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ISSN : 2693 - 6356 

2020 | Vol 3 | Issue 6 

 

CTMJ | traditionalmedicinejournals.com  

 

 

For the treatment of dry eyes caused by the suppression of the 

JAK2/STAT3 pathway, a combination of Runmu fengye tang 

preparation and hydroxysugar glycolic acid eye drops is 

recommended. 

Dr.P.Aravinda Reddy 1, Dr.V.Ravikumar 2,Dr.Rafia 3,Aashish r hajare 4, 
Assistant professor 1,2,3,4, 

Department of Pharmacy, 
Samskruti College of Pharmacy, 

Kondapur (V), Ghatkesar (M) Medchal Dist, Telangana, India. 
 

Abstract 

The goal of this study is to identify therapeutic approaches that successfully address dry eye in clinical settings.  

Methods: Eye drops containing glycerol, dextran 70, and Runmu Fengliang tang (RMFS) were given to rabbits in a 

model of scopolamine-induced dry eye (HGA). Dry eye symptoms and lacrimal gland damage were assessed using 

Schirmer's I test (SIt), break-up time (BUT), and histopathologic exams (H&E). Apoptotic cell count and Th17/Treg 

percentages were determined by flow cytometry, and JAK2/STAT3 pathway protein expression was assessed by 

Western blot test. Findings: In the rabbit scopolamine-induced dry eye model, the combination of RMFS with HGA 

considerably enhanced tear production (p < 0.001), decreased tear break-up time (p < 0.001), restored ocular 

surface damage, and decreased apoptosis (p < 0.05) as compared to the group that received just one injection of the 

medication. Furthermore, it suppressed the JAK2/SATA3 pathway and controlled the balance of cytokines 

associated to Th17 and Tregs. In conclusion, scopolamine-induced dry eye symptoms are alleviated in rabbit models 

when RMFS and HGA are administered together, suggesting that this medication may be useful in the treatment of 

dry eye illness. Collecting clinical data to examine the combination's effectiveness and safety should be the focus of 

future investigations. Topics covered include: hypromellose 2910, runmu fengliang tang, glycerol eye drops, the 

th17/treg and JAK2/SATA3 pathways, and dry eye syndrome. 

 

 INTRODUCTION  

Dry eye disease (DED) is a multifactorial ocular 

surface disease characterized by tear film 

homeostasis, ocular surface inflammatory response 

and damage, and ocular discomfort [1]. The reported 

prevalence of DED ranges from 5 to 34 %, with a 

higher prevalence in women and older adults [2,3]. In 

recent years, with the changes in the living 

environment and the extensive use of video 

terminals, the incidence of dry eye disease is 

increasing year by year and there is a trend of 

rejuvenation [4]. The DED is often associated with 

symptoms such as itching, foreign body sensation 

and burning sensation in both eyes, which reduce the 

quality of life of affected individuals. The chronic 

inflammatory state involved in DE lead to vision loss 

or blindness if not treated promptly with appropriate 

therapies. However, treatment of DED is difficult and 

effective treatments are still lacking. Thus, an 

investigation into effective drugs required for the 

prevention and treatment of dry eye is a key scientific 

task that needs to be done, as it will have practical 

and effective implications on the patients and 

therapeutics in general. In recent years, the study of 

immunomodulation has gained increasing attention 

and researchers have found that regulatory T cells 

(Treg) and the helper T cell subset 17 cells (Th17) 

play a very important role in immune-inflammatory 

diseases [5]. It has been shown that the development 

of dry eye disease is significantly associated with 

disturbed Treg/Th17 cell homeostasis and that 

blocking IL-17 in vivo significantly reduces the 

severity and progression of the disease by restoring 

the Treg/Th17 cell ratio [6]. Therefore, protection of 



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the homeostatic balance of Th17/Treg cells may 

contribute to the treatment of dry eye.  

Traditional Chinese medicine may also play an 

important role in the treatment of dry eye disease. 

Therefore, the aim of this study was investigate the 

efficacy of a combined remedy using RMFS and 

HGA in the treatment of dry eye symptoms in model 

rabbits.  

EXPERIMENTAL  

Animals and design  

A total of 30 healthy New Zealand rabbits (2 - 3 

months old, males = females = 15, 1.5 kg ± 0.45 kg) 

were obtained from Key Laboratory of Medical 

Biotechnology and Translational Medicine, Embryo 

Engineering Laboratory, Guilin Medical University 

(Guilin, China). All animal experiments were 

approved by the Ethics Committee of Affiliated 

Hospital of Guilin Medical University for the use of 

animals (Grant no. GXZYC20220296) and conducted 

in accordance with the National Institutes of Health 

Laboratory Animal Care and Use Guidelines [7]. All 

rabbits were housed in a single standard rabbit cage 

(2 rabbits/cage) at 21 ± 2 °C, 58 ± 9 % relative 

humidity and 12 h light/dark cycle. Water and 

standard feed were provided ad libitum and they were 

allowed to acclimatize for 5 days. Prior to the 

experiments, the animals were carefully examined 

and found to be free of ocular inflammation or 

obvious signs of abnormality.  

The rabbits were randomly divided into 5 groups, 

with 6 rabbits in each group. The five groups were 

control group, model group, model + RMFS group, 

model + HGA group and model + RMFS + HGA 

group. Control group did not receive any treatment 

while the remaining four model groups were treated 

by subcutaneous injection of 0.2 mg/kg scopolamine 

(Sigma-Aldrich, St. Louis, MO, USA) four times a 

day (injected at 8:00, 11:00, 14:00 and 17:00 hours, 

respectively) for 28 consecutive days to induce dry 

eye. For the model + RMFS group, 51.85 g/kg of 

Runmu Fengliang Tang (RMFS) was administered by 

gavage, twice daily for 28 days. In the model + HGA 

group, Hypromellose 2910, Dextran 70 and Glycerol 

Eye Drops (HGA, Alcon Laboratories. Inc, TX, 

USA) was administered into the eyes of the rabbits at 

1 to 2 drops (approximately 0.025 - 0.05 mL) 4 times 

daily, for 28 days. Rabbits in model + RMFS + HGA 

group were treated with a combination of RMFS and 

HGA for 28 days. Tear volume (Schirmer’s I test 

(SIt)) and tear film rupture break-up time (BUT) 

were measured on day 0, 7, 14, 17, 21 and 28 for 

each group of rabbits and the experimental animals 

were euthanized on the 28th day.  

Schirmer’s I test (SIt)  

As previously reported, one end of the Color Bar 

Schirmer strips (EagleVision, Memphis TN) was 

folded and placed into the conjunctival sac in the 

outer 1/3 of the rabbit's lower eyelid. After 5 minutes, 

the filter paper was collected and the length of 

wetting was measured from the point of folding [8].  

Tear break up time (BUT)  

Placing 1 μL of 0.1 % liquid sodium fluorescein into 

the conjunctival sac caused 3 blinks, which were 

recorded over several seconds and this was observed 

under a slit-lamp microscope with cobalt blue light 

(CKX41, Olympus, Tokyo, Japan) until the first 

dryness of the tear film spot appeared. The time from 

eyelid opening to the appearance of the first dry spot 

was recorded and measured. The experiment was 

repeated three times and the average calculated.  

Hematoxylin and eosin (H&E)  

The lacrimal glands of rabbits in each group were 

removed and treated with 4 % paraformaldehyde 

immediately and embedded in paraffin. Then, tissues 

were cut into 4 μm slices and subsequently de-

paraffinized. Thereafter, the samples were rehydrated 

and stained with hematoxylin and eosin (H&E). The 

images were examined under a light microscope and 

three pathologists who were unaware of the grouping 

of the animals were asked to evaluate each group of 

sections.  

Flow cytometry  

For apoptosis detection experiments, rabbit corneal 

tissues from each group were removed and 

homogenates were prepared (one homogenate was 

made from each group of collected tissues). Then 

they were digested with enzymes and undigested 

sections were filtered out using strainers to form 

single cell suspensions. Next, the cells were stained 

with Annexin V-fluorescein isothiocyanate 

(FITC)/propidium iodide (PI) reagent (Vazyme, 

Nanjing, China) under dark conditions for 15 

minutes. Subsequently, flow cytometry (BD, 

FACSCalibur, USA) was used to analyze the 

percentage of apoptosis.  

For experiments to measure Th17 and Treg cells, 

lacrimal glands of rabbits in each group were taken 

and dried for 5 days and then homogenized (one 

homogenate was made from each group of collected 



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tissues). They were digested with pancreatic enzyme 

and undigested sections were filtered out using 

strainers to form single cell suspensions. Then, single  

 

cell suspensions of the lacrimal gland were subjected 

to flow cytometry using the following specific 

antibodies: anti-CD4 antibody, fluorophore-

conjugated anti-IL17 antibody and anti-Foxp3. The 

negative control samples were stained with the 

appropriate isotype-matched antibodies. Data was 

analyzed using FlowJo software (Tree Star, Ashland, 

OR, USA).  

Western blotting (WB)  

The lacrimal gland tissues isolated from the rabbits 

were lysed using 1X radioimmunoprecipitation 

(RIPA) lysis buffer (20-188, Millipore, USA). The 

concentration of total protein was determined using a 

BCA protein assay kit (Beyotime, Shanghai, China). 

Protein lysates were separated by electrophoresis on a 

10 % sodium SDS-polyacrylamide gel (SDS-PAGE), 

then transferred to PVDF membranes (Millipore, 

China) and treated with 5 % non-fat milk for 1 hour 

at room temperature. The protein was identified by 

incubating with specific primary antibodies overnight 

at 4 °C.  

Information on the specific primary antibodies used 

in this study is as follows: anti-BCL2 (ab196495, 

1:1000, Abcam, Cambridge, MA, USA), anti-

Cleaved caspase3 (ab2302, 1:1000, Abcam, 

Cambridge, MA, USA), anti-BAX (ab104156, 

1:1000, Abcam, Cambridge, MA, USA), anti-RORγt 

(ab91187, 1:1000, Abcam, Cambridge, MA, USA), 

anti-Foxp3 (ab75763, 1:1000, Abcam, Cambridge, 

MA, USA), anti-p-STAT3 (ab30647, 1:1000, Abcam, 

Cambridge, MA, USA), anti-STAT3 (ab31370, 

1:1000, Abcam, Cambridge, MA, USA), anti-p-JAK2 

(ab195055, 1:1000, Abcam, Cambridge, MA, USA), 

anti-JAK2 (ab245303, 1:1000, Abcam, Cambridge, 

MA, USA) and anti-β-actin (ab8227, 1:1000 dilution, 

Abcam, Cambridge, MA, USA). The following day, 

PVDF membrane were washed 3 times in TBST and 

incubated with HRP-conjugated secondary IgG 

antibody ((ab6734, 1:2000 dilution, Abcam,  

 

 

 

Cambridge, MA, USA) for 1 hour at room 

temperature. Image J was used for quantification.  

Statistical analysis  

Mean ± standard deviation (SD) are used to express 

all the data. Each set of experiments were repeated 

three times. GraphPad Prism (version 7.04) was used 

for statistical analysis. Student's t-test was used for 

comparison between two groups, while one-way 

ANOVA was used for comparisons between multiple 

groups. P < 0.05 was considered statistically 

significant.  

RESULTS  

Treatment with RMFS and HGA repairs ocular 

surface damage  

In the model group, the SIt value decreased 

significantly with time compared to control group (p 

< 0.001), whereas treatment with RMFS or HGA 

alone restored the Sit value. Interestingly, the 

increase in SIt was more when combined treatment of 

RMFS and HGA was used (Figure 1 A). 

Furthermore, as demonstrated in Figure 1 B, the BUT 

of the model group was significantly shorter than that 

of control group and the decrease was inversely 

proportional to incubation time, while treatment with 

RMFS or HGA alone enhanced the BUT of the 

model group. The BUT of the model group treated 

with a combination of RMFS and HGA was longer 

than the single-administration group. Next, 

pathological sections of the lacrimal gland tissues 

were made on each group of animals. The results 

showed that, compared to control group, the lacrimal 

gland structure was unclear, and the vesicles and 

lacrimal epithelium were of different sizes and 

disorganized in the model group. This observation 

was better modified when combined RMFS and HGA 

treatment was used (Figure 1 C). The combination of 

Runmufengye soup and hydroxysugar glycolic acid 

eye drops could improve dry eye symptoms and 

repair ocular surface damage in a rabbit dry eye 

model. 



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Figure 1: Combined treatment with RMFS and HGA 

repairs ocular surface damage in the rabbit dry eye 

model. (A) The Schirmer’s test to evaluate tear 

secretion in the respective groups; (B) Break-up time 

(BUT) and (C) Pathological sections of the lacrimal 

gland tissue was performed by H&E in the various 

groups. *P < 0.05, **p < 0.01, *** p < 0.001, 

compared with control group; #p < 0.05, ##p < 0.01, 

###p < 0.001, vs. model group; &p < 0.05, &&p < 

0.01, &&&p < 0.001, vs. model + RMFS group; ^p < 

0.05, ^^p < 0.01, ^^^p < 0.001 vs. model + HGA 

group 

Treatment with RMFS and HGA inhibits cell 

apoptosis  

As depicted in Figure 2 A, apoptosis rate in the 

cornea tissues significantly increased in model group 

compared with control group (p < 0.001). However, 

the rate of apoptosis was found to decrease 

significantly in both treatment groups with a more 

significant reduction observed in the co-

administration group. This trend was also observed in 

the regulation of apoptosis and anti-apoptotic 

proteins as revealed in the Western blot results. The 

protein levels of Bax and cleaved caspase3 were 

significantly increased, while that of BCL2 was 

significantly decreased in the model groups (Figure 2 

B). Interestingly, this observation was significantly 

reversed by the combination of RMFS and HGA. 

Taken together, the combined treatment with RMFS 

and HGA inhibited cell apoptosis of cornea tissues in 

rabbit dry eye model.  

Treatment with RMFS and HGA regulates 

Th17/Treg related cytokine balance  

Flow cytometry results show that the dry eye model 

group had a significantly increased proportion of 

Th17 cells in the lacrimal gland, while RMFS 

combined with HGA significantly suppressed this 

effect (Figure 3 A). The proportion of Treg cells in 

the lacrimal gland was slightly increased in the model 

group (p < 0.05), significantly increased in the RMFS 

or HGA group (p < 0.001), with the most significant 

increase in Treg cell population seen in the co-

treatment group (p < 0.001; Figure 3 B). 



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Figure 2: Combined treatment with RMFS and HGA 

inhibited cell apoptosis of ocular surface in the rabbit 

dry eye model. (A) Cell apoptosis as determined by 

flow cytometry and (B) Protein levels of Bax, 

Cleaved caspase3 and Bcl2 was measured by WB in 

the model group treated with the indicated drug. *p < 

0.05, **p < 0.01, *** p < 0.001, vs. control group; # 

p < 0.05, ## p < 0.01, ### p < 0.001, vs. model 

group; &p < 0.05, &&p < 0.01, &&&p < 0.001, vs. 

model + RMFS group; ^p < 0.05, ^^p < 0.01, ^^^p < 

0.001, vs. model + HGA group 

Th17 and Foxp3, the transcription factor associated 

with Treg, were upregulated in the model group 

compared to control group, while the combination of 

RMFS and HGA significantly inhibited RORγt 

expression but caused a further increase in Foxp3 

expression (p < 0.001; Figure 3 C).  

Treatment with RMFS and HGA inhibited the 

JAK2/STAT3 pathway  

As depicted in Figure 4, the protein levels of p-JAK2 

and p-STAT3 were upregulated in the model group, 

while the combination of RMFS and HGA treatment 

decreased the protein levels of p-JAK2 as well as p-

STAT3 (p < 0.001). Taken together, the combination 

of Runmufengye soup and hydroxysugar glycolic 

acid eye drops inhibited the JAK2/STAT3 pathway.  

DISCUSSION  

Dry eye disease is a multifactorial ocular surface 

disease characterized by tear film homeostasis, ocular 

surface inflammatory response and damage and 

ocular discomfort. It is highly prevalent and with 

symptoms such as foreign body sensation, burning 

and stinging, seriously affect an individual's quality 

of life and may lead to loss of vision or blindness if 

not treated promptly and appropriately [1]. However, 

the clinical therapy of DED is difficult and effective 

treatments are still lacking. 



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Figure 3: Combined treatment with RMFS and HGA 

regulates Th17/Treg related cytokine balance in the 

rabbit dry eye model. The proportion of (A) Th17 

and (B) Treg cells in lacrimal gland tissues of the 

model group treated with RMFS and HGA alone or 

combined was measured by flow cytometry (C) The 

protein level of RORγt and Foxp3 was measured by 

Western blotting. *P < 0.05, **p < 0.01, ***p < 

0.001, vs. control group; #p < 0.05, ##p < 0.01, ###p 

< 0.001, vs. model group; &p < 0.05, &&p < 0.01, 

&&&p < 0.001, vs. model + RMFS group; ^p < 0.05, 

^^p < 0.01, ^^^p < 0.001, vs. model + HGA group 

 

Figure 4: Combined treatment with RMFS and HGA 

inhibited the JAK2/STAT3 pathway. The protein 

levels of p-JAK2, JAK2, p-STAT3 and STAT3 in the 

various groups as shown by Western Blot. *P < 0.05, 

**p < 0.01, *** p < 0.001, vs. control group; #p < 

0.05, ##p < 0.01, ###p < 0.001, vs. model group; &p 

< 0.05, &&p < 0.01, &&&p < 0.001, vs. model + 

RMFS group; ^p < 0.05, ^^p < 0.01, ^^^p < 0.001, 

vs. model + HGA group 

Recently, Chinese medicine has also played an 

important role in the treatment of dry eye disease. For 

example, Astragaloside IV is a single compound 

extracted from Astragalus membranaceus. It has a 

protective effect on the dry eye model induced by 

benzalkonium chloride (BAC) and showed clinical 

amelioration effected by regulating the MUC1-ErbB1 

pathway [9]. Buddleja officinalis Maxim Eye Drops 

downregulated the expressions of apoptotic factors 

Bax, Fas and FasL in the lacrimal gland of the dry 

eye rabbit model, thereby inhibiting lacrimal cell 

apoptosis and maintaining the basal amount of 

lacrimal secretion [10]. In this study, the efficacy of 

RMFS in treating dry eye disease was investigated. 

RMFS is composed of Lilii Bulbus (Baihe), 

Rehmanniae Radix Praeparata (Shudi), Angelicae 

Sinensis Radix (Danggui), Atractylodes 



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Macrocephala Koidz. (Baizhu), Rhizoma Dioscoreae 

(Shanyao), Fructus Ligustri Lucidi (Nvzhenzi), 

Amygdalus Communis Vas (Xingren), Glehniae 

Radix (Shashen), Polygonati Odorati Rhizoma 

(Yuzhu), Platycodon Grandiforus (Jiegeng), 

Buddlejae Flos (Mimenghua), Chrysanthemi Flos 

(Juhua) and licorice (Gancao). RMFS has the effect 

of protecting the liver, strengthening the spleen, 

tonifying the liver and the kidney, fixing the lungs, 

dispersing wind, brightening the eyes and generating 

fluids, which repair the tear film function, thereby 

improving the symptoms of dry eyes. In this study, it 

was demonstrated that RMFS could improve dry eye 

symptoms and repair ocular surface damage. 

Hypromellose 2910, Dextran 70 and Glycerol Eye 

Drops (HGA) are artificial tears with the same pH, 

ionic concentration and protein composition as 

normal human tears, which improve clinical 

symptoms and are commonly used in the treatment of 

dry eye [11]. However, the drug is only a 

symptomatic treatment, as it does not completely 

cure dry eye, and it is not effective for some patients.  

The results of this study show that the combined 

Chinese and Western medicine therapy based on 

RMFS and HGA has a therapeutic effect on dry eye 

patients. However, the specific mechanism of the 

effect of the combined treatment is not clear. By 

elucidating its molecular mechanism, it is possible to 

provide theoretical guidance for its clinical 

application. Here, it was demonstrated that the 

combined treatment with RMFS and HGA is able to 

modify the symptoms of dry eyes, including 

increasing tear secretion as well as repairing ocular 

surface damage.  

Modern medicine believes that the occurrence of dry 

eye is closely related to neuroinflammation, apoptosis 

and reduced levels of sex hormones, and that these 

factors promote and influence each other [3-5]. The 

apoptosis of the corneal and conjunctiva epithelium 

caused by immune inflammatory response in the 

lacrimal gland is the main cause of the deterioration 

of the dry eye disease [12]. As reported in the present 

study, the corneal epithelial tissue in the rabbit dry 

eye model had more apoptotic cells than control 

group and combined treatment with RMFS and HGA 

reduced the number of apoptotic cells of cornea 

tissues in the rabbit dry eye model.  

In recent years, regulatory T cells (Treg) and helper T 

cell subset 17 (Th17) cells have been found to play a 

very important role in immune inflammatory diseases 

[5]. Among them, Th17 cells promote inflammatory 

responses by secreting IL-17, a cytokine, and retinoic 

acid-related orphan receptor γt (RORγt), a specific 

transcription factor whose expression directly affect 

the differentiation and function of Th17 cells [13,14].  

Treg has an immunosuppressive function, preventing 

the activation of autoimmune T cells, regulating the 

body's immune response, maintaining immune 

homeostasis and suppressing the development of 

immune diseases [11,15]. Thus, Th17 and Treg cells 

exhibit functional antagonism towards each other, 

which may be an important factor in the homeostasis 

of immune function. It has been found that the 

development of dry eye disease was associated with a 

disruption in the homeostatic balance of Treg/Th17 

cells, and that blocking IL-17 significantly reduced 

the severity and progression of the disease by 

restoring the Treg/Th17 cell ratio [6].  

A number of subsequent studies have confirmed that 

the inflammatory response mediated by an imbalance 

in the Th17/Treg cell ratio was an important cause of 

dry eye and that drugs increased tear film rupture 

time and tear production by modulating the 

Th17/Treg cell ratio, thereby restoring the 

histological changes in tissues such as cornea, 

conjunctiva and lacrimal glands caused by dry eye 

[16-18]. Therefore, maintaining the homeostatic 

balance of Th17/Treg cells may contribute to the 

treatment of dry eye. In the present study, an 

imbalance in Th17/ Treg ratio was found in the 

lacrimal gland of the model group and co-treatment 

with of RMFS and HGA regulated the balance of 

Th17/Treg related cytokine in the rabbit dry eye 

model.  

The Janus kinase 2 signal transducer/transcription 

activator 3 (JAK2/STAT3) signaling pathway 

regulates inflammatory mediators involved in 

extracellular signaling pathways and plays an overall 

regulatory role in inflammatory responses and cell 

survival [19]. Most importantly, the JAK2/STAT3 

signaling pathway is also involved in the regulation 

of Th17/Treg homeostasis [20]. In T lymphocytes, 

activated STAT3 mediates its downstream signaling 

pathway to enhance RORγt expression in initial 

CD4+ T lymphocytes, thereby contributing to the 

differentiation of CD4+ T cells to Th17 [21]. 

Previous reports have established that the expression 

levels of JAK2 and STAT3 are significantly 

increased in the lacrimal gland of a dry eye 

inflammation model and tear secretion in this model 

is promoted by inhibiting the activation of the 

JAK2/STAT3 signaling pathway [22,23]. As reported 

in this study, the combination treatment with RMFS 

and HGA remarkably decreased the protein levels of 

the p-JAK2 and p-STAT3 in the model group.  



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CONCLUSION  

The combination of RMFS and HGA regulates 

Th17/Treg balance to inhibit inflammatory response 

and reduces cell apoptosis by inhibiting the 

JAK/STAT3 pathway. This treatment could be a 

potential therapeutic strategy for the management of 

dry eye disease. However, this study lacks clinical 

data to show the efficacy and safety of combined 

treatment with RMFS and HGA. Furthermore, there 

may be other molecular mechanisms of action for the 

combination of RMFS and HGA in treatment of dry 

eyes that are yet to be identified. Therefore, future 

studies should focus on clinical data collection to 

investigate the efficacy and safety of the 

combination. In addition, other pathogenic 

mechanisms of dry eye disease need to be 

investigated. 

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