Pattern recognition receptors (PRRs) are a class of receptors that can directly recognize the specific molecular structures on the surface of pathogens, apoptotic host cells, and damaged senescent cells. PRRs bridge nonspecific immunity and specific immunity. Through the recognition and binding of ligands, PRRs can produce nonspecific anti-infection, antitumor, and other immunoprotective effects. Most PRRs in the innate immune system of vertebrates can be classified into the following five types based on protein domain homology: Toll-like receptors (TLRs), nucleotide oligomerization domain (NOD)-like receptors (NLRs), retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), C-type lectin receptors (CLRs), and absent in melanoma-2 (AIM2)-like receptors (ALRs). PRRs are basically composed of ligand recognition domains, intermediate domains, and effector domains. PRRs recognize and bind their respective ligands and recruit adaptor molecules with the same structure through their effector domains, initiating downstream signaling pathways to exert effects. In recent years, the increased researches on the recognition and binding of PRRs and their ligands have greatly promoted the understanding of different PRRs signaling pathways and provided ideas for the treatment of immune-related diseases and even tumors. This review describes in detail the history, the structural characteristics, ligand recognition mechanism, the signaling pathway, the related disease, new drugs in clinical trials and clinical therapy of different types of PRRs, and discusses the significance of the research on pattern recognition mechanism for the treatment of PRR-related diseases.

/pdf/pattern-recognition-receptors-in-health-and-diseases-gsboefdzb0.pdf

Pattern recognition receptors in health and diseases.

RIG-I (Retinoic acid-inducible gene I) and MDA5 (Melanoma Differentiation-Associated protein 5), collectively known as the RIG-I-like receptors (RLRs), are key protein sensors of the pathogen-associated molecular patterns (PAMPs) in the form of viral double-stranded RNA (dsRNA) motifs to induce expression of type 1 interferons (IFN1) (IFNα and IFNβ) and other pro-inflammatory cytokines during the early stage of viral infection. While RIG-I and MDA5 share many genetic, structural and functional similarities, there is increasing evidence that they can have significantly different strategies to recognize different pathogens, PAMPs, and in different host species. This review article discusses the similarities and differences between RIG-I and MDA5 from multiple perspectives, including their structures, evolution and functional relationships with other cellular proteins, their differential mechanisms of distinguishing between host and viral dsRNAs and interactions with host and viral protein factors, and their immunogenic signaling. A comprehensive comparative analysis can help inform future studies of RIG-I and MDA5 in order to fully understand their functions in order to optimize potential therapeutic approaches targeting them.

/pdf/comparative-structure-and-function-analysis-of-the-rig-i-2bunvnvgsr.pdf

Comparative Structure and Function Analysis of the RIG-I-Like Receptors: RIG-I and MDA5

RIG-I is our first line of defense against RNA viruses, serving as a pattern recognition receptor that identifies molecular features common among dsRNA and ssRNA viral pathogens. RIG-I is maintained in an inactive conformation as it samples the cellular space for pathogenic RNAs. Upon encounter with the triphosphorylated terminus of blunt-ended viral RNA duplexes, the receptor changes conformation and releases a pair of signaling domains (CARDs) that are selectively modified and interact with an adapter protein (MAVS), thereby triggering a signaling cascade that stimulates transcription of interferons. Here, we describe the structural determinants for specific RIG-I activation by viral RNA, and we describe the strategies by which RIG-I remains inactivated in the presence of host RNAs. From the initial RNA triggering event to the final stages of interferon expression, we describe the experimental evidence underpinning our working knowledge of RIG-I signaling. We draw parallels with behavior of related proteins MDA5 and LGP2, describing evolutionary implications of their collective surveillance of the cell. We conclude by describing the cell biology and immunological investigations that will be needed to accurately describe the role of RIG-I in innate immunity and to provide the necessary foundation for pharmacological manipulation of this important receptor.

The molecular mechanism of RIG-I activation and signaling.

The TANK-binding kinase 1 (TBK1) is a serine/threonine kinase belonging to the non-canonical inhibitor of nuclear factor-κB (IκB) kinase (IKK) family. TBK1 can be activated by pathogen-associated molecular patterns (PAMPs), inflammatory cytokines, and oncogenic kinases, including activated K-RAS/N-RAS mutants. TBK1 primarily mediates IRF3/7 activation and NF-κB signaling to regulate inflammatory cytokine production and the activation of innate immunity. TBK1 is also involved in the regulation of several other cellular activities, including autophagy, mitochondrial metabolism, and cellular proliferation. Although TBK1 mutations have not been reported in human cancers, aberrant TBK1 activation has been implicated in the oncogenesis of several types of cancer, including leukemia and solid tumors with KRAS-activating mutations. As such, TBK1 has been proposed to be a feasible target for pharmacological treatment of these types of cancer. Studies suggest that TBK1 inhibition suppresses cancer development not only by directly suppressing the proliferation and survival of cancer cells but also by activating antitumor T-cell immunity. Several small molecule inhibitors of TBK1 have been identified and interrogated. However, to this point, only momelotinib (MMB)/CYT387 has been evaluated as a cancer therapy in clinical trials, while amlexanox (AMX) has been evaluated clinically for treatment of type II diabetes, nonalcoholic fatty liver disease, and obesity. In this review, we summarize advances in research into TBK1 signaling pathways and regulation, as well as recent studies on TBK1 in cancer pathogenesis. We also discuss the potential molecular mechanisms of targeting TBK1 for cancer treatment. We hope that our effort can help to stimulate the development of novel strategies for targeting TBK1 signaling in future approaches to cancer therapy. 

/pdf/the-role-of-tbk1-in-cancer-pathogenesis-and-anticancer-i4cmwe70.pdf

The role of TBK1 in cancer pathogenesis and anticancer immunity

https://jeccr.biomedcentral.com/track/pdf/10.1186/s13046-022-02352-y

LGP2 plays a critical role in MDA5-mediated antiviral activity against duck enteritis virus.

Duck RIG-I restricts duck enteritis virus infection.

Biological characteristic and cytokines response of passages duck plague virus in ducks.

AIMS
This study analyzed major trends and topics in the field of gestational diabetes mellitus research between 2000 and 2020.


METHODS
Studies that investigated gestational diabetes mellitus published between 2000 and 2020 were retrieved from the Web of Science Core Collection database. Data from the identified studies were analyzed using CiteSpace software.


RESULTS
A total of 22,713 publications were retrieved, among which 21,722 publications were included in this scientometric analysis. Clustering analysis revealed 13 themes across all fields. Physical activity is an emerging trend. Co-word analysis showed that subject high-frequency keywords were: risk factor, obesity, insulin resistance, prevalence, and association. Centrality indices identified the most influential keywords to be: body mass index, risk factors, gestational weight gain, and obesity. Burst keywords revealed that there were six research frontier subtopics: i) prediction of adverse neonatal outcomes in gestational diabetes mellitus; ii) postpartum period research - blood glucose levels and insulin resistance; iii) meta-analysis - understanding the best evidence in pregnancy gestational diabetes mellitus; iv) gene expression profiles and DNA methylation in gestational diabetes mellitus; v) biomarkers for predicting higher birth and children weights; and vi) discussion on diagnostic criteria for gestational diabetes mellitus classification.


CONCLUSION
The number of studies on gestational diabetes mellitus is increasing. For two decades, the United States has been the global leader in the number of published studies. Studies on gestational diabetes mellitus are mainly from developed countries, with a few of them being from developing countries. An emerging field of research aims at elucidating the association between physical activity and gestational diabetes mellitus.

Global Research Trends in Gestational Diabetes Mellitus from 2000 to 2020: A Bibliometric Study.

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LGP2 plays a critical role in MDA5-mediated antiviral activity against duck enteritis virus.

Duck RIG-I restricts duck enteritis virus infection.

Biological characteristic and cytokines response of passages duck plague virus in ducks.

Global Research Trends in Gestational Diabetes Mellitus from 2000 to 2020: A Bibliometric Study.