Evidence for a role of metformin in preventing olfactory dysfunction among older adults.

BACKGROUND: Olfactory dysfunction (OD) is increasingly recognized as a hallmark of unhealthy aging and is intimately associated with mortality, but therapies remain elusive. Recognizing the increased prevalence of OD in individuals with diabetes, and the potential anti-aging effects of metformin, we studied the association of metformin use with OD. METHODS: Cross-temporal study of participants from Waves 2 (2010-11) and 3 (2015-16) of the National Social Life, Health, and Aging Project (NSHAP), a nationally representative cohort study of community-dwelling older adults. We included participants with diabetes who had complete data on olfaction and relevant covariates at Wave 2 and were not lost to follow-up at Wave 3. Olfactory identification (OI), the ability to identify the odorant, and olfactory sensitivity (OS), the ability to detect the presence of an odorant, were tested. Weighted multivariable logistic regression was used to study the association between metformin use at Wave 2 (baseline) and odds of having impaired OI/OS at Wave 3, adjusted for age, sex, race/ethnicity, education, smoking, BMI, HbA1c, years since diabetes diagnosis, and insulin use. RESULTS: Among 228 participants with diabetes (mean age=70 years, 53% female, 21% Black), 112 (49%) used metformin at baseline. Relative to nonusers, users had 58% lower odds of impaired OI and 67% lower odds of impaired OS at Wave 3. Among participants with normal baseline OS (N=62), users had 97% lower odds of impaired OS at Wave 3. CONCLUSIONS: Metformin use is associated with lower odds of OD among individuals with diabetes, suggesting a potential protective effect on olfaction. Future work including a larger sample and additional information on metformin use is needed to establish whether these findings are independent of diabetic control.

Plasma levels of protein C pathway proteins and brain magnetic resonance imaging volumes in multiple sclerosis.

BACKGROUND AND PURPOSE: The involvement of protein C (PC) pathway components in multiple sclerosis (MS) has scarcely been explored. The aim was to investigate their levels in relation to clinical and neurodegenerative magnetic resonance imaging (MRI) outcomes in patients. METHODS: In all, 138 MS patients and 42 healthy individuals were studied. PC, protein S (PS) and soluble endothelial protein C receptor (sEPCR) were evaluated by multiplex assays and enzyme-linked immunosorbent assay. Regression analyses between 3 T MRI outcomes and PC pathway components were performed. ancova was used to compare MRI volumes based on protein level quartiles. Partial correlation was assessed amongst levels of PC pathway components and hemostasis protein levels, including soluble thrombomodulin (sTM), heparin cofactor II (HCII), plasminogen activator inhibitor 1 (PAI-1) and factor XII (FXII). The variation of PC concentration across four time points was evaluated in 32 additional MS patients. RESULTS: There was an association between PC concentration, mainly reflecting the zymogen PC, and MRI measures for volumes of total gray matter (GM) (P = 0.003), thalamus (P = 0.007), cortex (P = 0.008), deep GM (P = 0.009) and whole brain (P = 0.026). Patients in the highest PC level quartile were characterized by the lowest GM volumes. Correlations of PC-HCII, PC-FXII and sEPCR-sTM values were detectable in MS patients, whilst PC-PS and PS-PAI-1 correlations were present in healthy individuals only. CONCLUSIONS: Protein C plasma concentrations might be associated with neurodegenerative MRI outcomes in MS. Several differences in correlation amongst protein plasma levels suggest dysregulation of PC pathway components in MS patients. The stability of PC concentration over time supports a PC investigation in relation to GM atrophy in MS.

Cholesterol and neurodegeneration: longitudinal changes in serum cholesterol biomarkers are associated with new lesions and gray matter atrophy in multiple sclerosis over 5 years of follow-up.

BACKGROUND AND PURPOSE: Cholesterol is an important structural component of myelin and essential for brain homeostasis. Our objective was to investigate whether longitudinal changes in cholesterol biomarkers are associated with neurodegeneration in multiple sclerosis (MS). METHODS: This prospective, longitudinal study (n = 154) included 41 healthy controls, 76 relapsing-remitting MS subjects and 37 progressive MS subjects. Neurological examination, brain magnetic resonance imaging and blood samples were obtained at baseline and at 5-year follow-up visits. Cholesterol biomarkers measured included plasma total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol and the apolipoproteins ApoA-I, Apo-II, ApoB, ApoC-II and ApoE. Key cholesterol pathway single nucleotide polymorphisms were genotyped. RESULTS: Greater percentage increases in HDL-C and ApoA-I levels were associated with a lower rate of gray matter and cortical volume loss. Greater percentage increases in low-density lipoprotein cholesterol were associated with increases in new T2 lesions. The percentage increases in HDL-C (P = 0.032) and ApoA-I (P = 0.007) were smaller in patients with relapsing-remitting MS at baseline who converted to secondary progressive MS during the 5-year follow-up period. Changes in HDL-C and ApoA-I were associated with lipoprotein lipase rs328 genotype status. CONCLUSIONS: Increases in HDL-C and ApoA-I have protective associations with magnetic resonance imaging measures of neurodegeneration in MS.

Identification and neuroprotective evaluation of a potential c-Jun N-terminal kinase 3 inhibitor through structure-based virtual screening and in-vitro assay.

The c-Jun N-terminal kinase 3 (JNK3) signaling cascade is activated during cerebral ischemia leading to neuronal damage. The present study was carried out to identify and evaluate novel JNK3 inhibitors using in-silico and in-vitro approach. A total of 380 JNK3 inhibitors belonging to different organic groups was collected from the previously reported literature. These molecules were used to generate a pharmacophore model. This model was used to screen a chemical database (SPECS) to identify newer molecules with similar chemical features. The top 1000 hits molecules were then docked against the JNK3 enzyme coordinate following GLIDE rigid receptor docking (RRD) protocol. Best posed molecules of RRD were used during induced-fit docking (IFD), allowing receptor flexibility. Other computational predictions such as binding free energy, electronic configuration and ADME/tox were also calculated. Inferences from the best pharmacophore model suggested that, in order to have specific JNK3 inhibitory activity, the molecules must possess one H-bond donor, two hydrophobic and two ring features. Docking studies suggested that the main interaction between lead molecules and JNK3 enzyme consisted of hydrogen bond interaction with methionine 149 of the hinge region. It was also observed that the molecule with better MM-GBSA dG binding free energy, had greater correlation with JNK3 inhibition. Lead molecule (AJ-292-42151532) with the highest binding free energy (dG = 106.8 Kcal/mol) showed better efficacy than the SP600125 (reference JNK3 inhibitor) during cell-free JNK3 kinase assay (IC50 = 58.17 nM) and cell-based neuroprotective assay (EC50 = 7.5 µM).

The first target specific, highly diastereoselective synthesis, design and characterization of pyranoquinolinyl acrylic acid diastereomers as potential α-glucosidase inhibitors.

In the present investigation we report the first target specific, highly diastereoselective synthesis of new class of pyranoquinolinyl/furoquinolinyl-acrylic acid diastereomers and evaluation of their invitro α-glucosidase inhibitory activity. All the products were thoroughly characterized by 1H NMR, 13C NMR, FT-IR, Mass spectral and CHN analysis. A highly diastereoselective target specific route of synthesis for the biologically active diastereomers were developed by usingchiral catalyst Europium tris[3-heptafluoropropylhydroxyl methylene]-(-)-camphorate (A) or Europiumtris[3-(trifluoromethyl)hydroxylmethylene]-(+)-camphorate (B). It was found that among a set of 4 diastereomeric products obtained, exodiasteromers of pyranoquinolinyl acrylic acid adducts exhibited relatively high α-glucosidase inhibitory activity. The newly synthesized compounds exhibited IC50 values in the range of (0.40 ±â€¯0.02-30.3 ±â€¯0.84 µM) as compared to standard acarbose (IC50 = 0.65 ±â€¯0.02 µM). It was found that compounds 11a, 11c, 11d and 12d were found to be more active than standard acarbose. It was also found that unsubstituted compound (11a) or compounds with chlorine or methoxy substituent (11c, 11d, 12d) showed potential α-glucosidase inhibitory activity. However a reversal in activity was observed with Nitro substituent (11b, 13b) wherein the endodiastereomers were found to be more active than exodiastereomers. Molecular docking studies were used for design of the compound and understand the mode of binding between the compound and target enzyme. A plausible mechanism for the diastereoselective synthesis was also proposed.

Hemostasis biomarkers in multiple sclerosis.

BACKGROUND AND PURPOSE: The aim was to investigate the plasma levels of hemostasis components in multiple sclerosis (MS) and their association with clinical and magnetic resonance imaging (MRI) outcomes. METHODS: In all, 138 MS patients [85 with relapsing-remitting MS (RR-MS) and 53 with progressive MS (P-MS) with a mean age of 54 years; 72.5% female; median Expanded Disability Status Scale 3.5; mean disease duration 21 years] and 42 age- and sex-matched healthy individuals (HI) were studied. All subjects were examined with 3 T MRI and clinical examinations. Plasma levels of hemostasis factors [procoagulant, factor XII (FXII)] and inhibitors [tissue factor pathway inhibitor (TFPI), thrombomodulin, heparin cofactor II, a disintegrin-like and metalloprotease with thrombospondin type 1 motif 13 (ADAMTS13) and plasminogen activator inhibitor 1 (PAI-1)] were evaluated by magnetic Luminex assays and enzyme-linked immunosorbent assay. Associations between hemostasis plasma levels and clinical and MRI outcomes were assessed. RESULTS: Lower ADAMTS13 levels were found in MS patients compared to HI (P = 0.008) and in MS patients presenting with cerebral microbleeds compared to those without (P = 0.034). Higher PAI-1 levels were found in MS patients compared to HI (P = 0.02). TFPI levels were higher in the P-MS subgroup compared to RR-MS patients (P = 0.011) and compared to HI (P = 0.002). No significant associations between hemostasis plasma levels and clinical or MRI outcomes were found. CONCLUSIONS: Decreased ADAMTS13, particularly in MS patients with cerebral microbleeds, which deserves further investigation, and increased PAI-1 and TFPI levels were observed in MS patients, which deserves further investigation. No relationship between hemostasis plasma levels and measures of disease severity was detected.

Hiding in Plain Sight: A Case of Ornithine Transcarbamylase Deficiency Unmasked Post-Liver Transplantation.

Ornithine transcarbamylase deficiency represents the most common inherited defect of the urea cycle. This enzyme, predominantly found in the liver, plays a crucial role in recycling free ammonia, with deficiencies often leading to fatal complications. Here, we present the case of a 63-year-old man with alcoholic cirrhosis who underwent orthotopic liver transplantation, gradual worsening of his mental status, and progressive elevation of ammonia levels. Liver allograft function was deemed normal, raising concern for a donor-derived metabolic disorder of the urea cycle. Evaluation of the donor patient's blood revealed that the donor was heterozygous for the OTC gene. Posttransplantation changes in mental status should prompt a clinician to consider the most likely causes; however, once these have been ruled out, it is important to consider the less common causes of metabolic derangements. The rarity of these disorders makes expertise of diagnosis, standardization of evaluation, and treatment strategies challenging.

Design, synthesis and biological evaluation of 2-(4-phenylthiazol-2-yl) isoindoline-1,3-dione derivatives as anti-prostate cancer agents.

The structural modification and molecular docking-based screening approaches on thiazole-based isoindolinediones were imposed to find the novel 2-(4-phenylthiazol-2-yl) isoindoline-1,3-dione derivatives. The best fit compounds (6a-n) were synthesized and evaluated their antiproliferative activities on the prostate cancer cell lines (PC-3 & LNCaP). Among them, the compound, 6m exhibited good activity, particularly on LNCaP (IC50=5.96±1.6µM), moderately active against PC-3 cell lines as compared to bicalutamide. The compound, 6m decreased the androgen-mediated transcription of ARE-mRNA in PSA, TMPRSS2, c-myc and cyclin D1 than R-bicalutamide. The compounds, 6e and 6f were reconfirmed through single crystal XRD analysis. The ADME profiling of the test compounds was evaluated to find the drug-likeness and pharmacokinetic parameters. These findings may provide vital information for the development of anti-prostate cancer agents.

Concurrent determination of olanzapine, risperidone and 9-hydroxyrisperidone in human plasma by ultra performance liquid chromatography with diode array detection method: application to pharmacokinetic study.

A simple and sensitive ultra-performance liquid chromatography (UPLC) method has been developed and validated for simultaneous estimation of olanzapine (OLZ), risperidone (RIS) and 9-hydroxyrisperidone (9-OHRIS) in human plasma in vitro. The sample preparation was performed by simple liquid-liquid extraction technique. The analytes were chromatographed on a Waters Acquity H class UPLC system using isocratic mobile phase conditions at a flow rate of 0.3 mL/min and Acquity UPLC BEH shield RP18 column maintained at 40°C. Quantification was performed on a photodiode array detector set at 277 nm and clozapine was used as internal standard (IS). OLZ, RIS, 9-OHRIS and IS retention times were found to be 0.9, 1.4, .1.8 and 3.1 min, respectively, and the total run time was 4 min. The method was validated for selectivity, specificity, recovery, linearity, accuracy, precision and sample stability. The calibration curve was linear over the concentration range 1-100 ng/mL for OLZ, RIS and 9-OHRIS. Intra- and inter-day precisions for OLZ, RIS and 9-OHRIS were found to be good with the coefficient of variation <6.96%, and the accuracy ranging from 97.55 to 105.41%, in human plasma. The validated UPLC method was successfully applied to the pharmacokinetic study of RIS and 9-OHRIS in human plasma.

Optimal ablation volumes are achieved at submaximal power settings in a 2.45-GHz microwave ablation system.

INTRODUCTION: Local ablative therapies, including microwave ablation (MWA), are common treatment modalities for in situ tumor destruction. Currently, 2.45-GHz ablation systems are gaining prominence because of the shorter application times required. The aims of this study were to determine optimal power and time to ablation volume (AbV) ratios for a new 1.8-mm-2.45-GHz antenna using ex vivo tissue models. METHODS: The 1.8-mm-2.45-GHz Accu2i MWA system was employed to perform ablations in bovine liver, porcine muscle, and porcine kidney ex vivo. Whole tissues were prewarmed (35°C) and multiple ablations performed at power settings of 60 to 180 W for 2- to 6-minute time intervals. Postablation, tissues were dissected, AbVs calculated, and correlations to power and time settings made. RESULTS: Significant increases in AbV were measured between each of the time points for a constant power setting in all 3 tissues. Increasing power settings led to significant increases in AbV at power settings ≤140 W. However, no significant increase in AbV was obtained at power settings >140 W. CONCLUSIONS: Optimal efficiency for MWA using a new 1.8-mm-2.45-GHz system is achieved at settings of ≤140 W for 6 minutes in a range of ex vivo tissue and no additional benefit occurs by increasing the power setting to 180 W in these tissues.

Training and practice of the next generation HPB surgeon: analysis of the 2014 AHPBA residents' and fellows' symposium survey.

BACKGROUND: Hepato-pancreato-biliary (HPB) surgery is a complex subspecialty drawing from varied training pools, and the need for competency is rapidly growing. However, no board certification process or standardized training metrics in HPB surgery exist in the Americas. This study aims to assess the attitudes of current trainees and HPB surgeons regarding the state of training, surgical practice and the HPB surgical job market in the Americas. STUDY DESIGN: A 20-question survey was distributed to members of Americas Hepato-Pancreato-Biliary Association (AHPBA) with a valid e-mail address who attended the 2014 AHPBA. Descriptive statistics were generated for both the aggregate survey responses and by training category. RESULTS: There were 176 responses with evenly distributed training tracks; surgical oncology (44, 28%), transplant (39, 24.8%) and HPB (38, 24.2%). The remaining tracks were HPB/Complex gastrointestinal (GI) and HPB/minimally invasive surgery (MIS) (29, 16% and 7, 4%). 51.2% of respondents thought a dedicated HPB surgery fellowship would be the best way to train HPB surgeons, and 68.1% felt the optimal training period would be a 2-year clinical fellowship with research opportunities. This corresponded to the 67.5% of the practicing HPB surgeons who said they would prefer to attend an HPB fellowship for 2 years as well. Overall, most respondents indicated their ideal job description was clinical practice with the ability to engage in clinical and/or outcomes research (52.3%). CONCLUSIONS: This survey has demonstrated that HPB surgery has many training routes and practice patterns in the Americas. It highlights the need for specialized HPB surgical training and career education. This survey shows that there are many ways to train in HPB. A 2-year HPB fellowship was felt to be the best way to train to prepare for a clinically active HPB practice with clinical and outcomes research focus.

Outcomes of surgical resection and loco-regional therapy in patients with stage 3A hepatocellular carcinoma: a retrospective review from the national cancer database.

OBJECTIVES: In advanced stages, hepatocellular carcinoma (HCC) is often associated with major vascular involvement (cava, portal vein). The aim of the present study was to analyse the role of surgical resection (SR) and loco-regional therapy (LRT) in these advanced stage patients to determine if there was a survival benefit. METHODS: The study is a retrospective analysis from the Commission on Cancer's National Cancer Data Base (NCDB) from 1998 to 2011. In total, 148,882 patients with liver cancer were identified, of which 126,984 had HCC. Of these, 64,264 patients (1998-2006) had 5-year survival data available and 8825 patients had Stage 3A disease based on AJCC classification. Of these patients, 884 had SR, 771 had LRT and 7170 patients had neither intervention. Kaplan-Meier curves and log-rank tests were used for statistical analysis. RESULTS: Eight thousand eight hundred and twenty-five patients met analysis criteria. The mean age (years) in the SR, LRT and no intervention group were 62.5, 64.3 and 64.2, respectively. Most patients were males in all three groups (77.5%, 74.5% and 68.1%). The mean tumour size (cm) in the three groups was 9.8, 6.4 and 8.4, respectively. SR and LRT were primarily performed in major academic and comprehensive cancer programmes compared with community cancer programmes and other centres (SR: 93% versus 7%; LRT: 94.6% versus 5.4%). The median 5-year survival (months) was 26.6 in SR, 16.5 in LRT and 4.8 in the no intervention group (P < 0.0001). CONCLUSION: A SR and LRT offer a survival benefit in select patients diagnosed with Stage 3A HCC.

Laparoscopic microwave ablation of human liver tumours using a novel three-dimensional magnetic guidance system.

BACKGROUND: Accurate antenna placement is essential for effective microwave ablation (MWA) of lesions. Laparoscopic targeting is made particularly challenging in liver tumours by the needle's trajectory as it passes through the abdominal wall into the liver. Previous optical three-dimensional guidance systems employing infrared technology have been limited by interference with the line of sight during procedures. OBJECTIVE: The aim of this study was to evaluate a newly developed magnetic guidance system for laparoscopic MWA of liver tumours in a pilot study. METHODS: Thirteen patients undergoing laparoscopic MWA of liver tumours gave consent to their participation in the study and were enrolled. Lesion targeting was performed using the InnerOptic AIM™ 3-D guidance system to track the real-time position and orientation of the antenna and ultrasound probe. RESULTS: A total of 45 ablations were performed on 34 lesions. The median number of lesions per patient was two. The mean ± standard deviation lesion diameter was 18.0 ± 9.2 mm and the mean time to target acquisition was 3.5 min. The first-attempt success rate was 93%. There were no intraoperative or immediate postoperative complications. Over an average follow-up of 7.8 months, one patient was noted to have had an incomplete ablation, seven suffered regional recurrences, and five patients remained disease-free. CONCLUSIONS: The AIM™ guidance system is an effective adjunct for laparoscopic ablation. It facilitates a high degree of accuracy and a good first-attempt success rate, and avoids the line of site interference associated with infrared systems.

Retinal nerve fiber layer thickness and thalamus pathology in multiple sclerosis patients.

BACKGROUND AND PURPOSE: Visual impairments are frequent in multiple sclerosis (MS). Optic neuritis can directly reduce retinal nerve fiber layer (RNFL) thickness. Our objectives were to evaluate associations of the RNFL thickness (RNFLT) of MS patients with magnetic resonance imaging (MRI) measures of regional brain atrophy and tissue injury in the post-chiasmatic deep gray matter (GM) section of the visual pathway. METHODS: Retinal nerve fiber layer thickness was measured using optical coherence tomography (OCT) in 96 relapsing-remitting MS (RR-MS) patients and 46 controls. MRI was obtained within ±3 months of OCT. RNFLT associations with MRI measures from diffusion tensor imaging and regional and tissue specific atrophy were assessed. RESULTS: In RR-MS, lower RNFLT was associated with lower white matter volume and lower whole brain volume. Lower RNFLT was associated with lower total deep gray matter volume and lower thalamus volume. Lower RNFLT was associated with greater mean diffusivity (MD) in normal appearing (NA) brain tissue and NA gray matter. Trends were found for lower RNFLT with greater MD in NA white matter and thalamus. RNFLT in controls was not associated with MD. CONCLUSIONS: Lower RNFLT is associated with microscopic tissue injury in NA regions of the brain and with neurodegeneration of the deep gray matter and thalamus in RR-MS.

Survival analysis of patients with stage I and II hepatocellular carcinoma after a liver transplantation or liver resection.

INTRODUCTION: Liver transplantation (LT) is a treatment option in select patients with hepatocellular carcinoma (HCC). The aim of the present study was to compare survival in Stage I or II HCC patients undergoing either liver transplant (LT) or a liver resection (LR). METHOD: The study is a retrospective analysis of the National Cancer Data Base (1998-2011). In total, 148,882 patients with liver cancer were identified, of which 5-year survival data (1998-2006) were available for 64,227 patients. Patients were stratified by the American Joint Committee on Cancer (AJCC) clinical stage I and II. Kaplan-Meier curves and log-rank tests were used for statistical analysis. RESULTS: 3340 HCC patients met analysis criteria. Among stage I HCC, 860 had LT and 871 had LR. Among stage II HCC, 833 had LT and 776 LR. In stage I patients the median survival for LT and LR were 127.9 and 56.7 months, respectively, (P < 0.0001) and in stage II patients the median survival was 110.8 and 42.8 months (P < 0.0001). Unlike LT patients, LR patients with Stage I HCC had a longer median survival compared with Stage II patients (P = 0.0002). CONCLUSION: Liver transplantation offers a survival advantage compared with a liver resection among patients with Stage I and II HCC. LT is the best surgical treatment for early stage (I/II) HCC in patients with advanced fibrosis or cirrhosis, whereas LR provides equivalent outcomes to LT in patients without advanced fibrosis and should be considered as the first surgical option.

Piceatannol selectively inhibited the JNK3 enzyme and augmented apoptosis through inhibition of Bcl-2/Cyt-c/caspase-dependent pathways in the oxygen-glucose deprived SHSY-5Y cell lines: In silico and in vitro study.

JNK3, a neuronal kinase activated by stress, plays a role in stress-induced apoptosis, leading to neuronal cell death following cerebral ischemia. This study investigates the neuroprotective effects of piceatannol (PCT) in SHSY-5Y neuroblastoma cells after hypoxic injury and its interaction with JNK3. We analyzed the crystal coordinates, interaction energies, and amino acid interactions to determine PCT's selectivity for JNK3. The electrostatic potential was computed using density functional theory, while molecular dynamics assessed the stability and structural consistency of the JNK3-PCT complex. We used SP600125 (SP6), a JNK3 inhibitor, as a reference compound. Additionally, we performed cell-free JNK 1, 2, and 3 kinase assays to evaluate the isoform selectivity of PCT. Cytotoxicity and cell viability were determined by an MTT test. To assess apoptosis, we used acridine orange/ethidium bromide dual fluorescent labeling and ANNEXIN A5-FITC flow cytometry. Western blot was used to evaluate the attenuation of JNK3 and apoptotic proteins. In silico studies revealed a stronger binding affinity between PCT and JNK3 compared to JNK1 and JNK2, which was further supported by the in vitro kinase assay. PCT-treated cells exhibited a decrease in Cyt-c and caspase-3 expression and an increase in Bcl-2 level, compared to hypoxic control (p < .001). PCT also demonstrated superior efficacy over SP6 in inhibiting JNK3 phosphorylation (p < .001). Furthermore, PCT significantly increased the expression of neuronal genes, including NgN1, neuroD2, and survivin (p < .001). In conclusion, PCT is a potential JNK3 inhibitor, since it inhibited phosphorylation and the Bcl-2/Cyt-C/caspase-3-dependent apoptotic pathway after ischemic/hypoxic insult.

Piceatannol improved cerebral blood flow and attenuated JNK3 and mitochondrial apoptotic pathway in a global ischemic model to produce neuroprotection.

Cerebral ischemia is one of the leading causes of death and disability worldwide. The only FDA-approved treatment is recanalization with systemic tissue plasminogen activators like alteplase, although reperfusion caused by recanalization can result in neuroinflammation, which can cause brain cell apoptosis. Therefore, after an ischemic/reperfusion injury, interventions are needed to minimize the neuroinflammatory cascade. In the present study, piceatannol (PCT) was studied for its neuroprotective efficacy in a rat model of global ischemic injury by attenuating c-Jun N-terminal kinase 3 (JNK3) downstream signaling. PCT is a resveratrol analog and a polyphenolic stilbenoid naturally occurring in passion fruit and grapes. The neuroprotective efficacy of PCT (1, 5, 10 mg/kg) in ischemic conditions was assessed through pre- and post-treatment. Cerebral blood flow (CBF) and tests for functional recovery were assessed. Protein and gene expression were done for JNK3 and other inflammatory markers. A docking study was performed to identify the amino acid interaction. The results showed that PCT improved motor and memory function as measured by a functional recovery test believed to be due to an increase in cerebral blood flow. Also, the caspase signaling which promotes apoptosis was found to be down-regulated; however, nitric oxide synthase expression was up-regulated, which could explain the enhanced cerebral blood flow (CBF). According to our findings, PCT impeded c-Jun N-terminal kinase 3 (JNK3) signaling by suppressing phosphorylation and disrupting the mitochondrial apoptotic pathway, which resulted in the neuroprotective effect. Molecular docking analysis was performed to investigate the atomic-level interaction of JNK3 and PCT, which reveals that Met149, Leu206, and Lys93 amino acid residues are critical for the interaction of PCT and JNK3. According to our current research, JNK3 downstream signaling and the mitochondrial apoptosis pathway are both inhibited by PCT, which results in neuroprotection under conditions of global brain ischemia. Piceatannol attenuated JNK3 phosphorylation during the ischemic condition and prevented neuronal apoptosis.

Nattokinase Attenuated Excitatory Amino Acids and Cytokines Release and Restored Cerebral Blood Flow in a Thrombolytic Focal Cerebral Ischemic Rat Model.

OBJECTIVE: Nattokinase (NK), a protease enzyme present in traditional fermented Japanese food, has shown fibrinolytic properties in vitro as well as in cardiac ischemia. In the present study, the Neuroprotective effect of standardized NK was evaluated in the thrombolytic focal cerebral ischemic model. METHODOLOGY: The parameters of behavioural assessment, cerebral blood flow, inflammatory mediators, excitatory amino acids, and immunohistochemistry were measured to support the NK effect. NK was administered at 150 and 300 mg/kg, and its effects were compared with streptokinase (STK) (100µl/rat). Each mg of NK contains 5.5 Units of the enzyme, which can cause lysis of the fibrin. RESULTS: The results indicate that 7 days of treatment of 300 mg NK restored the cerebral blood flow and prevented the release of cytokine and excitatory amino acids. Similarly, neurological scores were reduced, and grip strength increased significantly with NK treatment. The GFAP and synaptophysin staining of the hippocampus (CA1) and cerebrum have shown recovery of neurons from ischemic damage in comparison to vehicle-treated ischemic-reperfused rats. The NK (300 mg/kg) fibrinolytic effect is comparable to STK treatment. CONCLUSION: To conclude, NK, a serine protease, protects the brain from ischemic degeneration in thrombolytic cerebral ischemia. Consumption of this Japanese food might exhibit prophylactic activity.

SYMPHONY, an information-theoretic method for gene-gene and gene-environment interaction analysis of disease syndromes.

We develop an information-theoretic method for gene-gene (GGI) and gene-environmental interactions (GEI) analysis of syndromes, defined as a phenotype vector comprising multiple quantitative traits (QTs). The K-way interaction information (KWII), an information-theoretic metric, was derived for multivariate normal distributed phenotype vectors. The utility of the method was challenged with three simulated data sets, the Genetic Association Workshop-15 (GAW15) rheumatoid arthritis data set, a high-density lipoprotein (HDL) and atherosclerosis data set from a mouse QT locus study, and the 1000 Genomes data. The dependence of the KWII on effect size, minor allele frequency, linkage disequilibrium, population stratification/admixture, as well as the power and computational time requirements of the novel method was systematically assessed in simulation studies. In these studies, phenotype vectors containing two and three constituent multivariate normally distributed QTs were used and the KWII was found to be effective at detecting GEI associated with the phenotype. High KWII values were observed for variables and variable combinations associated with the syndrome phenotype compared with uninformative variables not associated with the phenotype. The KWII values for the phenotype-associated combinations increased monotonically with increasing effect size values. The KWII also exhibited utility in simulations with non-linear dependence between the constituent QTs. Analysis of the HDL and atherosclerosis data set indicated that the simultaneous analysis of both phenotypes identified interactions not detected in the analysis of the individual traits. The information-theoretic approach may be useful for non-parametric analysis of GGI and GEI of complex syndromes.

Cholesterol affects retinal nerve fiber layer thickness in patients with multiple sclerosis with optic neuritis.

BACKGROUND AND PURPOSE: To evaluate the associations between retinal nerve fiber layer (RNFL) thickness and lipid profiles in multiple sclerosis (MS). METHODS: This study enrolled 136 patients with MS (n = 272 eyes; 108 females, 28 males, mean age: 46.7 ± 8.9 years); 45% had a history of optic neuritis (ON). Subjects received optical coherence tomography (OCT) testing to assess RNFL thickness and visual acuity testing with Snellen charts. A subset of 88 patients received pattern reversal visual-evoked potential (PRVEP) testing. Lipid profiles consisting of serum high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol and total cholesterol (TC) levels were obtained within ± 6 months of OCT. Regression analyses were used to assess the associations between RNFL thickness and lipid profile variables. RESULTS: Low RNFL thickness (P = 0.008) and higher PRVEP latency (P = 0.017) were associated with high LDL cholesterol > 100 mg/dl status. Low RNFL thickness (P = 0.008) and higher PRVEP latency (P = 0.043) were associated with high HDL cholesterol levels. Low RNFL thickness was also associated with HDL cholesterol > 60 mg/dl status (P = 0.001) and with TC > 200 mg/dl status (P = 0.015). The probability of average RNFL thickness in the lowest tertile (≤ 33rd percentile) was associated with interactions between TC > 200 mg/dl status (P = 0.001, odds ratio = 7.5, 95% confidence interval = 2.7-21) with affected/unaffected by ON status. CONCLUSIONS: High cholesterol adversely affects RNFL thickness in patients with MS with ON.