Startseite Lebenswissenschaften Safety assessment and modulation of hepatic CYP3A4 and UGT enzymes by Glycyrrhiza glabra aqueous extract in female Sprague–Dawley rats
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Safety assessment and modulation of hepatic CYP3A4 and UGT enzymes by Glycyrrhiza glabra aqueous extract in female Sprague–Dawley rats

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Abstract

Licorice is generally regarded as safe; however, concerns over potential modulation of hepatic drug-metabolizing enzymes (DMEs) with long-term/repeated high-dose exposure have been reported. The objective of this study was to determine the safety and in vivo effects of licorice aqueous extract on Phase I (cytochrome P450 3A4 [CYP3A4]) and II (uridine diphosphate glucuronosyltransferase [UGT]) hepatic DMEs in female Sprague–Dawley rats (n = 6) following a 14-day repeated oral dose. The 24 rats, weighing 140 ± 10 g, were divided into four groups and administered licorice extract (50, 100, and 200 mg/kg) orally for 14 days. Blood samples were obtained using cardiac puncture for serum biochemical analysis. Liver homogenates were prepared to quantify CYP3A4 and UGT levels using double antibody sandwich ELISA kits. Data were analyzed using Dunnett’s test. There were no signs of systemic toxicity/organ damage. Although serum biochemical values remained normal across all treatment groups, CYP3A4 levels were significantly reduced (p < 0.01), while UGT levels were significantly elevated (p < 0.01). Licorice was non-toxic at the tested doses over 14 days but significantly altered the expression of key hepatic enzymes, highlighting a potential risk of herb–drug interactions when licorice-containing products are coadministered with conventional medications, particularly with those metabolized by the CYP3A4 and UGT pathways.

Keywords: cytochrome P450 3A4; uridine diphosphate glucuronosyltransferase; licorice; rat liver

1 Introduction

Herbal medicines are widely used for health promotion and disease management worldwide [1], 2]. Licorice (Glycyrrhiza spp.) is among the most commonly consumed herbs, valued for its antiviral, anti-inflammatory, and immunomodulatory properties [3], [4], [5]. However, adverse events such as hypokalemia, hypertension, and rhabdomyolysis have been reported after long-term or high-dose intake, raising concerns about herb–drug interactions. Of particular importance are cytochrome P450 3A4 (CYP3A4), the most abundant Phase I drug-metabolizing enzyme, and uridine diphosphate glucuronosyltransferases (UGTs), key Phase II enzymes. Both play central roles in drug clearance and are frequent sites of clinically significant interactions [6], [7], [8].

Natural products have long been recognized for their broad pharmacological and health-promoting benefits, including hepatoprotective, anti-inflammatory, and antioxidant activities [9], [10], [11]. For example, flavonoids and saponins derived from medicinal plants exhibit potent anticancer and hepatoprotective effects [9], 10], while vitamin C and other natural antioxidants have been shown to protect hepatic and renal function [11]. Several patented formulations based on Glycyrrhiza glabra and related phytochemicals have also been developed for therapeutic use, including crocin–sorafenib and safranal–sorafenib combination therapies for liver cancer [12], 13]. These reports highlight the translational importance of herbal constituents in modern drug discovery and safety evaluation. Recent studies further highlight the dual nature of licorice (Glycyrrhiza spp.) as both a health-promoting herbal medicine and a potential source of herb–drug interactions. Clinical data indicate that a standardized G. glabra extract with low glycyrrhizic acid content did not cause clinically relevant pharmacokinetic interactions with CYP1A2, CYP2C9, CYP2D6, or CYP3A4/5 probe drugs after 14 days of supplementation [14]. In contrast, multiple in vitro studies demonstrate that licorice constituents, including glycyrrhetinic acid, licochalcone A, and liquiritigenin, can strongly inhibit UDP-glucuronosyltransferase (UGT) isoforms and modulate CYP3A4 activity [15], [16], [17], [18]. These findings justify the need for in vivo assessments, as performed in the present work, to clarify whether changes in enzyme expression in animal models could translate into pharmacokinetic consequences in humans.

The three common licorice species used in TCM and as medicinal materials in other countries are Glycyrrhiza uralensis Fisch, G. glabra L., and Glycyrrhiza inflata Batalin [19], 20]. G. glabra L. is the most commonly used medicinal plant in China, India, and Korea for the treatment of respiratory tract infections (including cough, cold, and asthma) and other disorders such as gastritis and skin eruption [21], 22]. Modern studies have shown that licorice contains compounds that exhibit antiviral, anti-inflammatory, and immunomodulatory effects. Due to these properties, it gained significant popularity during COVID-19 among herbal consumers.

While consumption of licorice is generally safe, adverse events possibly related to long-term or high-dose use have been reported [23]. For instance, a 45-year-old woman with hypertension developed severe hypokalemia, rhabdomyolysis, muscle paralysis, and breathing difficulties after drinking up to six cups of licorice tea per day [24]. Such findings have raised concerns about the potential toxic effects and herb–drug interactions after long-term use in humans.

Drug interactions are categorized as either pharmacokinetic or pharmacodynamic interactions. While pharmacokinetic interactions refer to how the body processes the drug through absorption, distribution, metabolism, and excretion, pharmacodynamic interactions refer to how the drug affects the body at its target site. Approximately 40 % of pharmacokinetic interactions are metabolic drug–drug interactions, and they are clinically significant because they involve changes in drug metabolism mediated by enzymes such as cytochrome P450 (CYP), reductase, peroxidase, monooxygenase, and hydrolase.

The liver is the main site of drug metabolism. Within the liver, the CYP450 mixed-function oxidase system, located in microsomes, is a critical enzyme system responsible for biotransformation. A total of 70 % of CYP3A4 is located in the intestine, while the remaining 30 % is located in the liver [25]. Uridine diphosphate glucuronosyltransferases (UGTs) are key phase II enzymes that conjugate xenobiotic derivatives with glucuronic acid and are eventually excreted in the urine or bile [26]. In view of the conflicting in vitro and limited in vivo data regarding licorice constituents on drug-metabolizing enzymes, this study was designed to (1) assess the short-term safety of a traditional aqueous extract of G. glabra in female SD rats and (2) quantitatively evaluate the changes in hepatic CYP3A4 and UGT protein expression after 1 and 14 days of repeated oral administration. These data aim to inform the potential for herb–drug interactions involving CYP3A4-or UGT-metabolized medications.

The objective of this study was to determine the safety and in vivo effects of licorice aqueous extract on Phase I (CYP3A4) and II (UGT) hepatic drug-metabolizing enzymes (DMEs) in female Sprague–Dawley (SD) rats (n = 6) following a 14-day repeated oral dose.

2 Materials and methods

2.1 Chemicals and reagents

All the chemicals and reagents used in the study, such as phosphate-buffered saline (PBS), were purchased from a local supplier. Both the CYP3A4 (Catalog No.: MBS2602859) and UGT (Catalog No.: MBS8805724) ELISA kits were sourced from MyBioSource, Inc. (San Diego, CA, USA).

2.2 Preparation and phytochemical screening of licorice aqueous extract

Licorice roots cultivated in China were purchased from a licensed traditional Chinese medicine (TCM) shop in Kuala Lumpur, Malaysia, and their identity was verified according to pharmacopoeial standards [27], 28]. Dried roots of G. glabra were air-dried and ground into a fine powder prior to extraction. For aqueous extraction, 300 g of powdered root were macerated in 1,200 mL of distilled water (Fisher Scientific, Catalog No.: BP2470) and heated in a temperature-controlled bath at 100 °C for 30 min. The mixture was cooled to room temperature and filtered through Whatman No.1 filter paper (Cytiva, Catalog No.: 1,001-125). The extraction was repeated twice, and the pooled filtrates were freeze-dried using an Alpha 1–2 LD plus freeze dryer (Martin Christ GmbH, Osterode am Harz, Germany) to obtain a brownish powder. The extraction yield was recorded, and aliquots were stored at −20 °C until use.

Phytochemical screening was performed using standard qualitative tests to confirm the presence of saponins, flavonoids, and glycosides. Although full chromatographic fingerprinting (HPLC or LC–MS) was not performed in this study – a recognized limitation – the extract was processed under controlled conditions, and future work will include detailed chemical profiling.

The purchased material consisted solely of dried roots; therefore, no whole plant or voucher specimen could be deposited. Future studies should include authenticated herbarium samples to improve reproducibility and traceability.

2.3 Animal selection

Twenty-four albino female SD rats, weighing 150 ± 20 g, were procured from Jutacom (M) Private Limited, Malaysia. The rats were utilized following the OECD Guideline 423 for acute and repeated-dose toxicity studies [29]. The rats were housed in standard animal cages (6 rats per cage) under controlled environmental conditions: temperature of 25 ± 2 °C and a 12-h light/dark cycle, with free access to clean water and a standard rodent pellet diet (approved by a veterinary doctor). Prior to the experiment, the rats were acclimatized to the laboratory conditions for 5 days. The study protocol was conducted in accordance with the methods approved by the University Animal Ethics Committee (U/SERC/253/2022) and complied with the OECD Guideline 423.

Justification for the use of female rats:

Female Sprague Dawley rats were selected primarily to minimize variability associated with androgen-driven metabolic fluctuations that are more pronounced in males. Previous studies have reported sex-based differences in hepatic cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) expression, with female rats exhibiting more stable baseline enzyme activity levels, which improves the interpretability of drug–enzyme interaction studies [30]. Moreover, female SD rats are widely used in subacute and chronic toxicity studies because they exhibit lower aggression and reduced stress-related variability, particularly under repeated oral dosing conditions [29], 31]. Their use in this study was therefore intended to ensure consistent pharmacokinetic and toxicological profiling while adhering to OECD testing guidelines.

Rats were allocated into groups based on body weight to ensure comparable mean values across treatment groups at baseline. This weight-based randomization approach minimized variability in metabolic and physiological parameters that could confound treatment effects. All biochemical and ELISA assays were performed by investigators not directly involved in sample collection to reduce potential bias. The sample size (n = 6 per group) was determined based on prior studies of hepatic enzyme modulation, assuming an expected effect size of approximately 1.2, with a statistical power of 0.8 and α = 0.05.

Ethical approval: The research related to animal use has been complied with all the relevant national regulations and institutional policies for the care and use of animals, and has been approved by the Scientific and Ethical Review Committee of Universiti Tunku Abdul Rahman, Malaysia (approval number: U/SERC/253/2022; approval date: November 29, 2022).

2.4 Experimental design

The selected licorice extract doses (50, 100, and 200 mg/kg) were determined based on previously published reports evaluating the subacute oral toxicity and pharmacological activity of G. glabra extracts in rats. Studies have demonstrated that oral administration of licorice root extract up to 500 mg/kg is well tolerated and produces dose-dependent modulation of hepatic enzyme systems without inducing hepatotoxicity [32], 33]. In addition, our recent study on the impact of licorice supplementation on cardiac biomarkers and histomorphological changes in rats confirmed that repeated oral administration of up to 500 mg/kg was safe and did not cause systemic or organ toxicity [34]. Preliminary range-finding experiments in our laboratory further indicated no observable adverse effects (NOAEL) up to 500 mg/kg. Therefore, doses below this threshold (50–200 mg/kg) were selected to evaluate dose-dependent biochemical responses while minimizing potential toxicity.

The rats were randomly divided into four equal groups, each consisting of six animals: Group 1 served as the vehicle control and received distilled water, while Groups 2–4 were administered licorice extract orally at 50, 100, and 200 mg/kg, respectively, once daily for 14 days. During the experimental period, food and water were withheld for 2 h before dosing (between 10:00 a.m. and 11:00 a.m.) to optimize absorption of the test substance. The maximum oral administration volume was 10 mL/kg body weight, in accordance with OECD Guideline 423 [29]. Following each administration, all rats were observed closely for the first 4 h to detect any behavioral changes or signs of toxicity through cage-side monitoring.

2.5 Blood sampling

Prior to blood collection, the rats were subjected to overnight fasting (for at least 16 h). Twenty-four hours after the last dose administration, the rats were anesthetized with CO2 for blood sampling via cardiac puncture and remained anesthetized throughout the experimental period. Blood samples were collected in heparinized microcentrifuge tubes (Thermo Scientific, Catalog No.: T4010) and centrifuged at 3,000 rpm for 10 min at 5 °C using a refrigerated centrifuge (Centrifuge 5424R, Eppendorf, Germany). Plasma was transferred to 1.5 mL microcentrifuge tubes (Axygen, Catalog No.: MCT-150-C) and stored at −80 °C. The blood samples were then sent to a private diagnostic laboratory in Selangor for biochemical analyses. Liver function tests (aspartate transaminase [AST], alanine transaminase [ALT], and alkaline phosphatase [ALP]), kidney function tests (urea and creatinine), lipid profiles (total cholesterol and triacylglycerol), hematological examinations (hemoglobin), and others (sodium, potassium) were also performed. The animals were euthanized, followed by a gross examination of their vital organs, including the liver, kidney, heart, spleen, and lungs, to determine any toxic effects.

2.6 Preparation of rat liver microsomes

To obtain microsomal fractions enriched in CYP3A4 and UGT, liver tissues from each rat were weighed and homogenized in ice-cold phosphate-buffered saline (PBS, pH 7.4; Sigma-Aldrich, Catalog No.: P4417) using a glass homogenizer. The homogenates were first centrifuged at 3,000×g for 20 min at 4 °C to remove cell debris and nuclei. The resulting supernatant was then ultracentrifuged at 100,000×g for 60 min at 4 °C using a Beckman Coulter Optima L-100XP ultracentrifuge [35]. The microsomal pellet was resuspended in PBS and stored at −80 °C until further analysis. Protein concentrations were determined using the Bradford assay (Bio-Rad, USA) prior to ELISA.

2.7 Determination of CYP3A4 and UGT concentration in rat liver microsomes

CYP3A4 and UGT protein expression levels were quantified using commercially available double-antibody sandwich ELISA kits (MyBioSource, USA: CYP3A4, Cat. No. MBS2602859; UGT1A1, Cat. No. MBS8805724), consistent with previously described approaches for CYP/UGT protein expression analysis [36]. All procedures were carried out in strict accordance with the manufacturer’s instructions.

Briefly, samples and biotinylated detection antibodies were sequentially added to 96-well plates pre-coated with anti-rat CYP3A4 monoclonal antibody, followed by washing with PBS to remove unbound material. Avidin–peroxidase conjugate was then added, and after incubation, 3,3′,5,5′-tetramethylbenzidine (TMB) substrate solution was introduced to develop color. The reaction was stopped with an acidic stop solution, and absorbance was measured at 450 nm using a microplate reader (BioTek Epoch, Agilent Technologies, USA).

Concentrations were calculated from a standard curve generated using a four-parameter logistic (4-PL) model. The intra- and inter-assay coefficients of variation (CVs) were not determined in this study but were reported by the manufacturer to be within acceptable limits (<15 %). All assays were performed by investigators not directly involved in sample collection to minimize bias.

It should be noted that this method measures protein concentration, not catalytic enzyme activity; therefore, the results reflect relative expression rather than confirmed functional modulation. A similar protocol was used for UGT quantification, with plates pre-coated with antibodies specific to UGT1A1.

2.8 Data analysis

All data were expressed as mean ± standard deviation (SD) based on six animals per group (n = 6). Statistical analyses were carried out using IBM SPSS Statistics version 22.0 (IBM Corp., Armonk, NY, USA). Prior to analysis, data were examined for normality using the Shapiro–Wilk test and for homogeneity of variances using Levene’s test, in accordance with established biostatistical procedures [37].

When both assumptions of normality and homogeneity were met, one-way analysis of variance (ANOVA) was conducted, followed by Dunnett’s multiple comparison test to identify differences between each treatment group and the negative control. For non-normally distributed data, the Kruskal–Wallis test was applied, followed by Dunn’s post-hoc test with Bonferroni correction for pairwise comparisons.

Exact p-values and corresponding test statistics (F for ANOVA or H for Kruskal–Wallis) were reported wherever possible. Statistical significance was considered at p < 0.05. In addition, effect sizes (η2 for ANOVA and Cohen’s d for pairwise comparisons) and 95 % confidence intervals were calculated where appropriate to provide a quantitative measure of treatment effects.

In tables, results showing no significant difference compared with the control were annotated as p > 0.05, while figures indicated significance using asterisks (p < 0.05 or p < 0.01). All statistical methods were applied consistently across biochemical, hematological, and enzyme expression data.

3 Results

3.1 Licorice aqueous extract yield

The percentage yield of dried licorice root extracts (prepared using the maceration method in distilled water) is shown in Table 1.

Table 1:

Percentage yield of licorice aqueous extract preparation.

Cold aqueous extract
Weight of roots (g) 300.0
Weight of extracts (g) 47.1
Percentage yield of extraction (%) 15.7

3.2 Effects of 14-day repeated oral administration of licorice extract at different doses on serum biochemical parameters

Licorice extract administered orally to the female SD rats at a dose of 50, 100, and 200 mg/kg for 14 days showed no toxicity on the liver and kidneys. This is evidenced by insignificant changes in the mean serum biochemical parameters in liver (AST, ALT, and ALP) and kidney (urea and creatinine) function tests, compared to the negative control group (Table 2). Hematological examinations (hemoglobin) and electrolytes (sodium and potassium) also showed insignificant differences when compared with the control group (Table 2).

Table 2:

Effect of 14-day oral administration of licorice extract on serum biochemical parameters in female SD rats.

Parameter Group 1: Negative control (distilled water) Group 2: Experimental (50 mg/kg of licorice extract) Group 3: Experimental (100 mg/kg of licorice extract) Group 4: Experimental (200 mg/kg of licorice extract)
AST (U/L) 84.5 ± 4.37 83.7 ± 3.44 81.6 ± 2.89 81.4 ± 4.93
ALT (U/L) 35.0 ± 4.21 32.5 ± 1.96 30.2 ± 0.96 28.5 ± 2.15
ALP (U/L) 140.6 ± 8.09 132.1 ± 6.15 133.3 ± 3.72 127.6 ± 1.88
Urea (mg/dL) 13.0 ± 0.69 12.5 ± 0.37 12.3 ± 0.34 12.1 ± 0.08
Creatinine (mg/dL) 0.5 ± 0.01 0.5 ± 0.01 0.5 ± 0.01 0.5 ± 0.01
Total cholesterol (mg/dL) 96.0 ± 2.85 88.6 ± 1.99 88.1 ± 0.62 86.1 ± 0.12
TAG (mg/dL) 39.2 ± 5.55 39.9 ± 0.78 37.3 ± 3.62 37.8 ± 1.72
Hemoglobin (g/dL) 14.8 ± 0.26 14.7 ± 0.08 14.9 ± 0.09 15.0 ± 0.16
Sodium (mmol/L) 140.2 ± 0.71 139.7 ± 0.52 139.6 ± 0.46 139.7 ± 1.09
Potassium (mg/dL) 4.5 ± 0.08 4.17 ± 0.12 4.0 ± 0.05 4.0 ± 0.08

  1. Data = mean ± standard deviation; n = 6. Analyzed using Dunnett’s test. No significant difference with p > 0.05 in all experimental groups compared with the control group.

In terms of body weight, no significant changes were observed after the treatment (Table 3). Similarly, no mortality, abnormal behavioral, nor toxicity-induced changes on the vital organs were observed after the treatment (Tables 4 and 5).

Table 3:

Effect of 14 days of oral administration of licorice extract on the body weight in female SD rats.

Sr. Week Body weight (g)
Group 1: Negative control (distilled water) Group 2: Experimental (single oral dose of 50 mg/kg of licorice extract) Group 3: Experimental (single oral dose of 100 mg/kg of licorice extract) Group 4: Experimental (single oral dose of 200 mg/kg of licorice extract)
1 Week 0 146.4 ± 4.50 149.6 ± 3.26 150.4 ± 3.01 147.6 ± 4.72
2 Week 1 149.0 ± 4.52 152.4 ± 3.26 153.6 ± 3.32 151.2 ± 4.26
3 Week 2 156.2 ± 3.54 160.4 ± 3.01 160.4 ± 2.65 158.0 ± 4.38

  1. Data = mean ± standard deviation; n = 6. Analyzed using Dunnett’s test. No significant difference with p > 0.05 in all experimental groups compared with the control group.

Table 4:

Cage-side observation for behavior changes and clinical signs.

Observations Licorice extract (mg/kg b.w.)
Control 50 100 200
General condition Normal Normal Normal Normal
Eye inflammation Absent Absent Absent Absent
Movements and posture Normal Normal Normal Normal
Piloerection Absent Absent Absent Absent
Fur color Normal Normal Normal Normal
Food and water intake Normal Normal Normal Normal
Defecation Normal Normal Normal Normal
Urination Normal Normal Normal Normal
Breathing difficulties Absent Absent Absent Absent

  1. n = 6.

Table 5:

Relative organ weights.

Organ index (g/100 g b.w.) Licorice extract (mg/kg b.w.)
Control 50 100 200
Heart 0.41 ± 0.018 0.41 ± 0.026 0.42 ± 0.065 0.42 ± 0.027
Lungs 0.46 ± 0.042 0.47 ± 0.037 0.46 ± 0.042 0.49 ± 0.044
Liver 3.49 ± 0.345 3.56 ± 0.181 3.54 ± 0.166 3.51 ± 0.256
Stomach 0.20 ± 0.001 0.19 ± 0.007 0.20 ± 0.011 0.20 ± 0.017
Spleen 0.42 ± 0.096 0.42 ± 0.062 0.44 ± 0.032 0.43 ± 0.069
Kidneys 0.79 ± 0.016 0.80 ± 0.041 0.79 ± 0.037 0.79 ± 0.032

  1. Data were expressed as mean ± standard deviation, n = 6. There was no significant difference between all treatment groups compared with the control group.

3.3 Modulation of hepatic CYP3A4 and UGT levels after 1 and 14 days of licorice root extract administration

Licorice extract contained active ingredients that could alter the hepatic CYP3A4 and UGT enzymes in female SD rats. As shown in Figure 1, compared to the control group, rats treated with 50 mg/kg of licorice extract exhibited a significant decrease in CYP3A4 protein levels (p < 0.05) to 7.1 % reduction, those treated with 100 mg/kg exhibited a significant decrease of 14.3 % (p < 0.05), and rats treated with 200 mg/kg demonstrated the most pronounced reduction in CYP3A4 enzyme concentration to 29.8 % (p < 0.01).

Figure 1: In vivo effect of the 14-day licorice extract treatment on hepatic CYP3A4 levels in female SD rats. CYP3A4 concentration (ng/ml) was determined using the double antibody sandwich ELISA technique. Hepatic CYP3A4 enzymes in female SD rats were reduced significantly after treating with licorice root extract at 50 mg/kg, 100 mg/kg, and 200 mg/kg for 14 days. Data = mean ± standard deviation; n = 6. Analyzed using Dunnett’s test. *p < 0.05 and **p < 0.01 indicate significant differences compared with the control group.
Figure 1:

In vivo effect of the 14-day licorice extract treatment on hepatic CYP3A4 levels in female SD rats. CYP3A4 concentration (ng/ml) was determined using the double antibody sandwich ELISA technique. Hepatic CYP3A4 enzymes in female SD rats were reduced significantly after treating with licorice root extract at 50 mg/kg, 100 mg/kg, and 200 mg/kg for 14 days. Data = mean ± standard deviation; n = 6. Analyzed using Dunnett’s test. *p < 0.05 and **p < 0.01 indicate significant differences compared with the control group.

Oral administration of licorice extracts at 50–200 mg/kg for 14 days significantly (p < 0.01) increased the concentration of hepatic UGT enzyme in female SD rats (Figure 2). Compared with the control group, the three licorice experimental groups showed increased UGT protein expression of approximately 60 %, 77 %, and 110 %.

Figure 2: In vivo effect of the 14-day licorice extract treatment on hepatic UGT levels in female SD rats. UGT concentration (ng/ml) was determined using the double antibody sandwich ELISA technique. Hepatic UGT enzymes in female SD rats were increased significantly after treating with licorice root extract at 50 mg/kg, 100 mg/kg, and 200 mg/kg for 14 days. Data = mean ± standard deviation; n = 6. Analyzed using Dunnett’s test. **p < 0.01 indicates a significant difference compared with the control group.
Figure 2:

In vivo effect of the 14-day licorice extract treatment on hepatic UGT levels in female SD rats. UGT concentration (ng/ml) was determined using the double antibody sandwich ELISA technique. Hepatic UGT enzymes in female SD rats were increased significantly after treating with licorice root extract at 50 mg/kg, 100 mg/kg, and 200 mg/kg for 14 days. Data = mean ± standard deviation; n = 6. Analyzed using Dunnett’s test. **p < 0.01 indicates a significant difference compared with the control group.

4 Discussion

The incidence of herb-induced liver injury due to herb–drug interactions is closely associated with alterations in cytochrome P450 (CYP450) expression. Among these enzymes, CYP3A4 is the most abundant hepatic isoform, responsible for the metabolism of approximately half of all clinically used drugs, thereby playing a crucial role in hepatic drug clearance. CYP3A4 expression can be induced or suppressed by various exogenous and endogenous compounds [38]. In this study, licorice extract reduced hepatic CYP3A4 protein levels, suggesting that licorice consumption could potentially interfere with drug metabolism mediated by CYP3A4. Such suppression may increase systemic exposure to coadministered drugs, prolong pharmacological effects, and raise the risk of drug accumulation or toxicity [39]. However, since only protein expression was measured, further investigations assessing enzyme activity and pharmacokinetics are warranted to confirm these findings [14].

Our results are consistent with Li et al. [40], who reported that G. glabra moderately inhibited CYP2B6, CYP2C8, CYP2C9, and CYP2C19, and weakly inhibited CYP3A4 in vitro. These findings support the notion that licorice and its bioactive constituents can modulate hepatic CYP activity. Other studies have also shown that glycyrrhizin and glycyrrhetinic acid downregulate CYP3A and CYP2C expression in both rodent and human hepatocyte models [41], 42], reinforcing our observation of CYP3A4 suppression after repeated oral exposure.

In addition to phase I metabolism, licorice extract also influenced phase II enzymes, particularly UDP-glucuronosyltransferases (UGTs). UGTs play a critical role in detoxification and drug elimination; however, excessive activation may contribute to idiosyncratic hepatotoxicity through the formation of reactive acyl glucuronides from drugs such as diclofenac and tolmetin. Previous reports have shown that induction of UGT1A enzymes enhances glucuronidation capacity but may also alter xenobiotic metabolic profiles [43], 44]. In this study, licorice extract significantly elevated UGT protein expression after 14 days of administration, indicating a potential modulatory effect of licorice-derived flavonoids and saponins on conjugation pathways. These results are in agreement with studies showing that licochalcone A and liquiritigenin can either induce or inhibit hepatic UGT activity in a concentration-dependent manner [45]. Beyond its enzyme-modulating activity, G. glabra exhibits a broad spectrum of therapeutic effects, including antioxidant, anti-inflammatory, hepatoprotective, and immunomodulatory properties [3], 4]. Comparable findings have been reported for other medicinal plants and plant-derived compounds with enzyme-modulating and hepatoprotective activities. For instance, metal-based phytoconjugates and flavonoid-enriched extracts have been shown to enhance hepatic detoxification and reduce oxidative stress through cytochrome- and UGT-mediated pathways [46], [47], [48]. Likewise, chalcone and organometallic derivatives demonstrated notable antioxidant and hepatoprotective activity associated with modulation of drug-metabolizing enzymes [49], [50], [51]. These findings collectively suggest that phytochemicals, including licorice-derived saponins and flavonoids, not only modulate hepatic enzymes but may also confer adaptive or protective responses against hepatocellular injury. Future investigations should further explore these therapeutic mechanisms in models of drug-induced liver injury and oxidative stress.

Recent pharmacokinetic investigations have provided further evidence of such modulation. Coadministration of Glycyrrhiza extract has been reported to alter plasma concentrations of probe substrates metabolized by CYP3A and UGT1A, leading to clinically meaningful changes in systemic drug clearance [52], [53], [54]. “These findings underscore the clinical relevance of herb–drug interactions involving licorice, especially in patients taking drugs with narrow therapeutic windows. Importantly, modulation of drug-metabolizing enzymes may be mediated via nuclear receptors such as the pregnane X receptor (PXR) and constitutive androstane receptor (CAR), which control transcriptional regulation of CYP3A4 and UGT1A genes [55].

Licorice has established hepatoprotective and immunomodulatory properties, and its flavonoids and triterpenoids have been shown to mitigate hepatic oxidative stress and inflammatory responses, in part via activation of the Nrf2 antioxidant pathway and inhibition of MAPK/NF-κB signaling [56], which may indirectly influence the expression of detoxification enzymes. Therefore, the dual effects observed in this study – CYP3A4 suppression and UGT induction – could represent both protective and adaptive hepatic responses to licorice exposure.

Overall, our findings contribute to the growing body of evidence demonstrating that licorice exerts multifaceted effects on hepatic drug-metabolizing enzymes. While no overt toxicity was observed wijthin the study period, the modulation of CYP3A4 and UGT indicates a potential risk of pharmacokinetic interactions with coadministered drugs. These findings emphasize the importance of cautious use of licorice-containing products, especially among patients undergoing polypharmacy or long-term herbal therapy. Future studies should include enzyme activity assays, transcriptomic profiling, and long-term exposure assessments to elucidate the mechanistic basis and clinical relevance of these interactions.

5 Limitations

This study has several limitations. First, only female Sprague–Dawley rats were used, which may not capture sex-dependent variability. Second, the treatment period was limited to 14 days, precluding conclusions on long-term or chronic exposure. Third, CYP3A4 and UGT levels were quantified at the protein expression level using ELISA, which does not directly reflect enzymatic activity. Fourth, no pharmacokinetic assessment with probe substrates was conducted, and therefore the functional implications for drug metabolism and potential herb–drug interactions remain speculative. Finally, the licorice roots were purchased without depositing a voucher specimen, and no detailed phytochemical fingerprinting was performed, limiting reproducibility and traceability of the herbal material.

It should also be noted that while natural products such as tea polyphenols and sprouted grains have demonstrated antioxidant, anti-inflammatory, and metabolic benefits through similar biochemical pathways [57], 58], translating these effects into clinically safe and effective therapies remains challenging. Furthermore, the current work focused solely on hepatic enzyme modulation; other therapeutic aspects of G. glabra – including its hepatoprotective, immunomodulatory, and anti-oxidative potentials – were not explored experimentally. Future studies should therefore include both sexes, extended treatment durations, validated enzyme activity assays, pharmacokinetic and transcriptomic analyses, as well as evaluation of its therapeutic mechanisms in hepatotoxicity or oxidative stress models. Authentication of plant material and comprehensive phytochemical profiling are also recommended to ensure reproducibility, translational relevance, and safety assessment for clinical application.

6 Conclusions

Repeated oral administration of G. glabra aqueous extract (50–200 mg/kg, 14 days) did not produce hepatic or renal toxicity in female Sprague–Dawley rats but significantly modulated key hepatic drug-metabolizing enzymes – suppressing CYP3A4 and enhancing UGT expression. These findings underscore licorice’s dual nature as both a hepatoprotective agent and a potential modulator of drug metabolism. The observed enzyme alterations highlight the need for caution when coadministering licorice-containing products with conventional drugs metabolized by these pathways. Future studies should evaluate enzyme activity, chronic exposure effects, and the therapeutic potential of licorice in models of drug-induced liver injury to better define its safety and clinical utility.

Corresponding authors Yuzhu Liu, and Jin Han Chin, Faculty of Medicine, MAHSA University, Jalan SP 2, Bandar Saujana Putra, 42610, Jenjarom, Selangor, Malaysia, E-mail: (Y. Liu), (J. H. Chin)

Acknowledgments

We express our sincere gratitude to MAHSA University, Selangor, Malaysia, for providing crucial research facilities and the necessary research grant (RP194-10/22).

  1. Funding information: This research was supported by MAHSA University, Selangor, Malaysia (grant number: RP194-10/22).

  2. Author contribution: Conceptualization: Yuzhu Liu, Jin Han Chin. Methodology: Mingyang Zhang, Fei Li. Investigation: Mingyang Zhang, Fei Li. Formal analysis and statistical plan: Fei Li. Resources and supervision: Siew Choo Soon, Siew-Keah Lee, Jin Han Chin. Writing – original draft: Fei Li, Mingyang Zhang. Writing – review & editing: Siew Choo Soon, Siew-Keah Lee, Jin Han Chin, Yuzhu Liu. Funding acquisition: Jin Han Chin. All authors read and approved the final manuscript and accept responsibility for submission.

  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: 2025-06-26
Accepted: 2025-11-03
Published Online: 2026-01-01

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

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

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  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
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  112. Analgesic and toxicological evaluation of cannabidiol-rich Moroccan Cannabis sativa L. (Khardala variety) extract: Evidence from an in vivo and in silico study
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  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
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  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
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  219. Impact of saline sprouting on antioxidant properties and bioactive compounds in chia seeds
  220. The dilemma of food genetics and improvement
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  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-2025-1227
Schlagwörter für diesen Artikel
cytochrome P450 3A4; uridine diphosphate glucuronosyltransferase; licorice; rat liver
Creative Commons
BY 4.0

Artikel in diesem Heft

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  117. Biogenic Cu/Ni nanotherapeutics from Descurainia sophia (L.) Webb ex Prantl seeds for the treatment of lung cancer
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  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
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  139. Can coronavirus disease 2019 affect male fertility or cause spontaneous abortion? A two-sample Mendelian randomization analysis
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  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
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  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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Heruntergeladen am 31.3.2026 von https://www.degruyterbrill.com/document/doi/10.1515/biol-2025-1227/html
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