Based on engineered or bacterial nucleases, the development of genome editing technologies has opened up the possibility of directly targeting and modifying genomic sequences in almost all eukaryotic ...cells. Genome editing has extended our ability to elucidate the contribution of genetics to disease by promoting the creation of more accurate cellular and animal models of pathological processes and has begun to show extraordinary potential in a variety of fields, ranging from basic research to applied biotechnology and biomedical research. Recent progress in developing programmable nucleases, such as zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and clustered regularly interspaced short palindromic repeat (CRISPR)-Cas-associated nucleases, has greatly expedited the progress of gene editing from concept to clinical practice. Here, we review recent advances of the three major genome editing technologies (ZFNs, TALENs, and CRISPR/Cas9) and discuss the applications of their derivative reagents as gene editing tools in various human diseases and potential future therapies, focusing on eukaryotic cells and animal models. Finally, we provide an overview of the clinical trials applying genome editing platforms for disease treatment and some of the challenges in the implementation of this technology.
Coronavirus disease 2019 (COVID‐19) has brought about a great threat to global public health. Recently, a new severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) variant B.1.1.529 has been ...reported in South Africa and induced a rapid increase in COVID‐19 cases. On November 24, 2021, B.1.1.529 named Omicron was designated as a variant under monitoring (VUM) by World Health Organization (WHO). Two days later, the Omicron variant was classified as a variant of concern (VOC). This variant harbors a high number of mutations, including 15 mutations in the receptor‐binding domain (RBD) of spike. The Omicron variant also shares several mutations with the previous VOC Alpha, Beta, and Gamma variants, which immediately raised global concerns about viral transmissibility, pathogenicity, and immune evasion. Here we described the discovery and characteristics of the Omicron variant, compared the mutations of the spike in the five VOCs, and further raised possible strategies to prevent and overcome the prevalence of the Omicron variant.
Delta variant possesses the L452R and T478K mutations in the receptor‐binding domain (RBD), while 15 mutations have been accumulated in the RBD of the Omicron variant. Among these substitutions, a bunch of residues are located nearby the bound angiotensin‐converting enzyme 2 (ACE2) receptor.
Over the past decades, great interest has been given to biomimetic nanoparticles (BNPs) since the rise of targeted drug delivery systems and biomimetic nanotechnology. Biological vectors including ...cell membranes, extracellular vesicles (EVs), and viruses are considered promising candidates for targeted delivery owing to their biocompatibility and biodegradability. BNPs, the integration of biological vectors and functional agents, are anticipated to load cargos or camouflage synthetic nanoparticles to achieve targeted delivery. Despite their excellent intrinsic properties, natural vectors are deliberately modified to endow multiple functions such as good permeability, improved loading capability, and high specificity. Through structural modification and transformation of the vectors, they are pervasively utilized as more effective vehicles that can deliver contrast agents, chemotherapy drugs, nucleic acids, and genes to target sites for refractory disease therapy. This review summarizes recent advances in targeted delivery vectors based on cell membranes, EVs, and viruses, highlighting the potential applications of BNPs in the fields of biomedical imaging and therapy industry, as well as discussing the possibility of clinical translation and exploitation trend of these BNPs.
As the fifth variant of concern of the SARS‐CoV‐2 virus, the Omicron variant (B.1.1.529) has quickly become the dominant type among the previous circulating variants worldwide. During the Omicron ...wave, several subvariants have emerged, with some exhibiting greater infectivity and immune evasion, accounting for their fast spread across many countries. Recently, two Omicron subvariants, BQ.1 and XBB lineages, including BQ.1.1, XBB.1, and XBB.1.5, have become a global public health issue given their ability to escape from therapeutic monoclonal antibodies and herd immunity induced by prior coronavirus disease 2019 (COVID‐19) vaccines, boosters, and infection. In this respect, XBB.1.5, which has been established to harbor a rare mutation F486P, demonstrates superior transmissibility and immune escape ability compared to other subvariants and has emerged as the dominant strain in several countries. This review provides a comprehensive overview of the epidemiological features, spike mutations, and immune evasion of BQ.1 and XBB lineages. We expounded on the mechanisms underlying mutations and immune escape from neutralizing antibodies from vaccinated or convalescent COVID‐19 individuals and therapeutic monoclonal antibodies (mAbs) and proposed strategies for prevention against BQ.1 and XBB sublineages.
In the Omicron wave, two emerging subvariants, BQ.1 and XBB, have rapidly become a global public health concern. This diagram illustrates the critical spike mutations in these subvariants, which can lead to immune escape from prior COVID‐19 vaccines, boosters, and therapeutic monoclonal antibodies (mAbs). Notably, XBB.1.5, which carries a rare F486P mutation, has demonstrated significantly higher receptor‐binding domain (RBD)‐ACE2 binding affinity and transmissibility compared to other subvariants, making it the dominant strain in several countries.
Currently, SARS-CoV-2 has caused a global pandemic and threatened many lives. Although SARS-CoV-2 mainly causes respiratory diseases, growing data indicate that SARS-CoV-2 can also invade the central ...nervous system (CNS) and peripheral nervous system (PNS) causing multiple neurological diseases, such as encephalitis, encephalopathy, Guillain-Barré syndrome, meningitis, and skeletal muscular symptoms. Despite the increasing incidences of clinical neurological complications of SARS-CoV-2, the precise neuroinvasion mechanisms of SARS-CoV-2 have not been fully established. In this review, we primarily describe the clinical neurological complications associated with SARS-CoV-2 and discuss the potential mechanisms through which SARS-CoV-2 invades the brain based on the current evidence. Finally, we summarize the experimental models were used to study SARS-CoV-2 neuroinvasion. These data form the basis for studies on the significance of SARS-CoV-2 infection in the brain.
Evidence shows that neutrophils can protect the host against pathogens in multiple ways, including the formation and release of neutrophil extracellular traps (NETs). NETs are web‐like structures ...composed of fibers, DNA, histones, and various neutrophil granule proteins. NETs can capture and kill pathogens, including bacteria, viruses, fungi, and protozoa. The process of NET formation is called NETosis. According to whether they depend on nicotinamide adenine dinucleotide phosphate (NADPH), NETosis can be divided into two categories: “suicidal” NETosis and “vital” NETosis. However, NET components, including neutrophil elastase, myeloperoxidase, and cell‐free DNA, cause a proinflammatory response and potentially severe diseases. Compelling evidence indicates a link between NETs and the pathogenesis of a number of diseases, including sepsis, systemic lupus erythematosus, rheumatoid arthritis, small‐vessel vasculitis, inflammatory bowel disease, cancer, COVID‐19, and others. Therefore, targeting the process and products of NETosis is critical for treating diseases linked with NETosis. Researchers have discovered that several NET inhibitors, such as toll‐like receptor inhibitors and reactive oxygen species scavengers, can prevent uncontrolled NET development. This review summarizes the mechanism of NETosis, the receptors associated with NETosis, the pathology of NETosis‐induced diseases, and NETosis‐targeted therapy.
NETs are involved in the pathogenesis and progression of various diseases, such as sepsis, SLE, RA, SVV, IBD, cancer, and COVID‐19. Components of NETs may act as autoantigens, leading to inflammation and autoimmune diseases. In addition, some diseases aggravate NETosis and cause a vicious circle.
Surgical resection is a common therapeutic option for primary solid tumors. However, high cancer recurrence and metastatic rates after resection are the main cause of cancer related mortalities. This ...implies the existence of a “fertile soil” following surgery that facilitates colonization by circulating cancer cells. Myeloid-derived suppressor cells (MDSCs) are essential for premetastatic niche formation, and may persist in distant organs for up to 2 weeks after surgery. These postsurgical persistent lung MDSCs exhibit stronger immunosuppression compared with presurgical MDSCs, suggesting that surgery enhances MDSC function. Surgical stress and trauma trigger the secretion of systemic inflammatory cytokines, which enhance MDSC mobilization and proliferation. Additionally, damage associated molecular patterns (DAMPs) directly activate MDSCs through pattern recognition receptor-mediated signals. Surgery also increases vascular permeability, induces an increase in lysyl oxidase and extracellular matrix remodeling in lungs, that enhances MDSC mobilization. Postsurgical therapies that inhibit the induction of premetastatic niches by MDSCs promote the long-term survival of patients. Cyclooxygenase-2 inhibitors and β-blockade, or their combination, may minimize the impact of surgical stress on MDSCs. Anti-DAMPs and associated inflammatory signaling inhibitors also are potential therapies. Existing therapies under tumor-bearing conditions, such as MDSCs depletion with low-dose chemotherapy or tyrosine kinase inhibitors, MDSCs differentiation using all-trans retinoic acid, and STAT3 inhibition merit clinical evaluation during the perioperative period. In addition, combining low-dose epigenetic drugs with chemokine receptors, reversing immunosuppression through the
Enhanced Recovery After Surgery
protocol, repairing vascular leakage, or inhibiting extracellular matrix remodeling also may enhance the long-term survival of curative resection patients.
Abstract
The recently emerged Omicron (B.1.1.529) variant has rapidly surpassed Delta to become the predominant circulating SARS-CoV-2 variant, given the higher transmissibility rate and immune ...escape ability, resulting in breakthrough infections in vaccinated individuals. A new generation of SARS-CoV-2 vaccines targeting the Omicron variant are urgently needed. Here, we developed a subunit vaccine named RBD-HR/trimer by directly linking the sequence of RBD derived from the Delta variant (containing L452R and T478K) and HR1 and HR2 in SARS-CoV-2 S2 subunit in a tandem manner, which can self-assemble into a trimer. In multiple animal models, vaccination of RBD-HR/trimer formulated with MF59-like oil-in-water adjuvant elicited sustained humoral immune response with high levels of broad-spectrum neutralizing antibodies against Omicron variants, also inducing a strong T cell immune response in vivo. In addition, our RBD-HR/trimer vaccine showed a strong boosting effect against Omicron variants after two doses of mRNA vaccines, featuring its capacity to be used in a prime-boost regimen. In mice and non-human primates, RBD-HR/trimer vaccination could confer a complete protection against live virus challenge of Omicron and Delta variants. The results qualified RBD-HR/trimer vaccine as a promising next-generation vaccine candidate for prevention of SARS-CoV-2, which deserved further evaluation in clinical trials.
Abstract
The occurrence of cancer entails a series of genetic mutations that favor uncontrollable tumor growth. It is believed that various factors collectively contribute to cancer, and there is no ...one single explanation for tumorigenesis. Epigenetic changes such as the dysregulation of enzymes modifying DNA or histones are actively involved in oncogenesis and inflammatory response. The methylation of lysine residues on histone proteins represents a class of post-translational modifications. The human Jumonji C domain-containing (JMJD) protein family consists of more than 30 members. The JMJD proteins have long been identified with histone lysine demethylases (KDM) and histone arginine demethylases activities and thus could function as epigenetic modulators in physiological processes and diseases. Importantly, growing evidence has demonstrated the aberrant expression of JMJD proteins in cancer and inflammatory diseases, which might serve as an underlying mechanism for the initiation and progression of such diseases. Here, we discuss the role of key JMJD proteins in cancer and inflammation, including the intensively studied histone lysine demethylases, as well as the understudied group of JMJD members. In particular, we focused on epigenetic changes induced by each JMJD member and summarized recent research progress evaluating their therapeutic potential for the treatment of cancer and inflammatory diseases.
PDF
