Astragaloside IV Protects Against Podocyte Injury by Upregulating Mitophagy via the Mfn2/Pink1/Parkin Axis.

BACKGROUND: Podocyte injury is the most important pathological hallmark of kidney diseases. Autophagy is a critical factor that involves podocyte injury. Here, we sought to determine whether Astragaloside IV (AS-IV) was able to improve renal function and reverse podocyte injury through the regulation of autophagy. METHODS: Using the Adriamycin (ADR) mice model, cultured immortalized mouse podocytes were exposed to AS-IV. Western blotting, immunofluorescence, and histochemistry were used to analyze markers of autophagy, mitochondrial dysfunction, podocyte apoptosis, and glomerulopathy in the progression of focal segmental glomerular sclerosis. RESULTS: We observed that AS-IV can inhibit podocyte apoptosis, increased reactive oxygen species (ROS) generation, mitochondrial fragmentation, and dysfunction by inducing the Mfn2/Pink1/Parkin mitophagy pathway both in vivo and in vitro. Overexpression of Mfn2 reduced puromycin aminonucleoside (PAN)-induced podocyte injury, while downregulation of Mfn2 expression limited the renal protective effect of AS-IV by regulating mitophagy. CONCLUSION: AS-IV ameliorates renal function and renal pathological changes in ADR mice and inhibits PAN-induced podocyte injury by directly enhancing Mfn2/Pink1/Parkin-associated autophagy.

Haemoglobin, albumin, lymphocyte, and platelet score as an independent predictor for renal prognosis in IgA nephropathy.

Objective: The haemoglobin, albumin, lymphocyte, and platelet (HALP) score, a convenient and composite laboratory biomarker, can reflect inflammation and systemic nutritional status. This study was performed to investigate the effect of the HALP score on the prognosis of patients with IgA nephropathy (IgAN). Methods: This is a retrospective single centre study that enrolled 895 biopsy-confirmed IgAN patients from June 2019 to June 2022 who were followed for more than 1 year. Kaplan-Meier curves and Cox regression analyses were performed to determine the relationship between HALP and adverse outcomes. The restricted cubic splines was used to identify the possible associations. The optimal cut-off value of HALP for renal poor outcome was identified by the area under the receiver operating characteristic curve (AUC). Results: A total of 895 patients finally participated in the study and were divided into three groups (tertial 1-3) according to the baseline HALP score. More severe clinicopathologic features were observed in the lower HALP group, and Kaplan-Meier analysis showed patients in tertial 1 had a higher risk of kidney failure than the other groups (log-rank=11.02, P= 0.004). Multivariate Cox regression revealed that HALP score was an independent risk factor for renal prognosis in IgAN (adjusted HR: 0.967, 95% CI: 0.945-0.990, P = 0.006). The results of subgroup analysis suggested that HALP was more important in patients under the age of 50, BMI ≤ 23.9 and eGFR ≤ 90 mL/min/1.73 m2. The best cut-off HALP for renal survival was 38.83, sensitivity 72.1%, and specificity 55.9% (AUC: 0.662). Patients were further grouped according to HALP cut-off values and propensity matched. Multivariate Cox regression analysis revealed that HALP remained an independent predictor of IgAN in the matched cohort (HR 0.222, CI: 0.084-0.588, P=0.002). Conclusion: HALP is a novel and potent composite parameter to predict kidney outcome in patients with IgAN.

Exploration of formation and in vitro release mechanism of supramolecular self-assembled Licochalcone A eutectogel for food application.

Licochalcone A (LCA) is extracted from licorice plants and used as a food additive. Citric acid (CA) and alanine (Ala) are food additives with good regulatory functions. This study aims to investigate the formation and in vitro release mechanism of the LCA eutectogel using supramolecular self-assembly technology. The mechanism of self-assembly indicates that the resulting eutectogel has strong intermolecular interactions. The formation mechanism of LCA eutectogel suggests that LCA is dispersed in nano form in the DES solution before self-assembly and dispersed in molecular form in the eutectogel after self-assembly. Mesoscopic MD simulation studies indicate that the interaction energy between LCA Ala-CA(5:5) eutectogel and the solvent interface is relatively low, suggesting it may have a better drug release rate, consistent with the in vitro release results. In conclusion, the study successfully prepares LCA eutectogel and provides theoretical guidance for the development and application of novel eutectogel for food application.

Biomimetic "nano-spears" for CAFs-targeting: splintered three "shields" with enhanced cisplatin anti-TNBC efficiency.

The treatment dilemma of triple-negative breast cancer (TNBC) revolves around drug resistance and metastasis. Cancer-associated fibroblasts (CAFs) contribute to cisplatin (Cis) resistance and further metastasis in TNBC, making TNBC a difficult-to-treat disease. The dense stromal barrier which restricts drug delivery, invasive phenotype of tumor cells, and immunosuppressive tumor microenvironment (TME) induced by CAFs serve as three "shields" for TNBC against Cis therapy. Here, we designed a silybin-loaded biomimetic nanoparticle coated with anisamide-modified red blood cell membrane (ARm@SNP) as a "nanospear" for CAFs-targeting, which could shatter the "shields" and significantly exhibit inhibitory effect on 4T1 cells in combination with Cis both in vitro and in vivo. The ARm@SNP/Cis elicited 4T1 tumor growth arrest and destroyed three "shields" as follows: disintegrating the stromal barrier by inhibiting blood vessels growth and the expression of fibronectin; decreasing 4T1 cell invasion and metastasis by affecting the TGF-ß/Twist/EMT pathway which impeded EMT activation; reversing the immunosuppressive microenvironment by increasing the activity and infiltration of immunocompetent cells. Based on CAFs-targeting, ARm@SNP reversed the resistance of Cis, remodeled the TME and inhibited invasion and metastasis while significantly improving the therapeutic effect of Cis on 4T1 tumor-bearing mice, providing a promising approach for treating intractable TNBC.

Proteostatic reactivation of the developmental transcription factor TBX3 drives BRAF/MAPK-mediated tumorigenesis.

MAPK pathway-driven tumorigenesis, often induced by BRAFV600E, relies on epithelial dedifferentiation. However, how lineage differentiation events are reprogrammed remains unexplored. Here, we demonstrate that proteostatic reactivation of developmental factor, TBX3, accounts for BRAF/MAPK-mediated dedifferentiation and tumorigenesis. During embryonic development, BRAF/MAPK upregulates USP15 to stabilize TBX3, which orchestrates organogenesis by restraining differentiation. The USP15-TBX3 axis is reactivated during tumorigenesis, and Usp15 knockout prohibits BRAFV600E-driven tumor development in a Tbx3-dependent manner. Deleting Tbx3 or Usp15 leads to tumor redifferentiation, which parallels their overdifferentiation tendency during development, exemplified by disrupted thyroid folliculogenesis and elevated differentiation factors such as Tpo, Nis, Tg. The clinical relevance is highlighted in that both USP15 and TBX3 highly correlates with BRAFV600E signature and poor tumor prognosis. Thus, USP15 stabilized TBX3 represents a critical proteostatic mechanism downstream of BRAF/MAPK-directed developmental homeostasis and pathological transformation, supporting that tumorigenesis largely relies on epithelial dedifferentiation achieved via embryonic regulatory program reinitiation.

A Hexanuclear Gadolinium(III)-Based Nanoprobe for Magnetic Resonance Imaging of Tumor Apoptosis.

Magnetic resonance imaging (MRI) is instrumental in the noninvasive evaluation of tumor tissues in patients subjected to chemotherapy, thereby yielding essential diagnostic data crucial for the prognosis of tumors and the formulation of therapeutic strategies. Currently, commercially available MRI contrast agents (CAs) predominantly consist of mononuclear gadolinium(III) complexes. Because there is only one Gd(III) atom per molecule, these CAs often require administration in high doses to achieve the desired contrast quality, which inevitably leads to some adverse events. Herein, we develop a six-nuclei, apoptosis-targeting T1 CA, Gd6-ZnDPA nanoprobe, which consists of a hexanuclear gadolinium nanocluster (Gd6) with an apoptosis-targeting group (ZnDPA). The amplification of Gd(III) by the hexanuclear structure generates its high longitudinal relaxivity (44.67 mM-1 s-1, 1T) and low r1/r2 ratio (0.68, 1T). Based on the Solomon-Bloembergen-Morgan (SBM) theory, this notable improvement is primarily ascribed to a long correlation tumbling time (τR). More importantly, the Gd6-ZnDPA nanoprobe shows excellent tumor apoptosis properties with an enhanced MR signal ratio (∼74%) and a long MRI imaging acquisition time window (∼48 h) in 4T1 tumor-bearing mice. This study introduces an experimental gadolinium-based CA for the potential imaging of tumor apoptosis in the context of MRI.

Copper Ion-Inspired Dual Controllable Drug Release Hydrogels for Wound Management: Driven by Hydrogen Bonds.

Bacterial infections and inflammation progression yield huge trouble for the management of serious skin wounds and burns. However, some hydrogel dressing exhibit poor wound-healing capabilities. Additionally, little information is given on the molecular theory of hydrogel gelation mechanisms and drug release performance from drug-polymer network in the water environment. Herein, cationic guar gum (CG) is first mixed with dipotassium glycyrrhizinate (DG), and then crosslinked Cu2+ to strengthen the mechanical strength followed by encapsulating mussel adhesive protein (MAP) as composite dressings. Intriguingly, CG-Cu2+ 0.5-DG10 possessed proper rheological properties and mechanical strength predominantly driven by strong CG-H2O-Cu2+ and Cu2+-CG hydrogen bonding interaction. Weak DG-CG hydrogen bonding only controlled DG release in the initial 4 h, while strong hydrogen bonding is the main force regulating the sustained release of Cu2+ within 48 h. The incorporation of MAP further loosened the tight crosslinking of CG-Cu2+ 0.5-DG10. The screened CG-Cu2+ 0.5-DG10/MAP possessed excellent self-healing, injectability, antibacterial, anti-inflammatory, cell proliferation-promotion activities with high biocompatibility. Therefore, CG-Cu2+ 0.5-DG10/MAP hydrogel expedited wound closure on S. aureus-infected full-thickness skin wound model and lowered necrosis progression to the unburned interspaces on a rat burn model. The results highlight the promising translational potential of Cu2+-inspired hydrogels for the management of burns and infected wounds.

Chest wall pain after single-fraction thoracic stereotactic ablative Radiotherapy: Dosimetric analysis from the iSABR trial.

BACKGROUND AND PURPOSE: Concerns over chest wall toxicity has led to debates on treating tumors adjacent to the chest wall with single-fraction stereotactic ablative radiotherapy (SABR). We performed a secondary analysis of patients treated on the prospective iSABR trial to determine the incidence and grade of chest wall pain and modeled dose-response to guide radiation planning and estimate risk. MATERIALS AND METHODS: This analysis included 99 tumors in 92 patients that were treated with 25 Gy in one fraction on the iSABR trial which individualized dose by tumor size and location. Toxicity events were prospectively collected and graded based on the CTCAE version 4. Dose-response modeling was performed using a logistic model with maximum likelihood method utilized for parameter fitting. RESULTS: There were 22 grade 1 or higher chest wall pain events, including five grade 2 events and zero grade 3 or higher events. The volume receiving at least 11 Gy (V11Gy) and the minimum dose to the hottest 2 cc (D2cc) were most highly correlated with toxicity. When dichotomized by an estimated incidence of ≥ 20 % toxicity, the D2cc > 17 Gy (36.6 % vs. 3.7 %, p < 0.01) and V11Gy > 28 cc (40.0 % vs. 8.1 %, p < 0.01) constraints were predictive of chest wall pain, including among a subset of patients with tumors abutting or adjacent to the chest wall. CONCLUSION: For small, peripheral tumors, single-fraction SABR is associated with modest rates of low-grade chest wall pain. Proximity to the chest wall may not contraindicate single fractionation when using highly conformal, image-guided techniques with sharp dose gradients.

Strain engineering of Bacillus coagulans with high osmotic pressure tolerance for effective L-lactic acid production from sweet sorghum juice under unsterile conditions.

Open unsterile fermentation of the low-cost non-food crop, sweet sorghum, is an economically feasible lactic acid biosynthesis process. However, hyperosmotic stress inhibits microbial metabolism and lactic acid biosynthesis, and engineering strains with high osmotic tolerance is challenging. Herein, heavy ion mutagenesis combined with osmotic pressure enrichment was used to engineer a hyperosmotic-tolerant Bacillus coagulans for L-lactic acid production. The engineered strain had higher osmotic pressure tolerance, when compared with the parental strain, primarily owing to its improved properties such as cell viability, cellular antioxidant capacity, and NADH supply. In a pilot-scale open unsterile fermentation using sweet sorghum juice as a feedstock, the engineered strain produced 94 g/L L-lactic acid with a yield of 91 % and productivity of 6.7 g/L/h, and optical purity of L-lactic acid at the end of fermentation was 99.8 %. In short, this study provided effective and low-cost approach to produce polymer-grade L-lactic acid.

Development of 3D Printed Biodegradable, Entirely X-ray Visible Stents for Rabbit Carotid Artery Implantation.

Biodegradable stents are considered a promising strategy for the endovascular treatment of cerebrovascular diseases. The visualization of biodegradable stents is of significance during the implantation and long-term follow-up. Endowing biodegradable stents with X-ray radiopacity can overcome the weakness of intrinsic radioparency of polymers. Hence, this work focuses on the development of an entirely X-ray visible biodegradable stent (PCL-KIO3) composed of polycaprolactone (PCL) and potassium iodate via physical blending and 3D printing. The in vitro results show that the introduction of potassium iodate makes the 3D-printed PCL stents visualizable under X-ray. So far, there is inadequate study about polymeric stent visualization in vivo. Therefore, PCL-KIO3 stents are implanted into the rabbit carotid artery to evaluate the biosafety and visibility performance. During stent deployment, the visualization of the PCL-KIO3 stent effectively helps to understand the position and dilation status of stents. At 6-month follow-up, the PCL-KIO3 stent could still be observed under X-ray and maintains excellent vessel patency. To sum up, this study demonstrates that PCL-KIO3 stent may provide a robust strategy for biodegradable stent visualization.

Research on the evolution characteristics, driving mechanisms and multi-scenario simulation of habitat quality in the Guangdong-Hong Kong-Macao Greater Bay based on multi-model coupling.

Since the 20th century, the global urbanization has led to a series of pollution issues, posing a severe threat to the habitat quality of human habitat. The quality of habitat determines whether ecosystems can provide suitable living conditions for humans and other species. Therefore, systematic study of the habitat quality is essential for the maintenance of sustainable development. In this study, we coupled models such as SD, InVEST and PLUS with a series of indicators to analyze the characteristics of land cover and habitat quality evolution in the Guangdong-HongKong-Macao Greater Bay Area (GBA) from 2000 to 2020 and deconstruct the driving mechanisms of habitat quality. Then simulate the evolution of land cover and habitat quality under different scenarios in 2030. The results show that: 1) Over the historical research period, the GBA exhibited "rapid expansion of artificial surfaces and rapid shrinkage of ecological land". Artificial surfaces increased by approximately 4878.95km2,while ecological land, such as agricultural land, decreased by about 3095.93km2.2) The degradation of habitat quality gradually accelerated and the habitat quality was characterized by "stepwise decline from the periphery to the interior", which was directly related to the land cover changes brought about by the topographic gradient effect in the Bay Area.3) Pollution control driven by environmental investments has had a moderating effect on habitat degradation, but it has not been able to change the overall degradation trend. 4) Scenario analysis suggests that future habitat quality in the GBA will degrade to a certain extent due to the impact of artificial surface expansion. We deduce that this will affect the structure of the city's ecological network as well as the conservation function of the ecological zones. This study provides a scientific basis for understanding the historical and future trends of habitat quality in the GBA, offering new insights into the intrinsic driving mechanisms of habitat quality. It also provides a theoretical support for relevant authorities to undertake sustainable development initiatives.

Comparative Analysis of Growth, Survival, and Virulence Characteristics of Listeria monocytogenes Isolated from Imported Meat.

Listeria monocytogenes is an important foodborne pathogen with worldwide prevalence. Understanding the variability in the potential pathogenicity among strains of different subtypes is crucial for risk assessment. In this study, the growth, survival, and virulence characteristics of 16 L. monocytogenes strains isolated from imported meat in China (2018-2020) were investigated. The maximum specific growth rate (µmax) and lag phase (λ) were evaluated using the time-to-detection (TTD) method and the Baranyi model at different temperatures (25, 30, and 37 °C). Survival characteristics were determined by D-values and population reduction after exposure to heat (60, 62.5, and 65 °C) and acid (HCl, pH = 2.5, 3.5, and 4.5). The potential virulence was evaluated via adhesion and invasion to Caco-2 cells, motility, and lethality to Galleria mellonella. The potential pathogenicity was compared among strains of different lineages and subtypes. The results indicate that the lineage I strains exhibited a higher growth rate than the lineage II strains at three growth temperatures, particularly serotype 4b within lineage I. At all temperatures tested, serotypes 1/2a and 1/2b consistently demonstrated higher heat resistance than the other subtypes. No significant differences in the log reduction were observed between the lineage I and lineage II strains at pH 2.5, 3.5, and 4.5. However, the serotype 1/2c strains exhibited significantly low acid resistance at pH 2.5. In terms of virulence, the lineage I strains outperformed the lineage II strains. The invasion rate to Caco-2 cells and lethality to G. mellonella exhibited by the serotype 4b strains were higher than those observed in the other serotypes. This study provides meaningful insights into the growth, survival, and virulence of L. monocytogenes, offering valuable information for understanding the correlation between the pathogenicity and subtypes of L. monocytogenes.

Licorice flavonoid ameliorates ethanol-induced gastric ulcer in rats by suppressing apoptosis via PI3K/AKT signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Licorice is the dry roots and rhizomes of Glycyrrhiza uralensis Fisch., Glycyrrhiza glabra L. and Glycyrrhiza inflata Bat., which was first recorded in Shengnong's herbal classic. Licorice flavonoid (LF) is the main compound isolated from licorice with an indispensable action in treating gastric ulcer (GU). However, the underlying mechanisms need to be further explored. AIM OF THE STUDY: This study aimed to investigate and further elucidate the mechanisms of LF against ethanol-induced GU using an integrated approach. MATERIALS AND METHODS: The anti-GU effects of LF were evaluated in an ethanol-induced gastric injury rat model. Then, the metabolomics approach was applied to explore the specific metabolites and metabolic pathways. Next, the network pharmacology combined with metabolomics strategy was employed to predict the targets and pathways of LF for GU. Finally, these predictions were validated by molecular docking, RT-qPCR, and western blotting. RESULTS: LF had a positive impact on gastric injury and regulated the expression of GU-related factors. Upon serum metabolomics analysis, 25 metabolic biomarkers of LF in GU treatment were identified, which were primarily involved in amino acid metabolism, carbohydrate metabolism, and other related processes. Subsequently, a "components-targets-metabolites" network was constructed, revealing six key targets (HSP90AA1, AKT1, MAPK1, EGFR, ESR1, PIK3CA) that may be associated with GU treatment. More importantly, KEGG analysis highlighted the importance of the PI3K/AKT pathway including key targets, as a critical route through which LF exerted its anti-GU effects. Molecular docking analyses confirmed that the core components of LF exhibited a strong affinity for key targets. Furthermore, RT-qPCR and western blotting results indicated that LF could reverse the expression of these targets, activate the PI3K/AKT pathway, and ultimately reduce apoptosis. CONCLUSION: LF exerted a gastroprotective effect against gastric ulcer induced by ethanol, and the therapeutic mechanism may involve improving metabolism and suppressing apoptosis through the PI3K-AKT pathway.

Thermal inactivation kinetics of Listeria monocytogenes in milk under isothermal and dynamic conditions.

Thermal processing is a widely used method to ensure the microbiological safety of milk. Predictive microbiology plays a crucial role in quantifying microbial growth and decline, providing valuable guidance on the design and optimization of food processing operations. This study aimed to investigate the thermal inactivation kinetics of Listeria monocytogenes in milk under both isothermal and dynamic conditions. The thermal inactivation of L. monocytogenes was conducted under isothermal and non-isothermal conditions in sterilized and pasteurized milk, with and without background microbiota, respectively. Furthermore, a secondary model was developed between the shoulder effect and temperature, which was then integrated into the dynamic model. The results showed that L. monocytogenes grown in Tryptic Soy Yeast Extract Broth (TSBYE) prior to thermal inactivation exhibited higher heat resistance compared to cells grown in sterilized milk at isothermal temperatures of 60.0, 62.5, and 65℃. Moreover, the presence of background microbiota in milk significantly enhanced the heat resistance of L. monocytogenes, as evidenced by the increased D-values from 1.13 min to 2.34 min, from 0.46 min to 0.53 min, and from 0.25 min to 0.34 min at 60.0, 62.5, and 65 °C, respectively, regardless of whether the background microbiota was inactivated after co-growth or co-inactivated with L. monocytogenes. For non-isothermal inactivation, the one-step dynamic model based on the log-linear with shoulder model effectively described the microbial inactivation curve and exhibited satisfactory model performance. The model developed contributes to improved risk assessment, enabling dairy processors to optimize thermal treatment and ensure microbiological safety.

Induction of mesenchymal stem cell (MSC) differentiation from iPS cells using MSC medium.

Mesenchymal stem cells (MSCs) and induced pluripotent stem (iPS) cells have great potential as cell sources for tissue engineering and regenerative medicine. This study aimed to investigate whether iPS cells can be differentiated into MSCs using MSCGM, a commercially available MSC culture system. The cells were characterized by flow cytometry, immunostaining, and gene expression analyses. We also examined their potential to differentiate into osteoblasts and chondrocytes. Our results showed that iPS cells cultured in MSCGM (iPS-MSCGM) exhibited a fibroblast-like morphology and expressed CD73 and CD90 genes, as well as positive markers for CD73, CD90, and CD105. Moreover, iPS-MSCGM cells demonstrated the ability to differentiate into osteoblasts and chondrocytes in vitro. This study demonstrates a new and simple method for inducing the differentiation of iPS cells to MSCs using MSCGM.

Exploring the molecular mechanism of Licorice rose beverage anti-melasma based on network pharmacology, molecular docking technology and in vivo and in vitro experimental verification.

Melasma is a pigmentation disease with refractory and high recurrence risk. Therefore, finding effective treatment has become the focus of research. This study aimed to reveal the mechanism of Licorice rose beverage (LRB) in treating melasma from the perspective of network pharmacology and in vitro and in vivo experimental techniques. Network pharmacological studies have shown that Isolicoflavonol, quercetin, and kaempferol are the main active components of anti-melasma and tyrosinase is the main target. Molecular docking studies have shown that these compounds have a good affinity for these targets. In vitro tyrosinase inhibition experiments showed that LRB could significantly inhibit tyrosinase activity. In vivo studies showed that LRB could significantly improve skin damage and skin pigmentation, reduce the activities of serum and skin tyrosinase in model mice, increase the activity of SOD in serum, and reduce the content of MDA in mice, showing a good effect of anti-melasma. In conclusion, these findings reveal the molecular mechanism of LRB in treating melasma and provide the scientific basis for this product's development and clinical application.

A DARPin promotes faster onset of botulinum neurotoxin A1 action.

In this study, we characterize Designed Ankyrin Repeat Proteins (DARPins) as investigative tools to probe botulinum neurotoxin A1 (BoNT/A1) structure and function. We identify DARPin-F5 that completely blocks SNAP25 substrate cleavage by BoNT/A1 in vitro. X-ray crystallography reveals that DARPin-F5 inhibits BoNT/A1 activity by interacting with a substrate-binding region between the α- and ß-exosite. This DARPin does not block substrate cleavage of BoNT/A3, indicating that DARPin-F5 is a subtype-specific inhibitor. BoNT/A1 Glu-171 plays a critical role in the interaction with DARPin-F5 and its mutation to Asp, the residue found in BoNT/A3, results in a loss of inhibition of substrate cleavage. In contrast to the in vitro results, DARPin-F5 promotes faster substrate cleavage of BoNT/A1 in primary neurons and muscle tissue by increasing toxin translocation. Our findings could have important implications for the application of BoNT/A1 in therapeutic areas requiring faster onset of toxin action combined with long persistence.

The implications of lipid mobility, drug-enhancers (surfactants)-skin interaction, and TRPV1 activation on licorice flavonoid permeability.

Licorice flavonoids (LFs) are derived from perennial herb licorice and have been attaining a considerable interest in cosmetic and skin ailment treatments. However, some LFs compounds exhibited poor permeation and retention capability, which restricted their application. In this paper, we systematically investigated and compared the enhancement efficacy and mechanisms of different penetration enhancers (surfactants) with distinct lipophilicity or "heat and cool" characteristics on ten LFs compounds. Herein, the aim was to unveil how seven different enhancers modified the stratum corneum (SC) surface and influence the drug-enhancers-skin interaction, and to relate these effects to permeation enhancing effects of ten LFs compounds. The enhancing efficacy was evaluated by enhancement ratio (ER)permeation, ERretention, and ERcom, which was conducted on the porcine skin. It was summarized that heat capsaicin (CaP) and lipophilic Plurol® Oleique CC 497 (POCC) caused the most significance of SC lipid fluidity, SC water loss, and surface structure alterations, thereby resulting in a higher permeation enhancing effects than other enhancers. CaP could completely occupied drug-skin interaction sites in the SC, while POCC only occupied most drug-skin interactions. Moreover, the enhancing efficacy of both POCC and CaP was dependent on the log P values of LFs. For impervious LFs with low drug solubility, enhancing their drug solubility could help them permeate into the SC. For high-permeation LFs, their permeation was inhibited ascribed to the strong drug-enhancer-skin strength in the SC. More importantly, drug-surfactant-skin energy possessed a good negative correlation with the LFs permeation amount for most LFs molecules. Additionally, the activation of transient receptor potential vanilloid 1 (TRPV1) could enhance LFs permeation by CaP. The study provided novel insights for drug permeation enhancement from the viewpoint of molecular pharmaceutics, as well as the scientific utilization of different enhancers in topical or transdermal formulations.