Plasma cytokines profile in patients with Alzheimer's and Parkinson's Disease: a comparative study in terms of inflammation.

BACKGROUND: Neurodegenerative disorders such as Alzheimer's and Parkinson's disease inflict economic and health burdens on societies. Alzheimer's disease (AD), the most prevalent form of dementia, is accompanied by progressive degradation of memory, decision-making, and judgment. Parkinson's disease (PD) is characterized by resting tremor, rigidity, bradykinesia, and loss of balance. Extensive research has pinpointed inflammation as a cause of the onset and progression of both diseases. However, it has not been confirmed which one is more formidable in terms of inflammation. METHODS: To assess the extent of inflammation that is implicated in AD and PD and answer the question of which one is more inflammatory, serum levels of inflammatory biomarkers, including cytokines, chemokines, and prostaglandin E2 (PEG2), were measured in AD and PD patients as well as a healthy group. RESULTS: Our results showed a significant increase in IL-1α, IL-1ß, IL-4, IL-6, IL-10, IL-12p70, IP-10, MCP-1, PEG2, and TNF-α in AD and PD patients compared with the control. Interestingly, IFN-γ did not manifest any significant difference in AD or PD patients compared with the control. CONCLUSION: As a hallmark of our results, it could be inferred that inflammation, as the underlying etiological cause, plays a more crucial role in PD compared with AD. Based on our results, it is proposed that anti-inflammatory remedies would be putatively more effective in PD rather than AD.

Boswellia serrata extract shows cognitive benefits in a double-blind, randomized, placebo-controlled pilot clinical trial in individuals who suffered traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) is a major cause of death and disability. TBI can result in neuropsychiatric and cognitive problems as well as neurodegenerative pathologies that can appear right after or develop and persist years after injury. METHOD: We conducted a double-blind, randomized, placebo-controlled clinical trial on patients who suffered from TBI three months to three years ago. The patients were randomized to placebo (n = 34) or K-Vie™ group (n = 46) for a treatment period of 3 months. The main primary outcomes include cognitive assessment in the Rey Auditory Verbal Learning Test-Recognition Test (RAVLT), Wechsler adult intelligence Digit Symbol Substitution Test (DSST) and trail-making test part B (TMT-B). Assessments were performed at baseline and at the month 3 follow-up visit. Linear mixed models were carried out to evaluate cognitive changes from baseline across all cognitive assessment tests. RESULT: The current study showed significant (p < 0.05) improvement in cognitive function of patients who were given K-Vie™ compared with placebo across the RAVLT, DSST and TMT-B performance assessments. A larger cohort would be beneficial to further confirm the clinical utility of K-Vie™ and assess its effects in acute phases of TBI.

Conformational change and GTPase activity of human tubulin: A comparative study on Alzheimer's disease and healthy brain.

In Alzheimer's disease (AD), the most common form of dementia, microtubules (MTs) play a pivotal role through their highly dynamic structure and instability. They mediate axonal transport that is crucial to synaptic viability. MT assembly, dynamic instability and stabilization are modulated by tau proteins, whose detachment initiates MT disintegration. Albeit extensive research, the role of GTPase activity in molecular mechanism of stability remains controversial. We hypothesized that GTPase activity is altered in AD leading to microtubule dynamic dysfunction and ultimately to neuronal death. In this paper, fresh tubulin was purified by chromatography from normal young adult, normal aged, and Alzheimer's brain tissues. Polymerization pattern, assembly kinetics and dynamics, critical concentration, GTPase activity, interaction with tau, intermolecular geometry, and conformational changes were explored via Förster Resonance Energy Transfer (FRET) and various spectroscopy methods. Results showed slower MT assembly process in samples from the brains of people with AD compared with normal young and aged brains. This observation was characterized by prolonged lag phase and increased critical and inactive concentration of tubulin. In addition, the GTPase activity in samples from AD brains was significantly higher than in both normal young and normal aged samples, concurrent with profound conformational changes and contracted intermolecular MT-tau distances as revealed by FRET. These alterations were partially restored in the presence of a microtubule stabilizer, paclitaxel. We proposed that alterations of both tubulin function and GTPase activity may be involved in the molecular neuropathogenesis of AD, thus providing new avenues for therapeutic approaches.

Discovering the signature of a lupus-related microRNA profile in the Gene Expression Omnibus repository.

Lupus is one of the most prevalent systemic autoimmune diseases. It is a multifactorial disease in which genetic, epigenetic and environmental factors play significant roles. The pathogenesis of lupus is not yet well understood. However, deregulation of microRNAs (miRNAs) - one of the post-transcriptional regulators of genes - can contribute to the development of autoimmune diseases. Over the last two decades, advances in the profiling of miRNA using microarray have received much attention, and it has been demonstrated that miRNAs play a regulatory role in the pathogenesis of lupus. Therefore, dysregulated miRNAs can be considered as promising diagnostic biomarkers for lupus. This article is an overview of lupus-related miRNA profiling studies and arrays in the Gene Expression Omnibus (GEO) database. The aims of our study were to widen current knowledge of known dysregulated miRNAs as potential biomarkers of SLE and to introduce a bioinformatics approach to using microarray data and finding novel miRNA and gene candidates for further study. We identified hsa-miR-4709-5p, hsa-miR-140, hsa-miR-145, hsa-miR-659, hsa-miR-134, hsa-miR-150, hsa-miR-584, hsa-miR-409 and hsa-miR-152 as potential biomarkers by integrated bioinformatics analysis.

Serum pro-inflammatory and anti-inflammatory cytokines and the pathogenesis of experimental autoimmune encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE) as an experimental model of multiple sclerosis (MS) is characterized by demyelination, infiltration of inflammatory cells into the nervous system and dysregulation of serum inflammatory cytokines. We investigated the correlation of serum cytokines and other inflammatory markers with the EAE pathogenesis. After EAE induction, the levels of different serum cytokine/inflammatory mediators were measured. Furthermore, motor functions, myelination, and lymphocyte infiltration in EAE mice were also assessed. Our results revealed that the serum concentrations of T-helper 1 (Th1) and Th17 cytokines, interleukin (IL)-6, IL-1ß, IL-1α and prostaglandin E2 in EAE mice were significantly higher than controls. The ratios of pro- to anti-inflammatory cytokines were different between the EAE and the control group. A statistically significant positive correlation was found between the IL-6/IL-10 ratio and the EAE severity, demyelination rate, and lymphocyte infiltration in EAE mice. Results indicate that the profiles of serum pro- and anti-inflammatory cytokines might be useful as biomarkers for monitoring the pathological manifestation of EAE. Furthermore, evaluating the dynamic interplay of serum cytokine levels and the correlation with pathogenic mechanisms of EAE may provide diagnostic and therapeutic insights for MS and some other inflammatory disorders.

Design, synthesis and biological evaluation of flexible and rigid analogs of 4H-1,2,4-triazoles bearing 3,4,5-trimethoxyphenyl moiety as new antiproliferative agents.

Several flexible and rigid analogs of 4H-1,2,4-triazoles (compounds 8a-g and 9a-g) bearing trimethoxyphenyl pharmacophoric unit, were designed and synthesized as potential anticancer agents. The in vitro cytotoxic assay indicated that both flexible and rigid analogs (8 and 9, respectively) can potentially inhibit the growth of cancerous cells (A549, MCF7, and SKOV3), with IC50 values less than 5.0 µM. Furthermore, compounds 10a-l as regional isomers of compounds 9 exhibited remarkable cytotoxic activity with IC50 values ranging from 0.30 to 5.0 µM. The rigid analogs 9a, 10h and 10k were significantly more potent than etoposide against MCF7, SKOV3 and A549 cells, respectively. These compounds showed high selectivity towards cancer cells over normal cells, as they had no significant cytotoxicity against L929 cells. In addition, the representative compounds 9a and 10h could inhibit the tubulin polymerization at micro-molar levels. By determining changes in the colchicine-tubulin fluorescence, it was suggested that compound 10h could bind to the tubulin at the colchicine pocket. The molecular docking study further confirmed the inhibitory activity of promising compounds 9a, 10h and 10k on tubulin polymerization through binding to the colchicine-binding site.

Functional improvement and immune-inflammatory cytokines profile of ischaemic stroke patients after treatment with boswellic acids: a randomized, double-blind, placebo-controlled, pilot trial.

Ischaemic stroke represents one of the main causes of disability. According to the broad investigations, it is widely assumed that the contribution of inflammatory mediators is strongly involved in its pathogenesis. Hence, it seems that stroke treatment needs more efficient and inflammatory-targeted compounds to modulate inflammatory-related pathways. Such strategies paved the way to achieve better clinical outcomes along with conventional therapies. Boswellic acids (BAs), the main bioactive compounds of Boswellia sp. resin; are triterpenoids with well-documented anti-inflammatory properties. Compared with NSAIDs, BAs cross blood-brain barrier yet they do not cause serious gastrointestinal adverse effects. Considering BAs anti-inflammatory features, we conducted a randomized double-blind placebo-controlled pilot trial of these compounds as a supplementary therapy. This trial randomized 80 ischaemic stroke patients (40-80-years old) with a 4-20 score according to the National Institutes of Health Stroke Scale (NIHSS), within 72 h of neurological sign onset, in 1-month follow-up period. We assessed NIHSS as primary and plasma levels of TNF-α, IL-1α, IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IFN-γ, IP-10, MCP-1, 8-isoprostane, and PGE2 as secondary outcomes. According to NIHSS evaluation, patients who were allocated to BA group had a significant recovery in neurological function during the 1-month follow-up, compared with the placebo. The levels of plasma inflammatory markers were significantly decreased in BA group after 7 days of intervention in TNF-α, IL-1ß, IL-6, IL-8, and PGE2. As a preliminary controlled trial in ischaemic stroke, BAs could improve clinical outcome in the early phases of stroke along with promising changes in plasma inflammatory factors.Clinical trial registrationhttps://www.irct.ir Unique identifier: IRCT20170315033086N5. IRCT is a primary registry in the WHO registry network (https://www.who.int/ictrp/network/primary/en/).

S1 Transforaminal Epidural Anesthesia in Percutaneous Transforaminal Endoscopic Discectomy: A Case-Series Study.

Background: Percutaneous transforaminal endoscopic discectomy (PTED) has become popular over the years due to its safety and low invasiveness. This surgery can be performed with different anesthesia techniques; however, the extent to which the surgeon and patient are satisfied with the analgesia is debatable. Objectives: This study investigated the efficiency of the S1 transforaminal epidural block. Methods: This retrospective study was conducted on 60 patients with L4 - L5 lumbar disc herniation who underwent PTED under the S1 transforaminal epidural block. All patients had clinical symptoms associated with unilateral radiculopathy and were candidates for surgery. Percutaneous transforaminal endoscopy and S1 epidural block were performed by a surgeon for all patients. Results: Of the 60 evaluated cases, 61.7% and 38.3% were female and male, respectively, with a mean age of 42.98 ± 10.79 years. The mean pain score before surgery was 7.83 ± 0.69, which decreased to 2.58 ± 0.65 during surgery and 0.50 ± 0.50 48 hours after surgery (P < 0.001). The mean duration of operation in these patients was 58.58 ± 16.95 minutes, and the mean onset time was 10.08 ± 3.12 minutes. Moreover, the mean bleeding was 124.17 ± 25.20 cc. Conclusions: The PTED with S1 epidural anesthesia is a simple, safe, and effective method that causes good analgesia during the operation and cooperates well with the surgeon in neurological monitoring due to patient consciousness.

Boswellic Acids Improve Clinical Cognitive Scores and Reduce Systemic Inflammation in Patients with Mild to Moderate Alzheimer's Disease.

BACKGROUND: Recent therapeutic approaches for Alzheimer's disease (AD) have had limited success. Considering the association of neuroinflammation with AD symptoms as demonstrated in multiple studies, assessment of the clinical efficacy of molecules that reduce systemic or brain inflammation is warranted. OBJECTIVE: This clinical trial assessed whether boswellic acids can improve cognitive and neuropsychiatric symptoms while reducing inflammation in AD patients. METHODS: A double-blind, placebo-controlled, study was conducted on 85 AD patients randomized to boswellic acids (K-Vie™ as the main ingredient in Memowell™) or placebo for 6 months. Clinical Dementia Rating-Sum of Boxes (CDR-SOB) and Mini-Mental State Examination (MMSE) scores were compared to baseline and between groups and constituted the co-primary clinical efficacy endpoints. Secondary outcomes included neuropsychiatric assessment (Neuropsychiatric Inventory-Questionnaire, NPI-Q) and assessment of AD and inflammation biomarkers. RESULTS: Patients on K-Vie™ showed a 3.1- and 1.6-unit improvement in MMSE and CDR-SOB scores, respectively, when compared to patients on placebo. NPI-Q analysis revealed significant improvement in the K-Vie™ but not in the placebo group. Only mild gastrointestinal side effects were reported in a few patients. Patients on K-Vie™ showed improvement in plasma AD biomarkers and reduction of key inflammatory cytokines including IL-6 and TNF. CONCLUSION: Our results support the positive cognitive effects of boswellic acids by reducing the systemic inflammation.

Acetyl-11-Keto-Beta-Boswellic Acid Has Therapeutic Benefits for NAFLD Rat Models That Were Given a High Fructose Diet by Ameliorating Hepatic Inflammation and Lipid Metabolism.

Acetyl-11-keto-beta-boswellic acid (AKBA), a potent anti-inflammatory compound purified from Boswellia species, was investigated in a preclinical study for its potential in preventing and treating non-alcoholic fatty liver disease (NAFLD), the most common chronic inflammatory liver disorder. The study involved thirty-six male Wistar rats, equally divided into prevention and treatment groups. In the prevention group, rats were given a high fructose diet (HFrD) and treated with AKBA for 6 weeks, while in the treatment group, rats were fed HFrD for 6 weeks and then given a normal diet with AKBA for 2 weeks. At the end of the study, various parameters were analyzed including liver tissues and serum levels of insulin, leptin, adiponectin, monocyte chemoattractant protein-1 (MCP-1), transforming growth factor beta (TGF-ß), interferon gamma (INF-ϒ), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α). Additionally, the expression levels of genes related to the inflammasome complex and peroxisome proliferator-activated receptor gamma (PPAR-ϒ), as well as the levels of phosphorylated and non-phosphorylated AMP-activated protein kinase alpha-1 (AMPK-α1) protein, were measured. The results showed that AKBA improved NAFLD-related serum parameters and inflammatory markers and suppressed PPAR-ϒ and inflammasome complex-related genes involved in hepatic steatosis in both groups. Additionally, AKBA prevented the reduction of the active and inactive forms of AMPK-α1 in the prevention group, which is a cellular energy regulator that helps suppress NAFLD progression. In conclusion, AKBA has a beneficial effect on preventing and avoiding the progression of NAFLD by preserving lipid metabolism, improving hepatic steatosis, and suppressing liver inflammation.

Plasma Cytokines Profile in Subjects with Alzheimer's Disease: Interleukin 1 Alpha as a Candidate for Target Therapy.

Background: Alzheimer's disease (AD) is the main cause of the neurodegenerative disorder, which is not detected unless the cognitive deficits are manifested. An early prediagnostic specific biomarker preferably detectable in plasma and hence non-invasive is highly sought-after. Various hypotheses refer to AD, with amyloid-beta (Aß) being the most studied hypothesis and inflammation being the most recent theory wherein pro-and anti-inflammatory cytokines are the main culprits. Materials and Methods: In this study, the cognitive performance of AD patients (n=39) was assessed using mini-mental state examination (MMSE), AD assessment scale-cognitive subscale (ADAS-cog), and clinical dementia rating (CDR). Their neuropsychiatric symptoms were evaluated through neuropsychiatric inventory-questionnaire (NPI-Q). Moreover, plasma levels of routine biochemical markers, pro-/anti-inflammatory cytokines such as tumor necrosis factor α (TNF-α), interleukin-1 α (IL-1α), IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-12p70, IL-10, Interferon-gamma, chemokines, including prostaglandin E2 (PGE-2), monocyte chemoattractant protein-1, interferon gamma-induced protein 10, Aß peptide species (42, 40) and Transthyretin (TTR) were measured. Results: Our results revealed that Aß 42/40 ratio and TTR were correlated (r=0.367, P=0.037). IL-1α was directly correlated with ADAS-cog (r=0.386, P=0.017) and Aß 40 (r=0.379, P=0.019), but was inversely correlated with IL-4 (r=-0.406, P=0.011). Negative correlations were found between MMSE and PGE2 (r=-0.405, P=0.012) and TNF-α/ IL-10 ratio (r=-0.35, P=0.037). CDR was positively correlated with both PGE2 (r=0.358, P=0.027) and TNF-α (r=0.416, P=0.013). There was a positive correlation between NPI-caregiver distress with CDR (r=0.363, P=0.045) and ADAS-cog (r=0.449, P=0.019). Conclusion: Based on the observed correlation between IL-1α, as a clinical moiety, and ADAS-cog, as a clinical manifestation of AD, anti-IL-1α therapy in AD could be suggested.

New thiazole-2(3H)-thiones containing 4-(3,4,5-trimethoxyphenyl) moiety as anticancer agents.

A new series of thiazole-2(3H)-thiones containing 4-(3,4,5-trimethoxyphenyl) moiety were synthesized as diaryl-heterocylic analogs of combretastatin A-4 with anticancer activity. The cytotoxicity evaluation of synthesized compounds against cancer cell lines (A549, MCF-7 and SKOV3) revealed that most of them had potent cytotoxic activity toward all tested cell lines (IC50s < 10 µg/mL). Among them, 3-(chlorobenzyl) derivatives 5c and 5d showed the best inhibitory effect on MCF-7 cells (IC50 values of 1.14 and 2.41 µg/mL, respectively). Furthermore, the ability of tubulin polymerization inhibition and apoptosis induction were evaluated for the promising compounds 5c and 5d. Results suggested that these compounds remarkably inhibit tubulin polymerization and induce apoptosis resulting in cell death. In vitro studies revealed that these compounds had no significant cytotoxicity against normal cells at the concentrations required for growth inhibition of cancer cells. In vitro biding assay and in silico docking study also confirmed the binding of prototype compound to the colchicine binding site of tubulin.

Analgesic Effect and Hemodynamic Changes Due to Dexmedetomidine Versus Fentanyl During Elective Colonoscopy: A Double-Blind Randomized Clinical Trial.

BACKGROUND: There are different methods used for anesthesia during a colonoscopy procedure. OBJECTIVES: The aim of this study was to compare the analgesic effect and hemodynamic changes due to dexmedetomidine and fentanyl during elective colonoscopy. METHODS: This double-blind clinical trial was conducted on 80 patients aged 20 - 70 years, candidates for elective colonoscopy, who were randomly divided into two equal groups. In the intervention group (group D), dexmedetomidine 1 mcg/kg was given 10 minutes before starting the colonoscopy and then, 0.5 mcg/kg/hour during colonoscopy was prescribed. In the control group (group F), fentanyl 0.5 mcg/kg was prescribed three minutes before starting the colonoscopy and then, the normal saline infusion was used as maintenance. Propofol 20 mg was prescribed as the rescue dose if needed (pain or severe discomfort during colonoscopy) during the procedure. Demographic and basic clinical data and blood pressure, heart rate, respiratory rate, peripheral oxygen saturation (SpO2), and pain score (based on the visual analogue scale) were recorded from the start of the colonoscopy (time 0) and every 5 minutes until the recovery. RESULTS: The two groups had no significant difference in the duration of colonoscopy, colonoscopist's satisfaction, and patients' satisfaction (P > 0.05). The mean pain score during colonoscopy was lower in the dexmedetomidine group (P = 0.039). Heart rate was less in the dexmedetomidine group than in the fentanyl group and this difference was statistically significant. The mean arterial pressure had no difference between the two groups. CONCLUSIONS: The results of the present study showed pain score was lower in the dexmedetomidine group than in the fentanyl group.