A comprehensive review on RAGE-facilitated pathological pathways connecting Alzheimer’s disease, diabetes mellitus, and cardiovascular diseases

Background Alzheimer’s disease (AD), cardiovascular disease (CVD), and diabetes are some of the most common causes of morbidity and mortality among the aging populations and cause a heavy burden on the worldwide healthcare system. In this review, we briefly highlighted cellular inflammation-based pathways of diabetes mellitus and CVD through receptor for advanced glycation end products AGEs or RAGE leading to Alzheimer’s disease and interrelation between these vascular and metabolic disorders. The articles were retrieved from Google Scholar, Science Direct, and PubMed databases using the following terms: Alzheimer’s; AGEs; RAGE; RAGE in Alzheimer’s; AGEs in Alzheimer’s; RAGE in diabetes; RAGE related pathways of CVD; RAGE in hypertension; RAGE and RAS system; RAGE and oxidative stress. Main body of the abstract AD is a neurodegenerative disease characterized by cognitive dysfunction and neuronal cell death. Vascular complications like hypertension, coronary artery disease, and atherosclerosis as well as metabolic syndromes like obesity and diabetes are related to the pathophysiology of AD. RAGE plays significant role in the onset and progression of AD. Amyloid plaques and neurofibrillary tangles (NFT) are two main markers of AD that regulates via RAGE and other RAGE/ligands interactions which also induces oxidative stress and a cascade of other cellular inflammation pathways leading to AD. Though AD and diabetes are two different disorders but may be inter-linked by AGEs and RAGE. In long-term hyperglycemia, upregulated AGEs interacts with RAGE and produces reactive oxygen species which induces further inflammation and vascular complications. Aging, hypercholesterolemia, atherosclerosis, hypertension, obesity, and inflammation are some of the main risk factors for both diabetes and dementia. Chronic hypertension and coronary artery disease disrupt the functions of the blood-brain barrier and are responsible for the accumulation of senile plaques and NFTs. Short conclusion RAGE plays a role in the etiology of Aβ and tau hyperphosphorylation, both of which contribute to cognitive impairment. So far, targeting RAGE may provide a potential sight to develop therapies against some metabolic disorders.

Anti-Inflammation and Protective Effects of Anethum graveolens L. (Dill Seeds) on Esophageal Mucosa Damages in Reflux Esophagitis-Induced Rats

Anethum graveolens L. (dill seeds) are important medicinal and functional foods in Europe and central and south Asia, often used as a seasoning in daily diets. Anethum graveolens L. seeds (AGS) are used to treat indigestion and have shown physiological activities such as those against hypoglycemia and gastroesophageal disease. This study explored the protective effects of AGS extract on mucosal damages and inflammation in reflux esophagitis rats. AGS inhibited cellular inflammation including NO production and the expression of inflammatory proteins (iNOS and COX2 etc.), cytokines (IL-1β and TNF-α) and nuclear transfer factor related to NF-κB signaling caused by LPS stimulation in vitro. Furthermore, reflux esophagitis-induced rats were used to observe the anti-inflammatory effect of AGS. Tissue staining and inflammation-related protein expression of rats with acute reflux esophagitis indicated that AGS improved this inflammatory response, such as COX-2 and TNF-α in mucosa. In conclusion, AGS have good physiological activity and the possibility of being used as a medicinal food and a functional resource for the prevention and therapy of gastroesophageal diseases.

Murine Type III interferons are functionally redundant and correlate with bacterial burden during influenza/bacterial super-infection

Background Type III interferon, or interferon lambda (IFNλ) is a crucial antiviral cytokine induced by influenza infection. While IFNλ is important for anti-viral host defense, published data demonstrate that IFNλ is pathogenic during influenza/bacterial super-infection. It is known that polymorphisms in specific IFNλ genes affect influenza responses, but the effect of IFNλ subtypes on bacterial super-infection is unknown. Methods Using an established model of influenza, Staphylococcus aureus super-infection, we studied IFNλ3-/- and control mice to model a physiologically relevant reduction in IFNλ and to address its role in super-infection. Results Surprisingly, IFNλ3-/- mice did not have significantly lower total IFNλ than co-housed controls, and displayed no change in viral or bacterial clearance. Importantly, both control and IFNλ3-/- mice displayed a positive correlation between viral burden and total IFNλ in the bronchoalveolar lavage during influenza/bacterial super-infection, suggesting that higher influenza viral burden drives a similar total IFNλ response regardless of IFNλ3 gene integrity. Interestingly, total IFNλ levels positively correlated with bacterial burden, while viral burden and bronchoalveolar lavage cellularity did not. Conclusions These data suggest IFNλ2 can compensate for IFNλ3 to mount an effective antiviral and defense, revealing a functional redundancy in these highly similar IFNλ subtypes. Further, the IFNλ response to influenza, as opposed to changes in cellular inflammation or viral load, significantly correlates with susceptibility to bacterial super-infection. Moreover, the IFNλ response is regulated and involves redundant subtypes, suggesting it is of high importance to pulmonary pathogen defense.

A Systematic Review of the Biological Effects of Cordycepin

We conducted a systematic review of the literature on the effects of cordycepin on cell survival and proliferation, inflammation, signal transduction and animal models. A total of 1204 publications on cordycepin were found by the cut-off date of 1 February 2021. After application of the exclusion criteria, 791 papers remained. These were read and data on the chosen subjects were extracted. We found 192 papers on the effects of cordycepin on cell survival and proliferation and calculated a median inhibitory concentration (IC50) of 135 µM. Cordycepin consistently repressed cell migration (26 papers) and cellular inflammation (53 papers). Evaluation of 76 papers on signal transduction indicated consistently reduced PI3K/mTOR/AKT and ERK signalling and activation of AMPK. In contrast, the effects of cordycepin on the p38 and Jun kinases were variable, as were the effects on cell cycle arrest (53 papers), suggesting these are cell-specific responses. The examination of 150 animal studies indicated that purified cordycepin has many potential therapeutic effects, including the reduction of tumour growth (37 papers), repression of pain and inflammation (9 papers), protecting brain function (11 papers), improvement of respiratory and cardiac conditions (8 and 19 papers) and amelioration of metabolic disorders (8 papers). Nearly all these data are consistent with cordycepin mediating its therapeutic effects through activating AMPK, inhibiting PI3K/mTOR/AKT and repressing the inflammatory response. We conclude that cordycepin has excellent potential as a lead for drug development, especially for age-related diseases. In addition, we discuss the remaining issues around the mechanism of action, toxicity and biodistribution of cordycepin.

The role of pumpkin pulp extract carotenoids against mycotoxin damage in the blood brain barrier in vitro

Some mycotoxins such as beauvericin (BEA), ochratoxin A (OTA), and zearalenone (ZEA) can cross the blood brain barrier, which is why we tested the anti-inflammatory action of a pumpkin carotenoid extract (from the pulp) against these mycotoxins and their combinations (OTA+ZEA and OTA+ZEA+BEA) on a blood brain barrier model with co-cultured ECV304 and C6 cells using an untargeted metabolomic approach. The cells were added with mycotoxins at a concentration of 100 nmol/L per mycotoxin and pumpkin carotenoid extract at 500 nmol/L. For control we used only vehicle solvent (cell control) or vehicle solvent with pumpkin extract (extract control). After two hours of exposure, samples were analysed with HPLC-ESI-QTOF-MS. Metabolites were identified against the Metlin database. The proinflammatory arachidonic acid metabolite eoxin (14,15-LTE4) showed lower abundance in ZEA and BEA+OTA+ZEA-treated cultures that also received the pumpkin extract than in cultures that were not treated with the extract. Another marker of inflammation, prostaglandin D2-glycerol ester, was only found in cultures treated with OTA+ZEA and BEA+OTA+ZEA but not in the ones that were also treated with the pumpkin extract. Furthermore, the concentration of the pumpkin extract metabolite dihydromorelloflavone significantly decreased in the presence of mycotoxins. In conclusion, the pumpkin extract showed protective activity against cellular inflammation triggered by mycotoxins thanks to the properties pertinent to flavonoids contained in the pulp.

Previous Influenza Infection Exacerbates Allergen Specific Response and Impairs Airway Barrier Integrity in Pre-Sensitized Mice

In this study we assessed the effects of antigen exposure in mice pre-sensitized with allergen following viral infection on changes in lung function, cellular responses and tight junction expression. Female BALB/c mice were sensitized to ovalbumin and infected with influenza A before receiving a second ovalbumin sensitization and challenge with saline, ovalbumin (OVA) or house dust mite (HDM). Fifteen days post-infection, bronchoalveolar inflammation, serum antibodies, responsiveness to methacholine and barrier integrity were assessed. There was no effect of infection alone on bronchoalveolar lavage cellular inflammation 15 days post-infection; however, OVA or HDM challenge resulted in increased bronchoalveolar inflammation dominated by eosinophils/neutrophils or neutrophils, respectively. Previously infected mice had higher serum OVA-specific IgE compared with uninfected mice. Mice previously infected, sensitized and challenged with OVA were most responsive to methacholine with respect to airway resistance, while HDM challenge caused significant increases in both tissue damping and tissue elastance regardless of previous infection status. Previous influenza infection was associated with decreased claudin-1 expression in all groups and decreased occludin expression in OVA or HDM-challenged mice. This study demonstrates the importance of the respiratory epithelium in pre-sensitized individuals, where influenza-infection-induced barrier disruption resulted in increased systemic OVA sensitization and downstream effects on lung function.

Dietary Phytochemicals: As a Natural Source of Antioxidants

Since time immemorial, plants are used as the source of food and medicine. It can be traced back to the start of humanity. Bringing plant-based food, such as fruits, vegetables, and whole grains, rich in phytochemicals, with beneficial nutrients, opens the door for healthy living. The health benefits are partly attributed to the compounds which possess antioxidants. Several epidemiological observations have shown an opposite relationship between consumption of plant-based foods, rich in phytochemicals, and many diseases including cancer. The majority of the ailments are related to oxidative stress induced by free radicals. Free radicals are extremely unstable with a very short half-life, highly reactive molecule which leads to oxidative damage to macromolecules such as proteins, DNA, and lipids. Free radical induced cellular inflammation appears to be a major contributing factor to cause aging, and degenerative diseases such as cancer, cardiovascular diseases, diabetes, hepatic diseases, renal ailments, and brain dysfunction. Free radicals have been caught up in the pathogenesis of several diseases. Providentially, free radical formation is controlled naturally by phytochemicals, through their antioxidant potential which plays a key role in preventing many diseases including cancer by suppressing oxidative stress-induced DNA damage. Keeping these facts in mind, an attempt has been made to highlight the oxidative stress, enzymatic and non-enzymatic antioxidant, dietary phytochemicals and their role of in disease prevention and cure.

Agmatine Alleviates Epileptic Seizures and Hippocampal Neuronal Damage by Inhibiting Gasdermin D-Mediated Pyroptosis

Background: Epilepsy is a common neurological disease, and neuroinflammation is one of the main contributors to epileptogenesis. Pyroptosis is a type of pro-inflammatory cell death that is related to epilepsy. Agmatine, has anti-inflammatory properties and exerts neuroprotective effects against seizures. Our study investigated the effect of agmatine on the core pyroptosis protein GSDMD in the context of epilepsy.Methods: A chronic epilepsy model and BV2 microglial cellular inflammation model were established by pentylenetetrazole (PTZ)-induced kindling or lipopolysaccharide (LPS) stimulation. H&E and Nissl staining were used to evaluate hippocampal neuronal damage. The expression of pyroptosis and inflammasome factors was examined by western blotting, quantitative real-time PCR, immunofluorescence and enzyme-linked immunosorbent assay (ELISA).Results: Agmatine disrupted the kindling acquisition process, which decreased seizure scores and the incidence of full kindling and blocked hippocampal neuronal damage. In addition, agmatine increased BV2 microglial cell survival in vitro and alleviated seizures in vivo by suppressing the levels of PTZ-induced pyroptosis. Finally, the expression of TLR4, MYD88, phospho-IκBα, phospho-NF-κB and the NLRP3 inflammasome was significantly upregulated in LPS-induced BV2 microglial cells, while agmatine suppressed the expression of these proteins.Conclusions: Our results indicate that agmatine affects epileptogenesis and exerts neuroprotective effects by inhibiting neuroinflammation, GSDMD activation, and pyroptosis. The inhibitory effect of agmatine on pyroptosis was mediated by the suppression of the TLR4/MYD88/NF-κB/NLRP3 inflammasome pathway. Therefore, agmatine may be a potential treatment option for epilepsy.

Impact of Coffee Containing Medium-Chain Triglyceride Oil and Ghee on Markers of Cellular Inflammation in Young Healthy Humans

Objectives Low-carbohydrate, high-fat “ketogenic” food supplements have become increasingly popular in recent years with claims of improving body composition and cognition, while reducing hunger. However, acute consumption of high-fat foods has been shown to promote dietary endotoxemia; the release of bacterial lipopolysaccharide from the gut into the blood, which is linked to proinflammatory responses through activating toll like receptor (TLR) 4 on circulating monocytes. Bulletproof Coffee is a popular high-fat beverage consisting of coffee, medium chain triglyceride (MCT) oil, and grass-fed ghee. The purpose of this study is to determine whether consuming this high-fat coffee beverage would impact cellular inflammation assessed by increases in the number of circulating monocytes and monocyte surface TLR4 expression. We hypothesize that consuming one high-fat “Bulletproof Coffee” will elevate concentrations of circulating monocytes and increase TLR4 expression when compared to a black coffee comparator drink. Methods This study is a single-blind (researcher), randomized crossover design wherein participants consume either a freshly prepared coffee (1 pod with 12oz water; ∼1 kcal), or high-fat bulletproof coffee (1 pod with 12 oz water containing 1 tbsp MCT oil and 1 tbsp ghee; 27 g fat; ∼250 kcal) separated by ∼7 days. Participants provided blood samples in the fasted state and at 60- and 180-minutes following beverage consumption. Blood samples were analyzed by flow cytometry. Results Six healthy adults (n = 5 females) aged 25 ± 8 years who consume coffee regularly have completed both conditions. Preliminary statistical analysis using a linear mixed model has shown no significant time x condition interaction (P = 0.184) or main effect of time (P = 0.211) for the concentration of circulating monocytes. Similarly, no interaction (P = 0.675) or main effects of time (P = 0.337) were observed for monocyte surface TLR4 expression. Conclusions Preliminary data suggests that consuming a single high-fat bulletproof coffee does not appear to increase circulating monocyte concentrations or monocyte TLR4 expression. Further research will be required to determine whether acute consumption of a high-fat coffee beverage impacts inflammation in humans. Funding Sources This study is funded by a Natural Sciences and Engineering Research Council (NSERC) of Canada grant.

A Purified Biflavonoid Extract From Selaginella moellendorffii Alleviates Gout Arthritis via NLRP3/ASC/Caspase-1 Axis Suppression

Background: Activation of nucleotide oligomerization domain-like receptor protein 3 (NLRP3) inflammasome plays a crucial role in gout. Selaginella moellendorffii has been confirmed effective for the treatment of gout in hospital preparations. Flavonoids, such as amentoflavone (AM), are the main active components of this medicine.Purpose: We aimed to investigate the flavonoid extract (TF) and AM's effects on NLRP3 inflammasome in vitro and their preventive effects on gout in vivo.Methods: LC-MS method was employed to investigate the chemical profile of TF. The cellular inflammation model was established by lipopolysaccharide (LPS) or monosodium urate (MSU) stimulation. The cell membrane integrality and morphological characteristics were determined by using Lactate dehydrogenase (LDH) assay kits, propidium iodide (PI) stain, and scanning electron microscopy (SEM). The inflammatory cytokines and NLRP3 inflammasome activation were determined using enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (RT-PCR), immunofluorescence staining, and western blotting. The acute gout mouse model was induced by MSU injection into footpads, and then the paw edema, inflammatory mediators, and histological examination (HE) were analyzed.Results: The main constituents in TF are AM and robustaflavone. In the cellular inflammation model, TF down-regulated the levels of nitric oxide (NO), TNF-α, and LDH, suppressed NLRP3 inflammasome-derived interleukin-1β (IL-1β) secretion, decreased caspase-1 activation, repressed mature IL-1β expression, inhibited ASC speck formation and NLRP3 protein expression. In an acute gout mouse model, oral administration of TF to mice effectively alleviated paw edema, reduced inflammatory features, and decreased the levels of IL-1β in mouse foot tissue. Similarly, the characteristic constituent AM was also able to down-regulated the levels of NO, TNF-α, and LDH, down-regulate the mRNA expression of IL-1β, TNF-α, caspase-1, and NLRP3. Besides, the foot thickness, lymphocyte infiltration, and IL-1β level were also prevented by AM.Conclusion: The results indicated that TF and its main constituent AM alleviate gout arthritis via NLRP3/ASC/Caspase-1 axis suppression.