Fabrication and characterization of anti-rosacea 3D nanofibrous customized sheet masks as a novel scaffold for repurposed use of spironolactone with pre-clinical studies.

The repurposed oral use of spironolactone (SP) as an anti-rosacea drug faces many challenges that hinder its efficacy and compliance. In this study, a topically applied nanofibers (NFs) scaffold was evaluated as a promising nanocarrier that enhances SP activity and avoids the friction routine that exaggerates rosacea patients' inflamed, sensitive skin. SP-loaded poly-vinylpyrrolidone (40% PVP) nanofibers (SP-PVP NFs) were electrospun. Scanning electron microscopy showed that SP-PVP NFs have a smooth homogenous surface with a diameter of about 426.60 nm. Wettability, solid state, and mechanical properties of NFs were evaluated. Encapsulation efficiency and drug loading were 96.34% ± 1.20 and 11.89% ± 0.15, respectively. The in vitro release study showed a higher amount of SP released over pure SP with a controlled release pattern. Ex vivo results showed that the permeated amount of SP from SP-PVP NFs sheets was 4.1 times greater than that of pure SP gel. A higher percentage of SP was retained in different skin layers. Moreover, the in vivo anti-rosacea efficacy of SP-PVP NFs using croton oil challenge showed a significant reduction in erythema score compared to the pure SP. The stability and safety of NFs mats were proved, indicating that SP-PVP NFs are promising carriers of SP.

Elafibranor modulates ileal macrophage polarization to restore intestinal integrity in NASH: Potential crosstalk between ileal IL-10/STAT3 and hepatic TLR4/NF-κB axes.

Experimental and clinical evidence implicate disrupted gut barrier integrity in provoking innate immune responses, specifically macrophages, towards the progression of non-alcoholic steatohepatitis (NASH). Peroxisome proliferator-activated receptors (PPARs), a subset of the nuclear receptor superfamily, act to fine-tune several metabolic and inflammatory processes implicated in NASH. As such, the current study was carried out to decipher the potential role of dual PPAR α/δ activation using elafibranor (ELA) on ileal macrophage polarization (MP) and its likely impact on the liver in a NASH setting. To achieve this aim, an in vitro NASH model using fat-laden HepG2 cells was first used to validate the impact of ELA on hepatic fat accumulation. Afterwards, ELA was used in a combined model of dietary NASH and chronic colitis analogous to the clinical presentation of NASH parallel with intestinal barrier dysfunction. ELA mitigated fat accumulation in vitro as evidenced by Oil Red-O staining and curbed triglyceride levels. Additionally, ELA restored the expression of tight junctional proteins, claudin-1 and occludin, along with decreasing intestinal permeability and inflammation skewing ileal macrophages towards the M2 phenotype, as indicated by boosted arginase-1 (Arg1) and curtailed inducible nitric oxide synthase (iNOS) expression levels. These changes were aligned with a modulation in hepatic toll-like receptor-4 (TLR4)/nuclear factor kappa B (NF-κB) along with ileal interleukin-10 (IL-10)/signal transducer and activator of transcription-3 (STAT3) axes. Overall, the present findings suggest that the dual PPAR α/δ agonist, ELA, may drive MP in the ileum towards the M2 phenotype improving intestinal integrity towards alleviating NASH.

Obeticholic acid orchestrates the crosstalk between ileal autophagy and tight junctions in non-alcoholic steatohepatitis: Role of TLR4/TGF-ß1 axis.

An interplay exists between non-alcoholic steatohepatitis (NASH) and intestinal barrier dysfunction. A plethora of mechanisms are implicated in the regulation of intestinal integrity, among which is autophagy. Farnesoid X receptor (FXR) is a key metabolic regulator in the liver, however, its impact on ileal autophagy and barrier integrity in the context of NASH has not yet been unraveled. Accordingly, the present study aimed at investigating the impact of the FXR agonist, obeticholic acid (OCA), on modulating the aberrant ileal autophagy and barrier dysfunction in NASH, exploring the possible implication of the TLR4/TGF-ß1 axis. High-fat diet (HFD) and dextran sulfate sodium (DSS, MW ∼40 kDa) were used for 13 weeks to induce NASH with distorted intestinal integrity in Swiss albino male mice. Post-treatment with OCA (5 mg/kg/day; p.o; 4 weeks), histopathological evaluation revealed a restoration of normal hepatic and ileal architectures. OCA partially restored intestinal permeability, as evidenced by the FITC-dextran leakage assay, with no change in serum LPS or LBP levels. Meanwhile, ileal expression of the tight junctions; claudin-1, zonulin-1, and occludin, was upregulated. Hepatic and ileal TLR-4 and TGF-ß1 immunoreactivities were also decreased with no change observed in ileal phosphorylated Akt. In addition, ATG5 gene expression and LC3II/I protein ratio were upregulated in the ileum. Overall, the present study suggests a protective role of OCA on intestinal integrity in NASH, possibly through autophagy induction via interfering with the TLR4/TGF-ß1 pathway.

Activation of FXR modulates SOCS3/Jak2/STAT3 signaling axis in a NASH-dependent hepatocellular carcinoma animal model.

Despite the recent substantial progress in the treatment of hepatocellular carcinoma (HCC) from viral etiology, non-alcoholic steatohepatitis (NASH) is on a trajectory to become the fastest growing indication for HCC-related liver transplantation. The Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily with multifaceted roles in several metabolic disorders, particularly NASH. Its role as a tumor suppressor was also highlighted. Herein, we investigated the effect of obeticholic acid (OCA), as an FXR agonist, on NASH-associated HCC (NASH-HCC) animal model induced by diethylnitrosamine and high fat choline-deficient diet, exploring the potential impact on the suppressor of cytokine signaling 3 (SOCS3)/Janus kinase 2 (Jak2)/signal transducer and activator of transcription 3 (STAT3) pathway. Results indicated that OCA treatment upregulated FXR and its key mediator, small heterodimer partner (SHP), with remarkable amelioration in the dysplastic foci observed in the NASH-HCC group. This was paralleled with noticeable downregulation of alpha fetoprotein along with reduction in interferon gamma and transforming growth factor beta-1 hepatic levels besides caspase-3 and p53 upregulation. Moreover, sirtuin-1 (SIRT-1), a key regulator of FXR that controls the regenerative response of the liver, was elevated following OCA treatment. Modulation in the SOCS3/Jak2/STAT3 signaling axis was also reported. In conclusion, OCA attenuated the development and progression of NASH-dependent HCC possibly by interfering with SOCS3/Jak2/STAT3 pathway suggesting the potential use of FXR activators in NASH-related disorders, even at later stages of the disease, to impede its progression to the more deteriorating condition of HCC.

The FXR Agonist, Obeticholic Acid, Suppresses HCC Proliferation & Metastasis: Role of IL-6/STAT3 Signalling Pathway.

The nuclear receptor, farnesoid X receptor (FXR), has been recently considered as a tumor suppressor in HCC. IL-6/Janus kinase 2 (Jak-2)/signal transducer and activator of transcription 3 (STAT3) pathway has been implicated as a key player in many cancer types. This study aimed at investigating the potential effect of the FXR agonist, obeticholic acid (OCA), on HCC and the involvement of IL-6/STAT3 pathway. The potential regulation of STAT3 by its main feedback inhibitor target gene, the suppressor of cytokine signaling 3 (SOCS3), triggered by OCA was also explored. Cytotoxicity studies were performed on HepG2, Huh7, and SNU-449 cell lines using OCA alone and combined with the FXR antagonist guggulsterone (Gugg). OCA cytotoxic effect was significantly hampered in presence of Gugg. OCA also caused cell cycle arrest and inhibited invasion and migration of HCC cells. Decrease in STAT3 phosphorylation and SOCS3 upregulation were also observed. Moreover, Jak-2, IL-1ß, and IL-6 levels were decreased. These results were correlated with an upregulation of FXR and small heterodimer partner (SHP) levels. Effects of OCA on IL-6/STAT3 main key players were reversed in presence of Gugg. Overall, these findings suggest a potential effect of OCA in HCC via interfering with IL-6/STAT3 signalling pathway in vitro.

Enhanced efficacy and reduced side effects of diazepam by kava combination.

The long term use of antiepileptic drugs possesses many unwanted effects; thus, new safe combinations are urgently mandated. Hence, the present study aimed to investigate the anticonvulsant effect of kava alone or in combination with a synthetic anticonvulsant drug, diazepam (DZ). To this end, female Wistar rats were divided into two subsets, each comprising 6 groups as follows: group (i) received 1% Tween 80 p.o. and served as control, while groups (ii) and (iii) received kava at two dose levels (100 and 200 mg/kg, p.o.). The remaining three groups received (iv) DZ alone (10 mg/kg p.o.) or kava in combination with DZ (v) (5 mg/kg, p.o.) or (vi) (10 mg/kg, p.o.). Results of the present study revealed that kava increased the maximal electroshock seizure threshold (MEST) and enhanced the anticonvulsant effect of diazepam following both acute and chronic treatment. Moreover, neither kava nor its combination with DZ impaired motor co-ordination either acutely or chronically. Furthermore, kava ameliorated both the reduction in locomotor activity as well as changes in liver function tests induced by chronic administration of DZ. Moreover, no elevation was shown in the creatinine concentration vs. control group following chronic administration of kava or DZ either alone or in combination with kava. In conclusion, the present study suggests the possibility of combining a low dose DZ with kava to reduce harmful effects and might be recommended for clinical use in patients chronically treated with this synthetic anticonvulsant drug.