The role of the cGAS-STING signaling pathway in viral infections, inflammatory and autoimmune diseases.

Pattern recognition receptors are an essential part of the immune system, which detect pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) and help shape both innate and adaptive immune responses. When dsDNA is present, cyclic GMP-AMP Synthase (cGAS) produces a second messenger called cyclic GMP-AMP (cGAMP), which then triggers an adaptor protein called STING, and eventually activates the expression of type I interferon (IFN) and pro-inflammatory cytokines in immune cells. The cGAS-STING signaling pathway has been receiving a lot of attention lately as a key immune-surveillance mediator. In this review, we summarize the present circumstances of the cGAS-STING signaling pathway in viral infections and inflammatory diseases, as well as autoimmune diseases. Modulation of the cGAS-STING signaling pathway provides potential strategies for treating viral infections, inflammatory diseases, and autoimmune diseases.

Introduction of a Novel, Continuous, Noninvasive Estimation of Intracranial Pressure and Cerebral Perfusion Pressure Based on Tympanic Membrane Temperature.

OBJECTIVE: Hydrocephalus is a common but potentially life-threatening condition. However, valve malfunction makes further diagnosis difficult. Thus, we tried to develop a noninvasive method to detect the hydrocephalus intracranial pressure (ICP) during routine follow-up. METHODS: In group I, the patient was recruited because a spinal tap test was necessary for either disease diagnosis or treatment. In group II, patients were diagnosed with high ICP hydrocephalus and received shunt surgery. The tympanic membrane temperatures (TMTs) were recorded and plotted against the spinal tap pressure (STP) and shunt valve pressures. RESULTS: All patients in group I showed an above-normal STP (from 180 to 400 mm H2O). The STP presents with an inverted U-shaped curve when it is plotted against TMT (R2 = 0.9). When the STP was 286.1 mm H2O, the TMT approached its peak value, which was 38.61°C (101.5°F). However, when ICP was in the normal range (50-200 mm H2O), the TMT correlated with ICP in a linear regression model (R2 = 0.69; P < 0.001). In addition, the cerebral perfusion pressure (CPP) was calculated and plotted against TMT. The TMT-CPP was also shown as a parabola (R2 = 0.74). Based on the TMT-ICP algorithm, we invented a noninvasive ICP monitor system, which performs in a manner comparable to the Codman ICP Transducer (R2 = 0.9; P < 0.01). CONCLUSIONS: Both Y-Jiang TMT-ICP and TMT-CPP algorithms are useful to monitor the shunt outcomes and identify potential shunt failure. More importantly, these algorithms open the possibility for the rational acquisition of ICP and CPP noninvasively.

Nomogram for Predicting Chemotherapy-Induced Nausea and Vomiting for Breast Cancer Patients.

Chemotherapy-induced nausea and vomiting (CINV) is a common side effect of cancer treatment. The factors influencing CINV in breast cancer patients remain unclear. In this study, we developed a nomogram for predicting the occurrence of CINV in this group using prospective clinical data. We pooled data from multiple studies which focused on the emetogenic chemotherapy. Then, we collected 334 breast cancer patients at Hunan Cancer Hospital (training set) to analyze the demographic and clinical variables. Using multivariate logistic regression, we identified the five significant factors that were associated with CINV: history of CINV, chemotherapy regimen, chemotherapy cycle, metastasis, and symptoms of distress. Then, we construct a prediction nomogram. The external validation set comprised an additional 66 patients. The reliability of the nomogram was assessed by bootstrap resampling. The C-index was 0.78 (95% confidence interval [CI], 0.73-0.85) for the training set and 0.74 (95% CI, 0.62-0.85) for the validation set. Calibration curves showed good concordance between predicted and actual occurrence of CINV. In conclusions, our nomogram model can reliably predict the occurrence of CINV in breast cancer patients based on five significant variables, which might be useful in clinical decision-making.

Global trend of diabetes mortality attributed to vascular complications, 2000-2016.

BACKGROUND: The global epidemic of diabetes mellitus continues to grow and affects developed and developing countries alike. Intensive glycemic control is thought to modify the risks for vascular complications, hence the risks for diabetes-related death. We investigated the trend of diabetic vascular complication-related deaths between 2000 and 2016 in the global diabetes landscape. METHODS: We collected 17 years of death certificates data from 108 countries in the World Health Organization mortality database between 2000 and 2016, with coding for diabetic complications. Crude and age-standardized proportions and rates were calculated. Trend analysis was done with annual average percentage change (AAPC) of rates computed by joinpoint regression. RESULTS: From 2000 through 2016, 7,108,145 deaths of diabetes were reported in the 108 countries. Among them, 26.8% (1,904,787 cases) were attributed to vascular complications in damaged organs, including the kidneys (1,355,085 cases, 71.1%), peripheral circulatory (515,293 cases, 27.1%), nerves (28,697 cases, 1.5%) and eyes (5751 cases, 0.3%). Overall, the age-standardized proportion of vascular complication-related mortality was 267.8 [95% confidence interval (95% CI), 267.5-268.1] cases per 1000 deaths and the rate was 53.6 (95% CI 53.5-53.7) cases per 100,000 person-years. Throughout the 17-year period, the overall age-standardized proportions of deaths attributable to vascular complications had increased 37.9%, while the overall age-standardized mortality rates related to vascular complications had increased 30.8% (AAPC = 1.9% [1.4-2.4%, p < 0.05]). These increases were predominantly driven by a 159.8% increase in the rate (AAPC = 2.7% [1.2-4.3%, p < 0.05]) from renal complications. Trends in the rates and AAPC of deaths varied by type of diabetes and of complications, as well as by countries, regions and domestic income. CONCLUSION: Diabetic vascular complication-related deaths had increased substantially during 2000-2016, mainly driven by the increased mortality of renal complications.

Overexpression of SLC12A5 is associated with tumor progression and poor survival in ovarian carcinoma.

INTRODUCTION: The solute carrier family 12 member 5 (SLC12A5) gene is playing a putative oncogenic role in colorectal carcinoma. However, the status of SLC12A5 amplification and expression in ovarian carcinoma and its potential clinical and/or prognostic significance has not yet been investigated. METHODS: In the present study, semi-quantitative staining and fluorescence in situ hybridization were used to investigate SLC12A5 protein expression and gene amplification levels. Samples were obtained from archival, formalin-fixed, paraffin-embedded pathological specimens consisting of 30 normal ovaries, 30 ovarian cystadenomas, 30 borderline ovarian tumors, and 147 invasive ovarian carcinomas. SLC12A5 immunohistochemical staining results, pathological parameters, and patient prognosis were then evaluated using various statistical models. Patient survival rate was also assessed using receiver-operator curve analysis. RESULTS: Our results revealed no SLC12A5 protein overexpression in normal ovaries. However, 7% of cystadenomas had SLC12A5 protein overexpression along with 17% of borderline tumors and 37% of ovarian carcinomas (P<0.01). Amplification of SLC12A5 was detected in 10.3% of ovarian carcinomas. Further correlational analyses showed that SLC12A5 protein overexpression in ovarian carcinomas was significantly associated with ascending histological grade, pT/pN/pM status, as well as FIGO stage (P<0.05). A subsequent univariate survival analysis of our ovarian carcinoma cohorts resulted in a significant association between SLC12A5 protein overexpression and decreased patient survival (44.3 and 85.9 months for high and low SLC12A5 protein expression, respectively; P<0.001). Importantly, additional multivariate analysis revealed that SLC12A5 protein expression was a significant, independent prognostic factor for overall survival in ovarian carcinoma patients (P=0.003). CONCLUSIONS: Collectively, these findings support the conclusion that SLC12A5 protein overexpression could indicate an invasive and/or aggressive phenotype of ovarian carcinoma. Future work will need to investigate whether SLC12A5 protein can serve as an independent prognostic molecular marker in patients with ovarian carcinoma.

Chinese herbal medicine for the treatment of cough variant asthma: a study protocol for a double-blind randomized controlled trial.

BACKGROUND: Cough variant asthma (CVA) is one of the leading causes of chronic coughing. The main treatment is currently anti-inflammatory medication. However, the coughing may return or be aggravated and lung function may deteriorate once the anti-inflammatory treatment is stopped. The effect of Chinese herbal medicine (CHM) on chronic coughing is remarkable, but high-quality evidence supporting its effectiveness is still lacking. This trial aims to evaluate the safety and efficacy, especially the long-term efficacy, of CHM plus anti-inflammatory medications for the treatment of CVA. METHODS/DESIGN: A randomized placebo-controlled double-blind trial will be conducted. It will consist of a 3-month intervention followed by a 6-month follow-up period. The target sample size is 60 patients with CVA who are between 18 and 70 years old. The eligible subjects will be allocated randomly into the experimental or control group in a ratio of 1:1. Patients in the experimental group will take CHM granules (4.9 g twice daily), while patients in the control group will be given a matched placebo. An administration of salmeterol/fluticasone propionate combination for 12 weeks will be the basic therapy for the two groups. The primary outcome is the cough visual analog scales (CVAS). The secondary outcomes include quality of life, rate of symptom relapse, lung function, and blood tests. A safety assessment will also be performed during the trial. DISCUSSION: The evidence gathered by the trial will be a valuable addition to informing treatment options for patients with CVA. TRIAL REGISTRATION: http://www.chictr.org.cn , ID: ChiCTR-IOR-16009148. Registered on 3 September 2016.

Involvement of mitochondrial dysfunction in human islet amyloid polypeptide-induced apoptosis in INS-1E pancreatic beta cells: An effect attenuated by phycocyanin.

Misfolded human islet amyloid polypeptide (hIAPP) in pancreatic islets is associated with the loss of insulin-secreting beta cells in type 2 diabetes. Insulin secretion impairment and cell apoptosis can be due to mitochondrial dysfunction in pancreatic beta cells. Currently, there is little information about the effect of hIAPP on mitochondrial function. In this study, we used INS-1E rat insulinoma beta cells as a model to investigate the role of mitochondria in hIAPP-induced apoptosis and the protective effects of phycocyanin (PC). We demonstrated that hIAPP induced apoptosis in INS-1E cells was associated with the disruption of mitochondrial function, as evidenced by ATP depletion, mitochondrial mass reduction, mitochondrial fragmentation and loss of mitochondrial membrane potential (ΔΨ(m)). Further molecular analysis showed that hIAPP induced changes in the expression of Bcl-2 family members, release of cytochrome c and apoptosis-inducing factor (AIF) from mitochondria into cytosol, activation of caspases and cleavage of poly (ADP-ribose) polymerase. Interestingly, the hIAPP-induced mitochondrial dysfunction in INS-1E cells was effectively restored by co-treatment of PC. Moreover, there was crosstalk between the extrinsic and intrinsic apoptotic pathways as demonstrated by cleavage of Bid by caspase-8 in the apoptotic process triggered by hIAPP. Taken together, we demonstrated for the first time the involvement of mitochondrial dysfunction in hIAPP-induced INS-1E cell apoptosis. Attenuation of mitochondrial dysfunction provides a mechanism for the protective effects of PC.

Renin-angiotensin system activation in renal adipogenesis.

The kidney is one of the major organs involved in whole-body homeostasis while chronic renal impairment usually leads to fat redistribution and hyperlipidemia. The aim of this study was to elucidate the role of tissue renal renin-angiotensin system (RAS) components, lipogenic peroxisome proliferator-activated receptor-gamma (PPARgamma), and cytokine TNF-alpha in the development of ectopic adipogenesis and lipid deposition. Adult male Sprague-Dawley rats were randomized into three groups: untreated uninephrectomized (UNX) rats, UNX rats treated with an angiotensin-converting enzyme inhibitor (ACEI), lisinopril, and sham-operated rats. All animals were euthanized at 10 mo postoperation. The untreated UNX rats showed increased protein expression of renin, angiotensinogen, PPARgamma, and the angiotensin II type 2 receptor (AT2R) but reduced protein expression of AT1R and TNF-alpha in their remnant kidneys. Immunofluorescence staining revealed increased reactivity of angiotensinogen and angiotensin I/II in renal tubular cells and adipocytes of the untreated UNX rats. ACEI treatment largely prevented these disorders in association with restored normolipidemia and normalized renal adipogenesis and lipid deposition. These findings support the notion that tissue RAS, PPARgamma, and TNF-alpha collectively play an important role in the renal adipogenesis and lipid metabolism.

Phycocyanin protects INS-1E pancreatic beta cells against human islet amyloid polypeptide-induced apoptosis through attenuating oxidative stress and modulating JNK and p38 mitogen-activated protein kinase pathways.

It is widely accepted that human islet amyloid polypeptide (hIAPP) aggregation plays an important role in the loss of insulin-producing pancreatic beta cells. hIAPP-induced cytotoxicity is mediated by generation of reactive oxygen species (ROS). Phycocyanin (PC) is a natural compound from blue-green algae that is widely used as food supplement. Currently, little is known about the effects of PC on beta cells with the presence of hIAPP. The aim of this study was to investigate the in vitro protective effects of PC on INS-1E rat insulinoma beta cells against hIAPP-induced cell death, as well as the underlying mechanisms. Our results showed that hIAPP-induced cell death with apoptotic characteristics including growth inhibition, chromatin condensation and DNA fragmentation. However, cytotoxicity of hIAPP was significantly attenuated by co-incubation of the cells with PC. The results of Western blotting showed that activation of caspase-3 and cleavage of poly (ADP-ribose) polymerase (PARP) in hIAPP-treated cells was blocked by PC. Moreover, PC significantly prevented the hIAPP-induced overproduction of intracellular ROS and malondialdehyde (MDA), as well as changes in activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) enzymes. Furthermore, hIAPP triggered the activation of mitogen-activated protein kinases (MAPKs), and these effects were effectively suppressed by PC. Taken together, our results suggest that PC protects INS-1E pancreatic beta cells against hIAPP-induced apoptotic cell death through attenuating oxidative stress and modulating c-Jun N-terminal kinase (JNK) and p38 pathways.

Fat redistribution and adipocyte transformation in uninephrectomized rats.

Dyslipidemia complicates renal function leading to disturbances of major homeostatic organs in the body. Here we examined the effect of chronic renal dysfunction induced by uninephrectomy on fat redistribution and lipid peroxidation in rats treated with an angiotensin-converting enzyme (ACE) inhibitor (lisinopril) for up to 10 months. Uninephrectomized rats developed fat redistribution and hypercholesterolemia typical of chronic renal failure when compared with sham-operated rats or lisinopril-treated uninephrectomized rats. The weight of the peri-renal fat was significantly less in the untreated compared to the lisinopril-treated uninephrectomized rats or those rats with a sham operation. We also found that there was a shift of heat-protecting unilocular adipocytes to heat-producing multilocular fat cells in the untreated uninephrectomized rats. Similarly in these rats we found a shift of subcutaneous and visceral fat to ectopic fat with excessive lipid accumulation and lipofuscin pigmentation. Lisinopril treatment prevented fat redistribution or transformation and lipid peroxidation. This study shows that ACE inhibition may prevent the fat anomalies associated with chronic renal dysfunction.