Inflammation-associated Disorders Research Articles

WTAP mediated m6A-modified circ_0056856 contributes to the proliferation, migration, and invasion of IL-22-stimulated human keratinocyte by miR-197-3p/CDK1 axis.

Psoriasis is a chronic inflammation-associated skin disorder, and interleukin-22 (IL-22) is involved in psoriasis pathogenesis by boosting the proliferation and migration of keratinocytes. Mounting evidence has shown that circRNAs might play an important role in several aspects of psoriasis. This study is designed to explore the role and mechanism of circ_0056856 in regulating the phenotypes of IL-22-induced keratinocytes (HaCaT cells). Circ_0056856, microRNA-197-3p (miR-197-3p), Cyclin-dependent kinase 1 (CDK1), and Wilms tumor 1-associated protein (WTAP) levels were detected using real-time quantitative polymerase chain reaction (RT-qPCR). Cell viability, proliferation, migration, and invasion were analyzed using 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT), 5-ethynyl-2'-deoxyuridine (EdU), Wound scratch, and Transwell assays. After being predicted by Circinteractome or TargetScan, binding between miR-197-3p and circ_0056856 or CDK1 was verified by a dual-luciferase reporter assay. CDK1 and WTAP protein levels were determined using Western blot. Interaction between WTAP and circ_0056856 was assessed using methylated RNA immunoprecipitation (MeRIP) assay. Increased circ_0056856, CDK1, and WTAP were observed in psoriasis patients and IL-22-treated HaCaT cells. Moreover, circ_0056856 knockdown might repress IL-22-induced HaCaT cell proliferation, migration, and invasion in vitro. In mechanism, circ_0056856 might function as a sponge of miR-197-3p to modulate CDK1 expression, and WTAP improved circ_0056856 expression via m6A methylation. WTAP-guided m6A modified circ_0056856 facilitates IL-22-stimulated HaCaT cell damage through the miR-197-3p/CDK1 axis, which could provide novel insights into psoriasis treatment.

Interferons in vitreoretinal diseases; a review on their clinical application, and mechanism of action.

This review investigates the therapeutic benefits of interferons (IFNs) in vitreoretinal diseases, focusing on their regulatory roles in innate immunological reactions and angiogenesis. The study aims to categorize the clinical outcomes of IFN applications and proposes a molecular mechanism underlying their action. A systematic review was conducted using MEDLINE/PubMed, Web of Science, EMBASE, and Google Scholar databases to identify randomized clinical trials, case series, and case-control studies related to IFNs' impact on vitreoretinal diseases (1990-2022). The data synthesis involved an in-depth analysis of the anti-inflammatory and anti-angiogenesis effects of IFNs across various studies. Our findings indicate that IFNs exhibit efficacy in treating inflammation-associated vitreoretinal disorders. However, a lack of sufficient evidence exists regarding the suitability of IFNs in angiogenesis-associated vitreoretinal diseases like choroidal neovascularization and diabetic retinopathies. The synthesis of data suggests that IFNs may not be optimal for managing advanced stages of angiogenesis-associated disorders. While IFNs emerge as promising therapeutic candidates for inflammation-related vitreoretinal diseases, caution is warranted in their application for angiogenesis-associated disorders, especially in advanced stages. Further research is needed to elucidate the nuanced molecular pathways of IFN action, guiding their targeted use in specific vitreoretinal conditions.

N,N-Diarylsulfonamide Reduces Proinflammatory Cytokine Interleukin-6 Levels in Cells through Nuclear Factor-κB Regulation.

The arylsulfonamides were synthesized from aryl sulfonyl chloride and aromatic amines in dichloromethane in the presence of pyridine. The aryne chemistry was used to prepare diarylsulfonamide from arylsulfonamides and O-silylaryl triflate with CsF in acetonitrile at room temperature for 30 min. The synthesized compounds were evaluated for cytotoxicity followed by the cytokine/inflammatory marker's inhibition capability and its mechanism of action in RAW-264.7 cells. Elevated interleukin-6 (IL-6) levels have been reported in inflammatory conditions and inflammation-associated disorders. Hence, reducing the IL-6 levels in inflammatory conditions can serve as an attractive therapeutic target in dealing the inflammation. Among 42 compounds, seven compounds showed significant inhibition of IL-6 levels in lipopolysaccharide (LPS) challenged RAW-264.7 cells at 12.5 μM concentration. Further, investigation revealed that the IC50 value of these compounds for reducing IL-6 levels was found to be in the range of 2.6 to 9.7 μM. The promising compounds 5y (IC50 of 2.6 μM) and 5n (IC50 of 4.1 μM) along with other derivatives fulfil drug-likeness parameters laid down by Lipinski's rule of five. Further, RT-qPCR and Western-blot analysis revealed that treatment with 5n significantly reduced the expression of pro-inflammatory, inflammatory and macrophage marker's expression (IL-1β, CCL2, COX2 and CD68) compared to LPS control. The mechanistic evaluation showed that 5n exhibited anti-inflammatory properties by modulating the nuclear factor-κB (NF-κB) activation. The identified compound can be a promising candidate for further discovery efforts to generate a preclinical candidate effective in inflammation.

Innate lymphoid cells: New players in osteoimmunology.

Innate lymphoid cells (ILCs) are the most recently identified immune cell types existing in lymphoid and nonlymphoid organs. Albeit they lack the expression of antigen receptors, ILCs play vital roles in innate immune responses by producing multiple effector cytokines. The ILC family includes conventional natural killer cells and cytokine-producing ILCs, which are divided into group 1, group 2, and group 3 ILCs based on their effector cytokines and developmental requirements. Emerging evidence has indicated that ILCs are essential immune regulators of bone homeostasis, playing a critical role in osteoimmunology. In this mini-review, we discuss recent advances in the understanding of ILC functions in bone homeostasis under physiological and pathological conditions, with an emphasis on the communication between ILCs and bone cells including osteoclasts and osteoblasts, as well as the underlying immunoregulatory networks involving ILC-derived cytokines and growth factors. This review also discusses future research directions and the potential of targeting ILCs for the treatment of inflammation-associated bone disorders.

Anti-inflammatory Activity and Computational Biology Study of Indole/Pyrimidine Hybrids

Abstract: This research paper embarks on an interdisciplinary exploration encompassing synthetic chemistry, pharmacology, and computational biology. The development of novel anti-inflammatory agents is an imperative endeavor within pharmaceutical research. Pyrimidines and thienopyrimidines are class of heterocyclic compounds that have gained prominence for their diverse pharmacological properties, including potential anti-inflammatory effects. When augmented with an indole moiety, these compounds exhibit structural diversity that can profoundly influence their biological activities. The integration of computational biology specifically molecular docking, plays a crucial role in predicting and understanding the binding interactions between these compounds and select protein targets associated with inflammatory pathways. This computational approach expedites the screening of potential drug candidates and elucidates the molecular underpinnings of their anti-inflammatory actions. Pyrimidine and thienopyrimidines tethering indole scaffold were obtained according to our reported methods. Subsequently, in vivo evaluation of anti-inflammatory is indispensable to gauge the anti-inflammatory potential of these compounds and establish structure-activity relationships. The experimental and computational biology studies of the target indole-pyrimidines hybrids revealed that these compounds can serve as anti-inflammatory agents. This paper can potentially open new avenues for therapeutic strategies against inflammation-associated disorders. The synergy of synthetic innovation, pharmacological evaluation, and computational insights offers a holistic approach to advance our understanding of pyrimidines with an indole moiety as potential agents for mitigating inflammation.

Anthocyanins-rich purple potato extract prevents low-grade chronic inflammation-associated metabolic disorders

Dietary polyphenols including anthocyanins possess strong antioxidant and anti-inflammatory properties, and are known to help reduce risks of oxidative stress-induced chronic diseases. However, their effects on various aspects of the gut microenvironment towards preventing the unhealthy diet-induced metabolic disorders are still not well understood. The present study aims to verify the in vitro antioxidant and anti-inflammatory effects of the anthocyanin-rich extracts of purple potato (PPE), using a lipopolysaccharide (LPS) and high-fat diet (HFD)-induced obesity C57/BL6J mouse model, and to examine the effects of PPE on LPS+HFD-impaired metabolic homeostasis and the underlying mechanisms. We found that PPE, especially at higher dose significantly improved the glucose and lipid metabolism, and reduced inflammation in the plasma and various tissues. It significantly improved intestinal barrier integrity, altered fecal metabolite profile and gut microbiota composition. Our findings provide new insights into the roles of highly-pigmented vegetable-derived anthocyanins in maintaining gut health and ameliorating metabolic syndrome.

Berberine attenuates depression-like behavior by modulating the hippocampal NLRP3 ubiquitination signaling pathway through Trim65

ObjectiveIncreasing evidence suggests that inflammation appears to play a role in the genesis of depression. Berberine has potent anti-inflammatory effects and potential antidepressant activity, although the mechanism by which it works is yet unclear. Our study aimed to investigate the molecular mechanisms through which berberine treats depression and reduces inflammation. MethodsThe CUMS model and behavioral evaluation were utilized in this study to evaluate the efficacy of berberine in the treatment of depression. Berberine’s effect on the inflammatory response in CUMS mice was evaluated via ELISA assays and western blotting. Nissl staining was used to observe hippocampal neuronal functional damage. Western blotting, ELISA, ubiquitination tests, and immunoprecipitation were utilized in conjunction with in vitro experiments to study the involvement of Trim65 in the antidepressant effects of berberine. ResultsThe results suggest that berberine effectively alleviates depressive symptoms, suppresses the expression of genes associated with the NLRP3 inflammasome (NLRP3, cleaved caspase-1, ASC, GSDMD-N, Pro-IL-1β, IL-1β, Pro-IL-18, and IL-18), and reduces hippocampal neuronal functional damage in CUMS mice. Further studies showed that knockdown of Trim65 reversed the effects of berberine and increased NLRP3 inflammasome activity. Finally, K285, an important site for Trim65 binding to NLRP3, was identified. ConclusionOur study describes the mechanism of berberine limiting NLRP3 inflammasome activity by promoting the conjugation of Trim65 to NLRP3 and NLRP3 ubiquitination, and suggests NLRP3 inflammasome activation as a prospective target for treating inflammation-associated disorders such as depression.

Discovery of 2-(Methylcarbonylamino) thiazole as PDE4 inhibitors via virtual screening and biological evaluation

Phosphodiesterase-4, the primary enzyme responsible for cAMP degradation in the majority of immune and inflammatory cells, plays a critical role in the regulation of intracellular cAMP levels. Consequently, small molecular entities capable of inhibiting PDE4 have been employed in the treatment of inflammation-associated disorders, such as chronic obstructive pulmonary disease (COPD), psoriasis, atopic dermatitis (AD), inflammatory bowel diseases (IBD), rheumatic arthritis (RA). In the present investigation, a multi-faceted approach was employed to identify novel PDE4 inhibitors, utilizing the co-crystallization structure of PDE4B available in the Protein Data Bank (PDB) database, drug-like screening, false positive filtration, similarity and ADMET screen, as well as molecular docking via multiple software platforms, in conjunction with bioactivity assays. A thiazol-3-propanamides derivative, designated MR9, was discovered to inhibit PDE4B activity with IC50 values of 2.12 μM and suppress cellular inflammatory factor TNF-α release with an EC50 value of 3.587 μM. These findings suggest that the innovative active scaffold of MR9 offers a promising foundation for further structural refinement aimed at developing more potent PDE4 inhibitors.

Alisma Shugan Decoction attenuates hepatic fibrosis and endoplasmic reticulum stress in mice with carbon tetrachloride-induced fibrosis.

Over the years, Alisma Shugan Decoction (ASD), because of its potent anti-inflammation activity, has been used in traditional Chinese medicine (TCM) for treatment of many inflammation-associated disorders including those of the heart, blood vessel and brain. Herein, we examined the probable therapeutic effect of ASD in carbon tetrachloride (CCl4)-induced liver injury and fibrosis mice models. Our results demonstrate that ASD dose-dependently reduced the fibrosis-related increased collagen deposition secondary to liver tissue exposure to CCl4. Data from our biochemical analyses showed significantly less liver damage biomarkers including ALT, AST and hydroxyproline in the ASD-treated samples, suggesting hepato-protective effect of ASD. Furthermore, we demonstrated that treatment with ASD significantly reversed CCl4-induced elevation of TNF-α, IL-6, IL-1β and MP-1. Interestingly, NF-κB signalling, a principal regulator of inflammation was markedly suppressed by ASD treatment. In addition, treatment with ASD deregulated stress signalling pathways by suppressing the expression of markers of unfolded protein response, such as ATF6, IRE and GRP78. In conclusion, the present study provides preclinical evidence for the use of ASD as an efficacious therapeutic option in cases of chemical-induced liver damage and/or fibrosis. Further large-cohort validation of these findings is warranted.

An overview of natural products that modulate the expression of non-coding RNAs involved in oxidative stress and inflammation-associated disorders.

Oxidative stress is a state in which oxidants are produced in excess in the body's tissues and cells, resulting in a biological imbalance amid the generation of reactive oxygen and nitrogen species (RONS) from redox reactions. In case of insufficient antioxidants to balance, the immune system triggers signaling cascades to mount inflammatory responses. Oxidative stress can have deleterious effects on major macromolecules such as lipids, proteins, and nucleic acids, hence, Oxidative stress and inflammation are among the multiple factors contributing to the etiology of several disorders such as diabetes, cancers, and cardiovascular diseases. Non-coding RNAs (ncRNAs) which were once referred to as dark matter have been found to function as key regulators of gene expression through different mechanisms. They have dynamic roles in the onset and development of inflammatory and oxidative stress-related diseases, therefore, are potential targets for the control of those diseases. One way of controlling those diseases is through the use of natural products, a rich source of antioxidants that have drawn attention with several studies showing their involvement in combating chronic diseases given their enormous gains, low side effects, and toxicity. In this review, we highlighted the natural products that have been reported to target ncRNAs as mediators of their biological effects on oxidative stress and several inflammation-associated disorders. Those natural products include Baicalein, Tanshinone IIA, Geniposide, Carvacrol/Thymol, Triptolide, Oleacein, Curcumin, Resveratrol, Solarmargine, Allicin, aqueous extract or pulp of Açai, Quercetin, and Genistein. We also draw attention to some other compounds including Zanthoxylum bungeanum, Canna genus rhizome, Fuzi-ganjiang herb pair, Aronia melanocarpa, Peppermint, and Gingerol that are effective against oxidative stress and inflammation-related disorders, however, have no known effect on ncRNAs. Lastly, we touched on the many ncRNAs that were found to play a role in oxidative stress and inflammation-related disorders but have not yet been investigated as targets of a natural product. Shedding more light into these two last points of shadow will be of great interest in the valorization of natural compounds in the control and therapy of oxidative stress- and inflammation-associated disorders.

Sulfated polygalactofucan from triangular sea bell Turbinaria decurrens attenuates inflammatory cytokines on THP-1 human monocytic macrophages

Inflammation is one of the most significant causes of several chronic diseases, which includes the expression of cytokines activating immune cells to up-regulate the inflammatory cascade. Polysaccharides from marine macroalgae are promising anti-inflammatory agents because of their potential to attenuate inflammatory cytokines. The triangular sea bell Turbinaria decurrens (Sargassaceae) among marine macroalgae is ubiquitous in oceanic waters, and a sulfated polygalactofucan SPTd-2 [→3-(α-L-fucp-(2-OSO3−)-(1 → 4)-α-L-fucp-(3-OAc)-(1 → 4)-β-D-galp-(1→] was purified from the species. The studied polygalactofucan SPTd-2 exhibited anti-inflammatory activities against cyclooxygenase-2 (IC50 10.56 μM) and 5-lipoxygenase (IC50 3.36 μM) with a greater selectivity index (2.35) than ibuprofen (0.44), besides attenuating pro-inflammatory cytokine production, including tumor necrosis factor-α, transforming growth factor-β, interleukin-2, 1β, and interferon-γ. Quantitative real-time polymerase chain reaction displayed that SPTd-2 blocked the mRNA of interferon-γ and interleukin-2, in the human monocytic cell line THP-1. The results showed the potential of SPTd-2 to attenuate inflammation-associated disorders.

CNTN1 Aggravates Neuroinflammation and Triggers Cognitive Deficits in Male Mice by Boosting Crosstalk between Microglia and Astrocytes.

A wealth of knowledge regarding glial cell-mediated neuroinflammation, which contributes to cognitive deficits in Alzheimer's disease (AD) has emerged in recent years. Contactin 1(CNTN1), a member of the cell adhesion molecule and immunoglobulin supergene family, is centrally involved in axonal growth regulation and is also a key player in inflammation-associated disorders. However, whether CNTN1 plays a role in inflammation-related cognitive deficits and how this process is triggered and orchestrated remain to be fully elucidated. In this study, we examined postmortem brains with AD. CNTN1 immunoreactivity was markedly increased, particularly in the CA3 subregion, as compared with non-AD brains. Furthermore, by applying an adeno-associated virus-based approach to overexpress CNTN1 directly via stereotactic injection in mice, we demonstrated that hippocampal CNTN1 overexpression triggered cognitive deficits detected by novel object-recognition, novel place-recognition and social cognition tests. The mechanisms underlying these cognitive deficits could be attributed to hippocampal microglia and astrocyte activation, which led to aberrant expression of excitatory amino acid transporters (EAAT)1/EAAT2. This resulted in long-term potentiation (LTP) impairment that could be reversed by minocyline, an antibiotic and the best-known inhibitor of microglial activation. Taken together, our results identified Cntn1 as a susceptibility factor involved in regulating cognitive deficits via functional actions in the hippocampus. This factor correlated with microglial activation and triggered astrocyte activation with abnormal EAAT1/EAAT2 expression and LTP impairment. Overall, these findings may significantly advance our understanding of the pathophysiological mechanisms underlying the risk of neuroinflammation related cognitive deficits.

Design, synthesis, and biological evaluation of morpholinopyrimidine derivatives as anti-inflammatory agents.

Here, we outline the synthesis of a few 2-methoxy-6-((4-(6-morpholinopyrimidin-4-yl)piperazin-1-yl)(phenyl)methyl)phenol derivatives and assess their anti-inflammatory activity in macrophage cells that have been stimulated by LPS. Among these newly synthesized morpholinopyrimidine derivatives, 2-methoxy-6-((4-methoxyphenyl)(4-(6-morpholinopyrimidin-4-yl)piperazin-1-yl)methyl)phenol (V4) and 2-((4-fluorophenyl)(4-(6-morpholinopyrimidin-4-yl)piperazin-1-yl)methyl)-6-methoxyphenol (V8) are two of the most active compounds which can inhibit the production of NO at non-cytotoxic concentrations. Our findings also showed that compounds V4 and V8 dramatically reduced iNOS and cyclooxygenase mRNA expression (COX-2) in LPS-stimulated RAW 264.7 macrophage cells; western blot analysis showed that the test compounds decreased the amount of iNOS and COX-2 protein expression, hence inhibiting the inflammatory response. We find through molecular docking studies that the chemicals had a strong affinity for the iNOS and COX-2 active sites and formed hydrophobic interactions with them. Therefore, use of these compounds could be suggested as a novel therapeutic strategy for inflammation-associated disorders.

Advances in Fucoxanthin Research for the Prevention and Treatment of Inflammation-Related Diseases.

Owing to its unique structure and properties, fucoxanthin (FX), a carotenoid, has attracted significant attention. There have been numerous studies that demonstrate FX's anti-inflammatory, antioxidant, antitumor, and anti-obesity properties against inflammation-related diseases. There is no consensus, however, regarding the molecular mechanisms underlying this phenomenon. In this review, we summarize the potential health benefits of FX in inflammatory-related diseases, from the perspective of animal and cellular experiments, to provide insights for future research on FX. Previous work in our lab has demonstrated that FX remarkably decreased LPS-induced inflammation and improved survival in septic mice. Further investigation of the activity of FX against a wide range of diseases will require new approaches to uncover its molecular mechanism. This review will provide an outline of the current state of knowledge regarding FX application in the clinical setting and suggest future directions to implement FX as a therapeutic ingredient in pharmaceutical sciences in order to develop it into a treatment strategy against inflammation-associated disorders.

The Role of Kynurenine and Its Metabolites in Comorbid Chronic Pain and Depression.

Chronic pain and depression affect millions of people worldwide, and their comorbidity tends to exacerbate the severity of each individual condition. Intersecting brain regions and molecular pathways could probably explain the unique yet complex bidirectional relationship between these two disorders. Recent studies have found that inflammatory reactions, frequently identified in both chronic pain and depression, stimulate certain enzymes in the kynurenine pathway, while concurrently suppressing others. Kynurenine, a major tryptophan derivative, and its metabolites have been implicated in several inflammation-associated pain syndromes and depressive mood disorders. Due to inflammation, 95% of tryptophan is metabolized via the kynurenine pathway, which drives the reaction towards the production of metabolites that have distinct roles in the pathophysiology of these disorders. Diminished levels of the neuroprotective metabolite, kynurenic acid (KYNA), and elevated levels of the neurotoxic metabolite, quinolinic acid (QUIN), have been frequently identified in human patients formally diagnosed with these disorders, as well as animal models commonly used in medical research. This review not only explores the epidemiology of comorbid chronic pain and depression, but also highlights the involvement of kynurenine and its metabolites, specifically KYNA and QUIN, in these pervasive conditions.

USP25 UPREGULATION BOOSTS GSDMD -MEDIATED PYROPTOSIS OF ACINAR CELLS IN ACUTE PANCREATITIS.

Acute pancreatitis (AP) is an inflammation-associated disorder in the digestive system. Ubiquitin-specific peptidase 25 ( USP25 ) can modulate inflammation in diseases. This study expounded on the role of USP25 in pyroptosis of acinar cells in AP. Acinar cells were treated with lipopolysaccharide (LPS) and caerulein (CRE) to induce AP. Afterward, the expression patterns of USP25 , microRNA (miR)-10a-5p, and Krüppel-like factor 4 ( KLF4 ) in acinar cells were examined. Then, acinar cell viability and levels of NLR family pyrin-domain containing 3 (NLRP3), cleaved caspase-1, cleaved N -terminal gasdermin D ( GSDMD - N ), interleukin (IL)-1β, and IL-18 were determined. We observed that USP25 was highly expressed in AP models, and silencing USP25 increased cell viability and inhibited pyroptosis of AP acinar cells. The bindings of USP25 to KLF4 and miR-10a-5p to KLF4 and the GSDMD 3'UTR sequence were validated. We found that USP25 binding to KLF4 inhibited ubiquitination degradation of KLF4 , KLF4 transcriptionally decreased miR-10a-5p expression, and miR-10a-5p targeted GSDMD expression. Finally, rescue experiments proved that KLF4 overexpression or miR-10a-5p suppression enhanced pyroptosis of AP acinar cells. Overall, USP25 stabilized KLF4 expression through deubiquitination, limited miR-10a-5p expression, and increased GSDMD expression, finally promoting pyroptosis of acinar cells in AP.

Therapeutic management of arthritis: A review on structural and target‐based approaches

Inflammation is the natural defense mechanism against any external stimuli in the human body and it saves us from foreign entities that may alter our bodies' normal functioning. Any anomaly in this natural defense system leads to the development of different pathological conditions associated with chronic inflammation like rheumatoid arthritis, osteoarthritis, atopy, asthma, allergic rhino-conjunctivitis, coronary artery disease, cardiac arrhythmias, obesity, insulin resistance and type-2 diabetes, depression, and aging. These disorders impair the quality of life of affected people in different ways. Among these, rheumatoid arthritis and osteoarthritis are the most common chronic inflammation-associated disorders. Different therapeutic strategies are already available for the treatment of rheumatoid arthritis and osteoarthritis, but all with pros and cons. Here, we discuss the emergence of several antiarthritic analogs developed by different researchers which could provide the basis for the evolution of newer therapeutic strategies with better activity and safety profiles.

Association between Higher Circulating Leucine-Rich α-2 Glycoprotein 1 Concentrations and Specific Plasma Ceramides in Postmenopausal Women with Type 2 Diabetes.

Background: Although ceramides are involved in the pathophysiology of cardiovascular disease and other inflammation-associated disorders, there is a paucity of data on the association between plasma ceramides and inflammatory biomarkers in type 2 diabetes mellitus (T2DM). Therefore, we explored whether there was an association between plasma leucine-rich α-2 glycoprotein 1 (LRG1) concentrations (i.e., a novel proinflammatory signaling molecule) and specific plasma ceramides in postmenopausal women with T2DM. Methods: We measured six previously identified plasma ceramides, which have been associated with increased cardiovascular risk [plasma Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/20:0), Cer(d18:1/22:0), Cer(d18:1/24:0) and Cer(d18:1/24:1)], amongst 99 Caucasian postmenopausal women with non-insulin-treated T2DM (mean age 72 ± 8 years, mean hemoglobin A1c 6.9 ± 0.7%), who consecutively attended our diabetes outpatient service during a 3-month period. Plasma ceramide and LRG1 concentrations were measured with a targeted liquid chromatography-tandem mass spectrometry assay and a Milliplex® MAP human cardiovascular disease magnetic bead kit, respectively. Results: In linear regression analyses, higher plasma LRG1 levels (1st tertile vs. 2nd and 3rd tertiles combined) were associated with higher levels of plasma Cer(d18:1/16:0) (standardized β coefficient: 0.289, p = 0.004), Cer(d18:1/18:0) (standardized β coefficient: 0.307, p = 0.002), Cer(d18:1/20:0) (standardized β coefficient: 0.261, p = 0.009) or Cer(d18:1/24:1) (standardized β coefficient: 0.343, p < 0.001). These associations remained significant even after adjusting for age, body mass index, systolic blood pressure, total cholesterol level, hemoglobin A1c, insulin resistance and statin use. Conclusions: The results of our pilot exploratory study suggest that higher plasma LRG1 concentration was associated with higher levels of specific high-risk plasma ceramide molecules in elderly postmenopausal women with metabolically well-controlled T2DM, even after adjusting for known cardiovascular risk factors and other potential confounding variables.

Evidence of Failed Resolution Mechanisms in Arrhythmogenic Inflammation, Fibrosis and Right Heart Disease.

Inflammation is a complex program of active processes characterized by the well-orchestrated succession of an initiation and a resolution phase aiming to promote homeostasis. When the resolution of inflammation fails, the tissue undergoes an unresolved inflammatory status which, if it remains uncontrolled, can lead to chronic inflammatory disorders due to aggravation of structural damages, development of a fibrous area, and loss of function. Various human conditions show a typical unresolved inflammatory profile. Inflammatory diseases include cancer, neurodegenerative disease, asthma, right heart disease, atherosclerosis, myocardial infarction, or atrial fibrillation. New evidence has started to emerge on the role, including pro-resolution involvement of chemical mediators in the acute phase of inflammation. Although flourishing knowledge is available about the role of specialized pro-resolving mediators in neurodegenerative diseases, atherosclerosis, obesity, or hepatic fibrosis, little is known about their efficacy to combat inflammation-associated arrhythmogenic cardiac disorders. It has been shown that resolvins, including RvD1, RvE1, or Mar1, are bioactive mediators of resolution. Resolvins can stop neutrophil activation and infiltration, stimulate monocytes polarization into anti-inflammatory-M2-macrophages, and activate macrophage phagocytosis of inflammation-debris and neutrophils to promote efferocytosis and clearance. This review aims to discuss the paradigm of failed-resolution mechanisms (FRM) potentially promoting arrhythmogenicity in right heart disease-induced inflammatory status.

Osteoporosis and periodontal diseases - An update on their association and mechanistic links.

Periodontitis and osteoporosis are prevalent inflammation-associated skeletal disorders that pose significant public health challenges to our aging population. Both periodontitis and osteoporosis are bone disorders closely associated with inflammation and aging. There has been consistent intrigue on whether a systemic skeletal disease such as osteoporosis will amplify the alveolar bone loss in periodontitis. A survey of the literature published in the past 25years indicates that systemic low bone mineral density (BMD) is associated with alveolar bone loss, while recent evidence also suggests a correlation between clinical attachment loss and other parameters of periodontitis. Inflammation and its influence on bone remodeling play critical roles in the pathogenesis of both osteoporosis and periodontitis and could serve as the central mechanistic link between these disorders. Enhanced cytokine production and elevated inflammatory response exacerbate osteoclastic bone resorption while inhibiting osteoblastic bone formation, resulting in a net bone loss. With aging, accumulation of oxidative stress and cellular senescence drive the progression of osteoporosis and exacerbation of periodontitis. Vitamin D deficiency and smoking are shared risk factors and may mediate the connection between osteoporosis and periodontitis, through increasing oxidative stress and impairing host response to inflammation. With the connection between systemic and localized bone loss in mind, routine dental exams and intraoral radiographs may serve as a low-cost screening tool for low systemic BMD and increased fracture risk. Conversely, patients with fracture risk beyond the intervention threshold are at greater risk for developing severe periodontitis and undergo tooth loss. Various Food and Drug Administration-approved therapies for osteoporosis have shown promising results for treating periodontitis. Understanding the molecular mechanisms underlying their connection sheds light on potential therapeutic strategies that may facilitate co-management of systemic and localized bone loss.