-
BioRxiv : the Preprint Server For... May 2024The double-stranded DNA (dsDNA) sensor STING has been increasingly implicated in responses to "sterile" endogenous threats and pathogens without nominal DNA or cyclic...
The double-stranded DNA (dsDNA) sensor STING has been increasingly implicated in responses to "sterile" endogenous threats and pathogens without nominal DNA or cyclic di-nucleotide stimuli. Previous work showed an endoplasmic reticulum (ER) stress response, known as the unfolded protein response (UPR), activates STING. Herein, we sought to determine if ER stress generated a STING ligand, and to identify the UPR pathways involved. Induction of IFN-β expression following stimulation with the UPR inducer thapsigargin (TPG) or oxygen glucose deprivation required both STING and the dsDNA-sensing cyclic GMP-AMP synthase (cGAS). Furthermore, TPG increased cytosolic mitochondrial DNA, and immunofluorescence visualized dsDNA punctae in murine and human cells, providing a cGAS stimulus. N-acetylcysteine decreased IFN-β induction by TPG, implicating reactive oxygen species (ROS). However, mitoTEMPO, a mitochondrial oxidative stress inhibitor did not impact TPG-induced IFN. On the other hand, inhibiting the inositol requiring enzyme 1 (IRE1) ER stress sensor and its target transcription factor XBP1 decreased the generation of cytosolic dsDNA. iNOS upregulation was XBP1-dependent, and an iNOS inhibitor decreased cytosolic dsDNA and IFN-β, implicating ROS downstream of the IRE1-XBP1 pathway. Inhibition of the PKR-like ER kinase (PERK) pathway also attenuated cytoplasmic dsDNA release. The PERK-regulated apoptotic factor Bim was required for both dsDNA release and IFN-β mRNA induction. Finally, XBP1 and PERK pathways contributed to cytosolic dsDNA release and IFN-induction by the RNA virus, Vesicular Stomatitis Virus (VSV). Together, our findings suggest that ER stressors, including viral pathogens without nominal STING or cGAS ligands such as RNA viruses, trigger multiple canonical UPR pathways that cooperate to activate STING and downstream IFN-β via mitochondrial dsDNA release.
PubMed: 38798499
DOI: 10.1101/2024.05.10.593557 -
Discovery Medicine May 2024The number of chronic kidney disease (CKD) patients requiring renal replacement therapy is increasing, often exhibiting oral manifestations including periodontal... (Review)
Review
The number of chronic kidney disease (CKD) patients requiring renal replacement therapy is increasing, often exhibiting oral manifestations including periodontal disease, gingival hyperplasia, altered saliva composition, and uremic stomatitis. Uremic stomatitis, xerostomia, and candidiasis are very frequent, particularly among patients undergoing dialysis or kidney transplant recipients. CKD patients also experience profound alterations in bone metabolism inherent in the homeostasis of calcium, phosphorus, vitamin D, parathyroid hormone, and fibroblast growth factor (FGF). These alterations lead to demineralization of the jaw bones, reduced bone trabeculae, reduced cortical bone thickness, fibrocystic bone lesions, bone fractures, and delayed wound healing post-tooth extraction. Consequently, oral health management of elderly hemodialysis patients poses serious clinical problems. This review focused on the oral health and rehabilitation of patients with CKD or on dialysis.
Topics: Humans; Oral Health; Renal Insufficiency, Chronic; Dental Implants; Oral Surgical Procedures; Renal Dialysis
PubMed: 38798248
DOI: 10.24976/Discov.Med.202436184.82 -
Biotechnology Journal May 2024Small extracellular vesicles (sEVs) are nanosized vesicles enclosed in a lipid membrane released by nearly all cell types. sEVs have been considered as reliable...
Small extracellular vesicles (sEVs) are nanosized vesicles enclosed in a lipid membrane released by nearly all cell types. sEVs have been considered as reliable biomarkers for diagnostics and effective carriers. Despite the clear importance of sEV functionality, sEV research faces challenges imposed by the small size and precise imaging of sEVs. Recent advances in live and high-resolution microscopy, combined with efficient labeling strategies, enable us to investigate the composition and behavior of EVs within living organisms. Here, a modified sEVs was generated with a near infrared fluorescence protein mKate2 using a VSVG viral pseudotyping-based approach for monitoring sEVs. An observed was made that the mKate2-tagged protein can be incorporated into the membranes of sEVs without altering their physical properties. In vivo imaging demonstrates that sEVs labeled with mKate2 exhibit excellent brightness and high photostability, allowing the acquisition of long-term investigation comparable to those achieved with mCherry labeling. Importantly, the mKate2-tagged sEVs show a low toxicity and exhibit a favorable safety profile. Furthermore, the co-expression of mKate2 and rabies virus glycoprotein (RVG) peptide on sEVs enables brain-targeted visualization, suggesting the mKate2 tag does not alter the biodistribution of sEVs. Together, the study presents the mKate2 tag as an efficient tracker for sEVs to monitor tissue-targeting and biodistribution in vivo.
Topics: Extracellular Vesicles; Animals; Mice; Humans; Luminescent Proteins; Brain; Tissue Distribution
PubMed: 38797724
DOI: 10.1002/biot.202400128 -
Immune checkpoint inhibitor associated epidermal necrosis, beyond SJS and TEN: a review of 98 cases.Archives of Dermatological Research May 2024Immune checkpoint inhibitor (ICI) therapies carry the risk of major immune-related adverse events (irAEs). Among the most severe irAEs is epidermal necrosis that may... (Review)
Review
Immune checkpoint inhibitor (ICI) therapies carry the risk of major immune-related adverse events (irAEs). Among the most severe irAEs is epidermal necrosis that may clinically mimic Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN). The aim of this study was to provide a summary of the clinical and histological features of ICI-associated epidermal necrosis, with a special focus on factors associated with fatal outcomes in cases of extensive disease. A total of 98 cases, 2 new cases and 96 reported on PubMed and in the literature, of ICI-associated epidermal necrosis were assessed. Development of epidermal necrosis occurred between 1 day and 3 years after starting ICI therapy, with an average onset of 13.8 weeks for patients with limited (< 30% BSA) and 11.3 weeks for those with extensive (≥ 30% BSA) involvement, and a median onset of 5.8 weeks and 4 weeks respectively. A preceding rash was seen in 52 cases and was more common in extensive cases. Mucosal involvement was only reported in 65% of extensive cases but was significantly associated with fatal reactions. Co-administration of cytotoxic chemotherapy was associated with more extensive disease. Recovery was observed in 96% and 65% of those with limited and extensive involvement respectively and no specific therapy was associated with improved survival. Young age was significantly associated with poor outcomes in extensive disease, the average age of surviving patients was 64.5 years old versus 55.1 years old for deceased patients, p < 0.01. Both superficial perivascular and interface/lichenoid inflammatory infiltrates were commonly seen. These findings suggest that ICI-associated epidermal necrosis should be considered a distinct clinical entity from drug-induced SJS/TEN.
Topics: Humans; Immune Checkpoint Inhibitors; Stevens-Johnson Syndrome; Necrosis; Epidermis; Middle Aged; Female; Male; Aged; Adult
PubMed: 38795205
DOI: 10.1007/s00403-024-03061-6 -
British Dental Journal May 2024Peri-implant mucositis is characterised by inflammation of soft tissues surrounding a dental implant without associated bone loss beyond initial remodelling. Early... (Review)
Review
Peri-implant mucositis is characterised by inflammation of soft tissues surrounding a dental implant without associated bone loss beyond initial remodelling. Early detection and timely intervention are critical to prevent its progression to peri-implantitis. This paper focuses on various treatment options for treating peri-implant mucositis. The cornerstone of professional treatment lies in the mechanical disruption and removal of microbial biofilms around the implant. This can be achieved through careful use of manual or powered instruments, such as ultrasonic scalers or air polishing devices. However, there is a need for further research to determine the most effective single approach for treating peri-implant mucositis. Current evidence does not support the combination of mechanical debridement with locally administered antibiotics. Contrarily, evidence strongly supports the removal, cleaning, and modifications of prostheses to improve both self-performance and professional cleanability. The use of adjunctive therapies like photodynamic therapy and diode laser, in conjunction with mechanical instrumentation, is not currently recommended due to the limited strength of available evidence. Preventive measures emphasise the importance of comprehensive oral hygiene care, encompassing professional guidance and at-home practices, to manage biofilms effectively. This encompasses oral hygiene instruction, regular debridement, and maintenance care. Supporting peri-implant therapy is also vital for ongoing implant monitoring, preventing the recurrence of mucositis, and halting its progression to peri-implantitis. This multifaceted approach is key to effectively managing and treating peri-implant mucositis.
Topics: Humans; Dental Implants; Peri-Implantitis; Stomatitis; Biofilms; Clinical Decision-Making; Oral Hygiene; Debridement; Anti-Bacterial Agents
PubMed: 38789757
DOI: 10.1038/s41415-024-7397-5 -
British Dental Journal May 2024Peri-implant diseases are frequent complications that occur around osseointegrated endosseous implants and are the result of an imbalance between the bacterial challenge... (Review)
Review
Peri-implant diseases are frequent complications that occur around osseointegrated endosseous implants and are the result of an imbalance between the bacterial challenge and host response. Peri-implant diseases may affect the peri-implant mucosa only (peri-implant mucositis) or also involve the supporting bone (peri-implantitis). Early detection of peri-implant diseases and timely treatment is important for the success of dental implant treatment. Peri-implant probing is essential to assess the peri-implant health status and should be done at each recall visit. Dental practitioners should be familiar with the clinical and radiological features of both conditions in order to make an accurate diagnosis and determine the appropriate treatment required. This article aims to provide clinicians with an understanding of the key differences between peri-implant health, peri-implant mucositis and peri-implantitis.
Topics: Humans; Dental Implants; Mucositis; Peri-Implantitis; Stomatitis
PubMed: 38789756
DOI: 10.1038/s41415-024-7402-z -
Journal of Fungi (Basel, Switzerland) Apr 2024Denture stomatitis (DS) is a very common disease in wearers of removable complete and partial dentures with a worldwide prevalence in the range of 20-67%. Both... (Review)
Review
Denture stomatitis (DS) is a very common disease in wearers of removable complete and partial dentures with a worldwide prevalence in the range of 20-67%. Both industrially developed and impoverished nations are affected by the illness. DS is often associated with ill-fitting dentures or a fungal infection with spp. is normally found in the oral cavity microbiota, but it can be harmful to the health of elderly people with underlying diseases. Therefore, the purpose of the present study is to offer the most recent information about the epidemiology, etiology, and global distribution of species associated with DS through a systematic review. Several databases, including Medline, Web of Science, and Scopus, were used to conduct an extensive search of the literature published in the previous 20 years. The selection of studies was performed by two authors. The extracted data were as follows: author, year of publication, country, sample, frequency of DS, method of diagnosing stomatitis, species of , risk factors, and etiology of the disease. The JBI Critical appraisal tools were used to assess the quality of the studies. Eventually, twenty-eight studies were included in the systematic review. Twenty-one studies investigated DS, while seven studies examined colonization in patients using removable dentures. The results show that the main causes of DS include the type of dentures, continuous wearing of dentures, and the formation of a biofilm, which is facilitated by poor dental hygiene. Additionally, previous studies have pinpointed the significance of the salivary flow, saliva composition, and salivary pH. The findings of the current review indicate that it is crucial to monitor denture wearers for the appearance of DS, especially the patients whose immunity has been impaired due to a systemic condition. Finally, frequent follow-ups should include a clinical examination and microbial swabs of the palatal mucosa and the mucosal surface of the denture.
PubMed: 38786683
DOI: 10.3390/jof10050328 -
Biomolecules May 2024Mucositis is a pathological condition characterised by inflammation and ulceration of the mucous membranes lining the alimentary canal, particularly in the mouth (oral... (Review)
Review
Mucositis is a pathological condition characterised by inflammation and ulceration of the mucous membranes lining the alimentary canal, particularly in the mouth (oral mucositis) and the gastrointestinal tract. It is a common side effect of cancer treatments, including chemotherapy and radiotherapy, and it is sometimes responsible for treatment interruptions. Preventing mucositis throughout the alimentary tract is therefore crucial. However, current interventions mainly target either oral or gastrointestinal side effects. This review aimed to investigate the use of systemically administered anti-inflammatory agents to prevent mucositis in cancer patients undergoing cancer treatment. PubMed, Ovid, Scopus, Web of Science, WHO ICTRP and ClinicalTrials.gov were screened to identify eligible randomised controlled trials (RCTs). The published literature on anti-inflammatory agents provides mixed evidence regarding the degree of efficacy in preventing/reducing the severity of mucositis in most anticancer treatments; however, sample size continued to be a significant limitation, alongside others discussed. Our review yielded a list of several anti-inflammatory agents that exhibit potential mucositis-preventive effects in cancer patients undergoing cancer treatment, which can be used to inform clinical practice.
Topics: Humans; Randomized Controlled Trials as Topic; Anti-Inflammatory Agents; Chemoradiotherapy; Mucositis; Neoplasms; Stomatitis
PubMed: 38785967
DOI: 10.3390/biom14050560 -
Zhonghua Yi Xue Za Zhi May 2024Immune checkpoint inhibitors (ICIs) have emerged as crucial therapeutic agents for various malignancies by activating the host immune system against tumor cells....
Immune checkpoint inhibitors (ICIs) have emerged as crucial therapeutic agents for various malignancies by activating the host immune system against tumor cells. However, many different types of skin adverse reactions may occur during its use, including eruption, pruritus, blistering, hypopigmentation, alopecia, and even severe cases, Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). These cutaneous immune-related adverse events (cirAEs) had a high incidence, which seriously affected patients' quality of life and antitumor treatment decisions. Some severe cutaneous adverse reactions (SCARs) even endanger patients' lives. Therefore, the Chinese Society of Dermatology, the Chinese Dermatologist Association of the Chinese Medical Doctor Association, the Dermatology Division of the Chinese Geriatrics Society, and other relevant experts jointly discussed and formulated the 'Chinese Expert Consensus on the Diagnosis and Treatment of Immune Checkpoint Inhibitor-Related Cutaneous Adverse Reactions'. This consensus covers the name, epidemiology, pathogenesis, clinical features, classification and grading of cirAEs, principles of management and the re-initiation of ICIs. It aims to provide a more scientific and authoritative reference for the diagnosis and treatment of cirAEs in China in the future.
Topics: Humans; Immune Checkpoint Inhibitors; China; Consensus; Stevens-Johnson Syndrome; Drug-Related Side Effects and Adverse Reactions; Quality of Life; Skin; Neoplasms; Drug Eruptions
PubMed: 38782747
DOI: 10.3760/cma.j.cn112137-20240112-00091 -
Virus Research Aug 2024Parapoxviruses (PPV) of animals are spread worldwide. While the Orf virus (ORFV) species is a molecularly well-characterized prototype pathogen of small ruminants, the...
Parapoxviruses (PPV) of animals are spread worldwide. While the Orf virus (ORFV) species is a molecularly well-characterized prototype pathogen of small ruminants, the genomes of virus species affecting large ruminants, namely Bovine papular stomatitis virus (BPSV) and Pseudocowpox virus (PCPV), are less well known. Using Nanopore sequencing we retrospectively show the whole genome sequences (WGS) of six BPSV, three PCPV isolates and an attenuated ORFV strain, originating from different geographic locations. A phylogenetic tree shows that the de novo assembled genomes belong to PPV species including WGS of reference PPV. Remarkably, Nanopore sequencing allowed the molecular resolution of inverted terminal repeats (ITR) and the hairpin loop within the de novo assembled WGS. Additionally, peculiarities regarding map location of two genes and the heterogeneity of a genomic region were noted. Details for the molecular variability of an interferon response modulatory gene (ORF116) and the PCPV specificity of gene 073.5 are reported. In summary, WGS gained by Nanopore sequencing allowed analysis of complete PPV genomes and confident virus species attribution within a phylogenetic tree avoiding uncertainty of limited gene-based diagnostics. Nanopore-based WGS provides robust comparison of PPV genomes and reliable identity determination of new Poxviruses.
Topics: Animals; Phylogeny; Genome, Viral; Cattle; Parapoxvirus; Poxviridae Infections; Whole Genome Sequencing; Retrospective Studies; Cattle Diseases; Nanopore Sequencing; DNA, Viral
PubMed: 38782262
DOI: 10.1016/j.virusres.2024.199404