Palmatine as an Agent Against Metabolic Syndrome and Its Related Complications: A Review

Figures & data

Table 1 Protective Effect of Palmatine on MetS Components

Researcher	Study Design	Findings
Cell Culture Studies
Choi et al 2014^Citation36	Cell line: 3T3-L1 mouse pre-adipocytes Mode of disease/model induction: Adipocyte differentiation Treatment: 12.5, 25 and 50 µM palmatine for 24 hrs NC: Untreated cells DC: Cells with adipocyte differentiation media PC: n.a.	↓ lipid accumulation, PPAR-γ and C/EBP-α compared to DC
Ma et al 2016^Citation51	Cell line: Human liver cancer HepG2 cells Mode of disease/model induction: none Treatment: 0.584, 2.92, 14.6 µM of palmatine for 24 hrs NC: Untreated cells PC: Metformin (0.2–5 µg/mL)	Inhibit glucose uptake in non-concentration dependent manner
Animal Studies
Ning et al 2015^Citation37	Animals: 60 male Syrian golden hamsters (4 weeks old, 100 ± 5 g) Mode of disease induction: HFD-induced hyperlipidaemia Treatment: HFD with 23.35, 46.70 and 70.05 mg/kg/day of palmatine for 4 weeks NC: Distilled water DC: HFD group PC: 1.2 mg/kg/day of simvastatin for 4 weeks	↓ HFD-induced body weight gain and upregulation of serum TC, TG & LDL-c in a dose-dependent manner NS for HDL-c level compared to DC Further ↑ faecal excretion of TC and TBA compared to DC Restore HFD-induced downregulation of LDLR and CYP7A1 mRNA and protein expression ↓ HFD-induced upregulation of ASBT NS for HMGCR mRNA and protein expression on DC or palmatine groups compared to NC
He et al 2016^Citation45	Animals: 54 male Syrian golden hamsters (5 weeks old, 100 ± 10 g) Mode of disease induction: HFHC-induced hyperlipidemia Treatment: 46.70 mg/kg/day of palmatine for 140 days NC: Distilled water DC: HFHC group PC: 1.2 mg/kg/day of orlistat for 140 days	↓ body weight and epididymal adipose weight gain compared to DC ↓ HFHC-induced upregulation of serum TC and LDL-c Further ↑ serum HDL-c and faecal excretion of TC & TBA compared to DC ↓ HMGCR and ↑ LDLR, CYP7A1 and UCP-2 mRNAs and proteins expression compared to DC
Ma et al 2016^Citation51	Animals: Female KK-Ay mice (8 weeks old, 40 ± 5 g) Mode of disease induction: HFD-induced diabetes Treatment: 25, 50, 100 mg/kg/day of palmatine for 40 days NC: n.a. DC: 0.9% saline PC: 0.32 mL of 225 mg/kg/day of metformin for 40 days	↓ serum TC, TG and liver/body weight ratio and ↑ HDL-c compared to DC ↓ water intake but NS for body weight gain, food consumption, urine output, fasting blood glucose, postprandial blood glucose and LDL-c levels compared to DC
Semwal et al 2010^Citation52	Animals: Swiss albino mice of either sex (35–50 g) Mode of disease induction: Alloxan-induced diabetes Treatment: 25, 50, and 100 mg/kg 11-hydroxypalmatine NC: 0.9% saline without alloxan DC: 60 mg/kg alloxan intravenous injection PC: 5 mg/kg/day of glibenclamide for 24 hours on diabetic mice	↓ blood glucose level compared to NC
Pakseresht et al 2016^Citation32	Animals: 32 male Wistar rats (35–50 g) Mode of disease induction: STZ-induced diabetes Treatment: 10 mg/kg/day of palmatine for 6 weeks NC: no treatment DC: Intraperitoneal STZ injection (55 mg/kg) PC: n.a.	↓ STZ-induced hyperglycaemia and ↑ STZ-induced hypoinsulinemia Restore STZ-induced upregulation of nitric oxide activity and downregulation of SOD level

Abbreviations: ↓, decrease or downregulate; ↑, increase or upregulate; ASBT, apical sodium-dependent bile acid transporter; C/EBP-α, CCAAT/enhancer-binding protein-α; CYP7A1, cholesterol 7α-hydroxylase; DC, disease control/model; HDL-c, high-density lipoprotein cholesterol; HFD, high-fat diet; HFHC, high-fat high-carbohydrate diet; HMGCR, 3-hydroxy-3-methyl glutaryl coenzyme A reductase; LDL-c, low-density lipoprotein cholesterol; LDLR, low-density lipoprotein receptor; MDA, malondialdehyde; n.a., not available; NC, negative control; NS, not significant; PC, positive control; PPAR-γ, proliferator-activated receptor-γ; SOD, superoxide dismutase; STZ, streptozotocin; TBA, total bile acids; TC, total cholesterol; TG, triglyceride; UCP-2, uncoupling protein-2.

Table 2 Health Benefits of Palmatine Related to the Cardiovascular and Musculoskeletal System

Researcher	Study Design	Findings
Cardioprotective activity
Kim et al 2009^Citation31	Cell lines: Human aortic endothelial HAEC and murine macrophage RAW 264.7 cells Mode of disease induction: LPS-induced inflammation (RAW 264.7 cells) Treatment: 1, 2, 5, 10 µM of palmatine for 8 hrs (HAEC) or 16 hrs (RAW 264.7 cells) NC: Untreated cells PC: 1 µg/mL LPS-induced cells (RAW 264.7 cells) Negative: no treatment PC: n.a.	↑ HO-1 expression in HAEC cells via a concentration-dependent manner ↓ LPS-induced HMGB1 release in RAW264.7 cells via a concentration-dependent manner and restore to baseline level at 10 µM
Kim et al 2009^Citation31	Animals: Male Sprague–Dawley rats (200–250 g) Mode of disease induction: I/R-mediated acute myocardial injury Treatment: 25 and 50mg/kg of palmatine 1 hr before ischemia NC: Sham with 0.25 mL DMSO 1 hr before ischemia DC: 30 mins ischemia followed by either 6h reperfusion (biochemical analysis) or 24 hrs reperfusion (infarct size and heart function) PC: n.a.	Restore I/R-increased LVEDP to baseline ↑ I/R-reduced ±dp/dt of left ventricular pressure ↓ infarct size compared to DC ↓ I/R-upregulated serum MDA, LDH, CK and ↑ I/R-reduced SOD and CAT activities ↓ I/R-upregulated COX-2 and iNOS protein expressions in myocardial tissues
Antiarthritic activity
Zhou et al 2016^Citation78	Cell line: Primary rabbit chondrocytes Mode of disease induction: IL-1β-induced OA Treatment: 29.20, 73.01, 146.02, and 292.05 µM palmatine for 6 hrs pre-treatment NC: Untreated cells DC: 24 hrs of 10 ng/mL IL-1β PC: n.a.	↑ IL-1β-downregulated TIMP, collagenase II, aggrecan and DKK-1 mRNAs and ↓ IL-1β-upregulated MMP-1, MMP-3, MMP-13, β-catenin, GSK-3β, Ihh, Shh and Gli-2 mRNAs in a concentration-dependent manner ↓ β-catenin, Ihh & Shh mRNAs compared to NC ↑ IL-1β-downregulated TIMP protein expression and ↓ IL-1β-upregulated MMP-3, β-catenin, Ihh, Shh and Gli-2 protein levels in a concentration-dependent manner
Zhou et al 2016^Citation78	Animals: 21 New Zealand rabbits weighing (4-week-old, 2.0–2.5 kg) Mode of disease induction: bilateral ACLTs-induced OA Treatment: 0.3 mL articular injection of 100 mg/L/week of palmatine for 5 weeks NC: 0.3 mL of D-Hanks Balanced Salt Solutions DC: OA by ACLTs on knee joints PC: n.a.	↑ TIMP-1 mRNA compared to DC and NC groups ↓ OA-upregulated MMP-3, β-catenin, Ihh, Shh, Gli-2, and TNF-α mRNAs ↓ OA-upregulated MMP-3, β-catenin, Ihh, Shh, Gli-2, and TNF-α mRNAs ↓ OA-upregulated β-catenin, Shh and Gli-2 protein expression in articular cartilage via immunohistochemical staining ↓ erosion and osteophyte formation compared to DC ↓ cartilage degradation compared to DC
Antiosteoporotic activity
Lee et al 2010^Citation27	Cell lines: RAW264.7, BMCs, ST2 cells and BMMs	NS for RANKL-induced osteoclast formation in mouse BMMs
Lee et al 2010^Citation71	Mode of disease induction: 1α,25-dihydroxyvitamin D3-induced osteoclastogenesis Treatment: 1, 10, 20 and 40 µM of palmatine for 1 hr NC: Untreated cells DC: RANKL or 1α,25-dihydroxyvitamin D3-treated cells PC: n.a.	↓ RANKL (NS for OPG & M-CSF) mRNA expression in ST2 cells compared to DC Inhibit pit formation and actin ring formation by BMCs and ST2 co-culture compared to DC
Ishikawa et al 2015^Citation70	Cell line: MC3T3-E1 cells Mode of disease induction: LPS induction Treatment: 1, 5, 10, 40, 100, and 200 μM of palmatine for 3 days Negative: no treatment NC: Untreated cells DC: 1 µg/mL LPS for 24 hrs PC: n.a.	↓ LPS-upregulated RANKL and OPG levels in culture supernatants and their mRNAs expression
Ishikawa et al 2016^Citation69	Cell lines: RAW 264.7 and MC3T3-E1 cells Treatment: 1, 5, 10, 40 and 100 μM of palmatine for 5 days NC: Untreated co-culture DC: no PC: n.a.	↓ osteoclast number compared to NC ↓ bone resorption activity with the reduced total pit formation and fluorescent intensity of conditioned media compared to NC
Ishikawa et al 2015^Citation70	Animals: Pathogen-free ICR female mice (7-week-old) Mode of disease induction: OVX-induced OP model Treatment: Daily gavage of 1 and 10 mg/kg/day of palmatine for 13 weeks NC: Sham operation mice DC: Bilaterally ovariectomised mice PC: n.a.	↓ OVX-mediated upregulation of osteoclast number, serum RANKL, OPG and RANKL/OPG ratio in a dose-dependent manner

Abbreviations: ↓, decrease or downregulate; ↑, increase or upregulate; ±dp/dt, first derivative; ACLTs, anterior cruciate ligament transections; BMMs, bone marrow macrophages; CAT, catalase; CK, creatine phosphokinase; COX-2, cyclooxygenase-2; DC, disease control/model; DKK-1, Dickkopf-related protein 1; DMSO, dimethyl sulfoxide; GSK-3β, glycogen synthase kinase-3β; HEAC, human aortic endothelial cells; HMGB1, high mobility group box 1; HO-1, heme oxygenase-1; Ihh, Indian hedgehog, IL-1β, interleukin-1β; iNOS, inducible NO synthase; I/R, ischemia/reperfusion; LDH, lactate dehydrogenase; LPS, lipopolysaccharride; MDA, malonaldehyde; MMP-3, matrix metalloproteinases-3; n.a., not available; NC, negative control; NS, not significant; OA, osteoarthritis; OP, osteoporosis; OPG, osteoprotegerin; OVX, ovariectomy; PC, positive control; RANKL, receptor activator of nuclear factor-kB ligand; Shh, Sonic hedgehog; SOD, superoxide dismutase; ST2, mouse stromal cells from bone marrow; TIMP-1, tissue inhibitors of metalloproteinases; TNF-α, tumor necrosis factor-α.

Figure 1 The protective effects of palmatine on MetS and the associated diseases.

Abbreviations: ↓, decrease or downregulate; ↑, increase or upregulate; ┬, inhibit or suppress; AGEs, advanced glycosylation end products; ASBT, apical sodium-dependent bile acid transporter; CAT, catalase; COX, cyclooxygenase; C/EBP-α, CCAAT/enhancer-binding protein-α; HDL-c, high-density lipoprotein cholesterol; HFD, high fat diet; HMGB1, high mobility group box 1; HMGCR, 3-hydroxy-3-methyl glutaryl coenzyme A reductase; HO-1, heme oxygenase −1; iNOS, inducible NO synthase; Ihh, Indian hedgehog; LDL-c, low-density lipoprotein cholesterol; LDLR, low-density lipoprotein receptor; MAPKs, mitogen-activated protein kinases; MI, myocardial infarction; MMP, matrix metalloproteinases; NFκB, nuclear factor kappa B; O₂, oxygen; OA, osteoarthritis; OP, osteoporosis; OPG, osteoprotegerin; PAL, palmatine; PPAR-γ, proliferator-activated receptor-γ; RANKL, receptor activator of nuclear factor-kB ligand; Shh, Sonic hedgehog; SOD, superoxide dismutase; TG, triglyceride; TIMP-1, tissue inhibitors of metalloproteinases 1; TNF-α, tumor necrosis factor-α; UCP-2, uncoupling protein-2.

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