSA-NP was assessed using confocal microscope scanning.
Results
Apa-HA-BSA-NPs prepared under optimal conditions showed size, PdI and zeta potential: 222.2±3.56 nm, 0.221±0.02 and −37.3±1.8 mV, respectively. High EE% (69±1%), biphasic sustained release profile with an initial burst effect and mucoadhesion was attained. No evidence of cytotoxicity was observed on RCE cells. In vivo histopathological studies on DR rat model revealed alleviated retinal micro- and ultrastructural changes in the topical HA-Apa-BSA-NP treated eyes with normal basement membrane and retinal thickness comparable to normal control and intravitreally injected nanoparticles. Improved retinal accumulation for HA-BSA-NP was also observed by confocal microscopy.
Conclusion
Findings present HA-Apa-BSA-NPs as a platform for enhanced topical therapy of DR overcoming the devastating ocular complications of the intravitreal route.
Background: Several molecular mechanisms contribute to the initiation and progression of nonalcoholic fatty liver disease (NAFLD); however, the exact mechanism is not completely understood. Cyclic adenosine monophosphate (cAMP) is one of the most promising pathways that regulates various cellular functions including lipid and carbohydrate metabolism. cAMP induces gene transcription through phosphorylation of the transcription factor, cAMP response element-binding protein (CREB). The action of cAMP is tightly regulated by its level and repression. Among the repressors, Inducible cAMP Early Repressor (ICER) is the only inducible CRE-binding protein. The present study aimed to evaluate the role of hepatic CREB level in the development of experimental NAFLD model to clarify the pathogenesis of the disease. NAFLD 35 male Wistar rats fed a high fat diet for a period of 14 weeks were studied compared with 35 control rats fed a standard diet. Five fasting rats were sacrificed each 2 weeks intervals for a period of 14 weeks. Results: NAFLD group revealed a remarkable duration-dependent elevation in cAMP and CREB levels in the liver tissue compared to control group (P value < 0.004, P value < 0.006, respectively). In contrast, ICER gene expression, as a dominant-negative regulator of CREB, was downregulated in the liver of NAFLD group compared to control group. We also demonstrated that CREB levels were positively correlated with liver function tests, and glucose homeostasis parameters. Conclusions: Our results indicate that cAMP/CREB pathway provides an early signal in the progression to NAFLD representing a noninvasive biomarker that can early detect NAFLD and a promising therapeutic target for the treatment of the disease as well.
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