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p-Cymene inhibits pro-fibrotic and inflammatory mediators to prevent hepatic dysfunction

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Published/Copyright: April 15, 2025
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Open Life Sciences
From the journal Open Life Sciences Volume 20 Issue 1

Abstract

This study evaluated the hepatoprotective potential of p-cymene (p-CYM) against two models of liver damage: ethanol (EtOH)-induced hepatocellular injury and diethylnitrosamine-carbon tetrachloride (DEN-CCl4)-induced liver fibrosis (LF). HepG2 cells were treated with p-CYM or silymarin (SIL) before exposure to 10% EtOH in order to induce cellular injury. LF was induced in Sprague–Dawley rats using a single dose of DEN followed by increasing doses of CCl4 over 60 days. Rats were treated twice weekly with p-CYM or SIL from day 21 to day 60. Results showed that p-CYM effectively mitigated EtOH-induced cell death in HepG2 cells by enhancing the activity of superoxide dismutase and glutathione reductase. In vivo findings revealed that p-CYM attenuated DEN– CCl4-induced liver damage by preventing weight loss, improving serum biomarkers (e.g., aspartate transaminase, alanine aminotransferase, alkaline phosphatase, and bilirubin), and reducing liver fibrotic changes. It also decreased the expression of pro-inflammatory and pro-fibrotic markers such as TNF-α, IL-1β, IL-6, TGF-β1, COL1A1, and TIMP-1. Molecular docking further supported the experimental findings, showing strong interactions between p-CYM and the target proteins. These results indicate that the hepatoprotective effects of p-CYM are likely due to its combined antioxidant, anti-inflammatory, and anti-fibrotic properties.

Graphical abstract

Keywords: p-cymene; HepG2; DEN- CCl4; liver fibrosis; hepatoprotective; TGF-β1

1 Introduction

Liver fibrosis (LF) is a condition characterized by the excessive accumulation of extracellular matrix (ECM) proteins, primarily type I and III cross-linked collagens, which form fibrous scars in response to chronic liver injury. This scarring replaces damaged tissue and impairs liver functionality [1]. LF typically results from two primary types of chronic liver damage: hepatotoxic and cholestatic. Cholestatic damage occurs due to bile flow obstruction caused by conditions such as primary and secondary biliary cholangitis, sclerosing cholangitis, and biliary atresia [2]. Hepatotoxic damage, on the other hand, is caused by factors such as alcohol, carbon tetrachloride (CCl4), paracetamol, and metabolic syndrome, which lead to steatohepatitis and chronic hepatocyte injury [3,4,5].

Alcohol consumption accounts for approximately 5% of deaths worldwide, with the liver being the primary site for ethanol (EtOH) metabolism [3]. EtOH is metabolized into acetaldehyde, a toxic byproduct, which is further broken down into acetate by acetaldehyde dehydrogenase in liver mitochondria. However, acetaldehyde accumulation and the production of ethyl esters of long-chain fatty acids through non-oxidative metabolic pathways disrupt mitochondrial function, making the liver particularly vulnerable to alcohol-induced damage [5,6,7]. Similarly, CCl4 exposure can cause centrilobular hepatic necrosis. Both EtOH and CCl4 are metabolized by cytochrome P450 2E1 (CYP2E1), which generates reactive free radicals that contribute to severe hepatotoxicity [4,5,8].

Despite advancements, treatment options for LF remain limited. A variety of drugs, including thalidomide, colchicine, corticosteroids, curcumin, glycyrrhizin, interferons, nitric oxide, resveratrol, silymarin (SIL), and sulfoadenosyl methionine, have gained attention for their anti-fibrotic properties [9,10]. Glycyrrhizin has also shown hepatoprotective effects in patients with sub-acute liver failure, but additional controlled clinical trials are needed [11]. Similarly, thalidomide, resveratrol, and curcumin have demonstrated potential as preventive and therapeutic agents for liver diseases, though their effectiveness across larger populations remains unproven. In cases of end-stage liver disease, liver transplantation remains the only definitive treatment, emphasizing the need for novel therapeutic options to enhance patient outcomes [12].

Medicinal herbs have been used for centuries to treat various diseases, and natural compounds derived from plants continue to attract significant interest in modern medicine [13,14]. One such compound, p-cymene (p-CYM), is an alkyl-substituted aromatic compound with a wide range of pharmacological properties, including antioxidant, anti-inflammatory, antibacterial, antifungal, antiviral, anti-parasitic, anti-diabetic, and anticancer effects [15,16]. A recent study highlighted that p-CYM enhanced the levels of anti-oxidants and reduced inflammatory cytokines in hyperlipidemic rats [17]. Given its reported anti-inflammatory activities and diverse therapeutic potential, p-CYM has been hypothesized to offer hepatoprotective benefits. This hypothesis was tested using a human hepatoma (HepG2) cell line and an LF model to assess its efficacy in mitigating hepatic damage and protecting liver function.

2 Materials and methods

2.1 Reagents

CCl4 (Cat. No. 289116) and SIL (Cat. No. 65666-07-01) were purchased from Sigma-Aldrich Company (St. Louis, MO, USA). Diethylnitrosamine (DEN; Cat. No. 55-18-5) was purchased from Rhawn Chemicals (Shanghai, China) and p-CYM (Cat. No. 99-87-6) from Tokyo Chemical Industry (Tokyo, Japan). All other chemicals used in this research were of standard analytical quality.

2.2 Culturing of HepG2 cells

HepG2 cell line was obtained from Cell and Tissue Culture Laboratory (The University of Lahore). Cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM; Cat. No. D5030) supplemented with streptomycin (100 g/ml; Cat. No. S9137), penicillin (100 units/ml; Cat. No. P3032), and 10% fetal bovine serum (Cat. No. F4135) in a humidified incubator at 37°C. Subculturing was done when the cells attained a confluency of 70–80%. Cells were washed with 1× PBS, and adherent cells were detached with 1× trypsin (Cat. No. T4799). The cellular detachment was verified using a phase-contrast inverted microscope. The cell suspension was centrifuged at 2,000 rpm for 5 min, and the obtained cell pellets were resuspended in complete DMEM [18].

2.3 Cytotoxicity assessment of p-CYM and EtOH

Cell viability assay was conducted to determine the optimal concentrations of p-CYM and EtOH. Different concentrations of EtOH (1, 3, 5, 8, and 10%) were prepared in complete DMEM, and 1 M stock solution of p-CYM in DMSO (Cat. No. D8418) was prepared. Several dilutions of p-CYM (10, 50, 100, 500, and 1,000 µM) were later formulated from 1 M stock solution. HepG2 cells were seeded on a 96-well plate and incubated at 37℃ overnight. The next day, the medium was removed, and the cells were washed with 1× PBS. Various concentrations of EtOH and p-CYM (100 µl) were introduced into the wells. Cell viability of the treated cells was assessed using the 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay according to the manufacturer’s protocol [19].

2.4 Determination of the hepatoprotective effect of p-CYM

HepG2 cells were cultivated on 96- and 6-well plates, and after overnight incubation, they were washed with 1× PBS and pretreated with 100 µl of either SIL (200 µg/ml) or various doses of p-CYM for 24 h. Following p-CYM/SIL treatments, cells were again rinsed with 1× PBS and subsequently treated with 10% EtOH for 24 h. After EtOH injury, cells grown on a 96-well plate were subjected to the MTT, Trypan blue, crystal violet, and PI staining assays. Cells grown on 6-well plates were harvested in TRIZOL reagent for gene expression study, while supernatants were collected for ELISA and anti-oxidant assays [19].

HepG2 cells were divided into the following groups (n = 3 in each group):

  1. Control: complete DMEM

  2. DMSO control: 0.1% DMSO dissolved in complete DMEM

  3. Disease control: 10% EtOH dissolved in complete DMEM

  4. SIL (200 µg/ml): 200 µg/ml SIL in complete DMEM

  5. P-CYM 10 µM: 10 µM p-CYM in complete DMEM

  6. P-CYM 50 µM: 50 µM p-CYM in complete DMEM

  7. P-CYM 100 µM: 100 µM p-CYM in complete DMEM

  8. P-CYM 500 µM: 500 µM p-CYM in complete DMEM

2.5 Cell viability assays

In order to calculate the cell viability of pretreated HepG2 cells, MTT and crystal violet assays were performed in which different concentrations of the abovementioned dilutions were tested on cells cultured in 96-well plates.

2.5.1 MTT assay

Pretreated cells were washed with 1× PBS followed by 3–4 h of incubation with 100 µl of DMEM and 25 µl of MTT (Cat. No. M5655) solution. Formazan crystals were solubilized with 10% sodium dodecyl sulfate (SDS), and absorbance at 570 nm was measured using a microplate reader. Percentage cell viability was calculated from the mean absorbance values [18].

2.5.2 Crystal violet assay

Pretreated cells were rinsed with 1× PBS and treated with a mixture of 0.1% crystal violet dye and 2% EtOH, followed by incubation for 15 min at room temperature (RT). Wells were thoroughly washed with 1× PBS, and the dye was carefully disposed of to prevent cells from lifting out of the wells. The stain was then solubilized by adding 100 µl of 1% SDS to each well. Finally, the absorbance was measured at 595 nm using a microplate reader [18].

2.6 Dead cell detection

For dead cell detection, a trypan blue assay was performed.

2.6.1 Trypan blue staining

Trypan blue reagent was used to distinguish between live and dead cells. Briefly, pretreated cells were washed three times with 1× PBS and subsequently stained with trypan blue (Cat. No. T6146). The blue-stained cells were designated as dead, which were counted using a compound microscope.

2.7 Antioxidant assays

2.7.1 Glutathione reductase (GSH) assay

GSH levels in the samples were quantified using the Bioassay Technology Laboratory ELISA Kit (Cat. No. EA0142Hu). Reagents, standard solutions, and samples were prepared according to the kit’s instructions and equilibrated to RT prior to use. For the assay, 50 µl of the standard solution was added to the standard wells, and 40 µl of the sample was added to the sample wells. Subsequently, 10 µl of anti-GSH antibody was added to each well, followed by 50 µl of streptavidin-HRP to the sample wells. The contents were mixed thoroughly, sealed with a plate sealer, and incubated at 37°C for 60 min. After incubation, the sealer was removed, and the plate was washed five times using 300 µl of wash buffer per well, with each wash lasting 30 s to 1 min. Following the washes, 50 µl of substrate solution A and 50 µl of substrate solution B were sequentially added to each well. The plate was then incubated in the dark for 10 min at 37°C. After incubation, 50 µl of stop solution was added to each well, resulting in an immediate color change from blue to yellow. The optical density (OD) of each well was measured immediately using a Bio-Rad microplate ELISA reader (Model PR4100) set to a wavelength of 450 nm [20].

2.7.2 Superoxide dismutase (SOD) assay

SOD was measured using the ELISA Kit from Bioassay Technology Laboratory (Cat. No. E4502Hu), and the same procedure was adopted, as described for the GSH assay.

2.8 Animals used

Male Sprague–Dawley rats weighing 150–200 g were purchased from the University of Veterinary and Animal Sciences (Lahore, Pakistan). Animals were kept under standard conditions (temperature: 22 ± 2°C and humidity: 60 ± 10%) with a 12 h light and dark cycle at the Animal House of the Faculty of Pharmacy (The University of Lahore). All the animals were given free access to food and water throughout the adaptation and experimental period. This study was performed in accordance with ARRIVE guidelines.

  1. Ethical approval: The research related to animal use has complied with all the relevant national regulations and institutional policies for the care and use of animals and has been approved by the Institutional Research Ethics Committee (IREC) of the Department of Pharmacology, Faculty of Pharmacy, The University of Lahore, Lahore, Pakistan (Approval Number: IREC-2022-46).

2.9 LF experimental design

Animals were randomly divided into five groups (n = 4 in each group): control, disease (CCl4), standard (SIL), and treatment (p-CYM) groups. The control group received twice a week intraperitoneal (i.p.) injection of olive oil (0.5 ml/kg). LF was induced using a single dose of DEN, followed by increasing doses of CCl4 for 60 days (D). Briefly, a day after DEN administration, CCl4 (0.5 ml/kg) was injected intraperitoneally (i.p.) twice a week for 40D. On D41, animals were treated twice a week with 1 ml/kg of CCl4 for 18 D, i.e., D41–D58, which was later increased to 2 ml/kg for the last 2 days, i.e., D59–D60. To investigate the protective effects of p-CYM and SIL, animals were treated with SIL (100 mg/kg) and p-CYM (50 and 100 mg/kg) twice a week from D21 to D60. On D60, the body weights of animals were measured, and later, they were sacrificed by intraperitoneal injection of pentobarbital sodium (200 mg/kg) to collect blood and liver samples for subsequent biochemical, histopathological, and RT-qPCR analyses. Care was taken to minimize the suffering of animals.

2.10 Biochemical and histopathological analyses

Serum aspartate transferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and bilirubin levels were measured using standard ELISA kits. Liver samples fixed in 10% buffered formalin were sectioned using the paraffin embedding technique and stained with hematoxylin and eosin for histopathological analysis.

2.11 Real-time PCR analysis

Total RNA was isolated from liver samples using the Trizol method, which was later reverse-transcribed using the WizScript cDNA Synthesis Kit (Wizbio solutions, New Mexico, USA; Cat. No. W2202). The relative transcript levels of genes were measured by the ΔΔC T method using Zokeyo 2xSYBR Green qPCR mixture (Cat. No. HPR012-01). The following PCR conditions were used to measure the CT values: initial denaturation was carried out at 94°C for 2 min, followed by 40 cycles of denaturation at 94°C for 1 min, annealing at 60°C for 30 s, and elongation at 72°C for 15 s. Hypoxanthine guanine phosphoribosyltransferase (HPRT) was used as an internal standard. A list of primers (Macrogen, South Korea) used in the study is provided in Table S1.

2.12 Molecular docking analysis

2.12.1 Retrieval of tumor necrosis factor-alpha (TNF-α) and matrix metalloproteinase-1 (MMP-1) structures from Protein Data Bank

The three-dimensional (3D) structures of human TNF-α and MMP-1 were obtained from the Protein Data Bank (PDB) using PDB IDs 2AZ5 and 4AUO, respectively. The target proteins were prepared for docking analysis using the Autodock Tool program. Proteins were reduced in energy, given Gasteiger charges, and saved in a pdbqt format. Discovery Studio 4.1 Client (2012) was used to generate Ramachandran plots. VADAR 1.8 was used to access the protein architecture and statistical percentages of helices, β-sheets, coils, and turns [21].

2.12.2 Ligand molecular docking

P-CYM was drawn in Discovery Studio Client and saved in a pdb format as a ligand. The most stable conformation of the ligand was prepared using Autodock Tools. The Kolman and Gasteiger charges were added before the ligand was saved in a pdbqt format. The synthetic ligand (p-CYM) was subjected to a molecular docking experiment using PyRx’s virtual screening tool and the Auto Dock VINA Wizard method [22].

2.13 Statistical analysis

Data of 3–4 biological replicates were presented as the mean ± SD and were analyzed by one-way ANOVA followed by Tukey’s multiple comparison test. Statistical analyses were performed using Graph Pad Prism 8.0 software (Graphpad Software, Inc., San Diego, USA). A probability of less than 0.05 was considered significant. The level of significance was expressed as *** ≤ 0.001, ** ≤ 0.01, * ≤ 0.05.

3 Results

3.1 P-CYM treatment did not alter the viability of HepG2 cells

The cytotoxicity of p-CYM in HepG2 cells was assessed using the MTT assay to determine its safe and tolerable concentrations. HepG2 cells were treated with increasing concentrations of p-CYM (10, 50, 100, 500, and 1,000 µM) for 24 h to evaluate its impact on cell viability. The assay results demonstrated that p-CYM did not significantly affect cell viability at lower concentrations, specifically 10, 50, 100, and 500 µM, indicating that these doses are non-toxic to the cells and can be considered safe for further experimental use. However, at a concentration of 1,000 µM, p-CYM exhibited cytotoxic effects, as evidenced by a significant reduction in cell viability. These findings suggest that while p-CYM is generally well tolerated at moderate doses, high concentrations may compromise cellular health, emphasizing the importance of dose optimization for its potential therapeutic applications (Figure S1).

3.2 Cytotoxic effects of EtOH in HepG2 cells

To determine the toxic effects of EtOH on HepG2 cells, the cells were exposed to increasing concentrations of EtOH (ranging from 1 to 10%) for a duration of 24 h. Cell viability was then assessed to evaluate the extent of toxicity. At lower concentrations, specifically between 1 and 4%, EtOH did not induce any significant reduction in cell viability. This suggests that these concentrations are relatively safe and do not cause notable cellular damage. However, as the concentration of EtOH increased, a gradual decrease in cell viability was observed. At 6% EtOH, the reduction in cell viability was minimal, but it became more pronounced at 8%. The most substantial decline in cell viability occurred at the highest concentration tested, 10% EtOH, where cell viability dropped by over 50%. This indicates that EtOH has a dose-dependent toxic effect on HepG2 cells, with significant cellular damage occurring at concentrations of 8% and 10%. These findings suggest that high concentrations of EtOH can induce severe cytotoxicity, potentially through mechanisms like oxidative stress or disruption of cellular functions (Figure S2).

3.3 P-CYM protected against EtOH-induced toxicity in HepG2 cells

The cytoprotective effects of p-CYM against EtOH-induced cell injury were investigated by treating HepG2 cells with various concentrations of p-CYM (10, 50, 100, and 500 µM) prior to EtOH exposure. EtOH exposure significantly reduced cell viability by approximately 50% compared to the p-CYM- and SIL-treated groups, demonstrating the toxic impact of EtOH on liver cells. However, pretreatment with p-CYM at concentrations ranging from 10 to 500 µM resulted in a dose-dependent attenuation of EtOH-induced cytotoxicity. The protective effect of p-CYM was most prominent at 500 µM, where it demonstrated cytoprotective effects comparable to those of SIL, a well-known hepatoprotective agent (Figure 1).

Figure 1 Cytoprotective effects of p-CYM against EtOH-induced damage in HepG2 cells. (a) The absorbance of MTT dye was measured. (b) Percentage cell viability was measured from the absorbance values. Pre-treatment of p-CYM (50, 100, and 500 µM) significantly reduced EtOH toxicity compared to the disease control group. *** ≤ 0.001, ** ≤ 0.01, * ≤ 0.05 (treated groups vs disease group); one-way ANOVA followed by Tukey’s multiple comparison test; n = 3.
Figure 1

Cytoprotective effects of p-CYM against EtOH-induced damage in HepG2 cells. (a) The absorbance of MTT dye was measured. (b) Percentage cell viability was measured from the absorbance values. Pre-treatment of p-CYM (50, 100, and 500 µM) significantly reduced EtOH toxicity compared to the disease control group. *** ≤ 0.001, ** ≤ 0.01, * ≤ 0.05 (treated groups vs disease group); one-way ANOVA followed by Tukey’s multiple comparison test; n = 3.

To further assess the impact of p-CYM on cell viability, a crystal violet assay was performed, showing a reduction in cell viability of around 40% upon exposure to EtOH, which aligns with the initial findings. However, p-CYM treatment was able to effectively restore cell viability in a significant manner, suggesting its potential to counteract EtOH-induced damage. Interestingly, the cellular growth observed in the p-CYM-treated group was even more pronounced than in the SIL-treated group, indicating that p-CYM might have a stronger or more favorable effect on promoting cell recovery and proliferation after ethanol-induced injury. These results highlight the strong protective and restorative capabilities of p-CYM, positioning it as a promising agent for preventing or mitigating liver damage caused by EtOH (Figure S3).

3.4 P-CYM prevented EtOH-induced cell death

The Trypan blue assay was used to assess cell death in HepG2 cells following exposure to EtOH. The results showed that EtOH induced cell death in more than 50% of the HepG2 cells, confirming its toxic effects on the cells. However, pretreatment with p-CYM demonstrated a dose-dependent reduction in cell death compared to the disease control group. At concentrations of 500 µM, its cytoprotective effects were even more pronounced than those observed in the SIL-treated group. This indicates that p-CYM not only reduced cell death but also showed superior efficacy in protecting HepG2 cells from EtOH-induced toxicity, highlighting its potential as a more effective therapeutic agent compared to SIL (Figure 2).

Figure 2 P-CYM reduced EtOH-induced cell death. Trypan blue staining showed an increased cell death with EtOH treatment. P-CYM and SIL treatments significantly reduced EtOH-induced cell death in HepG2 cells. *** ≤ 0.001 (treated groups vs disease group); one-way ANOVA followed by Tukey’s multiple comparison test; n = 3.
Figure 2

P-CYM reduced EtOH-induced cell death. Trypan blue staining showed an increased cell death with EtOH treatment. P-CYM and SIL treatments significantly reduced EtOH-induced cell death in HepG2 cells. *** ≤ 0.001 (treated groups vs disease group); one-way ANOVA followed by Tukey’s multiple comparison test; n = 3.

3.5 P-CYM attenuated EtOH-induced oxidative stress and transcript levels of inflammatory and fibrotic modulators

SOD and GSH activity increased in p-CYM- and SIL-treated groups compared to the disease group showing that p-CYM reduced oxidative stress induced by EtOH. Moreover, higher doses of p-CYM displayed more potent effects compared to SIL (Figure 3). The relative mRNA expression of biomarkers, including TNF-α, transforming growth factor-beta1 (TGF-β1), interleukin-6 (IL-6), glutathione peroxidase-7 (GPX-7), collagen type 1 (COL1A1), MMP-1, and tissue inhibitor of MMP-1 (TIMP-1) were assessed to examine the molecular mechanism behind the hepatoprotective activity of p-CYM. The findings of this study showed that p-CYM significantly reduced the expression rate of the abovementioned biomarkers. These findings were equivalent to the standard drug “SIL.” In contrast to the treated groups, the expression rate of these biomarkers was higher in the disease group, which could be ascribed to toxicity induced by EtOH. The hepatoprotective role of p-CYM can be ascribed to the down-regulation of inflammatory and fibrotic markers (Figure 4).

Figure 3 P-CYM prevented EtOH-induced oxidative stress by inducing anti-oxidants. P-CYM and SIL induced the levels of SOD (a) and GSH (b). *** ≤ 0.001 (treated groups vs disease group); one-way ANOVA followed by Tukey’s multiple comparison test; n = 3.
Figure 3

P-CYM prevented EtOH-induced oxidative stress by inducing anti-oxidants. P-CYM and SIL induced the levels of SOD (a) and GSH (b). *** ≤ 0.001 (treated groups vs disease group); one-way ANOVA followed by Tukey’s multiple comparison test; n = 3.

Figure 4 P-CYM displayed hepatoprotective effects by reducing transcript levels of TNF-α, TGF-β1, IL-6, GPX-7, COL1A1, MMP-1, and TIMP-1. *** ≤ 0.001 (treated groups vs disease group); one-way ANOVA followed by Tukey’s multiple comparison test; n = 3.
Figure 4

P-CYM displayed hepatoprotective effects by reducing transcript levels of TNF-α, TGF-β1, IL-6, GPX-7, COL1A1, MMP-1, and TIMP-1. *** ≤ 0.001 (treated groups vs disease group); one-way ANOVA followed by Tukey’s multiple comparison test; n = 3.

3.6 P-CYM prevented CCl4-induced weight reduction and protected against CCl4-induced liver damage

One of the characteristics of chronic liver illness is weight loss, which may be caused by the liver’s metabolic dysfunction and a decrease in bile production, which in turn leads to a reduction in lipid emulsification and absorption [2,23]. The present findings also revealed that CCl4 reduced the body weight of rats, which was restored by treatment with SIL and p-CYM. Interestingly, the highest dose of p-CYM restored the body weight to normal levels, and this effect was much more prominent than in the SIL-treated group (Figure S4). Moreover, increased LFT levels reflect a variety of aberrant liver activities, including (a) hepatocellular instability, (b) decreased bile synthesis, and (c) altered protein synthesis, and are therefore indirect indicators of LF [2,23,24]. In current study, the exposure to CCl4 also led to increased levels of ALP, AST, ALT, and bilirubin, signaling liver damage. However, SIL and p-CYM treatment reduced these elevated markers, indicating their hepatoprotective effects (Figure S5).

3.7 Histopathological and real-time PCR analyses revealed anti-fibrotic effects of p-CYM

The liver tissue samples of the disease group showed fibrotic scarring enriched with collagen and swollen hepatocytes. Treatment with SIL showed mild infiltration of inflammatory cells, while p-CYM (50 mg/kg)-treated tissue appeared normal with mild swelling of hepatocytes. At a higher dose (100 mg/kg), p-CYM did not display any inflammation or scarring, and the tissue also had a normal appearance. The above findings clearly indicated the protective effects of p-CYM against DEN–CCl4-induced LF (Figure 5, Table S2). RT-qPCR findings also demonstrated that CCl4 induced transcript levels of pro-fibrotic markers (TIMP-1, IL-1β, COL1A1, and TGF-β1) and reduced anti-fibrotic markers (MMP-1). Treatment with SIL and p-CYM restored these markers, indicating their anti-fibrotic effects (Figure 6).

Figure 5 Histopathology of liver samples displayed anti-fibrotic effects of p-CYM.
Figure 5

Histopathology of liver samples displayed anti-fibrotic effects of p-CYM.

Figure 6 Modulation of pro- and anti-fibrotic markers by p-CYM. P-CYM and SIL reduced the transcript levels of TIMP-1, IL-1β, COL1A1, and TGF-β1 and induced MMP1, indicating its anti-fibrotic effects. *** ≤ 0.001, ** ≤ 0.01, and * ≤ 0.05 (treated groups vs disease group); one-way ANOVA followed by Tukey’s multiple comparison test; n = 3.
Figure 6

Modulation of pro- and anti-fibrotic markers by p-CYM. P-CYM and SIL reduced the transcript levels of TIMP-1, IL-1β, COL1A1, and TGF-β1 and induced MMP1, indicating its anti-fibrotic effects. *** ≤ 0.001, ** ≤ 0.01, and * ≤ 0.05 (treated groups vs disease group); one-way ANOVA followed by Tukey’s multiple comparison test; n = 3.

3.8 P-CYM displayed strong binding affinity with TNF-α and modest affinity with MMP-1

The affinity between the ligands and protein targets was examined by molecular docking. The docking analysis was conducted using the AutoDock Vina [22] tool and PyRx [25] user interface. The best-docked posture complex and protein’s affinity were evaluated using the E-value (kcal/mol). It offered a prediction of the binding constant and free energy for docked ligands. Usually, if the binding energy is more negative, stronger is the interaction between ligand and target protein. P-CYM’s docking tests displayed strong binding interactions with TNF-α and MMP-1, and the results were in line with the pharmacological effects. The binding energies of p-CYM with TNF-α and MMP-1 were −6.1 and −5.4 kcal/mol, respectively. These findings indicate that p-CYM-induced anti-fibrotic effects could be due to direct interaction with TNF-α and MMP-1 (Figure 7).

Figure 7 Binding interactions of p-CYM with TNF-α and MMP-1. 2D and 3D representation of binding interactions of p-CYM with the amino acid residues of the binding site of MMP-1 (a) and (b) and TNF-α (c) and (d).
Figure 7

Binding interactions of p-CYM with TNF-α and MMP-1. 2D and 3D representation of binding interactions of p-CYM with the amino acid residues of the binding site of MMP-1 (a) and (b) and TNF-α (c) and (d).

4 Discussion

LF is a critical stage in the progression of chronic liver disease, occurring after the initial development of fatty liver disease. If left untreated, LF leads to significant liver damage, where the liver tissue undergoes structural changes, resulting in shrinkage and the formation of nodules, a condition known as cirrhosis. The progression from LF to cirrhosis and potentially to hepatocellular carcinoma (HCC) underscores the importance of targeting LF as a key therapeutic intervention to prevent further liver damage and mitigate the risk of life-threatening complications [26]. Despite its critical role in the progression of liver disease, LF remains a major clinical challenge due to the lack of effective treatments that can fully reverse or significantly alleviate fibrosis once it has developed. Currently, available therapies are limited in their ability to halt or reverse the fibrotic process, and no universally accepted treatment can cure or effectively manage LF on a long-term basis. This highlights the urgent need for the development of new, more effective therapies that can address LF at its core, prevent progression to cirrhosis, and reduce the risk of developing HCC.

In this study, we elucidated the cytoprotective ability of p-CYM against EtOH-induced injury in HepG2 cells and its anti-fibrotic potential against DEN–CCl4-induced LF in rats. Chronic consumption of EtOH accelerates liver damage, contributing to a range of liver diseases, such as cirrhosis, HCC, alcoholic hepatitis, and alcoholic steatosis [27,28]. High levels of EtOH intake induce oxidative stress and fat accumulation in hepatocytes, leading to liver injury. Reactive oxygen species (ROS) play a central role in oxidative stress-induced cell death [29,30]. Studies have shown that excessive ROS production in the liver causes abnormal protein expression, oxidative DNA damage, and disruption of cell membranes, worsening liver function [31,32]. To prevent the progression of alcoholic liver disease (ALD), reducing EtOH-induced oxidative stress and fat buildup in the liver could be beneficial [33]. In addition to EtOH, DEN and CCl4 are commonly used in animal models to induce LF. In both wild-type and transgenic animal models, administration of DEN and CCl4 for 3–4 weeks causes centrilobular and periportal LF. CCl4 specifically activates macrophages and hepatic stellate cells (HSCs), triggering the upregulation of pro-fibrotic mediators and increasing ROS generation. This leads to fibrogenesis and cirrhosis, primarily driven by the overproduction of TGF-β [26]. The key features of DEN–CCl4-induced LF include weight loss, increased LFTs, and fibrotic changes in the liver [23,24]. These findings highlight the importance of targeting oxidative stress and fibrotic pathways to prevent or treat ALD and associated liver damage.

Moreover, studies have shown that anti-oxidants alter the redox state of the cell and reduce the generation of free radicals. Some of these agents include vitamins E and C, N-acetylcysteine (NAC), mitoquinone, and polyenylphosphatidylcholine. Vitamin E stabilizes the free radical compounds by forming complexes with the unpaired electrons and prevents the activation of HSCs [34]. In a small open-label study, vitamin E treatment (1200 IU/day) for 8 weeks stopped the fibrogenesis cascade in six patients who were refractory to interferon. This was demonstrated by decreased levels of malonaldehyde and reduced activation of HSCs [34]. Similarly, a moderate reduction in serum ALT to 63 IU/l from baseline levels of 73 IU/l was observed in 17 patients who received vitamin E treatment (500 mg/day) for three months [35]. Previous studies report that humans experience severe functional and structural alterations after ingesting EtOH, which disrupts metabolism. GSH and SOD depletion occurs in case of EtOH exposure owing to their rapid utilization by ROS [36,37].

In our study, several assays also suggested that pre-treatment of HepG2 cells with p-CYM significantly reduced EtOH-induced oxidative stress and cell death. The present findings indicated that pre-treatment with p-CYM prevented the decrease in GSH and SOD levels in HepG2 cells. The restoration of the intracellular GSH and SOD levels in HepG2 cells pre-exposed with p-CYM indicated that increased amounts of EtOH-induced ROS could be scavenged, which subsequently resulted in reduced cellular damage. Furthermore, the pathological changes associated with DEN–CCl4-induced LF were significantly reduced by p-CYM, illustrating its beneficial effects in the resolution of LF.

In order to elucidate the possible molecular mechanism behind the hepatoprotective effects of p-CYM, we assessed the transcription levels of several pro- and anti-fibrotic biomarkers. Studies have revealed that pro-inflammatory mediators are crucial to the process of fibrogenesis, and those who suffer from chronic liver conditions have elevated IL-1β levels in their serum [38,39]. IL-1β is currently regarded as a key regulator of tissue injury and inflammation in chronic liver disorders because of its critical role in the transformation of steatosis into steatohepatitis and LF [40,41,42]. Our tested compound, p-CYM, showed potential anti-fibrotic properties by significantly reducing mRNA expression of IL-1β in rats.

Other cytokine family members that promote both acute and chronic inflammation in the liver include TNF-α and IL-6 [43,44,45]. The IKK and JNK pathways are activated by TNF receptor interactions by bringing in the adaptor molecules [46]. IKK phosphorylates IκB and p65, resulting in NF-κB activation [47]. Increased JNK activity tips the scales in favor of cell death by causing the E3 ligase to be phosphorylated, followed by the ubiquitination and degradation of the NF-κB-regulated caspase-8 inhibitor “c-Flip.” Prolonged activation of JNK necessitates TNF-α-induced ROS generation and moves the balance toward cell death [48]. Moreover, liver inflammation caused by EtOH is believed to be exacerbated by the pro-inflammatory cytokine IL-6, which plays a critical role in the progression of liver damage [49,50,51]. Elevated levels of IL-6 have been linked to the activation of several downstream signaling pathways, including the Janus kinase (JAK)/signal transducer and activator of the transcription 3 (STAT3) pathway. This pathway is a key mediator of LF and contributes to the chronic inflammatory environment associated with ALD. The activation of JAK/STAT3 by IL-6 leads to the transcription of target genes involved in fibrosis, inflammation, and cell survival, promoting the persistence of HSC activation and ECM deposition. This cascade not only worsens liver inflammation but also accelerates the progression of fibrosis, thereby playing a pivotal role in the pathogenesis of EtOH-induced liver injury [52]. Our study also revealed an increased expression rate of these biomarkers in EtOH-intoxicated HepG2 cells, and p-CYM effectively reduced the transcript levels of TNF-α and IL-6, reiterating its protective mechanism.

TGF-β1 is another significant regulator of liver cell growth and plays a role in the progression of chronic liver damage [53]. Numerous studies have shown that EtOH-induced inflammation results in the production of TGF-β1, which is thought to be crucial for the pathophysiology and development of ALD [54]. One of the primary proteins that promotes fibrogenesis is TGF-β1, which stimulates HSC and causes them to activate and produce ECM proteins [55]. Previous studies have indicated that LF is associated with high levels of TGF-β1 and COL1A1 expression, and the collagen deposition increases as the fibrosis progresses [56,57,58,59]. In the present study, we also witnessed increased levels of TGF-β1 and COL1A1 in EtOH- and DEN–CCl4-induced hepatic damage, while p-CYM significantly reduced these biomarkers, illustrating its anti-fibrotic effect.

TIMP and MMP proteins normally exist in equilibrium in healthy tissue; however, due to chronic liver damage, TIMP-1 levels increase than MMP-1 levels, which results in inhibition of ECM breakdown [60,61]. Advanced stages of LF include almost six times the normal amount of ECM, which includes proteoglycans, fibronectin, elastin, laminin, hyaluronan, and collagens I, III, and IV. Both increased synthesis and decreased degradation lead to the accumulation of ECM proteins [62]. The primary cause of the decreased activity of ECM-removing MMPs is the overexpression of their particular inhibitors (TIMPs). The breakdown of ECM proteins and programmed cell death of HSCs are the mechanisms underlying the MMP-derived inhibition of the fibrogenic response [63,64]. In this study, we also witnessed a reduction in TIMP-1 and induction in MMP-1 levels upon treatment with p-CYM, indicating that p-CYM has the ability to reduce fibrogenic response by promoting ECM degradation.

Overall, this study highlights the therapeutic potential of p-CYM against EtOH- and CCl₄-induced hepatotoxicity, suggesting its viability as a protective agent against liver damage. Despite its promise, one key limitation of p-CYM, like many natural compounds, may be its relatively low bioavailability, which can restrict its therapeutic efficacy. To address this challenge, future research could focus on developing a nanoformulation of p-CYM.

Nanoformulations have emerged as a cutting-edge approach in drug delivery, particularly for compounds that face challenges related to solubility, stability, or targeted delivery. By incorporating p-CYM into nanocarriers, its bioavailability can be significantly improved, ensuring more effective systemic circulation and cellular uptake. Moreover, nanomaterials offer several distinct advantages that make them highly suitable for this purpose. These include their large drug-loading capacity, which allows for the encapsulation of significant amounts of therapeutic agents, and their surface modification capabilities, enabling the development of targeted delivery systems. Such targeted systems could direct p-CYM specifically to the liver, minimizing off-target effects and enhancing therapeutic precision. Additionally, nanocarriers can offer controlled release profiles, ensuring sustained therapeutic levels of the drug over time [65,66,67].

Given the substantial progress in the field of nanotechnology, this approach could transform p-CYM from a promising natural compound into a highly effective therapeutic agent. Future investigations could explore various nanocarrier systems, such as liposomes, polymeric nanoparticles, or lipid-based nanocarriers, to identify the most suitable platform for p-CYM delivery. Collectively, these advancements could pave the way for the clinical translation of p-CYM as a novel hepatoprotective therapy.

5 Conclusion

Based on in vitro findings, it can be concluded from this study that EtOH intoxication in the HepG2 cell line induces oxidative stress, inflammation, and collagen synthesis, as evident by reduced anti-oxidants (GSH and SOD) and increased levels of inflammatory (IL-1β and TNF-α) and pro-fibrotic (TGF-β1 and COL1A1) biomarkers. P-CYM protected HepG2 cells from EtOH-induced cell death owing to its anti-oxidant and anti-inflammatory properties. Moreover, p-CYM also reduced the levels of pro-fibrotic mediators under in vitro settings. Similarly, under in vivo conditions, DEN- CCl4 induced oxidative stress and fibrosis, while treatment with p-CYM effectively reversed pro-fibrotic effects of DEN–CCl4. In a nutshell, it is conceivable from this study that the hepatoprotective effects of p-CYM could be attributed to its anti-oxidant, anti-inflammatory, and ECM modulatory activities.

# Contributed equally.

Acknowledgments

The authors extend their appreciation to researchers supporting the project number (RSPD2025R885) at King Saud University, Riyadh, Saudi Arabia, for supporting this research. We would like to thank Dr. Ahsan Sattar (Institute of Molecular Biology, The University of Lahore) for providing us with the platform for cell culture studies.

  1. Funding information: The authors extend their appreciation to researchers supporting the project number (RSPD2025R885) at King Saud University, Riyadh, Saudi Arabia, for supporting this research.

  2. Author contributions: M.A. performed all the cell culture experiments, performed data analyses, and wrote the first version of the manuscript. M.N.H.M. designed and supervised the project, arranged all the resources, analyzed and validated the experimental data, and edited the final version of the manuscript. T.G.A. performed docking studies, validated all the data, and edited the final version of the manuscript. M.A. performed in vivo experiments, data analyses, and edited the final version of the manuscript. H.M.B. performed in vivo experiments and validated all data. W.Y., K.S.A., and S.I.A. performed ELISA and histopathological assays. B.A. and I.A. performed histopathological and statistical analyses. S.J. and T.M. performed qPCR and data analyses. G.F.B.S. analyzed and validated all data and edited the final version of the manuscript. All authors participated in editing the final version of the manuscript.

  3. Conflict of interest: Authors state no conflict of interest.

  4. Data availability statement: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Received: 2024-07-25
Revised: 2024-12-16
Accepted: 2024-12-31
Published Online: 2025-04-15

© 2025 the author(s), published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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  34. Ephedra fragilis plant extract: A groundbreaking corrosion inhibitor for mild steel in acidic environments – electrochemical, EDX, DFT, and Monte Carlo studies
  35. Langerhans cell histiocytosis in an adult patient with upper jaw and pulmonary involvement: A case report
  36. Inhibition of mast cell activation by Jaranol-targeted Pirin ameliorates allergic responses in mouse allergic rhinitis
  37. Aeromonas veronii-induced septic arthritis of the hip in a child with acute lymphoblastic leukemia
  38. Clusterin activates the heat shock response via the PI3K/Akt pathway to protect cardiomyocytes from high-temperature-induced apoptosis
  39. Research progress on fecal microbiota transplantation in tumor prevention and treatment
  40. Low-pressure exposure influences the development of HAPE
  41. Stigmasterol alleviates endplate chondrocyte degeneration through inducing mitophagy by enhancing PINK1 mRNA acetylation via the ESR1/NAT10 axis
  42. AKAP12, mediated by transcription factor 21, inhibits cell proliferation, metastasis, and glycolysis in lung squamous cell carcinoma
  43. Association between PAX9 or MSX1 gene polymorphism and tooth agenesis risk: A meta-analysis
  44. A case of bloodstream infection caused by Neisseria gonorrhoeae
  45. Case of nasopharyngeal tuberculosis complicated with cervical lymph node and pulmonary tuberculosis
  46. p-Cymene inhibits pro-fibrotic and inflammatory mediators to prevent hepatic dysfunction
  47. GFPT2 promotes paclitaxel resistance in epithelial ovarian cancer cells via activating NF-κB signaling pathway
  48. Transfer RNA-derived fragment tRF-36 modulates varicose vein progression via human vascular smooth muscle cell Notch signaling
  49. RTA-408 attenuates the hepatic ischemia reperfusion injury in mice possibly by activating the Nrf2/HO-1 signaling pathway
  50. Decreased serum TIMP4 levels in patients with rheumatoid arthritis
  51. Sirt1 protects lupus nephritis by inhibiting the NLRP3 signaling pathway in human glomerular mesangial cells
  52. Sodium butyrate aids brain injury repair in neonatal rats
  53. Interaction of MTHFR polymorphism with PAX1 methylation in cervical cancer
  54. Convallatoxin inhibits proliferation and angiogenesis of glioma cells via regulating JAK/STAT3 pathway
  55. The effect of the PKR inhibitor, 2-aminopurine, on the replication of influenza A virus, and segment 8 mRNA splicing
  56. Effects of Ire1 gene on virulence and pathogenicity of Candida albicans
  57. Small cell lung cancer with small intestinal metastasis: Case report and literature review
  58. GRB14: A prognostic biomarker driving tumor progression in gastric cancer through the PI3K/AKT signaling pathway by interacting with COBLL1
  59. 15-Lipoxygenase-2 deficiency induces foam cell formation that can be restored by salidroside through the inhibition of arachidonic acid effects
  60. FTO alleviated the diabetic nephropathy progression by regulating the N6-methyladenosine levels of DACT1
  61. Clinical relevance of inflammatory markers in the evaluation of severity of ulcerative colitis: A retrospective study
  62. Zinc valproic acid complex promotes osteoblast differentiation and exhibits anti-osteoporotic potential
  63. Primary pulmonary synovial sarcoma in the bronchial cavity: A case report
  64. Metagenomic next-generation sequencing of alveolar lavage fluid improves the detection of pulmonary infection
  65. Uterine tumor resembling ovarian sex cord tumor with extensive rhabdoid differentiation: A case report
  66. Genomic analysis of a novel ST11(PR34365) Clostridioides difficile strain isolated from the human fecal of a CDI patient in Guizhou, China
  67. Effects of tiered cardiac rehabilitation on CRP, TNF-α, and physical endurance in older adults with coronary heart disease
  68. Changes in T-lymphocyte subpopulations in patients with colorectal cancer before and after acupoint catgut embedding acupuncture observation
  69. Modulating the tumor microenvironment: The role of traditional Chinese medicine in improving lung cancer treatment
  70. Alterations of metabolites related to microbiota–gut–brain axis in plasma of colon cancer, esophageal cancer, stomach cancer, and lung cancer patients
  71. Research on individualized drug sensitivity detection technology based on bio-3D printing technology for precision treatment of gastrointestinal stromal tumors
  72. CEBPB promotes ulcerative colitis-associated colorectal cancer by stimulating tumor growth and activating the NF-κB/STAT3 signaling pathway
  73. Oncolytic bacteria: A revolutionary approach to cancer therapy
  74. A de novo meningioma with rapid growth: A possible malignancy imposter?
  75. Diagnosis of secondary tuberculosis infection in an asymptomatic elderly with cancer using next-generation sequencing: Case report
  76. Hesperidin and its zinc(ii) complex enhance osteoblast differentiation and bone formation: In vitro and in vivo evaluations
  77. Research progress on the regulation of autophagy in cardiovascular diseases by chemokines
  78. Anti-arthritic, immunomodulatory, and inflammatory regulation by the benzimidazole derivative BMZ-AD: Insights from an FCA-induced rat model
  79. Immunoassay for pyruvate kinase M1/2 as an Alzheimer’s biomarker in CSF
  80. The role of HDAC11 in age-related hearing loss: Mechanisms and therapeutic implications
  81. Evaluation and application analysis of animal models of PIPNP based on data mining
  82. Therapeutic approaches for liver fibrosis/cirrhosis by targeting pyroptosis
  83. Fabrication of zinc oxide nanoparticles using Ruellia tuberosa leaf extract induces apoptosis through P53 and STAT3 signalling pathways in prostate cancer cells
  84. Haplo-hematopoietic stem cell transplantation and immunoradiotherapy for severe aplastic anemia complicated with nasopharyngeal carcinoma: A case report
  85. Modulation of the KEAP1-NRF2 pathway by Erianin: A novel approach to reduce psoriasiform inflammation and inflammatory signaling
  86. The expression of epidermal growth factor receptor 2 and its relationship with tumor-infiltrating lymphocytes and clinical pathological features in breast cancer patients
  87. Innovations in MALDI-TOF Mass Spectrometry: Bridging modern diagnostics and historical insights
  88. BAP1 complexes with YY1 and RBBP7 and its downstream targets in ccRCC cells
  89. Hypereosinophilic syndrome with elevated IgG4 and T-cell clonality: A report of two cases
  90. Electroacupuncture alleviates sciatic nerve injury in sciatica rats by regulating BDNF and NGF levels, myelin sheath degradation, and autophagy
  91. Polydatin prevents cholesterol gallstone formation by regulating cholesterol metabolism via PPAR-γ signaling
  92. RNF144A and RNF144B: Important molecules for health
  93. Analysis of the detection rate and related factors of thyroid nodules in the healthy population
  94. Artesunate inhibits hepatocellular carcinoma cell migration and invasion through OGA-mediated O-GlcNAcylation of ZEB1
  95. Endovascular management of post-pancreatectomy hemorrhage caused by a hepatic artery pseudoaneurysm: Case report and review of the literature
  96. Efficacy and safety of anti-PD-1/PD-L1 antibodies in patients with relapsed refractory diffuse large B-cell lymphoma: A meta-analysis
  97. SATB2 promotes humeral fracture healing in rats by activating the PI3K/AKT pathway
  98. Overexpression of the ferroptosis-related gene, NFS1, corresponds to gastric cancer growth and tumor immune infiltration
  99. Understanding risk factors and prognosis in diabetic foot ulcers
  100. Atractylenolide I alleviates the experimental allergic response in mice by suppressing TLR4/NF-kB/NLRP3 signalling
  101. FBXO31 inhibits the stemness characteristics of CD147 (+) melanoma stem cells
  102. Immune molecule diagnostics in colorectal cancer: CCL2 and CXCL11
  103. Inhibiting CXCR6 promotes senescence of activated hepatic stellate cells with limited proinflammatory SASP to attenuate hepatic fibrosis
  104. Cadmium toxicity, health risk and its remediation using low-cost biochar adsorbents
  105. Pulmonary cryptococcosis with headache as the first presentation: A case report
  106. Solitary pulmonary metastasis with cystic airspaces in colon cancer: A rare case report
  107. RUNX1 promotes denervation-induced muscle atrophy by activating the JUNB/NF-κB pathway and driving M1 macrophage polarization
  108. Morphometric analysis and immunobiological investigation of Indigofera oblongifolia on the infected lung with Plasmodium chabaudi
  109. The NuA4/TIP60 histone-modifying complex and Hr78 modulate the Lobe2 mutant eye phenotype
  110. Experimental study on salmon demineralized bone matrix loaded with recombinant human bone morphogenetic protein-2: In vitro and in vivo study
  111. A case of IgA nephropathy treated with a combination of telitacicept and half-dose glucocorticoids
  112. Analgesic and toxicological evaluation of cannabidiol-rich Moroccan Cannabis sativa L. (Khardala variety) extract: Evidence from an in vivo and in silico study
  113. Wound healing and signaling pathways
  114. Combination of immunotherapy and whole-brain radiotherapy on prognosis of patients with multiple brain metastases: A retrospective cohort study
  115. To explore the relationship between endometrial hyperemia and polycystic ovary syndrome
  116. Research progress on the impact of curcumin on immune responses in breast cancer
  117. Biogenic Cu/Ni nanotherapeutics from Descurainia sophia (L.) Webb ex Prantl seeds for the treatment of lung cancer
  118. Dapagliflozin attenuates atrial fibrosis via the HMGB1/RAGE pathway in atrial fibrillation rats
  119. Glycitein alleviates inflammation and apoptosis in keratinocytes via ROS-associated PI3K–Akt signalling pathway
  120. ADH5 inhibits proliferation but promotes EMT in non-small cell lung cancer cell through activating Smad2/Smad3
  121. Apoptotic efficacies of AgNPs formulated by Syzygium aromaticum leaf extract on 32D-FLT3-ITD human leukemia cell line with PI3K/AKT/mTOR signaling pathway
  122. Novel cuproptosis-related genes C1QBP and PFKP identified as prognostic and therapeutic targets in lung adenocarcinoma
  123. Bee venom promotes exosome secretion and alters miRNA cargo in T cells
  124. Treatment of pure red cell aplasia in a chronic kidney disease patient with roxadustat: A case report
  125. Comparative bioinformatics analysis of the Wnt pathway in breast cancer: Selection of novel biomarker panels associated with ER status
  126. Kynurenine facilitates renal cell carcinoma progression by suppressing M2 macrophage pyroptosis through inhibition of CASP1 cleavage
  127. RFX5 promotes the growth, motility, and inhibits apoptosis of gastric adenocarcinoma cells through the SIRT1/AMPK axis
  128. ALKBH5 exacerbates early cardiac damage after radiotherapy for breast cancer via m6A demethylation of TLR4
  129. Phytochemicals of Roman chamomile: Antioxidant, anti-aging, and whitening activities of distillation residues
  130. Circadian gene Cry1 inhibits the tumorigenicity of hepatocellular carcinoma by the BAX/BCL2-mediated apoptosis pathway
  131. The TNFR-RIPK1/RIPK3 signalling pathway mediates the effect of lanthanum on necroptosis of nerve cells
  132. Longitudinal monitoring of autoantibody dynamics in patients with early-stage non-small-cell lung cancer undergoing surgery
  133. The potential role of rutin, a flavonoid, in the management of cancer through modulation of cell signaling pathways
  134. Construction of pectinase gene engineering microbe and its application in tobacco sheets
  135. Construction of a microbial abundance prognostic scoring model based on intratumoral microbial data for predicting the prognosis of lung squamous cell carcinoma
  136. Sepsis complicated by haemophagocytic lymphohistiocytosis triggered by methicillin-resistant Staphylococcus aureus and human herpesvirus 8 in an immunocompromised elderly patient: A case report
  137. Sarcopenia in liver transplantation: A comprehensive bibliometric study of current research trends and future directions
  138. Advances in cancer immunotherapy and future directions in personalized medicine
  139. Can coronavirus disease 2019 affect male fertility or cause spontaneous abortion? A two-sample Mendelian randomization analysis
  140. Heat stroke associated with novel leukaemia inhibitory factor receptor gene variant in a Chinese infant
  141. PSME2 exacerbates ulcerative colitis by disrupting intestinal barrier function and promoting autophagy-dependent inflammation
  142. Hyperosmolar hyperglycemic state with severe hypernatremia coexisting with central diabetes insipidus: A case report and literature review
  143. Efficacy and mechanism of escin in improving the tissue microenvironment of blood vessel walls via anti-inflammatory and anticoagulant effects: Implications for clinical practice
  144. Merkel cell carcinoma: Clinicopathological analysis of three patients and literature review
  145. Genetic variants in VWF exon 26 and their implications for type 1 Von Willebrand disease in a Saudi Arabian population
  146. Lipoxin A4 improves myocardial ischemia/reperfusion injury through the Notch1-Nrf2 signaling pathway
  147. High levels of EPHB2 expression predict a poor prognosis and promote tumor progression in endometrial cancer
  148. Knockdown of SHP-2 delays renal tubular epithelial cell injury in diabetic nephropathy by inhibiting NLRP3 inflammasome-mediated pyroptosis
  149. Exploring the toxicity mechanisms and detoxification methods of Rhizoma Paridis
  150. Concomitant gastric carcinoma and primary hepatic angiosarcoma in a patient: A case report
  151. YAP1 inhibition protects retinal vascular endothelial cells under high glucose by inhibiting autophagy
  152. Identification of secretory protein related biomarkers for primary biliary cholangitis based on machine learning and experimental validation
  153. Integrated genomic and clinical modeling for prognostic assessment of radiotherapy response in rectal neoplasms
  154. Stem cell-based approaches for glaucoma treatment: a mini review
  155. Bacteriophage titering by optical density means: KOTE assays
  156. Neutrophil-related signature characterizes immune landscape and predicts prognosis of esophageal squamous cell carcinoma
  157. Integrated bioinformatic analysis and machine learning strategies to identify new potential immune biomarkers for Alzheimer’s disease and their targeting prediction with geniposide
  158. TRIM21 accelerates ferroptosis in intervertebral disc degeneration by promoting SLC7A11 ubiquitination and degradation
  159. TRIM21 accelerates ferroptosis in intervertebral disc degeneration by promoting SLC7A11 ubiquitination and degradation
  160. Histone modification and non-coding RNAs in skin aging: emerging therapeutic avenues
  161. A multiplicative behavioral model of DNA replication initiation in cells
  162. Biogenic gold nanoparticles synthesized from Pergularia daemia leaves: a novel approach for nasopharyngeal carcinoma therapy
  163. Creutzfeldt-Jakob disease mimicking Hashimoto’s encephalopathy: steroid response followed by decline
  164. Impact of semaphorin, Sema3F, on the gene transcription and protein expression of CREB and its binding protein CREBBP in primary hippocampal neurons of rats
  165. Iron overloaded M0 macrophages regulate hematopoietic stem cell proliferation and senescence via the Nrf2/Keap1/HO-1 pathway
  166. Revisiting the link between NADPH oxidase p22phox C242T polymorphism and ischemic stroke risk: an updated meta-analysis
  167. Exercise training preferentially modulates α1D-adrenergic receptor expression in peripheral arteries of hypertensive rats
  168. Overexpression of HE4/WFDC2 gene in mice leads to keratitis and corneal opacity
  169. Tumoral calcinosis complicating CKD-MBD in hemodialysis: a case report
  170. Mechanism of KLF4 Inhibition of epithelial-mesenchymal transition in gastric cancer cells
  171. Dissecting the molecular mechanisms of T cell infiltration in psoriatic lesions via cell-cell communication and regulatory network analysis
  172. Circadian rhythm-based prognostic features predict immune infiltration and tumor microenvironment in molecular subtypes of hepatocellular carcinoma
  173. Ecology and Environmental Science
  174. Optimization and comparative study of Bacillus consortia for cellulolytic potential and cellulase enzyme activity
  175. The complete mitochondrial genome analysis of Haemaphysalis hystricis Supino, 1897 (Ixodida: Ixodidae) and its phylogenetic implications
  176. Epidemiological characteristics and risk factors analysis of multidrug-resistant tuberculosis among tuberculosis population in Huzhou City, Eastern China
  177. Indices of human impacts on landscapes: How do they reflect the proportions of natural habitats?
  178. Genetic analysis of the Siberian flying squirrel population in the northern Changbai Mountains, Northeast China: Insights into population status and conservation
  179. Diversity and environmental drivers of Suillus communities in Pinus sylvestris var. mongolica forests of Inner Mongolia
  180. Global assessment of the fate of nitrogen deposition in forest ecosystems: Insights from 15N tracer studies
  181. Fungal and bacterial pathogenic co-infections mainly lead to the assembly of microbial community in tobacco stems
  182. Influencing of coal industry related airborne particulate matter on ocular surface tear film injury and inflammatory factor expression in Sprague-Dawley rats
  183. Temperature-dependent development, predation, and life table of Sphaerophoria macrogaster (Thomson) (Diptera: Syrphidae) feeding on Myzus persicae (Sulzer) (Homoptera: Aphididae)
  184. Eleonora’s falcon trophic interactions with insects within its breeding range: A systematic review
  185. Agriculture
  186. Integrated analysis of transcriptome, sRNAome, and degradome involved in the drought-response of maize Zhengdan958
  187. Variation in flower frost tolerance among seven apple cultivars and transcriptome response patterns in two contrastingly frost-tolerant selected cultivars
  188. Heritability of durable resistance to stripe rust in bread wheat (Triticum aestivum L.)
  189. Molecular mechanism of follicular development in laying hens based on the regulation of water metabolism
  190. Molecular identification and control studies on Coridius sp. (Hemiptera: Dinidoridae) in Al-Khamra, south of Jeddah, Saudi Arabia
  191. 10.1515/biol-2025-1218
  192. Animal Science
  193. Effect of sex ratio on the life history traits of an important invasive species, Spodoptera frugiperda
  194. Plant Sciences
  195. Hairpin in a haystack: In silico identification and characterization of plant-conserved microRNA in Rafflesiaceae
  196. Widely targeted metabolomics of different tissues in Rubus corchorifolius
  197. The complete chloroplast genome of Gerbera piloselloides (L.) Cass., 1820 (Carduoideae, Asteraceae) and its phylogenetic analysis
  198. Field trial to correlate mineral solubilization activity of Pseudomonas aeruginosa and biochemical content of groundnut plants
  199. Correlation analysis between semen routine parameters and sperm DNA fragmentation index in patients with semen non-liquefaction: A retrospective study
  200. Plasticity of the anatomical traits of Rhododendron L. (Ericaceae) leaves and its implications in adaptation to the plateau environment
  201. Effects of Piriformospora indica and arbuscular mycorrhizal fungus on growth and physiology of Moringa oleifera under low-temperature stress
  202. Effects of different sources of potassium fertiliser on yield, fruit quality and nutrient absorption in “Harward” kiwifruit (Actinidia deliciosa)
  203. Comparative efficiency and residue levels of spraying programs against powdery mildew in grape varieties
  204. The DREB7 transcription factor enhances salt tolerance in soybean plants under salt stress
  205. Using plant electrical signals of water hyacinth (Eichhornia crassipes) for water pollution monitoring
  206. Response of hybrid grapes (Vitis spp.) to two biotic stress factors and their seedlessness status
  207. Metabolomic profiling reveals systemic metabolic reprogramming in Alternaria alternata under salt stress
  208. Effects of mixed salinity and alkali stress on photosynthetic characteristics and PEPC gene expression of vegetable soybean seedlings
  209. Food Science
  210. Phytochemical analysis of Stachys iva: Discovering the optimal extract conditions and its bioactive compounds
  211. Review on role of honey in disease prevention and treatment through modulation of biological activities
  212. Computational analysis of polymorphic residues in maltose and maltotriose transporters of a wild Saccharomyces cerevisiae strain
  213. Optimization of phenolic compound extraction from Tunisian squash by-products: A sustainable approach for antioxidant and antibacterial applications
  214. Liupao tea aqueous extract alleviates dextran sulfate sodium-induced ulcerative colitis in rats by modulating the gut microbiota
  215. Toxicological qualities and detoxification trends of fruit by-products for valorization: A review
  216. Polyphenolic spectrum of cornelian cherry fruits and their health-promoting effect
  217. Optimizing the encapsulation of the refined extract of squash peels for functional food applications: A sustainable approach to reduce food waste
  218. Advancements in curcuminoid formulations: An update on bioavailability enhancement strategies curcuminoid bioavailability and formulations
  219. Impact of saline sprouting on antioxidant properties and bioactive compounds in chia seeds
  220. The dilemma of food genetics and improvement
  221. Causal effects of trace elements on congenital foot deformities and their subtypes: a Mendelian randomization study with gut microbiota mediation
  222. Honey meets acidity: a novel biopreservative approach against foodborne pathogens
  223. Bioengineering and Biotechnology
  224. Impact of hyaluronic acid-modified hafnium metalorganic frameworks containing rhynchophylline on Alzheimer’s disease
  225. Emerging patterns in nanoparticle-based therapeutic approaches for rheumatoid arthritis: A comprehensive bibliometric and visual analysis spanning two decades
  226. Application of CRISPR/Cas gene editing for infectious disease control in poultry
  227. Preparation of hafnium nitride-coated titanium implants by magnetron sputtering technology and evaluation of their antibacterial properties and biocompatibility
  228. Preparation and characterization of lemongrass oil nanoemulsion: Antimicrobial, antibiofilm, antioxidant, and anticancer activities
  229. Fluorescent detection of sialic acid–binding lectins using functionalized quantum dots in ELISA format
  230. Smart tectorigenin-loaded ZnO hydrogel nanocomposites for targeted wound healing: synthesis, characterization, and biological evaluation
  231. Corrigendum
  232. Corrigendum to “Utilization of convolutional neural networks to analyze microscopic images for high-throughput screening of mesenchymal stem cells”
  233. Corrigendum to “Effects of Ire1 gene on virulence and pathogenicity of Candida albicans”
  234. Retraction
  235. Retraction of “Down-regulation of miR-539 indicates poor prognosis in patients with pancreatic cancer”
https://doi.org/10.1515/biol-2022-1054
Keywords for this article
p-cymene; HepG2; DEN- CCl4; liver fibrosis; hepatoprotective; TGF-β1
Creative Commons
BY 4.0

Articles in the same Issue

  1. Safety assessment and modulation of hepatic CYP3A4 and UGT enzymes by Glycyrrhiza glabra aqueous extract in female Sprague–Dawley rats
  2. Adult-onset Still’s disease with hemophagocytic lymphohistiocytosis and minimal change disease
  3. Role of DZ2002 in reducing corneal graft rejection in rats by influencing Th17 activation via inhibition of the PI3K/AKT pathway and downregulation of TRAF1
  4. Biomedical Sciences
  5. Mechanism of triptolide regulating proliferation and apoptosis of hepatoma cells by inhibiting JAK/STAT pathway
  6. Maslinic acid improves mitochondrial function and inhibits oxidative stress and autophagy in human gastric smooth muscle cells
  7. Comparative analysis of inflammatory biomarkers for the diagnosis of neonatal sepsis: IL-6, IL-8, SAA, CRP, and PCT
  8. Post-pandemic insights on COVID-19 and premature ovarian insufficiency
  9. Proteome differences of dental stem cells between permanent and deciduous teeth by data-independent acquisition proteomics
  10. Optimizing a modified cetyltrimethylammonium bromide protocol for fungal DNA extraction: Insights from multilocus gene amplification
  11. Preliminary analysis of the role of small hepatitis B surface proteins mutations in the pathogenesis of occult hepatitis B infection via the endoplasmic reticulum stress-induced UPR-ERAD pathway
  12. Efficacy of alginate-coated gold nanoparticles against antibiotics-resistant Staphylococcus and Streptococcus pathogens of acne origins
  13. Battling COVID-19 leveraging nanobiotechnology: Gold and silver nanoparticle–B-escin conjugates as SARS-CoV-2 inhibitors
  14. Neurodegenerative diseases and neuroinflammation-induced apoptosis
  15. Impact of fracture fixation surgery on cognitive function and the gut microbiota in mice with a history of stroke
  16. COLEC10: A potential tumor suppressor and prognostic biomarker in hepatocellular carcinoma through modulation of EMT and PI3K-AKT pathways
  17. High-temperature requirement serine protease A2 inhibitor UCF-101 ameliorates damaged neurons in traumatic brain-injured rats by the AMPK/NF-κB pathway
  18. SIK1 inhibits IL-1β-stimulated cartilage apoptosis and inflammation in vitro through the CRTC2/CREB1 signaling
  19. Rutin–chitooligosaccharide complex: Comprehensive evaluation of its anti-inflammatory and analgesic properties in vitro and in vivo
  20. Knockdown of Aurora kinase B alleviates high glucose-triggered trophoblast cells damage and inflammation during gestational diabetes
  21. Calcium-sensing receptors promoted Homer1 expression and osteogenic differentiation in bone marrow mesenchymal stem cells
  22. ABI3BP can inhibit the proliferation, invasion, and epithelial–mesenchymal transition of non-small-cell lung cancer cells
  23. Changes in blood glucose and metabolism in hyperuricemia mice
  24. Rapid detection of the GJB2 c.235delC mutation based on CRISPR-Cas13a combined with lateral flow dipstick
  25. IL-11 promotes Ang II-induced autophagy inhibition and mitochondrial dysfunction in atrial fibroblasts
  26. Short-chain fatty acid attenuates intestinal inflammation by regulation of gut microbial composition in antibiotic-associated diarrhea
  27. Application of metagenomic next-generation sequencing in the diagnosis of pathogens in patients with diabetes complicated by community-acquired pneumonia
  28. NAT10 promotes radiotherapy resistance in non-small cell lung cancer by regulating KPNB1-mediated PD-L1 nuclear translocation
  29. Phytol-mixed micelles alleviate dexamethasone-induced osteoporosis in zebrafish: Activation of the MMP3–OPN–MAPK pathway-mediating bone remodeling
  30. Association between TGF-β1 and β-catenin expression in the vaginal wall of patients with pelvic organ prolapse
  31. Primary pleomorphic liposarcoma involving bilateral ovaries: Case report and literature review
  32. Effects of de novo donor-specific Class I and II antibodies on graft outcomes after liver transplantation: A pilot cohort study
  33. Sleep architecture in Alzheimer’s disease continuum: The deep sleep question
  34. Ephedra fragilis plant extract: A groundbreaking corrosion inhibitor for mild steel in acidic environments – electrochemical, EDX, DFT, and Monte Carlo studies
  35. Langerhans cell histiocytosis in an adult patient with upper jaw and pulmonary involvement: A case report
  36. Inhibition of mast cell activation by Jaranol-targeted Pirin ameliorates allergic responses in mouse allergic rhinitis
  37. Aeromonas veronii-induced septic arthritis of the hip in a child with acute lymphoblastic leukemia
  38. Clusterin activates the heat shock response via the PI3K/Akt pathway to protect cardiomyocytes from high-temperature-induced apoptosis
  39. Research progress on fecal microbiota transplantation in tumor prevention and treatment
  40. Low-pressure exposure influences the development of HAPE
  41. Stigmasterol alleviates endplate chondrocyte degeneration through inducing mitophagy by enhancing PINK1 mRNA acetylation via the ESR1/NAT10 axis
  42. AKAP12, mediated by transcription factor 21, inhibits cell proliferation, metastasis, and glycolysis in lung squamous cell carcinoma
  43. Association between PAX9 or MSX1 gene polymorphism and tooth agenesis risk: A meta-analysis
  44. A case of bloodstream infection caused by Neisseria gonorrhoeae
  45. Case of nasopharyngeal tuberculosis complicated with cervical lymph node and pulmonary tuberculosis
  46. p-Cymene inhibits pro-fibrotic and inflammatory mediators to prevent hepatic dysfunction
  47. GFPT2 promotes paclitaxel resistance in epithelial ovarian cancer cells via activating NF-κB signaling pathway
  48. Transfer RNA-derived fragment tRF-36 modulates varicose vein progression via human vascular smooth muscle cell Notch signaling
  49. RTA-408 attenuates the hepatic ischemia reperfusion injury in mice possibly by activating the Nrf2/HO-1 signaling pathway
  50. Decreased serum TIMP4 levels in patients with rheumatoid arthritis
  51. Sirt1 protects lupus nephritis by inhibiting the NLRP3 signaling pathway in human glomerular mesangial cells
  52. Sodium butyrate aids brain injury repair in neonatal rats
  53. Interaction of MTHFR polymorphism with PAX1 methylation in cervical cancer
  54. Convallatoxin inhibits proliferation and angiogenesis of glioma cells via regulating JAK/STAT3 pathway
  55. The effect of the PKR inhibitor, 2-aminopurine, on the replication of influenza A virus, and segment 8 mRNA splicing
  56. Effects of Ire1 gene on virulence and pathogenicity of Candida albicans
  57. Small cell lung cancer with small intestinal metastasis: Case report and literature review
  58. GRB14: A prognostic biomarker driving tumor progression in gastric cancer through the PI3K/AKT signaling pathway by interacting with COBLL1
  59. 15-Lipoxygenase-2 deficiency induces foam cell formation that can be restored by salidroside through the inhibition of arachidonic acid effects
  60. FTO alleviated the diabetic nephropathy progression by regulating the N6-methyladenosine levels of DACT1
  61. Clinical relevance of inflammatory markers in the evaluation of severity of ulcerative colitis: A retrospective study
  62. Zinc valproic acid complex promotes osteoblast differentiation and exhibits anti-osteoporotic potential
  63. Primary pulmonary synovial sarcoma in the bronchial cavity: A case report
  64. Metagenomic next-generation sequencing of alveolar lavage fluid improves the detection of pulmonary infection
  65. Uterine tumor resembling ovarian sex cord tumor with extensive rhabdoid differentiation: A case report
  66. Genomic analysis of a novel ST11(PR34365) Clostridioides difficile strain isolated from the human fecal of a CDI patient in Guizhou, China
  67. Effects of tiered cardiac rehabilitation on CRP, TNF-α, and physical endurance in older adults with coronary heart disease
  68. Changes in T-lymphocyte subpopulations in patients with colorectal cancer before and after acupoint catgut embedding acupuncture observation
  69. Modulating the tumor microenvironment: The role of traditional Chinese medicine in improving lung cancer treatment
  70. Alterations of metabolites related to microbiota–gut–brain axis in plasma of colon cancer, esophageal cancer, stomach cancer, and lung cancer patients
  71. Research on individualized drug sensitivity detection technology based on bio-3D printing technology for precision treatment of gastrointestinal stromal tumors
  72. CEBPB promotes ulcerative colitis-associated colorectal cancer by stimulating tumor growth and activating the NF-κB/STAT3 signaling pathway
  73. Oncolytic bacteria: A revolutionary approach to cancer therapy
  74. A de novo meningioma with rapid growth: A possible malignancy imposter?
  75. Diagnosis of secondary tuberculosis infection in an asymptomatic elderly with cancer using next-generation sequencing: Case report
  76. Hesperidin and its zinc(ii) complex enhance osteoblast differentiation and bone formation: In vitro and in vivo evaluations
  77. Research progress on the regulation of autophagy in cardiovascular diseases by chemokines
  78. Anti-arthritic, immunomodulatory, and inflammatory regulation by the benzimidazole derivative BMZ-AD: Insights from an FCA-induced rat model
  79. Immunoassay for pyruvate kinase M1/2 as an Alzheimer’s biomarker in CSF
  80. The role of HDAC11 in age-related hearing loss: Mechanisms and therapeutic implications
  81. Evaluation and application analysis of animal models of PIPNP based on data mining
  82. Therapeutic approaches for liver fibrosis/cirrhosis by targeting pyroptosis
  83. Fabrication of zinc oxide nanoparticles using Ruellia tuberosa leaf extract induces apoptosis through P53 and STAT3 signalling pathways in prostate cancer cells
  84. Haplo-hematopoietic stem cell transplantation and immunoradiotherapy for severe aplastic anemia complicated with nasopharyngeal carcinoma: A case report
  85. Modulation of the KEAP1-NRF2 pathway by Erianin: A novel approach to reduce psoriasiform inflammation and inflammatory signaling
  86. The expression of epidermal growth factor receptor 2 and its relationship with tumor-infiltrating lymphocytes and clinical pathological features in breast cancer patients
  87. Innovations in MALDI-TOF Mass Spectrometry: Bridging modern diagnostics and historical insights
  88. BAP1 complexes with YY1 and RBBP7 and its downstream targets in ccRCC cells
  89. Hypereosinophilic syndrome with elevated IgG4 and T-cell clonality: A report of two cases
  90. Electroacupuncture alleviates sciatic nerve injury in sciatica rats by regulating BDNF and NGF levels, myelin sheath degradation, and autophagy
  91. Polydatin prevents cholesterol gallstone formation by regulating cholesterol metabolism via PPAR-γ signaling
  92. RNF144A and RNF144B: Important molecules for health
  93. Analysis of the detection rate and related factors of thyroid nodules in the healthy population
  94. Artesunate inhibits hepatocellular carcinoma cell migration and invasion through OGA-mediated O-GlcNAcylation of ZEB1
  95. Endovascular management of post-pancreatectomy hemorrhage caused by a hepatic artery pseudoaneurysm: Case report and review of the literature
  96. Efficacy and safety of anti-PD-1/PD-L1 antibodies in patients with relapsed refractory diffuse large B-cell lymphoma: A meta-analysis
  97. SATB2 promotes humeral fracture healing in rats by activating the PI3K/AKT pathway
  98. Overexpression of the ferroptosis-related gene, NFS1, corresponds to gastric cancer growth and tumor immune infiltration
  99. Understanding risk factors and prognosis in diabetic foot ulcers
  100. Atractylenolide I alleviates the experimental allergic response in mice by suppressing TLR4/NF-kB/NLRP3 signalling
  101. FBXO31 inhibits the stemness characteristics of CD147 (+) melanoma stem cells
  102. Immune molecule diagnostics in colorectal cancer: CCL2 and CXCL11
  103. Inhibiting CXCR6 promotes senescence of activated hepatic stellate cells with limited proinflammatory SASP to attenuate hepatic fibrosis
  104. Cadmium toxicity, health risk and its remediation using low-cost biochar adsorbents
  105. Pulmonary cryptococcosis with headache as the first presentation: A case report
  106. Solitary pulmonary metastasis with cystic airspaces in colon cancer: A rare case report
  107. RUNX1 promotes denervation-induced muscle atrophy by activating the JUNB/NF-κB pathway and driving M1 macrophage polarization
  108. Morphometric analysis and immunobiological investigation of Indigofera oblongifolia on the infected lung with Plasmodium chabaudi
  109. The NuA4/TIP60 histone-modifying complex and Hr78 modulate the Lobe2 mutant eye phenotype
  110. Experimental study on salmon demineralized bone matrix loaded with recombinant human bone morphogenetic protein-2: In vitro and in vivo study
  111. A case of IgA nephropathy treated with a combination of telitacicept and half-dose glucocorticoids
  112. Analgesic and toxicological evaluation of cannabidiol-rich Moroccan Cannabis sativa L. (Khardala variety) extract: Evidence from an in vivo and in silico study
  113. Wound healing and signaling pathways
  114. Combination of immunotherapy and whole-brain radiotherapy on prognosis of patients with multiple brain metastases: A retrospective cohort study
  115. To explore the relationship between endometrial hyperemia and polycystic ovary syndrome
  116. Research progress on the impact of curcumin on immune responses in breast cancer
  117. Biogenic Cu/Ni nanotherapeutics from Descurainia sophia (L.) Webb ex Prantl seeds for the treatment of lung cancer
  118. Dapagliflozin attenuates atrial fibrosis via the HMGB1/RAGE pathway in atrial fibrillation rats
  119. Glycitein alleviates inflammation and apoptosis in keratinocytes via ROS-associated PI3K–Akt signalling pathway
  120. ADH5 inhibits proliferation but promotes EMT in non-small cell lung cancer cell through activating Smad2/Smad3
  121. Apoptotic efficacies of AgNPs formulated by Syzygium aromaticum leaf extract on 32D-FLT3-ITD human leukemia cell line with PI3K/AKT/mTOR signaling pathway
  122. Novel cuproptosis-related genes C1QBP and PFKP identified as prognostic and therapeutic targets in lung adenocarcinoma
  123. Bee venom promotes exosome secretion and alters miRNA cargo in T cells
  124. Treatment of pure red cell aplasia in a chronic kidney disease patient with roxadustat: A case report
  125. Comparative bioinformatics analysis of the Wnt pathway in breast cancer: Selection of novel biomarker panels associated with ER status
  126. Kynurenine facilitates renal cell carcinoma progression by suppressing M2 macrophage pyroptosis through inhibition of CASP1 cleavage
  127. RFX5 promotes the growth, motility, and inhibits apoptosis of gastric adenocarcinoma cells through the SIRT1/AMPK axis
  128. ALKBH5 exacerbates early cardiac damage after radiotherapy for breast cancer via m6A demethylation of TLR4
  129. Phytochemicals of Roman chamomile: Antioxidant, anti-aging, and whitening activities of distillation residues
  130. Circadian gene Cry1 inhibits the tumorigenicity of hepatocellular carcinoma by the BAX/BCL2-mediated apoptosis pathway
  131. The TNFR-RIPK1/RIPK3 signalling pathway mediates the effect of lanthanum on necroptosis of nerve cells
  132. Longitudinal monitoring of autoantibody dynamics in patients with early-stage non-small-cell lung cancer undergoing surgery
  133. The potential role of rutin, a flavonoid, in the management of cancer through modulation of cell signaling pathways
  134. Construction of pectinase gene engineering microbe and its application in tobacco sheets
  135. Construction of a microbial abundance prognostic scoring model based on intratumoral microbial data for predicting the prognosis of lung squamous cell carcinoma
  136. Sepsis complicated by haemophagocytic lymphohistiocytosis triggered by methicillin-resistant Staphylococcus aureus and human herpesvirus 8 in an immunocompromised elderly patient: A case report
  137. Sarcopenia in liver transplantation: A comprehensive bibliometric study of current research trends and future directions
  138. Advances in cancer immunotherapy and future directions in personalized medicine
  139. Can coronavirus disease 2019 affect male fertility or cause spontaneous abortion? A two-sample Mendelian randomization analysis
  140. Heat stroke associated with novel leukaemia inhibitory factor receptor gene variant in a Chinese infant
  141. PSME2 exacerbates ulcerative colitis by disrupting intestinal barrier function and promoting autophagy-dependent inflammation
  142. Hyperosmolar hyperglycemic state with severe hypernatremia coexisting with central diabetes insipidus: A case report and literature review
  143. Efficacy and mechanism of escin in improving the tissue microenvironment of blood vessel walls via anti-inflammatory and anticoagulant effects: Implications for clinical practice
  144. Merkel cell carcinoma: Clinicopathological analysis of three patients and literature review
  145. Genetic variants in VWF exon 26 and their implications for type 1 Von Willebrand disease in a Saudi Arabian population
  146. Lipoxin A4 improves myocardial ischemia/reperfusion injury through the Notch1-Nrf2 signaling pathway
  147. High levels of EPHB2 expression predict a poor prognosis and promote tumor progression in endometrial cancer
  148. Knockdown of SHP-2 delays renal tubular epithelial cell injury in diabetic nephropathy by inhibiting NLRP3 inflammasome-mediated pyroptosis
  149. Exploring the toxicity mechanisms and detoxification methods of Rhizoma Paridis
  150. Concomitant gastric carcinoma and primary hepatic angiosarcoma in a patient: A case report
  151. YAP1 inhibition protects retinal vascular endothelial cells under high glucose by inhibiting autophagy
  152. Identification of secretory protein related biomarkers for primary biliary cholangitis based on machine learning and experimental validation
  153. Integrated genomic and clinical modeling for prognostic assessment of radiotherapy response in rectal neoplasms
  154. Stem cell-based approaches for glaucoma treatment: a mini review
  155. Bacteriophage titering by optical density means: KOTE assays
  156. Neutrophil-related signature characterizes immune landscape and predicts prognosis of esophageal squamous cell carcinoma
  157. Integrated bioinformatic analysis and machine learning strategies to identify new potential immune biomarkers for Alzheimer’s disease and their targeting prediction with geniposide
  158. TRIM21 accelerates ferroptosis in intervertebral disc degeneration by promoting SLC7A11 ubiquitination and degradation
  159. TRIM21 accelerates ferroptosis in intervertebral disc degeneration by promoting SLC7A11 ubiquitination and degradation
  160. Histone modification and non-coding RNAs in skin aging: emerging therapeutic avenues
  161. A multiplicative behavioral model of DNA replication initiation in cells
  162. Biogenic gold nanoparticles synthesized from Pergularia daemia leaves: a novel approach for nasopharyngeal carcinoma therapy
  163. Creutzfeldt-Jakob disease mimicking Hashimoto’s encephalopathy: steroid response followed by decline
  164. Impact of semaphorin, Sema3F, on the gene transcription and protein expression of CREB and its binding protein CREBBP in primary hippocampal neurons of rats
  165. Iron overloaded M0 macrophages regulate hematopoietic stem cell proliferation and senescence via the Nrf2/Keap1/HO-1 pathway
  166. Revisiting the link between NADPH oxidase p22phox C242T polymorphism and ischemic stroke risk: an updated meta-analysis
  167. Exercise training preferentially modulates α1D-adrenergic receptor expression in peripheral arteries of hypertensive rats
  168. Overexpression of HE4/WFDC2 gene in mice leads to keratitis and corneal opacity
  169. Tumoral calcinosis complicating CKD-MBD in hemodialysis: a case report
  170. Mechanism of KLF4 Inhibition of epithelial-mesenchymal transition in gastric cancer cells
  171. Dissecting the molecular mechanisms of T cell infiltration in psoriatic lesions via cell-cell communication and regulatory network analysis
  172. Circadian rhythm-based prognostic features predict immune infiltration and tumor microenvironment in molecular subtypes of hepatocellular carcinoma
  173. Ecology and Environmental Science
  174. Optimization and comparative study of Bacillus consortia for cellulolytic potential and cellulase enzyme activity
  175. The complete mitochondrial genome analysis of Haemaphysalis hystricis Supino, 1897 (Ixodida: Ixodidae) and its phylogenetic implications
  176. Epidemiological characteristics and risk factors analysis of multidrug-resistant tuberculosis among tuberculosis population in Huzhou City, Eastern China
  177. Indices of human impacts on landscapes: How do they reflect the proportions of natural habitats?
  178. Genetic analysis of the Siberian flying squirrel population in the northern Changbai Mountains, Northeast China: Insights into population status and conservation
  179. Diversity and environmental drivers of Suillus communities in Pinus sylvestris var. mongolica forests of Inner Mongolia
  180. Global assessment of the fate of nitrogen deposition in forest ecosystems: Insights from 15N tracer studies
  181. Fungal and bacterial pathogenic co-infections mainly lead to the assembly of microbial community in tobacco stems
  182. Influencing of coal industry related airborne particulate matter on ocular surface tear film injury and inflammatory factor expression in Sprague-Dawley rats
  183. Temperature-dependent development, predation, and life table of Sphaerophoria macrogaster (Thomson) (Diptera: Syrphidae) feeding on Myzus persicae (Sulzer) (Homoptera: Aphididae)
  184. Eleonora’s falcon trophic interactions with insects within its breeding range: A systematic review
  185. Agriculture
  186. Integrated analysis of transcriptome, sRNAome, and degradome involved in the drought-response of maize Zhengdan958
  187. Variation in flower frost tolerance among seven apple cultivars and transcriptome response patterns in two contrastingly frost-tolerant selected cultivars
  188. Heritability of durable resistance to stripe rust in bread wheat (Triticum aestivum L.)
  189. Molecular mechanism of follicular development in laying hens based on the regulation of water metabolism
  190. Molecular identification and control studies on Coridius sp. (Hemiptera: Dinidoridae) in Al-Khamra, south of Jeddah, Saudi Arabia
  191. 10.1515/biol-2025-1218
  192. Animal Science
  193. Effect of sex ratio on the life history traits of an important invasive species, Spodoptera frugiperda
  194. Plant Sciences
  195. Hairpin in a haystack: In silico identification and characterization of plant-conserved microRNA in Rafflesiaceae
  196. Widely targeted metabolomics of different tissues in Rubus corchorifolius
  197. The complete chloroplast genome of Gerbera piloselloides (L.) Cass., 1820 (Carduoideae, Asteraceae) and its phylogenetic analysis
  198. Field trial to correlate mineral solubilization activity of Pseudomonas aeruginosa and biochemical content of groundnut plants
  199. Correlation analysis between semen routine parameters and sperm DNA fragmentation index in patients with semen non-liquefaction: A retrospective study
  200. Plasticity of the anatomical traits of Rhododendron L. (Ericaceae) leaves and its implications in adaptation to the plateau environment
  201. Effects of Piriformospora indica and arbuscular mycorrhizal fungus on growth and physiology of Moringa oleifera under low-temperature stress
  202. Effects of different sources of potassium fertiliser on yield, fruit quality and nutrient absorption in “Harward” kiwifruit (Actinidia deliciosa)
  203. Comparative efficiency and residue levels of spraying programs against powdery mildew in grape varieties
  204. The DREB7 transcription factor enhances salt tolerance in soybean plants under salt stress
  205. Using plant electrical signals of water hyacinth (Eichhornia crassipes) for water pollution monitoring
  206. Response of hybrid grapes (Vitis spp.) to two biotic stress factors and their seedlessness status
  207. Metabolomic profiling reveals systemic metabolic reprogramming in Alternaria alternata under salt stress
  208. Effects of mixed salinity and alkali stress on photosynthetic characteristics and PEPC gene expression of vegetable soybean seedlings
  209. Food Science
  210. Phytochemical analysis of Stachys iva: Discovering the optimal extract conditions and its bioactive compounds
  211. Review on role of honey in disease prevention and treatment through modulation of biological activities
  212. Computational analysis of polymorphic residues in maltose and maltotriose transporters of a wild Saccharomyces cerevisiae strain
  213. Optimization of phenolic compound extraction from Tunisian squash by-products: A sustainable approach for antioxidant and antibacterial applications
  214. Liupao tea aqueous extract alleviates dextran sulfate sodium-induced ulcerative colitis in rats by modulating the gut microbiota
  215. Toxicological qualities and detoxification trends of fruit by-products for valorization: A review
  216. Polyphenolic spectrum of cornelian cherry fruits and their health-promoting effect
  217. Optimizing the encapsulation of the refined extract of squash peels for functional food applications: A sustainable approach to reduce food waste
  218. Advancements in curcuminoid formulations: An update on bioavailability enhancement strategies curcuminoid bioavailability and formulations
  219. Impact of saline sprouting on antioxidant properties and bioactive compounds in chia seeds
  220. The dilemma of food genetics and improvement
  221. Causal effects of trace elements on congenital foot deformities and their subtypes: a Mendelian randomization study with gut microbiota mediation
  222. Honey meets acidity: a novel biopreservative approach against foodborne pathogens
  223. Bioengineering and Biotechnology
  224. Impact of hyaluronic acid-modified hafnium metalorganic frameworks containing rhynchophylline on Alzheimer’s disease
  225. Emerging patterns in nanoparticle-based therapeutic approaches for rheumatoid arthritis: A comprehensive bibliometric and visual analysis spanning two decades
  226. Application of CRISPR/Cas gene editing for infectious disease control in poultry
  227. Preparation of hafnium nitride-coated titanium implants by magnetron sputtering technology and evaluation of their antibacterial properties and biocompatibility
  228. Preparation and characterization of lemongrass oil nanoemulsion: Antimicrobial, antibiofilm, antioxidant, and anticancer activities
  229. Fluorescent detection of sialic acid–binding lectins using functionalized quantum dots in ELISA format
  230. Smart tectorigenin-loaded ZnO hydrogel nanocomposites for targeted wound healing: synthesis, characterization, and biological evaluation
  231. Corrigendum
  232. Corrigendum to “Utilization of convolutional neural networks to analyze microscopic images for high-throughput screening of mesenchymal stem cells”
  233. Corrigendum to “Effects of Ire1 gene on virulence and pathogenicity of Candida albicans”
  234. Retraction
  235. Retraction of “Down-regulation of miR-539 indicates poor prognosis in patients with pancreatic cancer”
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