Progress in Molecular Biology and Translational Science最新文献

The ongoing global health challenges posed by the SARS-CoV-2, the virus responsible for the COVID-19 pandemic, necessitate a deep understanding of its intricate strategies to evade the innate immune system. This chapter aims to provide insights into the sophisticated mechanisms employed by SARS-CoV-2 in its interaction with pattern recognition receptors (PRRs), with particular emphasis on Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs). By skillfully circumventing these pivotal components, the virus manages to elude detection and impairs the initiation of crucial antiviral immune responses. A notable aspect of SARS-CoV-2's immune evasion tactics lies in its strategic manipulation of cytokine production. This orchestrated modulation disrupts the delicate balance of inflammation, potentially leading to severe complications, including the notorious cytokine storm. In this regard, key viral proteins, such as the spike protein and nucleocapsid protein, emerge as pivotal players in the immune evasion process, further highlighting their significance in the context of COVID-19 pathogenesis. Acquiring a comprehensive understanding of these intricate immune evasion mechanisms holds immense promise for the development of effective treatments against COVID-19. Moreover, it is imperative for vaccine development to consider these evasion strategies to maximize vaccine efficacy. Future therapeutic interventions may involve targeting alternative pathways or augmenting the antiviral immune responses, thereby mitigating the impact of immune evasion, and fostering successful outcomes. By unraveling the underlying mechanisms of innate immune evasion, we advance our comprehension of COVID-19 pathogenesis and pave the way for the development of innovative therapeutic strategies. This comprehensive understanding catalyzes progress, enabling researchers and clinicians to devise novel approaches that combat the challenges posed by SARS-CoV-2 and ultimately improve patient outcomes.

COVID-19 is a highly contagious viral disease caused by SARS-CoV-2, leading to a tragic global pandemic, where it was ranked in 2020 as the third leading cause of death in the USA, causing approximately 375,000 deaths, following heart disease and cancer. The CDC reports that the risk of death increases with age and preexisting comorbidities such as such as hypertension, diabetes, respiratory system disease, and cardiovascular disease. this report will delineate and analyze the paramount comorbidities and their repercussions on individuals infected with SARS-CoV-2.

Huntington's disease (HD) is a progressive neurodegenerative condition resulting from a CAG repeat expansion in the huntingtin gene (HTT). Recent advancements in understanding HD's cellular and molecular pathways have paved the way for identifying various effective small-molecule candidates to treat the disorder. Two small molecules, Tetrabenazine and Deutetrabenazine, are approved for managing chorea associated with HD, and several others are under clinical trials. Notably, the field of small-molecule therapeutics targeting HD is rapidly progressing, and there is anticipation of their approval in the foreseeable future. This chapter provides a comprehensive overview of the emergence of small-molecule therapeutics in various stages of clinical development for HD therapy. The emphasis is placed on detailing their structural design, therapeutic effects, and specific mechanisms of action. Additionally, exploring key drivers implicated in HD pathogenesis offers valuable insights, as a foundational principle for designing prospective anti-HD therapeutic leads.

One of the hallmarks of multiple neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, is deposition of insoluble amyloid fibrils, which are toxic proteinaceous structures containing cross β-sheets. Several inhibitory strategies have been devised by researchers to impede or slow down the generation of such toxic species. Small compounds, peptides, and antibodies have been studied as possible inhibitors to interfere with key steps in amyloid production. Furthermore, adjusting environmental variables, such as temperature and pH have been known to impact the amyloid fibrillation process. Additionally, strategies are also available to reduce the possibility of protein misfolding so as to inhibit the subsequent development of fibrils, simply by stabilizing native protein conformations. It is very promising to develop targeted inhibitory therapies and comprehend the complexities of amyloid fibrillation in order to develop effective therapeutics to slow the progression of neurodegenerative disorders linked to misfolding and aggregation of proteins.

Alzheimer's disease (AD), caused by damage to the brain's nerve cells, is a progressive neurodegenerative disease that insidiously erodes cognitive function, and primarily affecting elderly adults. AD is associated with a considerable economic burden arising from multiple expenditure categories. The programed cell death, in normal cells, plays importance roles in biological processes, ensuring homeostasis and controlling development in multicellular organisms. However, AD is characterized by a high degree of pathological-related neuronal death, which is observable in various regions of the brain. This chapter aims to examine the diverse forms of cell death involved in AD, including apoptosis, necroptosis, autophagy-related cell death, and excitotoxicity; as well as elucidates the molecular mechanisms linking cell death to AD pathogenesis, including amyloid-beta, tau pathology, neuroinflammation, mitochondrial dysfunction, and genetic factors. Targeting these cell death pathways offers a promising avenue for future AD therapeutics and drug development.

Cell death mechanisms represent fundamental biological processes essential for homeostasis, development, and disease response. Recent advances have expanded our comprehension of these processes and contributed to the identification of novel mechanisms that orchestrate these processes. Apoptosis, a well-characterized form of cell death involving characteristic morphological changes and multiple enzymes that orchestrate the biochemical process, with minimal damage to surrounding cells or tissues and clearing off the apoptotic bodies by phagocytic cells. Dysregulation in the biochemical process could eventually lead to various pathologies including cancer and neurodegenerative disorders. Autophagy primarily a cell survival process that recycles cellular components, can paradoxically contribute to cell death under specific conditions especially when apoptosis is inhibited. Necrosis, once considered purely accidental, is now recognized to include regulated forms such as necroptosis, with defined molecular triggers and execution pathways. In this review, we will explore a general overview of the current comprehension of these major known cell death pathways such as apoptosis, autophagic cell death, necrosis, and necroptosis along with their crosstalk and potential targets in the biochemical mechanisms for therapeutic modulation of these processes that have major clinical implications.

Various autoantibodies, such as antinuclear antibodies (ANA), anti-Ro/SSA, rheumatoid factor, lupus anticoagulant, and antibodies against interferon type I (IFN-I), have been frequently detected in COVID-19 patients, indicating a significant prevalence of autoimmune reactions following viral exposure. Additionally, the identification of human proteins with structural similarities to SARS-CoV-2 peptides as potential autoantigens underscores the complex interplay between the virus and the immune system in triggering autoimmunity. The chapter discusses probable pathways contributing to COVID-19-related autoimmunity, including bystander activation due to hyperinflammatory states, viral persistence, and the formation of neutrophil extracellular traps. These mechanisms illuminate a spectrum of autoimmune-related symptoms that can manifest, ranging from organ-specific to systemic autoimmune and inflammatory diseases. Importantly, there is emerging evidence of de novo autoimmunity arising after COVID-19 infection or vaccination, where new autoimmune conditions develop in previously healthy individuals. While various COVID-19 vaccines have received emergency use authorization, concerns regarding potential autoimmune side effects persist. Ongoing research is crucial to clarify these relationships and enhance our understanding of the risks associated with COVID-19 infections and vaccinations.

Aggregation of α-Synuclein (α-Syn) is the hallmark of the pathophysiology of Parkinson's disease. Apart from aggregates, α-Syn can exist in multiple abnormal forms such as oligomers, protofibrils, fibrils amorphous aggregates etc. These forms initiate aggressive, selective and progressive neuronal atrophy through various modes such as mitochondrial dysfunction, lysosomal malfunction, and disruption of calcium homeostasis in various α-Syn-related neurodegenerative disorders. Structurally α-Syn is divided into three domains: N-terminal region made by amino acids1-67 (amphipathic, lysine-rich and interacts with acidic lipid membranes), Non-amyloid-β component (NAC) region made by amino acids 67-95 (hydrophobic region, central to α-syn aggregation) and C-terminal region made by amino acids 96-140 (acidic and proline-rich region responsible for interaction with other proteins). α-Syn follows the pattern of a typical intrinsically disordered protein and lacks a proper folded conformation and exist majorly in a random coil form, though on lipid binding the protein assumes an α-helical structure. The central random coil region of α-Syn is involved in fibril formation transforming into β-sheet rich secondary structures which is a characteristic of amyloids. This chapter entails an elaborate explanation of factors influencing the structure, function and aggregation of α-Syn. Major factors being abnormally high physiological expression of the protein, mutations, posttranslational modifications and also interactions with small molecules such as osmolytes in the cellular milieu. Studying the factors responsible for misfolding and aggregation of α-Syn along with the mechanism involved is crucial to understanding their implications in Parkinson's disease, and will yield valuable insights into disease mechanisms, potential therapeutic strategies.

Cell death, a highly conserved and regulated process, plays a key role in development of an organism, immune responses, and tissue homeostasis. Often viewed in a negative light, it tightly regulates the proper balance of cell numbers and this fine balance carries the weight of life. In Drosophila melanogaster, a well-established genetic model, several forms of cell death including autophagy, apoptosis, and necrosis-like pathways are observed in response to the diverse bodily signals and infections. These distinct cell deaths are triggered through specific signaling pathways such as the Jun N-terminal kinase (JNK) pathway, the Toll and Imd immune pathways, and mitochondrial reactive oxygen species (ROS) mediated responses. This chapter explores the molecular regulation of these cell death pathways, emphasizing tissue-specific responses in Drosophila during bacterial and fungal infections. By understanding how various tissues, including the brain, gut, fat body, and muscles, differentially regulate cell death, we gain valuable insights into evolutionarily conserved strategies for host defense. Understanding these mechanisms helps reveal key biological principles relevant to immunity, pathology, and therapeutic development.