Stimulator of interferon genes promotes diabetic sarcopenia by targeting peroxisome proliferator activated receptors γ degradation and inhibiting fatty acid oxidation.

BACKGROUND: Declined skeletal muscle mass and function are inevitable consequences of long-term diabetes and bring about many adverse events. Muscle fibre atrophy and interstitial fibrosis are major pathological manifestations of diabetic sarcopenia. Stimulator of interferon genes (STING) participates in various metabolic diseases. We aimed to explore whether and how STING regulates the above pathological manifestations of diabetic sarcopenia. METHODS: Wild-type and STINGgt/gt C57BL/6J mice and C2C12 myotubes were used to study the role of STING in the regulation of diabetic sarcopenia and the underlying mechanisms. RESULTS: STING was abnormally activated in diabetic muscles and in PA-treated myotubes (P < 0.01 for all parameters). The diabetic mice demonstrated decreased forelimb grip strength, lean mass, muscle weight and hanging impulse, which were improved by STING deficiency due to alleviated muscle fibre atrophy and interstitial fibrosis (P < 0.05 for all parameters). STING deficiency alleviated muscle fibre atrophy through the following mechanisms. Firstly, STING deficiency or inhibition increased the contents of pDRP1Ser616 , PINK1, Parkin and LC3-II, decreased p62 content, and increased the amount of mito-Keima fluorescent dots at 578 nm in diabetic state (P < 0.05 for all parameters), suggesting improved mitofission and mitophagy. Secondly, STING deficiency or inhibition increased the expression of pAKTSer473 and GLUT4 post-insulin change in diabetic state (P < 0.05 for all), indicating alleviated insulin resistance (IR). Mechanically, STING deficiency or inhibition increased peroxisome proliferator activated receptors γ (PPARγ) protein content by reducing the degradation of ubiquitinated PPARγ through the proteasome pathway and thus increased the expression of fatty acid oxidation (FAO)-related proteins in diabetic state (P < 0.05 for all parameters). Decreased expression of FAO-related proteins caused by PPARγ inhibition abolished the improvements in mitofission, mitophagy and IR achieved by STING inhibition in PA-treated myotubes and thus promoted muscle fibre atrophy (P < 0.05 for all parameters). STING deficiency alleviated interstitial fibrosis by decreasing TGFß1 expression in diabetic state and TGFß1 promoted the fibrogenic differentiation of fibro-adipogenic progenitors (P < 0.05 for all parameters). PPARγ inhibition abolished the effect of STING inhibition on reducing TGFß1 content in PA-treated myotubes (P < 0.01). CONCLUSIONS: STING deficiency exerted protective effects in diabetic sarcopenia by inhibiting the degradation of ubiquitinated PPARγ through the proteasome pathway and enhancing PPARγ-mediated FAO, which alleviated muscle fibre atrophy by promoting mitophagy and ameliorating IR, and alleviated interstitial fibrosis by reducing TGFß1 production and suppressing the fibrogenic differentiation of fibro-adipogenic progenitors.

Efficacy and safety of sacubitril/valsartan after six months in patients with heart failure with reduced ejection fraction and asymptomatic hypotension.

BACKGROUND: It is not clear whether sacubitril/valsartan is beneficial for patients with heart failure (HF) with reduced ejection fraction (HFrEF) and low systolic blood pressure (SBP). This study aimed to investigate the efficacy and tolerability of sacubitril/valsartan in HFrEF patients with SBP < 100 mmHg. METHODS & RESULTS: An observational study was conducted on 117 patients, 40.2% of whom had SBP < 100 mmHg without symptomatic hypotension, and 59.8% of whom had SBP ≥ 100 mmHg in an optimized HF follow-up management system. At the 6-month follow-up, 52.4% of patients with SBP < 100 mmHg and 70.0% of those with SBP ≥ 100 mmHg successfully reached the target dosages of sacubitril/valsartan. A reduction in the concentration of N-terminal pro-B-type natriuretic peptide was similar between patients with SBP < 100 mmHg and SBP ≥ 100 mmHg (1627.5 pg/mL and 1340.1 pg/mL, respectively; P = 0.75). The effect of sacubitril/valsartan on left ventricular ejection fraction was observed in both SBP categories, with a 10.8% increase in patients with SBP < 100 mmHg (P < 0.001) and a 14.0% increase in patients with SBP ≥ 100 mmHg (P < 0.001). The effects of sacubitril/valsartan on SBP were statistically significant and inverse across both SBP categories (P = 0.001), with an increase of 7.5 mmHg in patients with SBP < 100 mmHg and a decrease of 11.5 mmHg in patients with SBP ≥ 100 mmHg. No statistically significant differences were observed between the two groups in terms of the occurrence of symptomatic hypotension, deteriorating renal function, hyperkalemia, angioedema, or stroke. CONCLUSIONS: Within an optimized HF follow-up management system, sacubitril/valsartan exhibited excellent tolerability and prompted left ventricular reverse remodeling in patients with HFrEF who presented asymptomatic hypotension.

Knowledge, attitude, practice and factors that influence the awareness of college students with regards to breast cancer.

BACKGROUND: Breast cancer has the highest incidence of all global cancers. Recent data show that breast cancer is becoming more prevalent in the younger population. Therefore, preventing breast cancer in young populations is a significant priority for public health. Relevant investigations of the incidence of breast cancer in young females have already been undertaken in China; however, none of these previous studies investigated the awareness of female college students with regards to breast cancer. AIM: To investigate the knowledge, attitude, and practice (KAP) of female college students in Yunnan with regards to breast cancer and a series of influential factors. METHODS: A random sample of 1387 female college students from two universities in Dali city were investigated by questionnaires. RESULTS: The total KAP scores for breast cancer were 9.86 ± 2.50, 3.19 ± 2.01 and 13.31 ± 2.49, respectively. Multiple linear regression analysis showed that educational grade was the most significant influential factor underlying the level of knowledge female college students had with regards to the treatment of breast cancer (P < 0.05). Registered residence and educational grade were the most significant factors that influenced attitude (P < 0.05). Age, registered residence, grade and major, were the most significant factors that influenced behavior (P < 0.05). The KAP of female college students in western Yunnan with regards to breast cancer were low. CONCLUSION: There is an urgent need to provide standardized publicity and educational strategies in China to improve the knowledge, attitude, and practice, of college students with regards to breast cancer.

Ethnobotanical survey of antifertility medicinal plants in Dali District, Yunnan Province, China.

In recent years, contraceptive medication has been widely used for birth control. It is worth noting that contraceptive medication from botanical source has great potential for clinical use. Yunnan is the province with the most species of plants in China and is known as the "plant kingdom". This study aims to archive herbal remedies traditionally used as antifertility remedies in Dali District, Yunnan Province, P. R. China. The survey was conducted from February 2011 to September 2016 in the population distributed in Dali and the surrounding counties. The data were collected from three groups of practitioners within the study area: therapists using traditional medicines (n = 104), aboriginal families (n = 37), and herbalists in commercial stalls (n = 12), and a total number of 117 plant species were recorded. Among the 117 plant species, 104 of which have been authenticated by a plant taxonomist from the Dali Herbarium. These plants were classified into 98 genera and 54 families, including Leguminosae (12 species), Liliaceae (7 species), Cucurbitaceae, Rosaceae and Rutaceae (5 species, respectively), Malvaceae, Compositae and Euphorbiaceae (4 species, respectively). Our data provides an in-depth delineation of the contraceptive plants used in Dali, which serve as valuable information for the practitioners of traditional Chinese medicine in contraceptive use. In addition, these data also hint that plants from different genus contain contraceptive components, which should be avoided by pregnant women. Future studies are required to identify the active contraceptive components, assess the toxicology, and elucidate the pharmacological mechanism of action.

Deficient Chaperone-Mediated Autophagy Promotes Lipid Accumulation in Macrophage.

Chaperone-mediated autophagy (CMA) serves as a critical upstream regulator of lipophagy and lipid metabolism in hepatocyte. However, the role of CMA in lipid metabolism of macrophage, the typical component of atherosclerotic plaque, remains unclear. In our study, LAMP-2A (L2A, a CMA marker) was reduced in macrophages exposed to high dose of oleate, and lipophagy was impaired in advanced atherosclerosis in ApoE (-/-) mice. Primary peritoneal macrophages isolated from macrophage-specific L2A-deficient mice exhibited pronounced intracellular lipid accumulation. Lipid regulatory enzymes, including long-chain-fatty-acid-CoA ligase 1 (ACSL1) and lysosomal acid lipase (LAL), were increased and reduced in L2A-KO macrophage, respectively. Other lipid-related proteins, such as SR-A, SR-B (CD36), ABCA1, or PLIN2, were not associated with increased lipid content in L2A-KO macrophage. In conclusion, deficient CMA promotes lipid accumulation in macrophage probably by regulating enzymes involved in lipid metabolism. CMA may represent a novel therapeutic target to alleviate atherosclerosis by promoting lipid metabolism. Graphical abstract.

Ginsenoside Rb1 enhances atherosclerotic plaque stability by skewing macrophages to the M2 phenotype.

Atherosclerosis (AS) is characterized as progressive arterial plaque, which is easy to rupture under low stability. Macrophage polarization and inflammation response plays an important role in regulating plaque stability. Ginsenoside Rb1 (Rb1), one of the main active principles of Panax Ginseng, has been found powerful potential in alleviating inflammatory response. However, whether Rb1 could exert protective effects on AS plaque stability remains unclear. This study investigated the role of Rb1 on macrophage polarization and atherosclerotic plaque stability using primary peritoneal macrophages isolated from C57BL/6 mice and AS model in ApoE-/- mice. In vitro, Rb1 treatment promoted the expression of arginase-I (Arg-I) and macrophage mannose receptor (CD206), two classic M2 macrophages markers, while the expression of iNOS (M1 macrophages) was decreased. Rb1 increased interleukin-4 (IL-4) and interleukin-13 (IL-13) secretion in supernatant and promoted STAT6 phosphorylation. IL-4 and/or IL-13 neutralizing antibodies and leflunomide, a STAT6 inhibitor attenuated the up-regulation of M2 markers induced by Rb1. In vivo, the administration of Rb1 promoted atherosclerotic lesion stability, accompanied by increased M2 macrophage phenotype and reduced MMP-9 staining. These data suggested that Rb1 enhanced atherosclerotic plaque stability through promoting anti-inflammatory M2 macrophage polarization, which is achieved partly by increasing the production of IL-4 and/or IL-13 and STAT6 phosphorylation. Our study provides new evidence for possibility of Rb1 in prevention and treatment of atherosclerosis.

Low n-6/n-3 PUFA Ratio Improves Lipid Metabolism, Inflammation, Oxidative Stress and Endothelial Function in Rats Using Plant Oils as n-3 Fatty Acid Source.

Lipid metabolism, inflammation, oxidative stress and endothelial function play important roles in the pathogenesis of cardiovascular disease (CVD), which may be affected by an imbalance in the n-6/n-3 polyunsaturated fatty acid (PUFA) ratio. This study aimed to investigate the effects of the n-6/n-3 PUFA ratio on these cardiovascular risk factors in rats fed a high-fat diet using plant oils as the main n-3 PUFA source. The 1:1 and 5:1 ratio groups had significantly decreased serum levels of total cholesterol, low-density lipoprotein cholesterol, and proinflammatory cytokines compared with the 20:1 group (p < 0.05). Additionally, the 20:1 group had significantly increased serum levels of E-Selectin, von Willebrand factor (vWF), and numerous markers of oxidative stress compared with the other groups (p < 0.05). The 1:1 group had a significantly decreased lipid peroxide level compared with the other groups (p < 0.05). Serum levels of malondialdehyde, reactive oxygen species and vWF tended to increase with n-6/n-3 PUFA ratios increasing from 5:1 to 20:1. We demonstrated that low n-6/n-3 PUFA ratio (1:1 and 5:1) had a beneficial effect on cardiovascular risk factors by enhancing favorable lipid profiles, having anti-inflammatory and anti-oxidative stress effects, and improving endothelial function. A high n-6/n-3 PUFA ratio (20:1) had adverse effects. Our results indicated that low n-6/n-3 PUFA ratios exerted beneficial cardiovascular effects, suggesting that plant oils could be used as a source of n-3 fatty acids to prevent CVD. They also suggested that we should be aware of possible adverse effects from excessive n-3 PUFA.

[Research progress of lactoferrin as drug carriers].

Lactoferrin (Lf) is one of the food protein belonged to the innate immune system. Apart from its main biological function of binding and transport of iron ions, lactoferrin also has many other functions and properties such as antibacterial, antiviral, antiparasitic, catalytic, anti-cancer, anti-allergic and radioprotecting. Lf is usually used as additives of food and cosmetics. The research of lactoferrin has been increasingly reported, and the application of lactoferrin as a drug carrier has drawn extensive attention over the recent year. In this paper, researches of lactoferrin as drug carriers are classified and summarized in brain targeting, liver tumor targeting, lung tumor targeting and oral delivery systems according to their different characteristics.

[The effects and its mechanism of N-arginine chitosan as transdermal enhancer].

The purpose of this study is to investigate the penetration effects and mechanism of N-arginine chitosan (ACS). This novel transdermal enhancer with a mimetic structure of cell-penetration peptides was synthesized by introducing hydrophilic arginine groups to the amino-group on chitosan's side chain. The structure of ACS was confirmed by FT-IR, 1H NMR and element analysis. In addition, attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR) was used to study the protein conformation and the water content of stratum corneum, and the result suggested that ACS can change the orderly arrangement of the molecules in the stratum corneum, making the stack structure of keratin become loose. And ACS can increase the water content of the stratum corneurn. Inverted fluorescence microscope and flow cytometry were used to examine penetration effect of ACS on Hacat cell. The result confirmed that the uptake of ACS was enhanced with increased substitution degree of arginine by 4-8 folds compared to chitosan. In vitro penetration studies on three electrical types of drugs were carried out using three model drugs of negatively charged aspirin, positively charged terazosin and neutral drug isosorbide mononitrate by the method of Franz diffusion cells. The results showed that ACS has obviously penetration of the negatively charged drug aspirin, and certain penetration of neutral drug issorbide mononitrate, but inhibition of positively charged terazosin. In vivo imaging technology research results show that the ACS can significantly enhance the fluorescence intensity of morin, which is the auto-fluorescence anionic drug. These obtained results suggested that ACS, as a promising transdermal enhancer, can change the structure of the keratinocytes and analog penetrating peptides promote absorption, but have certain selectivity for the drug.

[In situ rat intestine absorption of paclitaxel-loaded solid lipid nanoparticles modified with cell-penetrating peptides].

To investigate the rat intestinal absorption of stearic acid-octaarginine (SA-R8) modified solid lipid nanoparticles containing paclitaxel (SA-R8-PTX-SLN), compared with the commercially available preparation of PTX (Taxol) and PTX-loaded solid lipid nanoparticles (PTX-SLN), the in situ intestinal absorption of SA-R8-PTX-SLN was investigated by means of single-pass rat intestinal perfusion technique. The absorptions of the preparations were investigated at different intestinal segments, different drug concentrations and in the presence of P-glycoprotein inhibitor (verapamil). The results showed that PTX could be absorbed at each intestinal segment and the three preparations all showed maximum absorptions at the duodenum. The cumulative absorptions of three preparations at each intestinal segment appeared SA-R8-PTX-SLN > PTX-SLN > Taxol (P < 0.05). SA-R8-PTX-SLN showed a liner absorption manner at the duodenum in the examined drug concentration range. The cumulative absorptions of Taxol and PTX-SLN were significantly promoted after the addition of P-glycoprotein inhibitor (verapamil) into the preparation (P < 0.05), but absorption of SA-R8-PTX-SLN existed no significantly difference compared with the preparation without verapamil (P > 0.05). SA-R8 and SLN might both effectively improve the oral absorption of PTX in the intestinal tract.

[An overview of glycoconjugates for cancer targeting therapy and diagnosis].

Because of the changed metabolic behaviors of cancer cells, tumor cells uptake a corresponding larger amount of glucose in physiological condition when compared with normal cells. And they were prone to metabolize glucose for generating energy in anaerobic glycolysis ways in order to grow quickly. Anaerobic glycolysis consumes more glucose than aerobic way when the same amount of energy is obtained, which also results in large demand of glucose in tumor cells. This review briefly describes therapy methods related to characteristic mentioned above, and summarizes the research progress of drugs, diagnostic reagents and carriers conjugated with glucose, glucose derivatives or other kinds of sugars for cancer targeting. Furthermore, typically relative research reports from 2012 till now were listed and analyzed.

[Synthesis and characterization of N-octyl-N-arginine chitosan--a chitosan derivant with a mimetic structure of cell-penetrating peptides].

A novel chitosan derivant, N-octyl-N-arginine chitosan (OACS) with a mimetic structure of cell-penetrating peptides was synthesized by introducing hydrophilic arginine groups and hydrophobic octyl groups to the amino-group on chitosan's side chain. Structure of the obtained polymer was characterized by FT-IR and 1H NMR. The substitution degree of octyl and arginine groups was calculated through element analysis and spectrophotometric method, separately. The critical micelle concentration of OACS was 0.12 - 0.27 mgmL(-1) tested by fluorescence spectrometry. The solubility test showed OACS could easily dissolve in pH 1 - 12 solutions and self-assemble to form a micelle solution with light blue opalescence. The OACS micelles have a mean size of 158.4 - 224.6 nm, polydisperse index of 0.038 - 0.309 and a zeta potential of +19.16 - +30.80 mV determined by malvern zetasizer. AFM images confirmed free OACS micelle has a regular sphere form with a uniform particle size. MTT test confirmed that OACS was safe in 50 - 1 000 micromol-L(-1). The result of HepG2 cell experiment showed that the cell internalization of OACS micelles enhanced with increased substitution degree of arginine by 40 folds compared to chitosan. Thus, OACS micelles were a promising nano vehicle with permeation enhancement and drug carrier capability.

[Regulation of 2-methoxyestradiol-induced cell apoptosis by mcl-1 and bax genes in myelodysplastic syndrome].

The purpose of this study was to explore the mechanism underlying the regulation of 2-methoxyestradiol (2-ME)-induced cell apoptosis by mcl-1 and bax gene in myelodysplastic syndrome (MDS). The MUTZ-1 cells were pretreated with 2-ME; then the activity of caspases-3 was determined by fluorescent colorimetry; the mRNA expressions of apoptosis-related genes (mcl-1) and bcl-2-related X protein (bax) were determined by RT-PCR. The results showed that as compared with control, the 2-ME enhanced the activity of caspase-3 in MUTZ-1 cells in a dose-and time-dependent manners (p<0.05); along with increasing of 2-ME concentration, the expression of intracellular mcl-1 mRNA reduced (p<0.05), meanwhile the expression level of mcl-1 mRNA negatively correlated to the activity of caspase-3 at the corresponding time points (r=-0.992, p<0.01), but the expression of bax mRNA did not show significant change (p>0.05). It is concluded that 2-ME can regulate the apoptosis of MDS cells through the pathway of down-regulating the expression of mcl-1 mRNA and activating the caspase-3.

Pathological mechanisms of erythrocyte-induced vulnerability of atherosclerotic plaques.

Erythrocytes are considered a new culprit contributing to atherosclerosis. Plaques with intraplaque hemorrhage are prone to new plaque hemorrhage, which may not only stimulate the progression of atherosclerosis but also promote the transition from a stable to an unstable lesion. However, the role of erythrocytes in inducing the vulnerability of plaque with intraplaque hemorrhage and the possible mechanism involved are not well understood. Recently, increased cholesterol level from erythrocytes was reported to expand the lipid core of plaque. As well, heme, iron and phospholipids derived from erythrocytes trigger peroxidization in vitro, which is strongly associated with the progression of atherosclerosis. We speculate that erythrocytes trapped in plaque may induce vulnerability of atherosclerotic plaques not only by accumulating lipids but also by promoting peroxidization within plaques, thereby expanding the lipid core, increasing the infiltration of inflammatory cells and attenuating the fibrous cap of plaques. This proposition may provide clues into the development of novel treatments to increase the stability of atherosclerotic plaques.

[Alterations of telomerase activity and apoptosis induced by 2-methoxyestradiol in human myelodysplastic syndrome cell line MUTZ-1].

OBJECTIVE: To study the effect of 2-methoxyestradiol(2-ME) on telomerase activity expression and apoptosis in human myelodysplastic syndrome cells line MUTZ-1. METHODS: MUTZ-1 cells were incubated with different concentrations of 2-ME, apoptosis rate and cell cycle were measured by flow cytometry (FCM). Telomerase activity in MUTZ-1 cells was examined by telomeric repeat amplification protocol-Enzyme linked immunosorbent assay (TRAP-ELISA). RESULTS: The FCM analysis showed that cells in G0/G1 phase and S phase were decreased, while in G2/M phase increased after exposed to 1,2 and 4 micromol/L of 2-ME for 12 hours (P < 0.05). 1 and 2 micromol/L of 2-ME had no notable effect on MUTZ-1 cells as compared with the control group (P > 0. 05). Cells incubated with 1, 2 and 4 micromol/L of 2-ME for 36 hours were induced apoptosis, the percentage of apoptosis was between (12.87 +/- 0.86)% and (21.82 +/- 1.71)% with a dose- and time- dependent manner. Telomerase activity was significantly inhibited in these concentration and negatively correlated with cell number in G2/M phase (r = -0.979, P = 0.021) and increased apoptosis (r = -0.970, P = 0.030 ), respectively. Moreover, the inhibition effect of telomerase activity was enhanced in a dose- and time- dependent manner. CONCLUSIONS: 2-ME-induced apoptosis and inhibition of telomerase activity provide a possible mechanism for explaining the 2-ME's anticancer activity.

Pathological mechanisms and dose dependency of erythrocyte-induced vulnerability of atherosclerotic plaques.

To test our hypothesis that erythrocytes may induce plaque vulnerability and investigate the mechanism involved, we established a novel model of intraplaque hemorrhage in 56 New Zealand white rabbits with established plaques. Three distinct abdominal aortic plaques with similar thickness were identified in each rabbit with use of intravascular ultrasound (IVUS) imaging. Rabbits were equally divided into 4 groups depending on dosage of treatment; with the guidance of IVUS, one of the three plaques from each rabbit was injected from adventitia with autologous erythrocytes (RBC) or cholesterol (CH) for the following groups: RBC, 50 microL or 100 microL, and CH, 50 microL or 100 microL. One of the other two plaques in each rabbit received an equal volume of normal saline (NS) and one received no injection. Plaques in the 100 microL RBC group had a higher plaque rupture rate than its respective NS or blank controls plaques (57.1% vs. 14.3% or 14.3%, P<0.05). Plaques from the RBC or cholesterol groups showed, dose-dependently, more macrophage infiltration, more superoxide and lipid content, thinner plaque fibrous cap, higher mRNA level of MCP-1, IL-1 or IFN-gamma and higher vulnerability index than controls, especially in the RBC group. Thus, erythrocyte treatment can dose-dependently induce the vulnerability of plaques. Accumulation of lipid content and augmentation of oxidative stress and inflammation in the plaques are the probable pathological mechanisms involved.

Mechanism of 2-methoxyestradiol-induced apoptosis in myelodysplastic syndrome MUTZ-1 cell line.

The study was aimed to investigate the mechanism of proliferation inhibition and apoptosis of MDS-RAEB MUTZ-1 cells induced by 2-methoxyestradiol (2-ME), the cell proliferation was determined by MTT assay, apoptosis rate was determined with annexinV-FITC/PI double staining and cell cycle was analyzed by flow cytometry (FCM) after MUTZ-1 cells were treated with different concentrations of 2-ME; the changes of morphologic features of MUTZ-1 cells were observed with Wright-Giemsa's staining; lactate dehydrogenase was determined by Beckman Counter; and agarose gel electrophoresis was used to verify whether 2-ME can induce apoptosis of MUTZ-1 cells. The results showed that 2-ME inhibited the proliferation of MUTZ-1 cells in a dose-and time-dependent manner and caused a sustained arrest at G(2)/M phase in MUTZ-1 cells; the typical apoptotic morphological features appeared in MUTZ-1 cells; the production of lactate dehydrogenase was up-regulated and the marked DNA ladder pattern of internucleosomal fragmentation was observed. It is concluded that the mechanism of proliferation inhibition and apoptosis of MUTZ-1 cells induced by 2-ME is probably related with the G(2)/M cell cycle arrest; 2-ME may be a potentially adjunctive anticancer drug useful to treat myelodysplastic syndrome.