Progress in Molecular Biology and Translational Science最新文献

Regulated cell death (RCD) is an essential aspect of cellular homeostasis and coordinates important physiological processes, such as immune regulation, embryogenesis, and tissue remodeling. In cancer, the regulation of RCD is disrupted to allow tumor cells to resist apoptosis, modify their function to survive microenvironmental stresses, and become resistant to standard therapies. Beyond apoptosis, new modalities of RCD including necroptosis, pyroptosis, ferroptosis, and parthanatos, play multifaceted roles in tumor suppression and progression, determined by interactions with the tumor microenvironment (TME). These RCD pathways possess unique molecular regulators and exhibit distinctive immunological and pathological connotations with novel therapeutic potential. Here, in the current study, the mechanistic complexity of RCD pathways and their interactions with the TME, particularly in their immune evasion, tumor progression and therapy resistance roles, are reviewed. Furthermore, the therapeutic potential of the modulation of RCD pathways by using small-molecule inhibitors, immune checkpoint inhibitors, and combination therapies that repurpose the TME, were tested. The newly emerging technologies, such as nanotechnology and biomimetic delivery systems, are proposed to deliver novel solutions to escalating the specificity and potency of RCD-targeted therapy and confronting systemic toxicity as well as adaptive resistance. By combining mechanistic knowledge with innovative therapy, the transformative potential of RCD modulation in treating cancers is highlighted in the current review to improve precision oncology strategies that augment the efficacy of therapies and increase patient benefit.

The COVID-19 pandemic has significantly impacted global healthcare systems, revealed vulnerabilities and prompted a re-evaluation of medical practices. Acute complications from the virus, including cardiovascular and neurological issues, have underscored the necessity for timely medical interventions. Advances in diagnostic methods and personalized therapies have been pivotal in mitigating severe outcomes. Additionally, Long COVID has emerged as a complex challenge, affecting various body systems and leading to respiratory, cardiovascular, neurological, psychological, and musculoskeletal problems. This broad spectrum of complications highlights the importance of multidisciplinary management approaches that prioritize therapy, rehabilitation, and patient-centered care. Vulnerable populations such as paediatric patients, pregnant women, and immunocompromised individuals face unique risks and complications, necessitating continuous monitoring and tailored management strategies to reduce morbidity and mortality associated with COVID-19.

Neutrophils are the first line of defense against pathogens, most effectively by forming Neutrophil Extracellular Traps (NETs). Neutrophiles are further classified into several subpopulations during their development, eliminating pathogens through various mechanisms. However, due to the chaotic and uncontrolled immune response, NETs are often severely resulting in tissue damage and lung infections. The uncontrolled and poorly acknowledged host response regarding the cytokine storm is one of the major causes of severe COVID-19 conditions. Specifically, the increased formation of low-density neutrophils (LDNs), together with neutrophil extracellular traps (NETs) is closely linked with the severity and poor prognosis in patients with COVID-19. In this review, we discuss in detail the ontogeny of neutrophils at different stages and their recruitment and activation after infections, focusing on SARS-CoV-2. In addition, this chapter summarized the research progress on potential targeted drugs (NETs and Cytokine inhibitors) for neutrophil medical therapy and hoped to provide reference for the development of related therapeutic drugs for critically ill COVID-19 patients.

A new era in genomic medicine has been brought by the development of CRISPR-Cas technology, which presents hitherto unheard-of possibilities for the treatment of metabolic illnesses. The treatment approaches used in CRISPR/Cas9-mediated gene therapy, emphasize distribution techniques such as viral vectors and their use in preclinical models of metabolic diseases like hypercholesterolemia, glycogen storage diseases, and phenylketonuria. The relevance of high-throughput CRISPR screens for target identification in discovering new genes and pathways associated with metabolic dysfunctions is an important aspect of the discovery of new approaches. With cutting-edge options for genetic correction and cellular regeneration, the combination of CRISPR-Cas technology with stem cell therapy has opened new avenues for the treatment of metabolic illnesses. The integration of stem cell therapy and CRISPR-Cas technology is an important advance in the treatment of metabolic diseases, which are difficult to treat because of their intricate genetic foundations. This chapter addresses the most recent developments in the application of stem cell therapy and CRISPR-Cas systems to treat a variety of metabolic disorders, providing fresh hope for effective and maybe curative therapies. This chapter examines techniques and developments that have been made recently to address a variety of metabolic disorders using CRISPR-Cas systems. Our chapter focuses on the foundational workings of CRISPR-Cas technology and its potential uses in gene editing, gene knockout, and activation/repression-based gene modification.

Ocular disorders encompass a broad spectrum of phenotypic and clinical symptoms resulting from several genetic variants and environmental factors. The unique anatomy and physiology of the eye facilitate validation of cutting-edge gene editing treatments. Genome editing developments have allowed researchers to treat a variety of diseases, including ocular disorders. The clustered regularly interspaced short palindromic repeats (CRISPR/Cas9) system holds considerable promise for therapeutic applications in the field of ophthalmology, including repair of aberrant genes and treatment of retinal illnesses related to the genome or epigenome. Application of CRISPR/Cas9 systems to the study of ocular disease and visual sciences have yielded innovations including correction of harmful mutations in patient-derived cells and gene modifications in several mammalian models of eye development and disease. In this study, we discuss the generation of several ocular disease models in mammalian cell lines and in vivo systems using a CRISPR/Cas9 system. We also provide an overview of current uses of CRISPR/Cas9 technologies for the treatment of ocular pathologies, as well as future challenges.

Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is a life threatening disease, which accounts for millions of lives annually. Mtb is an intracellular bacterium, has coevolved with humans to premeditate its machinery to surpass the immunity mounted against it in order to persist for long durations in the system. Cell death is a fundamental process required not only for tissue homeostasis but also for providing protection against intracellular pathogens. Various forms of cell death processes are known including apoptosis, pyroptosis, necroptosis, autophagy etc., that have been shown to play important roles in anti-TB immunity against Mtb. Moreover, inhibition of these pathways by Mtb is considered as one of the virulence mechanisms by which the pathogen is able to survive and replicate inside the host. Apart from identification of newer drug targets and development of anti-TB drugs that solely target the pathogen, recent advancements have been made in developing host-directed therapies against TB, which are aimed at modulating the host responses to reduce excessive inflammation and tissue damage. Thus, understanding the proteins and signaling cascades associated with cell death modalities and their relation with Mtb infection will give us new insights into the area of host-pathogen interactions and help us design better host-directed therapies.

One of the top gynecological health problems for women is ovarian cancer (OC) and it causes a huge disease burden not only for women but for all of humanity. The disease's immense burden comes from it often detected at advanced stages, current treatments such as chemotherapy or radiotherapy are not very effective, leading to a low 5-year survival rate. Therefore, discovering new therapeutic approaches that target the processes contributing to ovarian tumor formation and metastasis is urgently needed. Among them, regulating cell death processes is emerging as a promising therapy for eliminating cancer including ovarian cancer. Many scientists have been researching and clinically testing methods and drug molecules to control cell death processes consisting of apoptosis, necroptosis, ferroptosis, cuproptosis, or pyroptosis to destroy tumors. In this work, we displayed an overview about the importance of cell death in the control of ovarian carcinoma cells. According to the current knowledge of the mechanisms of cell death, targeted drugs and approaches have been studied to modulate the activation/inhibition of this process in the treatment of ovarian tumor. Thanks to that, new hopes are explored to help improve the effectiveness of cancer diagnosis and treatment.

In recent decades, the conventional protein folding paradigm has been challenged by intriguing properties of disordered peptide sequences that do not adopt stably folded conformations. Such intrinsically disordered proteins and protein regions (IDPs and IDRs) are poised uniquely in biology due to their propensity for self-aggregation, amyloidogenesis, and correlations with a cluster of debilitating diseases. Complexities underlying their structural and functional manifestations are enhanced in the presence of molecular crowding via non-specific protein-protein and protein-solvent contacts. Enabled by technological advances, physics-based algorithms, and data science, modern computer simulations provide unprecedented insights into the structure, function, dynamics, and thermodynamics of complex macromolecular systems. These characteristics are frequently correlated and manifest into unique observables. This chapter presents an overview of how such methodologies can lend insights and drive investigations into the molecular trifecta of crowding, protein self-aggregation, and amyloidogenesis. It begins with a general overview of disordered proteins in relation to biological function and of a suite of relevant experimental methods. Specific examples are showcased in the biological context. This is followed by a description of the computational approaches that supplant experimental efforts, with an elaboration on enhanced molecular simulation methods. The chapter concludes by alluding to expanded possibilities in disease amelioration.