Atherosclerosis is a progressive, chronic inflammation in arterial walls. Long noncoding RNAs (lncRNAs) participate in inflammation, but the exact mechanism in atherosclerosis is unclear. Our ...microarray analyses revealed that the levels of lncRNA-FA2H-2 were significantly decreased by oxidized low-density lipoprotein (OX-LDL). Bioinformatics analyses indicated that mixed lineage kinase domain-like protein (MLKL) might be regulated by lncRNA-FA2H-2. In vitro experiments showed that lncRNA-FA2H-2 interacted with the promoter of the MLKL gene, downregulated MLKL expression, and the binding sites between -750 and 471 were necessary for lncRNA-FA2H-2 responsiveness to MLKL. Silencing lncRNA-FA2H-2 and overexpression of MLKL could activate inflammation and inhibited autophagy flux. Both lncRNA-FA2H-2 knockdown and overexpression of MLKL could significantly aggravate inflammatory responses induced by OX-LDL. We found that the 3-methyladenine (3-MA) and Atg7-shRNA enhanced inflammatory responses induced by knockdown of lncRNA-FA2H-2 and overexpression of MLKL. We demonstrated that the effects of MLKL on autophagy might be associated with a mechanistic target of rapamycin (mTOR)-dependent signaling pathways. In vivo experiments with apoE knockout mice fed a western diet demonstrated that LncRNA-FA2H-2 knockdown decreased microtubule-associated expression of microtubule-associated protein 1 light chain 3 II and lysosome-associated membrane protein 1, but increased expression of sequestosome 1 (p62), MLKL, vascular cell adhesion molecule-1, monocyte chemoattractant protein-1, and interleukin-6 in atherosclerotic lesions. Our findings indicated that the lncRNA-FA2H-2-MLKL pathway is essential for regulation of autophagy and inflammation, and suggested that lncRNA-FA2H-2 and MLKL could act as potential therapeutic targets to ameliorate atherosclerosis-related diseases.
Immunotherapy has revolutionized cancer treatment, however, not all tumor types and patients are completely responsive to this approach. Establishing predictive pre‐clinical models would allow for ...more accurate and practical immunotherapeutic drug development. Mouse models are extensively used as in vivo system for biomedical research. However, due to the significant differences between rodents and human, it is impossible to translate most of the findings from mouse models to human. Pharmacological development and advancing personalized medicine using patient‐derived xenografts relies on producing mouse models in which murine cells and genes are substituted with their human equivalent. Humanized mice (HM) provide a suitable platform to evaluate xenograft growth in the context of a human immune system. In this review, we discussed recent advances in the generation and application of HM models. We also reviewed new insights into the basic mechanisms, pre‐clinical evaluation of onco‐immunotherapies, current limitations in the application of these models as well as available improvement strategies. Finally, we pointed out some issues for future studies.
Establishing predictive pre‐clinical models leads toward more accurate and practical immunotherapeutic development. Humanized mice (HM) provide a suitable platform to discern human‐specific disease pathogenesis and evaluate an array of novel therapeutics. This review discusses recent progresses in the production and deployment of HM in the study of cancer immunotherapy.
This study investigated the effect of melatonin on clinical outcomes in patients with coronavirus disease 2019 (COVID‐19). We searched PubMed, the Web of Science, the Cochrane Library, Ovid MEDLINE, ...and Clinicaltrials.gov for randomized controlled trials (RCTs) published before September 11, 2021. Only RCTs that compared the clinical efficacy of melatonin with a placebo in the treatment of patients with COVID‐19 were included. The primary outcome measure was the clinical recovery rate. We included three RCTs in this meta‐analysis. Melatonin 3 mg three times daily was administered in one RCT, and 3 or 6 mg daily before bedtime in the other two trials. Treatment duration was 14 days in two RCTs and 7 days in one trial. The clinical recovery rates were 94.2% (81/86) and 82.4% (70/85) in the melatonin and control groups, respectively. Overall, patients receiving melatonin had a higher clinical recovery rate than did the controls (odds ratio OR: 3.67; 95% CI: 1.21−11.12; I2 = 0%, p = 0.02). The risk of intensive care unit admission was numerically lower in the melatonin group than in the control group (8.3% 6/72 vs. 17.6% 12/68, OR: 0.45; 95% CI: 0.16−1.25; I2 = 0%, p = 0.13), and the risk of mortality was numerically lower in the melatonin group than in the control group (1.4% 1/72 vs. 4.4% 3/68, OR: 0.32; 95% CI: 0.03−3.18; I2 = 0%, p = 0.33). In conclusion, melatonin may help improve the clinical outcomes of patients with COVID‐19.
Highlight
This study investigated the effect of melatonin on clinical outcomes in patients with coronavirus disease 2019.
Patients receiving melatonin had a higher clinical recovery rate than did the controls (odds ratio: 3.67; 95% CI: 1.21−11.12; I2 = 0%, p = 0.02).
The risk of intensive care unit admission was only insignificantly lower in the melatonin group than in the control group.
The risk of mortality was insignificantly lower in the melatonin group than in the control group.
Abstract
The repertoire of peptides presented by major histocompatibility complex class I (MHC-I) molecules on the cell surface is tailored by the ER-resident peptide loading complex (PLC), which ...contains the exchange catalyst tapasin. Tapasin stabilizes MHC-I molecules and promotes the formation of stable peptide-MHC-I (pMHC-I) complexes that serve as T cell antigens. Exchange of suboptimal by high-affinity ligands is catalyzed by tapasin, but the underlying mechanism is still elusive. Here we analyze the tapasin-induced changes in MHC-I dynamics, and find the catalyst to exploit two essential features of MHC-I. First, tapasin recognizes a conserved allosteric site underneath the α
2-1
-helix of MHC-I, ‘loosening’ the MHC-I F-pocket region that accomodates the C-terminus of the peptide. Second, the scoop loop
11–20
of tapasin relies on residue L18 to target the MHC-I F-pocket, enabling peptide exchange. Meanwhile, tapasin residue K16 plays an accessory role in catalysis of MHC-I allotypes bearing an acidic F-pocket. Thus, our results provide an explanation for the observed allele-specificity of catalyzed peptide exchange.
Atherosclerosis is a complex inflammatory disease that involves disrupted cellular cholesterol levels and formation of foam cells. Studies about long noncoding RNA (lncRNA) have revealed its function ...in the development of atherosclerosis, by mediating reverse cholesterol transport and formation of foam cells. In this study, we found that oxidized low‐density lipoprotein (ox‐LDL) markedly decreased lncRNA AC096664.3 in vascular smooth muscle cells (VSMCs) and THP‐1 macrophages. We also found that ox‐LDL reduced ATP‐binding cassette (ABC) G1 through inhibiting lncRNA AC096664.3 in VSMCs. Further experiments showed that the downregulation of lncRNA AC096664.3 reduced ABCG1 expression through inhibiting the expression of peroxisome proliferator–activated receptor‐γ (PPAR‐γ) and that ox‐LDL reduced ABCG1 expression through inhibiting the expression of PPAR‐γ. Furthermore, we discovered that ox‐LDL inhibited ABCG1 via the lncRNA AC096664.3/PPAR‐γ/ABCG1 pathway, which led to an increase in total and free cholesterol in VMSCs. Thus, we confirmed that ox‐LDL induces cholesterol accumulation via the lncRNA AC096664.3/PPAR‐γ/ABCG1 pathway in VSMCs, indicating a promising novel therapy in protecting against atherosclerosis.
Atherosclerosis is a complex inflammatory disease that involves disrupted cellular cholesterol level and formation of foam cells. Studies about long noncoding RNA (lncRNA) reveal its function in the development of atherosclerosis by mediating reverse cholesterol transport and the formation of foam cells. In this study, we confirmed that oxidized low‐density lipoprotein could induce cholesterol accumulation via the lncRNA AC096664.3/peroxisome proliferator–activated receptor‐γ/ATP‐binding cassette G1 pathway in vascular smooth muscle cells, indicating a promising novel therapy in protecting against atherosclerosis.
As characterized by repeated exposure of others’ trauma, vicarious traumatization is a common negative psychological reaction during the COVID-19 pandemic and plays a crucial role in the development ...of general mental distress. This study aims to identify functional connectome that encodes individual variations of pandemic-related vicarious traumatization and reveal the underlying brain-vicarious traumatization mechanism in predicting general distress. The eligible subjects were 105 general university students (60 females, aged from 19 to 27 years) undergoing brain MRI scanning and baseline behavioral tests (October 2019 to January 2020), whom were re-contacted for COVID-related vicarious traumatization measurement (February to April 2020) and follow-up general distress evaluation (March to April 2021). We applied a connectome-based predictive modeling (CPM) approach to identify the functional connectome supporting vicarious traumatization based on a 268-region-parcellation assigned to network memberships. The CPM analyses showed that only the negative network model stably predicted individuals’ vicarious traumatization scores (q2 = -0.18, MSE = 617, r predicted, actual = 0.18, p = 0.024), with the contributing functional connectivity primarily distributed in the fronto-parietal, default mode, medial frontal, salience, and motor network. Furthermore, mediation analysis revealed that vicarious traumatization mediated the influence of brain functional connectome on general distress. Importantly, our results were independent of baseline family socioeconomic status, other stressful life events and general mental health as well as age, sex and head motion. Our study is the first to provide evidence for the functional neural markers of vicarious traumatization and reveal an underlying neuropsychological pathway to predict distress symptoms in which brain functional connectome affects general distress via vicarious traumatization.
Quasi-racemic crystallography has been used to determine the X-ray structures of K27-linked ubiquitin (Ub) chains prepared through total chemical synthesis. Crystal structures of K27-linked di- and ...tri-ubiquitins reveal that the isopeptide linkages are confined in a unique buried conformation, which provides the molecular basis for the distinctive function of K27 linkage compared to the other seven Ub chains. K27-linked di- and triUb were found to adopt different structural conformations in the crystals, one being symmetric whereas the other triangular. Furthermore, bioactivity experiments showed that the ovarian tumor family de-ubiquitinase 2 significantly favors K27-linked triUb than K27-linked diUb. K27-linked triUb represents the so-far largest chemically synthesized protein (228 amino acids) that has been crystallized to afford a high-resolution X-ray structure.
Tapasin (Tsn) plays a critical role in antigen processing and presentation by major histocompatibility complex class I (MHC-I) molecules. The mechanism of Tsn-mediated peptide loading and exchange ...hinges on the conformational dynamics governing the interaction of Tsn and MHC-I with recent structural and functional studies pinpointing the critical sites of direct or allosteric regulation. In this review, we highlight these recent findings and relate them to the extensive molecular and cellular data that are available for these evolutionary interdependent proteins. Furthermore, allotypic differences of MHC-I with regard to the editing and chaperoning function of Tsn are reviewed and related to the mechanistic observations. Finally, evolutionary aspects of the mode of action of Tsn will be discussed, a short comparison with the Tsn-related molecule TAPBPR (Tsn-related protein) will be given, and the impact of Tsn on noncanonical MHC-I molecules will be described.
Breast cancer (BC) is a common gynaecological malignancy worldwide. Long noncoding RNAs (lncRNAs) were identified to take part in the regulation of the occurrence and development of tumors. LncRNA ...The role of LINC00467 in lung adenocarcinoma has been reported, but its mechanism remains unclear in BC. To explore the role of LINC00467 deeply, we designed and performed a series of experiments. According to the result, it was discovered that LINC00467 was overexpressed in BC tissues and cells, and then the knockdown of LINC00467 resulted in a decline in cell growth and metastasis. Mechanistically, miR-18a/b-5p was screened out and validated to bind with LINC00467. Additionally, LINC00467 was negatively correlated with miR-18a/b-5p. Hereafter, there is evidence that miR-18a/b-5p targets MAPK4. Rescue assays suggested that MAPK4 amplification recovered the inhibitive effect of LINC00467 knockdown on cell growth and metastasis. In a word, LINC00467 enhanced BC cell growth and metastasis by targeting miR-18a/b-5p/MAPK4, which implies a potential revelation for exploring the therapeutic tactic of BC.
Cancer immunotherapy is exploited for the treatment of disease by modulating the immune system. Since the conventional
animal and 2D
models insufficiently recapitulate the complex tumor immune ...microenvironment (TIME) of the original tumor. In addition, due to the involvement of the immune system in cancer immunotherapy, more physiomimetic cancer models, such as patient-derived organoids (PDOs), are required to evaluate the efficacy of immunotherapy agents. On the other hand, the dynamic interactions between the neoplastic cells and non-neoplastic host components in the TIME can promote carcinogenesis, tumor metastasis, cancer progression, and drug resistance of cancer cells. Indeed, tumor organoid models can properly recapitulate the TIME by preserving endogenous stromal components including various immune cells, or by adding exogenous immune cells, cancer-associated fibroblasts (CAFs), vasculature, and other components. Therefore, organoid culture platforms could model immunotherapy responses and facilitate the immunotherapy preclinical testing. Here, we discuss the various organoid culture approaches for the modeling of TIME and the applications of complex tumor organoids in testing cancer immunotherapeutics and personalized cancer immunotherapy.
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