The value of plasma presepsin as a diagnostic and prognostic biomarker for sepsis in Southern China.

BACKGROUND: Presepsin is a soluble CD14 subtype that has been considered as a novel marker for patients with sepsis. This study explored the clinical value of presepsin for sepsis in Southern China, and further established models for diagnosis and prognosis of sepsis through using machine learning (ML), by combining presepsin and other laboratory parameters. METHODS: 269 subjects (105 infected patients, 164 sepsis and septic shock) and 198 healthy controls were enrolled. Laboratory parameters (hematological parameters, coagulation parameters, liver function indices, renal function indices, and inflammatory markers) were collected. Plasma presepsin was tested by chemiluminescence enzyme immunoassay. ML of DxAI™ Research platform was used to establish diagnostic and prognostic models. Sensitivity, specificity, and other performance indicators were used to evaluate the performance of each model. RESULTS: The level of presepsin was obviously increased in sepsis and sepsis shock, compared with that of infected and healthy group (all P < 0.0001). Presepsin concentration was positively correlated with positive blood culture and 30-day mortality in sepsis and septic shock patients. Through ROC curve analysis, Hb, UREA, APTT, CRP, PCT, and presepsin were incorporated into machine learning to construct diagnosis models. Ada Boost model had the best diagnostic efficiency (AUC: 0.94 (95% CI 0.919-0.968) in the training set and AUC: 0.86 (95% CI 0.813-0.900) in validation set). Furthermore, AST, APTT, UREA, PCT, and presepsin were included in the prognosis ML models, and the Bernoulli NB model had greater predictive ability for 30-day mortality risk of sepsis (AUC: 0.706), which was higher than that of PCT (AUC: 0.617) and presepsin (AUC: 0.634) alone. CONCLUSION: Machine-learning model based on presepsin and routinely laboratory parameters showed good performance of diagnostic and prognostic ability for sepsis patients.

Comparison of Beneficial Effects of Acupuncture at PC6, LU7 & Non- acupuncture Points on Cardiac Cell Function in Myocardial Ischemia (MI) Rats by Testing Protein Expression of L-type Calcium Channel Protein and its Related Protein.

The mechanism of why electro-acupuncture (EA) at PC6 improves the heart function was investigated by studying how the L-type cardiac voltage-dependent calcium channel in myocardial ischemia (MI) is regulated. Cava,., Cavo and Cava2-61 are main component proteins of L-type calcium channel; CaM and Calmodulin kinase II (CaMKII) are Ca2+ channel associated proteins. In this experiment, MI was induced by injection of isoproterenol (ISO) in rats and electrocardiograms (ECGs) were recorded before and after every injection, and protein expressions of Cava,c, Cavp, Cava2_61, CaM and CaMKII were higher [The protein expression increased 43.39%, 54.85%, 47.08%, 48.29% and 50.36% respectively] than the control rats significantly (p<0.05). After MI induction, the MI rats were divided into three groups, including PC6 (Neiguan-point), LU7 (Lieque-point) and Non-acupuncture-point group, which were acupunctured once a day for 7 days respectively. After EA at PC6, the protein expressions showed obvious decrease [EA at PC6: the protein expressions of Cava1c, CavP, Cava2-81, CaM and CaMKII decreased 26.36%, 27.58%, 25.21%, 27.21% and 26.61% respectively.] and they are all lower than MI rats significantly (p<0.05). After EA at LU7 and Non-acupuncture-point, the protein expressions showed no significant changes. The effect of EA at PC6 was significantly better than LU7 and Non- acupuncture-point (p<0.05). PC6 is an acupoint of the pericardium meridian, and the pericardium meridian, which corresponds to opioid system according to Li P's research, can affect the cardio-vascular function directly. LU7 is located on the lung meridian; it cannot affect the heart function directly although the lung is related to the heart in blood circulation function so PC6 showed the target treating effect of meridian specificity on regulating the L-type calcium channel in MI.

Effect of acupuncture at Neiguan (PC 6) on cardiac function using echocardiography in myocardial ischemia rats induced by isoproterenol.

OBJECTIVE: To investigate the effect of acupuncture at Neiguan (PC 6) on cardiac function using echocardiography in rat models of myocardial ischemia (MI) induced by isoproterenol (ISO). METHODS: Twenty-seven Sprague-Dawley rats were randomly assigned to normal, model, and acupuncture groups. The model and acupuncture groups were given injections of ISO (85 mg/kg) to establish the MI model. After model establishment, the acupuncture group was treated with acupuncture at Neiguan (PC 6) for 30 min. Echocardiography was used to monitor diastolic and systolic function for 30 min starting from the time after the acupuncture needles were removed. Changes in the length of left ventricular internal diameter at end-diastole (LVIDd), length of left ventricular internal diameter at end-systole (LVIDs), the ratio of mitral peak velocity at early diastole and atrial contraction (E/A), ejection fraction (EF), fractional shortening (FS), and stroke volume (SV) were measured. RESULTS: Compared with the model group at 0 and 15 min after needles were removed, the means of LVIDd and LVIDs were significantly lower (P < 0.01) and E/A, EF, FS, and SV significantly higher (P < 0.01) in the acupuncture group. In the acupuncture group, the means of LVIDd and LVIDs 15 min after the needles were removed were significantly higher (P < 0.01) than those at 0 min. The means of E/A, EF, FS, and SV significantly decreased (P < 0.01) from 0 to 15 min in the acupuncture group. CONCLUSION: These findings indicate that acupuncture at Neiguan (PC 6) can affect cardiac function by increasing left ventricular diastolic and systolic function in MI rat models, but the effect only lasts for 15 min.

The value of lactate dehydrogenase to albumin ratio and immune inflammation biomarkers in colorectal cancer.

Background: Colorectal cancer (CRC) is one of the most prevalent gastrointestinal cancers. Evidence for the importance of inflammation and immunology in the development and progression of CRC is growing steadily. The purpose of this study was to determine the clinical importance of Lactic Dehydrogenase (LDH) to Albumin (ALB) Ratio (LAR) and immune-inflammation biomarkers (IIBs) in patients with CRC. Methods: This study enrolled 382 CRC patients. The LAR was determined as the serum LDH(U/l) to ALB(g/l) ratio. We compared the levels of LAR and IIBs in different TNM stages and tumor differentiation. The relationship between LAR and IIBs and overall survival (OS) of CRC was determined by Cox regression models. A prognostic nomogram was created using the results of the multivariate analysis and the effectiveness of the nomogram was assessed using the ROC, calibration, and decision curves. We evaluated the relationship between LAR and IIBs and clinical features of CRC. Results: The levels of LAR, SII, NLR and PLR in TNM IV stage group (LAR:5.92 (5.23-8.24); SII: 1040.02 (499.51-1683.54); NLR: 2.87 (2.07-5.3); PLR:187.08 (125.31-276.63)) were significantly higher than those in other groups. LAR and NLR showed no significant difference in different tumor differentiation groups, while SII and PLR in undifferentiated groups (SII:543.72 (372.63-1110.20); PLR: 147.06 (106.04-203.92)) were significantly higher than those in well and moderate groups (SII: 474.29 (323.75-716.01); PLR: 126.28 (104.31-167.88)). LAR (HR = 1.317, 95% CI = 1.019-1.454), TNM stage (HR = 2.895, 95% CI = 1.838-4.559), age (HR = 1.766, 95% CI = 1.069-2.922) and lymphocytes (HR = 0.663, 95% CI = 0.456-0.963) were predictors of OS. IIBs, including SII, NLR, and PLR are independent of OS. The LAR-based nomogram AUCs of 1-year, 3-year and 5-year survival probabilities in the training cohort were 0.86, 0.72, and 0.71, respectively, and the AUCs of the validation cohort were 0.85, 0.71, and 0.69 respectively. The LAR-based nomogram's ROC curves and calibration curves demonstrated higher OS discriminative performance. The decision curves demonstrated greater net benefit in the survival prediction. Conclusion: Preoperative LAR is a potential prognostic marker in CRC patients, while SII, NLR, and PLR are independent of OS. LAR was associated with tumor stage in CRC patients, but not with tumor differentiation.

Plasma Exosomal miRNAs Associated With Metabolism as Early Predictor of Gestational Diabetes Mellitus.

To date, the miRNA expression profile of plasma exosomes in women whose pregnancy is complicated by gestational diabetes mellitus (GDM) has not been fully clarified. In this study, differentially expressed miRNAs in plasma exosomes were identified by high-throughput small-RNA sequencing in 12 pregnant women with GDM and 12 with normal glucose tolerance (NGT) and validated in 102 pregnant women with GDM and 101 with NGT. A total of 22 exosomal miRNAs were found, five of which were verified by real-time qPCR. Exosomal miR-423-5p was upregulated, whereas miR-122-5p, miR-148a-3p, miR-192-5p, and miR-99a-5p were downregulated in women whose pregnancy was complicated by GDM. IGF1R and GYS1 as target genes of miR-423-5p, and G6PC3 and FDFT1 as target genes of miR-122-5p were associated with insulin and AMPK signaling pathways and may participate in the regulation of metabolism in GDM. The five exosomal miRNAs had an area under the curve of 0.82 (95%CI, 0.73, ∼0.91) in early prediction of GDM. Our study demonstrates that dysregulated exosomal miRNAs in plasma from pregnant women with GDM might influence the insulin and AMPK signaling pathways and could contribute to the early prediction of GDM.

Cupping Therapy for Diseases: An Overview of Scientific Evidence from 2009 to 2019.

Cupping therapy has been accepted worldwide, and many studies have been conducted to reveal its curative effects and mechanisms. To comprehensively evaluate the effect of cupping therapy, database including China Network Knowledge Infrastructure (CNKI), Chinese Scientific Journal Database VIP, Wan Fang Database, Chinese Biomedicine (CBM), PubMed and Web of Science were searched from 2009-2019. We summarized all the meta-analyses, randomized controlled trials, clinical trials and the mechanisms studies of cupping therapy in the previous 10 years, hoping to provide a reference for the clinical applications and studies.

Paeonol for the Treatment of Atherosclerotic Cardiovascular Disease: A Pharmacological and Mechanistic Overview.

With improvement in living standards and average life expectancy, atherosclerotic cardiovascular disease incidences and mortality have been increasing annually. Paeonia suffruticosa, a natural herb, has been used for the treatment of atherosclerotic cardiovascular disease for thousands of years in Eastern countries. Paeonol is an active ingredient extracted from Paeonia suffruticosa. Previous studies have extensively explored the clinical benefits of paeonol. However, comprehensive reviews on the cardiovascular protective effects of paeonol have not been conducted. The current review summarizes studies reporting on the protective effects of paeonol on the cardiovascular system. This study includes studies published in the last 10 years. The biological characteristics of Paeonia suffruticosa, pharmacological mechanisms of paeonol, and its toxicological and pharmacokinetic characteristics were explored. The findings of this study show that paeonol confers protection against atherosclerotic cardiovascular disease through various mechanisms, including inflammation, platelet aggregation, lipid metabolism, mitochondria damage, endoplasmic reticulum stress, autophagy, and non-coding RNA. Further studies should be conducted to elucidate the cardiovascular benefits of paeonol.

Role of Endoplasmic Reticulum Stress in Atherosclerosis and Its Potential as a Therapeutic Target.

Endoplasmic reticulum (ER) stress is closely associated with atherosclerosis and related cardiovascular diseases (CVDs). It occurs due to various pathological factors that interfere with ER homeostasis, resulting in the accumulation of unfolded or misfolded proteins in the ER lumen, thereby causing ER dysfunction. Here, we discuss the role of ER stress in different types of cells in atherosclerotic lesions. This discussion includes the activation of apoptotic and inflammatory pathways induced by prolonged ER stress, especially in advanced lesional macrophages and endothelial cells (ECs), as well as common atherosclerosis-related ER stressors in different lesional cells, which all contribute to the clinical progression of atherosclerosis. In view of the important role of ER stress and the unfolded protein response (UPR) signaling pathways in atherosclerosis and CVDs, targeting these processes to reduce ER stress may be a novel therapeutic strategy.

Polydatin for treating atherosclerotic diseases: A functional and mechanistic overview.

With the advancement of science and technology, the living standards of human beings have continuously improved, but the incidence and mortality from atherosclerosis worldwide have also increased by year. Although interventional surgery and the continuous development of new drugs have significant therapeutic effects, their side effects cannot be ignored. Polydatin, an active ingredient isolated from the natural medicine Polygonum cuspidatum, has been shown to have a prominent role in the treatment of cardiovascular diseases. Polydatin treats atherosclerosis mainly from three aspects: anti-inflammatory, regulating lipid metabolism and anti-oxidative stress. This article will review the pharmacological mechanism of polydatin in anti-atherosclerosis, the biological characteristics of Polygonum cuspidatum, the toxicology and pharmacokinetics of polydatin and will provide ideas for further research.

Continuous elevation of plasma asprosin in pregnant women complicated with gestational diabetes mellitus: A nested case-control study.

INTRODUCTION: To investigate the expression of asprosin, a novel insulin resistance-related factor, in plasma and placenta of pregnant women with and without gestational diabetes mellitus (GDM). METHODS: This is a nested case-control study within the prospective study named Early Diagnosis of Gestational Diabetes Mellitus (EDoGDM). Forty pregnant women with GDM and forty control cases with normal glucose tolerance (NGT) were recruited in the present study. Asprosin levels were tested by ELISA in maternal plasma at 18-20 and 24-28 gestational weeks and before delivery, as well as in umbilical plasma. Asprosin concentrations were compared between GDM and NGT groups, and the relationship between asprosin and other parameters were analyzed. Expression of asprosin in placenta was examined by Western blot and immunohistochemistry. RESULTS: Asprosin was elevated in plasma of GDM pregnant women and their offspring, after adjusted by maternal and neonatal clinical characteristics and lipid profiles. Asprosin was expressed in placenta from both GDM and NGT pregnant women. DISCUSSION: Protein asprosin is expressed in human placenta and is elevated in the plasma of pregnant women complicated with GDM and their offspring. As an insulin resistance-related factor increased before 20 gestational weeks, asprosin may play a role as a potential early biomarker of GDM.

Effect of Berberine on Atherosclerosis and Gut Microbiota Modulation and Their Correlation in High-Fat Diet-Fed ApoE-/- Mice.

Atherosclerosis and its associated cardiovascular diseases (CVDs) are serious threats to human health and have been reported to be associated with the gut microbiota. Recently, the role of berberine (BBR) in atherosclerosis and gut microbiota has begun to be appreciated. The purposes of this study were to observe the effects of high or low doses of BBR on atherosclerosis and gut microbiota modulation, and to explore their correlation in ApoE-/- mice fed a high-fat diet. A significant decrease in atherosclerotic lesions was observed after treatment with BBR, with the effect of the high dose being more obvious. Both BBR treatments significantly reduced total cholesterol, APOB100, and very low-density lipoprotein cholesterol levels but levels of high/low-density lipoprotein cholesterol and lipoprotein (a) were only reduced by high-dose BBR. Decreased pro-inflammatory cytokines tumor necrosis factor-alpha, interleukin (IL)-1ß, IL-6 and increased anti-inflammatory IL-10 and adiponectin levels were observed in the high-dose BBR group, but no decrease in IL-6 or increase in IL-10 was evident using the low-dose of BBR. 16S rRNA sequencing showed that BBR significantly altered the community compositional structure of gut microbiota. Specifically, BBR enriched the abundance of Roseburia, Blautia, Allobaculum, Alistipes, and Turicibacter, and changed the abundance of Bilophila. These microbiota displayed good anti-inflammatory effects related to the production of short-chain fatty acids (SCFAs) and were related to glucolipid metabolism. Alistipes and Roseburia were significantly enriched in high-dose BBR group while Blautia and Allobaculum were more enriched in low-dose, and Turicibacter was enriched in both BBR doses. Metagenomic analysis further showed an elevated potential for lipid and glycan metabolism and synthesis of SCFAs, as well as reduced potential of TMAO production after BBR treatment. The findings demonstrate that both high and low-dose BBR can improve serum lipid and systemic inflammation levels, and alleviate atherosclerosis induced by high-fat diet in ApoE-/- mice. The effects are more pronounced for the high dose. This anti-atherosclerotic effect of BBR may be partly attributed to changes in composition and functions of gut microbiota which may be associated with anti-inflammatory and metabolism of glucose and lipid. Notably, gut microbiota alterations showed different sensitivity to BBR dose.

Hawthorn Extract Alleviates Atherosclerosis through Regulating Inflammation and Apoptosis Related Factors: An Experimental Study.

OBJECTIVE: To determine the effects of hawthorn extract on serum lipid levels, pathological changes in aortic atherosclerosis plaque, inflammatory factors, and apoptosis-related protein and mRNA expression in apolipoprotein E gene knockout (ApoE-/-) mice. METHODS: Thirty-six ApoE-/- mice were fed with a high-fat diet starting at the age of 8 weeks. Mice were randomly divided into 3 groups by a random number table including model group, hawthorn extract group, and simvastatin group, 12 mice in each group. Twelve 8-week-old C57BL/6 mice were fed a basic diet and served as control. The mice in the control and model groups were administered 0.2 mL saline daily, the mice in the hawthorn extract and simvastatin groups were administered with 50 mg/kg hawthorn extract or 5 mg/kg simvastatin daily for 16 weeks. After 16 weeks, plasma lipids including total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were determined by an enzymatic assay. Aortic atherosclerotic lesions were observed by light microscopy, scanning and transmission electron microscopy, respectively. Plasma levels of monocyte chemoattractant protein-1 (MCP-1), interleukin-1ß (IL-1ß), adiponectin (APN), and hypersensitive C-reactive protein (hs-CRP) were measured by enzyme-linked immunosorbent assay (ELISA). Protein and mRNA expressions of Bax and Bcl-2 in the aorta were assessed by Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR), respectively. RESULTS: Compared to the control group, the plasma levels of TC, TG and LDL-C were significantly increased and HDL-C were significantly decreased in the model group (P<0.01). Compared to the model group, treatment with hawthorn extract significantly decreased the plasma levels of TC, TG, and LDL-C and increased the plasma level of HDL-C in ApoE-/- mice (P<0.01). The levels of MCP-1, IL-1ß, and hs-CRP in the model group were significantly increased and APN was significantly decreased compared with the control group (P<0.01). Compared to the model group, treatment with hawthorn extract decreased the levels of MCP-1, IL-1ß, and hs-CRP and increased the APN level (P<0.01). Compared to the control group, the protein and mRNA expression of Bax in the model group were significantly increased and the expression of Bcl-2 was significantly decreased (P<0.01). Hawthorn extract also reduced the protein and mRNA expression of Bax and increased the Bcl-2 expression in the aorta (P<0.01). CONCLUSION: Hawthorn extract has anti-atherosclerosis and stabilizing unstable plaque effects. The mechanism may be related to the inflflammation and apoptosis signaling pathways.

Effects of acupuncture on the tissue distribution of Paclitaxel in lung carcinoma mice.

OBJECTIVE: To study whether acupuncture affects the tissue distribution of Paclitaxel in mouse lung carcinoma. METHODS: Totally 90 mice were divided into Paclitaxel group, Paclitaxel + Feishu (BL13) group, and Paclitaxel + Lingtai (DU10) group. Each group was consisted of 30 mice. After Paclitaxel injection, the mice received electro-acupuncture at Feishu or Lingtai acupoints once a day for 8 days. The effect of acupuncture on the tissue distribution of Paclitaxel was evaluated using high-performance liquid chromatography at 1, 2, and 3 h, respectively. The lung, liver, spleen, and kidney were examined for the concentration of Paclitaxel seperately. RESULTS: Paclitaxel was widely distributed in various organs, particularly in the lung, liver, and kidney. Acupuncture at Lingtai or Feishu acupoints resulted in an obvious decrease of Paclitaxel distribution in kidney and delayed Paclitaxel distribution in liver. Meanwhile, it increased the time of metabolism. Acupuncture at Feishu acupoint facilitated the delivery of Paclitaxel to lung more effectively than did acupuncture at Lingtai acupoint. CONCLUSIONS: Applying acupuncture at particular acupoints can influence tissue distribution of Paclitaxel. Tissue distribution change might be one of the mechanisms of acupuncture treatment during chemotherapy.

Role of a novel functional variant in the PPP2R1A promoter on the regulation of PP2A-Aalpha and the risk of hepatocellular carcinoma.

Previously, we identified the genetic variant -241 (-/G) (rs11453459) in the PP2A-Aα gene (PPP2R1A) promoter and demonstrated that this variant influences the DNA-binding affinity of nuclear factor-kappa B (NF-κB). In this study, we further confirmed that the transcriptional activity of PPP2R1A may be regulated by NF-κB through the functional genetic variant -241 (-/G). Moreover, we also demonstrated that the methylation status of CpG islands in the promoter of PPP2R1A influences the activity of this gene promoter. Few studies have examined the role of this -241 (-/G) variant in genetic or epigenetic regulation in hepatocellular carcinoma (HCC). To investigate whether this functional variant in the PPP2R1A promoter is associated with the risk of HCC and confirm the function of the -241 (-/G) variant in the HCC population, we conducted a case-control study involving 251 HCC cases and 252 cancer-free controls from a Han population in southern China. Compared with the -241 (--) homozygote, the heterozygous -241 (-G) genotype (adjusted OR  = 0.32, 95% confidence interval (CI)  = 0.17-0.58, P<0.001) and the -241 (-G)/(GG) genotypes (adjusted OR  = 0.38, 95% CI  = 0.22-0.67, P  = 0.001) were both significantly associated with a reduced risk of HCC. Stratification analysis indicated that the protective role of -241 (-G) was more pronounced in individuals who were ≤ 40 years of age, female and HBV-negative. Our data suggest that the transcriptional activity of PPP2R1A is regulated by NF-κB through the -241 (-/G) variant and by the methylation of the promoter region. Moreover, the functional -241 (-/G) variant in the PPP2R1A promoter contributes to the decreased risk of HCC. These findings contribute novel information regarding the gene transcription of PPP2R1A regulated by the polymorphism and methylation in the promoter region through genetic and epigenetic mechanisms in hepatocarcinogenesis.