Unraveling the NLRP family: Structure, function, activation, critical influence on tumor progression, and potential as targets for cancer therapy.

The innate immune system serves as the body's initial defense, swiftly detecting danger via pattern recognition receptors (PRRs). Among these, nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing proteins (NLRPs) are pivotal in recognizing pathogen-associated and damage-associated molecular patterns, thereby triggering immune responses. NLRPs, the most extensively studied subset within the NLR family, form inflammasomes that regulate inflammation, essential for innate immunity activation. Recent research highlights NLRPs' significant impact on various human diseases, including cancer. With differential expression across organs, NLRPs influence cancer progression by modulating immune reactions, cell fate, and proliferation. Their clinical significance in cancer makes them promising therapeutic targets. This review provides a comprehensive overview of the structure, function, activation mechanism of the NLRPs family and its potential role in cancer progression. In addition, we particularly focused on the concept of NLRP as a therapeutic target and its potential value in combination with immune checkpoint inhibitors.

Pathogenesis of Inflammation in Skin Disease: From Molecular Mechanisms to Pathology.

Many skin diseases begin with inflammatory changes on a molecular level. To develop a more thorough understanding of skin pathology and to identify new targets for therapeutic advancements, molecular mechanisms of inflammation in the context of skin disease should be studied. Current research efforts to better understand skin disease have focused on examining the role of molecular processes at several stages of the inflammatory response such as the dysregulation of innate immunity sensors, disruption of both transcriptional and post-transcriptional regulation, and crosstalk between immune and neuronal processes (neuro-immune crosstalk). This review seeks to summarize recent developments in our understanding of inflammatory processes in skin disease and to highlight opportunities for therapeutic advancements. With a focus on publications within the past 5 years (2019-2024), the databases PubMed and EBSCOhost were used to search for peer-reviewed papers regarding inflammatory molecular mechanisms and skin disease. Several themes of research interest regarding inflammatory processes in skin disease were determined through extensive review and were included based on their relative representation in current research and their focus on therapeutic potential. Several skin diseases such as psoriasis, atopic dermatitis, hidradenitis suppurativa, and scleroderma were described in the paper to demonstrate the widespread influence of inflammation in skin disease.

Alternatives to ß-Lactams as Agents for the Management of Dentoalveolar Abscess.

Dentoalveolar abscess are localized infections within the tooth or the surrounding alveolar bone, often resulting from untreated dental caries or dental trauma causing alveolar bone resorption or even loss. Serious consequences arising from the spread of a dental abscess can often lead to significant morbidity and mortality. The acute dentoalveolar abscess is a polymicrobial infection comprising strict anaerobes, such as anaerobic cocci i.e., Prevotella fusobacterium species, and facultative anaerobes i.e., Streptococci viridians and Streptococcus anginosus. Moreover, inappropriately managed dental infections can progress to severe submandibular space infections with associated serious complications, such as sepsis and airway obstruction. An audit of the Hull Royal Infirmary between 1999 and 2004 showed an increase in the number of patients presenting to oral and maxillofacial surgery services with dental sepsis. Thus, the scientific community is forced to focus on treatment strategies for the management of dentoalveolar abscess (DAA) and other related dental problems. The current treatment includes antibiotic therapy, including ß-lactams and non-ß- lactams drugs, but it leads to the development of resistant microorganisms due to improper and wide usage. Furthermore, the currently used ß-lactam therapeutics is non-specific and easily hydrolyzed by the ß-lactamase enzymes. Thus, the research focused on the non-ß-lactams that can be the potential pharmacophore and helpful in the management of DAA, as the appropriate use and choice of antibiotics in dentistry plays an important role in antibiotic stewardship. The newer target for the choice is NLRP inflammasome, which is the major chemical mediator involved in dental problems. This review focused on pathogenesis and current therapeutics for the treatment of dentoalveolar abscesses.

NLRP inflammasomes in health and disease.

NLRP inflammasomes are a group of cytosolic multiprotein oligomer pattern recognition receptors (PRRs) involved in the recognition of pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) produced by infected cells. They regulate innate immunity by triggering a protective inflammatory response. However, despite their protective role, aberrant NLPR inflammasome activation and gain-of-function mutations in NLRP sensor proteins are involved in occurrence and enhancement of non-communicating autoimmune, auto-inflammatory, and neurodegenerative diseases. In the last few years, significant advances have been achieved in the understanding of the NLRP inflammasome physiological functions and their molecular mechanisms of activation, as well as therapeutics that target NLRP inflammasome activity in inflammatory diseases. Here, we provide the latest research progress on NLRP inflammasomes, including NLRP1, CARD8, NLRP3, NLRP6, NLRP7, NLRP2, NLRP9, NLRP10, and NLRP12 regarding their structural and assembling features, signaling transduction and molecular activation mechanisms. Importantly, we highlight the mechanisms associated with NLRP inflammasome dysregulation involved in numerous human auto-inflammatory, autoimmune, and neurodegenerative diseases. Overall, we summarize the latest discoveries in NLRP biology, their forming inflammasomes, and their role in health and diseases, and provide therapeutic strategies and perspectives for future studies about NLRP inflammasomes.

Quantum-Dot-Based Iron Oxide Nanoparticles Activate the NLRP3 Inflammasome in Murine Bone Marrow-Derived Dendritic Cells.

Inflammasomes are cytosolic complexes composed of a Nod-like receptor, NLR, the adaptor protein, ASC, and a proteolytic enzyme, caspase-1. Inflammasome activation leads to caspase-1 activation and promotes functional maturation of IL-1ß and IL-18, two prototypical inflammatory cytokines. Besides, inflammasome activation leads to pyroptosis, an inflammatory type of cell death. Inflammasomes are vital for the host to cope with foreign pathogens or tissue damage. Herein, we show that quantum-dot-based iron oxide nanoparticles, MNP@QD, trigger NLRP3 inflammasome activation and subsequent release of proinflammatory interleukin IL-1ß by murine bone marrow-derived dendritic cells (BMDCs). This activation is more pronounced if these cells endocytose the nanoparticles before receiving inflammatory stimulation. MNP@QD was characterized by using imaging techniques like transmission electron microscopy, fluorescence microscopy, and atomic force microscopy, as well as physical and spectroscopical techniques such as fluorescence spectroscopy and powder diffraction. These findings may open the possibility of using the composite MNP@QD as both an imaging and a therapeutic tool.

The Significance of NLRP Inflammasome in Neuropsychiatric Disorders.

The NLRP inflammasome is a multi-protein complex which mainly consists of the nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain. Its activation is linked to microglial-mediated neuroinflammation and partial neuronal degeneration. Many neuropsychiatric illnesses have increased inflammatory responses as both a primary cause and a defining feature. The NLRP inflammasome inhibition delays the progression and alleviates the deteriorating effects of neuroinflammation on several neuropsychiatric disorders. Evidence on the central effects of the NLRP inflammasome potentially provides the scientific base of a promising drug target for the treatment of neuropsychiatric disorders. This review elucidates the classification, composition, and functions of the NLRP inflammasomes. It also explores the underlying mechanisms of NLRP inflammasome activation and its divergent role in neuropsychiatric disorders, including Alzheimer's disease, Huntington's disease, Parkinson's disease, depression, drug use disorders, and anxiety. Furthermore, we explore the treatment potential of the NLRP inflammasome inhibitors against these disorders.

Mitochondrial-related effects of pentabromophenol, tetrabromobisphenol A, and triphenyl phosphate on murine BV-2 microglia cells.

The predominant reliance on bromated flame retardants (BFRs) is diminishing with expanded use of alternative organophosphate flame retardants. However, exposure related issues for susceptible populations, the developing, infirmed, or aged, remain given environmental persistence and home-environment detection. In this regard, reports of flame retardant (FR)-related effects on the innate immune system suggest process by which a spectrum of adverse health effects could manifest across the life-span. As representative of the nervous system innate immune system, the current study examined changes in microglia following exposure to representative FRs, pentabromophenol (PBP), tetrabromobisphenol A (2,2',6,6',-tetrabromo-4,4'-isopropylidine diphenol; TBBPA) and triphenyl phosphate (TPP). Following 18hr exposure of murine BV-2 cells, at dose levels resulting in ≥80% viability (10 and 40 µM), limited alterations in pro-inflammatory responses were observed however, changes were observed in mitochondrial respiration. Basal respiration was altered by PBP; ATP-linked respiration by PBP and TBBPA, and maximum respiration by all three FRs. Basal glycolytic rate was altered by PBP and TBBPA and compensatory glycolysis by all three. Phagocytosis was decreased for PBP and TBBPA. NLRP3 inflammasome activation was assessed using BV-2-ASC (apoptosis-associated speck-like protein containing a CARD) reporter cells to visualize aggregate formation. PBP, showed a direct stimulation of aggregate formation and properties as a NLRP3 inflammasome secondary trigger. TBBPA showed indications of possible secondary triggering activity while no changes were seen with TPP. Thus, the data suggests an effect of all three FRs on mitochondria metabolism yet, different functional outcomes including, phagocytic capability and NLRP3 inflammasome activation.

The Role of NLRP3 Inflammasome in Radiation-Induced Cardiovascular Injury.

The increasing risk of long-term adverse effects from radiotherapy on the cardiovascular structure is receiving increasing attention. However, the mechanisms underlying this increased risk remain poorly understood. Recently, the nucleotide-binding domain and leucine-rich-repeat-containing family pyrin 3 (NLRP3) inflammasome was suggested to play a critical role in radiation-induced cardiovascular injury. However, the relationship between ionizing radiation and the NLRP3 inflammasome in acute and chronic inflammation is complex. We reviewed literature detailing pathological changes and molecular mechanisms associated with radiation-induced damage to the cardiovascular structure, with a specific focus on NLRP3 inflammasome-related cardiovascular diseases. We also summarized possible therapeutic strategies for the prevention of radiation-induced heart disease (RIHD).

Melatonin alleviates acute lung injury through inhibiting the NLRP3 inflammasome.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are clinically severe respiratory disorders, and there are currently no Food and Drug Administration-approved drug therapies. Melatonin is a well-known anti-inflammatory molecule, which has proven to be effective in ALI induced by many conditions. Emerging studies suggest that the NLRP3 inflammasome plays a critical role during ALI. How melatonin directly blocks activation of the NLRP3 inflammasome in ALI remains unclear. In this study, using an LPS-induced ALI mouse model, we found intratracheal (i.t.) administration of melatonin markedly reduced the pulmonary injury and decreased the infiltration of macrophages and neutrophils into lung. During ALI, the NLRP3 inflammasome is significantly activated with a large amount of IL-1ß and the activated caspase-1 occurring in the lung. Melatonin inhibits the activation of the NLRP3 inflammasome by both suppressing the release of extracellular histones and directly blocking histone-induced NLRP3 inflammasome activation. Notably, i.t. route of melatonin administration opens a more efficient therapeutic approach for treating ALI.