Release Of Inflammatory Mediators Research Articles

Role of Platelet-Activating Factor in the Pathogenesis of Chronic Spontaneous Urticaria

Chronic spontaneous urticaria (CSU) is a debilitating condition characterized by mast cell activation. Platelet-activating factor (PAF) is produced by various immune cells, including mast cells, basophils, lymphocytes, and eosinophils, which play crucial roles in CSU pathogenesis. It induces mast cell degranulation, increases vascular permeability, and promotes the chemotaxis of inflammatory cells. These effects result in the release of inflammatory mediators, the development of edema, and the persistence of inflammation, which are key features of CSU. Notably, elevated PAF levels have been linked to heightened disease activity and resistance to antihistamine treatment in CSU patients. Despite these findings, the precise role of PAF in CSU pathogenesis remains unclear. Rupatadine, an antihistamine, and heat shock protein 10, a natural anti-inflammatory peptide that selectively inhibits PAF-induced mast cell degranulation, have demonstrated anti-PAF activity. Furthermore, with the molecular structure of the PAF receptor now identified, several experimental PAF receptor antagonists have been synthesized. However, there remains a significant need for the development of therapeutic options targeting PAF in CSU management.

Multiple Aspects of Irritable Bowel Syndrome and the Role of the Immune System: An Overview of Systematic Reviews with a Focus on Polyphenols

Irritable bowel syndrome (IBS) is a complex and often debilitating condition that significantly impacts the gastrointestinal system and the overall quality of life of those affected. IBS is characterized by a variety of distressing symptoms, including cramping, abdominal pain, and irregular bowel movements, underlined by an intricate interplay of immune system dysfunction in its pathology. Numerous studies highlight an increased cellular immune response, with elevated levels of proinflammatory cytokines, mucosal alterations due to immune imbalance, and visceral hypersensitivity. Notably, studies indicate increased levels of proinflammatory cytokines, immune imbalances that lead to mucosal changes, and heightened visceral sensitivity. The roles of effector and regulatory T cells are particularly intriguing, as their modification appears to amplify inflammation and may even contribute to autoimmune disorders. This overview of systematic reviews explores the connections between IBS and immune responses, with a focus on immune cell alterations and proliferation of lymphocytes and mast cells in affected individuals. Furthermore, we explore various aspects of IBS management, including its pharmacological approaches. A systematic search of PubMed and Web of Science yielded 676 articles, which were ultimately narrowed down to 9 key studies that met our inclusion criteria. These studies collectively underscore the activation of the immune system with the degranulation of the mast cells in patients with IBS, where the release of inflammatory mediators can compromise intestinal permeability, exacerbating symptoms further. Additionally, we examine the multifaceted management strategies for IBS, emphasizing the potential therapeutic benefits of dietary polyphenols as antioxidants. The present study aims to enhance our understanding of IBS and offer insights into more effective treatment strategies for this challenging condition.

Homocysteine aggravates intestinal inflammation through promotion of 5-LOX and COX-2 in IBD

BackgroundHomocysteine (Hcy) is a pro-inflammatory molecule that has the potential to induce oxidative damage to cells and stimulate the release of inflammatory mediators. Hcy has been observed to enhance the production of inflammatory agents in vascular endothelial cells. However, the impact of Hcy on intestinal mucosal inflammation remains largely unexplored. Therefore, the objective of this study was to examine the potential of Hcy to stimulate the synthesis of inflammatory mediators and elucidate the underlying mechanisms in the intestinal mucosa.MethodsA total of 99 patients diagnosed with inflammatory bowel disease (IBD) and 10 healthy individuals were included in this study to assess the impact of homocysteine (Hcy) on the levels of leukotriene E4 (LTE4) and prostaglandin E2 (PGE2). The underlying mechanism responsible for the generation of LTE4 and PGE2 induced by Hcy was investigated using colitis rats and Caco-2 cells. 32 Sprague–Dawley rats were categorized into four groups: normal control, TNBS model, normal with Hcy injection, and TNBS model with Hcy injection. The mRNA expressions of 5-LOX, COX-2, and NF-κB were assessed using reverse transcription quantitative polymerase chain reaction (RT-qPCR). Caco-2 cells were subjected to treatment with varying concentrations (10, 20, 50, 100 μmol/L) of Hcy and incubated for different durations (1, 3, 6 h). The alterations in NF-κB activity, as well as the levels of Hcy, LTE4, and PGE2, were measured using enzyme-linked immunosorbent assay (ELISA).ResultsThe excretion of Hcy, LTE4, and PGE2 in urine exhibited significant increases in patients with inflammatory bowel disease (IBD), Crohn's disease (CD), and ulcerative colitis (UC). In addition, Hcy demonstrated a significant increase in the expression of 5-LOX, COX-2, and NF-κB, as well as elevated levels of LTE4 and PGE2 in rats with colitis. Furthermore, Hcy was found to induce NF-κB activation and nuclear translocation, thereby contributing to the enhanced synthesis of LTE4 and PGE2 in Caco-2 cells.ConclusionsHcy was found to enhance the expression of 5-LOX and COX-2 by activating NF-κB, thereby augmenting the production of LTE4 and PGE2, which ultimately exacerbates colonic inflammation in individuals with inflammatory bowel disease (IBD).

Cardioprotective effect of tofisopam against isoprenaline-induced myocardial infarction in rats via modulation of NLRP3\\IL-1β\\caspase-1 pathway

Purpose Cardiovascular diseases (CVDs) are a leading cause of morbidity and mortality worldwide. Ischemic heart diseases, particularly acute myocardial infarction (MI), represent the most common cause of death. MI is influenced by multiple factors, including the release of inflammatory mediators. A significant percentage of individuals with CVD experience psychological effects, such as anxiety and depression, which are linked to an increased risk of coronary heart disease. Certain anti-anxiety medications have demonstrated immunomodulatory and anti-inflammatory effects. Tofisopam, a 2,3-benzodiazepine with anxiolytic properties, has been shown to exert in vitro anti-inflammatory and immunomodulatory effects. The present study investigates the potential of tofisopam as a protective adjuvant against isoprenaline-induced MI in rats and explores the possible underlying mechanisms. Methods The study included four groups: a control group, a group pretreated with tofisopam, an isoprenaline toxic group, and an isoprenaline toxic group pretreated with tofisopam. Results The findings demonstrated that isoprenaline significantly increased cardiac enzyme levels, as well as elevated oxidative and inflammatory stress parameters, along with evident apoptosis in cardiac cells. In contrast, the tofisopam-pretreated group showed a significant reversal of the cardiac damage induced by isoprenaline. Conclusions Tofisopam protects against isoprenaline-induced MI through its antioxidant, anti-inflammatory, and anti-apoptotic properties.

MiR-144/451: A Regulatory Role in Inflammation.

Inflammation is the natural defense mechanism of the body in response to injury, infection, or other stimuli. Excessive or persistent inflammatory responses can lead to the development of inflammatory diseases. Therefore, elucidating the regulatory mechanisms of inflammatory cells is crucial for understanding the pathogenesis of such diseases and devising novel therapeutic approaches. Moreover, miR-144/451 plays an important role in erythroid maturity and tumour development. Herein, we have reviewed the regulatory role of miR-144/451 in inflammation. Papers on miR-144, miR-451, and inflammation were retrieved from PubMed and Web of Science to be analysed and summarised. miR-144/451 plays a significant role in modulating inflammatory responses. Pro- and anti-inflammatory gene transcription is regulated by miR-144/451 binding to the 3' untranslated regions. Studies have shown that miR-451 inhibits the activation of various inflammatory cells, including macrophages, neutrophils, and T lymphocytes, thereby reducing the release of inflammatory mediators. However, miR-144 expression varies in different inflammatory diseases. miR-144 expression is downregulated in macrophages after induction by lipopolysaccharide, cysteine, or Mycobacterium tuberculosis, which promotes the secretion of inflammatory mediators; nonetheless, miR-144-3p overexpression in macrophages can aggravate atherosclerosis. Meanwhile, miR-144 overexpression prevents disruption of the lung endothelial cell barrier, whereas it exacerbates endothelial cell injury in Crohn's disease. miR-144/451 may serve as a potential target for the treatment of inflammatory diseases.

The exploration of active components of 701 Dieda Zhentong patch and analgesic properties on chronic constriction injury rats.

An increasing number of traditional Chinese medicine(TCM) have been confirmed to possess analgesic bioactivity. 701 Dieda Zhentong patch(701-DZP) which includes 14 kinds of TCMs exhibited excellent efficacy in alleviating back or leg pain after a soft-tissue injury. In this study, UPLC/MS was used to construct the fingerprint of 701-DZP and excavate the potential bioactive ingredients of it. 21 compounds were detected and identified in the fingerprint including 12 compounds that pass through the skin and 6 compounds observed in the plasma. Then, the role of 701-DZP in neuropathic pain(NPP) was assessed by network pharmacology and CCI rats. 701-DZP inhibited pain sensitization(MWT and TWL) and the release of inflammation mediators(IL-1β and IL-6) in CCI rats which were in keeping with the core targets of the PPI network. The results of IHC and Western blot showed that the expression of the P2X3 receptor in the DRG and SC of CCI rats was significantly reduced after the treatment with 701-DZP. Moreover, the 701-DZP down-regulated the level of phosphorylation of ERK1/2 MAPK instead of P38 MAPK in the DRG of CCI rats. In conclusion, this study has clarified 6 potential analgesic active compounds of 701-DZP and explored the analgesic properties, which may inhibit the expression of the P2X3 receptor to reduce the release of inflammatory mediators based on the ERK1/2 MAPK pathway to alleviate the NPP.

Spleen tyrosine kinase: a novel pharmacological target for sepsis-induced cardiac dysfunction and multi-organ failure

Sepsis is a systemic condition caused by a dysregulated host response to infection and often associated with excessive release of proinflammatory cytokines resulting in multi-organ failure (MOF), including cardiac dysfunction. Despite a number of effective supportive treatments (e.g. ventilation, dialysis), there are no specific interventions that prevent or reduce MOF in patients with sepsis. To identify possible intervention targets, we re-analyzed the publicly accessible Gene Expression Omnibus accession GSE131761 dataset, which revealed an increased expression of spleen tyrosine kinase (SYK) in the whole blood of septic patients compared to healthy volunteers. This result suggests a potential involvement of SYK in the pathophysiology of sepsis. Thus, we investigated the effects of the highly selective SYK inhibitor PRT062607 (15mg/kg; i.p.) on sepsis-induced cardiac dysfunction and MOF in a clinically-relevant, murine model of sepsis. PRT062607 or vehicle (saline) was administered to 10-weeks-old C57BL/6 mice at 1h after the onset of sepsis induced by cecal ligation and puncture (CLP). Antibiotics (imipenem/cilastatin; 2mg/kg; s.c.) and analgesic (buprenorphine; 0.05mg/kg; i.p.) were administered at 6h and 18h post-CLP. After 24h, cardiac function was assessed in vivo by echocardiography and, after termination of the experiments, serum and cardiac samples were collected to evaluate the effects of SYK inhibition on the systemic release of inflammatory mediators and the degree of organ injury and dysfunction. Our results show that treatment of CLP-mice with PRT062607 significantly reduces systolic and diastolic cardiac dysfunction, renal dysfunction and liver injury compared to CLP-mice treated with vehicle. In addition, the sepsis-induced systemic inflammation (measured as an increase in inflammatory cytokines and chemokines in the serum) and the cardiac activation of NF-kB (IKK) and the NLRP3 inflammasome were significantly reduced in CLP-mice treated with PRT062607. These results demonstrate, for the first time, that SYK inhibition 1h after the onset of sepsis reduces the systemic inflammation, cardiac dysfunction and MOF, suggesting a potential role of the activation of SYK in the pathophysiology of sepsis. Novel therapeutic strategies that inhibit SYK activity may be of benefit in patients with diseases associated with local or systemic inflammation including sepsis.

Mechanistic insights into antihypertensive activity of mushroom-derived protein-peptides via metabolomic and proteomic approaches

Stropharia rugosoannulata mushroom peptides have well-defined sequences, specific structures, and excellent antihypertensive activity. In this study, metabolomic and proteomic analyses revealed the antihypertensive mechanism of mushroom-derived protein-peptides, GQEDYDRLRPL (GL-11P) and KSWDDFFTR (KR-9P), to demonstrate their potential antihypertensive buck-regulation systems and pathways. Protein-peptides were predominantly down-regulated expression of endogenous metabolites in antihypertensive regulation, and bile acid analogs were key endogenous differentially expressed metabolic markers. Antihypertensive treatment with protein-peptides activated the immune and signal transduction systems, affected extracellular regions, metal ion binding, and receptor binding ability. The ECM-receptor interaction pathway, with differentially expressed proteins in antihypertensive treatment, distinguished the protein-peptides from blank control and was also a critical pathway that distinguished the two protein-peptides. Up-regulatory pathways of protein expression dominated by GL-11P's antihypertensive regulation, while down-regulatory pathways of protein expression dominated by KR-9P's antihypertensive regulation. Protein-peptides exerted antihypertensive regulatory effects by enhancing immune responses, up-regulating protein and enzyme binding capacity, and down-regulating inflammatory mediator release. Differentially expressed protein interactions produced in protein-peptides antihypertensive therapy mostly up-regulated the Reactome pathway and were dominated by immune system regulation. This study provided data support for utilizing mushroom-derived protein-peptides in antihypertensive therapy, and enriched the theoretical basis of protein-peptides' antihypertensive regulation mechanisms.

Lysimachia mauritiana Lam. Extract Alleviates Airway Inflammation Induced by Particulate Matter Plus Diesel Exhaust Particles in Mice.

The respiratory-protective effects of Lysimachia mauritiana (LM) against airway inflammation were evaluated in a mouse model exposed to a fine dust mixture of diesel exhaust particles and particulate matter with a diameter of less than 10 µm (PM10D). To induce airway inflammation, PM10D was intranasally injected into BALB/c mice three times a day for 12 days, and LM extracts were given orally once per day. The immune cell subtypes, histopathology, and expression of inflammatory mediators were analyzed from the bronchoalveolar lavage fluid (BALF) and lungs. LM alleviated the accumulation of neutrophils and the number of inflammatory cells in the lungs and the BALF of the PM10D-exposed mice. LM also reduced the release of inflammatory mediators (MIP-2, IL-17, IL-1α, CXCL1, TNF-α, MUC5AC, and TRP receptor channels) in the BALF and lungs. Lung histopathology was used to examine airway inflammation and the accumulation of collagen fibers and inflammatory cells after PM10D exposure and showed that LM administration improved this inflammation. Furthermore, LM extract inhibited the MAPK and NF-κB signaling pathway in the lungs and improved expectoration activity through an increase in phenol red release from the trachea. LM alleviated PM10D-exposed neutrophilic airway inflammation by suppressing MAPK/NF-κB activation. This study indicates that LM extract may be an effective therapeutic agent against inflammatory respiratory diseases.

Inhibition of Glycolysis Alleviates Chronic Unpredictable Mild Stress-Induced Neuroinflammation and Depression-like Behavior

Background: Growing evidence suggests that glucose metabolism plays a crucial role in activated immune cells, significantly contributing to the occurrence and development of neuroinflammation and depression-like behaviors. Chronic stress has been reported to induce microglia activation and disturbances in glucose metabolism in the hippocampus. Aims: This study aims to investigate how chronic stress-mediated glycolysis promotes neuroinflammation and to assess the therapeutic potential of the glycolysis inhibitor, 2-deoxy-D-glucose (2-DG), in a model of chronic stress-induced neuroinflammation and depression-like behavior. Methods: In in vitro studies, we first explored the effects of 2-DG on the inflammatory response of microglia cells. The results showed that corticosterone (Cort) induced reactive oxygen species (ROS) production, increased glycolysis, and promoted the release of inflammatory mediators. However, these effects were reversed by intervention with 2-DG. Subsequently, we examined changes in depression-like behavior and hippocampal glycolysis in mice during chronic stress. The results indicated that chronic stress led to prolonged escape latency in the Morris water maze, increased platform-crossing frequency, reduced sucrose preference index, and extended immobility time in the forced swim test, all of which are indicative of depression-like behavior in mice. Additionally, we found that the expression of the key glycolytic enzyme hexokinase 2 (HK2) was upregulated in the hippocampus of stressed mice, along with an increased release of inflammatory factors. Further in vivo experiments investigated the effects of 2-DG on glycolysis and pro-inflammatory mediator production, as well as the therapeutic effects of 2-DG on chronic stress-induced depression-like behavior in mice. The results showed that 2-DG alleviated chronic stress-induced depression-like behaviors, such as improving escape latency and platform-crossing frequency in the Morris water maze, and increasing the time spent in the center of the open field. Additionally, 2-DG intervention reduced the level of glycolysis in the hippocampus and decreased the release of pro-inflammatory mediators. Conclusions: These findings suggest that 2-DG can mitigate neuroinflammation and depressive behaviors by inhibiting glycolysis and inflammatory responses. Overall, our results highlight the potential of 2-DG as a therapeutic agent for alleviating chronic stress-induced neuroinflammation through the regulation of glycolysis.

The Biological Changes of Synaptic Plasticity in the Pathological Process of Sepsis-associated Encephalopathy.

Sepsis-associated encephalopathy (SAE) is a form of cognitive and psychological impairment resulting from sepsis, which occurs without any central nervous system infection or structural brain injury. Patients may experience long-term cognitive deficits and psychiatric disorders even after discharge. However, the underlying mechanism remains unclear. As cognitive function and mental disease are closely related to synaptic plasticity, it is presumed that alterations in synaptic plasticity play an essential role in the pathological process of SAE. Here, we present a systematic description of the pathogenesis of SAE, which is primarily driven by glial cell activation and subsequent release of inflammatory mediators. Additionally, we elucidate the alterations in synaptic plasticity that occur during SAE and comprehensively discuss the roles played by glial cells and inflammatory factors in this process. In this review, we mainly discuss the synaptic plasticity of SAE, and the main aim is to show the consequences of SAE on inflammatory factors and how they affect synaptic plasticity. This review may enhance our understanding of the mechanism underlying cognitive dysfunction and provide valuable insights into identifying appropriate therapeutic targets for SAE.

Immune Modulatory Profile of the Pateamines PatA and Des-Methyl Des-Amino PatA.

Pateamines act as inhibitors of the RNA helicase eIF4A and exhibit antiviral and anticancer properties. Recently, we observed that inhibition of eIF4A by rocaglates affects the immune response. To investigate whether the observed immunomodulatory effects are specific to rocaglates or the inhibition of eIF4A, a comprehensive study was conducted on the influence of pateamines that exhibit the same inhibitory mode of action as rocaglates on various immune cells. The effects of pateamine A (PatA) and des-methyl des-amino pateamine A (DMDA) on the expression of surface markers, release of cytokines, cell proliferation, inflammatory mediators and metabolic activity in primary human monocyte-derived macrophages (MdM), T cells and B cells were assessed. Additionally, safety and bioavailability profiles were determined. DMDA revealed almost no immunomodulatory effects within the tested concentration range of 0.5-5 nM. PatA reduced B cell activation, as shown by reduced immune globulin release and decreased chemokine release from macrophages, while T cell function remained unaffected. Both DMDA and PatA showed low permeability in Caco-2 and Calu-3 cell barrier assays and no mutagenic potential. However, 10 nM PatA exhibited genotoxic potential, as shown by the micronucleus assay. In conclusion, DMDA had a good safety profile but exhibited low permeability, whereas PatA had a poor safety profile and also low permeability. The observed immunomodulatory effects of elF4A inhibitors on B cells appear to be target-specific.

Environmental house calls can reduce symptoms of chemical intolerance: a demonstration of personalized exposure medicine.

The goals of this investigation were to 1) identify and measure exposures inside homes of individuals with chemical intolerance (CI), 2) provide guidance for reducing these exposures, and 3) determine whether our environmental house calls (EHCs) intervention could reduce both symptoms and measured levels of indoor air contaminants. CI is an international public health and clinical concern, but few resources are available to address patients' often disabling symptoms. Numerous studies show that levels of indoor air pollutants can be two to five (or more) times higher than outdoor levels. Fragranced consumer products, including cleaning supplies, air fresheners, and personal care products, are symptom triggers commonly reported by susceptible individuals. A team of professionals trained and led by a physician/industrial hygienist and a certified indoor air quality specialist conducted a series of 5 structured EHCs in 37 homes of patients reporting CI. We report three case studies demonstrating that an appropriately structured home intervention can teach occupants how to reduce indoor air exposures and associated symptoms. Symptom improvement, documented using the Quick Environmental Exposure and Sensitivity Inventory Symptom Star, corresponded with the reduction of indoor air volatile organic compounds, most notably fragrances. These results provide a deeper dive into 3 of the 37 cases described previously in Perales et al. (2022). We address the long-standing dilemma that worldwide reports of fragrance sensitivity have not previously been confirmed by human or animal challenge studies. Our ancient immune systems' 'first responders', mast cells, which evolved 500 million years ago, can be sensitized by synthetic organic chemicals whose production and use havegrown exponentially since World War II. We propose that these chemicals, which include now-ubiquitous fragrances, trigger mast cell degranulation and inflammatory mediator release in the olfactory-limbic tract, thus altering cerebral blood flow and impairing mood, memory, and concentration (often referred to as 'brain fog'). The time has come to translate these research findings into clinical and public health practice.

Prophylactic regimens for the prevention of pseudophakic cystoid macular edema: systematic review and meta-analysis

BackgroundPseudophakic cystoid macular edema (PCME) is a known complication of cataract surgery that contributes to decreased visual acuity. Mechanical manipulation associated with the release of inflammatory mediators is the leading hypothesis for PCME. To date, no standardized prophylactic protocol has been established to effectively reduce the incidence of PCME. This study assessed the efficacy and safety of nonsteroidal anti-inflammatory drops (NSAIDs) and corticosteroids for the prevention of PCME.MethodWe searched the following databases MEDLINE, EMBASE, and Cochrane Central. Register of Controlled Trials and included randomized controlled trials (RCTs) that studied the efficacy of NSAID vs. placebo, NSAID vs. steroid, or NSAID + steroid vs. placebo, reporting the incidence of PCME, macular thickness, and best-corrected visual acuity. The risk ratio (RR) with a 95% confidence interval (CI) and a random-effects model was used. The risk of bias was assessed using the revised Cochrane risk-of-bias tool.ResultsA total of 18 RCTs were included in this study (n = 2959). Nine RCT showed low risk of bias, 7 RCT showed unclear risk of bias, and 2 RCT had high risk of bias. The incidence of cystoid macular edema among patients treated with NSAIDs was significantly lower (RR = 0.33, P < 0.001). Subgroup analysis revealed a statistically significant low risk of edema among patients treated with NSAIDs alone (P < 0.001) compared to others. NSAIDs were associated with significantly low mean corrected visual acuity values using LogMar (P < 0.001).ConclusionNSAID alone or in combination with steroids showed its efficacy in reducing the incidence of PCME post-operatively. Future double-blind randomized controlled trials are required to standardize the protocol for different patient population.

Plumbagin, a novel TRPV2 inhibitor, ameliorates microglia activation and brain injury in a middle cerebral artery occlusion/reperfusion mouse model.

Transient receptor potential vanilloid 2 (TRPV2) is a Ca2+-permeable non-selective cation channel. Despite the significant roles of TRPV2 in immunological response, cancer progression and cardiac development, pharmacological probes of TRPV2 remain to be identified. We aimed to discover TRPV2 inhibitors and to elucidate their molecular mechanism of action. Fluorescence-based Ca2+ assay in HEK-293 cells expressing murine TRPV2 was used to identify plumbagin as a novel TRPV2 inhibitor. Patch-clamp, in silico docking and site-directed mutagenesis were applied to investigate the molecular mechanisms critical for plumbagin interaction. ELISA and qPCR were used to assess nitric oxide release and mRNA levels of inflammatory mediators, respectively. si-RNA interference was used to knock down TRPV2 expression, which was validated by western blotting. Neurological and histological analyses were used to examine brain injury of mice following middle cerebral artery occlusion/reperfusion (MCAO/R). Plumbagin is a potent TRPV2 negative allosteric modulator with an IC50 value of 0.85 μM, exhibiting >14-fold selectivity over TRPV1, TRPV3 and TRPV4. Plumbagin suppresses TRPV2 activity by decreasing the channel open probability without affecting the unitary conductance. Moreover, plumbagin binds to an extracellular pocket formed by the pore helix and flexible loop between transmembrane helices S5 and S6 of TRPV2. Plumbagin effectively suppresses LPS-induced inflammation of BV-2 microglia and ameliorates brain injury of MCAO/R mice. Plumbagin is a novel pharmacological probe to study TRPV2 pathophysiology. TRPV2 is a novel molecular target for the treatment of neuroinflammation and ischemic stroke.

Bioguided isolation of anti-inflammatory and anti-urolithiatic active compounds from the decoction of Cissus gongylodes leaves

Ethnopharmacological relevanceThe Cissus gongylodes has traditionally been used in the diet of indigenous people in Brazil and in traditional medicine for kidney stone removal and inflammatory diseases. The active compounds responsible for these pharmacological activities are unknown. Aim of the StudyThis study aims to isolate, for the first time, the compounds in the decoction of C. gongylodes leaves responsible for their anti-inflammatory and anti-urolithiatic ethnopharmacological properties. Materials and MethodsThe most active fractions of the C. gongylodes leaf decoction were fractionated using SPE-C18 and the compounds were purified through HPLC-UV-DAD. The decoction fractions and isolated compounds were evaluated for their anti-inflammatory and anti-urolithiatic activities. The anti-inflammatory activity was assessed using an ex vivo assay in human blood induced by LPS and calcium ionophore, measuring inflammatory mediators, PGE2 and LTB4. The anti-urolithiatic activity was evaluated using an in vitro experimental model with human urine to determine the dissolution of the most recurrent calcium oxalate (CaOx) crystals. Additionally, the decoction was chemically characterized through metabolomic analysis using UHPLC-ESI-HRMS. ResultsThe isolated compounds from the decoction of C. gongylodes, including rutin, eriodictyol 3’-O-glycoside, and isoquercetin, have demonstrated significant multi-target actions. These components act as anti-inflammatory agents by inhibiting the release of main inflammatory mediators, PGE2 and LTB4. Additionally, they exhibit anti-urolithiatic properties, promoting the dissolution of calcium oxalate (CaOx) crystals. Furthermore, the characterization of the decoction by UHPLC-ESI-HRMS revealed a high content of flavonoids, mainly glycosylated flavonoids. ConclusionsThe results support the traditional use of C. gongylodes decoction, identifying the compounds responsible for its anti-inflammatory and anti-urolithiatic effects. The decoction fractions and isolated compounds exhibited dual anti-inflammatory activity, effectively inhibiting key inflammatory pathways and potentially presenting fewer adverse effects while also promoting the dissolution of CaOx crystals associated with urolithiasis. The multi-target action displayed by C. gongylodes is particularly desirable in the treatment of urolithiasis, as inflammation and PGE2 production precede and contribute to the formation of CaOx crystals in the kidneys. Based on these actions, C. gongylodes emerges as a potent source of active compounds for the development of new treatments for urolithiasis.

Coumarin-chalcone derivatives as dual NLRP1 and NLRP3 inflammasome inhibitors targeting oxidative stress and inflammation in neurotoxin-induced HMC3 and BE(2)-M17 cell models of Parkinson's disease.

In Parkinson's disease (PD) brains, microglia are activated to release inflammatory factors to induce the production of reactive oxygen species (ROS) in neuron, and vice versa. Moreover, neuroinflammation and its synergistic interaction with oxidative stress contribute to the pathogenesis of PD. In this study, we investigated whether in-house synthetic coumarin-chalcone derivatives protect human microglia HMC3 and neuroblastoma BE(2)-M17 cells against 1-methyl-4-phenyl pyridinium (MPP+)-induced neuroinflammation and associated neuronal damage. Treatment with MPP+ decreased cell viability as well as increased the release of inflammatory mediators including cytokines and nitric oxide in culture medium, and enhanced expression of microglial activation markers CD68 and MHCII in HMC3 cells. The protein levels of NLRP3, CASP1, iNOS, IL-1β, IL-6, and TNF-α were also increased in MPP+-stimulated HMC3 cells. Among the four tested compounds, LM-016, LM-021, and LM-036 at 10 μM counteracted the inflammatory action of MPP+ in HMC3 cells. In addition, LM-021 and LM-036 increased cell viability, reduced lactate dehydrogenase release, ameliorated cellular ROS production, decreased caspase-1, caspase-3 and caspase-6 activities, and promoted neurite outgrowth in MPP+-treated BE(2)-M17 cells. These protective effects were mediated by down-regulating inflammatory NLRP1, IL-1β, IL-6, and TNF-α, as well as up-regulating antioxidative NRF2, NQO1, GCLC, and PGC-1α, and neuroprotective CREB, BDNF, and BCL2. The study results strengthen the involvement of neuroinflammation and oxidative stress in PD pathogenic mechanisms, and indicate the potential use of LM-021 and LM-036 as dual inflammasome inhibitors in treating both NLRP1- and NLRP3-associated PD.

Tangeretin inhibits airway inflammatory responses by reducing early growth response 1 (EGR1) expression in mice exposed to cigarette smoke and lipopolysaccharide

BackgroundTangeretin, a natural polymethoxyflavone compound, possesses potent anti-inflammatory activity that improves respiratory inflammation in chronic obstructive pulmonary disease (COPD). However, the molecular mechanisms underlying the anti-COPD effects of tangeretin remain unclear. In this study, we aimed to investigate the key molecular mechanisms by which tangeretin suppresses COPD-related inflammatory responses. MethodsWe conducted the investigation in phorbol-12-myristate-13-acetate (PMA)-stimulated human airway epithelial cells (in vitro) and cigarette smoke (CS)/lipopolysaccharide (LPS)-exposed mice (in vivo). ResultsTangeretin decreased the release of inflammatory mediators, including tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), and mucin 5AC (MUC5AC), by suppressing early growth response 1 (EGR1) expression in vitro. Tangeretin and EGR1 small interfering ribonucleic acid (siRNA) combination showed a synergistic reduction in MUC5AC and TNF-α secretion. Tangeretin administration significantly inhibited the levels of reactive oxygen species (ROS) production, elastase activity, TNF-α, IL-6, and monocyte chemoattractant protein-1 (MCP-1) secretion, and macrophage and neutrophil numbers in the bronchoalveolar lavage fluid of CS/LPS-exposed mice. Tangeretin also prevented CS/LPS-induced abnormal pathological changes and excessive MUC5AC and EGR1 expression in lung tissue. ConclusionComprehensively, tangeretin inhibits the lung inflammatory response associated with COPD by reducing EGR1 expression in PMA-induced human epithelial cells and in a CS/LPS-stimulated mouse model. This study shows that tangeretin has anti-COPD properties and can be a promising alternative (or complementary) treatment for inflammatory lung disease.

Adrenaline bolus rescue for refractory carcinoid crises during surgical manipulation of metastatic neuroendocrine tumor of pancreas: A case report

Carcinoid crisis is a potentially fatal condition with severe hemodynamic instability. A 25-year-old female with metastatic pancreatic neuroendocrine tumor with recurrent carcinoid crises was posted for surgical debulking. Intraoperatively, the patient was on crisis during manipulation of the lesion by the surgeon, which was unresponsive to octreotide, infusions of phenylephrine, and norepinephrine agents. The patient was then effectively managed with adrenaline blouses at 10 µg along with infusion of adrenaline. Use of inotropes and vasopressors is not encouraged in carcinoid due to release of inflammatory mediators which can precipitate the hemodynamic instability. Here, we managed her with adrenaline boluses and infusion.

Vitiligo: From mechanisms of disease to treatable pathways

AbstractVitiligo is a chronic autoimmune‐mediated disease characterised by the loss of pigmentary melanocytes in the epidermis. Vitiligo is associated with loss of functional epithelium and significant reductions in quality of life with limited long‐term treatment options, highlighting a continued unmet clinical need. A comprehensive understanding of the pathophysiology and newly investigated treatment pathways may guide multimodal treatment strategies and identify future drug targets. The pathology of vitiligo is multifactorial; however, environmental insults in genetically susceptible populations may lead to disease development. Autoreactive CD8+ T‐cells that target melanocytes and release inflammatory mediators, including interferon‐γ and interleukins 2, 6, 15, 17 and 33 among others, have been identified in vitiligo pathogenesis. Treatment modalities for vitiligo revolve around six broad disease concepts, including procedural modalities (tissue and cellular grafting), phototherapy, stem cells, anti‐inflammatories, genetic polymorphisms and antioxidants/vitamins/herbals. Genetic polymorphisms, such as catalase gene variations and toll‐like receptor polymorphisms, along with stem cell targets such as melanocytes derived from stem cells, have been implicated in vitiligo onset and possible treatment. Novel JAK‐STAT inhibitors have been recently investigated for vitiligo, whereas topical corticosteroids and calcineurin inhibitors continue to be used. Vitamin D, vitamin E, zinc, copper, piperine, pseudo catalase and other vitamins/herbals may improve vitiligo outcomes primarily through antioxidant supplementation pathways. Future studies should investigate alternative drug pathways and targets implicated in vitiligo in large patient cohorts, as well as treatments that target suspected causative immune cells, including memory T‐cells, which may provide long‐lasting disease‐free remission.