Messenger RNA (mRNA) therapeutics involve delivering in vitro transcribed mRNA into specific cells to produce target proteins for the treatment or prevention of diseases. However, the development of mRNA therapeutics relies largely on mRNA delivery systems. Lipid nanoparticles (LNPs) represent the most widely used mRNA carriers in clinical applications. Composed of ionizable lipids, zwitterionic phospholipids, cholesterol, and polyethylene glycol-lipids, LNPs can address critical challenges in mRNA drug development, such as poor in vivo stability and the difficulty in crossing biological barriers. Ultimately, LNPs enable safe, efficient, and targeted mRNA delivery to the liver, lung, spleen, and other organs. This review outlines the roles of the four lipid components in LNPs for mRNA delivery. It then introduces targeted mRNA delivery to various organs/tissues such as the liver, lung, spleen, pancreas, bone marrow, and placenta, using strategies such as antibody modification, lipid structure alteration, and specialized administration routes. Additionally, this review discusses the applications and challenges of LNP-based mRNA therapeutics in disease treatment, aiming to provide insights for the clinical translation of mRNA therapies and for further innovations in LNP delivery systems.
Humans ; RNA, Messenger/administration & dosage* ; Nanoparticles/chemistry* ; Lipids/chemistry* ; Drug Delivery Systems ; Animals ; Liposomes

With the continuous development of messenger RNA (mRNA) technology, mRNA-based drugs have shown broad application prospects in recent years. Since mRNA is easy to be degraded and difficult to enter cells directly, the mRNA delivery vectors have always been one of the focuses in the development of mRNA-based drugs. Although lipid nanoparticles (LNPs) have been widely used for the delivery of mRNA, they tend to accumulate in the liver, and repeated administration can easily induce inflammatory response which leads to tissue damage. Compared with LNPs, virus-like particles (VLPs) have the advantages of high biocompatibility and safety, being expected to offer new solutions for mRNA delivery. Based on the practical application requirements, this review summarized the research progress in VLPs according to the mRNA delivery steps: particle assembly, delivery into cells, and intracellular release. We hope to provide a basis and design ideas for the development of new VLPs as delivery vectors, promote the application of VLPs in mRNA delivery, and provide new possibilities for the research and application of mRNA-based therapeutics.
RNA, Messenger/administration & dosage* ; Humans ; Nanoparticles/chemistry* ; Genetic Vectors ; Lipids/chemistry* ; Drug Delivery Systems/methods* ; Virion ; Animals ; Gene Transfer Techniques ; Liposomes

Camellia oil has become an important plant oil in China in recent years, but its effects on non-alcoholic fatty liver disease (NAFLD) have not been documented. In this study, the effects of camellia oil, soybean oil, and olive oil on NAFLD were evaluated by analyzing the fatty acid profiles of the plant oils, the serum lipids and lipoproteins of rats fed different oils, and by cytological and ultrastructural observation of the rats' hepatocytes. Analysis of fatty acid profiles showed that the polyunsaturated fatty acid (PUFA) n-6/n-3 ratio was 33.33 in camellia oil, 12.50 in olive oil, and 7.69 in soybean oil. Analyses of serum lipids and lipoproteins of rats showed that the levels of total cholesterol and low-density lipoprotein cholesterol in a camellia oil-fed group (COFG) were lower than those in an olive oil-fed group (OOFG) and higher than those in a soybean oil-fed group (SOFG). However, only the difference in total cholesterol between the COFG and SOFG was statistically significant. Cytological observation showed that the degree of lipid droplet (LD) accumulation in the hepatocytes in the COFG was lower than that in the OOFG, but higher than that in the SOFG. Ultrastructural analysis revealed that the size and number of the LDs in the hepatocytes of rats fed each of the three types of oil were related to the degree of damage to organelles, including the positions of nuclei and the integrity of mitochondria and endoplasmic reticulum. The results revealed that the effect of camellia oil on NAFLD in rats was greater than that of soybean oil, but less than that of olive oil. Although the overall trend was that among the three oil diets, those with a lower n-6/n-3 ratio were associated with a lower risk of NAFLD, and the effect of camellia oil on NAFLD was not entirely related to the n-6/n-3 ratio and may have involved other factors. This provides new insights into the effect of oil diets on NAFLD.
Animals ; Camellia/chemistry* ; Fatty Acids/analysis* ; Hepatocytes/ultrastructure* ; Lipid Droplets/physiology* ; Lipids/blood* ; Male ; Non-alcoholic Fatty Liver Disease/pathology* ; Plant Oils/administration & dosage* ; Rats ; Rats, Sprague-Dawley

OBJECTIVE: The present study aims at determining the stability of a popular type 2 diabetes rat model induced by a high-fat diet combined with a low-dose streptozotocin injection. METHODS: Wistar rats were fed with a high-fat diet for 8 weeks followed by a one-time injection of 25 or 35 mg/kg streptozotocin to induce type 2 diabetes. Then the diabetic rats were fed with regular diet/high-fat diet for 4 weeks. Changes in biochemical parameters were monitored during the 4 weeks. RESULTS: All the rats developed more severe dyslipidemia and hepatic dysfunction after streptozotocin injection. The features of 35 mg/kg streptozotocin rats more resembled type 1 diabetes with decreased body weight and blood insulin. Rats with 25 mg/kg streptozotocin followed by normal diet feeding showed normalized blood glucose level and pancreatic structure, indicating that normal diet might help recovery from certain symptoms of type 2 diabetes. In comparison, diabetic rats fed with high-fat diet presented decreased but relatively stable blood glucose level, and this was significantly higher than that of the control group (P<0.05). CONCLUSIONS This model easily recovers with normal diet feeding. A high-fat diet is suggested as the background diet in future pharmacological studies using this model.
Animals ; Blood Glucose ; metabolism ; Diabetes Mellitus, Experimental ; blood ; etiology ; physiopathology ; Diabetes Mellitus, Type 2 ; blood ; etiology ; physiopathology ; Diet, High-Fat ; adverse effects ; Insulin ; blood ; Lipids ; blood ; Liver ; drug effects ; pathology ; physiopathology ; Male ; Malondialdehyde ; blood ; Oxidative Stress ; Rats ; Rats, Wistar ; Streptozocin ; administration & dosage ; toxicity ; Superoxide Dismutase ; blood ; Uric Acid ; blood

BACKGROUNDThe pathogenesis of some types of preeclampsia is related to fatty acid oxidation disorders. Rapamycin can regulate fatty acid metabolism. This study aimed to investigate the effects of rapamycin on the clinical manifestations and blood lipid parameters in different preeclampsia-like mouse models.

METHODSTwo preeclampsia-like mouse models and a control group were established: L-NA (injected with Nω-nitro-L-arginine methyl ester), LPS (injected with lipopolysaccharide), and the control group with normal saline (NS). The mouse models were established at preimplantation (PI), early- and late-pregnancy (EP, LP) according to the time of pregnancy. The administration of rapamycin (RA; L-NA+RA, LPS+RA, and NS+RA) or vehicle as controls (C; L-NA+C, LPS+C, NS+C) were followed on the 2nd day after the mouse models' establishment. Each subgroup consisted of eight pregnant mice. The mean arterial pressure (MAP), 24-h urinary protein, blood lipid, fetus, and placental weight were measured. The histopathological changes and lipid deposition of the liver and placenta were observed. Student's t-test was used for comparing two groups. Repeated measures analysis of variance was used for blood pressure analysis. Qualitative data were compared by Chi-square test.

RESULTSThe MAP and 24-h urinary protein in the PI, EP, and LP subgroups of the L-NA+C and LPS+C groups were significantly higher compared with the respective variables in the NS+C group (P < 0.05). The preeclampsia-like mouse models were established successfully. There was no significant difference in the MAP between the PI, EP, and LP subgroups of the L-NA+RA and L-NA+C groups and the LPS+RA and LPS+C groups. The 24-h urine protein levels in the PI and EP subgroups of the L-NA+RA group were significantly lower compared with the respective levels in the L-NA+C groups (1037 ± 63 vs. 2127 ± 593 μg; 976 ± 42 vs. 1238 ± 72 μg; bothP < 0.05), also this effect appeared similar in the PI and EP subgroups of the LPS+RA and LPS+C groups (1022 ± 246 vs. 2141 ± 432 μg; 951 ± 41 vs. 1308 ± 30 μg; bothP < 0.05). The levels of serum-free fatty acid (FFA) in the PI and EP subgroups of the L-NA+RA groups were significantly lower compared with the respective levels in the L-NA+C group (2.49 ± 0.44 vs. 3.30 ± 0.18 mEq/L; 2.23 ± 0.29 vs. 2.84 ± 0.14 mEq/L; bothP < 0.05). The levels of triglycerides (TG) and total cholesterol in the PI subgroup of the L-NA+RA group were significantly lower compared with the respective levels in the L-NA+C (1.51 ± 0.16 vs. 2.41 ± 0.37 mmol/L; 2.11 ± 0.17 vs. 2.47 ± 0.26 mmol/L; bothP < 0.05), whereas high-density lipoprotein serum concentration was significantly higher (1.22 ± 0.19 vs. 0.87 ± 0.15 mmol/L;P < 0.05) and low-density lipoprotein serum concentration did not exhibit a significant difference. There were no significant differences in the FFA of the PI, EP, and LP subgroups between the LPS+RA and the LPS+C groups. The levels of TG in the PI subgroup of the LPS+RA group were significantly lower compared with the respective levels in the LPS+C group (0.97 ± 0.05 vs. 1.22 ± 0.08 mmol/L;P < 0.05).

CONCLUSIONRapamycin can improve clinical manifestations and blood lipid profile in part of the preeclampsia-like mouse models.

Animals ; Blood Pressure ; drug effects ; Chi-Square Distribution ; Cholesterol ; blood ; Disease Models, Animal ; Female ; Lipid Metabolism ; drug effects ; Lipids ; blood ; Lipoproteins, HDL ; blood ; Lipoproteins, LDL ; blood ; Mice ; Mice, Inbred C57BL ; Placenta ; drug effects ; metabolism ; Pre-Eclampsia ; blood ; drug therapy ; Pregnancy ; Pregnancy Outcome ; Sirolimus ; therapeutic use ; Triglycerides ; administration & dosage ; blood

OBJECTIVETo systematically evaluate the clinical effectiveness and safety of Danshen Injection (, DS) as one adjuvant treatment for conventional therapy with Western medicine (WM) for unstable angina pectoris (UAP).

METHODSUsing literature databases, a thorough and systematic retrieval of randomized controlled trials (RCTs) comparing DS plus WM with WM was conducted from inception to April 2015. The extracted data from included studies was analyzed by Review Manager 5.2 software. The Cochrane risk of bias tool was used to assess the quality of included studies, and Begg's and Egger's tests conducted by Stata 12.0 were used to evaluate the potential presence of publication bias.

RESULTSA total of 17 RCTs, which involving 1,433 participants, were identified and reviewed. The meta-analysis indicated that the combined use of DS and WM was significantly superior to WM alone for UAP in terms of the total effectiveness rate of angina pectoris [risk ratio (RR) =1.23, 95% confidence interval (CI): 1.17, 1.29, P<0.01] and the total effectiveness rate of electrocardiogram (ECG) [RR=1.18, 95%CI: 1.06, 1.30, P=0.001]. Additionally, DS could also further reduce the content of fibrinogen, adjust blood lipid level, correct T wave inversion, and so on. Fifteen adverse drug reactions were reported in two studies, Four of which appeared in the experimental group.

CONCLUSIONBased on the systematic review, the combined use of DS and WM was more effective than WM alone, it can be further widely used in clinic, however, there was no exact conclusion for its safety.

Adjuvants, Pharmaceutic ; therapeutic use ; Aged ; Aged, 80 and over ; Angina, Unstable ; blood ; drug therapy ; Drugs, Chinese Herbal ; administration & dosage ; therapeutic use ; Electrocardiography ; Female ; Fibrinogen ; metabolism ; Humans ; Injections ; Lipids ; blood ; Male ; Middle Aged ; Publication Bias ; Treatment Outcome

Objective: To evaluate the effects of Testosterone Undecanoate Pills (TUP) on insulin resistance (IR) in type-2 diabetes men with hypogonadism. METHODS: We randomly divided 82 type-2 diabetes patients with hypogonadism into a treatment (n = 42) and a control group (n = 40), both maintaining their glucose- and lipid-reducing therapies, while the former treated orally with TUP in addition. After 6 months of medication, we compared the body mass index (BMI), waist circumference (WC), blood glucose level, HbA1c, lipid profile, IR index obtained by homeostatic model assessment (HOMA-IR), insulin sensitivity index (ISI), sex hormone levels, and sexual function scores between the two groups of patients. RESULTS: Compared with the baseline, the patients in the treatment group showed significant decreases after medication in BMI (［26.71 ± 2.39］ vs ［25.15 ± 2.28］ kg/m2, P <0.05), WC (［89.96 ± 9.13］ vs ［85.03 ± 9.58］ cm, P <0.05), HbA1C (［7.73 ± 1.31］ vs ［7.01 ± 1.25］ %, P <0.05), and triglyeride (［1.97 ± 0.83］ vs ［1.41 ± 0.69］ mmol/L, P <0.05), a markedly elevated level of total testosterone (［7.16 ± 2.21］ vs ［14.22 ± 2.63］ nmol/L, P <0.05), and remarkable improvement in HOMA-IR (3.76 ± 1.18 vs 2.55 ± 1.03, P <0.05), ISI (96 ± 51 vs 138 ± 53, P <0.05) and total scores of the Aging Males' Symptoms (P <0.05). But no significant changes were observed in the scores of the International Index of Erectile Function (IIEF) after treatment (13.28 ± 6.38 vs 14.95 ± 6.08, P >0.05). CONCLUSIONS TUP can significantly improve insulin resistance in type-2 diabetes men with hypogonadism.
Androgens ; administration & dosage ; therapeutic use ; Blood Glucose ; analysis ; Body Mass Index ; Diabetes Mellitus, Type 2 ; blood ; complications ; drug therapy ; Glycated Hemoglobin A ; analysis ; Humans ; Hypogonadism ; blood ; drug therapy ; Insulin Resistance ; Lipids ; blood ; Male ; Testosterone ; administration & dosage ; analogs & derivatives ; therapeutic use ; Waist Circumference

OBJECTIVETo observe anti-atherosclerotic effect of Xuefu Zhuyu Granule (XZU) and Danlou Tablet (DT) on blood lipids, platelet derived growth factor (PDGF), vascular smooth muscle cells (VSMCs) proliferation, extracellular signal-regulated kinase (ERK) signal pathway in atherosclerosis (AS) model rats, and to explore their potential mechanisms.

METHODSForty male Wistar rats were randomly divided into five groups, i.e., the normal control group, the model group, the Atorvastatin group, the DT group, the XZG group, 8 in each group. Rats in the normal control group were fed with basic forage for 12 weeks, while rats in the other four groups were fed with high fat forage plus intraperitoneal injection of vitamin D3 to build AS model. Then rats in the model control group, the Atorvastatin group, the DT group, the XZG group were administered with normal saline, Atorvastatin suspension (0.18 mg/mL), DT suspension (45 mg/mL), and XZG (1 g/mL) by gastrogavage for 8 successive weeks, respectively. After intervention serum levels of TC, TG, LDL-C, HDL-C, and PDGF were detected by ELISA. Pathological changes in thoracic aorta were observed by HE staining. Protein expression levels of ERK1/2 and pERK1/2 in thoracic aorta were measured by Western blot.

RESULTSCompared with the normal group, serum TC, TG, LDL-C, PDGF levels, and expression levels of ERK1/2 and pERK1/2 significantly increased (P <0. 05) in the model control group. HE staining showed irregular intimal thickness, accumulated endothelial foam cells, lipids deposited, disarranged media VSMCs, forming typical AS plaque. Compared with the model group, TC and PDGF levels decreased in all medicated groups (P < 0.05, P < 0.01). Serum levels of TG and LDL-C significantly decreased in the Atorvastatin group and the DT group (P < 0.01, P < 0.05). Expressions of ERK1/2 and pERK1/2 significantly decreased in the Atorvastatin group, the DT group, and the XZG group (P < 0.01). HE staining also showed typical AS plaque in three medicated groups, but with reduced pathological degree of endometrial hyperplasia and plaque area.

CONCLUSIONSXZG and DT could reduce the plaque area and attenuate pathological degree of AS in model rats, thereby postponing the progress of AS. Its mechanism might be achieved through reducing serum lipids and release of PDGF, inhibiting ERK signal pathway activation and VSMC proliferation.

Animals ; Aorta, Thoracic ; Atherosclerosis ; drug therapy ; Drugs, Chinese Herbal ; administration & dosage ; pharmacology ; therapeutic use ; Extracellular Signal-Regulated MAP Kinases ; Lipids ; Male ; Plaque, Atherosclerotic ; Rats ; Rats, Wistar ; Tablets

PURPOSE: Clinical trials have studied the use of soy protein for treating type 2 diabetes (T2D) and metabolic syndrome (MS). The purpose of this study was to outline evidence on the effects of soy protein supplementation on clinical indices in T2D and MS subjects by performing a meta-analysis of randomized controlled trials (RCTs). MATERIALS AND METHODS: We searched PubMed, EMBASE, and Cochrane databases up to March 2015 for RCTs. Pooled estimates and 95% confidence intervals (CIs) were calculated by the fixed-and-random-effects model. A total of eleven studies with eleven clinical variables met the inclusion criteria. RESULTS: The meta-analysis showed that fasting plasma glucose (FPG) [weighted mean difference (WMD), -0.207; 95% CI, -0.374 to -0.040; p=0.015], fasting serum insulin (FSI) (WMD, -0.292; 95% CI, -0.496 to -0.088; p=0.005), homeostasis model of assessment for insulin resistance index (HOMA-IR) (WMD, -0.346; 95% CI, -0.570 to -0.123; p=0.002), diastolic blood pressure (DBP) (WMD, -0.230; 95% CI, -0.441 to -0.019; p=0.033), low-density lipoprotein cholesterol (LDL-C) (WMD, -0.304; 95% CI, -0.461 to -0.148; p=0.000), total cholesterol (TC) (WMD, -0.386; 95% CI, -0.548 to -0.225; p=0.000), and C-reactive protein (CRP) (WMD, -0.510; 95% CI, -0.722 to -0.299; p=0.000) are significant reduced with soy protein supplementation, compared with a placebo control group, in T2D and MS patients. Furthermore, soy protein supplementation for longer duration (≥6 mo) significantly reduced FPG, LDL-C, and CRP, while that for a shorter duration (<6 mo) significantly reduced FSI and HOMA-IR. CONCLUSION: Soy protein supplementation could be beneficial for FPG, FSI, HOMA-IR, DBP, LDL-C, TC, and CRP control in plasma.
Aged ; Blood Glucose/*metabolism ; Blood Pressure ; C-Reactive Protein/metabolism ; Cardiovascular Diseases/prevention & control ; Cholesterol/blood ; Diabetes Mellitus, Type 2/blood/*therapy ; *Dietary Supplements ; Humans ; Lipids/blood ; Metabolic Syndrome X/*blood/prevention & control ; Randomized Controlled Trials as Topic ; Soybean Proteins/*administration & dosage ; *Soybeans

BACKGROUNDWhile combined oral contraceptives (COCs) are commonly used to treat polycystic ovary syndrome (PCOS), comparative data regarding metabolic effects of different progestogens on this patient population are missing. This study aimed to compare the different effects of drospirenone (DRP)-containing COCs with cyproterone acetate (CPA)-containing COCs, combined with metformin and lifestyle modifications in women with PCOS and metabolic disorders.

METHODSNinety-nine women with PCOS and a metabolic disorder between January 2011 and January 2013 were enrolled into this prospective randomized clinical trial. Participants were randomized into two groups such as DRP-containing COCs, and CPA-containing COCs. Participants took COCs cyclically for 6 months, combined with metformin administration (1.5 g/d) and lifestyle modifications (diet and exercise). Clinical measures and biochemical and hormone profiles were compared. Comparisons for continuous variables were evaluated with paired and unpaired Student's t-tests. The Wilcoxon signed rank test was used when the data were not normally distributed. Analysis of covariance was used to control for age, body mass index (BMI), and baseline data of each analyzed parameter when compared between the two groups.

RESULTSA total of 68 patients have completed the study. The combination regimen of COCs, metformin, and lifestyle modifications in these patients resulted in a significant decrease in BMI, acne, and hirsutism scores when compared to baseline levels in both groups (P < 0.05). Blood pressure (BP) was significantly different in the CPA group when compared to baseline (75.14 ± 6.77 mmHg vs. 80.70 ± 5.60 mmHg, P < 0.01), and after 6 months of treatment, only the change in systolic BP was significantly different between the two groups (4.00 [-6.00, 13.00] mmHg vs. -3.50 [-13.00, 9.00] mmHg, P = 0.009). Fasting glucose, fasting insulin, and homeostasis model assessment-insulin resistance decreased significantly in the DRP group (5.40 ± 0.41 mmol/L vs. 5.21 ± 0.32 mmol/L, P = 0.041; 13.90 [10.50, 18.40] μU/ml vs. 10.75 [8.60, 13.50] μU/ml, P = 0.020; 3.74 [2.85, 4.23] vs. 2.55 [1.92, 3.40], P = 0.008) but did not differ between the two groups. While individual lipid profiles increased in both groups, no statistically significant difference was observed.

CONCLUSIONSDRP-containing COCs combined with metformin and lifestyle modifications could better control BP and correct carbohydrate metabolism in women with PCOS and metabolic disorders compared with CPA-containing COCs.

TRIAL REGISTRATIONChinese Clinical Trial Registry, ChiCTR-TRC-11001143; http://www.chictr.org.cn/showproj.aspx?proj=8395.

Adolescent ; Adult ; Androstenes ; administration & dosage ; Carbohydrate Metabolism ; Contraceptives, Oral ; administration & dosage ; Cyproterone Acetate ; administration & dosage ; Female ; Humans ; Insulin Resistance ; Life Style ; Lipids ; blood ; Metformin ; administration & dosage ; Polycystic Ovary Syndrome ; blood ; drug therapy ; metabolism ; Prospective Studies