Proteomics analysis of lung tissue reveals protein makers for the lung injury of adjuvant arthritis rats.

Lung injury is one of the common extra­articular lesions in rheumatoid arthritis (RA). Due to its insidious onset and no obvious clinical symptoms, it can be easily dismissed in the early stage of diagnosis, which is one of the reasons that leads to a decline of the quality of life and subsequent death of patients with RA. However, its pathogenesis is still unclear and there is a lack of effective therapeutic targets. In the present study, tandem mass tag­labeled proteomics was used to research the lung tissue proteins in RA model (adjuvant arthritis, AA) rats that had secondary lung injury. The aim of the present study was to identify the differentially expressed proteins related to RA­lung injury, determine their potential role in the pathogenesis of RA­lung injury and provide potential targets for clinical treatment. Lung tissue samples were collected from AA­lung injury and normal rats. The differentially expressed proteins (DEPs) were identified by tandem mass spectrometry. Bioinformatic analysis was used to assess the biological processes and signaling pathways associated with these DEPs. A total of 310 DEPs were found, of which 244 were upregulated and 66 were downregulated. KEGG anlysis showed that 'fatty acid degradation', 'fatty acid metabolism', 'fatty acid elongation', 'complement and coagulation cascades', 'peroxisome proliferator­activated receptor signaling pathway' and 'hypoxia­inducible factor signaling pathway' were significantly upregulated in the lung tissues of AA­lung injury. Immunofluorescence staining confirmed the increased expression of clusterin, serine protease inhibitors and complement 1qc in lung tissue of rats with AA lung injury. In the present study, the results revealed the significance of certain DEPs (for example, C9, C1qc and Clu) in the occurrence and development of RA­lung injury and provided support through experiments to identify potential biomarkers for the early diagnosis and prevention of RA­lung injury.

Cross-Sectional Association of Blood Selenium with Glycemic Biomarkers among U.S. Adults with Normoglycemia in the National Health and Nutrition Examination Survey 2013-2016.

Selenium (Se) remains to have an inconsistent relationship with glycemic biomarkers and the risk of developing type 2 diabetes (T2D). Few studies have investigated the relationship between blood Se and glycemic biomarkers among people with normoglycemia. We conducted a cross-sectional analysis using the U.S. National Health and Nutrition Examination Survey 2013-2016. Multivariable linear regression models were developed to examine the associations of blood Se with glycemic biomarkers, namely, fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), insulin, and the oral glucose tolerance test (OGTT). Blood Se was treated as continuous (per log-10 increment) and categorical exposure (in quartiles) in separate regression models. We assessed the dose-response relationships by restricted cubic spline analysis. After excluding the participants with T2D or incomplete data, 2706 participants were analyzed. The highest quartile of blood Se was associated with increased FPG [adjusted ß = 0.12, 95% Confidence Intervals (CI) = 0.04, 0.20], OGTT (adjusted ß = 0.29, 95% CI = 0.02, 0.56), HbA1c (adjusted ß = 0.04, 95% CI = 0.00, 0.07), and insulin (adjusted ß = 2.50, 95% CI = 1.05, 3.95) compared with the lowest quartile. Positive associations were also observed between every log-10 increment of blood Se level and glycemic biomarkers, except for OGTT. A positive linear dose-response relationship existed between blood Se and FPG (Poverall = 0.003, Pnonlinear = 0.073) and insulin (Poverall = 0.004, Pnonlinear =0.060). BMI, age, and smoking status modified the associations of the highest quartile of Se (compared with the lowest quartile) with glycemic biomarkers. Overall, positive associations of blood Se with glycemic biomarkers were observed among U.S. adults with normoglycemia. These findings implied that people with normoglycemia need to be aware of the level of Se and other mineral intakes from diet and supplements. Further research is required to identify the mechanisms of excess Se in the progression of diabetes.

Contribution to the knowledge of the genus Agalope Walker from mainland China, with descriptions of four new species (Lepidoptera, Zygaenidae, Chalcosiinae).

New information of the genus Agalope Walker, 1854 from mainland China is presented. Three new species of the Agalope pica species-group are described: A. haoi S.-Y. Huang sp. n. from Weixi County, Yunnan, A. chayuensis S.-Y. Huang Pan sp. n. from Chayu County, Southeastern Xizang and A. owadai S.-Y. Huang sp. n. from Bomi and Jiali Counties, Southeastern and Eastern Xizang. The little-known Agalope aurelia Oberthr, 1923 and A. lucia Oberthr, 1923 were rediscovered, with the male of the latter reported for the first time. Based on the newly discovered male, Agalope lucia is found to be a close relative of A. dejeani, hence it is excluded from the A. pica species-group and transferred to the A. bieti species-group. A new species of the Agalope hyalina species-group is also described: A. jianqingi S.-Y. Huang sp. n. from Pianma, Western Yunnan. Adults and genitalia of the aforementioned and related taxa are illustrated. An updated checklist of the genus is also provided.

Molecular Mechanisms and Potential New Therapeutic Drugs for Liver Fibrosis.

Liver fibrosis is the pathological process of excessive extracellular matrix deposition after liver injury and is a precursor to cirrhosis, hepatocellular carcinoma (HCC). It is essentially a wound healing response to liver tissue damage. Numerous studies have shown that hepatic stellate cells play a critical role in this process, with various cells, cytokines, and signaling pathways engaged. Currently, the treatment targeting etiology is considered the most effective measure to prevent and treat liver fibrosis, but reversal fibrosis by elimination of the causative agent often occurs too slowly or too rarely to avoid life-threatening complications, especially in advanced fibrosis. Liver transplantation is the only treatment option in the end-stage, leaving us with an urgent need for new therapies. An in-depth understanding of the mechanisms of liver fibrosis could identify new targets for the treatment. Most of the drugs targeting critical cells and cytokines in the pathogenesis of liver fibrosis are still in pre-clinical trials and there are hardly any definitive anti-fibrotic chemical or biological drugs available for clinical use. In this review, we will summarize the pathogenesis of liver fibrosis, focusing on the role of key cells, associated mechanisms, and signaling pathways, and summarize various therapeutic measures or drugs that have been trialed in clinical practice or are in the research stage.

Clinical outcome of chronic myeloid leukemia patients who switch from first-line therapy with a second generation tyrosine kinase inhibitor to an alternative TKI.

While second generation tyrosine kinase inhibitors (2GTKIs) are highly effective therapies for chronic myeloid leukemia (CML), a significant minority of patients who initiate a 2GTKI will require a switch to an alternative TKI. The long-term outcomes of those who require a change in therapy after front-line 2GTKI therapy are largely undescribed. Here we describe the clinical outcomes associated with switch to an alternative TKI after first-line therapy with a 2GTKI. Of 232 patients who initiated a 2GTKI during the study period, 76 (33 %) switched to an alternative TKI. Reasons for switching included intolerance (79 %) and resistance (21 %). Among the 60 patients who switched due to intolerance, 53 (88 %) were able to achieve or maintain a major molecular response (MMR) with 5-year progression-free survival (PFS) 90.5 % (95 % CI 90.4-90.6 %). Amongst the 16 patients who switched due to resistance, 8 patients (50 %) were able to achieve MMR with 5-year PFS 80.4 % (95 % CI 80.2-80.6 %). Most patients who switched due to intolerance remained on their second-line TKI. Approximately 25 % of patients who initiate first-line 2GTKI in a real world setting will ultimately switch to an alternate TKI due to intolerance. Patients who switch for intolerance continue to enjoy excellent clinical outcomes.

Prolonged Hyperbilirubinemia in a Neonate with a Novel Mutation in the UDP-glucuronosyltransferase 1A1 Gene.

The total bilirubin value of a male infant was 385 µmol/l on day 5. Liver function test results were normal and there was no evidence of sepsis and no hemolysis reaction. Phototherapy was administered and on day 8 the patient's total bilirubin level was 255 µmol/l. Intermittent episodes of hyperbilirubinemia occurred without phototherapy, with the total bilirubin level reaching 335 µmol/l on day 19. A 3-day regimen of phenobarbital was administered and on day 24 his total bilirubin level was 180 µmol/l. The patient was discharged. At the age of 2 months, the total bilirubin value was 27 µmol/l. His direct bilirubin value was <15% of total bilirubin in every determination. A family study of the UDP-glucuronosyltransferase(UGT)1A1 gene showed that the infant carries a homozygous mutation at nucleotide -3279 plus compound heterozygous mutations at nucleotides 782 and 1091. The mutation at nucleotide 782 is a novel finding. Gilbert's syndrome was diagnosed.

Leaf cDNA-AFLP analysis reveals novel mechanisms for boron-induced alleviation of aluminum-toxicity in Citrus grandis seedlings.

Little information is available on the molecular mechanisms of boron (B)-induced alleviation of aluminum (Al)-toxicity. 'Sour pummelo' (Citrus grandis) seedlings were irrigated for 18 weeks with nutrient solution containing different concentrations of B (2.5 or 20µM H3BO3) and Al (0 or 1.2mM AlCl3·6H2O). B alleviated Al-induced inhibition in plant growth accompanied by lower leaf Al. We used cDNA-AFLP to isolate 127 differentially expressed genes from leaves subjected to B and Al interactions. These genes were related to signal transduction, transport, cell wall modification, carbohydrate and energy metabolism, nucleic acid metabolism, amino acid and protein metabolism, lipid metabolism and stress responses. The ameliorative mechanisms of B on Al-toxicity might be related to: (a) triggering multiple signal transduction pathways; (b) improving the expression levels of genes related to transport; (c) activating genes involved in energy production; and (d) increasing amino acid accumulation and protein degradation. Also, genes involved in nucleic acid metabolism, cell wall modification and stress responses might play a role in B-induced alleviation of Al-toxicity. To conclude, our findings reveal some novel mechanisms on B-induced alleviation of Al-toxicity at the transcriptional level in C. grandis leaves.

New insight of vitamin D in chronic liver diseases.

BACKGROUND: Vitamin D is a fat-soluble sterol derivative that is predominantly synthesized in the liver and has multiple functions. The accumulative data showed that the clinical manifestations and prognosis of chronic liver diseases are associated with serum vitamin D levels. DATA SOURCES: A PubMed and Google Scholar search using terms: "vitamin D", "25(OH)D", "liver disease", "viral hepatitis", "non-alcoholic fatty liver disease", "liver fibrosis", "cirrhosis", "hepatocellular carcinoma" and "autoimmune liver disease" was performed, and relevant articles published in English between January 2000 and March 2014 were reviewed. Full-text publications relevant to the field were selected and relevant articles from reference lists were also included. RESULTS: The insufficiency or deficiency of vitamin D is common in various kinds of chronic liver diseases including viral hepatitis B and C. Serum 25-hydroxyvitamin D and vitamin D receptors are possibly interrelated with the incidence, treatment and prognosis of diseases. Though the evidence of vitamin D supplementation in viral hepatitis and associated liver diseases is still limited, there is great potential to apply this adjuvant therapy to improve the treatments. CONCLUSIONS: Although the exact role and mechanisms of vitamin D have not been fully elucidated in chronic liver diseases, it is potentially beneficial in the treatment of chronic liver diseases. Further mechanistic studies are needed to validate its clinical application.

Liquid oral suspension adefovir dipivoxil (GS-02-526): an update on treatments for hepatitis B infection.

Though the global epidemiology of hepatitis B virus infection has declined due to effective immunization, chronic hepatitis B (CHB) remains a serious public health problem and there is still a need for more treatment options that are efficient, safe and simple for different kinds of CHB patients. Adefovir dipivoxil (ADV) liquid suspension (GS-02-526), as a new form of oral ADV, not only has competent antiviral efficacy, but is also more convenient for patients with swallowing difficulties or patients with impaired renal function requiring dosage adjustment. The clinical data evaluating the safety, tolerability and antiviral activity of liquid suspension of ADV as well as its tablet are summarized in this article. The availability of liquid oral suspension of ADV would allow more patients to receive timely and reasonable antiviral treatments.

Preparation of nasal temperature-sensitive in situ gel of Radix Bupleuri and evaluation of the febrile response mechanism.

OBJECTIVE: This study developed a nasal temperature-sensitive in situ gel system for Radix Bupleuri. METHOD: Using 20% Poloxamer 407 as the gel base and 6% PEG 4000 adjusting the gelation temperature. RESULTS: The system is liquid at 4 degrees C. It can change its phase to gel above 30 degrees C, which is close to the temperature in nasal cavity. The antipyretic effect produced by Radix Bupleuri in situ gel formulation was investigated in fevered rabbits. The results show that it can prolong the effective time to 24 hours compared with 4-6 hours in Radix Bupleuri intranasal solution. The antipyretic response mechanism was researched by evaluating the relationship between body temperature and concentrations of cyclic adenosine monophosphate in cerebrospinal fluid. The results showed that the two parameters were positively correlated (r = 0.9435, P < 0.05). Six hours later after given in situ gel, the concentrations of cAMP were significantly lower than those in the solution group. It confirmed that temperature-sensitive Radix Bupleuri in situ gel applied in the nasal sprays had a longer residence and release time. CONCLUSION: Radix Bupleuri nasal temperature-sensitive in situ gel has a higher medical effect and a longer effective time. Compared to the traditional nasal spray, it is more applicable for the treatment of fever.

A novel nasal delivery system of a Chinese traditional medicine, Radix Bupleuri, based on the concept of ion-activated in situ gel.

The purpose of this study was to develop a nasal in situ gel system for Radix Bupleuri employing gellan gum as a polymer. Radix Bupleuri in situ gel containing 0.2 mL essential oil extracted from 450 g Radix Bupleuri, proper solubilizing agents and gellan gum (0.5% w/v) was prepared and characterized. The antipyretic effect produced by in situ gel formulation was investigated in fevered rabbits and compared to an intranasal solution. The resulting in situ gel was a clear and light-yellow liquid, with viscosity of 346 mPa x s and caproic acid content of 1.31 +/- 0.01 mg/mL. Intranasal administration of this preparation to fevered rabbits decreased body temperature markedly (1.1 degree C at the doses of oil from 1.5 g Bupleuri/body) and the effect could last for 20-30 h. The results suggest that Radix Bupleuri in situ gel can be greater effective than the solution in the treatment of fever.

[Endothelial function evaluation in salt-sensitive normotensive and mild hypertensive subjects and effects of potassium supplement].

OBJECTIVE: Salt-sensitivity plays an important role in essential hypertension and is associated with more severe target organ injury and higher mortality in patients with essential hypertension. However, the pathologic mechanism of salt-sensitivity is poorly understood and endothelial dysfunction might be involved in salt-sensitive hypertension. We, therefore, observed the endothelial function changes by measuring plasma and urine nitric oxide (NO) concentrations in salt-sensitive (SS) normotensive and mild hypertensive subjects underwent various salt loading protocols and the effects of potassium supplement. METHODS: Thirty-nine normotensive and mild hypertensive subjects (< 160/100 mm Hg), aged 16-60, were enrolled and the study protocol is as follows: 3 days baseline investigation, 1 week low-salt loading (3 g/day), 1 week. high-salt loading (18 g/day) and 1 week high-salt loading plus potassium chloride (4.5 g/day). RESULTS: Plasma and urine NO levels were significantly lower in SS (n = 8) subjects at baseline, low-salt and high-salt loading phases compared with salt-resistant subjects (SR, n = 31) and oral potassium supplement to SS subjects with high salt loading significantly increased plasma and urine NO levels. CONCLUSION: Endothelial function is impaired in normotensive and mild hypertensive SS subjects. Oral potassium supplement could improve endothelial function in normotensive and mild hypertensive SS subjects.

Chronic mesenteric ischemia: use of in vivo MR imaging measurements of blood oxygen saturation in the superior mesenteric vein for diagnosis.

PURPOSE: To determine if dogs and humans with chronic mesenteric ischemia demonstrate a decrease in the percentage of oxygenated hemoglobin (%HbO2) in the superior mesenteric vein (SMV) after a meal. MATERIALS AND METHODS: In 10 dogs, ameroid rings were surgically implanted around the superior mesenteric arteries to create gradual stenosis. Pre- and postoperative angiograms and pre- and postprandial magnetic resonance (MR) oximetry measurements of the SMV %HbO2, with flow-independent T2 measurements of venous blood, were obtained at different times. In 10 patients with atherosclerotic disease and six patients with symptomatic chronic mesenteric ischemia, the same measurements were obtained after at least 6 hours of fasting and at 15, 35, and 45 minutes after ingestion of a liquid nutritional supplement. RESULTS: In seven dogs, the postprandial SMV %HbO2 increased an average of 2.5% +/- 0.8 before surgery and decreased an average of 6.3% +/- 2.1 when hemodynamically significant (>70%) stenosis of the superior mesenteric artery developed 7-14 days after surgery. In the 10 patients without ischemia, the SMV %HbO2 increased by 4.6% +/- 0.6, whereas in the symptomatic patients a postprandial decrease of 8.8% +/- 0.7 occurred (P < .0001). CONCLUSION: Measurement of the SMV %HbO2 with MR oximetry is a promising test for diagnosis of chronic mesenteric ischemia.

Modeling of internal pH, ion concentration, and bioenergetic changes during myocardial ischemia.

Arrhythmias are caused by the interdependent processes of change in energy metabolism and alterations in sarcolemmal ion gradients that occur during ischemia. Depletion of energy metabolites and increased proton concentrations in ischemic heart may underlie the observed phenomena of reduced contractile force and also of malignant ventricular arrhythmias that can lead to tachycardia and ventricular fibrillation. Recent advances in measuring changes in ion concentrations and metabolites during cardiac ischemia have provided a wealth of detail on the processes involved. Some of the experimental data have been used to construct a computer model that integrates cardiac energetics with electrophysiological changes. This is a novel approach to studying myocardial ischemia, and the resulting model would aid in the prediction of the effects of therapeutic interventions.