Cannabis use moderates the relationship between pain and negative affect in adults with opioid use disorder

IntroductionAdults in Medication-Assisted Treatment (MAT) for opioid addiction are at risk for substance use relapse and opioid overdose. They often have high rates of cannabis use and comorbid symptoms of pain, depression, and anxiety. Low levels of self-efficacy (confidence that one can self-manage symptoms) are linked to higher symptom burdens and increased substance use. The effects of cannabis use on symptom management among adults with MAT are currently unclear. Therefore, the primary purpose of this study is to examine whether cannabis use moderates the relationships between pain and negative affect (i.e., depression and anxiety) and whether self-efficacy influences these interactions.MethodsA total of 150 adults receiving MAT and attending one of two opioid treatment program clinics were administered a survey containing measures of pain, depression, anxiety, self-efficacy, and cannabis use.ResultsCannabis use frequency moderated the relationships between pain and depression as well as pain and anxiety. Specifically, as cannabis use frequency increased, the positive relationships between pain and depression and pain and anxiety grew stronger. However, cannabis use was no longer a significant moderator after controlling for self-efficacy.ConclusionsResults suggest that cannabis use strengthens, rather than weakens, the relationships between pain and depression and pain and anxiety. These effects appear to be driven by decreased self-efficacy in cannabis users. It is important to understand how self-efficacy can be improved through symptom self-management interventions and whether self-efficacy can improve distressing symptoms for people in MAT.     

NLRP3 Inflammasome Mediates Chronic Mild Stress-Induced Depression in Mice via Neuroinflammation

Background:

Evidence from both clinical and experimental research indicates that the immune-brain interaction plays a pivotal role in the pathophysiology of depression. A multi-protein complex of the innate immune system, the NLRP3 inflammasome regulates cleavage and secretion of proinflammatory cytokine interleukin-1β. The inflammasome detects various pathogen-associated molecule patterns and damage-associated molecule patterns, which then leads to a series of immune-inflammatory reactions.

Methods:

To explore the role of inflammasome activation in the underlying biological mechanisms of depression, we established a mouse model of depression with unpredictable chronic mild stress.

Results:

Mice subjected to chronic mild stress for 4 weeks had significantly higher serum corticosterone levels, serum interleukin-1β levels, and hippocampal active interleukin-1β protein levels. They also displayed depressive-like symptoms, including decreased sucrose preference and increased immobility time. Moreover, the hippocampi of chronic mild stress-exposed mice had significantly higher activity of caspase-1, which accompanied by higher protein levels of NLRP3 and the apoptotic speck-containing protein with a card. Pretreatment with the NLRP3 inflammasome inhibitor VX-765 decreased serum and hippocampal levels of interleukin-1β protein and significantly moderated the depressive-like behaviors induced by chronic mild stress.

Conclusions:

These data suggest the NLRP3 inflammasome mediates stress-induced depression via immune activation. Future procedures targeting the NLRP3 inflammasome may have promising effects in the prevention and treatment of depression.     

Pristimerin protects against inflammation and metabolic disorder in mice through inhibition of NLRP3 inflammasome activation

Excessive activation of NLRP3 inflammasome is associated with the pathogenesis of inflammatory diseases. Pristimerin (Pri) is a quinonoid triterpene derived from traditional Chinese medical herb Celastraceae and Hippocrateaceae. Pri has shown antifungal, antibacterial, antioxidant, and anticancer activities. In this study we investigated whether NLRP3 inflammasome was associated with the anti-inflammatory activity of Pri. We showed that Pri (0.1−0.4 μM) dose-dependently blocked caspase-1 activation and IL-1β maturation in LPS-primed mouse bone-marrow-derived macrophages (BMDMs). Pri specifically inhibited NLRP3 inflammasome activation, had no visible effects on NLRC4 and AIM2 inflammasome activation. Furthermore, we demonstrated that Pri blocked the assembly of the NLRP3 inflammasome via disturbing the interaction between NEK7 and NLRP3; the α, β-unsaturated carbonyl moiety of Pri was essential for NLRP3 inflammasome inactivation. In LPS-induced systemic inflammation mouse model and MSU-induced mouse peritonitis model, preinjection of Pri (500 μg/kg, ip) produced remarkable therapeutic effects via inhibition of NLRP3 inflammasome in vivo. In HFD-induced diabetic mouse model, administration of Pri (100 μg· kg⁻¹ ·d⁻¹, ip, for 6 weeks) reversed HFD-induced metabolic disorders via suppression of NLRP3 inflammasome activation. Taken together, our results demonstrate that Pri acts as a NLRP3 inhibitor, suggesting that Pri might be useful for the treatment of NLRP3-associated diseases.     

Sigma receptor modulators: a patent review

Introduction: Sigma receptors are involved in several central nervous system (CNS) disorders, including mood disorders (depression and anxiety), psychosis, schizophrenia, movement disorders (i.e., Parkinson's disease) and memory deficits (i.e., Alzheimer's disease). Recently, the involvement of sigma receptors in neuropathic pain and cancer has also been observed.

Areas covered: This review aims at highlighting the research advancements published in the patent literature between 1986 and 2012, dividing patents according to both their time frame and applicants. The review especially focuses on the development of sigma receptor modulators and their application over the years with respect to CNS diseases, neuropathic pain and neurodegenerative pathologies. The literature was sought through Espacenet, Orbit, ISI Web and PubMed databases.

Expert opinion: In recent years, considerable progress in the knowledge of the biology and pharmacology of sigma receptors has encouraged research on the potential benefits of sigma modulators in a wide range of pathologies. So far, only few potent agonists and antagonists of sigma receptors are in clinical trial for acute and chronic neurodegenerative diseases (SA4503 and ANAVEX 2-73) or neuropathic pain (E-52862).     

Acetylase inhibitor SI-2 is a potent anti-inflammatory agent by inhibiting NLRP3 inflammasome activation

Aberrant activation of Nod-like receptor family pyrin domain-containing-3 (NLRP3) inflammasome is implicated in a variety of inflammatory diseases. Targeting NLRP3 inflammasome represents a promising therapy to cure such diseases. We and others recently demonstrated that acetylation of NLRP3 promotes the inflammasome activity and also suggested lysine acetyltransferases inhibitors could be a kind of promising agents for treating NLRP3 associated disorders. In this study, by searching for kinds of lysine acetyltransferases inhibitors, we showed that SI-2 hydrochloride (SI-2), a specific inhibitor of lysine acetyltransferase KAT13B (lysine acetyltransferases 13B), specifically blocks NLRP3 inflammasome activation both in mice in vivo and in human cells ex vivo. Intriguingly, SI-2 does not affect the acetylation of NLRP3. Instead, it disrupts the interaction between NLRP3 and adaptor apoptosis-associated speck-like protein containing CARD (ASC), then blocks the formation of ASC speck. Thus, our study identified a specific inhibitor for NLRP3 inflammasome and suggested SI-2 as a potential inhibitory agent for the therapy of NLRP3-driven diseases.     

Mitochondria and the NLRP3 inflammasome: physiological and pathological relevance

The NLRP3 inflammasome is assembled and activated in certain types of myeloid cells upon sensing microbe-derived toxins or host-derived danger signals. Activation of the NLRP3 inflammasome by endogenous ligands has been discovered in various disorders, including metabolic syndrome, type 2 diabetes, atherosclerosis, gout, reperfusion injury of the heart, neurodegeneration, such as Alzheimer’s disease, chronic kidney diseases, and macular degeneration of the eyes. Despite the potential significance of the NLRP3 inflammasome in the pathogenesis of several diseases, details on the activation mechanism of the NLRP3 inflammasome by a variety of stimulators have yet to be reported. Emerging evidence suggests that mitochondrial events are associated with NLRP3 activation in disease conditions. Mitochondrial dysfunction acts upstream of NLRP3 activation by providing reactive oxygen species (ROS) to trigger NLRP3 oligomerization or by inducing α-tubulin acetylation to relocate mitochondria to the proximity of NLRP3. In addition, mitochondria work as a platform for inflammasome assembly. Mitochondrial events may also lie downstream of NLRP3 activation. While the molecular mechanisms of mitochondrial dysfunction associated with NLRP3 activation are still unclear, they may involve the perturbation of mitochondria by K⁺ efflux and subsequent intracellular disequilibrium. Thus, mitochondria and NLRP3 machinery appear to be closely interwoven at multiple levels.     

Adenovirus-delivered angiopoietin-1 ameliorates phosgene-induced acute lung injury via inhibition of NLRP3 inflammasome activation

Objective: Angiopoietin-1 (Ang1) is reported to have the ability to attenuate endothelial permeability and inflammation during the stress condition and is considered to play a critical role in vascular stabilization. The aim of this study was to investigate the mechanisms involved in the protective effects of adenovirus-delivered Ang1 in phosgene-induced acute lung injury (ALI).

Methods: ALI was induced in rats by phosgene exposure at 8.33?g/m³ for 5?min, followed by an intravenous injection of adenovirus-Ang1 (Ad/Ang1). The histologic changes of the lung were evaluated with H&;E staining. The levels of cytokines in the serum and bronchoalveolar lavage fluid (BALF) were determined by ELISA. NLRP3 inflammasome activation was assessed with immunohistochemistry, RT-PCR, Western blotting and TUNEL staining.

Results: Histologic analyses suggested that reduced severity in phosgene-induced ALI with Ad/Ang1 treatment. Reduced levels of IL-1β, IL-18 and IL-33 were found in both serum and BALF samples from Ad/Ang1-treated ALI rats induced by phosgene. Moreover, immunohistochemistry analysis revealed that Ad/Ang1 treatment inhibited the NLRP3 inflammasome activation. Decreased mRNA and protein levels of NLRP3 and caspase-1 were found in phosgene-exposed rats treated with Ad/Ang1. In addition, TUNEL staining indicated a decrease in pyroptosis in phosgene-exposed rats treated with Ad/Ang1.

Conclusions: Ang1 exerts beneficial effects on phosgene-induced lung injury via inhibition of NLRP3 inflammasome activation. Disruption of NLRP3 inflammasome activation might be served as therapeutic modality for the treatment of phosgene-induced ALI.     

Neurokinin-1-receptor antagonism decreases anxiety and emotional arousal circuit response to noxious visceral distension in women with irritable bowel syndrome: a pilot study

Background Irritable bowel syndrome is characterised by chronic abdominal pain and frequent comorbid anxiety. The substance P/neurokinin‐1 receptor system is implicated in the regulation of both pain and anxiety, suggesting a potential therapeutic target in IBS. Aim To determine whether inhibition of the neurokinin‐1 receptor (NK1R) will change pain ratings and brain responses to experimental visceral pain and anxiety symptoms in women with IBS or not. Methods Rome II positive IBS women were recruited for a double‐blind, placebo‐controlled, cross‐over study of NK1R antagonist AV608. Treatment periods were 3 weeks with a 2‐week washout period. Functional MRI during a visceral distension paradigm was performed before first treatment and after treatment blocks. SPM8 was used to compare brain activity during painful and nonpainful visceral stimuli in regions associated with emotional arousal and interoception. Negative affect, anxiety symptoms and pain ratings were assessed. Results Eleven subjects completed the study and eight subjects provided fMRI data. AV608, compared with placebo, was associated with reduced anxiety, negative affect, and pain ratings. During AV608 treatment, the amygdala, hippocampus and anterior cingulate gyrus showed decreased activity during visceral distension. AV608 was also associated with decreases in activity in brain regions associated with interoception (posterior insula, anterior mid‐cingulate gyrus). Conclusions Chronic treatment with AV608 in IBS is associated with improved mood and pain ratings and activity of emotional arousal related brain regions. This suggests that further exploration of NK1R antagonists is warranted in visceral pain disorders, particularly in patients with comorbid anxiety symptoms.     

Piezo1 activates the NLRP3 inflammasome in nucleus pulposus cell-mediated by Ca2+/NF-κB pathway

Studying and understanding the mechanism of inflammation in nucleus pulposus is the key to understand and prevent intervertebral disc degeneration. We propose a model of mechanical sensitive ion channel Piezo1 mediated inflammation of nucleus pulposus cells. Piezo1 can up-regulate the level of interleukin-1β (IL-1β) in nucleus pulposus cells once it is activated. It is suggested that Piezo1 may mediate inflammation by activating Nod-like receptor protein 3 (NLRP3) inflammasome to accelerate the production and maturation of IL-1β. The primary objective of this study was to explore whether Piezo1 activates NLRP3 inflammasome in nucleus pulposus cells. Piezo1 sensitization was induced by mechanical stretch following which we analyzed the priming and assembly of NLRP3 inflammasome and also studied if the downstream Ca²⁺/NF-κB pathway mediated this activation in nucleus pulposus cells. The expression of Piezo1 and NLRP3 inflammasome increased in a time-dependent manner upon mechanical stretch. Piezo1 activation promoted NLRP3 inflammasome assembly, which was demonstrated by the upregulation of caspase-1 activation and IL-1β production. Transfection of Piezo1-siRNA reversed this process. The inhibition of Ca²⁺/NF-κB pathway reduced Piezo1-dependent activation of NLRP3 inflammasome. Thus, we propose that activation of NLRP3 inflammasome in nucleus pulposus cells mediated by Piezo1 through the Ca²⁺/NF-κB pathway is a novel pathogenesis for the progress of intervertebral disc degeneration. As per our knowledge this is the first study which has provided evidence linking Piezo1-mediated inflammation in nucleus pulposus cells with the production of NLRP3 inflammasome.     

Increased Depression and Anxiety Symptoms are Associated with More Breakdowns in Cognitive Control to Cocaine Cues in Veterans with Cocaine Use Disorder

Objective: Cue-elicited craving is a clinically important aspect of cocaine addiction directly linked to cognitive control breakdowns and relapse to cocaine-taking behavior. However, whether craving drives breakdowns in cognitive control toward cocaine cues in veterans, who experience significantly more co-occurring mood disorders, is unknown. The present study tests whether veterans have breakdowns in cognitive control because of cue-elicited craving or current anxiety or depression symptoms. Methods: Twenty-four veterans with cocaine use disorder were cue-exposed, then tested on an antisaccade task in which participants were asked to control their eye movements toward cocaine or neutral cues by looking away from the cue. The relationship among cognitive control breakdowns (as measured by eye errors), cue-induced craving (changes in self-reported craving following cocaine cue exposure), and mood measures (depression and anxiety) was investigated. Results: Veterans made significantly more errors toward cocaine cues than neutral cues. Depression and anxiety scores, but not cue-elicited craving, were significantly associated with increased subsequent errors toward cocaine cues for veterans. Conclusions: Increased depression and anxiety are specifically related to more cognitive control breakdowns toward cocaine cues in veterans. Depression and anxiety must be considered further in the etiology and treatment of cocaine use disorder in veterans. Furthermore, treating depression and anxiety as well, rather than solely alleviating craving levels, may prove a more effective combined treatment option in veterans with cocaine use disorder.     

Fluoxetine treatment of depressed patients with comorbid anxiety disorders

Major depression with comorbid anxiety disorder is associated with poor antidepressant outcome compared to major depression without comorbid anxiety disorder. The purpose of our study was to assess changes in severity of both depressive and anxiety symptoms in outpatients with major depression with comorbid anxiety disorder following fluoxetine treatment. We enrolled 123 outpatients (mean age 38.9 +/- 10.8 years; 49% women) with major depressive disorder accompanied by one or more current comorbid anxiety disorders in our study. Patients were treated openly with fluoxetine 20 mg/day for 8 weeks. Efficacy assessments included the 17-item Hamilton Rating Scale for Depression (HAM-D) and the patient-rated Symptom Questionnaire (SQ) Scales for Depression and Anxiety. The mood and anxiety disorder modules of the Structured Clinical Interview for DSM-III-R were administered at screen and endpoint. We used 'intent-to-treat' analysis in examining all patients assigned to treatment and completing the baseline visit. The mean number of comorbid anxiety disorders per patient was 1.5 +/- 0.68. The mean HAM-D-17 score and mean Clinical Global Impressions-Severity scores decreased significantly from baseline to endpoint (week 8) following fluoxetine treatment (p < 0.0001). There were significant decreases in all four SQ scale scores, from baseline to endpoint: depression, anxiety, somatic symptoms and anger-hostility (p < 0.0001). Fifty-three percent of patients (n = 65) were depression responders (i.e. > or = 50% decrease in HAM-D-17 score at endpoint) and 46% (n = 57) were remitters (HAM-D-17 < or = 7 at endpoint). Patients with panic disorder had significantly higher baseline HAM-D-17 scores compared to those without panic disorder (p < 0.01). Patients with comorbid obsessive-compulsive disorder (OCD) were significantly less likely to be responders to fluoxetine at endpoint (> or = 50% decrease in HAM-D-17) and to be remitters (HAM-D-17 score of s 7 at endpoint) compared to patients without comorbid OCD (p < 0.01). Of the 41 patients on whom endpoint Structured Clinical Interview for DSM-III-R modules for anxiety disorders were available, 49% (n = 20) no longer met criteria for one or more of their anxiety disorder diagnoses at endpoint. Our preliminary findings suggest that fluoxetine is effective in treating outpatients with major depression with comorbid anxiety disorders, with a significant effect on both depression and anxiety symptoms. Further double-blind, placebo-controlled trials are required in larger samples to confirm our findings.     

5-HT3 Receptor Antagonism: A Potential Therapeutic Approach for the Treatment of Depression and other Disorders

BackgroundDepression or Major depressive disorder (MDD) is a prolonged condition of sadness. MDD is the most common mental disorder that affects more than 264 million people worldwide. According to the monoamine hypothesis, serotonin (5-hydroxy tryptamine, 5-HT), dopamine (DA) and norepinephrine (NE) are the major neurotransmitters (NTs) involved in depression.MethodsThe methodology adopted for writing this review article is essentially based on the secondary literature search through a systematic literature review. This review mainly focussed on the role of 5-HT₃ receptor antagonists (5-HT₃RA) in depression and comorbid disorders like anxiety.ResultsOut of three major NTs mentioned above, serotonin has a predominant role in the pathophysiology of depression. The serotonin type-3 receptors (5-HT₃R) are well renowned to be expressed in the central nervous system (CNS) in regions which have significance in the vomiting reflex, perception of pain, the reward system, cognition, depression and anxiety control. 5-HT₃R are the receptors of serotonergic family that belong to ligand-gated ion channel. 5-HT₃RA inhibit the binding of serotonin to postsynaptic 5-HT₃R and increases its availability to other receptors like 5-HT_1A, _1B and _1D as well as 5-HT₂ receptors and produces anti-depressant-like effect. 5-HT₃RA also have an important role in mood and stress disorders. Some of the studies have shown the effectiveness of these agents in stress disorder.ConclusionThe present article focussed on the role of 5-HT₃R and their antagonists in the treatment of depression and anxiety. Further studies are warranted to prove their efficacy with respect to other standard anti-depressants.     

Examining the link between psychological distress,mental health disorders and sharing behaviors among cocaine users

BackgroundPsychiatric problems and cocaine use are associated with heightened vulnerability for HIV and Hepatitis C infections. Little is known regarding the relationship between psychiatric symptoms, psychiatric diagnoses and injection risk behaviors among cocaine users. We examined the association between psychological distress and injection material sharing among cocaine users, while accounting for comorbid anxious and mood disorders.MethodsParticipants included cocaine users who inject drugs recruited in a prospective cohort study in Montreal, Canada. Diagnosis of mood and anxiety disorders in the year preceding baseline were established using the Composite International Diagnostic Interview (CIDI) questionnaire. Psychological distress based on the Kessler scale and injection material sharing in the past 3 months were assessed at baseline and at each of the five follow-up visits at 3-month intervals. Statistical analyses were conducted using generalized estimation equation.ResultsOf the 387 participants (84.5% male; 80.1%, ≥ 30 y.o.), 35% reported severe psychological distress, 43% qualified for an anxiety disorder diagnosis and 29% for a mood disorder diagnosis at baseline. Psychological distress was not associated with any injection risk behavior when adjusting for socio-demographic and psychiatric disorders. Participants with anxiety disorders were more likely to share needle (adjusted odds ratio: 1.89, 95% CI: 1.17–3.03). Sharing of injection material other than needle was not associated with psychiatric disorders or with psychological distress in multivariate analyses.ConclusionsAnxiety disorders are associated with needle sharing among cocaine users. Our results suggest the importance of screening for anxiety disorders as part of preventive interventions to decrease blood-borne viruses' transmission.     

Treatment of pain syndromes with venlafaxine

Major depressive disorder (MDD) and anxiety disorders such as generalized anxiety disorder (GAD) are often accompanied by chronic painful symptoms. Examples of such symptoms are backache, headache, gastrointestinal pain, and joint pain. In addition, pain generally not associated with major depression or an anxiety disorder, such as peripheral neuropathic pain (e.g., diabetic neuropathy and postherpetic neuralgia), cancer pain, and fibromyalgia, can be challenging for primary care providers to treat. Antidepressants that block reuptake of both serotonin and norepinephrine, such as the tricyclic antidepressants (e.g., amitriptyline), have been used to treat pain syndromes in patients with or without comorbid MDD or GAD. Venlafaxine, a serotonin and norepinephrine reuptake inhibitor, has been safe and effective in animal models, healthy human volunteers, and patients for treatment of various pain syndromes. The use of venlafaxine for treatment of pain associated with MDD or GAD, neuropathic pain, headache, fibromyalgia, and postmastectomy pain syndrome is reviewed. Currently, no antidepressants, including venlafaxine, are approved for the treatment of chronic pain syndromes. Additional randomized, controlled trials are necessary to fully elucidate the role of venlafaxine in the treatment of chronic pain.     

Astragaloside IV attenuates sepsis-induced intestinal barrier dysfunction via suppressing RhoA/NLRP3 inflammasome signaling

Intestinal barrier dysfunction is a trigger for sepsis progression. NLRP3 inflammasome and RhoA contribute to sepsis and intestinal inflammation. The current study aimed to explore the effects of Astragaloside IV (AS-IV), a bioactive compound from Astragalus membranaceus, on sepsis-caused intestinal barrier dysfunction and whether NLRP3 inflammasome and RhoA are involved. Septic mice modeled by cecal ligation and puncture (CLP) operation were administered with 3 mg/kg AS-IV intravenously. AS-IV decreased mortality, cytokines release, I-FABP secretion, intestinal histological score and barrier permeability, and increased tight junction (TJ) expression in intestine in CLP model. Also, in Caco-2 cells subjected to lipopolysaccharide (LPS), 200 μg/mL AS-IV co-incubation reduced cytokines levels and enhanced in vitro gut barrier function without cytotoxicity. Subsequently, NLRP3 inflammasome and RhoA were highly activated both in intestinal tissue in vivo and in Caco-2 cells in vitro, both of which were significantly suppressed by AS-IV treatment. In addition, the benefits of AS-IV on Caco-2 monolayer barrier were largely counteracted by RhoA agonist CN03 and NLRP3 gene overexpression, respectively. Furthermore, LPS-induced NLRP3 inflammasome activation was abrogated by RhoA inhibitor C3 exoenzyme. However, NLRP3 knockdown by siRNA hardly affected RhoA activation in Caco-2 cells. These data suggest that AS-IV protects intestinal epithelium from sepsis-induced barrier dysfunction via inhibiting RhoA/NLRP3 inflammasome signal pathway.     

Agmatine Reverses Sub‐chronic Stress induced Nod‐like Receptor Protein 3 (NLRP3) Activation and Cytokine Response in Rats

The activation of Nod‐like receptor protein 3 (NLRP3) has lately been implicated in stress and depression as an initiator mechanism required for the production of interleukin (IL)‐1β and IL‐18. Agmatine, an endogenous polyamine widely distributed in mammalian brain, is a novel neurotransmitter/neuromodulator, with antistress, anxiolytic and antidepressant‐like effects. In this study, we examined the effect of exogenously administered agmatine on NLRP3 inflammasome pathway/cytokine responses in rats exposed to restraint stress for 7 days. The rats were divided into three groups: stress, stress+agmatine (40 mg/kg; i.p.) and control groups. Agmatine significantly down‐regulated the gene expressions of all stress‐induced NLRP3 inflammasome components (NLRP3, NF‐κB, PYCARD, caspase‐1, IL‐1β and IL‐18) in the hippocampus and prefrontal cortex (PFC) and reduced pro‐inflammatory cytokine levels not only in both brain regions, but also in serum. Stress‐reduced levels of IL‐4 and IL‐10, two major anti‐inflammatory cytokines, were restored back to normal by agmatine treatment in the PFC. The findings of the present study suggest that stress‐activated NLRP3 inflammasome and cytokine responses are reversed by an acute administration of agmatine. Whether antidepressant‐like effect of agmatine can somehow, at least partially, be mediated by the inhibition of NLRP3 inflammasome cascade and relevant inflammatory responses requires further studies in animal models of depression.     

Interruption of Helicobacter pylori-Induced NLRP3 Inflammasome Activation by Chalcone Derivatives

Helicobacter pylori causes chronic gastritis through cag pathogenicity island (cagPAI), vacuolating cytotoxin A (VacA), lipopolysaccharides (LPS), and flagellin as pathogen-related molecular patterns (PAMPs), which, in combination with the pattern recognition receptors (PRRs) of host cells promotes the expression and secretion of inflammation-causing cytokines and activates innate immune responses such as inflammasomes. To identify useful compounds against H. pylori-associated gastric disorders, the effect of chalcone derivatives to activate the nucleotide-binding oligomerization domain (NOD)-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome was examined in an H. pylori-infected human monocytic THP-1 cell line in this study. Among the five synthetic structurally-related chalcone derivatives examined, 2’-hydroxy-4’,6’-dimethoxychalcone (8) and 2’-hydroxy-3,4,5-trimethoxychalcone (12) strongly blocked the NLRP3 inflammasome in H. pylori-infected THP-1 cells. At 10 μM, these compounds inhibited the production of active IL-1β, IL-18, and caspase-1, and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) oligomerization, but did not affect the expression levels of NLRP3, ASC, and pro-caspase-1. The interruption of NLRP3 inflammasome activation by these compounds was found to be mediated via the inhibition of the interleukin-1 receptor-associated kinase 4 (IRAK4)/IκBα/NF-κB signaling pathway. These compounds also inhibited caspase-4 production associated with non-canonical NLRP3 inflammasome activation. These results show for the first time that certain chalcones could interrupt the activation of the NLRP3 inflammasome in H. pylori-infected THP-1 cells. Therefore, these chalcones may be helpful in alleviating H. pylori-related inflammatory disorders including chronic gastritis.     

Impact of comorbid depression or anxiety on patterns of treatment and economic outcomes among patients with diabetic peripheral neuropathic pain

ABSTRACT

Objective: The objective of this retrospective analysis was to assess the correlation of comorbid depression and/or anxiety to patterns of treatment, healthcare utilization, and associated costs among diabetic peripheral neuropathic pain (DPNP) patients, employing a large US administrative claims database.

Research design and methods: Patients under age 65 with commercial insurance and patients aged 65 and older with employer-sponsored Medicare supplemental insurance were selected for the study if they had at least one diagnosis of DPNP in 2005. The first observed DPNP claim was considered the ‘index date.’ All individuals had a 12-month pre-index and 12-month follow-up period. For both populations, two subgroups were constructed for individuals with depression and/or anxiety (DPNP-DA cohort) or without these disorders (DPNP-only cohort). Patients’ demographic characteristics, clinical characteristics, and medication use were compared over the pre-index period. Healthcare expenditures and resource utilization were measured for the post-index period. Two-part models were used to examine the impact of comorbid depression and/or anxiety on healthcare utilization and costs, controlling for demographic and clinical characteristics.

Results: The study identified 11?854 DPNP-only and 1512 DPNP-DA patients in the Medicare supplemental cohort, and 11?685 and 2728 in the commercially insured cohort. Compared to DPNP-only patients over the follow-up period, a significantly higher percentage of DPNP-DA patients were dispensed pain and DPNP-related medication. All components of healthcare utilization, except home healthcare visits and physician office visits, were more likely to be provided to DPNP-DA patients versus the DPNP-only cohort (all p?<?0.01). Controlling for differences in demographic and clinical characteristics, DPNP-DA patients had significantly higher total costs than those of DPNP-only patients for Medicare ($9134, p?<?0.01) and commercially insured patients ($11?085, p?<?0.01).

Limitations: Due to the use of a retrospective administrative claims database, limitations of this study include the potential for selection bias between study cohorts, mis-identification of DPNP and/or depression, and inability to assess indirect costs as well as use and cost of over-the-counter medications.

Conclusions: These findings indicate that the healthcare costs were significantly higher for DPNP patients comorbid with depression and/or anxiety relative to those without such disorders.     

The Ketone Body β-Hydroxybutyrate Does Not Inhibit Synuclein Mediated Inflammasome Activation in Microglia

Parkinson's disease (PD) is recognized as the most common neurodegenerative movement disorder and results in debilitating motor deficits. The accumulation and spread of neurotoxic synuclein aggregates in the form of Lewy bodies is a key pathological feature of PD. Chronic activation of the NLRP3 inflammasome by protein aggregates is emerging as a major pathogenic mechanism in progressive neurodegenerative disorders and is considered an important therapeutic target. Recently the ketone body, β-hydroxy butyrate (BHB), was shown to efficiently inhibit the NLRP3 inflammasome in macrophages, and in vivo models of inflammatory disease. Furthermore, BHB can readily cross the blood brain barrier suggesting that it could have therapeutic benefits for the management of PD. In this study, we evaluated if BHB could inhibit chronic microglial inflammasome activation induced by pathological fibrillar synuclein aggregates. Interestingly, we found that BHB treatment almost completely blocked all aspects of inflammasome activation and pyroptosis induced by ATP and monosodium urate (MSU) crystals, consistent with previously published reports in macrophages. Surprisingly however, BHB did not inhibit inflammasome activation and release of IL-1β or caspase-1 induced by synuclein fibrils. Our results demonstrate that BHB does not block the upstream pathways regulating inflammasome activation by synuclein fibrils and suggest that synuclein mediated inflammasome activation proceeds via distinct mechanisms compared to traditional NLRP3 activators such as ATP and MSU.