The emergent outbreak of coronavirus disease 2019 (COVID-19) has caused a global pandemic. Acute respiratory distress syndrome (ARDS) and multiorgan dysfunction are among the leading causes of death ...in critically ill patients with COVID-19. The elevated inflammatory cytokines suggest that a cytokine storm, also known as cytokine release syndrome (CRS), may play a major role in the pathology of COVID-19. However, the efficacy of corticosteroids, commonly utilized antiinflammatory agents, to treat COVID-19-induced CRS is controversial. There is an urgent need for novel therapies to treat COVID-19-induced CRS. Here, we discuss the pathogenesis of severe acute respiratory syndrome (SARS)-induced CRS, compare the CRS in COVID-19 with that in SARS and Middle East respiratory syndrome (MERS), and summarize the existing therapies for CRS. We propose to utilize interleukin-6 (IL-6) blockade to manage COVID-19-induced CRS and discuss several factors that should be taken into consideration for its clinical application.
•Cytokine release syndrome (CRS) contributes to life-threatening multiple organ dysfunction in coronavirus disease 2019 (COVID-19) and represents a potential therapeutic target.•Mechanistic understanding of CRS permits the design of novel immunotherapies.•Targeting key molecules within the inflammatory cytokine network, such as interleukin-6 (IL-6), is a novel strategy for COVID-19-induced CRS and warrants further investigation.
Cost-effective, efficacious therapeutics are urgently needed to combat the COVID-19 pandemic. In this study, we used camelid immunization and proteomics to identify a large repertoire of highly ...potent neutralizing nanobodies (Nbs) to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein receptor binding domain (RBD). We discovered Nbs with picomolar to femtomolar affinities that inhibit viral infection at concentrations below the nanograms-per-milliliter level, and we determined a structure of one of the most potent Nbs in complex with the RBD. Structural proteomics and integrative modeling revealed multiple distinct and nonoverlapping epitopes and indicated an array of potential neutralization mechanisms. We bioengineered multivalent Nb constructs that achieved ultrahigh neutralization potency (half-maximal inhibitory concentration as low as 0.058 ng/ml) and may prevent mutational escape. These thermostable Nbs can be rapidly produced in bulk from microbes and resist lyophilization and aerosolization.
Interventions against variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are urgently needed. Stable and potent nanobodies (Nbs) that target the receptor binding domain (RBD) of ...SARS-CoV-2 spike are promising therapeutics. However, it is unknown if Nbs broadly neutralize circulating variants. We found that RBD Nbs are highly resistant to variants of concern (VOCs). High-resolution cryoelectron microscopy determination of eight Nb-bound structures reveals multiple potent neutralizing epitopes clustered into three classes: Class I targets ACE2-binding sites and disrupts host receptor binding. Class II binds highly conserved epitopes and retains activity against VOCs and RBD
. Cass III recognizes unique epitopes that are likely inaccessible to antibodies. Systematic comparisons of neutralizing antibodies and Nbs provided insights into how Nbs target the spike to achieve high-affinity and broadly neutralizing activity. Structure-function analysis of Nbs indicates a variety of antiviral mechanisms. Our study may guide the rational design of pan-coronavirus vaccines and therapeutics.
B lymphocytes play an important role in the immunopathogenesis of autoimmune diabetes. We hypothesized that the altered B-cell subset phenotype is associated with autoimmune diabetes.
Patients with ...type 1 diabetes (T1D) (n = 81), latent autoimmune diabetes in adults (LADA) (n = 82), or type 2 diabetes (T2D) (n = 95) and healthy control subjects (n = 218) with normal glucose tolerance (NGT) were recruited. We determined the percentage of circulating B-lymphocyte subsets, including CD19(+)CD23(-)CD21(+) (marginal zone B MZB), CD19(+)CD23(+)CD21(-) (follicular B FoB), and CD19(+)CD5(+)CD1d(hi) (interleukin-10-producing regulatory B B10) cells by flow cytometry.
Patients with T1D or LADA had increased percentages of MZB cells and decreased percentages of FoB cells compared with healthy control subjects with NGT and patients with T2D. Moreover, patients with T1D showed the lowest frequency of B10 cells compared with patients with LADA or T2D, whereas healthy control subjects expressed the highest frequency of B10 cells. Of note, the frequency of MZB cells was negatively associated and the frequency of FoB cells was positively associated with fasting C-peptide (FCP). The frequency of B10 cells was positively correlated with FCP and negatively correlated with hemoglobin A(1c).
The data show that patients with T1D or LADA express an altered frequency of B-cell subsets, which is associated with islet function and glycemia. These findings suggest that B lymphocytes may be involved in loss of self-tolerance and β-cell destruction and could be used as a biomarker and potential target for immunological intervention.
Actively transcribed regions of the genome are protected by transcription-coupled DNA repair mechanisms, including transcription-coupled homologous recombination (TC-HR). Here we used reactive oxygen ...species (ROS) to induce and characterize TC-HR at a transcribed locus in human cells. As canonical HR, TC-HR requires RAD51. However, the localization of RAD51 to damage sites during TC-HR does not require BRCA1 and BRCA2, but relies on RAD52 and Cockayne Syndrome Protein B (CSB). During TC-HR, RAD52 is recruited by CSB through an acidic domain. CSB in turn is recruited by R loops, which are strongly induced by ROS in transcribed regions. Notably, CSB displays a strong affinity for DNA:RNA hybrids in vitro, suggesting that it is a sensor of ROS-induced R loops. Thus, TC-HR is triggered by R loops, initiated by CSB, and carried out by the CSB-RAD52-RAD51 axis, establishing a BRCA1/2-independent alternative HR pathway protecting the transcribed genome.
Adult non-insulin requiring diabetes includes latent autoimmune diabetes of adults (LADA), distinguished from type 2 diabetes by the presence of islet autoantibodies. LADA China determined the ...characteristics of Chinese LADA. This nationwide, multicenter, clinic-based cross-sectional study was conducted in 46 university-affiliated hospitals in 25 Chinese cities. All 4,880 ketosis-free diabetic patients (<1 year postdiagnosis, without insulin therapy for >6 months, aged ≥30 years) had GAD antibody (GADA) and HLA-DQ genotype measured centrally with clinical data collected locally. GADA-positive subjects were classified as LADA. Of the patients, 5.9% were GADA positive with LADA. LADA showed a north-south gradient. Compared with GADA-negative type 2 diabetes, LADA patients were leaner, with lower fasting C-peptide and less metabolic syndrome. Patients with high GADA titers are phenotypically different from those with low GADA titers, while only a higher HDL distinguished the latter from those with type 2 diabetes. HLA diabetes-susceptible haplotypes were more frequent in LADA, even in those with low-titer GADA. HLA diabetes-protective haplotypes were less frequent in LADA. Our study implicates universal immunogenetic effects, with some ethnic differences, in adult-onset autoimmune diabetes. Autoantibody positivity and titer could be important for LADA risk stratification and accurate therapeutic choice in clinical practice.
T lymphocytes are key players in the pathogenesis of autoimmune diabetes. We recruited subjects with T1D (n=81), LADA (n=82), T2D (n=95) and NGT (n=218) and analyzed the percentages of T-lymphocyte ...subsets, including T helper 1 (Th1), T helper 2 (Th2), T helper 17 (Th17), T cytotoxic 1 (Tc1), regulatory T cells (Tregs), effector T (Teff), naïve T, central memory T (Tcm), and effector memory T (Tem) cells by flow cytometry. LADA patients possessed similar frequencies of IFN-γ
+
CD4
+
T (Th1), IFN-γ
+
CD8
+
T and CD4
+
Teff cells compared with T1D patients, but much lower than those of NGT subjects. Like T2D patients, LADA patients had increased frequencies of CD4
+
Tem and CD8
+
Tem cells with respect to T1D and NGT subjects. In LADA patients, Th2 cells were decreased while CD4
+
Tcm cells were increased compared with NGT subjects. Notably, we observed significant negative correlations between the CD4
+
Tcm cell frequency and C-peptide in LADA subjects. These data demonstrates that LADA patients possess T-cell subset changes resembling both T1D and T2D and represent the middle of the diabetes spectrum between T1D and T2D. Based on these T-cell subset alterations, we speculate that autoimmunity-induced β-cell destruction and inflammation-induced insulin resistance might both be involved in the pathogenesis of LADA.
Globally, there is an urgency to develop effective, low-cost therapeutic interventions for coronavirus disease 2019 (COVID-19). We previously generated the stable and ultrapotent homotrimeric ...Pittsburgh inhalable Nanobody 21 (PiN-21). Using Syrian hamsters that model moderate to severe COVID-19 disease, we demonstrate the high efficacy of PiN-21 to prevent and treat SARS-CoV-2 infection. Intranasal delivery of PiN-21 at 0.6 mg/kg protects infected animals from weight loss and substantially reduces viral burdens in both lower and upper airways compared to control. Aerosol delivery of PiN-21 facilitates deposition throughout the respiratory tract and dose minimization to 0.2 mg/kg. Inhalation treatment quickly reverses animals' weight loss after infection, decreases lung viral titers by 6 logs leading to drastically mitigated lung pathology, and prevents viral pneumonia. Combined with the marked stability and low production cost, this innovative therapy may provide a convenient and cost-effective option to mitigate the ongoing pandemic.
Roles of TRPM channels in glioma Chen, Zhigang; Xie, Han; Liu, Jun ...
Cancer biology & therapy,
12/2024, Volume:
25, Issue:
1
Journal Article
Peer reviewed
Open access
Gliomas are the most common type of primary brain tumor. Despite advances in treatment, it remains one of the most aggressive and deadly tumor of the central nervous system (CNS). Gliomas are ...characterized by high malignancy, heterogeneity, invasiveness, and high resistance to radiotherapy and chemotherapy. It is urgent to find potential new molecular targets for glioma. The TRPM channels consist of TRPM1-TPRM8 and play a role in many cellular functions, including proliferation, migration, invasion, angiogenesis, etc. More and more studies have shown that TRPM channels can be used as new therapeutic targets for glioma. In this review, we first introduce the structure, activation patterns, and physiological functions of TRPM channels. Additionally, the pathological mechanism of glioma mediated by TRPM2, 3, 7, and 8 and the related signaling pathways are described. Finally, we discuss the therapeutic potential of targeting TRPM for glioma.
Super-enhancers (SEs) consist of multiple typical enhancers enriched at high density with transcription factors, histone-modifying enzymes and cofactors. Oncogenic SEs promote tumorigenesis and ...malignancy by altering protein-coding gene expression and noncoding regulatory element function. Therefore, they play central roles in the treatment of cancer. Here, we review the structural characteristics, organization, identification, and functions of SEs and the underlying molecular mechanism by which SEs drive oncogenic transcription in tumor cells. We then summarize abnormal SE complexes, SE-driven coding genes, and noncoding RNAs involved in tumor development. In summary, we believe that SEs show great potential as biomarkers and therapeutic targets.
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