BLG was used for thousands years in China and was recognized by our ancients to have anti-infection activity. We used BLG to reduce radiation mucositis clinically and in mice. These data suggested the anti-inflammatory effect and enhanced the immune cell proliferation. But the exact active compounds, mechanisms and pathways still need further analysis and evaluation.
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Table 1. The RTOG describes five grades of acute mucositis.
Grade Mucous membrane
0 No change over base line
1 Injection; mild pain not requiring analgesics
2 Patchy mucositis which may produce an inflammatory serosanguinous discharge; may experience moderate pain requiring analgesics
3 Confluent fibrinous mucositis; may include severe pain requiring narcotics
4 Ulceration, haemorrhage or necrosis
Table 2. The RTOG describes five grades of anorexia.
Grade Mucous membrane
0 No change over base line
1 Loss of appetite without alteration in eating habits
2 Oral intake altered without significant weight loss or malnutrition; oral nutritional supplements indicated
3 Associated with significant weight loss or malnutrition (e.g., inadequate oral caloric and/or fluid intake); IV fluids, tube feedings or TPN indicated
4 Life-threatening consequences
Table 3. The RTOG describes five grades of dyshpagia.
Grade Mucous membrane
0 No change over base line
1 Symptomatic, able to eat regular diet
2 Symptomatic and altered eating/swallowing (e.g., altered dietary habits, oral supplements); IV fluids indicated <24 hrs 3 Symptomatic and severely altered eating/swallowing (e.g.,
inadequate oral caloric or fluid intake); IV fluids, tube feedings, or TPN indicated ≥24 hrs
4 Life-threatening consequences (e.g., obstruction, perforation)
Table 4. Patient characteristics
Baseline factors BLG group N=11
Control Group
N=9 P value Mean age (years) 56.5±10.6 57.9±13.1 P=0.789a Body weight 62.3±12.8 58.9±11.6 P=0.548 a
Gender
Male 9 9
Female 2 0
Radiation Dose 6787.3±754.7 6820.0±651.8 P=0.920 a
Chemotherapy 5 5
Diagnosis
Nasopharyngeal cancer 2 2
Oropharyngeal cancer 7 6
Salivary gland cancer 2 1
a Data was analyzed with independent F-test and present here as mean ± SD. The BLG group was no significant difference when compare with control group.
Table 5. Distribution of clinical parameters between the two groups Clinical parameter BLG group
N=11
Control Group
N=9 P value
Maximum mucositis grade P=0.01*a
Grade 0 0 0
* P < 0.05, ** P < 0.01 indicated the BLG group was significantly difference that compare with control group. a Data was analyzed with Mann-Whitney U test, b data was analyzed with independent F-test and present here as mean ± SD.
Table 6. Blood contents expression between BLG and control group Serum parameter BLG group Control Group P value a
WBC (/mm3)
Pre-treatment 5830.0±1280.1 6183.3±2143.3 P=0.1295 1st week 7045.6±1959.0 8471.1±7484.3 P=0.0003***
3rd week 5564.6±2006.2 5087.8±2452.7 P=0.5416 5th week 4972.4±2196.1 6502.2±4365.0 P=0.0462*
7th week 4894.6±1910.7 5448.8±1946.8 P=0.9253
Neutrophil (/mm3)
1st week 4813.0±1681 5771.1±4526.9 P=0.0052**
3rd week 4012.6±1669.2 4143.4±1555.9 P=0.8587 5th week 3622.0±1776.5 4825.0±3289.6 P=0.0721 7th week 3597.6±1552.7 4029.1±158.2 P=0.7673
Monocyte (/mm3)
1st week 1437.5±595.3 1274.6±967.4 P=0.1524
3rd week 901.4±366.2 915.5±697.5 P=0.0606 difference that compare with control group. a Data was analyzed with independent F-test and present here as mean ± SD.
Table 7. Serum cytokines expressions between BLG and control groups Serum parameter BLG group Control Group P value a Blood contents
IL-1β (pg/ml)
1st week 9.4±10.6 5.0±7.5 P=0.3293
3rd week 10.0±11.8 3.5±3.8 P=0.0039**
5th week 11.3±19.2 9.9±12.0 P=0.1974
7th week 8.5±7.8 6.3±6.1 P=0.5347
IL-6 (pg/ml)
1st week 13.7±4.3 62.5±60.5 P<0.001***
3rd week 19.1±9.9 32.4±18.7 P=0.065 5th week 16.9±5.3 51.1±58.9 P<0.001***
7th week 11.6±5.1 35.4±25.6 P<0.001***
** P < 0.01, *** P < 0.001 indicated the BLG group was significantly difference that compare with control group. a Data was analyzed with independent F-test and present here as mean ± SD.
Table 8. Immune organs of irradiated mice (mg)
Group Thymus Spleen Pancreas
Control
49.8±7.6
###113.1±19.4
###28.5±10.6
###Radiation condition Water
(R.O. 10 ml/kg/day) 25.6±3.2 29.0±0.8 9.3±1.1
BLG-L
(0.195 g/kg/day, 1×) 28.4±3.8 31.0±3.6
13.0±3.9*
BLG-M
(0.585 g/kg/day, 3×)
30.1±3.0* 31.5±1.8* 15.6±4.1**
BLG-H
(1.170 g/kg/day, 5×)
30.0±2.8* 33.7±3.0**
11.0±3.1 Glutamine(0.520 g/kg/day, 1×)
28.5±2.0* 30.4±1.6*
11.0±3.5### P<0.001 indicated the radiation condition in water group was very significantly decrease when compare with control group. * P < 0.05, ** P < 0.01 indicated the medication treatments were significantly difference that compare with the water group in radiation condition. Data were analyzed with one-way ANOVA and present here as mean ± SD.
Table 9 . Absolute blood contents of irradiated mice (/mm3)
Group Leukocyte Granulocyte Monocyte Lymphocyte Control 24643±3443### 1283±266### 1292±195### 5676±560###
Radiation group Water
(R.O. 10 ml/kg/day) 3917±826 342±47 418±138 1298±361 BLG-L
(0.195 g/kg/day, 1×) 9303±3240** 565±87** 693±413 2775±361*
BLG-M
(0.585 g/kg/day, 3×) 10897±2997** 752±326* 1090±679* 3631±1076**
BLG-H
(1.170 g/kg/day, 5×) 8383±1584** 735±166** 1083±347** 3979±688**
Glutamine
(0.520 g/kg/day, 1×) 7264±2788* 294±61 267±85* 1646±161*
### P<0.001 indicated the radiation condition in water group was very significantly decrease when compare with control group. * P < 0.05, ** P < 0.01 indicated the medication treatments were significantly difference that compare with the water group in radiation condition. Data were analyzed with one-way ANOVA and present here as mean ± SD.
Table 10. Serum cytokines of irradiated mice (pg/ml)
Group TNF-α IL-1β IL-6
Control
7.10±1.74
###4.82±2.52
##215.53±58.33
# Radiation groupWater
(R.O. 10 ml/kg/day) 27.36±17.64 10.37±5.04 490.59±233.15 BLG-L
(0.195 g/kg/day, 1×)
13.41±8.40*
7.47±3.49 354.13±332.29 BLG-M(0.585 g/kg/day, 3×)
7.51±1.91* 6.06±2.00* 279.56±114.61*
BLG-H
(1.170 g/kg/day, 5×)
7.31±1.13* 5.43±2.47* 211.12±71.93*
Glutamine
(0.520 g/kg/day, 1×)
9.49±3.04*
7.79±6.19 369.41±324.72# P<0.05, ## P<0.01, ### P<0.001 indicated the radiation condition in water group was significantly difference when compare with control group. * P < 0.05 indicated the medication treatments were significantly difference that compare with the water group in radiation condition. Data were analyzed with one-way ANOVA and present here as mean ± SD.
Table 11. Histopathologic assessment of irradiated mice.
Group Villi number (/mm) Villi height (mm)
Control
12.67±0.52
#0.49±0.09
#(1.170 g/kg/day, 5×)
10.83±0.75*
0.39±0.07Glutamine
(0.520 g/kg/day, 1×)
11.00±1.26*
0.35±0.09# P<0.05 indicated the radiation condition in water group was significantly difference when compare with control group. * P < 0.05 indicated the medication treatments were significantly difference that compare with the water group in radiation condition. Data were analyzed with one-way ANOVA and present here as mean ± SD.
Figure 1. Structure of mucosa
Epithelium Fibroblast
Vessels
Figure 2. Possible cellular signals pathway in radiation mucositis
Radiation
NF-κB
COX-2 expression
IL-1β TNF-α
IL-6
Energy-derived photons produced larger oxidative free radicals
Secondary inflammatory response
Figure 3. Clinical photography of patient oral mucosa
Group Pre-radiotherapy Post-radiotherapy
Control 1
Grade o mucositis Grade 2 mucositis Control 2
Grade o mucositis Grade 3 mucositis Control 3
Grade o mucositis Grade 3 mucositis Control 4
Grade o mucositis Grade 3 mucositis
Control 5
Grade o mucositis Grade 3 mucositis Control 6
Grade o mucositis Grade 3 mucositis Control 7
Grade o mucositis Grade 2 mucositis BLG 1
Grade o mucositis Grade 1 mucositis
BLG 2
BLG 3
Grade o mucositis Grade 2 mucositis BLG 4
Grade o mucositis Grade 1 mucositis BLG 5
Grade o mucositis Grade 2 mucositis BLG 6
Grade o mucositis Grade 2 mucositis BLG 7
Grade o mucositis Grade 1 mucositis
BLG 8
Grade o mucositis Grade 2 mucositis BLG 9
Grade o mucositis Grade 3 mucositis BLG 10
Grade o mucositis Grade 2 mucositis BLG 11
Grade o mucositis Grade 2 mucositis
Figure 4. WBC count expression of human during radiotherapy
BLG Control BLG Control BLG C ontrol BLG Control
WBC (/mm3)
1s t wk 3rd wk 5th wk 7th wk
***
*
* P < 0.05, *** P<0.001 indicated the BLG treatments were significantly difference that compare with the control group. Data were analyzed with one-way ANOVA and present here as mean ± SD. This data showed that less WBC counts was found in BLG group, especially in 5th weeks after start of radiotherapy (4972.4±2196.1 vs. 6502.2±4365.0 /mm3, P=0.046). Differential count of WBC disclosed that less eosinophils and lymphocytes. These results may explain why less WBC was found in 5th weeks.
Figure 5. Hgb expression of human during radiotherapy
-2.0 4.0 6.0 8.0 10.0 12.0 14.0 16.0
BLG Control BLG Control BLG Control BLG Control
Hgb (mg/dL)
1s t wk 3rd wk 5th wk 7th wk
Data were analyzed with one-way ANOVA and present here as mean ± SD. This data showed no difference in hemoglobin (Hgb) level between BLG and control group. This result implicated that BLG take no effect in myeloproliferated pathway.
Figure 6. Absolute neutrophils expression of human during radiotherapy
0 2000 4000 6000 8000 10000 12000
BLG Control BLG Control BLG Control BLG Control
Neutrophils (/mm3)
1s t wk 3rd wk 5th wk 7th wk
**
* P < 0.05 indicated the BLG treatments were significantly difference that compare with the control group. Data were analyzed with one-way ANOVA and present here as mean ± SD. This data disclosed lower neutrophils was observed in BLG group in 1st week when compared with control group.
Figure 7. Absolute lymphocyte expression of human during radiotherapy
-500 1,000 1,500 2,000 2,500
BLG Control BLG Control BLG C ontrol BLG Control
Lymphocytes (/mm3)
1s t wk 3rd wk 5th wk 7th wk
*
* P < 0.05 indicated the BLG treatments were significantly difference that compare with the control group. Data were analyzed with one-way ANOVA and present here as mean ± SD. This data showed no difference in lymphocyte expression except in 5th week, higher lymphocytes were found in control group.
Figure 8. Absolute monocyte expression of human during radiotherapy
-200 400 600 800 1,000 1,200 1,400
BLG Control BLG Control BLG Control BLG Control
Monocytes (/mm3)
1s t wk 3rd wk 5 th wk 7 th wk
**
**
** P<0.01 indicated the BLG treatments were very significantly difference that compare with the control group. Data were analyzed with one-way ANOVA and present here as mean ± SD. This data disclosed that higher monocyte level was found in 1st and 7th week.
Figure 9. Absolute eosinophils expression of human during radiotherapy
-100 200 300 400 500 600 700
BLG Control BLG C ontrol BLG Control BLG Control
Eosinophils (/mm3)
1s t wk 3rd wk 5th wk 7th wk
** * **
* P < 0.05, ** P<0.01 indicated the BLG treatments were significantly difference that compare with the control group. Data were analyzed with one-way ANOVA and present here as mean ± SD. This data showed that higher eosinophils were observed in BLG group in 1st, 5th and 7th week in significantly.
Figure 10. Serum IL-1βexpression of human during radiotherapy
-5.0 10.0 15.0 20.0 25.0 30.0 35.0
BLG Control BLG Control BLG Control BLG Control
IL-1beta, pg/ml
1s t wk 3rd wk 5th wk 7th wk
**
** P<0.01 indicated the BLG treatments were significantly difference that compare with the control group. Data were analyzed with one-way ANOVA and present here as mean ± SD. This data showed higher IL-1β was found in BLG group in 3rd week in significantly. These results disclosed the complicated cytokines expression and implicate the potential radio-protective role of BLG.
Figure 11. Serum IL-6 expression of during radiotherapy
-20.0 40.0 60.0 80.0 100.0 120.0 140.0
BLG Control BLG Control BLG Control BLG Control
IL-6, pg/ml
***
1s t wk 3rd wk 5th wk 7th wk
***
***
*** P<0.001 indicated the BLG treatments were significantly difference that compare with the control group. Data were analyzed with one-way ANOVA and present here as mean ± SD. This data showed that BLG group has lower IL-6 expression in 1st, 5th and
*** P<0.001 indicated the BLG treatments were significantly difference that compare with the control group. Data were analyzed with one-way ANOVA and present here as mean ± SD. This data showed that BLG group has lower IL-6 expression in 1st, 5th and