TABLE 2.
Study (year) | Species (sex, n = treatment/control group, age, weight) | Modeling method and standard | Berberine intervention (administration, drug dose, duration) | Outcomes | Intergroup difference |
---|---|---|---|---|---|
Bhutada et al. (2011) | Wistar rats (male, 18/6, 200–220 g) | Intraperitoneal injection of STZ (60 mg/kg), | By intragastric | 1. FBG | 1. p < 0.01 |
BG > 250 mg/dl | 25/50/100 mg/kg/d | 2. MWM | 2. p < 0.05 | ||
4 weeks | 3. LPO | 3. p < 0.01 | |||
4. GSH | 4. p < 0.01 | ||||
5. AChE | 5. p < 0.01 | ||||
Ma et al. (2012a) | Sprague-Dawley rats (male, 18/6, 180–220 g) | Intraperitoneal injection of STZ (40 mg/kg) + HSFD | By intragastric | 1. FBG | 1. p < 0.01 |
BG > 11.1 mmol/L | 50/100/200 mg/kg/d | 2. MWM | 2. p < 0.05 | ||
4 weeks | 3. SOD, MDA | 3. p < 0.05 | |||
4. AChE | 4. p < 0.01 | ||||
5. Bax, Bcl-2 | |||||
6. IGF-1 | |||||
Ma et al. (2012b) | Sprague-Dawley rats (male, 18/6, 180–220 g) | Intraperitoneal injection of STZ (40 mg/kg) + HSFD | By intragastric | 1. FBG | 1. p < 0.05 |
BG ≥ 16.7 mmol/L | 50/100/200 mg/kg/d | 2. CAT | 2. p < 0.01 | ||
4 weeks | 3. LPO | 3. p < 0.01 | |||
4. GSH | 4. p < 0.01 | ||||
5. BDNF | |||||
Kalalian-Moghaddam et al. (2013) | Wistar rats (male, 12/6, 225–285 g) | Intraperitoneal injection of STZ (55 mg/kg) | By intragastric | 1. FBG | 1. p < 0.01 |
BG > 250 mg/dl | 50/100 mg/kg/d | 2. Y-maze | 2. p < 0.05 | ||
11 weeks | 3. Passive avoidance | 3. p < 0.05 | |||
4. PS, EPSP | 4. p < 0.01 | ||||
5. Nissl/TUNEL neuron | 5.p < 0.05 | ||||
Moghaddam et al. (2013) | Wistar rats (male, 20/10, 225–285 g) | Intraperitoneal injection of STZ (55 mg/kg), | By intragastric | 1. FBG | 1. p < 0.01 |
BG > 250 mg/dl | 50/100 mg/kg/d | 2. PS, EPSP | 2. p < 0.01 | ||
12 weeks | |||||
Moghaddam et al. (2014) | Wistar rats (male, 24/12, 225–285 g) | Intraperitoneal injection of STZ (55 mg/kg), | By intragastric | 1. FBG | 1. p < 0.05 |
BG > 250 mg/dl | 50/100 mg/kg/d | 2. MDA | 2. p < 0.05 | ||
8 weeks | 3. SOD | 3. p < 0.05 | |||
4. NO | 4. p < 0.05 | ||||
5. GFAP | 5. p < 0.05 | ||||
Zhou et al. (2016) | Wistar rats (male, 10/10, 180–220 g) | Intraperitoneal injection of STZ (35 mg/kg) + HSFD | By intragastric | 1. FBG | 1. p < 0.01 |
BG > 16.7 mmol/L | 100 mg/kg/d | 2. HbA1c | 2. p < 0.01 | ||
23 weeks | 3. MWM | 3. p < 0.01 | |||
4. TG, TC | 4. p < 0.01 | ||||
5. p-p38/p38 6. p-JNK/JNK 7.p-ERK/ERK |
5. p < 0.01 | ||||
6. p < 0.01 | |||||
7. p > 0.05 | |||||
Chen et al. (2017) | Wistar rats (male, 8/8, aged 4–5 weeks, about 200 g) | Caudal vein injection of STZ (25 mg/kg) + HSFD | By intragastric | 1. Conditioned fear | 1. p < 0.01 |
BG ≥ 11.2 mmol/L | 187.75 mg/kg/d | 2. PDG PET | 2. p < 0.01 | ||
10 weeks | 3. p-IRS-1 | 3. p < 0.01 | |||
4. p-PI3K/PI3K | 4. p < 0.05 | ||||
5. p-Akt/Akt | 5. p < 0.05 | ||||
6. p-GSK3β/GSK3β 7. p-IKKβ, p-NF-κB/NF-κB 8. p-JNK/JNK |
6. p < 0.05 | ||||
9. IL-1β, TNF-α | 7. p < 0.05 | ||||
10. GLUT3 | 8. p < 0.05 | ||||
11. PKC | 9. p > 0.05 | ||||
12. APP | 10. p < 0.01 | ||||
13. BACE1 | 11. p < 0.05 | ||||
12. p < 0.01 | |||||
13. p < 0.05 | |||||
Wang et al. (2018) | Wistar rats (male, 15/12, aged 5–6 weeks, 180–200 g) | Caudal vein injection of STZ (25 mg/kg) + HFD, | By intragastric | 1. FBG | 1. p < 0.05 |
BG ≥ 11.2 mmol/L | 100/200 mg/kg/d | 2. Serum insulin | 2. p < 0.05 | ||
10 weeks | 3. MWM | 3. p < 0.01 | |||
4. p-Tau Ser202/Tau-5 | 4. p < 0.01 | ||||
5. p-Tau Ser404/Tau-5 6. p-PI3K/PI3K |
5. p < 0.01 | ||||
7. p-Akt/Ak | 6. p < 0.01 | ||||
8. p-GSK3β/GSK3β | 7. p < 0.01 | ||||
8. p < 0.01 | |||||
Li et al. (2018) | db/db mice (female, 8/8,7 weeks) | Spontaneous diabetic model | By intragastric | 1. Serum insulin | 1. p < 0.05 |
50 mg/kg/d | 2. 2hBG of OGTT | 2. p > 0.05 | |||
10 weeks | 3. 2hBG of ITT | 3. p < 0.05 | |||
4. MWM | 4. p < 0.05 | ||||
5. Y-maze, conditioned fear | 5. p < 0.01 | ||||
6. TG, TC, HDL-C | 6. p < 0.05 | ||||
7. LDL-C | 7. p < 0.01 | ||||
8. PSD95, SYN, NGF | 8. p < 0.01 | ||||
9. TNF-α, NF-κB | 9. p < 0.05 | ||||
10. SIRT1 11. p-PERK/PERK |
10. p < 0.05 | ||||
12. p-IRE1α/IRE1α | 11. p < 0.05 | ||||
13. p-eIF2α/eIF2α | 12. p < 0.05 | ||||
14. CHOP | 13. p < 0.05 | ||||
14. p < 0.05 | |||||
Wang et al. (2019) | Wistar rats (male, 8/8, aged 4–5 weeks, 180–200 g) | Caudal vein injection of STZ (25 mg/kg) + HSFD, | By intragastric | 1. FBG | 1. p < 0.01 |
BG > 11.2 mmol/L | 187.75 mg/kg/d | 2. Serum insulin | 2. p < 0.01 | ||
10 weeks | 3. MWM | 3. p < 0.01 | |||
4. PDG PET | 4. p < 0.01 | ||||
5. IL-18, IL-1β | 5. p < 0.05 | ||||
6. TNF-α 7. p-IKK/IKK 8. p-NF-κB/NF-κB |
6. p < 0.01 | ||||
9. GFAP | 7. p < 0.05 | ||||
10. AChE | 8. p < 0.05 | ||||
11. Insulin receptor, p-IRS1 | 9. p < 0.01 | ||||
12. PI3K, p-Akt/Akt | 10. p < 0.05 | ||||
13. APP, BACE1 | 11. p < 0.05 | ||||
14. Aβ42 | 12. p < 0.01 | ||||
13. p < 0.01 | |||||
14. p < 0.05 | |||||
Tong et al. (2019) | Sprague-Dawley rats (male, 9/9, 170–200 g) | Intraperitoneal injection of STZ (55 mg/kg), | By intragastric | 1. FBG | 1. p > 0.05 |
BG > 16.7 mmol/L | 60 mg/kg/d | 2. MWM | 2. p < 0.05 | ||
6 weeks | 3. Bcl-2, Caspase-3 | 3. p < 0.05 | |||
4. Notch1 | 4. p < 0.05 | ||||
5. TUNEL neuron | 5. p < 0.01 | ||||
6. Brain pathology | |||||
Xuan (2021) | ICR mice (male, 15/15, aged 8 weeks) | Intraperitoneal injection of STZ (50 mg/kg) + HSFD, | By intragastric | 1. FBG | 1. p < 0.05 |
BG ≥ 13.9 mmol/L | 50 mg/kg/d | 2. MWM | 2. p < 0.05 | ||
8 weeks | 3. Nissl neuron | 3. p < 0.01 | |||
4. MDA | 4. p < 0.01 | ||||
5. Bcl-2, Bax | 5. p < 0.01 | ||||
6. Caspase-3 | 6. p < 0.01 | ||||
7. Nrf2, HO-1 | 7. p < 0.01 | ||||
8. NQO1 | 8. p < 0.01 | ||||
Liu (2021) | ICR mice (male, 15/15, aged 8 weeks, 25–30 g) | Intraperitoneal injection of STZ (50 mg/kg) + HSFD, | By intragastric | 1. FBG | 1. p < 0.05 |
BG ≥ 13.9 mmol/L | 50 mg/kg/d | 2. MWM | 2. p < 0.05 | ||
8 weeks | 3. Nissl neuron | 3. p < 0.05 | |||
4. MDA | 4. p < 0.05 | ||||
5. NF-κB | 5. p < 0.01 | ||||
6. TNF-α | 6. p < 0.05 | ||||
7. IL-1β | 7. p < 0.01 | ||||
8. Nrf2, HO-1 | 8. p < 0.01 | ||||
9. NQO1 | 9. p < 0.05 | ||||
Adefegha et al. (2021) | Rats (16/8, 200–230 g) | Intraperitoneal injection of STZ (50 mg/kg) | By intragastric | 1. FBG | 1. p < 0.05 |
BG ≥ 250 mg/dl | 50/100 mg/kg/d | 2. AChE | 2. p < 0.01 | ||
2 weeks | 3. BChE | 3. p < 0.05 | |||
4. MAO, MDA | 4. p < 0.01 | ||||
5. SOD, GSH-Px | 5. p < 0.05 | ||||
6. GSH | 6. p > 0.05 | ||||
Zhang et al. (2021) | Sprague-Dawley rats (male, 8/8, 180–220 g) | Intraperitoneal injection of STZ (30 mg/kg) + HFD | By intragastric | 1. 2hBG of OGTT | 1. p < 0.01 |
BG > 16.7 mmol/L | 150 mg/kg/d | 2. MWM | 2. p < 0.01 | ||
4 weeks | 3. Aβ | 3. p < 0.05 | |||
4. Tau | 4. p < 0.01 | ||||
5. p-Tau | 5. p < 0.05 | ||||
6. Insulin receptor | 6. p < 0.01 | ||||
7. Nissl/TUNEL neuron | 7. p < 0.01 | ||||
Wu et al. (2021) | Wistar rats (male, aged 6–8 weeks, 180–200 g) | Caudal vein injection of STZ (25 mg/kg) + HSFD | By intragastric | 1. MWM | 1. p <0.05 |
BG > 11.2 mmol/L | 200 mg/kg/d | 2. p-IRS-1 | |||
13 weeks | 3. PI3K, PKC | ||||
4. GLUT3 | |||||
Cao et al. (2021) | db/db mice (female, 8/8, aged 10 weeks) | Spontaneous diabetic model | By intragastric | 1. FBG | 1. p < 0.01 |
135 mg/kg/d | 2. 2hBG of OGTT | 2. p < 0.01 | |||
10 weeks | 3. 2hBG of ITT | 3. p < 0.01 | |||
4. HbA1c | 4. p < 0.01 | ||||
5. MWM | 5. p < 0.05 | ||||
6. TNF-α | 6. p < 0.01 | ||||
7. IL-1β, IL-6 | 7. p < 0.01 | ||||
8. NLRP3 | 8. p < 0.01 | ||||
Tian et al., 2021 | Wistar rats (male, 8/8, aged 6–8 weeks, 180–200 g) | caudal vein injection of STZ (25 mg/kg) + HSFD | By intragastric | 1. FBG | 1. p < 0.01 |
BG > 11.2 mmol/L | 50/200 mg/kg/d | 2. MWM | 2. p < 0.01 | ||
4 weeks | 3. MMP | 3. p < 0.01 | |||
4. ROS, GSH, MDA | 4. p < 0.01 | ||||
5. RhoC, ROCK | 5. p < 0.01 | ||||
Ma and Liu et al. (2021) | Kunming mice (male, 27/10, 20–25 g) | Intraperitoneal injection of STZ (40 mg/kg) | By intragastric | 1. MWM | 1. p < 0.05 |
BG > 11.1 mmol/L | 20/40/80 mg/kg/d | 2. TNF-α | 2. p < 0.05 | ||
4 weeks | 3. IL-1β | 3. p < 0.05 | |||
4. AGEs | 4. p < 0.05 | ||||
5. RAGE | 5. p < 0.05 | ||||
6. NF-κB | 6. p < 0.01 |
AChE, acetylcholinesterase; AGEs, advanced glycation end products; Akt, protein kinase B; APP, amyloid precursor protein; Aβ, amyloid β; BACE1, beta-secretase 1; BChE, butyrylcholinesterase; Bcl-2, B-cell lymphoma-2; Bax, bcl2-associated x; BDNF, brain-derived neurotrophic factor; CAT, catalase; CHOP, C/EBP homologous protein; eIF2α, eukaryotic initiation factor 2α; EPSP, excitatory post-synaptic potential; EPK, extracellular-regulated protein kinases; BG, blood glucose; FBG, fasting blood glucose; FDG PET, fluorodeoxyglucose positron emission tomography; GFAP, glial fibrillary acidic protein; GLUT3, glucose transporter 3; GSH, glutathione; GSH-Px, glutathione peroxidase; GSK3β, glycogen synthase kinase 3β; HbA1c, hemoglobin A1c; HDL-C, high-density lipoprotein cholesterol; HO-1, haeme oxygenase-1; HFD, high-fat diet; HSFD, high-sugar and high fat diet; IGF-1, insulin-like growth factor 1; IKK, inhibitor of kappa B kinase; IL-1β, interleukin-1β; IRE1α, inositol-requiring enzyme 1α; IRS, insulin receptor substrate; ITT, insulin tolerance test; JNK, c-Jun N-terminal kinases; LDL-C, low-density lipoprotein cholesterol; LPO, lipid peroxidation; MAO, monoamine oxidase; MDA, malondialdehyde; MWM, Morris water maze; MMP, matrix metalloproteinase; NF-κB, nuclear factor-κB; NGF, nerve growth factor; NO, nitric oxide; NQO1, NADPH quinone oxidoreductase 1; Nrf2, nuclear factor erythroid-2 related factor 2; OGTT, oral glucose tolerance test; PERK, protein kinase R-like ER kinase; PI3K, phosphatidylinositide 3-kinases; PKC, protein kinase C; PS, population spike; PSD95, postsynapticdensity 95; RAGE, receptors for advanced glycation end products; ROCK, Rho-associated kinase; ROS, reactive oxygen species; SIRT1, sirtuin1; SOD, superoxide dismutase; STZ, streptozotocin; SYN, synaptophysin; TC, total cholesterol; TG, triglyceride; TNF-α, tumor necrosis factor α.