| 生物活性 |
Propagermanium is an orally active and selective CCR2 inhibitor. Propagermanium enhances IFN-γ, IL-2, 2',5'-oligoadenylate synthetase, and unspecified cytokine production, and induces mature cytolytic NK cell subsets. Propagermanium reduces HBe antigen and HBV DNA polymerase levels, promotes HBV clearance, lowers serum ALT, improves hepatic function, and ameliorates hepatic necro-inflammation. Propagermanium downregulates STAT1, inhibits pro-inflammatory microglia polarization, pro-inflammatory cytokine release, and monocyte/macrophage infiltration, and suppresses atherosclerotic lesion formation. Propagermanium attenuates diet-induced insulin resistance, white adipose tissue inflammation, and non-alcoholic steatohepatitis development. Propagermanium can be used for the research of chronic hepatitis B, ischemic stroke, Tay-Sachs disease, atherosclerosis, breast cancer, non-alcoholic steatohepatitis, insulin resistance, refractory gastric cancer, refractory oral cancer, multiple myeloma, type 2 diabetes, and acute liver injury[1][2][3][4][5][6][7][8][9][10][11][12][13].
|
体内研究
(In Vivo) |
Propagermanium 可通过免疫刺激在多种小鼠肿瘤模型中发挥抗肿瘤活性[1]。
Propagermanium (500-1000 mg/kg；腹腔注射；每日给药；连续数月) 不会在大鼠中引发显著的体重变化或主要器官组织学异常[1]。
Propagermanium (125-500 mg/kg；静脉注射；每日；6 个月) 对比格犬的体重增长、体温或心率无影响，且与对照组相比，给药动物的生理状态有所改善[1]。
Propagermanium (腹腔注射；单次给药) 对小鼠的腹腔注射 LD50 为 2.8 g/kg[1]。
Propagermanium (25-50 mg/kg/天；口服；每 8 小时 1 次；持续 3 天) 可通过减小梗死面积、减轻脑水肿、改善神经功能损伤、抑制促炎细胞因子释放和小胶质细胞极化，以及下调 STAT1 磷酸化，对小鼠缺血性卒中发挥保护作用[2]。
Propagermanium (8 mg/kg；每日；标准饮食喂养 20 天) 可降低 Hexa-/-Neu3-/- Tay-Sachs 小鼠的皮质神经炎症基因表达及星形胶质细胞增生，并减少部分小脑神经炎症基因的表达；当给药方式为 (8 mg/kg；每日；生酮饮食联合给药 10 天) 时，与生酮饮食单独给药相比，它可进一步降低皮质 Ccl5 和 Cxcl10 的表达及小脑神经炎症标志物水平，但无法降低皮质巨噬细胞/单核细胞密度，也不能单独降低小脑巨噬细胞/单核细胞或星形胶质细胞密度[4]。
Propagermanium (0.005%；口服；每日；1 周) 可使雄性 C57BL/6 小鼠在注射后第 4 天硫代乙醇酸盐诱导的总炎症细胞浸润减少约 46%，巨噬细胞浸润减少约 52%[5]。
Propagermanium (5 mg/kg；口服；每日；持续 8 或 12 周) 可使饲喂致动脉粥样硬化饮食的 apoE-KO 小鼠在第 8 周时主动脉根部动脉粥样硬化病变面积减少 50%，第 12 周时减少 36%，并在第 8 周时使病变处巨噬细胞浸润减少 66%[5]。
Propagermanium (9 mg/kg；口服；每日一次；持续 3 个月) 可显著抑制 WHHL 兔的动脉粥样硬化病变形成、内膜增厚及巨噬细胞聚集，且不影响血清脂质谱[6]。
Propagermanium (0.05% w/w；口服；12/18周) 早期给药可显著减轻雄性 C57BL/6J 小鼠中高脂饮食诱导的胰岛素抵抗、白色脂肪组织炎症及非酒精性脂肪性肝炎的发生，而晚期给药的作用较弱或无统计学显著性，仅能降低肝脏 M1/M2 巨噬细胞比值[8]。
Propagermanium (2,400 ppm；口服；每日；8 周) 对正常雄性 Wistar 大鼠无显著肾毒性[10]。
Propagermanium (480-2,400 ppm；口服；每日；8 周) 不会加重 adriamycin 诱导的雄性 Wistar 大鼠肾小球肾损伤[10]。
Propagermanium (2,400 ppm；口服；每日；3 天) 对雄性 Wistar 大鼠氯化汞诱导的急性近端肾小管肾损伤无毒性作用，且有降低相关 BUN 升高的趋势[10]。
Propagermanium (50 mg/kg/天；口服；每日给药；持续 3 个月) 可通过抗炎和抗氧化作用，改善雄性 2 型糖尿病 GK 大鼠 (非高脂饮食组和高脂饮食组) 的空腹血糖、胰岛素抵抗与内皮功能，恢复其血管周围脂肪组织的抗收缩特性，且不会改变非高脂饮食组大鼠的血脂谱[12]。
Propagermanium (0.1-3.0 mg/kg；口服；每日 1 次；连续 4 天) 可剂量依赖性地减轻 C. parvum/LPS 处理小鼠的急性肝损伤，在剂量≥0.3 mg/kg 时可观察到显著的保肝活性，其中 3.0 mg/kg 剂量下 IFN-γ 的产生量降低 53%[13]。
Propagermanium (1.0-3.0 mg/kg；口服；每日 1 次；连续 4 天) 可加速 C. parvum 致敏小鼠的抗原特异性免疫反应，在 3.0 mg/kg 剂量下可使 IFN-γ 的产生量显著升高 1.6 倍[13]。
Propagermanium (1.0-3.0 mg/kg；口服) 对单独使用 LPS 处理的小鼠的肝损伤无影响，剂量最高可达 3.0 mg/kg[13]。
MCE has not independently confirmed the accuracy of these methods. They are for reference only.
| Animal Model: |
C57BL/6 J (male, 22-24 g, middle cerebral artery occlusion for 45 minutes followed by reperfusion)[2] |
| Dosage: |
25 mg/kg/day; 50 mg/kg/day |
| Administration: |
p.o.; once every 8 hours; 3 days |
| Result: |
Significantly reduced infarct size (P < 0.01).
Alleviated brain edema (P < 0.01).
Improved neurologic behavioral impairment (P < 0.05 for 25 mg/kg, P < 0.01 for 50 mg/kg).
Increased relative apparent diffusion coefficient (rADC) at 50 mg/kg dose compared to MCAO controls (P < 0.05).
Blunted the MCAO-induced increase in pro-inflammatory cytokines TNF-α, IFN-γ, IL-1β, IL-6, IL-12, IL-17, and IL-23 (P < 0.01 or P < 0.05).
Had no effect on anti-inflammatory cytokines TGF-β and IL-10.
Downregulated mRNA expression of pro-inflammatory markers iNOS and CD86 (P < 0.05).
Had no effect on anti-inflammatory markers Arg1 and CD206.
Significantly reduced the percentage of CD16+/Iba1+ pro-inflammatory microglia (P < 0.01).
Had no effect on CD206+/Iba1+ anti-inflammatory microglia.
Decreased the ratio of p-STAT1/STAT1 compared to MCAO controls (P < 0.05 for 25 mg/kg, P < 0.01 for 50 mg/kg). |
| Animal Model: |
Hexa-/-Neu3-/- (Tay-Sachs disease model, genetically engineered with GM2 ganglioside accumulation-induced neuroinflammation)[4] |
| Dosage: |
8 mg/kg |
| Administration: |
daily; 10 or 20 days |
| Result: |
Reduced cortical neuroinflammation-related gene expression ratios: Ccl2 from ~0.0013 to ~0.0003, Ccl3 from ~0.006 to ~0.003, Ccl5 from ~0.0022 to ~0.0008, Cxcl10 from ~0.004 to ~0.002, and Gfap from ~0.38 to ~0.17.
Reduced cortical GFAP-positive astrocyte intensity from ~25,000 to ~15,000.
Did not significantly reduce cortical MOMA-2-positive macrophage/monocyte intensity (~33,000 in untreated mice).
Reduced cerebellar neuroinflammatory gene expression ratios: Ccl2 from ~0.0022 to ~0.0003, Ccl3 from ~0.0055 to ~0.0032, and Gfap from ~0.25 to ~0.22.
Did not significantly reduce cerebellar GFAP-positive astrocyte intensity (~40,000 in untreated mice) or MOMA-2-positive macrophage/monocyte intensity (~43,000 in untreated mice).
Further reduced cortical Ccl5 and Cxcl10 expression compared to ketogenic diet alone.
Reduced cerebellar GFAP-positive astrocyte intensity from ~40,000 to ~27,000.
Reduced cerebellar MOMA-2-positive macrophage/monocyte intensity compared to untreated mice.
Did not alter anxiety-related behavior in the open field test or neuromotor activity in the rotarod test compared to untreated mice. |
| Animal Model: |
C57BL/6 (male)[5] |
| Dosage: |
0.005% |
| Administration: |
p.o.; daily; 1 week |
| Result: |
Reduced total infiltrated cells to 1466 ×10000 cells at 4 days post-thioglycollate injection.
Reduced macrophage counts to 1082 ×10000 cells at 4 days post-thioglycollate injection.
Did not affect granulocyte or lymphocyte counts at either 1 day or 4 days post-injection. |
| Animal Model: |
apoE-KO (male, female; backcrossed onto C57BL/6 background; weaned at 4 weeks, fed atherogenic high cholesterol diet)[5] |
| Dosage: |
0.005%; 5 mg/kg per day |
| Administration: |
p.o.; daily; 8 or 12 weeks |
| Result: |
Reduced aortic root atherosclerotic lesion area to 0.62 mm2 (50% reduction) after 8 weeks on diet.
Reduced macrophage-positive lesion area to 0.23 mm2 (66% reduction) after 8 weeks on diet.
Reduced percentage of macrophage-positive area relative to total lesion area to 36.1% (32% reduction) after 8 weeks on diet.
Reduced aortic root lesion area to 1.36 mm2 (36% reduction) after 12 weeks on diet.
Reduced descending thoracic aorta atherosclerotic lesion coverage to 6.2% (37% reduction) after 12 weeks on diet.
Did not affect plasma lipid levels, MCP-1 levels, body weight, or T lymphocyte infiltration in lesions. |
| Animal Model: |
WHHL (2.5-month-old, 2.7 kg, genetically lacking LDL receptors)[6] |
| Dosage: |
9 mg/kg |
| Administration: |
p.o.; daily; 3 months |
| Result: |
Did not alter serum lipid profiles (total cholesterol, LDL, HDL, triglyceride, lipid peroxides) compared to baseline or controls.
Significantly suppressed the oil red O-positive atherosclerotic lesion area in the aortic arch, thoracic aorta, and total aorta (p < 0.05), and tended to suppress lesions in the abdominal aorta.
Significantly suppressed maximal intimal thickness in the aortic arch, abdominal aorta, and total aorta (p < 0.05 or p < 0.01).
Significantly suppressed intimal area in the abdominal aorta and total aorta (p < 0.05 or p < 0.01).
Significantly suppressed RAM11-positive macrophage accumulation in the aortic arch, thoracic aorta, and abdominal aorta (p < 0.05 or p < 0.01). |
| Animal Model: |
C57BL/6J (male, 9-week-old at study start, acclimatized to 12 weeks old before diet initiation, HFD-induced NASH)[8] |
| Dosage: |
0.05% w/w |
| Administration: |
p.o.; 18 weeks (early intervention); 12 weeks (late intervention) |
| Result: |
Significantly reduced fasting plasma insulin levels, C-peptide levels, and HOMA-IR compared to HFD controls (early intervention only).
Significantly increased plasma adiponectin levels compared to HFD controls (early intervention only).
Significantly reduced WAT gene expression of pro-inflammatory markers Mcp-1 and CD11c compared to HFD controls (early intervention only); late intervention showed non-significant trend toward reduced CD11c expression.
Significantly reduced hepatic macrovesicular steatosis by 37% compared to HFD controls (early intervention only); late intervention showed non-significant 31% reduction.
Showed borderline significant reduction (p=0.05) in hepatic lobular inflammatory cell aggregates compared to HFD controls (early intervention only).
Significantly reduced hepatic M1/M2 macrophage ratio (CD11c/Arginase-1 expression) compared to HFD controls (both early and late interventions). |
| Animal Model: |
Wistar (male, 7 weeks old after 1 week acclimation)[10] |
| Dosage: |
2,400 ppm |
| Administration: |
p.o.; ad libitum daily; 8 weeks |
| Result: |
Showed very slight basophilic changes of tubules in one rat (also present in a control rat).
Showed basophilic change in distal tubular epithelium, tubular dilatation, interstitial mononuclear cell infiltration, urinary casts, and hemorrhage in a second rat.
Had no renal lesions in all other rats.
Observed no significant renal toxic effects overall. |
| Animal Model: |
Wistar (male, 7 weeks old after 1 week acclimation, adriamycin-induced glomerular damage)[10] |
| Dosage: |
480 ppm; 2,400 ppm |
| Administration: |
p.o.; ad libitum daily; 8 weeks |
| Result: |
Caused no alterations to renal changes observed in adriamycin-only control rats, including light microscopic findings (hyalin droplets in podocytes, basophilic changes of tubules, urinary casts, tubular dilatation, focal and segmental glomerular sclerosis, interstitial mononuclear cell infiltration, hemorrhage) and ultrastructural findings (swelling of glomerular podocytes, partial fusion of foot processes, electron dense droplets/vacuoles in podocytes, proximal tubular changes like decreased cell organelles, flattened epithelium, thickened basal lamina). |
| Animal Model: |
Wistar (male, 7 weeks old after 1 week acclimation, mercuric chloride-induced proximal tubular damage)[10] |
| Dosage: |
2,400 ppm |
| Administration: |
p.o.; ad libitum daily; 3 days |
| Result: |
Showed histopathological changes (basophilic changes of tubules, mitosis of tubular epithelium, desquamation of tubular epithelium, urinary casts, tubular dilatation, dilatation of interstitial capillaries at end of treatment; basophilic changes, urinary casts, tubular dilatation, mononuclear cell infiltration after recovery) similar in incidence and grade to mercuric chloride-only control rats.
Tended to reduce BUN elevation from 65 mg/dL in controls to 46 mg/dL, though this change was not statistically significant. |
| Animal Model: |
Goto-Kakizaki (GK) (male, initial mean body weight 294 g, 8 months old at study endpoint; spontaneous type 2 diabetes model; separate arm fed high-fat diet for 5 months to induce metabolic impairment)[12] |
| Dosage: |
50 mg/kg/day |
| Administration: |
p.o.; daily; 3 months |
| Result: |
Reduced fasting glucose levels by 18% (p < 0.01) in non-high-fat diet GK rats.
Reduced insulin resistance by 32% (p < 0.05) in non-high-fat diet GK rats.
Improved endothelial-dependent relaxation in aortas without PVAT by 23% (from 52.6% to 75.6%, p < 0.05) and with PVAT by 33% (from 34.04% to 72.5%, p < 0.05) in non-high-fat diet GK rats.
Reduced PVAT inflammation by 56% (p < 0.05) and oxidative stress by 55% (p < 0.05) in non-high-fat diet GK rats.
Reduced PVAT CD36 levels to ~140% of non-high-fat diet GK control (p < 0.05) in non-high-fat diet GK rats.
Reduced PVAT nitrotyrosine levels to ~140% of non-high-fat diet GK control (p < 0.05) in non-high-fat diet GK rats.
Reduced serum alanine aminotransferase (ALT) levels in non-high-fat diet GK rats.
Improved vascular sensitivity to sodium nitroprusside (SNP) in non-high-fat diet GK rats.
Reduced fasting glucose levels to 81.5 mg/dL (p < 0.01 vs. high-fat diet GK controls) in high-fat diet-fed GK rats.
Reduced triglyceride levels by 18% (p < 0.05 vs. high-fat diet GK controls) in high-fat diet-fed GK rats.
Increased total cholesterol levels by 22% (p < 0.01 vs. high-fat diet GK controls) in high-fat diet-fed GK rats.
Reduced insulin resistance (p < 0.05 vs. high-fat diet GK controls) in high-fat diet-fed GK rats.
Improved endothelial-dependent relaxation in aortas without PVAT and with PVAT (p < 0.001 vs. high-fat diet GK controls) in high-fat diet-fed GK rats.
Reduced PVAT inflammation and oxidative stress in high-fat diet-fed GK rats.
Reduced PVAT CD36 levels to ~170% of high-fat diet GK control (p < 0.05 vs. high-fat diet GK controls) in high-fat diet-fed GK rats.
Reduced PVAT nitrotyrosine levels to ~190% of high-fat diet GK control (p < 0.05 vs. high-fat diet GK controls) in high-fat diet-fed GK rats.
Reduced serum ALT and alkaline phosphatase (ALP) levels in high-fat diet-fed GK rats.
Improved vascular sensitivity to SNP in high-fat diet-fed GK rats. |
| Animal Model: |
ICR mice (female, 7 weeks old, acute liver injury induced by i.v. heat-killed Corynebacterium parvum followed by i.v. lipopolysaccharide)[13] |
| Dosage: |
0.1 mg/kg; 0.3 mg/kg; 1.0 mg/kg; 3.0 mg/kg |
| Administration: |
p.o.; once daily; 4 days |
| Result: |
Reduced serum AST and ALT levels to 38% of control values (AST: P < 0.001, ALT: P < 0.01 versus control), significantly inhibited hepatocellular necrosis, and reduced liver infiltration of mononuclear cells at 1.0 mg/kg.
Caused significant attenuation of serum ALT and AST activity, reduced IFN-γ production, and prevented infiltration of CD4- and CD11b-positive cells into the liver at 0.3 mg/kg.
Reduced IFN-γ production by 53% (P < 0.05 versus control), significantly inhibited IL-12 production (reduced by 51% at 3 hours and 58% at 4 hours versus control), prevented infiltration of CD4- and CD11b-positive cells into the liver, and reduced liver mononuclear cell infiltration and hepatocellular necrosis at 3.0 mg/kg.
Reduced TNF-α production by 20% and IL-1α production by 28% (not statistically significant) at 3.0 mg/kg.
Resulted in only 1 mouse with severe liver injury (grade 4) at 1.0 mg/kg, compared to 7 mice in the control group (P < 0.05 versus control). |
| Animal Model: |
ICR mice (female, 7 weeks old, Corynebacterium parvum immune primed by i.v. heat-killed C. parvum)[13] |
| Dosage: |
1.0 mg/kg; 3.0 mg/kg |
| Administration: |
p.o.; once daily; 4 days |
| Result: |
Significantly augmented serum IFN-γ concentration to 1.6 times that of C. parvum-primed control mice (P < 0.05 versus control) at 3.0 mg/kg. |
| Animal Model: |
ICR mice (female, 7 weeks old, LPS-induced liver injury by i.v. lipopolysaccharide)[13] |
| Dosage: |
1.0 mg/kg; 3.0 mg/kg |
| Administration: |
p.o. |
| Result: |
Did not alter serum AST levels compared to LPS-only control mice. |
|
Powered by Bioz
