MedComm - Future medicine最新文献

The coronavirus disease 2019 (COVID-19) is a global infectious disease aroused by RNA virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients may suffer from severe respiratory failure or even die, posing a huge challenge to global public health. Retinoic acid-inducible gene I (RIG-I) is one of the major pattern recognition receptors, function to recognize RNA viruses and mediate the innate immune response. RIG-1 and melanoma differentiation-associated gene 5 contain an N-terminal caspase recruitment domain that is activated upon detection of viral RNA in the cytoplasm of virus-infected cells. Activated RIG-I and mitochondrial antiviral signaling (MAVS) protein trigger a series of corresponding immune responses such as the production of type I interferon against viral infection. In this review, we are summarizing the role of the structural, nonstructural, and accessory proteins from SARS-CoV-2 on the RIG-I-MAVS pathway, and exploring the potential mechanism how SARS-CoV-2 could evade the host antiviral response. We then proposed that modulation of the RIG-I-MAVS signaling pathway might be a novel and effective therapeutic strategy to against COVID-19 as well as the constantly mutating coronavirus.

Glaucoma is the leading cause of irreversible blindness globally and is associated with retinal ganglion cell (RGC) death. Brain-derived neurotrophic factor (BDNF) is a potent neurotrophin that promotes neuronal survival via its receptor, tropomyosin receptor kinase B (TrkB) encoded by NTRK2. Our current understanding of the mechanism of action and therapeutic potential of the BDNF pathway is limited by the lack of knowledge of its interaction with TrkB at atomic resolution. We developed an artificial intelligence (AI) model to predict the three-dimensional protein structures of BDNF and TrkB, as well as their interaction. The AI model was further applied to compare small-molecule drugs that mimic BDNF–TrkB interaction, leading to the identification of 7,8-dihydroxyflavone (DHF) as an agonist of TrkB. We verified the neuroprotective effects of DHF in an in vivo acute glaucoma model in which RGC apoptosis caused by acute elevation of intraocular pressure was prevented by the intraocular application of DHF and to a lesser extent by BDNF. Our results provide AI-enabled prediction of ligand–receptor interactions between BDNF and TrkB at the atomic level and demonstrate the great potential for AI-enabled drug discovery.

Monkeypox cases are steadily increasing worldwide. Phylogenetic characterization of the monkeypox virus (MPXV) responsible is important for epidemiological studies. Isidro et al. performed shotgun metagenomics sequencing analysis of MPXV isolated from cases in the current outbreak, published in Nature Medicine.¹ The results revealed for the first time that these samples cluster with a lower fatality clade of MPXV and that the current outbreak had a common origin. Furthermore, the study found evidence of accelerated evolution in the samples. This study highlights the importance of timely and sustained sequencing efforts to track the potential evolutionary trajectory of MPXV to mitigate its potential impact on global health.

The COVID-19 pandemic and other severe infectious disease outbreaks in recent years have in common among them the ability to cause infections across borders, likely facilitated by air travel and our changing relationship with rural areas.² The recovery of cross-country travel following the COVID-19 slowdown increases the possibility of bringing predominantly endemic infectious diseases to naïve populations. Reports of monkeypox around the world may be an example and potentially represents the next infectious disease challenge. The first case was recorded on May 6, 2022 in the United Kingdom.³ As of June 27, 2022, over 4300 laboratory-confirmed monkeypox cases have been recorded across six continents.⁴ We grouped daily new cases into weekly bins (Figure 1A), and it is clear that the number of cases is showing a persistent increase.

Monkeypox is caused by MPXV, a group of linear double-stranded DNA viruses part of the Orthopoxvirus genus.⁵ Notable Orthopoxviruses include the Variola virus, the causative agent of smallpox and Molluscum contagiosum. All Orthopoxviruses are morphologically similar, with a brick-like structure (Figure 1B). The genome of Orthopoxviruses contains several hundred nonoverlapping open reading frames (ORFs). Many of these ORFs are highly conserved among members and are required for replication and morphogenesis. Others are divergent and result in heterogeneity in the host range, immune modulation properties, and pathogenesis. All Orthopoxviruses replicate in the cytoplasm of infected cells. Their life cycle is illustrated in Figure 1C.

Monkeypox has a variable incubation period (5–21 days), and is a self-limiting disease with symptoms lasting between 2 and 4 weeks.⁶ The disease can be divided into two phases. The invasive prodromal phase is characterized by generalized systemic symptoms, such as fever, headache, lymphadenopathy, fatigue, and myalgia. The characteristic monkeypox rash is a feature of the cutaneous phase, which begins 1–3 days after fever onset. These are well-circumscribed, deep-seated, and painful maculopapular sk

Metabolic reprogramming manifested as glycolysis is considered a character of metabolic activity in tumor cells. Glucose used in glycolysis is the major energy source to support the growth and development of tumor cells, contributing to the high glycolytic flux production for the accumulation of cell mass. Of note, beside high consumption of glucose, the glutamine of nonessential amino acids (NEAAs) could be used as a carbon and nitrogen source. However, glucose and glutamine alone are still not enough to serve as the nutritional source for tumors. Other NEAAs are also important, such as serine, asparagine, and arginine. Related studies have confirmed in cells and animal models that either increase or decrease of NEAAs can limit the growth of tumor cells. Therefore, NEAAs deprivation diet has attracted more attention in recent years and it has been gradually applied in clinical practice for further research. In this review, the possible mechanism and potential applications of NEAAs in diet deprivation therapy are summarized, which may provide a direction for the future application in cancer treatment.

A recent paper published in Nature by Caroline Junqueira et al. (2022)¹ reveals that FcγR and opsonizing antibodies can mediate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection of monocytes/macrophages, which can then activate NLRP3 inflammasomes, caspase-1, and Gasdermin D (GSDMD), and thereby trigger pyroptosis and severe inflammatory reaction.

Since the first description in late 2019, coronavirus disease 2019 (COVID-19), caused by RS-CoV-2, has emerged as one of the most significant global public health crises. In some patients, SARS-CoV-2 infection can induce a severe inflammatory cytokine storm that can lead to respiratory syndrome and multiorgan failure.^{1, 2} From a biological perspective, when myeloid cells sense invasive infection, they activate inflammasomes, which recruit apoptotic speck protein containing a caspase recruitment domain (ASC) adaptors and further activate downstream caspase-1, which cleaves the suppressant C-domain and releases the pore-forming N-domain of GSDMD (a pyroptosis execution protein that can be activated by caspase-1), leading to cell membrane breaks, pyroptosis, and the release of inflammatory cytokines³ (Figure 1).

In this paper, Junqueira et al.¹ reported that SARS-CoV-2 can also infect monocytes/macrophages, and this is through the Fcγ receptors-mediated uptake of antibody-opsonized virus. They then showed that SARS-CoV-2 triggers NLRP3 inflammasomes, caspase-1, and GSDMD-dependent pyroptosis, an inflammation-induced programmed cell death,⁴ exacerbating systemic inflammation and the symptoms of COVID-19. The pyroptosis blocks the infectious virus production despite the replication of the viral genome in monocytes.

The study began with the detection of inflammasome activation and pyroptosis in blood samples obtained from SARS-CoV-2-infected patients. They found that approximately 6% of circulating monocytes from SARS-CoV-2 infected patients were stained by Zombie dye, a sign of membrane damage consistent with pyroptosis. A series of pyroptosis biomarkers, including GSDMD, interleukin 1β (IL-1β), IL-1RA, IL-18, and lactate dehydrogenase activity, were studied and found to be elevated. Through imaging flow cytometry, they found that about 4% of monocytes from COVID-19 patients exhibit activation of canonical inflammasomes, which form large micron-sized inflammasome-ASC-caspase-1 specks. ASC specks were colocalized with caspase-1, NLRP3 (a canonical inflammasome), and AIM2. Moreover, the lung-resident macrophages were also found to contain activated inflammasomes.¹ Previous studies have proven that several SARS-CoV-2 proteins are involved in NLRP3 inflammasome activation. Nucleocapsid (N) protein directly interacts with NLRP3 and contributes to severe inflammatory responses in patients.^{5, 6} Spike (

Accurate prediction of metastasis is an important determinant for selecting appropriate treatment for advanced colorectal cancer (CRC). In this study, 1250 patients in two hospitals from 2014 to 2019 histologically diagnosed with CRC were enrolled. We performed the transcriptome analysis on 141 CRC patients. RNA-seq analysis revealed that long noncoding RNA (LncRNA) colorectal neoplasia differentially expressed (CRNDE) played an important role in CRC metastasis. The least absolute shrinkage and selection operator regression was used to select features and develop radiomics model. Multivariate logistic regression analysis was used to develop combined model. The radiomics model with 13 filtered radiomics features had good discrimination in predicting expression level of LncRNA CRNDE in training set (receiver operating characteristic [AUC] = 0.809) and testing set (AUC = 0.755). Furthermore, the radiomics model could predict the metastasis of CRC in internal validation set (AUC, 0.665) and in external validation set (AUC = 0.690). The combined model developed with radiomics score and carcinoembryonic antigen had better performance, and the AUC was 0.708, 0.700 in internal validation set and in external validation set, respectively. In conclusion, we proposed a radiomics model and combined model, which could predict the expression level of LncRNA CRNDE and further predict CRC metastasis, thereby helping clinician make treatment decisions.