RESUMEN

Neuroinflammation is a key pathophysiological feature of stroke-associated brain injury. A local innate immune response triggers neuroinflammation following a stroke via activating inflammasomes. The nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome has been heavily implicated in stroke pathobiology. Following a stroke, several stimuli have been suggested to trigger the assembly of the NLRP3 inflammasome. Recent studies have advanced the understanding and revealed several new players regulating NLRP3 inflammasome-mediated neuroinflammation. This article discussed recent advancements in NLRP3 assembly and highlighted stroke-induced mitochondrial dysfunction as a major checkpoint to regulating NLRP3 activation. The NLRP3 inflammasome activation leads to caspase-1-dependent maturation and release of IL-1ß, IL-18, and gasdermin D. In addition, genetic or pharmacological inhibition of the NLRP3 inflammasome activation and downstream signaling has been shown to attenuate brain infarction and improve the neurological outcome in experimental models of stroke. Several drug-like small molecules targeting the NLRP3 inflammasome are in different phases of development as novel therapeutics for various inflammatory conditions, including stroke. Understanding how these molecules interfere with NLRP3 inflammasome assembly is paramount for their better optimization and/or development of newer NLRP3 inhibitors. In this review, we summarized the assembly of the NLRP3 inflammasome and discussed the recent advances in understanding the upstream regulators of NLRP3 inflammasome-mediated neuroinflammation following stroke. Additionally, we critically examined the role of the NLRP3 inflammasome-mediated signaling in stroke pathophysiology and the development of therapeutic modalities to target the NLRP3 inflammasome-related signaling for stroke treatment.

Asunto(s)

Lesiones Encefálicas , Accidente Cerebrovascular , Humanos , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Enfermedades Neuroinflamatorias , Accidente Cerebrovascular/tratamiento farmacológico , Interleucina-1beta/metabolismo

RESUMEN

Stroke, a debilitating condition with limited treatment options, presents a significant therapeutic challenge. A comprehensive grasp of stroke pathophysiology is imperative for designing newer and more effective therapeutic approaches. Notably, the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway has emerged as a central orchestrator of the poststroke immune response. It regulates pivotal processes, including immune cell activation, cytokine production, neuroinflammation, apoptosis, and tissue regeneration. Modulating this pathway shows immense potential in improving stroke outcomes, necessitating the development of selective inhibitors and activators. This review provides an overview of the cGAS-STING pathway's role in ischemic stroke and explores emerging therapies, including cGAS and STING inhibitors and STING agonist preconditioning. It also addresses challenges like specificity, timing, and off-target effects.

Asunto(s)

Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Humanos , Accidente Cerebrovascular/tratamiento farmacológico , Nucleotidiltransferasas , Transducción de Señal , Inmunidad

RESUMEN

INTRODUCTION: Ischemic stroke is a significant global health challenge with limited treatment options. Neuroinflammation, driven by microglial activation, plays a critical role in stroke pathophysiology. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway has emerged as a key player in microglial activation, sterile neuroinflammation, and cell death following stroke. Understanding the interplay between this pathway and stroke pathophysiology is crucial for exploring newer therapeutics for stroke patients. AREAS COVERED: This review discusses the pivotal role of the cGAS-STING pathway in ischemic stroke. It explores the interplay between cGAS-STING activation, neuroinflammation, microglia activation, M2 polarization, neutrophil infiltration, and cytokine release. Additionally, the authors examine its contributions to various cell death programs (pyroptosis, apoptosis, necroptosis, lysosomal cell death, autophagy, and ferroptosis). The review summarizes recent studies on targeting cGAS-STING signaling in stroke, highlighting the therapeutic potential of small molecule inhibitors and RNA-based approaches in mitigating neuroinflammation, preventing cell death, and improving patient outcomes. EXPERT OPINION: Understanding cGAS-STING signaling in ischemic stroke offers an exciting avenue for drug discovery. Targeting this pathway holds promise for developing novel therapeutics that effectively mitigate neuroinflammation, prevent cell death, and enhance patient outcomes. Further research and development of therapeutic strategies are warranted to fully exploit the potential of this pathway as a therapeutic target for stroke.

Asunto(s)

Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Humanos , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Enfermedades Neuroinflamatorias , Accidente Cerebrovascular/tratamiento farmacológico , Descubrimiento de Drogas , Nucleotidiltransferasas

RESUMEN

Background Development of new antibiotics has been slow in the past decades, despite the urgent need. Final-year undergraduate students, interns, and postgraduate students are future prescribers of antimicrobials. It is important they have proper knowledge and attitude toward antibiotic prescription, so that antibiotic resistance could be dealt wisely. Aims The aim of this study was to assess the knowledge and attitude of undergraduate, interns, and postgraduate medical students regarding antimicrobials, antibiotics resistance, and associated factors. Methodology A total of 150 final-year medical students, interns, and resident doctors were included, 50 in each group. Participants were contacted individually and were asked to fill a prevalidated questionnaire. Information was collected on three broad categories: basic information about antimicrobials, knowledge regarding treatment of common infections, and belief and attitude toward antimicrobials. Percentages were calculated for the categorical data and chi-squared test was used for univariate analysis of the categorical data, where p -value less than 0.05 was considered to be significant. Results Precisely, 80.67% were able to answer which type of infections need antibiotics; 19.33% responded that both viral and bacterial infections need antibiotics; 44.67% preferred using broad-spectrum antibiotics for definitive treatment; 28.66% answered macrolides as most commonly used for upper respiratory tract infection; 56% considered fluoroquinolones are most commonly used for urinary tract infection with p -value less than 0.05 between the groups; 43.33% were unaware of the infection control program; while 72.66% were unaware about the antibiotic policy in their institute. Conclusion The majority had sufficient basic knowledge about antibiotics, yet there were areas for concern. Study findings may help to formulate new learning objectives for medical students to inculcate proper knowledge and attitude toward antibiotic prescription.