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Oxaliplatin-induced chronic painful neuropathy is the most common dose-limiting adverse event that negatively affects cancer patients' quality of life. However, the underlying molecular mechanisms are still unclear. In the present study, we found that the intraperitoneal administration of oxaliplatin at 4 mg/kg for five consecutive days noticeably upregulated the expression of CXC motif ligand 12 (CXCL12) in the dorsal root ganglion, and the intrathecal injection of an anti-CXCL12 neutralizing antibody or CXCL12 siRNA attenuated the mechanical allodynia and thermal hyperalgesia induced by oxaliplatin. We also found that the signal transducers and transcription activator 3 (STAT3) was activated in the dorsal root ganglion, and inhibition of STAT3 with S3I-201 or the injection of AAV-Cre-GFP into STAT3flox/flox mice prevented the upregulation of CXCL12 expression in the dorsal root ganglion and chronic pain following oxaliplatin administration. Double-label fluorescent immunohistochemistry findings also showed that p-STAT3 was mainly localized in CXCL12-positive cells in the dorsal root ganglion. Furthermore, the results of a chromatin immunoprecipitation assay revealed that p-STAT3 might be essential for oxaliplatin-induced CXCL12 upregulation via binding directly to the specific position of the CXCL12 gene promoter. Finally, we found that cytokine TNF-α and IL-1β increases mediated the STAT3 activation following oxaliplatin treatment. Taken together, these findings suggested that the upregulation of CXCL12 via TNF-α/IL-1β-dependent STAT3 activation contributes to oxaliplatin-induced chronic pain. [ABSTRACT FROM AUTHOR]

Purpose: To explore the neuroprotective efficacy of a-lipoic acid (ALA) against hypoxic-ischemic encephalopathy (HIE) in neonatal rats. Methods: Forty-eight rats (P7-pups) were randomly assigned to one of four groups: group I received saline; group II (HI) underwent unilateral carotid artery ligation and hypoxia (92 % N2 and 8 % O2) for 2.5 h; and groups III and IV (ALA 50 and 100) were treated with 50 or 100 mg ALA/kg for 7 days prior to against hypoxic-ischemic (HI) insult. Cerebral antioxidant status, edema, and the levels of inflammatory markers were determined. Results: ALA administration substantially (p < 0.01) attenuated both cerebral infarct area and degree of edema while decreasing the levels of several inflammatory markers (TNF-α, NF-p65, IL-1β, IL-6). In addition, in the ALA groups, antioxidant enzyme (SOD, CAT, GSH) activities were significantly elevated, while the expressions of TNF-α and IL-1β protein were significantly (p < 0.01) down-regulated. Conclusion: The neuroprotective efficacy of ALA in HIE can be attributed to its suppression of both oxidative stress and the levels of inflammatory markers. [ABSTRACT FROM AUTHOR]

Motivation: Differential transcript expression (DTE) analysis without predefined conditions is critical to biological studies. For example, it can be used to discover biomarkers to classify cancer samples into previously unknown subtypes such that better diagnosis and therapy methods can be developed for the subtypes. Although several DTE tools for population data, i.e. data without known biological conditions, have been published, these tools either assume binary conditions in the input population or require the number of conditions as a part of the input. Fixing the number of conditions to binary is unrealistic and may distort the results of a DTE analysis. Estimating the correct number of conditions in a population could also be challenging for a routine user. Moreover, the existing tools only provide differential usages of exons, which may be insufficient to interpret the patterns of alternative splicing across samples and restrains the applications of the tools from many biology studies. Results: We propose a novel DTE analysis algorithm, called SDEAP, that estimates the number of conditions directly from the input samples using a Dirichlet mixture model and discovers alternative splicing events using a new graph modular decomposition algorithm. By taking advantage of the above technical improvement, SDEAP was able to outperform the other DTE analysis methods in our extensive experiments on simulated data and real data with qPCR validation. The prediction of SDEAP also allowed us to classify the samples of cancer subtypes and cell-cycle phases more accurately. [ABSTRACT FROM AUTHOR]

Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is an autosomal recessive disorder resulting from biallelic mutations of the SLC25A13 gene. Due to the lack of well-recognized clinical or biochemical diagnostic criteria, the definitive diagnosis of this disease relies on the genetic analysis of SLC25A13 at present. As novel large deletion/insertion mutations of the SLC25A13 gene are difficult to detect using routine DNA analytic approaches, the timely diagnosis of patients with these types of mutations remains a challenge. The present study aimed to examine SLC25A13 mutations in an infant with a suspected diagnosis of NICCD. DNA was extracted from blood samples, and SLC25A13 mutations were examined by screening for high-frequency mutations and Sanger sequencing. Reverse transcription-polymerase chain reaction and cDNA cloning analyses were then performed using peripheral blood lymphocytes (PBLs) to identify the obscure mutation. The results demonstrated that the infant was heterozygous for a paternally-inherited mutation, c.851_854del4, and a maternally-inherited large deletion, c.1019_1177+893del, which has not been reported previously. A positive diagnosis of NICCD was made, and the infant responded favorably to a galactose-free and medium-chain triglyceride-enriched formula. The present study confirmed the effectiveness of this formula in NICCD therapy, enriched the SLC25A13 mutational spectrum and supported the feasibility of cDNA cloning analysis using PBLs as a molecular tool for facilitating the identification of large SLC25A13 deletions. [ABSTRACT FROM AUTHOR]

Aim To evaluate the efficacy of probiotics in the treatment of adult and childhood non-alcoholic fatty liver disease (NAFLD). Methods Randomized controlled trials on the efficacy of probiotics in the treatment of adult and childhood NAFLD published before July 2015 were searched in multiple databases, including Cochrane Library, PubMed/MEDLINE, EBSCO, OVID, SCI, CNKI, and VIP. Article identification and data extraction were carried out by two reviewers based on the inclusion and exclusion criteria. RevMan 5.3 software was used for the meta-analysis. Results Nine randomized controlled trials with a total of 535 cases of NAFLD were included. Statistical differences in homeostasis model assessment, total cholesterol, high density lipoprotein, triglyceride, and tumor necrosis factor-α were detected between the probiotics and control groups with variations in different patient populations. No significant differences in body mass index (BMI), glucose, or insulin were detected between the two groups. Statistical differences in low density lipoprotein, alanine aminotransferase, aspartate transaminase, and BMI were detected between the two childhood groups ( P ≤ 0.05). Conclusion Probiotics provided improvements in the outcomes of homeostasis model assessment, total cholesterol, high density lipoprotein, and tumor necrosis factor-α in any NAFLD patients and triglyceride in Italian and Spanish patients, but no improvement in the outcomes of BMI, glucose, or insulin in adult NAFLD patients. The currently available data are not sufficient to compare the effects of probiotics between adult and childhood NAFLD patients. [ABSTRACT FROM AUTHOR]

Background: Grape seeds extract (GSE) is a famous health food supplement for its antioxidant property. Different concentrations of GSE may have different impacts on cellular oxidative/reduction homeostasis. Antiproliferative effect of GSE has been reported in many cancers but rarely in oral cancer. Methods: The aim of this study is to examine the antioral cancer effects of different concentrations of GSE in terms of cell viability, apoptosis, reactive oxygen species (ROS), mitochondrial function, and DNA damage. Results: High concentrations (50-400 µg/ml) of GSE dose-responsively inhibited proliferation of oral cancer Ca9-22 cells but low concentrations (1-10 µg/ml) of GSE showed a mild effect in a MTS assay. For apoptosis analyses, subG1 population and annexin V intensity in high concentrations of GSE-treated Ca9-22 cells was increased but less so at low concentrations. ROS generation and mitochondrial depolarization increased dose-responsively at high concentrations but showed minor changes at low concentrations of GSE in Ca9-22 cells. Additionally, high concentrations of GSE dose-responsively induced more yH2AX-based DNA damage than low concentrations. Conclusions: Differential concentrations of GSE may have a differentially antiproliferative function against oral cancer cells via differential apoptosis, oxidative stress and DNA damage. [ABSTRACT FROM AUTHOR]

Background/Purpose Temporomandibular joint disorder (TMD) is a general term for diseases of the temporomandibular joint and orofacial muscles. In this study, we tested whether laser acupuncture was effective for the treatment of TMD. Methods Twenty patients with TMD were treated with diode K-Laser (wavelength 800 nm, energy density 100.5 J/cm²) once a week at four acupuncture points including three standard ipsilateral local points (ST6, ST7, Ashi point) and one contralateral distal point (LI4). A 10-cm visual analogue scale (0 no pain and 10 the most severe pain) was used for measuring the pain intensity before and after the treatment. Results Seventeen out of 20 patients (85%) showed various degrees of pain relief after laser acupuncture treatment. The average pain score was 6.3 ± 1.6 before treatment and 2.5 ± 2.2 after treatment. Significant pain relief after laser acupuncture treatment was achieved (p = 0.0003, Wilcoxon signed rank test). The 17 patients showed an average pain relief of 63 ± 31%. There were six patients who showed no TMD symptoms after an average of four treatments of laser acupuncture. The other 11 patients showed partial relief of TMD symptoms after treatment. Although the pain was still present, it was less and was acceptable. No side effects were reported in any patients during or after laser acupuncture treatments. Conclusion Laser acupuncture may be an alternative treatment modality for TMD because it is non-invasive, results in partial or total relief of pain, and has no side effects. [ABSTRACT FROM AUTHOR]

Protein-protein interactions are critical determinants in biological systems. Engineered proteins binding to specific areas on protein surfaces could lead to therapeutics or diagnostics for treating diseases in humans. But designing epitope-specific protein-protein interactions with computational atomistic interaction free energy remains a difficult challenge. Here we show that, with the antibody-VEGF (vascular endothelial growth factor) interaction as a model system, the experimentally observed amino acid preferences in the antibody-antigen interface can be rationalized with 3-dimensional distributions of interacting atoms derived from the database of protein structures. Machine learning models established on the rationalization can be generalized to design amino acid preferences in antibody-antigen interfaces, for which the experimental validations are tractable with current high throughput synthetic antibody display technologies. Leave-one-out cross validation on the benchmark system yielded the accuracy, precision, recall (sensitivity) and specificity of the overall binary predictions to be 0.69, 0.45, 0.63, and 0.71 respectively, and the overall Matthews correlation coefficient of the 20 amino acid types in the 24 interface CDR positions was 0.312. The structure-based computational antibody design methodology was further tested with other antibodies binding to VEGF. The results indicate that the methodology could provide alternatives to the current antibody technologies based on animal immune systems in engineering therapeutic and diagnostic antibodies against predetermined antigen epitopes. [ABSTRACT FROM AUTHOR]

The aim of this study was to estimate efficacy of mechanical bowel preparation with polyethylene glycol (PEG) in prevention of postoperative complications in elective colorectal surgery. A literature search of MEDLINE (PubMed), EMBASE, and the Cochrane Library was done to identify randomized controlled trials involving comparison of postoperative complications after mechanical bowel preparation with PEG (PEG group) and no preparation (control group). A meta-analysis was set up to distinguish overall difference between the two groups. A total of five randomized controlled trials was identified according to our inclusion criteria. The use of PEG for mechanical bowel preparation did not significantly reduce the rate of surgical site infection (SSI; odds ratio (OR) 95% confidence interval (CI), 1.39 (0.85–2.25); P = 0.19) including incisional SSI (OR 95% CI, 1.44 (0.88–2.33); P = 0.15), organ/space SSI (OR 95% CI, 1.10 (0.43–2.78); P = 0.49), anastomotic leak (OR 95% CI,1.78 (0.95–3.33; P = 0.07), mortality (OR 95% CI, 1.24 (0.37–4.14; P = 0.73), infectious complications (OR 95% CI, 1.14 (0.62–2.08); P = 0.67), and hospital stay (weighted mean difference 95% CI, 2.17 (−2.90–7.25); P = 0.40) except main complications (OR 95% CI, 1.76 (1.09–2.85); P = 0.02), of which the rate increased significantly in the PEG group. The use of mechanical bowel preparation with PEG does not significantly lower postoperative complications in elective colorectal surgery. [ABSTRACT FROM AUTHOR]

BACKGROUND Increased growth and contraction of vascular smooth muscle cells (VSMCs) are major abnormalities in many vascular disorders. To investigate the signaling pathways that mediate these processes, we studied the expression of smooth muscle myosin light chain kinase (smMLCK) in VSMCs. METHODS Primary cultured VSMCs isolated from normotensive Wistar-Kyoto (WKY) rats were treated with angiotensin II (Ang II). smMLCK expression was examined in the cells using western blot analysis. In vivo, a specific inhibitor of smMLCK or MAP kinase kinase (MEK) was delivered to spontaneously hypertensive rats (SHRs) using an osmotic pump, and their blood pressures were measured using tail-cuff sphygmomanometry. RESULTS Expression of smMLCK protein is rapidly increased by Ang II, an important agonist responsible for increased vasoconstriction and vascular remodeling, in concert with increased myosin light chain phosphorylation. Inhibiting Ang II type 1 (AT1) receptor, Ras, or MEK blocked the Ang II-induced increase in smMLCK expression. In vivo, inhibiting MEK decreased smMLCK expression, blood pressure, and vascular thickening in SHRs. Moreover, inhibiting smMLCK activity decreased blood pressure and smooth muscle mass in arteries in SHRs. CONCLUSIONS The regulation of smMLCK expression by Ang II via Ras signaling is important in the regulation of vascular remodeling and blood pressure. Targeting this pathway could be an effective strategy for developing novel therapeutics to treat hypertension. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the effects of herbal medicines in treating periodontal diseases. Three Chinese herbal composites [Conth Su (CS), Chi Tong Ning (CTN) and Xi Gua Shuang (XGS)], widely used for prevention and treatment of periodontal diseases, and the major components of these composites were tested for their ability to: (1) alleviate disease progression of experimental periodontitis in hamsters, (2) inhibit bacterial growth, and (3) induce mutations. Our results indicate that in treating experimental periodontitis, there were no significant differences between the animal groups with or without the use of Chinese herbal medicines in terms of the degree of inflammation, alveolar bone resorption, and rate of repair. However, hamsters treated with CS presented earlier regenerative epithelium. CTN demonstrated superior bacterial inhibition ability among all tested herbs (MIC 0.025 g/ml); CS showed good anti-bacterial abilities at a concentration of 0.05 g/ml. It is interesting to note that while both CS and CTN were capable of inhibiting bacterial growth, none of the individual herb components showed comparable bacterial inhibition abilities. None of the tested herbal composites or their components showed signs of inducing cell mutations using the Ames test. These results indicated that traditional Chinese herbal medicines, which have been used to treat periodontal diseases for hundreds of years by Chinese people, can effectively inhibit bacterial growth without causing cell mutation. Further investigation into their possible clinical applications in periodontal therapy is encouraged. [ABSTRACT FROM AUTHOR]

Reports a case of a late-onset angioedema caused by angiotensin-converting enzyme inhibitor (ACEI). Side effects of ACEI; Pathophysiology of angioedema; Treatment of the illness; Factors that may be precipitated by idiopathic angioedema.

AbstractObjective:To test the therapeutic efficacy of low-level energy diode laser on burning mouth syndrome. Background:Burning mouth syndrome is characterized by burning and painful sensations in the mouth, especially the tongue, in the absence of significant mucosal abnormalities. Although burning mouth syndrome is relatively common, little is known regarding its etiology and pathophysiology. As a result, no treatment is effective in all patients. Low-level energy diode laser therapy has been used in a variety of chronic and acute pain conditions, including neck, back and myofascial pain, degenerative osteoarthritis, and headache. Methods:A total of 17 patients who had been diagnosed with burning mouth syndrome were treated with an 800-nm wavelength diode laser. A straight handpiece was used with an end of 1-cm diameter with the fiber end standing 4 cm away from the end of handpiece. When the laser was applied, the handpiece directly contacted or was immediately above the symptomatic lingual surface. The output used was 3 W, 50 msec intermittent pulsing, and a frequency of 10 Hz, which was equivalent to an average power of 1.5 W/cm2(3 W × 0.05 msec × 10 Hz = 1.5 W/cm2). Depending on the involved area, laser was applied to a 1-cm2area for 70 sec until all involved area was covered. Overall pain and discomfort were analyzed with a 10-cm visual analogue scale. Results:All patients received diode laser therapy between one and seven times. The average pain score before the treatment was 6.7 (ranging from 2.9 to 9.8). The results showed an average reduction in pain of 47.6% (ranging from 9.3% to 91.8%). The burning sensation remained unchanged for up to 12 months. Conclusion:Low-level energy diode laser may be an effective treatment for burning mouth syndrome. [ABSTRACT FROM AUTHOR]

It has been widely reported that ketamine rescues chronic stress-induced depression-like behavior, but the underlying cellular mechanisms of the rapid antidepressant actions of ketamine remain largely unclear. Both male and female Sprague-Dawley rats were used and received modified learned helplessness paradigm to induce depression-like behavior. Depression-like behavior was assayed and manipulated using forced swim tests, sucrose preference tests and pharmacological microinjection. We conducted whole-cell patch-clamp electrophysiological recordings in the midbrain ventrolateral periaqueductal gray (vlPAG) neurons. Surface and cytosolic glutamate receptor 1 (GluR1) α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor expression were analyzed using Western blotting. Phosphorylated GluR1 expression was quantified using Western blotting analysis. The results showed that a single systemic administration of a ketamine metabolite (2R,6R)-hydroxynorketamine (2R,6R-HNK) rapidly rescued chronic stress-induced depression-like behavior and persisted for up to 21 days. Consistently, the chronic stress-induced diminished glutamatergic transmission and surface GluR1 expression in the vlPAG were also reversed by a single systemic injection of (2R,6R)-HNK. Furthermore, bath application of (2R,6R)-HNK increased the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs) in the vlPAG. Further evidence for the antidepressant action of (2R,6R)-HNK is provided by the finding that microinjection of (2R,6R)-HNK into the vlPAG exhibited a rapid-acting and long-lasting antidepressant effect. This antidepressant effect of (2R,6R)-HNK was prevented by the intra-vlPAG microinjection of AMPA receptor antagonist CNQX. Together, the current results provide evidence that (2R,6R)-HNK rescues chronic stress-induced depression-like behavior with rapid-acting and long-lasting antidepressant effects through enhancement of AMPA receptor-mediated transmission in the vlPAG. [ABSTRACT FROM AUTHOR]

Abstract: 7-N-Acetamide-4-methoxy-2-aminobenzothiazole 4-fluorobenzamide (compound 1) was chosen as a drug-like and non-xanthine based starting point for the discovery of A2B receptor antagonists because of its slight selectivity against A1 and A2A receptors and modest A2B potency. SAR exploration of compound 1 described herein included modifications to the 7-N-acetamide group, substitution of the 4-methoxy group by halogens as well as replacement of the p-flouro-benzamide side chain. This work culminated in the identification of compound 37 with excellent A2B potency, modest selectivity versus A2A and A1 receptors, and good rodent PK properties. [Copyright &y& Elsevier]