The Baseline Gut Microbiota Directs Dieting-Induced Weight Loss Trajectories.

BACKGROUND & AIMS: Elucidating key factors affecting personal responses to food is the first step toward implementing personalized nutrition strategies in for example weight loss programs. Here, we aimed to identify factors of importance for individual weight loss trajectories in a natural setting where participants were provided dietary advice but otherwise asked to self-manage the daily caloric intake and data reporting. METHODS: A 6-month weight-reduction program with longitudinal collection of dietary, physical activity, body weight, and fecal microbiome data as well as single-nucleotide polymorphism genotypes in 83 participants was conducted, followed by integration of the high-dimensional data to define the most determining factors for weight loss in a dietician-guided, smartphone-assisted dieting program. RESULTS: The baseline gut microbiota was found to outperform other factors as a predieting predictor of individual weight loss trajectories. Weight loss was also linked to the magnitude of changes in abundances of certain bacterial species during dieting. Ruminococcus gnavus (MGS0160) was significantly enriched in obese individuals and decreased during weight loss. Akkermansia muciniphila (MGS0120) and Alistipes obesi (MGS0342) were significantly enriched in lean individuals, and their abundance increased during dieting. Finally, Blautia wexlerae (MGS0575) and Bacteroides dorei (MGS0187) were the strongest predictors for weight loss when present in high abundance at baseline. CONCLUSION: Altogether, the baseline gut microbiota was found to excel as a central personal factor in capturing the relationship between dietary factors and weight loss among individuals on a dieting program.

Quality control of Semen Hoveniae by high-performance liquid chromatography coupled to Fourier transform-ion cyclotron resonance mass spectrometry.

A method based on high-performance liquid chromatography and Fourier transform-ion cyclotron resonance mass spectrometry was developed to control the quality of Semen Hoveniae. First, the chromatographic fingerprint was established in combination with the chemometrics methods such as similarity analysis, cluster analysis, principal component analysis, and orthogonal partial least squares discriminant analysis to discover the qualitative markers. Then, an high-performance liquid chromatography mass spectrometry method was developed to identify the chemical constituents in Semen Hoveniae. Moreover, the content of dihydromyricetin and dihydroquercetin in Semen Hoveniae were determined by high-performance liquid chromatography. As a result, nine common peaks were assigned in the fingerprints and the similarity of the 13 batch samples varied from 0.425 to 0.993, indicating an obviously different quality. Dihydromyricetin and dihydroquercetin were the main qualitative markers to differ the quality of Semen Hoveniae. Meanwhile, a total of 21 chemical compounds were characterized by high-performance liquid chromatography mass spectrometry and six of them were identified by comparing with information of reference standards. Finally, the content of dihydromyricetin and dihydroquercetin in 13 batch samples varied from 0.824  to 7.499 mg/g and from 0.05941  to 4.258 mg/g , respectively. In conclusion, the methods developed here will provide sufficient qualitative and quantitative information for the quality control of Semen Hoveniae.

[Correlation of the single nucleotide polymorphisms rs34349826 and rs6521 of the LHB gene with male infertility in Chinese men].

Objective: To study the relationship of the single nucleotide polymorphisms (SNP) rs34349826 (c.104 A>G) and rs6521 (c.114 C>G) of the luteinizing hormone beta-subunit (LHB) gene with male infertility in Chinese men. METHODS: This case-control study included 405 males with primary infertility (the infertility group) and 424 normal fertile men (the control group), the former again divided into subgroups of oligospermia, severe oligozoospermia and azoospermia according to the sperm concentration. Clinical data were collected from all the subjects and genomic DNA obtained from their peripheral blood for genotyping rs34349826 and rs6521 of the LHB gene by Sequence MassArray. We analyzed the correlation of male infertility with the SNPs of the two loci using the logistic regression model as well as its association with their haplotype combination with the SHEsis online software. RESULTS: There were statistically significant differences between the control and infertility groups in the semen volume (ï¼»3.51 ± 1.36ï¼½ vs ï¼»3.74 ± 1.71ï¼½ ml, P <0.05), sperm concentration (ï¼»79.21 ± 61.60ï¼½ vs ï¼»27.37 ± 30.80ï¼½ ×106/ml, P <0.01), percentage of progressively motile sperm (ï¼»39.40 ± 9.64ï¼½ % vs ï¼»11.90 ± 14.72ï¼½ %, P <0.01), and levels of serum luteinizing hormone (LH) (ï¼»3.29 ± 1.39ï¼½ vs ï¼»6.25 ± 4.83ï¼½ IU/L, P <0.01) and follicle-stimulating hormone (FSH) (ï¼»4.56 ± 2.31ï¼½ vs ï¼»15.64 ± 17.03ï¼½ IU/L, P <0.01). Logistic regression analysis revealed no correlation between male infertility and the genotypes of the rs34349826 and rs6521 loci of the LHB gene, and similar results were found in the subgroups of the infertile males. SHEsis analysis on the haplotypes of the rs34349826 and rs6521 loci showed the GG genotype combination to be a protective factor against male infertility. CONCLUSIONS: The rs34349826 and rs6521 loci of the LHB gene were not related to male infertility, which can be further confirmed by larger-sample studies. The GG genotype combination is a protective factor against male infertility.

[Correlation of the single nucleotide polymorphism rs662 of PON1 with the risk of male infertility].

Objective: To investigate the correlation between the single nucleotide polymorphism (SNP) rs662 of the paraoxonase 1 gene (PON1) and the risk of male infertility. METHODS: This case-control study included 403 male idiopathic infertility patients aged 29.00 ± 4.48 years in the case group and 329 normal fertile men aged 28.28 ± 4.08 years as healthy controls. We obtained DNA from the peripheral venous blood of the subjects, genotyped the SNP rs662 of PON1 by Sequenom MassArray, and analyzed the association between different genotypes of PON1 rs662 and male infertility using the logistic regression model. RESULTS: Compared with the normal controls, the infertility patients showed a significantly increased level of follicle-stimulating hormone (FSH) (ï¼»16.30 ± 17.76ï¼½ vs ï¼»4.72 ± 2.51ï¼½ U/L, P < 0.01) but a decreased percentage of progressively motile sperm (PMS) (ï¼»7.40 ± 14.17ï¼½ % vs ï¼»41.93 ± 9.06ï¼½ %, P < 0.01) and sperm concentration (ï¼»2.74 ± 3.64ï¼½ vs ï¼»75.83 ± 63.66ï¼½ ×106/ml, P < 0.01). Statistically significant differences were not found in the other parameters between the two groups of subjects, nor in the correlation of male infertility with the heterozygous genotype GA versus the wild homozygous genotype GG (OR = 0.98, 95% CI: 0.63－1.53, P = 0.923) or the homozygous genotype AA versus the wild homozygous genotype GG (OR = 0.87, 95% CI: 0.56－1.34, P = 0.525). CONCLUSIONS: The SNP rs662 of PON1 was not correlated with male infertility, which, however, needs to be confirmed by further studies with larger samples from a larger area.

[Kallmann syndrome with deafness caused by SOX10 mutation: Advances in research].

The transcription factor SOX10, as a major actor in the development of the neural crest, plays a key role in the maintenance of progenitor cell multipotency, lineage specification, and cell differentiation. Abnormalities of neural crest development in humans lead to a number of genetic diseases known as neurocristopathies or neural crest disorders. The mutation of SOX10 can cause Kallmann syndrome (KS), which is a clinically and genetically heterogeneous condition and defined by the association between anosmia and hypogonadotropic hypogonadism due to incomplete migration of neuroendocrine gonadotropin-releasing hormone (GnRH) cells along the olfactory, vomeronasal, and terminal nerves. Since then, there have been a number of related reports that mutation of SOX10 will lead to KS with deafness. This review focuses on the SOX10 gene and the advances in the diagnosis and genetic studies of KS with deafness caused by the mutatuin of SOX10.

[Single nucleotide polymorphism of the TP53 gene is not correlated with male infertility].

OBJECTIVE: To investigate the correlation of the single nucleotide polymorphism (SNP) rs1042522 of the tumor protein p53 (TP53) gene with the risk of male infertility. METHODS: This casecontrol study included 380 male patients with idiopathic infertility and 398 normal fertile men as controls from the Nanjing area. We genotyped the SNP rs1042522 of the TP53 gene by Sequence Mass Array and analyzed the correlation of the SNP with male infertility using the logistic regression model. RESULTS: Compared with the normal controls, the patients with idiopathic infertility showed significantly decreased sperm concentration (ï¼»77.34±49.24ï¼½ vs ï¼»13.13±24.96ï¼½ ×106/ml), percentage of progressively motile sperm (ï¼»42.55±9.57ï¼½ vs ï¼»10.38±5.57ï¼½%), serum testosterone level (ï¼»14.07±5.36ï¼½ vs ï¼»11.89±4.50ï¼½ nmol/L), and folliclestimulating hormone level (ï¼»16.80±18.20ï¼½ vs ï¼»4.55±7.17ï¼½ U/L) (P < 0.05) but no statistically significant differences in other parameters. No correlation was observed between the SNP frequencies and male infertility and similar results were found in the subgroups of the cases. CONCLUSIONS: SNP rs1042522 of the TP53 gene is not significantly correlated with the risk of male infertility.

[Nucleotide polymorphism rs4880 of the SOD2 gene and the risk of male infertility].

OBJECTIVE: To investigate the correlation of the single nucleotide polymorphism (SNP) rs4880 of the superoxide dismutase 2 (SOD2) gene with the risk of male infertility. METHODS: This casecontrol study included 519 male patients with idiopathic infertility (aged 19－40 ï¼»28.93±4.93ï¼½ years) in the case group and 338 fertile men (aged 19－40 ï¼»28.40±4.25ï¼½ years) in the control group. We collected the clinical data, genotyped the SNP rs4880 of the SOD2 gene by Sequenom Mass Array, and analyzed the association of different genotypes with male infertility using the logistic regression model. RESULTS: Statically significant differences were observed between the case and control groups in the level of folliclestimulating hormone (FSH) (ï¼»4.72±2.51ï¼½ vs ï¼»15.65±17.24ï¼½ U/L, P< 0.01), the percentage of progressively mobile sperm (ï¼»9.12±13.5ï¼½ vs ï¼»41.95±9.03ï¼½%, P< 0.01), and sperm concentration (ï¼»12.95±24.38ï¼½ vs ï¼»72.88±45.60ï¼½ ×106/ml, P< 0.01), but not in other parameters. No correlation was found between male infertility and the heterozygous genotype TC (OR = 0.90, 95% CI: 0.65－1.25, P = 0.516) or the homozygous genotype CC (OR=1.49, 95% CI: 0.38－5.81, P = 0.566) as compared with the wild genotype TT, and similar results were obtained in the analysis of the subgroups. CONCLUSIONS: The SNP rs4880 of the SOD2 gene was not correlated with male infertility, which, however, is to be supported by further studies with larger samples from more areas.

Oral absorption enhancement of probucol by PEGylated G5 PAMAM dendrimer modified nanoliposomes.

Probucol (PB), an antioxidant drug, is commonly used as a lipid concentration lowering drug to reduce blood plasma cholesterol levels in the clinic. However, the therapeutic effects of this drug are negatively impacted by its poor water solubility and low oral absorption efficiency. In this study, a PEGylated G5 PAMAM dendrimer (G5-PEG) modified nanoliposome was employed to increase water solubility, transepithelial transport, and oral absorption of PB. The uptake mechanism was explored in vitro in Caco-2 cells with the results suggesting that the absorption improvement of G5-PEG modified PB-liposome (PB-liposome/G5-PEG) was related to P-glycoprotein (P-gp) efflux pump but was independent of caveolae endocytosis pathways. Additionally, plasma lipid concentration lowering effects of PB-liposome/G5-PEG were evaluated in vivo in a LDLR-/- hyperlipidemia mouse model. Compared with saline treated group, treatment with PB-liposome/G5-PEG significantly inhibited the increase of plasma total cholesterol (TC) and triglyceride (TG) of mice induced by a high fat diet. Moreover, its lipid concentration lowering effects and plasma drug concentration were greater than PB alone or commercial PB tablets. Our results demonstrated that PB-liposome/G5-PEG significantly increased the oral absorption of PB and therefore significantly improved its pharmacodynamic effects.

Recent Advances in Dendrimer Research for Cardiovascular Diseases.

Dendrimers, as a type of artificially synthesized polymers, have been increasingly attracting attention in many research fields, including the material and medical sciences, due to their unique characteristics that include their highly branched and well-defined molecular architecture, multivalency and tunable chemical compositions. These advantages make dendrimers potential carriers for the delivery of therapeutic and diagnostic agents. Herein, we review the recent advances in dendrimer research for the prevention and treatment of cardiovascular diseases, with special focus on their applications as carriers for drug and gene delivery, as contrast agents, and as potential new drugs.

Lingguizhugan decoction protects PC12 cells against Aß25-35-induced oxidative stress and neuroinflammation by modulating NF-κB/MAPK signaling pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Alzheimer's disease (AD) is recognized as one of the most prevalent neurodegenerative diseases. Lingguizhugan decoction (LGZGD) is a classical traditional Chinese medicine (TCM). Many studies have shown that LGZGD can alleviate the symptoms of AD. AIM OF THE STUDY: The aim of this study was to assess the neuroprotective effects of LGZGD and elucidate its molecular mechanism on Aß25-35-induced PC12 cells. MATERIALS AND METHODS: PC12 cells were used MTT assays, ELISA, fluorescence probe analyses, Hoechst 33342 staining, immunofluorescent staining and western blot analyses were systematically conducted to evaluate the underlying mechanisms of LGZGD. RESULTS: In Aß25-35-induced PC12 cells, LGZGD remarkably increased cell viability, reduced the generation of TNF-α, IL-1ß, IL-6, MDA and ROS, increased the activity of GSH-Px, inhibited cell apoptosis, downregulated the expression of Bax and cleaved caspase-3, and upregulated the expression of Bcl-2. Moreover, LGZGD modulated the NF-κB/MAPK signaling pathways by upregulating the levels of IκBα and phospho-ERK, while downregulating the levels of phospho-p65, phospho-IκBα, and phospho-p38. Furthermore, LGZGD repressed the nuclear translocation activity of NF-κB p65. Meanwhile, LGZGD increased the expression of phospho-GSK-3ß and reversed the hyperphosphorylation of Tau proteins by inhibiting the activation of the ERK MAPK pathway. CONCLUSIONS: Taken together, the present study suggested that LGZGD may be a valuable drug candidate that can attenuate the neurotoxicity induced by Aß25-35 by modulating the NF-κB/MAPK signaling pathways in PC12 cells.

Inhibitory effects of doxycycline on the onset and progression of abdominal aortic aneurysm and its related mechanisms.

The objective of this study was to investigate whether doxycycline (DOX) given at different doses and via different administration routes had protective or therapeutic effects on abdominal aortic aneurysm (AAA) induced by elastase in mice. Moreover, the anti-AAA mechanism of DOX was studied in TNF-α-stimulated vascular smooth muscle cell (VSMC) in vitro. For in vivo study, either daily administration of 30mg/kg of DOX by gavage or intraperitoneal injection of 15mg/kg DOX every other day for 14 days significantly prevented the development of AAA at its early stage. Further study showed that intraperitoneal injection of 15mg/kg DOX every other day for 7 times in total could also cure the established AAA. In vitro study showed that treating VSMCs with TNF-α together with DOX remarkably inhibited the expressions and activities of MMPs (MMP-2 and MMP-9), significantly suppressed the activation of protein kinase B (AKT) signaling pathway and mitogen-activated protein kinases (MAPKs) signal proteins, including extracellular signal-regulated kinase (ERK), c-Jun amino-terminal kinases (JNK) and p38, and downregulated mRNA levels of interleukin-6 (IL-6) and monocyte chemotactic protein 1 (MCP-1), and significantly upregulated mRNA levels of transforming growth factor beta (TGF-ß), heme oxygenase 1 (HO-1) and superoxide dismutase 1 (SOD-1), indicating that DOX inhibits activities of MMPs through reducing oxidative stress, suppressing MAPKs and AKT signaling pathways and ameliorating inflammation in VSMCs, and therefore, exerts preventive as well as therapeutic effects on AAA.

Grape-seed Polyphenols Play a Protective Role in Elastase-induced Abdominal Aortic Aneurysm in Mice.

Abdominal aortic aneurysm (AAA) is a kind of disease characterized by aortic dilation, whose pathogenesis is linked to inflammation. This study aimed to determine whether grape-seed polyphenols (GSP) has anti-AAA effects and what mechanism is involved, thus to find a way to prevent occurrence and inhibit expansion of small AAA. In our study, AAA was induced by incubating the abdominal aorta of the mice with elastase, and GSP was administrated to the mice by gavage at different doses beginning on the day of the AAA inducement. In in vivo experiments, 800 mg/kg GSP could significantly reduce the incidence of AAA, the dilatation of aorta and elastin degradation in media, and dramatically decrease macrophage infiltration and activation and expression of matrix metalloproteinase (MMP) -2 and MMP-9 in the aorta, compared to the AAA model group. Meanwhile, 400 mg/kg GSP could also but not completely inhibit the occurrence and development of AAA. In in vitro experiments, GSP dose-dependently inhibited mRNA expression of interleukin (IL)-1ß, IL-6 and monocyte chemoattractant protein-1 (MCP-1), and significantly inhibited expression and activity of MMP-2 and MMP-9, thus prevented elastin from degradation. In conclusion, GSP showed great anti-AAA effects and its mechanisms were related to inhibition of inflammation.

Thermosensitive Hydrogel Containing Doxycycline Exerts Inhibitory Effects on Abdominal Aortic Aneurysm Induced By Pancreatic Elastase in Mice.

Doxycycline (DOX) is reported to exert therapeutic effects against abdominal aortic aneurysm (AAA), a severe degenerative disease. In this study, a DOX hydrogel formulation of DOX/PECTgel is studied, and its phase transition behavior and in vitro release profiles are explored. In addition, the anti-AAA effects and bioavailability of DOX/PECTgel are evaluated in an elastase induced AAA mouse model. The results show that the phase transition temperature of 30% poly(e-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-undecanone) (PECT) solution is above 34 °C. In vitro release profiles of DOX/PECTgel indicate a fast release of DOX at the first two days, followed by a slow and sustained release for 14 d. In vivo single-dose single subcutaneous injection of DOX/PECTgel containing 8.4 or 4.2 mg mL-1 DOX presents comparatively preventive effects on AAA, compared to intraperitoneal injections of DOX alone at a dose of 15 mg kg-1 for seven injections, while DOX bioavailability of the DOX/PECTgel treated groups is 1.39 times or 1.19 times of the DOX alone treated group, respectively.

Polymorphisms of protamine genes contribute to male infertility susceptibility in the Chinese Han population.

Protamine (PRM) plays important roles in the packaging of DNA within the sperm nucleus. To investigate the role of PRM1/2 and transition protein 1 (TNP1) polymorphisms in male infertility, 636 infertile men and 442 healthy individuals were recruited into this case-controlled study of the Chinese Han population, using MassARRAY technology to analyze genotypes. Our analysis showed that there were no significant differences between controls and infertile cases among the five single nucleotide polymorphisms identified in PRM1, PRM2 and TNP1 [rs737008 (G/A), rs2301365 (C/A), rs2070923 (C/A), rs1646022 (C/G) and rs62180545 (A/G)]. However, we found that the PRM1 and PRM2 haplotypes GCTGC, TCGCA and TCGCC exhibited significant protective effects against male infertility compared to fertile men, while TCGGA, GCTCC and TCGGC represented significant risk factors for spermatogenesis. Our data showed that rs737008 and rs2301365 in PRM1, and rs1646022 in PRM2, were significantly associated with male infertility and that gene-gene interaction played a role in male infertility. A linkage disequilibrium plot for the five SNPs showed that rs737008 was strongly linked with both rs2301365 and rs2070923. These findings are likely to help improve our understanding of the etiology of male infertility. Further studies should include a larger number of genes and SNPs, particularly growing critical genes; such studies will help us to unravel the effect of individual genetic factors upon male infertility.

Aggravated restenosis and atherogenesis in ApoCIII transgenic mice but lack of protection in ApoCIII knockouts: the effect of authentic triglyceride-rich lipoproteins with and without ApoCIII.

AIM: Previously, our group and others have demonstrated a causative relationship between severe hypertriglyceridaemia and atherogenesis in mice. Furthermore, clinical investigations have shown high levels of plasma Apolipoprotein C-III (ApoCIII) associated with hypertriglyceridaemia and even cardiovascular disease. However, it remains unclear whether ApoCIII affects restenosis in vivo, and whether such an effect is mediated by ApoCIII alone, or in combination with hypertriglyceridaemia. We sought to investigate ApoCIII in restenosis and clarify how smooth muscle cells (SMCs) respond to authentic triglyceride-rich lipoproteins (TRLs) with or without ApoCIII (TRLs ± ApoCIII). METHODS AND RESULTS: ApoCIII transgenic (ApoCIIItg) and knockout (ApoCIII-/-) mice underwent endothelial denudation to model restenosis. Here, ApoCIIItg mice displayed severe hypertriglyceridaemia and increased neointimal formation compared with wild-type (WT) or ApoCIII-/- mice. Furthermore, increased proliferating cell nuclear antigen (PCNA)-positive cells, Mac-3, and vascular cell adhesion protein-1 (VCAM-1) expression, and 4-hydroxynonenal (4HNE) production were found in lesion sites. ApoCIIItg and ApoCIII-/- mice were then crossed to low-density lipoprotein receptor-deficient (Ldlr-/-) mice and fed an atherogenic diet. ApoCIIItg/Ldlr-/- mice had significantly increased atherosclerotic lesions. However, there was no statistical difference in restenosis between ApoCIII-/- and WT mice, and in atherosclerosis between ApoCIII/Ldlr double knockout and Ldlr-/- mice. SMCs were then incubated in vitro with authentic TRLs ± ApoCIII isolated from extreme hypertriglyceridaemia glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1-deficient (GPIHBP1-/-) mice crossed with ApoCIIItg or ApoCIII-/- mice. It was shown that TRLs + ApoCIII promoted SMC proliferation, VCAM-1 expression, and reactive oxygen species (ROS) production, and activated the Akt pathway. Scavenging ROS significantly reduced SMC activation caused by TRLs + ApoCIII. CONCLUSIONS: Severe hypertriglyceridaemia resulting from ApoCIII overexpression promotes restenosis and atherosclerosis. Furthermore, we demonstrated that TRLs + ApoCIII promotes SMC proliferation.

G5-PEG PAMAM dendrimer incorporating nanostructured lipid carriers enhance oral bioavailability and plasma lipid-lowering effect of probucol.

This work aimed to improve the oral bioavailability and plasma lipid-lowering effect of probucol (PB) by constructing a combined drug delivery system (CDDS) composed of nanostructured lipid carrier (NLC) and PEGylated poly(amidoamine) dendrimer (PEG-PAMAM). PEG-PAMAM with dendrimer generations of 5 (G5-PEG) or 7 (G7-PEG) were incorporated in PB-NLCs to form PB-CDDSs, PB-NLCs/G5-PEG and PB-NLCs/G7-PEG. The resultant two kinds of PB-CDDSs were characterized by particle size, zeta potential, drug encapsulation efficacy, PB release rates, and physical stability. Formulation effects of NLC and CDDS on the cellular uptake of hydrophobic drug were explored in Caco-2 cells by fluorescent Cy5 dye as a hydrophobic drug model. Furthermore, in vivo pharmacokinetics of the PB-CDDS composed of G5-PEG and PB-NLCs were investigated in a low density lipoprotein receptor knockout (LDLr-/-) mouse model, including plateau plasma PB concentrations after oral administration of multiple doses, and bioavailability after oral administration of a single dose of different PB formulations. In addition, lipid-lowering effect of PB-NLCs/G5-PEG was studied. The results indicate that both G5-PEG and G7-PEG significantly improved aqueous solubility of PB. The two PB-CDDSs exhibited similar particle size (around 150nm) as PB-NLCs, but slower PB burst release rate, higher total PB release amount, and better particle morphology and storage stability than PB-NLCs. In comparison with traditional NLC, CDDS dramatically enhanced cellular uptake of Cy5 into Caco-2 cells. In vivo results demonstrate that PB-NLCs/G5-PEG had the highest plateau plasma PB concentration and oral bioavailability, and the greatest cholesterol-lowering effect in comparison with PB suspensions and PB-NLCs. Therefore, G5-PEG incorporating NLC can be exploited as a promising drug delivery system to improve oral bioavailability and lipid-lowering effect of PB.

The role of caveolin-1 and syndecan-4 in the internalization of PEGylated PAMAM dendrimer polyplexes into myoblast and hepatic cells.

To improve gene delivery efficiency of PEGylated poly(amidoamine) dendrimers in livers and muscles, the roles of syndecan-4 receptor and caveolin-1 protein in the endocytosis of PEGylated generation 5 (G5-PEG) or 7 (G7-PEG) dendrimers and plasmid DNA polyplexes were explored in C2C12 and HepG2 cells. Expression levels of syndecan-4 for both cell lines were downregulated by transfection of the cells with syndecan-4 specific siRNA. Caveolin-1 was upregulated by infecting the cells with adenovirus vector expressed caveolin-1 (Ad-CAV-1). The impact of syndecan-4 and caveolin-1 on endocytosis of G5-PEG/DNA or G7-PEG/DNA polyplexes was then measured by flow cytometry. Our results demonstrate that downregulation of syndecan-4 and upregulation of caveolin-1 significantly improved internalization of PEG-PAMAM dendrimer polyplexes in HepG2 cells; however, in C2C12 cells, downregulation of syndecan-4 decreased the internalization of the polyplexes while upregulation of caveolin-1 had no effect on internalization. Gene expression results for G5-PEG/pGFP on the two cell lines exhibited the same trends for syndecan-4 and caveolin-1 as was observed for endocytosis of the polyplexes. This study gives a clue how to take strategies by up- or down-regulation of the expressions of syndecan-4 and caveolin-1 to improve in vivo gene delivery efficiency of the PEG-PAMAM dendrimers in clinical transgenic therapy.