Roles of the Caspase-11 Non-Canonical Inflammasome in Rheumatic Diseases.

Inflammasomes are intracellular multiprotein complexes that activate inflammatory signaling pathways. Inflammasomes comprise two major classes: canonical inflammasomes, which were discovered first and are activated in response to a variety of pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), and non-canonical inflammasomes, which were discovered recently and are only activated in response to intracellular lipopolysaccharide (LPS). Although a larger number of studies have successfully demonstrated that canonical inflammasomes, particularly the NLRP3 inflammasome, play roles in various rheumatic diseases, including rheumatoid arthritis (RA), infectious arthritis (IR), gouty arthritis (GA), osteoarthritis (OA), systemic lupus erythematosus (SLE), psoriatic arthritis (PA), ankylosing spondylitis (AS), and Sjögren's syndrome (SjS), the regulatory roles of non-canonical inflammasomes, such as mouse caspase-11 and human caspase-4 non-canonical inflammasomes, in these diseases are still largely unknown. Interestingly, an increasing number of studies have reported possible roles for non-canonical inflammasomes in the pathogenesis of various mouse models of rheumatic disease. This review comprehensively summarizes and discusses recent emerging studies demonstrating the regulatory roles of non-canonical inflammasomes, particularly focusing on the caspase-11 non-canonical inflammasome, in the pathogenesis and progression of various types of rheumatic diseases and provides new insights into strategies for developing potential therapeutics to prevent and treat rheumatic diseases as well as associated diseases by targeting non-canonical inflammasomes.

Development of a Protocol for the Direct Breastfeeding of Premature Infants in Neonatal Intensive Care Units.

PURPOSE: This study aimed to develop a direct breastfeeding protocol for premature infants admitted to neonatal intensive care units (NICUs) and investigate its efficacy. BACKGROUND: Direct breastfeeding increases the amount and duration of breastfeeding. However, NICUs have low direct feeding rates owing to medical staff anxiety, lack of knowledge and experience, and fear of overwork. Accordingly, this study developed a protocol for direct breastfeeding in the NICU and evaluated its effect. METHODS: The protocol was developed through a literature review, expert validation, and preliminary investigation. Its application effects were identified using a nonexperimental, evidence-based research design targeting premature infants, their mothers, and NICU nurses. RESULTS: The protocol comprised 5 areas and 23 items. Application of the protocol resulted in continuous weight gain of the infants and increased self-efficacy in the mothers' direct breastfeeding ( t = 3.219, P = .004). Significant increases were noted in NICU nurses' direct breastfeeding activities ( t = 3.93, P < .001), breastfeeding rates in the NICU ( P = .037), and direct breastfeeding rates ( P = .007). CONCLUSIONS: Results underscore the value of an evidence-based protocol for improving breastfeeding rates in premature infants. This study highlights the need for continuous nursing education on protocol applications and human resource support.

A Novel Model for Predicting the Sagittal Length of the Distal Tibia Using CT Imaging and Statistics.

The purpose of this study was to determine the ratio of sagittal length to coronal length of the distal tibia for predicting the sagittal length of the distal tibia. A total of 202 ankles were measured based on CT imaging availability. We measured the coronal length (Width, W) parallel to the Chaput tubercle from CT scans. Sagittal length was divided into 3 points (Diameter D1, D2, D3) in the axial plane on the same level. The relationship between coronal length and each sagittal length was determined through correlation analysis. A prediction model was then developed using multiple regression. We also analyzed the quality of the prediction model and validated the prediction model with a validation cohort. Each sagittal length (D1, D2, D3) and coronal length had a significant positive correlation (p < .01). In the prediction model, sex, height, and W were significantly associated with D1, D2, and D3 (p < .05). Prediction models were made for each sagittal length (D1, D2, D3). Concordance correlation coefficient (CCC) values of prediction models for D1, D2, and D3 were 0.78, 0.72, and 0.72 for the derivation cohort and 0.69, 0.63, and 0.61 for the validation cohort, respectively. Accuracies of models as ± 2SD for D1, D2, and D3 were 93.9%, 94.9%, and 94.9%, respectively. This study predicted the sagittal length of the distal tibia for preoperative planning by measuring the coronal length of the distal tibia. Prediction of the sagittal length of the distal tibia can help foot and ankle surgeons fixate screws stably to prevent iatrogenic injury of posterior structures of the distal tibia.

Inflammation, Inflammatory Diseases, and Inflammasomes.

Inflammation represents the innate immune response of the body tissues against invading microbes and cellular danger signals, and, in this way, it is beneficial [...].

Regulatory Roles of Flavonoids in Caspase-11 Non-Canonical Inflammasome-Mediated Inflammatory Responses and Diseases.

Inflammasomes are multiprotein complexes that activate inflammatory responses by inducing pyroptosis and secretion of pro-inflammatory cytokines. Along with many previous studies on inflammatory responses and diseases induced by canonical inflammasomes, an increasing number of studies have demonstrated that non-canonical inflammasomes, such as mouse caspase-11 and human caspase-4 inflammasomes, are emerging key players in inflammatory responses and various diseases. Flavonoids are natural bioactive compounds found in plants, fruits, vegetables, and teas and have pharmacological properties in a wide range of human diseases. Many studies have successfully demonstrated that flavonoids play an anti-inflammatory role and ameliorate many inflammatory diseases by inhibiting canonical inflammasomes. Others have demonstrated the anti-inflammatory roles of flavonoids in inflammatory responses and various diseases, with a new mechanism by which flavonoids inhibit non-canonical inflammasomes. This review discusses recent studies that have investigated the anti-inflammatory roles and pharmacological properties of flavonoids in inflammatory responses and diseases induced by non-canonical inflammasomes and further provides insight into developing flavonoid-based therapeutics as potential nutraceuticals against human inflammatory diseases.

Korean Red Ginseng Saponins Play an Anti-Inflammatory Role by Targeting Caspase-11 Non-Canonical Inflammasome in Macrophages.

We previously reported that Korean red ginseng (KRG) exerts an anti-inflammatory role through inhibiting caspase-11 non-canonical inflammasome in macrophages; however, the components responsible for the anti-inflammatory role remained unclear. This study explored the anti-inflammatory activity of the KRG saponin fraction (KRGSF) in caspase-11 non-canonical inflammasome-activated macrophages. KRGSF inhibited pyroptosis, pro-inflammatory cytokine secretion, and inflammatory mediator production in caspase-11 non-canonical inflammasome-activated J774A.1 cells. A mechanism study revealed that KRGSF-induced anti-inflammatory action was mediated via suppressing the proteolytic activation of caspase-11 and gasdermin D (GSDMD) in caspase-11 non-canonical inflammasome-activated J774A.1 cells. Moreover, KRGSF increased the survival of lethal septic mice. Taken together, these results reveal KRGSF-mediated anti-inflammatory action with a novel mechanism, by inhibiting caspase-11 non-canonical inflammasome in macrophages.

Various Flexible Fixation Techniques Using Suture Button for Ligamentous Lisfranc Injuries: A Review of Surgical Options.

Contrary to Lisfranc joint fracture-dislocation, ligamentous Lisfranc injury can lead to additional instability and arthritis and is difficult to diagnose. Appropriate procedure selection is necessary for a better prognosis. Several surgical methods have recently been introduced. Here, we present three distinct surgical techniques for treating ligamentous Lisfranc employing flexible fixation. First is the "Single Tightrope procedure", which involves reduction and fixation between the second metatarsal base and the medial cuneiform via making a bone tunnel and inserting Tightrope. Second is the "Dual Tightrope Technique", which is similar to the "Single Tightrope technique", with additional fixation of an intercuneiform joint using one MiniLok Quick Anchor Plus. Last but not least, the "internal brace approach" uses the SwiveLock anchor, particularly when intercueniform instability is seen. Each approach has its own advantages and disadvantages in terms of surgical complexity and stability. These flexible fixation methods, on the other hand, are more physiologic and have the potential to lessen the difficulties that have been linked to the use of conventional screws in the past.

Selective Formation of Mononuclear Palladium and Acetonitrile-Bridged Dinuclear Palladium Complexes Containing a Chiral Tridentate Ligand.

From the chiral Schiff base tridentate ligand LPh, unusual acetonitrile-bridged dinuclear palladium complex 1 and organopalladium complex 1' were synthesized selectively by using acetonitrile and ethanol, respectively. The chiral tridentate Schiff base ligand was bound to the palladium metal center with different chelation modes ([ONO] for 1 and [CNO] for 1'). Complex 1 constitutes the first example of dinuclear metal complexes connected only by a bridging acetonitrile, in which an exceptionally short C≡N bond distance [0.945(12) Å] of bridged acetonitrile was observed. To study the influence of a phenyl group attached to an imine, the phenyl-free ligand LH was prepared and used. In that case, an acetonitrile bridge was not observed. Theoretical calculation studies supporting the formation of 1 and 1' are favored.

Regulatory Roles of Caspase-11 Non-Canonical Inflammasome in Inflammatory Liver Diseases.

An inflammatory response consists of two consecutive steps: priming and triggering, to prepare and activate inflammatory responses, respectively. The cardinal feature of the triggering step is the activation of intracellular protein complexes called inflammasomes, which provide a platform for the activation of inflammatory signaling pathways. Despite many studies demonstrating the regulatory roles of canonical inflammasomes in inflammatory liver diseases, the roles of newly discovered non-canonical inflammasomes in inflammatory liver diseases are still largely unknown. Recent studies have reported the regulatory roles of the caspase-11 non-canonical inflammasome in inflammatory liver diseases, providing strong evidence that the caspase-11 non-canonical inflammasome may play key roles in the pathogenesis of inflammatory liver diseases. This review comprehensively discusses the emerging roles of the caspase-11 non-canonical inflammasome in the pathogenesis of inflammatory liver diseases, focusing on non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and inflammatory liver injuries and its underlying mechanisms. This review highlights the current knowledge on the regulatory roles of the caspase-11 non-canonical inflammasome in inflammatory liver diseases, providing new insights into the development of potential therapeutics to prevent and treat inflammatory liver diseases by targeting the caspase-11 non-canonical inflammasome.

Editorial of Special Issue "Inflammasomes and Inflammation".

Although inflammation is a host-protective mechanism from infection and cellular danger signals, chronic inflammation is a major risk factor for various human diseases [...].

Editorial of Special Issue "Roles of Inflammasomes and Methyltransferases in Inflammation".

Inflammation is the first line of defense against pathogens and cellular dangers [...].

14-3-3 epsilon is an intracellular component of TNFR2 receptor complex and its activation protects against osteoarthritis.

OBJECTIVES: Osteoarthritis (OA) is the most common joint disease; however, the indeterminate nature of mechanisms by which OA develops has restrained advancement of therapeutic targets. TNF signalling has been implicated in the pathogenesis of OA. TNFR1 primarily mediates inflammation, whereas emerging evidences demonstrate that TNFR2 plays an anti-inflammatory and protective role in several diseases and conditions. This study aims to decipher TNFR2 signalling in chondrocytes and OA. METHODS: Biochemical copurification and proteomics screen were performed to isolate the intracellular cofactors of TNFR2 complex. Bulk and single cell RNA-seq were employed to determine 14-3-3 epsilon (14-3-3ε) expression in human normal and OA cartilage. Transcription factor activity screen was used to isolate the transcription factors downstream of TNFR2/14-3-3ε. Various cell-based assays and genetically modified mice with naturally occurring and surgically induced OA were performed to examine the importance of this pathway in chondrocytes and OA. RESULTS: Signalling molecule 14-3-3ε was identified as an intracellular component of TNFR2 complexes in chondrocytes in response to progranulin (PGRN), a growth factor known to protect against OA primarily through activating TNFR2. 14-3-3ε was downregulated in OA and its deficiency deteriorated OA. 14-3-3ε was required for PGRN regulation of chondrocyte metabolism. In addition, both global and chondrocyte-specific deletion of 14-3-3ε largely abolished PGRN's therapeutic effects against OA. Furthermore, PGRN/TNFR2/14-3-3ε signalled through activating extracellular signal-regulated kinase (ERK)-dependent Elk-1 while suppressing nuclear factor kappa B (NF-κB) in chondrocytes. CONCLUSIONS: This study identifies 14-3-3ε as an inducible component of TNFR2 receptor complex in response to PGRN in chondrocytes and presents a previously unrecognised TNFR2 pathway in the pathogenesis of OA.

Caspase-11 Noncanonical Inflammasome: A Novel Key Player in Murine Models of Neuroinflammation and Multiple Sclerosis.

Inflammasomes are intracellular protein complexes consisting of the pattern recognition receptors and inflammatory molecules in the inflamed cells. In response to various ligands, inflammasomes play a pivotal role to execute the inflammatory responses by inducing the pyroptosis and the secretion of pro-inflammatory cytokines, interleukin (IL)-1ß, and IL-18. Unlike canonical inflammasomes, including NOD-like receptor family inflammasomes, such as NLRP1, NLRP3, NLRC4, and absence in melanoma 2 inflammasomes, noncanonical inflammasomes, such as mouse caspase-11 and human caspase-4/5 were recently discovered, and their roles in the inflammatory responses have been poorly understood. However, emerging studies have been successfully demonstrating the regulatory roles of these noncanonical inflammasomes on inflammatory responses and the pathogenesis of inflammatory/autoimmune diseases. This review summarizes and discusses the recent studies investigating the regulatory roles of the caspase-11 noncanonical inflammasome in neuroinflammation and the pathogenesis of multiple sclerosis (MS), which provides the insight for the validation of caspase-11 noncanonical inflammasome to develop novel and promising therapeutics for MS.

Functional Interplay between Methyltransferases and Inflammasomes in Inflammatory Responses and Diseases.

An inflammasome is an intracellular protein complex that is activated in response to a pathogenic infection and cellular damage. It triggers inflammatory responses by promoting inflammatory cell death (called pyroptosis) and the secretion of pro-inflammatory cytokines, interleukin (IL)-1ß and IL-18. Many types of inflammasomes have been identified and demonstrated to play a central role in inducing inflammatory responses, leading to the onset and progression of numerous inflammatory diseases. Methylation is a biological process by which methyl groups are transferred from methyl donors to proteins, nucleic acids, and other cellular molecules. Methylation plays critical roles in various biological functions by modulating gene expression, protein activity, protein localization, and molecular stability, and aberrant regulation of methylation causes deleterious outcomes in various human diseases. Methylation is a key determinant of inflammatory responses and diseases. This review highlights the current understanding of the functional relationship between inflammasome regulation and methylation of cellular molecules in inflammatory responses and diseases.

Flavonoids: Nutraceuticals for Rheumatic Diseases via Targeting of Inflammasome Activation.

Inflammation, an innate immune response that prevents cellular damage caused by pathogens, consists of two successive mechanisms, namely priming and triggering. While priming is an inflammation-preparation step, triggering is an inflammation-activation step, and the central feature of triggering is the activation of inflammasomes and intracellular inflammatory protein complexes. Flavonoids are natural phenolic compounds predominantly present in plants, fruits, and vegetables and are known to possess strong anti-inflammatory activities. The anti-inflammatory activity of flavonoids has long been demonstrated, with the main focus on the priming mechanisms, while increasing numbers of recent studies have redirected the research focus on the triggering step, and studies have reported that flavonoids inhibit inflammatory responses and diseases by targeting inflammasome activation. Rheumatic diseases are systemic inflammatory and autoimmune diseases that primarily affect joints and connective tissues, and they are associated with numerous deleterious effects. Here, we discuss the emerging literature on the ameliorative role of flavonoids targeting inflammasome activation in inflammatory rheumatic diseases.

Editorial of Special Issue "Regulatory Roles of Inflammasomes in Human Diseases".

Inflammation is an innate immunity protecting the body from pathogens and cellular damages and comprises two steps; 1) priming (preparatory step) and triggering (activation step). The key feature of the triggering step is the activation of inflammasomes that are intracellular protein complexes consisting of pattern recognition receptors and inflammatory molecules. Inflammasomes are activated in response to various ligands, leading to the caspase-1-mediated maturation and secretion of pro-inflammatory cytokines, IL-1ß and IL-18 and the gasdermin D-mediated pyroptosis, an inflammatory form of cell death. Previous studies have demonstrated that inflammasome activation is a key determinant of inflammatory responses and many human diseases; therefore, inflammasomes have been attracted much attention as critical drug targets to prevent and treat various human diseases.

A Novel Prediction Model for Determining Coronal Length of Calcaneus Using CT: A Guide for Surgery of Calcaneal Fracture.

The objective of this study was to determine the anatomical relationship between the calcaneus and its neighboring bones. Furthermore we tested a prediction model that enables to estimate safe screw length during the surgery of calcaneus fractures. A total of 169 feet were used for the study based on CT scans. We measured two horizontal and two parallel lines. The coronal length of the cuboid bone (CL) was a horizontal line anterior to the calcaneocuboidal joint, and W1 of calcaneus was a horizontal line posterior to the articular surface of the calcaneocuboidal joint. The subtalar articular length (STA) was a parallel line above the talocalcaneal joint, and W2 of calcaneus was a parallel line below to the talocalcaneal joint. Relationship of each measurement was determined through correlation analysis. A prediction model was developed based on observed correlations and the quality analyzed and validated. The CL and W1 had a significant positive correlation (r = 0.899, p < .001). The STA and W2 also had a significant positive correlation (r = 0.939, p < .001). Based on these correlations, the prediction model was made. In the quality analysis, the values of concordance correlation coefficient (CCC) for W1 and W2 were 0.894, and 0.937 respectively. In the validation analysis, the values of CCC for W1, W2 were 0.79, and 0.8, respectively. This study made it possible to predict the anatomical reference point using preoperative coronal length of the calcaneus to guide safety margin of screw length, and thereby to prevent the iatrogenic injuries on medial neurovascular structures of the calcaneus.

Efficacy of Lesion Specific Portals in Endoscopic Treatment of Calcaneal Bone Cyst: A Case Report and Literature Review.

Background: Calcaneal bone cysts rarely occur and most of them are known to be benign. Among them, simple bone cysts (SBCs) third most commonly occur in the calcaneus and of the many surgical treatment options, endoscopic curettage is recently gaining popularity among surgeons due to its advantages of minimal invasiveness and optimal visualization. As for portal placement for endoscopy, two lateral portals are considered a standard technique, but no rationale has been established for SBCs with abnormal geometry. This case report suggests an SBC with secondary aneurysmal change located outside the Ward's triangle, as well as an appropriate endoscopic approach. Case Presentation: An 18-year-old male high school student presented with a main complaint of pain at the hind foot level for the past one year, without significant improvement from conservative treatment. An endoscopic curettage through the lesion specific two posterior portals and bone graft using allogeneic cancellous bone were performed. SBC with a secondary aneurysmal bone cyst was diagnosed on pathology. At a one-year follow-up, the patient was painless and had returned to his regular activities. Physical and radiographic examinations revealed that the lesion was completely healed without any evidence of recurrence. Conclusion: For calcaneal bone cysts located at the posterior aspect of the calcaneus, eccentrically medial and abnormally long anterior-posteriorly, we suggest an endoscopic procedure using lesion specific portals such as two posterior portals.

Functional crosstalk between non-canonical caspase-11 and canonical NLRP3 inflammasomes during infection-mediated inflammation.

Inflammation is a part of the body's immune response for protection against pathogenic infections and other cellular damages; however, chronic inflammation is a major cause of various diseases. One key step in the inflammatory response is the activation of inflammasomes, intracellular protein complexes comprising pattern recognition receptors and other inflammatory molecules. The role of the NLRP3 inflammasome in inflammatory responses has been extensively investigated; however, the caspase-11 inflammasome has been recently identified and has been classified as a 'non-canonical' inflammasome, and emerging studies have highlighted its role in inflammatory responses. Because the ligands and the mechanisms for the activation of these two inflammasomes are different, studies to date have separately described their roles, although recent studies have reported the functional cooperation between these two inflammasomes during an inflammatory response. This review discusses the studies investigating the functional crosstalk between non-canonical caspase-11 and canonical NLRP3 inflammasomes in the context of inflammatory responses; moreover, it provides insight for the development of novel anti-inflammatory therapeutics to prevent and treat infectious and inflammatory diseases.

Tarsal tunnel syndrome secondary to osteochondroma of the calcaneus: a case report.

BACKGROUND: Tarsal tunnel syndrome is an entrapment neuropathy that can be provoked by either intrinsic or extrinsic factors that compresses the posterior tibial nerve beneath the flexor retinaculum. Osteochondroma, the most common benign bone tumor, seldom occur in foot or ankle. This is a rare case of tarsal tunnel syndrome secondary to osteochondroma of the sustentaculum tali successfully treated with open surgical excision. CASE PRESENTATION: A 15-year-old male presented with the main complaint of burning pain and paresthesia on the medial plantar aspect of the forefoot to the middle foot region. Hard mass-like lesion was palpated on the posteroinferior aspect of the medial malleolus. On the radiological examination, 2.5 × 1 cm sized bony protuberance was found below the sustentaculum tali. Surgical decompression of the posterior tibial nerve was performed by complete excision of the bony mass connected to the sustentaculum tali. The excised mass was diagnosed to be osteochondroma on the histologic examination. After surgery, the pain was relieved immediately and hypoesthesia disappeared 3 months postoperatively. Physical examination and radiographic examination at 2-year follow up revealed that tarsal tunnel was completely decompressed without any evidence of complication or recurrence. CONCLUSIONS: As for tarsal tunnel syndrome secondary to the identifiable space occupying structure with a distinct neurologic symptom, we suggest complete surgical excision of the causative structure in an effort to effectively relieve symptoms and prevent recurrence.