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. 2024 Aug 17;13(3):101071. doi: 10.1016/j.imr.2024.101071

Protective effect of Korean red ginseng water extract on levothyroxine-induced hyperthyroidism and propylthiouracil-induced hypothyroidism in rats

Lei Huang a, Won Young Jang b, Ji Hye Yoon a, Zhenyan Piao b, Jinghan Su b, Dong Seon Kim b, Ki Woong Kwon b, Ji Won Kim b, Sang Hee Park a, Sunggyu Kim a,b, Jong-Hoon Kim c,⁎, Jae Youl Cho a,b,⁎
PMCID: PMC11388169  PMID: 39263445

Abstract

Background

Korean red ginseng extract (KRGE) (Family: Araliaceae) is one of the most widely used traditional herbs in Asia. Multiple studies have shown that KRGE has anti-inflammation, anti-fatigue, anti-obesity, anti-oxidant, and anti-cancer effects.

Methods

Sprague-Dawley rats were divided into five groups for PTU-induced hypothyroidism and six groups for LT4-induced hyperthyroidism. At the experiment's conclusion, rats were sacrificed, and blood, thyroid gland, and liver samples were collected. Body weight was recorded weekly, and serum hormone levels were assessed using enzyme-linked immunoassay. Thyroid gland and liver tissues were stained with hematoxylin and eosin. KRGE was prepared in 0.5% CMC and stored at 4 °C before administration.

Results

In the LT4-induced hyperthyroidism model, KRGE prevented decreases in body weight, thyroid gland weight, liver weight, serum glucose, and thyroid hormone levels compared to the PTU group. It also reduced increases in T3, T4, and serum aspartate aminotransferase levels after LT4 treatment. Additionally, KRGE improved thyroid gland and liver histopathology, effects not observed in the PTU-induced hypothyroidism model.

Conclusion

All things considered, our research points to KRGE's potential protective role in rat hyperthyroidism caused by LT4 by lowering thyroid hormone production.

Keywords: Hyperthyroidism, Hypothyroidism, Panax ginseng, Korean red ginseng water extract, Levothyroxine, Thyroid stimulating hormone

1. Introduction

Thyrotoxicosis is a clinical condition with a variety of etiologies, symptoms, and potential treatments and is caused by abnormally high thyroid hormone action in tissues due to abnormally high tissue thyroid hormone levels. Hyperthyroidism refers to a type of thyrotoxicosis caused by excessive production and secretion of thyroid hormones, T4 and T3, from the thyroid gland, for example. Effective thyrotoxicosis treatment necessitates an accurate diagnosis. Thyroidectomy, for instance, is acceptable for some types of thyrotoxicosis but not for others. Furthermore, beta blockers are effective in practically all types of thyrotoxicosis, but antithyroid medications are only effective in a subset of cases.1,2

Hypothyroidism is a chronic disease characterized by a lack of thyroid hormones T4 and T3. In the vast majority of cases, around 99%, hypothyroidism arises from primary dysfunction, where the thyroid gland fails to generate sufficient thyroid hormones. The residual 1% comprises secondary and tertiary hypothyroidism, which result from pituitary or hypothalamic malfunctions, and peripheral hypothyroidism. Together, central hypothyroidism (secondary and tertiary) and peripheral cases constitute less than 1% of occurrences.3 In the United States, the prevalence of hyperthyroidism is about 1.2% (0.5% overt and 0.7% subclinical). Onset can occur at all ages; however, presentation peaks between the ages of 20 and 50 years due to the higher prevalence of Graves’ disease. Toxic multinodular goiter usually appears after the age of 50 years, in contrast to toxic adenoma, which appears at a younger age. Thyroid illness in general is more common in women, and the most prevalent causes are Graves' disease (GD), toxic multinodular goiter (TMNG), and toxic adenoma (TA).1

Some of the symptoms of hyperthyroidism include weight loss (often accompanied by increased appetite), heat intolerance, weakness, and hair loss (especially of the outer third of the eyebrows).4 Untreated hypothyroidism can result in infertility, heart disease, and neurological concerns. Worldwide, environmental iodine deficiency and autoimmune thyroiditis in iodine-adequate regions stand as frequent culprits. While the complete scope of its societal impact remains somewhat elusive, up to 5% may be affected, with undiagnosed cases potentially reaching 5%. The economic implications are substantial, given related conditions and suboptimal treatment. Furthermore, hypothyroidism significantly diminishes quality of life, amplifies sick leave, and even raises mortality rates.5 Thyroid hormone is produced by follicles of the thyroid gland that iodinate tyrosine residues in the glycoprotein thyroglobulin.6 The TSH receptor (TSH-R), which is present on the basolateral membrane of thyroid follicular cells, is directly impacted by TSH, which is secreted by the anterior pituitary gland in response to feedback from circulating thyroid hormone. TSH regulates iodide uptake through the sodium/iodide symporter, which results in a number of actions necessary for the optimal synthesis and secretion of thyroid hormones.7 Thyroid hormone is important for appropriate development, growth, brain differentiation, and metabolic regulation in mammals and is required for amphibian metamorphosis. These activities are particularly visible during development in the settings of thyroid hormone insufficiency, such as maternal iodine shortage or untreated congenital hypothyroidism.8

Red ginseng is reddish-colored ginseng that has been steamed and dried. Red ginseng is more resistant to decay than white ginseng. It is ginseng that is been peeled, steamed at standard boiling temperatures of 100 °C (212°F), and then dried or sun-dried. Traditionally, ginseng root has served as an adaptogen, believed to normalize bodily functions and reinforce systems strained by stress. Adaptogens are thought to act as a shield against various environmental and emotional pressures on health. Korean Red Ginseng is recognized for bolstering immunity, restoring vital energy, easing fatigue, promoting better blood circulation, delivering antioxidants, enhancing memory, and mitigating menopausal symptoms. To combat deterioration at room temperature, fresh ginseng is transformed into red ginseng through steaming and drying, or into white ginseng through a simple drying process.9 According to conventional wisdom, red ginseng provides significantly greater biological benefits with fewer side effects than its fresh and white counterparts.10 "Treatise on Febrile and Miscellaneous Diseases", also known as "Treatise on Febrile Diseases", was written by Zhang Zhongjing in the Eastern Han Dynasty. This book is considered to be a classic of internal science of Han medicine, laying the foundation of Chinese medicine. Another traditional Chinese medicine literatures called "Li Clan Secret Recipe (Li Zu Mi Fang)", describe the uses for thyroid problems of red ginseng. The Donguibogam, a compilation of mostly East Asian folk medicines written by Jun Heo (1610), describes several uses of red ginseng. Anti-inflammatory, anti-obesity, and anti-oxidative properties are among them.11

A well-known herbal remedy for immune modulation, KRGE may have anti-inflammatory and anti-cancer properties and control autophagy. KRGE activity has been linked to ginsenoside components, according to efficacy studies.12 KRGE inhibits IL-8 production in Helicobacter pylori-infected gastric epithelial cells, decreases isoproterenol's ability to cause heart damage, and prevents cadmium's ability to cause lung damage.13 Nevertheless, there has been minimal research conducted on the impact of KRGE in relation to thyroid problems. Therefore, in this study, we investigated such effects of KRGE in a rat model of hyperthyroidism induced by LT4 and hypothyroidism induced by PTU.

2. Methods

2.1. Materials

Korean Ginseng Corporation (Daejeon, Korea) supplied KRGE, a water extract of Korean red ginseng (KRG). Rat TSH, rat T3, and rat T4 enzyme-linked immunoassay (ELISA) kit were purchased from Cusabio (China). Propylthiouracil (Ca# P3755, 10 g), levothyroxine (CA# T2376, 1 g), and carboxymethylcellulose sodium salt (CMC, C5678–500 G) were bought from Sigma (St. Louis, MO, USA). Rectal thermometer (JD-DT08G) was purchased from JEUNGDO BIO AND PLANT CO., LTD. (Seoul, Korea). A KOVAXSYRINGE 1 mL 26 G 1/2 was purchased from Korea Vaccine Co. Ltd. (Ansan, Gyeonggi-do, Korea).

2.2. Preparation of KRGE and analysis of ginsenosides

Korean red ginseng root was extracted in distilled water 7 times at 87 °C for 12 h. KRGE contains 11 ginsenosides of G-Rg1 (1.30 mg/g), G-Re (1.50 mg/g), G-Rf (1.12 mg/g), G-Rg2s (1.15 mg/g), G-Rb1 (5.95 mg/g), G-Rc (2.33 mg/g), G-Rb2 (2.01 mg/g), G-Rd (0.85 mg/g), G-Rg3s (2.02 mg/g), G-Rg3r (0.86 mg/g), and G-Rh1 (0.85 mg/g), as shown in Supplementary Table 1.

2.3. Animals and husbandry

Orientbio (Seongnam, Korea) supplied five-week-old male Sprague-Dawley rats weighing 190–224 g. Three rats were kept in each cage in a temperature (20–25 °C)- and humidity (40–45%)-controlled room at a light:dark cycle of 12 h:12 h. Animals were fed a chow diet and water ad libitum during acclimatization, as described previously.14

2.4. Experimental design and drug treatment for LT4-induced hyperthyroidism model

After 7 days of acclimatization, the rats were randomly divided into 6 groups of 6 rats each and treated as indicated: (a) Group 1 (Normal): euthyroid; 0.5% CMC (week 1–week 6) orally administered, saline intraperitoneally treated (week 4–week 6), and saline subcutaneously treated (week 4–week 6); (b) Group 2, hyperthyroid control (LT4): 0.5% CMC (week 1–week 6) orally administered, LT4 0.5 mg/kg intraperitoneally treated (week 4–week 6), and saline subcutaneously treated (week 4–week 6); (c) Group 3, hyperthyroid with KRGE 200 mg/kg–treated group (KRGE 200): KRGE 200 mg/kg (week 1–week 6) orally administered, LT4 0.5 mg/kg intraperitoneally treated (week 4–week 6), and saline subcutaneously treated (week 4–week 6); (d) Group 4, hyperthyroid with KRGE 400 mg/kg-treated group (KRGE 400): KRGE 400 mg/kg (week 1–week 6) orally administered, LT4 0.5 mg/kg intraperitoneally treated (week 4–week 6), and saline subcutaneous treated (week 4–week 6); (e) Group 5, hyperthyroid with KRGE 600 mg/kg–treated group (KRGE 600): KRGE 600 mg/kg (week 1–week 6) orally administered, LT4 0.5 mg/kg intraperitoneally treated (week 4–week 6), and saline subcutaneous treated (week 4–week 6); (f) Group 6, hyperthyroid with propylthiouracil (PTU, 10 mg/kg, s.c.)-treated positive group (PTU): 0.5% CMC (week 1–week 6) orally administered, LT4 (i.p.) treated (week 4–week 6), and PTU subcutaneous treated (week 4–week 6), as shown in Fig. 1A.

Fig. 1.

Fig 1

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The experimental schedule for this study.

Figure note. A: Experimental design for the LT4-induced hyperthyroid rat model. Animals were divided into 6 groups (Normal, LT4, KRGE 200, KRGE 400, KRGE 600, and PTU); each group contained 6 rats. The injection methods of KRGE, LT4, and PTU were orally, intraperitoneally, and subcutaneously, respectively. B: Experimental design for the PTU-induced hypothyroid rat model. KRGE, Korean red ginseng extract; PTU, Propylthiouracil; LT4, Levothyroxine/L-thyroxine.

2.5. Experimental design and drug treatment for PTU-induced hypothyroidism model

After 7 days of acclimatization, the rats were randomly divided into 5 groups of 6 rats each and treated as indicated: (a) Group 1 (Normal): euthyroid; saline subcutaneously treated (week 1–week 4), 0.5% CMC (week 3–week 4) orally administered, and saline intraperitoneally treated (week 3–week 4); (b) Group 2, hypothyroid control (PTU): PTU subcutaneous treated (week 1–week 4), 0.5% CMC (week 3–week 4) orally administered, and saline intraperitoneally treated (week 3–week 4); (c) Group 3, hypothyroid with KRGE 200 mg/kg–treated group (KRGE 200): PTU subcutaneous treated (week 1–week 4), KRGE 200 mg/kg (week 3–week 4) orally administered, and saline intraperitoneally treated (week 3–week 4); (d) Group 4, hypothyroid with KRGE 400 mg/kg–treated group (KRGE 400): PTU subcutaneous treated (week 1–week 4), KRGE 400 mg/kg (week 3–week 4) orally administered, and saline intraperitoneally treated (week 3–week 4); (e) Group 5, hypothyroid with levothyroxine (LT4, 0.5 mg/kg, i.p.)-treated positive group (LT4): PTU subcutaneous treated (week 1–week 4), 0.5% CMC (week 3–week 4) orally administered, and LT4 (i.p.) treated (week 4–week 6), as shown in Fig. 1B.

2.6. Measurements of body weights and organ weights

Body weight was measured from week 1 to week 6 utilizing a computerized electronic balance for LT4-induced hyperthyroidism model. For PTU-induced hypothyroidism model body weight was checked from week 1 to week 4. At the time of the sacrifice, each organ was weighed separately in grams (absolute weights). To reduce the differences among individuals, the relative weights (% of body weight) were calculated (data not shown).

2.7. Serum hormone level analysis

Blood samples were obtained, then, serum was separated by centrifugation at 4 °C at 3000 rpm for 15 min. Before analysis separated serum was kept at −70 °C. The levels of TSH, T3, and T4 were measured using ELISA kits (Cusabio, China), according to the manufacturer's instructions, as previously reported.15

2.8. Serum biochemistry (GLU and AST)

Serum GLU and AST concentrations were determined using an automated blood analyzer at Sungkyunkwan University (Suwon, Korea).16,17

2.9. Histopathological analysis

Following organ weight measurements. For optical microscopy, representative sections were stained with hematoxylin and eosin (H&E). We looked at the histological profiles of the various organs, as previously reported.18

2.10. Statistical analysis

Data are presented as the mean ± SD (standard deviation) of each group (n = 6 per group). The graphs were drawn using Sigma Plot. P-values less than 0.05 and less than 0.01 were considered statistically significant and extremely statistically significant, respectively.

3. Results

3.1. Effects of krge on body weights

In LT4-induced hyperthyroidism model, KRGE was used to pre-treat rats for 28 days before establishment of the model with LT4. From 29 days after the first LT4 treatment, body weights decreased in the LT4 group compared to the normal group. The treatment of PTU and KRGE 200, 400, and 600 mg/kg considerably reduced these body weight losses (P < 0.01 or P < 0.05) (Fig. 2A, Left panel). In PTU-induced hypothyroidism model, PTU was used to treat rats for 14 days to induce hypothyroidism model. In order to investigate the effects of red ginseng on changes in body weight in PTU-induced hypothyroidism model, weekly measurements of weight fluctuations were taken. The results revealed a notable reduction in weight within the hypothyroidism-induced control group, which was administered PTU for 2 weeks (P < 0.01), 3 weeks (P < 0.01), and 4 weeks (P < 0.01), as compared to the normal group. Furthermore, a significant increase in body weight was observed in the LT4-treated group compared to the control group, starting from the second to the fourth week of PTU administration. Conversely, in the red ginseng group administered 200 mg/kg and 400 mg/kg, fewer fluctuations in body weight were noted in comparison to the control group (Fig. 2A, Right panel).

Fig. 2.

Fig 2

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Effects of KRGE on body and organ weights.

Figure note. A, Left panel: Body weight was measured once a week in LT4-induced hyperthyroid rat model. A, Right panel: Body weight was measured once a week in PTU-induced hypothyroid rat model. B, Left panel and Right panel: The absolute weights of thyroid gland and liver were measured using an automatic electronic balance in LT4-induced hyperthyroid rat model (Normal: a; LT4: b; LT4+KRGE 200: c; LT4+KRGE 400: d; LT4+KRGE 600: e; LT4+PTU: f). C, Left panel and Right panel: The absolute weights of thyroid gland and liver were measured in PTU-induced hypothyroid rat model (Normal: a; PTU: b; PTU+KRGE 200: c; PTU+KRGE 400: d; PTU+LT4: e). #P < 0.05 and ##P < 0.01 compared with the normal group. *P < 0.05 and ⁎⁎P < 0.01 compared with the LT4 or PTU groups. KRGE, Korean red ginseng extract; PTU, Propylthiouracil; LT4, Levothyroxine/L-thyroxine.

3.2. Effects on thyroid gland and liver weights

In LT4-induced hyperthyroidism model, absolute weights of thyroid gland and liver were significantly decreased compared with organ weights in normal group rats (P < 0.01 or P < 0.05). Treatment with PTU and all three dosages of KRGE (200, 400, and 600 mg/kg) considerably enhanced these aberrant changes in liver weights (P < 0.01 or P < 0.05). PTU 10 mg/kg treatment significantly inhibited thyroid gland weight decreases (P < 0.01) and KRGE (P < 0.05) (Fig. 2B, Left panel and Right panel). In PTU-induced hypothyroidism model, a significant absolute increase in thyroid weight was noted compared to the normal group (P < 0.05), while in the LT4-treated group, a significant absolute decrease in thyroid weight was observed compared to the PTU-induced control group (P < 0.05). Conversely, the red ginseng group, treated with two doses (200 mg/kg and 400 mg/kg), displayed less pronounced variations compared to the control group. The absolute thyroid weights were recorded as 0.203 ± 0.017 g, 0.236 ± 0.027 g, 0.237 ± 0.029 g, 0.216 ± 0.013 g, and 0.024 ± 0.019 g for the normal (Vehicle) group, PTU-induced control group, red ginseng 200 mg/kg and 400 mg/kg groups, and LT4 group, respectively. Relative thyroid weights were observed as 0.052 ± 0.004%, 0.083 ± 0.012%, 0.086 ± 0.011%, 0.088 ± 0.011%, and 0.061 ± 0.006% of body weights for the same groups (Fig. 2C, Left panel). A significant absolute decrease in liver weight was observed compared to the normal group (P < 0.01). However, in the LT4-treated group (P < 0.01) and the red ginseng 400 mg/kg group (P < 0.05), both absolute liver weight increase and relative liver weight increase were recognized compared to the PTU-induced control group. Conversely, in the red ginseng group treated with doses of 200 mg/kg and 400 mg/kg, lesser variations were noted compared to the control group. Absolute liver weight measurements were recorded as 14.323 ± 1.395 g, 7.185 ± 0.947 g, 7.633 ± 0.555 g, 7.556 ± 0.821 g, and 14.069 ± 1.518 g for the normal (Vehicle) group, PTU-induced control group, red ginseng 200 mg/kg and 400 mg/kg groups, and LT4 group, respectively (Fig. 2C, Right panel).

3.3. Effects on serum ast and glu levels

Serum AST levels was higher in the LT4 group of rats than in the normal group. The AST concentration in the serum of PTU and KRGE (400 and 600 mg/kg)-treated group rats was significantly lower than that of the LT4 group rats (P < 0.05) (Fig. 3A, Left panel). Decreases of serum GLU level were detected in LT4 group rats compared with normal group rats, but LT4 treatment had no significant effects on GLU level compared with the normal group rats. GLU concentration in serum of PTU and all three KRGE group rats were significantly decreased compared with LT4 group rats (P < 0.01 or P < 0.05) (Fig. 3A, Right panel). Moreover, to assess the impact of PTU-induced hypothyroidism and red ginseng treatment on liver function, changes in serum AST levels was examined. The results indicated elevated AST levels in the control group compared to the normal group (Fig. 3B, Left panel). To explore the influence of red ginseng on glucose metabolism changes prompted by induced hypothyroidism, the concentration of serum GLU was measured. The results revealed a significant increase in GLU secretion (P < 0.01) in the PTU-induced hypothyroidism control group compared to the normal group. Furthermore, treatment with red ginseng doses of 200 mg/kg and 400 mg/kg, as well as LT4, resulted in a significant reduction in GLU secretion increase compared to the control group (Fig. 3B, Right panel).

Fig. 3.

Fig 3

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Serum AST and GLU concentrations.

Figure note. A and B: Serum samples were collected by centrifugation at 3000 rpm for 15 min at 4 °C. Samples were measured using an automated blood analyzer. AST (A and B, Left panel) and GLU (A and B, Right panel) levels were detected in the LT4 or PTU group and compared with levels in the Normal group. KRGE 200, KRGE 400, and KRGE 600 levels were compared with those in the LT4 group or KRGE 200 and KRGE 400, levels were compared with those in the PTU group. The PTU group served as a positive control in LT4-induced hyperthyroid rat model and the LT4 group served as a positive control in PTU-induced hypothyroid rat model. Data are mean ± standard deviation of 6 animals. #P < 0.05, LT4 vs. Normal. *P < 0.05, ⁎⁎P < 0.01, KRGE or PTU(LT4) vs. LT4(PTU). AST, aspartate aminotransferase; GLU, Glucose; KRGE, Korean red ginseng extract; PTU, Propylthiouracil; LT4, Levothyroxine/L-thyroxine.

3.4. Effect on serum thyroid hormones

To examine the effects of KRGE on serum thyroid hormones, ELISA was used as described previously.19 When compared to the normal group, the LT4-treated groups had significantly higher serum T3 and T4 levels and lower TSH levels (P < 0.01). These abnormal changes were reversed by treatment of KRGE (200, 400, and 600 mg/kg). PTU normalized TSH levels as well

(Fig. 4A, B, and C). On the other hand, the results indicated that TSH levels increased in the PTU-induced hypothyroidism control group compared to the normal control group. However, in the red ginseng groups treated with doses of 200 mg/kg and 400 mg/kg, as well as LT4, TSH levels decreased in comparison to the control group, although not significantly (Fig. 4D). T4 secretion significantly decreased in the control group compared to the normal control group (P < 0.01). In the red ginseng groups treated with doses of 200 mg/kg and 400 mg/kg, T4 levels showed a slight increase compared to the control group, but without statistical significance. In the LT4-treated group, T4 levels displayed a significant increase (P < 0.01) compared to the control group (Fig. 4E). T3 secretion was significantly lower in the control group than in the normal control group (P < 0.01). In the LT4-treated group and the red ginseng groups treated with doses of 200 mg/kg and 400 mg/kg, T3 levels exhibited a slight increase compared to the control group, but without statistical significance (Fig. 4F).

Fig. 4.

Fig 4

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Effects of KRGE on serum thyroid hormones.

Figure note. A-F: Serum samples were collected by centrifugation at 3000 rpm for 15 min at 4 °C. The levels of TSH (A and D), T3 (C and F), and T4 (B and E) were detected in samples by ELISA kits. The TSH, T3, and T4 levels were detected in the LT4 group compared with the Normal group. KRGE 200, KRGE 400, and KRGE 600 were compared with the LT4 group. The PTU group was the positive control. The TSH, T3, and T4 levels were detected in the PTU group compared with the Normal group. KRGE 200 and KRGE 400 were compared with the PTU group. The LT4 group was the positive control. #P < 0.05, ##P < 0.01, LT4 vs. Normal. *P < 0.05, ⁎⁎P < 0.01, KRGE or PTU(LT4) vs. LT4(PTU). KRGE, Korean red ginseng extract; TSH, thyroid hormone–thyroid stimulating hormone; T3, tri-iodothyronine; T4, Thyroxine; ELISA, enzyme-linked immunoassay; LT4, Levothyroxine/L-thyroxine.; PTU, Propylthiouracil.

3.5. Effect on organ histological changes

To investigate the effects of KRGE on thyroid and liver tissues, H&E staining was performed.20,21 When the LT4 group was compared to the normal group, there were observable atrophic changes in the thyroid glands, reductions in the total thyroid glands and thickness of the follicular lining epithelium, and increased follicular sizes. Similar to the PTU-treated group, treatment with KRGE at 200, 400, and 600 mg/kg inhibited these histopathological changes. Follicular sizes were significantly larger in the LT4 group compared to the control group, but observably smaller in both the groups treated with PTU and all three doses of KRGE (Fig. 5A). In the LT4 group, the thickness of the follicular lining of the epithelium was also dramatically decreased, whereas it was significantly increased following KRGE or PTU treatment. The LT4 group had decreased sinusoidal space in the liver due to hepatocyte hyperplasia (Fig. 5C). Treatment with all three doses of KRGE or PTU significantly inhibited these LT4 treatment-related histopathological changes of the thyroid gland and liver (Fig. 5B and 5D).

Fig. 5.

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Representative histopathological profiles in thyroid gland and liver.

Figure note. A-D: Effects of KRGE on the histological changes of thyroid and liver tissues in LT4-induced hyperthyroid rats. Thyroid and liver tissues were isolated to prepare paraffin-embedded slides, and stained with H&E dye. Histological profiles of the thyroid gland (A) were examined at magnifications ranging from 2X to 60X. Morphological changes (B) were observed under a microscopic analysis at 10X and 40X magnifications, with arrows indicating the epithelium and thyroid follicles, respectively. Histological profiles in liver (C) were also examined at magnifications from 2X to 60X. Morphological changes (D) in the liver were observed under a microscopic analysis at 10X and 40X magnifications, with arrows indicating the nucleus and hepatocytes, respectively. E-H: Effects of KRGE on histological changes in thyroid and liver tissues in a PTU-induced hypothyroid rat model. Thyroid and liver tissues were isolated, to prepare paraffin-embedded slides, and stained with H&E dye. Histological profiles of the thyroid gland (E) were examined at magnifications from 2X to 60X. Morphological changes (F) were observed under a microscope at 10X and 40X magnifications, with arrows indicating the epithelium and thyroid follicles, respectively. Histological profiles of the liver (G) were examined at magnifications from 2X to 60X. Morphological changes in the liver (H) were observed under a microscope at 10X and 40X magnifications, with arrows indicating the nucleus and hepatocytes, respectively.

In the PTU-induced control group, evident thyroid follicular cell proliferation leading to hypertrophy was observed, accompanied by a decrease in follicular diameter and colloid content within the follicles, compared to the normal control group. An increase in overall thyroid thickness and membrane thickness was noted in conjunction with the average decrease in thyroid follicular diameter. Conversely, the proliferative and hypertrophic features of thyroid tissue induced by PTU were significantly suppressed by LT4 and both doses of red ginseng administration. Specifically, the LT4 and two red ginseng dose groups exhibited reductions in overall thyroid thickness and membrane thickness, along with an increase in average thyroid follicular diameter, as compared to the PTU-induced control group (Fig. 5E and 5F). In the PTU-induced control group, there was a significant decrease in the number of hepatocytes per unit area due to notable hepatocellular swelling, as compared to the normal control group. However, this hepatocellular swelling observed due to PTU administration was markedly inhibited by LT4 and both doses of red ginseng administration. Specifically, the LT4 and two red ginseng dose groups exhibited reductions in the number of hepatocytes per unit area as compared to the PTU-induced control group. (Fig. 5G and 5H).

4. Discussion

The thyroid is a vital endocrine organ that controls nearly every bodily function and multiple physiological processes, including growth, development, reproduction, digestion, neural function, and the cardiovascular system.22, 23, 24 As a result, changes in thyroid hormone production and/or release have a wide range of consequences. Hyperthyroidism is particularly dangerous and can result in a medical emergency. The liver is the main target organ of thyroid hormone, which has important biological and medical significance.25 Habershon originally described hepatic impairment in a hyperthyroid patient.26 Liver injury in hyperthyroid individuals is now widely recognized.17,27, 28, 29 Thyroid and liver interactions may involve liver damage caused by the systemic effects of hyperthyroidism, the direct toxic effects of thyroid hormones on the liver, changes in thyroid hormone metabolism caused by intrinsic liver illness, or subclinical physiologic effects of thyroid hormone on liver function.25

Before conducting this study, we performed preliminary experiments to ensure that LT4 or PTU can successfully induce a hyperthyroidism model or hypothyroidism model in rats (data not shown). Hyperthyroidism related with liver damages was induced by daily intraperitoneal injection of LT4 0.5 mg/kg, which has been reported in previous studies.20 In this study, the effects of KRGE were observed using rats with LT4-induced hyperthyroidism and PTU-induced hypothyroidism. Our results indicate KRGE may be a candidate to prevent or treat thyroid dysfunctional diseases.

In this regard, T3 and T4 levels were high, whereas TSH was low in LT4-induced rats, confirming the hyperthyroid condition in the experimental rats. These results are consistent with some earlier reports.30,31 Body weight loss was also observed in LT4-treated rats, which may be related to muscle atrophy and lipolysis in the experimentally produced hyperthyroid setting.32,33 In addition, serum AST and GLU levels were abnormal, which caused a drastic change of histomorphological profiles in both the thyroid gland and liver. These changes were significantly recovered with administration of KRGE at 200, 400, and 600 mg/kg.

Many studies suggest that red ginseng has anti-inflammatory, anti-oxidative, and other effects,34,35 and ginsenosides are the active component of KRGE.36 Hyperthyroidism causes oxidative damage to numerous organs,37, 38, 39, 40 and antioxidants or anti-inflammatory agents have been shown to have beneficial effects on hyperthyroidism.41,42 Since KRGE has been shown to exhibit powerful anti-inflammatory and anti-oxidative effects,43,44 we speculated that it may have favorable benefits on hyperthyroidism and associated organ issues. Ginsenoside Rb1 was the main component of KRGE, as shown in Supplementary Table 1. Many in vitro and in vivo studies have suggested that ginsenoside Rb1 has a variety of pharmacological effects, including anti-inflammatory and anti-oxidative effects, on metabolic disorders, vascular diseases, ovarian granulosa cell injury, osteoporosis, depressive-like behavior, and other conditions.45 We speculate that the protective effect of KRGE on LT4-inducd hyperthyroidism is due to the active ingredient ginsenoside Rb1. Some plants such as Ranunculus bulumei, Melicope accedens (Blume) T.G. Hartley, Chimonanthi Praecocis Flos, Torreya nucifera butanol fraction, Bupleurum falcatum L. (Umbelliferae), aloe gel, and MOK are potential sources of anti-inflammatory and anti-oxidative agents to combat various diseases.20,46, 47, 48, 49, 50, 51 Notably, several studies recently found that natural extracts such as Bupleurum falcatum L. (Umbelliferae), aloe gel, and Prunellae Spica Extract are effective in treating hyperthyroidism because of their anti-inflammatory and anti-oxidative activities.15,20

Although the role of KRGE in a variety of diseases has been extensively studied, its use in hyperthyroidism requires more research. We found that KRGE had no significant effect on body temperature, water intake, or food intake in rats (data not shown). This study has limitations, and more research is needed to conclude that KRGE is indeed helpful for hyperthyroidism. On the basis of these findings, we conclude that KRGE may aid in the treatment of hyperthyroidism and associated organ damage, although active searches for other potential treatments should continue.

Thyroid disease is a worldwide health issue that can have a significant impact on patient well-being. In this study, adult male rats were used for experiments. Since thyroid problems in general are significantly more common in women than in males (the reasons for this are yet unknown),52,53 in a subsequent study, we will examine male and female animals to determine whether KRGE has differential effects on the sexes in the hyperthyroidism model.

In conclusion, we demonstrated that KRGE may be a potential medicinal plant-derived extract that plays an important role in protecting thyroid, liver, and other organs from LT4-induced conditions. The proposed mechanisms are summarized in Fig. 6. In addition, we will improve the design of hypothyroid model in the following research.

Fig. 6.

Fig 6

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The schematic pathways of KRGE anti-inflammatory and anti-oxidative activities. KRGE, Korean red ginseng extract.

CRediT authorship contribution statement

Conceptualization: JHK, JYC. Methodology: LH, JYC. Investigation: LH, JHY, SHP. Formal analysis: WYJ, ZP, JS, DSK, KWK, JWK. Writing - Original Draft: LH. Writing - Review and Editing: LH, WYJ, JHY, ZP, JS, DSK, KWK, JWK, SHP, SK, JHK, JYC. Funding acquisition: JYC, SK. Supervision: JYC.

Declaration of competing interest

The authors declare that they have no conflicts of interest.

Acknowledgments

Funding

This research was supported by the National Research Foundation of Korea (NRF), the Ministry of Science and ICT, Republic of Korea (Grant No.: 2017R1A6A1A03015642 to J.Y.C.), by Korea Basic Science Institute (National Research Facilities and Equipment Center) grant funded by the Ministry of Education (Grant No.: 2020R1A6C101A191 to J.Y.C.), Republic of Korea, and by Korean Society of Ginseng (2022 to S.K.), Republic of Korea.

Ethical statement

The animal experiments were approved by the Institutional Animal Care and Use Committee at Chonbuk National University (Jeonju, Korea; Approval ID: JBNU 2022-018).

Data availability

All the data analyzed in this study were included in this article. Further inquiries can be directed to the corresponding authors.

Footnotes

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.imr.2024.101071.

Supplement 1. Types of ginsenoside included in KRGE.

Contributor Information

Jong-Hoon Kim, Email: jhkim1@chonbuk.ac.kr.

Jae Youl Cho, Email: jaecho@skku.edu.

Appendix. Supplementary materials

mmc1.docx (15.4KB, docx)

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

mmc1.docx (15.4KB, docx)

Data Availability Statement

All the data analyzed in this study were included in this article. Further inquiries can be directed to the corresponding authors.

Articles from Integrative Medicine Research are provided here courtesy of Korea Institute of Oriental Medicine

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