A Systematic Review of Potential Therapeutic Use of Lycium Barbarum Polysaccharides in Disease

Table 2

Translational studies demonstrating the systemic therapeutic effects of LBP.

Source	Country	Groups	Sample size	Method	Parameter(s)	Outcomes	Remarks
A. Metabolic effects
Pai et al. 2013 [15]	India	Mice: ND/HFD/HFD +ATV/HFD +LB (10mg/kg/day) /HFD +LB (20mg/kg/day)	6/6/6/6/6	In vivo	Blood lipid profile	TC, TG, VLDL: significant reduction in both LBP groups	Demonstrates improvement in lipid profile in LABP supplementation groups
						HDL: significant increase in LB 250mg/day only
						LDL: significant reduction in LB 500mg/day
Zhu et al, 2015 [17]	China	Normal control group (NC) vs hyperlipidemia group (H) vs hyperlipidemia + LBP group (HL) vs hyperlipidemia + chronic composite psychological stress group (HS) vs hyperlipidemia + LBP+ chronic composite psychological stress group (HLS)	9/9/9/9/9	In vivo	Blood lipid profile	H group had significantly higher TG and TC than NC group (P<0.05 & P<0.01). HL group had significantly lower TC and TG (P<0.05 for both) compared to H group. HLS group had significantly less TC and TG than NC and H group (P<0.01 and P<0.05 respectively).	Interesting study highlighting the possible molecular mechanism as to how LBP works which could be applicable to other disease models
					Hepatic MDA levels	MDA higher in each of the H and HS groups, as compared with the NC group (P<0.05 and P<0.01, respectively).
						Hepatic MDA in HL and HLS groups were lower relative to H group (P<0.05)
					ELISA for HSP-70	Increase in HSP-70 were observed in the HL and HLS groups (P<0.05 and P<0.01) while HSP-70 significantly lower in the HS group compared to H group (P<0.05)
					ELISA for Il-6	HS group had increased IL-6 which was reduced with LBP treatment (P<0.05 compared to HS group and P<0.01 compared to H group)
					Reverse transcriptase- quantitative polymerase chain reaction	mRNA CYP7A1 increased in the HL group compared with H and HS groups (P<0.05). CYP7A1 significantly reduced in the HS group (P<0.01)
B. Anti-aging
Zhang et al., 2013 [26]	China	LBP effect on free radical and ROS clearance rate	None	Chemical study	OH- clearance rate	Up to 89.45% clearance and IC50: 6.45μg/ml	Results of limited value as no cells or animals were involved in this study. Results can be basis for in vivo trials
					Superoxide clearance rate	IC50 is 7.13μg/ml
					ABTS clearance rate	IC50 47.158±6.231ug/ml
Liu & Yi et al, 2013 [27]	China	Rats: Control vs 100 mg/kg/day D-gal + 1 ml/100g/day saline or 10 ml/100g/day LBP or 20 ml/100g/day LBP or 40 ml/100g/day LBP or 5mg/100g	10/10/10/10/10/10	In vivo	SOD, MDA, CAT and GSH-px in mouse blood and mouse skin	Significant increase in MDA and reduced SOD, GSH-px and CAT of aging group compared to normal group (p<0.01)	Only assessed the levels of reactive oxygen species and free radicals but not the clinical implications of the effect. The effect of LBP on the skin could have been further investigated such as collagen organization
						LBP increases SOD, GSH-px and CAT significantly and reduces MDA in the aging group (p<0.01)
Xia et al., 2014 [30]	China	Zebrafish embryos: Control vs LBP of 1, 2, 3 or 4 mg/ml for 3 days	30	In vivo	Senescence assessment	AO staining: cell apoptosis reduced in 1–3 mg/ml LBPs in a dose-dependent manner,4mg/ml LBPs induced apoptosis	Demonstrates dose-dependent anti-apoptotic effects of LBP in vivo
						SA-β-gal quantification: 1, 2 and 3 mg/ml LBPs was 88.3%, 81.7% and 68.3% respectively of the staining observed in the control
					P53 signaling pathway gene expression	p53, p21 and Bax decreased in LBP treated compared to control
C. Hepatic effects
Xiao et al., 2014.[19]	China	Rats with NASH: Control vs LBP (0-12 weeks) vs LBP (9-12 weeks) vs NASH vs NASH +LBP (12 week) vs NASH + LBP (9-12 week)	6/6/6/6/6/6	In vivo and in vitro	Serum ALT, TNF-α, IL-1βa, COX-2 and MCP-1 levels	Reduced in LBP + NASH groups compared to NASH alone	Demonstrates beneficial effect of LBP supplementation directly through reduction in hepatitis and indirectly through reduction in body weight and insulin resistance
					Body weight	340.2 ± 13.4 g (LBP 3-12 weeks + NASH) vs 352.1 ± 14.0 g (LBP 9-12 weeks + NASH) vs 401.7 ± 10.7 g (NASH)
					Insulin resistance	Significantly reduced in LBP treated NASH rats compared to n treatment
Gan et al. 2018 [21]	China	Wistar Rats: Control vs CCl4 vs CCl4 + LBP (400 mg/kg, 800 mg/kg and 1600 mg/kg)	10/10/10/10/10	In vivo	ALT(U/L)	45.64 ± 3.49/124. 8 ± 9.78/ 89.69 ± 5.36/64.58 ± 4.95/ 60.12 ± 4.46c	Demonstrates anti-oxidant and anti-inflammatory effects of LBP supplementation in an in vivo model of hepatic injury
					Anti-oxidizing enzymes	LBP reversed decreased SOD, GSH-Px activities, GSH levels & reversed increases of MDA levels
					Pro-inflammatory cytokines	CCl4 + LBP 400 mg/kg, 800 mg/kg & 1600 mg/kg inhibited mRNA of TNF-α, IL-1β  &  MCP-1
D. Anti-cancer effects
Mao et al., 2011 [33]	China	MCF-7 cells treated with 0, 10,30, 100, or 300 μg/ml LBP for 24h	None	In vitro	Cell cycle distribution	G0/G1 phase: 49.06% to 22.68%). S phase: 45.29% to 71.10%	Demonstrates potential cytotoxic effects of LBP through inhibition of cell proliferation. This effect may not be limited to cancer cells.
					P53 and P21 expression	LBP decreased p53 and p-p53 and p21
Zhu and Zhang, 2013 [35]	China	HeLa cells, a human cervical carcinoma cell line treated with LBP (0, 6.25, 25 or 100 mg/ x4 days)	None	In vitro	HeLa cell proliferation	4 days LBP treatment at 6.25 mg/ml showed greatest inhibition of 35%
					cell cycle distribution	G0/G1 phase decrease significantly from 56.8% to 31.4% with LBP treatment
						Accumulation of cells in the S phase (33.5–59.4%) with LBP treatment
Wang et al. 2018 [34]	China	CT26-WT murine colon cancer line: LBP (0 μg/ml, 1 μg/ml, 10 μg/ml, and 100 μg/ml for 24/48 hours) cytotoxicity on	None	In vitro	LBP effect on DC-mediated CTL cytotoxicity	Proportion of CD3+CD8+ cells increased LBP for 4 days compared to control (80.9±7093% vs 54.5±4.26 %)	Demonstrates potential anti-cancer effects of LBP through priming of cell-mediated immunity
					Notch signaling in dendritic cells	Increased expression of Notch, Jagged, Hes1 and Hes5 upon LBP treatment
E. Immunomodulatory effects
Bo et al., 2017 [37]	China	Mice: Control vs CFA-OVA vs OVA vs LBP-OVA vs BL-OVA vs LBPL-OVA	20/20/20/20/20/20	In vivo	CD3+ and CD4+/CD8+ T cell activation	All increased in LBPL-OVA injected mice	Demonstrates beneficial effects of LBP supplementation on cell-mediated immunity
					Antigen transport to LN
Su et al., 2014 [36]	China	Mice: Control vs LBP 5/25/50 mg/kg for 7 days per os after immunized with LBP or LBP + rAd5VP1	5/5/5/5	In vivo	Follicular helper T cell generation	PD1+CXCR5+ Tfh cells: 5 mg/kg (2.17 ± 0.07%) 25 mg/kg (3.93 ± 0.74%), 50 mg/kg (3.84 ± 0.20%)	Demonstrates potential beneficial effects of LBP on cell mediated and humoral immunity
					Germinal center formation	B220+GL-7+ B cells: Control (1.80 ±0.49%),5mg/kg ((2.68 ±0.09%), 25mg/kg (3.95 ± 0.51%), 50mg/kg (4.00± 0.41%)
F. Neuroprotective effects
Chen at al, 2014 [4]	China	Rats: vehicle/saline vs vehicle/SCO vs LBP/SCO (LBP either 0.2mg/kg/day or 1mg/kg/day)	12/10/11	In vivo	NOR and OLR Task	Vehicle/SCO DI: 51.4±7.5% LBP/SCO DI: 65.6±18.6%	Well conducted study showing LBP’s protective effect in the hippocampus whole also highlighting its limitations.
					Morris Watermaze	LBP/SCO significantly decreases in the latency time and swim distance compared to SCO-treated
					Ki67 immunostaining	Ki67-immunoreactive nuclei were significantly increased in the LBP/SCO group (165.0±30.7) versus the vehicle/SCO group (52.0±19.4)
					IHC for DCX-Positive neurons	Vehicle/saline: 566.2±112.3 DCX-positive cells per field vs Vehicle/SCO:25.4±15.2 DCX-positive cells per field vs SCO/LBP: 685.5±132.6 DCX-positive cells per field
					AChE in hippocampus	AChE was significantly raised in SCO-treated compared to control, but LBP treatment resulted in no significant reduction.
Yu et al., 2018 [22]	China	Primary hippocampal neurons from C57BL/6 mice embryos	None	In vitro	MTT assay	OGD/R group had significant reduction of cell viability (p<0.01) with dose dependent increase of viability with LBP treatment	Thorough study which not only showed LBP’s neuroprotective effects but also the underlying mechanism and a good basis in studying the effect of LBP on Alzheimer’s disease in clinical trials. There is still a matter of whether LBP can prevent the onset of neurodegenerative diseases or mainly slow the progression once they’ve occurred.
					Lactate dehydrogenase (LDH) leakage assay	Dose-dependent reduction in LDH release with LBP pretreatment
					Western blot for apoptotic proteins	Bcl-2/Bax protein ratio was up-regulated ratio of cleaved Caspase-3/Caspase-3 was down-regulated in LBP treatment groups
					Western blot for autophagic proteins	Beclin 1 expression and LC3II/LC3I ratio were reduced, p62 expression increased in LBP pretreatment
					PI3K/Akt/mTOR signaling pathway analysis with Western blot	PI3K-specific inhibitor (LY294002) increased the expression of LC3II and cleaved Caspase-3 compared to LBP 60ug/ml
Liu et al, 2017 [23]	China	Rats: NG MCAO vs HG MCAO vs HG MCAO with LBP vs HG MCAO with insulin	27/29/29/29	In vivo	Infarct volume assessment	HG group had infarct volume than NG (p<0.05) while LBP and insulin groups had significantly reduced infarct volumes 24 hours after reperfusion (p <0.05)	Promising results regarding LBP’s effect on stroke which carries high mortality and morbidity globally. Results are a good basis for clinical trials.
					Neurological deficits score	HG group had more severe neurological deficit scores than NG group (p<0.05) while LBP or insulin treatment reduced the deficit score at 24 & 72 hours of reperfusion (p<0.05)
					T-maze	HG group spent less time than the NG group at target arm (p<0.05) while LBP or insulin groups spent longer times at target arm than the HG group at 24& 72 hours of reperfusion (p<0.05).
					H&E staining	HG group had significantly more pyknotic nuclei than NG group (p<0.05) while LBP or insulin pre-treatment reduced neuronal pyknosis at 24 and 72 hours reperfusion (p<0.05).
					Western blot	Opa1 significantly increased in LBP group compared to HG group at 24 hours reperfusion while ratio of phospho-Drp1/Drp1 was decreased in LBP group at 24&72 hours reperfusion (p<0.05)
Yang et al, 2017 [25]	Hong Kong	Mice: Group A- LBP treatment without retinal ischemia vs Group B- sham/ vehicle/ 1mg/kg or 10mg/kg of LBP	6/5/5/5/5/5	In vivo	Electroretinogram	LBP 10mg/kg treatment preserved b‐wave and OP amplitudes compared to vehicle treated (p < 0.05)	Results are a good basis for testing in patients with retinal disorders such as diabetic retinopathy and glaucoma.
					H&E stain	LBP treated had less pyknotic nuclei were noted in the GCL and INL and increased viable cells in GCL compared to vehicle‐treated group
					PKC‐α immunoreactivity	LBP treated retinae had stronger PKC‐α immunoreactivity compared to vehicle
					GFAP immunohistochemistry	Reduced GFAP positive staining in LBP‐treated retinae compared to vehicle-treated
Total papers= 16

Abbreviations. a-normal diet (ND), high fat diet (HFD), atorvastatin (AVT), Lycium barbarum polysaccharide (LBP), reactive oxygen species (ROS), non-alcoholic steatohepatitis (NASH), Carbon tetrachloride (CCl4), Michigan Cancer Foundation-7(MCF-7), middle cerebral artery occlusion (MCAO), normoglycemic (NG), hyperglycemic (HG), scopolamine (SCO) b- alanine transferase (ALT), tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1βa), cyclooxygenase 2 (COX-2), Monocyte Chemoattractant Protein-1 (MCP-1), dendritic cells (DC), cytotoxic T lymphocytes (CTL), novel object recognition (NOR), Immunohistochemistry (IHC), hematoxylin and eosin (H&E), 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT), Glial fibrillary acidic protein (GFAP), Protein kinase C (PKC), doublecortin (DCX), Enzyme-linked immunosorbent assay (ELISA) c- superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), Malondialdehyde (MDA), total cholesterol (TC), triglyceride (TG), very low density lipoproteins (VLDL), low density lipoproteins (LDL), high density lipoproteins (HDL), acridine orange (AO), Senescence associated-β-galactosidase (SA-β-gal), area under curve (AUC), mechanism of action (MOA), chemotherapy(CT), and IC50: half inhibitory concentration.