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Abstract

Objective

Honey is generally considered to be a natural product with rich nutritional value. However, the fructose contained in honey is harmful to the liver. This study aims to observe the effect of acacia honey (AH) on serum uric acid and liver injury in potassium oxonate model rats after drinking AH aqueous solution.

Materials and methods

Sixty male Sprague-Dawley (SD) rats were selected and randomly divided into control group (CON group), potassium oxonate model group (OA model group), 10% fructose group (10%F group) and different concentration AH groups (25%, 12.5% and 6.25% AH groups). 100 mg/kg OA solution combined with fructose solution or AH solution was administered to gavage model rats. After the 4 weeks test, blood and liver tissues were collected, serum uric acid content, biochemical indexes, activities of alanine transaminase and alanine transaminase were determined, and liver histological sections were observed.

Results

AH can significantly increase serum uric acid level, liver weight and liver to body weight ratio (p < 0.05). The levels of serum triglyceride (TG), free fatty acid (FFA), and high-density fatty acid cholesterol (HDL-C) were elevated in 25% and 12.5% AH groups compared with CON group or OA model group (p < 0.05), but serum levels of TG, FFA, HDL-C, total cholesterol (T-CHO) and low density lipoprotein cholesterol (LDL-C) were significantly increased in 6.25%AH group (p < 0.05).

Conclusion

AH can cause fatty liver disease in all rats in a dose dependent manner. In the dose range of the present study, AH can induce hyperuricemia, hypertriglyceridemia and fatty liver disease.

Keywords

Acacia honey fructose uric acid steatosis NAFLD

Introduction

With the improvement of living standards, non-alcoholic fatty liver disease (NAFLD) has become one of the most common chronic liver diseases, affecting approximately 25% of the global population.¹ NAFLD is a clinicopathological syndrome characterized primarily by excessive fat accumulation in liver cells over 5%, excluding liver damage caused by alcohol and other specific factors.² It is currently believed that NAFLD is associated with the occurrence of chronic metabolic diseases such as obesity and diabetes.³ Notably, numerous studies have demonstrated a significant correlation between blood uric acid levels and NAFLD.^4,5 The level of blood uric acid in the human body is closely related to fructose intake, with high fructose consumption leading to elevated blood uric acid levels, further exacerbating lipid metabolism disorders.^6-8

Honey is a sweet substance produced by bees through the collection and thorough processing of plant nectar, honeydew, or other plant secretions, combined with the bees’ own secretions. Typically, natural honey consists of 17.1% water, 82.4% carbohydrates (approximately 38.5% fructose, 31% glucose, and 12.9% other sugars), and 0.5% proteins, amino acids, vitamins, and other components.^9,10 Specially, honey is rich in phenolic compounds, which possess properties such as scavenging free radicals, anti-inflammatory effects, and immune modulation.¹¹ Honey also exhibits excellent antibacterial characteristics, aiding in wound healing and serving as a complementary treatment for various infections. Additionally, due to its high content of prebiotics, honey supports microbial balance, promoting gut health.¹² Thus, honey is widely recognized and utilized as a beneficial natural product. However, given its high fructose content, honey may potentially elevate uric acid levels in the body, thereby triggering or exacerbating the pathological progression of NAFLD. Moreover, the absence of uricase in the human body further increases the risk of hyperuricemia induced by fructose. In this study, male rats were subcutaneously injected with potassium oxonate to inhibit uricase, simulating the human condition of lacking uricase. The rats were then administered honey solutions of varying concentrations. The aim was to investigate the impact of honey on uric acid levels and its relationship with NAFLD, thereby providing scientific evidence regarding the potential toxicological characteristics of honey.

Materials and Methods

Experimental Reagents and Instruments

D-Fructose (food grade) was purchased from Hefei Qiansheng Biotechnology Co., Ltd; Acacia honey (AH) was obtained from Shanghai Guanshengyuan Bee Products Co.,Ltd; Oxonic acid potassium (OA) was purchased from Tianjin Baima Technology Co., Ltd; Sodium carboxymethyl cellulose (CMC-Na) was acquired from Chengdu Westia Chemical Co., Ltd; Uric acid (UA) assay kits (uricase colorimetric method) were sourced from Beijing Lanjieko Technology Co., Ltd; Triglyceride (TG) test kits, total cholesterol (T-CHO) test kits, free fatty acid (FFA) test kits (enzymatic method), high-density lipoprotein cholesterol (HDL-C) test kits, and low-density lipoprotein cholesterol (LDL-C) test kits were all purchased from Nanjing Jiancheng Bioengineering Institute Co., Ltd; The alanine aminotransferase (ALT) activity assay kits and aspartate aminotransferase (AST) activity assay kits were obtained from Beijing Solarbio Science &Technology Co., Ld

The microplate reader (DNM-9606) was purchased from Beijing Perlong New Technology Co., Ltd; the benchtop high-speed refrigerated centrifuge (Biofuge Primo R) was obtained from Kendro Laboratory Products, Germany; the fully automatic tissue processor (Leica ASP300S), semi-automatic microtome (Leica RM2245), and automatic stainer (Leica TS5015) were all purchased from Leica Microsystems, Germany; the optical microscope (Olympus BX53) and image analysis system (SC180) were purchased from Olympus Corporation, Japan.

Reagent Preparation

Acacia honey was purchased and obtained from healthy honeybee colonies colony at Shanghai Guanshengyuan Bee Products Co.,Ltd located in Jing ‘an District, Shanghai, China. Commercially available acacia honey was used in this study, with a fructose content of approximately 40 g per 100 g of honey. Several studies have demonstrated that a 10% fructose can lead to liver damage and elevated uric acid levels in rats.^13,14 Consequently, we selected gradient concentration of 2.5%, 5%, and 10% fructose as the concentrations for monitoring in this study. Accordingly, based on the fructose content in honey, we employed honey concentrations of 6.25%, 12.5%, and 25% to achieve the corresponding fructose concentrations. During the experiment, the honey was dissolved in double-distilled water to prepare 25%, 12.5%, and 6.25% honey solutions, corresponding to fructose concentrations of 10%, 5%, and 2.5%, respectively. Additionally, a 10% fructose solution was prepared in double-distilled water for the rats to consume.

Animal Experiment

A total of 60 male SPF-grade Sprague-Dawley rats (5-7 weeks old), weighing 180–200 g, were used in the study. The rats were randomly divided into six groups, with 10 rats in each group: the blank control group (CON group), the oxonic acid potassium model group (OA group), the 10% fructose group (10%F group), the 25% honey group (25%AH group), the 12.5% honey group (12.5%AH group), and the 6.25% honey group (6.25%AH group). The CON group received subcutaneous injections of 5% CMC-Na solution, while the other groups were injected subcutaneously with 100 mg/kg of OA suspended in 5% CMC-Na solution daily. All animals were fed maintenance chow daily. The CON and OA groups had access to sterile water, the 10%F group had access to a 10% fructose solution, and the remaining three groups had access to honey solutions of different concentrations. The experiment lasted for four weeks. All animals were housed in IVC cages with free access to food and water.

Measurement of serum Uric Acid Levels in Rats

Blood samples (0.4-0.5 mL) were collected from the tails of all rats before the experiment and weekly during the experiment. The samples were left to stand at 4 °C for 1 h, then centrifuged at 3000 rpm for 10 min. The supernatant was collected, and the serum uric acid levels were measured using a uric acid detection kit. The detection kit utilized the specific action of uricase on uric acid, resulting in a product that reacts with a color reagent to produce a red color. The kit was suitable for detecting serum samples from all species.

Measurement of serum Biochemical Indicators in Rats

At the end of the experiment, blood was collected from the abdominal aorta of the sacrificed rats. The samples were left to stand at 4 °C for 1 h, then centrifuged at 3000 rpm for 10 min. The supernatant was collected, and the serum levels of triglycerides, total cholesterol, free fatty acids, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol were measured according to the instructions of the respective assay kits. Additionally, using the detection kit, the activities of ALT and AST in serum samples were measured by the microplate reader.

Measurement of Liver Weight and Organ Coefficient in Rats

At the end of the experiment, the rats were anesthetized intraperitoneally, and the liver was harvested. After blotting off surface blood, the liver was weighed, and the organ coefficient was calculated using the formula: Organ Coefficient = (Organ Weight / Body Weight) × 100%.

Histological Observation of Liver Tissue

The liver was fixed in 10% formalin, followed by paraffin embedding, sectioning, and hematoxylin and eosin (HE) staining. The tissue sections were observed under a light microscope to assess pathological changes, and comparisons were made between the groups.

Statistical Analysis

Experimental data were expressed as mean ± standard deviation (χ̄ ± SD). Statistical analysis was performed using SPSS software. Depending on the normality and homogeneity of variance of the data, comparisons among multiple groups were conducted using one-way analysis of variance (ANOVA). In particular, if the data does not conform to a normal distribution, the Kruskal-Wallis test was adapted. Post-hoc comparisons between groups were made using the Least Significant Difference (LSD) method, with P < 0.05 considered statistically significant.

Results

The Impact of Honey on Uric Acid Levels in Rats

As shown in Table 1. Before the experiment, there were no statistically significant differences in blood uric acid levels among the rat groups (P > 0.05). After subcutaneous injection of OA (potassium oxonate), blood uric acid levels increased to varying degrees at all time points, except for the third week. The increase in uric acid levels was particularly significant at the fourth week (P < 0.05). When rats were given 10% fructose or different concentrations of honey solutions in addition to the OA injection, their blood uric acid levels also increased to varying degrees. Except for a few time points, the uric acid levels in these groups were higher than those in the OA model group.

Table 1.

Changes in Blood Uric Acid Level of Rats in Each Group.

Group	blood uric acid level（μmol/L）
Group	0 w	1 w	2 w	3 w	4 w
CON	59.49 ± 19.42	66.97 ± 19.35	59.92 ± 18.05	52.44 ± 6.44	49.20 ± 17.51
OA	57.34 ± 20.83	83.12 ± 28.50	75.55 ± 35.47	50.10 ± 14.85	72.46 ± 28.12 ^a
10%F	50.89 ± 20.68	98.95 ± 31.55^a	84.24 ± 20.08^a	82.97 ± 24.25^ab	80.51 ± 32.12
25%AH	55.90 ± 24.55	114.70 ± 24.32^ab	87.71 ± 26.99^a	76.71 ± 28.77^ab	95.72 ± 37.49^a
12.5%AH	60.21 ± 37.96	108.29 ± 47.94^a	86.84 ± 30.08^a	75.14 ± 34.85	70.67 ± 30.83
6.25%AH	61.64 ± 27.28	89.05 ± 22.59^a	65.13 ± 20.57	69.66 ± 15.85^ab	57.25 ± 33.26

Values indicate means ± SD, n = 10.

Significant difference: Compared with CON control group, ^aP<0.05; Compared with OA model group, ^bP<0.05.

The Impact of Honey on Lipid Metabolism-Related serum Indicators in Rats

As shown in Table 2. In normal SD rats, subcutaneous administration of 100 mg/kg of OA led to increased levels of serum TG, T-CHO, FFA, HDL-C, and LDL-C. When rats were given 10% fructose solution with the OA injection, there was a significant increase in serum TG, FFA, and HDL-C levels (P < 0.05), while T-CHO levels significantly decreased (P < 0.05). In contrast, when SD rats were given honey solutions along with OA, serum TG, FFA, and HDL-C levels also significantly increased. However, the 25% and 12.5% honey solutions had no significant effect on T-CHO and LDL-C levels, whereas the 6.25% honey solution led to an increase in T-CHO and LDL-C levels. In normal SD rats, subcutaneous administration of 100 mg/kg OA resulted in a slight increase in serum ALT and AST activity as shown in Table 3. However, the administration of 10% fructose or honey solutions reversed this effect, restoring serum ALT and AST activity to normal levels or even lower.

Table 2.

Changes of serum Biochemical Indexes of Rats in Each Group.

Group	TG （mmol/L）	T-CHO （mmol/L）	FFA （mmol/L）	HDL-C （mmol/L）	LDL-C （mmol/L）
CON	0.49 ± 0.13	1.62 ± 0.18	0.44 ± 0.13	0.07 ± 0.03	0.33 ± 0.05
OA	0.58 ± 0.17	1.68 ± 0.34	0.55 ± 0.21	0.08 ± 0.03	0.34 ± 0.09
10%F	0.90 ± 0.24 ^ab	1.38 ± 0.18 ^ab	0.63 ± 0.11 ^a	0.16 ± 0.04 ^ab	0.35 ± 0.04
25%AH	1.19 ± 0.29 ^ab	1.54 ± 0.14	0.50 ± 0.14	0.17 ± 0.07 ^ab	0.33 ± 0.06
12.5%AH	1.41 ± 0.39 ^ab	1.60 ± 0.24	0.74 ± 0.17 ^ab	0.16 ± 0.05 ^ab	0.33 ± 0.03
6.25%AH	1.14 ± 0.52 ^ab	1.89 ± 0.26 ^a	0.63 ± 0.15 ^a	0.12 ± 0.07	0.38 ± 0.05 ^a

Values indicate means ± SD, n = 10.

Significant difference: Compared with CON control group, ^aP<0.05; Compared with OA model group, ^bP<0.05.

Table 3.

Changes in the Activities of GLT and GST in Each Group.

Group	GLT (U/mL)	GST (U/mL)
CON	0.09 ± 0.02	0.22 ± 0.06
OA	0.10 ± 0.03	0.25 ± 0.05
10%F	0.08 ± 0.02	0.21 ± 0.03^b
25%AH	0.07 ± 0.03^b	0.22 ± 0.03
12.5%AH	0.07 ± 0.02^b	0.22 ± 0.04
6.25%AH	0.07 ± 0.04^b	0.21 ± 0.01^b

Values indicate means ± SD, n = 10.

Significant difference: Compared with CON control group, ^aP<0.05; Compared with OA model group, ^bP<0.05.

The Impact of Honey on Liver Weight and Organ Coefficients in Rats

After subcutaneous injection of OA in rats, both liver weight and organ coefficients increased, with the liver organ coefficient showing a significant statistical difference compared to the CON control group (P < 0.05). When rats received fructose or different concentrations of honey solutions alongside OA injection, liver weight increased significantly, with the 25% honey group showing the most pronounced increase (P < 0.05). Additionally, both fructose and the various concentrations of honey solutions led to a significant increase in organ coefficients (P < 0.05), with a dose-dependent effect observed in the different honey concentration groups. See Table 4 for details.

Table 4.

Changes of Liver Weight and Organ Coefficients in Each Group.

Group	Organ weight（g）	Organ coefficient（%）
CON	13.28 ± 1.61	3.03 ± 0.36
OA	13.39 ± 1.60	3.30 ± 0.18 ^a
10%F	13.49 ± 1.57	3.50 ± 0.39 ^a
25%AH	14.64 ± 0.88 ^ab	3.84 ± 0.27 ^ab
12.5%AH	14.24 ± 1.67	3.67 ± 0.46^ab
6.25%AH	14.25 ± 1.09	3.61 ± 0.17 ^ab

Values indicate means ± SD, n = 10.

Significant difference: Compared with CON control group, ^aP<0.05; Compared with OA model group, ^bP<0.05.

The Impact of Honey on the Physiological Structure of rat Liver Tissue

As shown in Figure 1,A, after continuous subcutaneous injection of 5% CMC-Na solution for 4 weeks in the CON control group rats, the liver tissue structure was normal. Hepatocytes were arranged radially around the central vein, forming liver cords. The portal triad included the interlobular vein, interlobular artery, and interlobular bile duct. There were no signs of hepatocyte degeneration, necrosis, or pathological changes such as sinusoidal dilation, congestion, or inflammatory cell infiltration. In comparison, the OA model group rats exhibited mild hepatocyte vacuolar degeneration in the liver. The 10% fructose (F) group showed slight to moderate vacuolar degeneration in hepatocytes. The 25% honey (AH) group had moderate to severe vacuolar degeneration in hepatocytes. The 12.5% AH group displayed mild to severe hepatocyte vacuolar degeneration, while the 6.25% AH group showed slight hepatocyte vacuolar degeneration. As illustrated in Figure 1,B, Oil Red O staining of liver tissues from the CON and 25% AH groups revealed that the 25% AH group had significantly more lipid droplets compared to the control group, indicating hepatic steatosis. The severity of liver tissue lesions across the groups, from most severe to least severe, was as follows: 25% AH group > 12.5% AH group > 10% F group > OA model group > 6.25% AH group > CON control group.

Figure 1.

The impact of honey on the physiological structure of rat liver tissue. (A) The liver tissue was stained with H&E, images presented are in ×200 magnification. Scale bar: 50 μm. A: CON group; B: OA group; C: 10%F group; D: 25%AH group; E: 12.5%AH group; F: 6.25%AH group. (B) The Oil red staining of liver tissue. images presented are in ×200 magnification. Scale bar: 50 μm. A: CON group; B: 25%AH group.

Discussion

The spectrum of NAFLD includes simple fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), and related conditions such as liver cirrhosis and hepatocellular carcinoma.¹⁵ The continuous rise in NAFLD incidence has emerged as a new public health challenge in China, imposing a significant burden on both individual health and socioeconomic conditions. NAFLD is closely associated with high fructose intake and elevated blood uric acid levels. Excessive fructose consumption can lead to visceral fat accumulation, resulting in obesity, hyperlipidemia, and hyperuricemia, which in turn contribute to the development of metabolic diseases such as diabetes, fatty liver, and gout.¹⁶

Honey is a naturally sweet substance rich in fructose and glucose, with fructose content reaching around 40%. In this study, we used a hyperuricemic rat model to observe how honey-induced lipid metabolism disorders and hepatic steatosis occur in rats. Unlike humans, rats naturally produce uricase, an enzyme that breaks down uric acid into allantoin for excretion.¹⁷ This difference prevents direct observation of hyperuricemia's impact on metabolism and liver pathology in rats. To address this, we subcutaneously injected rats with potassium oxonate, a uricase inhibitor, to evaluate the effects of honey on blood uric acid levels and liver function. The experiment showed that normal male rats exhibited varying degrees of elevated uric acid levels throughout the trial after subcutaneous injection of potassium oxonate. When these rats were also given fructose or honey solutions, their blood uric acid levels increased even more significantly, consistent with previous reports.^18,19

Additionally, honey led to a significant increase in liver weight and organ coefficients in the model rats, causing varying degrees of hepatic steatosis, aligning with findings from both animal studies and human intervention trials.^20,21 In this study, we found that hepatic steatosis was more pronounced in the rats given 25% and 12.5% honey solutions. This effect is likely due to the combined impact of honey's high fructose and glucose content along with elevated uric acid levels. In the liver, fructose is ultimately converted into glucose, glycogen, lactate, fatty acids, and lipids, promoting de novo lipogenesis.²² Therefore, excessive fructose intake increases fatty acid production, exacerbating oxidative stress and insulin resistance, which in turn raises the risk of non-alcoholic steatohepatitis, liver fibrosis, and hepatocellular carcinoma. Fructose is the only carbohydrate that generates uric acid during metabolism. In the liver, fructose is rapidly metabolized by ketohexokinase,²³ consuming ATP and promoting substantial uric acid production.²⁴ The increased uric acid can further stimulate aldose reductase in the polyol pathway through a positive feedback mechanism, leading to more endogenous fructose production. Uric acid also exacerbates insulin resistance by inhibiting nitric oxide synthase activity and increases fructokinase activity in a concentration-dependent manner, promoting fructose-induced steatosis. This vicious cycle further aggravates liver fat accumulation and organ coefficient increases in rats, leading to more severe hepatic steatosis.⁵

Uric acid is a byproduct of purine metabolism and is currently believed to be associated with the development of various metabolic diseases. Research has shown that serum uric acid levels are positively correlated with T-CHO, TG, and LDL-C, while inversely correlated with HDL-C.^25,26 In this study, we found that fructose and 25% or 12.5% honey solutions, while raising uric acid levels, also increased serum TG, FFA, and HDL-C levels in potassium oxonate-induced hyperuricemic rats, with T-CHO and LDL-C levels either slightly decreasing or remaining unchanged. In contrast, the 6.25% honey solution elevated the levels of TG, FFA, HDL-C, T-CHO, and LDL-C in these rats. This may be due to fructose or other components in honey activating additional receptors, such as liver X receptors (LXRs), and their downstream gene transcription while increasing blood uric acid levels. LXRs are key regulators of cholesterol and lipid metabolism.^27,28 Systemic activation of LXRs can lead to the synthesis and remodeling of HDL particles and subsequent reverse cholesterol transport, potentially causing hepatic steatosis and hypertriglyceridemia.²⁹ Studies have suggested that the fructose transporter GLUT5 is a target of the nuclear receptor LXR. Interestingly, in the potassium oxonate-induced hyperuricemic model group, serum ALT and AST levels were slightly elevated, but both fructose and honey were able to normalize or even lower these enzyme levels, a result that remains to be fully explained.³⁰

This study indicates that sustained intake of honey within a certain dosage range may lead to liver damage and elevated uric acid levels, but there are still limitations to this research. While rats are commonly used as experimental animals, there may be differences in uric acid metabolism compared to human physiology. Therefore, results from human studies will be crucial for validating this conclusion. We plan to conduct clinical trials to determine the safe dosage and frequency of intake in the future, which is particularly important. Additionally, the potential mechanisms and metabolic pathways through which honey or fructose causes liver damage and increased uric acid levels require further investigation.

In conclusion, while honey is commonly regarded as a functional health product, its high concentrations of fructose and glucose can disrupt lipid metabolism in the body, potentially triggering or exacerbating NAFLD. This study has demonstrated that honey can lead to elevated uric acid levels in rats, accompanied by the progression of NAFLD, thereby providing a theoretical foundation for the potential toxicological effects of honey. In the future, we plan to further investigate the relationship between honey and NAFLD from a clinical perspective, offering clinical evidence to guide the reasonable consumption of honey.

Footnotes

Acknowledgement and Funding Information

We sincerely appreciated the foundation for its support of our research. This work was supported by important and weak discipline construction of Jing'an district in shanghai under grant no.2021BR06; project about traditional Chinese medicine supported by Shanghai Municipaltiy Health Commission under grant No.2022QN057.

Author Contributions

Xiuhe Xu: Writing original draft, Data curation, Conceptualization, Formal analysis, Methodology, Formal analysis. Peiyan Zhang: Investigation, Validation, Visualization, Formal analysis. Qingke Cui: Data curation, Software, Methodology, Formal analysis. Xiaoli He: Formal analysis, Conceptualization, Methodology. Lizhu Pan: Methodology, Software, Data curation. Zhuojun Zhou: Formal analysis, Investigation, Data curation. Jiayue Li: Data curation, Formal analysis. Caixia Wang: Data curation. Xiaojuan Yang: Data curation, Funding acquisition, Investigation. Guiqi Zhu: Conceptualization, Project administration, Validation.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethical Approval

This study was approved by the Administration Committee of Shanghai Jing'an District Shibei Hospital, Shanghai Province, China. All animal procedures were performed in strict accordance with the guideline of the Administration Committee of Shanghai Jing'an District Shibei Hospital. The animal ethics certificate number for the use of animals is YL-20231019-34. The approval date of this experiment is 2023-10-19.

Funding

Project about traditional Chinese medicine was supported by Shanghai Municipaltiy Health Commission, Important and weak discipline construction of Jing'an district in shanghai, (grant number 2022QN057, 2021BR06).

Statement of Human and Animal Rights

All of the experimental procedures involving animals were conducted in accordance with the Institutional Animal Care guidelines and approved by the Administration Committee of Shanghai Jing'an District Shibei Hospital, Shanghai Province, China.

Statement of Informed Consent

There are no human subjects in this article and informed consent is not applicable.

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Effect of Acacia Honey on Serum Uric Acid Level and Liver Injury in Rats

Abstract

Objective

Materials and methods

Results

Conclusion

Keywords

Introduction

Materials and Methods

Experimental Reagents and Instruments

Reagent Preparation

Animal Experiment

Measurement of serum Uric Acid Levels in Rats

Measurement of serum Biochemical Indicators in Rats

Measurement of Liver Weight and Organ Coefficient in Rats

Histological Observation of Liver Tissue

Statistical Analysis

Results

The Impact of Honey on Uric Acid Levels in Rats

The Impact of Honey on Lipid Metabolism-Related serum Indicators in Rats

The Impact of Honey on Liver Weight and Organ Coefficients in Rats

The Impact of Honey on the Physiological Structure of rat Liver Tissue

Discussion

Footnotes

Acknowledgement and Funding Information

Author Contributions

Declaration of Conflicting Interests

Ethical Approval

Funding

Statement of Human and Animal Rights

Statement of Informed Consent

References