Thioacetamide (TAA) within the liver generates hepatotoxic metabolites that can be induce hepatic fibrosis, similar to the clinical pathological features of chronic human liver disease. The potential protective effect of Albiflorin (ALB), a monoterpenoid glycoside found in Paeonia lactiflora Pall, against hepatic fibrosis was investigated. The mouse hepatic fibrosis model was induced with an intraperitoneal injection of TAA. Hepatic stellate cells (HSCs) were subjected to treatment with transforming growth factor-beta (TGF-β), while lipopolysaccharide/adenosine triphosphate (LPS/ATP) was added to stimulate mouse peritoneal macrophages (MPMs), leading to the acquisition of conditioned medium. For TAA-treated mice, ALB reduced ALT, AST, HYP levels in serum or liver. The administration of ALB reduced histopathological abnormalities, and significantly regulated the expressions of nuclear receptor-related 1 protein (NURR1) and the P2X purinoceptor 7 receptor (P2×7r) in liver. ALB could suppress HSCs epithelial-mesenchymal transition (EMT), extracellular matrix (ECM) deposition, and pro-inflammatory factor level. ALB also remarkably up-regulated NURR1, inhibited P2×7r signaling pathway, and worked as working as C-DIM12, a NURR1 agonist. Moreover, deficiency of NURR1 in activated HSCs and Kupffer cells weakened the regulatory effect of ALB on P2×7r inhibition. NURR1-mediated inhibition of inflammatory contributed to the regulation of ALB ameliorates TAA-induced hepatic fibrosis, especially based on involving in the crosstalk of HSCs-macrophage. Therefore, ALB plays a significant part in the mitigation of TAA-induced hepatotoxicity this highlights the potential of ALB as a protective intervention for hepatic fibrosis.

Objectives: This study aimed to identify and develop a novel, safe, and effective transdermal penetration enhancer derived from the leaves of Perilla frutescens (L.) Britt, and to explore the underlying mechanisms of its penetration enhancement effects. Methods: To evaluate the safety profile of the penetration enhancer, both skin irritation tests and histopathological analyses were conducted. The transdermal enhancement capabilities of the penetration enhancer were assessed in vitro using five model drugs. Furthermore, to gain insights into the penetration enhancement mechanism of this novel penetration enhancer, a range of analytical methods were used, including a spectroscopic technique, differential scanning calorimetry, micro-optical techniques, and molecular docking simulations. Results: Perilla essential oil contained 93.70% perilla ketone (PEK), which exhibited a safety profile superior to that of azone. PEK significantly increased the cumulative skin permeation of all the model drugs (p < 0.05). PEK exhibited the most obvious impact on puerarin penetration, with quantitative enhancement ratios of 2.96 ± 0.07 and 3.39 ± 0.21 at concentrations of 3% and 5% (w/v), respectively. A strong correlation between the enhancement effect of PEK and the physicochemical properties of the drugs was observed. Mechanistic studies revealed that PEK facilitates drug distribution from the solution phase to the stratum corneum (SC). Conclusions: PEK, seldom discussed in former studies, was observed to show extensive penetration enhancement effects by inducing conformational changes in SC lipids and disrupting the tightly ordered bilayer arrangement of lipids. These findings highlight the potential of PEK as a promising and safe natural transdermal penetration enhancer.

This study aims to shed light on the relationship between drug content and adhesive properties in drug-in-adhesive transdermal patch, and to elucidate molecular mechanisms from the perspective of polymer chain mobility. Lidocaine was selected as model drug. Two acrylate pressure sensitive adhesives (PSAs) with different polymer chain mobility were synthesized. Tack adhesion, shear adhesion and peel adhesion of PSAs with 0, 5%, 10%, 15% and 20% w/w lidocaine contents were tested. Polymer chain mobility was determined by rheology and modulated differential scanning calorimetry experiments. Drug-PSA interaction was analyzed by FT-IR. The effect of drug content on free volume of PSA were determined by positron annihilation lifetime spectroscopy and molecular dynamics simulation. It was found that the polymer chain mobility of PSA was increased with increasing drug content. Due to the variation of polymer chain mobility, tack adhesion increased, and shear adhesion decreased. It was proved that interactions between polymer chains were destroyed by drug-PSA interactions, free volume between polymer chains was expanded, resulting in the increase of polymer chain mobility. We can conclude that the effect of drug content on polymer chain mobility should be considered, when designing a transdermal drug delivery system with controlled and satisfactory adhesion.

Transdermal drug delivery systems (TDDSs) have gained significant attention in pharmaceutical research due to their ability to bypass hepatic first-pass metabolism, maintain consistent plasma drug levels, and improve patient compliance. Despite these advantages, the highly organized “brick-and-mortar” architecture of the stratum corneum (SC) poses a substantial barrier, particularly to the permeation of hydrophilic drugs and macromolecules. Among the strategies developed to address this challenge, penetration enhancers (PEs) have emerged as a key approach, offering reversible modulation of the skin barrier to improve drug transport. This review provides an in-depth analysis of the diverse mechanisms by which PEs facilitate transdermal delivery, including disruption of lipid bilayers, alteration of keratin structure, enhancement of drug partitioning into the SC, and lipid extraction. The crucial contribution of advanced characterization techniques, such as Fourier-transform infrared spectroscopy, Raman spectroscopy, and nuclear magnetic resonance, in revealing atomic-scale interactions between PEs and SC components is discussed.

Procyanidin B1 (PB1) is a natural polyphenol abundant in whole-grain highland barley as well as in many fruits, vegetables, and medicinal plants. The current study investigated the hepatoprotective effect and potential mechanism of PB1 against hepatic fibrosis. C57BL/6 mice with hepatic fibrosis were induced with thioacetamide (TAA), followed by the administration of PB1 or a positive control, silymarin, or followed by gene silencing of the thyroid hormone-responsive protein (THRSP). Hepatic stellate cells (HSCs) were stimulated with transforming growth factor β (TGF-β) or an isolated mouse peritoneal macrophage (MPM)-primed conditioned medium and cultured with PB1, silymarin or the THRSP agonist. MPMs were cultured in the presence of LPS/ATP and/or PB1. It was found that PB1 decreased the release of inflammatory factors, such as caspase-1 and IL-1β. Moreover, PB1 could activate THRSP and decrease P2X7r-modulated NLRP3 inflammasome activation in the TAA-induced mice. Additionally, PB1 inhibited the expressions of α-SMA, collagen I, the TIMP-1/MMP13 ratio, inflammatory factors, P2X7r, and NLRP3 and increased THRSP expression in activated HSCs and macrophages. THRSP deficiency attenuated the regulatory effect of PB1 on the reverse inflammation of activated HSCs, promoting hepatic fibrosis in vivo and in vitro. PB1 reversed the activation of HSCs by increasing the THRSP-mediated P2X7r/NLRP3 axis, similar in function to THRSP overexpression. PB1 could reverse the activation of HSCs and mitigate hepatic inflammation and fibrogenesis in TAA-induced hepatic fibrosis. Targeting THRSP-mediated P2X7r/NLRP3 is crucial for PB1's action against hepatic fibrosis, underscoring a promising approach and the utility of PB1 for the treatment of hepatic fibrosis.