Background: Neutrophil/high-density lipoprotein (HDL) ratio (NHR), monocyte/HDL ratio (MHR), lymphocyte/HDL ratio (LHR), platelet/HDL ratio (PHR), systemic immune-inflammation index (SII), system inflammation response index (SIRI), and aggregate index of systemic inflammation (AISI) have been recently investigated as novel inflammatory markers. Herein, the correlation was investigated between these inflammatory biomarkers and peripheral arterial disease (PAD) in type 2 diabetes mellitus (T2DM) patients.Methods: In this retrospective observational study, the hematological parameter data of 216 T2DM patients without PAD (T2DM-WPAD) and 218 T2DM patients with PAD (T2DM-PAD) at Fontaine stages II, III or IV stage had been collected. Differences in NHR, MHR, LHR, PHR, SII, SIRI, and AISI were analyzed, and receiver operating characteristic (ROC) curves were used to analyze the diagnostic potential of these parameters.Results: The levels of NHR, MHR, PHR, SII, SIRI and AISI in T2DM-PAD patients were significantly higher than in T2DM-WPAD patients (P < 0.001). They were correlated with disease severity. Further, multifactorial logistic regression analyses showed that higher NHR, MHR, PHR, SII, SIRI, and AISI might be independent risk factors for T2DM-PAD (P < 0.001). The areas under the curve (AUCs) of the NHR, MHR, PHR, SII, SIRI, and AISI for T2DM-PAD patients was 0.703, 0.685, 0.606, 0.648, 0.711, and 0.670, respectively. The AUC of the NHR and SIRI combined model was 0.733.Conclusion: The levels of NHR, MHR, PHR, SII, SIRI, and AISI were higher in T2DM-PAD patients, and they were independently linked with its clinical severity. The combination model of NHR and SIRI was most valuable for predicting T2DM – PAD.

Our previous studies suggested that salidroside could alleviate hepatic steatosis in type 2 diabetic C57BLKS/Lepr^db (db/db) mice. The aim of the present study was to evaluate the therapeutic effect of salidroside on high‐fat diet‐ (HFD‐) induced nonalcoholic fatty liver disease (NAFLD) by investigating underlying mechanisms. Mice were fed with HFD or regular diet, randomly divided into two groups, and treated with salidroside or vehicle for 8 weeks. Then, biochemical analyses and histopathological examinations were conducted in vivo and in vitro. Salidroside administration attenuated HFD‐induced obesity, blood glucose variability, and hepatic lipid deposition, markedly increasing insulin sensitivity in HFD mice. In addition, salidroside suppressed oxidative stress, thioredoxin‐interacting protein (TXNIP) expression, and NLRP3 inflammasome activation in the liver. In cultured hepatocytes, salidroside dose dependently regulated lipid accumulation, reactive oxygen species (ROS) generation, and NLRP3 inflammasome activation as well as improved AMP‐activated protein kinase (AMPK) activity and insulin sensitivity. The inhibition of AMPK activation by inhibitor or short interfering RNA (siRNA) resulted in the suppression of the beneficial effects of salidroside in hepatocytes. Our findings demonstrated that salidroside protects against NAFLD by improving hepatic lipid metabolism and NLRP3 inflammasome activation, and these actions are related to the regulation of the oxidative stress and AMPK‐dependent TXNIP/NLRP3 pathways.

Atherosclerosis (AS) is the basis of diabetic macrovascular complications. The plasma low-density lipoprotein (LDL) particles transcytosis across endothelial cells (ECs) and deposition under the endothelium is the initiation step of AS. We previously reported that high glucose inhibits the autophagic degradation of Caveolin-1 and promote LDL transcytosis across ECs, which in turn accelerates atherosclerotic progression. Since Sirt6 is a chromatin-associated protein with deacetylation activity, whether it can regulate Caveolin-1 acetylation and regulating the autophagic degradation of Caveolin-1 remains elusive. Autophagy and histone acetylation were assessed in the umbilical cords of patients with gestational diabetes mellitus (GDM) by immunohistochemistry. An in vitro model of LDL transcytosis was established, and the role of Sirt6 in LDL transcytosis across endothelial cells was clarified. The effect of Sirt6 on the autophagic degradation of Caveolin-1 under hyperglycemic conditions was explored in a streptozotocin (STZ)-induced diabetic AS model established using the ApoE^-/- mice. Caveolin-1 and acetylated histone H3 levels were significantly increased, while LC3B and Sirt6 were downregulated in the monolayer of the vascular wall from GDM and type 2 diabetes mellitus (T2DM) patients. Immunoprecipitation assays showed that Sirt6 interacts with Caveolin-1 and specifically mediated its acetylation levels. Immuno-electron microscopy (EM) further indicated that Sirt6 overexpression triggered the autophagic lysosomal degradation of Caveolin-1. ECs-specific overexpression of Sirt6 by adeno-associated viral vector serotype 9 (AAV9) induced autophagy, reduced Caveolin-1 expression, and ameliorated atherosclerotic plaque formation in STZ-induced diabetic ApoE^-/- mice. Sirt6-mediated acetylation of Caveolin-1 activates its autophagic degradation and inhibits high glucose-stimulated LDL transcytosis. Thus, the Sirt6/Caveolin-1 autophagic pathway plays a crucial role in diabetic AS, and the overexpression or activation of Sirt6 is a novel therapeutic strategy.

Diabetes is a recognized high-risk factor for the development of atherosclerosis, in which macroautophagy/autophagy is emerging to play essential roles. The retention of low-density lipoprotein (LDL) particles in subendothelial space following transcytosis across the endothelium is the initial step of atherosclerosis. Here, we identified that high glucose could promote atherosclerosis by stimulating transcytosis of LDL. By inhibiting AMPK-MTOR-PIK3C3 pathway, high glucose suppresses the CAV-CAVIN-LC3B-mediated autophagic degradation of CAV1; therefore, more CAV1 is accumulated in the cytosol and utilized to form more caveolae in the cell membrane and facilitates the LDL transcytosis across endothelial cells. For a proof of concept, higher levels of lipids were accumulated in the subendothelial space of umbilical venous walls from pregnant women with gestational diabetes mellitus (GDM), compared to those of pregnant women without GDM. Our results reveal that high glucose stimulates LDL transcytosis by a novel CAV1-CAVIN1-LC3B signaling-mediated autophagic degradation pathway.

Objective: To elucidate the mechanism whereby advanced glycation end products (AGEs) accelerate atherosclerosis (AS) and to explore novel therapeutic strategies for atherosclerotic cardiovascular disease. Methods and results: The effect of AGEs on low-density lipoprotein (LDL) transcytosis across endothelial cells (ECs) was assessed using an in vitro model of LDL transcytosis. We observed that AGEs activated the receptor for advanced glycation end products (RAGE) on the surface of ECs and consequently upregulated Caveolin-1, which in turn increased caveolae-mediated LDL transcytosis and accelerated AS progression. Our molecular assessment revealed that AGEs activate the RAGE-NF-κB signaling, which then recruits the NF-κB subunit p65 to the RAGE promoter and consequently enhances RAGE transcription, thereby forming a positive feedback loop between the NF-κB signaling and RAGE expression. Increased NF-κB signaling ultimately upregulated Caveolin-1, promoting LDL transcytosis, and inhibition of RAGE suppressed AGE-induced LDL transcytosis. In ApoE^−/− mice on a high-fat diet, atherosclerotic plaque formation was accelerated by AGEs but suppressed by EC-specific knockdown of RAGE. Conclusion: AGEs accelerate the development of diabetes-related AS by increasing the LDL transcytosis in ECs through the activation of the RAGE/NF-κB/Caveolin-1 axis, which may be targeted to prevent or treat diabetic macrovascular complications.

Orphan drugs are intended to treat, prevent or diagnose rare diseases. In recent years, China healthcare policy makers and patients have become increasingly concerned about orphan drug issues. However, very few studies have assessed the availability and affordability of orphan drugs for rare diseases in China. The aim of this study was to provide an overview of the availability and affordability of orphan drugs in China and to make suggestions to improve patient access to orphan drugs. Two components of the availability of orphan drugs were examined. Market availability was assessed by the extent to which orphan drugs were marketed in China with a comparison to orphan drugs in international markets, such as the U.S., EU and Japan. We conducted surveys and collected data from 24 tertiary public hospitals in China to measure hospital-level availability of orphan drugs. The affordability of orphan drugs was calculated using hospital dispensary prices and was expressed as days of average daily income required for the cost of a course of treatment. Affordability was also analyzed under the Chinese basic medical insurance system. Orphan drugs approved in the U.S., EU and Japan had 37.8 %, 24.6 % and 52.4 % market availability in China, respectively. Median availability of 31 orphan drugs surveyed at the 24 tertiary public hospitals was 20.8 % (very low). Within a periodic treatment course, the average treatment cost of 23 orphan drugs is approximately 4, 843. 5 USD, which equates to 505.6 days of per capita net income for an urban resident with a middle income (187.4 days for a high-income urban resident) or 1,582.8 days’s income for a rural resident with a middle income (657.2 days for a high-income rural resident). Except for homoharringtonine, 22 orphan drugs for 14 rare diseases were unaffordable for the most of residents in China. With 5 % out-of-pocket expenses, only three generics could be afforded by middle-income residents, whereas seven drugs for high-income urban residents. The Chinese government can take more responsibility for improving the availability and affordability of orphan drugs through setting up incentive policies and public platforms for sharing of orphan drug information. Control of the high price of orphan drugs, combined with a joint funding model from both government and private enterprise can efficiently reduce the economic burden of affected patients in China.